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Predrag Sikiric - One of the best experts on this subject based on the ideXlab platform.
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stable gastric pentadecapeptide bpc 157 robert s stomach Cytoprotection adaptive Cytoprotection organoprotection and selye s stress coping response progress achievements and the future
Gut and Liver, 2020Co-Authors: Predrag Sikiric, Alenka Boban Blagaic, Ki Baik Hahm, Ante Tvrdeic, Katarina Horvat Pavlov, Andrea Petrovic, Antonio Kokot, Slaven Gojkovic, Ivan Krezic, Domagoj DrmicAbstract:: We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach Cytoprotection/adaptive Cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's Cytoprotection/adaptive Cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and P-GSK-3β (mitigating cancer cachexia).
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Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response: Progress, Achievements, and the Future.
Gut and liver, 2020Co-Authors: Predrag Sikiric, Alenka Boban Blagaic, Ki Baik Hahm, Katarina Horvat Pavlov, Andrea Petrovic, Antonio Kokot, Slaven Gojkovic, Ivan Krezic, Ante Tvrdeić, Domagoj DrmicAbstract:We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach Cytoprotection/adaptive Cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's Cytoprotection/adaptive Cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and p-GSK-3β (mitigating cancer cachexia).
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revised robert s Cytoprotection and adaptive Cytoprotection and stable gastric pentadecapeptide bpc 157 possible significance and implications for novel mediator
Current Pharmaceutical Design, 2010Co-Authors: Predrag Sikiric, Sven Seiwerth, Luka Brcic, Marko Sever, Robert Klicek, Bozo Radic, Domagoj Drmic, Spomenko Ilic, Danijela KolencAbstract:The significance of Cytoprotection and adaptive Cytoprotection and the peptides importance remained to be not completely determined. BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Roberts Cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the Cytoprotection and adaptive Cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the Cytoprotection phenomena and Cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in Cytoprotection and adaptative Cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well.
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New model of Cytoprotection/adaptive Cytoprotection in rats: endogenous small irritants, antiulcer agents and indomethacin.
European journal of pharmacology, 1999Co-Authors: Predrag Sikiric, željko Grabarevic, Sven Seiwerth, Slobodan Dešković, Anton Marovic, Rudolf Rucman, Marijan Petek, Paško Konjevoda, Stipislav Jadrijević, Tomislav ŠošaAbstract:Abstract Adaptive Cytoprotection in the stomach was originally defined by applying the exogenous irritants only. The contribution of endogenous irritants as inductors of initial lesions was not specially evaluated. No attempt was made to either focus antiulcer agent activity on adaptive Cytoprotection, or split their `Cytoprotection' into complex adaptive cytoprotective activity and simple cytoprotective effects. Agents had so far not been applied simultaneously with the second challenge with ethanol (or irritant), when differences between Cytoprotection and adaptive Cytoprotection appear. Gastrojejunal anastomosis for 24 h in rats was introduced as new model for analyzing Cytoprotection/adaptive Cytoprotection. The contribution of the up-normal level of endogenous irritants and the endogenous small irritant-induced minor lesions during the adaptive Cytoprotection were studied. The effect of late challenge with 96% ethanol in the presence of an up-normal level of endogenous irritants and endogenous small irritant-induced minor lesions was compared with results of classic studies of ethanol-induced gastric lesions in normal rats (1 ml/rat i.g.). Antiulcer agents or a prostaglandins-synthesis inhibitor, indomethacin, given once only in classic studies, were given at several points during injury induction: (i) surgery, (ii) mild ethanol, (iii) strong ethanol, (iv) strong ethanol applied after a suitable period following either mild ethanol or surgery). Their effects were compared in rats treated as follows: exogenous irritant studies (96% or 20% ethanol), exogenous/exogenous irritant studies (20% ethanol 1 h before 96% ethanol), endogenous irritant studies (gastrojejunal anastomosis for 24 h), and endogenous/exogenous irritant studies (gastrojejunal anastomosis for 24 h before 96% ethanol). Characteristic of the various irritants differed: the (preceding) small irritants (exogenous (i.e., mild ethanol in healthy intact rats) (exogenous irritant