Hepatoprotektivni učinak BPC-a 157 na modelu bilijarne ciroze u štakora [Hepatoprotective effect of BPC 157 on model of biliary cirrhosis in rats]

We examined hepatoprotective effect of pentadecapeptide BPC157 on rat model of cirhosis caused by common bile duct ligation. The animals received pentadecapeptide BPC157 daily (10μg/kg and 10 ng/kg (ip/po)) during 2, 4, 6 and 8 weeks. The control group received the equivalent volume of 0.9% NaCl. Blood samples were taken for liver enzymes measurement , bilirubin and albumin serum levels. We measured the body weight, liver weight with and without main bile duct. Histopathological analysis was performed on hematoxylin-eosin, Gomori¨s, Mallory stain and α SMA. The fibrosis degree and liver necroinflammatory activity were determined by Ishak classification. Hepatic fibrosis extent was assessed as collagen area percentage within microscopic field. Hepatocyte proliferative ability was determined according to the average number of double nuclei in five HPF. BPC157 animals had no jaundice, smaller liver weight, smaller bile stasis within bile duct, body weight similar to healthy animals. Histologicaly smaller collagen area and better preserved parenchyma was found in BPC157 animals vs. liver cirrhosis in control animals. Biochemical results shown lower bilirubin, liver enzymes and albumin values in BPC157 rats compared to control showing better preservation of liver activity. We can conclude that BPC157 could be pharmacological solution for liver cirrhosis

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

Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME

Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME

AIM: To counteract/reveal celecoxib-induced toxicity and NO system involvement. ----- METHODS: Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. ----- RESULTS: This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). ----- CONCLUSION: BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs' post-surgery application and NO system involvement

Hepatoprotective effect of BPC 157 on model of biliary cirrhosis in rats

Dugotrajna bilijarna staza uzrokuje oštećenje jetre koje rezultira cirozom s mogućim smrtnim ishodom. Unatoč brojnim ranijim studijama problem liječenja ciroze jetre još nije adekvatno riješen. Za pentadekapeptid BPC157 je već pokazan hepatoprotektivni učinak na oštećenjima jetre uzrokovanim alkoholom, visokim dozama inzulina i nesteroidnim upalnim lijekovima. U ovoj studiji ispitali smo učinak pentadekapeptida BPC157 na poznatom kirurški induciranom modelu bilijarne ciroze uzrokovane ligacijom zajedničkog žučovoda koja uzrokuje cirozu jetre u štakora. Za eksperiment su korišteni mužjaci Wistar štakora mase 180-200g. Postupkom randomizacije životinje su podijeljene u peptidom tretirane i kontrolne skupine. Nakon podvezivanja glavnog žučnog kanala, životinje su primale