as-605240 and Chemical-and-Drug-Induced-Liver-Injury

To evaluate the participation of the phosphatidylinositol 3-kinase pathway in the liver damage caused by nimesulide.. Liver damage been induced by nimesulide. Mice were treated with either 2% dimethyl sulfoxide or AS605240, a phosphatidylinositol 3-kinase gamma pathway antagonist. Blood samples were collected for function assays of liver. The liver was removed for analysis of liver weight/animal weight ratio, histopathological parameters, oxidative and nitrous stress, cytokine levels, and the immunostaining for cyclooxygenase 2 and nuclear factor kappa B.. Liver injured by nimesulide and treated with phosphatidylinositol 3-kinase gamma inhibitor significantly reversed (P < 0.05) the damage; it decreased the liver weight/animal weight ratio, histopathological scores, and neutrophil infiltration, consequently reducing oxidative stress. In addition, we show that phosphatidylinositol 3-kinase gamma is associated with hepatic damage induced by nimesulide, because it altered liver function and increased the protein immunostaining of cyclooxygenase 2 and nuclear factor kappa B in the liver tissue of nimesulide-treated animals.. The findings from the present study allows us to infer that nimesulide causes liver damage through the phosphatidylinositol 3-kinase gamma pathway.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclooxygenase Inhibitors; Dimethyl Sulfoxide; Free Radical Scavengers; Mice; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Quinoxalines; Sulfonamides; Thiazolidinediones; Treatment Outcome

A large amount of evidence suggests that monocytes/macrophages infiltration is implicated in a variety of inflammatory diseases including acute liver injury. Monocyte chemoattractant protein 1 (MCP-1) plays a crucial role in the process of macrophages recruitment. We herein presented a small-molecule library and a feasible quick screening method of evaluating potency of inhibition of chemotaxis of RAW264.7 cells stimulated by MCP-1. Fifty-three small molecules were synthesized and screened, and four compounds (2g, 2h, 4f, and 6h) showed inhibitory effects with IC(50) values range from 0.72 to 20.47 microM, with compound 4f being the most efficient. Further in vivo studies demonstrated that oral administration of 2g, 2h, 4f, or 6h decreases, most significantly for 4f, the serum levels of alanine aminotransaminase (ALT) and asparate aminotransaminase (AST) in ConA-induced acute livery injury BALB/c mice. Histopathological evaluation liver sections confirmed 4f as a potent, orally active compound for hepatoprotective effects against ConA-induced acute liver injury in BALB/c mice.

Topics: Animals; Cell Movement; Cells, Cultured; Chemical and Drug Induced Liver Injury; Concanavalin A; Disease Models, Animal; Drug Discovery; Drug Evaluation, Preclinical; Female; Liver Failure, Acute; Liver Function Tests; Mice; Mice, Inbred BALB C; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship; Thiazolidinediones

A pivotal role of phosphoinositide 3-kinase-gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. In present study we investigated the therapeutic efficiency of AS605240, a selective PI3Kgamma inhibitor, on hepatitis and liver fibrosis in murine models induced by concanavalin A (ConA). Orally administration of AS605240 significantly improved survival, decreased the serum levels of alanine aminotransaminase (ALT), prevented inflammatory infiltration to liver in ConA-induced hepatitis. TNF-alpha and IFN-gamma at protein levels in serum and mRNA levels in liver were markedly reduced. Downregulated phospho-Akt level of inflammatory cells infiltrating the liver by AS605240 treatment was detected by immunohistochemistry analysis in liver and further confirmed by Western blotting analysis in splenocytes. In ConA-induced chronic liver fibrosis model, accumulation of smooth-muscle actin (SMA)-expressing cells was partially inhibited by AS605240 treatment. These observations suggest that AS605240 might be of therapeutic value for the treatment of ConA-induced hepatic injury.

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Class Ib Phosphatidylinositol 3-Kinase; Concanavalin A; Cytokines; Enzyme Inhibitors; Isoenzymes; Liver; Liver Cirrhosis; Mice; Mitogens; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Quinoxalines; Thiazolidinediones