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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 | Empirical evaluation of the relationship between soil dielectric constant and volumetric water content as the basis for calibrating soil moisture measurements by TDR显示文摘 | Roth C H Malicki M A Plagge R | 1992 | Soil Sci1992，43，： | 1 |
| 3 | Synthesis and characterization of carbon-supported Pt-Ru-WOx catalysts by spectroscopic and diffraction methods 显示文摘 | Roth C Goetz M Fuess H | 2001 | Journal of Applied Electrochemistry2001，31，： | 1 |
| 4 | A laboratory model to evaluate cutout resistance of implants for pertrochanteric fracture fixation显示文摘 | Sommers MB Roth C Hall H | | 0，，06： | 1 |
| 5 | Role of the thromboxane A2 receptor in the vasoactive response to ischemia-reperfusion injury显示文摘 | MAZOLEWSKI P G ROTH A C SUCHY H | 1999 | Plast Reconstr Surg1999，104，： | 1 |
| 6 | Noninvasive assess ment of acute ureteral obstruction with diffusion-weighted MR imaging: a prospective study显示文摘 | Thoeny H C Binser T Roth B | 2009 | Radiology2009，25，3： | 1 |
| 7 | Simultaneous calibration of robot and a hand mounted camera显示文摘 | ZHUANG H Q WANG K C ROTH Z S | 1995 | IEEE Transactions on Robotics and Automation1995，11，5： | 1 |
| 8 | Reduced medial olivocochlear bundle system function in children with auditory processing disorders显示文摘 | Muchnik C Roth D Othman-Jebara R Putter-Katz H Shabtai E Hildesheimer M | | 0，，： | 1 |
| 9 | A laboratory model to evaluate cutuut resistance of implants fur pertruchanteric fracture fixatiun 显示文摘 | Sommers MB Roth C Hall H | 2004 | J OrthopTrauma2004，18，6： | 1 |
| 10 | Estrogen is essential for maintaining nigrostriatal dopanfine neurons in primates: implications for Parkinson' s disease and memory 显示文摘 | Leranth C Roth R H Elsworth J D | 2000 | J Neurosci2000，20，23： | 1 |
| 11 | A laboratory model to eval- uate cutout resistance of implants for pertrochanteric fracture fixation 显示文摘 | Sommers MB Roth C Hall H | 2004 | J Orhtop Trauma2004，18，6： | 1 |
| 12 | A laboratory model to evaluate cutout resistance of implants for pertrochanteric fracture fixation显示文摘 | Sommers MB Roth C Hall H | 2004 | J Orthop Trauma2004，18，6： | 1 |
| 13 | A New family of mesoporous molecular sieves prepared with liquid crystal templates显示文摘 | BECK J S VARTULI J C ROTH W J LEONOWICZ M E KRESGE C T SCHMITT K D CHU C T W OLSON D H SHEPPARD E W | 1992 | J Am Chem Soc1992，114，10： | 1 |
| 14 | A dielectric slit die for in-line monitoring of polymer compounding显示文摘 | BUR A J ROTH S C LEE Y H MCBREARTH M | 2004 | Rev Sci Instrum2004，75，4： | 1 |
| 15 | Analysis of temperature controlled ventilated embankment显示文摘 | YU Q H SIM C H NIU F J NAIWU H ROTH K | 2005 | Cold Regions Science and Technology2005，42，1： | 1 |
| 16 | Noninve asiveassessment of acute ureteral obstruction with diffusion-weighted MR ima- ging : a prospective study显示文摘 | Thoeny H C Binser T Roth B | 2009 | Radiology2009，252，3： | 1 |
| 17 | A laboratory model to evaluate cutout resistent of implants for pertrochanteric fracture fixation显示文摘 | Sommers MB Roth C Hall H | 2004 | J Orthop Trauma2004，18，3： | 1 |
| 18 | Empirical evalation of the realtionship between soil dielectric constant and volumetric water content as the basis for calibrating soil moisture measurements by TDR 显示文摘 | Roth C H Malieki M A Plagge R | 1992 | Soil Sci1992，43，： | 1 |
| 19 | Impacts of urbaniza- tion on long-term fog variation in Anhui Province, China显示文摘 | SHI C E ROTH M ZHANG H | 2008 | Atmospheric Environment2008，42，36： | 1 |
| 20 | FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae显示文摘 | JONES C H PINKNER J S ROTH R | 1995 | Proc Natl Acad Sci USA1995，92，： | 1 |
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