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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 | Calibration of near infrared reflectance spectroscopy to estimate nitrogen concentration in potato tissues显示文摘 | YOUNG M W MACKRRON D K L DAVIES H V | 1997 | PotatoResearch1997，，40： | 1 |
| 3 | Cellular events mediated by li- popolysaccharide-stimulated toll-like receptor 4 : MD-2 is required for activation of mitogen-activated protein kinases and Elk-1 显示文摘 | Yang H Young DW Gusovsky D | 2000 | J Bio Chem2000，75，20： | 1 |
| 4 | Numerical solution of three-dimensional backward heat conduction problems by the time evolution method of fundamental solutions 显示文摘 | Tsai C H Young D L Kolibal J | 2011 | International Journal of Heat and Mass Transfer2011，54，1112： | 1 |
| 5 | RFLP mapping in plant breeding :new tools for old sciences 显示文摘 | TANKS LEY S D YOUNG N D PATERSON A H | 1989 | Biotechnology1989，7，： | 1 |
| 6 | Mechanisms of PVDF membrane formation by immersion - precipitation in soft (1 octanol) and harsh (water) nonsolvents 显示文摘 | Young T H Cheng L P Lin D J | 1999 | Polymer1999，40，19： | 1 |
| 7 | RFLP mappingin plant breeding:new tools for old sciences 显示文摘 | Tanksley S D Young N D Paterson A H | 1989 | Biotechnology1989，7，： | 1 |
| 8 | A new quation equation of state (QEOS) for hot dense matter显示文摘 | More R M Warren K H Young D A | | 0，，： | 1 |
| 9 | Matching familiar and unfamiliar faces on identity and expression显示文摘 | Young A W McWeeny K H Hay D C | 1986 | Psychological Re- search1986，48，： | 1 |
| 10 | Comparing the interface and point scatter methods for attenuating internal multiples: a study with synthetic data-Part Ⅰ显示文摘 | Verschuur D J Berkhout A J Matson K H Weglein A B Young C Y | 1998 | Society of Exploration Geophysicists International Exposition and 68th Annual Meeting1998，，： | 1 |
| 11 | Effects of feeding high forage diets and supplemental fat on feed intake and lactation per- formance in dairy cows 显示文摘 | Abdullah M Young J W Tyler H D | 2000 | Asian-Aust J Anita Sci2000，13，4： | 1 |
| 12 | Menthol production by chi- tosan-elicited suspension culture 显示文摘 | Young D H Kohle H Kauss H | 1982 | American Society of Plant Physiol1982，70，： | 1 |
| 13 | The effects of antioxidative treatments on mutton flavour/odour intensity and species flavour differentiation 显示文摘 | Reid D H Young O A Braggins T J | 1993 | Meat Science1993，35，2： | 1 |
| 14 | A combined BEM - FEM model for the velocity - vortieity Formulation of the Navier - Stokes equations in three dimensions显示文摘 | Young D L Liu Y H Eldho T I | 2000 | Engineering Analysis with Boundary Elements2000，24，4： | 1 |
| 15 | Kinetic and equilibrium mass-dependent isotope fractionation laws in nature and their geochemical and eosmochemieal significance显示文摘 | Young E D Galy A Nagahara H | 2002 | Geochimiea et Cosmochimica Acta2002，66，： | 1 |
| 16 | Related function of mouse SOX3,SOX9 and SRY HMG domains assayed by male sex determina-tion 显示文摘 | Bergstrom D E Young M Albrecht K H | 2000 | Genesis2000，28，： | 1 |
| 17 | High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever显示文摘 | Library D H Young P R Picketing D | 2002 | J Infect Dis2002，186，： | 1 |
| 18 | Arabidopsis mesophyll protn- plasts:a versatile eell system for transient gene expression analy- sis显示文摘 | Sang D Y Young H C Jen S | 2007 | Nature Protocols2007，2，7： | 1 |
| 19 | Phylogeny of the phototrophic Rhizobium strain BTAil by polymerase chain reaction - based sequen- cing of a 16S rRNA gene segment显示文摘 | Young J P W Downer H L Eardly B D | 1991 | J Bacteriol1991，173，： | 1 |
| 20 | Corrosion of mild steel in the presence of elemental sulfur 显示文摘 | Fang H Young D | 2008 | Corrosion2008，，3： | 1 |
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