research on bpc 157

BPC-157 | Reviews, Clinical Trials, and Safety

Bpc-157 is a research peptide being studied for its wound healing and regenerative effects., compound overview, class of compound:, mechanism of action:.

BPC-157 is known to stimulate vascular endothelial growth factor, which triggers the formation of blood vessels. Also, it blocks the growth-inhibiting action of 4‐hydroxynonenal. Further, it upregulates multiple growth receptors in the body and stimulates the production of fibroblasts, vital to the synthesis of collagen.

Notable Studies:

• Pentadecapeptide BPC 157 and the central nervous system
• Fistulas healing. Stable gastric pentadecapeptide BPC 157 therapy
• BPC 157 counteracts QTc prolongation induced by haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats

Also Known As:

PL 14736, Body Protection Compound 157

Research Applications:

• Wound healing
• Digestive health
• Cognitive health
• Muscle growth
• Unclear safety profile
• Lack of randomized controlled trials
• Prohibited by WADA

Chemical Structure

What is bpc-157.

BPC-157 refers to Body Protection Compound-157 , a naturally occurring peptide found in human stomach juices. Composed of a sequence of 15 amino acids, the peptide can also be found in trace amounts in the gastric fluids of other mammals.

The peptide plays a fundamental role in preserving the lining of the GI tract. However, researchers are interested in its application in other areas of the body—particularly in regards to wound healing, neuroprotection, and muscle and tissue growth.

Much of the research on BPC-157 to date has been done in laboratory animals, but researchers are now using the findings to date to help direct further research into the ways BPC-157 may be beneficial for human subjects.

It’s important to understand the potential side effects and risks of BPC-157 - along with dosing considerations, and legal status of the peptide - before purchasing it for research.

Our research team covers all of these questions below, before providing our top recommendation on where qualified researchers can buy BPC-157 online .

What Does BPC-157 Do?

BPC-157 was first isolated from body protection compound (BPC), which is found in the gastric juices and is part of the digestive process [ 1 ]. It is composed of 15 amino acids, with the following chemical composition:

H-Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH [ 2 ].

The role of BPC in the gastric juice is an important one. As a compound that can promote healing, it helps protect the gastrointestinal tissues from damage and can help prevent and heal stomach ulcers or other injuries to the intestinal lining.

It also promotes angiogenesis, or the formation of new blood vessels, allowing for increased oxygenation to the tissues.

Because of these properties, isolated BPC-157 is of great interest to researchers. The peptide shows potential in a number of applications outside of the GI tract, including in its promotion of healing, muscle growth and repair, and injury recovery.

BPC-157 Benefits | Clinical Trials

Researchers have identified numerous potential benefits of BPC-157 in both laboratory animal and human studies, although the evidence available in humans is extremely limited at this time.

Here are some of the potential benefits of BPC-157:

Connects the brain and the digestive system: BPC-157 may play a role in the gut-brain axis, or the direct line of communication between the nervous system and the digestive system. Perhaps surprisingly, the two are deeply interconnected—with digestive health playing a significant role in neurological health and cognitive function [ 3 ].

Neuroprotection: BPC-157 has been shown to provide some neuroprotective effects in rats, helping to protect against harmful free radical damage or protect the brain and preserve brain function after exposure to harmful substances [ 3 ].

Improved memory: BPC-157 may help improve and preserve memory as a result of its neuroprotective effects.

Mood regulation: Its neuroprotective effects may also help with mood regulation.

Blood flow and angiogenesis: One of the most promising potential benefits of BPC-157 is its angiogenic effect, or its ability to promote the formation of new blood vessels, which may help improve vasculature and blood flow. This effect has been noted in rat studies [ 4 ].

Circulation and vasomotor tone pr: Some preclinical studies suggest have noted that BPC-157 modulates blood flow and vasomotor tone blood flow [ 4 , 5 , 6 ].

Reduced physical discomfort: Some early preclinical research suggests that BPC-157 may have nociceptive (pain relieving) properties. This effect was actually noted in a small chart review in humans—one of the few uses of BPC-157 that has human evidence at this time [ 7 ].

Increased energy: Because it can activate NO pathways, BPC-157 may help provide an energy boost. NO activators are a common ingredient in preworkout supplements [ 8 ].

Wound healing: The angiogenic properties of BPC-157 may also promote faster wound healing. It naturally occurs in the gastric juice and helps to prevent gastric ulcers, and researchers have found that it also helps promote faster healing of wounds in rats [ 9 ].

Liver protection: In laboratory animal studies, BPC-157 may be able to help protect the stomach, liver, and other tissues from NSAID medication overdoses. Researchers theorize it may offer similar protective benefits against alcohol and other toxins [ 10 ].

Muscle and tissue growth:  In test-tube studies, BPC-157 stimulates growth hormone receptor expression—signaling the body to create new tendon tissue. It may also offer similar effects for bone, skin, and muscle [ 11 ].

Buy BPC-157 from our top-rated vendor...

BPC-157 Side Effects

There is little scientific documentation of BPC-157 side effects in humans, so most potential side effects are extrapolated from preclinical studies and anecdotal reports of human use.

The most common side effects appear to be related to the method of administration, which is typically intramuscular or subcutaneous injection. Common side effects of injections include redness, swelling, itching or skin reactions at the injection site. When these reactions are mild, they typically aren't cause for concern.

In addition, because BPC-157 is a gastric peptide, there have been some informal reports of digestive side effects like nausea, diarrhea, appetite changes, gas and bloating related to its administration. Dizziness and headaches also have been reported.

As an pro-angiogenic agent, it's theoretically possible for BPC-157 to enable cancers to grow. However, not enough is known about this theoretical issue to elucidate a risk-benefit tradeoff and how timing of treatment works into such a tradeoff.

For more discussion of this concern, see our article on potential complications of BPC-157 .

We reiterate that there have been no definitive human studies investigating BPC-157 side effects.

BPC-157 administration and dosing should be handled by a researcher who is familiar with BPC-157. Under no circumstances should it be purchased for self-administration or unauthorized experimentation. Researchers may also want to learn more about how BPC-157 affects both erectile dysfunction and cancer .

Is BPC-157 Safe?

The peptide BPC-157 has not been evaluated for safety as part of the drug review process of the United States Food and Drug Administration (FDA), nor has it been formally evaluated for safety by any international regulatory counterpart of the FDA. Therefore, any claims or insinuations that BPC-157 is “safe” must be taken with a grain of salt.

However, in published research to date, BPC-157 administration has produced minimal side effects in both nonhumans and humans. Specifically, a review of clinical trials on the use of BPC-157 has characterized it as safe both in treating inflammatory bowel disease and wound healing, noting that no events of toxicity had been reported throughout those trials [ 12 ].

In fact, the peptide has actually been shown to prevent severe side effects associated with medications for diabetes and psychiatric conditions, including catalepsy, somatosensory disturbance, and QTc prolongation in the heart—which can lead to fatal arrythmia [ 13 , 14 ].

As with any research involving peptides, prudence and caution are required when administering BPC-157 to test subjects.

BPC-157 Dosage Calculator

Again, there is little research available in humans on BPC-157, so most BPC-157 dosage recommendations are loosely based on equivalent doses used in animal studies and anecdotal reports of human use.

In general, the most widely agreed upon daily dose of BPC-157 is about 250 mcg, delivered via intramuscular injection. A general rule of thumb that may be utilized by researchers is 2-4 mcg per kg of body weight.

However, there are other forms of BPC-157 available - in particular, sublingual capsule tablets which are dissolved under the tongue as well as nasal sprays .

Regardless, most research applications utilize the injected version, and this is also the form that is most often used in both research and clinical settings.

Where to Buy BPC-157 Online? | 2024 Edition

Researchers looking to acquire BPC-157 for their studies are advised to check out our recommended vendor below.

This vendor specialize in selling high-quality peptides for research purposes.

Here's our top recommendation:

Limitless Life

For researchers wondering where to source high quality research peptides, we highly recommend the vendor Limitless Life .

They partner with independent labs to conduct quality testing on all of their products.

They also offer a generous reship policy and they are committed to the safe distribution of research peptides only to qualified researchers.

Below, we’ve shared a little bit more about why we like Limitless Life :

• Partnerships with Third-Party Labs: Limitless Life ensures quality, purity, and potency of their products by employing third-party laboratories to conduct stringent tests on each product batch.
• Easy and Flexible Reship/Returns: Limitless Life ensures customer satisfaction through their incredibly flexible reship and/or return policy. Additionally, they offer optional shipping insurance for extra peace of mind.
• Commitment to Safe Peptide Distribution: Limitless Life is committed to safe and responsible peptide distribution by emphasizing in several places on their website that their peptides are intended for use only by qualified researchers.
• Excellent Reputation: Limitless Life is known in the peptide community as a reputable source of research peptides, and this is evidenced by their remarkably low rate of credit card charge-backs and numerous positive reviews online.
• Useful Resources. Their website offers a wealth of knowledge and advice on the science and terminology of research peptides.

Furthermore, the team at Peptides.org is impressed with the variety of unique offerings and formulations of BPC-157 from Limitless Life .

The research peptides source offers lyophilized powder BPC-157, but they also have options like:

• BPC-157 + TB-500 Nasal Spray
• BPC-157 Capsules

Last, but not least…

Researchers ordering from Limitless Life will get 10% off. Click the button below and then use this code:

peptidesorg10

Bacteriostatic water and bpc-157.

When experimenting with peptides like BPC-157 , researchers can’t neglect the importance of a properly equipped lab.

To adhere to the proper measures of peptide administration, prep, and storage, a researchers' toolkit should include bac water and sterile vials, to list just a few of the necessities.

While some researchers struggle to equip their labs, spending hours searching the web and navigating low-quality vendors, this is necessary prior to study.

BPC-157 is typically available in the form of powder that should be reconstituted using bacteriostatic or sterile water.

BPC-157 is typically administered via subcutaneous injection.

BPC-157 should be reconstituted with bacteriostatic or sterile water. Follow all safety precautions during the reconstitution process, including wiping the tops of vials with alcohol wipes and avoiding contact with the syringe used to pull the bacteriostatic or sterile water. For proper reconstitution, take care to drip the reconstituting liquid down the side of the peptide vial; avoid spraying the peptide. Allow the solution to dissolve on its own.

BPC-157 is a research chemical that may be purchased by qualified researchers in the United States. Where designated and sold as a reference material, the peptide is not for human use.

BPC-157 cannot be marketed as a dietary supplement or sold over the counter. Researchers in the U.S. should be wary of BPC-157 mislabeled as a “supplement” or as an active ingredient in a supplement in violation of the law. Where BPC-157 is sold as a reference material, it should be clearly labeled as such.

As of 2022, BPC-157 is prohibited under the World Anti-Doping Agency (WADA) Prohibited List, and may thus not be used by athletes who are subject to the rules of that body [ 15 ].

BPC-157 is a research peptide and should be administered with extreme care. While the peptide has exhibited minimal side effects in published research to date, researchers should note BPC-157’s properties as a gastric peptide and an angiogenic agent and screen subjects accordingly.

BPC-157 has been shown to effectively alleviate joint pain and improve joint mobility in test subjects. Research into further applications like digestive health, cognitive health, and muscle growth is ongoing.

No, BPC-157 is not an anabolic-androgenic steroid; it is a peptide.

No, BPC-157 does not act to boost testosterone production.

No, in published studies to date, BPC-157 has not been found to build muscle. However, it is currently being studied for this purpose. Further, BPC-157 has been found to accelerate the healing of wounds, including muscle injuries.

No, in published studies to date, BPC-157 has not been found to cause weight gain.

BPC-157. Just. Works.

BPC-157 is a fragment of body protection compound, a peptide found in gastric juices that helps protect against stomach ulcers.

It may offer neuroprotective, angiogenic, wound healing and tissue growth properties—and all of these benefits have been noted in preclinical studies, although human research is severely lacking.

BPC-157 is typically administered via subcutaneous injection, and little is known at this time about potential side effects.

It may be legally purchased in the United States for research purposes. As of 2022, it is included in WADA’s prohibited substances list.

For researchers looking to purchase BPC-157, we recommend this top-rated supplier. .

• Gwyer D, Wragg NM, Wilson SL. Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing. Cell Tissue Res. 2019;377(2):153-159. doi:10.1007/s00441-019-03016-8
• Chang CH, Tsai WC, Hsu YH, Pang JH. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules. 2014;19(11):19066-19077. Published 2014 Nov 19. doi:10.3390/molecules191119066
• Vukojevic J, Milavić M, Perović D, et al. Pentadecapeptide BPC 157 and the central nervous system. Neural Regen Res. 2022;17(3):482-487. doi:10.4103/1673-5374.320969
• Knezevic M, Gojkovic S, Krezic I, et al. Occlusion of the Superior Mesenteric Artery in Rats Reversed by Collateral Pathways Activation: Gastric Pentadecapeptide BPC 157 Therapy Counteracts Multiple Organ Dysfunction Syndrome; Intracranial, Portal, and Caval Hypertension; and Aortal Hypotension. Biomedicines. 2021;9(6):609. Published 2021 May 26. doi:10.3390/biomedicines9060609
• Hsieh MJ, Lee CH, Chueh HY, et al. Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway. Sci Rep. 2020;10(1):17078. Published 2020 Oct 13. doi:10.1038/s41598-020-74022-y
• Lozic M, Stambolija V, Krezic I, et al. In relation to NO-System, Stable Pentadecapeptide BPC 157 Counteracts Lidocaine-Induced Adverse Effects in Rats and Depolarisation In Vitro. Emerg Med Int. 2020;2020:6805354. Published 2020 May 27. doi:10.1155/2020/6805354
• Lee E, Padgett B. Intra-Articular Injection of BPC 157 for Multiple Types of Knee Pain. Altern Ther Health Med. 2021;27(4):8-13.
• Harty PS, Zabriskie HA, Erickson JL, Molling PE, Kerksick CM, Jagim AR. Multi-ingredient pre-workout supplements, safety implications, and performance outcomes: a brief review. J Int Soc Sports Nutr. 2018;15(1):41. Published 2018 Aug 8. doi:10.1186/s12970-018-0247-6
• Sikiric P, Drmic D, Sever M, et al. Fistulas Healing. Stable Gastric Pentadecapeptide BPC 157 Therapy. Curr Pharm Des. 2020;26(25):2991-3000. doi:10.2174/1381612826666200424180139
• Park JM, Lee HJ, Sikiric P, Hahm KB. BPC 157 Rescued NSAID-cytotoxicity Via Stabilizing Intestinal Permeability and Enhancing Cytoprotection. Curr Pharm Des. 2020;26(25):2971-2981. doi:10.2174/1381612826666200523180301
• National Center for Biotechnology Information. PubChem Compound Summary for CID 9941957. https://pubchem.ncbi.nlm.nih.gov/compound/Bpc-157. Accessed Sept. 10, 2021.
• Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, Sever M, Klicek R, Radic B, Drmic D, Ilic S, Kolenc D, Aralica G, Safic H, Suran J, Rak D, Dzidic S, Vrcic H, Sebecic B. Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Curr Pharm Des. 2013;19(1):76-83. doi: 10.2174/13816128130111. PMID: 22950504.
• Strinic D, Belosic Halle Z, Luetic K, Nedic A, Petrovic I, Sucic M, Zivanovic Posilovic G, Balenovic D, Strbe S, Udovicic M, Drmic D, Stupnisek M, Lovric Bencic M, Seiwerth S, Sikiric P. BPC 157 counteracts QTc prolongation induced by haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats. Life Sci. 2017 Oct 1;186:66-79. doi: 10.1016/j.lfs.2017.08.006. Epub 2017 Aug 7. PMID: 28797793.
• Jelovac N, Sikiric P, Rucman R, Petek M, Marovic A, Perovic D, Seiwerth S, Mise S, Turkovic B, Dodig G, Miklic P, Buljat G, Prkacin I. Pentadecapeptide BPC 157 attenuates disturbances induced by neuroleptics: the effect on catalepsy and gastric ulcers in mice and rats. Eur J Pharmacol. 1999 Aug 20;379(1):19-31. doi: 10.1016/s0014-2999(99)00486-0. PMID: 10499368.
• United States Anti-Doping Agency. BPC-157: experimental peptide creates risk for athletes. USADA website. https://www.usada.org/spirit-of-sport/education/bpc-157-peptide-risk/

• Research article
• Open access
• Published: 02 July 2019

Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and lead to functional recovery in rats

• Darko Perovic 1 ,
• Danijela Kolenc 2 ,
• Vide Bilic 1 ,
• Nenad Somun 1 ,
• Domagoj Drmic 1 ,
• Esmat Elabjer 1 ,
• Gojko Buljat 1 ,
• Sven Seiwerth 2 &
• Predrag Sikiric   ORCID: orcid.org/0000-0002-7952-2252 1  

Journal of Orthopaedic Surgery and Research volume  14 , Article number:  199 ( 2019 ) Cite this article

25k Accesses

22 Citations

10 Altmetric

Metrics details

We focused on the therapeutic effects of the stable gastric pentadecapeptide BPC 157 in spinal cord injury using a rat model. BPC 157, of which the LD1 has not been achieved, has been implemented as an anti-ulcer peptide in inflammatory bowel disease trials and recently in a multiple sclerosis trial. In animals, BPC 157 has an anti-inflammatory effect and therapeutic effects in functional recovery and the rescue of somatosensory neurons in the sciatic nerve after transection, upon brain injury after concussive trauma, and in severe encephalopathies. Additionally, BPC 157 affects various molecular pathways.

Therefore, BPC 157 therapy was administered by a one-time intraperitoneal injection (BPC 157 (200 or 2 μg/kg) or 0.9% NaCl (5 ml/kg)) 10 min after injury. The injury procedure involved laminectomy (level L2-L3) and a 60-s compression (neurosurgical piston (60–66 g) of the exposed dural sac of the sacrocaudal spinal cord). Assessments were performed at 1, 4, 7, 15, 30, 90, 180, and 360 days after injury.

All of the injured rats that received BPC 157 exhibited consistent clinical improvement, increasingly better motor function of the tail, no autotomy, and resolved spasticity by day 15. BPC 157 application largely counteracted changes at the microscopic level, including the formation of vacuoles and the loss of axons in the white matter, the formation of edema and the loss of motoneurons in the gray matter, and a decreased number of large myelinated axons in the rat caudal nerve from day 7. EMG recordings showed a markedly lower motor unit potential in the tail muscle.

Axonal and neuronal necrosis, demyelination, and cyst formation were counteracted. The functional rescue provided by BPC 157 after spinal cord injury implies that BPC 157 therapy can impact all stages of the secondary injury phase.

Introduction

We focused on the application of the stable gastric pentadecapeptide BPC 157 [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ] to improve the outcomes of spinal cord injury in rats.

Spinal cord injury generally involves the preclusion of neural relays across the lesion site and is thereby predictably associated with a lack of functional improvement [ 12 , 13 ]. On the other hand, there is evidence that spinal cord injury triggers a cascade of secondary degenerative events that cause further damage to the injured area and induce local inflammation along with hemorrhage and edema [ 12 , 13 ] and that the therapeutic agents imatinib (which has been shown to inhibit cytokine production and reduce hemorrhage, edema, and inflammation) [ 14 ] and ibuprofen initiate favorable axonal growth and functional recovery through Rho inhibition [ 15 ]. Likewise, there is favorable evidence to support the engraftment of neural stem cells [ 16 ] or bone marrow stromal cells [ 17 ] into the lesion site. However, there are disputes about the relevant applicability of this evidence [ 18 , 19 ], particularly considering the low survival rate of bone marrow stromal cells transplanted into the contused adult rat spinal cord [ 20 , 21 ] and the need to completely fill the lesion site with neural stem cells [ 22 ]. Consequently, there have been attempts to improve the therapeutic effectiveness with combined treatments (i.e., neural stem cells with fibrin and a growth factor cocktail (BDNF; NT-3; mGDNF; IGF; bFGF; EGF; PDF; aFGF; and HGF) [ 23 ] or bone marrow stromal cells with the application of cyclosporine, minocycline, and methylprednisolone [ 24 ]). Likewise, considering the beneficial effect of the deletion of the Nogo Receptor 1 (NgR1) gene, a sequential combination of Nogo-A suppression (by anti-Nogo-A antibody treatment) and treadmill rehabilitative training was examined [ 25 ].

It is generally believed that further attempts are fully justified [ 26 ]. In comparison, the stable gastric pentadecapeptide BPC 157, an emerging treatment with potential therapeutic applications, appears to be unrestricted by the limitations seen in previous therapies. The stable gastric pentadecapeptide BPC 157, an original cytoprotective antiulcer peptide that is used in ulcerative colitis and recently in a multiple sclerosis trial and that has an LD1 that has not been achieved [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], is known to have pleiotropic beneficial effects [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ] and to interact with several molecular pathways [ 2 , 27 , 28 , 29 , 30 , 31 , 32 ]. BPC 157 has beneficial effects on inflammation, hemorrhage, and edema after traumatic brain injury [ 33 ], various severe encephalopathies (which follow gastrointestinal and/or liver lesions), NSAID overdose [ 34 , 35 , 36 , 37 ], or insulin overdose seizures [ 38 ] and on severe muscle weakness after exposure to the specific neurotoxin cuprizone in a rat multiple sclerosis model [ 39 ] or magnesium overdose [ 40 ]. In other studies, it was shown that BPC 157 counteracts increased levels of proinflammatory and procachectic cytokines such as IL-6 and TNF-α [ 2 ]. Finally, BPC 157 improves sciatic nerve healing [ 41 ] when applied intraperitoneally, intragastrically, or locally at the site of anastomosis shortly after injury or directly into the tube after non-anastomosed nerve tubing (7-mm nerve segment resection).

Therefore, we used a model of spinal cord injury that has many characteristics found in human spastic syndrome [ 42 ] and can be used long-term to provide a realistic model of spasticity development in the tail muscle.

The administered therapy was a one-time intraperitoneal application of the stable gastric pentadecapeptide BPC 157, much like the one-time engraftment of neural stem cells [ 16 ] or bone marrow stromal cells [ 17 ] into the lesion site. This experiment will provide evidence that BPC 157 treatment can recover tail function, resolve spasticity, and improve neurologic recovery.

Materials and methods

Wistar albino male rats (aged 12 weeks, 350–400 g b.w.) were bred in-house (the animal facility at the Department of Pharmacology, School of Medicine, Zagreb, Croatia; registered by Directorate of Veterinary; Reg. No: HR-POK-007), acclimated for 5 days, and randomly assigned to experimental groups (at least 6 animals per experimental group and interval). The experiments were approved by the Local Ethics Committee. The laboratory animals were housed in PC cages in conventional laboratory conditions at a temperature of 22.4 °C, a relative humidity of 40–70%, and a noise level of 60 dB. Each cage was identified by the date, study number, group, dose, number, and sex of each animal. Fluorescent lighting provided illumination 12 h per day. A standard GLP diet and fresh water were provided ad libitum. Furthermore, all experiments were carried out under a blind protocol, and the effects were assessed by examiners who were completely unaware of the protocol. We certify that government regulations concerning the ethical use of animals were adhered to during this research.

The pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419) (Diagen, Ljubljana, Slovenia) dissolved in 0.9% NaCl was used in all experiments [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. The peptide BPC 157 is part of the sequence of the human gastric juice protein BPC and is freely soluble in water and 0.9% NaCl at pH 7.0. BPC 157 was prepared as described previously with 99% high-pressure liquid chromatography (HPLC) purification, expressing 1-des-Gly peptide as an impurity [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].

Surgery and spinal cord injury

Deeply anesthetized (3% isoflurane, ketamine 50 mg/kg b.w.) rats were subjected to laminectomy at lumbar level L2–L3, which corresponds to the sacrocaudal spinal cord (S2-Co1) as described previously [ 42 ]. A neurosurgical piston with a graduated force of 60–66 g was placed over the exposed dura and left for 60 s to induce a compression injury. After the piston was removed, the muscle and skin incisions were closed. A single injection (0.9% NaCl 5 ml/kg b.w.; pentadecapeptide BPC 157 200 μg/kg b.w. or 2 μg/kg b.w.) was administered intraperitoneally 10 min postinjury. Thereafter, the animals were returned to their cages in pairs, and food and water were provided ad libitum. According to previously assigned interval groups (7, 15, 30, 90, 180, and 360 days), the animals were sacrificed with an overdose of 3% isoflurane. To establish secondary spinal cord injury, four animals were sacrificed 10 min after spinal injury immediately prior to the administration of therapy. Four animals were subjected only to laminectomy without spinal cord injury and sacrificed after 360 days.

Clinical evaluation

Tail motor function was scored 8 h and 1, 4, 7, 15, 30, 90, 180, and 360 days after injury (0—autotomy; 1—complete loss of tail function; 2—maximum elevation of 1/4 of the tail length; 3—maximum elevation of 1/2 of the tail length; 4—maximum elevation of 3/4 of the tail length; 5—normal function). At the same intervals, the tails were observed for spasticity; after manual stimulation with the standardized stretch/rub maneuver, the tails were scored according to the Bennett scale [ 42 ]: 0—normal phenotype; 1—flaccid tail; 2—hypertonic flexor muscle with coiled and stiff tail; 3—hyperreflexia, e.g., coiling flexor spasm and clonus in response to light touch or stretch; and 4—hypertonic flexor and extensor muscles, clonus and hyperreflexia, the latter including a positive curling reaction.

Electrophysiology recordings

Before sacrifice, the animals from the 30-, 90-, 180-, and 360-day postspinal cord injury interval groups were placed in a wooden box with their tails exposed. Three pairs of monopolar needles were stabbed 3 mm deep into the tail 10, 60, and 100 mm caudal to the tail base. Using a TECA 15 electromyography apparatus with a signal filter between 50 Hz and 5 kHz, voluntary muscle activity was recorded from the most caudal pair of electrodes, and the average motor unit potential (MUP) was recorded. Thereafter, the compound motor action potential (CMAP) was recorded from the same pair of electrodes after stimulating the first and second electrodes (a repetition of 1 Hz and a stimulus duration of 0.05 ms). The amplitude, polyphasic changes, and the proximal and distal CMAP latencies were recorded, and the nerve conduction velocity was calculated according to previous studies [ 41 , 43 ].

A 10-mm long piece of the spinal column (the L2–L3 vertebral body) and the surrounding muscle were collected from each sacrificed animal and fixed in 4% formaldehyde in phosphate buffer (pH 7.4). Upon fixation, the spinal cord was decalcinated, dehydrated in graded ethanol solutions, and embedded in paraffin. Serial 5-μm cross-sections were deparaffinated in xylene, rehydrated in graded ethanol solutions, and stained with hematoxylin/eosin and toluidine blue (Kemica, Croatia). Part of the spinal cord gray and white matter was used for analysis under light microscopy (magnification × 300). According to previous studies [ 13 , 33 ], the intensity and distribution of the following pathological spinal cord changes were evaluated semiquantitatively (0—no changes; 1—small or focal changes; 2—moderate changes; 3—numerous confluent changes): (a) the hemorrhagic zone, (b) edema, (c) the loss of neurons in anterior horn and intermediate gray matter, (d) vacuoles, and (e) the loss of lateral and posterior spinal column tracts.

For peripheral nerve analysis, a 5-mm-long piece of tail 15 mm distal from the tail base was collected from each sacrificed animal, fixed in 4% formaldehyde in phosphate buffer (pH 7.4), decalcinated, and impregnated with 1% osmium tetroxide for a few days. The specimens were dehydrated in graded ethanol solutions, embedded in paraffin, cut into 5-μm sections, deparaffinated in xylene, rehydrated in graded ethanol solutions, and mounted on glass slides. Representative field images of four caudal nerves from each tail were taken using light microscopy (magnification × 500) with a CCD camera using ISSA 3.1 software (VamStec, Zagreb) according to a previous study [ 41 ]. Axonal myelination was analyzed according to the following quantifications: (a) the total number of myelinated axons per 10,000 μm 2 ; (b) the number of myelinated axons with a diameter ≥ 7 μm per 10,000 μm 2 ; and (c) the average axonal diameter.

Statistical analyses

Scoring data are expressed as the median, min, and max and were analyzed by Kruskal–Wallis ANOVA ( P values < 0.05 were considered significant) followed by the Mann–Whitney U test ( P values < 0.025 were considered significant) with Bonferroni correction; these tests are considered nonparametric alternatives to one-way ANOVA and Student’s t test. Numeric data are expressed as the mean ± standard deviation (SD) and were analyzed by one-way ANOVA followed by LSD test. The statistical program Statistica for Windows, ver. 12.1 (StatSoft Inc. Tulsa, OK, USA) was used for statistical analysis. P values < 0.05 were considered significant.

Clinical examinations

Tail motor function score.

As expected, the tail motor function scores demonstrated persistent debilitation in the rats that underwent spinal cord injury and received saline postinjury.

In contrast, after initial disability, the rats that underwent spinal cord injury and received BPC 157 exhibited consistent improvement in motor function compared to that in the corresponding controls (Fig.  1 ). In particular, from day 180, autotomy was noted in the rats that underwent spinal cord injury but not in those that had been treated with BPC 157 (Fig.  2 ).

Tail motor function ( a , b ) in rats that underwent spinal cord injury. Thirty days following injury. Debilitated rats underwent spinal cord injury that received saline post-injury ( a ). Contrarily, rats that had received BPC 157 ( b ) exhibit tail motor function rescue and consistently better motor function than the corresponding controls ( a )

In rats that underwent spinal cord injury, debilitated and rescued tail motor function (BPC 157 (200 or 2 μg/kg) or saline 5 ml/kg intraperitoneally at 10 min after injury) presented by tail motor function score. Mark presents median score, and vertical bars correspond to maximum and minimum score. * P  < 0.025 vs. control

Tail spasticity

Interestingly, the development of spasticity began earlier in the rats that underwent spinal cord injury and had been treated with BPC 157 than in the corresponding controls. However, the controls exhibited sustained spasticity until the end of the experiment (day 360) while the BPC 157 rats exhibited resolved spasticity by day 15 (Fig.  3 ).

In rats that underwent spinal cord injury, debilitated and rescued tail spasticity (BPC 157 (200 or 2 μg/kg) or saline 5 ml/kg intraperitoneally at 10 min after injury) according to Bennett scoring. Mark presents median, and vertical bars correspond to maximum and minimum score. * P  < 0.025 vs. control

Histology results

Before the initiation of therapy, at 10 min after injury induction, a large hemorrhagic zone was present over the lateral and posterior white columns in all of the rats, but there were no changes in the gray matter. Notably, after the application of saline or BPC 157, the injury progression in the rats from the different experimental groups was fundamentally different. Beginning on day 7, vacuoles and the loss of posterior and lateral spinal column tracts were observed instead of hemorrhagic areas in all controls, disturbances that were largely counteracted in the BPC 157-treated rats (Table  1 and Fig.  4 ). Likewise, beginning on day 7, the controls exhibited edema and the loss of neurons in the anterior horn and intermediate gray matter, disturbances that were largely counteracted the in BPC 157-treated rats (Table  2 and Fig.  5 ).

Microscopic presentation of lateral columns of rat spinal cord at the lesion site. a Ten minutes after injury, all animals have numerous fields of hemorrhage—arrowheads. b – d Histology 30 days after injury: b control animals, numerous confluent vacuoles—arrows; c BPC 157 2 μg/kg, few small vacuoles—arrows; d BPC 157200 μg/kg, only occasionally small vacuoles—arrows. Staining H&E, magnification × 300

Microscopic presentation of posttraumatic spinal cord changes in the intermediate gray matter at the lesion site. a Ten min after injury, all animals have no difference compared to healthy animals. b – d Histology 30 days after injury: b control animals, huge edema and loss of neurons; c BPC 157 2 μg/kg, minimal edema changes and occasionally loss of neurons; d BPC 157 200 μg/kg, no difference to healthy animal. Staining H&E, magnification × 300

While the significance of this finding remains to be determined, it is probably worth mentioning that a decrease in the number of large myelinated axons in rat caudal nerves was observed in all animals until day 30, with a markedly greater number in controls and fewer in injured rats that received BPC 157 treatment. Interestingly, after 180 days, recovery occurred, and the number of large myelinated axons in the controls reached that in the BPC 157-treated rats, and this finding persisted through the end of the experiment (Fig.  6 ).

A number of myelinated axons with diameter ≥ 7 μm in rat caudal nerve per 10,000 μm 2 in corresponding days. Columns present mean and vertical bars standard deviation. P value * P  < 0.05 BPC 157 groups vs. saline. + P  < 0.05 saline and BPC 157 groups vs. laminectomy animals

Electrophysiology results

Based on a well-known phenomenon in peripheral nerve injury (i.e., as the number of preserved motoneurons decreases, the MUP (giant potential) in the tail muscle increases), it is conceivable that the BPC 157-treated rats that underwent spinal cord injury and were subjected to EMG recordings exhibited a markedly lower MUP in the tail muscle than that in the corresponding controls (Table  3 ). Consistently, the motor nerve conduction study confirmed the absence of demyelinated processes in the tail caudal nerves after spinal cord injury (the CMAP showed normal biphasic potentials, similar amplitudes, and similar conduction velocities in all of the rats) (Table  4 ).

This study attempted to demonstrate that the application of the stable gastric pentadecapeptide BPC 157 (by either of the used regimens) can improve the symptoms of spinal cord injury and lead to functional recovery in rats. In general, the one-time intraperitoneal application of the stable gastric pentadecapeptide BPC 157 is much like the engraftment of neural stem cells [ 16 ] or bone marrow stromal cells [ 17 ] into the lesion site. One should consider the primary phase lesion and hemorrhaging that results from mechanical damage during SCI as well as the secondary phase lesion that lasts several hours or even several months and is accompanied by edema, hemorrhage, inflammation, and cytotoxic edema [ 44 , 45 , 46 , 47 ] and may extend to the white matter area and lead to white matter degeneration and damage [ 48 , 49 ]. This substantiates the evidence that the spared white matter holds the key to the functional motor recovery of the hind limbs after SCI and is closely correlated with the functional restoration of the paralyzed hind limbs [ 50 , 51 , 52 ]. On the other hand, spontaneous and often substantial functional improvements [ 53 , 54 , 55 ] after partial lesioning of the spinal cord are associated with the spontaneous sprouting of axons in the corticospinal tract [ 56 , 57 , 58 ] and the formation of neural circuits by spared spinal cord tissue [ 26 ]; these processes lead to partial functional recovery [ 59 ] or the formation of the neural fiber connection between the central pattern generator (CPG) and interneurons in the spinal cord, which can enable rhythmic movement [ 60 , 61 , 62 ].

Thus, to illustrate these combining points (i.e., [ 13 , 44 , 63 ]), considering that white matter injury is the major cause of functional loss after SCI [ 45 , 52 ], it is important to note that cysts and the loss of axons instead of hemorrhagic areas were observed in the white matter in all of the controls beginning on day 7 and that the rats exhibited a tail motor score that persisted with only small improvements, sustained debilitation, sustained tail spasticity until the end of the experiment (day 360), a decrease in the number of large myelinated axons in the caudal nerve, a higher MUP (giant potential) in the tail muscle, and a group of atrophic fibers that likely represented a large unit that acquired many fibers through collateral reinnervation and then degenerated. Autotomy that occurs long after injury may appear as pain that occurs below the level of the injury (below-level pain) [ 64 , 65 ], and the late spontaneous worsening may be the result of complete deafferentation of one or several spinal segments the stimulation of the nerve plexus, or dorsal root injury [ 66 ]. Together, these findings illustrate definitive spinal cord injury with very small spontaneous improvements in functional loss.

In contrast, it is possible that the administration of BPC 157 counteracts these disturbances to lead to considerable functional recovery. The vacuoles and the loss of axons in the white matter were largely counteracted in BPC 157-treated rats (Table  1 and Fig.  3 ). This result suggests that BPC 157-treated rats exhibit continual improvement in motor function even before tissue recovery, as observed by microscopy assessment. The resolution of spasticity by day 15 (Fig.  2 ) suggests that BPC 157 administration prevents the chain of events after spinal cord injury that is mediated by the loss of local segmental inhibition and/or by an increased sensory afferent drive that results in the exacerbation of α-motoneuron activity [ 66 ]. These findings substantiate the number of large myelinated axons in the caudal nerve and the lower MUP in the tail muscle.

Likewise, autotomy was completely prevented, much like in a previous study that showed recovery in BPC 157-treated rats that underwent traumatic nerve injury [ 41 ]; this suggests the counteraction of the chain of events that otherwise leads to painful sensations and refers to denervated regions and the preservation of one or more spinal segments [ 41 ].

It is possible that BPC 157 may affect voltage-gated sodium channels (VGSCs), which play a major role in the generation and propagation of action potentials in primary afferents [ 67 ].

The abnormal processing of sensory inputs in the CNS [ 68 ]. Moreover, evidence that the compromised white matter integrity of specific spinal pathways has been linked to clinical disability [ 69 , 70 , 71 ], and cortical reorganization [ 72 ] should be considered in relation to the pleiotropic beneficial effect of BPC 157 administration observed in distinctive brain areas and lesions [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. These beneficial effects include the counteractions of traumatic brain injury and severe encephalopathies after NSAID overdose, insulin overdose, magnesium overdose, and exposure to the neurotoxin cuprizone in a rat model of multiple sclerosis [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. These beneficial effects may be due to the formation of detour circuits—which encompass spared tissue surrounding the lesion—and could reconnect locomotor circuits [ 69 ], thus enabling afferent inputs to be processed and conveyed to the cortex [ 73 ] and improving spinal reflexes, even below the injury [ 74 ].

Much like in the rats that underwent spinal cord injury recovery, rats with other disorders that are treated with BPC 157 maintain functional abilities that are otherwise impaired; for example, consciousness is maintained after brain trauma, and BPC 157 counteracts seizures, catalepsy akinesia, and severe muscle weakness [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 75 , 76 ]. The effect of BPC 157 on muscle function is combined with the counteraction of increased levels of pro-inflammatory and pro-cachectic cytokines and of downstream pathways to abolish muscle cachexia [ 2 ]. Likewise, BPC 157 ameliorates healing and recovers the impaired function of severely injured muscles that otherwise fail to spontaneously heal and plays a role after complete transection, crush, and denervation injuries [ 77 , 78 , 79 , 80 ] and after succinylcholine intramuscular application, muscle lesion, neuromuscular junction failure, fasciculations, paralysis, and hyperalgesia [ 81 ]. Likewise, given that the gray matter is particularly vulnerable during the primary phase [ 44 , 63 ], we should note that, from day 7, the controls presented with edema and the loss of motoneurons in the gray matter, disturbances that were largely counteracted in BPC 157-treated rats (Table  2 and Fig.  4 ).

In summary, this effect may be the cause or a consequence of the beneficial effects of BPC 157 on related disturbances [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. As demonstrated, BPC 157 counteracts free radical formation and free radical-induced lesions [ 32 , 82 , 83 , 84 ]. An interesting point would be the use of the same dose range in BPC 157 studies [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Finally, further studies should clarify the molecular pathways involved and extend the one-time application (much like the engraftment of neural stem cells [ 16 ] or bone marrow stromal cells [ 17 ] into the lesion site) to the continuous application for the recovery of pre-existing spinal cord injury.

In conclusion, this manuscript tried to prove the therapeutic effects of BPC 157 in spinal cord injury using a rat model. Spinal cord injury recovery was achieved in BPC 157-treated rats, meaning that this therapy affects the acute, subacute, subchronic, and chronic stages of the secondary injury phase. Thus, despite the limitations of rat studies, the results showed that treatment with BPC 157 led to the recovery of tail function and the resolution of spasticity and improved the neurologic recovery; thus, BPC 157 may represent a potential therapy for spinal cord injury.

Availability of data and materials

All data are included in the manuscript.

Abbreviations

Compound motor action potential

Central nervous system

Cone-extracellular matrix

Early growth response-1 gene

Electromyography

Focal adhesion kinase

Good laboratory practice

4-Hydroxynonenal

High-pressure liquid chromatography

Janus kinase 2

Lethal dose 1

Leukotriene B4

Myeloperoxidase

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Motor unit potential

Nerve growth factor 1-A binding protein-2

Non-steroid anti-inflammatory drugs

Spinal cord injury

Thromboxane B2

Seiwerth S, Rucman R, Turkovic B, Sever M, Klicek R, Radic B, et al. BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing, lessons from tendon, ligament, muscle and bone healing. Curr Pharm Des. 2018;24(18):1972–89.

Article   CAS   PubMed   Google Scholar  

Kang EA, Han YM, An JM, Park YJ, Sikiric P, Kim DH, et al. BPC157 as potential agent rescuing from cancer cachexia. Curr Pharm Des. 2018;24(18):1947–56.

Sikiric P, Rucman R, Turkovic B, Sever M, Klicek R, Radic B, et al. Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular recruitment and gastrointestinal tract healing. Curr Pharm Des. 2018;24(18):1990–2001.

Sikiric P, Seiwerth S, Rucman R, Drmic D, Stupnisek M, Kokot A, et al. Stress in gastrointestinal tract and stable gastric pentadecapeptide BPC 157. Finally, do we have a solution? Curr Pharm Des. 2017;23(27):4012–28.

CAS   PubMed   Google Scholar  

Sikiric P, Seiwerth S, Rucman R, Kolenc D, Vuletic LB, Drmic D, et al. Brain-gut axis and pentadecapeptide BPC 157: theoretical and practical implications. Curr Neuropharmacol. 2016;14(8):857–65.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Seiwerth S, Brcic L, Vuletic LB, Kolenc D, Aralica G, Misic M, et al. BPC 157 and blood vessels. Curr Pharm Des. 2014;20(7):1121–5.

Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, et al. Stable gastric pentadecapeptide BPC 157-NO-system relation. Curr Pharm Des. 2014;20(7):1126–35.

Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, et al. Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Curr Pharm Des. 2013;19(1):76–83.

Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, et al. Focus on ulcerative colitis: stable gastric pentadecapeptide BPC 157. Curr Med Chem. 2012;19(1):126–32.

Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, et al. Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract. Curr Pharm Des. 2011;17(16):1612–32.

Sikiric P, Seiwerth S, Brcic L, Sever M, Klicek R, Radic B, et al. Revised Robert’s cytoprotection and adaptive cytoprotection and stable gastric pentadecapeptide BPC 157. Possible significance and implications for novel mediator. Curr Pharm Des. 2010;16(10):1224–34.

Kjell J, Olson L. Rat models of spinal cord injury: from pathology to potential therapies. Dis Mod Mech. 2016;9:1125–37.

Article   CAS   Google Scholar  

Ek CJ, Habgood MD, Dennis R, Dziegielewska KM, Mallard C, Wheaton B, et al. Pathological changes in the white matter after spinal contusion injury in the rat. PLoS One. 2012;7(8):e43484.

Abrams MB, Nilsson I, Lewandowski SA, Kjell J, Codeluppi S, Olson L, et al. Imatinib enhances functional outcome after spinal cord injury. PLoS One. 2012;7(6):e38760.

Kopp MA, Liebscher T, Niedeggen A, Laufer S, Brommer B, Jungehulsing GJ, et al. Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell Tissue Res. 2012;349(1):119–32.

Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150(6):1264–73.

Ritfeld GJ, Nandoe Tewarie RD, Vajn K, Rahiem ST, Hurtado A, Wendell DF, et al. Bone marrow stromal cell-mediated tissue sparing enhances functional repair after spinal cord contusion in adult rats. Cell Transplant. 2012;21(7):1561–75.

Article   PubMed   Google Scholar  

Sharp KG, Yee KM, Steward O. A re-assessment of treatment with a tyrosine kinase inhibitor (imatinib) on tissue sparing and functional recovery after spinal cord injury. Exp Neurol. 2014;254:1–11.

Sharp KG, Yee KM, Stiles TL, Aguilar RM, Steward O. A re-assessment of the effects of treatment with a non-steroidal anti-inflammatory (ibuprofen) on promoting axon regeneration via RhoA inhibition after spinal cord injury. Exp Neurol. 2013;248:321–37.

Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A. 2002;99:2199–204.

Nandoe Tewarie RDS, Hurtado A, Ritfeld GJ, Rahiem ST, Wendell DF, Barroso MMS, et al. Bone marrow stromal cells elicit tissue sparing after acute but not delayed transplantation into the contused adult rat thoracic spinal cord. J Neurotrauma. 2009;26(12):2313–22.

Sharp KG, Yee KM, Steward O. A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury. Exp Neurol. 2014;257:186–204.

Lu P, Graham L, Wang Y, Wu D, Tuszynski M. Promotion of survival and differentiation of neural stem cells with fibrin and growth factor cocktails after severe spinal cord injury. J Vis Exp. 2014;27(89):e50641. https://doi.org/10.3791/50641

Ritfeld GJ, Nandoe Tewarie RD, Rahiem ST, Hurtado A, Roos RA, Grotenhuis A, et al. Reducing macrophages to improve bone marrow stromal cell survival in the contused spinal cord. Neuroreport. 2010;21(3):221–6.

Chen K, Marsh BC, Cowan M, Al'Joboori YD, Gigout S, Smith CC, et al. Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats. Exp Neurol. 2017;292:135–44.

Filli L, Schwab ME. Structural and functional reorganization of propriospinal connections promotes functional recovery after spinal cord injury. Neural Regen Res. 2015;10(4):509–13.

Article   PubMed   PubMed Central   Google Scholar  

Hsieh M-J, Liu H-T, Wang C-N, Huang H-Y, Lin Y, Ko Y-S, et al. Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med. 2017;95:323–33.

Chang C-H, Tsai W-C, Lin M-S, Hsu Y-H, Pang J-HS. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol. 2011;110:774–80.

Chang C-H, Tsai W-C, Hsu Y-H, Pang J-HS. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules. 2014;19:19066–77.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Huang T, Zhang K, Sun L, Xue X, Zhang C, Shu Z, et al. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Drug Des Devel Ther. 2015;9:2485–99.

Tkalčević VI, Čužić S, Brajša K, Mildner B, Bokulić A, Šitum K, et al. Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol. 2007;570:212–21.

Article   PubMed   CAS   Google Scholar  

Vukojević J, Siroglavić M, Kašnik K, Kralj T, Stanćić D, Kokot A, et al. Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. Vasc Pharmacol. 2018;106:54–66.

Tudor M, Jandric I, Marovic A, Gjurasin M, Perovic D, Radic B, et al. Traumatic brain injury in mice and pentadecapeptide BPC 157 effect. Regul Pept. 2010;160(1–3):26–32.

Drmic D, Kolenc D, Ilic S, Bauk L, Sever M, Zenko Sever A, et al. Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME. World J Gastroenterol. 2017;23(29):5304–12.

Ilic S, Drmic D, Franjic S, Kolenc D, Coric M, Brcic L, et al. Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions. Life Sci. 2011;88(11–12):535–42.

Ilic S, Drmic D, Zarkovic K, Kolenc D, Brcic L, Radic B, et al. Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats. Eur J Pharmacol. 2011;667(1–3):322–9.

Ilic S, Drmic D, Zarkovic K, Kolenc D, Coric M, Brcic L, et al. High hepatotoxic dose of paracetamol produces generalized convulsions and brain damage in rats. A counteraction with the stable gastric pentadecapeptide BPC 157 (PL 14736). J Physiol Pharmacol. 2010;61(2):241–50.

Ilic S, Brcic I, Mester M, Filipovic M, Sever M, Klicek R, et al. Over-dose insulin and stable gastric pentadecapeptide BPC 157. Attenuated gastric ulcers, seizures, brain lesions, hepatomegaly, fatty liver, breakdown of liver glycogen, profound hypoglycemia and calcification in rats. J Physiol Pharmacol. 2009;60(Suppl 7):107–14.

PubMed   Google Scholar  

Klicek R, Kolenc D, Suran J, Drmic D, Brcic L, Aralica G, et al. Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability. J Physiol Pharmacol. 2013;64(5):597–612.

Medvidovic-Grubisic M, Stambolija V, Kolenc D, Katancic J, Murselovic T, Plestina-Borjan I, et al. Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen. Inflammopharmacology. 2017;25(4):439–49.

Gjurasin M, Miklic P, Zupancic B, Perovic D, Zarkovic K, Brcic L, et al. Peptide therapy with pentadecapeptide BPC 157 in traumatic nerve injury. Regul Pept. 2010;160(1–3):33–41.

Bennett DJ, Gorassini M, Fouad K, Sanelli L, Han Y, Cheng J. Spasticity in rats with sacral spinal cord injury. J Neurotrauma. 1999;16(1):69–84.

Tanimoto K, Khoury B, Feng K, Cavanaugh JM. Evaluation of sciatic nerve function after ultrasonic and electrocautery muscle dissection: an electromyographic study. J Neurol Surg A Cent Eur Neurosurg. 2015;76(2):93–8.

Song W, Song G, Zhao C, Li X, Pei X, Zhao W, et al. Testing pathological variation of white matter tract in adult rats after severe spinal cord injury with MRI. Biomed Res Int. 2018;2018:4068156.

PubMed   PubMed Central   Google Scholar  

Kozlowski P, Raj D, Liu J, Lam C, Yung AC, Tetzlaff W. Characterizing white matter damage in rat spinal cord with quantitative MRI and histology. J Neurotrauma. 2008;25(6):653–76.

Borgens RB, Liu-Snyder P. Understanding secondary injury. Q Rev Biol. 2012;87(2):89–127.

Donnelly J, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008;209(2):378–88.

Wu J, Stoica BA, Dinizo M, Pajoohesh-Ganji A, Piao C, Faden AI. Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury. Cell Cycle. 2012;11(9):1782–95.

Wu W, Wang P, Cheng JX, Xu XM. Assessment of white matter loss using bond-selective photoacoustic imaging in a rat model of contusive spinal cord injury. J Neurotrauma. 2014;31(24):1998–2002.

Schucht P, Raineteau O, Schwab OE, Fouad K. Anatomical correlates of locomotor recovery following dorsal and ventral lesions of the rat spinal cord. Exp Neurol. 2002;176(1):143–53.

Basso DM, Beattie MS, Bresnahan JC. Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol. 1996;139(2):244–56.

Ward RE, Huang W, Kostusiak M, Pallier PN, Michael-Titus AT, Priestley JV. A characterization of white matter pathology following spinal cord compression injury in the rat. Neuroscience. 2014;260:227–39.

Rossignol S, Drew T, Brustein E, Jiang W. Locomotor performance and adaptation after partial or complete spinal cord lesions in the cat. Prog Brain Res. 1999;123:349–65.

Wernig A, Müller S. Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries. Paraplegia. 1992;30(4):229–38.

Dietz V, Wirz M, Curt A, Colombo G. Locomotor pattern in paraplegic patients: training effects and recovery of spinal cord function. Spinal Cord. 1998;36(6):380–90.

Li X, Yang Z, Zhang A, Wang T, Chen W. Repair of thoracic spinal cord injury by chitosan tube implantation in adult rats. Biomaterials. 2009;30(6):1121–32.

Fouad K, Pedersen V, Schwab ME, Brösamle C. Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses. Curr Biol. 2001;11(22):1766–70.

Raineteau O, Schwab ME. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci. 2001;2(4):263–73.

Rosenzweig ES, Courtine G, Jindrich DL, Brock JH, Ferguson AR, Strand SC, et al. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci. 2010;13(12):1505–10.

Cazalets JR, Borde M, Clarac F. Localization and organization of the central pattern generator for hindlimb locomotion in newborn rat. J Neurosci. 1995;15(7 Pt 1):4943–51.

Kremer E, Lev-Toy A. Localization of the spinal network associated with generation of hindlimb locomotion in the neonatal rat and organization of its transverse coupling system. J Neurophysiol. 1997;77(3):1155–70.

Chau C, Rossignol S. Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats. Brain Res Bull. 1993;30(3–4):387–93.

Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord. 2003;41(7):369–78.

Wieseler J, Ellis AL, McFadden A, Brown K, Starnes C, Maier SF, et al. Below level central pain induced by discrete dorsal spinal cord injury. J Neurotrauma. 2010;27(9):1697–707.

Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol. 2001;429:23–37.

Kupcova Skalnikova H, Navarro R, Marsala S, Hrabakova R, Vodicka P, Gadher SJ, et al. Signaling proteins in spinal parenchyma and dorsal root ganglion in rat with spinal injury-induced spasticity. J Proteome. 2013;91:41–57.

Persson AK, Thun J, Xu XJ, Wiesenfeld-Hallin Z, Ström M, Devor M, et al. Autotomy behavior correlates with the DRG and spinal expression of sodium channels in inbred mouse strains. Brain Res. 2009;1285:1–13.

Zhang SH, Blech-Hermoni Y, Faravelli L, Seltzer Z. Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat. Pain. 2008;139(2):293–305.

Freund P, Curt A, Friston K, Thompson A. Tracking changes following spinal cord injury: insights from neuroimaging. Neuroscientist. 2013;19(2):116–28.

Cohen-Adad J, El Mendili MM, Lehéricy S, Pradat PF, Blancho S, Rossignol S, et al. Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI. Neuroimage. 2011;55(3):1024–33.

Petersen JA, Wilm BJ, von Meyenburg J, Schubert M, Seifert B, Najafi Y, et al. Chronic cervical spinal cord injury: DTI correlates with clinical and electrophysiological measures. J Neurotrauma. 2012;29(8):1556–66.

Freund P, Wheeler-Kingshott CA, Nagy Z, Gorgoraptis N, Weiskopf N, Friston K, et al. Axonal integrity predicts cortical reorganisation following cervical injury. J Neurol Neurosurg Psychiatry. 2012;83(6):629–37.

Courtine G, Song B, Roy RR, Zhong H, Herrmann JE, Ao Y, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med. 2008;14:69–74.

Hubli M, Dietz V, Bolliger M. Spinal reflex activity: a marker for neuronal functionality after spinal cord injury. Neurorehabil Neural Repair. 2012;26:188–96.

Jelovac N, Sikiric P, Rucman R, Petek M, Marovic A, Perovic D, et al. Pentadecapeptide BPC 157 attenuates disturbances induced by neuroleptics: the effect on catalepsy and gastric ulcers in mice and rats. Eur J Pharmacol. 1999;379(1):19–31.

Sikiric P, Marovic A, Matoz W, Anic T, Buljat G, Mikus D, et al. A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson’s disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine. J Physiol Paris. 1999;93(6):505–12.

Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S, et al. Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthop Res. 2006;24:1109–17.

Novinscak T, Brcic L, Staresinic M, Jukic I, Radic B, Pevec D, et al. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today. 2008;38:716–25.

Pevec D, Novinscak T, Brcic L, Sipos K, Jukic I, Staresinic M, et al. Impact of pentadecapeptide BPC 157 on muscle healing impaired by systemic corticosteroid application. Med Sci Monit. 2010;16:81–8.

Google Scholar  

Mihovil I, Radic B, Brcic I, Drmic D, Vukoja I, Boban Blagaic A, et al. Beneficial effect of pentadecapeptide BPC 157 on denervated muscle in rats. Int Congress Myol Myol. 2008;431:26–30.

Stambolija V, Stambolija TP, Holjevac JK, Murselovic T, Radonic J, Duzel V, et al. BPC 157: the counteraction of succinylcholine, hyperkalemia, and arrhythmias. Eur J Pharmacol. 2016;781:83–91.

Duzel A, Vlainic J, Antunovic M, Malekinusic D, Vrdoljak B, Samara M, et al. Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: new insights. World J Gastroenterol. 2017;23(48):8465–88.

Belosic Halle Z, Vlainic J, Drmic D, Strinic D, Luetic K, Sucic M, et al. Class side effects: decreased pressure in the lower oesophageal and the pyloric sphincters after the administration of dopamine antagonists, neuroleptics, anti-emetics, L-NAME, pentadecapeptide BPC 157 and L-arginine. Inflammopharmacology. 2017;25(5):511–22.

Luetic K, Sucic M, Vlainic J, Halle ZB, Strinic D, Vidovic T, et al. Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology. 2017;25(2):255–64.

Download references

Acknowledgements

Not applicable

This research was supported by the Ministry of Science, Education and Sports, Republic of Croatia (grant number 108-1083570-3635). There was no role of the funding body in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript should be declared.

Author information

Authors and affiliations.

Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia

Darko Perovic, Vide Bilic, Nenad Somun, Domagoj Drmic, Esmat Elabjer, Gojko Buljat & Predrag Sikiric

Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000, Zagreb, Croatia

Danijela Kolenc & Sven Seiwerth

You can also search for this author in PubMed   Google Scholar

Contributions

DP, DK, DD, GB, SS, and PS performed the experiments. DP, DK, VB, NS, DD, EE, GB, SS, and PS collected and analyzed data. DP, DK, GB, SS, and PS wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Predrag Sikiric .

Ethics declarations

Ethics approval and consent to participate.

Approved by Ethics Committee, School of Medicine, University of Zagreb, 04-1121-2006 for experiments with rats.

Consent for publication

Competing interests.

The authors declare that they have no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Cite this article.

Perovic, D., Kolenc, D., Bilic, V. et al. Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and lead to functional recovery in rats. J Orthop Surg Res 14 , 199 (2019). https://doi.org/10.1186/s13018-019-1242-6

Download citation

Received : 10 January 2019

Accepted : 18 June 2019

Published : 02 July 2019

DOI : https://doi.org/10.1186/s13018-019-1242-6

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Spinal cord

Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X

• Submission enquiries: [email protected]

Information

• Author Services

Initiatives

You are accessing a machine-readable page. In order to be human-readable, please install an RSS reader.

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https://www.mdpi.com/openaccess .

Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications.

Feature papers are submitted upon individual invitation or recommendation by the scientific editors and must receive positive feedback from the reviewers.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

Original Submission Date Received: .

• Active Journals
• Find a Journal
• Proceedings Series
• For Authors
• For Reviewers
• For Editors
• For Librarians
• For Publishers
• For Societies
• For Conference Organizers
• Open Access Policy
• Institutional Open Access Program
• Special Issues Guidelines
• Editorial Process
• Research and Publication Ethics
• Article Processing Charges
• Testimonials
• Preprints.org
• SciProfiles
• Encyclopedia

Article Menu

• Subscribe SciFeed
• Recommended Articles
• PubMed/Medline
• Google Scholar
• on Google Scholar
• Table of Contents

Find support for a specific problem in the support section of our website.

Please let us know what you think of our products and services.

Visit our dedicated information section to learn more about MDPI.

JSmol Viewer

Stable gastric pentadecapeptide bpc 157 may recover brain–gut axis and gut–brain axis function.

1. Introduction

2. behavior, 4. brain injury concomitant pathology, 5. thrombosis, 6. conclusions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

• Sikiric, P.; Gojkovic, S.; Knezevic, M.; Tepes, M.; Strbe, S.; Vukojevic, J.; Duzel, A.; Kralj, T.; Krezic, I.; Zizek, H.; et al. Stable gastric pentadecapeptide BPC 157: Prompt particular activation of the collateral pathways. Curr. Med. Chem. 2023 , 30 , 1568–1573. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Udovicic, M.; Barisic, I.; Balenovic, D.; Zivanovic Posilovic, G.; Strinic, D.; Uzun, S.; Sikiric, S.; Krezic, I.; Zizek, H.; et al. Stable gastric pentadecapeptide BPC 157 as useful cytoprotective peptide therapy in the hearth disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis presentation. Biomedicines 2022 , 10 , 2696. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Rucman, R.; Turkovic, B.; Sever, M.; Klicek, R.; Radic, B.; Drmic, D.; Stupnisek, M.; Misic, M.; Vuletic, L.B.; et al. Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular recruitment and gastrointestinal tract healing. Curr. Pharm. Des. 2018 , 24 , 1990–2001. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Seiwerth, S.; Rucman, R.; Drmic, D.; Stupnisek, M.; Kokot, A.; Sever, M.; Zoricic, I.; Zoricic, Z.; Batelja, L.; et al. Stress in gastrointestinal tract and stable gastric pentadecapeptide BPC 157. Finally, do we have a solution? Curr. Pharm. Des. 2017 , 23 , 4012–4028. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Seiwerth, S.; Rucman, R.; Kolenc, D.; Vuletic, L.B.; Drmic, D.; Grgic, T.; Strbe, S.; Zukanovic, G.; Crvenkovic, D.; et al. Brain-gut axis and pentadecapeptide BPC 157: Theoretical and practical implications. Curr. Neuropharmacol. 2016 , 14 , 857–865. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Staresinic, M.; Japjec, M.; Vranes, H.; Prtoric, A.; Zizek, H.; Krezic, I.; Gojkovic, S.; Smoday, I.M.; Oroz, K.; Staresinic, E.; et al. Stable gastric pentadecapeptide BPC 157 and striated, smooth, and heart muscle. Biomedicines 2022 , 10 , 3221. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Skrtic, A.; Gojkovic, S.; Krezic, I.; Zizek, H.; Lovric, E.; Sikiric, S.; Knezevic, M.; Strbe, S.; Milavic, M.; et al. Gastric pentadecapeptide BPC 157 in cytoprotection to resolve major vessel occlusion disturbances, ischemia-reperfusion injury following Pringle maneuver, and Budd-Chiari syndrome. World J. Gastroenterol. 2022 , 28 , 23–46. [ Google Scholar ] [ CrossRef ]
• Seiwerth, S.; Milavic, M.; Vukojevic, J.; Gojkovic, S.; Krezic, I.; Vuletic, L.B.; Pavlov, K.H.; Petrovic, A.; Sikiric, S.; Vranes, H.; et al. Stable gastric pentadecapeptide BPC 157 and wound healing. Front. Pharmacol. 2021 , 12 , 627533. [ Google Scholar ] [ CrossRef ]
• Vukojevic, J.; Milavic, M.; Perovic, D.; Ilic, S.; Cilic, A.Z.; Duran, N.; Strbe, S.; Zoricic, Z.; Filipcic, I.; Brecic, P.; et al. Pentadecapeptide BPC 157 and the central nervous system. Neural Regen. Res. 2022 , 17 , 482–487. [ Google Scholar ] [ CrossRef ]
• Rozé, C. Neurohumoral control of gastrointestinal motility. Reprod. Nutr. Dev. 1980 , 20 , 1125–1141. [ Google Scholar ] [ CrossRef ]
• Dockray, G.J.; Gregory, R.A. Relations between neuropeptides and gut hormones. Proc. R. Soc. Lond. B. Biol. Sci. 1980 , 210 , 151–164. [ Google Scholar ] [ PubMed ]
• Krieger, D.T. Brain peptides: What, where, and why? Science 1983 , 222 , 975–985. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Robert, A. Cytoprotection by prostaglandins. Gastroenterology 1979 , 77 , 761–767. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Robert, A.; Lum, J.T.; Lancaster, C.; Olafsson, A.S.; Kolbasa, K.P.; Nezamis, J.E. Prevention by prostaglandins of caerulein-induced pancreatitis in rats. Lab. Investig. 1989 , 60 , 677–691. [ Google Scholar ]
• Elliott, G.; Whited, B.A.; Purmalis, A.; Davis, J.P.; Field, S.O.; Lancaster, C.; Robert, A. Effect of 16,16-dimethyl PGE2 on renal papillary necrosis and gastrointestinal ulcerations (gastric, duodenal, intestinal) produced in rats by mefenamic acid. Life Sci. 1986 , 39 , 423–432. [ Google Scholar ] [ CrossRef ]
• Szabo, S.; Usadel, K.H. Cytoprotection—Organoprotection by somatostatin: Gastric and hepatic lesions. Experientia 1982 , 38 , 254–256. [ Google Scholar ] [ CrossRef ]
• Szabó, S. Role of sulfhydryls and early vascular lesions in gastric mucosal injury. Acta Physiol. Hung. 1984 , 64 , 203–214. [ Google Scholar ]
• Szabo, S. Experimental basis for a role for sulfhydryls and dopamine in ulcerogenesis: A primer for cytoprotection--organoprotection. Klin Wochenschr. 1986 , 64 (Suppl. 7), 116–122. [ Google Scholar ]
• Szabo, S.; Trier, J.S.; Brown, A.; Schnoor, J. Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat. Gastroenterology 1985 , 88 , 228–236. [ Google Scholar ] [ CrossRef ]
• Szabo, S. Mechanism of mucosal protection. In Gastric Cytoprotection: A Clinician’s Guide ; Hollander, D., Tarnawski, A., Eds.; Plenum Medical Book Co.: New York, NY, USA, 1989; pp. 49–90. [ Google Scholar ]
• Pihan, G.; Majzoubi, D.; Haudenschild, C.; Trier, J.S.; Szabo, S. Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate. Gastroenterology 1986 , 91 , 1415–1426. [ Google Scholar ] [ CrossRef ]
• Chang, M.M.; Leeman, S.E.; Niall, H.D. Amino-acid sequence of substance P. Nat. New Biol. 1971 , 232 , 86–87. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Vogler, K.; Haefely, W.; Studier, R.O.; Lergier, W.; Strassle, R.; Bernies, K.H. A new purification procedure and biological properties of substance P. Ann N. Y. Acad. Sci. 1963 , 104 , 378–390. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Carraway, R.; Leeman, S.E. The amino acid sequence of a hypothalamic peptide, neurotensin. J. Biol. Chem. 1975 , 250 , 1907–1911. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Carraway, R.; Leeman, S.E. The synthesis of neurotensin. J. Biol. Chem. 1975 , 250 , 1912–1918. [ Google Scholar ] [ CrossRef ]
• Dockray, G.J. Immunochemical evidence of cholecystokinin-like peptides in brain. Nature 1976 , 264 , 568–570. [ Google Scholar ] [ CrossRef ]
• Bryant, M.G. Vasoactive intestinal peptide (VIP). J. Clin. Pathol. Suppl. (Assoc. Clin. Pathol.) 1978 , 8 , 63–67. [ Google Scholar ] [ CrossRef ]
• Yanaihara, C.; Sato, H.; Yanaihara, N.; Naruse, S.; Forssmann, W.G.; Helmstaedter, V.; Fujita, T.; Yamaguchi, K.; Abe, K. Motilin-, substance P- and somatostatin-like immunoreactivities in extracts from dog, tupaia and monkey brain and GI tract. Adv. Exp. Med. Biol. 1978 , 106 , 269–283. [ Google Scholar ]
• Brown, M.; Allen, R.; Villarreal, J.; Rivier, J.; Vale, W. Bombesin-like activity: Radioimmunologic assessment in biological tissues. Life Sci. 1978 , 23 , 2721–2728. [ Google Scholar ] [ CrossRef ]
• Erspamer, V.; Melchiorri, P.; Erspamer, C.F.; Negri, L. Polypeptides of the amphibian skin active on the gut and their mammalian counterparts. Adv. Exp. Med. Biol. 1978 , 106 , 51–64. [ Google Scholar ]
• Arimura, A.; Sato, H.; Dupont, A.; Nishi, N.; Schally, A.V. Somatostatin: Abundance of immunoreactive hormone in rat stomach and pancreas. Science 1975 , 189 , 1007–1009. [ Google Scholar ] [ CrossRef ]
• Polak, J.M.; Bloom, S.R.; Sullivan, S.N.; Facer, P.; Pearse, A.G. Enkephalin-like immunoreactivity in the human gastrointestinal tract. Lancet 1977 , 1 , 972–974. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Morley, J.E.; Dawson, M.; Hodgkinson, H.; Kalk, W.J. Galactorrhea and hyperprolactinemia associated with chest wall injury. J. Clin. Endocrinol. Metab. 1977 , 45 , 931–935. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Seiwerth, S.; Rucman, R.; Turkovic, B.; Rokotov, D.S.; Brcic, L.; Sever, M.; Klicek, R.; Radic, B.; Drmic, D.; et al. Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Curr. Pharm. Des. 2013 , 19 , 76–83. [ Google Scholar ] [ PubMed ]
• Ilic, S.; Brcic, I.; Mester, M.; Filipovicm, M.; Sever, M.; Klicek, R.; Barisic, I.; Radic, B.; Zoricic, Z.; Bilic, V.; et al. Over-dose insulin and stable gastric pentadecapeptide BPC 157. Attenuated gastric ulcers, seizures, brain lesions, hepatomegaly, fatty liver, breakdown of liver glycogen, profound hypoglycemia and calcification in rats. J. Physiol. Pharmacol. 2009 , 60 , 107–114. [ Google Scholar ]
• Ilic, S.; Drmic, D.; Zarkovic, K.; Kolenc, D.; Coric, M.; Brcic, L.; Klicek, R.; Radic, B.; Sever, M.; Djuzel, V.; et al. High hepatotoxic dose of paracetamol produces generalized convulsions and brain damage in rats. A counteraction with the stable gastric pentadecapeptide BPC 157 (PL 14736). J. Physiol. Pharmacol. 2010 , 61 , 241–250. [ Google Scholar ]
• Ilic, S.; Drmic, D.; Franjic, S.; Kolenc, D.; Coric, M.; Brcic, L.; Klicek, R.; Radic, B.; Sever, M.; Djuzel, V.; et al. Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: Diclofenac-induced gastrointestinal, liver, and encephalopathy lesions. Life Sci. 2011 , 88 , 535–542. [ Google Scholar ] [ CrossRef ]
• Ilic, S.; Drmic, D.; Zarkovic, K.; Kolenc, D.; Brcic, L.; Radic, B.; Djuzel, V.; Blagaic, A.B.; Romic, Z.; Dzidic, S.; et al. Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats. Eur. J. Pharmacol. 2011 , 667 , 322–329. [ Google Scholar ] [ CrossRef ]
• Drmic, D.; Kolenc, D.; Ilic, S.; Bauk, L.; Sever, M.; Zenko Sever, A.; Luetic, K.; Suran, J.; Seiwerth, S.; Sikiric, P. Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME. World J. Gastroenterol. 2017 , 23 , 5304–5312. [ Google Scholar ] [ CrossRef ]
• Lojo, N.; Rasic, Z.; Sever, A.Z.; Kolenc, D.; Vukusic, D.; Drmic, D.; Zoricic, I.; Sever, M.; Seiwerth, S.; Sikiric, P. Effects of diclofenac, L-NAME, L-arginine, and pentadecapeptide BPC157 on gastrointestinal, liver, and brain lesions, failed anastomosis, and intestinal adaptation deterioration in 24 h-short-bowel rats. PLoS ONE 2016 , 11 , e0162590. [ Google Scholar ] [ CrossRef ]
• Park, J.M.; Lee, H.J.; Sikiric, P.; Hahm, K.B. BPC 157 rescued NSAID-cytotoxicity via stabilizing intestinal permeability and enhancing cytoprotection. Curr. Pharm. Des. 2020 , 26 , 2971–2981. [ Google Scholar ] [ CrossRef ]
• Stupnisek, M.; Franjic, S.; Drmic, D.; Hrelec, M.; Kolenc, D.; Radic, B.; Bojic, D.; Vcev, A.; Seiwerth, S.; Sikiric, P. Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin. Thromb. Res. 2012 , 129 , 652–659. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Stupnisek, M.; Kokot, A.; Drmic, D.; Hrelec Patrlj, M.; Zenko Sever, A.; Kolenc, D.; Radic, B.; Suran, J.; Bojic, D.; Vcev, A.; et al. Pentadecapeptide BPC 157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, L-NAME and L-arginine. PLoS ONE 2015 , 10 , e0123454. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Konosic, S.; Petricevic, M.; Ivancan, V.; Konosic, L.; Goluza, E.; Krtalic, B.; Drmic, D.; Stupnisek, M.; Seiwerth, S.; Sikiric, P. Intragastric application of aspirin, clopidogrel, cilostazol, and BPC 157 in rats: Platelet aggregation and blood clot. Oxid. Med. Cell Longev. 2019 , 2019 , 9084643. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kang, E.A.; Han, Y.M.; An, J.M.; Park, Y.J.; Sikiric, P.; Kim, D.H.; Kwon, K.A.; Kim, Y.J.; Yang, D.; Tchah, H.; et al. BPC157 as potential agent rescuing from cancer cachexia. Curr. Pharm. Des. 2018 , 24 , 1947–1956. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Belosic Halle, Z.; Vlainic, J.; Drmic, D.; Strinic, D.; Luetic, K.; Sucic, M.; Medvidovic-Grubisic, M.; Pavelic Turudic, T.; Petrovic, I.; Seiwerth, S.; et al. Class side effects: Decreased pressure in the lower oesophageal and the pyloric sphincters after the administration of dopamine antagonists, neuroleptics, anti-emetics, L-NAME, pentadecapeptide BPC 157 and L-arginine. Inflammopharmacology 2017 , 25 , 511–522. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Luetic, K.; Sucic, M.; Vlainic, J.; Halle, Z.B.; Strinic, D.; Vidovic, T.; Luetic, F.; Marusic, M.; Gulic, S.; Pavelic, T.T.; et al. Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology 2017 , 25 , 255–264. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sucic, M.; Luetic, K.; Jandric, I.; Drmic, D.; Sever, A.Z.; Vuletic, L.B.; Halle, Z.B.; Strinic, D.; Kokot, A.; Seiwerth, R.S.; et al. Therapy of the rat hemorrhagic cystitis induced by cyclophosphamide. Stable gastric pentadecapeptide BPC 157, L-arginine, L-NAME. Eur. J. Pharmacol. 2019 , 861 , 172593. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sever, A.Z.; Sever, M.; Vidovic, T.; Lojo, N.; Kolenc, D.; Vuletic, L.B.; Drmic, D.; Kokot, A.; Zoricic, I.; Coric, M.; et al. Stable gastric pentadecapeptide BPC 157 in the therapy of the rats with bile duct ligation. Eur. J. Pharmacol. 2019 , 847 , 130–142. [ Google Scholar ] [ CrossRef ]
• Japjec, M.; Horvat Pavlov, K.; Petrovic, A.; Staresinic, M.; Sebecic, B.; Buljan, M.; Vranes, H.; Giljanovic, A.; Drmic, D.; Japjec, M.; et al. Stable gastric pentadecapeptide BPC 157 as a therapy for the disable myotendinous junctions in rats. Biomedicines 2021 , 9 , 1547. [ Google Scholar ] [ CrossRef ]
• Knezevic, M.; Gojkovic, S.; Krezic, I.; Zizek, H.; Malekinusic, D.; Vrdoljak, B.; Vranes, H.; Knezevic, T.; Barisic, I.; Horvat Pavlov, K.; et al. Occlusion of the superior mesenteric artery in rats reversed by collateral pathways activation: Gastric pentadecapeptide BPC 157 therapy counteracts multiple organ dysfunction syndrome; intracranial, portal and caval hypertension; and aortal hypotension. Biomedicines 2021 , 9 , 609. [ Google Scholar ] [ CrossRef ]
• Knezevic, M.; Gojkovic, S.; Krezic, I.; Zizek, H.; Malekinusic, D.; Vrdoljak, B.; Knezevic, T.; Vranes, H.; Drmic, D.; Staroveski, M.; et al. Occluded superior mesenteric artery and vein. Therapy with the stable gastric pentadecapeptide BPC 157. Biomedicines 2021 , 9 , 792. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Knezevic, M.; Gojkovic, S.; Krezic, I.; Zizek, H.; Vranes, H.; Malekinusic, D.; Vrdoljak, B.; Knezevic, T.; Pavlov, K.H.; Drmic, D.; et al. Complex syndrome of the complete occlusion of the end of the superior mesenteric vein, opposed with the stable gastric pentadecapeptide BPC 157 in rats. Biomedicines 2021 , 9 , 1029. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kolovrat, M.; Gojkovic, S.; Krezic, I.; Malekinusic, D.; Vrdoljak, B.; Kasnik Kovac, K.; Kralj, T.; Drmic, D.; Barisic, I.; Horvat Pavlov, K.; et al. Pentadecapeptide BPC 157 resolves Pringle maneuver in rats, both ischemia and reperfusion. World J. Hepatol. 2020 , 12 , 184–206. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Duzel, A.; Vlainic, J.; Antunovic, M.; Malekinusic, D.; Vrdoljak, B.; Samara, M.; Gojkovic, S.; Krezic, I.; Vidovic, T.; Bilic, Z.; et al. Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: New insights. World J. Gastroenterol. 2017 , 23 , 8465–8488. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Strbe, S.; Gojkovic, S.; Krezic, I.; Zizek, H.; Vranes, H.; Barisic, I.; Strinic, D.; Orct, T.; Vukojevic, J.; Ilic, S.; et al. Over-dose lithium toxicity as an occlusive-like syndrome in rats and gastric pentadecapeptide BPC 157. Biomedicines 2021 , 9 , 1506. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Barisic, I.; Balenovic, D.; Udovicic, M.; Bardak, D.; Strinic, D.; Vlainic, J.; Vranes, H.; Smoday, I.M.; Krezic, I.; Milavic, M.; et al. Stable gastric pentadecapeptide BPC 157 may counteract myocardial infarction induced by isoprenaline in rats. Biomedicines 2022 , 10 , 265. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cesar, L.B.; Gojkovic, S.; Krezic, I.; Malekinusic, D.; Zizek, H.; Vuletic, L.B.; Petrovic, A.; Pavlov, K.H.; Drmic, D.; Kokot, A.; et al. Bowel adhesion and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine in rats. World J. Gastrointest. Pharmacol. Ther. 2020 , 11 , 93–109. [ Google Scholar ] [ CrossRef ]
• Hsieh, M.J.; Liu, H.T.; Wang, C.N.; Huang, H.Y.; Lin, Y.; Ko, Y.S.; Wang, J.S.; Chang, V.H.; Pang, J.S. Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J. Mol. Med. 2017 , 95 , 323–333. [ Google Scholar ] [ CrossRef ]
• Hsieh, M.J.; Lee, C.H.; Chueh, H.Y.; Chang, G.J.; Huang, H.Y.; Lin, Y.; Pang, J.S. Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway. Sci. Rep. 2020 , 10 , 17078. [ Google Scholar ] [ CrossRef ]
• Huang, T.; Zhang, K.; Sun, L.; Xue, X.; Zhang, C.; Shu, Z.; Mu, N.; Gu, J.; Zhang, W.; Wang, Y.; et al. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Drug Des. Devel. Ther. 2015 , 9 , 2485–2499. [ Google Scholar ] [ CrossRef ]
• Huang, B.S.; Huang, S.C.; Chen, F.H.; Chang, Y.; Mei, H.F.; Huang, H.Y.; Chen, W.Y.; Pang, J.S. Pentadecapeptide BPC 157 efficiently reduces radiation-induced liver injury and lipid accumulation through Kruppel-like factor 4 upregulation both in vivo and in vitro. Life Sci. 2022 , 310 , 121072. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Chang, C.H.; Tsai, W.C.; Lin, M.S.; Hsu, Y.H.; Pang, J.H.S. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J. Appl. Physiol. 2011 , 110 , 774–780. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Chang, C.H.; Tsai, W.C.; Hsu, Y.H.; Pang, J.H.S. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 2014 , 19 , 19066–19077. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wang, X.Y.; Qu, M.; Duan, R.; Shi, D.; Jin, L.; Gao, J.; Wood, J.d.; Li, J.; Wang, G.D. Cytoprotective mechanism of the novel gastric peptide BPC157 in gastrointestinal tract and cultured enteric neurons and glial cells. Neurosci. Bull. 2019 , 35 , 167–170. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tkalcevic, V.I.; Cuzic, S.; Brajsa, K.; Mildner, B.; Bokulic, A.; Situm, K.; Perovic, D.; Glojnaric, I.; Parnham, M.J. Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur. J. Pharmacol. 2007 , 570 , 212–221. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Vukojevic, J.; Siroglavic, M.; Kasnik, K.; Kralj, T.; Stancic, D.; Kokot, A.; Kolaric, D.; Drmic, D.; Sever, A.Z.; Barisic, I.; et al. Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. Vascul. Pharmacol. 2018 , 106 , 54–66. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Vukojevic, J.; Vrdoljak, B.; Malekinusic, D.; Siroglavic, M.; Milavic, M.; Kolenc, D.; Boban Blagaic, A.; Bateljam, L.; Drmic, D.; Seiwerth, S.; et al. The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats. Brain Behav. 2020 , 10 , e01726. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Seiwerth, S.; Rucman, R.; Turkovic, B.; Rokotov, D.S.; Brcic, L.; Sever, M.; Klicek, R.; Radic, B.; Drmic, D.; et al. Stable gastric pentadecapeptide BPC 157-NO-system relation. Curr. Pharm. Des. 2014 , 20 , 1126–1135. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Seiwerth, S.; Grabarevic, Z.; Rucman, R.; Petek, M.; Jagic, V.; Turkovic, B.; Rotkvic, I.; Mise, S.; Zoricic, I.; et al. The influence of a novel pentadecapeptide, BPC 157, on N(G)-nitro-L-arginine methylester and L-arginine effects on stomach mucosa integrity and blood pressure. Eur. J. Pharmacol. 1997 , 332 , 23–33. [ Google Scholar ] [ CrossRef ]
• Turkovic, B.; Sikiric, P.; Seiwerth, S.; Mise, S.; Anic, T.; Petek, M. Stable gastric pentadecapeptide BPC 157 studied for inflammatory bowel disease (PLD-116, PL14736, Pliva) induces nitric oxide synthesis. Gastroenterology 2004 , 126 , 287. [ Google Scholar ]
• Sikiric, P.; Seiwerth, S.; Rucman, R.; Turkovic, B.; Brcic, L.; Sever, M.; Klicek, R.; Radic, B.; Drmic, D.; Ilic, S.; et al. Focus on ulcerative colitis: Stable gastric pentadecapeptide BPC 157. Curr. Med. Chem. 2012 , 19 , 126–132. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Seiwerth, S.; Rucman, R.; Turkovic, B.; Sever, M.; Klicek, R.; Radic, B.; Drmic, D.; Stupnisek, M.; Misic, M.; Vuletic, L.B.; et al. BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing, lessons from tendon, ligament, muscle and bone healing. Curr. Pharm. Des. 2018 , 24 , 1972–1989. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Liu, L.; Zhu, G. Gut–brain axis and mood disorder. Front. Psychiatry 2018 , 9 , 223. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Aziz, Q.; Thompson, D.G. Brain-gut axis in health and disease. Gastroenterology 1998 , 114 , 559–578. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Abildgaard, A.; Elfving, B.; Hokland, M.; Lund, S.; Wegener, G. Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats. Brain Behav. Immun. 2017 , 65 , 33–42. [ Google Scholar ] [ CrossRef ]
• Bakke, H.K. CNS effects on gastric functions: From clinical observations to peptidergic brain-gut interactions. J. Physiol. Paris 1993 , 87 , 265–271. [ Google Scholar ] [ CrossRef ]
• Hanscom, M.; Loane, D.J.; Shea-Donohue, T. Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury. J. Clin. Investig. 2021 , 131 , e143777. [ Google Scholar ] [ CrossRef ]
• Robert, A.; Saperas, E.; Zhang, W.R.; Olafsson, A.S.; Lancaster, C.; Tracey, D.E.; Chosay, J.G.; Taché, Y. Gastric cytoprotection by intracisternal interleukin-1 beta in the rat. Biochem. Biophys. Res. Commun. 1991 , 174 , 1117–1124. [ Google Scholar ] [ CrossRef ]
• Gojkovic, S.; Krezic, I.; Vrdoljak, B.; Malekinusic, D.; Barisic, I.; Petrovic, A.; Horvat Pavlov, K.; Kolovrat, M.; Duzel, A.; Knezevic, M.; et al. Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats. World J. Gastrointest. Pathophysiol. 2020 , 11 , 1–19. [ Google Scholar ] [ CrossRef ]
• Gojkovic, S.; Krezic, I.; Vranes, H.; Zizek, H.; Drmic, D.; Pavlov, K.H.; Petrovic, A.; Batelja, L.; Milavic, M.; Sikiric, S.; et al. BPC 157 therapy and the permanent occlusion of the superior sagittal sinus in rat. Vascular recruitment. Biomedicines 2021 , 9 , 744. [ Google Scholar ] [ CrossRef ]
• Gojkovic, S.; Krezic, I.; Vranes, H.; Zizek, H.; Drmic, D.; Batelja Vuletic, L.; Milavic, M.; Sikiric, S.; Stilinovic, I.; Simeon, P.; et al. Robert’s intragastric alcohol-induced gastric lesion model as an escalated general peripheral and central syndrome, counteracted by the stable gastric pentadecapeptide BPC 157. Biomedicines 2021 , 9 , 1300. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tepes, M.; Gojkovic, S.; Krezic, I.; Zizek, H.; Madzar, Z.; Santak, G.; Batelja, L.; Milavic, M.; Sikiric, S.; Kocman, I.; et al. Stable gastric pentadecapeptide BPC 157 therapy for primary abdominal compartment syndrome in rats. Front. Pharmacol. 2021 , 12 , 718147. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Smoday, I.M.; Petrovic, I.; Kalogjera, L.; Vranes, H.; Zizek, H.; Krezic, I.; Gojkovic, S.; Skorak, I.; Hriberski, K.; Brizic, I.; et al. Therapy effect of the stable gastric pentadecapeptide BPC 157 on acute pancreatitis as vascular failure-induced severe peripheral and central syndrome in rats. Biomedicines 2022 , 10 , 1299. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Seiwerth, S.; Brcic, L.; Sever, M.; Klicek, R.; Radic, B.; Drmic, D.; Ilic, S.; Kolenc, D. Revised Robert’s cytoprotection and adaptive cytoprotection and stable gastric pentadecapeptide BPC 157. Possible significance and implications for novel mediator. Curr. Pharm. Des. 2010 , 16 , 1224–1234. [ Google Scholar ] [ CrossRef ]
• Udovicic, M.; Sever, M.; Kavur, L.; Loncaric, K.; Barisic, I.; Balenovic, D.; Zivanovic Posilovic, G.; Strinic, D.; Uzun, S.; Batelja Vuletic, L.; et al. Stable gastric pentadecapeptide BPC 157 therapy for monocrotaline-induced pulmonary hypertension in rats leads to prevention and reversal. Biomedicines 2021 , 9 , 822. [ Google Scholar ] [ CrossRef ]
• Akhtar, A. The flaws and human harms of animal experimentation. Camb. Q. Healthc. Ethics. 2015 , 24 , 407–419. [ Google Scholar ] [ CrossRef ]
• Zemba Cilic, A.; Zemba, M.; Cilic, M.; Balenovic, I.; Strbe, S.; Ilic, S.; Vukojevic, J.; Zoricic, Z.; Filipcic, I.; Kokot, A.; et al. Pentadecapeptide BPC 157 counteracts L-NAME-induced catalepsy. BPC 157, L-NAME, L-arginine, NO-relation, in the suited rat acute and chronic models resembling ‘positive-like’ symptoms of schizophrenia. Behav. Brain Res. 2021 , 396 , 112919. [ Google Scholar ] [ CrossRef ]
• Jelovac, N.; Sikiric, P.; Rucman, R.; Petek, M.; Marovic, A.; Perovic, D.; Seiwerth, S.; Mise, S.; Turkovic, B.; Dodig, G.; et al. Pentadecapeptide BPC 157 attenuates disturbances induced by neuroleptics: The effect on catalepsy and gastric ulcers in mice and rats. Eur. J. Pharmacol. 1999 , 379 , 19–31. [ Google Scholar ] [ CrossRef ]
• Jelovac, N.; Sikiric, P.; Rucman, R.; Petek, M.; Perovic, D.; Konjevoda, P.; Marovic, A.; Seiwerth, S.; Grabarevic, Z.; Sumajstorcic, J.; et al. A novel pentadecapeptide, BPC 157, blocks the stereotypy produced acutely by amphetamine and the development of haloperidol-induced supersensitivity to amphetamine. Biol. Psychiatry. 1998 , 43 , 511–519. [ Google Scholar ] [ CrossRef ]
• Jelovac, N.; Sikiric, P.; Rucman, R.; Petek, M.; Perovic, D.; Marovic, A.; Anic, T.; Seiwerth, S.; Mise, S.; Pigac, B.; et al. The effect of a novel pentadecapeptide BPC 157 on development of tolerance and physical dependence following repeated administration of diazepam. Chin. J. Physiol. 1999 , 42 , 171–179. [ Google Scholar ]
• Sikiric, P.; Jelovac, N.; Jelovac-Gjeldum, A.; Dodig, G.; Staresinic, M.; Anic, T.; Zoricic, I.; Rak, D.; Perovic, D.; Aralica, G.; et al. Pentadecapeptide BPC 157 attenuates chronic amphetamine-induced behavior disturbances. Acta Pharmacol. Sin. 2002 , 23 , 412–422. [ Google Scholar ] [ PubMed ]
• Sikiric, P.; Jelovac, N.; Jelovac-Gjeldum, A.; Dodig, G.; Staresinic, M.; Anic, T.; Zoricic, I.; Ferovic, D.; Aralica, G.; Buljat, G.; et al. Anxiolytic effect of BPC-157, a gastric pentadecapeptide: Shock probe/burying test and light/dark test. Acta Pharmacol. Sin. 2001 , 22 , 225–230. [ Google Scholar ] [ PubMed ]
• Zemba, M.; Cilic, A.Z.; Balenovic, I.; Cilic, M.; Radic, B.; Suran, J.; Drmic, D.; Kokot, A.; Stambolija, V.; Murselovic, T.; et al. BPC 157 antagonized the general anaesthetic potency of thiopental and reduced prolongation of anaesthesia induced by L-NAME/thiopental combination. Inflammopharmacology 2015 , 23 , 329–336. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Seiwerth, S.; Brcic, L.; Blagaic, A.B.; Zoricic, I.; Sever, M.; Klicek, R.; Radic, B.; Keller, N.; Sipos, K.; et al. Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva, Croatia). Full and distended stomach, and vascular response. Inflammopharmacology 2006 , 14 , 214–221. [ Google Scholar ] [ CrossRef ]
• Blagaic, A.B.; Blagaic, V.; Romic, Z.; Sikiric, P. The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. Eur. J. Pharmacol. 2004 , 499 , 285–290. [ Google Scholar ] [ CrossRef ]
• Boban-Blagaic, A.; Blagaic, V.; Romic, Z.; Jelovac, N.; Dodig, G.; Rucman, R.; Petek, M.; Turkovic, B.; Seiwerth, S.; Sikiric, P. The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. The effect of N(G)-nitro-L-arginine methyl ester and L-arginine. Med. Sci. Monit. 2006 , 12 , 36–45. [ Google Scholar ]
• Foster, A.C.; Kemp, J.A. Glutamate- and GABA-based CNS therapeutics. Curr. Opin. Pharmacol. 2006 , 6 , 7–17. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Petek, M.; Rucman, R.; Seiwerth, S.; Grabarevic, Z.; Rotkvic, I.; Turkovic, B.; Jagic, V.; Mildner, B.; Duvnjak, M.; et al. A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. J. Physiol. Paris 1993 , 87 , 313–327. [ Google Scholar ] [ CrossRef ]
• Möhler, H. GABAergic synaptic transmission. Regulation by drugs. Arzneimittelforschung 1992 , 42 , 211–214. [ Google Scholar ]
• Carta, M.; Murru, L.; Barabino, E.; Talani, G.; Sanna, E.; Biggio, G. Isoniazid-induced reduction in GABAergic neurotransmission alters the function of the cerebellar cortical circuit. Neuroscience 2008 , 154 , 710–719. [ Google Scholar ] [ CrossRef ]
• Osen, K.K.; Lopez, D.E.; Slyngstad, T.A.; Ottersen, O.P.; Storm-Mathisen, J. GABA-like and glycine-like immunoreactivities of the cochlear root nucleus in rat. J. Neurocytol. 1991 , 20 , 17–25. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Zemba Cilic, A.; Zemba, M.; Cilic, M.; Strbe, S.; Ilic, S.; Vukojevic, J.; Zoricic, Z.; Filipcic, I.; Kokot, A.; Smoday, I.M.; et al. BPC 157, L-NAME, L-arginine, NO-relation, in the suited rat ketamine models resembling “negative-like” symptoms of schizophrenia. Biomedicines 2022 , 10 , 1462. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Prkacin, I.; Aralica, G.; Perovic, D.; Separovic, J.; Gjurasin, M.; Lovric-Bencic, M.; Stancic-Rokotov, D.; Ziger, T.; Anic, T.; Sikiric, P.; et al. Chronic cytoprotection: Pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats. J. Physiol. Paris 2001 , 95 , 295–301. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Prkacin, I.; Separovic, J.; Aralica, G.; Perovic, D.; Gjurasin, M.; Lovric-Bencic, M.; Stancic-Rokotov, D.; Staresinic, M.; Anic, T.; Mikus, D.; et al. Portal hypertension and liver lesions in chronically alcohol drinking rats prevented and reversed by stable gastric pentadecapeptide BPC 157 (PL-10, PLD-116), and propranolol, but not ranitidine. J. Physiol. Paris 2001 , 95 , 315–324. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Becejac, T.; Cesarec, V.; Drmic, D.; Hirsl, D.; Madzarac, G.; Djakovic, Z.; Bunjevac, I.; Zenko Sever, A.; Sepac, A.; Batelja Vuletic, L.; et al. An endogeous defensive concept, renewed cytoprotection/adaptive cytoprotection: Intra(per)-oral/intragastric strong alcohol in rat. Involvement of pentadecapeptide BPC 157 and nitric oxide system. J. Physiol. Pharmacol. 2018 , 69 , 429–440. [ Google Scholar ]
• Boban Blagaic, A.; Blagaic, V.; Mirt, M.; Jelovac, N.; Dodig, G.; Rucman, R.; Petek, M.; Turkovic, B.; Anic, T.; Dubovecak, M.; et al. Gastric pentadecapeptide BPC 157 effective against serotonin syndrome in rats. Eur. J. Pharmacol. 2005 , 512 , 173–179. [ Google Scholar ] [ CrossRef ]
• Tohyama, Y.; Sikirić, P.; Diksic, M. Effects of pentadecapeptide BPC157 on regional serotonin synthesis in the rat brain: Alpha-methyl-L-tryptophan autoradiographic measurements. Life Sci. 2004 , 76 , 345–357. [ Google Scholar ] [ CrossRef ]
• Tohyama, Y.; Yamane, F.; Fikre Merid, M.; Blier, P.; Diksic, M. Effects of serotine receptors agonists, TFMPP and CGS12066B, on regional serotonin synthesis in the rat brain: An autoradiographic study. J. Neurochem. 2002 , 80 , 788–798. [ Google Scholar ] [ CrossRef ]
• Diksic, M. Labelled alpha-methyl-L-tryptophan as a tracer for the study of the brain serotonergic system. J. Psychiatry Neurosci. 2001 , 26 , 293–303. [ Google Scholar ]
• Diksic, M.; Young, S.N. Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan. J. Neurochem. 2001 , 78 , 1185–1200. [ Google Scholar ] [ CrossRef ]
• Diksic, M.; Nagahiro, S.; Grdisa, M. The regional rate of serotonin synthesis estimated by the alpha-methyl-tryptophan method in rat brain from a single time point. J. Cereb. Blood Flow Metab. 1995 , 15 , 806–813. [ Google Scholar ] [ CrossRef ]
• Lovric, M.; Separovic, J.; Sikiric, P.; Ferek, B.; Balenovic, D.; Konjevoda, P.; Aralica, G.; Boban-Blagaic, A. Gastric pentadecapeptide BPC 157 antiarrhytmic effect in animal challenged with barium chloride or digitalis. Dig. Dis. Sci. 2003 , 48 , 1880. [ Google Scholar ]
• Lovric-Bencic, M.; Sikiric, P.; Hanzevacki, J.S.; Seiwerth, S.; Rogic, D.; Kusec, V.; Aralica, G.; Konjevoda, P.; Batelja, L.; Blagaic, A.B. Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: Reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse. J. Pharmacol. Sci. 2004 , 95 , 19–26. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Separovic, J.; Buljat, G.; Anic, T.; Stancic-Rokotov, D.; Mikus, D.; Marovic, A.; Prkacin, I.; Duplancic, B.; Zoricic, I.; et al. The antidepressant effect of an antiulcer pentadecapeptide BPC 157 in Porsolt’s test and chronic unpredictable stress in rats. A comparison with antidepressants. J. Physiol. Paris 2000 , 94 , 99–104. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rampino, A.; Marakhovskaia, A.; Soares-Silva, T.; Torretta, S.; Veneziani, F.; Beaulieu, J.M. Antipsychotic drug responsiveness and dopamine receptor signaling; Old players and new prospects. Front. Psychiatry 2019 , 9 , 702. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wada, M.; Noda, Y.; Iwata, Y.; Tsugawa, S.; Yoshida, K.; Tani, H.; Hirano, Y.; Koike, S.; Sasabayashi, D.; Katayama, H.; et al. Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. Mol. Psychiatry 2022 , 27 , 2950–2967. [ Google Scholar ] [ CrossRef ]
• Heal, D.J.; Smith, S.L.; Gosden, J.; Nutt, D.J. Amphetamine, past and present—A pharmacological and clinical perspective. J. Psychopharmacol. 2013 , 27 , 479–496. [ Google Scholar ] [ CrossRef ]
• Strzelecki, A.; Weafer, J.; Stoops, W.W. Human behavioral pharmacology of stimulant drugs: An update and narrative review. Adv. Pharmacol. 2022 , 93 , 77–103. [ Google Scholar ]
• Sikiric, P.; Marovic, A.; Matoz, W.; Anic, T.; Buljat, G.; Mikus, D.; Stancic-Rokotov, D.; Separovic, J.; Seiwerth, S.; Grabarevic, Z.; et al. A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson’s disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine. J. Physiol. Paris 1999 , 93 , 505–512. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Separovic, J.; Buljat, G.; Anic, T.; Stancic-Rokotov, D.; Mikus, D.; Duplancic, B.; Marovic, A.; Zoricic, I.; Prkacin, I.; et al. Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157. J. Physiol. Paris 2000 , 94 , 105–110. [ Google Scholar ] [ CrossRef ]
• Strinic, D.; Belosic Halle, Z.; Luetic, K.; Nedic, A.; Petrovic, I.; Sucic, M.; Zivanovic Posilovic, G.; Balenovic, D.; Strbe, S.; Udovicic, M.; et al. BPC 157 counteracts QTc prolongation induced by haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats. Life Sci. 2017 , 186 , 66–79. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bilic, I.; Zoricic, I.; Anic, T.; Separovic, J.; Stancic-Rokotov, D.; Mikus, D.; Buljat, G.; Ivankovic, D.; Aralica, G.; Prkacin, I.; et al. Haloperidol-stomach lesions attenuation by pentadecapeptide BPC 157, omeprazole, bromocriptine, but not atropine, lansoprazole, pantoprazole, ranitidine, cimetidine and misoprostol in mice. Life Sci. 2001 , 68 , 1905–1912. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Mazul, B.; Seiwerth, S.; Grabarevic, Z.; Rucman, R.; Petek, M.; Jagic, V.; Turkovic, B.; Rotkvic, I.; Mise, S.; et al. Pentadecapeptide BPC 157 interactions with adrenergic and dopaminergic systems in mucosal protection in stress. Dig. Dis. Sci. 1997 , 42 , 661–671. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Boban Blagaic, A.; Turcic, P.; Blagaic, V.; Dubovecak, M.; Jelovac, N.; Zemba, M.; Radic, B.; Becejac, T.; Stancic Rokotov, D.; Sikiric, P. Gastric pentadecapeptide BPC 157 counteracts morphine-induced analgesia in mice. J. Physiol. Pharmacol. 2009 , 60 , 177–181. [ Google Scholar ]
• Correll, C.U.; Schooler, N.R. Negative symptoms in schizophrenia: A review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr. Dis. Treat. 2020 , 16 , 519–534. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Krystal, J.H.; Karper, L.P.; Seibyl, J.P.; Freeman, G.K.; Delaney, R.; Bremner, J.D.; Heninger, G.R. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 1994 , 51 , 199–214. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Boultadakis, A.; Georgiadou, G.; Pitsikas, N. Effects of the nitric oxide synthase inhibitor L-NAME on different memory components as assessed in the object recognition task in the rat. Behav. Brain Res. 2010 , 207 , 208–214. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pitsikas, N.; Boultadakis, A.; Sakellaridis, N. Effects of sub-anesthetic doses of ketamine on rats’ spatial and non-spatial recognition memory. Neuroscience 2008 , 154 , 454–460. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Trevlopoulou, A.; Touzlatzi, N.; Pitsikas, N. The nitric oxide donor sodium nitroprusside attenuates recogniton memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats. Psychopharmacology 2016 , 233 , 1045–1054. [ Google Scholar ] [ CrossRef ]
• Koros, E.; Rosenbrock, H.; Birk, G. The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, inducessocial isolation in rats. Neuropsychopharmacology 2007 , 32 , 562–576. [ Google Scholar ] [ CrossRef ]
• Zoupa, E.; Gravanis, A.; Pitsikas, N. The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts behaviouraldeficits induced by the NMDA receptor antagonist ketamine in rats. Neuropharmacology 2019 , 151 , 74–83. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Willner, P. Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation. Psychopharmacology 1997 , 134 , 319–329. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kandratavicius, L.; Balista, P.A.; Wolf, D.C.; Abrao, J.; Evora, P.R.; Rodrigues, A.J.; Chaves, C.; Maia-de-Oliveira, J.P.; Leite, J.P.; Dursun, S.M.; et al. Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia. BMC Neurosci. 2015 , 16 , 9. [ Google Scholar ] [ CrossRef ]
• Mazarati, A.; Shin, D.; Auvin, S.; Caplan, R.; Sankar, R. Kindling epileptogenesis in immature rats leads to persistent depressive behavior. Epilepsy Behav. 2007 , 10 , 377–383. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Grivas, V.; Markou, A.; Pitsikas, N. The metabotropic glutamate 2/3 receptor agonist LY379268 induces anxiety-like behavior at the highest dose tested in two rat models of anxiety. Eur. J. Pharmacol. 2013 , 715 , 105–110. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bath, K.G.; Scharfman, H.E. Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research. Epilepsy Behav. 2013 , 26 , 427–439. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Szabo, S.; Cho, C.H. From cysteamine to MPTP: Structure-activity studies with duodenal ulcerogens. Toxicol. Pathol. 1988 , 16 , 205–212. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Rotkvic, I.; Mise, S.; Petek, M.; Rucman, R.; Seiwerth, S.; Zjacic-Rotkvic, V.; Duvnjak, M.; Jagic, V.; Suchanek, E.; et al. Dopamine agonists prevent duodenal ulcer relapse. A comparative study with famotidine and cimetidine. Dig. Dis. Sci. 1991 , 36 , 905–910. [ Google Scholar ] [ CrossRef ]
• Ozdemir, V.; Jamal, M.M.; Osapay, K.; Jadus, M.R.; Sandor, Z.; Hashemzadeh, M.; Szabo, S. Cosegregation of gastrointestinal ulcers and schizophrenia in a large national inpatient discharge database: Revisiting the “brain-gut axis” hypothesis in ulcer pathogenesis. J. Investig. Med. 2007 , 55 , 315–320. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Geber, J.; Ivanovic, D.; Suchanek, E.; Gjuris, V.; Tucan-Foretic, M.; Mise, S.; Cvitanović, B.; Rotkvić, I. Dopamine antagonists induce gastric lesions in rats. Eur. J. Pharmacol. 1986 , 131 , 105–109. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Rotkvic, I.; Mise, S.; Krizanac, S.; Suchanek, E.; Petek, M.; Gjuris, V.; Geber, J.; Tucan-Foretic, M.; Udovicic, I.; et al. The influence of dopamine agonists and antagonists on gastric lesions in mice. Eur. J. Pharmacol. 1987 , 144 , 237–239. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Masuda, Y.; Murai, S.; Saito, H.; Abe, E.; Fujiwara, H.; Kohori, I.; Itoh, T. The enhancement of the hypomotility induced by small doses of haloperidol in the phase of dopaminergic supersensitivity in mice. Neuropharmacology 1991 , 30 , 35–40. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Protais, P.; Costentin, J.; Schwartz, J.C. Climbing behavior induced by apomorphine in mice: A simple test for the study of dopamine receptors in the striatum. Psychopharmacology 1976 , 50 , 1–6. [ Google Scholar ] [ CrossRef ]
• Costentin, J.; Protais, P.; Schwartz, J.C. Rapid and dissociated changes in sensitivities of different dopamine receptors in mouse brain. Nature 1975 , 257 , 405–407. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tudor, M.; Jandric, I.; Marovic, A.; Gjurasin, M.; Perovic, D.; Radic, B.; Blagaic, A.B.; Kolenc, D.; Brcic, L.; Zarkovic, K.; et al. Traumatic brain injury in mice and pentadecapeptide BPC 157 effect. Regul. Pept. 2010 , 160 , 26–32. [ Google Scholar ] [ CrossRef ]
• Perovic, D.; Kolenc, D.; Bilic, V.; Somun, N.; Drmic, D.; Elabjer, E.; Buljat, G.; Seiwerth, S.; Sikiric, P. Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and lead to functional recovery in rats. J. Orthop. Surg. Res. 2019 , 14 , 199. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Perovic, D.; Milavic, M.; Dokuzovic, S.; Krezic, I.; Gojkovic, S.; Vranes, H.; Bebek, I.; Bilic, V.; Somun, N.; Brizic, I.; et al. Novel therapeutic effects in rat spinal cord injuries: Recovery of the definitive and early spinal cord injury by the administration of pentadecapeptide BPC 157 therapy. Curr. Issues Mol. Biol. 2022 , 44 , 1901–1927. [ Google Scholar ] [ CrossRef ]
• Klicek, R.; Kolenc, D.; Suran, J.; Drmic, D.; Brcic, L.; Aralica, G.; Sever, M.; Holjevac, J.; Radic, B.; Turudic, T.; et al. Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability. J. Physiol. Pharmacol. 2013 , 64 , 597–612. [ Google Scholar ]
• Staresinic, M.; Petrovic, I.; Novinscak, T.; Jukic, I.; Pevec, D.; Suknaic, S.; Kokic, N.; Batelja, L.; Brcic, L.; Boban-Blagaic, A.; et al. Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157. J. Orthop. Res. 2006 , 24 , 1109–1117. [ Google Scholar ] [ CrossRef ]
• Novinscak, T.; Brcic, L.; Staresinic, M.; Jukic, I.; Radic, B.; Pevec, D.; Mise, S.; Tomasovic, S.; Brcic, I.; Banic, T.; et al. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg. Today. 2008 , 38 , 716–725. [ Google Scholar ] [ CrossRef ]
• Pevec, D.; Novinscak, T.; Brcic, L.; Sipos, K.; Jukic, I.; Staresinic, M.; Mise, S.; Brcic, I.; Kolenc, D.; Klicek, R.; et al. Impact of pentadecapeptide BPC 157 on muscle healing impaired by systemic corticosteroid application. Med. Sci. Monit. 2010 , 16 , 81–88. [ Google Scholar ]
• Mihovil, I.; Radic, B.; Brcic, L.; Brcic, I.; Vukoja, I.; Ilic, S.; Boban Blagaic, A.; Seiwerth, S.; Sikiric, P. Beneficial effect of pentadecapeptide BPC 157 on denervated muscle in rats. J. Physiol. Pharmacol. 2009 , 60 , 69. [ Google Scholar ]
• Brcic, L.; Brcic, I.; Staresinic, M.; Novinscak, T.; Sikiric, P.; Seiwerth, S. Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing. J. Physiol. Pharmacol. 2009 , 60 , 191–196. [ Google Scholar ] [ PubMed ]
• Balenovic, D.; Barisic, I.; Prkacin, I.; Horvat, I.; Udovicic, M.; Uzun, S.; Strinic, D.; Pevec, D.; Drmic, D.; Radic, B.; et al. Mortal furosemide-hypokalemia-disturbances in rats NO-system related shorten survival by L-NAME. Therapy benefit with BPC 157 peptide more than with L-arginine. J. Clin. Exp. Cardiolog. 2012 , 3 , 201. [ Google Scholar ] [ CrossRef ]
• Barisic, I.; Balenovic, D.; Klicek, R.; Radic, B.; Nikitovic, B.; Drmic, D.; Udovicic, M.; Strinic, D.; Bardak, D.; Berkopic, L.; et al. Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. Regul. Pept. 2013 , 181 , 50–66. [ Google Scholar ] [ CrossRef ]
• Medvidovic-Grubisic, M.; Stambolija, V.; Kolenc, D.; Katancic, J.; Murselovic, T.; Plestina-Borjan, I.; Strbe, S.; Drmic, D.; Barisic, I.; Sindic, A.; et al. Hypermagnesemia disturbances in rats, NO-related: Pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen. Inflammopharmacology 2017 , 25 , 439–449. [ Google Scholar ] [ CrossRef ]
• Stambolija, V.; Stambolija, T.P.; Holjevac, J.K.; Murselovic, T.; Radonic, J.; Duzel, V.; Duplancic, B.; Uzun, S.; Zivanovic-Posilovic, G.; Kolenc, D.; et al. BPC 157: The counteraction of succinylcholine, hyperkalemia, and arrhythmias. Eur. J. Pharmacol. 2016 , 781 , 83–91. [ Google Scholar ] [ CrossRef ]
• Lozic, M.; Stambolija, V.; Krezic, I.; Dugandzic, A.; Zivanovic-Posilovic, G.; Gojkovic, S.; Kovacevic, J.; Vrdoljak, L.; Mirkovic, I.; Kokot, A.; et al. In relation to NO-system, stable pentadecapeptide BPC 157 counteracts lidocaine-induced adverse effects in rats and depolarisation in vitro. Emerg. Med. Int. 2020 , 2020 , 6805354. [ Google Scholar ] [ CrossRef ]
• Mirkovic, I.; Kralj, T.; Lozic, M.; Stambolija, V.; Kovacevic, J.; Vrdoljak, L.; Zlatar, M.; Milanovic, K.; Drmic, D.; Predovic, J.; et al. Pentadecapeptide BPC 157 shortens duration of tetracaine- and oxybuprocaine-induced corneal anesthesia in rats. Acta Clin. Croat. 2020 , 59 , 394–406. [ Google Scholar ] [ CrossRef ]
• Reese, T.; Pórszász, R.; Baumann, D.; Bochelen, D.; Boumezbeur, F.; McAllister, K.H.; Sauter, A.; Bjelke, B.; Rudin, M. Cytoprotection does not preserve brain functionality in rats during the acute post-stroke phase despite evidence of non-infarction provided by MRI. NMR Biomed. 2000 , 13 , 361–370. [ Google Scholar ] [ CrossRef ]
• Petrovic, I.; Dobric, I.; Drvis, P.; Shejbal, D.; Brcic, L.; Blagaic, A.B.; Batelja, L.; Kokic, N.; Tonkic, A.; Mise, S.; et al. An experimental model of prolonged esophagitis with sphincter failure in the rat and the therapeutic potential of gastric pentadecapeptide BPC 157. J. Pharmacol. Sci. 2006 , 102 , 269–277. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Dobric, I.; Drvis, P.; Petrovic, I.; Shejbal, D.; Brcic, L.; Blagaic, A.B.; Batelja, L.; Sever, M.; Kokic, N.; Tonkic, A.; et al. Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J. Pharmacol. Sci. 2007 , 104 , 7–18. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Petrovic, I.; Dobric, I.; Drmic, D.; Sever, M.; Klicek, R.; Radic, B.; Brcic, L.; Kolenc, D.; Zlatar, M.; Kunjko, K.; et al. BPC 157 therapy to detriment sphincters failure-esophagitis-pancreatitis in rat and acute pancreatitis patients low sphincters pressure. J. Physiol. Pharmacol. 2011 , 62 , 527–534. [ Google Scholar ] [ PubMed ]
• Cesarec, V.; Becejac, T.; Misic, M.; Djakovic, Z.; Olujic, D.; Drmic, D.; Brcic, L.; Rokotov, D.S.; Seiwerth, S.; Sikiric, P. Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur. J. Pharmacol. 2013 , 701 , 203–212. [ Google Scholar ] [ CrossRef ]
• Skorjanec, S.; Kokot, A.; Drmic, D.; Radic, B.; Sever, M.; Klicek, R.; Kolenc, D.; Zenko, A.; Lovric Bencic, M.; Belosic Halle, Z.; et al. Duodenocutaneous fistula in rats as a model for “wound healing-therapy” in ulcer healing: The effect of pentadecapeptide BPC 157, L-nitro-arginine methyl ester and L-arginine. J. Physiol. Pharmacol. 2015 , 66 , 581–590. [ Google Scholar ] [ PubMed ]
• Vitaic, S.; Stupnisek, M.; Drmic, D.; Bauk, L.; Kokot, A.; Klicek, R.; Vcev, A.; Luetic, K.; Seiwerth, S.; Sikiric, P. Nonsteroidal anti-inflammatory drugs-induced failure of lower esophageal and pyloric sphincter and counteraction of sphincters failure with stable gatric pentadecapeptide BPC 157 in rats. J. Physiol. Pharmacol. 2017 , 68 , 265–272. [ Google Scholar ] [ PubMed ]
• Djakovic, Z.; Djakovic, I.; Cesarec, V.; Madzarac, G.; Becejac, T.; Zukanovic, G.; Drmic, D.; Batelja, L.; Zenko Sever, A.; Kolenc, D.; et al. Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine, aggravated by L-NAME. World J. Gastroenterol. 2016 , 22 , 9127–9140. [ Google Scholar ] [ CrossRef ]
• Kokot, A.; Zlatar, M.; Stupnisek, M.; Drmic, D.; Radic, R.; Vcev, A.; Seiwerth, S.; Sikiric, P. NO system dependence of atropine-induced mydriasis and L-NAME- and L-arginine-induced miosis: Reversal by the pentadecapeptide BPC 157 in rats and guinea pigs. Eur. J. Pharmacol. 2016 , 771 , 211–219. [ Google Scholar ] [ CrossRef ]
• Kralj, T.; Kokot, A.; Zlatar, M.; Masnec, S.; Kasnik Kovac, K.; Milkovic Perisa, M.; Batelja Vuletic, L.; Giljanovic, A.; Strbe, S.; Sikiric, S.; et al. Stable gastric pentadecapeptide BPC 157 therapy of rat glaucoma. Biomedicines 2021 , 10 , 89. [ Google Scholar ] [ CrossRef ]
• Jandric, I.; Vrcic, H.; Jandric Balen, M.; Kolenc, D.; Brcic, L.; Radic, B.; Drmic, D.; Seiwerth, S.; Sikiric, P. Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats. Med. Sci. Monit. Basic Res. 2013 , 19 , 93–102. [ Google Scholar ] [ CrossRef ]
• Rasic, D.; Zenko Sever, A.; Rasic, F.; Strbe, S.; Rasic, Z.; Djuzel, A.; Duplancic, B.; Boban Blagaic, A.; Skrtic, A.; Seiwerth, S.; et al. Stable gastric pentadecapeptide BPC 157 heals established vesicovaginal fistula and counteracts stone formation in rats. Biomedicines 2021 , 9 , 1206. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sikiric, P.; Seiwerth, S.; Grabarevic, Z.; Rucman, R.; Petek, M.; Jagic, V.; Turkovic, B.; Rotkvic, I.; Mise, S.; Zoricic, I.; et al. Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity. Dig. Dis. Sci. 1996 , 41 , 1604–1614. [ Google Scholar ] [ CrossRef ]
• Sever, M.; Klicek, R.; Radic, B.; Brcic, L.; Zoricic, I.; Drmic, D.; Ivica, M.; Barisic, I.; Ilic, S.; Berkopic, L.; et al. Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats. Dig. Dis. Sci. 2009 , 54 , 2070–2083. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Vuksic, T.; Zoricic, I.; Brcic, L.; Sever, M.; Klicek, R.; Radic, B.; Cesarec, V.; Berkopic, L.; Keller, N.; Blagaic, A.B.; et al. Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat. Surg. Today 2007 , 37 , 768–777. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Linan-Rico, A.; Ochoa-Cortes, F.; Beyder, A.; Soghomonyan, S.; Zuleta-Alarcon, A.; Coppola, V.; Christofi, F.L. Mechanosensory signaling in enterochromaffin cells and 5-HT release: Potential implications for gut inflammation. Front. Neurosci. 2016 , 10 , 564. [ Google Scholar ] [ CrossRef ]
• Gershon, M.D.; Tack, J. The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology 2007 , 132 , 397–414. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wood, J.D. Enteric nervous system neuropathy: Repair and restoration. Curr. Opin. Gastroenterol. 2011 , 27 , 106–111. [ Google Scholar ] [ CrossRef ]
• Gershon, M.D. Serotonin is a sword and a shield of the bowel:serotonin plays offense and defense. Trans. Am. Clin. Climatol. Assoc. 2012 , 123 , 268–280. [ Google Scholar ]
• Smith, T.K.; Gershon, M.D. Cross talk proposal: 5-HT is necessary for peristalsis. J. Physiol. 2015 , 593 , 3225–3227. [ Google Scholar ] [ CrossRef ]
• Fadini, G.P.; Pauletto, P.; Avogaro, A.; Rattazzi, M. The good and the bad in the link between insulin resistance and vascular calcification. Atherosclerosis 2007 , 193 , 241–244. [ Google Scholar ] [ CrossRef ]
• Velísek, L.; Velísková, J.; Chudomel, O.; Poon, K.L.; Robeson, K.; Marshall, B.; Sharma, A.; Moshé, S.L. Metabolic environment in substantia nigra reticulata is critical for the expression and control of hypoglycemia-induced seizures. J. Neurosci. 2008 , 28 , 9349–9362. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bilic, Z.; Gojkovic, S.; Kalogjera, L.; Krezic, I.; Malekinusic, D.; Knezevic, M.; Sever, M.; Lojo, N.; Kokot, A.; Kasnik, K.; et al. Novel insight into Robert’s cytoprotection: Complex therapeutic effect of cytoprotective pentadecapeptide pentadecapeptide BPC 157 in rats with perforated stomach throughout modulation of nitric oxide-system. Comparison with L-arginine, ranitidine and pantoprazole therapy and L-N G -nitro-L-arginine methyl ester worsening. J. Physiol. Pharmacol. 2021 , 72 , 939–955. [ Google Scholar ]
• Drmic, D.; Samara, M.; Vidovic, T.; Malekinusic, D.; Antunovic, M.; Vrdoljak, B.; Ruzman, J.; Milkovic Perisa, M.; Horvat Pavlov, K.; Jeyakumar, J.; et al. Counteraction of perforated cecum lesions in rats: Effects of pentadecapeptide BPC 157, L-NAME and L-arginine. World J. Gastroenterol. 2018 , 24 , 5462–5476. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hrelec, M.; Klicek, R.; Brcic, L.; Brcic, I.; Cvjetko, I.; Seiwerth, S.; Sikiric, P. Abdominal aorta anastomosis in rats and stable gastric pentadecapeptide BPC 157, prophylaxis and therapy. J. Physiol. Pharmacol. 2009 , 60 (Suppl. 7), 161–165. [ Google Scholar ]
• Stancic-Rokotov, D.; Sikiric, P.; Seiwerth, S.; Slobodnjak, Z.; Aralica, J.; Aralica, G.; Perovic, D.; Anic, T.; Zoricic, I.; Buljat, G.; et al. Ethanol gastric lesion aggravated by lung injury in rat. Therapy effect of antiulcer agents. J. Physiol. Paris 2001 , 95 , 289–293. [ Google Scholar ] [ CrossRef ]
• Stancic-Rokotov, D.; Slobodnjak, Z.; Aralica, J.; Aralica, G.; Perovic, D.; Staresinic, M.; Gjurasin, M.; Anic, T.; Zoricic, I.; Buljat, G.; et al. Lung lesions and anti-ulcer agents beneficial effect: Anti-ulcer agents pentadecapeptide BPC 157, ranitidine, omeprazole and atropine ameliorate lung lesion in rats. J. Physiol. Paris 2001 , 95 , 303–308. [ Google Scholar ] [ CrossRef ]
• Grabarevic, Z.; Tisljar, M.; Artukovic, B.; Bratulic, M.; Dzaja, P.; Seiwerth, S.; Sikiric, P.; Peric, J.; Geres, D.; Kos, J. The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicken. J. Physiol. Paris 1997 , 91 , 139–149. [ Google Scholar ] [ CrossRef ]
• Sikiric, P.; Seiwerth, S.; Grabarevic, Z.; Rucman, R.; Petek, M.; Rotkvic, I.; Turkovic, B.; Jagic, V.; Mildner, B.; Duvnjak, M.; et al. Hepatoprotective effect of BPC 157, a 15-amino acid peptide, on liver lesions induced by either restraint stress or bile duct and hepatic artery ligation or CCl4 administration. A comparative study with dopamine agonists and somatostatin. Life Sci. 1993 , 53 , 291–296. [ Google Scholar ] [ CrossRef ]
• Vranes, H.; Krezic, I.; Gojkovic, S.; Zizek, H.; Durasin, T.; Petrovic, A.; Horvat Pavlov, K.; Vuletic, L.B.; Seiwerth, S.; Sikiric, P.; et al. In hydronephrosis-rats, BPC 157 exerts a strong anti-ulcer effect in both stomach and duodenum along with marked kidney recovery. FASEB J. 2020 , 34 , 1. [ Google Scholar ] [ CrossRef ]
• Drmic, D.; Sucic, M.; Zenko Sever, A.; Kolenc, D.; Suran, J.; Seiwerth, S.; Sikiric, P. BPC 157 counteracts gastric lesions after bilateral nephrectomy and attenuates deleterious course in rats. FASEB J. 2015 , 29 , 628-10. [ Google Scholar ] [ CrossRef ]
• Drmic, D.; Sucic, M.; Zenko Sever, A.; Kolenc, D.; Andrijasevic, V.; Suran, J.; Seiwerth, S.; Sikiric, P. Attenuation of the deleterious couse and gastric lesions after bilateral nephrectomy in rats, NO-system relation. BPC 157, L-arginine, L-NAME. FASEB J. 2016 , 30 , 720-2. [ Google Scholar ]
• Balenovic, D.; Bencic, M.L.; Udovicic, M.; Simonji, K.; Hanzevacki, J.S.; Barisic, I.; Kranjcevic, S.; Prkacin, I.; Coric, V.; Brcic, L.; et al. Inhibition of methyldigoxin-induced arrhythmias by pentadecapeptide BPC 157: A relation with NO-system. Regul. Pept. 2009 , 156 , 83–89. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bosnjak, Z.J.; Graf, B.M.; Sikiric, P.; Stowe, D.F. Protective effects of newly isolated gastric peptide following hypoxic and reoxygenation injury in the isolated guinea pig heart. FASEB J. 1994 , 8 , A12. [ Google Scholar ]
• Sikiric, P.; Gyires, K.; Seiwerth, S.; Grabarevic, Z.; Rucman, R.; Petek, I.; Rotkvic, B.; Turkovic, I.; Udovicic, V.; Jagic, B.; et al. The effect of pentadecapeptide BPC 157 on inflammatory, non-inflammatory, direct and indirect pain and capsaicin neurotoxicity. Inflammopharmacology 1993 , 2 , 121–127. [ Google Scholar ] [ CrossRef ]
• Zivanovic-Posilovic, G.; Balenovic, D.; Barisic, I.; Strinic, D.; Stambolija, V.; Udovicic, M.; Uzun, S.; Drmic, D.; Vlainic, J.; Bencic, M.L.; et al. Stable gastric pentadecapeptide BPC 157 and bupivacaine. Eur. J. Pharmacol. 2016 , 793 , 56–65. [ Google Scholar ] [ CrossRef ]
• Jung, Y.H.; Kim, H.; Kim, H.; Kim, E.; Baik, J.; Kang, H. The anti-nociceptive effect of BPC-157 on the incisional pain model in rats. J. Dent. Anesth. Pain Med. 2022 , 22 , 97–105. [ Google Scholar ] [ CrossRef ]
• Park, S.Y.; Choi, S.R.; Kim, J.H.; Lee, S.C.; Jeong, S.Y.; Jeong, J.H.; Lee, T.Y. Antinociceptive effect of BPC-157 in the formalin-induced pain model. Kosin Med. J. 2021 , 36 , 1–13. [ Google Scholar ] [ CrossRef ]
• Lee, E.; Padgett, B. Intra-articular injection of BPC 157 for multiple types of knee pain. Altern. Ther. Health Med. 2021 , 27 , 8–13. [ Google Scholar ]
• Staresinic, M.; Sebecic, B.; Patrlj, L.; Jadrijevic, S.; Suknaic, S.; Perovic, D.; Aralica, G.; Zarkovic, N.; Borovic, S.; Srdjak, M.; et al. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J. Orthop. Res. 2003 , 21 , 976–983. [ Google Scholar ] [ CrossRef ]
• Krivic, A.; Anic, T.; Seiwerth, S.; Huljev, D.; Sikiric, P. Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: Promoted tendon-to-bone healing and opposed corticosteroid aggravation. J. Orthop. Res. 2006 , 24 , 982–989. [ Google Scholar ] [ CrossRef ]
• Krivic, A.; Majerovic, M.; Jelic, I.; Seiwerth, S.; Sikiric, P. Modulation of early functional recovery of achilles tendon to bone unit after transection by BPC 157 and methylprednisolone. Inflamm. Res. 2008 , 57 , 205–210. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cerovecki, T.; Bojanic, I.; Brcic, L.; Radic, B.; Vukoja, I.; Seiwerth, S.; Sikiric, P. Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat. J. Orthop. Res. 2010 , 28 , 1155–1161. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sebecic, B.; Nikolic, V.; Sikiric, P.; Seiwerth, S.; Sosa, T.; Patrlj, L.; Grabarević, Z.; Rucman, R.; Petek, M.; Konjevoda, P.; et al. Osteogenic effect of a gastric pentadecapeptide BPC 157, on the healing of segmental bone defect in rabbits. A comparison with bone marrow and autologous cortical bone implantation. Bone 1999 , 24 , 195–202. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tlak Gajger, I.; Ribaric, J.; Smodis Skerl, M.; Vlainic, J.; Sikiric, P. Stable gastric pentadecapeptide BPC 157 in honeybee (Apis mellifera) therapy, to control Nosema ceranae invasions in apiary conditions. J. Vet. Pharmacol. Ther. 2018 , 41 , 614–621. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tlak Gajger, I.; Smodis Skerl, M.I.; Sostaric, P.; Suran, J.; Sikiric, P.; Vlainic, J. Physiological and immunological status of Adult honeybees ( Apis mellifera ) fed sugar syrup supplemented with pentadecapeptide BPC 157. Biology 2021 , 10 , 891. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Xu, C.; Sun, L.; Ren, F.; Huang, P.; Tian, Z.; Cui, J.; Zhang, W.; Wang, S.; Zhang, K.; He, L.; et al. Preclinical safety evaluation of body protective compound-157, a potential drug for treating various wounds. Regul. Toxicol. Pharmacol. 2020 , 114 , 104665. [ Google Scholar ] [ CrossRef ]
• Gamulin, O.; Oroz, K.; Coric, L.; Krajacic, M.; Skrabic, M.; Dretar, V.; Strbe, S.; Talapko, J.; Juzbasic, M.; Krezic, I.; et al. Fourier transform infrared spectroscopy reveals molecular changes in blood vessels of rats treated with pentadecapeptide BPC 157. Biomedicines 2022 , 10 , 3130. [ Google Scholar ] [ CrossRef ]
• Wood, J.D. The first nobel prize for integrated systems physiology: Ivan Petrovich Pavlov, 1904. Physiology 2004 , 19 , 326–330. [ Google Scholar ] [ CrossRef ]
• Gwyer, D.; Wragg, N.M.; Wilson, S.L. Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing. Cell Tissue Res. 2019 , 377 , 153–159. [ Google Scholar ] [ CrossRef ]
• Szabo, S.; Yoshida, M.; Filakovszky, J.; Juhasz, G. “Stress” is 80 years old: From Hans Selye original paper in 1936 to recent advances in GI ulceration. Curr. Pharm. Des. 2017 , 23 , 4029–4041. [ Google Scholar ] [ CrossRef ]
• Deek, S.A. BPC 157 as potential treatment for COVID-19. Med. Hypotheses 2021 , 158 , 110736. [ Google Scholar ] [ CrossRef ] [ PubMed ]

Share and Cite

Sikiric, P.; Gojkovic, S.; Krezic, I.; Smoday, I.M.; Kalogjera, L.; Zizek, H.; Oroz, K.; Vranes, H.; Vukovic, V.; Labidi, M.; et al. Stable Gastric Pentadecapeptide BPC 157 May Recover Brain–Gut Axis and Gut–Brain Axis Function. Pharmaceuticals 2023 , 16 , 676. https://doi.org/10.3390/ph16050676

Sikiric P, Gojkovic S, Krezic I, Smoday IM, Kalogjera L, Zizek H, Oroz K, Vranes H, Vukovic V, Labidi M, et al. Stable Gastric Pentadecapeptide BPC 157 May Recover Brain–Gut Axis and Gut–Brain Axis Function. Pharmaceuticals . 2023; 16(5):676. https://doi.org/10.3390/ph16050676

Sikiric, Predrag, Slaven Gojkovic, Ivan Krezic, Ivan Maria Smoday, Luka Kalogjera, Helena Zizek, Katarina Oroz, Hrvoje Vranes, Vlasta Vukovic, May Labidi, and et al. 2023. "Stable Gastric Pentadecapeptide BPC 157 May Recover Brain–Gut Axis and Gut–Brain Axis Function" Pharmaceuticals 16, no. 5: 676. https://doi.org/10.3390/ph16050676

Article Metrics

Article access statistics, further information, mdpi initiatives, follow mdpi.

