title: Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity.
abstract: Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100 mg/kg) 24 h after administration of 4 mg/kg mercuric chloride (HgCl2). The results showed that luteolin ameliorated HgCl2induced anemia and hepatotoxicity, regulating radical oxygen species (ROS) production and hepatocyte viability in vitro and oxidative stress and apoptosis in vivo. Furthermore, luteolin reversed the changes in levels of inflammation- and apoptosis-related proteins involving NF-κB, TNF-α, Sirt1, mTOR, Bax, p53, and Bcl-2, and inhibited p38 MAPK activation. Luteolin enhanced antioxidant defense system based on Keap1, Nrf2, HO-1, NQO1, and KLF9. Moreover, luteolin did not affect miRNA-146a expression. Collectively, our findings, for the first time, elucidate a precise mechanism for attenuation of HgCl2-induced liver dysfunction by dietary luteolin via regulating Sirt1/Nrf2/TNF-α signaling pathway, and provide a foundation for further study of luteolin as a novel therapeutic agent against inorganic mercury poisoning.
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Daqian
authors.initials: D
authors.lastname: Yang
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tan
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Lv
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Biying
authors.initials: B
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Ruiqi
authors.initials: R
authors.lastname: Baiyun
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Lu
authors.affiliation: College of Veterinary Medicine, Northeast Agricultural University, 59 Mucai Street, Harbin, 150030, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D047311:Luteolin / Q000494:pharmacology; D008297:Male; D008627:Mercuric Chloride / Q000633:toxicity*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008627:Mercuric Chloride; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D047311:Luteolin