studies) vs. endogenous (e.g., (increased) gastric acid secretion, duodenal reflux in gastric content in rats with termino-lateral gastrojejunal anastomosis) (endogenous irritant studies)). These factors caused modifications of agents' activities not, as initially thought, giving simple `Cytoprotection', but being only cytoprotective, or adaptive cytoprotective, or both cytoprotective and adaptive cytoprotective. Atropine (10 mg/kg i.p.) and ranitidine (10 mg) had only cytoprotective activity (exogenous irritant-studies), whereas pentadecapeptide BPC157 (10 μg or 10 ng), and omeprazole (10 mg) had mainly adaptive cytoprotective activity (endogenous/exogenous irritant studies) or both cytoprotective and adaptive cytoprotective activities (exogenous/exogenous irritant studies). Augmentation of the lesions by indomethacin (5 mg/kg s.c.), showed that only events preceding the late challenge with ethanol may be prostaglandin-dependent in both models. The second, adaptive cytoprotective part, seen after late ethanol challenge, may be either prostaglandin-dependent (exogenous/exogenous irritant studies) or non-dependent (endogenous/exogenous irritant studies). Both spontaneous lesion reduction, as an essential mechanism of adaptive Cytoprotection, and the further lesion reduction by agents, such as pentadecapeptide BPC 157 and omeprazole, suggests that these agents function as an essential link between the various reactions in Cytoprotection/adaptive Cytoprotection.
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Pentagastrin Cytoprotection in Ethanol-Induced Gastric Mucosal Lesions in Rats
Journal of Veterinary Medicine Series A-physiology Pathology Clinical Medicine, 1993Co-Authors: Marija Dodig, Tatjana Drahotusky, S. Ðačić, Ivo Rotkvić, Damir Erceg, Predrag Sikiric, željko Grabarevic, Sven SeiwerthAbstract:Summary To establish pentagastrin Cytoprotection, the effectiveness of various doses of pentagastrin on ethanol induced gastric mucosal lesions was investigated in Wistar rats. Significant protection was obtained only after parenteral pretreatment with the exception of the lowest dose (1 μg/kg b.w.). Pentagastrin Cytoprotection is not mediated either by a dopamine, muscarinic or gastrin/CCK receptor or by prostaglandin synthesis. However, the protective effect of pentagastrin is abolished by prior vagotomy, although this procedure alone or sham operation is ineffective to influencing control-ethanol lesions. In secretory studies pentagastrin increased both the volume of gastric juice and total acid output. Unlike Cytoprotection, these were reversed by vagotomy, but also with atropine and problumide, whereas domperidone and indomethacin were ineffective.
Chi Hin Cho - One of the best experts on this subject based on the ideXlab platform.
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Histological Study of Mechanisms of Adaptive Cytoprotection on Ethanol-Induced Mucosal Damage in Rat Stomachs
Digestive Diseases and Sciences, 1998Co-Authors: Chi Hin ChoAbstract:Adaptive Cytoprotection in the gastric mucosacould be induced by exposure to low concentrations ofnoxious agents. However, experimental results reportedso far were based on macroscopic studies. We aimed to investigate the phenomenon of gastricadaptive Cytoprotection of mild irritants and itscorrelation with intramucosal mucus at the histologicallevel. It was found that histological damage induced by ethanol had a negative correlation with thelength of the mucus-secreting layer in the gastricmucosa. Mild irritants such as 20% ethanol and 5% NaClpreserved the 100% ethanol-induced intramucosal mucus depletion, but only the former agentdemonstrated a cytoprotective effect against thehistological damage, indicating that preservation ofintramucosal mucus may not necessarily play a permissiverole in adaptive Cytoprotection. Thecapsaicin-sensitive sensory afferent neurons, sensorychemoreceptors, muscarinic receptors,α_2-adrenoceptors and peripheraldopamine D_2-receptors were found to be thecomponents of the autonomic nervous system involved in thecytoprotective processes of 20% ethanol. Endogenousmediators including nitric oxide, prostaglandins, andpossibly nonprotein sulfhydryl compounds also seemed to participate in such protection.Nevertheless, 0.3 M HCl did not show any effect eitheron mucosal damage or depletion of intramucosal mucusinduced by absolute ethanol. These findings suggest thatonly 20% ethanol shows histological Cytoprotection,which would involve various components of the autonomicnervous system and endogenous mediators. Furthermore,this investigation also implies a new perspective: that in order to study a true adaptiveCytoprotection, histological examination of the gastricmucosa should be performed.
