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Gastric pentadecapeptide BPC 157 in cytoprotection to resolve major vessel occlusion disturbances,ischemia-reperfusion injury following Pringle maneuver,and Budd-Chiari syndrome

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World Journal of Gastroenterology 2022年第1期28卷 23-46页

作者： Predrag Sikiric Anita Skrtic Slaven Gojkovic ivan krezic Helena Zizek Eva Lovric Suncana Sikiric Mario Knezevic Sanja Strbe Marija Milavic Antonio Kokot Alenka Boban Blagaic Sven Seiwerth Department of Pharmacology School of MedicineUniversity of ZagrebZagreb 10000Croatia Department of Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia Department of Anatomy and Neuroscience Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijek 31000Croatia

The stable gastric pentadecapeptide BPC 157 counteracts various venous occlusion-induced syndromes.Summarized are all these arguments,in the Robert’s cytoprotection concept terms,to substantiate the resolution of different major vessel occlusion disturbances,in particular ischemia-reperfusion injury following the Pringle maneuver and Budd-Chiari syndrome,which was obtained by BPC 157 therapy.Conceptually,there is new point(bypassed occluded or ruptured vessel,the equation endothelium maintenance→epithelium maintenance=blood vessel recruitment and activation towards defect or bypassing vessel occlusion),the recruitment of collateral blood vessels to compensate for vessel occlusion and reestablish blood flow.In this paper,we summarize the evidence of the native cytoprotective gastric pentadecapeptide BPC 157,which is stable in the human gastric juice,is a membrane stabilizer and counteracts gut-leaky syndrome.As a particular target,it is distinctive from the standard peptide growth factors,with particular molecular pathways involved,controlling VEGF and NO pathways.In the early 1990s,BPC 157 appeared as a late outbreak of the Robert’s and Szabo’s cytoprotection-organoprotection concept,epithelium,endothelium protection as previous theoretical/practical breakthrough in the 1980s,and brain-gut axis and gut-brain axis.As the time went on,with its reported effects,it is likely most useful theory practical implementation and justification.Meantime,several reviews suggest that BPC 157,which does not have a lethal dose(LD1),has profound cytoprotective activity,used to be demonstrated in ulcerative colitis and invented to multiple sclerosis trials.Likely,it may bring the theory to practical application,starting with the initial argument,no degradation in human gastric juice for more than 24 h,and thereby,the therapeutic effectiveness(including therapeutic per-oral regimen)and pleiotropic beneficial effects.

关键词： Gastric pentadecapeptide BPC 157 Cytoprotection Major vessel occlusion disturbances Pringle maneuver Budd-Chiari syndrome Therapy

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Stomach perforation-induced general occlusion/occlusion-like syndrome and stable gastric pentadecapeptide BPC 157 therapy effect

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World Journal of Gastroenterology 2023年第27期29卷 4289-4316页

作者： Luka Kalogjera ivan krezic ivan Maria Smoday Hrvoje Vranes Helena Zizek Haidi Yago Katarina Oroz Vlasta Vukovic ivana Kavelj Luka Novosel Slavica Zubcic ivan Barisic Lidija Beketic Oreskovic Sanja Strbe Marko Sever Ivica Sjekavica Anita Skrtic Alenka Boban Blagaic Sven Seiwerth Predrag Sikiric Department of Pharmacology School of MedicineZagreb 10000Croatia Division of Oncology and Radiotherapy University Hospital for TumorsSestre milosrdnice University Hospital CentreZagreb 10000Croatia Department of Pathology School of MedicineZagreb 10000Croatia