pentadekapeptid BPC157 svakodnevno, u dozi od 10 ug / kg i 10 ng / kg intraperitonealno ili oralno. Kontrolna grupa dobila je ekvivalentan volumen 0.9% NaCl-a. Nakon vremenskih intervala od 2, 4, 6 i 8 tjedana, životinje su žrtvovane. Uzeti su uzorci krvi za mjerenje jetrenih enzima (ALT, AST, GGT, AP), bilirubina i razine serumskog albumina kao indikatora funkcije jetre. Izmjerena je tjelesna težina životinja, težine jetri sa i bez proširenog glavnog žučnog kanala. Uzeti su uzorci jetrenog parenhima, fiksirani, obrađeni te potom bojani hemalaun eozinom, po Gomoriju, Malloriju te imunohistokemijski α SMA. Histološki je određen stupanj fibroze (0-6) i nekroinflamatorni skor (0-18) po Ishak klasifikaciji. Izmjeren je postotak površine kolagena. Proliferativna sposobnost hepatocita određena je prema prosječnom broju dvostrukih jezgara po vidnom polju. Pentadekapeptid BPC157 tretirane životinje nisu imale žuticu, imale su manju težinu jetre, tjelesnu težinu sličnu zdravim životinjama. Histološki manje površine zahvaćene kolagenom uz bolje očuvani jetreni parenhim (BPC157 životinje) za razliku od kontrolnih životinja kod kojih je nađena razvijena jetrena ciroza. Biokemijski nalazi pokazali su niže vrijednosti bilirubina, jetrenih enzima i više vrijednosti albumina u usporedbi s kontrolnim životinjama što pokazuje bolju očuvanost i funkcionalnu aktivnost jetre. Na temelju dobivenih rezultata možemo zaključiti da bi pentadekapeptid BPC157 mogao biti potencijalno farmakološko rješenje kod problema jetrene ciroze.We examined hepatoprotective effect of pentadecapeptide BPC157 on rat model of cirhosis caused by common bile duct ligation. The animals received pentadecapeptide BPC157 daily (10μg/kg and 10 ng/kg (ip/po)) during 2, 4, 6 and 8 weeks. The control group received the equivalent volume of 0.9% NaCl. Blood samples were taken for liver enzymes measurement , bilirubin and albumin serum levels. We measured the body weight, liver weight with and without main bile duct. Histopathological analysis was performed on hematoxylin-eosin, Gomori¨s, Mallory stain and α SMA. The fibrosis degree and liver necroinflammatory activity were determined by Ishak classification. Hepatic fibrosis extent was assessed as collagen area percentage within microscopic field. Hepatocyte proliferative ability was determined according to the average number of double nuclei in five HPF. BPC157 animals had no jaundice, smaller liver weight, smaller bile stasis within bile duct, body weight similar to healthy animals. Histologicaly smaller collagen area and better preserved parenchyma was found in BPC157 animals vs. liver cirrhosis in control animals. Biochemical results shown lower bilirubin, liver enzymes and albumin values in BPC157 rats compared to control showing better preservation of liver activity. We can conclude that BPC157 could be pharmacological solution for liver cirrhosis

