title: The role of autophagy in usnic acid-induced toxicity in hepatic cells.
abstract: The use of usnic acid and usnic acid-containing products is associated with acute liver failure; however, mechanistic studies of hepatotoxicity caused by usnic acid are limited. In this study, we investigated and characterized the possible mechanisms, especially the role of autophagy in usnic acid's toxicity in human HepG2 cells. Usnic acid caused apoptosis as demonstrated by an increased caspase-3/7 activity and an increased subdiploid nucleus formation. Usnic acid-induced autophagy as demonstrated by the conversion of LC3B-I to LC3B-II, degradation of P62, and an increased number of puncta. Inhibition of autophagy by treating cells with autophagy inhibitors (3-methyladenine or chloroquine) or by small interfering RNA against Atg7 aggravated usnic acid-induced apoptosis and decreased cell viability, indicating that autophagy plays a protective role against usnic acid-induced toxicity. Moreover, usnic acid activated the MAPK signaling pathway. Usnic acid-elicited apoptosis was enhanced and autophagy was decreased when JNK was suppressed by a specific inhibitor. Additionally, inhibition of autophagy decreased the activity of JNK. Taken together, our results suggest that usnic acid perturbs various interrelated signaling pathways and that autophagy induction is a defensive mechanism against usnic acid-induced cytotoxicity.
authors: Division of Biochemical Toxicology.
authors: Si
authors: S
authors: Chen
authors: Division of Genetic and Molecular Toxicology.
authors: Vasily N
authors: VN
authors: Dobrovolsky
authors: Division of Neurotoxicology, National Center for Toxicological Research/U.S. FDA, Jefferson, Arkansas 72079.
authors: Fang
authors: F
authors: Liu
authors: Division of Biochemical Toxicology.
authors: Yuanfeng
authors: Y
authors: Wu
authors: Division of Genetic and Molecular Toxicology.
authors: Zhuhong
authors: Z
authors: Zhang
authors: Division of Genetic and Molecular Toxicology.
authors: Nan
authors: N
authors: Mei
authors: Division of Biochemical Toxicology lei.guo@fda.hhs.gov.
authors: Lei
authors: L
authors: Guo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001572:Benzofurans / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects
chemical_list: D001572:Benzofurans; C073339:usnic acid; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053179:Caspase 7
keywords: MAPK pathway; apoptosis; autophagy; liver toxicity; usnic acid