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Stimulation of p38 MAPk by hormal preconditioning with atrial natriuretic peptide

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World Journal of Gastroenterology 2002年第4期8卷 707-711页

作者： alexandra k. kiemer Stefanie kulhanek-Heinze Tobias Gerwig Alexander L. Gerbes Angelika M. Vollmar Department of Pharmacy Center of Drug ResearchUniversity of MunichGermany Department of Medicine ⅡKlinikum GrosshadernUniversity of MunichGermany Department of Medicine Ⅱ Klinikum GrosshadernUniversity of MunichGermany Department of Pharmacy Center of Drug ResearchUniversity of MunichGermany

AIM：Stress-activated signaling pathways responsible for hepatic ischemia reperfusion injury and their modulation by protective interventions are widely *** of rat livers with Atrial Natriuretic Peptide(ANP)attenuates ischemia reperfusion injury(Gerbes et ***1998,18:1309-1317),SinANP has recently been shown to be a regulator of the p38MAPkpathway in endothelial cells(kiemer et ***2002,90:874-881).aim of this thudy was to investigate activities of MAPk during ischemia and reperfusion and effects of ANP on ***:Rat livers were perfused with kH-buffer in the presence or absence of ANP for 20min,kept in cold UWsloution for 24h,and reperfused forupto120min,Activities of p38MAPkand JNkwas determined by in vitro phosphorylation assays using MBP and c-jun as *** SDS/PAGE electrophoresis,gels were quantified by ***:Activity of p38MAPkin control organs decreased in the course of ischemia and reperfusion by85%,whereas ANPincreased p38 activity by up to *** of control livers increased in the course of ischemia and reperfusion by up to *** increase in JNk activrity was slightly elevated in ANP preconditioned ***:This work represents a systematic investigation of MAPk activation during liver ischemia and *** ANP,for the first time a pharmacological approach to modulate these central signal transduction molecules is presented.

关键词：血浆心纳素 p38MAPk 缺血预处理肝脏缺血

Reduction of ischemia reperfusion injury after liver resection and hepatic inflow occlusion by α-lipoic acid in humans

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World Journal of Gastroenterology 2006年第42期12卷 6812-6817页

作者： Fritz Dünschede kirsten Erbes Achim kircher Stefanie Westermann Joachim Seifert Arno Schad kempski Oliver alexandra k kiemer Junginger Theodor Department of General and Abdominal Surgery University hospital Mainz Germany Institute for Pathology University hospital Mainz Germany Institute for Neurosurgical Pathophysiology University hospital Mainz Germany Department of Pharmacy Pharmaceutical Biology Saarland University Germany

AIM： To evaluate the protective effects of preconditioning by α-lipoic acid （LA） in patients undergoing hepatic resection under inflow occlusion of the liver. METHODS： Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCI 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver. RESULTS： Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNEL-positive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion. CONCLUSION： This is the first report on the potential for LA reducing ischemia/reperfusion injury （IRI） of the liver in humans who were undergoing liver surgery. Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.

关键词： Liver ischemia Pringle manoeuvre Pharmacological pre-treatment Liver preconditioning Apoptosis Adenosine triphosphate

PI 3-kinase pathway is responsible for antiapoptotic effects of atrial natriuretic peptide in rat liver transplantation

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World Journal of Gastroenterology 2006年第7期12卷 1049-1055页

作者： Uwe Grutzner Melanie keller Michael Bach alexandra k kiemer Herbert Meissner Manfred Bilzer Stefan Zahler Alexander L Gerbes Angelika M Vollmar Institute for Surgical Research Klinikum GroBhadernUniversity of MunichD-81377 MunichGermany Department of Pharmacy University of MunichD-81377 MunichGermany Department Institute of Pathology University of MunichD-81377 MunichGermany

AIM： To investigate the in vivo effect of atrial natriuretic peptide （ANP） and its signaling pathway during orthotopic rat liver transplantation.METHODS： Rats were infused with NaCI, ANP （5 μg/ kg）, wortmannin （WH, 16μg/kg）, or a combination of both for 20 min. Livers were stored in UW solution （4℃） for 24 h, transplanted and reperfused. Apoptosis was examined by caspase-3 activity and TUNEL staining. Phosphorylation of Akt and Bad was visualized by Western blotting and phospho-Akt-localization by confocal microscopy.RESULTS： ANP-pretreatment decreased caspase-3 activity and TUNELopositive cells after cold ischemia, indicating antiapoptotic effects of ANP in vivo. The an- tiapoptotic signaling of ANP was most likely caused by phosphorylation of Akt and Bad, since pretreatment with PI 3-kinase inhibitor WM abrogated the ANP-induced reduction of caspase-3 activity. Interestingly, analysis of liver tissue by confocal microscopy showed translocation of phosphorylated Akt to the plasma membrane of hepa- tocytes evoked by ANP.CONCLUSION： ANP activates the PI-3-kinase pathway in the liver in vivo leading to phosphorylation of Bad an event triggering antiapoptotic signaling cascade in ischemic liver.

