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Polyethylene glycol 35 ameliorates pancreatic inflammatory response in cerulein-induced acute pancreatitis in rats

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World Journal of Gastroenterology 2020年第39期26卷 5970-5982页

作者： Ana Ferrero-Andrés Arnau Panisello-roselló joan roselló-catafau Emma Folch-Puy Experimental Pathology Department Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicasBarcelona 08036CataloniaSpain Experimental Pathology Department Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicasCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstitut d'Investigacions Biomèdiques August Pi i SunyerBarcelona 08036CataloniaSpain

BACKGROUND Acute pancreatitis(AP)is a sudden inflammatory process of the pancreas that may also involve surrounding tissues and/or remote *** and parenchymal cell death are common pathological features of this condition and determinants of disease *** glycols(PEGs)are nonimmunogenic,non-toxic water-soluble polymers widely used in biological,chemical,clinical and pharmaceutical *** To evaluate the protective effect of a 35-kDa molecular weight PEG(PEG35)on the pancreatic damage associated to cerulein-induced acute pancreatitis in vivo and in *** Wistar rats were assigned at random to a control group,a cerulein–induced AP group and a PEG35 treatment *** was induced by five hourly intraperitoneal injections of cerulein(50μg/kg/bw),while the control animals received saline ***35 was administered intraperitoneally 10 minutes before each cerulein injection in a dose of 10 mg/*** AP induction,samples of pancreatic tissue and blood were collected for ***42J pancreatic acinar cells were treated with increasing concentrations of PEG35 prior to exposure with tumor necrosis factorα(TNFα),staurosporine or *** severity of AP was determined on the basis of plasma levels of lipase,lactate dehydrogenase activity,pancreatic edema and histological *** evaluate the extent of the inflammatory response,the gene expression of inflammation-associated markers was determined in the pancreas and in AR42J-treated ***-induced cell death was also measured in models of in vivo and in vitro pancreatic *** Administration of PEG35 significantly improved pancreatic damage through reduction on lipase levels and tissue edema in cerulein-induced AP *** increased associated inflammatory response caused by cerulein administration was attenuated by a decrease in the gene expression of inflammation-related cytokines and inducible nitric oxide synthase enzyme in the *** contr

关键词： Acute pancreatitis Inflammation Polyethylene glycols Cytokines AR42J cells Cell death

Effects of Institut Georges Lopez-1 and Celsior preservation solutions on liver graft injury

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World Journal of Gastroenterology 2015年第14期21卷 4159-4168页

作者： Donia Tabka Mohamed Bejaoui James Javellaud joan roselló-catafau Jean-Michel Achard Hassen Ben Abdennebi Unité de recherche "Biologie et anthropologie moléculaire appliquées au développe- mentetàla santé" (UR12ES11) University of MonastirFaculty of Pharmacy Experimental Hepatic Ischemia--Reperfusion Unit Institut d’Investigacions Biomèdiques de Barcelona--Consejo Superior de Investigaciones Cientificas INSERM Unité Mixte de Recherche S-8508000 LimogesFrance

AIM: To compare Institut Georges Lopez(IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury(IRI).METHODS: Two experimental models were *** the first one, acetylcholine-induced endotheliumdependent relaxation(EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions(24 h at 4 ℃).To determine nitric oxide(NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester(L-NAME), an inhibitor of endothelium nitric oxide synthase(e NOS), or with L-NAME plus indomethacin, an inhibitor of *** the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 ℃ and then perfused "ex vivo " for 2 h at 37 ℃.Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pA kt, pA MPK, eN OS and MAPKs proteins ***: After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly *** isolated arteries, EDR was exclusively mediated by ***, cold-stored arteries showed NOand COX-dependent *** decrease in NO-dependent relaxation after cold storage was significantly more marked with *** second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than *** injury was reduced, function was improved and there was less oxidative ***-1 solution activated Akt and AMPK, which was concomitant with increased eN OS expression and nitrite/nitrate ***, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were ***: IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solutio

关键词： Organ preservation solutions Institut Georges Lope

How to protect liver graft with nitric oxide

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World Journal of Gastroenterology 2011年第24期17卷 2879-2889页

作者： Hassen Ben Abdennebi Mohamed Amine Zaoualí Izabel Alfany-Fernandez Donia Tabka joan roselló-catafau Laboratory of Human Physiology Faculty of PharmacyUniversity of Monastir Unit of Experimental Hepatic IschemiaReperfusion Institut of d'Investigacions Biomèdiques de BarcelonaConsejo Superior de Investigaciones Científicas Unitat de Transplantament de Fetge i Viabilitat de l'Empelt Institut d'Investigacions Biomèdiques August Pi i Sunyer

Organ preservation and ischemia reperfusion injury associated with liver transplantation play an important role in the induction of graft injury. One of the earliest events associated with the reperfusion injury is endothelial cell dysfunction. It is generally accepted that endothelial nitric oxide synthase （e-NOS） is cell-pro- tective by mediating vasodilatation, whereas inducible nitric oxide synthase mediates liver graft injury after transplantation. We conducted a critical review of the literature evaluating the potential applications of regulating and promoting e-NOS activity in liver preservation and transplantation, showing the most current evidence to support the concept that enhanced bioavailability of NO derived from e-NOS is detrimental to ameliorate graft liver preservation, as well as preventing subse- quent graft reperfusion injury. This review deals mainly with the beneficial effects of promoting ＂endogenous＂ pathways for NO generation, via e-NOS inducer drugs in cold preservation solution, surgical strategies such as ischemic preconditioning, and alternative ＂exogenous＂ pathways that focus on the enrichment of cold storage liquid with NO donors. Finally, we also provide a basic bench-to-bed side summary of the liver physiology and cell signalling mechanisms that account for explaining the e-NOS protective effects in liver preservation and transplantation.

关键词： Cold ischemia reperfusion injury Endotheli-al nitric oxide synthase Nitric oxide Liver graft preser-vation Ischemic preconditioning Liver transplantation

Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury:An update

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World Journal of Gastroenterology 2018年第27期24卷 2984-2994页

作者： Arnau Panisello-roselló Alexandre Lopez Emma Folch-Puy Teresa Carbonell Anabela Rolo Carlos Palmeira René Adam Marc Net joan roselló-catafau Department of Experimental Pathology Institute of Biomedical Research of Barcelona(IIBB)-CSICBarcelona 08036Spain Centre Hepatobiliare AP-HP Hopital Paul BrousseVillejuif 75008France Department of Physiology Faculty of BiologyUniversitat de BarcelonaBarcelona 08036Spain Center for Neuroscience and Cell Biology University of CoimbraCoimbra 3004-517Portugal Institute Georges Lopez Lissieu 69380France

Aldehyde dehydrogenase 2(ALDH2) is best known for its critical detoxifying role in liver alcohol metabolism. However, ALDH2 dysfunction is also involved in a wide range of human pathophysiological situations and is associated with complications such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases and aging. A growing body of research has shown that ALDH2 provides important protection against oxidative stress and the subsequent loading of toxic aldehydes such as 4-hydroxy-2-nonenal and adducts that occur in human diseases, including ischemia reperfusion injury(IRI). There is increasing evidence of its role in IRI pathophysiology in organs such as heart, brain, small intestine and kidney; however, surprisingly few studies have been carried out in the liver, where ALDH2 is found in abundance. This study reviews the role of ALDH2 in modulating the pathways involved in the pathophysiology of IRI associated with oxidative stress, autophagy and apoptosis. Special emphasis is placed on the role of ALDH2 in different organs, on therapeutic "preconditioning" strategies, and on the use of ALDH2 agonists such as Alda-1, which may become a useful therapeutic tool for preventing the deleterious effects of IRI in organ transplantation.