Hepatoprotective effect of BPC 157 on model of biliary cirrhosis in rats

Dugotrajna bilijarna staza uzrokuje oštećenje jetre koje rezultira cirozom s mogućim smrtnim ishodom. Unatoč brojnim ranijim studijama problem liječenja ciroze jetre još nije adekvatno riješen. Za pentadekapeptid BPC157 je već pokazan hepatoprotektivni učinak na oštećenjima jetre uzrokovanim alkoholom, visokim dozama inzulina i nesteroidnim upalnim lijekovima. U ovoj studiji ispitali smo učinak pentadekapeptida BPC157 na poznatom kirurški induciranom modelu bilijarne ciroze uzrokovane ligacijom zajedničkog žučovoda koja uzrokuje cirozu jetre u štakora. Za eksperiment su korišteni mužjaci Wistar štakora mase 180-200g. Postupkom randomizacije životinje su podijeljene u peptidom tretirane i kontrolne skupine. Nakon podvezivanja glavnog žučnog kanala, životinje su primale pentadekapeptid BPC157 svakodnevno, u dozi od 10 ug / kg i 10 ng / kg intraperitonealno ili oralno. Kontrolna grupa dobila je ekvivalentan volumen 0.9% NaCl-a. Nakon vremenskih intervala od 2, 4, 6 i 8 tjedana, životinje su žrtvovane. Uzeti su uzorci krvi za mjerenje jetrenih enzima (ALT, AST, GGT, AP), bilirubina i razine serumskog albumina kao indikatora funkcije jetre. Izmjerena je tjelesna težina životinja, težine jetri sa i bez proširenog glavnog žučnog kanala. Uzeti su uzorci jetrenog parenhima, fiksirani, obrađeni te potom bojani hemalaun eozinom, po Gomoriju, Malloriju te imunohistokemijski α SMA. Histološki je određen stupanj fibroze (0-6) i nekroinflamatorni skor (0-18) po Ishak klasifikaciji. Izmjeren je postotak površine kolagena. Proliferativna sposobnost hepatocita određena je prema prosječnom broju dvostrukih jezgara po vidnom polju. Pentadekapeptid BPC157 tretirane životinje nisu imale žuticu, imale su manju težinu jetre, tjelesnu težinu sličnu zdravim životinjama. Histološki manje površine zahvaćene kolagenom uz bolje očuvani jetreni parenhim (BPC157 životinje) za razliku od kontrolnih životinja kod kojih je nađena razvijena jetrena ciroza. Biokemijski nalazi pokazali su niže vrijednosti bilirubina, jetrenih enzima i više vrijednosti albumina u usporedbi s kontrolnim životinjama što pokazuje bolju očuvanost i funkcionalnu aktivnost jetre. Na temelju dobivenih rezultata možemo zaključiti da bi pentadekapeptid BPC157 mogao biti potencijalno farmakološko rješenje kod problema jetrene ciroze.We examined hepatoprotective effect of pentadecapeptide BPC157 on rat model of cirhosis caused by common bile duct ligation. The animals received pentadecapeptide BPC157 daily (10μg/kg and 10 ng/kg (ip/po)) during 2, 4, 6 and 8 weeks. The control group received the equivalent volume of 0.9% NaCl. Blood samples were taken for liver enzymes measurement , bilirubin and albumin serum levels. We measured the body weight, liver weight with and without main bile duct. Histopathological analysis was performed on hematoxylin-eosin, Gomori¨s, Mallory stain and α SMA. The fibrosis degree and liver necroinflammatory activity were determined by Ishak classification. Hepatic fibrosis extent was assessed as collagen area percentage within microscopic field. Hepatocyte proliferative ability was determined according to the average number of double nuclei in five HPF. BPC157 animals had no jaundice, smaller liver weight, smaller bile stasis within bile duct, body weight similar to healthy animals. Histologicaly smaller collagen area and better preserved parenchyma was found in BPC157 animals vs. liver cirrhosis in control animals. Biochemical results shown lower bilirubin, liver enzymes and albumin values in BPC157 rats compared to control showing better preservation of liver activity. We can conclude that BPC157 could be pharmacological solution for liver cirrhosis

Hepatoprotective effect of BPC 157 on model of biliary cirrhosis in rats

Dugotrajna bilijarna staza uzrokuje oštećenje jetre koje rezultira cirozom s mogućim smrtnim ishodom. Unatoč brojnim ranijim studijama problem liječenja ciroze jetre još nije adekvatno riješen. Za pentadekapeptid BPC157 je već pokazan hepatoprotektivni učinak na oštećenjima jetre uzrokovanim alkoholom, visokim dozama inzulina i nesteroidnim upalnim lijekovima. U ovoj studiji ispitali smo učinak pentadekapeptida BPC157 na poznatom kirurški induciranom modelu bilijarne ciroze uzrokovane ligacijom zajedničkog žučovoda koja uzrokuje cirozu jetre u štakora. Za eksperiment su korišteni mužjaci Wistar štakora mase 180-200g. Postupkom randomizacije životinje su podijeljene u peptidom tretirane i kontrolne skupine. Nakon podvezivanja glavnog žučnog kanala, životinje su primale pentadekapeptid BPC157 svakodnevno, u dozi od 10 ug / kg i 10 ng / kg intraperitonealno ili oralno. Kontrolna grupa dobila je ekvivalentan volumen 0.9% NaCl-a. Nakon vremenskih intervala od 2, 4, 6 i 8 tjedana, životinje su žrtvovane. Uzeti su uzorci krvi za mjerenje jetrenih enzima (ALT, AST, GGT, AP), bilirubina i razine serumskog albumina kao indikatora funkcije jetre. Izmjerena je tjelesna težina životinja, težine jetri sa i bez proširenog glavnog žučnog kanala. Uzeti su uzorci jetrenog parenhima, fiksirani, obrađeni te potom bojani hemalaun eozinom, po Gomoriju, Malloriju te imunohistokemijski α SMA. Histološki je određen stupanj fibroze (0-6) i nekroinflamatorni skor (0-18) po Ishak klasifikaciji. Izmjeren je postotak površine kolagena. Proliferativna sposobnost hepatocita određena je prema prosječnom broju dvostrukih jezgara po vidnom polju. Pentadekapeptid BPC157 tretirane životinje nisu imale žuticu, imale su manju težinu jetre, tjelesnu težinu sličnu zdravim životinjama. Histološki manje površine zahvaćene kolagenom uz bolje očuvani jetreni parenhim (BPC157 životinje) za razliku od kontrolnih životinja kod kojih je nađena razvijena jetrena ciroza. Biokemijski nalazi pokazali su niže vrijednosti bilirubina, jetrenih enzima i više vrijednosti albumina u usporedbi s kontrolnim životinjama što pokazuje bolju očuvanost i funkcionalnu aktivnost jetre. Na temelju dobivenih rezultata možemo zaključiti da bi pentadekapeptid BPC157 mogao biti potencijalno farmakološko rješenje kod problema jetrene ciroze.We examined hepatoprotective effect of pentadecapeptide BPC157 on rat model of cirhosis caused by common bile duct ligation. The animals received pentadecapeptide BPC157 daily (10μg/kg and 10 ng/kg (ip/po)) during 2, 4, 6 and 8 weeks. The control group received the equivalent volume of 0.9% NaCl. Blood samples were taken for liver enzymes measurement , bilirubin and albumin serum levels. We measured the body weight, liver weight with and without main bile duct. Histopathological analysis was performed on hematoxylin-eosin, Gomori¨s, Mallory stain and α SMA. The fibrosis degree and liver necroinflammatory activity were determined by Ishak classification. Hepatic fibrosis extent was assessed as collagen area percentage within microscopic field. Hepatocyte proliferative ability was determined according to the average number of double nuclei in five HPF. BPC157 animals had no jaundice, smaller liver weight, smaller bile stasis within bile duct, body weight similar to healthy animals. Histologicaly smaller collagen area and better preserved parenchyma was found in BPC157 animals vs. liver cirrhosis in control animals. Biochemical results shown lower bilirubin, liver enzymes and albumin values in BPC157 rats compared to control showing better preservation of liver activity. We can conclude that BPC157 could be pharmacological solution for liver cirrhosis

Stable Gastric Pentadecapeptide BPC 157 Heals Established Vesicovaginal Fistula and Counteracts Stone Formation in Rats

With the stable gastric pentadecapeptide BPC 157 therapy known to heal various both external and internal rat fistulas, we attempt to approach vesicovaginal fistula, continuous urine leaking through vagina, bladder stones, and a possible therapy solution among rats with well-formed 2 week-fistulas (vaginal/vesical 4 mm large defects) started with delayed therapy. Subsequent control fistula course (the subsequent 1, 2, 4, and 6 weeks) since beginning revealed the failed healing, fistula leaking, adhesions, urinary leaking through vagina, failed epithelization, collagenization, granulation tissue and neovascularization, increased inflammation, and necrosis. Thereby, the later intervals revealed the persistent inability to sustain even minimal volume, vesical, and vaginal defects and stone formation at the end of the experiment (fistula-time day 56). BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once time daily or perorally in drinking water until sacrifice) was initiated with a considerable delay (at 2 weeks after fistula formation). Already within 1 week therapy, all BPC 157 regimens stopped urinary leaking through vagina, reversed the otherwise resistant poor healing course to the increased epithelization, collagenization, granulation tissue and neovascularization, decreased inflammation, and decreased necrosis. Thereby, at later intervals, all BPC 157 rats exhibited a five times larger volume that can be sustained before leaking as in healthy, vesical, and vaginal defects completely closed and no stone formation. Thus, macro/microscopic and functional recovery, and counteracted stone formation. Concluding, BPC 157 therapy’s beneficial effects resulted in healing and no stone formation, with µg- and ng-regimens, either given daily perorally in drinking water or intraperitoneally