关键词： Bad Apoptosis Hormonal preconditioning Ischemia reperfusion injury

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

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World Journal of Gastroenterology 2014年第47期20卷 17839-17850页

作者： Yvette Simon Sonja M kessler katja Gemperlein Rainer M Bohle Rolf Müller Johannes Haybaeck alexandra k kiemer Department of Pharmacy Pharmaceutical BiologySaarland University66123 SaarbrückenGermany Medical University of Graz Institute of PathologyGraz 8036Austria Department of Pharmacy Pharmaceutical BiotechnologySaarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)Helmholtz Centre for Infection Research (HZI)66123 SaarbrückenGermany Saarland University Department of Pathology66421 HomburgGermany

AIM: To characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.

关键词： Insulin-like growth factor 2 mRNA binding protein 2-2 Methionine/choline deficient Non-alcoholic fatty liver disease Filipin Iron

Hepatocyte cytoskeleton during ischemia and reperfusion -influence of ANP-mediated p38 MAPk activation

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World Journal of Gastroenterology 2005年第47期11卷 7418-7429页

作者： Melanie keller Alexander L Gerbes Stefanie kulhanek-Heinze Tobias Gerwig Uwe Grützner Nico van Rooijen Angelika M Vollmar alexandra k kiemer Department of Pharmacy Centre of Drug ResearchUniversity of MunichButenandtstr. 5-1381377 MunichGermany Department of Medicine Ⅱ Klinikum GroβhadernUniversity of MunichMarchionistr. 1781377 MunichGermany Angelika M Vollmar Alexandra K KiemerDepartment of PharmacyCentre of Drug ResearchUniversity of MunichButenandtstr. 5-1381377 MunichGermany Department of Pharmacy Centre of Drug ResearchUniversity of MunichButenandtstr. 5-1381377 MunichGermany Department of Medicine ⅡKlinikum GroβhadernUniversity of MunichMarchionistr. 1781377 MunichGermany Institute for Surgical Research Klinikum GroβhadernUniversity of MunichMarchionistr. 1781377 MunichGermany Vrije Universiteit VUMCDepartment of Molecular Cell BiologyFaculty of Medicine1081 BT AmsterdamThe Netherlands

AIM： To determine functional consequences of this activation, whereby we focused on a potential regulation of the hepatocyte cytoskeleton during ischernia and reperfusion. METHODS： For in vivo experiments, animals received ANP （5 μg/kg） intravenously. In a different experimental setting, isolated rat livers were perfused with kH-buffer ＋ANP （200 nmol/L）＋SB203580 （2 μmol/L）. Livers were then kept under ischernic conditions for 24 h, and either transplanted or reperfused. Actin, Hsp27, and phosphorylated Hsp27 were determined by Western blotting, p38 MAPk activity by in vitro phosphorylation assay. F-actin distribution was determined by confocal microscopy. RESULTS： We first confirmed that ANP preconditioning leads to an activation of p38 MAPk and observed alterations of the cytoskeleton in hepatocytes of ANP- preconditioned organs. ANP induced an increase of hepatic F-actin after ischemia, which could be prevented by the p38 MAPk inhibitor SB203580 but had no effect on bile flow. After ischemia untreated livers showed a translocation of Hsp27 towards the cytoskeleton and an increase in total Hsp27, whereas ANP preconditioning prohibited translocation but caused an augmentation of Hsp27 phosphorylation. This effect is also mediated via p38 MAPk, since it was abrogated by the p38 MAPk inhibitor SB203580. CONCLUSION： This study reveals that ANP-mediated p38 MAPk activation leads to changes in hepatocyte cytoskeleton involving an elevation of phosphorylated Hsp27 and thereby for the first time shows functional consequences of ANP-induced hepatic p38 MAPk activation.

