The Cytoprotective Effect of Hyperoside against Oxidative Stress Is Mediated by the Nrf2-ARE Signaling Pathway through GSK-3β Inactivation

• DOI: 10.1371/journal.pone.0145183
• Publication Date: 2015-12-16T18:51:33Z
• Authors: Hai-Yan Xing; Yong-Qing Cai; Xian-Feng Wang; Lin-Li Wang; Pan Li; Guan-Ying Wang; Jian-Hong Chen
• Keywords: Hyperoside; Cytoprotection; KEAP1

Glycogen synthase kinase-3β (GSK-3β) acts as a negative regulator of NF-E2 related factor 2 (Nrf2) by inducing Nrf2 degradation and nuclear export. Our previous study demonstrated that the flavonoid hyperoside elicits cytoprotection against oxidative stress activating Keap1-Nrf2-ARE signaling pathway, thus increasing expression antioxidant enzymes, such heme oxygenase-1 (HO-1), superoxide dismutase (SOD) catalase. However, role GSK-3β in hyperoside-mediated activation is unclear. Here, we demonstrate normal human hepatocyte cell line, (L02), capable phosphorylation at Ser9 without affecting protein levels its Thr390. Lithium chloride (LiCl) short interfering RNA (siRNA)-mediated inhibition significantly enhanced ability to protect L02 liver cells from H2O2-induced damage, leading increased survival shown maintenance membrane integrity elevated glutathione (GSH), one endogenous biomarkers. Further showed LiCl siRNA-mediated hyperoside-induced HO-1 expression, effect was dependent upon translocation gene expression. These activities were followed ARE-mediated transcriptional presence hyperoside, which abolished transfection with siRNA. Furthermore, Keap1 also accumulation relatively smaller than effects obtained siRNA administration. Moreover, administration alone had no significant on GSK-3β. Collectively, our data provide evidence attenuates H2O2 -induced damage Nrf2-ARE pathway through both an increase inhibitory exhibits more effects.