{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:41:34Z","timestamp":1790905294729,"version":"4.1.0"},"reference-count":106,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Zagreb, Zagreb, Croatia","award":["BM 10106-22-3071"],"award-info":[{"award-number":["BM 10106-22-3071"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas\u2019 severe course, tracheocutaneous fistula \u2192 air leak \u2192 compensatory diaphragmatic\/abdominal \u201cheaving\u201d, NO-system failed relations, and therapy resolution. Stable gastric pentadecapeptide BPC 157 was proposed. Methods: Tracheocutaneous fistula rats received daily medication (\/kg), alone or combined, BPC 157 therapy (10 \u00b5g, 10 ng, in drinking water or intraperitoneally) along with a triple NO-agent approach (L-NAME 5 mg, L-arginine 100 mg, and L-NAME+L-arginine, intraperitoneally). Results: Tracheocutaneous fistulas occurred as specific and NO-system-related as follows: NO system: blockade (L-NAME-aggravation) over-activity (L-arginine-amelioration) or immobilization (L-NAME+L-arginine oppose each other\u2019s effects). Controls presented severe clinical signs of respiratory distress, failed healing, skin and tracheal defects, a not-healed and open, macro\/microscopically, and fistulous tract that was well-formed and wide, tracheal shrinking below the fistula, and clinically, open-mouth breathing, \u201cheaving abdomen\u201d, cyanosis (bluish snout, ears, extremities), abundant secretion through the fistula, and weight loss. Fistula tissue NO level decreased, and the malondialdehyde (MDA) level increased. The BPC 157 therapy (both application routes) resulted in rapid recovery. Healing of defects (skin and trachea) and fistula closure, macro\/microscopically, corresponded with clinical findings, avoiding observable clinical signs of dyspnea, reducing weight loss, and avoiding any sign of \u201cheaving abdomen\u201d. BPC 157-treated rats displayed regular breathing movements without observable signs of respiratory distress. Finally, when combined, BPC 157 therapy upgrades L-arginine amelioration, abolishes L-NAME-induced worsening, and restores full healing after NO immobilization (L-NAME+L-arginine). BPC 157 counteracted increase in NO level and counteracted increase in MDA level. Conclusions: Thus, first, acting systemically, BPC 157 reverses tracheocutaneous fistula course in rats. It acts through the NO system.<\/jats:p>","DOI":"10.3390\/ph19010145","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:12:04Z","timestamp":1768403524000},"page":"145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tracheocutaneous Fistula Resolved by Pentadecapeptide BPC 157 Therapy Through the NO-System\u2014Triple NO-Agent Approach in Rats"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5999-4391","authenticated-orcid":false,"given":"Goran","family":"Madzarac","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomislav","family":"Becejac","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Penovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Drazenovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucija","family":"Kralj","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5844-2130","authenticated-orcid":false,"given":"Marta","family":"Popovi\u0107 Dolic","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suncana","family":"Sikiric","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidija","family":"Beketic Oreskovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Oreskovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Strbe","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Tubikanec","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihovil","family":"Penavic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3544-8385","authenticated-orcid":false,"given":"Hrvoje","family":"Vranes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Krezic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Kordic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2758-8396","authenticated-orcid":false,"given":"Antun","family":"Koprivanac","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tinka","family":"Vidovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3113-420X","authenticated-orcid":false,"given":"Josipa","family":"Vlainic","sequence":"additional","affiliation":[{"name":"Laboratory for Advanced Genomics, Division of Molecular Medicine, Institute Ruder Boskovic, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinko","family":"Stancic Rokotov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alenka","family":"Boban Blagaic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5894-419X","authenticated-orcid":false,"given":"Sven","family":"Seiwerth","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-7283","authenticated-orcid":false,"given":"Anita","family":"Skrtic","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7952-2252","authenticated-orcid":false,"given":"Predrag","family":"Sikiric","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1186\/s13287-022-02994-x","article-title":"The therapeutic effect of stem cells from human exfoliated deciduous teeth on a rat model of tracheal fistula","volume":"13","author":"Wang","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.21037\/joma-23-40","article-title":"Perioperative management of tracheocutaneous fistula closure: A narrative review","volume":"3","author":"Selby","year":"2024","journal-title":"J. Oral Maxillofac. Anesth."