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Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation

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World Journal of Gastroenterology 2004年第6期10卷 864-870页

作者： RolfJ.Schauer SinanKalmuk alexander l.gerbes Rosemarie leiderer Herbert Meissner Friedrich W.Schildberg Konrad Messmer Manfred Bilzer Surgical Department Klinikum GrosshadernLudwig-Maximilians-University of MunichGermany Department Institute for Surgical Research Klinikum GrosshadernLudwig-Maximilians-University of MunichGermany Institute of Pathology Klinikum GrosshadernLudwig-Maximilians-University of MunichGermany

AIM:To investigate the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation. METHODS:livers of male lewis rats were transplanted after 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic *** a 2-h reperfusion period either saline (controls,n=8) or GSH (50 or 100 μmol/(h·kg),n=5 each) was continuously administered via the jugular vein. RESUlTS:Two hours after starting reperfusion plasma AlT increased to 1 457±281 U/l (mean±SE) in controls but to only 908±187 U/l (Pls treated with 100 μmol GSH/(h·kg).No protection was conveyed by 50μmol GSH/(h·kg).Cytoprotection was confirmed by morphological findings on electron microscopy:GSH treatment prevented detachment of sinusoidal endothelial cells (SECs) as well as loss of microvilli and mitochondrial swelling of ***,postischemic bile flow increased *** fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal *** infusion of 50μmol and 100 μmol GSH/(h·kg),plasma GSH increased to 65±7 mol/l and 97±18 mol/l,but to only 20±3 mol/l in untreated recipients. Furthermore,plasma glutathione disulfide (GSSG) increased to 7.5±1.0 mol/l in animals treated with 100μmol/(h·kg) GSH but infusion of 50μmol GSH/(h·kg) did not raise levels of untreated controls (1.8±0.5 mol/l vs 2.2±0.2 mol/l). CONClUSION:Plasma GSH levels above a critical level may act as a “sink” for ROS produced in the hepatic vasculature during reperfusion of liver ***,GSH can be considered a candidate antioxidant for the Drevention of reperfusion injury after liver transplantation,in particular since it has a low toxicity in humans.

关键词： liver Circulation liver Transplantation Animals Glutathione dosage Hepatocytes Infusions, Intravenous Male Postoperative Period Rats Rats, Inbred lew Reperfusion Injury control

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腹水的治疗

Oncology and Translational Medicine 1996年第3期13卷 143-143页

作者： alexander l.gerbes 刘梅 Medizinische Klinik Ⅱ Klinik Grosshadern der Universitt München Germany 同济医科大学附属同济医院

影响肝硬化腹水形成的重要因素有:门脉高压、周围血管扩张、肾血管收缩及有效中心循环血容量下降。选择治疗方法时应考虑上述致肾钠潴留因素。肝脏疾病所致腹水的治疗包括卧床休息、限制食盐摄入、利尿药物、治疗性腹腔穿刺放腹水、腹腔... 详细信息

影响肝硬化腹水形成的重要因素有:门脉高压、周围血管扩张、肾血管收缩及有效中心循环血容量下降。选择治疗方法时应考虑上述致肾钠潴留因素。肝脏疾病所致腹水的治疗包括卧床休息、限制食盐摄入、利尿药物、治疗性腹腔穿刺放腹水、腹腔-颈静

关键词：腹水难治性卧床休息治疗性颈静脉水肿分流术

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

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

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

Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model

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World Journal of Hepatology 2016年第8期8卷 401-410页

作者： Florian P Reiter Ralf Wimmer lena Wottke Renate Artmann Jutta M Nagel Manuel O Carranza Doris Mayr Christian Rust Peter Fickert Michael Trauner alexander l.gerbes Simon Hohenester Gerald U Denk Department of Medicine Ⅱ Liver Center Munich University of Munich Institute of Pathology University of Munich Department of Medicine Ⅰ Krankenhaus Barmherzige Brüder Research Unit for Experimental and Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine Hans Popper laboratory of Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine Ⅲ Medical University of Vienna Transplant Center Munich of the University of Munich