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Endogenous mediators in adaptive Cytoprotection against ethanol-induced gastric gland damage in rabbits
Life sciences, 1995Co-Authors: Chi Hin ChoAbstract:Abstract The present study determined the participation of different endogenous mediators in adaptive Cytoprotection against gastric gland damage caused by ethanol in rabbits. Using the isolated gland preparation, pretreatment with 10 −5 M of either indomethacin, N w -nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM), but not of substance P antagonist, intensified the 10% (v/v) ethanol-induced gastric gland damage and lessened the degree of Cytoprotection evoked by 2% (v/v) ethanol to a significant level. Co-administration with 10 −4 M of prostaglandin E 2 , L-arginine or glutathione to the respective groups completely reversed the above adverse effects. These results demonstrate the involvement of endogenous prostaglandins, nitric oxide and glutathione in gastric adaptive Cytoprotection against the damaging action of ethanol in the rabbit gastric glands.
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A correlative study on the mechanism of adaptive Cytoprotection against ethanol-induced gastric lesion formation in rats.
Journal of gastroenterology and hepatology, 1994Co-Authors: Chi Hin Cho, Clive W. OgleAbstract:The protective effect of mild irritants against the subsequent gastric injury induced by necrotizing agents has been termed ‘adaptive Cytoprotection'. In this study, the possible pathway and mechanisms of adaptive Cytoprotection induced by 20% ethanol were investigated. An ex-vivo gastric chamber preparation was used. The gastric mucosa was exposed to 20% ethanol before subsequent administration of 100% ethanol 15 min later. Subdiaphragmatic vagotomy or drug pretreatment was carried out in order to elucidate the mechanisms of adaptive Cytoprotection by 20% ethanol. The results showed that 20% ethanol pre-exposure significantly protected the gastric mucosa against damage caused by 100% ethanol. This protective action was completely abolished by atropine or lidocaine pretreatment, whereas vagotomy and hexamethonium failed to have a significant influence. The cytoprotective effect, however, was independent of the gastric secretory volume, titratable acid content, luminal soluble mucus level and gastric mucosal blood flow. Exposure of only half the gastric mucosa to the mild irritant resulted in the protection of both sides of the mucosa. All these findings indicate that the adaptive Cytoprotection of 20% ethanol involves the participation of chemoreceptors and muscarinic receptors in the gastric mucosa. An internal enteric reflex arc, with transmission of signals within the gastric mucosa, may also contribute to the cytoprotective process of the mild irritant.
Domagoj Drmic - One of the best experts on this subject based on the ideXlab platform.
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stable gastric pentadecapeptide bpc 157 robert s stomach Cytoprotection adaptive Cytoprotection organoprotection and selye s stress coping response progress achievements and the future
Gut and Liver, 2020Co-Authors: Predrag Sikiric, Alenka Boban Blagaic, Ki Baik Hahm, Ante Tvrdeic, Katarina Horvat Pavlov, Andrea Petrovic, Antonio Kokot, Slaven Gojkovic, Ivan Krezic, Domagoj DrmicAbstract:: We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach Cytoprotection/adaptive Cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's Cytoprotection/adaptive Cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and P-GSK-3β (mitigating cancer cachexia).
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Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response: Progress, Achievements, and the Future.