},{"key":"ref_3","first-page":"170S","article-title":"Comparison between flap and primary closures of persistent tracheocutaneous fistula: A scoping review","volume":"102","author":"Almutairi","year":"2023","journal-title":"Ear Nose Throat J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/coa.14292","article-title":"Outcome of surgical treatment for tracheocutaneous fistula in paediatric population: A meta-analysis","volume":"50","author":"Saniasiaya","year":"2025","journal-title":"Clin. Otolaryngol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/lary.26080","article-title":"Systematic review of surgery for persistent pediatric tracheocutaneous fistula","volume":"127","author":"Lewis","year":"2017","journal-title":"Laryngoscope"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sikiric, P., Seiwerth, S., Skrtic, A., Staresinic, M., Strbe, S., Vuksic, A., Sikiric, S., Bekic, D., Soldo, D., and Grizelj, B. (2025). Stable gastric pentadecapeptide BPC 157 as a therapy and safety key: A special beneficial pleiotropic effect controlling and modulating angiogenesis and the NO-system. Pharmaceuticals, 18.","DOI":"10.3390\/ph18060928"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sikiric, P., Seiwerth, S., Skrtic, A., Staresinic, M., Strbe, S., Vuksic, A., Sikiric, S., Bekic, D., Soldo, D., and Grizelj, B. (2025). BPC 157 therapy: Targeting angiogenesis and nitric oxide\u2019s cytotoxic and damaging actions, but maintaining, promoting, or recovering their essential protective functions. Comment on J\u00f3zwiak et al. multifunctionality and possible medical application of the BPC 157 peptide\u2014Literature and patent review. Pharmaceuticals, 18.","DOI":"10.3390\/ph18101450"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Seiwerth, S., Milavic, M., Vukojevic, J., Gojkovic, S., Krezic, I., Vuletic, L.B., Pavlov, K.H., Petrovic, A., Sikiric, S., and Vranes, H. (2021). Stable gastric pentadecapeptide BPC 157 and wound healing. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.627533"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.2174\/1381612824666180712110447","article-title":"BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing, lessons from tendon, ligament, muscle and bone healing","volume":"24","author":"Seiwerth","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sikiric, P., Seiwerth, S., Skrtic, A., Staresinic, M., Strbe, S., Vuksic, A., Sikiric, S., Bekic, D., Penovic, T., and Drazenovic, D. (2025). Acute compartment syndrome and intra-abdominal hypertension, decompression, current pharmacotherapy, and stable gastric pentadecapeptide BPC 157 solution. Pharmaceuticals, 18.","DOI":"10.3390\/ph18060866"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bajramagic, S., Sever, M., Rasic, F., Staresinic, M., Skrtic, A., Beketic Oreskovic, L., Oreskovic, I., Strbe, S., Loga Zec, S., and Hrabar, J. (2024). Stable gastric pentadecapeptide BPC 157 and intestinal anastomoses therapy in rats\u2014A review. Pharmaceuticals, 17.","DOI":"10.3390\/ph17081081"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.2174\/1381612826666200424180139","article-title":"Fistulas healing. Stable gastric pentadecapeptide BPC 157 therapy","volume":"26","author":"Sikiric","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.2174\/0929867329666221005111553","article-title":"Stable gastric pentadecapeptide BPC 157: Prompt particular activation of collateral pathways","volume":"30","author":"Sikiric","year":"2023","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.2174\/13816128113190990411","article-title":"Stable gastric pentadecapeptide BPC 157\u2013NO-system relation","volume":"20","author":"Sikiric","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_15","first-page":"349","article-title":"Stable gastric pentadecapeptide BPC 157 and NO-system","volume":"Volume 22","author":"Ray","year":"2023","journal-title":"Nitric Oxide: From Research to Therapeutics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0014-2999(97)01033-9","article-title":"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","volume":"332","author":"Sikiric","year":"1997","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","first-page":"287","article-title":"Stable gastric pentadecapeptide BPC 157 studied for inflammatory bowel disease (PLD-116, PL14736, Pliva) induces nitric oxide synthesis","volume":"126","author":"Turkovic","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Stupnisek, M., Kokot, A., Drmic, D., Hrelec-Patrlj, M., Zenko-Sever, A., Kolenc, D., Radic, B., Suran, J., Bojic, D., and Vcev, A. (2015). Pentadecapeptide BPC 157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, L-NAME and L-arginine. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123454"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5599","DOI":"10.2147\/DDDT.S284163","article-title":"Clopidogrel-induced gastric injury in rats is attenuated by stable gastric pentadecapeptide BPC 157","volume":"14","author":"Wu","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17078","DOI":"10.1038\/s41598-020-74022-y","article-title":"Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway","volume":"10","author":"Hsieh","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s00109-016-1488-y","article-title":"Therapeutic potential of pro-angiogenic BPC 157 is associated with VEGFR2 activation and up-regulation","volume":"95","author":"Hsieh","year":"2017","journal-title":"J. Mol. Med."},{"key":"ref_22","first-page":"1073","article-title":"Inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME): Evidence for a direct inhibitory effect on nitric oxide synthase","volume":"225","author":"Pfeiffer","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1161\/01.CIR.0000029749.16101.44","article-title":"Long-term treatment with N(\u03c9)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice","volume":"106","author":"Suda","year":"2002","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S1734-1140(12)70846-0","article-title":"L-NAME in the cardiovascular system\u2014Nitric oxide synthase activator?","volume":"64","year":"2012","journal-title":"Pharmacol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0893-133X(95)00138-4","article-title":"Nitric oxide synthase inhibitors. Preclinical studies of potential use for treatment of opioid withdrawal","volume":"13","author":"Vaupel","year":"1995","journal-title":"Neuropsychopharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.pedneo.2013.09.005","article-title":"Renoprotective effects of melatonin in young spontaneously hypertensive rats with L-NAME","volume":"55","author":"Cheng","year":"2014","journal-title":"Pediatr. Neonatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1681\/ASN.V12122585","article-title":"Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats","volume":"12","author":"Attia","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e01049","DOI":"10.1002\/rcr2.1049","article-title":"Silver nitrate therapy for persistent tracheocutaneous fistula following prolonged tracheostomy and invasive ventilation: A case report","volume":"10","author":"Sweeney","year":"2022","journal-title":"Respirol. Case Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1093\/jrr\/rrs073","article-title":"Effects of ozone oxidative preconditioning on radiation-induced organ damage in rats","volume":"54","author":"Gultekin","year":"2012","journal-title":"J. Radiat. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.3390\/curroncol29100557","article-title":"Botulinum neurotoxin A in the treatment of pharyngocutaneous fistula after salvage surgery in head and neck cancer patients: Our preliminary results","volume":"29","author":"Marchese","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_31","first-page":"85","article-title":"Efficacy of mesenchymal stem cells in treating tracheoesophageal fistula via the TLR4\/NF-\u03baB pathway in beagle macrophages","volume":"15","author":"Cui","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1055\/s-2002-33237","article-title":"Endoscopic treatment of postoperative fistulas resistant to conservative management using biological fibrin glue","volume":"34","author":"Ventosa","year":"2002","journal-title":"Endoscopy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17534666211044411","DOI":"10.1177\/17534666211044411","article-title":"Therapeutic closure of bronchopleural fistulas using ethanol","volume":"15","author":"Abramian","year":"2021","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1378\/chest.122.1.374","article-title":"Central bronchopleural fistulas closed by bronchoscopic injection of absolute ethanol","volume":"122","author":"Takaoka","year":"2002","journal-title":"Chest"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.jtcvs.2008.10.054","article-title":"Silver nitrate through flexible bronchoscope in the treatment of bronchopleural fistulae","volume":"138","author":"Stratakos","year":"2009","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/hed.20182","article-title":"Use of becaplermin in the closure of pharyngocutaneous fistulas","volume":"27","author":"Jakubowicz","year":"2005","journal-title":"Head Neck"},{"key":"ref_37","first-page":"803","article-title":"Effect of basic fibroblast growth factor, trafermin, on entero-related fistulae: Report of two cases","volume":"54","author":"Yamaguchi","year":"2007","journal-title":"Hepatogastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100221","DOI":"10.3748\/wjg.v31.i9.100221","article-title":"Perianal fistulizing Crohn\u2019s disease: Mechanisms and treatment options focusing on cellular therapy","volume":"31","author":"Bhatnagar","year":"2025","journal-title":"World J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Adamska, P., Kaczoruk-Wieremczuk, M., Pyli\u0144ska-D\u0105browska, D., Stasiak, M., Bartma\u0144ski, M., Zedler, A., and Studniarek, M. (2024). Treatment of oroantral communication and fistulas with the use of blood-derived platelet-rich preparations rich in growth factors: A systematic review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111507"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Liang, S., Zheng, Z., Li, Y., Yang, Y., Qin, L., Zhao, Z., Wang, L., and Wang, H. (2023). A review of platelet-rich plasma for enteric fistula management. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1287890"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7660118","DOI":"10.1155\/2022\/7660118","article-title":"Autologous bioactive compound concentrated growth factor ameliorates fistula healing of anal fistula in a pig model and promotes proliferation and migration of human skin fibroblasts via regulating the MEK\/ERK pathway","volume":"2022","author":"Zhang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s00384-019-03290-6","article-title":"Platelet-rich plasma (PRP) versus fibrin glue in cryptogenic fistula-in-ano: A phase III single-center, randomized, double-blind trial","volume":"34","author":"Maestre","year":"2019","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ejphar.2012.11.055","article-title":"Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy","volume":"701","author":"Cesarec","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s10620-008-0332-9","article-title":"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","volume":"54","author":"Skorjanec","year":"2009","journal-title":"Dig. Dis. Sci."},{"key":"ref_45","first-page":"581","article-title":"Duodenocutaneous fistula in rats as a model for \u201cwound healing-therapy\u201d in ulcer healing: The effect of pentadecapeptide BPC 157, L-nitro-arginine methyl ester and L-arginine","volume":"66","author":"Skorjanec","year":"2015","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1254\/jphs.FP0072161","article-title":"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","volume":"108","author":"Klicek","year":"2008","journal-title":"J. Pharmacol. Sci."},{"key":"ref_47","first-page":"89","article-title":"Duodenocolic fistula healing by pentadecapeptide BPC 157 in rats. A cytoprotection viewpoint","volume":"75","author":"Vukusic","year":"2024","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Rasic, D., Zenko Sever, A., Rasic, F., Strbe, S., Rasic, Z., Djuzel, A., Duplancic, B., Boban Blagaic, A., Skrtic, A., and Seiwerth, S. (2021). Stable gastric pentadecapeptide BPC 157 heals established vesicovaginal fistula and counteracts stone formation in rats. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091206"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2016.02.038","article-title":"Stable gastric pentadecapeptide BPC 157 heals rat colovesical fistula","volume":"780","author":"Grgic","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.lfs.2016.02.029","article-title":"Stable gastric pentadecapeptide BPC 157 heals rectovaginal fistula in rats","volume":"148","author":"Baric","year":"2016","journal-title":"Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/0016-5085(79)90235-X","article-title":"Cytoprotection by prostaglandins","volume":"77","author":"Robert","year":"1979","journal-title":"Gastroenterology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0090-6980(81)90123-4","article-title":"Current history of cytoprotection","volume":"21","author":"Robert","year":"1981","journal-title":"Prostaglandins"},{"key":"ref_53","first-page":"G113","article-title":"Mild irritants prevent gastric necrosis through \u201cadaptive cytoprotection\u201d mediated by prostaglandins","volume":"245","author":"Robert","year":"1983","journal-title":"Am. J. Physiol."},{"key":"ref_54","first-page":"40","article-title":"Cytoprotection and prostaglandins","volume":"64","author":"Robert","year":"1986","journal-title":"Klin. Wochenschr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/0016-5085(89)91598-9","article-title":"Response to an editorial on gastric cytoprotection","volume":"96","author":"Robert","year":"1989","journal-title":"Gastroenterology"},{"key":"ref_56","first-page":"203","article-title":"Role of sulfhydryls and early vascular lesions in gastric mucosal injury","volume":"64","author":"Szabo","year":"1984","journal-title":"Acta Physiol. Hung."