title: Synergistic effect of cyanidin and PPAR agonist against nonalcoholic steatohepatitis-mediated oxidative stress-induced cytotoxicity through MAPK and Nrf2 transduction pathways.
abstract: Nonalcoholic steatohepatitis (NASH) is caused by an elevation in oxidative stress, which might further lead to hepatic fibrogenesis. Importantly, both peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) play roles in modulating oxidative stress-mediated hepatic dysfunction. The objective of this study was to investigate the mechanisms of the multifunctional effects of cyanidin on regulating antioxidant enzymes and oxidative stress-induced hepatotoxicity. The data indicated that cyanidin-mediated antioxidant enzyme expression involved the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways and Nrf2 activation. Furthermore, the synergistic effect of cyanidin and the PPAR agonist, troglitazone, on Nrf2-PPAR activation, was also observed. Besides, treatment of cyanidin and troglitazone abolished H₂O₂-induced downregulation of genes involved in lipid metabolism. In addition, H₂O₂-mediated cytotoxicity, which was caused by inducing ROS formation and apoptotic cell death, was also ameliorated upon cyanidin and troglitazone stimulation. In conclusion, mitogen-activated protein kinases (MAPKs) and the transcription factor Nrf2 played regulatory roles in cyanidin-mediated antioxidant enzyme activation. Furthermore, the combination of cyanidin and troglitazone activated PPARγ-Nrf2 and improved H₂O₂-mediated perturbation of genes involved in lipid metabolism. These data suggested that cyanidin and PPAR agonists might have synergistic benefits against metabolic dysfunction-related oxidative damage.
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuokuang Road, Taichung 40227, Taiwan.
authors.forename: Ping-Hsiao
authors.initials: PH
authors.lastname: Shih
authors.forename: Sam-Long
authors.initials: SL
authors.lastname: Hwang
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.forename: Gow-Chin
authors.initials: GC
authors.lastname: Yen
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000187:drug effects*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D000872:Anthocyanins; D002839:Chromans; D051267:NF-E2-Related Factor 2; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; C017154:cyanidin; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000077288:Troglitazone