title: Protective effect of SKLB010 against D-galactosamine/lipopolysaccharide-induced acute liver failure via nuclear factor-κB signaling pathway in macrophages.
abstract: Acute liver failure is characterized by the sudden loss of hepatic function and a high mortality. SKLB010, a derivative of thiazolidinediones, has been proved to be effective in protecting mice from acute liver failure caused by concanavalin A and carbon tetrachloride in our previous work. The purpose of the current study was to evaluate whether SKLB010 could prevent acute liver injury caused by d-galactosamine/lipopolysaccharide (LPS) in mice, and to investigate the underlying mechanisms. In the macrophage-mediated D-GalN/LPS model of acute liver injury, serum enzyme activity was suppressed and liver injury was attenuated by SKLB010. The serum levels of TNF-α and hepatic TNF-α mRNA expression were also markedly decreased after the treatment of SKLB010. In the liver of mice receiving injections of D-GalN/LPS, hepatocytes apoptosis and the infiltration of monocytes/macrophages were blocked by SKLB010. Furthermore, the survival rate of mice following D-GalN/LPS treatment was significantly improved by a single injection with SKLB010. In vivo, the luminescence intensity was suppressed by SKLB010 in NF-κB-luc mice after D-GalN/LPS treatment. In vitro, the production of tumor necrosis factor (TNF)-α and nitrite/nitrate in LPS-stimulated RAW264.7 macrophages was decreased by SKLB010 in a dose-dependent manner. Our further studies demonstrated that SKLB010 inhibited the phosphorylation of IκBα and p38MAPK, and the DNA binding activity of NF-κB in RAW264.7 cells. In conclusion, treatment with only a single injection of SKLB010 could significantly attenuate acute inflammation in mice induced by D-GalN/LPS, and these effects are likely associated with the inhibition of NF-κB activity.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Caifeng
authors.initials: C
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Jingjing
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key laboratory of Trauma, Burns & Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Li
authors.affiliation: The First People's Hospital of Ji'an City, Jiangxi, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China. Electronic address: lijuanchen125@163.com.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005688:Galactosamine / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C546799:5-(4-methoxybenzylidene)thiazolidine-2,4-dione; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020011:Protective Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Acute liver failure; LPS; Macrophage; NF-κB; SKLB010