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| 1 | INT-767 improves histopathological features in a dietinduced ob/ob mouse model of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis(NASH).METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lep^(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep^(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH. | Jonathan D Roth Michael Feigh Sanne S Veidal Louise KD Fensholdt Kristoffer T Rigbolt Henrik H Hansen Li C Chen Mathieu Petitjean Weslyn Friley Niels Vrang Jacob Jelsing Mark Young | 2018 | World Journal of Gastroenterology2018，24，2： | 7 |
| 2 | Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial显示文摘 | JY Douillard D Cunningham AD Roth M Navarro RD James P Karasek P Jandik T Iveson J Carmichael M Alakl G Gruia L Awad P Rougier | 2000 | The Lancet2000，，9209： | 4 |
| 3 | G蛋白信号转导调节因子5的缺失激活脑卒中时的神经血管保护显示文摘在缺血性脑卒中发生时,血脑屏障的破坏加重了脑损伤。周细胞脱离导致血脑屏障破坏和神经血管功能障碍,但对其在脑卒中中的调节知之甚少。在该研究中,研究者研究了周细胞中G蛋白信号转导调节因子5(Gprotein signaling5,RGS5)的缺失如何影响脑卒中时血脑屏障的破坏及其后果。 | zen I Roth M Barbariga M Gaceb A Deierborg T Genové G Paul G 刘青 叶鹏 | 2018 | 中华高血压杂志2018，26，9： | 2 |
| 4 | Satellite derived urban heat islands from three coastal cities and the utilization of such data in urban climatology 显示文摘 | Roth M Oke T R and Emery W J | 1989 | International Journal of Remote Sensing1989，10，11： | 2 |
| 5 | Ordered mesoporous molecular sieves synthesized by a liquid crystal templates mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 6 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | Kressge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 7 | Fetuin-A and Its Relation to Metabolic Syndrome and Fatty Liver Disease in Obese Children Before and After Weight Loss显示文摘 | Reinehr T Roth CL | 2008 | J Clin Endocrinol Metab2008，93，11： | 1 |
| 8 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism 显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 9 | Assessment of cardiac pre- load and left ventricular function under increasing levels of positive end expiratory pressure显示文摘 | Luecke T Roth H Henlnann P | 2004 | Intensive Care Med2004，30，1： | 1 |
| 10 | Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens 显示文摘 | Borrn T Falk P Roth KA | 1993 | Science1993，262，5141： | 1 |
| 11 | High-b-value diffusion-weighted MR imaging for pretreatment prediction and early monitoring of tumor response to therapy in mice显示文摘 | Roth Y Tichler T Kostenich G | | 0，，03： | 1 |
| 12 | Ordered mesoporous molecular sieves syntherized by a liquid-crystal template mechanism显示文摘 | KRESGE C T LEONOWlCZ M E ROTH W J | 1992 | Nature1992，359，6397： | 1 |
| 13 | Diffusion tensor imaging of skeletal muscle-correlation of fractional anisotropy to muscle power 显示文摘 | Scheel M Prokscha T von Roth P | 2013 | Rofo2013，185，： | 1 |
| 14 | Sleep disturbance and psychiatric disorders:a longitudinal epidemiological study of young adults显示文摘 | Breslau N Roth T Rosenthal L | 1996 | Biological psychiatry1996，39，6： | 1 |
| 15 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | KRESEGE C T LEONNWICZ M E ROTH W J | 1992 | Nature1992，359，： | 1 |
| 16 | Increased NMDA current and spine density in mcelaeking the NMDA receptor subunit- NR3A显示文摘 | Das S Sasaki Y F Rothe T | 1998 | Nature1998，，393： | 1 |
| 17 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism 显示文摘 | KRESGE C T LEONOWICZ M E ROTH W J | 1992 | Nature1992，359，6397： | 1 |
| 18 | Satellite Derived Urban Heat Islands from Three Coastal Cities and the Utilisation of Such Data in Urban Climatology显示文摘 | Roth M Oke T R Emery W J | 1989 | International Journal of Re- mote Sensing1989，10，： | 1 |
| 19 | Ordered mesoporous molecular-sieves synthesized by a liquid-crystal template mechanism显示文摘 | Leonowicz M E Roth W J | 1992 | Nature1992，56，359： | 1 |
| 20 | Insomnia: definition, prevalence, etiology and consequences显示文摘 | Roth T | 2007 | J Clin Sleep Med2007，，： | 1 |
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