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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 | Predictors of disease severity in ulcerative colitis patients from Southwestern Ontario显示文摘AIM:To understand the demographic characteristics of patients in Southwestern Ontario,Canada with ulcerative colitis(UC)in order to predict disease severity. METHODS:Records from 1996 to 2001 were exam- ined to create a database of UC patients seen in the London Health Sciences Centre South Street Hospital Inflammatory Bowel Disease Clinic.To be included, patients'charts were required to have information of their disease presentation and a minimum of 5 years of follow-up.Charts were reviewed using standardized data collection forms.Disease severity was generated during the chart review process,and non-endoscopic Mayo Score criteria were collected into a composite. RESULTS:One hundred and two consecutive patients'data were entered into the database.Demographic analyses revealed that 51%of the patients were male, the mean age at diagnosis was 39 years,13.7%had a first degree relative with inflammatory bowel disease (IBD),61.8%were nonsmokers and 24.5%were ex-smokers.In 22.5%of patients the disease was limited to the rectum,in 21.6%disease was limited to the sigmoid colon,in 22.5%disease was limited to the left colon,and 32.4%of patients had pancolitis. Standard multiple regression analysis which regressed a composite of physician global assessment of disease severity,average number of bowel movements,and average amount of blood in bowel movements on year of diagnosis and age at time of diagnosis was significant,R 2=0.306,F(7,74)=4.66,P<0.01. Delay from symptoms to diagnosis of UC,gender, family history of IBD,smoking status and disease severity at the time of diagnosis didnot significantly predict the composite measure. CONCLUSION:UC severity is associated with younger age at diagnosis and year of diagnosis in a longitudinal cohort of UC patients,and may identify prognostic UC indicators. | Lee S Roth Nilesh Chande Terry Ponich Maya L Roth James Gregor | 2010 | World Journal of Gastroenterology2010，16，2： | 4 |
| 3 | 周期性压力下椎间盘细胞中肌动蛋白的变化及其意义 | 于胜吉 邱贵兴 Yang BL Roth S Whyne C Yee AJ | 2005 | 中华骨科杂志2005，25，9： | 4 |
| 4 | Aminophylline for bradyasystolic cardiac arrest refractory to atropine and epinephrine显示文摘 | Viskin S Belhassen B Roth A | 1993 | Ann Inter Med1993，118，： | 2 |
| 5 | 机械负荷调节猪腰椎间盘细胞表达α5β1整合素的体外研究显示文摘目的研究α5β1整合素在体外培养的猪腰椎间盘细胞中的表达和机械负荷对其的影响。方法取10只年龄5~6周、体重25~30kg的猪,处死后12h内,无菌条件下切取完整的腰椎,剔除腰椎周围的韧带和软组织,尤其是椎间盘周围的韧带。从腹侧一次性切开椎间盘取出髓核(nucleuspulpous,NP),仔细分离纤维环(anulusfibrous,AF),将两者立即置于Hanks平衡盐溶液中,制成细胞悬液。分别对腰椎间盘的AF和NP细胞施加1MPa、1Hz,3h/d,共3d的周期性液压,通过对细胞的形态学观察、Western免疫印迹和免疫组织化学染色,检测α5β1整合素在正常腰椎间盘AF细胞和NP细胞中的表达及周期性压力对其的影响。结果经周期性液压后,NP细胞的存活率大于90%,AF细胞的存活率大于85%,加压后的AF细胞和NP细胞均可见体积缩小。α5β1整合素在正常腰椎间盘AF细胞和NP细胞中的表达呈强阳性。Western免疫印迹结果显示:加压后α5β1整合素在AF细胞中的表达均明显减少,P值分别为0.000、0.003,与对照组比较差异有统计学意义;α5β1整合素在NP细胞中的表达也明显减少,P值分别为0.001、0.015,与对照组比较差异有统计学意义。结论机械负荷可引起腰椎间盘细胞中α5β1整合素的变化,提示α5β1整合素在腰椎间盘细胞中可能发挥力学传感器的作用。 | 于胜吉 邱贵兴 Yang B Roth S Whyne C Yee AJ | 2006 | 中华骨科杂志2006，26，6： | 2 |
| 6 | Calibration of multi-beam laser tracking systems显示文摘 | ZHUANG Hanqi MOTAGHEDI S H ROTH Z S | 2003 | Robotics and Computer Integrated Manufacturing2003，19，4： | 1 |
| 7 | NAT and viral safety in blood transfusion显示文摘 | Roth WK Buhr S Drosten C | 2000 | Vox Sang2000，78，2： | 1 |
| 8 | Laboratory assessment of hepatic injury in the woodchuck (Marmota monax)显示文摘 | Hornbuckle W E Graham E S Roth L | 1985 | Lab Anim Sci1985，35，： | 1 |
| 9 | Release of non-neuronal acetylcholine from t he human placenta: difference toneuronal acetylcholine显示文摘 | Roth E Schwarze S | 2001 | Naunyn Schmiedebergs Arch Pharmacol2001，364，： | 1 |
| 10 | Piezoelectric properties of lead zirconate-lead titanate solid-solution cramics显示文摘 | Roth R S Marzullo S | 1954 | J Appl Phys1954，25，： | 1 |
| 11 | Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma显示文摘 | Mukherjee S Roth M J Dawsey SM et ai | | J Transl Med0，，1： | 1 |
| 12 | Simplified method for polariantionsensitive optical coherence tomography显示文摘 | ROTH J E KOZAK J A YAZDANFAR S | 2001 | Opt Lett2001，14，： | 1 |
| 13 | A new family of mesoporous molecular sieve prepared with liquid crystal templates显示文摘 | Beck J S Vartuli J C Roth W J | 1992 | J Am Chem Soc1992，114，10： | 1 |
| 14 | Effect of nitric oxide synthase inhibition on blood flow after retinal ischemia in cats显示文摘 | Ostwald P Goldstein IM Pachnanda A Roth S | 1995 | Invest Ophthalmol Vis Sci1995，36，12： | 1 |
| 15 | Magnetic properties and hyperfine interactions in the β″ phase of potassium ferrite 显示文摘 | Romanov V P Candela G A Roth R S | 1979 | J Appl Phys1979，50，： | 1 |
| 16 | 显示文摘 | Howe JR Roth S Ringold JC | 1998 | Science1998，280，： | 1 |
| 17 | 显示文摘 | Roth S Stoca M Degmova J | 2006 | J Magn Magn Mater2006，304，2： | 1 |
| 18 | Learning to detect objects in images via a sparse, part-based representation显示文摘 | Agarwal S Awan A Roth D | 2004 | Pattern Anal- ysis and Machine Intelligence IEEE Transactions on2004，26，11： | 1 |
| 19 | The American society of anesthesiologists postoperative visual loss registry:a- nalysis of 93 spine surgery cases with postoperative vis- ual loss 显示文摘 | Lee LA Roth S Posner KL | 2006 | Anesthesiology2006，105，4： | 1 |
| 20 | Increased NMDA current and spine density in mcelaeking the NMDA receptor subunit- NR3A显示文摘 | Das S Sasaki Y F Rothe T | 1998 | Nature1998，，393： | 1 |
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