BACKGROUND Using rat stomach perforation as a prototypic direct lesion applied in cytoprotection research,we focused on the first demonstration of the severe occlusion/occlusion-like syndrome induced by stomach perforation.The revealed stomachinduced occlusion/occlusion-like syndrome corresponds to the previously described occlusion/occlusion-like syndromes in rats suffering multicausal pathology and shared severe vascular and multiorgan failure.This general point was particularly reviewed.As in all the described occlusion/occlusion-like syndromes with permanent occlusion of major vessels,peripheral and central,and other similar noxious procedures that severely affect endothelium function,the stable gastric pentadecapeptide BPC 157 was resolving therapy.AIM To reveal the stomach perforation-induced general occlusion/occlusion-like syndrome and BPC 157 therapy effect.METHODS The procedure included deeply anesthetized rats,complete calvariectomy,laparotomy at 15 min thereafter,and stomach perforation to rapidly induce vascular and multiorgan failure occlusion/occlusion-like syndrome.At 5 min post-perforation time,rats received therapy[BPC 157(10μg or 10 ng/kg)or saline(5 mL/kg,1 mL/rat)(controls)]into the perforated defect in the stomach).Sacrifice was at 15 min or 60 min post-perforation time.Assessment(gross and microscopy;volume)included:Brain swelling,peripheral vessels(azygos vein,superior mesenteric vein,portal vein,inferior caval vein)and heart,other organs lesions(i.e.,stomach,defect closing or widening);superior sagittal sinus,and peripherally the portal vein,inferior caval vein,and abdominal aorta blood pressures and clots;electrocardiograms;and bleeding time from the perforation(s).RESULTS BPC 157 beneficial effects accord with those noted before in the healing of the perforated defect(raised vessel presentation;less bleeding,defect contraction)and occlusion/occlusion-like syndromes counteraction.BPC 157 therapy(into the perforated defect),induced immediate shrinking and contraction of the whole stomach(

关键词： Stomach perforation General occlusion/occlusion-like syndrome Stable gastric pentadecapeptide BPC 157 Cytoprotection Therapy Rats

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Pentadecapeptide BPC 157 resolves Pringle maneuver in rats,both ischemia and reperfusion

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World Journal of Hepatology 2020年第5期12卷 184-206页

作者： Marijan Kolovrat Slaven Gojkovic ivan krezic Dominik Malekinusic Borna Vrdoljak Katarina Kasnik Kovac Tamara Kralj Domagoj Drmic ivan Barisic Katarina Horvat Pavlov Andreja Petrovic Antonija Duzel Mario Knezevic ivan Mirkovic Antonio Kokot Alenka Boban Blagaic Sven Seiwerth Predrag Sikiric Departments of Pharmacology and Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia

BACKGROUND The Pringle maneuver[portal triad obstruction(PTO)]provides huge disturbances during ischemia and even more thereafter in reperfusion.Contrarily,a possible solution may be stable gastric pentadecapeptide BPC 157,with already documented beneficial effects in ischemia/reperfusion conditions.Recently,BPC 157,as a cytoprotective agent,successfully resolved vessel occlusions in rats(ischemic colitis;deep vein thrombosis,superior anterior pancreaticoduodenal vein;bile duct cirrhosis)through rapid collateral vessel recruitment to circumvent vessel occlusion.Thereby,medication BPC 157 regimens were administered as a single challenge before and during ischemia or,alternatively,at various time points during reperfusion.AIM To introduce BPC 157 therapy against pringle maneuver-damage.METHODS In deeply anesthetised rats,the portal triad was clamped up for 30 min.Rats then underwent reperfusion for either 15 min or 24 h.Medication[(10μg,10 ng/kg)regimens,administered as a single challenge]picked(a)ischemia,PTO period[at 5 min before(ip)or at 5 or 30 min of ligation time(as a bath to PTO)]or(b)reperfusion,post-PTO period[at 1 or 15 min(bath during surgery)or 24 h(ip)reperfusion-time].We provided gross,microscopy,malondialdehyde,serum enzymes,electrocardiogram,portal,caval,and aortal pressure,thrombosis and venography assessments.RESULTS BPC 157 counteracts electrocardiogram disturbances(increased P wave amplitude,S1Q3T3 QRS pattern and tachycardia).Rapidly presented vascular pathway(portal vein-superior mesenteric vein-inferior mesenteric vein-rectal veins-left ileal vein-inferior caval vein)as the adequate shunting immediately affected disturbed haemodynamics.Portal hypertension and severe aortal hypotension during PTO,as well as portal and caval hypertension and mild aortal hypotension in reperfusion and refractory ascites formation were markedly attenuated(during PTO)or completely abrogated(reperfusion);thrombosis in portal vein tributaries and inferior caval vein or hepatic artery was counteracted during portal

关键词： BPC 157 Pringle maneuver Rats Portal hypertension Caval hypertension Ischemia

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Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine

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World Journal of Gastroenterology 2018年第47期24卷 5366-5378页

作者： Fedor Amic Domagoj Drmic Zdenko Bilic ivan krezic Helena Zizek Marina Peklic Robert Klicek Alen Pajtak Enio Amic Tinka Vidovic Mislav Rakic Marija Milkovic Perisa Katarina Horvat Pavlov Antonio Kokot Ante Tvrdeic Alenka Boban Blagaic Mario Zovak Sven Seiwerth Predrag Sikiric Department of Pharmacology Medical Faculty University of Zagreb Department of Pathology Medical Faculty University of Zagreb

AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide(NO) system involvement.METHODS Male Wistar rats underwent superior anterior pancreaticoduodenal vein(SAPDV)-ligation and were treated with a bath at the ligated SAPDV site(BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 m L bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation(filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein(IAPDV) and superior mesenteric vein(SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO-and oxidative stress [malondialdehyde(MDA)]-levels in duodenum.RESULTS Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues.CONCLUSION BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, aneffect related to the NO system and reduction of free radical formation.

关键词： Major venous occlusion Duodenal lesions BPC 157 L-NAME Bypassing L-arginine Reduction of free radical formation Rats

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Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: New insights

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World Journal of Gastroenterology 2017年第48期23卷 8465-8488页

作者： Antonija Duzel Josipa Vlainic Marko Antunovic Dominik Malekinusic Borna Vrdoljak Mariam Samara Slaven Gojkovic ivan krezic Tinka Vidovic Zdenko Bilic Mario Knezevic Marko Sever Nermin Lojo Antonio Kokot Marijan Kolovrat Domagoj Drmic Jaksa Vukojevic Tamara Kralj Katarina Kasnik Marko Siroglavic Sven Seiwerth Predrag Sikiric Departments of Pharmacology and Pathology Medical Faculty University of Zagreb Medical Faculty J.J.Strossmayer University of Osijek OsijekCroatia Rudjer Boskovic Institute Department of Molecular Medicine

AIM To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157. METHODS Medication [BPC 157,L-NAME,L-arginine(alone/combined),saline] was bath at the blood deprived colon segment. During reperfusion,medication was BPC 157 or saline. We recorded(USB microscope camera) vessel presentation through next 15 min of ischemic colitis(ICrats) or reperfusion(removed ligations)(IC + RL-rats);oxidative stress as MDA(increased(IC-and IC + RLrats)) and NO levels(decreased(IC-rats);increased(IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction(OB)] for 3 d(IC + OBrats),then received BPC 157 bath. RESULTS Commonly,in colon segment(25 mm,2 ligations on left colic artery and vein,3 arcade vessels within ligated segment),in IC-,IC + RL-,IC + OB-rats,BPC 157(10 μg/kg) bath(1 m L/rat) increased vessel presentation,inside/outside arcade interconnections quickly reappeared,mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME(5 mg) and L-arginine(100 mg). MDA-and NO-levels were normal in BPC 157 treated IC-rats and IC + RLrats. In addition,on day 10,BPC 157-treated IC + OBrats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects;the treated colon segment was of normal diameter,and only small adhesions were present.CONCLUSION BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system.

关键词： Ischemic colitis Blood flow rescue Collaterals BPC 157 L-NAME L-arginine Oxidative stress NO Rats

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Bowel adhesion and therapy with the stable gastric pentadecapeptide BPC 157,L-NAME and L-arginine in rats

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2020年第5期11卷 93-109页

作者： Lidija Berkopic Cesar Slaven Gojkovic ivan krezic Dominik Malekinusic Helena Zizek Lovorka Batelja Vuletic Andreja Petrovic Katarina Horvat Pavlov Domagoj Drmic Antonio Kokot Josipa Vlainic Sven Seiwerth Predrag Sikiric Department of Pharmacology School of MedicineUniversity of ZagrebZagreb 10000Croatia Department of Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia Institute Ruder Boskovic Zagreb 10000Croatia

BACKGROUND After parietal peritoneum excision with an underlying superficial layer of muscle tissue in rats,there is failed vasculature,and finally,increased adhesion formation.We hypothesized that unlike nitric oxide(NO)-agents,L-NAME and/or L-arginine,the application of the stable gastric pentadecapeptide BPC 157 with its most recent vascular effects(“vascular recruitment”)means attenuated bowel adhesion formation and NO-and malondialdehyde(MDA)-tissue values.AIM To focused on the bowel adhesion and the therapy with the BPC 157,its most and application of NO-agents.METHODS Along with defect creation,medication was(1)during surgery,once,at 1 min after defect creation as an abdominal bath(1 mL/rat),BPC 157(10μg/kg,10 ng/kg,1 mL/rat),an equivolume of saline,L-NAME(5 mg/kg),L-arginine(200 mg/kg)alone and/or combined.Alternatively,medication was(2)intraperitoneally once daily,first application at 30 min after surgery,last application 24 h before assessment at d 7 or d 14.As a postponed therapy to preexisting adhesion(3),BPC 157(10μg/kg,10 ng/kg intraperitoneally,1 mL/rat)was given once daily since d 7.RESULTSThe recovery effect of the BPC 157 regimens goes with the presence of abundant vascular vessels in and near the defect,which occurs rapidly.Lastly,also applied as post-treatment,BPC 157 creates attenuated adhesions,minimal or no adhesion.Contrarily,NO-agents have diverse initial and final effects:The initial weakening of blood vessel disappearance and finally,severe worsening of adhesions(LNAME)vs the initial weakening of blood vessel disappearance and finally,attenuation of adhesions formation(L-arginine),which counteract each other response given together.Importantly,BPC 157 maintains its beneficial effect also when given with NO-agents(L-NAME+BC 157;L-arginine+BPC 157;L-NAME+L-arginine+BPC 157).Finally,with respect to the increased NO-and MDAvalues-adhesion tissue formation relation,unlike diverse effect of the NO-agents,the BPC 157 application effect regularly combines decrease on the increased NOand MDA-val

关键词： Abdominal wall defect Adhesions BPC 157 Vascular recruitment Nitric oxide-agents Rats

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Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in ratsPentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats

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World Journal of Gastrointestinal Pathophysiology 2020年第1期11卷 1-19页

作者： Slaven Gojkovic ivan krezic Borna Vrdoljak Dominik Malekinusic ivan Barisic andreja Petrovic Katarina Horvat Pavlov Marijan Kolovrat Antonija Duzel Mario Knezevic Katarina Kasnik Kovac Domagoj Drmic Lovorka Batelja Vuletic Antonio Kokot Alenka Boban Blagaic Sven Seiwerth Predrag Sikiric Departments of Pharmacology and Pathology Medical Faculty University of ZagrebZagreb 10000Croatia

BACKGROUND Recently,as a possible therapy resolving solution,pentadecapeptide BPC 157 therapy,has been used in alleviating various vascular occlusion disturbances.BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach,and gut-brain axis,beneficial therapy in gastrointestinal tract,with particular reference to vascular recruitment,ulcerative colitis and tumor cachexia,and other tissues healing.Here we raised new hypothesis about BPC 157 therapy in the Budd-Chiari syndrome in rats,rapid bypassing of the suprahepatic inferior caval vein occlusion,and rats recovery with the active and effective pharmacotherapy treatment.AIM To investigate Budd-Chiari syndrome model(inferior caval vein suprahepatic occlusion)resolution,since BPC 157 resolves various rat vascular occlusion.METHODS We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt,counteracted caval/portal hypertension,aortal hypotension,venous/arterial thrombosis,electrocardiogram disturbances,liver and gastrointestinal lesions(i.e.,stomach and duodenum hemorrhages,in particular,congestion).Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min,15 min,24 h,or 48 h post-ligation.Medication consisted of 10μg/kg BPC 157,10 ng BPC 157 or 5 m L/kg saline,administered once as an abdominal bath or intragastric application.Gross and microscopic observations were made,in addition to assessments of electrical activity of the heart(electrocardiogram),portal and caval hypertension,aortal hypotension,thrombosis,hepatomegaly,splenomegaly and venography.Furthermore,levels of nitric oxide,malondialdehyde in the liver and serum enzymes were determined.RESULTS BPC 157 counteracted increased P wave amplitude,tachycardia and ST-elevation,i.e.,right heart failure from acute thrombotic coronary occlusion.The bypassing pathway of the inferior vena cava-azygos(hemiazygos)vein-superior vena cava and portocaval shunt occurred rapidly

关键词： BPC 157 Budd Chiari syndrome Portal/caval hypertension

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Method for passivation of propellant residues in orbital stage tank of launch vehicle

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Chinese Journal of Aeronautics 2024年第1期37卷 64-76页

作者： Valeriy TRUSHLYAKOV ivan LESNYAK Alexey PANICHKIN Department of Aviation and Rocket Building Omsk State Technical UniversityOmsk 644050Russia Sobolev Institute of Mathematics of the Siberian Branch of Russian Academy of Sciences Novosibirsk 630090Russia

The problem of removing unused liquid propellant residues from the tanks of spent spacecraft and orbital stages of Launch Vehicles(LV)leads to their explosion and the formation of space debris in orbits.To provide a solution to this problem,a method for removing liquid propellant residues from the LV tanks after the mission completion is proposed.The method is based on the gasification of liquid propellant residues in the tanks under acoustic-vacuum exposure and the discharge of the gasification products into the surrounding outer space.Experimental investigations were carried out on a Ground-based Experimental Installation(GEI)to determine the coefficient of heat transfer from the surface of an acoustic radiator to a liquid.The obtained coefficient was then used to calculate the energy costs for the gasification of kerosene.Numerical estimates are given on the example of the tank with kerosene residues from a spent second stage of the LV“Soyuz-2.1 v”.The optimal discharge rate at which kerosene does not freeze is 0.14 m^(3)/s.Moreover,the acoustic exposure leads to an increase in the mass of evaporated kerosene over a given time by96.1%,and the energy costs are 1756.7 kJ(approximately 50% of the remaining electrical energy).

关键词： Propellant Weightlessness Liquid evaporation Heat and mass transfer Acoustics Vacuum Vapor bubbles

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Liquid superlubricity of lubricants containing hydroxyl groups and their aqueous solution under rolling/sliding conditions

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Friction 2024年第1期12卷 164-173页

作者： Tomáš POLÁČEK Petr ŠPERKA ivan KŘUPKA Faculty of Mechanical Engineering Brno University of TechnologyBrno 61669Czech Republic

Macroscale rolling/sliding conditions are in the superlubricity,a little-studied topic so far.The purpose of this paper is to examine the formation of elastohydrodynamic lubrication(EHL)films by water-based lubricants(glycerol and polyethylene glycol(PEG)),providing superlubricous friction.Experiments were carried out on an optical ball-on-disc tribometer under rolling/sliding conditions.The film thickness was measured by the thin film colorimetric interferometry,and the viscosity of liquids was measured by rotational and high-pressure falling body viscometers.The results show that tribochemical reactions are not the mandatory reason for friction to reach the superlubricity level when using the water-based lubricants.The studied liquids themselves are almost Newtonian.With the addition of water,the signs of shear thinning behavior disappear even more.Suitable conditions for this type of lubricant can be predicted using the known Hamrock–Dowson equations.An anomaly in the thickness of the lubricants was observed as an abrupt change at certain conditions.The more PEG there is in the lubricant,the higher the thickness at the beginning of the jump.

关键词： macroscale superlubricity super low traction water-based lubricants elastohydrodynamic lubrication(EHL) film thickness

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Witness for resolution: post-conflict quadratic affiliation in semi-free ranging pigs

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Current Zoology 2024年第2期70卷 233-243页

作者： ivan Norscia Edoardo Collarini Carlo Robino Elena Chierto Giada Cordoni Department of Life Sciences and Systems Biology University of TorinoVia Accademia Albertina 1310123 TorinoItaly Department of Public Health Sciences and Pediatric s University of TorinoC.So Galileo Galilei 2210126 TorinoItaly

In social mammals,post-conflict resolution can involve the reunion of former opponents(reconciliation),spontaneous/solicited post-conflict affliation of a third party with either opponent(triadic contacts),and affiliation between other individuals(hereafter bystanders;quadratic contacts).Quadratic contacts-possibly informing complex cognitive abilities-have been neglected in post-conflict studies.We investi-gated quadratic affliation in semi-free ranging pigs Sus scrofa,at the ethical farm Parva-Domus(Cavagnolo,Italy).Kinship was known.We collected behavioral data on adult pigs(n=104)via video recordings(43 h)followed by video analyses.Affiliative and anxiety behaviors between bystanders were collected under post-conflict(PC;following a conflict between non-bystanders)and matched-control(MC;no conflict)conditions.Quadratic affiliation was present in pigs,as bystanders affliated more in PC than MC,and such affiliation was followed by a decrease in the anxiety behaviors of both the interacting bystanders.Thus,quadratic contacts may be partly aimed at reducing one's own anxiety(intrinsic regulation).Quadratic affiliation was highest between closely related bystanders,which suggests that such affiliation may be most effective when close kin is involved.Quadratic affiliation was lowest after reconciliation and spontaneous triadic contacts.This suggests that direct peacemaking between opponents and spontaneous triadic contacts with close kin may most likely replace quadratic affiliation.Hence,pigs can be influenced by the negative events that affect other pigs-but not themselves-and their response may be modulated by social factors.Such non-random quadratic affiliation may point toward the presence of elements of social appraisal abilities inpigs.

关键词： anxiety reduction emotional regulation reconciliation social appraisal triadic contacts.

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