title: TP-58, a novel thienopyridine derivative, protects mice from concanavalinA-induced hepatitis by suppressing inflammation.
abstract: Hepatitis represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. In this study, we investigated the effect and mechanism of TP-58, a novel thienopyridine derivative, on a murine fulminant hepatitis model induced by concanavalin A (ConA). We found TP-58 markedly alleviated ConA-caused liver injury and increased survival ratio of mice injected with a lethal dose of ConA. Oral administration of TP-58 significantly alleviated ConA-caused liver injury in mice by the reduction of serum aminotransferases and liver necrosis.The analysis of proinflammatory cytokines showed that TP-58 decreased both hepatic mRNA expressions and serum protein levels of TNF-α and IL-6. And the result from LPS-stimulated RAW 264.7 cells showed TP-58 suppressed the production of TNF-α, IL-6, and Nitro Oxide (NO) in the supernatant of LPS-stimulated RAW 264.7 cells. The study of activation of nuclear factor-κB (NF-κB) by electrophoretic mobility shift assay (EMSA) showed that TP-58 inhibited the activation of NF-κB both in vivo and in vitro. The inhibitory effect was also accompanied by a parallel reduction of IκB phosphorylation. These results indicate that TP-58 protects against liver injury by inhibition of the NF-κB-mediated inflammation and suggest a potential role of TP-58 against acute liver injury and other inflammatory diseases.
authors.affiliation: Laboratory of Ethnopharmacology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Zhen-ling
authors.initials: ZL
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.forename: Qing-yi
authors.initials: QY
authors.lastname: Tong
authors.forename: Yu-quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Yong
authors.initials: Y
authors.lastname: Qing
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D003208:Concanavalin A; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt