title: Troxerutin protects against 2,2',4,4'-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD⁺-depletion.
abstract: Emerging evidence indicates that 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD(+)-depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD(+)-depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-κB p65 and the acetylation of NF-κB p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced hepatotoxicity.
authors.affiliation: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province, PR China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
authors.forename: Zi-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.affiliation: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province, PR China.
authors.forename: Yan-Qiu
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Fan
authors.affiliation: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: ylzheng@jsnu.edu.cn.
authors.forename: Yuan-Lin
authors.initials: YL
authors.lastname: Zheng
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wu
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Shan
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D015386:Hazardous Substances / Q000633:toxicity*; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000975:Antioxidants; D055768:Halogenated Diphenyl Ethers; D015386:Hazardous Substances; D006896:Hydroxyethylrutoside; D016328:NF-kappa B; C511295:2,2',4,4'-tetrabromodiphenyl ether; C005865:troxerutin
keywords: Inflammation; NAD(+); Oxidative stress; Polybrominated diphenyl ethers; Troxerutin