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| 1 | Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model显示文摘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 model.METHODS: 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 < 0.001; MannWhitney U-test) and 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 < 0.05; Mann-Whitney U-test). Reduced 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 < 0.05; Mann-Whitney U-test) and significantly 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-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice. | 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 | 2016 | World Journal of Hepatology2016，8，8： | 3 |
| 2 | Association of the GNAS1 T393C polymorphism with tumor stage and survival in gastric cancer显示文摘AIM:To analyze the impact of the GNAS1 T393C polymorphism on prognosis and histopathology of gastric cancer.METHODS:Genomic DNA was extracted from paraffinembedded tissues of 122 patients with primary gastric carcinoma and from the blood of 820 healthy white individuals.Allelic discrimination was performed by quantitative real-time polymerase chain reaction.Genotyping was correlated with histopathologic parameters and with overall survival according to the Kaplan-Meier approach and with multivariate analysis by multiple stepwise regression.RESULTS:Thirty-nine(32%) patients displayed a CC genotype,57(46.7%) a CT genotype and 26(21.3%) a TT genotype.The frequency of the C allele(fC) in the patient group was 0.55,which was not signif icantly different from that of healthy blood donors.The distribution was compatible with the Hardy-Weinberg equilibrium.Analysis of clinicopathological parameters did not show any signif icant correlation of the T393C genotype with gender(P=0.50),differentiation(P=0.29),pT-category(P=0.19),pN-category(P=0.30),pM-category(P=0.25),R-category(P=0.95),the classifications according to WHO(P=0.34),Laurén(P=0.16),Goseki(P=1.00) and Ming(P=0.74).Dichotomization between C+(CC+CT) and C-genotypes(TT),however,revealed signif icantly more advanced tumor stages(P=0.023) and lower survival rates(P=0.043) for C allele carriers.CONCLUSION:The present study provides strong evidence to suggest that the GNAS1 T393C allele carrier status influences tumor progression and survival in gastric cancer with higher tumor stages and a worse outcome for C allele carriers. | Hakan Alakus Stefan P Mnig Ute Warnecke-Eberz Gül Alakus Günther Winde Uta Drebber Klaus J Schmitz Kurt W Schmid Kathrin Riemann Winfried Siffert Elfriede Bollschweiler Arnulf H Hlscher Ralf Metzger | 2009 | World Journal of Gastroenterology2009，15，48： | 3 |
| 3 | Mutations of Helicobacterpylori genes rdxA and pbp1 cause resistance against metronidazole显示文摘 | Ralf P Stefan P Klaus M | 2001 | Antimicrob Agents Chemother2001，45，3： | 1 |
| 4 | Incidence of neurologic complications related to thoracic epidural catheterization显示文摘 | Reiner MG Ralf US Jurgen P | 1997 | Anesthesiology1997，86，1： | 1 |
| 5 | Characterization of polyploid wheat genomic diversity using a high-density 90 000 single nucleotide polymorphism array 显示文摘 | Wang SC Debbie W Kerrie F Alexandra A Shiaoman C Bevan EH Marco M Silvio S Sara GM Luigi C Anna MM Alex W Stuart S Gary B Ralf W Joerg P International Wheat Genome Sequencing Consortium Morten L Diane M Rudi A Rudy D Gina BG Abraham K Alina RA Catherine F Jerome S Michele M Curtis P Luo MC Jan DMM Jorge D Martin G Roberto T Cindy L Ivan M Colin C Keith JE Matthew H Eduard A | 2014 | Plant Biotechnol J2014，12，： | 1 |
| 6 | Diminished thrombus formation and alleviation of myocardial infarction and reperfusion injury through antibody-or small-molecule-mediated inhibition of selectin-dependent platelet functions 显示文摘 | Gertie JO Miroslava P Ralf JL | 2007 | Haematologica2007，92，4： | 1 |
| 7 | Using fuzzy bases to resolve nonlinear programming problems显示文摘 | Wang P Z Ralf Ostermark Rajah Alex | 2001 | Fuzzy Sets and Systems2001，117，： | 1 |
| 8 | AACE/AME/ETA thyroid nodule guideline显示文摘 | Hossein G Enrico P Ralf P | 2010 | Endocr Pract2010，16，1： | 1 |
| 9 | Droplet Based Mi-crofluidics显示文摘 | Ralf S Martin B Thomas P | 2012 | Reports on Progress in Physics2012，75，01： | 1 |
| 10 | Effect of pore structure on electrical resistivity in carbonates显示文摘 | Klaas V Gregor P E Ralf J W | 2011 | AAPG Bulletin2011，95，2： | 1 |
| 11 | Effect of Pore Structure on Electrical Resistivity in Carbonates显示文摘 | Klaas Verwer Gregor P Eberli Ralf J Weger | 2011 | AAPG Bulletin2011，95，2： | 1 |
| 12 | Quantification of pore structure and its effect on sonic velocity and permeabili- ty in carbonates显示文摘 | Ralf J W Gregor P E Gregor T B | 2009 | AAPG Bulletin2009，93，10： | 1 |
| 13 | The governance in project-based organiza- tions 显示文摘 | SOFIA P RALF M | 2012 | International Journal of Project Management2012，，30： | 1 |
| 14 | Genetic diversity and bark physiology of the European beech(Fagus sylvatica ):a co-evolutionary re- lationship with the beech scale 显示文摘 | Doris K Ralf P | 2000 | Tree Physiology2000，20，： | 1 |
| 15 | UHF PD Detection in Gas-insulated Switchgear-Suitability and Sensitivity of the UHF Method in Comparison with the IEC 270 Method显示文摘 | NICHOLAS D BRANKO C RALF P | 1996 | IEEE Electrical Insulation Magazine1996，12，6： | 1 |
| 16 | In search of the 'hair cycle clock': a guided tour differentiation显示文摘 | Ralf P Kerstin F | 2004 | Differentiation2004，72，： | 1 |
| 17 | Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes显示文摘 | Ralf B Rüdiger P | 2003 | Circulation2003，107，： | 1 |
| 18 | Anti-atherosclerotic mechanisms of statin therapy显示文摘 | Andrea Babelova Daniel G Sedding Ralf P Brandes | 2013 | Current Opinion in Pharmacology2013，，2： | 1 |
| 19 | Dissolution of alumina, sintering, and crystallization in glass ceramic composites for LTCC 显示文摘 | RALF M ROBERT M BURKHARD P | 2009 | Journal of the American Ceramic Society2009，92，8： | 1 |
| 20 | Tissue Engineering of heart valves: in vitro experience显示文摘 | RALF S SIMON P HOERSTRUP S P | 2002 | Ann Thorac Surg2002，70，： | 1 |
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