A novel small molecule, LAS-0811, inhibits alcohol-induced apoptosis in VL-17A cells.
One of the pathways by which alcohol induces hepatocyte apoptosis is via oxidative stress. We screened several chemically-synthesized small molecules and found LAS-0811, which inhibits oxidative stress. In this study, we elucidated its role in inhibiting alcohol-induced apoptosis in hepatocyte-like VL-17A cells. VL-17A cells were pre-incubated with LAS-0811, followed by ethanol incubation. Ethanol-induced reactive oxygen species and apoptosis were significantly inhibited in LAS-0811 pre-treated cells. VL-17A cells were transfected with a reporter (ARE/TK-GFP) plasmid containing green fluorescent protein (GFP) as a reporter gene and the anti-oxidant response element as the promoter. LAS-0811 pre-treatment significantly induced the GFP expression compared to the cells treated with ethanol alone. LAS-0811 induced the activation of nrf2 and enhanced the expression and activity of glutathione peroxidase, one of the downstream targets of nrf2. The results indicate that LAS-0811 protects VL-17A cells against ethanol-induced oxidative stress and apoptosis at least in part via nrf2 activation.
Kim
Tae-Hun
TH
Department of Internal Medicine, Transplant Research Program, University of California Davis Medical Center, 4635 2nd Ave. Research Building I, Room 1001, Sacramento, CA 95817, USA.
Venugopal
Senthil K
SK
Zhu
Ming
M
Wang
Si-Si
SS
Lau
Derick
D
Lam
Kit S
KS
Clemens
Dahn L
DL
Zern
Mark A
MA
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D019610:Cytoprotection; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017930:Genes, Reporter / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; D000431:Ethanol