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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 | 含有菊粉但不含羽扇豆的饲粮有助预防实验诱导的猪痢疾显示文摘猪痢疾是一种传染性黏膜出血的腹泻疾病,由定植于肠道的猪痢疾短螺旋体引起,能够诱发盲肠和结肠发炎。据报道饲料中添加菊苣根和甜羽扇豆可预防猪痢疾。本试验旨在验证是菊苣根中的菊粉而不是羽扇豆中的半乳糖起到保护作用的假设。 | Hansen C F Phillips N D La T.(等) 闫轶洁(译) 无 | 2010 | 养猪2010，，6： | 2 |
| 3 | Crisis in corporate America:The role of strategy 显示文摘 | HANSEN F D SMITH M C | 2003 | Business Horizons2003，15，1： | 1 |
| 4 | Thalassiolins A-C: new marine-derived inhibitors of HIV eDNA integrase显示文摘 | Rowley D C Hansen M S T Rhodes D | 2002 | Bioorg Med Chen2002，10，： | 1 |
| 5 | The design of systems to control actively periodic sound transmission into enclosed spaces, Part II: Mechanisms and trends显示文摘 | Snyder S D Hansen C H | 1994 | J Sound and Vibration1994，170，4： | 1 |
| 6 | The suitability of decadal image data sets for mapping tropical forest cover change in the Democratic Republic of Congo:implications for the global land survey 显示文摘 | Lindquist E J Hansen M C Roy D P | 2008 | International Journal of Remote Sensing2008，29，2324： | 1 |
| 7 | The use of the L-curve in the regularization of discrete ill-posed problems显示文摘 | Hansen P C O'Leary D P | 1993 | SIAM Journal on Numerical Analysis1993，14，6： | 1 |
| 8 | Intraoperative neurophysiological monitoring during spine surgery:a review显示文摘 | Gonzalez A A Jeyanandarajan D Hansen C | 2009 | Neurosurg Focus2009，27，4： | 1 |
| 9 | Strength of recycled concrete made fromcrushed concrete coarse aggregate显示文摘 | HANSEN T C NARU D H | 1983 | Concrete International1983，1，1： | 1 |
| 10 | Genesis and effects of lon8waves in the equatorial Pacific显示文摘 | HANSEN D V PAUL C A | 1984 | JGeophys Res1984，89，10： | 1 |
| 11 | Dynamic responde of an overhead crane system 显示文摘 | Oguamanam D C D Hansen J S Heppler G R | 1998 | Journal of Sound and Vibration1998，213，5： | 1 |
| 12 | Do gene variants influencing adult adiposity affect birth weight? A population-based study of 24 loci in 4,744 Danish individuals显示文摘 | Andersson E A Pilgaard K Pisinger C Harder M N Grarup N Faerch K Sandholt C Poulsen P Witte D R Jorgensen T Vaag A Pedersen O and Hansen T | | 0，，12： | 1 |
| 13 | Tikhonov regularization and total least squares显示文摘 | Golub G H Hansen P C O'Leary D P | 1999 | SIAM Journal on Matrix Analysis and Applications1999，21，1： | 1 |
| 14 | Effect of salt on structure-function relationships of cheese 显示文摘 | Pastorino A Hansen C Mcmahon D J | 2003 | Journal of Dairy Science2003，86，1： | 1 |
| 15 | Wind models for simulation of power fluctuations from wind farms 显示文摘 | SRENSEN P HANSEN A D ROSAS P A C | 2002 | Journal of Wind Engineering and Industrial Aerodynamics2002，90，12： | 1 |
| 16 | Malthus to Solow 显示文摘 | HANSEN GARY D EDWARD C PRESCOTt | 2002 | American Economic Review2002，92，： | 1 |
| 17 | Regularization by truncated total least squares显示文摘 | Fierro R D Golub G H Hansen P C | 1997 | SIAM Journal on Scientific Computing1997，18，4： | 1 |
| 18 | The Use of the L-Curve in the Regularization of Discrete Ill-Posed Problems显示文摘 | Hansen P C O'Leary D P | 1993 | SlAM J Sci Comput1993，14，6： | 1 |
| 19 | Effect of Salt on Structure-Function Relationships of Cheese显示文摘 | Pastorino A J Hansen C L McMahon D J | 2003 | J Dairy Sci2003，86，： | 1 |
| 20 | Calculation of vibratory power transmission for use in active vibration control 显示文摘 | Howard C Q Snyder S D Hansen C H | 2000 | Journal of Sound and Vibration2000，234，4： | 1 |
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