Subscribe to receive issue release notifications and newsletters from MDPI journals

Advertisement

Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing

• Open access
• Published: 27 March 2019
• Volume 377 , pages 153–159, ( 2019 )

Cite this article

You have full access to this open access article

• Daniel Gwyer 1 ,
• Nicholas M. Wragg 2 &
• Samantha L. Wilson 2  

55k Accesses

24 Citations

58 Altmetric

Explore all metrics

There is a current need for a therapy that can alleviate the social and economic burden that presents itself with debilitating and recurring musculoskeletal soft tissue injuries and disorders. Currently, several therapies are emerging and undergoing trials in animal models; these focus on the manipulation and administration of several growth factors implicated with healing. However, limitations include in vivo instability, reliance on biocompatible and robust carriers and restricted application procedures (local and direct). The aim of this paper is therefore to critically review the current literature surrounding the use of BPC 157, as a feasible therapy for healing and functional restoration of soft tissue damage, with a focus on tendon, ligament and skeletal muscle healing. Currently, all studies investigating BPC 157 have demonstrated consistently positive and prompt healing effects for various injury types, both traumatic and systemic and for a plethora of soft tissues. However, to date, the majority of studies have been performed on small rodent models and the efficacy of BPC 157 is yet to be confirmed in humans. Further, over the past two decades, only a handful of research groups have performed in-depth studies regarding this peptide. Despite this, it is apparent that BPC 157 has huge potential and following further development has promise as a therapy to conservatively treat or aid recovery in hypovascular and hypocellular soft tissues such as tendon and ligaments. Moreover, skeletal muscle injury models have suggested a beneficial effect not only for disturbances that occur as a result of direct trauma but also for systemic insults including hyperkalamia and hypermagnesia. Promisingly, there are few studies reporting any adverse reactions to the administration of BPC 157, although there is still a need to understand the precise healing mechanisms for this therapy to achieve clinical realisation.

Similar content being viewed by others

Regenerative Rehabilitative Medicine for Joints and Muscles

Regenerative Options for Musculoskeletal Disorders

Prevention of heterotopic ossification: an experimental study using a plasma expander in a murine model.

Avoid common mistakes on your manuscript.

Introduction

Some of the most frequently injured sites of the human body involve ‘soft tissues’ including skeletal muscles, tendons and ligaments. Musculoskeletal injuries of this nature can occur during both sporting and everyday activities. The majority of injury complaints, particularly those of a sporting nature, result from some form of incomplete or complete tear in the fibres that comprise the structure of the functioning tissue or ‘musculotendinous unit’ (Sloan 2008 ). The healing capacity and timelines of recovery for these tissues vary significantly, depending on several factors. Some of these factors include the cellular composition and vascular nature of the tissue(s) in question.

The general healing process can be divided into three overlapping phases: (1) inflammatory phase (days 1–5), (2) repair/proliferative phase (days 5–14) and (3) remodelling phase (days 14–90+) (Hope and Saxby 2007 ). As an example, tendon tissue is composed primarily of tendon fibroblastic cells and extracellular matrix, which contains predominantly type I collagen, type III collagen and glycoproteins (Fukuta et al. 1998 ). Following the remodelling phase, a higher proportion of synthesised type I collagen, a corresponding decrease in cellularity, glycosaminoglycan content and type III collagen (Sharma and Maffulli 2005 ) can be observed. This change, coupled with the tissues already hypocellular and hypovascular nature (Liu et al. 2011 ), results in a ‘slow’ process of healing, particularly when addressing complete ruptures, which often require surgery. Even after 12 months post-injury or surgical intervention, the tissue still lacks the biomechanical and ultrastructural characteristics it had prior to the injury (Fox et al. 2017 ).

In the USA, figures from 2008 show that 33 million musculoskeletal injuries are reported per year, with 50% involving ligament and tendon injuries (James et al. 2008 ). Figures also show that an estimated 300,000 tendon and ligament repair surgeries are performed annually in the US alone (Pennisi 2002 ). Prevalence of injury is also mirrored in professional sporting populations, with the diagnostic grouping of ‘most common injury’ as skeletal muscle/tendon in nature, accounting for 45% of all diagnosed injuries (Brooks 2005 ). Thus, the need for a therapy that can alleviate the social and economic burden that presents itself with debilitating and recurring soft tissue injuries is apparent.

Currently, there are several therapies emerging and undergoing trials in animal models that focus on the manipulation and administration of several growth factors implicated in the healing process (Halper 2014 ; Park et al. 2017 ). However, limitations exist in the form of in vivo instability, the reliance on carriers that are biocompatible and robust and limited sites of application (local and direct) (Park et al. 2017 ). In comparison, an emerging treatment with potential therapeutic application, in the form of a pentadecapeptide known as BPC 157 (body protection compound), appears to be somewhat unrestricted by the limitations seen in previous therapies.

The aim of this paper is therefore to critically review the current literature surrounding the use of BPC 157, as a feasible therapy for soft tissue healing, with a focus on musculoskeletal tissues.

Human gastric juice-derived protein: BPC 157

The human gastric juice-derived protein labelled BPC 157, also known as Bepecin (Cox et al. 2017 ), PL 14736 and PL10 (Tkalčević et al. 2007 ) is a stable gastric pentadecapeptide that was first introduced and overviewed in the Journal of Physiology (Paris) by Sikirić et al. ( 1993 ). BPC 157 is a 15 amino acid fragment (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) that is often termed as ‘synthetic’; although the compounds are ‘natural’, they are not known to exist in nature and are derived from another protein (Bódis et al. 1997 ). Since these early studies BPC 157 has shown significant promise in the healing of an abundance of tissues including but not limited to tendon (Staresinic et al. 2003 ; Krivic et al. 2006 ; Chang et al. 2010 ), ligaments (Lovric-Bencic et al. 2004 ; Cerovecki et al. 2010 ), skeletal muscle (Staresinic et al. 2006 ; Novinscak et al. 2008 ; Brcic et al. 2009 ) and bone (Šebečić et al. 1999 ). The following sections aim to explore and evaluate tissue-specific results, with an emphasis on musculoskeletal soft tissues.

Tendon and ligament healing

Due to a limited blood supply, the spontaneous healing of both tendons and ligaments is inherently poor. Thus, these soft tissues are highly prevalent in BPC 157 research. One of the earlier studies in literature investigated the applicability and therapeutic efficacy of BPC 157 via intraperitoneal administration, specifically the effect of BPC 157 on healing following the transection of the Achilles tendon in rats (Staresinic et al. 2003 ). It was revealed that, in comparison to the severely compromised healing observed in sham and control rats, the systemic delivery of BPC 157 significantly improved recovery measures (Staresinic et al. 2003 ). This was evidenced biochemically, micro- and macroscopically. Biomechanically, the healed tendons (over 14 days) showed an increased load to tendon failure and significantly higher functionality (Achilles functional Index—AFI). Microscopic analysis revealed a greater mononuclear count, less granulocytes, an increase in fibroblasts and superior formation of the reticulin and collagen fibres. Macroscopically, the defects treated with BPC 157 were smaller in size and depth and subsequently full tendon integrity was re-established (Staresinic et al. 2003 ). Similar results have also been shown in rat models investigating the healing of the medial collateral ligament (MCL) following surgical transection (Cerovecki et al. 2010 ). Treatment of BPC 157 was administered orally in drinking water, topically via a thin cream and via intraperitoneal administration over a 90-day period. This suggests that the peptide has a therapeutic benefit via a wide range of delivery mechanisms (Fig.  1 ).

Examples of successful administration mechanisms for the delivery of BPC 157; all routes, local and systemic, have been reported to have positive healing outcomes

A further study investigating tendon-to-bone healing following the transection and detachment of the Achilles tendon in rats went on to reveal that BPC 157 is also capable of promoting tendon-to-bone healing despite the presence of corticosteroids (Krivic et al. 2006 ). This is of significance since although corticosteroid use has long been and remains controversial for healing of tissues (Carrico et al. 1984 ; Walsh et al. 1995 ; Waters et al. 2000 ), it still remains a prevalent treatment choice clinically for soft tissue damage and inflammation. Thus, the fact that BPC 157 has the apparent ability to counteract corticosteroid aggravation (Krivic et al. 2006 ) lends itself to being applied alongside conventional treatments to improve both understanding and biomechanical outcomes.

Chang et al. ( 2010 ) attempted to elucidate the potential mechanism by which BPC 157 stimulates the outgrowth and proliferation of tendon fibroblasts. Results showed that BPC 157 significantly accelerated the outgrowth of tendon explants; furthermore, the in vitro migration and rate of spreading of tendon fibroblasts increased in a dose-dependent manner, which was attributed to the activation of the FAK-paxillin pathway. Although BPC 157 had no direct effect on the proliferation of cultured tendon fibroblasts (Achilles), cell survival following H 2 O 2 stress was significantly increased. The apparent lack of a direct effect was noted due to the in vitro environment not mimicking the inherent environment of a tendon in vivo.

Skeletal muscle healing

In addition to tendon and ligament healing, the positive therapeutic effect of BPC 157 has also been extended and applied to muscle injury models, both traumatic and systemic. Following the compete transection of the quadriceps muscle in rats, a traumatic definitive defect under normal healing conditions would not be compensated (Staresinic et al. 2006 ); it was reported that the systemic delivery of BPC 157 promoted healing. More importantly, the study demonstrated that this healing continued for a sustained period (72 days) whilst maintaining the functional restoration (Staresinic et al. 2006 ).

Novinscak et al. ( 2008 ) went on to compare the effectiveness of both systemic (intraperitoneal) and local treatment (as a thin cream layer) over a period of 14 days in crushed muscle (gastrocnemius muscle complex) in rats. BPC 157 significantly improved healing outcomes in both sites of treatment: macroscopically, microscopically and functionally, in addition to improving enzymatic activity (a decrease in muscle proteolysis) (Farges et al. 2002 ). The authors concluded that BPC 157 accelerated post-injury skeletal muscle healing in addition to restoring full muscle function that is similar to the finding in tendons reported by Staresinic et al. ( 2006 ).

Pevec et al. ( 2010 ), akin to the tendon-to-bone healing study of Krivic et al. ( 2006 ), proposed BPC 157 as an effective treatment that could improve muscle healing, when administered despite corticosteroid treatment, 6a-methylprednisolone, following gastrocnemius muscular injury. With a similar administrative procedure as previously outlined (topical and intraperitoneal), corticosteroid administration was shown to aggravate healing across all parameters. BPC 157, in contrast, induced faster rates of healing and induced full functional restoration, which is also in agreement with the aforementioned studies on tendons (Krivic et al. 2006 ). When administered with corticosteroid, the restorative effects of BPC 157 were not significantly affected in functional, macroscopic or histological measures.

In addition to muscle injuries caused by direct trauma, there have been a number of studies that have indicated that BPC 157 may have the ability to recover systemic muscular disturbances in response to induced nervous, electrolyte disturbances and/or skeletal muscle wasting (Petek et al. 1999 ; Barisic et al. 2013 ; Klicek et al. 2013 ; Stambolija et al. 2016 ; Medvidovic-Grubisic et al. 2017 ; Kang et al. 2018 ). Since systemic muscle pain is attributed to infection, autoimmune conditions, illness or side effects from medication, they are considered to be more serious that stress or exercise-related muscle injuries.

Prolonged therapeutic benefits

In a study conducted by Hsieh et al. ( 2017 ), the authors aimed to explore the proangiogenic and therapeutic effect of BPC 157. Demonstrated by chick chorioallantoic membrane (CAM) and endothelial tube formation assays, both in vivo and in vitro, BPC 157 was shown to increase both vessel density and accelerate the recovery of blood flow in ischemic muscle, indicating a promotional effect on angiogenesis. Histological analysis was shown to confirm enhanced expression of vascular endothelial growth factor receptor 2 (VEGFR2) in rats treated with BPC 157. This was further confirmed in vitro using human vascular endothelial cells. BPC 157 was also shown to time-dependently activate the VEGFR2-Akt-eNOS signalling pathway. The study therefore demonstrates the pro-engiogenic effects of BPC 157 associated with VEGFR2 and VEGFR2-Akt-eNOS signalling.

It is worth noting that there does appear to be a trial administering BPC 157 (rectally administered) in human participants for the treatment and healing of acute to mild ulcerative colitis (Veljaca et al. 2002 ; Veljaca et al. 2003 ); however, details on the studies are limited and are not overly informative. Similarly, a pilot study in 2015, a clinical trial (randomised) on 42 healthy human participants, receiving oral (tablet form) dosages of BPC 157 was carried out (Clinicaltrials.gov 2018 ): 0.25, 0.5, 1 and 2 μg/kg. The details and results for this trial are still pending.

Although the mechanisms of action for BPC 157 are not yet fully understood, both in the currently reviewed and other surrounding literature, some light has been shed on a few potential systems involving nitric oxide (NO) (Sikiric et al. 2014 ), the FAK-paxillin pathway (Chang et al. 2010 ), VEGF (Hsieh et al. 2017 ) and the upregulation of growth hormone (receptor) (Chang et al. 2014 ).

Comparison of published studies

General strengths seen in all of the studies previously reported include the use of appropriate timelines for adequate stages of healing to take place; longer study periods are given for soft tissues that take longer to heal. All of the studies used both in vivo and some form of in vitro methods of data collection in order to observe different treatment effects, allowing for biomechanical, functional (use of AFI index and load to failure), macroscopic and microscopic histological analysis. All studies also reported the purity of BPC 157 in the methodologies (99% high-pressure liquid chromatography (HPLC)).

Other strengths included allowing for appropriate time following administration of anaesthetic before biomechanical and functional testing to ensure that there was no interference between measures. The study conducted by Pevec et al. ( 2010 ) also compared effects following the combination of BPC 157 and corticosteroids; this allows a further understanding of how well BPC 157 interacts with other agents and therefore its applicability in post-operative cases or following previous treatment. The studies specifically looking at soft tissue healing also spread the assessment of healing markers throughout the research period, involving data collection at various time points, for example, 1, 4, 7, 10 and 14 days throughout a 14-day study; this allows for a time-dependant relationship to be highlighted (Staresinic et al. 2003 ; Cerovecki et al. 2010 ; Pevec et al. 2010 ). Furthermore, different methods of administration—oral, intraperitoneal and topical—can be compared in order to establish a systemic effect. All studies used a range of dosages, from 10 μg, 10 ng, 10 pg and 0 .1pg per different body masses (kg/bw) and volumes (mL) BPC 157 in in vitro cultures (Staresinic et al. 2003 ; Hsieh et al. 2017 ). This allows for a dose-dependent relationship to be established, as well as allowing the authors to gauge what dosages will affect micro vs macro level measurements.

Some of the most robust studies and methodologies were those that investigated the potential mechanisms surrounding the healing effects of BPC 157. For example, in the study by Novinscak et al. ( 2008 ), measures of enzyme activity were used (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase), allowing a gauge of trauma response (proteolysis) and therefore the ability to further understand the mechanisms of action. In the study conducted by Chang et al. ( 2010 ), both MTT and Transwell filter migration assays were used to establish cell proliferation of tendon fibroblasts, along with staining (FITC-phalloidin) and Western blot analysis to determine the protein expression and activation of FAK and paxillin. Finally, Hsieh et al. ( 2017 ) conducted chick chorioallantoic membrane (CAM), endothelial tube formation and enzyme-linked immunosorbent assays. One significant positive in this study is that they also used laser Doppler scanning (recovery of blood flow in the ischemic muscle) to indicate the promotion of angiogenesis alongside Western blot and real-time PCR for the expression of VEGFR2.

Limitations of current studies

When considering the limitations, not all studies used the same level of microscopic assessment, however, this is to be expected; the studies looking more specifically at mechanistic pathways of action will typically be focused on micro-analysis, whereas those looking at the level of tissue healing on a macro-scale will be focused on biomechanical and functional measures.

Despite the use of rodents and small mammals being commonplace in research, in particular for the development of novel therapeutic agents, caution still needs to be practiced when extrapolating research data to clinical applications. Notwithstanding the impressive results that have been published to date, there is still a requirement for successful human trials to be completed prior to clinical translation. Since there are obvious differences between rodent and human physiology, it cannot be ignored that this may have a significant impact on the efficacy and safety of (any) novel agents. However, it should also be noted that BPC 157 is a peptide derived from human gastric juices; therefore, some level of safety in human subjects can be assumed. However, this still cannot be taken as fact; thus, future studies should focus on elucidating as to whether the reported benefits of BPC 157 extend beyond research animals.

Another limitation of many of the cited studies was that although the majority of the authors gave justification for research (hypothesis specifically was not always outlined), they did not appear to critically evaluate their own methodologies. Finally, very few studies have touched upon any negatives associated with the use of BPC 157 (having no known toxicity level), as well as no obvious conflicts in literature-based ideas being seen; this could be due to a lack of understanding regarding its mechanisms, as well as the fact that over the past two decades, only a handful of studies have researched the peptide (many from the same laboratory or group).

Moving forwards, it would be beneficial for further research to progress to larger animal models. If more complex animal systems were observed in their stages of healing (larger animals with potentially more complex healing), this could provide more insight into the healing capabilities seen in larger mammals, such as humans. Another significant area of research would be into mechanisms of action, shedding more light on the supposed systemic healing capabilities of BPC 157. This could involve confirmation and further study of the mechanisms already suspected to be impacted in the healing process. A recently published review by Seiwerth et al. ( 2018 ) used the current understanding from tendon, ligament and bone and applied this to gastrointestinal tract healing, which could provide a pathway for understanding of the systemic healing capabilities for applications to other tissues. Contemporary studies looking at animal models with diseases that affect the vascular and endothelial systems have also provided new insight into how BPC 157 works (Radeljak et al. 2004 ; Sever et al. 2009 ; Duzel et al. 2017 ; Sikiric et al. 2018 ; Vukojević et al. 2018 ).

Despite the tumour-promoting effects of many growth factors and peptides, BPC 157 has been shown to inhibit and counteract increased expression of VEGF and subsequent signalling pathways (Radeljak et al. 2004 ; Sever et al. 2009 ) thus avoiding VEGF-tumorigenesis (Radeljak et al. 2004 ). Furthermore, BPC 157 inhibits the growth of several tumour lines and can counteract tumour cachexia (Kang et al. 2018 ).

Vukojević et al. ( 2018 ) and Duzel et al. ( 2017 ) recently submitted works utilising BPC 157 for the treatment of inferior caval vein ligatures and colitis in rats, respectively. ICV is used to represent Virchow’s triad—hypercoagulability, heamodynamic changes and endothelial injury/dysfunction—and represents a subset of deep vein thrombosis (DVT). Application of BPC 157, which has innate endotheium protective properties, counteracted direct vein injuries, thrombosis and thrombocytopenia and prolonged bleeding (Vukojević et al. 2018 ). Furthermore, additional detrimenal consequences of ICV ligation were completely eliminated. When utilised as a protoype cryoprotective agent, BPC 157 has been seen to positively control blood vessel function in respsonse to performation and obstruction, thus re-establishing blood flow (Sikiric et al. 2018 ). Duzel et al. ( 2017 ) revealed that BPC 157 is fundamental to the tretament of colitis in rats; BPC 157 promotes the restoration of blood supply and vascular perfusion with spared mucosa. The integrity of the endothelium and oxidative damage could be restored and reversed respectively, which was linked to the increased expression and internalisation of VEGFR2.

Although not currently prescribed for human use, it is important for athletes to proceed with caution when looking at potential agents to prevent and treat injury. While not currently on the WADA list of banned substances (Wada-ama.org 2018 ), due to what some individuals would term as the synthetic nature of BPC 157, there may be issues associated with the use of this peptide, as seen by some sport organisations.

The reviewed research uses indicators of healing success in the form of in vitro, in vivo, macroscopic and microscopic level measures in various models. There appears to be no obvious conflict between studies surrounding the mechanisms of BPC 157. However, this may be due to BPC 157’s clinical infancy and the limited number of published clinical trial articles exploring the use of the peptide. Nevertheless, all of the studies to date that have tested BPC 157 as a treatment therapy have demonstrated extremely positive healing effects for various injury types in a number of soft tissues. However, at present, studies are predominantly limited to small animal models (predominantly rodents) and the efficacy of BPC 157 is yet to be confirmed in human subjects. From the recent literature, it can be said that BPC 157 appears to avoid the majority of practical pitfalls for healing typically seen using peptidergic growth factors. Although further research is required in order to better understand its mechanisms and efficacy in practical settings, BPC 157 has the potential to be developed as a new therapy to conservatively treat or aid recovery following surgery in typically hypovascular and hypocellular soft tissues such as tendon and ligament tissue.

Barisic I, Balenovic D, Klicek R, Radic B, Nikitovic B, Drmic D, Udovicic M, Strinic D, Bardak D, Berkopic L, Djuzel V (2013) Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. Regul Pept 181:50–66

Article   CAS   PubMed   Google Scholar  

Bódis B, Karádi O, Németh P, Dohoczky C, Kolega M, Mózsik G (1997) Evidence for direct cellular protective effect of PL-10 substances (synthesized parts of body protection compound, BPC) and their specificity to gastric mucosal cells. Life Sci 61:PL243–PL248

Article   Google Scholar  

Brcic L, Brcic I, Staresinic M, Novinscak T, Sikiric P, Seiwerth S (2009) Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing. J Physiol Pharmacol 60:191–196

PubMed   Google Scholar  

Brooks J (2005) Epidemiology of injuries in English professional rugby union: part 2 training injuries. Br J Sports Med 39:767–775

Article   CAS   PubMed   PubMed Central   Google Scholar  

Chang C, Tsai W, Hsu Y, Pang J (2014) Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 19:19066–19077

Carrico TJ, Mehrhof AI Jr, Cohen IK (1984) Biology of wound healing. Surg Clin N Am 64:721–733

Cerovecki T, Bojanic I, Brcic L, Radic B, Vukoja I, Seiwerth S, Sikiric P (2010) Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat. J Orthop Res 28:1155–1161

Chang C-H, Tsai W-C, Lin M-S, Hsu Y-H, Pang J-HS (2010) The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol 110:774–780

Clinicaltrials.gov. (2018) PCO-02 - Safety and pharmacokinetics trial - Full Text View - ClinicalTrials.gov . NCT02637284 [online] Available at: https://clinicaltrials.gov/ct2/show/NCT02637284 [Accessed 20 Apr. 2018]

Cox H, Miller G, Eichner D (2017) Detection and in vitro metabolism of the confiscated peptides BPC 157 and MGF R23H. Drug Testing and Analysis 9:1490–1498

Duzel A, Vlainic J, Antunovic M, Malekinusic D, Vrdoljak B, Samara M, Gojkovic S, Krezic I, Vidovic T, Bilic Z, Knezevic M (2017) Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: new insights. World J Gastroenterol 23:465–8488

Farges M, Balcerzak D, Fisher B, Attaix D, Béchet D, Ferrara M, Baracos V (2002) Increased muscle proteolysis after local trauma mainly reflects macrophage-associated lysosomal proteolysis. American Journal of Physiology-Endocrinology and Metabolism 282:E326–E335

Fox G, Gabbe B, Richardson M, Oppy A, Page R, Edwards E, Hau R, Ekegren C (2017) Twelve-month outcomes following surgical repair of the Achilles tendon. J Sci Med Sport 20:e36–e37

Fukuta S, Oyama M, Kavalkovich K, Fu F, Niyibizi C (1998) Identification of types II, IX and X collagens at the insertion site of the bovine Achilles tendon. Matrix Biol 17:65–73

Halper J (2014) Advances in the use of growth factors for treatment of disorders of soft tissues. Adv Exp Med Biol 1:59–76

Article   CAS   Google Scholar  

Hope M, Saxby T (2007) Tendon healing. Foot Ankle Clin 12:553–567

Article   PubMed   Google Scholar  

Hsieh MJ, Liu HT, Wang CN, Huang HY, Lin Y, Ko YS, Wang JS, Chang VH, Pang JH (2017) Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med 95(3):323–333

James R, Kesturu G, Balian G, Chhabra A (2008) Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options. The Journal of hand surgery 33:102–112

Kang EA, Han YM, An JM, Park YJ, Sikiric P, Kim DH, Kwon KA, Kim YJ, Yang D, Tchah H, Hahm KB (2018) BPC157 as potential agent rescuing from cancer cachexia. Curr Pharm Des 24:1947–1956

Kliček R, Kolenc D, Šuran J, Drmić D, Brčić L, Aralica G, Sever M, Holjevac J, Radić B, Turudić T, Kokot A (2013) Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability. J Physiol Pharmacol 64:597–612

Krivic A, Anic T, Seiwerth S, Huljev D, Sikiric P (2006) Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: promoted tendon-to-bone healing and opposed corticosteroid aggravation. J Orthop Res 24:982–989

Liu C, Aschbacher-Smith L, Barthelery N, Dyment N, Butler D, Wylie C (2011) What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspective. Tissue Eng B Rev 17:165–176

Lovric-Bencic M, Sikiric P, Hanzevacki JS, Seiwerth S, Rogic D, Kusec V, Aralica G, Konjevoda P, Batelja L, Blagaic AB (2004) Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse. J Pharmacol Sci 95:19–26

Medvidovic-Grubisic M, Stambolija V, Kolenc D, Katancic J, Murselovic T, Plestina-Borjan I, Strbe S, Drmic D, Barisic I, Sindic A, Seiwerth S (2017) Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, l-NAME and l-arginine worsen. Inflammopharmacology 25:439–449

Novinscak T, Brcic L, Staresinic M, Jukic I, Radic B, Pevec D, Mise S, Tomasovic S, Brcic I, Banic T (2008) Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today 38:716–725

Park J, Hwang S, Yoon I (2017) Advanced growth factor delivery systems in wound management and skin regeneration. Molecules 22:1259

Article   CAS   PubMed Central   Google Scholar  

Pennisi E (2002) Tending Tender Tendons. Science 295:1011–1011

Pevec D, Novinscak T, Brcic L, Sipos K, Jukic I, Staresinic M, Mise S, Brcic I, Kolenc D, Klicek R, Banic T (2010) Impact of pentadecapeptide BPC 157 on muscle healing impaired by systemic corticosteroid application. Med Sci Monit 16(3):BR81-8

Sharma P, Maffulli N (2005) Basic biology of tendon injury and healing. Surgeon 3:309–316

Petek M, Sikiric P, Anic T, Buljat G, Šeparovic J, Stancic-Rokotov D, Seiwerth S, Grabarevic Z, Rucman R, Mikus D, Zoricic I (1999) Pentadecapeptide BPC 157 attenuates gastric lesions induced by alloxan in rats and mice. Journal of Physiology Paris 93:501–504

Radeljak S, Seiwerth S, Sikiric P (2004) BPC 157 inhibits cell growth and VEGF signalling via the MAPK kinase pathway in the human melanoma cell line. Melanoma Res 14:A14–A15

Seiwerth S, Rucman R, Turkovic B, Sever M, Klicek R, Radic B, Drmic D, Stupnisek M, Misic M, Vuletic LB, Pavlov KH (2018) BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing, lessons from tendon, ligament, muscle and bone healing. Curr Pharm Des 24:1972–1989

Šebečić B, Nikolić V, Sikirić P, Seiwerth S, Šoša T, Patrlj L, Grabarević Ž, Ručman R, Petek M, Konjevoda P (1999) Osteogenic effect of a gastric pentadecapeptide, BPC 157, on the healing of segmental bone defect in rabbits: a comparison with bone marrow and autologous cortical bone implantation. Bone 24:195–202

Sever M, Klicek R, Radic B, Brcic L, Zoricic I, Drmic D, Ivica M, Barisic I, Ilic S, Berkopic L, Blagaic AB (2009) Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats. Dig Dis Sci 54:2070–2083

Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov D, Brcic L, Sever M, Klicek R, Radic B, Drmic D, Ilic S, Kolenc D, Aralica G, Stupnisek M, Suran J, Barisic I, Dzidic S, Vrcic H, Sebecic B (2014) Stable gastric pentadecapeptide BPC 157-NO-system relation. Curr Pharm Des 20:1126–1135

Sikirić P, Petek M, Ručman R, Seiwerth S, Grabarević Z, Rotkvić I, Turković B, Jagić V, Mildner B, Duvnjak M, Lang N, Danilović Z, Cviko A, Kolega M, Sallmani A, Djačić S, Bura M, Brkić T, Banić M, Dodig M, Corić V, Šimičević V, Veljaca M, Erceg D, Ježek D, Simunić-Banek L, Skroza N, Bulić K, Buljat G, Hanževački M, Orihovać V, Lučinger D, Culig J, Separović J, Marović A, Miše S, Suchanek E, Matoz W, Perović D, Gjurašin M, Mikulandra S, Derniković K, Cuk V, Karakas I (1993) A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. Journal of Physiology-Paris 87:313–327

Sikiric P, Rucman R, Turkovic B, Sever M, Klicek R, Radic B, Drmic D, Stupnisek M, Misic M, Vuletic LB, Pavlov KH (2018) Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular recruitment and gastrointestinal tract healing. Curr Pharm Des 24:1990–2001

Sloan J (2008) Soft tissue injuries: introduction and basic principles. Emerg Med J 25:33–37

Stambolija V, Stambolija TP, Holjevac JK, Murselovic T, Radonic J, Duzel V, Duplancic B, Uzun S, Zivanovic-Posilovic G, Kolenc D, Drmic D (2016) BPC 157: the counteraction of succinylcholine, hyperkalemia, and arrhythmias. Eur J Pharmacol 781:83–91

Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S, Kokic N, Batelja L, Brcic L, Boban-Blagaic A (2006) Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthop Res 24:1109–1117

Staresinic M, Sebecic B, Patrlj L, Jadrijevic S, Suknaic S, Perovic D, Aralica G, Zarkovic N, Borovic S, Srdjak M (2003) Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J Orthop Res 21:976–983

Tkalčević V, Čužić S, Brajša K, Mildner B, Bokulić A, Šitum K, Perović D, Glojnarić I, Parnham M (2007) Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol 570:212–221

Veljaca, M, Krnic, Z and Brajsa, K (2002) The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI. Section symposium, Honolulu, Hawaii, 13:0–32

Veljaca M, Sladoljev P, Mildner B (2003) Tolerability and pharmacokinetics of PL 14736, a novel agent for treatment of ulcerative colitis, in healthy male volunteers. Gut 3:A309

Google Scholar  

Vukojević J, Siroglavić M, Kašnik K, Kralj T, Stanćić D, Kokot A, Kolarić D, Drmić D, Sever AZ, Barišić I, Šuran J (2018) Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. Vasc Pharmacol 106:54–66

Wada-ama.org. (2018) [online] Available at: https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf [Accessed 25 Apr. 2018]

Walsh W, Wiggins M, Fadale P, Ehrlich M (1995) Effects of a delayed steroid injection on ligament healing using a rabbit medial collateral ligament model. Biomaterials 16:905–910

Waters RV, Gamradt SC, Asnis P, Vickery BH, Avnur Z, Hill E, Bostrom M (2000) Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model. Acta Orthop Scand 71:316–321

Download references

Author information

Authors and affiliations.

National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Epinal Way, Loughborough, Leicestershire, LE11 3TU, UK

Daniel Gwyer

Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Epinal Way, Loughborough, Leicestershire, LE11 3TU, UK

Nicholas M. Wragg & Samantha L. Wilson

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Samantha L. Wilson .

Ethics declarations

Conflict of interest.

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Reprints and permissions

About this article

Gwyer, D., Wragg, N.M. & Wilson, S.L. Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing. Cell Tissue Res 377 , 153–159 (2019). https://doi.org/10.1007/s00441-019-03016-8

Download citation

Received : 01 June 2018

Accepted : 27 February 2019

Published : 27 March 2019

Issue Date : 14 August 2019

DOI : https://doi.org/10.1007/s00441-019-03016-8

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Pentadecapeptide
• Soft tissue injury
• Corticosteroid interaction
• Angiogenesis
• Find a journal
• Publish with us
• Track your research

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Focus on ulcerative colitis: stable gastric pentadecapeptide BPC 157

Affiliation.

• 1 Department of Pharmacology, Medical Faculty University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia. [email protected]
• PMID: 22300085
• DOI: 10.2174/092986712803414015

Stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419) may be the new drug stable in human gastric juice, effective both in the upper and lower GI tract, and free of side effects. BPC 157, in addition to an antiulcer effect efficient in therapy of inflammatory bowel disease (IBD) (PL 14736) so far only tested in clinical phase II, has a very safe profile, and exhibited a particular wound healing effect. It also has shown to interact with the NO-system, providing endothelium protection and angiogenic effect, even in severely impaired conditions (i.e., it stimulated expression of early growth response 1 gene responsible for cytokine and growth factor generation and early extracellular matrix (collagen) formation (but also its repressor nerve growth factor 1-A binding protein-2)), important to counteract severe complications of advanced and poorly controlled IBD. Hopefully, the lessons from animal studies, particularly advanced intestinal anastomosis healing, reversed short bowel syndrome and fistula healing indicate BPC 157's high significance in further IBD therapy. Also, this supportive evidence (i.e., no toxic effect, limit test negative, LD1 not achieved, no side effect in trials) may counteract the problems commonly exercised in the use of peptidergic agents, particularly those used on a long-term basis.

PubMed Disclaimer

Similar articles

• Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract. Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, Sever M, Klicek R, Radic B, Drmic D, Ilic S, Kolenc D, Vrcic H, Sebecic B. Sikiric P, et al. Curr Pharm Des. 2011;17(16):1612-32. doi: 10.2174/138161211796196954. Curr Pharm Des. 2011. PMID: 21548867 Review.
• Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat. Vuksic T, Zoricic I, Brcic L, Sever M, Klicek R, Radic B, Cesarec V, Berkopic L, Keller N, Blagaic AB, Kokic N, Jelic I, Geber J, Anic T, Seiwerth S, Sikiric P. Vuksic T, et al. Surg Today. 2007;37(9):768-77. doi: 10.1007/s00595-006-3498-9. Epub 2007 Aug 27. Surg Today. 2007. PMID: 17713731
• Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva, Croatia). Full and distended stomach, and vascular response. Sikiric P, Seiwerth S, Brcic L, Blagaic AB, Zoricic I, Sever M, Klicek R, Radic B, Keller N, Sipos K, Jakir A, Udovicic M, Tonkic A, Kokic N, Turkovic B, Mise S, Anic T. Sikiric P, et al. Inflammopharmacology. 2006 Dec;14(5-6):214-21. doi: 10.1007/s10787-006-1531-7. Inflammopharmacology. 2006. PMID: 17186181 Review.
• Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, Sever M, Klicek R, Radic B, Drmic D, Ilic S, Kolenc D, Aralica G, Safic H, Suran J, Rak D, Dzidic S, Vrcic H, Sebecic B. Sikiric P, et al. Curr Pharm Des. 2013;19(1):76-83. doi: 10.2174/13816128130111. Curr Pharm Des. 2013. PMID: 22950504 Review.
• Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability. Klicek R, Kolenc D, Suran J, Drmic D, Brcic L, Aralica G, Sever M, Holjevac J, Radic B, Turudic T, Kokot A, Patrlj L, Rucman R, Seiwerth S, Sikiric P. Klicek R, et al. J Physiol Pharmacol. 2013 Oct;64(5):597-612. J Physiol Pharmacol. 2013. PMID: 24304574
• Stable Gastric Pentadecapeptide BPC 157 May Recover Brain-Gut Axis and Gut-Brain Axis Function. Sikiric P, Gojkovic S, Krezic I, Smoday IM, Kalogjera L, Zizek H, Oroz K, Vranes H, Vukovic V, Labidi M, Strbe S, Baketic Oreskovic L, Sever M, Tepes M, Knezevic M, Barisic I, Blagaic V, Vlainic J, Dobric I, Staresinic M, Skrtic A, Jurjevic I, Boban Blagaic A, Seiwerth S. Sikiric P, et al. Pharmaceuticals (Basel). 2023 Apr 30;16(5):676. doi: 10.3390/ph16050676. Pharmaceuticals (Basel). 2023. PMID: 37242459 Free PMC article. Review.
• Stable Gastric Pentadecapeptide BPC 157 and Striated, Smooth, and Heart Muscle. Staresinic M, Japjec M, Vranes H, Prtoric A, Zizek H, Krezic I, Gojkovic S, Smoday IM, Oroz K, Staresinic E, Dretar V, Yago H, Milavic M, Sikiric S, Lovric E, Batelja Vuletic L, Simeon P, Dobric I, Strbe S, Kokot A, Vlainic J, Blagaic AB, Skrtic A, Seiwerth S, Sikiric P. Staresinic M, et al. Biomedicines. 2022 Dec 12;10(12):3221. doi: 10.3390/biomedicines10123221. Biomedicines. 2022. PMID: 36551977 Free PMC article. Review.
• Novel Therapeutic Effects in Rat Spinal Cord Injuries: Recovery of the Definitive and Early Spinal Cord Injury by the Administration of Pentadecapeptide BPC 157 Therapy. Perovic D, Milavic M, Dokuzovic S, Krezic I, Gojkovic S, Vranes H, Bebek I, Bilic V, Somun N, Brizic I, Skorak I, Hriberski K, Sikiric S, Lovric E, Strbe S, Kubat M, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Perovic D, et al. Curr Issues Mol Biol. 2022 Apr 27;44(5):1901-1927. doi: 10.3390/cimb44050130. Curr Issues Mol Biol. 2022. PMID: 35678659 Free PMC article.
• The anti-nociceptive effect of BPC-157 on the incisional pain model in rats. Jung YH, Kim H, Kim H, Kim E, Baik J, Kang H. Jung YH, et al. J Dent Anesth Pain Med. 2022 Apr;22(2):97-105. doi: 10.17245/jdapm.2022.22.2.97. Epub 2022 Mar 25. J Dent Anesth Pain Med. 2022. PMID: 35449779 Free PMC article.
• Stable Gastric Pentadecapeptide BPC 157 Therapy for Primary Abdominal Compartment Syndrome in Rats. Tepes M, Gojkovic S, Krezic I, Zizek H, Vranes H, Madzar Z, Santak G, Batelja L, Milavic M, Sikiric S, Kocman I, Simonji K, Samara M, Knezevic M, Barisic I, Lovric E, Strbe S, Kokot A, Sjekavica I, Kolak T, Skrtic A, Seiwerth S, Boban Blagaic A, Sikiric P. Tepes M, et al. Front Pharmacol. 2021 Dec 13;12:718147. doi: 10.3389/fphar.2021.718147. eCollection 2021. Front Pharmacol. 2021. PMID: 34966273 Free PMC article.

Publication types

• Search in MeSH

Related information

• PubChem Compound (MeSH Keyword)

LinkOut - more resources

Full text sources.

• Bentham Science Publishers Ltd.
• Ingenta plc

Other Literature Sources

• The Lens - Patent Citations
• Genetic Alliance
• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

BPC-157 Tablets vs. Injection: Weighing the Pros and Cons

• Home Peptides BPC-157 Tablets vs. Injection: Weighing the Pros and Cons
• No comment yet
• February 22, 2024

BPC-157 is a peptide known for its potential health benefits, but understanding its effects and risks is essential. In this article, we will explore the positive effects of BPC-157, as well as its potential side effects. We will also compare the administration methods of tablets versus injections , discuss dosage guidelines, and outline the expected results and timeline. We will address the legality of BPC-157 and answer common FAQs about this peptide. Join us as we weigh the pros and cons of BPC-157 tablets versus injections.

Introduction to BPC-157

Understanding BPC-157

Understanding BPC-157 involves looking into its mechanism of action, its role in the healing process, and its application in peptide therapy. BPC-157, a synthetic peptide derived from a protective protein found in the human stomach, exerts its healing effects by interacting with several biological pathways that promote tissue repair and regeneration. When administered, BPC-157 enhances:

• Blood flow to damaged tissues
• Accelerates the formation of new blood vessels
• Stimulates the production of growth factors, such as fibroblast growth factor and vascular endothelial growth factor, crucial for tissue rebuilding

This peptide has demonstrated anti-inflammatory properties, aiding in reducing inflammation and pain, thus creating an optimal environment for the body’s natural healing mechanisms to thrive.

Benefits and Risks

Positive Effects

Buy from our top rated vendor and use code JOE15 for 15% off

Potential Side Effects

While BPC-157 offers significant benefits, potential side effects may include interactions with gastric juices in the intestinal area, leading to specific concerns that should be monitored. When BPC-157 comes in contact with gastric juices in the intestinal area, it may lead to digestive discomfort, such as bloating or mild stomach upset. These side effects are typically mild and transient, resolving on their own as the body adjusts to the peptide. If these symptoms persist or worsen over time, it is crucial to consult a healthcare professional for further evaluation. Regular monitoring of any unusual reactions is essential to ensure the safe use of BPC-157 and to address any potential risks promptly.

Administration Methods

BPC-157 can be administered through various methods, including oral administration using tablets or injections , each with its unique benefits and considerations. Regarding oral administration through tablets , one of the key advantages is the convenience it offers. Tablets can be easily taken anywhere, without the need for needles or specialized equipment, making it a more user-friendly option. Additionally, tablets typically have a longer shelf life than liquid forms, providing greater stability. On the other hand, injections are known for their fast absorption rate, delivering BPC-157 directly into the bloodstream for immediate effect. This method may be preferred for individuals who require rapid results or have digestive issues that could impact tablet absorption.

Comparison: Tablets vs. Injections

• Dosage accuracy
• Absorption rates
• Availability of research peptides

Regarding dosage accuracy, injections offer a more precise delivery method as the dosage can be controlled with higher granularity compared to tablets. With tablets, ensuring exact dosage can be challenging due to factors like individual variation in absorption rates. Bioavailability plays a crucial role in how effectively the peptide is utilized by the body. Tablets vs. injections : which is more effective? Injections typically provide higher bioavailability as the peptide bypasses the digestive system, leading to quicker absorption into the bloodstream. Research-grade peptides are often more readily available for injection methods, allowing for comprehensive studies on their efficacy and safety, which can have a significant impact on treatment outcomes and patient experience.

Dosage Guidelines

Establishing proper dosage guidelines for BPC-157 is crucial for maximizing its therapeutic benefits and ensuring safe usage, with recommendations tailored to individual needs and treatment objectives. Regarding determining the appropriate BPC-157 dosage, several factors must be considered, including the specific condition being treated, the severity of the symptoms, and the individual’s weight and overall health status. Studies have shown that BPC-157 can be administered at varying doses, typically ranging from 200-500 mcg per day, depending on the desired effects. It is essential to divide the total daily dosage into smaller, equally spaced doses to maintain stable blood levels throughout the day.

Recommended Dosage and Frequency

The recommended BPC-157 dosage and frequency depend on factors such as:

• Therapeutic potential
• Desired outcomes
• Interaction with growth hormone levels in the body

When determining the appropriate dosage, it is crucial to consider the individual’s specific condition and the severity of symptoms. For mild to moderate conditions, a typical starting dose ranges from 250-500 micrograms per day, administered orally or subcutaneously. In cases of more severe injuries or chronic issues, dosages may be higher, with some protocols suggesting up to 1,000 micrograms per day. Frequency of administration can vary widely, but common recommendations include once or twice daily for general healing and tissue repair purposes. For performance enhancement or athletic recovery, some experts advocate for dosing multiple times per day for optimal results.

Results and Timeline

Tracking the results of BPC-157 treatment and understanding the healing timeline can offer valuable insights into its effectiveness and impact on the body’s healing processes. Research and clinical trials have shown that patients undergoing BPC-157 treatment have experienced:

• Accelerated wound healing
• Reduced inflammation
• Improved muscle and tendon recovery

Many individuals observed decreased pain and increased mobility within a few weeks of starting the treatment. In a study conducted on athletes with sports-related injuries, the majority reported significant improvements in their condition after just a few weeks of using BPC-157. These positive outcomes were attributed to the peptide’s ability to enhance tissue repair and modulate various molecular pathways involved in the healing process.

Expected Results

Anticipating the expected results of BPC-157 treatment involves considering its effects on tissue repair, regenerative properties, as demonstrated in animal models and scientific studies. Animal model studies have revealed the profound impact of BPC-157 on accelerating the healing process of tendons, ligaments, muscles, and various other tissues. The peptide has shown promising results in enhancing the synthesis of collagen, a crucial protein for tissue strength and repair. Scientific data suggest that BPC-157 may aid in reducing inflammation and promoting angiogenesis, the formation of new blood vessels crucial for tissue regeneration. Patients undergoing BPC-157 therapy often experience:

• Quicker recovery times
• Reduced pain levels
• Improved overall functionality of the treated area

The therapy’s regenerative properties play a vital role in enhancing tissue repair mechanisms and supporting long-term healing outcomes.

Legality of BPC-157

The legality of BPC-157 usage, particularly in peptide therapy, is influenced by regulatory considerations and compliance with authorized guidelines, such as those outlined by peptides.org. It is crucial for individuals interested in incorporating BPC-157 in their treatment plans to understand the legal implications surrounding its usage. By adhering to the guidelines provided by reputable sources like peptides.org, one can navigate the complex landscape of peptide therapy within the boundaries of the law. Consulting with licensed healthcare professionals is not just recommended but essential for ensuring both legal and ethical compliance. These experts can offer valuable insights into the appropriate administration, dosages, and potential interactions with existing medications, helping individuals make informed decisions about incorporating BPC-157 in their therapeutic regimens.

Legal Status

The legal status of BPC-157 usage is determined by regulatory bodies like the FDA, requiring oversight by licensed physicians and adherence to guidelines set forth by regulatory authorities in the United States. These regulations exist to safeguard public health and ensure the proper use of BPC-157 for therapeutic purposes. Any substance classified as a drug, like BPC-157, must undergo rigorous evaluation by the FDA to guarantee its safety and efficacy before being made commercially available. Physicians play a crucial role in the management of BPC-157 therapy, as their oversight is essential in prescribing the correct dosage and monitoring any potential side effects. Compliance with FDA regulations is vital to avoid legal issues and safeguard patient well-being, emphasizing the importance of informed and responsible usage.

FAQs about BPC-157

Addressing common queries about BPC-157 involves providing insights into its application for patients, its therapeutic potential, and the current status of clinical trials investigating its efficacy. When considering patient considerations, it is important to consult with a healthcare provider to determine the appropriate dosage and treatment duration for individual needs. BPC-157 is known for its potential in promoting tissue healing and reducing inflammation, making it a promising option for various conditions. Ongoing clinical trials aim to further explore its effectiveness in treating conditions such as:

• Tendon and ligament injuries
• Inflammatory bowel diseases
• Muscle tears

Common Queries

Common queries related to BPC-157 usage among athletes often revolve around its effects on growth hormone levels, compliance with WADA regulations, and the impact on performance enhancement. Athletes are understandably concerned about how BPC-157 may interact with their natural growth hormone production. Research suggests that BPC-157 does not directly stimulate growth hormone secretion, but its ability to promote healing and recovery could indirectly support overall performance. Regarding WADA regulations, it is crucial for athletes to stay informed. While currently not listed on the prohibited substances list, it’s always prudent to check for updates to ensure compliance. As for performance enhancement, some athletes report faster recovery times and reduced inflammation when using BPC-157, potentially contributing to improved training consistency and overall athletic output.  

Leave a Reply Cancel reply

Your email address will not be published. Required fields are marked *

Save my name, email, and website in this browser for the next time I comment.

BPC-157 Peptide for Neurological & CNS Disorders: Preliminary Research

BPC 157, a stable gastric pentadecapeptide, has recently emerged as a promising therapeutic agent due to its multifaceted role in treating various central nervous system disorders.

Its ability to mitigate conditions like stroke, schizophrenia, and spinal cord injuries while promoting neural recovery and functional improvement is capturing the interest of the medical community.

Highlights :

• BPC 157 Counteracts Neural Damage : This peptide has shown remarkable results in reducing neuronal damage and promoting recovery post-stroke.
• Potential in Schizophrenia and Parkinson’s Disease : BPC 157 has been found to alleviate symptoms related to schizophrenia and Parkinson’s disease in animal models.
• Spinal Cord Recovery : It has demonstrated the ability to facilitate significant recovery post-spinal cord injuries.
• Cytoprotective Abilities : BPC 157 possesses strong cytoprotective properties, aiding in the protection and regeneration of cells.

Source : Neural Regeneration Research

What is BPC 157 Peptide?

BPC 157, or Body Protection Compound 157, is a peptide chain consisting of 15 amino acids.

It is a partial sequence of body protection compounds derived from human gastric juice.

Its stability and potent cytoprotective properties have made it the subject of numerous biomedical studies.

BPC 157 is known to enhance the healing of many different wounds, including tendon-to-bone healing and superior healing of damaged ligaments.

Additionally, it has protective effects extending beyond the stomach and gastrointestinal tract, offering promising potential in a variety of neurological and other conditions.

BPC 157 in Action: Research in CNS & Neurological Disorders (2023)

Stroke occurs when the blood supply to part of the brain is interrupted, leading to brain tissue damage. Recovery involves re-establishing blood flow and minimizing neuronal damage.

• BPC 157’s Role : The peptide has been shown to counteract the effects of a stroke induced by bilateral clamping of the common carotid arteries in rats. It’s suggested that BPC 157 enhances the recovery and repair of neuronal pathways and reduces overall neuronal damage.
• Mechanisms : BPC 157 likely promotes angiogenesis, enhancing blood flow to damaged areas. It may also regulate gene expression related to recovery and repair and protect against reperfusion injury by combating oxidative stress.
• Evidence : Animal studies have shown promising results where BPC 157-treated rats demonstrated improved outcomes in memory, locomotion, and coordination post-stroke.

2. Schizophrenia

Schizophrenia is a chronic brain disorder characterized by distorted thinking, perceptions, emotions, language, sense of self, and behavior.

• BPC 157’s Role : It’s suggested that BPC 157 may counteract some symptoms of schizophrenia, possibly by modulating the complex interaction between the nitric oxide system and dopamine pathways.
• Mechanisms : The peptide may influence the NO system and interact with dopaminergic systems, which are often implicated in schizophrenia. It might balance the over- or under-activity of neurotransmitter systems related to the disorder.
• Evidence : Animal model research revealed that BPC 157 mitigated behaviors associated with schizophrenia. However, human studies are needed to confirm its efficacy.

3. Traumatic Brain Injury (TBI)

TBI results from a blow or jolt to the head leading to brain dysfunction. Recovery involves managing inflammation and promoting neuronal repair.

• BPC 157’s Role : BPC 157 might reduce brain lesions and support recovery from TBIs. It could improve outcomes by reducing the extent of the injury and enhancing the repair processes.
• Mechanisms : Its neuroprotective effects may stem from reducing oxidative stress, modulating inflammatory cytokines, and promoting angiogenesis to repair damaged brain tissue.
• Evidence : Preclinical studies have shown reduced brain damage and improved recovery markers in animal models of TBI treated with BPC 157.

4. Spinal Cord Injury

Spinal cord injuries involve damage to the spinal cord resulting from trauma, loss of its normal function, and potential paralysis.

• BPC 157’s Role : The peptide has shown potential in aiding recovery from spinal cord injuries by promoting healing and functional recovery.
• Mechanisms : It may enhance angiogenesis, modulate inflammatory responses, and protect neurons and other cells from oxidative damage, thus aiding in the repair of the spinal cord.
• Evidence : Animal studies suggest that BPC 157-treated subjects had better recovery outcomes, including functional improvements.

5. Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain, leading to symptoms like tremors, stiffness, and movement difficulties.

• BPC 157’s Role : BPC 157 is hypothesized to offer neuroprotective effects in Parkinson’s disease models by potentially safeguarding dopaminergic neurons and modulating neurotransmitter systems.
• Mechanisms : It might protect neurons through antioxidative effects, modulate the dopaminergic system, and reduce inflammation, all of which are crucial in Parkinson’s pathology.
• Evidence : BPC 157 has been studied in rat models of Parkinson’s disease, indicating potential benefits. However, detailed outcomes and human trials are necessary to confirm its efficacy.

Other Medical Conditions Investigated for BPC 157 Therapy

Gastrointestinal Disorders : BPC 157 is primarily known for its potent healing effects on the gastrointestinal tract. It may help treat ulcers, inflammatory bowel disease, and promote healing in cases of gut inflammation and damage.

Musculoskeletal Injuries : BPC 157 has shown potential in accelerating the healing of injuries such as torn ligaments, muscle sprains, and even bone fractures. It may enhance tendon-to-bone healing and improve recovery from joint injuries.

Cardiovascular Health : BPC 157 might contribute to cardiovascular health by promoting angiogenesis, healing damaged blood vessels, and possibly helping in recovery post-myocardial infarction.

Skin Wound Healing : Due to its regenerative properties, BPC 157 may benefit the healing of cuts, burns, and other skin injuries. It can accelerate the healing process and reduce scarring.

Diabetic Wound Healing : BPC 157 may have a role in enhancing wound healing particularly in diabetic patients, where the process is typically slower and more complicated.

Depression and Anxiety : Some studies suggest BPC 157 may have a role in modulating neurotransmitter systems, which could make it beneficial in treating certain symptoms of depression and anxiety.

Peripheral Nerve Damage : BPC 157 might assist in the regeneration of peripheral nerves after injury, suggesting a potential role in the treatment of conditions like neuropathies.

Liver Damage : Due to its regenerative and protective effects, BPC 157 might help in the healing process of liver injuries and in combating liver diseases.

Alcohol and Drug Toxicity : BPC 157 has been suggested to have protective effects against damage caused by various toxins, including alcohol and certain drugs.

