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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 | Functional Analysis of Yeast bcs1 Mutants Highlights the Role of Bcs1p-Specific Amino Acids in the AAA Domain显示文摘 | Cécile Nouet Gilles Truan Lise Mathieu Geneviève Dujardin | 2009 | Journal of Molecular Biology2009，，2： | 2 |
| 3 | Development of 5-iodo-2'-deoxyuridine milling process to reduce initial burst release from PLGA microparticles显示文摘 | Geze A Venier-Julienne M C Mathieu D | 1999 | Int J Pharm1999，178，2： | 1 |
| 4 | First-line tuberculosis therapy and drug-re-sistant Mycobacterium tuberculosis in prisons显示文摘 | Coninx R Mathieu C Debacker M | 1999 | Lancet1999，353，9157： | 1 |
| 5 | In Situ Dynamics of Microbial Communities during Decomposition of Wheat,Rape,and Alfalfa Residues显示文摘 | Pascault N Cécillon L Mathieu O Hénault C Sarr A Lév(e)que J Fatty P Ranjard L Maron PA | | 0，，04： | 1 |
| 6 | SGLT2-inhibitors:a novel class for the treatment of type 2 diabetes introduction of SGLT2-inhibitors in clinical practice显示文摘 | Cuypers J Mathieu C Benhalima K | 2013 | Acta Clin Belg2013，68，4： | 1 |
| 7 | A corrosion study of the main constituent phases of AZ91 magnesium alloys 显示文摘 | MATHIEU S RAPIN C STEINMETZ J STEINMETZ P | 2003 | Corrosion Science2003，45，12： | 1 |
| 8 | Cross-cultural differences in test perceptions: Women in Kuwait and the United States Journal of Cross-Cultural Psychology 显示文摘 | Jerrell C Cassady Ayoub Mohammed Lauren Mathieu | 2004 | Thousand oaks:2004，35，6： | 1 |
| 9 | Acorrosion study of the main constituent phases of AZ91 magnesiumalloys 显示文摘 | MATHIEU S RAPIN C STEINMETZ J STEINMETZ P | 2003 | Corrosion Science2003，45，： | 1 |
| 10 | In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice 显示文摘 | Mathieu C Van Etten E Gysemans C | 2001 | J Bone Miner Res2001，16，11： | 1 |
| 11 | New potential and applications of contrast-enhanced ultrasound of the breast:Own investigations and review of the literature显示文摘 | Balleyguier C Opolon P Mathieu M C | 2009 | Eur J Radiol2009，69，1： | 1 |
| 12 | Diabetes and peripheral vascular disease显示文摘 | Huysman F Mathieu C | 2009 | Acta Chirurgica Belgica2009，109，5： | 1 |
| 13 | New potential and applications of contrast-enhanced ultrasound of the breast: Own investigations and review of the literature显示文摘 | Balleyguier C Opolon P Mathieu MC | 2009 | Eur J Radiol2009，69，1： | 1 |
| 14 | Complications of Gamma Knife surgery:an early report from 2 Canadian centers显示文摘 | Vachhrajani S Fawaz C Mathieu D | 2008 | J Neurosurg2008，109，6： | 1 |
| 15 | Prolonged blockade of CD40-CIMO ligand interactions by gene transfer of CIMOIg results in long-term heart allograft survival and donor-specific hyporesponsiveness, but does not prevent chronic rejection显示文摘 | Guillot C Guillonnean C Mathieu P et ol | 2002 | J Immunol2002，168，4： | 1 |
| 16 | Kashin - Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status显示文摘 | Moreno - Reyes R Suetens C Mathieu F | 1998 | New England Journal of Medicine1998，339，16： | 1 |
| 17 | Wettability of heat-treated wood 显示文摘 | Petrissans Mathieu C erardin Philippe E Bakali Idriss etc | 2003 | Holzforsehung2003，57，3： | 1 |
| 18 | Synthesis of (l'R,3S,4S)-3-- 4 -( cyclopropylcarbonyloxy ) azetidin -2-one显示文摘 | Mathieu L Marcel C Marchand-Brynaert Jacquelline | 2006 | Eur J Org Chem2006，，16： | 1 |
| 19 | Progesterone in gestational diabetes mellitus : guilty or not guilty? 显示文摘 | Branisteanu DD Mathieu C | 2003 | Trends En- docrinol Metab2003，14，2： | 1 |
| 20 | The coming of age of 1,25-dihydroxyvitamin D3 analogs as immunomodulatory agents显示文摘 | Mathieu C Adorini L | | 0，，04： | 1 |
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