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beta-Lapachone increases phase II antioxidant enzyme expression via NQO1-AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes

Title
beta-Lapachone increases phase II antioxidant enzyme expression via NQO1-AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes
Authors
Park, Jin-SunLee, Yu-YoungKim, JisunSeo, HyemyungKim, Hee-Sun
Ewha Authors
김희선박진선
SCOPUS Author ID
김희선scopus; 박진선scopus
Issue Date
2016
Journal Title
FREE RADICAL BIOLOGY AND MEDICINE
ISSN
0891-5849JCR Link1873-4596JCR Link
Citation
vol. 97, pp. 168 - 178
Keywords
beta-LapachoneAstrocytePhase II antioxidant enzymeNQO1AMPKNrf2/ARE signaling
Publisher
ELSEVIER SCIENCE INC
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
beta-Lapachone (beta-LAP) is a naturally occurring quinine that exerts a number of pharmacological actions including antibacterial, antifungal, antimalarial, and antitumor activities. In the present study, we investigated whether beta-LAP has an antioxidant effect in rat primary astrocytes. beta-LAP suppressed intracellular reactive oxygen species (ROS) production induced by hydrogen peroxide and inhibited astroglial cell death. It also increased astrocytic expression of phase II antioxidant enzymes such as heme oxygenase-1 (H0-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), manganese superoxide dismutase (MnSOD), and catalase. Further mechanistic studies revealed that beta-LAP activated AMPK and Akt, and pretreatment of cells with an AMPK inhibitor (compound C) or PI3K/Akt inhibitor (LY294002) suppressed beta-LAP-induced antioxidant enzyme expression by inhibiting Nrf2/antioxidant response element (ARE) signaling. Compound C also decreased Akt phosphorylation, suggesting that AMPK is upstream of PI3K/ Akt. Furthermore, the AMPK activator 5-aminoimidazole-4-carboxamide 1-beta-D ribo furanoside mimicked the effect of beta-LAP by increasing Akt phosphorylation and ARE-mediated transcription, suggesting that AMPK plays a pivotal role in beta-LAP-mediated antioxidant enzyme expression. Because beta-LAP effects are usually associated with NQ01 activity, we examined the effect of NQ01 knockdown on antioxidant enzyme expression. Small interfering RNA (siRNA) specific for NQ01 inhibited beta-LAP-induced AMPK/Akt phosphorylation and downstream antioxidant enzyme expression. Collectively, the results suggest that beta-LAP increases antioxidant enzyme gene expression in astrocytes by modulating NQ01-AMPK/PI3KNrf2/ARE signaling. (C) 2016 Elsevier Inc. All rights reserved.
DOI
10.1016/j.freeradbiomed.2016.05.024
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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