Gut and liver, 2020Co-Authors: Predrag Sikiric, Alenka Boban Blagaic, Ki Baik Hahm, Katarina Horvat Pavlov, Andrea Petrovic, Antonio Kokot, Slaven Gojkovic, Ivan Krezic, Ante Tvrdeić, Domagoj DrmicAbstract:We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach Cytoprotection/adaptive Cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's Cytoprotection/adaptive Cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and p-GSK-3β (mitigating cancer cachexia).
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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
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2018Co-Authors: Tomislav Becejac, Domagoj Drmic, Vedran Cesarec, Dorian Hirsl, Goran Madzarac, Zeljko Djakovic, I Bunjevac, A A Zenko Sever, Ana Sepac, L Batelja VuleticAbstract:With intra(per)-oral strong alcohol application at the tongue, swallowed, we renewed Robert's stomach Cytoprotection/adaptive Cytoprotection concept. We assessed strong (96%) alcohol-induced severe or minute lesions in stomach, tongue-esophagus-stomach-duodenum lesions, and sphincter pressure (lower esophageal and pyloric) upon administration intragastrically (at 1 h) or intra(per)-orally at the tongue, and swallowed (at 1, 5, 15, 30 min; and 1, 2, 24 h). The assessment also included combined administrations (intra(per)-oral at the tongue, swallowed and intragastric (at 1 h)). Immediate post-alcohol intraperitoneal medication (mg/kg) was the stable gastric pentadecapeptide BPC 157 (0.01, 0.00001; a Robert's Cytoprotection mediator; with a therapeutic effect), NOS-blocker L-NAME (5), and NOS-substrate L-arginine (100 mg), (NO-system involvement). After intragastric strong alcohol administration, severe stomach ulcerations appeared along with widespread tongue, esophagus, duodenum redness, and minimal sphincter pressures. By contrast, a particular syndrome (immediate overlapping of Cytoprotection/adaptive Cytoprotection) (minute gastric lesion or largely attenuated hemorrhagic ulceration, tongue affected, minute esophageal and duodenal lesions, but with intact mucosa; sphincters pressures lowered) appeared after intra(per)-oral administration (1 min-24 h) as well as after combined administrations (intra(per)-oral + intragastric). BPC 157 apparently cured all alcohol-lesions, amplified the spontaneously initiated strong mucosal beneficial effect, rescued sphincter pressures; NO-agents (L-arginine (slight mucosal amelioration) and L-NAME (aggravation)) showed NO-system involvement, but no comparable effects on dropped sphincters pressures. In conclusion, minute gastric lesions (with oral application of strong alcohol at the tongue and swallowed, without, or with intragastric application of strong alcohol) renew and revise Robert's stomach Cytoprotection/adaptive Cytoprotection concept. The tongue becomes a new initial target, resulting in spontaneous reversal of strong alcohol-stomach lesions. BPC 157 therapy functions also within the redirected complexity of Robert's stomach Cytoprotection/adaptive Cytoprotection concept.
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revised robert s Cytoprotection and adaptive Cytoprotection and stable gastric pentadecapeptide bpc 157 possible significance and implications for novel mediator
Current Pharmaceutical Design, 2010Co-Authors: Predrag Sikiric, Sven Seiwerth, Luka Brcic, Marko Sever, Robert Klicek, Bozo Radic, Domagoj Drmic, Spomenko Ilic, Danijela KolencAbstract:The significance of Cytoprotection and adaptive Cytoprotection and the peptides importance remained to be not completely determined. BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Roberts Cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the Cytoprotection and adaptive Cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the Cytoprotection phenomena and Cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in Cytoprotection and adaptative Cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well.
Douglas L Mann - One of the best experts on this subject based on the ideXlab platform.
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the cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor associated factor 2 in the heart
Circulation-heart Failure, 2010Co-Authors: Jana S Burchfield, Jianwen Dong, Yasushi Sakata, Feng Gao, Hueiping Tzeng, V K Topkara, Mark L Entman, Natarajan Sivasubramanian, Douglas L MannAbstract:Background— Activation of both type 1 and type 2 tumor necrosis factor (TNF) receptors (TNFR1 and TNFR2) confers Cytoprotection in cardiac myocytes. Noting that the scaffolding protein TNF receptor...
Ciro Isidoro - One of the best experts on this subject based on the ideXlab platform.
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Preconditioning-induced Cytoprotection in hepatocytes requires Ca2+-dependent exocytosis of lysosomes
Journal of Cell Science, 2004Co-Authors: Rita Carini, Roberta Castino, Maria Grazia De Cesaris, Roberta Splendore, Marina Démoz, Emanuele Albano, Ciro IsidoroAbstract:A short period of hypoxia reduces the cytotoxicity produced by a subsequent prolonged hypoxia in isolated hepatocytes. This phenomenon, termed hypoxic preconditioning, is mediated by the activation of adenosine A2A-receptor and is associated with the attenuation of cellular acidosis and Na+ overload normally occurring during hypoxia. Bafilomycin, an inhibitor of the vacuolar H+/ATPase, reverts the latter effects and abrogates the preconditioning-induced Cytoprotection. Here we provide evidence that the acquisition of preconditioning-induced Cytoprotection requires the fusion with plasma membrane and exocytosis of endosomal-lysosomal organelles. Poisons of the vesicular traffic, such as wortmannin and 3-methyladenine, which inhibit phosphatydilinositol 3-kinase, or cytochalasin D, which disassembles the actin cytoskeleton, prevented lysosome exocytosis and also abolished the preconditioning-associated protection from acidosis and necrosis provoked by hypoxia. Preconditioning was associated with the phosphatydilinositol 3-kinase-dependent increase of cytosolic [Ca2+]. Chelation of free cytosolic Ca2+ in preconditioned cells prevented lysosome exocytosis and the acquisition of Cytoprotection. We conclude that lysosome-plasma membrane fusion is the mechanism through which hypoxic preconditioning allows hepatocytes to preserve the intracellular pH and survive hypoxic stress. This process is under the control of phosphatydilinositol 3-kinase and requires the integrity of the cytoskeleton and the rise of intracellular free calcium ions.
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Preconditioning-induced Cytoprotection in hepatocytes requires Ca(2+)-dependent exocytosis of lysosomes.
Journal of cell science, 2004Co-Authors: Rita Carini, Roberta Castino, Maria Grazia De Cesaris, Roberta Splendore, Marina Démoz, Emanuele Albano, Ciro IsidoroAbstract:A short period of hypoxia reduces the cytotoxicity produced by a subsequent prolonged hypoxia in isolated hepatocytes. This phenomenon, termed hypoxic preconditioning, is mediated by the activation of adenosine A2A-receptor and is associated with the attenuation of cellular acidosis and Na+ overload normally occurring during hypoxia. Bafilomycin, an inhibitor of the vacuolar H+/ATPase, reverts the latter effects and abrogates the preconditioning-induced Cytoprotection. Here we provide evidence that the acquisition of preconditioning-induced Cytoprotection requires the fusion with plasma membrane and exocytosis of endosomal-lysosomal organelles. Poisons of the vesicular traffic, such as wortmannin and 3-methyladenine, which inhibit phosphatydilinositol 3-kinase, or cytochalasin D, which disassembles the actin cytoskeleton, prevented lysosome exocytosis and also abolished the preconditioning-associated protection from acidosis and necrosis provoked by hypoxia. Preconditioning was associated with the phosphatydilinositol 3-kinase-dependent increase of cytosolic [Ca2+]. Chelation of free cytosolic Ca2+ in preconditioned cells prevented lysosome exocytosis and the acquisition of Cytoprotection. We conclude that lysosome-plasma membrane fusion is the mechanism through which hypoxic preconditioning allows hepatocytes to preserve the intracellular pH and survive hypoxic stress. This process is under the control of phosphatydilinositol 3-kinase and requires the integrity of the cytoskeleton and the rise of intracellular free calcium ions.
