TY - JOUR T1 - A Novel Small Molecule, (<em>E</em>)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5′-methyl-7,7′-dimethoxy-4,4′-bibenzo[<em>d</em>][1,3]dioxole-5,5′-dicarboxylate (<strong>7k</strong>), Alleviates the Development of <span class="sc">d</span>-Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure by Inhibiting Macrophage Infiltration and Regulating Cytokine Expression JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 146 LP - 155 DO - 10.1124/jpet.111.189498 VL - 341 IS - 1 AU - Chongyang Deng AU - Juan Liu AU - Guangcheng Wang AU - Liang Ma AU - Caifeng Xie AU - Xuewei Wang AU - Xiuxia Li AU - Lijuan Chen Y1 - 2012/04/01 UR - http://jpet.aspetjournals.org/content/341/1/146.abstract N2 - 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. ER -