Corneal Healing : Some research indicates that BPC 157 can promote the healing of corneal injuries, making it a potential therapy for eye injuries.

It’s important to note that while BPC 157 has shown potential benefits in these areas based on preclinical studies, not all have substantial human clinical trial data to confirm efficacy and safety.

BPC 157 Therapeutic Mechanisms of Action (Possibilities)

Modulation of Nitric Oxide (NO) System : BPC 157 interacts with the nitric oxide system, which plays a crucial role in inflammation, vasodilation, and neurotransmission.

Angiogenesis : It promotes the growth of new blood vessels, which is crucial for healing damaged tissues.

Gene Expression Modulation : BPC 157 influences the expression of genes involved in cytoskeleton remodeling, healing, and cellular survival.

Protection against Oxidative Stress : It exhibits antioxidant properties, reducing damage caused by free radicals.

Regulation of Neurotransmitters : BPC 157 may influence the levels and activity of neurotransmitters like dopamine and serotonin, relevant in conditions like depression and schizophrenia.

Endothelial Protection : It protects and stabilizes the endothelium, which is vital for vascular health and healing.

Immune Modulation : BPC 157 might modulate the immune system, reducing excessive inflammation and promoting healing.

Existing Research of BPC 157 in Animal Models & Humans

Animal studies.

Most of the current knowledge about BPC 157 comes from animal studies.

These studies have shown promising results in various conditions, from gastrointestinal damage to neuroprotective effects in models of stroke.

BPC 157 has been observed to accelerate healing in rodents, improve outcomes in brain injury models, and enhance recovery in musculoskeletal injuries.

Human Studies

While the bulk of research has been in animal models, a few preliminary studies and clinical trials have begun exploring the effects of BPC 157 in humans.

These studies are in the early stages, but they are crucial for understanding the peptide’s safety, optimal dosing, and potential therapeutic effects in human subjects.

As of now, BPC 157 is not an FDA-approved treatment, and more extensive human trials are necessary to establish its efficacy and safety profile.

The Future of BPC 157: Potential in Medicine

The broad spectrum of BPC 157’s therapeutic effects opens new doors for treating various neurological disorders.

Its multifaceted action and potential for synergy with other treatments make it a promising candidate for future drug development.

While the current data is promising, more extensive clinical trials and research are necessary to fully understand and harness BPC 157’s potential.

Understanding its mechanisms in human subjects and optimizing its delivery and dosage will be crucial steps forward.

As with any emerging therapy, ethical considerations and rigorous clinical testing are paramount to ensure safety and efficacy.

The potential of BPC 157 must be balanced with a cautious and ethical approach to its development and use.

Conclusion: BPC 157 as a Potential Game-Changer in Neurology

BPC 157, with its cytoprotective, regenerative, and neuroprotective properties, stands as a beacon of hope in the treatment of central nervous system disorders.

From mitigating stroke damage to offering new avenues for schizophrenia and spinal cord injury treatments, its potential is vast and promising.

As research continues to unfold the layers of this remarkable peptide, the medical community watches with anticipation for the next breakthroughs BPC 157 will bring to neuroscience and medicine at large.

• Paper : Pentadecapeptide BPC 157 and the central nervous system (2021)
• Authors : Jakša Vukojević et al.

Related Posts:

• Myo-Inositol for Traumatic Brain Injury (TBI): Targeting BATF2 for Epigenetic & Transcriptomic Changes (2024 Study)
• TMS For Cognitive Enhancement (Transcranial Magnetic Stimulation)
• Toxoplasma gondii Infection in Schizophrenia Linked to High Glucocorticoid Levels in Hair (2024 Study)
• Personalized TMS for Psychiatric Disorders: Targeting Functional Connectivity (FC) in the Brain (2024 Review)
• Genetics of Female Reproductive Behaviors & Psychiatric Disorders: Age of First Sexual Intercourse Significant (2023 Study)

MHD News (100% Free)

Leave a comment cancel reply.

This site uses Akismet to reduce spam. Learn how your comment data is processed .

• Bodybuilding
• Supplements

BPC 157: Benefits, Side Effects, Dosage, and More

October 25, 2023

by: Inside Bodybuilding

Reviewed by: Dr. Thomas O'Connor, MD, PA

BPC 157 is a peptide consisting of 15 amino acids and is naturally occurring in human gastric juice ( 1 ). Thus, BPC 157 possesses gastrointestinal protective properties, including alleviation from ulcers, bowel issues, or Crohn’s disease. We see much promise for BPC 157 in medicine as a potent systemic healing agent when injected or taken orally.

BPC 157 has been described as a “miracle agent” due to its Wolverine-like healing capabilities.

• 1 BPC 157 Benefits
• 2 Recommended BPC 157 Source
• 3 BPC 157 Side Effects
• 4 BPC 157 Dosage
• 5 BPC 157 Reviews
• 6.1 1. Sports Technology Labs
• 6.2 2. Amino Asylum
• 6.3 3. Peak Body
• 6.4 4. Deus Power
• 7 Does BPC 157 Help With Erectile Dysfunction?
• 8 BPC 157: Injection vs. Oral
• 9 BPC 157 and TB-500
• 10 Is BPC 157 Legal?
• 11 Conclusion

BPC 157 Benefits

• Wounds and tissue healing
• Lowers blood pressure
• Muscle recovery
• Pain reduction
• Reduction in fat mass
• Some anabolic effects
• Increased well-being

BPC 157 has very positive effects on the muscles, tendons, CNS (central nervous system), and inflammation. It also has a profound impact on wound healing and tissue damage, commonly caused by corticosteroid use.

We have also found BPC 157 to have cardioprotective attributes, inducing angiogenesis (new blood vessel formation).

In bodybuilding, BPC 157 is becoming increasingly popular among men and women looking to recover from injuries caused by lifting heavy weights. It also enhances muscle recovery, enabling greater volume and training frequency while reducing pain.

With BPC 157 being an anabolic peptide, it may also stimulate subcutaneous fat loss while synergistically increasing muscle hypertrophy and strength.

As with other growth hormone-boosting peptides, we see BPC 157 stimulate collagen synthesis, inducing anti-aging effects.

BPC 157 provides significant pain relief due to its increase in dopamine and serotonin in the brain. Scar tissue may also reduce (especially when applied directly to the area) due to it accelerating the body’s healing factor.

As a consequence of these two reward system neurotransmitters being elevated, BPC 157 has provided antidepressant effects in some of our patients. They have also reported brain fog and clarity of thought improving due to this cognitive shift.

Disclosure : We do not accept any form of advertising on Inside Bodybuilding. We monetize our practice via doctor consultations and carefully chosen supplement recommendations, which have given our patients excellent results.

Recommended BPC 157 Source

Discount code : Save 15% on Sports Technology Labs' peptides by using the discount code inside15 .

BPC 157 Side Effects

There is limited research conducted on BPC 157; however, clinically, there appear to be no noteworthy side effects associated with this peptide.

There are anecdotal reports of users taking BPC 157 for years without any obvious side effects ( 2 ).

However, there are several factors to be aware of. BPC 157 is a growth agent; thus, it will cause tissue proliferation like growth hormone. Thus, if someone has cancer, taking BPC 157, in theory, could exacerbate their condition. Thus, cancer patients should not take this peptide.

We have found that BPC 157 can have a reductive effect on blood pressure; thus, individuals on blood pressure medication should be careful of their blood pressure dropping to very low levels, which may cause dizziness or fainting if not monitored.

Unlike other GH-boosting compounds, BPC 157 is not believed to increase blood sugar levels, thus inhibiting any potential rise in blood pressure.

BPC 157 does not appear to pose any toxicity to the liver, kidneys, or heart.

BPC 157 may affect mood post-cycle, as serotonin and dopamine levels spike on-cycle. We do not know if these return to baseline levels or rise temporarily. However, with BPC 157 being a peptide, it is reasonable to believe neurotransmitter levels will return to normal shortly after cycle cessation.

BPC 157 may cause mild headaches in certain individuals.

Update : Although relatively uncommon, we have seen a few users experience histamine reactions to BPC 157 upon initial dosing. Taking cautious dosages to begin with and increasing the dose slowly has helped to mitigate such histamine spikes, enabling affected patients to continue their regimens.

BPC 157 Dosage

An official therapeutic dosage is yet to be established for BPC 157 via a medical authority, as it is not currently FDA-approved.

However, anecdotally, users are having great success when taking  500–1,000 mcg/day orally. Or 400–600 mcg/day  when injected under the skin (around the injured area).

Higher dosages can be split in half and thus administered twice a day. Lower dosages can produce very positive effects, in our experience. Thus, higher dosages may only be necessary in extreme cases.

BPC 157 is cycled by some users (like steroids) or taken continuously by others for several years. We need more research to conclude the absolute safety of this peptide over the long term. However, several users have reported no adverse effects while doing so.

BPC 157 Reviews

The following reviews were published in our private group.

I’ve been deeply invested in using peptides like TB 500, BPC 157, Sermorelin, and CJC-1295/Ipamorelin over the years for growth hormone enhancement and overall recovery. I had really bad knee and back pain that put me out of commission for years; I couldn’t exercise or do anything physical. Navigating the world of peptides was challenging initially, especially when trying to pinpoint reliable clinics and pharmacies that prioritize genuine care over mere profit. Determining the correct dosage, method of administration, and length of each treatment was a steep learning curve. What I came to understand was the power of complementing peptides with the right nutrition and incorporating targeted mobility and strength training for recovery. This holistic approach not only accelerates healing but also ensures long-lasting benefits. Combining specific peptides for synergistic effects further amplified my results. Thanks to meticulous research and a tenacious spirit, I shifted from a sedentary, pain-ridden lifestyle to feeling more alive and being in peak physical shape, even in my 40s. The transformation peptides offered me is nothing short of miraculous. I’m eager to share more and learn from all of you!

After trying several peptides individually, I found that only the synergistic combo of BPC-157 and TB-4 worked on my connective tissue issues. I’ve only injected subcutaneously, and my hip that used to pop out of place doesn’t anymore. Also, I’ve read that it doesn’t matter where you inject, though I’ve had the best results when injecting near the area.

I have arthritis in my legs and hips, and I have been injecting there with good results. My ring finger started acting up and would be very stubborn to bend when I wanted to (very jerky). I injected once in the finger, and now it doesn’t do that. It’s only been two weeks since I injected my finger, but so far, so good.

Best Sources to Buy BPC 157

• Sports Technology Labs 🇺🇸
• Amino Asylum 🇺🇸
• Peak Body 🇬🇧
• Deus Power 🇪🇺

1. Sports Technology Labs

• Website : Sportstechnologylabs.com (15% discount code: inside15 )
• Price : $54.99
• Countries : 🇺🇸

Sports Technology Labs’ BPC 157 is our most trusted source for US customers due to their guarantee of at least 98% purity. However, in our experience, the percentage is usually higher than this, with the last BPC 157 certificate of analysis confirming 99.9% purity.

Note : Customers from non-US countries may want to avoid buying BPC 157 from Sports Technology Labs, as they have warned of vast delays at the border, which are out of their control.

2. Amino Asylum

• Website : Aminoasylum.shop
• Price : $34.99
• Countries: 🇺🇸

Amino Asylum provides a considerably cheaper alternative for US customers, with their BPC 157 priced $20 cheaper than Sports Technology Labs. However, this comes with some risk, as no reliable COAs are supplied to customers (no guaranteed purity percentage). Although Amino Asylum’s reputation is generally positive, there have been a few complaints of ineffective products.

3. Peak Body

• Website : Peakbody.co.uk
• Price : £19.95
• Countries : 🇬🇧

Peak Body is our most reliable source of BPC 157 for UK customers, with its headquarters located in the north of England. Customers can expect to receive their package in just one business day when spending over £100. If you order below this amount, it will take 3-5 days. If you order before 1 p.m., you can have your package shipped the same day.

4. Deus Power

• Website : Deuspower.shop
• Price : €39
• Countries : 🇪🇺

Deus Power is the best peptide company for stealth shipping, meaning they bypass typical delays when shipping overseas. Their European warehouse location enables them to deliver packages to EU customers in just one week. It can take two weeks for packages to be delivered to non-EU countries. Also, if there are any issues with the shipment, they will send another one promptly.

Their BPC 157 is also lab-tested, and their customer support is excellent (via Telegram or email).

Does BPC 157 Help With Erectile Dysfunction?

Some users report an instant erection upon taking BPC 157, which may be attributed to a surge in dopamine levels. Dopamine induces oxytocinergic neurons in the paraventricular nucleus; thus, higher levels may increase sexual function in men.

Other men with injuries to the penis (such as tissue damage from venous leaks) may also benefit from BPC 157, due to its repair and rejuvenation properties on a cellular level. Some users have also reported improvements in libido when taking BPC 157 (a consequence of higher dopamine levels).

BPC 157: Injection vs. Oral

Intramuscular injections are the most optimal way to administer BPC 157 for injuries and isolated pain. However, if injections are not preferable, taking BPC 157 orally (swallowing the liquid) is still effective in healing and repair.

If BPC 157 is being utilized for its gastroprotective properties, oral consumption is suitable.

BPC 157 and TB-500

TB-500 is another peptide that can also be utilized as a healing agent. TB-500 is essentially a synthetic version of thymosin beta-4, a protein in the thymus gland.

In our experience, both of these peptides are similar in potency regarding healing bones, joints, and connective tissue.

However, we find TB-500 to be the superior peptide for promoting ancillary strength and muscle development.

BPC 157 is the more optimal compound for gastrointestinal issues due to its extraction from this area.

Both peptides can be taken simultaneously for even greater results, as they have different yet complementary mechanisms for stimulating healing.

TB-500 works systemically and thus does not need to be administered to a specific target. BPC 157, anecdotally at least, may have some localized healing effects, so it can be advantageous to inject near the injured area.

TB-500 can be utilized in dosages of 10–20 mg per week. It should be administered 1-2 times per week for peak efficacy.

Is BPC 157 Legal?

BPC 157 is legal to purchase in most countries (including the US, Canada, and the UK) for research purposes. This includes administering it to animals and observing its effects. However, it is not supposed to be used by humans due to a lack of FDA approval.

As of January 1st, 2022, WADA officially added BPC 157 as a prohibited substance ( 3 ). Thus, athletes will need to check their respective sporting bodies to see if they will be tested for BPC 157 in the off-season as a means to heal quicker from injuries.

Although anecdotal reports deem BPC 157 to be a safe peptide with few adverse interactions, more long-term research is needed for the FDA to confirm this.

Co Authors :

For TRT inquiries, please contact Dr. O’Connor via the Anabolic Doc App.

Over the last 20 years, Dr. O’Connor has successfully treated thousands of men who have taken anabolic steroids, SARMs, and other PEDs, giving him first-hand experience of their effects. Board-certified MD since 2005.

(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096228/

(2) https://www.youtube.com/watch?v=KBCHy6r3ZAc

(3) https://www.usada.org/spirit-of-sport/education/bpc-157-peptide-prohibited/

(4) https://pubmed.ncbi.nlm.nih.gov/30915550/

OUR TEAM HAS BEEN FEATURED ON

Inside Bodybuilding is a virtual health clinic that specializes in treating bodybuilders who have taken AAS (anabolic androgenic steroids). Read more

Disclaimer : The content on insidebodybuilding.com is not medical advice or a substitute for professional medical care, diagnosis, or treatment. During consultations, your doctor will determine your specific needs and advise you personally on what medication to take. Dr. Touliatos provides services to Inside Bodybuilding in the form of online consultations. 

© 2024 Inside Bodybuilding | Terms & Conditions   |  Privacy Policy |  Covid-19  

BPC-157 is most often used for

Fact-checked

BPC-157 is a synthetic peptide that is being investigated for its regenerative effects. It shows high efficacy for rats suffering toxic or surgical trauma, but there is currently little evidence that it provides benefits for people.

Last Updated: November 15, 2023

What are BPC-157’s main benefits?

More research is needed to determine whether BPC-157 has any potential benefits in humans. Studies conducted in rodents and cultured cells have suggested that BPC-157 may support the healing of various tissues, including tendons, joints, nerves, the intestinal tract, the stomach, and skin. [1] [2] [3]

What are BPC-157’s main drawbacks?

BPC-157’s potential drawbacks are uncertain, given the lack of human evidence. No clear toxicity or negative side effects have been reported in studies conducted in rodents, [4] [5] [1] but this research is limited. Therefore, the biggest drawback of BPC-157 is that there is insufficient evidence of its safety.

How does BPC-157 work?

BPC-157 has various possible (potentially overlapping) mechanisms of action, including promoting nitric oxide synthesis, activating cells involved in tissue repair, stimulating the synthesis of growth factors, and inhibiting inflammation. [2] [6] [7]

BPC-157 can be taken orally, topically, or via injection. Oral ingestion of peptides like BPC-157 wouldn’t normally be expected to have a direct effect on tissues outside of the gastrointestinal tract (like tendons and nerves) because peptides aren’t easily absorbed into circulation. However, studies in rodents have suggested that oral ingestion can have systemic effects, meaning that the feasibility of this route of delivery can’t be ruled out. [8]

What is BPC-157?

Body Protection Compound 157 (BPC-157) is a peptide composed of 15 amino acids. Although the researchers who patented BPC-157 say that it was derived from a stomach protein, this claim isn’t well-substantiated. [9] BPC-157 is thought to improve the repair of damaged tissues, although there is currently no human evidence to support this hypothesis. [1]

What are other names for BPC-157

Dosage information medical disclaimer.

The closest possible recommended dose is based on rat studies where oral administration showed benefit, as most studies administer the supplement via injection. The oral dose that was effective in rats, 10 μg/kg, is estimated to be equivalent to 1.6 μg/kg, or:

• 110 μg for a 150lb person
• 145 μg for a 200lb person
• 180 μg for a 250lb person

There are currently no human pharmacokinetic studies to assess species differences.

Frequently asked questions

Update history, corrected an error minor, research breakdown.

Sources and Composition

Physicochemical Properties

Molecular Targets

Angiogenesis

Pharmacology

Dopaminergic Neurotransmission

Serotonergic Neurotransmission

Neuroprotection

Bone and Joint Health

Collagen and Joints

Peripheral Organ Systems

Other Medical Conditions

Parkinson's

Multiple Sclerosis

• ^ Gwyer D, Wragg NM, Wilson SL Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing. Cell Tissue Res . ( 2019-Aug )
• ^ Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, Sever M, Klicek R, Radic B, Drmic D, Ilic S, Kolenc D, Stambolija V, Zoricic Z, Vrcic H, Sebecic B Focus on ulcerative colitis: stable gastric pentadecapeptide BPC 157 Curr Med Chem . ( 2012 )
• ^ Vukojevic J, Milavić M, Perović D, Ilić S, Čilić AZ, Đuran N, Štrbe S, Zoričić Z, Filipčić I, Brečić P, Seiverth S, Sikirić P Pentadecapeptide BPC 157 and the central nervous system. Neural Regen Res . ( 2022-Mar )
• ^ Sikiric P, Seiwerth S, Rucman R, Turkovic B, Rokotov DS, Brcic L, Sever M, Klicek R, Radic B, Drmic D, Ilic S, Kolenc D, Aralica G, Safic H, Suran J, Rak D, Dzidic S, Vrcic H, Sebecic B Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Curr Pharm Des . ( 2013 )
• ^ Deek SA BPC 157 as Potential Treatment for COVID-19. Med Hypotheses . ( 2021-Nov-09 )
• ^ Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JH The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration J Appl Physiol (1985) . ( 2011 Mar )
• ^ Japjec M, Horvat Pavlov K, Petrovic A, Staresinic M, Sebecic B, Buljan M, Vranes H, Giljanovic A, Drmic D, Japjec M, Prtoric A, Lovric E, Batelja Vuletic L, Dobric I, Boban Blagaic A, Skrtic A, Seiwerth S, Predrag S Stable Gastric Pentadecapeptide BPC 157 as a Therapy for the Disable Myotendinous Junctions in Rats. Biomedicines . ( 2021-Oct-27 )
• ^ Sven Seiwerth, Marija Milavic, Jaksa Vukojevic, Slaven Gojkovic, Ivan Krezic, Lovorka Batelja Vuletic, Katarina Horvat Pavlov, Andrea Petrovic, Suncana Sikiric, Hrvoje Vranes, Andreja Prtoric, Helena Zizek, Tajana Durasin, Ivan Dobric, Mario Staresinic, Sanja Strbe, Mario Knezevic, Marija Sola, Antonio Kokot, Marko Sever, Eva Lovric, Anita Skrtic, Alenka Boban Blagaic, Predrag Sikiric Stable Gastric Pentadecapeptide BPC 157 and Wound Healing Front Pharmacol . ( 2021 Jun 29 )
• ^ Sikirić P, Petek M, Rucman R, Seiwerth S, Grabarević Z, Rotkvić I, Turković B, Jagić V, Mildner B, Duvnjak M A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. J Physiol Paris . ( 1993 )

• Get new issue alerts Get alerts
• Submit a Manuscript

Secondary Logo

Journal logo.

Colleague's E-mail is Invalid

Your message has been successfully sent to your colleague.

Save my selection

Pentadecapeptide BPC 157 and the central nervous system

Vukojević, Jakša MD, PhD 1,* ; Milavić, Marija 2 ; Perović, Darko 1 ; Ilić, Spomenko 1 ; Čilić, Andrea Zemba 3 ; Đuran, Nataša 4 ; Štrbe, Sanja 3 ; Zoričić, Zoran 5 ; Filipčić, Igor 6 ; Brečić, Petrana 4 ; Seiverth, Sven 2 ; Sikirić, Predrag 1

1 Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia

2 Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia

3 University Clinical Hospital Center “Zagreb”, Zagreb, Croatia

4 University Psychiatric Hospital “Vrapče”, Zagreb, Croatia

5 University Clinical Hospital Center “Sestre Milosrdnice”, Zagreb, Croatia

6 Psychiatric Hospital “Sveti Ivan”, Zagreb, Croatia

Correspondence to: Jakša Vukojević, [email protected] .

Author contributions: Manuscript conception and design: JV, PS, SS; data collection and literature search: DP, NĐ, SI, AZĆ, SŠ; data integration: MM, ZZ, IF, PB; draft manuscript preparation: JV, SS, PS; intellectual contribution to the final manuscript; MM, ZZ, IF, PB. All authors reviewed and approved the final version of the manuscript.

Received October 29, 2020

Received in revised form December 08, 2020

Accepted March 08, 2021

We reviewed the pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157, three very recent demonstrations that may be essential in the gut-brain and brain-gut axis operation, and therapy application in the central nervous system disorders, in particular. Firstly, given in the reperfusion, BPC 157 counteracted bilateral clamping of the common carotid arteries-induced stroke, sustained brain neuronal damages were resolved in rats as well as disturbed memory, locomotion, and coordination. This therapy effect supports particular gene expression in hippocampal tissues that appeared in BPC 157-treated rats. Secondly, there are L-NG-nitro arginine methyl ester (L-NAME)- and haloperidol-induced catalepsy as well as the rat acute and chronic models of ‘positive-like’ schizophrenia symptoms, that BPC 157 counteracted, and resolved the complex relationship of the nitric oxide-system with amphetamine and apomorphine (dopamine agents application), MK-801 (non-competitive antagonist of the N-methyl-D-aspartate receptor) and chronic methamphetamine administration (to induce sensitivity). Thirdly, after rat spinal cord compression, there were advanced healing and functional recovery (counteracted tail paralysis). Likewise, in BPC 157 therapy, there is specific support for each of these topics: counteracted encephalopathies; alleviated vascular occlusion disturbances (stroke); counteracted dopamine disturbances (dopamine receptors blockade, receptors super sensitivity development, or receptor activation, over-release, nigrostriatal damage, vesicles depletion), and nitric oxide-system disturbances (“L-NAME non-responsive, L-arginine responsive,” and “L-NAME responsive, L-arginine responsive”) (schizophrenia therapy); inflammation reduction, nerve recovery in addition to alleviated hemostasis and vessels function after compression (spinal cord injury therapy). Thus, these disturbances may be all resolved within the same agent’s beneficial activity, i.e., the stable gastric pentadecapeptide BPC 157.

Introduction

The pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157 have been reported in several organ systems (Sikiric et al., 2013, 2018, 2020a, b; Seiwerth et al., 2014, 2018; Kang et al., 2018; Gwyer et al., 2019; Park et al., 2020) (for an illustration; Additional Table 1 ). In this review, we focus on the effects of BPC 157 in central nervous system (CNS) pathology, with a specific focus on three very recent studies that highlight the essential role of the gut-brain axis in therapy application for CNS disorders (Perovic et al., 2019; Vukojevic et al., 2020; Zemba Cilic et al., 2021). Vukojevic et al. (2020) examined the therapeutic effects of BPC 157 in rats subjected to stroke and hippocampal ischemia/reperfusion injuries. Zemba Cilic et al. (2021) explored how BPC 157 can prevent catalepsy induced by L-NG-nitro arginine methyl ester (L-NAME) and haloperidol and counteracts deficits in acute and chronic rat models resembling ‘positive-like’ schizophrenia symptoms. Finally, Perovic et al. (2019) investigated the beneficial effects exerted by BPC 157 after rat spinal cord compression, namely advanced healing and functional recovery (counteracted tail paralysis).

BPC 157 is a native gastric pentadecapeptide that is non-toxic and has profound cytoprotective activity; it has been used in ulcerative colitis and multiple sclerosis trials (Sikiric et al., 2013, 2018, 2020a, b; Seiwerth et al., 2014, 2018; Kang et al., 2018; Gwyer et al., 2019; Park et al., 2020). In human gastric juice, BPC 157 is stable for more than 24 hours (Veljaca et al., 1995), and thus it has good oral bioavailability (always given alone) and beneficial effects in the entire gastrointestinal tract (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020). Furthermore, there is no need for carrier(s); this is an important distinction from the other standard peptides, which are functionally dependent on the addition of carrier(s) (Seiwerth et al., 2018) or are otherwise rapidly destroyed in human gastric juice (Veljaca et al., 1995). Consequently, stable BPC 157 is suggested to be a mediator of Robert’s cytoprotection, which maintains the integrity of gastrointestinal mucosa (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020). We suggest that the contribution of BPC 157 to Robert’s cytoprotection – that is, the ability to counteract fundamental alcohol-induced gastric lesions, which Robert called cytoprotection – and the ability to counteract lesions arising from the direct injurious contact of the noxious agent with the cell represent the peripheral connection between the gut and the brain axis.

Search Strategy and Selection Criteria

Studies cited in this review, which were published in the period from 1995 to 2020, were searched on the PubMed and the Google scholar database using the following keywords: BPC, BPC 157, pentadecapeptide BPC.

BPC 157 and Brain Lesions

In our recent study, we found that BPC 157 has a direct therapeutic effect in rats after a stroke (i.e., counteracts the injuries due to hippocampal ischemia/reperfusion). Specifically, BPC 157 was given after bilateral clamping of the common carotid arteries for 20 minutes, followed by reperfusion (Vukojevic et al., 2020). In the rats subjected to ischemia, BPC 157 was administered during reperfusion; it counteracted both early and delayed neural damage (i.e., 24 and 72 hours after reperfusion). In addition, BPC 157 promoted full functional recovery; this compound ameliorated the declines in several behavioral tasks: the Morris water maze, inclined beam-walking, and lateral push tests (Vukojevic et al., 2020). We also examined changes in messenger RNA (mRNA) expression in the brain 1 and 24 hours after the injury to determine the potential BPC 157 mechanism of action. BPC 157 treatment led to the upregulation of Egr1, Akt1, Kras, Src, Foxo, Srf, Vegfr2, Nos3 , and Nos1 and the downregulation of Nos2 and Nfkb compared with untreated rats ( Mapk1 was not activated) (Vukojevic et al., 2020). The marked Egr1 and Vegfr2 upregulation suggests that BPC 157 has vascularisation properties, and this mechanism likely underlies its ability to modulate ischemia/reprofusion injury. The most interesting finding is the strong upregulation of Nos3 , slight upregulation of Nos1 , and suppression of Nos2 compared with control animals. These effects may potentially provide a novel therapeutic solution for stroke, imparting specific beneficial effects on the CNS (i.e., for reperfusion, the amelioration of neuronal damage and, thereby, recovery without memory, locomotor, and coordination disturbances, and the expression of the particular genes in the hippocampus) (Vukojevic et al., 2020).

Reinforcing our findings, BPC 157 also counteracts various encephalopathies that appear after exposure to different agents or noxious procedures irrespective of the affected brain area: traumatic brain injury (Tudor et al., 2010), selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs; i.e., brain cyclooxygenases are a preferential inhibitory target of paracetamol; Sikiric et al., 2013; Lojo et al., 2016; Drmic et al., 2017), massive intestinal resection, cuprizone-induced multiple sclerosis-like pathology, insulin overdose, or magnesium overdose (Sikiric et al., 2013; Medvidovic-Grubisic et al., 2017). BPC 157 can also be applied to ameliorate concomitant convulsions due to NSAID-induced encephalopathy (Sikiric et al. 2013) ( Additional Table 1 ). BPC 157 treatment regimens markedly attenuate brain damage induced by traumatic brain injury (a falling weight); there is an improved early outcome and minimal postponed mortality throughout the 24-hour post-injury period in mice (Tudor et al., 2010). Ultimately, BPC 157 therapy induces an apparent improvement: the subarachnoid and intraventricular hemorrhage, brain lacerations, hemorrhagic laceration, and consecutive brain edema becomes less intense (Tudor et al., 2010). Furthermore, BPC 157 treatment promoted recovery from severe muscle weakness that appears alongside brain lesions (Sikiric et al., 2013; Medvidovic-Grubisic et al., 2017).

When applied directly to the brain (Belosic Halle et al., 2017), BPC 157 may act as a possible antioxidant (Duzel et al., 2017; Drmic et al., 2018; Kolovrat et al., 2020). Notably, BPC 157 may scavenge reactive oxygen species due to its structure: it contains four carboxylic groups, and when they are reactivated (by glutathione or enzymes), the antioxidant activity is very high (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020). In addition, because most tissues contain BPC 157 (Seiwerth et al., 2018), it can bind and inactivate reactive free radicals at crucial positions not reachable by other antioxidants (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020).

The beneficial effects of BPC 157 on hippocampal ischemia/reperfusion injury (caused by bilateral clamping of the common carotid arteries) (Vukojevic et al., 2020) are supported by the course of Robert’s cytoprotection, originally described for intragastric absolute alcohol-induced epithelial/endothelial injuries (Sikiric et al., 2020b), regarded as the Virchow triad. The ability to counteract Robert’s gastric hemorrhagic lesion – the epithelial, endothelial, and thrombotic lesions arising from the direct, injurious contact of a noxious agent with a cell – underscores the cytoprotection (Szabo et al., 1986; Sikiric et al. 2020b). The cause–consequence relationship attributes the beneficial effects of BPC 157 with cytoprotection and implicates a rapid injury defense response (Sikiric et al., 2020b). BPC 157 directly protects the endothelium (Sikiric et al., 2006). Furthermore, after abdominal aorta anastomosis and major vein occlusion, BPC 157 both stops thrombosis formation and resolves already formed thrombi (Vukojevic et al., 2018; Gojkovic et al., 2020; Kolovrat et al., 2020). BPC 157 can also alleviate peripheral vascular occlusion disturbances and consequent syndromes by rapidly activating alternative bypass pathways (Duzel et al., 2017; Drmic et al., 2018; Vukojevic et al., 2018, 2020; Berkopic et al., 2020; Gojkovic et al., 2020; Kolovrat et al., 2020). The therapeutic effect is stable, despite continuous ligation (occlusion), and the ligation-induced disturbances do not reappear (Duzel et al., 2017; Vukojevic et al., 2018, 2020; Gojkovic et al., 2020; Kolovrat et al., 2020). Thereby, the evidence has demonstrated that the advanced injurious circle may be stopped and reversed with BPC 157 therapy. Namely, BPC 157-treated animals exhibit more extensive and faster reperfusion. Such recovery of vascular capacity may be an essential mechanism by which BPC 157 administration facilitates reperfusion because it counteracts all pre-existing disturbances and markedly attenuates organ lesions (Vukojevic et al., 2018; Kolovrat et al., 2020). Thus, it is likely that such rapid rescue of vascular capacity may contribute to the beneficial effects of BPC 157 on rats subjected to stroke and hippocampal ischemia/reperfusion damage recovery (Vukojevic et al., 2020).

There is additional evidence that BPC 157 leads to a rapid rescue of vascular capacity. In an acute ethanol intoxication in mice, there is sustained anesthesia, hypothermia, increased ethanol blood values, and 25% fatality over a 90-minute assessment period (Blagaic et al., 2004). BPC 157, regardless of whether it is administered before or after ethanol intoxication, rapidly counteracts the above-mentioned negative effects (Blagaic et al., 2004). Furthermore, BPC 157, when given after abrupt cessation of ethanol – continuous drinking of 20% alcohol drinking for 13 days, with a provocation on day 14 – attenuates withdrawal (assessed over 24 hours) (Blagaic et al., 2004). BPC 157 maintains vascular integrity to counteract alcohol leakage to tissues (Sikiric et al., 2020b), an effect that substantiates the previously emphasized evidence that BPC 157 directly protects the endothelium (Sikiric et al., 2006; 2018), which is a hallmark in cytoprotection studies (Szabo et al., 1986). Consequently, researchers have consistently shown that BPC 157 strongly counteracts the effects of alcohol administered into the rat stomach, namely the rapid damage to the endothelium (Sikiric et al., 2006; 2018; Becejac et al., 2018). In addition, BPC 157 is a strong membrane stabilizer (Park et al., 2020). Therefore, BPC 157 also counteracts portal hypertension induced by chronic alcohol consumption. Based on the role that BPC 157 may play a role in antagonizing the effects of alcohol, Zemba et al. (2015) showed that BPC 157 can mitigate the general anesthetic potency of thiopental as well as the more prolonged anesthesia induced by the L-NAME/thiopental combination.

BPC 157 and Behavioral Disorders

Researchers have increasingly reported the importance of the nitric oxide (NO) system in the therapy of schizophrenia (MacKay et al., 2010) and extrapyramidal deficits linked with the more severe psychiatric symptoms (Weng et al., 2019), such as haloperidol-induced catalepsy (Jelovac et al., 1999a). Recently, Zemba Cilic et al. (2021) demonstrated that BPC 157 counteracts catalepsy induced by L-NAME and haloperidol as well as the deficits of acute and chronic rat models resembling “positive-like” schizophrenia symptoms in rat models (Moore and Grace, 2002; Rung et al., 2005). That combined counteraction may be the key to resolve the complex relationship between the NO system, amphetamine and apomorphine (the application of dopaminergic agents), MK-801 (a non-competitive antagonist of the N-methyl-D-aspartate receptor), and chronic methamphetamine administration (to induce sensitivity) (Zemba Cilic et al., 2021). This finding implicates interactions between BPC 157, dopamine, glutamate, and NO, which seem to be well-controlled by BPC 157 administration (Zemba Cilic et al., 2021). BPC 157 application resolves the unusual parallel matching action in counteracting the amphetamine-induced disturbances that L-NAME and L-arginine may cause, as well as the deficits in rat models resembling “positive-like” symptoms of schizophrenia (Przewlocka et al., 1996). We identified two distinctive NO system responses. Effects induced by acute apomorphine, chronic methamphetamine, acute MK-801, or acute haloperidol administration (catalepsy) are “L-NAME non-responsive, L-arginine responsive” (Zemba Cilic et al., 2021). Acute amphetamine-induced effects are “L-NAME responsive, L-arginine responsive” (Zemba Cilic et al., 2021). The fact that the NO-mediated effects are responsive to BPC 157 (Zemba Cilic et al., 2021) may be a consequence of the aforementioned counteracting potential of BPC 157 on disturbances induced by dopamine (Jelovac et al., 1999a; Sikiric et al., 2020b) and NO (Zemba et al., 2015; Kokot et al., 2016; Duzel et al., 2017). Besides, BPC 157 counteracts the symptoms in Parkinson’s disease rodent models (induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or reserpine (Zemba Cilic et al., 2021)). Likewise, BPC 157 mitigates gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or reserpine (Zemba Cilic et al., 2021). Thus, the BPC 157/dopamine relationship exerts many effects. It includes the interference with dopamine receptor blockade (Jelovac et al., 1999a), the development of receptor supersensitivity (Jelovac et al., 1999a), dopamine receptor activation (Zemba Cilic et al., 2021), dopamine over-release (Zemba Cilic et al., 2021), damage to nigrostriatal dopaminergic neurons (Sikiric et al., 2020b), and depletion of dopamine vesicles (Sikiric et al., 2020b). BPC 157 also counteracts the adverse effects of neuroleptic application that appear outside of the CNS, such as prolonged QT intervals observed with electrocardiography (Strinic et al., 2017) or adverse effects in the gastrointestinal tract, such as gastric lesions or sphincter dysfunction (Belosic Halle et al., 2017). Consequently, BPC 157 might be essential for adequate dopamine function, and vice versa. Serotonin and BPC 157 show a similar relationship (Tohyama et al., 2004; Boban Blagaic et al., 2005). In rats, BPC 157 counteracts the symptoms of Porsolt’s depression model and the chronic unpredictable stress depression model; it also fully counteracts all manifestations of serotonin syndrome and induces acute and chronic serotonin release in specific brain nigrostriatal regions (Tohyama et al., 2004; Boban Blagaic et al., 2005). Thus, unlike imipramine, BPC 157 exhibits a particular antidepressant effect, even when given systemically (Tohyama et al., 2004; Boban Blagaic et al., 2005).

Considering the BPC 157/NO relationship (Zemba et al., 2015; Kokot et al., 2016; Duzel et al., 2017), studies in stomach tissue have revealed that BPC 157 alone induces NO release, even in a condition that precludes the effect of L-arginine (Turkovic et al., 2004). In the most recent study, the authors reported that BPC 157 induces NO generation in the isolated aorta, likely through the activation of the Src/caveolin-1/endothelial nitric oxide synthase pathway (Hsieh et al., 2020). Thus, there is an advantage when using a substance (i.e, BPC 157) to modulate the NO system. This phenomenon may counteract the adverse effects of L-NAME, a nitric oxide synthase inhibitor, and L-arginine, a nitric oxide synthase substrate – that is, both L-NAME-induced hypertension and L-arginine-induced hypotension. Researchers have investigated how this effect may be practically translated into enhanced clinical efficacy regarding its interactions with the NO system, based on its particular effects seen in various models and species. There is also a supporting analogy with its counteracting effect on dopamine-induced adverse effects. A particular example is an amphetamine-induced stereotypy and haloperidol-induced catalepsy, both of which are counteracted by BPC 157 administration (Jelovac et al., 1999a; Zemba Cilic et al., 2021).

Although animal models have possible limitations (Jones et al., 2011), the BPC 157 mechanism of action, the BPC 157/dopamine/glutamate/NO interaction and effects, and the safe clinical profile of BPC 157 cannot be neglected (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020). These findings suggest that BPC 157 may influence essential functions and counteract the dysfunction underlying schizophrenia-like symptoms (Zemba Cilic et al., 2021). A contributing factor may be that BPC 157 increases serotonin release in nigrostriatal brain areas (during either acute or chronic administration, determined with highly specific alpha methyl-L-tryptophan autoradiography measurements). This release has a consequent antidepressant effect (including counteraction of serotonin syndrome) and relationships with the serotonin system (Tohyama et al., 2004; Boban Blagaic et al., 2005). Together with the counteracting effects of BPC 157 against ethanol exposure (Blagaic et al., 2004) and diazepam withdrawal (Jelovac et al., 1999b), we may speculate that BPC 157 has a particular modulatory effect, which may be necessary for maintaining the proper functioning of several systems.

BPC 157 is a novel and efficacious ethanol antagonist; it always counteracts negative effects due to ethanol exposure. Given that few pharmacological agents consistently act as ethanol antagonists, the negative effects elicited by acute or chronic alcohol disturbances (Blagaic et al., 2004) cannot be modulated by traditional pharmacotherapy (for a review, see Fadda and Rossetti, 1998). The GABAergic transmission was long ago implicated in the regulation of dopamine-mediated events (associated with extrapyramidal systems) and behavior that is dependent on striatal functions (catalepsy, stereotypies). Hence, it is interesting that BPC 157 counteracts GABA system disturbances, such as diazepam-induced tolerance/withdrawal (Jelovac et al., 1999b). Perrault et al. (1992) examined physical dependence, which is commonly studied in similar models as increased sensitivity to convulsant challenge, in mice that were chronically treated with diazepam for different times. After discontinuation of diazepam conditioning, the authors examined the latency to convulse induced by the convulsant challenge (Perrault et al., 1992). The development of tolerance and physical dependence are among the most serious side effects of benzodiazepine therapy. Importantly, BPC 157 has anticonvulsant activity against several challenges (Sikiric et al., 2013; Lozic et al., 2020).

Boban Blagaic et al. (2009) addressed how BPC 157 application affects morphine-induced analgesia compared with the opioid antagonist naloxone. The authors used the hot plate test to determine how naloxone and BPC 157 counteract morphine-induced analgesia. Naloxone had an immediate counteracting effect on morphine-induced analgesia, but BPC 157 required more time (30 minutes) to produce an effect (Boban Blagaic et al., 2009). Haloperidol, a central dopamine antagonist, enhances morphine-induced analgesia, and BPC 157 counteracts this enhancement; this represents an additional dopamine-related effect. On the contrary, naloxone completely abrogates the analgesic effect; specifically, the pain reaction returns to basic levels. BPC 157, naloxone, and haloperidol per se fail to exert analgesic action (Boban Blagaic et al., 2009). It had been noted that in mice, BPC 157 counteracts inflammatory and non-inflammatory, prostaglandin-dependent and prostaglandin-independent pain (i.e., tail pinching, acetic acid, and magnesium sulfate-induced writhing in mice). Thus, BPC 157 may specifically interact with the opioid system and the pain reaction. In rats, BPC 157, in relation to the NO system, counteracts lidocaine-induced adverse effects and also prolongs local anesthesia (Lozic et al., 2020). Likewise, BPC 157 counteracts lidocaine-induced depolarisation in vitro (Lozic et al., 2020).

It is evident that BPC 157 has a particularly safe profile, which is quite distinctive from standard pharmacological agents. Indeed, unlike neuroleptics and antidepressants, BPC 157 has a particular cardioprotective and antiarrhythmic activity (Strinic et al., 2017; Lozic et al., 2020).

BPC 157 and Spinal Cord Injury

Perovic et al. (2019) reported that BPC 157 has a marked therapeutic effect pertaining to the recovery of rats with a spinal cord injury with tail paralysis (1-minute compression injury of the sacrocaudal spinal cord [S2–Co1]). Specifically, a single intraperitoneal BPC 157 administration at 10 minutes post-injury counteracts the negative effects. By contrast, the spinal cord injury and tail paralysis persist in untreated rats, assessed days, weeks, months, and a year after the injury (Perovic et al., 2019). Of note, BPC 157 attenuates the commonly caused damage (i.e., the substantial hemorrhagic zone in lateral and posterior white columns with sparing of the grey matter) (Perovic et al., 2019). Thereby, BPC 157 therapy results in evident functional (recovered tail paralysis), microscopic, and electrophysiologic recovery (Perovic et al., 2019). Of note, in rats with spinal cord injury, there is permanent reperfusion. Once BPC 157 is administered 10 minutes post-compression injury (which represents the advanced reperfusion stage), there is continuous protection and no spontaneous spinal cord injury-induced disturbances reappear (Perovic et al., 2019).

All spinal cord injuries immediately provoke hemorrhage, with subsequent death of neurons and oligodendrocytes (Fan et al., 2016). Hence, it is conceivable that early hemostasis may be beneficial and enable functional recovery after spinal cord contusion in rats (Fan et al., 2016). However, the effect exerted by BPC 157 is likely different from the simple hemostatic effect that would attenuate spinal cord injury (Fan et al., 2016), because BPC 157 also markedly improves thrombocyte function in rats without affecting coagulation factors (Stupnisek et al., 2015; Vukojevic et al., 2018; Konosic et al., 2019). During recovery from spinal cord injury, BPC 157 also directly protects the endothelium (Sikiric et al., 2006), alleviates peripheral vascular occlusion disturbances, rapidly activates alternative bypass pathways, and counteracts venous occlusion–induced syndromes (Duzel et al., 2017; Drmic et al., 2018; Vukojevic et al., 2018, 2020; Berkopic et al., 2020; Gojkovic et al., 2020; Kolovrat et al., 2020). Thus, assuming that there is a substantial venous contribution to the spinal cord compression (Bakker et al., 2015), it is conceivable that the reestablished blood flow mediated by BPC 157 may undoubtedly contribute to the rapid recovery effect (Perovic et al., 2019). Furthermore, considering that BPC 157 promotes permanent reperfusion after spinal cord compression, it should be noted that when BPC 157 is given during reperfusion, it counteracts stroke induced by bilateral clamping of the common carotid arteries. BPC 157 resolves neuronal damage and prevents memory, locomotor, and coordination deficits (Vukojevic et al., 2020). BPC 157 apparently exerts these effects by altering gene expression in the hippocampus (Vukojevic et al., 2020).

BPC 157 exerts multifactorial therapeutic activity in rats subjected to spinal cord injury (Perovic et al., 2019). There is the anti-inflammatory activity, amelioration of capsaicin-induced somatosensory neuronal damage (Sikiric et al., 1996), recovery of the sciatic nerve after transection (Gjurasin et al., 2008), and protection of cultured enteric neurons and glial cells (Wang et al., 2019). BPC 157 also ameliorates concussive trauma-induced brain injury (Tudor et al., 2010) and severe encephalopathies that affect various brain areas (Sikiric et al. 2013; Lojo et al., 2016; Drmic et al., 2017; Medvidovic-Grubisic et al., 2017). Furthermore, BPC 157 mitigates other consequences such as gastrointestinal and/or liver lesions (Sikiric et al. 2013; Lojo et al., 2016; Drmic et al., 2017) as well as severe muscle weakness (Medvidovic-Grubisic et al., 2017) ( Additional Table 1 ). In addition, BPC 157 induces healing of mechanically severed muscles due to complete transection, crush, and denervation injuries (Mihovil et al., 2009) and intramuscular succinylcholine application (Stambolija et al., 2016). These benefits include muscle function recovery and counteraction of muscle lesions due to neuromuscular junction failure, fasciculation, paralysis, and hyperalgesia (Mihovil et al., 2009; Stambolija et al., 2016). BPC 157 interacts with various molecular pathways (Tkalcević et al., 2007; Chang et al., 2011, 2014; Cesarec et al. 2013; Huang et al., 2015; Hsieh et al., 2017, 2020; Kang et al., 2018; Vukojevic et al., 2018, 2020; Wang et al., 2019; Park et al., 2020) and, thereby, counteracts the increased levels of pro-inflammatory and pro-cachectic cytokines and annihilates tumor induced-muscle cachexia (Kang et al., 2018). Finally, BPC 157 shows intrinsic antidotal activity against the adverse effect of lidocaine and local anesthetics (in particular, limb function failure due to L4–L5 spinal cord intrathecal block, bradycardia and tonic-clonic convulsions, and depolarisation of HEK293 cells) (Lozic et al., 2020).

Based on the myriad of beneficial effects mediated by BPC 157, the functional rescue of the paralyzed tail, as well as the mitigation of axonal and neuronal necrosis, demyelination, and cyst formation (Perovic et al., 2019), may be the cause or consequence of the beneficial effects of BPC 157 on related disturbances (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020). Thereby, BPC 157 may impact all stages of the secondary injury phase (Perovic et al., 2019).

In conclusion, BPC 157 exerts beneficial effects on stroke, schizophrenia, and spinal cord injury (Perovic et al., 2019; Vukojevic et al., 2020; Zemba Cilic et al., 2021). Researchers have consistently demonstrated that BPC 157 exerts a myriad of beneficial effects throughout the body. There is no reason to indicate that the benefits of BPC 157 are limited by the validity of the utilized models and/or methodology limitations. Indeed, we can argue that the effectiveness, easy applicability, safe clinical profile and mechanism of BPC 157 (i.e., BPC 157/dopamine/glutamate/NO system) represent an alternative, likely successful, future therapeutic direction for neurological conditions. Therefore, additional studies are needed to clarify how potential BPC 157 therapy would specifically deal with a mechanism of action that involves multiple subcellular sites in the CNS. The influence on the function of most, if not all, neuronal systems at the molecular, cellular, and systemic levels should be explored. Some visceral repetitive relay of the CNS or circumventricular organs, one of the few regions in the brain without the blood-brain barrier, is a known pathway by which a systemically administered peptide can exert a central effect. Thus, it must act within the gut-brain axis, regardless of whether this action is direct or indirect.

• View Full Text | PubMed | CrossRef
• PubMed | CrossRef

Conflicts of interest: The authors declare no conflicts of interest.

Financial support: None.

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Open peer reviewers: Victor Diogenes Amaral Silva, Universidade Federal da Bahia, Brazil; Brijesh Kumar Singh, Columbia University, USA.

P-Reviewers: Silva VDA, Singh BK; C-Editors: Zhao M, Qiu Y; T-Editor: Jia Y

BPC 157; central nervous system; cytoprotection; injury; nitric oxide system; peptide; regeneration

• + Favorites
• View in Gallery

Readers Of this Article Also Read

P2x4 receptor participates in autophagy regulation in parkinson's disease, effect of stromal cell-derived factor-1/cxcr4 axis in neural stem cell....

BPC 157: Accelerated Healing and Recovery

Research Compound

Updated on: May 3, 2024

Body Protective Compound 157, or just BPC 157 , is a synthetic peptide comprised of 15 amino acid chains and was isolated from a molecule secreted by the human stomach’s gastric juice. 

BPC 157 is currently studied for its potential positive effects on several organ systems, notably the brain, body, and gut for its healing properties, earning it the title of the “Wolverine” peptide.

While BPC 157 doesn’t give you adamantium claws or the tall, good-looking, and charming features of our Aussie friend Hugh Jackman, it does give you the ability to heal and recover from your injuries quicker.

BPC 157 was discovered by Predrag Sikirić, a Croatian scientist, in the early 1990s.  You may also know BPC 157 from its other names like Pentadecapeptide, PL-14736, PLD 116, PL-10, and bepecin . 

Note: This is relevant info as most of the studies we’re going to explore will mention these names.

How It Works

Most studies show that BPC-157’s benefits have been particularly in animal trials, and even suggesting that the peptide has great potential in human trials, but how does it work? 

While our current science doesn’t fully understand how it works (for now), BPC 157 particularly affects our gut-brain axis , a network of nerves that controls how our digestive and central nervous system interacts. 

BPC 157 also boosts growth hormone receptors, anabolic receptors, and vascular endothelial growth factor (VEGF) through the FAK-paxillin pathway – a pathway that influences how cells stick to surfaces and move around.

What’s more remarkable about this peptide is that BPC 157 seems to boost nitric oxide levels in low dosages. Boosted nitric oxide levels open up your blood vessels and allow more blood, oxygen, and nutrients to enter your cells.

This physiological process allows your tissue regeneration, blood flow, and inflammation reduction rate to significantly improve immediately according to some researchers.

According to the results of a 2011 study published in the Journal of Applied Physiology BPC can take effect after just one application, and many researchers may see an enhanced effect after long-term usage.

For safety concerns, while BPC 157 could honestly use some more rigorous human clinical trials , several studies have proven that BPC 157 is safe to use and has no apparent side effects or toxicity.

Here are some health benefits and positive effects associated with BPC 157 usage: systematically enhances healing in every

Injury Healing

BPC 157 is widely known for its ability to facilitate healing faster as it can accelerate wound healing, and tendon repair , and increase collagen production through activation of the growth hormone receptors while reducing pain.

Below are some additional benefits and applications of BPC 157 for its healing effect:

Tendon Healing

https://www.facebook.com/groups/sarms.peptides.nootropics/permalink/1553127562209302

In a 2011 in-vitro study , researchers took fibroblasts (cells located in your Achilles tendon) from rats and dipped them in solutions containing either BPC 157 or without. While BPC 157 did not increase the fibroblasts’ strength, it did promote healing better than non-treated cells due to the presence of more growth hormone receptors . 

In a 2008 comparative study on the effects of BPC 157 and methylprednisolone on the early recovery of rats with cut Achilles tendons, 72 rats underwent surgery wherein their Achilles tendon was severed near the bone.

The treatments were administered separately to different groups of rats. 

BPC 157 was given at a dose of 10 micrograms, methylprednisolone at 5 milligrams, and normal saline (as a control) at 5 milliliters, all through intraperitoneal injections ( a common method of administering drugs to rodents) once a day, starting 30 minutes after surgery and ending 24 hours before analysis.

The results showed that BPC 157 improved functional recovery by reducing inflammation (measured by decreased myeloperoxidase activity and inflammatory cell influx) and increasing the formation of new blood vessels. 

Methylprednisolone also reduced inflammation but had a negative effect on new blood vessel formation and did not improve early functional recovery.

In simpler terms: BPC 157 helped the rats recover faster from Achilles tendon injury by reducing inflammation and promoting the growth of new blood vessels. 

While it is not noted whether BPC 157 helped the rats walk better after their surgery, a similar study noted that the peptide helped stronger tendon structure (biomechanically), better function, and enhanced tissue formation, which can improve walking post-injury.

Brain-Related Injuries

As BPC157 induces healing in various tissues, it can also promote brain and nerve healing after traumatic brain injuries in rats, aid in repairing the brain and reducing swelling after a hemorrhagic stroke , and protect the brain from seizures caused by an insulin overdose.

Expanding on traumatic brain injuries, in a 2010 experiment on the effectivity of BPC 157 in treating muscle crush injuries and traumatic brain injuries (TBI), mice were subjected to TBI by a falling weight and were administered BPC 157 either before or immediately after the injury.

While this is certainly distasteful, the research concluded that BPC 157 reduced the severity of traumatic brain lesions, such as bleeding in the brain and brain lacerations, and improved brain swelling.

Moreover,  when given before injury, it improved the outcome and reduced mortality rates in mice subjected to different levels of force. When given after injury, it still had beneficial effects, especially for less severe force impacts.

For more severe impacts, the timing of the BPC 157 administration was crucial. Administering it shortly before or after injury improved outcomes, suggesting its potential as a treatment for traumatic brain injuries.

BPC 157 for Gut Health

BPC 157 is mainly used for gut health benefits as traditionally treating the gut can be quite challenging. According to a 1994 comparative study , BPC 157 has beneficial effects on our gastrointestinal tract due to its ability to protect the endothelial cells lining the blood vessels.

In the study, BPC 157 was compared to several other medications (bromocriptine, amantadine, famotidine, cimetidine, and somatostatin) in three different ulcer models in rats. 

The results showed that only BPC 157 dose-dependent protection in one model and partial positive effects in another, while consistently preventing ulcers in all of the tested models.

Below are some additional benefits and applications of BPC 157 for gut health:

GERD – Gastroesophageal reflux disease, or GERD , is a condition where stomach acid and other contents flow backward into the esophagus.

A 2003 animal study evaluating the effect of BPC 157 on 50 adult rats with reflux laryngitis showed that rats with the peptide had better results in terms of the health of their laryngeal mucosa (the lining of their voice box) compared to the control group. 

Inflammatory Bowel Disease – BPC 157 can also treat inflammatory bowel disease (IBD) as studies show that they can significantly promote healing and complications in the intestines.

In a 2007 animal study investigating the healing effects of BPC 157 on ileoileal anastomosis (a surgery that connects two parts of your small intestine) in rats, the researchers found that those treated with the peptide had their wounds healed better compared to those not receiving the treatment.

Furthermore, the treated rats had fewer complications, better blood flow, and less swelling. As the healing process progressed, the treated rats showed improvements in tissue structure and strength, suggesting that BPC 157 helped in the overall healing of the surgical site.

Drug-related Damages – While NSAIDs are commonly used to relieve pain, reduce inflammation, and lower fever, they can also cause irritation and damage to the lining of the stomach and intestines. This leads to stomach ulcers, heartburn, lesions, bleeding and perforations.

A 2010 review highlighted BPC 157 usage in protecting the stomach from damage caused by alcohol and anti-inflammatory drugs which contributes to overall gastrointestinal health. 

Furthermore, Animal studies have shown that BPC 157 may be able to impart a positive effect against lesions brought by NSAID damage, as well as apply benefits to the gut , brain , and liver ,  in rats.

On an unrelated note, BPC 157 has also been shown to protect against excessive bleeding and low platelet counts caused by blood-thinning medications such as heparin, warfarin, or aspirin – improving survival rates in rats.

Furthermore, a 2016 animal study examined the effects of BPC 157 on muscle paralysis induced by succinylcholine, a medication used during anesthesia.

Results showed that whether given before or after succinylcholine administration, BPC 157 was able to reduce muscle paralysis and other related complications in rats, prevent hyperkalemia (high levels of potassium in the blood), arrhythmias (irregular heartbeats), and muscle damage caused by succinylcholine.

Improves Mental Health

BPC 157 can possibly positively influence depression and anxiety similarly to antidepressant drugs, according to a 2000 comparative study on the antidepressant effect of BPC 157 versus conventional antidepressants.

In this study, researchers used two different tests to measure depression-like behavior in rats: the forced swimming test and chronic unpredictable stress.

• In the forced swimming test, rats treated with BPC 157 showed less immobility, which is a sign of improved mood, similar to rats treated with conventional antidepressants like imipramine.
• In the chronic unpredictable stress test, rats were exposed to stressful situations, and those treated with BPC 157 consistently showed improvements in mood compared to rats treated with conventional antidepressants. BPC 157 was also effective even after a shorter treatment period, unlike conventional antidepressants, which required a longer period to show effects.

Overall, the study suggests that BPC 157 is better than putting the rats on conventional antidepressants, making it a potential candidate for further research in treating depression.

Additionally, BPC 157 can protect the brain against serotonin toxicity brought by serotonin syndrome . This life-threatening condition occurs only when there’s too much serotonin in the body, which could be exacerbated by medication interactions.

In a 2005 study on how BPC 157 affects serotonin syndrome in rats, the researchers discovered that the peptide reduced the severity and duration of serotonin syndrome symptoms, such as hyperthermia and abnormal movements.

Furthermore, BPC 157 specifically targeted certain serotonin receptors in the brain, safely reducing the symptoms brought serotonin syndrome without causing any negative effects on its own.

Parkinson’s Disease

According to a 1999 animal clinical trial on mice, BPC 157 can also help with Parkinson’s disease.

The results showed that BPC 157 significantly improved symptoms associated with Parkinson’s disease, such as tremors and movement difficulties, and even prevented lethal outcomes in some cases. 

Researchers also discovered that BPC 157 reduced stomach lesions caused by Parkinsonian agents, which suggests that BPC 157 can be a possible therapeutic option for Parkinson’s disease and stomach-related issues in the future.

Muscle Building and Recovery

BPC 157 has been shown to have potential benefits for muscle building and recovery as it can promote tissue repair and activate certain cells that perform these repairs like human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1)

IGF-1 is responsible for hyperplasia (expanding of your cells) like anabolic steroids, but unlike steroids that only inflate your muscles, IGF-1 also increases the number of cells present.

While the peptide by itself may not directly lead to muscle hypertrophy, it’s known to facilitate quicker recovery by enhancing cell survival and migration.  This can lead to a stronger, more robust muscle structure and potentially boost muscle resilience and stamina over time.

Administration Method

BPC 157 can be taken orally, subcutaneously injected, and nasally. Animal studies suggest common research dosages amount to 1 μg/kg to 10 ng/kg in rats.

https://www.facebook.com/groups/bpc157/permalink/1551555315418088

We have noticed that most researchers are divided on what’s the best administration method for BPC 157 – is it orally, subcutaneously, or nasally?

Some researchers even refrain from using BPC 157 orally as it gets broken down in your gut. However, BPC is a peptide already found in your gut.

Suppose you take something out of its natural habitat and put it back, will it survive?

Definitely, it could even survive for 24 hours.

Furthermore, BPC can theoretically be taken as a nasal spray its molecular weight is between 900-1600 Daltons. For context, the uppermost limit for intranasally-delivered peptides is only up to 6000 Daltons .

But according to several studies, it really doesn’t matter .

• In a 2010 study published in the Journal of Orthopaedic Research , researchers found that BPC 157 was highly effective in healing ligament injuries in rats, regardless of administration method.
• In another study published in 2013 in the Medical Science Monitor Basic Research , BPC 157 was again, highly effective in healing damaged smooth muscle tissue in the gastrointestinal system, regardless of administration method.

For unopened BPC 157 peptide vials, it’s generally safe to store them at 4°C or 39.2°F for a few days.

To extend BPC’s shelf life once the vial is open, you have to keep it around 2-8°C (or 35.6-46.4°F) in the fridge at all times. 

This should last you around 2-8 weeks before the peptide goes bad or until the manufacturer’s “best-by” date. Avoid repeatedly freezing and thawing the peptides to prevent degrading them.