关键词： Aldehyde dehydrogenase 2 4-hydroxy-2-nonenal autophagy Apoptosis Ischemia reperfusion injury Preconditioning

Role of sirtuins in ischemia-reperfusion injury

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World Journal of Gastroenterology 2013年第43期19卷 7594-7602页

作者： Eirini Pantazi Mohamed Amine Zaouali Mohamed Bejaoui Emma Folch-Puy Hassen Ben Abdennebi joan roselló-catafau Experimental Hepatic Ischemia-Reperfusion Unit Institut of Biomedical Research of Barcelona-Spanish National Research CouncilBarcelona08036 CataloniaSpain Molecular Biology and Anthropology applied to development and health (UR12ES11) Faculty of PharmacyMonastir 5000Tunisia Experimental Pathology Department Institute of Biomedical Research of Barcelona-Spanish National Research CouncilBarcelona08036 CataloniaSpain

Ischemia-reperfusion injury(IRI)remains an unresolved and complicated situation in clinical practice,especially in the case of organ *** factors contribute to its complexity;the depletion of energy during ischemia and the induction of oxidative stress during reperfusion initiate a cascade of pathways that lead to cell death and finally to severe organ ***,the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases has gained increasing attention from researchers,due to their involvement in the modulation of a wide variety of cellular *** are seven mammalian sirtuins and,among them,the nuclear/cytoplasmic sirtuin 1(SIRT1)and the mitochondrial sirtuin 3(SIRT3)are ubiquitously expressed in many tissue *** are known to play major roles in protecting against cellular stress and in controlling metabolic pathways,which are key processes during *** this review,we mainly focus on SIRT1 and SIRT3 and examine their role in modulating pathways against energy depletion during ischemia and their involvement in oxidative stress,apoptosis,microcirculatory stress and inflammation during *** present evidence of the beneficial effects of sirtuins against IRI and emphasize the importance of developing new strategies by enhancing their action.

关键词： Sirtuin 1 Sirtuin 3 Ischemia-reperfusion injury oxidative stress Apoptosis

Emerging concepts in liver graft preservation

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World Journal of Gastroenterology 2015年第2期21卷 396-407页

作者： Mohamed Bejaoui Eirini Pantazi Emma Folch-Puy Pedro M Baptista Agustín García-Gil René Adam joan roselló-catafau Experimental Hepatic Ischemia-Reperfusion Unit Institute of Biomedical Research of Barcelona-Spanish National Research CouncilCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas08036 BarcelonaCataloniaSpain Universidad de Zaragoza CIBER- ehdAragon Health Sciences Institute50009 ZaragozaSpain AP-HP H?pital Paul Brousse Centre Hépato-BiliaireUniversité Paris-Sud Villejuif75008 ParisFrance

The urgent need to expand the donor pool in order to attend to the growing demand for liver transplantation has obliged physicians to consider the use of suboptimal liver grafts and also to redefine the preservation strategies. This review examines the different methods of liver graft preservation, focusing on the latest advances in both static cold storage and machine perfusion(MP). The new strategies for static cold storage are mainly designed to increase the fatty liver graft preservation via the supplementation of commercial organ preservation solutions with additives. In this paper we stress the importance of carrying out effective graft washout after static cold preservation, and present a detailed discussion of the future perspectives for dynamic graft preservation using MP at different temperatures(hypothermia at 4 ℃, normothermia a t 3 7 ℃ and subnormothermia at 20 ℃- 2 5 ℃). Finally, we highlight some emerging applications of regenerative medicine in liver graft preservation. In conclusion, this review discusses the "state of the art" and future perspectives in static and dynamic liver graft preservation in order to improve graft viability.

