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Transforming growth factor-β1 induces intestinal myofibroblast differentiation and modulates their migration

World journal of Gastroenterology 2009年第12期15卷 1431-1442页

作者： julia Brenmoehl Sandra Nicole Miller Claudia Hofmann Daniela Vogl Werner Falk jrgen schlmerich Gerhard Rogler Department of Internal Medicine Ⅰ University of Regensburg93055 Regensburg Germany Department of Internal Medicine Ⅱ University of Jena07747 Jena Germany Clinic of Gastroenterology and Hepatology Department of Internal MedicineUniversity Hospital of Zurich8091 ZurichSwitzerland

AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were incubated with TGF-β1 and analyzed for production of m-smooth muscle actin （α-SMA）, fibronectin （FN） and FN isoforms. Migration assays were performed in a modified 48-well Boyden chamber. Levels of total and phosphorylated focal adhesion kinase （FAK） in CLPF were analyzed after induction of *** not change α-SMA levels, while TGF-β1 treatment for 6 d significantly increased α-SIVlA production. Short term incubation （6 h） with TGF-β1 enhanced CLPF migration, while long term treatment （6 d） of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells. FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1 （2 d） in contrast to long term incubation with TGF-β1 for 6 d. After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells.CONCLUSION： Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhanced α-SMA, reduced migratory potential and FAK phosphorylation, and increased FN production. In contrast, short term contact （6 h） of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction of α-SMA production.

关键词： Transforming growth factor β1 Colonicfibroblasts Myofibroblasts Migration Fibronectin

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Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension

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World journal of Gastroenterology 2010年第15期16卷 1837-1844页

作者： Lukas Moleda Lars jurzik Matthias Froh Erwin Gbele Claus Hellerbrand Rainer H Straub jürgen schlmerich Reiner Wiest Department of Internal Medicine I University Medical Center

AIM:To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension. METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with geldanamycin (specific inhibitor of HSP-90 signalling, 3 μg/mL) or L-NAME (non-specific NOSblocker, 10-4 mol/L). RESULTS: nNOS and HSP-90 expression was significantly increased in mesenteric nerves from PVL as compared to sham rats. Moreover, nNOS and HSP-90 were visualized in mesenteric nerves by immunofluorescence and immunoprecipitation of nNOS co-immunoprecitated HSP-90 in sham and PVL rats. PNS induced a frequencydependent vasorelaxation which was more pronounced in PVL as compared to sham rats. L-NAME and geldanamycin markedly reduced nNOS-mediated vasorelaxation abrogating differences between the study groups. The effect of L-NAME and geldanamycin on nNOS-mediated vasorelaxation was significantly greater in PVL than in sham animals. However, no difference in magnitude of effect between L-NAME and geldanamycin was noted. CONCLUSION: HSP-90 acts as a signalling mediator of nNOS-dependent nerve mediated vascular responses in mesenteric arteries, and the increased nitrergic vasorelaxation observed in portal hypertension is mediated largely by HSP-90.

关键词： Heat shock protein-90 Nitric oxide Vasodilation Portal hypertension Mesenteric circulation

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Significance of scintigraphy for the localisation of obscure gastrointestinal bleedings

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World journal of Gastroenterology 2008年第32期14卷 5015-5019页

作者： Tanja Brünnler Frank Klebl Sascha Mundorff Christoph Eilles Michael Reng Hans von Korn jürgen schlmerich julia Langgartner Stefan Grüne Department of Internal Medicine I University of Regensburg Department of Surgery Hospital Neumarkt Department of Nuclear Medicine University of Regensburg Department of Internal Medicine Hospital Bogen Department of Internal Medicine II Hospital Hetzelstift

AIM： To determine the role of scintigraphy in patients with gastrointestinal （GI） bleeding of unknown Iocalisation. METHODS： We performed retrospective analyses on 92 patients receiving scintigraphies from 1993 to 2000 in the University of Regensburg hospital, which were done for Iocalisation of GI bleeding as a diagnostic step after an unsuccessful endoscopy. In addition to the scintigraphies, further diagnostic steps such as endoscopy, angiography or operations were performed. In some of the scintigraphies with negative results, a provocation test for bleeding with heparinisation was carried out. RESULTS： 73% of all scintigraphies showed a positive result. In 4.5% of the positive results, the source was located in the stomach, in 37% the source was the small bowel, in 25% the source was the right colon, in 4.5% the source was the left colon, and in 20% no clear Iocalisation was possible. Only 4% of all scintigraphies were false positive. A reliable positive scintigraphy was independent of the age of the examined patient. A provocation test for bleeding with heparin resulted in an additional 46% of positive scintigraphies with a reliable Iocalisation in primary negative scintigraphies. CONCLUSION- Our results show that scintigraphy and scintigraphy with heparin provocation tests are reliable procedures. They enable a reliable Iocalisation in about half of the obscure GI-bleeding cases. Scintigraphy is superior to angiography in locating a bleeding. It is shown that even in the age of video capsule endoscopy and double-balloon enteroscopy, scintigraphy provides a reliable and directed localization of GI bleeding and offers carefully targeted guidance for other procedures.

