Discovery of natural flavonoids as activators of Nrf2-mediated defense system: Structure-activity relationship and inhibition of intracellular oxidative insults. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Li, Yan-Ru; Li, Guo-Hui; Zhou, Ming-Xing; Xiang, Lan; Ren, Dong-Mei; Lou, Hong-Xiang; Wang, Xiao-Ning; Shen, Tao
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 18(2018)
• Page Start: 5140
• Page End: 5150
• Publication Date: 2018-10-01
• Subjects: Isoflavone -- 7-O-methylbiochanin A -- Oxidative stress -- Nrf2 activator; ARE antioxidant response element -- COPD chronic obstructive pulmonary disease -- γ-GCS γ-glutamyl cysteine synthetase -- GSH glutathione -- HO-1 heme oxygenase-1 -- Keap1 Kelch-like ECH-associated protein 1 -- MAPK mitogen-activated protein kinase -- 7-MBA 7-O-methylbiochanin A -- MQI maximum folds of QR inducing activity -- NQO1 NAD(P)H: quinone oxidoreductase 1 -- Nrf2 nuclear factor erythroid 2-related factor 2 -- PERK protein kinase R-like endoplasmic reticulum kinase -- PKC protein kinase C -- PI3K phosphatidylinositol-4, 5-bisphosphate 3-kinase -- QR NAD(P)H: quinone reductase -- ROS reactive oxygen species -- R.T. room temperature -- SF sulforaphane -- tBHQ tert-butylhydroquinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.09.010
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Continuous overproduction of reactive oxygen species (ROS), termed as oxidative stress, plays a crucial role in the onset and progression of many human diseases. Activation of nuclear transcription factor erythroid 2-related factor (Nrf2) by small molecules could eliminate ROS, and thus block the pathogenesis of oxidative stress-induced diseases. In this study, a natural flavonoid library was established and tested for their potential Nrf2 inducing effects. Based on QR inducing effect of flavonoids, their structure-activity relationship (SAR) on Nrf2 induction was summarized, and twenty flavonoids were firstly identified to be potential activators of Nrf2-mediated defensive response. Then, 7- O -methylbiochanin A (7-MBA) was further investigated for its capability on the Nrf2 activation and prevention against oxidative insults in human lung epithelial cells. Further studies indicated that 7-MBA activated Nrf2 signaling pathway and protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Activation of Nrf2 by 7-MBA upregulated intracellular antioxidant capacity, which was produced by enhancement of Nrf2 stabilization, blockage of Nrf2 ubiquitination, as well as Nrf2 phosphorylation by mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase R-like endoplasmic reticulum kinase (PERK), and phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K). Taken together, 7-MBA is a novel isoflavone-type Nrf2 activator displaying potential preventive effect against oxidative damages in human lung epithelial cells.