title: Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice.
abstract: Diammonium glycyrrhizinate (DG), an active compound extracted and purified from liquorices root, has been reported to exhibit antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect and underlying mechanisms of DG on the hepatotoxicity induced by valproic acid (VPA). DG at the dose of 60mg/kg was orally administered with VPA (100mg/kg) to mice once daily for 14 consecutive days. DG treatment attenuated VPA-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. DG prevented VPA-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. The effects of VPA and DG on Nrf2 expression in HepG2 cells were in consistent with that of mice. Furthermore, an increase in the nuclear levels of nuclear factor-kappaB (NF-κB) was observed in the livers of VPA-treated mice that coincided with induction of inflammatory cytokines. In contrast, DG inhibited NF-κB translocation and that subsequently decreased inflammatory cytokines. Taken together, these results demonstrate that DG attenuates VPA-induced liver injury through increasing the expression of Nrf2 mediated phase II/antioxidant enzymes and simultaneously decreasing the expression of inflammatory mediators.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: jinjing@mail.sysu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
authors.forename: Tianqin
authors.initials: T
authors.lastname: Xiong
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xiaozhe
authors.initials: X
authors.lastname: Sun
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Liao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China. Electronic address: zzx37@163.com.
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001483:Base Sequence; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D014635:Valproic Acid; D019695:Glycyrrhizic Acid
keywords: Cytokines; Diammonium glycyrrhizinate; Hepatotoxicity; NF-κB; Nrf2; Valproic acid