关键词： Gastrointestinal bleeding Scintigraphy Localisation Angiography

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Analysis of monocyte chemotactic protein-1 gene polymorphism in patients with spontaneous bacterial peritonitis

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World journal of Gastroenterology 2009年第44期15卷 5558-5562页

作者： Erwin Gbele Marcus Mhlbauer Hartwig Paulo Monika johann Christin Meltzer Franz Leidl Norbert Wodarz Reiner Wiest jrgen schlmerich Claus Hellerbrand Department of Internal Medicine University Medical Center RegensburgD-93042 RegensburgGermany Department of Psychiatry University Medical Center RegensburgD-93042 RegensburgGermany

AIM:To investigate a genetic polymorphism of the monocyte chemotactic protein-1 (MCP-1 ) gene in patients with spontaneous bacterial peritonitis (SBP).METHODS:MCP-1 genotyping was performed in 23 patients with SBP and 83 cirrhotic control patients with non-infected ***:The frequency of carriers of the G-allele was lower in SBP patients but this difference did not reach statistical significance. However,in the subgroup of patients with alcoholic cirrhosis (n=80),carriers of the G-allele were significantly less frequent in SBP-patients (38.1%) than in cirrhotic controls (67.8%,P=0.021). CONCLUSION:In patients with alcoholic liver cirrhosis,the-2518 MCP-1 genotype AA is a risk factor for the development of SBP.

关键词： Monocyte chemotactic protein-1 Chemokines Spontaneous bacterial peritonitis Polymorphism Livercirrhosis

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Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient

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World journal of Gastroenterology 2007年第45期13卷 6090-6093页

作者： Doris schacherer Martina Zeitoun Roland Büttner Cornelia Gelbmann Aiman Obed Hans-jürgen schlitt jürgen schlmerich Gabi I Kirchner Department of Internal MedicineⅠ University of Regensburg Regensburg 93042 Germany Department of Surgery University of Regensburg Regensburg 93042 Germany

We describe the first case of sirolimus-induced drug fever in a female liver transplant recipient, with a history of hepatitis C-induced end-stage liver cirrhosis in 1999. In 2005, six years after transplantation, she developed calcineurin inhibitor-induced renal function impairment. Immunosuppression was switched from tacrolimus to sirolimus. Two days after the intake of sirolimus, she developed daily fever spikes, but no infectious focus was found. Antibiotic therapy had no influence on the fever. After fourteen days, sirolimus was switched back to tacrolimus and the fever disappeared. In history, the patient developed ciclosporin-induced generalized seizures eleven days after liver transplantation, followed by the development of a motoric speech disorder. Magnetic resonance imaging (MRI) findings were consistent with leucoencephalopathy, therefore immunosuppressive therapy was changed from ciclosporin to tacrolimus and the neurologic symptoms improved significantly. Our case is the first reported case of sirolimus-induced drug fever. In addition, the patient showed the rare occurrence of ciclosporin-induced leukencephalopathy with seizures.

关键词： Liver transplantation Immunosuppression Side effects

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Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype

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World journal of Gastroenterology 2007年第48期13卷 6529-6537页

作者： Ulrike G Strauch Florian Obermeier Nicole Grunwald Nadja Dunger Heiko C Rath jürgen schlmerich A Steinmeyer U Zügel HH Herfarth Department of Internal MedicineⅠ University of Regensburg Medicinal Chemistry Schering AG Berlin Germany Research Business Area Dermatology Schering AG Berlin Germany

AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.

关键词： Dextran sodium sulfate colitis Calcitriol Colonic inflammation Dendritic cells

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Adiponectin and its receptors in rodent models of fatty liver disease and liver cirrhosis

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World journal of Gastroenterology 2006年第34期12卷 5490-5494页

作者： Markus Neumeier Claus Hellerbrand Erwin Gbele Roland Buettner Cornelius Bollheimer johanna Weigert Andreas schffler Thomas S Weiss Monika Lichtenauer jürgen schlmerich Christa Buechler Department of Internal Medicine I University of Regensburg D-93042 Regensburg Germany Department of Surgery Center for Liver Cell Research University of Regensburg Germany

AIM： To determine circulating and hepatic adiponectin in rodents with fatty liver disease or liver cirrhosis and investigate expression of the adiponectin receptors AdipoR1 on the mRNA and protein level and AdipoR2 on the mRNA level. METHODS： Fat fed rats were used as a model for fatty liver disease and bile duct ligation in mice to investigate cirrhotic liver. Expression of AdipoR1 and AdipoR2 mRNA was determined by real time RT-PCR. AdipoR1 protein was analysed by immunoblot. Adiponectin was measured by ELISA. RESULTS： Systemic adiponectin is reduced in fatfed rats but is elevated in mice after bile duct ligation （BDL）. Hepatic adiponectin protein is lower in steatotic liver but not in the liver of BE）L-mice when compared to controls. Adiponectin mRNA was not detected in human liver samples or primary human hepatocytes nor in rat liver but recombinant adiponectin is taken up by isolated hepatocytes in-vitro. AdipoR1 mRNA and AdipoR1 protein levels are similar in the liver tissue of control and fat fed animals whereas AdipoR2 mRNA is induced. AdipoR2 mRNA and AdipoR1 mRNA and protein is suppressed in the liver of BDL-mice. CONCLUSION： Our studies show reduced circulating adiponectin in a rat model of fatty liver disease whereas circulating adiponectin is elevated in a mouse model of cirrhosis and similar findings have been described in humans. Diminished hepatic expression of adiponectin receptors was only found in liver cirrhosis.