Side Effects

BPC-157 is mostly on the safer side as shown in clinical animal trials for inflammatory bowel disease , and intestinal anastomosis therapy, and is currently undergoing trials for multiple sclerosis .

However, there are still potential side effects when used for extended periods or administered to human subjects with pre-existing conditions. Common side effects may include:

• Mild headaches
• Blood Pressure fluctuations

Additionally, there are two major things to note:

One , corticosteroids (or anti-inflammatory steroids) may potentially reduce BPC-157’s ability to heal muscles .

Two , there is no conclusive research suggesting that BPC 157 contributes to or causes cancer growth apart from one study indicating that the peptide has angiogenic properties – a process associated with wound healing, tissue repair, and tumor growth .

With this, we cannot conclude a definitive stance as there are some studies suggesting a possible increase in cancer risk with BPC 157 usage, but there are also studies that show BPC 157 can be a potential therapeutic option in cancer treatment.

Other Things to Consider

Like most medications, you need a doctor’s prescription to obtain BPC 157 as it is not FDA-approved due to a lack of clinical trials. The World Anti-Doping Agency (WADA) also classified BPC 157 as “ not approved for human use. ”

However, BPC 157 is still classified under section 503A of the Federal Food, Drug, and Cosmetic Act. This means some compounding pharmacies can still honor prescriptions based on the needs of specific patients but still follow certain quality standards outlined in the United States Pharmacopeia (USP) and other guidelines.

Verdict: Should You Use BPC 157?

So, is BPC 157 worthy of the title as the “Wolverine” peptide? Preliminary evidence is in favor of this claim as BPC 157 can speed up healing in several areas of the body, and possibly more.

We honestly do not know the full potential of BPC 157 (yet) as most of the research was from animal studies and more human research is needed to solidify this.

If you’re considering using BPC 157 in your research, it may be beneficial to stack it with an HGH-releasing peptide like CJC-1295. Stacking these substances together could potentially enhance their regenerative properties through a synergistic effect. 

However, it’s essential to conduct thorough research and consult with medical professionals before experimenting with peptides or any other substances for research purposes.

As always, if you liked this guide, feel free to check out our other articles !

When does BPC 157 kick in?

BPC 157 kicks in immediately. According to specific studies about BPC 157 on ligament healing, it works best for acute injuries– or injuries that have just happened.

Is it better to inject BPC 157 at the site of the injury?

According to several studies mentioned before, it really doesn’t matter. BPC 157 is effective in tissue healing and gut repair, regardless of the administration method.

We believe that this false efficacy is due to a “placebo effect.”

For example: Your research subject has shoulder pain, and you inject BPC 157 directly at the site of injury. As the injection induces mild inflammation and pain at the site, your body’s response is to heal itself.

Can you use BPC 157 for dogs?

You can possibly use BPC 157 for dogs in your research. There are thousands of animal trials conducted on mice, rats, rabbits, and dogs that have reported no abnormal changes or toxicity in repeated-dose evaluations. 

According to a 2020 study , the only side effects of BPC 157 in dogs were slightly lower creatinine levels and mild irritations.

Can you stack BPC 157 and TB500?

https://www.facebook.com/groups/sarms.peptides.nootropics/permalink/1502333087288750

Some researchers and influencers stack TB-500 and BPC 157 alongside an HGH-inducing peptide such as Sermorelin , Tesamorelin , GHK-Cu , or CJC-1295 to maximize regenerative properties.

The idea of stacking them is to get a “synergistic effect” that facilitates healing quicker compared to taking them alone.

Leave a Comment Cancel reply

Save my name, email, and website in this browser for the next time I comment.

most recent

Sarms , Blog , SARM stacking

The ultimate guide to cjc-1295 with dac (dosing, benefits, side effects, and more).

Blog , Sarms

The ultimate guide to mk677 side effects and how to handle them.

SARM stacking , Blog , Sarms

The ultimate hexarelin breakdown: dosing, benefits, side effects, and more.

Blog , Anti-Aging

The ultimate guide to mots-c: benefits, side effects, dosing, and more.

How to PCT with Enclomiphene for Your Next Sarm Cycle: The Ultimate Guide! (Dosing, Side Effects, Benefits, and More!)

The Ultimate Guide To IGF-LR3 (Dosing, Side Effects, Benefits, and More!

24 M Drive East Hampton, NY 11937

It looks like you haven't added any items to your cart yet.

REVIEW article

Stable gastric pentadecapeptide bpc 157 and wound healing.

• 1 Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
• 2 Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
• 3 Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
• 4 Department of Anatomy and Neuroscience, School of Medicine Osijek, University of Osijek, Osijek, Croatia

Significance: The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing.

Recent Advances: BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested).

Critical Issues: By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion.

Future Directions: BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.

Scope and Significance

This stable gastric pentadecapeptide BPC 157 review ( Seiwerth et al., 2018 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ) is focused on the particular skin wound therapy, incisional/excisional wound ( Seiwerth et al., 1997 ), deep burns ( Mikus et al., 2001 ), diabetic ulcer ( Tkalecevic et al., 2007 ), alkali burns ( Huang et al., 2015 ), and healing of various other tissue types ( Staresinic et al., 2003 ; Staresinic et al., 2006 ; Sever et al., 2009 ; Masnec et al., 2015 ; Becejac et al., 2018 ). The defensive system pertaining to BPC 157 beneficial activities was already appraised in several reviews ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). A particular topic is its role in mediating Robert gastric cytoprotection and endothelial maintenance ( Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2017 ; Sikiric et al., 2018 ), as well as its therapeutic effect in the gastrointestinal tract ( Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2017 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), additionally acting as membrane stabilizer ( Park et al., 2020 ), with particular reference to ulcerative colitis ( Sikiric et al., 2011 ). Recently, to approach particular skin wound therapy, we and others reviewed the significance of its beneficial effect on muscle, tendon, ligament, and bone injuries ( Gwyer et al., 2019 ; Seiwerth et al., 2018 ).

Translational Relevance

A special point confronts BPC 157 effectiveness with standard growth angiogenic factors, and their healing effects on the tendon, ligament, muscle, and bone lesions vs. their healing effects on gastrointestinal tract lesions ( Seiwerth et al., 2018 ). Only BPC 157 has the same regimens, as used in the gastrointestinal healing studies, improving these lesions healing, accurately implementing its own healing angiogenic effect ( Seiwerth et al., 2018 ). Additionally, we reviewed its particular effects, such as the non-steroidal anti-inflammatory drugs (NSAIDs) toxicity counteraction ( Sikiric et al., 2013 ; Park et al., 2020 ), its relationship to the nitric oxide (NO)-system ( Sikiric et al., 2014 ), and blood vessels ( Sikiric et al., 2006 ; Seiwerth et al., 2014 ; Sikiric et al., 2018 ), and its role in the brain–gut and gut–brain axis ( Sikiric et al., 2016 ), along with its CNS-disturbances therapy ( Sikiric et al., 2016 ) and stress disorders ( Sikiric et al., 2017 ; Sikiric et al., 2018 ).

Clinical Relevance

As mentioned, the significance of its particular skin wound therapy was not especially reviewed. Namely, BPC 157 is always applied alone (i.e., its own effect ascribed only to the peptide (for review, see Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Seiwerth et al., 2018 ; Kang et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Unlike growth factors peptides, which need carrier(s) addition, and are rapidly degraded in human gastric juice, BPC 157, as an antiulcer peptide, is native and resistant to human gastric juice exciding one day period ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Therefore, BPC 157 practical applicability (given alone, with the same dose range, and the same equipotent routes of application, regardless of the injury tested) could be clearly generalized and used in the wound healing therapy.

Background or Overview

Stable gastric pentadecapeptide BPC 157 is still far less investigated ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ) than the generally established angiogenic growth factors, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) ( Tarnawski and Ahluwalia, 2012 ; Deng et al., 2013 ). Originally, BPC 157 appears as a cytoprotective antiulcer peptide, stable in human gastric juice, previously employed in ulcerative colitis clinical trials and now in those concerning multiple sclerosis ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ) without toxicity (lethal dose 1 (LD1) could be not obtained) ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). As a cytoprotective agent, mediating Robert’s cytoprotection, it maintains endothelium integrity and has a particular angiomodulatory effect ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ) (in various wound models, VEGF, factor VIII, CD34 peak appear in the early interval, while later depressed ( Brcic et al., 2009 )). In the sponge assay, BPC 157 exhibits an angiogenic effect greater than the standard antiulcer agents ( Sikiric et al., 1999a ). Besides, when we consider the general wound principles in tissue damage as a dynamic equilibrium between negative and positive events (i.e., necrosis and possibly pus formation vs. activation of macrophages and fibroblasts), BPC 157 shows the particular full extent of its healing actions ( Seiwerth et al., 1997 ). This includes in addition to the skin lesions, the concomitant lesions counteraction, that is, burn stress gastric lesions in severely burned mice ( Mikus et al., 2001 ). As an extending point, there appears to be fistula healing (i.e., simultaneous healing of the skin and other tissues wounds) ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). Illustratively, there are particular distinctions from the platelet-derived growth factor (PDGF-BB) activity ( Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ). In contrast to PDGF-BB, in diabetic wounds, induced by alloxan application, BPC 157 largely promoted mature collagen in granulation tissue ( Seveljevic-Jaran et al., 2006 ) (note, previously, BPC 157 healed alloxan-induced gastric lesions in rats ( Petek et al., 1999 )). In addition, BPC 157 has a particular beneficial effect when confronted with the major vessel occlusion ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ; Berkopic Cesar et al., 2020 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ). BPC 157 rapidly attenuates the major vessel occlusion severe consequences by rapidly activating collateral pathways occlusion ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ; Berkopic Cesar et al., 2020 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ). With permanent vessel obstruction, once the therapeutic effect begins, the beneficial action proceeds without further reappearance of the adverse effects of vessel obstruction ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ). Likewise, reestablished blood flow may certainly contribute to the rapid recovery effect noted.

This particular balanced modulatory action, which rapidly appears, along with this pentadecapeptide’s particular characteristics, will be especially reviewed. It may be even more interesting and more effective than that of comparative standard agents ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), the silver sulfadiazine cream ( Mikus et al., 2001 ) or systemic corticosteroids ( Sikiric et al., 2003 ), for possible wound healing therapy (i.e., incisional/excisional wound, deep burns, diabetic ulcer, and alkali burns) ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ). Additionally, BPC 157 administration counteracted various free radical–induced lesions and increased free radical formation in other organs ( Sikiric et al., 1993 ; Ilic et al., 2010 ; Belosic Halle et al., 2017 ; Duzel et al., 2017 ; Luetic et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ; Sucic et al., 2019 ; Berkopic Cesar et al., 2020 ; Kolovrat et al., 2020 ). The carboxylic groups of the pentadecapeptide BPC 157 may contribute to its role as an antioxidant. The cumulative antioxidant activity could be very high with the reactivation of the carboxylic groups (e.g., glutathione or enzymes). Additionally, BPC 157 is present in most tissues ( Seiwerth et al., 2018 ), where it can bind reactive free radicals and inactivate them at crucial positions not reachable by other antioxidants ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ).

Skin Wounds

This particular balanced modulatory action was indicated in the initial manuscript ( Seiwerth et al., 1997 ). This study already established that the combined triad of collagen-inflammatory cells–angiogenesis was accordingly upgraded, appearing at earlier intervals, more rapid, and advanced with BPC 157 therapy ( Seiwerth et al., 1997 ). Quantitative analysis of collagen development as well as granulation tissue formation and angiogenesis was performed in vivo models, incisional skin wounds, colon–colon anastomoses, and synthetic sponge implants ( Seiwerth et al., 1997 ). The applied rationale of skin and colon wounds ( Seiwerth et al., 1997 ) covers the different healing patterns and dynamics of these organs related to their collagen structures ( Eyre et al., 1984 ; Eckersley and Dudley, 1988 ; Hendriks and Mastboom, 1990 ). The noted wide effectiveness in all of these models postulates a quite general wound healing effect ( Seiwerth et al., 1997 ). Thereby, the subsequent burn studies were on the burns covering 20% of total body area on the back of mice, open flame for 5 or 7 s ( Mikus et al., 2001 ; Sikiric et al., 2003 ). The accelerated healing in burns of treated mice includes the activity of the pentadecapeptide BPC 157 ( Figure 1 ), given locally (as a cream) or systemically (ip), on the inflammatory cells, edema, reticulin, collagen, necrosis, blood vessel formation, number of preserved follicles, re-epithelization, tensile breaking strength, and water content in burned skin. BPC 157 regimens also attenuated burn stress-gastric lesions ( Mikus et al., 2001 ). Note, there is apparently smaller extent of the silver sulfadiazine cream effect ( Mikus et al., 2001 ). Further positive outcome appears in the corticosteroid animals with severe burns ( Mikus et al., 2001 ; Sikiric et al., 2003 ). With BPC 157 additional therapy, there are no characteristic corticosteroid adverse effects in the corticosteroid animals ( Sikiric et al., 2003 ). As a beneficial property, inhibition of the inflammatory response did not impair wound healing and did not induce failed collagen synthesis ( Mikus et al., 2001 ; Sikiric et al., 2003 ). In this, pentadecapeptide BPC 157 consistently (grossly, microscopically, and biomechanically) cured burn injuries, and counteracted corticosteroid (6α-methylprednisolone 1.0 or 10 mg/kg/day ip for 21 days)-induced impairment of burn healing ( Mikus et al., 2001 ; Sikiric et al., 2003 ). With pentadecapeptide BPC 157, less edema and less inflammatory cells, re-epithelization, tensile breaking force, relative elongation of the burned part skin appear together, and inhibition of inflammation and beneficial effects. This chain of events fails to occur in the corticosteroids animals after initial inflammation inhibition ( Sikiric et al., 2003 ). Even more importantly, BPC 157 accordingly inhibited corticosteroid-induced immunosuppression ( Sikiric et al., 2003 ). In vitro , in comparison with control, healthy animals, the assessment of splenic cells (day 21) demonstrated that the 6α-methylprednisolone animals had declined reactivity to nitrogen, while the addition of BPC 157 (1 μg/g cream) returned cell reactivity to normal values ( Mikus et al., 2001 ; Sikiric et al., 2003 ). A similar outcome appears in the CO 2 laser injury on the dorsal skin mice ( Bilic et al., 2005 ).

FIGURE 1 . Burn skin lesions in mice and BPC 157 therapy effect. The effects of the gastric pentadecapeptide BPC 157 were investigated on deep partial skin thickness burns (1.5 × 1.5 cm) covering 20% of the total body area, when administered topically or systemically in burned mice ( Mikus et al., 2001 ). Characteristic wound presentation at one week after injury, grossly, the poor healing in the untreated control or mice treated with vehicle only ( c (black letter) ) was completely reversed in BPC 157 cream–treated mice ( b (black letter) ) (1 μg/g neutral cream thin layer once time daily). Likewise, BPC 157 mice exhibited an increased breaking strength and relative elongation of burned skin and reduced water content in burned skin. Contrarily, silver sulfadiazine regimen did not achieve these healing effects. Microscopically (lower) , at the postinjury day 3, in control mice, the burned area exhibits severe edema in the dermis and subcutis as well as an exudate with abundant edematous fluid on the surface (white arrow). Coagulated blood vessel walls and a proportion of vessels with fibrin clots (dashed white arrow) (HE, x4 ( c ), x10 ( C )). Contrarily, BPC 157 mice have much less pronounced edema (black arrow), weak cellular infiltrate, and exudate, and the blood vessels walls seem to be more preserved (dashed black arrow) and in more vessels, endothelial cell can be observed. Almost no arterial clots (HE, x4 ( b ), x10 ( B )) were observed.

To find out a specific mechanism, a comparison with the becaplermin (recombinant human platelet–derived growth factor homodimer of B chains, PDGF-BB) was the focus of the two additional studies using excisional wounds in diabetic rats and mice ( Figure 2 ) ( Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ). Increased expression of the immediate response gene, early growth response gene-1 (egr-1), was shown in Caco-2 cells in vitro ( Tkalcevic et al., 2007 ). These studies, even in diabetic conditions ( Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ), revealed increased stimulation of early collagen organization in BPC 157 therapy. Importantly, BPC 157, but not PDGF-BB, stimulated earlier maturation of granulation tissue, soluble collagen concentration in the exudates (using sponge implantation), and organized collagen significantly more in wounds (i.e., on day 12 after daily treatment) ( Tkalcevic et al., 2007 ). As a rationale, the study proposed the evidence that stimulation of the Caco-2 cells with 10–100 μM BPC 157 resulted in an earlier, reproducible stimulation of the expression of mRNA for egr-1, with a peak after 15 min. The peak expression of mRNA for the egr-1 co-repressor, nerve growth factor 1-A binding protein-2 (nab2), was observed 30 min after BPC 157 stimulation ( Tkalcevic et al., 2007 ). This favors the possible controlling role of the BPC 157. Namely, we should consider egr-1 gene both positive and negative association. The beneficial significance of the egr-1 gene implies the healing process (i.e., trans-activation of many cognate target genes in healing tissue, including growth factors and cytokines ( Braddock et al., 1999 ; Braddock, 2001 ), the transcription of other genes, including those for collagen II (α1) and PDGF ( Alexander et al., 2002 ). Likewise, there is its negative association (i.e., elevated egr-1 levels associated with cardiovascular pathobiology ( Khachigian, 2006 ) or cholestatic liver injury ( Kim et al., 2006 ; Zhang et al., 2011 ). It may be that BPC 157 rapid activation of the egr-1 and its co-repressor, nab2, means an essential operating healing BPC 157 feedback axis controlling egr-1 levels along with nab2.

FIGURE 2 . Excisional wound in diabetic rats (0, 1) and in rats with ligation of the right iliac artery and vein (2) (upper) and BPC 157 therapy (lower) . At 3 days before wounding, alloxan (300 mg/kg sc), thin layer of the BPC 157 cream (1 µg/1 g neutral cream) (white number), or neutral cream (black number) was immediately given upon wounding ( 0, 0 ). Advanced wound healing presentation at 24 h in BPC 157 rats ( 1, white ), but not in controls ( 1, black ). Likewise, advanced healing in the rats with ligated right iliac arteries and veins, when ingested BPC 157 through drinking water (10 μg/kg, 10 ng/kg, 0.16 μg/ml, 0.16 ng/ml, and 12 ml/rat/day) at postsurgery day 4 ( 2, white ), but not in controls ( 2, black ).

Finally, BPC 157 administration cured the alkali burn-induced skin injury ( Huang et al., 2015 ). There were faster granulation tissue formation, re-epithelialization, dermal remodeling, and collagen deposition through extracellular signal–regulated kinases (ERK)1/2 signaling pathway as well as its downstream targets, including c-Fos, c-Jun, and egr-1. Likewise, there is greater proliferation of human umbilical vein endothelial cells (HUVECs), significantly promoted migration of HUVECs (transwell assay), and the upregulated expression of VEGF-a, and accelerated vascular tube formation in vitro ( Huang et al., 2015 ).

Finally, this effect is apparently not species specific, and it was seen in the bigger animals as well. A similar finding (i.e., rehabilitation of skin wound and maturation of granulation tissue markedly promoted by BPC 157) was obtained in small-type pigs ( Xue et al., 2004a ). Note, the same group also reported a therapy with a prominent beneficial effect on various stomach lesions after administration of BPC 157 ( Xue et al., 2004b ).

Practical Application as Support

The evidence reported for the BPC 157 is the effectiveness with peptide given alone ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Contrarily, when there is a peptide carrier, far more investigated and commonly implied angiogenic standard growth factors in the growth factor healing concept ( Tarnawski and Ahluwalia, 2012 ; Deng et al., 2013 ) have several limitations (i.e., local application, carrier addition, and weak and uncertain peptide activity of its own ( Seiwerth et al., 2018 )), delaying practical realization of the growth factor healing concept.

Illustratively, in the mentioned laser-wound studies, human albumin solder supplemented with transforming growth factor (TGF)-β1 only, but not with HB-EGF or bFGF, increased the early postoperative strength of laser-welded wounds ( Poppas et al., 1996 ), even though the superpulsed CO 2 laser enhanced fibroblast replication and appeared to stimulate bFGF and inhibit TGF-β1 secretion ( Nowak et al., 2000 ). Likewise, an essential problem with regard to the active (and effective) peptide is the continuous search for new delivery systems and new carriers, and new carriers and delivery systems together, with all standard angiogenic growth factors to improve their efficacy, although they are very extensive and highly sophisticated (for review, see Saghazadeh et al., 2018 ; Jee et al., 2019 ). Obviously, it may be unclear which one of the parts of peptide + carrier complex would be responsible for the activity (for review, see Urist, 1996 ). Thereby, this pitfall (i.e., the more carriers, the less own peptide activity) is commonly not considered ( Saghazadeh et al., 2018 ; Jee et al., 2019 ), despite the fact it is recognized ( Urist, 1996 ), and eventually jeopardizes the conclusions about these peptide activities and significance ( Tarnawski and Ahluwalia, 2012 ; Deng et al., 2013 ). Obviously, the effects of one growth factor could be not unified when obtained with addition (and help) of different carriers ( Seiwerth et al., 2018 ), and regardless given highly sophisticated evidence ( Tarnawski and Ahluwalia, 2012 ; Deng et al., 2013 ), they could make the erroneous conclusions. Thus, it may be that ignoring these attribution problems jeopardizes the current growth factor healing concept ( Tarnawski and Ahluwalia, 2012 ; Deng et al., 2013 ) since the needed certainty that the full healing evidence was correctly ascribed to the given peptid, is obviously lacking. For example, FGF studies in 1990s ( Damien et al., 1993 ; Thorén and Aspenberg, 1993 ; Siegall et al., 1994 ; Walter et al., 1996 ; Wang and Aspenberg, 1996 ; Yu et al., 1998 ; Tabata et al., 1999 ) are illustrative for the pertinence of the poorly resolved problem, illustrative for the diversity of the carriers (i.e., hyaluronate gel carrier ( Wang and Aspengberg, 1996 ), alginate/heparin–sacharose microspheres and films ( Yu et al., 1998 ), cellulose gel ( Thorén and Aspenberg, 1993 ), defective form of Pseudomonas exotoxin ( Siegall et al., 1994 ), fibrin adhesive carrier ( Walter et al., 1996 ), biodegredable hydrogen gelatin ( Tabata et al., 1999 ), natural coral, and collagen ( Damien et al., 1993 )). Obviously, as indicated ( Sikiric et al., 2018 ), there is an inescapable diversity of the carriers and thereby, an evident diversity of the obtained beneficial effects, and disable conclusion. Likewise, for bone morphogenic proteins (BMPs), at that time, besides bone matrix, the following biomaterials have been tested as carriers: calcium phosphate, collagen, gelatin, and starch ( Miyamoto et al., 1992 ; Gao et al., 1993 ; Katoh et al., 1993 ; Kawai et al., 1993 ; Cook et al., 1994 ; Kato et al., 1995 ; Kawakami et al., 1997 ). Some carriers (true ceramics and pure titanium) remain in the bone tissue, whereas others (collagen and synthetic polymers) are absorbed. Some are absorbed so quickly that there is no enough time for a population of host cells to gather ( Kawakami et al., 1997 ). Finally, the statement of Marshall Urist, the BMPs concept founder, about the mechanism of the release from BMP delivery system to mesenchymal cell receptor mechanisms as obscure and under intensive investigation in academic and industrial laboratories ( Urist, 1996 ) is true also nowadays, and it can be generally applied to any of the peptide + carrier complexes.

Contrarily, BPC 157 has a general healing argument as general application protocol. Namely, it is always applied alone ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Unlike other growth factors, which need carrier(s) addition, and are rapidly destroyed in human gastric juice, BPC 157 is native and stable in human gastric juice for more than 24 h ( Sikiric et al., 2018 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). As BPC 157 counteracts lesions in the whole gastrointestinal tract produced by various noxious procedures ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), it may be indeed that it may endogenously maintain gastrointestinal mucosa integrity ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Consequently, BPC 157 may have beneficial activity with the same dose range, and same equipotent routes of application, regardless of injury tested ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Therefore, this could be clearly generalized, and thus, its own effect unmistakably ascribed only to the given peptide (for review, see Seiwerth et al., 2018 ). Besides, as indicated specifically in skin wound healing ( Tkalcevic et al., 2007 ), BPC 157 half-life is long enough to exert a therapeutically stimulating effect on connective tissue growth ( Tkalcevic et al., 2007 ). In sponge exudates, it remains active at the site of wounds for several hours ( Tkalcevic et al., 2007 ).

The generalization of the skin wound healing therapy ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ) as a particular point, will be illustrated with the subsequent successful healing of the various fistulas (thereby, the simultaneous healing of the different tissues) ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ) (see Fistula Healing as Support ). Next, its particular therapeutic result on wound healing is decreased bleeding ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ), and during wounding and recovery, all four major events in clot formation and dissolution were accomplished ( Stupnisek et al., 2012 ). This was illustrated in the therapy of the bleeding disorders ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ) (see Therapy of Bleeding Disorders as Support ).

Fistula Healing as Support

BPC 157 application successfully cured various fistulas ( Sikiric et al., 2020a ). Anastomoses between two defects in the corresponding tissues (i.e., in esophagus and skin ( Cesarec et al., 2013 ), stomach and skin ( Skorjanec et al., 2009 ), duodenum and skin ( Skorjanec et al., 2015 ), colon and skin ( Klicek et al., 2008 ), colon and bladder ( Grgic et al., 2016 ), and rectum and vagina ( Baric et al., 2016 )) depict the various fistulas ( Sikiric et al., 2020a ). Likewise, these defects of the controlled size may fairly illustrate accelerated or enabled healing (i. e., closure) and wound/gastrointestinal ulcer relation ( Sikiric et al., 2020a ).

Of note, the methodology of this healing evidence ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ) may contrast with the miscellaneous underlying fistula causes, various origin and location and different occurrences ( Orangio, 2010 ; Visschers et al., 2012 ; Tonolini and Magistrelli, 2017 ). Likewise, this approach may contrast with therapeutic tactics for fistulas, which depend on their location and severity of occurrence ( Orangio, 2010 ; Visschers et al., 2012 ; Tonolini and Magistrelli, 2017 ). Also, it opposes the nowadays aggressive wound management if it considers in fistulas healing mostly local skin protection ( Orangio, 2010 ; Visschers et al., 2012 ; Tonolini and Magistrelli, 2017 ). On the other hand, this healing evidence as such ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ) may accommodate and resolve the mentioned fistula diversity ( Orangio, 2010 ; Visschers et al., 2012 ; Tonolini and Magistrelli, 2017 ) as a common healing denominator providing simultaneous healing of different tissues.

Consequently, we hold fistulas commonality ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ) and thereby, the revealing common resolution ( Sikiric et al., 2020a ). There are two different tissues simultaneously affected and a healing process that would organize synchronized healing ( Sikiric et al., 2020a ). Thus, the main implication of the fistula healing model as wounds with abnormal connections is the verification of the effectiveness of the skin wound healing as understood with BPC 157 effects in the skin wound models ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ). That healing may be smoothly generalized simultaneously to the other tissues ( Figure 3 ), and this particular balanced modulatory action may have the general significance, with the eventual healing of the affected tissues ( Figure 4 ) ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). Otherwise, the healing of the different tissues, which are normally not connected, would hardly provide a simultaneous wound healing effect, particularly in the most critical circumstances ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). Note that due to the relative small size of the rats, rat fistulas regularly appeared as large and complex, and thereby, in this respect, corresponded to the worst presentation in the patients ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). Harmful disturbances and poor healing of rectovaginal fistulas in patients ( Baric et al., 2016 ) may occur also in rats (i.e., fecal leaking through the vagina). Rats could not endure more than 4 days with esophagocutaneous fistulas ( Cesarec et al., 2013 ). However, with BPC 157 therapy, both skin and esophageal defect may be closed without mortality ( Cesarec et al., 2013 ). Thereby, that healing in rat fistulas in these experiments should be highly relevant ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). Obviously, a distinctive correlation follows with the major systems generally involved in the healing processes ( Sikiric et al., 2020a ).

FIGURE 3 . Tracheocutaneous fistulas and BPC 157 therapy. After injury induction, BPC 157 dissolved in saline (10 μg, 10 ng/kg body weight) given per-orally in drinking water till the sacrifice (0.16 μg/ml, 0.16 ng/ml, and 12 ml/day/rat). At postsurgery day 7, fistula closure, closed tracheal defect, and closed skin defect ( B, b ) (arrow) were observed in BPC 157 rats. Contrarily, in controls, fistula remained open, fistulous channel was formed in the skin, and open tracheal defects were observed ( C, c ) (arrow) (HE, x4).

FIGURE 4 . BPC 157 and fistulas closing. External (A–D) and internal (E, F) fistulas. External fistulas. (A) Persistent esophagocutaneous fistula and BPC 157 therapy effect. BPC 157 was given per-orally, in drinking water (10 μg/kg, 10 ng/kg, i.e., 0.16 μg/ml, 0.16 ng/ml, 12 ml/rat/day) until sacrifice, or intraperitoneally (10 μg/kg, 10 ng/kg) with first application at 30 min after surgery, last at 24 h before sacrifice. To establish NO-system involvement, L -NAME (5 mg/kg i.p.) (worsening) and/or L -arginine (100 mg/kg i.p.) (beneficial effect) were given alone or together; first application at 30 min after surgery, last at 24 h before sacrifice. BPC 157 (10 μg/kg, i.p. or p.o.) given with L -NAME (5 mg/kg i.p.) and/or L -arginine (100 mg/kg i.p.) and it maintained its original beneficial effect. A closely interrelated process of unhealed skin, esophageal defects, unhealed fistulas (upregulated eNOS, iNOS, and COX2 mRNA levels), usually lethal, particularly NO-system–related and therapy dependent, illustrate a largely open skin defect in controls at day 3 ( c ) and a closed skin defect in BPC 157 rats ( b ) ( Ceserec et al., 2013 ). (B ) Initial presentation of the persistent gastrocutaneous fistula and BPC 157 therapy effect. Huge gastrocutaneous fistula leaking at 1st postoperative day in control rats ( c ) and dried fistula without any leakage in BPC 157 rats ( b ( Skorjanec et al., 2009 ). The rats received pentadecapeptide BPC 157 (0.16 μg/ml) in drinking water (12 ml/rat) until sacrifice or drinking water only. A comparative study of the BPC 157 beneficial effect was done with intraperitoneal application, once daily, intraperitoneally (per kg body weight) 10 μg, 10 ng, or 10 pg BPC 157, while standard agents 10 mg atropine, 50 mg ranitidine, and 50 mg omeprazole provide only a weak effect. 6-alpha-methylprednisolone (1 mg/kg intraperitoneally, once daily) was given alone which produced a considerable worsening and was completely eliminated with coadministration of BPC 157 10 μg/kg intraperitoneally. (C) Persistent duodenocutaneous fistula and BPC 157 therapy effect. BPC 157 was given per-orally, in drinking water (10 μg/kg, 10 ng/kg, i.e., 0.16 μg/ml, 0.16 ng/ml, and 12 ml/rat/day) till sacrifice, or alternatively, 10 μg/kg and 10 ng/kg intraperitoneally; first application at 30 min after surgery, last at 24 h before sacrifice. To establish a connection with the NO-system, l -NAME (5 mg/kg intraperitoneally) (worsening) and/or L -arginine (100 mg/kg intraperitoneally) (beneficial effect) were given alone or together; first application at 30 min after surgery, last at 24 h before sacrifice. BPC 157 10 μg/kg, intraperitoneally or per-orally, was given with l -NAME (5 mg/kg intraperitoneally) and/or L -arginine (100 mg/kg intraperitoneally) and it maintained its original beneficial effect. Controls simultaneously received an equivolume of saline (5.0 ml/kg intraperitoneally) or water only. Duodenal fistula leaking through skin defect and still open duodenal defect at 2 weeks following fistula creation by anastomosis between the skin and duodenum defect ( c ). Closed both skin and duodenal defect in BPC 157 rats (fistula closed, b ) ( Skorjanec et al., 2015 ). (D) Persistent colocutaneous fistula and BPC 157 therapy effect. BPC 157 accelerated parenterally or per-orally the healing of colonic and skin defect, leading to the suitable closure of the fistula, macro/microscopically, biomechanically, and functionally (larger water volume sustained without fistula leaking) ( Klicek et al., 2013 ). In anesthetized rats, we created the colocutaneous fistula at 5 cm from the anus, colon defect of 5 mm, and skin defect of 5 mm. The rats received pentadecapeptide BPC 157 (0.16 μg/ml) or nothing in the drinking water (12.0 ml/rat) until the sacrifice or once daily, intraperitoneally BPC 157 10.0 μg/kg, 10.0 ng/kg, or saline (5.0 ml/kg b.w.); first application at 30 min after surgery, final 24 h before sacrifice. For comparison, sulfasalazine (50 mg/kg intraperitoneally, once daily) (moderately effective) or 6-α-methylprednisolone (1.0 mg/kg intraperitoneally, once daily) (aggravation) was given. To establish connection with the NO-system, L -NAME (5.0 mg/kg) (worsening) and L -arginine (200.0 mg/kg) (effective only with blunted NO-synthesis, but not alone) were given intraperitoneally alone or in combination ( d -arginine 200.0 mg/kg was not effective, data not shown). BPC 157 given with NO-agents, which maintained its original effect. Initial colon defect presentation at 4 weeks following fistula creation by anastomosis between the skin and colon defect (c, middle). Presentation after next 2 weeks ( c, b ): in control rats, drinking water was continuously given (12 ml/day/rat) (defecation through fistula, c ) and in BPC 157 rats, BPC 157 (10 μg/kg/day) was given in drinking water (0.16 μg/ml/day/rat) (fistula closed, b ). Internal fistulas. (E) Persistent colovesical fistula and BPC 157 therapy effect. With internal fistulas in the colon and the bladder, with BPC 157 therapy, the colon and bladder defects showed simultaneous healing effects, including closing of the colovesical fistula in a matching healing process ( Grgic et al., 2016 ). BPC 157 was given per-orally in drinking water (10 μg/kg, 12 ml/rat/day) until sacrifice, or 10 μg/kg or 10 ng/kg was given intraperitoneally once daily, with the first application at 30 min after surgery and the last application at 24 h before sacrifice. The controls simultaneously received an equivolume of saline (5.0 ml/kg ip) or water only (12 ml/rat/day). At postoperative day 28, voiding through fistula in controls (fecaluria) ( c ) and a normal voiding in BPC 157-rats ( b ). (F) Persistent rectovaginal fistula and BPC 157 therapy effect. We suggest BPC 157 healing of the rats’ rectovaginal fistulas (since spontaneous only poor healing as those in humans) as a realization of the internal fistula-healing concept, an efficient “wound-healing capability” as the therapy of the complicated internal fistula healing. BPC 157 was given per-orally, in drinking water (10 μg/kg or 10 ng/kg, 0.16 μg/ml, or 0.16 ng/ml 12 ml/rat/day) till sacrifice, or alternatively, 10 μg/kg and 10 ng/kg intraperitoneally once daily; first application at 30 min after surgery, last at 24 h before sacrifice. Controls simultaneously received an equivolume of saline (5.0 ml/kg ip) or water only (12 ml/rat/day). At postoperative day 21, defecation through vagina in controls ( c ) and a normal defecation in BPC 157 rats ( b ) ( Baric et al., 2016 ).

Basically, closure of fistulas may be a measure of particular agent’s capacity to cure, at the same time, the skin wound and other corresponding tissues’ wound ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). The healing of the skin and colon defect, as colocutaneous fistulas, stable gastric pentadecapeptide BPC 157, and the therapy regimens (per-oral, in drinking water; or intraperitoneal (once time daily) for 28 days) may serve as a prototype (for review, see Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ).

Also, a similar protocol was successful in the therapy of the other fistulas, that is, gastrocutaneous ( Skorjanec et al., 2009 ), esophagocutaneous ( Cesarec et al., 2013 ), duodenocutaneous ( Skorjanec et al., 2015 ), vesicovaginal ( Grgic et al., 2016 ), and rectovaginal ( Baric et al., 2016 ) in rats. Noteworthy, as shown in separate studies, BPC 157 counteracts the known lesions in the skin ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ), stomach ( Sikiric et al., 1997a ; Petek et al., 1999 ; Mikus et al., 2001 ; Xue et al., 2004b ; Becejac et al., 2018 ; Ilic et al., 2009 ; Ilic et al., 2011a ), duodenum ( Sikiric et al., 1994 ; Sikiric et al., 1997b ; Sikiric et al., 2001 ; Bedekovic et al., 2003 ; Amic et al., 2018 ), esophagus ( Sikiric et al., 1999b ; Petrovic et al., 2006 ; Dobric et al., 2007 ; Djakovic et al., 2016 ), colon ( Sikiric et al., 2001 ; Klicek et al., 2013 ), rectum ( Sikiric et al., 2001 ; Klicek et al., 2013 ), bladder ( Sucic et al., 2019 ), and vagina ( Jandric et al., 2013 ), whereas the fistula studies show an additional combining healing effect, providing different combinations of the lesions that were simultaneously included ( Figures 3 , 4 ), thereby a proof of the concept for a quite general healing effect ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ). A particular relationship was established with the NO-system, and the advantage of the BPC 157 over the corresponding standard agents (i.e., corticosteroids, sulfasalazine, H2 blockers, anticholinergics, and proton pump inhibitors) which showed only weak, if any, effect on these fistulas closing ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a ).

Gastrocutaneous ( Skorjanec et al., 2009 ) and/or duodenocutaneous ( Skorjanec et al., 2015 ) fistulas, as persistent lesions, are another instructive prototype of the “two-ways” model. Often, the peptic ulcers’ inability to heal is taken as analogous to the chronic skin wound inability to heal; thus, resistant peptic ulcers equal to resistant chronic skin ulcers, both unable to heal ( Skorjanec et al., 2009 ). Contrary to the use of the gastrocutaneous fistula for the secretory studies only ( Skorjanec et al., 2009 ), the wound/gastrointestinal ulcer relation of these gastrocutaneous fistulas healing exemplifies the reported particular “self-controlling healing system” ( Skorjanec et al., 2009 ). Only the simultaneous healing of the skin defect and the stomach defect would lead to the fistula closure ( Skorjanec et al., 2009 ). Since classic models are not combined, gastric/duodenal ulcer models ( Selye and Szabo, 1973 ; Robert, 1979 ; Okabe and Amagase, 2005 ) would define agents’ action. Likewise, skin defect models ( Rantfors and Cassuto, 2003 ; Numata et al., 2006 ; Rao et al., 2007 ) would explain agents’ action (“one-way” model). Thus, there is a practical advantage of the composed effects of the administered agents, and the gastrocutaneous fistulas as a combined (“two-ways”) model. For example, for mutual definition (model → agent; agent → model), there are prostaglandins analogues—ethanol model ( Robert, 1979 ) relationships, NSAIDs—acetic acid model ( Okabe and Amagase, 2005 ) relationships, dopamine agonists—cysteamine model ( Selye and Szabo, 1973 ) relationships, and H 2 blockers—cysteamine model ( Selye and Szabo, 1973 ) relationships. Thereby, studies of gastrocutaneous fistulas ( Skorjanec et al., 2009 ) may resolve in the wound/gastrointestinal ulcer relation. This may be the improvement or aggravation that tested agents can exhibit of healing. This may be healing of the skin or gastric wound, or both, or neither of them, simultaneously or not. This may identify the so-called parallel or non-parallel healing actions, with the final end result, positive (fistula closing) or negative (fistula remains open) ( Skorjanec et al., 2009 ). Besides, BPC 157 promptly ameliorates both skin and stomach mucosa healing and induces closure of fistulas, with no leakage after up to 20 ml water intragastrically, including also counteraction of 6-alpha-methylprednisolone aggravation ( Skorjanec et al., 2009 ).

Therapy of Bleeding Disorders as Support

The BPC 157 therapy of the bleeding disorders can be considered as an implementation and support of its wound healing effect ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ) that can be purposefully extended ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ). This particular balanced modulatory action in wound healing, which rapidly appears, along with this pentadecapeptide particular characteristics, may be even more interesting and more effective to be demonstrated in relation that in wounding, it decreases the bleeding. Namely, as curing of the wounds includes resolution of vessel constriction, the primary platelet plug, the secondary plug, and resolution of the clot ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ) stabilize gastric pentadecapeptide BPC 157, which is effective in wound healing ( Figures 1 – 6 ) ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ); it also counteracts the bleeding disorders, amputation, organ perforation, and/or anti-coagulants application or major vessel occlusion ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). This reversal was seen also on the background of the disturbed prostaglandins- and NO-systems, prostaglandins synthesis inhibition as well as NO-overstimulation (NOS-substrate L-arginine) or NO-blockade (N(G)-nitro- L -arginine methyl ester ( L -NAME)) ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ). This should be taken along with its endothelium maintenance as the follow-up of its cytoprotection capability ( Robert, 1979 ; Sikiric et al., 2010 ; Sikiric et al., 2018 ), along with the evidence that pentadecapeptide BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both developing and already formed both arterial thrombosis ( Hrelec et al., 2009 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ), and venous thrombosis ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). This therapy rapidly reversed the hind legs failure after abdominal aorta anastomosis ( Hrelec et al., 2009 ). After occlusion of the inferior caval vein, accordingly, BPC 157 counteracts the whole Virchow triad ( Vukojevic et al., 2018 ) and inferior caval vein syndrome ( Vukojevic et al., 2018 ). At a particular point, venography demonstrated a rapid recruitment of the collaterals to bypass occlusion and reestablish blood flow ( Vukojevic et al., 2018 ). In the rats with infrarenally occluded inferior caval vein, the left ovarian vein is rapidly presented as the major pathway ( Figure 7 ). The other veins (such as epigastric veins, intercostal veins, mammary veins, iliolumbar veins, paraumbilical vein, azygos vein, and right ovarian vein) accordingly appear. Together, this means rapidly activated efficient compensatory pathways and the ligation stop at the inferior caval vein efficiently bypassed ( Vukojevic et al., 2018 ). Both kidneys and canal systems and confluence of the inferior caval vein to the right heart demonstrated that the trapped blood volume is rapidly redistributed ( Vukojevic et al., 2018 ). This commonly occurred with all of the used BPC 157 therapeutic regimens as well as at both early and advanced stages ( Vukojevic et al., 2018 ). There is a similar beneficial effect in the rats with the Pringle maneuver, ischemia, reperfusion, and suprahepatic inferior caval vein occlusion (Budd–Chiari syndrome) ( Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Thus, confronted with major vessels occlusion, BPC 157 commonly alleviates the peripheral vascular occlusion disturbances ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ) rapidly activating alternative bypassing pathways to adequately reestablish the blood flow ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Once the therapeutic effect begun, the therapeutic effect is continuous, and neither of the continuous ligation-induced disturbances reappeared ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Furthermore, direct vein injury, thrombosis, thrombocytopenia, and prolonged bleeding were all counteracted ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Trapped blood volume redistribution rapidly occurred throughout rapid presentation of collaterals ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Venous hypertension and arterial hypotension and tachycardia, rapidly presented, which were collectively attenuated or counteracted, emphasize BPC 157s therapeutic effects ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). All these events mean that the counteraction of the full syndrome occurs ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). This also means the counteracted oxidative stress was as a result of the lysis of endothelial cells ( Vukojevic et al., 2018 ). Counteracted low NO-level in inferior caval vein and particular gene expression (i.e . Egr, Nos, Srf, Vegfr, Akt1, Plcɣ, and Kras ) provide a likely special point to explain how the dysfunction and its counteraction is causal to, or result of ( Vukojevic et al., 2018 ) (see Genes Expression as Support ).

FIGURE 5 . Hematoma formation following tibial diaphysis fracture and BPC 157 therapy effect, in analogy with accomplished all four events (vessel constriction, the primary platelet plug, the secondary plug, and resolution of the clot) that occur in a set order following the loss of vascular integrity ( Stupnisek et al., 2012 ) involved in the wound healing. We suggest BPC 157 healing starting with a rapid formation of the adequate hematoma as a connective scaffold between the stumps. BPC 157 (10 ng/kg) was given as a 1-ml bath to the injury, immediately after injury induction. Controls simultaneously received an equal of saline as a bath to the injury. At 1 min after application, hematoma within fracture gap ( b ) further progressed at 2 min ( B ) in BPC 157 rats. Diffuse bleeding in controls at 1 min ( c ) and 2 min ( C ), weak hematoma formed outside of the fracture gap.

FIGURE 6 . Perforated cecum defect and BPC 157 therapy effect. i . Presentation of the perforated cecum defect ( o -immediately after perforation, before therapy) as an illustration of the rapid healing effect immediately after wounding, with vessels “running” toward the defect augmented by BPC 157 bath application (10 μg/kg) (USB microcamera). b— vessels recruitment presentation immediately under the immersion of the BPC 157 bath, which had been applied at the cecum, and presentation immediately thereafter →b ) with corresponding controls (saline bath 1 ml/rat) presentation c, →c ). ii . Resultant bleeding from the perforated defect ( C (controls), decreased in BPC 157 rats (B). iii . Final failure of the perforated defect healing in controls (C) (postinjury day 7) and completely healed defect in BPC 157 rats (B). This beneficial effect goes along with counteraction of the worsening effect of both NOS-blocker L -NAME (5 mg/kg), or NOS substrate L -arginine (100 mg/kg) (directly applied to the perforated cecum, alone or combined, and spread through the abdominal cavity), and normalization of the increased MDA- and NO-values in the cecum ( Drmic et al., 2018 ).

FIGURE 7 . Venous occlusion and BPC 157 therapy. Given BPC 157 (as an abdominal bath) immediately before venography, at a particular point, venography demonstrated a rapid recruitment of the collaterals to bypass occlusion and reestablish blood flow. In the rats with infrarenally occluded inferior caval vein, venography in the inferior caval vein below the ligation shows that the left ovarian vein is rapidly presented as the major pathway. The other veins (such as epigastric veins, intercostal veins, mammary veins, iliolumbar veins, paraumbilical vein, azygos vein, and right ovarian vein) accordingly appear in BPC 157 rats ( B ), unlike in controls ( C ). Together, this means rapidly activated efficient compensatory pathways and the ligation-stop at the inferior caval vein efficiently bypassed ( Vukojevic et al., 2018 ). Both kidneys and canal systems and confluence of the inferior caval vein to the right heart demonstrated that redistribution of otherwise trapped blood volume was rapidly achieved ( Vukojevic et al., 2018 ). In the rats with occluded superior mesenteric vein, occlusion was made at the end of the superior mesenteric vein. Venography in superior mesenteric vein below the ligation shows that bypassing through inferior anterior pancreaticoduodenal vein and superior anterior pancreaticoduodenal vein to the pyloric vein toward the portal vein rapidly occurs in BPC 157 rats ( b ), unlike failed bypassing presentation in controls with occluded superior mesenteric vein ( c ).

Finally, therapy as the recovering effect it has on occluded vessels ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ) bypassing the occlusion ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ) appears as the specific effect of BPC 157 in ischemia/reperfusion ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). There is benefit in the inferior caval vein occlusion ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ), also in colitis ischemia/reperfusion ( Duzel et al., 2017 ), duodenal venous congestion lesions ( Amic et al., 2018 ), and cecum perforation ( Drmic et al., 2018 ), arising from BPC 157 therapy in addition to the deep vein thrombosis ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Recently, in the bile duct ligation-induced liver cirrhosis ( Sever et al., 2019 ), no portal hypertension development and reversal of the already preexisting portal hypertension to normal values ( Sever et al., 2019 ) have become possible.

Besides, BPC 157 had no effect on clotting parameters as shown in the previous amputation and/or anticoagulant studies ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ; Vukojevic et al., 2018 ), while counteracting prolonged bleeding and thrombocytopenia ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ; Vukojevic et al., 2018 ). Consistently, it was shown that BPC 157 maintains thrombocytes’ function ( Konosic et al., 2019 ).

Here, the concluding evidence may be that BPC 157 counteracted adhesion formation after abdominal wall injury. Additionally, its counteracting effect occurred even with pre-existing adhesions ( Berkopic Cesar et al., 2020 ).

Thus, with the damage of the peritoneum, two damaged peritoneal surfaces come into contact with each other, and the coagulation cascade is activated ( Fortin et al., 2015 ). Contrarily, BPC 157 counteracts the whole Virchow triad ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ), venous thrombosis ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ), and arterial thrombosis ( Hrelec et al., 2009 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Also, BPC 157 administration attenuates prolonged bleeding and thrombocytopenia after amputation, organ perforation, and anticoagulant use or prolonged major vessel occlusion ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ). Consequently, it may be likely that BPC 157 may also interfere with and reverse the process that would result in fusion to form a connection, for example, adhesion ( Berkopic Cesar et al., 2020 ). Therefore, less adhesion formation as well as reversing existing adhesions, the restoration of normal tissue structure and function, suggest that BPC 157 may act with the temporary role of fibrin in healing without adhesions that must be purposefully degraded by the fibrinolytic system ( Collen, 1980 ; Davey and Maher, 2017 ).

Gene Expression as Support

In general, as before ( Vukojevic et al., 2018 ), our focus was on the early and very early periods providing the general understanding of the precise coordination of cellular events, the formation and modification of the vascular system, and molecular signaling by numerous molecules which are responsible for fast activation and modulation of these events ( Vukojevic et al., 2018 ).

For this purpose, the findings obtained in the rats with infrarenal occlusion of the inferior caval vein may be noteworthy ( Vukojevic et al., 2018 ). The investigation was done at two particular intervals, at 1 and 24 h. Assessed were the inferior caval vein (which was occluded), right ovarian vein (which appears as blind vessel due to the infrarenal occlusion), and left ovarian vein (which serves as a bypassing pathway) ( Vukojevic et al., 2018 ). With BPC 157 administration, these beneficial effects were combined with particular specificities with the altered genes’ expression ( Egr, Nos, Srf, Vegr, Plcɣ , and Kras ) or no change ( Akt1 continuously remained unchanged) ( Vukojevic et al., 2018 ).

BPC 157 administration raises several questions regarding its therapeutic role in the process occurring in rats with obstructed vessels ( Sikiric et al., 2014 ; Duzel et al., 2017 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ) and with vessels that used to be obstructed ( Duzel et al., 2017 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ). Rapid endothelial restoration and activation of the major collaterals (in addition, there are abundant anastomoses between individual vessels on both surfaces of the large intestine ( Kachlik, et al., 2010 )) may reorganize blood flow ( Duzel et al., 2017 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Additionally, the rapid therapeutic effect of BPC 157 is evidenced by rapid reversal of the negative chain of events ( Vukojevic et al., 2018 ). This included circumvention of the complex downhill syndrome, as well as a sudden decrease of blood supply, decreased NO levels in the inferior caval vein tissue, an immediate heavy loss of endothelial cells from the vascular wall, a lower eNOS production ability ( Berra-Romani et al., 2013 ), and finally, the elimination of oxidative stress due to endothelial cell lysis ( Rangan and Bulkley, 1993 ; Schiller et al., 1993 ). BPC 157 has been able to restore endothelial integrity and reverse most oxidative stress-induced damage ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ). Moreover, it largely interacts with the NO-system ( Sikiric et al., 2014 ), the endothelium being significant in that demonstrates increased plasma NO-values, but normalized 3,4-methylenedioxyamphetamine (MDA)-values, as well as adequate endothelial NO-synthase (eNOS) system function ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ) and blood supply. After consideration of the aforementioned BPC 157–induced changes, several applications of BPC 157 with respect to its therapeutic effects on rats with preexisting ( Duzel et al., 2017 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ) or existing vessel obstruction ( Sikiric et al., 2014 ; Duzel et al., 2017 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ) can be foreseen.

More specifically, this may be observed with respect to certain genes, including Egr, Nos, Srf, Vegr, Akt1, Plcɣ , and Kras genes ( Vukojevic et al., 2018 ), all of which are responsible for the synthesis of factors necessary for a diverse set of processes. The factors have proadhesive, proinflammatory, and prothromobic roles, all of which become pertinent after vascular injury ( Schweighofer et al., 2007 ; Ansari et al., 2015 ; Hinterseher et al., 2015 ). In these, the described BPC 157 efficacy is considered as an important demonstration of the confirmation that BPC 157 could ensure a particular specificity within the Egr, Nos, Srf, Vegfr, Akt1, Plcɣ , and Kras pathways ( Vukojevic et al., 2018 ). After administering BPC 157 to rats with a ligated inferior caval vein, the beneficial effects induced by BPC 157 were complemented with altered Egr, Nos, Srf, Vegr , and Kras gene expression . Specifically, this included increased ( Egr, Nos, Srf, and Kras ) or decreased ( Egr, Vegfr, and Plcɣ ) gene expression, while Akt1 gene expression remained unchanged ( Vukojevic et al., 2018 ). These changes in gene expression are dependent on the time interval during which the genes were analyzed, as well as the type of vessel investigated. For example, increased levels of the Egr gene were observed at 1 h, Nos , Srf , and Kras genes demonstrated increased expression at 1 and 24 h in all vessels, and Egr expression was increased at 24 h in both ovarian veins. Likewise, decreased gene expression of Egr was evident at 24 h in the inferior caval vein, Vegfr expression was decreased at 1 h and 24 h in all vessels, and Plcɣ gene expression was decreased at 24 h in the inferior caval vein. Akt1 remained unchanged in the inferior caval vein, as well as in the right ovarian vein and left ovarian vein ( Vukojevic et al., 2018 ). Consequently, the aforementioned data suggest that particular pathways may have both local and systemic relevance. Collectively, these pathways may be responsible for the novel balance (of gene expression) achieved and ultimately, maintained. Finally, we should emphasize the rapid presentation of all of these effects. Obviously, they occurred before the initiation of angiogenesis ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Thus, we can assume that pathways additional to those involved in angiogenesis ( Vukojevic et al., 2018 ) are associated with the increased expression, internalization of VEGFR2, and the activation of the VEGFR2-Akt-eNOS signaling pathway ( Hsieh et al., 2017 ).

Furthermore, we additionally challenged the most immediate period after injury induction (skin defect) (i.e., 2, 5, and 10 min) ( Figure 8 ) due to the evidence that BPC 157 did ensure a particular specificity within the pathways (at least, Egr, Nos, Srf, Vegr, Akt1, Plcɣ , and Kras genes) ( Vukojevic et al., 2018 ). We emphasize the immediate relationship of the pentadecapeptide BPC 157 with the genes involved in cellular signaling pathways important for the regulation of angiogenesis. That point is supported with the extensive gene expression analysis. With the therapy done immediately after wounding, we performed the Akt1, Braf, Egfr, Egr1, Grb2, Hdac7, Kras, Mapk1, Mapk3, Mapk14, Nos3, Pik3cd, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf , and Vegfa genes expression analysis in the rats’ excision wounds, in the skin, and subcutaneous tissue, done at 2, 5, and 10 min following BPC 157 application ( Figure 8 ). Thus, considering the quite rapid presentation of the beneficial effect of BPC 157 in wound healing, it is likely indicative that the expression of all of the genes Akt1, Braf, Egfr, Egr1, Grb2, Hdac7, Kras, Mapk1, Mapk3, Mapk14, Nos3, Pik3cd, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa is increased at the 10-min interval. An additional indicative point is sequential involvement. The increased expression of the Akt1, Grb2, Nos3, Pik3cd, Prkcg, Ptk2, and Src appears immediately at 2-min interval. Increased expression of Braf, Egfr, Egr1, Hdac7, Mapk1, Mapk3, Mapk14, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa is noted at 5 min. The increased expression of the Kras appears at 10 min. Of note, an enormous number of the interactions between the genes involved obscure the final outcome. However, the evidence is obtained that BPC 157 action initially affects expression of particular genes (i.e., Akt1, Grb2, Nos3, Pik3cd, Prkcg, Ptk2, and Src ). Then, it involves other set of the genes ( Braf, Egfr, Egr1, Hdac7, Mapk1, Mapk3, Mapk14, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa ). Subsequently, it concludes with additional set of genes (i.e., Kras ). Together, these may likely represent the complex way of how the action, which will eventually resolve the lesion, may start and progress.

FIGURE 8 . Gene expression analysis and BPC 157 therapy. With the therapy done immediately after wounding, we performed the Akt1, Braf, Egfr, Egr1, Grb2, Hdac7, Kras, Mapk1, Mapk3, Mapk14, Nos3, Pik3cd, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf , and Vegfa genes expression analysis (○, no significant change in gene expression; ▲, increased gene expression) in the rats’ excision wound and in the skin and subcutaneous tissue, done at 2, 5, and 10 min following BPC 157 application. Thus, considering the quite rapid presentation of the BPC 157 beneficial effect in the wound healing, it is likely indicative that the expression of all of the genes Akt1, Braf, Egfr, Egr1, Grb2, Hdac7, Kras, Mapk1, Mapk3, Mapk14, Nos3, Pik3cd, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa is increased at the 10-min interval. An additional indicative point is sequential involvement. The increased expression of the Akt1, Grb2, Nos3, Pik3cd, Prkcg, Ptk2, and Src appears immediately at 2-min interval. Braf, Egfr, Egr1, Hdac7, Mapk1, Mapk3, Mapk14, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa increased expression is noted at 5 min. The increased expression of the Kras appears at 10 min. Of note, an enormous number of the interactions between the genes involved prevents a more definitive understanding of function insight outcome. However, the evidence is obtained that BPC 157 action initially affects expression of particular genes (i.e., Akt1, Grb2, Nos3, Pik3cd, Prkcg, Ptk2, Src ). Then, it involves other set of the genes ( Braf, Egfr, Egr1, Hdac7, Mapk1, Mapk3, Mapk14, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa ). Subsequently, it concludes with additional genes set (i.e., Kras ). Together, these may likely represent the complex way how the action, which will eventually resolve the lesion, may start and progress.

The Effect on Other Tissues Healing as Support

Defining of the adequate skin wound healing effect ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ) indicates its essential application in the other tissues healing, particularly, the muscle ( Figures 9 – 12 ), tendon ( Figure 12 ), ligament, and bone ( Figure 13 ) ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Especially, BPC 157 exhibits both special muscle healing (i.e., after transection of major muscle ( Figures 9 , 11 , 12 ), crush ( Figure 10 ), and denervation ( Figure 11 ) ( Staresinic et al., 2006 ; Novinscak et al., 2008 ; Mihovil et al., 2009 ; Pevec et al., 2010 )), and tendon healing ( Staresinic et al., 2003 ; Krivic et al., 2006 ; Krivic et al., 2008 ) (i.e., after the Achilles tendon transection and detachment from calcaneal bone), or ligament healing ( Cerovecki et al., 2010 ) (i.e., medial collateral ligament transection). In addition, along with function recovery ( Figure 11 ), BPC 157 counteracts muscle disability related to various noxious procedures, after abdominal aorta anastomosis ( Hrelec et al., 2009 ), L2-L3 compression ( Perovic et al., 2019 ), severe electrolytes disturbances ( Baric et al., 2016 ; Medvidovic-Grubisic et al., 2017 ), application of the succinylcholine ( Stambolija et al., 2016 ), neuroleptics ( Jelovac et al., 1999 ; Belosic Halle et al., 2017 ), or neurotoxin (MPTP, cuprizone) ( Sikiric et al., 1999c ; Klicek et al., 2013 ). Also, BPC 157 counteracts tumor cachexia ( Kang et al., 2018 ). There are counteracted muscle wasting, significantly corrected deranged muscle proliferation as well as myogenesis, counteracted increase of the proinflammatory cytokines such as IL-6 and TNF-α, looking at muscle metabolism relevant to cancer cachexia as well as the changes in the expression of FoxO3a, p-AKT, p-mTOR, and P-GSK-3β ( Kang et al., 2018 ). To illustrate the success of the application and the way of application efficacy, it may be instructive to mention the noted effect in the recovery of the transected sciatic nerve injury (providing the efficacy of the once intraperitoneal, intragastric application much like the application into the tube with inserted nerve stumps) ( Gjurasin et al., 2010 ). In support, recently BPC 157 increased the survival rate of cultured enteric neurons and the proliferation rate of cultured enteric glial cells ( Wang et al., 2019 ).

FIGURE 9 . (Left , 14 days) (right , 28 days). Transected muscle and BPC 157 therapy ( Staresinic et al., 2006 ). Quadriceps muscle was completely transected transversely 1.0 cm proximal to the patella means a definitive defect that cannot be compensated in rat. BPC 157 (10 μg, 10 ng, and 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. Throughout the whole 72-day period, BPC 157 consistently improves all muscle-healing parameters (biomechanic, function, macro/microscopy/immunochemistry, finally presentation close to normal non-injured muscle, and no postsurgery leg contracture). Controls exhibit stumps grossly weakly connected ( C ), at postsurgery day 14 and 28, microscopically (HE, x10), at postsurgery day 14, gap filled with fibrous tissue (white arrow) ( c ), and at postsurgery day 28, a gap filled with fat tissue (dashed white arrow); incorporating few collagen strands is interposed between the transection stumps and unsuccessful attempts of muscle fibers to cross the gap can be observed ( c ). Contrarily, BPC 157 rats exhibit stumps grossly well connected, approaching to presentation of the normal non-injured muscle ( B ), microscopically, at postsurgery day 14 and at postsurgery day 28, broad muscle (black arrow) fibers connecting the stumps, while the fat tissue is much less present ( b ) (dashed black arrow).

FIGURE 10 . Muscle crush injury and BPC 157 therapy ( Novinscak et al., 2008 ; Pevec et al., 2010 ). Force delivered was of 0.727 Ns/cm 2 (impulse force 0.4653 Ns, kinetic energy 0.7217 J), to a maximum diameter of gastrocnemius muscle complex (GMC), about 2 cm proximal to the insertion of the Achilles tendon. Regimens with similar effectiveness included (i) BPC 157 dissolved in saline (10 μg, 10 ng/kg body weight), (ii) pentadecapeptide BPC 157 in neutral cream (1.0 or 0.01 μg dissolved in distilled water/g commercial neutral cream). Controls received saline (5.0 ml/kg) applied intraperitoneally and or commercial neutral cream applied as a thin cream layer at the site of injury. All animals were treated only once, immediately after injury, if killed and assessed after 2 h. Alternatively, the animals were treated once daily, receiving a final dose 24 h before death and/or assessment (walking, muscle function, and a macroscopic analysis) at days 1, 2, 4, 7, and 14. Gross posttraumatic hematoma presentation at 2 h after injury induction ( C -control (white arrow), B -BPC 157 rats (thin cream layer at the site of the injury immediately after injury induction)). Microscopy assessment ( c1, b1 (postinjury day 4) , c2, b2 (postinjury day 7), and c3, b3 (postinjury day 14)). HE, x10. Controls. Severe atrophy with severe reduction of myocytes (black arrow) and no regeneration attempt, pronounced perimyocytic edema (postinjury day 4, c1 ); scarce to moderate regeneratory attempts in muscle with maturing granulation tissue (dashed black arrow) (postinjury day 7, c2 ); pronounced regeneration with a high number of smaller myocytes and some areas of scarring (postinjury day 14, c3 ). BPC 157. Clearly visible regenerative activity and less edema (postinjury day 4, b1 ); florid regenerative activity in myocytes with high number of relatively small myocytes and no scarring (postinjury day 7, b2 ); well-regenerated myocytes of appropriate size and very little scarring (postinjury day 14, b3 ).

FIGURE 11 . Denervated gracilis muscle and BPC 157 therapy (upper) ( Mihovil et al., 2009 ). Transected muscle induced injured leg function failure as induced leg contracture and BPC 157 therapy (lower) ( Staresinic et al., 2006 ). Presentation of the denervated gracilis muscle ( B, C ) and normal healthy gracilis muscle ( H ) in rats at 1 year after denervation. Characteristic denervated muscle presentation in controls ( C ). Counteraction by BPC 157 (10 μg/kg) therapy given per-orally, in drinking water (0.16 μg/ml, 12 ml/rat/day) till the sacrifice ( B ). Quadriceps muscle was completely transected transversely 1.0 cm proximal to patella to present a definitive defect that cannot be compensated in rats with a considerable injured leg contracture as presented at postsurgery day 21 in controls with maximal leg extension ( c ). Counteraction by various regimens of the BPC 157 (10 μg, 10 ng) therapy. Given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice ( b1 ); per-orally, in drinking water (0.16 μg/ml, 0.16 ng/ml, and 12 ml/rat/day) till the sacrifice ( b2 ); locally, thin layer of neutral cream 1 µg/1 g neutral cream once daily; the first application 30 min post-transection, the final 24 h before sacrifice ( b3 ).

FIGURE 12 . (Left , control), (right , BPC 157). Fibrosis and BPC 157 therapy. Summarized gross evidence. Presentation of the bile duct ligation rats (“yellow rats”) following 4 months of occlusion (as a model of the wound-healing response to chronic liver injury), gross rat presentation (C1), and after sacrifice, yellow ears (C2), and liver presentation (C3) ( Sever et al., 2019 ). Possible analogy goes with the dermal, muscle (proximal and distal stump of quadriceps muscle poorly connected at day 72 after transection ( c )), tendon (gap after tendon detached from calcaneus ( C )) and ligament fibrosis and scar formation, and failed function ( Mikus et al., 2001 ; Krivic et al., 2006 ; Staresinic et al., 2006 ; Cerovecki et al., 2010 ). In rats with bile duct ligation, BPC 157 counteracts cirrhosis and portal hypertension (gross rat presentation (B1), and after sacrifice, normal ears (B2), and liver presentation (B3)) much like it attenuates dermal, muscle (well-formed quadriceps muscle at day 72 after transection ( b ), tendon (tendon reattached to the calcaneous after detachement ( B )), and ligament fibrosis and scar formation, and regained function ( Mikus et al., 2001 ; Krivic et al., 2006 ; Staresinic et al., 2006 ; Cerovecki et al., 2010 ).

FIGURE 13 . Healing of the segmental osteoperiosteal bone defect (0.8 cm, in the middle of the left radius) in rabbits ( Sebecic et al., 1999 ). Incompletely healed defect in all controls (assessed during 6 weeks, in 2-weeks intervals ( c1 (week 2), c2 (week 4), and c3 (week 6)). Pentadecapeptide BPC 157 beneficial effect was consistently obtained (either percutaneously given locally (10 μg/kg) into the bone defect, or applied intramuscularly (intermittently, at postoperative days 7, 9, 14, and 16 at 10 μg/kg) or continuously (once per day, postoperative days 7–21 at 10 microg or 10 ng/kg)) ( b1 (week 2), b2 (week 4), and b3 (week 6)). Comparative regimens included percutaneous administration of autologous bone marrow locally (2 ml, postoperative day 7) as well as an autologous cortical graft inserted in the bone defect immediately after its formation. Saline-treated (2 ml intramuscularly (i.m.) and 2 ml locally into the bone defect), injured animals were used as controls ( Sebecic et al., 1999 ).

In the aforementioned study by Hsieh and collaborators ( Hsieh et al., 2017 ) that focused on the ischemic muscle model (achieved via removal of the femoral artery), the pro-angiogenic effects of BPC 157 are evident, given the increased expression, internalization of vascular endothelial growth factor receptor 2 (VEGFR2), and the activation of the VEGFR2-Akt-eNOS signaling pathway ( Hsieh et al., 2017 ). BPC 157 promotes angiogenesis in the chick choriallantoic membrane (CAM) assay and tube formation assay ( Hsieh et al., 2017 ). Additionally, it counteracts rat hind limb ischemia by accelerating blood flow recovery and vessel number ( Hsieh et al., 2017 ). BPC 157 upregulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157–induced VEGFR2 internalization is combined with VEGFR2-Akt-eNOS activation. Of note, that BPC 157 effect is particular (i.e., activated the phosphorylation of VEGFR2, Akt, and eNOS signaling pathway) and does not need other known ligands or shear stress ( Hsieh et al., 2017 ).

Also, this tissue-specific effect is demonstrated in tendon tissue-specific healing, which occurs without side effects that are present with other peptides ( Seiwerth et al., 2018 ). For instance, ossicle formation in Achilles tendon tissue appears with osteogenic protein 1 (OP-1) ( Forslund and Aspenberg, 1998 ). Contrary to this, it does not induce ossicle formation in tendon or ligament tissue ( Staresinic et al., 2003 ; Krivic et al., 2006 ; Krivic et al., 2008 ). Specifically, BPC 157 accelerates tendon- and ( Staresinic et al., 2003 ; Krivic et al., 2006 ; Krivic et al., 2008 ) ligament-healing ( Cerovecki et al., 2010 ) and has a strong osteogenic effect the in non-union model ( Sebecic et al., 1999 ) (and in other models, such as is observed with rat femoral head osteonecrosis ( Gamulin et al., 2013 ), or alveolar bone loss ( Keremi et al., 2009 ). Of note, in the tendon studies ( Chang et al., 2011 ; Chang et al., 2014 ), BPC 157–induced promotion of the ex vivo outgrowth of tendon fibroblasts from tendon explants, cell survival under stress, and the in vitro migration of tendon fibroblasts are the effects mediated by the activation of the focal adhesion kinase (FAK)–paxillin pathway ( Chang et al., 2011 ; Chang et al., 2014 ). Janus kinase (JAK) 2, the downstream signal pathway of growth hormone receptor, was activated in a time-dependent fashion via stimulation of the BPC 157–treated tendon fibroblasts with a growth hormone ( Chang et al., 2011 ; Chang et al., 2014 ). Thus, the BPC 157–induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferative effect of growth hormone and contribute to tendon healing ( Chang et al., 2011 ; Chang et al., 2014 ).

Similarly, as the next wound-healing focus with BPC 157 therapy ( Sever et al., 2019 ) administered per-orally, continuously in drinking water, or intraperitoneally, alleviated rats showed bile duct ligation (BDL) and counteracted BDL-induced liver cirrhosis ( Sever et al., 2019 ). BPC 157 normalized MDA and NO-levels in the liver of BDL rats ( Sever et al., 2019 ) and wound-healing response to chronic liver injury that may be accordingly modified ( Figure 12 ) ( Albanis and Friedman, 2001 ; Aller et al., 2008 ; Wynn, 2008 ; Sever et al., 2019 ). There were cured jaundice, weight loss, liver enlargement, microscopy (i.e., piecemeal necrosis, focal lytic necrosis, apoptosis and focal inflammation, and disturbed cell proliferation (Ki-67-staining), cytoskeletal structure in the hepatic stellate cell (α-SMA staining), collagen presentation (Mallory staining), and biochemistry presentation ( Sever et al., 2019 ), and counteracted the increased NOS3 expression, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β levels. There were both prophylactic and therapy effects. Developing portal hypertension as well as established portal hypertension were both rapidly counteracted in BDL rats (i.e., BPC 157 per-orally, in drinking water, since the end of week 4) ( Sever et al., 2019 ). The balanced collagen synthesis and counteracted hepatic fibrosis (considered as a model of the wound-healing response to chronic liver injury), are along with BPC 157s particular interaction with several molecular pathways ( Tkalcevic et al., 2007 ; Chang et al., 2011 ; Cesarec et al., 2013 ; Chang et al., 2014 ; Huang et al., 2015 ; Hsieh et al., 2017 ; Kang et al., 2018 ; Vukojevic et al., 2018 ; Sever et al., 2019 ; Park et al., 2020 ; Vukojevic et al., 2020 ). In addition, there is a likely analogy (see for review i.e., ( Seiwerth et al., 2018 )) with the attenuated fibrosis and scar formation in other tissues (i.e., the skin, muscle, tendon, and ligament) ( Mikus et al., 2001 ; Sikiric et al., 2003 ; Staresinic et al., 2003 ; Krivic et al., 2006 ; Staresinic et al., 2006 ; Krivic et al., 2008 ; Cerovecki et al., 2010 ). Also, they regained the dermal, muscle, tendon, and ligament functions ( Mikus et al., 2001 ; Sikiric et al., 2003 ; Staresinic et al., 2003 ; Krivic et al., 2006 ; Staresinic et al., 2006 ; Krivic et al., 2008 ; Cerovecki et al., 2010 ). These, as mentioned before, occur in the BPC 157s healing of the severe injuries, such as the skin burns ( Mikus et al., 2001 ; Sikiric et al., 2003 ) or muscle ( Staresinic et al., 2006 ) or tendon ( Staresinic et al., 2003 ; Krivic et al., 2006 ; Krivic et al., 2008 ) or ligament ( Cerovecki et al., 2010 ) transection.

In this issue, the already mentioned Tkalcevic and collaborators’ study may be illustrative ( Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ). A clear demonstration was obtained that BPC 157 stimulated both the egr-1 gene (critical in proliferation, differentiation, and inflammation during cholestatic liver injury, cytokine and growth factor generation, and early extracellular matrix (collagen) formation) ( Kim et al., 2006 ; Zhang et al., 2011 ) and its co-repressor gene nab2 ( Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ). Consequently, as also indicated in our other liver studies ( Ilic et al., 2009 ; Ilic et al., 2010 ; Ilic et al., 2011a ; Ilic et al., 2011b ), BPC 157 (with nab2) may be a particular feedback-controlling mechanism.

The final point of the wound-healing focus with BPC 157 therapy ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ) belongs to the controlling role of the pentadecapeptide BPC 157, considering that all of the described healing effects should avoid possible harmful outrage.

Illustratively, BPC 157 may interfere with NO-system activities ( Sikiric et al., 2014 ) and counteract harmful events, arising from either NO-blockade ( L -NAME-application) or L -arginine (NOS-substrate-application) ( Sikiric et al., 2014 ). As an indicative example, without its own effect on normal blood pressure, it counteracts L -NAME hypertension as well as L -arginine hypotension ( Sikiric et al., 1997a ). Also, BPC 157 counteracts chronic heart failure ( Lovric Bencic et al., 2004 ) or venous occlusion ( Vukojevic et al., 2018 )–induced hypotension ( Lovric Bencic et al., 2004 ; Vukojevic et al., 2018 ) as well as hyperkalemia-induced hypertension ( Barisic et al., 2013 ). Accordingly, BPC 157 provides the counteraction of the opposite effects of L -NAME (prothrombotic) and L -arginine (antithrombotic) application ( Stupnisek et al., 2015 ). Likewise, BPC 157 may interfere with prostaglandin system activities, that is, it strongly counteracts NSAIDs toxicity ( Sikiric et al., 2013 ), much like it counteracts developing and already formed adjuvant arthritis in rats ( Sikiric et al., 1997c ). Also, it strongly counteracts corticosteroid-induced adverse effects (i.e., eventual healing failure ( Klicek et al., 2008 ; Krivic et al., 2008 ; Skorjanec et al., 2009 ; Pevec et al., 2010 ) and worsening, and immunosuppression ( Sikiric et al., 2003 ).

That controlling point is also recognized in the most recent reviews ( Gwyer et al., 2019 ; Sikiric et al., 2018 ). As indicated, despite the tumor-promoting effects of many growth factors and peptides ( Gwyer et al., 2019 ; Sikiric et al., 2018 ), BPC 157 has been shown to inhibit and counteract uncontrolled cell proliferation (Ki-67 overproduction counteracted) and increased expression of VEGF and subsequent signaling pathways ( Radeljak et al., 2004 ; Sever et al., 2019 ), thus avoiding and directly counteracting VEGF tumorigenesis ( Radeljak et al., 2004 ). Furthermore, as mentioned ( Gwyer et al., 2019 ), BPC 157 inhibits the growth of several tumor lines and can counteract tumor cachexia ( Kang et al., 2018 ), a point combined, as mentioned, with counteracted pro-inflammatory and pro-cachectic cytokines such as IL-6, TNF-α, cancer cachexia–related pathways expression (i.e., FoxO3a, p-AKT, p-mTOR, and P-GSK-3β) ( Kang et al., 2018 ). Also, BPC 157 may counteract cyclophosphamide toxicity ( Luetic et al., 2017 ; Sucic et al., 2019 ), and in particular, BPC 157 consistently decreased elevated MDA values, while MDA itself, owing to its high cytotoxicity and inhibitory action on protective enzymes, is suggested to act as a tumor promoter and a cocarcinogenic agent ( Seven et al., 1999 ; Bakan et al., 2002 ).

Moreover, BPC 157 therapy generated from its distinctive healing effects in various tissues also functions as an eye drops therapy that heals perforating corneal ulcers in rats and rapidly regains corneal transparency ( Figures 14 , 15 ) ( Masnec et al., 2015 ). Epithelial defects completely healed within three or four days (2 µg or 2 ng regimens, respectively), aqueous cells were not present after four or five days after injury. Regularly, in control rats, developed new vessels grew from the limbus to the penetrated area. Contrarily, generally no new vessels grew in BPC 157–treated rats (i.e., those that did form in the limbus did not make contact with the penetrated area) ( Masnec et al., 2015 ), showing that BPC 157 therapy may acknowledge also “the angiogenic privilege” of the corneal avascularity as essential for corneal wound healing ( Tshionyi et al., 2012 ). This may be the clue that to regain the tissue integrity after wounding, BPC 157 may accommodate the healing depending on the tissue and injury conditions.

FIGURE 14 . Corneal ulcer and BPC 157 therapy, ophathalmoscopy and microscopy presentation ( Masnec et al., 2015 ). In deeply anesthetized rats, a penetrant linear 2-mm incision was made and two drops of 0.4% oxybuprocaine topical anesthetic were given (to inhibit possible eyelid reflex) in the paralimbal region of the left cornea at the 5 o’clock position with a 20-gauge MVR incision knife at 45° under an operating microscope. BPC 157 was dissolved in distilled water at 2 pg/ml, 2 ng/ml, and 2 μg/ml, and two eye drops were administered to the left eye in each rat immediately after induction of the injury and then every 8 h up to 120 h; controls received an equal volume of distilled water. Characteristic microscopy presentation (HE, x4) at 48 h after injury induction in control rats was much wider gap, not maturing and abundant granulation tissue, edematous with a lot of fibrin (clot-like) at the surface (white arrow). The surface epithelium is relatively unorganized and progressing over the gap showing a basal cell-like morphology ( C ) (dashed white arrow). In BPC 157–treated animals, the perforation channel is narrow, partly filled with well-vascularized but maturing, non-edematous granulation tissue (black arrow). The superficial epithelium progressing over the gap looks stratified ( B ) (dashed black arrow).

FIGURE 15 . Total debridement of corneal epithelium and BPC 157 therapy ( Lazic et al., 2005 ). Total debridement of corneal epithelium preformed in rats unilaterally and lesions stained (green) and photographed. Medication was distilled water (control group) or BPC 157 2 pg/ml, 2 ng/ml, and 2 μg/ml, two drops/rat eye started immediately after injury induction, every 8 h up to 40 h (i.e., at 0, 8, 16, 24, 32, and 40 h). Lesions presentation at 24 h in controls ( C ) and lesions attenuation in BPC 157 rats ( B ), lesions presentation at 32 h in controls ( C ) and lesions disappearance in BPC 157 rats ( B ).

In conclusion, since the wound healing therapy with the standard angiogenic growth factors may be of essential importance, we presented an overview of the stable gastric pentadecapeptide BPC 157 and wound-healing issue.

Ultimately, this review challenges the general strategy that the skin wound healing ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ), if properly accomplished, may be the principle largely generalized (see Skin Wounds ). The success of such an undertaking depends, however, on a few particular, both practical and theoretical, considerations.

With the BPC 157 application ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), this provides overcoming ( Seiwerth et al., 2018 ) of the technical and practical limitations now presented as shortage in the corresponding standard angiogenic growth factors applicability and diverse delivery and carrier systems (see Practical Application as Support ). In this, for the BPC 157 wound healing, we initially provided consistent argumentation for the accomplished successful skin wound healing (i.e., the combined triad collagen–inflammatory cells–angiogenesis was accordingly upgraded, appearing at earlier intervals, and the formation of granulation tissue containing mature collagen) ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004 ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ) (see Skin Wounds ). With the consistent application of the peptide alone, this skin-healing evidence ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ) was successfully applied to the other tissues healing (and thereby avoiding all shortages related to the peptide + carrier complex(es) (standard angiogenic growth factors application with diverse carriers)) (see Practical Application as Support ). The arguments include the same dose range and same equipotent routes of application, regardless of the injury tested ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), to induce a simultaneous healing, even in different tissues (and therefore the healing of diverse fistulas ( Klicek et al., 2008 ; Skorjanec et al., 2009 ; Cesarec et al., 2013 ; Skorjanec et al., 2015 ; Baric et al., 2016 ; Grgic et al., 2016 ; Sikiric et al., 2020a )). This also can be applied to the healing of anastomoses, as evidenced by the simultaneous healing of both stumps of the anastomosis (i.e., various gastrointestinal anastomoses ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), even those with large part of the bowel removal ( Sever et al., 2009 ; Lojo et al., 2016 ), but also other tissue anastomoses, i.e., vessels ( Numata et al., 2006 ) or nerve ( Jelovac et al., 1999 )) that occurs with the application of BPC 157. In addition, in BPC 157 short-bowel rats, the counteraction of the escalating short bowel syndrome provides that all three intestinal wall layers accordingly adapt in parallel with reaching the same weight gain as in normal rats ( Sever et al., 2009 ) (see Fistula Healing as Support ). The further proof of the concept includes much like the skin wound healing ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ), the muscle, tendon, ligament, and bone healing ( Sebecic et al., 1999 ; Staresinic et al., 2003 ; Krivic et al., 2006 ; Staresinic et al., 2006 ; Krivic et al., 2008 ; Novinscak et al., 2008 ; Keremi et al., 2009 ; Mihovil et al., 2009 ; Cerovecki et al., 2010 ; Pevec et al., 2010 ; Chang et al., 2011 ; Gamulin et al., 2013 ; Chang et al., 2014 ; Hsieh et al., 2017 ) (see The Effect on Other Tissues Healing as Support ). The combining clue may be also the particular effect on blood vessels as the follow-up of its cytoprotection capability ( Robert, 1979 ; Sikiric et al., 2010 ; Sikiric et al., 2018 ) (see Therapy of Bleeding Disorders as Support ). The accomplishment of wound healing includes resolution of all four major events (vessel constriction, the primary platelet plug, the secondary plug, and resolution of the clot) ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ). Therefore, stable gastric pentadecapeptide BPC 157 is effective in wound healing ( Seiwerth et al., 1997 ; Mikus et al., 2001 ; Sikiric et al., 2003 ; Xue et al., 2004a ; Bilic et al., 2005 ; Seveljevic-Jaran et al., 2006 ; Tkalcevic et al., 2007 ; Huang et al., 2015 ), much like it is effective also in counteracting bleeding disorders ( Stupnisek et al., 2012 ; Stupnisek et al., 2015 ; Vukojevic et al., 2018 ), produced by amputation, and/or anti-coagulants application, or major vessel occlusion, along with the evidence that pentadecapeptide BPC 157 may prevent and/or attenuate or eliminate, thus, counteracting both arterial thrombosis ( Hrelec et al., 2009 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ) and venous thrombosis ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ). Consequently, the therapy signifies the recovering effect BPC 157 has on occluded vessels ( Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ), bypassing the occlusion ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ), appears as the specific effect of BPC 157 in ischemia/reperfusion ( Duzel et al., 2017 ; Amic et al., 2018 ; Drmic et al., 2018 ; Vukojevic et al., 2018 ; Gojkovic et al., 2020 ; Kolovrat et al., 2020 ; Vukojevic et al., 2020 ). Finally, they reflect pathways likely additional to those involved in the angiogenesis ( Vukojevic et al., 2018 ), recently associated in particular with the increased expression, internalization of VEGFR2, and the activation of the VEGFR2-Akt-eNOS signaling pathway ( Hsieh et al., 2017 ) (see Genes Expression as Support ), given the rapid presentation of all of these effects, which occurred before the process of angiogenesis could be initiated ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Gwyer et al., 2019 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ). Thus, in rats with occluded blood vessels, at 1 and 24 h, BPC 157 demonstrated a particular specificity within the pathways (at least, Egr, Nos, Srf, Vegfr, Akt1, Plcɣ , and Kras ) and vessels involved ( Vukojevic et al., 2018 ). In the most immediate period after injury induction (skin defect) (i.e., 2, 5, and 10 min), BPC 157 increases Akt1, Braf, Egfr, Egr1, Grb2, Hdac7, Kras, Mapk1, Mapk3, Mapk14, Nos3, Pik3cd, Plcg1, Prkcg, Ptk2, Pxn, Src, Srf, and Vegfa gene expression in rats’ excision wounds in the skin. Finally, based on the noted beneficial effect, BPC 157 may balance collagen synthesis and affect hepatic fibrosis, as a model of the wound-healing response to chronic liver injury, which was modified ( Albanis and Friedman, 2001 ; Aller et al., 2008 ; Wynn, 2008 ; Sever et al., 2019 ). Namely, the BPC 157 effect, in addition to the counteracted BDL-induced liver cirrhosis and portal hypertension ( Sever et al., 2019 ) is also the attenuated dermal, muscle, tendon, and ligament fibrosis and scar formation, and regained function ( Mikus et al., 2001 ; Sikiric et al., 2003 ; Staresinic et al., 2003 ; Staresinic et al., 2006 ; Krivic et al., 2008 ; Cerovecki et al., 2010 ) (see The Effect on Other Tissues Healing as Support ). Controlling the role of BPC 157 likely involves its particular interaction with the major systems involved in wound healing, such as the NO-system (counteracted harmful events, arising from either NO-blockade or NOS-substrate application) ( Sikiric et al., 2014 ) and the prostaglandins system (i.e., large extent of the counteracted NSAIDs toxicity ( Sikiric et al., 2013 ) as well as counteracted developing and already formed adjuvant arthritis in rats ( Sikiric et al., 1997c )). For corticosteroid-related systems, we should emphasize the counteracted eventual healing failure ( Klicek et al., 2008 ; Krivic et al., 2008 ; Skorjanec et al., 2009 ; Pevec et al., 2010 ) and worsening, as well as immunosuppression ( Sikiric et al., 2003 ). Finally, there is the evidence of BPC 157 generation of NO in ex vivo condition ( Sikiric et al., 1997a ; Turkovic et al., 2004 ), resistant to L -NAME, even in conditions when L -arginine does not work, which has some physiologic importance ( Sikiric et al., 1997 ; Turkovic et al., 2004 ). Consequently, since it is formed constitutively in the gastric mucosa, stable, and present in human gastric juice ( Sikiric et al., 1993 ; Sikiric et al., 2006 ; Sikiric et al., 2010 ; Sikiric et al., 2011 ; Sikiric et al., 2012 ; Sikiric et al., 2013 ; Seiwerth et al., 2014 ; Sikiric et al., 2014 ; Sikiric et al., 2016 ; Sikiric et al., 2017 ; Kang et al., 2018 ; Seiwerth et al., 2018 ; Sikiric et al., 2018 ; Park et al., 2020 ; Sikiric et al., 2020a ; Sikiric et al., 2020b ), along with suggested significance of NO-synthase and the basal formation of NO in stomach mucosa, greater than that seen in other tissues ( Whittle et al., 1992 ), BPC 157 exhibits a general, effective competing with both L-arginine analogs (i.e., L -NAME) and L -arginine ( Sikiric et al., 2014 ). Additionally, there is a controlling role of the pentadecapeptide BPC 157 against the tumor-promoting effects of many growth factors and peptides ( Gwyer et al., 2019 ; Sikiric et al., 2018 ) as well as counteracting harmful escape from the initial healing effect (i.e., angiogenesis). VEGF tumorigenesis was avoided and counteracted ( Sikiric et al., 1997c ), and inhibition of the growth of several tumor lines and counteraction of tumor cachexia ( Kang et al., 2018 ) and counteraction of the uncontrolled cell proliferation (Ki-67 overexpression counteracted) ( Sever et al., 2019 ) were observed. BPC 157 stimulated both egr-1 and its co-repressor gene nab2 ( Tkalcevic et al., 2007 ). Since egr-1 is critical in proliferation, differentiation, and inflammation during cholestatic liver injury, cytokine and growth factor generation and early extracellular matrix (collagen) formation ( Kim et al., 2006 ; Zhang et al., 2011 ), BPC 157 (with nab2) may have an essential role as a particular feedback-controlling mechanism. In these terms, indicative is the rat corneal ulcer successfully closed with the BPC 157 eye drops and maintained corneal transparency ( Figure 14 ) ( Masnec et al., 2015 ). With BPC 157, corneal transparency was maintained and regained after total debridement of corneal epithelium ( Figure 15 ) and dry eye syndrome in rats when BPC 157 counteracts the damaging effects of lacrimal gland extirpation ( Lazic et al., 2005 ; Kralj et al., 2017 ).

Together, these findings indicate that with regard to wounds in operating instances, a BPC 157–defensive system exists that may accommodate the healing depending on the tissue and injury conditions. Of note, the possible contribution of the particular counteracting effect on the intravenous dextran- or egg white–induced anaphylactoid reaction ( Duplancic et al., 2014 ) should also be considered, although not specifically mentioned in this review. Unlike histamine receptor antagonists (H1 and H2), BPC 157 has a strong beneficial effect in both rats and mice. Upper and lower lip and snout edema, as well as extreme cyanosis and edema of paws and scrotum were markedly attenuated. Poor respiration and fatalities were not observed ( Duplancic et al., 2014 ). However, it remains to be seen when this particular balanced modulatory action will have further application in therapy.

Author Contributions

MS, SG, IK, and SS: conceptualization and methodology. ID, AK, HZ, and MK: validation. SS, AP, TD, and HV: formal analysis. LB, AP, KP, and EL: investigation. MS, AB, and MM: resources. JV, AS, SS, and PS: writing—original draft, review, and editing.

This study is supported by the University of Zagreb, Zagreb, Croatia, grant number 099.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Albanis, E., and Friedman, S. L. (2001). Hepatic fibrosis. Pathogenesis and principles of therapy. Clin. Liver Dis. 5 (2), 315. doi:10.1016/s1089-3261(05)70168-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Alexander, D., Judex, M., Meyringer, R., Weis-Klemm, M., Gay, S., Müller-Ladner, U., et al. (2002). Transcription factor Egr-1 activates collagen expression in immortalized fibroblasts or fibrosarcoma cells. Biol. Chem. 383 (12), 1845–1853. doi:10.1515/BC.2002.208

Aller, M. A., Arias, J. L., García-Domínguez, J., Arias, J. I., Durán, M., and Arias, J. (2008). Experimental obstructive cholestasis: the wound-like inflammatory liver response. Fibrogenesis Tissue Repair 1 (1), 6. doi:10.1186/1755-1536-1-6

Amic, F., Drmic, D., Bilic, Z., Krezic, I., Zizek, H., Peklic, M., et al. (2018). Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine. World J. Gastroenterol. 24 (47), 5366–5378. doi:10.3748/wjg.v24.i47.5366

Ansari, D., Ansari, D., Andersson, R., and Andrén-Sandberg, Å. (2015). Pancreatic cancer and thromboembolic disease, 150 years after Trousseau. Hepatobiliary Surg. Nutr. 4, 325–335. doi:10.3978/j.issn.2304-3881.2015.06.08

Bakan, E., Taysi, S., Polat, M. F., Dalga, S., Umudum, Z., Bakan, N., et al. (2002). Nitric oxide levels and lipid peroxidation in plasma of patients with gastric cancer. Jpn. J. Clin. Oncol. 32 (5), 162–166. doi:10.1093/jjco/hyf035

Baric, M., Sever, A. Z., Vuletic, L. B., Rasic, Z., Sever, M., Drmic, D., et al. (2016). Stable gastric pentadecapeptide BPC 157 heals rectovaginal fistula in rats. Life Sci. 148, 63–70. doi:10.1016/j.lfs.2016.02.029

Barisic, I., Balenovic, D., Klicek, R., Radic, B., Nikitovic, B., Drmic, D., et al. (2013). Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. Regul. Pept. 181, 50–66. doi:10.1016/j.regpep.2012.12.007

Becejac, T., Cesarec, V., Drmic, D., Hirsl, D., Madzarac, G., Djakovic, Z., et al. (2018). An endogeous defensive concept, renewed cytoprotection/adaptive cytoprotection: intra(per)-oral/intraastric strong alcohol in rat. Involvement of pentadecapeptide BPC 157 and nitric oxide system. J. Physiol. Pharmacol. 69 (3), 429–440. doi:10.26402/jpp.2018.3.11

Bedekovic, V., Mise, S., Anic, T., Staresinic, M., Gjurasin, M., Kopljar, M., et al. (2003). Different effect of antiulcer agents on rat cysteamine-induced duodenal ulcer after sialoadenectomy, but not gastrectomy. Eur. J. Pharmacol. 477 (1), 73–80. doi:10.1016/j.ejphar.2003.08.013

Belosic Halle, Z., Vlainic, J., Drmic, D., Strinic, D., Luetic, K., Sucic, M., et al. (2017). Class side effects: decreased pressure in the lower oesophageal and the pyloric sphincters after the administration of dopamine antagonists, neuroleptics, anti-emetics, L-NAME, pentadecapeptide BPC 157 and L-arginine. Inflammopharmacology 25, 511–522. doi:10.1007/s10787-017-0358-8

CrossRef Full Text | Google Scholar

Berkopic Cesar, L., Gojkovic, S., Krezic, I., Malekinusic, D., Zizek, H., Batelja Vuletic, L., et al. (2020). Bowel adhesion and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine in rats. World J. Gastrointest. Pharmacol. Ther. 11 (5). 93–109. doi:10.4292/wjgpt.v11.i5.93

Berra-Romani, R., Avelino-Cruz, J. E., Raqeeb, A., Della Corte, A., Cinelli, M., Montagnani, S., et al. (2013). Ca²⁺-dependent nitric oxide release in the injured endothelium of excised rat aorta: a promising mechanism applying in vascular prosthetic devices in aging patients. BMC Surg. 13 (2), S40. doi:10.1186/1471-2482-13-S2-S40

Bilic, M., Bumber, Z., Blagaic, A. B., Batelja, L., Seiwerth, S., and Sikiric, P. (2005). The stable gastric pentadecapeptide BPC 157, given locally, improves CO2 laser healing in mice. Burns 31 (3), 310–315. doi:10.1016/j.burns.2004.10.013

Braddock, M., Campbell, C. J., and Zuder, D. (1999). Current therapies for wound healing: electrical stimulation, biological therapeutics, and the potential for gene therapy. Int. J. Dermatol. 38 (11), 808–817. doi:10.1046/j.1365-4362.1999.00832.x

Braddock, M. (2001). The transcription factor Egr-1: a potential drug in wound healing and tissue repair. Ann. Med. 33 (5), 313–318. doi:10.3109/07853890109002083

Brcic, L., Brcic, I., Staresinic, M., Novinscak, T., Sikiric, P., and Seiwerth, S. (2009). Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing. J. Physiol. Pharmacol. 60 (7), 191–196.

PubMed Abstract | Google Scholar

Cerovecki, T., Bojanic, I., Brcic, L., Radic, B., Vukoja, I., Seiwerth, S., et al. (2010). Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat. J. Orthop. Res. 28 (9), 1155–1161. doi:10.1002/jor.21107

Cesarec, V., Becejac, T., Misic, M., Djakovic, Z., Olujic, D., Drmic, D., et al. (2013). Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur. J. Pharmacol. 701 (1-3), 203–212. doi:10.1016/j.ejphar.2012.11.055

Chang, C. H., Tsai, W. C., Hsu, Y. H., and Pang, J. H. (2014). Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 19 (11), 19066–19077. doi:10.3390/molecules191119066

Chang, C. H., Tsai, W. C., Lin, M. S., Hsu, Y. H., and Pang, J. H. (2011). The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J. Appl. Physiol. 110 (3), 774–780. doi:10.1152/japplphysiol.00945.2010

Collen, D. (1980). On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb. Haemost. 43, 77–89. doi:10.1055/s-0038-1650023

Cook, S. D., Baffes, G. C., Wolfe, M. W., Sampath, T. K., and Rueger, D. C. (1994). Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin. Orthop. Relat. Res. 301, 302–312. doi:10.1097/00003086-199404000-00046

Damien, C. J., Christel, P. S., Benedict, J. J., Patat, J. L., and Guillemin, G. (1993). A composite of natural coral, collagen, bone protein and basic fibroblast growth factor tested in a rat subcutaneous model. Ann. Chir Gynaecol. Suppl. 207, 117–128.

Davey, A. K., and Maher, P. J. (2007). Surgical adhesions: a timely update, a great challenge for the future. J. Minim. Invasive Gynecol. 14, 15–22. doi:10.1016/j.jmig.2006.07.013

Deng, X., Szabo, S., Khomenko, T., Tolstanova, G., Paunovic, B., French, S. W., et al. (2013). Novel pharmacologic approaches to the prevention and treatment of ulcerative colitis. Curr. Pharm. Des. 19 (1), 17–28. doi:10.2174/13816128130105

Djakovic, Z., Djakovic, I., Cesarec, V., Madzarac, G., Becejac, T., Zukanovic, G., et al. (2016). Esophagogastric anastomosis in rats: improved healing by BPC 157 and L-arginine, aggravated by L-NAME. World J. Gastroenterol. 22 (41), 9127–9140. doi:10.3748/wjg.v22.i41.9127

Dobric, I., Drvis, P., Petrovic, I., Shejbal, D., Brcic, L., Blagaic, A. B., et al. (2007). Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J. Pharmacol. Sci. 104 (1), 7–18. doi:10.1254/jphs.fp0061322

Drmic, D., Samara, M., Vidovic, T., Malekinusic, D., Antunovic, M., Vrdoljak, B., et al. (2018). Counteraction of perforated cecum lesions in rats: effects of pentadecapeptide BPC 157, L-NAME and L-arginine. World J. Gastroenterol. 24 (48), 5462–5476. doi:10.3748/wjg.v24.i48.5462

Duplancic, B., Stambolija, V., Holjevac, J., Zemba, M., Balenovic, I., Drmic, D., et al. (2014). Pentadecapeptide BPC 157 and anaphylactoid reaction in rats and mice after intravenous dextran and white egg administration. Eur. J. Pharmacol. 727, 75–79. doi:10.1016/j.ejphar.2014.01.046

Duzel, A., Vlainic, J., Antunovic, M., Malekinusic, D., Vrdoljak, B., Samara, M., et al. (2017). Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: new insights. World J. Gastroenterol. 23 (48), 8465–8488. doi:10.3748/wjg.v23.i48.8465

Eckersley, J. R., and Dudley, H. A. (1988). Wounds and wound healing. Br. Med. Bull. 44 (2), 423–436. doi:10.1093/oxfordjournals.bmb.a072259

Eyre, D. R., Paz, M. A., and Gallop, P. M. (1984). Cross-linking in collagen and elastin. Annu. Rev. Biochem. 53, 717–748. doi:10.1146/annurev.bi.53.070184.003441

Forslund, C., and Aspenberg, P. (1998). OP-1 has more effect than mechanical signals in the control of tissue differentiation in healing rat tendons. Acta Orthop. Scand. 69 (6), 622–626. doi:10.3109/17453679808999268

Fortin, C. N., Saed, G. M., and Diamond, M. P. (2015). Predisposing factors to post-operative adhesion development. Hum. Reprod. Update 21, 536–551. doi:10.1093/humupd/dmv021

Gamulin, O., Serec, K., Bilić, V., Balarin, M., Kosović, M., Drmić, D., et al. (2013). Monitoring the healing process of rat bones using Raman spectroscopy. J. Mol. Struct. 1044, 308–313. doi:10.1016/j.molstruc.2013.01.049

Gao, T. J., Lindholm, T. S., Marttinen, A., and Puolakka, T. (1993). Bone inductive potential and dose-dependent response of bovine bone morphogenetic protein combined with type IV collagen carrier. Ann. Chir Gynaecol. Suppl. 207, 77–84.

Gjurasin, M., Miklic, P., Zupancic, B., Perovic, D., Zarkovic, K., Brcic, L., et al. (2010). Peptide therapy with pentadecapeptide BPC 157 in traumatic nerve injury. Regul. Pept. 160 (1-3), 33–41. doi:10.1016/j.regpep.2009.11.005

Gojkovic, S., Krezic, I., Vrdoljak, B., Malekinusic, D., Barisic, I., Petrovic, A., et al. (2020). Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats. World J. Gastrointest. Pathophysiol 11 (1), 1–19. doi:10.4291/wjgp.v11.i1.1

Grgic, T., Grgic, D., Drmic, D., Sever, A. Z., Petrovic, I., Sucic, M., et al. (2016). Stable gastric pentadecapeptide BPC 157 heals rat colovesical fistula. Eur. J. Pharmacol. 780, 1–7. doi:10.1016/j.ejphar.2016.02.038

Gwyer, D., Wragg, N. M., and Wilson, S. L. (2019). Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing. Cell Tissue Res 377 (2), 153–159. doi:10.1007/s00441-019-03016-8

Hendriks, T., and Mastboom, W. J. (1990). Healing of experimental intestinal anastomoses. Parameters for repair. Dis. Colon Rectum 33, 891–901. doi:10.1007/BF02051930

Hinterseher, I., Schworer, C. M., Lillvis, J. H., Stahl, E., Erdman, R., Gatalica, Z., et al. (2015). Immunohistochemical analysis of the natural killer cell cytotoxicity pathway in human abdominal aortic aneurysms. Int. J. Mol. Sci. 16, 11196–11212. doi:10.3390/ijms160511196

Hrelec, M., Klicek, R., Brcic, L., Brcic, I., Cvjetko, I., Seiwerth, S., et al. (2009). Abdominal aorta anastomosis in rats and stable gastric pentadecapeptide BPC 157, prophylaxis and therapy. J. Physiol. Pharmacol. 60 (7), 161–165.

Hsieh, M. J., Liu, H. T., Wang, C. N., Huang, H. Y., Lin, Y., Ko, Y. S., et al. (2017). Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J. Mol. Med. 95 (3), 323–333. doi:10.1007/s00109-016-1488-y

Huang, T., Zhang, K., Sun, L., Xue, X., Zhang, C., Shu, Z., et al. (2015). Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro . Drug Des. Devel Ther. 9, 2485–2499. doi:10.2147/DDDT.S82030

Ilic, S., Brcic, I., Mester, M., Filipovic, M., Sever, M., Klicek, R., et al. (2009). Over-dose insulin and stable gastric pentadecapeptide BPC 157. Attenuated gastric ulcers, seizures, brain lesions, hepatomegaly, fatty liver, breakdown of liver glycogen, profound hypoglycemia and calcification in rats. J. Physiol. Pharmacol. 60 (7), 107–114.

Ilic, S., Drmic, D., Franjic, S., Kolenc, D., Coric, M., Brcic, L., et al. (2011a). Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions. Life Sci. 88 (11-12), 535–542. doi:10.1016/j.lfs.2011.01.015

Ilic, S., Drmic, D., Zarkovic, K., Kolenc, D., Brcic, L., Radic, B., et al. (2011b). Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats. Eur. J. Pharmacol. 667 (1-3), 322–329. doi:10.1016/j.ejphar.2011.05.038

Ilic, S., Drmic, D., Zarkovic, K., Kolenc, D., Coric, M., Brcic, L., et al. (2010). High hepatotoxic dose of paracetamol produces generalized convulsions and brain damage in rats. A counteraction with the stable gastric pentadecapeptide BPC 157 (PL 14736). J. Physiol. Pharmacol. 61 (2), 241–250.

Jandric, I., Vrcic, H., Jandric Balen, M., Kolenc, D., Brcic, L., Radic, B., et al. (2013). Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats. Med. Sci. Monit. Basic Res. 19, 93–102. doi:10.12659/MSMBR.883828

Jee, J. P., Pangeni, R., Jha, S. K., Byun, Y., and Park, J. W. (2019). Preparation and in vivo evaluation of a topical hydrogel system incorporating highly skin-permeable growth factors, quercetin, and oxygen carriers for enhanced diabetic wound-healing therapy. Int. J. Nanomedicine 14, 5449–5475. doi:10.2147/IJN.S213883

Jelovac, N., Sikiric, P., Rucman, R., Petek, M., Marovic, A., Perovic, D., et al. (1999). Pentadecapeptide BPC 157 attenuates disturbances induced by neuroleptics: the effect on catalepsy and gastric ulcers in mice and rats. Eur. J. Pharmacol. 379 (1), 19–31. doi:10.1016/s0014-2999(99)00486-0

Kachlik, D., Baca, V., and Stingl, J. (2010). The spatial arrangement of the human large intestinal wall blood circulation. J. Anat. 216 (3), 335–343. doi:10.1111/j.1469-7580.2009.01199.x

Kang, E. A., Han, Y. M., An, J. M., Park, Y. J., Sikiric, P., Kim, D. H., et al. (2018). BPC157 as potential agent rescuing from cancer cachexia. Curr. Pharm. Des. 24 (18), 1947–1956. doi:10.2174/1381612824666180614082950

Kato, N., Kawai, T., Maeda, H., Nagao, T., Murakami, H., Miyazawa, K., et al. (1995). A study of thecarrier of BMP – osteoinductive activity of poly-saccharide-BMP–complex. J. Hard Tissue Biol. 4, 15–22.

Google Scholar

Katoh, T., Sato, K., Kawamura, M., Iwata, H., and Miura, T. (1993). Osteogenesis in sintered bone combined with bovine bone morphogenetic protein. Clin. Orthop. Relat. Res. 287, 266–275. doi:10.1097/00003086-199302000-00042

Kawai, T., Mieki, A., Ohno, Y., Umemura, M., Kataoka, H., Kurita, S., et al. (1993). Osteoinductive activity of composites of bone morphogenetic protein and pure titanium. Clin. Orthop. Relat. Res. 290, 296–305. doi:10.1097/00003086-199305000-00038

Kawakami, T., Kawai, T., Takei, N., Kise, T., Eda, S., and Urist, M. R. (1997). Evaluation of heterotopic bone formation induced by squalane and bone morphogenetic protein composite. Clin. Orthop. Relat. Res. 337, 261–266. doi:10.1097/00003086-199704000-00029

Keremi, B., Lohinai, Z., Komora, P., Duhaj, S., Borsi, K., Jobbagy-Ovari, G., et al. (2009). Antiinflammatory effect of BPC 157 on experimental periodontitis in rats. J. Physiol. Pharmacol. 60 (7), 115–122.

Khachigian, L. M. (2006). Early growth response-1 in cardiovascular pathobiology. Circ. Res. 98 (2), 186–191. doi:10.1161/01.RES.0000200177.53882.c3

Kim, N. D., Moon, J. O., Slitt, A. L., and Copple, B. L. (2006). Early growth response factor-1 is critical for cholestatic liver injury. Toxicol. Sci. 90 (2), 586–595. doi:10.1093/toxsci/kfj111

Klicek, R., Kolenc, D., Suran, J., Drmic, D., Brcic, L., Aralica, G., et al. (2013). Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability. J. Physiol. Pharmacol. 64 (5), 597–612.

Klicek, R., Sever, M., Radic, B., Drmic, D., Kocman, I., Zoricic, I., et al. (2008). Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system. J. Pharmacol. Sci. 108 (1), 7–17. doi:10.1254/jphs.fp0072161

Kolovrat, M., Gojkovic, S., Krezic, I., Malekinusic, D., Vrdoljak, B., Kasnik Kovac, K., et al. (2020). Pentadecapeptide BPC 157 resolves Pringle maneuver in rats, both ischemia and reperfusion. World J. Hepatol. 12 (5), 184–206. doi:10.4254/wjh.v12.i5.184

Konosic, S., Petricevic, M., Ivancan, V., Konosic, L., Goluza, E., Krtalic, B., et al. (2019). Intragastric application of aspirin, clopidogrel, cilostazol, and BPC 157 in rats: platelet aggregation and blood clot. Oxid Med. Cell Longev 2019, 9084643. doi:10.1155/2019/9084643

Kralj, T., Kokot, A., Kasnik, K., Drmic, D., Zlatar, M., Seiwerth, S., et al. (2017). Effects of pentadecapeptide BPC 157 on experimental rat model of dry eye. FASEB J. 31 (1), 993.3. doi:10.1096/fasebj.31.1_supplement.993.3Abstract retrieved fromExperimental Biology 2017 Meeting

Krivic, A., Anic, T., Seiwerth, S., Huljev, D., and Sikiric, P. (2006). Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: promoted tendon-to-bone healing and opposed corticosteroid aggravation. J. Orthop. Res. 24 (5), 982–989. doi:10.1002/jor.20096

Krivic, A., Majerovic, M., Jelic, I., Seiwerth, S., and Sikiric, P. (2008). Modulation of early functional recovery of Achilles tendon to bone unit after transection by BPC 157 and methylprednisolone. Inflamm. Res. 57 (5), 205–210. doi:10.1007/s00011-007-7056-8

Lazic, R., Gabric, N., Dekaris, I., Bosnar, D., Boban-Blagai, A., and Sikiric, P. (2005). Gastric pentadecapeptide BPC 157 promotes corneal epithelial defects healing in rats. Coll. Antropol 29 (1), 321–325.

Lojo, N., Rasic, Z., Zenko Sever, A., Kolenc, D., Vukusic, D., Drmic, D., et al. (2016). Effects of diclofenac, L-NAME, L-arginine, and pentadecapeptide BPC 157 on gastrointestinal, liver, and brain lesions, failed anastomosis, and intestinal adaptation deterioration in 24 hour-short-bowel rats. PLoS One 11 (9), e0162590. doi:10.1371/journal.pone.0162590

Lovric-Bencic, M., Sikiric, P., Hanzevacki, J. S., Seiwerth, S., Rogic, D., Kusec, V., et al. (2004). Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse. J. Pharmacol. Sci. 95, 19–26. doi:10.1254/jphs.95.19

Luetic, K., Sucic, M., Vlainic, J., Halle, Z. B., Strinic, D., Vidovic, T., et al. (2017). Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology 25 (2), 255–264. doi:10.1007/s10787-017-0330-7

Masnec, S., Kokot, A., Zlatar, M., Kalauz, M., Kunjko, K., Radic, B., et al. (2015). Perforating corneal injury in rat and pentadecapeptide BPC 157. Exp. Eye Res. 136, 9–15. doi:10.1016/j.exer.2015.04.016

Medvidovic-Grubisic, M., Stambolija, V., Kolenc, D., Katancic, J., Murselovic, T., Plestina-Borjan, I., et al. (2017). Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen. Inflammopharmacology 25 (4), 439–449. doi:10.1007/s10787-017-0323-6

Mihovil, I., Radic, B., Brcic, L., Brcic, I., Vukoja, I., Ilic, S., et al. (2009). Beneficial effect of pentadecapeptide BPC 157 on denervated muscle in rats. J. Physiol. Pharmacol. 60 (2), 69.

Mikus, D., Sikiric, P., Seiwerth, S., Petricevic, A., Aralica, G., Druzijancic, N., et al. (2001). Pentadecapeptide BPC 157 cream improves burn-wound healing and attenuates burn-gastric lesions in mice. Burns 27 (8), 817–827. doi:10.1016/s0305-4179(01)00055-9

Miyamoto, S., Takaoka, K., Okada, T., Yoshikawa, H., Hashimoto, J., Suzuki, S., et al. (1992). Evaluation of polylactic acid homopolymers as carriers for bone morphogenetic protein. Clin. Orthop. Relat. Res. 278, 274–285.

Novinscak, T., Brcic, L., Staresinic, M., Jukic, I., Radic, B., Pevec, D., et al. (2008). Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg. Today 38 (8), 716–725. doi:10.1007/s00595-007-3706-2

Nowak, K. C., McCormack, M., and Koch, R. J. (2000). The effect of superpulsed carbon dioxide laser energy on keloid and normal dermal fibroblast secretion of growth factors: a serum-free study. Plast. Reconstr. Surg. 105 (6), 2039–2048. doi:10.1097/00006534-200005000-00019

Numata, Y., Terui, T., Okuyama, R., Hirasawa, N., Sugiura, Y., Miyoshi, I., et al. (2006). The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor. J. Invest. Dermatol. 126 (6), 1403–1409. doi:10.1038/sj.jid.5700253

Okabe, S., and Amagase, K. (2005). An overview of acetic acid ulcer models–the history and state of the art of peptic ulcer research. Biol. Pharm. Bull. 28 (8), 1321–1341. doi:10.1248/bpb.28.1321

Orangio, G. R. (2010). Enterocutaneous fistula: medical and surgical management including patients with Crohn's disease. Clin. Colon Rectal Surg. 23 (3), 169–175. doi:10.1055/s-0030-1262984

Park, J. M., Lee, H. J., Sikiric, P., and Hahm, K. B. (2020). BPC 157 rescued NSAID-cytotoxicity via stabilizing intestinal permeability and enhancing cytoprotection. Curr. Pharm. Des. 26 (25), 2971–2981. doi:10.2174/1381612826666200523180301

Perovic, D., Kolenc, D., Bilic, V., Somun, N., Drmic, D., Elabjer, E., et al. (2019). Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and lead to functional recovery in rats. J. Orthop. Surg. Res. 14 (1), 199. doi:10.1186/s13018-019-1242-6

Petek, M., Sikiric, P., Anic, T., Buljat, G., Separovic, J., Stancic-Rokotov, D., et al. (1999). Pentadecapeptide BPC 157 attenuates gastric lesions induced by alloxan in rats and mice. J. Physiol. Paris 93 (6), 501–504. doi:10.1016/s0928-4257(99)00120-5

Petrovic, I., Dobric, I., Drvis, P., Shejbal, D., Brcic, L., Blagaic, A. B., et al. (2006). An experimental model of prolonged esophagitis with sphincter failure in the rat and the therapeutic potential of gastric pentadecapeptide BPC 157. J. Pharmacol. Sci. 102 (3), 269–277. doi:10.1254/jphs.fp0060070

Pevec, D., Novinscak, T., Brcic, L., Sipos, K., Jukic, I., Staresinic, M., et al. (2010). Impact of pentadecapeptide BPC 157 on muscle healing impaired by systemic corticosteroid application. Med. Sci. Monit. 16 (3), 81–88.

Poppas, D. P., Massicotte, J. M., Stewart, R. B., Roberts, A. B., Atala, A., Retik, A. B., et al. (1996). Human albumin solder supplemented with TGF-beta 1 accelerates healing following laser welded wound closure. Lasers Surg. Med. 19 (3), 360–368. doi:10.1002/(SICI)1096-9101(1996)19:3<360::AID-LSM13>3.0.CO;2–8

Radeljak, S., Seiwerth, S., and Sikiric, P. (2004). BPC 157 inhibits cell growth and VEGF signalling via the MAPK kinase pathway in the human melanoma cell line. Melanoma Res. 14, 14–15.

Rangan, U., and Bulkley, G. B. (1993). Prospects for treatment of free radical-mediated tissu injury. Br. Med. Bull. 49 (3), 700–718. doi:10.1093/oxfordjournals.bmb.a072641

Rantfors, J., and Cassuto, J. (2003). Role of histamine receptors in the regulation of edema and circulation postburn. Burns 29 (8), 769–777. doi:10.1016/s0305-4179(03)00203-1

Rao, K. S., Patil, P. A., and Malur, P. R. (2007). Promotion of cutaneous wound healing by famotidine in Wistar rats. Indian J. Med. Res. 125 (2), 149–154.

Robert, A. (1979). Cytoprotection by prostaglandins. Gastroenterology 77 (4), 761–767.

Saghazadeh, S., Rinoldi, C., Schot, M., Kashaf, S. S., Sharifi, F., Jalilian, E., et al. (2018). Drug delivery systems and materials for wound healing applications. Adv. Drug Deliv. Rev. 127, 138–166. doi:10.1016/j.addr.2018.04.008

Schiller, H. J., Reilly, P. M., and Bulkley, G. B. (1993). Tissue perfusion in critical illnesses. Antioxidant therapy. Crit. Care Med. 21 (1), 92–102.

Schweighofer, B., Schultes, J., Pomyje, J., and Hofer, E. (2007). Signals and genes induced by angiogenic growth factors in comparison to inflammatory cytokines in endothelial cells. Clin. Hemorheol. Microcirc. 37, 57–62.

Sebecic, B., Nikolic, V., Sikiric, P., Seiwerth, S., Sosa, T., Patrlj, L., et al. (1999). Osteogenic effect of a gastric pentadecapeptide BPC 157, on the healing of segmental bone defect in rabbits. A comparison with bone marrow and autologous cortical bone implantation. Bone 24 (3), 195–202. doi:10.1016/s8756-3282(98)00180-x

Seiwerth, S., Brcic, L., Vuletic, L. B., Kolenc, D., Aralica, G., Misic, M., et al. (2014). BPC 157 and blood vessels. Curr. Pharm. Des. 20 (7), 1121–1125. doi:10.2174/13816128113199990421

Seiwerth, S., Rucman, R., Turkovic, B., Sever, M., Klicek, R., Radic, B., et al. (2018). BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing, lessons from tendon, ligament, muscle and bone healing. Curr. Pharm. Des. 24 (18), 1972–1989. doi:10.2174/1381612824666180712110447

Seiwerth, S., Sikiric, P., Grabarevic, Z., Zoricic, I., Hanzevacki, M., Ljubanovic, D., et al. (1997). BPC 157's effect on healing. J. Physiol. Paris 91 (3-5), 173–178. doi:10.1016/s0928-4257(97)89480-6

Selye, H., and Szabo, S. (1973). Experimental model for production of perforating duodenal ulcers by cysteamine in the rat. Nature 244 (5416), 458–459. doi:10.1038/244458a0

Seveljevic-Jaran, D., Cuzic, S., Dominis-Kramaric, M., Glojnaric, I., Ivetic, V., Radosevic, S., et al. (2006). Accelerated healing of excisional skin wounds by PL 14736 in alloxan-hyperglycemic rats. Skin Pharmacol. Physiol. 19 (5), 266–274. doi:10.1159/000093982

Seven, A., Civelek, S., Inci, E., Inci, F., Korkut, N., and Burcak, G. (1999). Evaluation of oxidative stress parameters in blood of patients with laryngeal carcinoma. Clin. Biochem. 32 (5), 369–373. doi:10.1016/s0009-9120(99)00022-3

Sever, A. Z., Sever, M., Vidovic, T., Lojo, N., Kolenc, D., Vuletic, L. B., et al. (2019). Stable gastric pentadecapeptide BPC 157 in the therapy of the rats with bile duct ligation. Eur. J. Pharmacol. 847, 130–142. doi:10.1016/j.ejphar.2019.01.030

Sever, M., Klicek, R., Radic, B., Brcic, L., Zoricic, I., Drmic, D., et al. (2009). Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats. Dig. Dis. Sci. 54 (10), 2070–2083. doi:10.1007/s10620-008-0598-y

Siegall, C. B., Gawlak, S. L., Chace, D. F., Merwin, J. R., and Pastan, I. (1994). In vivo activities of acidic fibroblast growth factor-Pseudomonas exotoxin fusion proteins. Bioconjug. Chem. 5 (1), 77–83. doi:10.1021/bc00025a010

Sikiric, P., Drmic, D., Sever, M., Klicek, R., Blagaic, A. B., Tvrdeic, A., et al. (2020a). Fistulas healing. Stable gastric pentadecapeptide BPC 157 therapy. Curr. Pharm. Des. 26 (25), 2991–3000. doi:10.2174/1381612826666200424180139

Sikiric, P., Hahm, K. B., Blagaic, A. B., Tvrdeic, A., Pavlov, K. H., Petrovic, A., et al. (2020b). Stable gastric pentadecapeptide BPC 157, Robert's stomach cytoprotection/adaptive cytoprotection/organoprotection, and Selye's stress coping response: progress, achievements, and the future. Gut Liver 14 (2), 153–167. doi:10.5009/gnl18490

Sikiric, P., Jadrijevic, S., Seiwerth, S., Sosa, T., Deskovic, S., Perovic, D., et al. (1999b). Long-lasting cytoprotection after pentadecapeptide BPC 157, ranitidine, sucralfate or cholestyramine application in reflux oesophagitis in rats. J. Physiol. Paris 93 (6), 467–477. doi:10.1016/s0928-4257(99)00124-2

Sikiric, P., Marovic, A., Matoz, W., Anic, T., Buljat, G., Mikus, D., et al. (1999c). A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson's disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine. J. Physiol. Paris 93 (6), 505–512. doi:10.1016/s0928-4257(99)00119-9

Sikiric, P., Mikus, D., Seiwerth, S., Grabarevic, Z., Rucman, R., Petek, M., et al. (1997b). Pentadecapeptide BPC 157, cimetidine, ranitidine, bromocriptine, and atropine effect in cysteamine lesions in totally gastrectromized rats: a model for cytoprotective studies. Dig. Dis. Sci. 42 (5), 1029–1037. doi:10.1023/a:1018893220943

Sikiric, P., Petek, M., Rucman, R., Seiwerth, S., Grabarevic, Z., Rotkvic, I., et al. (1993). A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. J. Physiol. Paris 87 (5), 313–327. doi:10.1016/0928-4257(93)90038-u

Sikiric, P., Rucman, R., Turkovic, B., Sever, M., Klicek, R., Radic, B., et al. (2018). Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular recruitment and gastrointestinal tract healing. Curr. Pharm. Des. 24 (18), 1990–2001. doi:10.2174/1381612824666180608101119

Sikiric, P., Seiwerth, S., Brcic, L., Blagaic, A. B., Zoricic, I., Sever, M., et al. (2006). Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva, Croatia). Full and distended stomach, and vascular response. Inflammopharmacology 14 (5-6), 214–221. doi:10.1007/s10787-006-1531-7

Sikiric, P., Seiwerth, S., Brcic, L., Sever, M., Klicek, R., Radic, B., et al. (2010). Revised Robert's cytoprotection and adaptive cytoprotection and stable gastric pentadecapeptide BPC 157. Possible significance and implications for novel mediator. Curr. Pharm. Des. 16 (10), 1224–1234. doi:10.2174/138161210790945977

Sikiric, P., Seiwerth, S., Grabarevic, Z., Balen, I., Aralica, G., Gjurasin, M., et al. (2001). Cysteamine-colon and cysteamine-duodenum lesions in rats. Attenuation by gastric pentadecapeptide BPC 157, cimetidine, ranitidine, atropine, omeprazole, sulphasalazine and methylprednisolone. J. Physiol. Paris 95 (1-6), 261–270. doi:10.1016/s0928-4257(01)00036-5

Sikiric, P., Seiwerth, S., Grabarevic, Z., Petek, M., Rucman, R., Turkovic, B., et al. (1994). The beneficial effect of BPC 157, a 15 amino acid peptide BPC fragment, on gastric and duodenal lesions induced by restraint stress, cysteamine and 96% ethanol in rats. A comparative study with H2 receptor antagonists, dopamine promotors and gut peptides. Life Sci. 54 (5), 63–68. doi:10.1016/0024-3205(94)00796-9

Sikiric, P., Seiwerth, S., Grabarevic, Z., Rucman, R., Petek, M., Jagic, V., et al. (1997c). Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats. J. Physiol. Paris 91 (3-5), 113–122. doi:10.1016/s0928-4257(97)89474-0

Sikiric, P., Seiwerth, S., Grabarevic, Z., Rucman, R., Petek, M., Jagic, V., et al. (1997a). The influence of a novel pentadecapeptide, BPC 157, on N(G)-nitro-L-arginine methylester and L-arginine effects on stomach mucosa integrity and blood pressure. Eur. J. Pharmacol. 332 (1), 23–33. doi:10.1016/s0014-2999(97)01033-9

Sikiric, P., Seiwerth, S., Mise, S., Staresinic, M., Bedekovic, V., Zarkovic, N., et al. (2003). Corticosteroid-impairment of healing and gastric pentadecapeptide BPC-157 creams in burned mice. Burns 29 (4), 323–334. doi:10.1016/s0305-4179(03)00004-4

Sikiric, P., Seiwerth, S., Rucman, R., Drmic, D., Stupnisek, M., Kokot, A., et al. (2017). Stress in gastrointestinal tract and stable gastric pentadecapeptide BPC 157. Finally, do we have a solution? Curr. Pharm. Des. 23 (27), 4012–4028. doi:10.2174/1381612823666170220163219

Sikiric, P., Seiwerth, S., Rucman, R., Kolenc, D., Vuletic, L. B., Drmic, D., et al. (2016). Brain-gut Axis and pentadecapeptide BPC 157: theoretical and practical implications. Curr. Neuropharmacol . 14 (8), 857–865. doi:10.2174/1570159x13666160502153022

Sikiric, P., Seiwerth, S., Rucman, R., Turkovic, B., Rokotov, D. S., Brcic, L., et al. (2012). Focus on ulcerative colitis: stable gastric pentadecapeptide BPC 157. Curr. Med. Chem. 19 (1), 126–132. doi:10.2174/092986712803414015

Sikiric, P., Seiwerth, S., Rucman, R., Turkovic, B., Rokotov, D. S., Brcic, L., et al. (2014). Stable gastric pentadecapeptide BPC 157-NO-system relation. Curr. Pharm. Des. 20 (7), 1126–1135. doi:10.2174/13816128113190990411

Sikiric, P., Seiwerth, S., Rucman, R., Turkovic, B., Rokotov, D. S., Brcic, L., et al. (2011). Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract. Curr. Pharm. Des. 17 (16), 1612–1632. doi:10.2174/138161211796196954

Sikiric, P., Seiwerth, S., Rucman, R., Turkovic, B., Rokotov, D. S., Brcic, L., et al. (2013). Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Curr. Pharm. Des. 19 (1), 76–83. doi:10.2174/13816128130111

Sikiric, P., Separovic, J., Anic, T., Buljat, G., Mikus, D., Seiwerth, S., et al. (1999a). The effect of pentadecapeptide BPC 157, H2-blockers, omeprazole and sucralfate on new vessels and new granulation tissue formation. J. Physiol. Paris 93 (6), 479–485. doi:10.1016/s0928-4257(99)00123-0

Skorjanec, S., Dolovski, Z., Kocman, I., Brcic, L., Blagaic Boban, A., Batelja, L., et al. (2009). Therapy for unhealed gastrocutaneous fistulas in rats as a model for analogous healing of persistent skin wounds and persistent gastric ulcers: stable gastric pentadecapeptide BPC 157, atropine, ranitidine, and omeprazole. Dig. Dis. Sci. 54 (1), 46–56. doi:10.1007/s10620-008-0332-9

Skorjanec, S., Kokot, A., Drmic, D., Radic, B., Sever, M., Klicek, R., et al. (2015). Duodenocutaneous fistula in rats as a model for “wound healing-therapy” in ulcer healing: the effect of pentadecapeptide BPC 157, L-nitro-arginine methyl ester and L-arginine. J. Physiol. Pharmacol. 66 (4), 581–590.

