Secoisolariciresinol and isotaxiresinol inhibit tumor necrosis factor-alpha-dependent hepatic apoptosis in mice.
The effects of secoisolariciresinol (1) and isotaxiresinol (2), two major lignans isolated from the wood of Taxus yunnanensis, on tumor necrosis factor-alpha (TNF-alpha)-dependent hepatic apoptosis induced by D-galactosamine (d-GalN)/lipopolysaccharide (LPS) were investigated in mice. Co-administration of d-GalN (700 mg/kg) and LPS (10 microg/kg) resulted in a typical hepatic apoptosis characterized by DNA fragmentation and the formation of apoptotic bodies. Serum glutamic pyruvic transaminase (sGPT) and glutamic oxaloacetic transaminase (sGOT) levels were also raised at 8 h after d-GalN/LPS intoxication due to a severe necrosis of hepatocytes. Pre-administration of 1 or 2 (50, 10 mg/kg, i.p.) 12 and 1 h before d-GalN/LPS significantly reduced DNA fragmentation and prevented chromatin condensation, apoptotic body formation and hepatitis. Pro-inflammatory cytokines such as TNF-alpha and interferon-gamma (IFN-gamma) secreted from LPS-activated macrophages are important mediators of hepatocyte apoptosis in this model. Pre-treatment with 1 or 2 significantly inhibited the elevation of serum TNF-alpha and IFN-gamma levels. In a separate experiment, both lignans had a significant dose-dependent protective effect on d-GalN/TNF-alpha-induced cell death in primary cultured mouse hepatocytes and TNF-alpha-mediated cell death in murine L929 fibrosarcoma cells. These results indicated that 1 and 2 prevent d-GalN/LPS-induced hepatic injury by inhibiting hepatocyte apoptosis through the blocking of TNF-alpha and IFN-gamma production by activated macrophages and direct inhibition of the apoptosis induced by TNF-alpha.
Banskota
Arjun H
AH
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630-Sugitani, Toyama 930-0194, Japan.
Nguyen
Nhan Trung
NT
Tezuka
Yasuhiro
Y
Le Tran
Quan
Q
Nobukawa
Takahiro
T
Kurashige
Youichi
Y
Sasahara
Masakiyo
M
Kadota
Shigetoshi
S
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D002072:Butylene Glycols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005688:Galactosamine / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000097:blood; D017705:Lignans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010946:Plants, Medicinal; D020946:Taxus; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
D002072:Butylene Glycols; D005663:Furans; D017705:Lignans; D008070:Lipopolysaccharides; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha; C483062:taxiresinol; D005688:Galactosamine; D007371:Interferon-gamma; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C060283:secoisolariciresinol