关键词： Static cold preservation Suboptimal liver grafts P

Relevance of proteolysis and proteasome activation in fatty liver graft preservation: An Institut Georges Lopez-1 vs University of Wisconsin appraisal

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World Journal of Gastroenterology 2017年第23期23卷 4211-4221页

作者： Mohamed Amine Zaouali Arnau Panisello-roselló Alexandre Lopez Carlos Castro Benítez Emma Folch-Puy Agustín García-Gil Teresa Carbonell RenéAdam joan roselló-catafau Experimental Hepatic Ischemia-Reperfusion Unit Institut d’Investigacions Biomèdiques de BarcelonaSpanish National Research Council Research Unit of Biology and molecular anthropology applied to development and Health(UR12ES11) Faculty of PharmacyUniversity of Monastir Tunisia and Institute of Biotechnology of Monastir University of Monastir Centre Hépatobiliaire AP-PHHopital Paul Brousse Hospital Clínico de Zaragoza Facultat Biologia Universitat de Barcelona

To compare liver proteolysis and proteasome activation in steatotic liver grafts conserved in University of Wisconsin (UW) and Institut Georges Lopez-1 (IGL-1) *** liver grafts from male obese Zücker rats were conserved in UW and IGL-1 solutions for 24 h at 4 °Cand subjected to “ex vivo” normo-thermic perfusion (2 h; 37 °C). Liver proteolysis in tissue specimens and perfusate was measured by reverse-phase high performance liquid chromatography. Total free amino acid release was correlated with the activation of the ubiquitin proteasome system (UPS: measured as chymotryptic-like activity and 20S and 19S proteasome), the prevention of liver injury (transaminases), mitochondrial injury (confocal microscopy) and inflammation markers (TNF 1 alpha, high mobility group box-1 (HGMB-1) and PPAR gamma), and liver apoptosis (TUNEL assay, cytochrome c and caspase 3).RESULTSProfiles of free AA (alanine, proline, leucine, isoleucine, methionine, lysine, ornithine, and threonine, among others) were similar for tissue and reperfusion effluent. In all cases, the IGL-1 solution showed a significantly higher prevention of proteolysis than UW (P < 0.05) after cold ischemia reperfusion. Livers conserved in IGL-1 presented more effective prevention of ATP-breakdown and more inhibition of UPS activity (measured as chymotryptic-like activity). In addition, the prevention of liver proteolysis and UPS activation correlated with the prevention of liver injury (AST/ALT) and mitochondrial damage (revealed by confocal microscopy findings) as well as with the prevention of inflammatory markers (TNF1alpha and HMGB) after reperfusion. In addition, the liver grafts preserved in IGL-1 showed a significant decrease in liver apoptosis, as shown by TUNEL assay and the reduction of cytochrome c, caspase 3 and P62 *** comparison of these two preservation solutions suggests that IGL-1 helps to prevent ATP breakdown more effectively than UW and subsequently achieves a hig

关键词： Liver proteolysis Proteasome activation Fatty liver preservation Institut Georges Lopez-1 University of Wisconsin High mobility group box 1 Cold ischemia reperfusion injury

Insulin like growth factor-1 increases fatty liver preservation in IGL-1 solution

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World Journal of Gastroenterology 2010年第45期16卷 5693-5700页

作者： Mohamed Amine Zaouali Susagna Padrissa-Altés Ismail Ben Mosbah Hassen Ben Abdennebi Olivier Boillot Antoni Rimola Dalila Saidane-Mosbahi joan roselló-catafau Experimental Hepatic Ischemia-Reperfusion Unit Institut d'Investigacions Biomèdiques de BarcelonaConsejo Superior de Investigaciones Científicas08036 BarcelonaSpain Unitat de Transplantament de Fetgei Viabilitat del' Empelt Institut d'Investigacions Biomèdiques August Pii Sunyer08036 BarcelonaSpain Laboratory of Human Physiology Faculty of PharmacyUniversity of Monastir5000 MonastirTunisia Unit of Hepatic Transplantation Edouard Herriot Hospital69003 LyonFrance Biomedical Research Center Esther Koplowitz CIBER-ehdInstitute of Health Carlos Ⅲ08036 BarcelonaSpain