关键词： Hepatic steatosis Adiponectin Liver cirrhosis Adiponectin receptor 1 Adiponectin receptor 2

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Harnessing naturally occurring mutations for T-cell therapy:a potential new avenue to enhance treatment efficacy

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1799-1801页

作者： Michael Hiltensperger jürgen Ruland Kilian schober Mikrobiologisches Institut-Klinische Mikrobiologie Immunologie und HygieneFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany Institute of Clinical Chemistry and Pathobiochemistry School of MedicineTechnical University of MunichMunichGermany TranslaTUM Center for Translational Cancer ResearchTechnical University of MunichMunichGermany German Cancer Consortium(DKTK) HeidelbergGermany German Center for Infection Research(DZIF) partner site MunichMunichGermany FAU Profile Center Immunomedicine Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany

In a recent study published in Nature,Garcia et *** a sophisticated approach to identify fitness-enhancing mutations for T cells that was inspired by cancer evolution.1 The identified CARD11-PIK3R3 gene fusion enhanced tumor rejection and persistence of engineered T cells in multiple tumor models and might have the potential to improve efficacy of adoptive T-cell therapies in cancer patients.

关键词： cancer potential

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Linkage Between European and East Asian Heatwaves on Synoptic Scales

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journal of Tropical Meteorology 2024年第2期30卷 97-105页

作者：蔡奋颖刘彩红杨崧邓开强 KURTHS jürgen school of Atmospheric Sciences Sun Yat-sen Universityand Southern Marine Science and Engineering Guangdong Laboratory(Zhuhai)ZhuhaiGuangdong 519082 China Department of Complexity Science Potsdam Institute for Climate Impact Research(PIK)Member of the Leibniz AssociationPotsdam 14473 Germany Department of Water and Climate Risk Institute for Environmental StudiesVrije Universiteit AmsterdamAmsterdam 1087HV Netherlands Guangdong Province Key Laboratory for Climate Change and Natural Disaster Studies Sun Yat-sen UniversityZhuhaiGuangdong 519082 China Department of Physics Humboldt-Universität zu BerlinBerlin 12489 Germany

Concurrent extreme weather events in geographically distant areas potentially cause high-end risks for *** using network analysis,the present study managed to identify significant nearly-simultaneous occurrences of heatwaves between the grid cells in East Asia and Eastern Europe,even though they are geographically far away from each *** further composite analysis,this study revealed that hot events first occurred in Eastern Europe,typically with a time lag of3-4 days before the East Asian heatwave *** eastward propagating atmospheric wave train,known as the circumglobal teleconnection(CGT)pattern,bridged the sequent occurrences of extreme events in these two remote *** blockings,amplified by surface warming over Eastern Europe,not only enhanced local heat extremes but also excited a CGT-like pattern characterized by alternative anomalies of high and low *** downstream anticyclones in the middle and upper troposphere reduced local cloud cover and increased downward solar radiation,thereby facilitating the formation of heatwaves over East *** half of East Asian heatwave events were preceded by Eastern European heatwave events in the 10-day time range before East Asian heatwave *** investigation of heatwave teleconnection in the two distant regions exhibits strong potential to improve the prediction accuracy of East Asian heatwaves.

关键词： concurrent heatwaves Eastern Europe East Asia circum-global teleconnection pattern

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Dirac-harmonic maps with the trivial index

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Science China Mathematics 2024年

作者： jürgen jost Linlin Sun jingyong Zhu Max Planck Institute for Mathematics in the Sciences school of Mathematics and Statistics Guangxi Normal University school of Mathematics Sichuan University

For a homotopy class [u] of maps between a closed Riemannian manifold M and a general manifold N, we want to find a Dirac-harmonic map with the map component in the given homotopy class. Most known results require the index to be nontrivial. When the index is trivial, the few known results are all constructive and produce uncoupled solutions. In this paper, we define a new quantity. As a byproduct of proving the homotopy invariance of this new quantity, we find a new simple proof for the fact that all the Dirac-harmonic spheres in surfaces are uncoupled. More importantly, by using the homotopy invariance of this new quantity,we prove the existence of Dirac-harmonic maps from manifolds in the trivial index case. In particular, when the domain is a closed Riemann surface, we prove the short-time existence of the α-Dirac-harmonic map flow in the trivial index case. Together with the density of the minimal kernel, we get an existence result for Dirac-harmonic maps from closed Riemann surfaces to K¨ahler manifolds, which extends the previous result of the first and third authors. This establishes a general existence theory for Dirac-harmonic maps in the context of the trivial index.

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