关键词： Hormonal preconditioning Atrial natriuretic peptide Hsp 27 Actin Polymerization

Protective effects of ischemic preconditioning and application of lipoic acid prior to 90 min of hepatic ischemia in a rat model

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World Journal of Gastroenterology 2007年第27期13卷 3692-3698页

作者： Friedrich Duenschede kirsten Erbes Nina Riegler Patrick Ewald Achim kircher Stefanie Westermann Arno Schad Imke Miesmer Simon Albrecht-Schck Ines Gockel alexandra k kiemer Theodor Junginger Department of General and Abdominal Surgery University hospital Mainz Langenbeckstr.1 D-55131 Mainz Germany Institute for Pathology University hospital Mainz Germany Department of Pharmacy Pharmaceutical Biology Saarland University 66123 Saarbrücken Germany

AIM： To compare different preconditioning strategies to protect the liver from ischemia/reperfusion injury focusing on the expression of pro- and anti-apoptotic proteins. Interventions comprised different modes of ischemic preconditioning （IP） as well as pharmacologic pretreatment by α-lipoic acid （LA）. METHODS： Several groups of rats were compared： sham operated animals, non-pretreated animals （nt）, animals receiving IP （10 rain of ischemia by clamping of the portal triad and 10 min of reperfusion） prior to sustained ischemia, animals receiving selective ischemic preconditioning （IPsel, 10 min of ischemia by selective clamping of the ischemic lobe and 10 rain of reperfusion） prior to sustained ichemia, and animals receiving 500 1μmol α-LA injected i.v. 15 min prior to the induction of 90 min of selective ischemia. RESULTS： Cellular damage was decreased only in the LA group. TUNEL-positive hepatocytes as well as necrotic hepatocyte injury were also decreased only by LA（19 ± 2 vs 10 ± 1, P〈 0.05 and 29 ± 5 vs 12 ± 1, P 〈 0.05）. Whereas caspase 3- activities in liver tissue were unchanged, caspase 9- activity in liver tissue was decreased only by LA pretreatment （3.1 ± 0.3 vs 1.8 ± 0.2, P 〈 0.05）. Survival rate as the endpoint of liver function was increased after IP and LA pretreatment but not after IPsel. Levels of lipid peroxidation （LPO） in liver tissue were decreased in the IP as well as in the LA group compared to the nt group. Determination of pro- and anti-apoptotic proteins showed a shift towards anti-apoptotic proteins by LA. In contrast, both our IP strategies failed to influence apototic cell death. CONCLUSION： IP, consisting of 10 min of ischemia and 10 min of reperfusion, ischemia/reperfusion injury protects only partly against of the liver prior to 90 min of selective ischemia. IPsel did not influence ischemic tolerance of the liver. LA improved tolerance to ischemia, possibly by downregulation of pro-apoptotic Bax.

关键词： Warm liver ischemia Liver preconditioning Apoptosis Lipid peroxidation Pharmacological preconditioning

Rapid chromatographic method to decipher distinct alterations in lipid classes in NAFLD/NASH

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World Journal of Hepatology 2013年第10期5卷 558-567页

作者： Stephan Laggai Yvette Simon Theo Ranssweiler alexandra k kiemer Sonja M kessler Department of Pharmacy Pharmaceutical Biology Saarland University

AIM: To establish a simple method to quantify lipid classes in liver diseases and to decipher the lipid profile in p62/IMP2-2/IGF2BP2-2 transgenic ***: Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein p62/IMP2-2/IGF2BP2-2 was used as a model for *** was induced by feeding a methioninecholine deficient diet. Steatosis was assessed histologically. For thin layer chromatographic analysis, lipids were extracted from freeze-dried tissues by hexane/2-propanol, dried, redissolved, and chromatographically separated by a two-solvent system. Dilution series of lipid standards were chromatographed, detected, andquantified. The detection was performed by either2',7'-dichlorofluoresceine or a sulfuric acid/ethanol ***: Histological analyses confirmed steatosis and steatohepatitis development. The extraction,chromatographic, and detection method showed high inter-assay reproducibility and allowed quantification of the different lipid classes. The analyses confirmed an increase of triglycerides and phosphatidylethanolamine and a decrease in phosphatidylcholine in the methionine-choline deficient diet. The method was used for the first time to asses the lipid classes induced in the p62-overexpressing mouse model and showed a significant increase in all detected lipid species with a prominent increase of triglycerides by 2-fold. Interestingly, the ratio of phosphatidylcholine to phosphatidylethanolamine was decreased, as previously suggested as a marker in the progression from steatosis to ***: The thin layer chromatography analysis allows a reliable quantification of lipid classes and provides detailed insight into the lipogenic effect of p62.

关键词： Non alcoholic steatohepatitis Non alcoholic fatty liver disease Thin layer chromatography IMP2/IGF2BP2 p62 Methionine choline deficient diet Polar lipids neutral lipids Phosphatidylcholine/phosphatidylethanolamine ratio Triglycerides