期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 52, 期 6, 页码 1054-1066出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.12.012
关键词
4-Ketopinoresinol; ARE activator; Nrf2; HO-1; PI3K/AKT; Free radicals
资金
- National Health Research Institutes [CA-100-PP-05]
- National Science Council [NSC98-2320-B-400-003-MY3]
- Department of Health, Taiwan, Republic of China [DOH99-TD-C-111-004]
The Nrf2/ARE pathway plays an important role in inducing phase 11 detoxifying enzymes and antioxidant proteins and has been considered a potential target for cancer chemoprevention because it eliminates harmful reactive oxygen species or reactive intermediates generated from carcinogens. The objectives of this Study were to identify novel Nrf2/ARE activators and to investigate the mechanistic signaling pathway involved in the activation of Nrf2-mediated cytoprotective effects against oxidative-induced cell injury. A stable ARE-driven luciferase reporter cell line was established to screen a potentially cytoprotective compound. 4-Ketopinoresinol (4-KPR), the (alpha-gamma) double-cyclized type of lignan obtained from adlay (Coix lachryma-jobi L. var. ma-yuen Stapf), activates ARE-driven luciferase activity more effectively than the classical ARE activator tert-butylhydroquinone. 4-KPR treatment resulted in a transient increase in AKT phosphorylation and subsequent phosphorylation and nuclear translocation of Nrf2, along with increased expression of ARE-dependent cytoprotective genes, such as heme oxygenase-1 (HO-1), aldo-keto reductases, and glutathione synthetic enzyme. 4-KPR suppresses oxidative stress-induced DNA damage and cell death via upregulation of HO-1. Inhibition of PI3K/AKT signaling by chemical inhibitors or RNA interference not only suppressed 4-KPR-induced Nrf2/HO-1 activation, but also eliminated the cytoprotective effect against oxidative damage. These observations in an ARE-regulated gene system suggest that 4-KPR is a novel Nrf2/ARE-mediated transcription activator, activates the Nrf2/HO-1 axis, and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling. (C) 2011 Elsevier Inc. All rights reserved.
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