Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K/AKT and ERK1/2 pathway.

Geraniin, an active compound with remarkable antioxidant activity, was isolated from Geranium sibiricum. The present study aimed to investigate whether geraniin has the ability to activate Nrf2, induce antioxidant enzyme expression and protect cells from oxidative damage. The cells were pretreated with geraniin for 24h and exposed to hydrogen peroxide (H₂O₂) for 4h. Intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential and apoptosis were measured. We also investigated intracellular glutathione (GSH) levels and changes in nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling cascade in cells treated with geraniin. We investigated the protective effects of geraniin against H₂O₂-induced apoptosis in HepG2 cells. Geraniin significantly reduced H₂O₂-induced oxidative damage in a dose dependent manner. Further, geraniin induced the expression of heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1) and level of glutathione (GSH) in a concentration- and time-dependent manner, and increased Nrf2 nuclear translocation. The Nrf2-related cytoprotective effects of geraniin were PI3K/AKT and extracellular signal-regulated protein kinase1/2 (ERK1/2) pathway-dependent. However, inhibitors of PI3K/AKT and ERK1/2 (LY294002 or U0126) not only suppressed geraniin-induced nuclear translocation of Nrf2 but also abolished the expression of HO-1, NQO1 and GSH. These results demonstrated that geraniin induced Nrf2-mediated expression of antioxidant enzymes HO-1 and NQO1, presumably via PI3K/AKT and ERK1/2 signaling pathways, thereby protecting cells from H₂O₂-induced oxidative cell death. Geraniin, at least in part, offers an antioxidant defense capacity to protect cells from the oxidative stress-related diseases.

Wang P ，Peng X ，Wei ZF ，Wei FY ，Wang W ，Ma WD ，Yao LP ，Fu YJ ，Zu YG ... -  《-》

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts.

Kang JS ，Choi IW ，Han MH ，Kim GY ，Hong SH ，Park C ，Hwang HJ ，Kim CM ，Kim BW ，Choi YH ... -  《-》

Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K/Akt.

The aim of the present study was to examine the cytoprotective effect of eckol, a phlorotannin found in Ecklonia cava and to elucidate underlying mechanisms. Heme oxygenase-1 (HO-1) is an important antioxidant enzyme that plays a role in cytoprotection against oxidative stress. Eckol-induced HO-1 expression both at the level of mRNA and protein in Chinese hamster lung fibroblast (V79-4) cells, resulting in increased HO-1 activity. The transcription factor NF-E2-related factor 2 (Nrf2) is a critical regulator of HO-1, achieved by binding to the antioxidant response element (ARE). Eckol treatment resulted in the enhanced level of phosphorylated form, nuclear translocation, ARE-binding, and transcriptional activity of Nrf2. Extracellular regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) contributed to ARE-driven HO-1 expression. Eckol activated both Erk and Akt, and treatments with U0126 (an Erk kinase inhibitor), LY294002 (a PI3K inhibitor), specific Erk1 siRNA, and Akt siRNA suppressed the eckol-induced activation of Nrf2, resulting in a decrease in HO-1 expression. ZnPP (a HO-1 inhibitor), HO-1 siRNA, and Nrf2 siRNA markedly abolished the cytoprotective effect of eckol against hydrogen peroxide-induced cell damage. Likewise, U0126 and LY294002 inhibited the eckol-induced cytoprotective effect against oxidative cell damage. These studies demonstrate that eckol attenuates oxidative stress by activating Nrf2-mediated HO-1 induction via Erk and PI3K/Akt signaling.

Kim KC ，Kang KA ，Zhang R ，Piao MJ ，Kim GY ，Kang MY ，Lee SJ ，Lee NH ，Surh YJ ，Hyun JW ... -  《-》

Punicalagin induces Nrf2 translocation and HO-1 expression via PI3K/Akt, protecting rat intestinal epithelial cells from oxidative stress.

Xu L ，He S ，Yin P ，Li D ，Mei C ，Yu X ，Shi Y ，Jiang L ，Liu F ... -  《-》

7,8-Dihydroxyflavone protects human keratinocytes against oxidative stress-induced cell damage via the ERK and PI3K/Akt-mediated Nrf2/HO-1 signaling pathways.

Ryu MJ ，Kang KA ，Piao MJ ，Kim KC ，Zheng J ，Yao CW ，Cha JW ，Chung HS ，Kim SC ，Jung E ，Park D ，Chae S ，Hyun JW ... -  《-》