title: A novel small molecule, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-bibenzo[d][1,3]dioxole-5,5'-dicarboxylate (7k), alleviates the development of D-galactosamine/lipopolysaccharide-induced acute liver failure by inhibiting macrophage infiltration and regulating cytokine expression.
abstract: Acute liver failure (ALF) is a relatively rare liver disorder that leads to the massive death of hepatocytes. Our previous study reported that a novel small-molecule agent, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-bibenzo[d][1,3]dioxole-5,5'-dicarboxylate (7k), possessed potent anti-inflammatory activity. In the present study, we further evaluated the therapeutic effects of 7k on lipopolysaccharide (LPS)-induced ALF and investigated the mechanisms of action. Our results demonstrated that 7k inhibited the migration of RAW264.7 macrophages, blocked the activity of nuclear factor-κB protein, and dose-dependently down-regulated the production of interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 as well as their corresponding mRNAs in RAW264.7 cells. Oral administration of 7k at a dose of 50 mg/kg significantly suppressed the serum level of enzyme activity and prevented the damage of liver tissue in D-galactosamine/LPS-induced ALF. Treatment with 7k also remarkably blocked the increase in the number of CD11b(+)- and CD68(+)-positive cells in the liver, and in vivo nuclear factor-κB activity, known to regulate inflammatory responses in many cell types, was effectively inhibited. The serum concentrations and hepatic mRNA expression of proinflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 were markedly down-regulated in mice by the treatment of 7k. In summary, 7k alleviated the development and progression of D-galactosamine/LPS-induced ALF by inhibiting macrophage infiltration and regulating the expression of cytokines.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, 1 Keyuan Road 4, Chengdu, Sichuan 610041, China.
authors.forename: Chongyang
authors.initials: C
authors.lastname: Deng
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Guangcheng
authors.initials: G
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Caifeng
authors.initials: C
authors.lastname: Xie
authors.forename: Xuewei
authors.initials: X
authors.lastname: Wang
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Li
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D002460:Cell Line; D002464:Cell Migration Inhibition / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005688:Galactosamine / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004149:Dioxoles; D008070:Lipopolysaccharides; D053778:Thiazolidines; D005688:Galactosamine