title: Protective effects of protostemonine on LPS/GalN-induced acute liver failure: Roles of increased hepatic expression of heme oxygenase-1.
abstract: Here, we explored protective effects of protostemonine (PSN), on mouse acute liver failure induced by lipopolysaccharide/d-galactosamine (LPS/GalN). PSN dose-dependently declined LPS/GalN-induced lethality of mice as well as increase of ALT/AST activities in their serum. Hepatoprotective effects of PSN were also supported by liver histopathological examinations. After LPS/GalN treatment, severe oxidative stresses in the liver could be detected by boosted MDA and ROS as well as decreased GSH. Moreover, hepatic expression of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, were sharply elevated. These symptoms were dose-dependently ameliorated by PSN. Mechanistically, PSN promoted the transcription and translation of heme oxygenase-1 (HO-1) in hepatocytes and liver Kupffer cells. Nrf2 is a master transcription factor contributing to the expression of HO-1. PSN elevated Nrf2 nuclear accumulation and enhanced Nrf2/HO-1 promoter interaction. Suppressing enzyme activity of HO-1 by co-treating mice with HO-1 inhibitor ZnPP abolished protective effects of PSN. ZnPP also abrogated alleviative impacts of PSN on LPS/GalN-mediated hepatic oxidative stresses and inflammatory responses. Finally, we showed that PSN exhibited undetectable toxic effects on vital organs of mice. Our findings suggested that PSN is able to attenuate LPS/GalN-induced acute liver failure and upregulating HO-1 expression is implicated in its hepatoprotective activity.
authors.affiliation: College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Endocrinology, Wuhan General Hospital of Guangzhou Military Command, Wuhan, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yue
authors.affiliation: College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhao
authors.affiliation: College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China.
authors.forename: Xinzhou
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China. Electronic address: shuguangwen@whu.edu.cn.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Shu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005688:Galactosamine; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007783:Lactones / Q000627:therapeutic use* / Q000633:toxicity; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D011759:Pyrrolidines / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D007783:Lactones; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011759:Pyrrolidines; C483261:stemonine; D005688:Galactosamine; D051547:Heme Oxygenase-1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Acute liver failure; Heme oxygenase-1; Lipopolysaccharide; Protostemonine; d-Galactosamine