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

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

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Emerging concepts in liver graft preservation

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世界胃肠病学杂志：英文版 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

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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

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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

AIM To compare liver proteolysis and proteasome activation in steatotic liver grafts conserved in University of Wisconsin(UW) and Institut Georges Lopez-1(IGL-1)*** Fatty liver grafts from male obese Zücker rats were conserved in UW and IGL-1 solutions for 24 h at 4 ℃and subjected to "ex vivo " normo-thermic perfusion(2 h; 37 ℃). 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 20 S and 19 S 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).RESULTS Profiles 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 levels. CONCLUSION Our comparison of these two preservation solutions suggests that IGL-1 helps to prevent ATP breakdown more effectively than UW and subsequently achieves a higher UPS

关键词：肝解朊作用 Proteasome 激活脂肪肝保藏 Institut Georges Lopez-1 威斯康星的大学高活动性组盒子 1 冷局部缺血灌注损害

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Peroxisome proliferator-activated receptor γ agonist reduces the severity of post-ERCP pancreatitis in rats

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World Journal of Gastroenterology 2006年第40期12卷 6458-6463页

作者： emma folch-puy Susana Granell Juan L Iovanna Marc Barthet Daniel Closa Department of Experimental Pathology IIBB-CSIC IDIBAPS Barcelona Spain INSERM U.624 Stress Cellulaire Marseille France

AIM: To determine the effects of prophylactic peroxi-some proliferator-activated receptor (PPARγ) agonist administration in an experimental model of post-endoscopic retrograde cholangiopancreatography (post-ERCP) acute ***: Post-ERCP pancreatitis was induced in male Wistar rats by infusion of contrast medium into the pancreatic duct. In additional group, rosiglitazone, a PPARγ agonist, was administered 1 h before infusion of contrast medium. Plasma and pancreas samples were obtained 6 h after the ***: Infusion of contrast medium into the pan-creatic duct resulted in an inflammatory process characterized by increased lipase levels in plasma, and edema and myeloperoxidase activity (MPO) in pancreas. This result correlated with the activation of nuclear factor κB (NFκB) and the inducible NO synthase (iNOS) expression in pancreatic cells. Rosiglitazone reduced the increase in lipase and the level of edema and the increase in myeloperoxidase as well as the activation of NFκB and iNOS ***: A single oral dose of rosiglitazone, given 1 h before post-ERCP pancreatitis induction is effective in reducing the severity of the subsequent inflammatory process. The protective effect of rosiglitazone was associated with NFκB inhibition and the blockage of leukocyte infiltration in pancreas.

关键词：病理治疗临床过氧物酶体胰腺炎

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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

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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

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Polyethylene glycol rinse solution:An effective way to prevent ischemia-reperfusion injury

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World Journal of Gastroenterology 2014年第43期20卷 16203-16214页

作者： Mohamed Amine Zaouali Mohamed Bejaoui Maria Calvo emma folch-puy Eirini Pantazi Gianfranco Pasut Antoni Rimola Hassen Ben Abdennebi René Adam Joan Roselló-Catafau Experimental Hepatic Ischemia-Reperfusion Unit IIBB-CSICCSIC-IDIBAPS08036 BarcelonaSpain Molecular Biology and Anthropology Applied to Development and Health (UR12ES11) Faculty of PharmacyUniversity of Monastir5000 MonastirTunisia Serveis Cientifico-Tècnics Universitat de Barcelona08036 BarcelonaSpain Pharmaceutical and Pharmacological Department University of Padova35122 PadovaItaly Hospital Clínic Networked Biomedical Research Center of Hepatic and Digestive Diseases (Ciber EHD)08036 BarcelonaSpain AP-HP H?pital Paul Brousse Centre Hepato-BiliaireUniv Paris-Sud Villejuif75008 ParisFrance

AIM:To test whether a new rinse solution containing polyethylene glycol 35(PEG-35)could prevent ischemia-reperfusion injury(IRI)in liver ***:Sprague-Dawley rat livers were stored in University of Wisconsin preservation solution and then washed with different rinse solutions(Ringer’s lactate solution and a new rinse solution enriched with PEG-35 at either 1 or 5 g/L)before ex vivo perfusion with Krebs-Heinseleit buffer *** assessed the following:liver injury(transaminase levels),mitochondrial damage(glutamate dehydrogenase activity),liver function(bile output and vascular resistance),oxidative stress(malondialdehyde),nitric oxide,liver autophagy(Beclin-1 and LCB3)and cytoskeleton integrity(filament and globular actin fraction);as well as levels of metalloproteinases(MMP2 and MMP9),adenosine monophosphate-activated protein kinase(AMPK),heat shock protein 70(HSP70)and heme oxygenase 1(HO-1).RESULTS:When we used the PEG-35 rinse solution,reduced hepatic injury and improved liver function were noted after *** PEG-35 rinse solution prevented oxidative stress,mitochondrial damage,and liver ***,it increased the expression of cytoprotective heat shock proteins such as HO-1 and HSP70,activated AMPK,and contributed to the restoration of cytoskeleton integrity after ***:Using the rinse solution containing PEG-35 was effective for decreasing liver graft vulnerability to IRI.

