title: Protective effects of rutin on liver injury induced by biliary obstruction in rats.
abstract: Rutin has been shown to possess beneficial health effects, including hepatoprotection. However, to date, it has not been demonstrated to have a hepatoprotective effect against cholestatic liver injury. This is the first report to show a protective effect of rutin on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily oral administration of rutin was started 1 week before injury and was maintained for 4 weeks. In comparison with the control group, the BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation, and oxidative stress. These pathophysiological changes were attenuated by rutin supplementation. Rutin alleviated BDL-induced transforming growth factor β1 (TGF-β1), interleukin-1β, connective tissue growth factor, and collagen expression. The antifibrotic effect of rutin was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity critical to the fibrogenic potential of TGF-β1. Rutin attenuated BDL-induced oxidative stress, leukocyte accumulation, NF-κB activation, and proinflammatory cytokine production. Further studies demonstrated an inhibitory effect of rutin on the redox-sensitive intracellular signaling molecule extracellular signal-regulated kinase (ERK). Rutin also attenuated BDL-induced reduction in NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and AMP-activated protein kinase (AMPK). Taken together, the beneficial effects of rutin were shown to be associated with antioxidative and anti-inflammatory effects as well as the downregulation of NF-κB and TGF-β/Smad signaling, probably via interference of ERK activation and/or enhancement of Nrf2, HO-1, and AMPK activity.
authors.affiliation: Department of Pediatrics, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan.
authors.forename: Pin-Ho
authors.initials: PH
authors.lastname: Pan
authors.affiliation: Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Division of Family Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Ya-Yu
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Chuang
authors.affiliation: Department of Anesthesiology, and Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan; Institute of Biomedical Sciences, and National Chung Hsing University, Taichung 402, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; Center for General Education, Tunghai University, Taichung 407, Taiwan; Graduate School of Nursing, Hungkuang University, Taichung 433, Taiwan. Electronic address: cjchen@vghtc.gov.tw.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use*; D001659:Biliary Tract / Q000473:pathology; D001662:Biliary Tract Surgical Procedures; D002779:Cholestasis / Q000188:drug therapy*; D003094:Collagen / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D053583:Interleukin-1beta / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000293:injuries*; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012431:Rutin / Q000627:therapeutic use*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D055372:AMP-Activated Protein Kinases; D000199:Actins; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D003094:Collagen; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D051547:Heme Oxygenase-1; D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009195:Peroxidase; D012431:Rutin; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C495637:Nfe2l2 protein, rat; C497784:Smad2 protein, rat; C497787:Smad3 protein, rat; C498862:Acta2 protein, rat
keywords: Cholestasis; Fibrosis; Flavonoids; Free radicals; Inflammation; Oxidative stress; Rutin