AIM: To investigate the benefits of insulin like growth factor-1 (IGF-1) supplementation to serum-free institut georges lopez-1 (IGL-1) solution to protect fatty liver against cold ischemia reperfusion injury. METHODS: Steatotic livers were preserved for 24 h in IGL-1  solution supplemented with or without IGF-1 and then perfused "ex vivo " for 2 h at 37℃. We examined the effects of IGF-1 on hepatic damage and function (transaminases, percentage of sulfobromophthalein clearance in bile and vascular resistance). We also studied other factors associated with the poor tolerance of fatty livers to cold ischemia reperfusion injury such as mitochondrial damage, oxidative stress, nitric oxide, tumor necrosis factor-α (TNF-α) and mitogen-activated protein ***: Steatotic livers preserved in IGL-1 solutionsupplemented with IGF-1 showed lower transaminase levels, increased bile clearance and a reduction in vascular resistance when compared to those preserved in IGL-1solution alone. These benefits are mediated by activation of AKT and constitutive endothelial nitric oxide synthase (eNOS), as well as the inhibition of inflammatory cytokines such as TNF-α. Mitochondrial damage and oxidative stress were also ***: IGL-1  enrichment with IGF-1 increasedfatty liver graft preservation through AKT and eNOS activation, and prevented TNF-α release during normothermic reperfusion.

关键词： AKT Institut georges lopez-1 solution Insulin like growth factor-1 Ischemia reperfusion injury Nitric oxide Oxidative stress Steatotic graft preservation

Losartan activates sirtuin 1 in rat reduced-size orthotopic liver transplantation

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World Journal of Gastroenterology 2015年第26期21卷 8021-8031页

作者： Eirini Pantazi Mohamed Bejaoui Mohamed Amine Zaouali Emma Folch-Puy Anabela Pinto Rolo Arnau Panisello Carlos Marques Palmeira joan roselló-catafau Experimental Pathology Department Experimental Hepatic Ischemia-Reperfusion UnitInstitute of Biomedical Research of Barcelona(IIBB-CSIC Department of Life Sciences Faculty of Science and TechnologyUniversity of Coimbra Portugal and Center for Neurosciences and Cell Biology University of Coimbra

AIM: To investigate a possible association between losartan and sirtuin 1(SIRT1) in reduced-size orthotopic liver transplantation(ROLT) in ***: Livers of male Sprague-Dawley rats(200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 ℃ prior to *** an additional group,an antagonist of angiotensin Ⅱ type 1 receptor(AT1R),losartan,was orally administered(5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the ***(as an indicator of liver injury),SIRT1 activity,and nicotinamide adenine dinucleotide(NAD+,a co-factor necessary for SIRT1 activity) levels were determined by biochemical *** expression of SIRT1,acetylated Fox O1(ac-Fox O1),NAMPT(the precursor of NAD+),heat shock proteins(HSP70,HO-1) expression,endoplasmic reticulum stress(GRP78,IRE1 a,p-e IF2) and apoptosis(caspase 12 and caspase 3) parameters were determined by Western *** alterations in protein expression of mitogen activated protein kinases(MAPK),such as p-p38 and p-ERK,were also ***,the SIRT3 protein expression and m RNA levels were ***: The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group,as evidenced by the significant decreases in alanine aminotransferase(358.3 ± 133.44 vs 206 ± 33.61,P < 0.05) and aspartate aminotransferase levels(893.57 ± 397.69 vs 500.85 ± 118.07,P < 0.05).The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity(5.27 ± 0.32 vs 6.08 ± 0.30,P < 0.05).This was concomitant with increased levels of NAD+(0.87 ± 0.22 vs 1.195 ± 0.144,P < 0.05) the co-factor necessary for SIRT1 activity,as well as with decreases in ac-Fox O1 *** treatment also provoked significant attenuation of endoplasmic reticulum stress parameters(GRP78,IRE1 a,p-e IF2) which was consistent with reduced levels of both caspase 12 and caspase 3.

关键词： Losartan Sirtuin 1 Endoplasmic reticulumstress Liver ischemia reperfusion injury Angiotensin Ⅱ