melitten and Chemical-and-Drug-Induced-Liver-Injury

The present study investigated the ameliorative effect of melittin, a major polypeptide in the venom of honeybee (Apis mellifera), on isoniazid-(INH) and rifampicin-(RIF) induced hepatotoxicity in male albino rats.. Thirty rats (140-200 g) were divided into five groups (n = 6): normal control (NC) received normal saline orally (NaCl, 0.9%; toxic (T) group received INH + RIF (each rat received 100 mg/kg, p.o.); melittin (Mel15, Mel30) groups (each rat received 15 or 30 μg/kg s.c); and normal recovery (NR) group received INH + RIF (each rat received 100 mg/kg, p.o.). Blood and liver samples were collected for biochemical, hematological and histopathological studies respectively.. The administration of melittin was found to prevent the antitubercular drug-induced alterations in the diagnostic markers; reduced glutathione (GSH), direct bilirubin (DB), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total serum protein (TSP). Besides, hematological alterations were significantly high in Mel groups when compared to the toxic group. The NR group exhibited lower levels of DB, TB, ALP, LDH and TSP. In addition, treatment with melittin offered protection in the NR group with respect to MDA levels.. Evidence from this study suggests that melittin is beneficial for the prevention of acute hepatic failure in antitubercular drug-induced hepatoxicity and could be used as a potential therapeutic agent.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Blood Proteins; Chemical and Drug Induced Liver Injury; Glutathione; Isoniazid; Liver; Male; Malondialdehyde; Melitten; Protective Agents; Rats; Rifampin

Transforming growth factor (TGF)-β1 plays a crucial role in the epithelial-to-mesenchymal transition (EMT) in hepatocytes and hepatic stellate cells (HSC), which contributes to the pathogenesis of liver fibrosis. Melittin (MEL) is a major component of bee venom and is effective in rheumatoid arthritis, pain relief, cancer cell proliferation, fibrosis and immune modulating activity. In this study, we found that MEL inhibits hepatic EMT in vitro and in vivo, regulating the TGFβ/Smad and TGFβ/nonSmad signaling pathways. MEL significantly inhibited TGF-β1-induced expression of EMT markers (E-cadherin reduction and vimentin induction) in vitro. These results were confirmed in CCl₄-induced liver in vivo. Treatment with MEL almost completely blocked the phosphorylation of Smad2/3, translocation of Smad4 and phosphorylation of JNK in vitro and in vivo. Taken together, these results suggest that MEL suppresses EMT by inhibiting the TGFβ/Smad and TGFβ/nonSmad-c-Jun N-terminal kinase (JNK)/Mitogen-activated protein kinase (MAPK) signaling pathways. These results indicated that MEL possesses potent anti-fibrotic and anti-EMT properties, which may be responsible for its effects on liver diseases.

Topics: Animals; Carbon Tetrachloride; Cell Line; Chemical and Drug Induced Liver Injury; Epithelial-Mesenchymal Transition; Hepatic Stellate Cells; Hepatocytes; JNK Mitogen-Activated Protein Kinases; Liver Cirrhosis; Male; Melitten; Mice, Inbred C57BL; Rats; Smad Proteins; Transforming Growth Factor beta1

Melittin is a cationic, hemolytic peptide that is the main toxic component in the venom of the honey bee (Apis mellifera). Melittin has multiple effects, including anti-bacterial, anti-viral and anti-inflammatory, in various cell types. However, the anti-apoptotic mechanisms of melittin have not been fully elucidated in hepatocytes. Apoptosis contributes to liver inflammation and fibrosis. Knowledge of the apoptotic mechanisms is important to develop new and effective therapies for treatment of cirrhosis, portal hypertension, liver cancer, and other liver diseases. In the present study, we investigated the anti-apoptotic effect of melittin on transforming growth factor (TGF)-β1-induced apoptosis in hepatocytes. TGF-β1-treated hepatocytes were exposed to low doses (0.5 and 1 μg/mL) and high dose (2 μg/mL) of melittin. The low doses significantly protected these cells from DNA damage in TGF-β1-induced apoptosis compared to the high dose. Also, melittin suppressed TGF-β1-induced apoptotic activation of the Bcl-2 family and caspase family of proteins, which resulted in the inhibition of poly-ADP-ribose polymerase (PARP) cleavage. These results demonstrate that TGF-β1 induces hepatocyte apoptosis and that an optimal dose of melittin exerts anti-apoptotic effects against TGF-β1-induced injury to hepatocytes via the mitochondrial pathway. These results suggest that an optimal dose of melittin can serve to protect cells against TGF-β1-mediated injury.

Topics: Animals; Apoptosis; Caspases; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Cytochromes c; Flow Cytometry; Hepatocytes; Immunoblotting; Melitten; Membrane Potential, Mitochondrial; Mice; Mitochondria, Liver; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Transforming Growth Factor beta1