Protective mechanisms of acacetin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice.
This study examined the hepatoprotective effects of acacetin (1), a flavonoid isolated from Agastache rugosa, against d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were given an intraperitoneal injection of 1 (25, 50, and 100 mg/kg), or the vehicle alone (5% dimethyl sulfoxide-saline), 1 h before GalN (800 mg/kg)/LPS (40 μg/kg) treatment and sacrificed at 6 h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, and these increases were attenuated by 1. GalN/LPS increased serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, while 1 attenuated TNF-α levels and further increased IL-6 levels. GalN/LPS increased protein expression of toll-like receptor 4, phosphorylation of extracellular signal-related kinase, and p38 and c-Jun N-terminal kinase and increased nuclear protein expression of nuclear factor κB; these increases were attenuated by 1. GalN/LPS increased Atg5 and Atg7 protein expressions, and these increases were augmented by 1. GalN/LPS activated autophagic flux as indicated by decreased microtubule-associated protein 1 light chain 3-II and sequestosome1/p62 protein expression. This activation was enhanced by 1. These findings suggest that 1 protects against GalN/LPS-induced liver injury by suppressing TLR4 signaling and enhancing autophagic flux.
School of Pharmacy, Sungkyunkwan University , Suwon 440-746, Republic of Korea.
Hong-Ik
HI
Cho
Jin-Hyun
JH
Park
Hyo-Sun
HS
Choi
Jong Hwan
JH
Kwak
Dong-Ung
DU
Lee
Sang Kook
SK
Lee
Sun-Mee
SM
Lee
D000818:Animals; D047309:Flavones / Q000494:pharmacology*; D005688:Galactosamine / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D017114:Liver Failure, Acute / Q000139:chemically induced*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D035261:Plant Components, Aerial / Q000737:chemistry; D056910:Republic of Korea; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000187:drug effects
D047309:Flavones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D048031:JNK Mitogen-Activated Protein Kinases; C023717:acacetin