Stambolija, V., Stambolija, T. P., Holjevac, J. K., Murselovic, T., Radonic, J., Duzel, V., et al. (2016). BPC 157: the counteraction of succinylcholine, hyperkalemia, and arrhythmias. Eur. J. Pharmacol. 781, 83–91. doi:10.1016/j.ejphar.2016.04.004

Staresinic, M., Petrovic, I., Novinscak, T., Jukic, I., Pevec, D., Suknaic, S., et al. (2006). Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J. Orthop. Res. 24 (5), 1109–1117. doi:10.1002/jor.20089

Staresinic, M., Sebecic, B., Jadrijevic, S., Suknaic, S., Perovic, D., Aralica, G., et al. (2003). Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J. Orthop. Res. 21 (6), 976–983. doi:10.1016/S0736-0266(03)00110-4

Stupnisek, M., Franjic, S., Drmic, D., Hrelec, M., Kolenc, D., Radic, B., et al. (2012). Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin. Thromb. Res. 129 (5), 652–659. doi:10.1016/j.thromres.2011.07.035

Stupnisek, M., Kokot, A., Drmic, D., Hrelec Patrlj, M., Zenko Sever, A., Kolenc, D., et al. (2015). Pentadecapeptide BPC 157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, L-NAME and L-arginine. PLoS One 10 (4), e0123454. doi:10.1371/journal.pone.0123454

Sucic, M., Luetic, K., Jandric, I., Drmic, D., Sever, A. Z., Vuletic, L. B., et al. (2019). Therapy of the rat hemorrhagic cystitis induced by cyclophosphamide. Stable gastric pentadecapeptide BPC 157, L-arginine, L-NAME. Eur. J. Pharmacol. 861, 172593. doi:10.1016/j.ejphar.2019.172593

Tabata, Y., Nagano, A., and Ikada, Y. (1999). Biodegradation of hydrogel carrier incorporating fibroblast growth factor. Tissue Eng. 5 (2), 127–138. doi:10.1089/ten.1999.5.127

Tarnawski, A. S., and Ahluwalia, A. (2012). Molecular mechanisms of epithelial regeneration and neovascularization during healing of gastric and esophageal ulcers. Curr. Med. Chem. 19 (1), 16–27. doi:10.2174/092986712803414088

Thorén, K., and Aspenberg, P. (1993). Effects of basic fibroblast growth factor on bone allografts. A study using bone harvest chambers in rabbits. Ann. Chir Gynaecol. Suppl. 207, 129–135.

Tkalcevic, V. I., Cuzic, S., Brajsa, K., Mildner, B., Bokulic, A., Situm, K., et al. (2007). Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur. J. Pharmacol. 570 (1-3), 212–221. doi:10.1016/j.ejphar.2007.05.072

Tonolini, M., and Magistrelli, P. (2017). Enterocutaneous fistulas: a primer for radiologists with emphasis on CT and MRI. Insights Imaging 8 (6), 537–548. doi:10.1007/s13244-017-0572-3

Tshionyi, M., Shay, E., Lunde, E., Lin, A., Han, K. Y., Jain, S., et al. (2012). Hemangiogenesis and lymphangiogenesis in corneal pathology. Cornea 31 (1), 74–80. doi:10.1097/ICO.0b013e31821dd986

Turkovic, B., Sikiric, P., Seiwerth, S., Mise, S., Anic, T., Petek, M., et al. (2004). Stable gastric pentadecapeptide BPC 157 studied for inflammatory bowel disease (PLD-116, PL14736, Pliva) induces nitric oxide synthesis. Gastroenterology 126, 287.

Urist, M. R. (1996). The first three decades of bone morphogenetic protein. Osteologie 4, 207–233.

Visschers, R. G., van Gemert, W. G., Winkens, B., Soeters, P. B., and Olde Damink, S. W. (2012). Guided treatment improves outcome of patients with enterocutaneous fistulas. World J. Surg. 36 (10), 2341–2348. doi:10.1007/s00268-012-1663-4

Vukojevic, J., Siroglavic, M., Kasnik, K., Kralj, T., Stancic, D., Kokot, A., et al. (2018). Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. Vascul Pharmacol. 106, 54–66. doi:10.1016/j.vph.2018.02.010

Vukojevic, J., Vrdoljak, B., Malekinusic, D., Siroglavic, M., Milavic, M., Kolenc, D., et al. (2020). The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats. Brain Behav. 10 (8), e01726. doi:10.1002/brb3.1726

Walter, M. A., Toriumi, D. M., Patt, B. S., Bhattacharyya, T. K., O'Grady, K., Caulfield, J. B., et al. (1996). Fibroblast growth factor-induced motor end plate regeneration in atrophic muscle. Arch. Otolaryngol. Head Neck Surg. 122 (4), 425–430. doi:10.1001/archotol.1996.01890160065012

Wang, J. S., and Aspenberg, P. (1996). Basic fibroblast growth factor promotes bone ingrowth in porous hydroxyapatite. Clin. Orthop. Relat. Res. 333, 252–260.

Wang, X. Y., Qu, M., Duan, R., Shi, D., Jin, L., Gao, J., et al. (2019). Cytoprotective mechanism of the novel gastric peptide BPC157 in gastrointestinal tract and cultured enteric neurons and glial cells. Neurosci. Bull. 35 (1), 167–170. doi:10.1007/s12264-018-0269-8

Whittle, B. J. R., Boughton-Smith, N. K., and Moncada, S. (1992). Biosynthesis and role of the endothelium-derived vasodilator, nitric oxide in gastric mucosa. Ann. NY Acad. Sci. 664, 126–139. doi:10.1111/j.1749-6632.1992.tb39755.x

Wynn, T. A. (2008). Cellular and molecular mechanisms of fibrosis. J. Pathol. 214 (2), 199–210. doi:10.1002/path.2277

Xue, X. C., Wu, Y. J., Gao, M. T., Li, W. G., Zhao, N., Wang, Z. L., et al. (2004a). Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats. World J. Gastroenterol. 10 (7), 1032–1036. doi:10.3748/wjg.v10.i7.1032

Xue, X. C., Wu, Y. J., Gao, M. T., Li, W. G., Zhao, N., Wang, Z. L., et al. (2004b). Study of the protective effects of pentadecapeptide BPC 157 on skin cut wounds in small type pigs. Chin. J. New Drugs 13, 602–605.

Yu, C., Cunningham, M., Rogers, C., Dinbergs, I. D., and Edelman, E. R. (1998). The biologic effects of growth factor-toxin conjugates in models of vascular injury depend on dose, mode of delivery, and animal species. J. Pharm. Sci. 87 (11), 1300–1304. doi:10.1021/js980086i

Zhang, Y., Bonzo, J. A., Gonzalez, F. J., and Wang, L. (2011). Diurnal regulation of the early growth response 1 (Egr-1) protein expression by hepatocyte nuclear factor 4alpha(HNF4alpha) and small heterodimer partner (SHP) cross-talk in liver fibrosis. J. Biol. Chem. 286 (34), 29635–29643. doi:10.1074/jbc.M111.253039

Keywords: stable gastric pentadecapeptide BPC 157, fistula, bleeding disorder, concept practical applicability, wound healing

Citation: Seiwerth S, Milavic M, Vukojevic J, Gojkovic S, Krezic I, Vuletic LB, Pavlov KH, Petrovic A, Sikiric S, Vranes H, Prtoric A, Zizek H, Durasin T, Dobric I, Staresinic M, Strbe S, Knezevic M, Sola M, Kokot A, Sever M, Lovric E, Skrtic A, Blagaic AB and Sikiric P (2021) Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front. Pharmacol. 12:627533. doi: 10.3389/fphar.2021.627533

Received: 09 November 2020; Accepted: 03 February 2021; Published: 29 June 2021.

Reviewed by:

Copyright © 2021 Seiwerth, Milavic, Vukojevic, Gojkovic, Krezic, Vuletic, Pavlov, Petrovic, Sikiric, Vranes, Prtoric, Zizek, Durasin, Dobric, Staresinic, Strbe, Knezevic, Sola, Kokot, Sever, Lovric, Skrtic, Blagaic and Sikiric. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Predrag Sikiric, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

The FDA Just Banned 17 Peptide Treatments

The agency banned peptides from certain pharmacies, but others blazed past new regulations.

By Rebekah Harding

Share this article

• facebook icon
• twitter icon
• linkedin icon

30-Second Takeaway

The FDA banned compounding pharmacies from selling certain peptide therapies. While unrestricted vendors may continue selling these treatments, this route is risky. Here’s what to do if your protocol was impacted by the new regulations.

Peptide therapy has recently gone mainstream thanks to popular peptides like semaglutide (Ozempic) and tirzepatide (Mounjaro). But bodybuilders, longevity buffs, health podcasters, and biohackers are reeling after the FDA recently banned 17 other popular peptides.

Peptides are a chain of amino acids that your body uses to perform essential functions ( 1 ). When injected or ingested, they can deliver longevity benefits including weight loss, muscle gain, brain health, libido, hormone management, and more.

But not all peptides are as well researched—which is one of the primary reasons why the FDA recently released new regulations limiting the sale of certain prescription peptide treatments. (There are still black market peptide pushers that sell the now-banned peptides without a valid prescription—but this route is risky and not recommended). 

Peptides that are well-studied and have a generic form were deemed okay by the FDA. However, peptides with little clinical research were on the chopping block due to concerns of impurities and dangerous side effects linked to compounded treatments.

Unlike regular pharmacies that sell pre-manufactured drugs, compounding pharmacies can put prescribed drugs into custom topical treatments, injectables, flavored liquids, and more at specified doses.  

However, compounded peptides run the risk of variability between treatments. Hence, the FDA cracking down on compounding pharmacies mixing peptides that the agency deems under-researched or dangerous.

While the ban is immediate, compounding pharmacies can still run through their current stock of the now-regulated peptides.

Curious if your go-to peptide therapy is on the list? The following peptides were affected by the FDA ban. Plus, alternatives for treatment if your protocol was impacted.

Peptides Impacted by FDA Restrictions

AOD-9604 is beloved by bodybuilders for its purported ability to speed up metabolism, burn stubborn fat, and amp muscle growth by boosting human growth hormone and curbing insulin resistance ( 2 ). 

Human growth hormone, or HGH, is released by the pituitary gland to promote height in puberty, muscle growth, and bone strength ( 3 ). As you age, your HGH levels fall ( 4 )—which makes AOD-9604 popular among people looking to boost muscle 

Why it was included in the FDA ban

AOD-9604 was cited as having a “risk for immunogenicity (the ability to trigger a negative immune reaction), peptide-related impurities, and limited safety-related information.”

BPC-157, aka the “magic peptide,” is a biohacking fan-favorite for its potential to improve brain function, boost gym gains, improve joint pain, and heal gut inflammation ( 5 , 6 , 7 ). Animal studies suggest this peptide may also promote angiogenesis—the process in which your body makes more blood vessels ( 8 ).

The FDA cites “risk for immunogenicity, peptide-related impurities, and limited safety-related information” as reasons for the BPC-157 ban. 

BPC-157 is still available as an oral pill. BPC-157 is one of the only peptides that can survive the acidic environment in your stomach ( 9 ), so oral treatment is likely very effective.

Expert Swaps : 

Pentosan polysulfate is an injectable peptide that has been shown to improve osteoarthritis and other joint pain ( 10 ). This peptide may work as an alternative if you primarily take BPC-157 for joint health.

Larazotide is a peptide that may reduce gut permeability  by strengthening your gut lining ( 11 ). Ask your doctor about using this peptide as a replacement if you take BPC-157 to promote gut health. 

BODY RE-COMP

At a glance, CJC-1295 seems like an all-around longevity-supporting peptide, touting better sleep, increased muscle mass and weight loss, boosted cognitive and immune function, and slowed skin aging ( 12 , 13 , 14 ) in animal studies. 

According to the FDA, CJC-1295 carries a risk for increased heart rate and cardiac events. Plus, compounded CJC-1295 runs the risk of peptide impurities and harmful immune responses, according to the agency.

Expert Swap: 

Like CJC-1295, Sermorelin also promotes healthy body composition by increasing growth hormone ( 15 ). 

DIHEXA is a blood-brain barrier-penetrating peptide commonly used by people concerned about their risk for degenerative diseases like Alzheimer’s, dementia, and Parkinson’s ( 16 ). Users claim that DIHEXA increases mental stamina, improves problem-solving skills, manages depression, and boosts memory.

While animal studies suggest that DIHEXA may tout these brain benefits ( 17 ), the FDA says it “has not identified any human exposure data.” Meaning: The safety and efficacy of DIHEXA for humans is still up in the air. 

Expert Swaps: 

Cerebrolysin is a brain recovery peptide that has shown promise in staving off neurodegenerative diseases like Alzheimer’s ( 18 ). (Fibroblast Growth Factor) may improve memory ( 19 ).

If you  can’t get to sleep, you may have stumbled across DSIP in a biohacking subreddit. DSIP is thought to increase production of GABA ( 20 )—a neurotransmitter that slows brain activity, promotes relaxation, and increases time spent in deep sleep. Research shows that increasing GABA levels may help improve insomnia ( 21 ). 

Research on DSIP in humans is still lacking, per the FDA. However, you can purchase GABA supplements at your local health foods store.

Epitalon is a synthetic version of the natural peptide Epithalamin, which is produced by the pineal gland ( 22 ). Epitalon may regulate the pineal gland, which can bump your production of sleep-supporting hormones serotonin and melatonin.

Some research also suggests that Epitalon can also lengthen your telomeres—the caps at the end of your chromosomes that shorten with age ( 23 ). Telomere length is a key marker used to calculate cellular aging, and maintaining longer telomeres is thought to slow down cellular aging.

Compounded Epitalon was banned because of a potential for peptide impurities and immune reactions. Epitalon is still available in pill form.

GHK-Cu 

GHK-Cu, or copper peptides, are a combination of tripeptide Glycyl-L-Histidyl-L-Lysine and copper ions. Research suggests that this peptide may stimulate collagen production—a protein that helps maintain skin elasticity and firmness—which has boosted its popularity in anti-aging skincare treatments ( 24 ). GHK-Cu is also thought to be a powerful antioxidant, which may support wound healing, reduce inflammation, and enhance skin regeneration.

Injectable GHK-Cu was banned because of a high risk for immune reactions and impurities during the compounding process. GHK-Cu is still available in topical skincare products.

Ipamorelin is a growth hormone-releasing peptide (GHRP) commonly used to stimulate muscle growth and improve post-workout recovery and metabolism ( 25 ). 

In the FDA release, the agency cites a study in which serious adverse events including death occurred when patients were given ipamorelin through an IV.

KPV—a relatively new anti-inflammatory peptide—is sought out for its ability to speed up healing, curb infection, and axe chronic inflammation ( 26 ). For example, one Reddit user claims that KPV treatment helped curb symptoms of their mast cell disease and histamine reactions.

There have been no human trials on KPV to date.  

LL-37 is a naturally occurring antimicrobial peptide which some research suggests might help your body fight off harmful bacteria, viruses, and fungi ( 27 ). This peptide has also been studied as a potential anti-inflammatory treatment, and research suggests it may show  promise in treating skin conditions like rosacea ( 27 ).

Nonclinical research findings suggest that LL-37 could negatively impact male fertility. Plus, LL-37 could be protumorigenic—meaning it could cause tumors to develop—in some tissues.

Melanotan II

Melanotan II mimics the hormone alpha-melanocyte-stimulating hormone (α-MSH), which controls skin pigmentation ( 28 ). People gravitate towards this peptide to deepen their tan.

Melanotan II was banned for reported adverse effects like melanoma skin cancers, posterior reversible encephalopathy syndrome (a seizure and headache disorder), sympathomimetic toxidrome (symptoms of poisoning), and priapism (dangerous, prolonged erections).

MOTS-C may boost metabolism and promote muscle repair. This peptide has also shown promise in boosting mitochondrial function and cellular energy ( 29 ).

Research has not yet proven MOTS-C to deliver the above benefits. However, the agency cites initial findings that show that it may be used for future treatment of age-related conditions and metabolic disorders.

Ibutamoren, often called MK-677, is a selective growth hormone secretagogue receptor (GHSR) agonist, meaning it stimulates the release of the muscle and bone-supporting growth hormone that your body naturally makes ( 30 ).

The FDA cites significant safety “risks due to the potential for congestive heart failure in certain patients” seen in a clinical trial that was terminated.

Selank is an anti-anxiety and nootropic (brain-boosting) peptide being researched for its ability to balance neurotransmitters like serotonin, dopamine, and norepinephrine ( 31 ). These neurotransmitters play a role in regulating mood and appetite. 

Selank has a high risk of immune reactions and impurities during the compounding process, according to the agency’s press release.

Semax is derived from adrenocorticotropic hormone (ACTH), which regulates cortisol and androgen production. Studies suggest that Semax may boost memory, attention, and learning by modulating neurotransmitter activity in the brain ( 32 ). Plus, this peptide has also shown neuroprotective properties by lowering oxidative stress and improving overall brain health in animal studies ( 33 ).

Semax has a high risk of immune reactions and impurities during the compounding process.

PE 22-28 is a peptide commonly used to improve depression, boost memory, and prevent stroke ( 34 ). Discuss this peptide with your prescriber if you take Semax.

Thymosin Beta 4 

Thymosin Beta 4 is a naturally occurring peptide that studies suggest may help with tissue repair and regeneration ( 35 ). Initial research has found that Thymosin Beta 4 has anti-inflammatory properties and may boost heart health ( 35 ).

The agency cited a lack of human trials and the risk for immune reactions and peptide impurities with injectable Thymosin Beta 4. The pill version of the peptide wasn’t impacted by the ban. 

Thymosin Alpha 1

Thymosin Alpha 1 is a synthetic version of the thymic peptide that has shown promise in boosting immune health ( 36 ). Some research shows that Thymosin Alpha 1 may increase your body’s natural T-cell production, which helps you fight infections and diseases ( 36 ).

Injectable Thymosin Alpha 1 may be linked to immune reactions.

What If I’m Already Taking a Banned Peptide?

If you’re already taking one of the peptides impacted by the new FDA regulations, take these steps to preserve your peptide therapy results. 

1. Talk to your provider about alternatives

The FDA hasn’t banned all peptides, and many of the regulations only cover compounded peptide treatments. You may be able to  continue treatment with a few tweaks in the administration method. 

For example, many oral versions of peptides (like BPC-157 and Thymosin Beta 4) are not banned—it’s just the injectables. Talk to your prescriber about a replacement oral version or injectable peptide that offers similar benefits.  

2. Be wary of compounds from unregulated pharmacies

While the FDA has banned compounding pharmacies from making certain peptides, there are other pharmacies—dubbed ‘unregulated pharmacies’—that are not regulated by the government. These pharmacies may still manufacture banned peptides—but be wary of quality and safety if you are intent on going this route.

Products from some unregulated pharmacies may be tainted with heavy metals like mercury.  

If you decide to get a peptide prescription through an unregulated pharmacy, ensure it has favorable reviews and a recent certificate of authenticity (COA).

You can also ask the pharmacy if you can send the peptide to a lab to verify the contents. If they give you hesitancy with that, then that’s a red flag.

Forbes, et al (2023) Biochemistry, Peptide

Ng, et al (2000) Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone

Brinkman, et al (2023) Physiology, Growth Hormone

Garcia, et al (2019) Growth Hormone in Aging

Vukojevic, et al (2022) Pentadecapeptide BPC 157 and the central nervous system

Lee, et al (2021) Intra-Articular Injection of BPC 157 for Multiple Types of Knee Pain

Sikiric, et al (2016) Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications

Hsieh, et al (2017) Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation

Seiwerth, et al (2021) Stable Gastric Pentadecapeptide BPC 157 and Wound Healing

Liu, et al (2023) The effect of pentosan polysulfate sodium for improving dyslipidaemia and knee pain in people with knee osteoarthritis: A pilot study

ScienceDirect (2022) Larazotide

Alba, et al (2006) Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Teichman, et al (2006) Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults

Gautam, et al (2009) Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Walker, et al (2006) Sermorelin: A better approach to management of adult-onset growth hormone insufficiency?

Sun, et al (2021) AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway

Weiss, et al (2021) Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies

Gauthier, et al (2015) Cerebrolysin in mild-to-moderate Alzheimer’s disease: a meta-analysis of randomized controlled clinical trials

Zellinger, et al (2014) Impact of the Neural Cell Adhesion Molecule-Derived Peptide FGL on Seizure Progression and Cellular Alterations in the Mouse Kindling Model

Tukhovskaya, et al (2021) Delta Sleep-Inducing Peptide Recovers Motor Function in SD Rats after Focal Stroke

Hepsomali, et al (2020) Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review

Khavinson, et al (2020) AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism

Shammas (2012) Telomeres, lifestyle, cancer, and aging

Pickart, et al (2018) Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data

Sinha, et al (2020) Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males

Xiao, et al (2017) Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis

Reinholz, et al (2012) Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease

Gilhooley, et al (2021) Melanotan II User Experience: A Qualitative Study of Online Discussion Forums

Mohtashami, et al (2022) MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases

Liu, et al (2021) Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren

Volkova, et al (2016) Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission

Glazova, et al (2021) Semax, synthetic ACTH(4–10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats

Sudarkina, et al (2021) Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4–7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia–Reperfusion

Djillani, et al (2017) Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity

Xing, et al (2021) Progress on the Function and Application of Thymosin β4

Dominari, et al (2020) Thymosin alpha 1: A comprehensive review of the literature

About the author

Rebekah Harding is a Health Writer at The Edge. She is an experienced health and lifestyle writer with both digital and print bylines in Men’s Health, Cosmopolitan, Yoga Journal, Giddy, and more.

Related Articles

Oct 27, 2022

Spoiler: the Best Gym Shorts You Can Buy Aren’t from Nike or Adidas

By Will Price

There's a chance Ten Thousand's internet-famous Interval shorts could get you through 10,000 workouts.

Jul 15, 2022

Try This Cable Fly Superset For a Massive Chest Pump

By Sydney Bueckert, C.S.C.S., NASM-C.P.T.

Don Saladino shares 3 fly variations to crush your chest.

Jan 18, 2023

The Secret to Jason Momoa’s Peak Health? This (Non-Gym) Workout

By Paul Schrodt

Climbing helps the Aquaman star stay in top physical and mental shape. Here's 5 reasons to try it yourself.

Feb 28, 2024

Chirp Wheel Review: Does It Really Help with Back Pain?

Using a Chirp Wheel feels somewhere between a John Mellencamp song and "I've fallen and I can't get up."

Nov 29, 2023

This Pulldown Variation Will Blow Up Your Back (Without the Shoulder and Wrist Pain)

Neutral grip pulldowns: the ultimate back workout for people with achy, stiff joints.

Jan 12, 2024

Does Jawzrsize Give You a Huberman-Level Jaw—or Is it a Looksmaxxing Flop?

The popular podcaster hasn't endorsed the device but that hasn't stopped fans from trying it.

Jul 02, 2024

Cardio Won’t Kill Your Muscle Gains—As Long As You Do This

By Tanner Bowden

Here’s why the common fear of gym-goers hoping to bulk up is largely a myth.

Oct 23, 2023

5 Surprising Ways Exercise Benefits Your Brain, According to a Neurophysiologist

Boost cognitive performance and reduce your risk of neurodegenerative disease.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Biomedicines

Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Peptide Therapy in the Heart Disturbances, Myocardial Infarction, Heart Failure, Pulmonary Hypertension, Arrhythmias, and Thrombosis Presentation

Predrag sikiric.

1 Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia

Mario Udovicic

2 Department of Internal Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia

Ivan Barisic

Diana balenovic, gordana zivanovic posilovic, dean strinic, sandra uzun, suncana sikiric.

3 Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia

Ivan Krezic

Helena zizek, slaven gojkovic, ivan maria smoday, luka kalogjera, hrvoje vranes, marija sola, sanja strbe, antun koprivanac, ivica premuzic mestrovic, tomislav mestrovic.

4 Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia

Predrag Pavic

Anita skrtic, alenka boban blagaic, martina lovric bencic, sven seiwerth, associated data.

The data presented in this study are available on request from the corresponding author.

In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.

1. Introduction

Numerous key clinical trials published or presented at major international conferences over the course of 2021 were reviewed as the most valuable contributions to clinical cardiology (for review, see, i.e., [ 1 ]). Heart failure data focused on trials with sodium–glucose cotransporter 2 (SGLT2) inhibitors, sacubitril/valsartan, and mavacamten for hypertrophic cardiomyopathy [ 1 ]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were centered in the prevention trials [ 1 ].

On the other hand, as a new attempt, from the cytoprotection viewpoint and potential involvement of the cytoprotective agents, we reviewed the potential significance in the heart disturbances of the therapy with the stable gastric pentadecapeptide BPC 157 (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]). It appeared, as a peptide native and stable in human gastric juice, as a late outbreak of the cytoprotection/organoprotection concept of Robert and Szabo, a concept mostly from the stomach studies [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] for epithelial and endothelial protection, like the previous theoretical/practical breakthroughs in the 1980s and brain–gut axis and gut–brain axis (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). However, its compelling basic highlights (particular vascular effect, activation of the collateral pathways) [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] in the most valuable animal models might still be far from the vast clinical evidence obtained in the huge number of clinical trials [ 1 ]. Nevertheless, it might challenge further therapy use.

The novel point, the particular vascular effect for the epithelial and endothelial protection, activation of the collateral pathways [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] might arise from the original BPC 157 cytoprotective evidence [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Given that the conceptual Robert and Szabo’s stomach/cytoprotection relation is translated to the protection of other tissues (Robert and Szabo’s organoprotection), BPC 157, as a peptidergic agent that is native and lacking degradation in the human gastric juice and is stable for more than 24 h, conceptually emerges as a novel cytoprotection mediator with particular cytoprotective capabilities, which are effectively translated into pleiotropic beneficial effects [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. With selective effect on both epithelial and even more endothelial tissue damage (maintaining both epithelial and endothelial integrity), it was very safe, and there were no side effects in clinical trials (i.e., used in ulcerative colitis); a lethal dose (LD1) was not achieved in toxicology studies [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Thus, in general terms, given its easy applicability (including via a therapeutic per-oral regimen), BPC 157 therapy leads to the upgraded minor vessel taking over the function of the failed major vessel to compensate and reestablish the reorganized blood flow [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], which occurs as the recovery of endothelium function [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Thereby, with BPC 157 “bypassing key”, there were reported the prevention and the reversal of the myocardial infarction (for review, see, i.e., [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]), arrhythmias (for review, see, i.e., [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]), and from different origins, heart failure [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ] and pulmonary hypertension [ 41 ] and thrombosis [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Together, these might be the compelling evidence for the implemented concept of cytoprotection (i.e., the process by which chemical compounds provide protection to cells against harmful agents) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ].

Furthermore, in Robert and Szabo’s original view [ 10 , 11 , 12 ], the realization of the cytoprotection/organoprotection concept benefits from the pleiotropic beneficial effects of the cytoprotection agents. Thus, more tissues are protected with better cytoprotective activity. Moreover, conceptually, cell protection per se precludes simultaneous adverse effects on other tissues as well. This wide cytoprotection agenda might be distinctively from a highly focused background, such as the concept of glucose toxicity of the SGLT2 inhibitors [ 42 , 43 , 44 ]. It should be noted that the prototype SGLT1 and SGLT2 blocker, phorizin, did not achieve suitability for human use due to considerable problems (i.e., diarrhea, dehydration, and malabsorption due to small intestine SGLT1 inhibition) [ 42 , 43 , 44 ]. Possibly, this cytoprotection approach [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ] might not limit the current therapy of heart failure SGLT2 inhibitors [ 42 , 43 , 44 ]. Ketoacidosis, urosepsis, pyelonephritis, acute kidney injury, anaphylaxis, and angioedema appeared as additional adverse effects of canagliflozin and empagliflozin use [ 42 , 43 , 44 ]. Moreover, it was pointed out that gliflozin-induced infection, cancers, liver injury, hypoglycemia, and hypovolemia dehydration, hypovolemia, but mostly hypotension or orthostatic hypotension, and hemoconcentration (and thereby, the risk for thrombosis) affected bone metabolism and increased the risk of fracture [ 42 , 43 , 44 ]. Likewise, the wide cytoprotection agenda might also be distinctive from the focused background of the angiotensin-converting-enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers [ 45 , 46 , 47 ], or beta-blockers [ 48 ].

Thus, there is hope that this particular vascular recovering effect of the BPC 157 therapy [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] could finally bring into practice the huge theoretical importance of cytoprotective agents (i.e., selectivity for the damaged epithelium and/or selectivity for the damaged endothelium [ 10 , 11 , 12 ]) long ago proposed in the series of cytoprotection funding reports [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. In the case of stable gastric pentadecapeptide BPC 157, the selectivity for both damaged epithelium and damaged endothelium might rapidly activate cytoprotection maxim endothelium maintenance → epithelium maintenance, making BPC 157 “bypassing key” capable of realizing all therapy aspects of the cytoprotection concept [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Furthermore, as a cytoprotection advantage, with this agenda (i.e., making possible the recruitment of collateral blood vessels, compensating vessel occlusion, and re-establishment of blood flow or bypassing the occluded or ruptured vessel), the stable gastric pentadecapeptide BPC 157/heart disturbances issue (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]) implied the innate resolving of the commonly presented Virchow [ 8 ] and wide beneficial therapeutic effects. Thereby, there was a therapeutic resolution of the severe syndromes, including vascular and multiorgan failure otherwise inducing following vessel(s) occlusion (arteries [ 18 , 19 , 20 ], veins [ 22 , 23 , 24 , 25 , 26 , 27 ], arteries and veins [ 28 , 29 , 30 ], peripherally and/or centrally), and other alike procedures [ 31 , 32 , 33 , 34 , 35 , 36 , 37 ] and damaging agents [ 38 , 39 , 40 , 41 ]. A large pathology that commonly appeared was resolved [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. The intra-cranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension were resolved [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. The severe lesions in the brain, heart (congestion and endocardial infarction), lung, liver, kidney, and gastrointestinal tract were counteracted [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Major vessels congestion (i.e., inferior caval vein, superior mesenteric vein) was reversed to normal vessel presentation, and the failure of the collapsed azygos vein presented as the reactivated pathway for blood flow direct delivery [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. The ECG disturbances [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ] were resolved. Otherwise, overwhelming arterial and venous thrombosis, peripherally and centrally, was almost annihilated as part of the resolved stasis [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Thereby, there was a selective effect on the damaged endothelium, depending on the injured vessel injury and rapid recruitment of the appropriately activated collaterals [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ] (i.e., in rat, azygos vein, in addition to providing direct blood flow delivery, i.e., [ 37 , 38 , 39 , 40 ], resembles the atrial myocardium [ 49 ]) as a useful peptide therapy given the BPC 157 “bypassing key”. This might rapidly occur upon its application [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ] (note, endothelium recovery is known to occur with cytoprotection agents within less than 1 min in stomach injury studies [ 12 ]).

Thereby, from this particular point of view, we will focus on the potential significance of the stable gastric pentadecapeptide BPC 157 in heart disturbances therapy. Possibly, this therapy might equally include the myocardial infarction (for review, see, i.e., [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]), arrhythmias (for review, see, i.e., [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]), acute and chronic heart failure [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ] and pulmonary hypertension [ 41 ] and thrombosis [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ], prevention and reversal, all as interrelated and closely connected effects.

Particular consideration may be in the interaction with many molecular pathways [ 3 , 4 , 5 , 6 , 20 , 22 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], taking as evidence the BPC 157/NO-system’s particular importance (i.e., the endothelium and thrombocytes function both maintained (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ])). BPC 157 therapy counteracted thrombocytopenia in rats underwent major vessel occlusion and deep vein thrombosis [ 22 ] and counteracted thrombosis in all vascular studies [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]), and coagulation pathways not affected [ 58 , 59 , 60 ]. Further arguments might be controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway [ 53 , 54 ]. This likely occurred as the particular modulatory effects on the nitric oxide (NO)-system as a whole, induced NO-release on its own [ 61 , 62 , 63 ], counteracted NO-synthase (NOS)-inhibition [ 61 ] (i.e., N(G)-nitro-L-arginine methylester (L-NAME)-hypertension and pro-thrombotic effect) [ 58 , 62 ], and counteracted NO-over-stimulation [ 61 ] (L-arginine-hypotension and anti-thrombotic, pro-bleeding effect) [ 58 , 62 ]. Likewise, the isoprenaline myocardial infarction was counteracted by NO-effect [ 38 ]. Furthermore, due to its close interaction with NO-system, as NO acts as an endogenous cardioprotectant antifibrillatory factor [ 64 , 65 ] and BPC 157 has no proarrhytmic effect by itself, BPC 157 might counteract various arrhythmias, including those aggravated by NOS-blockade [ 66 , 67 , 68 , 69 , 70 , 71 , 72 ] (note, first communication was about the shortened duration of arrhythmias during hypoxia and the reoxygenation period in isolated guinea pig hearts [ 73 ]). Moreover, there might be modulatory effects on the prostaglandins system [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 74 ]; BPC 157 counteracted NSAIDs toxicity (associated with the occurrence of symptoms of heart failure [ 75 , 76 ], including prolonged bleeding and thrombocytopenia [ 58 , 59 , 60 ] (for review, see, i.e., [ 74 ]) and indomethacin-induced leaky gut syndrome, in particular (for review, see, i.e., [ 5 ])).

1.1. Cytoprotection Background (Direct Epithelial Cell Protection) for BPC 157 Beneficial Activity

The wide applicability of the original postulates of Robert and Szabo’s cytoprotection concept (for review, see, i.e., [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]) might approach the entire problem of heart failure. This wide approach might be useful as a large number of the concomitant diseases with heart failure might be the key for the therapeutic effects [ 77 , 78 , 79 ], as the stable gastric pentadecapeptide BPC 157 pleiotropic effect belongs to the cytoprotective class of agents (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). Note the general background of the BPC 157 beneficial effects on various organs injuries (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]), which helps one recognize the wide significance of the cytoprotection concept of Robert’s (direct epithelial cell protection) [ 10 ] and Szabo’s (direct endothelium cell protection) [ 12 ] that is initiated in the stomach to be further generalized. The foundation of the cytoprotective agents’ putative activities in the stomach studies was the initial basic point for their possible therapy extension [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. In general, BPC 157 successfully follows the common cytoprotective principle: the original cytoprotective agent with a prime beneficial effect in the stomach (direct (epithelial) cell protection) had to be transmitted to similar beneficial effect in other organ lesions as well (cytoprotection → organoprotection) [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). Noteworthily, BPC 157 therapy, in practical terms (native and stable in human gastric juice for more than 24 h, and, thereby, easily applicable), unlike standard cytoprotective agents, fully presumes original cytoprotective requirements (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). Thereby, the extent of the obtained beneficial effects largely overrides the range of the beneficial effects commonly reported with the standard cytoprotective agents (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]) (i.e., prostaglandins’ beneficial effects on stomach [ 10 ], intestine [ 13 ], liver [ 80 ], pancreas [ 13 ], kidney [ 81 ], and heart [ 82 ]). Unlike the effectiveness only given before injury (prophylactic effect) of the standard cytoprotective agents (for review, see, i.e., [ 10 , 11 ]), BPC 157, in addition to its prophylactic effect, has a strong curative effect given even much later after injury induction, during ischemia as well as during reperfusion (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). Illustratively, as mentioned before, in the vascular studies, as a part of the severe vascular and multiorgan failure syndrome counteraction, there was counteraction of the brain, heart, lung, liver, kidney, and gastrointestinal lesions [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Moreover, in other separate studies, there was counteraction of the brain [ 83 ], spinal cord [ 35 , 36 ], heart failure [ 84 ], lung [ 41 , 85 , 86 , 87 ], liver lesions [ 88 , 89 , 90 ], liver, gastrointestinal and brain lesions [ 91 , 92 , 93 , 94 , 95 , 96 ], and kidney [ 97 , 98 , 99 ] and pancreas [ 100 , 101 ] lesions. There was also a strong wound-healing effect (for review, see, i.e., [ 3 , 102 ]). Thereby, there was the curing of the skin [ 53 , 55 , 103 , 104 , 105 ], nerve [ 106 ], tendon [ 50 , 51 , 107 , 108 , 109 , 110 , 111 ], muscle [ 110 , 111 , 112 , 113 , 114 , 115 ], ligament [ 116 ], and bone [ 117 , 118 , 119 ] injuries that spontaneously might not heal. In particular, there was a capability to simultaneously organize the healing of the different tissues (as an example occurred the healing of the osteotendinous junction [ 108 , 109 ] and the healing of the myotendinous junction [ 111 ] (and neuromuscular junction function recovering [ 68 ]) or the healing of the fistulas, external and internal [ 120 ]). Likewise, in particular regard for wounding [ 3 , 102 ], these realized healing effects in the various wounds [ 53 , 55 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ] might evidence the realized healing process after blood vessel are ruptured as a whole, and thereby, as we claimed [ 59 ], a distinctive effect on all four major events in clot formation and dissolution was fully accomplished. This meant a highly utilizable special effect, especially with heart failure therapy [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Moreover, BPC 157 is very safe, with no adverse effect in clinical trials (i.e., ulcerative colitis), and lethal dose (LD1) was not achieved in toxicology studies (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]).

Thereby, these beneficial effects (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]) fulfill the cytoprotection (organoprotection) frame at the general level (implied direct cell protection) [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ], with all of the mentioned beneficial effects as pre-requests for the resolved heart disturbances. In these terms, the effect on the heart (cardioprotection) might be an additional part of the cytoprotective activity (for review, see, i.e., [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 121 , 122 , 123 ]), and, in particular, it might be commonly taken as proof and consequence of its innate cytoprotective activity (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). In addition to being native and stable in human gastric juice for more than 24 h, BPC 157 was found in situ hybridization and immunostaining studies in humans to be largely distributed in tissues [ 3 , 102 ] and may have additional physiologic regulatory roles [ 8 , 102 ] as it is thought to be a novel cytoprotective mediator. Furthermore, there is a particular healing effect depending on the tissue involved (for review, see, i.e., [ 3 , 102 ]). Particularly, there is an improved healing effect (for review, see, i.e., [ 3 , 102 ]) for eye injuries (no angiogenesis) [ 124 ] versus advanced angiogenesis in other tissues (i.e., tendon, muscle) [ 110 ] (for review, see, i.e., [ 3 , 102 ]), which together might provide evidence that BPC 157s beneficial effect is even more complex and tissue specific. Illustratively, BPC 157 eye drops successfully closed perforating corneal incisions in rats; controls developed new vessels that grew from the limbus to the penetrated area, whereas BPC 157-treated rats generally had no new vessels, and those that did form in the limbus did not make contact with the penetrated area [ 124 ]. Thus, important for heart healing as well, BPC 157 certainly might control one of the most important aspects of the cytoprotection and cytoprotective agents activity in long terms (i.e., days): the angiogenesis (corneal avascularity as “angiogenic privilege”) (for review, see, i.e., [ 3 , 102 ]).

1.2. Cytoprotection Background (Direct Endothelial Cell Protection) for BPC 157 Beneficial Activity

Overwhelmingly focused on stomach cytoprotection, the pioneers, Robert (direct epithelial cell protection) [ 10 ] and Szabo (direct endothelium cell protection) [ 11 ], estimated in stomach damage studies the maxim endothelium maintenance → epithelium maintenance as rapid injury, rapid defensive response, vascular injury within less than 1 min, thrombus and stasis [ 11 ], thereby, although not claimed, Virchow triad circumstances. Moreover, finally, the rapid recovery of damaged endothelium occurred as a shared effect of the cytoprotective agents within stomach cytoprotection [ 11 ]. With BPC 157 effect (see above), there is an advanced practical realization of the original maxim functioning [ 8 ]. This might be the rapid upgrading of the minor vessel to take over the function of the disabled major vessel [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ], as the particular effect on the vessel relied on the given injury. Furthermore, this implies competing with the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion, and reestablishing blood flow or bypassing the occluded or ruptured vessel [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Illustrative examples might be the therapy of glaucoma in rats after the cauterization of three of the four episcleral veins [ 26 ], venous congestion, and the increased intraocular pressure and consequent glaucoma injurious course [ 26 ]. For the BPC 157 therapy importance estimation [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ], one remaining episcleral vein was upgraded so that BPC 157 therapy did compensate all functions; otherwise, inescapable venous congestion and the increased intraocular pressure and consequent glaucoma injurious course fully reversed [ 26 ]. Moreover, BPC 157 therapy (the rapid upgrading of the collateral pathways) has cured many severe syndromes, including multiorgan and vascular failure [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ], and heart dysfunction and thrombosis as cause–consequence, in particular. Otherwise, without therapy, these syndromes were commonly presented in rats with the permanent occlusion of major vessels (veins and/or arteries [ 18 , 19 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], peripherally and centrally), major intoxication (lithium, alcohol) [ 39 , 40 ], acute pancreatitis [ 37 ], myocardial infarction [ 37 ], and maintained intra-abdominal hypertension [ 31 ]. Its applicability in the rapid upgrading of the collateral pathways may likely provide an additional beneficial effect for the heart functions, and various vessel tributaries, and normalization/attenuation of the intracranial (sinus sagittal) hypertension, portal and caval hypertension and aortal hypotension, and counteraction of the multiorgan failure syndrome [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ].

We suggested these particular effects and this background as a network of the evidence for the physiologic significance of the revealed BPC 157/vascular-system interplay [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] (i.e., in situ hybridization and immunostaining studies in humans evidenced BPC 157 large distribution in tissues [ 102 ] and suggested its additional physiologic regulatory roles [ 8 , 102 ]).

In this agenda, we will further review heart disturbances and specifically indicate the particular effects of BPC 157 therapy.

2. Myocardial Infarction

2.1. isoprenaline myocardial infarction.

Myocardial infarction induced with the suited doses of isoprenaline and re-infarction (after two isoprenaline applications) [ 38 ] and reversed with the stable gastric pentadecapeptide BPC 157 (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]) may represent the usefulness of the peptide therapy ( Table 1 ). In consideration of the myocardial infarction, arrhythmias, heart failure, pulmonary hypertension, and thrombosis presentation, the therapy of myocardial infarction might occur as definitive proof of the successful outcome. Isoprenaline myocardial infarction was used as the first prototype of rapid methods in rats, verified to fairly mimic acute myocardial infarction in humans [ 125 ]. In addition, there is the additional therapy target, early vascular failure, recently pointed out [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ], and the upgrading of the minor vessel to take over the function of the disable major vessel, competing with the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels also in isoprenaline rats [ 38 ]. Therefore, important for the isoprenaline myocardial infarction, and generally, we revealed these antecedent early noxious effects [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ], and the early vascular failure as being isoprenaline-induced, which is, so far, less recognized, and less considered, peripherally and centrally. Centrally, without therapy, in the isoprenaline rats, there was intracranial (superior sagittal sinus) hypertension, severe brain swelling, large intracerebral hemorrhage, and intraventricular hemorrhage in the third ventricle, marked karyopyknosis in the cerebral, cerebellar cortex and hippocampus, while the hypothalamus appeared to be relatively spared (only rare karyopyknotic cells) [ 38 ]. Peripherally, there was portal and caval hypertension; aortal hypotension; congested (i.e., inferior caval vein and superior mesenteric vein) and failed (azygos vein) blood vessels; multiple organ lesions, i.e., the heart dilatation, myocardial congestion and confluent areas of subendocardial ischemic myocytes, ECG disturbances (i.e., giant T-wave); and severe congestion in the lung, liver, kidney, and gastrointestinal tract [ 38 ]. Venous and arterial thrombosis were progressing peripherally and centrally [ 38 ]. Essentially (i.e., providing common vascular disability point and heart dysfunction), this corresponds to the described large syndrome commonly seen with the endothelium damaging agent overdose, alcohol [ 40 ] and lithium [ 39 ], acute pancreatitis [ 37 ] and maintained intra-abdominal hypertension, grade III and grade IV [ 31 ], as well as corresponding to the described occlusion syndrome with major vessels occlusion, peripheral [ 19 , 24 , 29 ] or central [ 27 ]. Thus, these disturbances, and consequently, the beneficial counteraction by BPC 157 therapy, may have a general significance [ 38 ]. Commonly, these disturbances [ 38 ], presented as shared occlusion-like and occlusion syndromes [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ], may provide additional prototypes for the heart lesions, vascular failure, and therapy possibilities. Of note, all of these disturbances were consistently attenuated with BPC 157 therapy application and the activation of the collateral pathways, relayed on the given injury [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ].

Summarized presentation of the BPC 157 therapy effect on myocardial infarction and heart failure that were induced in the vascular studies [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ].

Thus, given the initial infarct induction and re-infarction (the myocardial lesions after two isoprenaline applications) and that BPC 157 markedly counteracts myocardial isoprenaline lesions, the findings provide multidirectional evidence [ 38 ]. Specifically, there is a large range of the BPC 157 regimens (ng-µg) [ 38 ] and huge range of the therapy possibilities (i.e., a sustained effect given before isoprenaline, and a rapid effect given after isoprenaline, mortality absent in BPC 157 rats) [ 38 ]. Thus, there is consistent and quite complete evidence (i.e., reduction in all of the routine necrosis markers, grossly no visible infarcted area, attenuated histological damage, ECG (no ST-T ischemic changes), and echocardiography (preservation of systolic left ventricular function) damage and oxidative stress parameters decreased) [ 38 ]. The interaction with eNOS and COX2 gene expression, and counteraction of the aggravation effect of the NOS-blocker, L-NAME [ 38 ], might suggest that NO system function might be accordingly recovered.

The given therapy effect on the initial heart infarct induction and re-infarction [ 38 ], as well as indicated anti-thrombotic [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ] and anti-arrhythmic effect [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]) of the BPC 157 therapy, might strongly support the comparable BPC 157 therapy effect on stroke in rats and therapy in the reperfusion after bilateral clamping of the common carotid arteries for a 20-min period [ 20 ]. As assessed at 24 h and 72 h of the reperfusion, the therapy counteracted both early and delayed neural hippocampal damage, achieving full functional recovery (Morris water maze test, inclined beam-walking test, lateral push test) [ 20 ]. mRNA expression studies at 1 and 24 hr, provided, in the hippocampus, strongly elevated (Egr1, Akt1, Kras, Src, Foxo, Srf, Vegfr2, Nos3, and Nos1) and decreased (Nos2, Nfkb) gene expression (Mapk1 not activated), as a way how BPC 157 may act [ 20 ]. Considering the ischemic event itself in rats with the occluded superior sagittal sinus, without therapy, the complete infarction was within 24 h and marked karyopyknosis at 48 h [ 27 ]. In all BPC 157 rats, the consistent neuroprotective effect appeared in all brain areas, and there were only a few karyopyknotic neurons [ 27 ].

In this, the BPC 157 therapy prompt activation of the azygos vein, as before upon BPC 157 therapy [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]) goes along with the combining notation about the atrial myocardium and azygos vein resemblance in the rat [ 49 ]. Consequently, the counteraction of the myocardial infarction course might go via azygos vein activation that BPC 157 therapy might promptly initiate (note, without BPC 157 therapy, the azygos vein remained completely collapsed, in the isoprenaline-treated rats, in particular) [ 38 ]. There might be prompt direct delivery of blood flow, compensation, and no more failed vessel (i.e., initially congested inferior caval vein and superior mesenteric vein recovered to the normal vein presentation), and blood flow reorganized, seeable with the absent caval and portal hypertension and the decreased brain swelling, and the decreased intracranial (superior sagittal sinus) hypertension [ 30 ]. The restored function immediately upon administration might regain reversal of the venous and intracranial hypertension [ 38 ] since recovered heart function [ 38 ] might ascertain the ability to drain venous blood adequately for a given cerebral blood inflow without raising venous pressures. Grossly, the counteracted progressing venous and arterial thrombosis, peripherally and centrally, counteracted ECG disturbances, and no heart dilatation and absent gastrointestinal (stomach) lesion [ 38 ] were present with all microscopic findings. The myocardial presentation was without congestion, and confluent areas of subendocardial ischemic myocytes and the lung, liver, kidney, and gastrointestinal tract were with only mild congestion. Intracerebral hemorrhage and intraventricular hemorrhage in the third ventricle were absent, and karyopyknosis was almost annihilated in all of the brain areas. As mentioned for isoprenaline-myocardial infarction [ 38 ], the same chain of events might be seen as a shared principle [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Illustratively, the rats underwent the endothelium damaging agent overdose, alcohol [ 40 ] and lithium [ 39 ], bile duct ligation, acute pancreatitis [ 37 ] and maintained intra-abdominal hypertension, grade III and grade IV [ 31 ], as well as the described occlusion syndrome with major vessels occlusion, peripheral [ 19 , 24 , 29 ] or central [ 27 ].

Thus, this might be recognized as a special heart-brain-blood vessels interacting axis (providing in the counteracted multiorgan failure, the attenuated myocardial lesions, and arrhythmias as an achieved important tool, either as a cause or as a consequence), peripheral and central interplay, as an essential defensive response [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. This would be further analyzed specifically with respect to the particular myocardial lesion and heart failure in the large syndrome commonly seen also with the endothelium damaging agent overdose, alcohol [ 40 ] and lithium [ 39 ], acute pancreatitis [ 37 ], and maintained intra-abdominal hypertension, grade III and IV [ 31 ], as well as in the described occlusion syndrome with major vessels occlusion, peripheral [ 19 , 24 , 29 ] or central [ 27 ].

It should be noted that to verify the suggested peripheral and central interplay, the studies also implied several routes of BPC 157 application, with equipotent beneficial therapy effect [ 19 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Local application at the swollen brain implies a direct effect; intraperitoneal or intragastric administrations mean a systemic effect; µg- and ng-regimens mean a common beneficial effect [ 27 ]. Conceptually, intragastric application benefits BPC 157 importance as an original cytoprotective anti-ulcer peptide (i.e., epithelium, endothelium maintenance and protection) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ].

2.2. Heart Failure

As a follow-up of the described therapy course in the rats with acute myocardial infarction [ 38 ], we evidenced that BPC 157 therapy might counteract acute heart failure as it might compensate for the effect of the severe blood flow restriction to the heart ( Table 1 ). This might occur in a very short time with the major vessel occlusion [ 19 , 24 , 27 , 29 ], artery [ 19 ] or vein [ 24 ], or artery and vein [ 29 ], peripherally and centrally, and trapped large blood volume [ 19 , 24 , 29 ]. The evidenced marked congestion within the myocardium and large coronary branches included the occlusion of the superior mesenteric vein [ 24 ], the occlusion of the superior mesenteric artery [ 19 ], the simultaneous occlusion of both the superior mesenteric artery and the superior mesenteric vein [ 29 ], and centrally, the occlusion of the superior sagittal sinus [ 27 ]. The subendocardial infarct, as well as congestion within the myocardium, regularly appeared in the rats with the occluded superior mesenteric vein and artery [ 29 ].

Furthermore, as mentioned before (see Section 2.1 , Isoprenaline-myocardial infarction [ 38 ]), we demonstrated that, in addition to the isoprenaline-myocardial infarction [ 38 ], the other major noxious events [ 31 , 37 , 38 , 39 , 40 ] also acutely caused the prominent heart failure and widespread dysfunction similar to that observed in rats after the occlusion of the peripheral [ 19 , 24 , 29 ] and central [ 27 ] vessels. These were the endothelium damaging agents, i.e., alcohol [ 32 ] or lithium [ 31 ], bile duct occlusion (acute pancreatitis) [ 29 ], organs and vessels compression (intra-abdominal hypertension) [ 31 ]. As emphasized before, these occlusion-like syndromes [ 19 , 24 , 27 , 29 ] shared the previously described peripheral and central deficits noted in the occlusion syndromes and were largely counteracted by the given BPC 157 therapy. Characteristically, with intragastric absolute alcohol, a prototype noxious agent in the cytoprotection studies, there was timely advancing heart failure [ 40 ]. There were rapidly produced heart dilatation and lesions worsening (i.e., 1 min < 5 min < 15 min < 30 min; moderate congestion ˂ tissue congestion and persistent hemorrhage < passive congestion in the myocardium, with acute subendocardial infarct (note contribution of low aortic pressure) < prominent congestion and acute subendocardial infarct) [ 40 ]. Rats treated with lithium sulfate overdose for three days since the beginning of treatment presented with severe myocardial congestion, along with subendocardial infarcts and neutrophilic infiltration of the infarcted areas, in particular after the second and third doses of lithium [ 39 ]. In the rats with a ligated bile duct, heart dilatation and marked myocardial congestion was consistently noted at 30 min, 5 h, and 24 h ligation time [ 37 ]. Already within a very short time with severe intra-abdominal hypertension 25 mmHg, grade III, there was myocardial congestion and sub-endocardial infarction, which appeared as the ultimate outcome [ 31 ]. The myocardial congestion and sub-endocardial infarction occurred in an even shorter time with the more severe intra-abdominal hypertension, grade IV (i.e., 30 mmHg/30 min, 40 mmHg/30 min, 50 mmHg/25 min) [ 31 ]. Rats with the occluded major vessel(s) superior mesenteric vessels or superior sagittal sinus commonly presented prominent congestion and acute subendocardial infarct (rats with the occluded superior mesenteric artery and vein) [ 19 , 24 , 27 , 29 ].

On the other hand, commonly, BPC 157 therapy counteracted heart failure, and the BPC 157 rats exhibited either normal heart microscopic presentation or markedly attenuated lesions [ 19 , 24 , 27 , 29 ]. With normal heart microscopic presentation of the rats, they were found with occluded major vessels [ 19 , 24 , 27 , 29 ], or challenged with intragastric absolute alcohol [ 40 ], an overdose of lithium [ 39 ], or maintained severe intra-abdominal hypertension, grade III and grade IV [ 31 ]. Likewise, with BPC 157, in the rats with the occluded bile duct, the early regimen resulted in no changes in 30 min ligation time and only mild myocardial congestion at 5 h and 24 h ligation time [ 37 ]. Thus, it might be that the countermeasures commonly achieved with BPC 157 therapy might ascertain the normal heart presentation despite the continuous presentation of the severely harmful circumstances of the major vessel(s) occlusion, bile duct occlusion, severe intra-abdominal hypertension, or noxious agents’ application [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Evidently, as mentioned before, the bypassing loops were reliant on the corresponding injurious occlusion and might reestablish the reorganized blood flow, thus compensating vessel occlusion and markedly attenuating the harmful syndrome severity [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. There, the number of vessels was identified as useful collateral. There were the left ovarian vein, inferior mesenteric vein, inferior anterior pancreaticoduodenal vein, superior anterior pancreaticoduodenal vein, pyloric vein, (para)sagittal venous collateral circulation, and azygos vein as venous pathways, the inferior mesenteric artery and inferior anterior pancreaticoduodenal artery as alternative arterial pathways (i.e., occluded superior mesenteric artery) [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Together, these might clearly suggest that this BPC 157 therapy effect might have common application [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ].

It might be claimed that this therapeutic effect might also ascertain the resolution of the concomitant arrhythmias in heart failure (in heart failure, arrhythmias are commonly acknowledged as the final cause of death [ 126 ]). Commonly, there was marked tachycardia, prolonged PQ and QTc intervals, and ST elevation (major vessel(s) occlusion, bile duct occlusion, alcohol intoxication) as identifiers of acute thrombotic coronary occlusion and right heart failure [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. These all rapidly disappeared under all the BPC 157 regimens (as also noticed in the Pringle maneuver ischemia, reperfusion, portal triad temporary occlusion, and in the Budd–Chiari syndrome with BPC 157 therapy in rats) [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Note, it might be a biventricular failure that was accordingly counteracted (as a follow-up of the right heart failure, there was marked congestion of the inferior caval vein, superior mesenteric vein, liver, kidney, and gastrointestinal tract while congested lung with hemorrhage also evidenced left heart failure, all counteracted by BPC 157 therapy) [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Lithium overload induced rapidly significant ST elevation, prolonged QTc intervals, and atrioventricular conduction disturbances (i.e., total AV block), in addition to marked bradycardia [ 39 ]. Contrarily, BPC 157-treated rats exhibited no repolarization changes, and they showed the conduction system of the heart functioned normally and the normal heart frequency at all time checkpoints and none of the atrioventricular conduction disturbances [ 39 ]. There might be additional particular relevance. Namely, the used regimen (500 mg/kg, ip, once daily for three consecutive days) (i.e., higher than usual lithium regimens [ 127 , 128 , 129 ] but markedly below usual LD50 for lithium application in rats [ 130 ]) might be closer to those used in patients considering the conversion of animal doses to human-equivalent doses based on body surface area [ 131 ]. Maintaining the severe intra-abdominal hypertension 30 mmHg/30 min, 40 mmHg/30 min, and 50 mmHg/25 min revealed the downhill course timely along with the nodal rhythm, with dominant ST-elevation and bradycardia [ 31 ]. Extreme bradycardia and asystole appeared as the ultimate outcome [ 31 ]. Contrarily, all BPC 157-treated rats exhibited consistently preserved heart function, with fewer ECG disturbances [ 31 ] (preserved sinus rhythm, with occasional first-degree AV block, without ST-elevation, extreme bradycardia and asystole) [ 31 ] and normal heart microscopic presentation. To emphasize the achieved therapy effect significance, we should stress the persisting worst circumstances of intra-abdominal hypertension, grade III and grade IV [ 31 ], pushing up the diaphragm, the most constrained thoracic cavity [ 31 ], the rapid transmission of the increased pressure between the three body cavities [ 31 ].

