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-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.