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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 | Random and site -specific immobilization of catalytic antibodies 显示文摘 | Spitznagel T M Jacobs J W Clark D S | 1993 | Enzyme Microbial Technol1993，15，： | 1 |
| 3 | The effects of supply chain integration on customer satisfaction and financial performance : An organizational learning perspective 显示文摘 | YU W T JACOBS M A SALISBURY W D ENNS H | 2013 | International Journal of Production Economies2013，146，1： | 1 |
| 4 | Blood flow and vascular permeability during motor dysfunction in a rabbit model of spinal cord ischemia 显示文摘 | Jacobs T P Kempski O Mckinley D | 1992 | Stroke1992，23，3： | 1 |
| 5 | Identifi- cation and subtyping of Francisella by pyrosequencing and signature matching of 16S rDNA fragments 显示文摘 | Jacob D Wahab T Edvinsson B Peterzon A Boskani T Farhadi L Barduhn A Grunow R Sandstrom G | 2011 | Lett Appl Microbiol2011，53，6： | 1 |
| 6 | OMEGA EP high-energy petawatt laser: progress and prospects显示文摘 | D N Maywar J H Kelly L J Waxer S F B Morse I A Begishev J Bromage C Dorrer J L Edwards L Folnsbee M J Guardalben S D Jacobs R Jungquist T J Kessler R W Kidder B E Kruschwitz S J Loucks J R Marciante R L McCrory D D Meyerhofer A V Okishev J B Oliver G Pien | 2008 | Journal of Physics: Conference Series2008，，3： | 1 |
| 7 | Fiber,sex,and colorectal adenoma:results of a pooled analysis显示文摘 | JACOBS E T LANZA E ALBERTS D S | 2006 | Am J Clin Nutr2006，83，2： | 1 |
| 8 | Multiple elements in Typha angustifolia rhizosphere and plants : wetland versus dryland 显示文摘 | Kissoon L T T Jacob D L Otte M L | 2011 | Environmen- tal and Experimental Botany2011，72，2： | 1 |
| 9 | Quantum computing using single photons and the Zeno effect 显示文摘 | FRANSON J D JACOBS B C PITTMAN T B | 2004 | Physical Review A2004，70，6： | 1 |
| 10 | Liquid chromatography-mass spectrometry identification of imidacloprid photolysis products 显示文摘 | Ding T Jacobs D Lavine B K | 2011 | Microchemical Journal2011，99，2： | 1 |
| 11 | rRNA sequences and evolutionary relationships among toxic and nontoxic cyanobacteria of the genus Microcystis 显示文摘 | Neilan B A Jacobs D DelDot T | 1997 | International Journal of Systeatic Bacteriology1997，47，3： | 1 |
| 12 | Genome sequence and analysis of the tuber crop potato显示文摘 | Xu X Pan S Cheng S Zhang B Mu D Ni P Zhang G Yang S Li R Wang J Orjeda G Guzman F Tones M Lnzano R Ponce O Martinez D De la Cruz G Chakrabarti S K Patil V U Skryabin K G Kuznetsov B B Ravin N V Kolganova T V Beletsky A V Mardanov A V Di Genova A Bolser D M Martin D M Li G Yang Y Kuang H Hu Q Xiong X Bishop G J Sagredo B Mejia N Zagorski W Gromadka R Gawor J Szczesny P Huang S Zhang Z Liang C He J Li Y He Y Xu J Zhang Y Xie B Du Y Qu D Bonierbale M Ghislain M Herrera Mdel R Giuliano G Pietrella M Perrotta G Faeella P O 'Brien K Feingold S E Barreiro L E Massa G A Diambra L Whitty B R Vaillancourt B Lin H Massa A N Geoffroy M Lundback S DellaPenna D Buell C R Sharma S K Marshall D F Waugh R Bryan G J Destefanis M Nagy I Milbourne D Thomson S J Fiefs M Jacobs J M Nielsen K L Sonderkaer M Iovene M Tortes G A Jiang J Veilleux R E Bachem C W de Boer J Bonn T Kloosterman B van Eck H Datema E Hekkert B Goverse A van Ham R C Visser R G | 2011 | Nature2011，475，7355： | 1 |
| 13 | Structural implications in cesium sorption 显示文摘 | Tamura T Jacobs D G | 1960 | Health Physics1960，6，2： | 1 |
| 14 | Carbohydrates, dietary fiber, and incident type 2 diabetes in older women 显示文摘 | Meyer K A Kushi L H Jacobs D R J Slavin J Sellers T A Folsom A R | 2000 | The American Journal of Clinical Nutrition2000，71，4： | 1 |
| 15 | Optimum culture conditions required for the locally isolated Dunaliella salina显示文摘 | Abu-Rezq T S Al-Hooti S Jacob D A J | 2010 | Al-gal Biomass Utln2010，1，2： | 1 |
| 16 | Global budgets of atmospheric glyoxal and methyl- glyoxal, and implications for formation of secondary organic aerosols 显示文摘 | Fu T M JACOB D J WITTROCK F | 2012 | Journal of Geophysical Research2012，113，15： | 1 |
| 17 | A search engine for 3D models 显示文摘 | FUNKHOUSER T MIN P KAZHDAN M CHEN J HALDERMAN A DOBKIN D JACOBS D | 2003 | ACM Transactions on Graphics2003，22，1： | 1 |
| 18 | The Basic Processes Affecting Two-step Aging in an Al-Mg-Si Alloy显示文摘 | Pashley D W Jacobs M H Vietz J T | 1967 | Philosophical Magazine1967，16，： | 1 |
| 19 | Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Psendomonas aeruginosa: A randomized, double-blind, placebo-controlled trial 显示文摘 | Francois B Luyt CE Dugard A Wolff M Diehl JL Jaber S Forel JM Garot D Kipnis E Mebazaa A Misset B Andremont A Ploy MC Jacobs A Yarranton G Pearce T Fagon JY Chastre J | 2012 | Crit Care Med2012，40，8： | 1 |
| 20 | Are your patients with risk of CVD getting the viscous soluble fiber they need显示文摘 | Shamliyan T A Jacobs D R Raatz S K Nordstrom D L Keenan J M | 2006 | The Journal of Family Practice2006，55，9： | 1 |
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