It might be claimed that this therapy recovery effect in heart failure might also ascertain the resolution of the concomitant thrombosis in heart failure [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. In all of the experiments, the progressing thrombosis in the veins and arteries, peripherally and centrally (i.e., as noted in the inferior caval vein, portal vein, lienal vein, superior mesenteric vein, superior sagittal sinus, abdominal aorta, hepatic artery, superior mesenteric artery) was almost annihilated [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. Therefore, along with recovered heart function and annihilated arrhythmias, resolved thrombosis might be the final identifier of the resolved stasis as well, and removed Virchow triad circumstances [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ].

Considering the more extended experiments, there was by BPC 157 therapy the counteraction of the monocrotaline-induced pulmonary hypertension in rats [ 41 ]. It might be that BPC 157 therapy might affect the monocrotaline course as a whole since pulmonary damage (hours), edema (after one week), pulmonary artery hypertension (after two weeks), right ventricle hypertrophy (after three weeks), and considerable fatal rate (after four weeks), given the same beneficial effect of both the prophylactic regimen and the delayed therapeutic regimen [ 41 ]. Analyzing how pentadecapeptide BPC 157 prevents and counteracts monocrotaline-induced pulmonary arterial hypertension and cor pulmonale in rats, the evidence seems to be quite compelling. The experimental protocol [ 41 ] comparable to the clinical situation [ 132 ] (pulmonary hypertension in the untreated monocrotaline group on day 14) meant the delayed therapy initiation (i.e., day 14) was well-chosen [ 133 ] (avoiding the misleading considering the therapeutic effect [ 132 ] with shorter premature intervals (day 11 or day 12) after monocrotaline [ 132 , 134 ]). Additionally, the range of the assessed disturbed parameters (which were all counteracted) fully corresponded to other studies [ 132 ]. They included disturbed wall thickness, total vessel area, and heart frequency; QRS axis deviation; QT interval prolongation (known to correlate with pulmonary pressure and right ventricle dilation and inversely correlate with right ventricle function [ 135 ]; right ventricle hypertrophy; increased right ventricle weight [ 136 , 137 ]; an increase in right ventricle systolic pressure; mortality; and bodyweights loss). In particular, the reduced body weight as a marker of clinical deterioration in the animal, as in the patient, again accords with previous studies [ 136 ]. Likewise, with respect to the timing of the initiation of therapy being crucial [ 132 ], there was the prophylactic effect (just after monocrotaline), pulmonary hypertension not even developed, as well as the therapeutic effect (on day 14 after monocrotaline) the advanced pulmonary hypertension was rapidly attenuated and then completely eliminated (delayed regimen) [ 41 ]. Thus, there is compelling evidence [ 41 ] that the right ventricle can be therapeutically targeted in pulmonary arterial hypertension [ 135 ].

Further extension toward the chronic heart failure effect [ 84 ] was based on the estimated role of the endothelin, and thereby NO-system [ 137 ], doxorubicin model [ 138 ], and delayed BPC 157 therapy application [ 84 ]. After the doxorubicin regimen (total dose of 15 mg/kg intraperitoneally, divided at six time points, every third day for 14 days to induce congestive heart failure), and after four weeks of rest, assessed in mice and rats with advanced disease, the increased big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT), before and after the subsequent 14 days of therapy, and clinical status (hypotension, increased heart rate, and respiratory rate, and ascites) every two days [ 84 ]. Without therapy, throughout 14 days, both rats and mice further raised BET-1 serum values and aggravated clinical status, while enzyme values maintained their initial increase [ 84 ]. BPC 157 (10 µg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC 157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC 157 (10 ng/kg) reduces AST and ALT serum values. The clinical status of chronic heart failure in rats and in mice is accordingly improved by the BPC 157 regimens and amlodipine [ 84 ]. However, indicatively, in translation to the counteracted hypotension, no dyspnea with increased heart and respiratory occurred in BPC 157 treated animals, whereas hypotension and dyspnea with increased heart rate and respiratory rate persisted in the losartan and amlodipine treated animals [ 84 ].

Thus, BPC 157 therapy as applied as intragastric application, per-oral in drinking water, might exert the reversal of the doxorubicin-induced congestive heart failure, effective even in the advanced status of failing heart in rats and mice studied by the reversal of the BET-1 plasma level [ 84 ]. These findings’ relevance goes with the known local activation of the big endothelin-1 (BET-1) system [ 139 , 140 , 141 , 142 ]. This characterizes most cardiovascular diseases (including doxorubicin-congestive heart failure [ 84 ]), renal failure, and functional and structural changes in the cardiovascular system [ 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 ]. Commonly, endothelin relationship with NO-system dysfunction and BET-1 plasma levels might well recognize the particular BPC 157/NO-system relation and BPC 157/vascular system interplay [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] along with its innate cytoprotection background (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]) on the severity of congestive heart failure [ 150 , 151 , 152 , 153 , 154 ], and the effects of therapy as well as the rate of ET-1 synthesis [ 143 , 144 , 152 , 153 , 154 ]. Note, BPC 157 therapy with counteracted heart lesions might actually improve the effectiveness of drugs used in chemotherapy for cancer patients, both solid tumors and leukemia, anthracyclines, i.e., doxorubicin, epirubicin, and daunorubicin, otherwise markedly limited with damage to the heart [ 155 , 156 , 157 ].

Moreover, particularly with respect to doxorubicin-heart lesions, BPC 157 may be more than one of a large number of the cardioprotective agents (for review, see, i.e., [ 155 ]) and might particularly consider the special vulnerability of the heart to injury from free radicals, and lower level of protective enzymes such as superoxide dismutase [ 158 , 159 ]. Namely, the evidence that BPC 157 may have a particular effect on the heart [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 84 ] goes with its acting as free radical scavenger [ 5 , 6 ], counteraction of the free radicals-induced lesions in different tissues [ 5 , 6 , 19 , 22 , 24 , 25 , 27 , 28 , 29 , 30 , 32 , 33 , 34 , 38 , 39 , 90 , 160 , 161 ], and thereby, due to its particular cytoprotective/cardioprotective activity [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], it might beneficially affect the myocardial lesions, in particular [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 84 ]. As an additional advantage, BPC 157 itself also showed a prominent anti-tumor effect [ 6 , 162 ] and might counteract the VEGF-tumor-promoting effect [ 163 ], as well as tumor cachexia [ 6 ]. Thus, its cardioprotective intervention during anthracycline therapy should be without reducing the anti-tumor efficacy and likely due to its pleiotropic beneficial effect [for review see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]), it should also decrease negative effects on toxicities other than cardiac damage (i.e., BPC 157 reduced cyclophosphamide-induced gastric and duodenal lesion, and bladder toxicity [ 160 , 161 ]).

2.3. Heart Failure Concomitant Pathology

As mentioned before in the acute myocardial infarction studies [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ] and BPC 157 therapy application, the evidence that the heart failure cause–consequence occurred with the wide range of the concomitant multiorgan failure and initiated multicausal noxious circuit that might also be counteracted by BPC 157 therapy, was specifically elaborated. This was conducted in a series of the different major noxious events and BPC 157 therapy effects, peripherally or centrally, and/or peripherally and centrally [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. As challenges confronted with BPC 157 therapy beneficial effects, we used distinctive noxious procedures. This was a confrontation with the occlusion of the superior mesenteric vein, the occlusion of the superior mesenteric artery, the occlusion of the superior mesenteric vein and artery, the occlusion of the superior sagittal sinus, the intragastric application of the absolute alcohol, subsequent intraperitoneal administrations of the lithium overdose, and maintained severe intra-abdominal hypertension grade III and grade IV [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. Thereby, there was a large range of the therapy effect, given the similar heart failure described before, and all concomitant similar to multiorgan failure, relayed to the various noxious conditions (i.e., constant major vessel(s) occlusion, constant mechanical compression of the organs and vessels, abrupt challenge of the intragastric bolus (absolute alcohol) or repeated subsequent applications of the lithium-overdose) [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. These multiple organ failure lesions might be perceived as the lesions following diverse noxious agents’ direct effect, highlighted in the cytoprotection studies, and vice versa; the counteraction, pleiotropic beneficial effect by BPC 157 therapy might also be understood in the general cytoprotection terms [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ].

Centrally, without therapy, there was intracranial (superior sagittal sinus) hypertension as a shared disturbance (note, the regular negative values (i.e., −27 mmHg) changed to the high positive values), quickly counteracted by BPC 157 therapy (reestablished negative pressure values) [ 27 ]. Thus, given the recovered heart failure, there was a recovered ability to drain venous blood adequately for a given cerebral blood inflow without raising venous pressure (in contrast, the harmful inability suddenly causes venous and intracranial hypertension) [ 27 ]. Moreover, the instant severe brain swelling was shared (i.e., in lithium-rats [ 39 ] as well as in the alcohol-rats [ 40 ]; the brain volume proportional with the change in the brain surface area revealed an immediate increase to 120% of the healthy presentation). Likewise, there was also shared therapy effect of BPC 157 therapy, and promptly attenuated brain swelling. Regularly, without therapy, all investigated noxious procedures (i.e., alcohol intoxication, lithium intoxication, maintained severe intra-abdominal hypertension, vessels occlusion, superior mesenteric artery and/or vein, and superior sagittal sinus) [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ] presented the severely damaged brain areas, i.e., cerebral and cerebellar cortex, hypothalamus/thalamus, and hippocampus. Prominent edema and large areas with increased numbers of karyopyknotic cells occurred as shared harmful and inevitable outcomes. These were all attenuated or even eliminated by BPC 157 therapy. As a distinctive point, there was a large intracerebral hemorrhage fully counteracted by BPC 157 therapy. Illustratively, the lithium rats exhibited hemorrhage in the deeper brain, both gray and white matter. Rats with bile duct occlusion presented pronounced intracerebral hemorrhage affecting large areas of the corpus callosum, amygdala, thalamus, neocortex, and striatum, and intraventricular hemorrhage in the third and lateral ventricles [ 39 ]. After intragastric alcohol, brain edema after 1 and 5 min, with vascular congestion progressed after 15 and 30 min to generalized congestion, edema, and intracerebral hemorrhage, with degenerative changes in the cerebral and cerebellar neurons indicating toxic changes created by the ethanol [ 40 ]. In the rats with occluded superior mesenteric artery and superior mesenteric vein [ 29 ], there was a subarachnoid hemorrhage at the base of the brain in the cerebellar area, and more karyopyknotic cells in the cerebral and cerebellar cortex, hippocampus, and hypothalamus/thalamus. In the rats with the occluded bile duct, there were timely progressing pronounced intracerebral hemorrhages in areas of the corpus callosum, amygdala, thalamus, neocortex, and striatum, intraventricular hemorrhage involving the third and lateral ventricles and more karyopyknotic cells in the cerebral and cerebellar cortex, hippocampus, and hypothalamus/thalamus [ 37 ]. In the rats with the occluded superior sagittal sinus, complete infarction appeared at 24 h and marked karyopyknosis at 48 h [ 27 ]. Rats with maintained severe intra-abdominal hypertension exhibited subarachnoid hemorrhage at the base of the brain in the cerebellar area and more karyopyknotic cells in the cerebral and cerebellar cortex, hippocampus, and hypothalamus/thalamus [ 31 ]. These brain lesions appeared to be distinctively affected by high intra-abdominal pressure; i.e., the most progressive hippocampal neuronal damage was found with the highest intra-abdominal pressure [ 31 ].

Thus, the indication of the brain lesions and hemorrhage and their counteraction evidence might be seen as particular maxim (i.e., occluded superior mesenteric vessels vs. occluded superior sagittal sinus vs. alcohol/lithium application vs. bile duct occlusion vs. maintained intra-abdominal pressure, prime peripheral lesions vs. prime central lesions vs. peripheral and central lesions) [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. This might suggest that the heart failure cause–consequence might occur in a bidirectional way that might be both beneficially affected by the BPC 157 therapy.

At the periphery, there were portal and caval hypertension and aortal hypotension, markedly attenuated or even eliminated by BPC 157 therapy [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. In particular, depending on the prime injurious challenge (i.e., vascular occlusion vs. bile duct occlusion vs. intragastric absolute alcohol vs. intraperitoneal lithium challenge vs. maintained intra-abdominal hypertension), the lesion shared considerable severity along with the described heart failure and prominent brain lesions [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. These were all attenuated or even eliminated by BPC 157 therapy [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Illustratively, rats with maintained severe intra-abdominal hypertension exhibited lung parenchyma with marked congestion and large areas of intra-alveolar hemorrhage, vascular dilation of the liver parenchyma, and severe congestion of renal tissue [ 31 ]. With a severity increase from the upper toward the lower part of the gastrointestinal tract, there was transmural hyperemia of the entire gastrointestinal tract, stomach, duodenum, and small and large bowel wall, along with a reduction in the villi in the intestinal mucosa, crypt reduction with focal denudation of superficial epithelia, and dilatation of the large bowel [ 31 ]. Likewise, without therapy, all of the rats with the occluded superior mesenteric vessel(s) (i.e., occluded superior mesenteric artery, or occluded superior mesenteric vein, or occluded both superior mesenteric artery and vein) exhibited marked transmural congestion in an ascending sequence from the stomach to the large bowel [ 19 , 24 , 29 ]. This might be the particular maxim: the stomach (dilated capillaries in the lamina propria) < duodenum (mild mucosal injury, blunt villi, and mild hyperplasia of the crypts) < small bowel wall (focal hemorrhage in the lamina propria) < large bowel wall (severe mucosal injury with lumen dilatation and reduction of crypts). There were the focal thickening of the alveolar membranes, lung congestion, pulmonary edema, intra-alveolar hemorrhage, focal interstitial neutrophil infiltration, mild activation of Kupffer cells, and severe enlargement of sinusoids with liver congestion, mild degeneration of proximal tubules, severe renal vascular congestion and interstitial edema [ 19 , 24 , 29 ]. A similar presentation appeared with the central occlusion [ 27 ]. In rats with the occluded superior sagittal sinus, the marked congestion in the heart tissue within the myocardium and large coronary branches exhibited huge additional pathology [ 27 ]. There were the gross stomach lesions, and microscopically, erosive gastritis, the liver congestion, and lung congestion with intra-alveolar hemorrhage and pyknotic hepatocyte nuclei, hyaline tubular cylinders, cell degeneration of proximal and distal tubule with cytoplasmic vacuolization in the kidney after both a short-term (15 min ligation time, and period thereafter) and a long-term (24 h, 48 h) period. In the rats challenged with the intragastric absolute alcohol instillation [ 40 ], the large gross hemorrhagic lesions and severe pathology in the stomach (i.e., mucosal surface erosion, even in the macroscopically intact areas) were along since very early time (i.e., 1 min post-alcohol) with the progression of the other lesions. They exhibited lung tissue congestion with persistent hemorrhage, liver lesions, congestion, and a ballooning of hepatocytes in zone three of the liver lobules and kidney lesions, congestion, and its progression in the renal tissues presented with dilated and congested small, medium, and large blood vessels, as well as glomeruli. In the rats challenged with the subsequent lithium overdose, along with the described heart failure, there was the progressing lesions presentation [ 39 ]. They exhibited in the lungs marked congestion, intra-alveolar hemorrhage, and interstitial neutrophil infiltration, liver with congestion and dilatation of central veins, sinusoids, and portal tracts vessels, marked congestion and vacuolization of the renal tubular epithelia with degenerative changes and marked congestion in the gastrointestinal tract (and gross stomach lesions). As an interesting point, severe muscular weakness might appear immediately, while a decrease in muscular fibers microscopically appears later. In the rats with the occluded bile duct, there was timely progress of a large range of lesions [ 37 ]. They exhibited marked lung parenchyma congestion along with intra-alveolar hemorrhage. Moreover, they had marked dilatation and congestion of blood vessels in the portal tracts, central veins, and sinusoids, along with the zones of confluent necrosis affecting the liver lobuli and the portal tract. There was marked dilatation and congestion of blood vessels in the kidney tissue as well as glomeruli and marked congestion in the gastrointestinal tract (and gross stomach and duodenal lesions). These were along with the timely progressing acute pancreatitis lesions. They exhibited grossly separate to confluent hemorrhagic zones and/or foci of necrosis, and microscopically to diffuse edema of interlobar septe, interlobular septe, interacinal spaces, diffuse expansion of intercellular spaces, increased number of necrotic acinar cells/HPF (extensive confluent necrosis) and foci of hemorrhage and fat necrosis, perivascular increased infiltration leukocytes/HPF, and confluent microabscesses [ 37 ].

Thus, the indication of the larger range of peripheral lesions and hemorrhage and their counteraction evidence might be seen as a particular and complex maxim. This complex maxim might be the particularity of the prime lesion (i.e., occluded superior mesenteric vessels vs. occluded superior sagittal sinus). This complex maxim equally supposed one prime lesion (alcohol-hemorrhagic lesions, bile duct occlusion pancreatitis) or many prime lesions (lithium application, maintained intra-abdominal pressure), and thereby, prime peripheral lesions vs. prime central lesions vs. peripheral and central lesions. This might suggest that the heart failure cause–consequence might occur in the periphery between the heart and affected organ (i.e., lung, liver, kidney, gastrointestinal tract) in a multidirectional way that might be all beneficially affected by the BPC 157 therapy.

As mentioned before, peripherally and centrally, there was progressing thrombosis in the vein and artery [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]. As emphasized before, the cloths were assessed in the inferior caval vein, portal vein, lienal vein, superior mesenteric vein, superior sagittal sinus, abdominal aorta, hepatic artery, and superior mesenteric artery. Thereby, the heart failure, the consistent large concomitant congestion multiorgan pathology, and widespread thrombosis cause–consequence relation might be the final identifier of the overspread stasis as well, and the overwhelming Virchow triad circumstances that therapy might counteract [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ].

Thereby, it might be that the alcohol intoxication [ 40 ], lithium intoxication [ 39 ], maintained severe intra-abdominal hypertension [ 31 ], and vessels occlusion, superior mesenteric artery and/or vein, and superior sagittal sinus [ 19 , 24 , 27 , 29 ] appeared as a multiple occlusion syndrome that could not be avoided unless therapy was given. Regularly, reciprocal changes in the abdominal, thoracic, and brain cavities rapidly transmitted through the venous system rapidly appeared as determinants of vascular failure. Therefore, with BPC 157, there might be a rapid improvement of venous system function as an essential common point to prevent and reverse the noxious chain of events and attenuate all harmful consequences. For illustration, an activated azygos vein as a rescuing pathway, avoiding both the lung and liver, combines the inferior caval vein and superior caval vein via direct blood delivery [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Thus, an activated azygos vein shunt could reorganize blood flow and instantly attenuate the consequences of maintained occlusion-induced vascular failure, both peripherally and centrally [ 19 , 23 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Consequently, as a chain of events that might be fully counteracted with BPC 157 therapy, there were counteracted in these rats with the occlusion and occlusion-like syndrome, the multiorgan failure (i.e., gastrointestinal, brain, heart failure, liver, and kidney lesions), portal and caval hypertension, aortal hypotension, intracranial (superior sagittal sinus) hypertension, and generalized thrombosis counteracted. This led to the useful BPC 157 therapy of the harmful circle, the counteraction of the generalized stasis, generalized Virchow triad presentation, and heart failure and severe ECG disturbances. As a prime and practical confirmation, rats with major vessel ligation and occlusion, in either artery and/or vein, and either peripherally or centrally, and other alike noxious occlusion-like procedures exhibited a similar syndrome (occlusion syndrome or occlusion-like syndrome) and shared full therapy benefit with the given BPC 157 therapy [ 18 , 19 , 23 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ].

Evidently, BPC 157 vascular recovery therapy was able to provide adequate compensation (i.e., activation of collateral pathways to reestablish blood flow), both rapid and sustained, as demonstrated with BPC 157 therapy [ 18 , 19 , 23 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. In support, there is an immense vascular network available for the rapid defense response that regularly failed, instead to be spontaneously activated. Thus, the BPC 157 therapy (i.e., endothelium function recovery and maintenance as innate cytoprotective effect) [ 8 ] might affect and reverse the shared innate inability to react spontaneously. Contrarily, not corrected, failed damaged endothelium function as an innate inability to react, would inevitably lead to the innate vascular and multiorgan failure and heart failure upon major vessel occlusion (ligation) as well as upon other similar noxious procedures (i.e., alcohol, lithium, isoprenaline, bile duct occlusion, maintained high intra-abdominal pressure) [ 18 , 19 , 23 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Given overwhelming thrombosis, peripherally and centrally, they might be seeable all as multiple occlusion syndrome, whether all vessels compressed (i.e., high intra-abdominal pressure [ 31 ]) or otherwise failed (i.e., occlusion [ 19 , 24 , 27 , 29 ], agent’s [ 38 , 39 , 40 ] or noxious other procedure [ 37 ] application), these might all be particular targets for BPC 157 bypassing key therapy.

3. Thrombosis

As mentioned before in the acute myocardial infarction and heart failure studies, counteraction of the harmful arrhythmias and thrombosis and the concomitant multiorgan failure and initiated multicausal noxious circuit that might also be counteracted all together might favor BPC 157 therapy as a particular cytoprotection application [ 18 , 19 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 37 , 38 , 39 , 40 , 41 ] ( Table 2 ). The compelling evidence that against harmful thrombosis, BPC 157 might have a special beneficial effect [ 18 , 19 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 37 , 38 , 39 , 40 , 41 ] that might be utilized to reverse the heart failure cause–consequence, as occurred with the wide range of BPC 157 therapy, was specifically elaborated.

BPC 157 administration might counteract the escalating thrombosis as a particular commonly shared point.

Commonly, illustrating thrombotic complications’ major role in patients with heart failure is a major issue in therapy; in 2021, several major trials attempted to resolve whether shortened dual antiplatelet therapy reduced bleeding risk without increasing the risk of further ischemic events [ 1 ].

On the other hand, it might be that BPC 157 (cytoprotection as endothelium function maintenance) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ] might collaborate with the evidence of heart failure innate etiopathology [ 163 ]. There are significant pro-thrombotic shifts and endothelial damage/dysfunction as a hallmark of heart failure, irrespective of any cause, related to the severity of heart failure [ 163 ]. Thereby, there are thrombi formations both within cardiac chambers (particularly in atrial fibrillation) and blood vessels, and both arterial endothelial dysfunction and venous dysfunction present in heart failure contribute to the pro-thrombotic state seen in this condition [ 163 ].

Given a special effect with BPC 157 therapy in the acute myocardial infarction and heart failure studies, the noted counteraction of the harmful arrhythmias and thrombosis and the concomitant multiorgan failure occurred simultaneously with the elimination/attenuation of the prominent hemorrhage and congestion in the many organs, such as brain, heart, lung, liver, kidney, and gastrointestinal tract [ 18 , 19 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 37 , 38 , 39 , 40 , 41 ].

Of note, conceptually, the cytoprotection rapidly went to the organoprotection (i.e., the stomach protection to the protection of other organs) [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ], and in the particular BPC 157 case, the BPC 157 cytoprotection effect rapidly goes to the wound healing (i.e., implied direct cell protection against direct injury [ 10 ]) [ 3 , 8 , 102 ]. There is particular evidence noted with BPC 157 effects, in particular, wounding (i.e., abdominal aorta anastomosis [ 18 ] vs. amputation of the leg or tail [ 58 , 59 , 60 ], i.e., obstructing thrombus formation counteracted, and fully established the obstructing thrombus as rapidly annihilated [ 18 ] vs. decreased post-amputation bleeding [ 58 , 59 , 60 ]). Thus, we claimed that the realized healing effects in the various wound healing [ 53 , 55 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ] might be evidence of the realized healing process after a ruptured blood vessel as a whole. Thereby, it might be the innate distinctive effect on all four major events in clot formation and dissolution fully accomplished that might be distinctively used depending on the given injury and agent application. This meant a special effect highly utilizable, possibly resolving the issue with heart failure therapy. Illustratively, BPC 157 therapy in rats with abdominal aorta anastomosis might prevent the occluding clot formation (early application soon after anastomosis creation) as well as annihilate already fully formed clot obstructing aorta (late application at 24 h after anastomosis creation). Simultaneously, BPC 157 therapy might both prevent leg disability and rapidly reestablish leg function [ 18 ]. Thus, there might be a well-functioning cytoprotection loop that might provide that the translation to the preserved muscle function consistently occurs.

BPC 157 attenuated the bleeding prolongation induced by anti-coagulants, anti-thrombotic agents, and NOS-substrate L-arginine, alone or with amputation (tail, leg), without affecting coagulation pathways [ 58 , 59 , 60 ]. Likewise, BPC 157 attenuated the bleeding from the leg or tail amputation [ 58 , 59 , 60 ], organ perforation or hemorrhagic mucosal lesions (cecum, stomach) [ 32 , 33 ], spinal cord compression [ 35 , 36 ], and intracerebral or intraventricular bleeding [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Furthermore, BPC 157 might specifically maintain the function of thrombocytes (as noted in aggregometry and thromboelastometry studies) [ 60 ]. Given with aspirin, clopidogrel, or cilostazol in rats, BPC 157 counteracted their inhibitory effects on aggregation activated by arachidonic acid, ADP, collagen, and arachidonic acid/PGE1 [ 60 ].

Providing strong interrelations between the arrhythmias, heart failure, and thrombosis [ 164 ], assuming the venous and arterial thrombosis as two aspects of the same disease [ 165 , 166 ], the BPC 157 counteracting effect might be reciprocally related. Thus, in heart failure therapy, the therapeutic effect of BPC 157 administration might counteract the escalating thrombosis as a shared common point [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. This might be the consequent reversal of the general stasis (i.e., otherwise large volumes trapped in the damaged stomach, CNS, and portal and caval vein tributaries, which may also perpetuate the brain and heart ischemia). Along with this, it might be the reversal of the failed activation of the collateral bypassing pathways. This rapidly appeared within minutes while the major veins which had been disabled (inferior caval and superior mesenteric veins failed as congested and the azygos vein failed as collapsed [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]) might be quickly recovered, rapidly made fully functional. At the same time (i.e., direct blood delivery by the activated azygos vein), in the heart failure recovery, the otherwise progressing thrombosis in veins and arteries might be markedly attenuated (or even eliminated) as well as the progressing intracerebral and interventricular bleeding markedly attenuated or even annihilated [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Thus, this might be the innate resolution of the Virchow triad consequences [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Likely, this might be the effect related to the modulatory interaction with NO-system [ 61 , 62 , 63 ]. As proof, BPC 157 therapy effects might counteract in the same dosage range NOS-blockade (L-NAME)-induced pro-thrombotic and hypertensive effect as well as NOS-over-activity (L-arginine)-induced anti-thrombotic and hypotensive effect [ 59 , 62 ].

4. Blood Pressure

Interestingly, in patients who were hospitalized for heart failure, the risks of mortality and readmission increased at low and high blood pressures, with similar trends for patients with heart failure with reduced ejection fraction and with heart failure with preserved ejection fraction [ 167 , 168 ].

Severe blood pressure disturbances (i.e., intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension) were mentioned before to be attenuated/eliminated with BPC 157 therapy in the acute myocardial infarction, and in all heart failure studies [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. These were along with noted counteraction of the harmful arrhythmias and thrombosis, and the concomitant multiorgan failure and initiated multicausal noxious circuit that might also be counteracted [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ].

On the other hand, in the severe hyperkalemic condition regularly fatal within 30 min time, BPC 157 therapy, along with ascertained survival and counteraction of arrhythmias, might counteract hyperkalemia-induced hypertension [ 67 ]. Likewise, BPC 157 therapy might counteract hypertension induced by unilateral renal artery stenosis or by unilateral renal artery stenosis and contralateral nephrectomy [ 169 ]. Moreover, as mentioned before, BPC 157 therapy might counteract NOS-blocker L-NAME-induced hypertension, an effect along with counteraction of the L-NAME-induced pro-thrombotic effect [ 58 , 61 , 62 ]. Finally, in glaucomatous rats, BPC 157 might normalize the increased intraocular pressure [ 26 ].

Furthermore, BPC 157 therapy might oppose hypovolemic shock, hypotension, and mortality after controlled blood volume withdrawal [ 169 ]. Likewise, as mentioned before, BPC 157 therapy might counteract the NOS-substrate L-arginine-induced hypotension, an effect along with counteraction of the L-arginine-induced anti-thrombotic effect [ 58 , 61 , 62 ]. As in the mentioned acute studies, in the heart failure chronic studies with doxorubicin, along with counteraction of the heart failure, BPC 157 therapy strongly opposed hypotension [ 84 ]. This effect was along with the counteraction of the increased big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) and improved clinical status in general [ 84 ].

Of note, low blood pressure is common in patients with heart failure and reduced ejection fraction [ 170 ]. The low blood pressure in heart failure with reduced ejection fraction shares multiple origins (i.e., low cardiac function, hypovolemia (i.e., diuretics (note, BPC 157 might counteract the harmful effects of furosemide overdose [ 69 ]), treatment-related vasodilatation, altered vasoreactivity (comorbidities, i.e., diabetes)) [ 171 ].

As a particular notation, BPC 157 had no effect on normal blood pressure [ 61 , 62 ]. Thus, the effect on blood pressure of BPC 157 therapy might be effectively related to the resolution of particular sick conditions, likely depending on the normalization of the heart function, as cytoprotection application is able to normalize either disturbed blood pressure or hypotension.

Smooth Muscle

BPC 157 therapy might exert the described particular effect on blood pressure given the relaxation noted in the aorta without endothelium ex vivo but not relaxation directly on the 3D model composed of vascular smooth muscle cells (unlike the effect of NO-donor sodium nitroprusside) [ 53 ]. Possibly, this might be the release of the NO by its own [ 61 , 62 , 63 ], activated phosphorilazation of eNOS [ 53 ] as a special modulatory effect, given the mentioned counteraction of the adverse effect of NOS-blockade (i.e., L-NAME-hypertension and pro-thrombotic effect), as well as the counteraction of the adverse effect of NOS-over-stimulation (i.e., L-arginine-hypertension and anti-thrombotic effect) [ 58 , 62 ]. Moreover, the VEGFR2-Akt-eNOS signaling pathway might be activated without the need for other known ligands or shear stress, controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway [ 53 , 54 ]. These might also be perceived as BPC 157/NO-system interaction in controlling blood pressure by a particular mechanism.

BPC 157 therapy might have a particular effect on other smooth muscles. During sick conditions, BPC 157 therapy might have a particularly beneficial effect on many sphincters (lower esophageal sphincter, pyloric sphincter [ 67 , 101 , 170 , 172 , 173 , 174 , 175 , 176 , 177 , 178 ], pupil [ 26 , 179 ], urinary sphincter [ 62 , 180 , 181 ]) and might recover their distinctive functions. This particular effect might suggest a distinctive therapy effect depending on the injury condition, along with the general agenda of the cytoprotection concept (i.e., maintained cell integrity against different noxious agents’ injurious effect) (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]). Moreover, it might maintain conditions of the sphincter’s normal functioning, modulating effect on distinctive sphincter functions, i.e., an anti-reflux effect (increases lower esophageal sphincter pressure, decreases pyloric sphincter pressure [ 170 ]) or maintained normal pupil diameter [ 179 ], or maintained normal leak point pressure [ 180 ].

5. Arrhythmias

In consideration of the BPC 157 therapy as a cytoprotection application, the counteraction of the arrhythmias was elaborated in the acute myocardial infarction and heart failure studies, along with the noted counteraction of the harmful thrombosis, and the concomitant multiorgan failure and initiated multicausal noxious circuit that might also be counteracted [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. Further studies specifically address particular arrhythmias counteraction ( Table 3 ). The BPC 157 therapy as antiarrhythmic agent follows the evidence that NO is commonly proposed as an endogenous cardioprotectant antifibrillatory factor [ 64 , 65 ] and that BPC 157 might modulate NO-effects (for review, see, i.e., [ 60 ]), and thereby might have a consistently strong beneficial effect against various arrhythmias and various agents and procedures that might produce arrhythmias [ 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. Moreover, BPC 157 activities might approach and modulate the long-ago suggested antiarrhythmic agents potential throughout myocardial ischemia-arrhythmia-local anesthetic-anti-convulsion potential (for review, see, i.e., [ 182 ]).

Summarized presentation of the BPC 157 therapy effect on arrhythmias [ 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. Note, in digitalis [ 66 ], potassium overdose [ 67 ], furosemide overdose [ 69 ], and bupivacaine [ 71 ] arrhythmias, BPC 157 might annihilate further worsening induced by NOS-blocker, L-NAME.

5.1. Digitalis

Without therapy, the used digitalis regimen was regularly fatal, and thereby, it might be a particular challenge for the BPC 157 therapy, which might be dose-dependent, to both prevent or attenuate the development of the digitalis intoxication and reverse already established digitalis intoxication [ 66 ]. Without therapy, the established digitalis intoxication (the grade 3 AV-block quickly developed) outcome was inevitably complicated by fatal ventricular tachycardia and fatality in all animals.

In digitalis rats, AV-block might be a particular target for the BPC 157 therapy [ 66 ].

Given prophylactically, ng regimens reduced just the AV-block duration, while higher dose regimens, BPC 157 μg regimens, aside from AV-block, also reduced the number of ventricular premature beats, prolonged the time until the onset of ventricular tachycardia, and reduced the duration of ventricular tachycardia [ 66 ].

BPC 157 therapy completely changed the outcome of the established digitalis intoxication outcome. All BPC 157 regimens shortened the AV block and dose-dependently mitigated a further methyldigoxin-toxicity course. Ventricular tachycardias were avoided (50 μg/kg) or markedly reduced (10 μg/kg,10 ng/kg). Fatal outcomes were avoided (50 μg/kg), reduced (10 μg/kg), or only delayed (10 ng/kg). Most probably, these digitalis disturbances occurred as NO-related disturbances that might also be resolved with BPC 157 therapy [ 66 ].

Moreover, BPC 157 therapy also had the potential to compensate for the additional aggravation that might occur in the digitalis rats. Illustratively, the BPC 157 effect as NO-system related activity might evidence the BPC 157 administration to annihilate the strong aggravation that occurred with NOS-blocker L-NAME application, given either prophylactically or in the established digitalis intoxication [ 66 ].

5.2. Hyperkalemia

The hyperkalemia challenge for the BPC 157 therapy was intraperitoneal KCl-solution application (9 mEq/kg). In regularly deadly hyperkalemia (>12 mmol/L), arrhythmias with an ultimate and a regularly inevitable lethal outcome within 30 min [ 67 ] were both prevented with BPC 157 given before KCl application, as well as cured with BPC 157 therapy given later, in the conditions of the advanced and established huge hyperkalemia-induced disturbances. Intraperitoneal prophylactic regimen goes with the recovered sinus rhythm, less prolongation of QRS, and without asystolic pause [ 67 ]. Given at the 10 min point of the severely advanced downhill course after KCl application, the therapeutic regimen required 5–10 min period to start recovery, with normal sinus rhythm at 1 h. Of note, the particular BPC 157 counteracting potential toward hyperkalemia might first encourage the similar results obtained with the intragastric KCl application (27 mEq/kg)—(hyperkalemia 7 mmol/L) and BPC 157 therapy protocol (i.e., peaked T waves, fully counteracted by BPC 157 application, applied 30 min before or 10 min after KCl [ 67 ]). Then, the supporting point is the evidence that BPC 157 administration might have the potential to compete with further worsening instances. Illustratively, the direct effect seeable on potassium conductance in HEK293 cells, hyperkalemic conditions (18.6 mM potassium concentrations), counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions, might annihilate L-NAME, NOS-blocker-induced aggravation, and thereby, BPC 157–hyperkalemia’s direct relationship might occur as a NO-system related interconnection. Likewise, other hyperkalemia disturbances (muscular weakness, hypertension, low sphincteric pressure with intraperitoneal KCl-application, severe stomach mucosal lesions, and sphincter failure with intragastric KCl-application) were also counteracted [ 67 ].

5.3. Succinylcholine

The counteraction/attenuation of the adverse effect of succinylcholine by BPC 157 therapy [ 68 ] might illustrate that, depending on the cause (potassium-overload [ 67 ]; succinylcholine application [ 68 ]), BPC 157 therapy (microgram and nanogram dose, intraperitoneal and peroral regimen) might distinctively affect hyperkalemia. While in the rats after potassium overload, the hyperkalemia persisted and the adverse effects were counteracted [ 67 ]. The illustrative might be the findings in the rats intramuscularly treated with succinylcholine (counteracted hyperkalemia, counteracted adverse effects). As succinylcholine acts as depolarizing neuromuscular blocker and disabling neuromuscular junction [ 68 ], this might indicate a particular recovering effect of BPC 157 therapy. Normokalemia and no arrhythmias, completely absent intermittent AV block and asystolic pauses, continuously maintained sinus rhythm, supplementing the evidence that BPC 157 therapy might attenuate the succinylcholine course as a whole. The therapeutic effect included the succinylcholine-induced behavioral agitation, muscle twitches, and motionless resting, and completely eliminated post-succinylcholine hyperalgesia, immediately eliminated leg contractures (intramuscular succinylcholine), counteracted both edema and the decrease in muscle fibers in the diaphragm and injected/non-injected anterior tibial muscles) [ 68 ]. Otherwise, succinylcholine-rats exhibited hyperkalemia with brisk arrhythmias (peaked T waves, widening of PR and QRS complexes, aggravation in intermittent AV block, and asystolic pauses (at 4–5 min period, but spontaneously recovered by the 15th min) [ 68 ].

5.4. Hypokalemia

The hypokalemia challenge for the BPC 157 therapy was a huge furosemide dose application and consequent efficacy in the otherwise deadly hypokalemia (<2.7 mmol/L) against the severe arrhythmias (i.e., polymorphic ventricular tachycardia (“torsades de pointes”)) (note, unlike full survival with BPC 157 therapy, without therapy, the lethal outcome occurred within 90–150 min) [ 69 ]. These were both prevented with BPC 157 given before furosemide application (AV block and abnormal ventricular rhythm were absent). Likewise, these were both annihilated with BPC 157 therapy given later after furosemide in the conditions of the advanced severe disturbances, i.e., the third-degree AV block and ventricular tachycardia, as complete restoration of the sinus rhythm occurred within a few minutes upon application of BPC 157 therapy [ 69 ]. In addition, the supporting point for BPC 157-hypokalemia particular relation is the evidence that BPC 157 administration might also counteract the further worsening. Illustratively, BPC 157 completely annihilated the aggravation induced by NOS-blocker L-NAME in the furosemide rats [ 69 ]. Moreover, BPC 157 therapy might have a direct effect on potassium conductance, seeable in HEK293 cells, BPC 157 (1 µM) abolished hyperpolarizations of HEK293 cells during hypokalemic (0.4 mM K) conditions [ 69 ]. Finally, as support of the effect on hypokalemia as a whole, all of the BPC 157 treated furosemide rats were without sudden, brief, shock-like, involuntary movements (i.e., hypokalemia-induced myoclonus), either completely prevented or rapidly reversed when they had been advanced along with arrhythmias [ 69 ].

Of note, the full practical significance of these BPC 157 findings [ 69 ] remained to be additionally elaborated (i.e., methyldigoxin toxicity depends particularly on hypokalemia [ 66 ]; variform ventricular tachycardia (“torsades de pointes“) also antagonized [ 69 ]). Furthermore, there is a strong working BPC 157 capability in either the hyperkalemic or hypokalemic conditions [ 67 , 68 , 69 ]. As such, these probably indicate the particular relations between the skeletal muscles (i.e., the largest single pool of K + in the body [ 67 , 183 ]) and BPC 157 therapy (i.e., upon injury, strongly recovered skeletal muscle function and healing [ 110 , 111 , 112 , 113 , 114 , 115 ], recovered neuromuscular junction function [ 68 ]). These might have a considerable role in balancing the interconnected hyperkalemia/hypokalemia (i.e., hyperkalemia (i.e., exercise) is rapidly corrected by reaccumulation of potassium into the muscle cells via Na + , K + pumps, often leading to hypokalemia [ 183 ]). Furthermore, BPC 157 might counteract the adverse effects (i.e., muscle weakness, brain lesions, myocardial infarction) of the overload with magnesium [ 184 ] or lithium [ 39 ] (both known to interfere with potassium functioning) [ 39 , 184 ]. Thus, BPC 157 might have a particularly beneficial effect as BPC 157 might also counteract the various forms of muscle weakness related to the large range of noxious events (i.e., those induced by tumor-cachexia [ 6 ], stroke [ 20 ], application of neurotoxins (cuprizone (mimicking multiple sclerosis) [ 185 ], 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine (MPTP, mimicking Parkinson’s disease) [ 186 ]), or neuroleptics [ 187 ]). This might be decisive for the maintenance of muscle contractility and heart function.

5.5. Local Anesthetics, Bupivacaine

After an overdose of bupivacaine or any of the related amide local anesthetic agents, cardiovascular collapse, or even death, may occur [ 178 ]. Thereby, providing the used dose of bupivacaine (100 mg/kg IP), there is important evidence that BPC 157 successfully prevents and counteracts bupivacaine cardiotoxicity [ 70 ]. As a highlight of the practical applicability, BPC 157 is effective even against the worst outcomes, such as a severely prolonged QRS complex [ 70 ].

Amide local anesthetic agents overdose, in particular an overdose of bupivacaine (note, we used 100 mg/kg IP), might be associated with cardiovascular collapse or even death [ 188 ]. Likewise, BPC 157 therapy might be associated with counteraction of bupivacaine cardiotoxicity (i.e., bradycardia, high-degree AV-block, ventricular ectopies and tachycardia, T-wave elevation, respiratory arrest, and asystole), even with the upmost counteraction that might be needed against the worst outcomes (counteraction of the severely prolonged QRS complex). BPC 157 has no apparent limitation considering the therapy initiation. It might be effective early (at 30 min before or at 1 min after the bupivacaine injection, counteraction encompassed 50 μg/kg, 10 μg/kg, 10 ng/kg, or 10 pg/kg IP BPC 157 regimens). Likewise, it might be effective after delaying treatment (at 6 min after bupivacaine administration, and after the development of prolonged QRS intervals (20 ms), the fatal outcome was markedly postponed). Together, this might indicate a particular direct competition with the escalating bupivacaine course since, in HEK293 cells, BPC 157 inhibited the bupivacaine-induced depolarization [ 70 ]. Likewise, it remains to be seen how BPC 157 might specifically interfere with the specific bupivacaine inhibitory targets, such as the transient outward K+ current in ventricular myocytes or the fast block of sodium channels during the action potential with slow recovery from block during diastole [ 189 , 190 ].

5.6. Local Anesthetics, Lidocaine

The antagonism of the entire spectrum of local anesthetic-induced neurotoxic and cardiotoxic effects [ 71 ] was the issue with lidocaine, as prototype application (intraperitoneal, intraplantar and axillary, and spinal (L4-L5) intrathecal block) toward the particular beneficial recovering effect of BPC 157 therapy, intraplantar, intraperitoneal, and intragastric application. First, BPC 157 counteracted lidocaine–bradycardia, which might be a severe one, prevented bradycardia development as well as reversed established bradycardia, given either before or after lidocaine [ 71 ]. Likewise, BPC 157, given before or after, counteracted the lidocaine-induced local anesthesia via the intraplantar application and axillary and spinal (L4-L5) intrathecal block. Moreover, BPC 157 counteracted lidocaine-induced convulsions. In vitro, BPC 157 counteracted lidocaine-induced HEK293 cell depolarization [ 71 ]. There might be BPC 157-lidocaine-NO-system interconnections [ 71 ], providing that BPC 157 administration might completely annihilate the strong aggravation that might occur with the NOS-blocker L-NAME application [ 71 ].

5.7. Neuroleptics and Prokinetics Induced Prolonged QTc Interval

The evidence of the beneficial BPC 157 effect with the neuroleptics and prokinetics application versus the prolonged QTc intervals is a known shared adverse effect of the neuroleptics and prokinetics application [ 72 ]. Here, with the prolonged QTc intervals effect after application of the dopamine neuroleptics and prokinetic metoclopramide, but not after domperidone (known to act peripherally), the neuroleptics and prokinetic prolonged QTc intervals occurred as the particular central effect [ 72 ]. Finally, the consistent antagonization and the use of the various neuroleptics, both typical (haloperidol, fluphenazine) and atypical (sulpiride, clozapine, quetiapine), might provide the BPC 157 therapy potential (i.e., the counteraction of the prolonged QTc intervals) as capable of antagonizing an essential class adverse effect [ 72 ]. Note that the potential involvement of pathological ion channel modulation might be shared disorder in the etiology of neurological disorders, cardiovascular disease, and, ultimately, arrhythmias [ 191 ]. Likewise, in the same dose regimens, BPC 157 therapy counteracted the neuroleptic-induced catalepsy and akinesia and gastrointestinal disturbances [ 173 , 192 ] and hippocampal ischemia/reperfusion injuries in rats in the stroke studies (therapy after reperfusion initiation, after carotid arteries clamping) [ 20 ]. Additionally, with BPC 157 therapy, there might be the brain–gut and gut–brain axis function recovery [ 2 , 193 ], while BPC 157, when given peripherally, might exert particular central beneficial effects [ 2 , 193 ]. Illustratively, these were the release of serotonin in the specific brain areas (i.e., nigrostriatum) [ 194 ], as opposed to the schizophrenia-like positive symptoms models [ 187 ] and schizophrenia-like negative symptoms models [ 195 ]. Finally, BPC 157 counteracted various encephalopathies [ 91 , 92 , 93 , 94 , 95 , 96 ].

Thus, as a particular point of the BPC 157 activities (i.e., BPC 157 counteracted lidocaine arrhythmias, local anesthetic effect, and convulsions [ 72 ]), it might be that BPC 157 activities might approach and modulate the long-ago suggested antiarrhythmic agents potential throughout myocardial ischemia-arrhythmia-local anesthetic-anti-convulsion potential (for review, see, i.e., [ 182 ]). Illustratively, in addition to the lidocaine-induced convulsion antagonization, BPC 157 might counteract standard convulsants (i.e., picrotoxine, strychnine, bicuculline, metrazole)-induced seizures [ 169 ], as well as the insulin-[ 96 ], paracetamol [ 91 ], alcohol withdrawal [ 196 ] and serotonin syndrome-[ 197 ] induced convulsion. In addition to the lidocaine-local anesthetic effect [ 71 ], BPC 157 also counteracted tetracaine and the oxybuprocaine effect on corneal anesthesia [ 198 ] and bupivacaine severe arrhythmias [ 70 ]. BPC 157 has an analgesic effect of its own [ 199 , 200 , 201 , 202 ]. Illustratively, BPC 157 produced analgesia in the MgSO 4 and acetic acid test in mice, a model of prolonged pain associated with tissue injury [ 199 ], counteracted succinylcholine muscle pain (violent screaming upon light touch) in rats [ 68 ], and intra-articular injection of BPC 157 for multiple types of knee pain in patients [ 201 ], likely as a part of its particular healing effect). Namely, on the other hand, it might antagonize the morphine-analgesia and haloperidol potentiation of the morphine-analgesia [ 203 ].

In summary, the arrhythmias/BPC 157 evidenced direct effect demonstrated in vivo and in vitro studies might reveal a quite large range of the arrhythmias [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ] that BPC 157 might counteract. The counteracting therapy effect occurred throughout even opposite circumstances (i.e., hyperkalemia vs. hypokalemia; hyperkalemia-depolarization vs. hypokalemia-hyperpolarization) and throughout particular targets (i.e., Na + , K + pump (digitalis), sodium channels (local anesthetics), potassium channels (hypokalemia/hyperkalemia, succinylcholine), dopamine receptors (neuroleptics)) [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. With BPC 157 therapy, all of the heart arrhythmias might be equally affected, as might also be affected the other noxious effects that occurred along with arrhythmias [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. BPC 157 therapy intercepting cardiac arrhythmias should be quite extensive, especially considering the wide range of the additional adverse effects [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ] that were also counteracted. This might be understood through a particular modulatory effect, direct cytoprotective cell protection (reestablished cell membrane potential in vitro, counteracted both hyperkalemia-depolarization and hypokalemia-hyperpolarization) [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ], that might, in general, compensate and maintain (cardiac) cell integrity and function against the failed circumstances created by the persisting noxious event (i.e., hyperkalemia, hypokalemia, different noxious agents application) [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. In general, the entire myocardial cell cytoprotective effect might mean the entire antiarrhythmic effect. In addition to the mentioned BPC 157/NO-system relation [ 61 ], this particular modulating cytoprotective point might be an innate defensive response that might resolve the still-existing paradox that antiarrhythmic drugs can also generate arrhythmias.

In general, all antiarrhythmic drugs in current use have various shortcomings, and neither is free from considerable side effects of one kind or another. Thereby, summarizing the findings of the antidysrhythmic effects of the BPC 157 therapy application, a particularly beneficial effect might be envisaged. It seemed that it might beneficially affect all groups of arrhythmias (i.e., extra beats, supraventricular tachycardias, ventricular arrhythmias, and bradyarrhythmias). Moreover, in a more general view, decisive for the maintenance of muscle contractility and heart function, the counteraction of arrhythmias as an interaction of several changes in the fundamental electrophysiological properties of cardiac muscle fibers might also consider the additional BPC 157 therapy effect. These might be the simultaneous beneficial recovery of the disabled striated muscle function [ 67 , 68 , 69 , 71 , 72 , 111 , 112 , 113 , 114 , 115 ] as well as recovery of the disabled smooth muscle [ 101 , 170 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 ], effectively working through hyperkalemic [ 67 , 68 ] and hypokalemic [ 69 ] conditions. Evidently, BPC 157 therapy annihilated lethal outcomes in both hyperkalemia [ 67 ] and hypokalemia [ 69 ]). Finally, for the large antidysrhythmic effects of the BPC 157 therapy [ 19 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 37 , 38 , 39 , 40 , 41 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ], the counteraction of the local myocardial ischemia consistently encountered with BPC 157 therapy as part of its cytoprotective effect [ 18 , 19 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 37 , 38 , 39 , 40 , 41 ] might be responsible.

6. Conclusions

As the essential new result of the stable gastric pentadecapeptide BPC 157 therapy, as a part of the implemented cytoprotective effect (see Section 1 , Section 1.1 and Section 1.2 ), specifically proved in the vascular studies, there was the particular activation of the collateral pathways [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Illustratively, in the rats with myocardial infarction and heart failure, the azygos vein might be completely collapsed (failed collateral pathways), while with BPC 157 therapy activated the azygos vein which might provide direct blood flow delivery to the superior caval vein and reestablish reorganized blood flow [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. With BPC 157 therapy, this might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and resolving the Virchow triad circumstances, which might be devastatingly present (i.e., almost annihilated thrombosis as a positive outcome of the regained endothelium function and resolved stasis). This might make possible the recruitment of collateral blood vessels, compensating vessel occlusion, and reestablishing blood flow or bypassing the occluded or ruptured vessel [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Thereby, the described BPC 157 therapy beneficial effects (see Section 2 , Section 2.1 , Section 2.2 , Section 3 , Section 4 and Section 5 ) might be seen as a network of the interrelated evidence that together might support each other effect for the physiologic significance of the revealed BPC 157/vascular-system interplay. As a part of the effectively realized BPC 157/vascular-system interplay (lack of the adverse effect), there was the heart failure innate recovery as a whole (including counteracted various arrhythmias and counteracted thrombosis, blood pressures disturbances (intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 84 ], or hypertension (hyperkalemia, NOS-blockade) [ 62 , 67 ] attenuated/eliminated peripherally and centrally). Moreover, as part of the general beneficial pleiotropic effect (as part of the cytoprotection background) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], there was the counteraction of the concomitant severe vessel and multiorgan failure syndrome [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ], the counteraction of the brain, lung, liver, kidney and gastrointestinal severe lesions, almost annihilated thrombosis, counteraction of the escalated general peripheral and central syndrome. Thus, given the obtained beneficial effects in the heart failure of the BPC 157 therapy and the counteraction of the concomitant pathology, it might be that the heart failure cause–consequence circuit might occur in a multidirectional way that BPC 157 therapy might beneficially affect as a whole. Centrally, illustrative heart failure cause–consequence circuit [ 27 ] goes as the comparable BPC 157 therapy effect on the stroke in rats, therapy in the reperfusion after bilateral clamping of the common carotid arteries for a 20-min period [ 20 ]. At the periphery, the heart failure cause–consequence circuit might occur between the heart and affected organ (i.e., lung, liver, kidney, gastrointestinal tract) in a multidirectional way that might be all beneficially affected by the BPC 157 therapy [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ]. Finally, the physiologic significance of the revealed BPC 157/vascular-system interplay goes with the BPC 157 found in situ hybridization and immunostaining studies in humans to be largely distributed in tissues [ 3 , 102 ], and similar effects and roles in other species (i.e., birds [ 86 ], and insects, honeybees [ 204 , 205 ]). There might also be additional physiologic regulatory roles [ 3 , 102 ] (i.e., plethora interactions with distinctive molecular pathways [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ] (in particular NO-system [ 53 , 54 , 61 , 62 , 63 ] and prostaglandin-system [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 74 ]), throughout the healing and vascular recovery). These might be along with the very safe BPC 157 profile (i.e., absent adverse effects in clinical trials (ulcerative colitis, phase II), LD1 could be not achieved in toxicological studies) (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 61 , 74 , 102 ]). This might be taken as a definitive advantage, as recently confirmed in a large study conducted by Xu and collaborators [ 206 ]. Together, these findings (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 61 , 74 , 102 ]) are suggestive of the BPC 157 cytoprotection application in further vascular injuries therapy, and suitable for use on myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis therapy as well (for a suited summary see concluding Figure 1 ).

Description of the BPC 157 therapy. Cytoprotection concept (for review, see [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]) born in the stomach appears with cytoprotective agents application as innate stomach epithelial cell protection (indicated as +1) to be generalized (Robert, Szabo) in other organs epithelia protection (organoprotection) supplemented by stomach endothelium cell protection (indicated as +2) (Szabo). Together (+1, +2), these result in cytoprotection stomach maxim endothelial maintenance→epithelial maintenance (indicated as = 3) as axis for the rapid defensive response to resolve the ongoing lesions, which is, however, not fully operative with the standard cytoprotective agents. As novel cytoprotection mediator, BPC 157 might exert prominent epithelial beneficial effects in the stomach and in the whole gastrointestinal tract and in the other organs (stomach cytoprotection→organoprotection) (+1) and endothelial beneficial effect in the stomach (+2). Therefore, BPC 157 therapy might make the stomach maxim endothelial maintenance→epithelial maintenance (indicated as =3) a fully operative axis (indicated as 3a). Further, BPC 157 therapy might extend the original cytoprotection maxim endothelial maintenance→epithelial maintenance from the stomach to the other vessels endothelium protection (3a) [ 18 , 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. In this, BPC 157 might induce particular vessel recruitment and activation depending on injury, i.e., when confronted with vessel occlusion, there was collateral activation to bypass vessel occlusion, as well as when confronted with perforated defect, vessel “running“ toward the defect (3a) [ 18 , 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. The rapid result is the re-establishing of the reorganized blood flow (3a). As consequence, there was a particular therapy that might beneficially affect thrombosis, arterial and venous, and lesions presentation (indicated as 4). For the BPC 157 therapy of the heart failure, BPC 157 therapy might induce particular upgrading of the minor vessel to take over function of the disabled major vessel, resolving Virchow triad circumstances devastatingly present, making possible collateral vessels activation, compensating function of the major vessel, reestablishing reorganized blood flow (direct blood flow by the activated azygos vein) (indicated as 5) [ 18 , 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. In confrontation with the severe syndrome (i.e., heart failure, in particular), the successful activation of the compensatory collateral circulation was ascribed to the counteraction of the vascular and multiorgan failure, counteraction of the intracranial (superior sagittal sinus), portal and caval hypertension and aortal hypotension (5) [ 18 , 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 ]. The final result of the BPC 157 therapy (indicated as 6) might be the heart failure innate recovery as a whole (including counteracted various arrhythmias and counteracted thrombosis, blood pressures disturbances (intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 84 ], or hypertension (hyperkalemia, NOS-blockade) [ 62 , 67 ] attenuated/eliminated peripherally and centrally). Moreover, as part of the general beneficial pleiotropic effect (as part of the cytoprotection background) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], there was the counteraction of the concomitant severe vessel and multiorgan failure syndrome [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 ], the counteraction of the brain, lung, liver, kidney and gastrointestinal severe lesions, almost annihilated thrombosis, counteraction of the escalated general peripheral and central syndrome. In addition, BPC 157 also acts as a free radical scavenger, counteracts free radical-induced lesions, and normalizes NO and MDA levels in tissues and during ischemia and reperfusion [ 5 , 6 , 19 , 22 , 24 , 25 , 27 , 28 , 29 , 30 , 32 , 33 , 34 , 38 , 39 , 90 , 160 , 161 ], and thereby, due to its particular cytoprotective/cardioprotective activity [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], it might beneficially affect the myocardial lesions, in particular [ 19 , 24 , 27 , 29 , 31 , 37 , 38 , 39 , 40 , 41 , 84 ]. Finally, in addition to the clear demonstration of the therapeutic efficacy in the most adequate animal models as proof of the concept, the additional evidence involves particular interaction with many molecular pathways [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 20 , 22 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Pleiotropic effects involving distinctive receptors, including VEGFR2 and growth hormone receptors, distinctive pathways, including VEGFR2-AKT-eNOS, ERK ½, FAK-paxillin, FoxO3a, p-AKT, p-mTOR and p-GSK-3β, and distinctive loops, including stimulation of the egr-1 gene and its corepressor gene naB2, and counteraction of increases in pro-inflammatory and procachectic cytokines, and counteraction of the leaky gut syndrome [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 20 , 22 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], likely minimize the inherent lack of full understanding of the mechanisms that may be involved. In the interaction with many molecular pathways [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 20 , 22 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], particular consideration should be given to the evidence of the BPC 157/ NO-system’s particular importance (i.e., the endothelium and thrombocytes function both maintained (for review, see, i.e., [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ])). BPC 157 therapy counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis [ 22 ] and counteracted thrombosis in all vascular studies [ 18 , 19 , 23 , 24 , 27 , 28 , 29 , 31 , 37 , 38 , 39 , 40 ]), and coagulation pathways not affected [ 58 , 59 , 60 ]. Further arguments might be controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway [ 53 , 54 ]. This likely occurred as the particular modulatory effects on NO-system as a whole, induced NO-release of its own [ 61 , 62 , 63 ], counteracted NOS-inhibition [ 61 ] (i.e., N(G)-nitro-L-arginine methylester (L-NAME)-hypertension and pro-thrombotic effect) [ 58 , 62 ], and counteracted NO-over-stimulation [ 61 ] (L-arginine-hypotension and anti-thrombotic, pro-bleeding effect) [ 58 , 62 ]. Likewise, the isoprenaline-myocardial infarction was counteracted as NO-effect [ 38 ]. Thus, due to its close interaction with NO-system as NO acts as an endogenous cardioprotectant antifibrillatory factor [ 64 , 65 ] and BPC 157 might have a particular therapeutic effect.

Stable gastric pentadecapeptide BPC 157 is a partial sequence of the human gastric juice protein BPC, which is freely soluble in water at pH 7.0 and in saline. BPC 157 (GEPPPGKPADDAGLV, molecular weight 1419; Diagen, Slovenia) was prepared as a peptide with 99% high-performance liquid chromatography (HPLC) purity, with 1-des-Gly peptide being the main impurity. PGs, prostaglandins; NO, nitric oxide; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; FoxO3a, transcription factor; p-AKT, phospho-AKT; p-mTOR, phospho mammalian target of rapamycin; p-GSK-3β, phospho glycogen synthase kinase 3β; MDA, malondialdehyde; GI, gastrointestinal.

Funding Statement

This work was funded by the University of Zagreb, Zagreb, Croatia (Grant BM 099).

Institutional Review Board Statement

This research was approved by the local Ethic Committee (case number 380-59-10106-17-100/290) and by the Directorate of Veterinary (UP/I-322-01/15-01/22).

Informed Consent Statement

Not applicable.

Data Availability Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.