AIM: To study the interleukin-1(Il-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse ***: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the Il-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m l Il-1β with or without 2.5 μg/m l Anakinra, an Il-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESUlTS: liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P ly lower Il-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-te

关键词： Cholestasis Primary sclerosing cholangitis The ATP-binding cassette transporter b4 liver fibrosis Interleukin-1

Development of 3D Scanning System for Robotic Plasma Processing of Medical Products with Complex Geometries

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Journal of Electronic Science and Technology 2020年第3期18卷 212-222页

作者： Darya l.Alontseva Elaheh Ghassemieh alexander l.Krasavin Albina T.Kadyroldina School of Information Technology and Intelligent Systems D.Serikbayev East Kazakhstan State Technical UniversityUst-Kamenogorsk 070004 Wolfson School of Mechanical Electrical and Manufacturing EngineeringLoughborough UniversityLoughborough LE113TU

This paper describes the development of an intelligent automated control system of a robot manipulator for plasma treatment of medical implants with complex *** two-layer coatings from the Ti wire and hydroxyapatite powders are applied on the surface of Ti medical implants by microplasma spraying to increase the biocompatibility of *** coating process requires precise control of a number of parameters,particularly the plasma spray distance and plasma jet traverse ***,the development of the robotic plasma surface treatment involves automated path *** key idea of the proposed intelligent automatic control system is the use of data of preliminary three-dimensional (3D) scanning of the processed implant by the robot *** segmentation algorithm of the point cloud from laser scanning of the surface is *** methodology is suitable for robotic 3D scanning systems with both non-contact laser distance sensors and video cameras,used in additive manufacturing and medicine.

关键词： Plasma processing point cloud robot manipulator surface segmentation three-dimensional(3D)scanning

Parasites of the liver:A global problem?

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World Journal of Gastroenterology 2024年第30期30卷 3554-3559页

作者： Vladislav V Tsukanov alexander V Vasyutin Julia l Tonkikh Clinical Department of the Digestive System Pathology of Adults and Children Federal Research Center“Krasnoyarsk Science Center”of the Siberian Branch of the Russian Academy of SciencesScientific Research Institute of Medical Problems of the NorthKrasnoyarsk 660022Russia

Parasitic liver diseases can be caused by trematodes,cestodes,nematodes,and *** pathology is significant because millions of people in different parts of the world have liver parasites,which can manifest themselves in the development of inflammation,liver cysts,cholecystitis,cholelithiasis,pancreatitis and liver cirrhosis that are often threatening their *** International Agency for Research on Cancer considers three species of trematodes,Schistosoma haematobium,Opisthorchis viverrini and Clonorchis sinensis,to be *** modern examination methods,in some cases including extensive screening of large populations,are required for diagnosing liver *** of parasitic liver diseases is differentiated and can involve a combination of surgical and therapeutic *** is no doubt that the clinical and epidemiological scale allows one to regard parasitic liver diseases as a global healthcare problem.

关键词： liver Parasites Epidemiology Diagnosis Clinics Treatment Echinococcosis Opisthorchiasis Fascioliasis Schistosomiasis

Phase field modeling with large driving forces

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npj Computational Materials 2023年第1期9卷 623-631页

作者： Jin Zhang alexander F.Chadwick David l.Chopp Peter W.Voorhees Department of Materials Science and Engineering Northwestern UniversityEvanstonIL 60208USA Department of Engineering Sciences and Applied Mathematics Northwestern UniversityEvanstonIL 60208USA

There is growing interest in applying phase field methods as quantitative tools in materials discovery and ***,large driving forces,common in many materials systems,lead to unstable phase field profiles,thus requiring fine spatial and temporal *** demands more computational resources,limits the ability to simulate systems with a suitable size,and deteriorates the capability of quantitative ***,we develop a strategy to map the driving force to a constant perpendicular to the *** with the third-order interpolation function,we find a stable phase field profile that is independent of the magnitude of the driving *** power of this approach is illustrated using three *** demonstrate that by using the driving force extension method,it is possible to employ a grid size orders of magnitude larger than traditional *** approach is general and should apply to many other phase field models.

关键词： forces interpolation apply