title: Hepatoprotective effect of lucidone against alcohol-induced oxidative stress in human hepatic HepG2 cells through the up-regulation of HO-1/Nrf-2 antioxidant genes.
abstract: Lucidone was previously reported to exhibit anti-inflammatory activity in vitro and in vivo. In the present study, we characterized the mechanisms underlying the hepatoprotective effect of lucidone against alcohol-induced oxidative stress in vitro. Human hepatoma (HepG2) cells were pretreated with lucidone (1-10μg/mL) and then hepatotoxicity was stimulated by the addition ethanol (100mM). With response to ethanol-challenge, increased amount of alanine aminotransferase (ALT) and aspirate aminotransferase (AST) release were observed, whereas lucidone pretreatment significantly inhibited the leakage of AST and ALT in HepG2 cells without appreciable cytotoxic effects. We also found that lucidone pretreatment significantly decreased ethanol-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), reactive oxygen species (ROS) and glutathione (GSH) depletion in HepG2 cells. Furthermore, Western blot and quantitative-PCR analyses showed that ethanol-exposure apparently down-regulated endogenous anti-oxidant hemoxygenase-1 (HO-1) expression, whereas pretreatment with lucidone significantly up-regulates HO-1 expression followed by the transcriptional activation of NF-E2 related factor-2 (Nrf-2). Interestingly, the profound up-regulation of HO-1 and Nrf-2 were observed in only ethanol-challenged cells, which evidenced that lucidone-induced induction of HO-/Nrf-2 were specific with oxidative stress. Thus, we concluded that lucidone-mediated up-regulation of phase-II enzymes and HO-1 via Nrf-2 signaling pathway may provide a pivotal mechanism for its hepatoprotective action.
authors.affiliation: Department of Forestry, National Chung Hsing University, Kou Kung Road, Taichung 402, Taiwan.
authors.forename: K J
authors.initials: KJ
authors.lastname: Senthil Kumar
authors.forename: Jiunn-Wang
authors.initials: JW
authors.lastname: Liao
authors.forename: Jun-Hong
authors.initials: JH
authors.lastname: Xiao
authors.forename: M
authors.initials: M
authors.lastname: Gokila Vani
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wang
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D000431:Ethanol / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D003517:Cyclopentanes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020011:Protective Agents; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C529637:lucidone; D009569:Nitric Oxide; D000431:Ethanol; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase