phenanthrenes and Hepatitis

Triptolide is a predominant active component of Triptergium wilfordii Hook. F, which has been used for the treatment of cancers and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and diabetic nephropathy. Therefore, triptolide and its derivates are considered to have promising prospects for development into drugs. However, the clinical application of triptolide is limited due to various organ toxicities, especially liver toxicity. The potential mechanism of triptolide-induced hepatotoxicity has attracted increasing attention. Over the past five years, studies have revealed that triptolide-induced liver toxicity is involved in metabolic imbalance, oxidative stress, inflammations, autophagy, apoptosis, and the regulation of cytochrome P450 (CYP450) enzymes, gut microbiota and immune cells. In this review, we summarize the pharmacological applications and hepatotoxicity mechanism of triptolide, which will provide solid theoretical evidence for further research of triptolide.

Topics: Chemical and Drug Induced Liver Injury; Diterpenes; Drug-Related Side Effects and Adverse Reactions; Epoxy Compounds; Hepatitis; Humans; Phenanthrenes

Interleukin-33 (IL-33), a cytokine belonging to the IL-1 family, is crucially involved in inflammatory pathologies including liver injury and linked to various modes of cell death. However, a link between IL-33 and necroptosis or programmed necrosis in liver pathology remains elusive. We aimed to investigate the regulation of IL-33 during necroptosis-associated liver injury. The possible regulation of IL-33 during liver injury by receptor-interacting protein kinase 1 (RIPK1) and poly(ADP-ribose) polymerase 1 (PARP-1) was investigated in mice in vivo and in hepatic stellate cells in vitro. The liver immunohistopathology, flow cytometry, serum transaminase measurement, ELISA, and qPCR-based cytokine measurement were carried out. By using a chemical approach, we showed that pretreatment of mice with Necrostatin-1 (Nec-1) (inhibitor of RIPK1) and/or PJ34 (inhibitor of PARP-1) significantly protected mice against concanavalin A (ConA) liver injury (aspartate amino-transferase (AST)/alanine amino-transferase (ALT)) associated with down-regulated hepatocyte-specific IL-33 expression. In contrast, the expression level of most systemic cytokines (except for IL-6) or activation of liver immune cells was not altered by chemical inhibitors rather an increased infiltration of neutrophils in the liver. During polyinosine-polycytidylic acid (Poly(I:C))-induced acute hepatitis, liver injury and hepatocyte-specific IL-33 expression was also inhibited by PJ34 without any protective effect of PJ34 in CCl4-induced liver injury. Moreover, PJ34 down-regulated the protein expression of IL-33 in activated hepatic stellate cells by cocktail of cytokines or staurosporine in vitro. In conclusion, we evidenced that the Nec-1/PJ34 is a potent inhibitor of liver injury and Nec-1/PJ34 down-regulated hepatocyte-specific IL-33 expression in the liver in vivo or in hepatic stellate cells in vitro, suggesting IL-33 as a possible readout of necroptosis-involved liver pathologies.. Necroptosis inhibitors can protect mice against liver injury induced by ConA or Poly(I:C). IL-33 expression in liver injury in vivo is inhibited by PJ34. IL-33 expression in hepatic stellate cells in vitro is inhibited by PJ34. Hepatocyte-specific IL-33 expression is down-regulated by Nec-1/PJ34 during hepatitis. IL-33 is a new marker of necroptosis-associated liver injuries.

Topics: Animals; Cell Death; Cells, Cultured; Down-Regulation; Hepatitis; Hepatocytes; Humans; Imidazoles; Indoles; Interleukin-33; Liver; Mice, Inbred C57BL; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors