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(2S)-5,6,7,3',4'-pentamethoxyflavanone, a citrus polymethoxyflavone ameliorates arsenic- and cigarette smoke extract- induced cytotoxicity via activating Nrf2-mediated defense system

Ming-Xing Zhou, Guo-Hui Li, Xue-Yi Wu, Lin Sun, Yan-Ru Li, Wen-Jing Yang, Dong-Mei Ren, Xiao-Ning Wang, Lan Xiang, Hong-Xiang Lou, Tao Shen
Journal of functional foods 2019 pp. -
Citrus, arsenic, cytotoxicity, enzyme inhibitors, epithelial cells, genes, human diseases, lungs, mitogen-activated protein kinase, oxidative stress, pathogenesis, phosphatidylinositol 3-kinase, polymethoxyflavones, protein kinase C, sodium, toxic substances, ubiquitination
Exogenous toxicants (e.g. arsenic, cigarette smoke), trigger oxidative stress, and initiate the pathogenesis of many human diseases. Induction of nuclear factor E2-related factor 2 (Nrf2) counteract exogenous toxicant-induced oxidative insults. Using a high-throughput screen, we firstly identified a citrus polymethoxyflavone, (2S)-5,6,7,3',4'-pentamethoxyflavanone (PMF), to be an Nrf2 activator, and an investigation targeting Nrf2 pathway was performed. Our study indicated that: (i) PMF activated Nrf2 and its downstream genes, NQO1 and γ-GCS, and enhanced the stabilization of Nrf2 through inhibiting Nrf2 ubiquitination. (ii) Inhibition of PI3K, p38 MAPK, PKC and PERK by specific kinase inhibitors suppressed PMF-induced activation of Nrf2. (iii) PMF conferred Nrf2-dependent protection against sodium arsenite- and cigarette smoke extract- induced cytotoxicity in lung epithelial cells. Collectively, our data demonstrate that PMF is a novel Nrf2 activator with potential prevention against oxidative insults. The diverse pharmacological functions of citrus polymethoxyflavone might be related to their ability of activating Nrf2 pathway.