关键词： Liver washout Liver transplantation Rinse solution

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Sirtuin 1 in rat orthotopic liver transplantation:An I GL-1 preservation solution approach

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World Journal of Gastroenterology 2015年第6期21卷 1765-1774页

作者： Eirini Pantazi Mohamed Amine Zaouali Mohamed Bejaoui emma folch-puy Hassen Ben Abdennebi Ana Teresa Varela Anabela Pinto Rolo Carlos Marques Palmeira Joan Roselló-Catafau Experimental Hepatic Ischemia Reperfusion Unit Institute of Biomedical Research of Barcelona Faculty of Pharmacy Molecular Biology and Anthropology Applied to Development and Health Department of Life Sciences and Center for Neuroscience and Cell Biology University of Coimbra Department of Biology University of Aveiro

AIM:To investigate the possible involvement of Sirtuin1(SIRT1)in rat orthotopic liver transplantation(OLT),when Institute Georges Lopez 1(IGL-1)preservation solution is enriched with trimetazidine(TMZ).METHODS:Male Sprague-Dawley rats were used as donors and *** were stored in IGL-1 preservation solution for 8h at 4℃,and then underwent OLT according to Kamada’s cuff technique without *** another group,livers were stored in IGL-1 preservation solution supplemented with TMZ,at10-6 mol/L,for 8 h at 4℃and then underwent *** were sacrificed 24 h after reperfusion,and liver and plasma samples were *** injury(transaminase levels),mitochondrial damage(glutamate dehydrogenase activity)oxidative stress(malondialdehyde levels),and nicotinamide adenine dinucleotide(NAD+),the cofactor necessary for SIRT1 activity,were determined by biochemical ***1 and its substrates(acFox O1,ac-p53),the precursor of NAD+,nicotinamide phosphoribosyltransferase(NAMPT),as well as the phosphorylation of adenosine monophosphate activated protein kinase(AMPK),p-m TOR,p-p70S6K(direct substrate of m TOR),autophagy parameters(beclin-1,LC3B)and MAP kinases(p-p38 and p-ERK)were determined by Western ***:Liver grafts preserved in IGL-1 solution enriched with TMZ presented reduced liver injury and mitochondrial damage compared with those preservedin IGL-1 solution *** addition,livers preserved in IGL-1+TMZ presented reduced levels of oxidative *** was consistent with enhanced SIRT1 protein expression and elevated SIRT1 activity,as indicated by decreased acetylation of p53 and Fox *** elevated SIRT1 activity in presence of TMZ can be attributed to the enhanced NAMPT protein and NAD+/NADH ***-regulation of SIRT1 was consistent with activation of AMPK and inhibition of phosphorylation of m TOR and its direct substrate(p-p70S6K).As a consequence,autophagy mediators(beclin-1 and LC3B)were ***,MAP kinases w

关键词： Sirtuin 1 Ischemia-reperfusion injury Liver transp

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Polyethylene glycols: An effective strategy for limiting liver ischemia reperfusion injury

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World Journal of Gastroenterology 2016年第28期22卷 6501-6508页

作者： Gianfranco Pasut Arnau Panisello emma folch-puy Alexandre Lopez Carlos Castro-Benítez Maria Calvo Teresa Carbonell Agustín García-Gil RenéAdam Joan Roselló-Catafau Department of Pharmaceutical and Pharmacological University of Padova and Veneto Institute of Oncology IRCCS 35128 Padova Italy Experimental Pathology Department Institute of Biomedical Research of Barcelona 08036 Barcelona Spain Centre Hepatobiliaire AP-HP Hopital Paul Brousse Inserm U935 Universite Paris-Sud Villejuif 75008 Paris France Unitat de Microscopia Optic Avancada CCiTUB Centre Cientifics i Tecnologics Faculty of Medicine University of Barcelona 08036 Barcelona Spain Physiology Department Faculty of Biology Universitat de Barcelona 08036 Barcelona Spain Hospital Clinico de Zaragoza 50009 Zaragoza Spain

Liver ischemia-reperfusion injury(IRI) is an inherent feature of liver surgery and liver transplantation in which damage to a hypoxic organ(ischemia) is exacerbated following the return of oxygen delivery(reperfusion). IRI is a major cause of primary nonfunction after transplantation and may lead to graft rejection, regardless of immunological considerations. The immediate response involves the disruption of cellular mitochondrial oxidative phosphorylation and the accumulation of metabolic intermediates during the ischemic period, and oxidative stress during blood flow restoration. Moreover, a complex cascade of inflammatory mediators is generated during reperfusion, contributing to the extension of the damage and finally to organ failure. A variety of pharmacological interventions(antioxidants, anticytokines, etc.) have been proposed to alleviate graft injury but their usefulness is limited by the local and specific action of the drugs and by their potential undesirable toxic effects. Polyethylene glycols(PEGs), which are non-toxic water-soluble compounds approved by the FDA, have been widely used as a vehicle or a base in food, cosmetics and pharmaceuticals, and also as adjuvants for ameliorating drug pharmacokinetics. Some PEGs are also currently used as additives in organ preservation solutions prior to transplantation in order to limit the damage associated with cold ischemia reperfusion. More recently, the administration of PEGs of different molecular weights by intravenous injection has emerged as a new therapeutic tool to protect liver grafts from IRI. In this review, we summarize the current knowledge concerning the use of PEGs as a useful target for limiting liver IRI.

关键词： Ischemia reperfusion injury Polyethylene glycol Liver preconditioning Liver transplantation UW solut

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