title: Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver.
abstract: Oxyresveratrol is a polyphenolic phytoalexin produced by plants as an antioxidant. This study investigated the hepatoprotective effects of oxyresveratrol as well as its underlying mechanism of action. Here, we evaluated the protective effects of oxyresveratrol against tert-butyl hydroperoxide (tBHP)-induced severe oxidative stress in HepG2 cells as well as acute liver injury caused by carbon tetrachloride (CCl4) in mice. tBHP-induced reactive oxygen species production and cell death in hepatocytes were blocked by oxyresveratrol, as indicated by MTT, TUNEL, and FACS analyses. Moreover, pretreatment with oxyresveratrol increased nuclear translocation and transactivation of NF-E2-related factor 2 (Nrf2), as assessed by antioxidant response element reporter gene expression and immunofluorescence staining, and transactivated expression of both hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. More importantly, oxyresveratrol induced phosphorylation of Nrf2 mediated through activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Further, ERK inhibitors such as PD98059 and U0126 blocked phosphorylation of Nrf2 as well as the protective effect of oxyresveratrol in mitochondria. In mice, oral administration of oxyresveratrol significantly prevented hepatocyte degeneration, inflammatory cell infiltration, as well as elevation of plasma markers such as ALT and AST induced by CCl4 injection. In conclusion, this study confirmed that oxyresveratrol protected hepatocytes against oxidative stress and mitochondrial dysfunction, which might be associated with activation of Nrf2.
authors.affiliation: Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Hee Yoon
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea; College of Korean Medicine, Dongguk University, Gyeongju 780-714, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Jegal
authors.affiliation: Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Il Je
authors.initials: IJ
authors.lastname: Cho
authors.affiliation: Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea. Electronic address: ywkim@dhu.ac.kr.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea. Electronic address: sckim@dhu.ac.kr.
authors.forename: Sang Chan
authors.initials: SC
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000627:therapeutic use*; D013267:Stilbenes / Q000627:therapeutic use*; D020122:tert-Butylhydroperoxide
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D013267:Stilbenes; C034912:puag-haad; D020122:tert-Butylhydroperoxide; D002251:Carbon Tetrachloride
keywords: Carbon tetrachloride; ERK; Nrf2; Oxidative stress; Oxyresveratrol; Oxyresveratrol (PubChem CID: 5281717); tert-Butyl hydroperoxide