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

[摘要]：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-kappa B protein, and dose-dependently down-regulated the production of interleukin (IL)-1 beta, tumor necrosis factor-alpha, 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-kappa B 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-alpha, IL-1 beta, and IL-6 were markedly downregulated 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.

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