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0016-5085(87)90834-1","article-title":"Ethanol-induced damage to mucosal capillaries of rat stomach: Ultrastructural features and effects of prostaglandin F2\u03b2 and cysteamine","volume":"92","author":"Trier","year":"1987","journal-title":"Gastroenterology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/0016-5085(86)90195-2","article-title":"Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate","volume":"91","author":"Pihan","year":"1986","journal-title":"Gastroenterology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S0016-5085(85)80176-1","article-title":"Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat","volume":"88","author":"Szabo","year":"1985","journal-title":"Gastroenterology"},{"key":"ref_60","first-page":"116","article-title":"Experimental basis for a role for sulfhydryls and dopamine in ulcerogenesis: A primer for cytoprotection\u2013organoprotection","volume":"64","author":"Szabo","year":"1986","journal-title":"Klin. Wochenschr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1007\/BF01945097","article-title":"Cytoprotection\u2013organoprotection by somatostatin: Gastric and hepatic lesions","volume":"38","author":"Szabo","year":"1982","journal-title":"Experientia"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"He, L., Feng, D., Guo, H., Zhou, Y., Li, Z., Zhang, K., Zhang, W., Wang, S., Wang, Z., and Hao, Q. (2022). Pharmacokinetics, distribution, metabolism, and excretion of body-protective compound 157, a potential drug for treating various wounds, in rats and dogs. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1026182"},{"key":"ref_63","first-page":"20","article-title":"Safety of intravenous infusion of BPC157 in humans: A pilot study","volume":"31","author":"Lee","year":"2025","journal-title":"Altern. Ther. Health Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"104665","DOI":"10.1016\/j.yrtph.2020.104665","article-title":"Preclinical safety evaluation of body protective compound-157, a potential drug for treating various wounds","volume":"114","author":"Xu","year":"2020","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_65","first-page":"A584","article-title":"A multicenter, randomized, double blind, placebo-controlled phase II study of PL 14736 enema in the treatment of mild-to-moderate ulcerative colitis","volume":"128","author":"Ruenzi","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_66","first-page":"A309","article-title":"Safety, tolerability and pharmacokinetics of PL14736, a novel agent for treatment of ulcerative colitis, in healthy male volunteers","volume":"51","author":"Veljaca","year":"2003","journal-title":"Gut"},{"key":"ref_67","first-page":"8","article-title":"Intra-articular injection of BPC 157 for multiple types of knee pain","volume":"27","author":"Lee","year":"2021","journal-title":"Altern. Ther. Health Med."},{"key":"ref_68","first-page":"12","article-title":"Effect of BPC-157 on symptoms in patients with interstitial cystitis: A pilot study","volume":"30","author":"Lee","year":"2024","journal-title":"Altern. Ther. Health Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s42826-025-00235-9","article-title":"An animal model of severe acute respiratory distress syndrome for translational research","volume":"41","author":"Chu","year":"2025","journal-title":"Lab. Anim. Res."},{"key":"ref_70","first-page":"4691","article-title":"Abdominal respiratory motor pattern in the rat","volume":"588","author":"Iizuka","year":"2010","journal-title":"J. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S1056-8719(98)00048-3","article-title":"A rat model of acute respiratory distress syndrome (ARDS): Part 1. Time dependency of histological and pathological changes","volume":"40","author":"Germann","year":"1998","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Udovicic, M., Sever, M., Kavur, L., Loncaric, K., Barisic, I., Balenovic, D., Zivanovic Posilovic, G., Strinic, D., Uzun, S., and Batelja Vuletic, L. (2021). Stable gastric pentadecapeptide BPC 157 therapy for monocrotaline-induced pulmonary hypertension in rats leads to prevention and reversal. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070822"},{"key":"ref_73","unstructured":"Tachikawa, S., Onimaru, H., Kumada, T., Ezure, K., Ikeda, K., Shiga, T., Kobayashi, M., Kuwana, Y., Omata, Y., and Dutschmann, M. (2016). Coordinated respiratory motor activity in nerves and spinal cord in situ: Abdominal expiratory activity in the rat brainstem\u2013spinal cord in situ\u2014Patterns, origins and implications for respiratory rhythm generation. Front. Physiol., 7."},{"key":"ref_74","first-page":"1941","article-title":"Effects of intra-abdominal pressure on respiratory system mechanics in mechanically ventilated rats","volume":"112","author":"Runck","year":"2012","journal-title":"J. Appl. Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"384","DOI":"10.3109\/00016489109137406","article-title":"Compensatory mechanisms induced by high oropharyngeal airway resistance in rats","volume":"111","author":"Kalogjera","year":"1991","journal-title":"Acta Otolaryngol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/laban0606-19","article-title":"Acute abdominal distension in a spinally transected rat","volume":"35","author":"Suckow","year":"2006","journal-title":"Lab. Anim."},{"key":"ref_77","first-page":"1452","article-title":"Effect of intra-abdominal pressure on respiratory mechanics","volume":"33","author":"Pelosi","year":"2007","journal-title":"Intensive Care Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1007\/s10620-008-0598-y","article-title":"Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats","volume":"54","author":"Sever","year":"2009","journal-title":"Dig. Dis. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.2174\/1381612824666180614082950","article-title":"BPC 157 as potential agent rescuing from cancer cachexia","volume":"24","author":"Kang","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Knezevic, M., Gojkovic, S., Krezic, I., Zizek, H., Malekinusic, D., Vrdoljak, B., Knezevic, T., Vranes, H., Drmic, D., and Staroveski, M. (2021). Occluded superior mesenteric artery and vein. Therapy with the stable gastric pentadecapeptide BPC 157. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070792"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Knezevic, M., Gojkovic, S., Krezic, I., Zizek, H., Vranes, H., Malekinusic, D., Vrdoljak, B., Knezevic, T., Pavlov, K.H., and Drmic, D. (2021). 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, 9.","DOI":"10.3390\/biomedicines9081029"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Gojkovic, S., Krezic, I., Vranes, H., Zizek, H., Drmic, D., Pavlov, K.H., Petrovic, A., Batelja, L., Milavic, M., and Sikiric, S. (2021). BPC 157 therapy and the permanent occlusion of the superior sagittal sinus in rat. Vascular recruitment. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070744"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Tepes, M., Gojkovic, S., Krezic, I., Zizek, H., Vranes, H., Madzar, Z., Santak, G., Batelja, L., Milavic, M., and Sikiric, S. (2021). Stable gastric pentadecapeptide BPC 157 therapy for primary abdominal compartment syndrome. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.718147"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Tepes, M., Krezic, I., Vranes, H., Smoday, I.M., Kalogjera, L., Zizek, H., Vukovic, V., Oroz, K., Kovac, K.K., and Madzar, Z. (2023). Stable gastric pentadecapeptide BPC 157: Effect on reperfusion following maintained intra-abdominal hypertension (grade III and grade IV) in rats. Pharmaceuticals, 16.","DOI":"10.3390\/ph16111554"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Smoday, I.M., Petrovic, I., Kalogjera, L., Vranes, H., Zizek, H., Krezic, I., Gojkovic, S., Skorak, I., Hriberski, K., and Brizic, I. (2022). Therapy effect of the stable gastric pentadecapeptide BPC 157 on acute pancreatitis as vascular failure-induced severe peripheral and central syndrome in rats. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061299"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.3748\/wjg.v29.i27.4289","article-title":"Stomach perforation-induced general occlusion\/occlusion-like syndrome and stable gastric pentadecapeptide BPC 157 therapy effect","volume":"29","author":"Kalogjera","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Demirta\u015f, H., \u00d6zer, A., Y\u0131ld\u0131r\u0131m, A.K., Dursun, A.D., Sezen, \u015e.C., and Arslan, M. (2025). Protective effects of BPC 157 on liver, kidney, and lung distant organ damage in rats with experimental lower-extremity ischemia\u2013reperfusion injury. Medicina, 61.","DOI":"10.3390\/medicina61020291"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Strbe, S., Gojkovic, S., Krezic, I., Zizek, H., Vranes, H., Barisic, I., Strinic, D., Orct, T., Vukojevic, J., and Ilic, S. (2021). Over-dose lithium toxicity as an occlusive-like syndrome in rats and gastric pentadecapeptide BPC 157. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111506"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Gojkovic, S., Krezic, I., Vranes, H., Zizek, H., Drmic, D., Batelja Vuletic, L., Milavic, M., Sikiric, S., Stilinovic, I., and Simeon, P. (2021). Robert\u2019s intragastric alcohol-induced gastric lesion model as an escalated general peripheral and central syndrome, counteracted by the stable gastric pentadecapeptide BPC 157. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101300"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Smoday, I.M., Krezic, I., Kalogjera, L., Vukovic, V., Zizek, H., Skoro, M., Kovac, K.K., Vranes, H., Barisic, I., and Sikiric, S. (2023). Pentadecapeptide BPC 157 as therapy for inferior caval vein embolization: Recovery of sodium laurate-post-embolization syndrome in rats. Pharmaceuticals, 16.","DOI":"10.3390\/ph16101507"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Premuzic Mestrovic, I., Smoday, I.M., Kalogjera, L., Krezic, I., Zizek, H., Vranes, H., Vukovic, V., Oroz, K., Skorak, I., and Brizic, I. (2023). Antiarrhythmic sotalol, occlusion\/occlusion-like syndrome in rats, and stable gastric pentadecapeptide BPC 157 therapy. Pharmaceuticals, 16.","DOI":"10.3390\/ph16070977"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Strbe, S., Smoday, I.M., Krezic, I., Kalogjera, L., Vukovic, V., Zizek, H., Gojkovic, S., Vranes, H., Barisic, I., and Sikiric, S. (2023). Innate vascular failure by application of neuroleptics, amphetamine, and domperidone rapidly induced severe occlusion\/occlusion-like syndromes in rats and stable gastric pentadecapeptide BPC 157 as therapy. Pharmaceuticals, 16.","DOI":"10.3390\/ph16060788"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Barisic, I., Balenovic, D., Udovicic, M., Bardak, D., Strinic, D., Vlainic, J., Vranes, H., Smoday, I.M., Krezic, I., and Milavic, M. (2022). Stable gastric pentadecapeptide BPC 157 may counteract myocardial infarction induced by isoprenaline in rats. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020265"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5366","DOI":"10.3748\/wjg.v24.i47.5366","article-title":"Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine","volume":"24","author":"Amic","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_95","first-page":"6805354","article-title":"In relation to NO-system, stable pentadecapeptide BPC 157 counteracts lidocaine-induced adverse effects in rats and depolarisation in vitro","volume":"2020","author":"Stambolija","year":"2020","journal-title":"Emerg. Med. Int."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10787-017-0323-6","article-title":"Hypermagnesemia disturbances in rats, NO-related: Pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen","volume":"25","author":"Stambolija","year":"2017","journal-title":"Inflammopharmacology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ejphar.2019.01.030","article-title":"Stable gastric pentadecapeptide BPC 157 in the therapy of the rats with bile duct ligation","volume":"847","author":"Sever","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"121072","DOI":"10.1016\/j.lfs.2022.121072","article-title":"Pentadecapeptide BPC 157 efficiently reduces radiation-induced liver injury and lipid accumulation through Kruppel-like factor 4 upregulation both in vivo and in vitro","volume":"310","author":"Huang","year":"2022","journal-title":"Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.2174\/1381612826666200523180301","article-title":"BPC 157 rescued NSAID-cytotoxicity via stabilizing intestinal permeability and enhancing cytoprotection","volume":"26","author":"Park","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"A14","DOI":"10.1097\/00008390-200408000-00050","article-title":"BPC 157 inhibits cell growth and VEGF signalling via the MAPK kinase pathway in the human melanoma cell line","volume":"14","author":"Radeljak","year":"2004","journal-title":"Melanoma Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1152\/japplphysiol.00945.2010","article-title":"The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration","volume":"110","author":"Chang","year":"2011","journal-title":"J. Appl. Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"19066","DOI":"10.3390\/molecules191119066","article-title":"Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts","volume":"19","author":"Chang","year":"2014","journal-title":"Molecules"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.2147\/DDDT.S82030","article-title":"Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro","volume":"9","author":"Huang","year":"2015","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ejphar.2007.05.072","article-title":"Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression","volume":"570","author":"Brajsa","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s12264-018-0269-8","article-title":"Cytoprotective mechanism of the novel gastric peptide BPC 157 in gastrointestinal tract and cultured enteric neurons and glial cells","volume":"35","author":"Wang","year":"2019","journal-title":"Neurosci. Bull."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Gamulin, O., Oroz, K., Coric, L., Krajacic, M., Skrabic, M., Dretar, V., Strbe, S., Talapko, J., Juzbasic, M., and Krezic, I. (2022). Fourier transform infrared spectroscopy reveals molecular changes in blood vessels of rats treated with pentadecapeptide BPC 157. 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