Caffeoylserotonin protects human keratinocyte HaCaT cells against H2 O2 -induced oxidative stress and apoptosis through upregulation of HO-1 expression via activation of the PI3K/Akt/Nrf2 pathway.

Caffeoylserotonin (CaS) has strong radical scavenging activity as well as antioxidant activities, protecting cells from lipid peroxidation, intracellular reactive oxygen species generation, DNA damage, and cell death. The molecular mechanism by which CaS protects against oxidative stress is not well understood. Here, we analyzed the cytoprotective activity of CaS in hydrogen peroxide (H2 O2 )-treated keratinocyte HaCaT cells. H2 O2 induced apoptosis in the cells through activation of pro-apoptotic p21, Bax, and caspase-3. Pretreatment with CaS inhibited apoptotic gene expression and activated the anti-apoptotic gene, Bcl-xL. Although CaS did not directly affect heme oxygenase-1 (HO-1) expression, pretreatment with CaS augmented HO-1 expression through an increase in NF-E2-related factor (Nrf2) stability and stimulation of Nrf2 translocation to the nucleus upon H2 O2 exposure. H2 O2 also induced the phosphorylation and subsequent activation of ERK, p38 MAPK, and Akt. Analysis using specific inhibitors of p38 MAPK and Akt demonstrated that only Akt activation was involved in HO-1 and Nrf2 expressions. In addition, PI3K and PKC inhibitors suppressed HO-1/Nrf2 expression and Akt phosphorylation. These results demonstrate that CaS protects against oxidative stress-induced keratinocyte cell death in part through the activation of Nrf2-mediated HO-1 induction via the PI3K/Akt and/or PKC pathways, but not MAPK signaling.

Nguyen CN ，Kim HE ，Lee SG 《-》

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 ... -  《-》

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 ... -  《-》

Rhein from Rheum rhabarbarum Inhibits Hydrogen-Peroxide-Induced Oxidative Stress in Intestinal Epithelial Cells Partly through PI3K/Akt-Mediated Nrf2/HO-1 Pathways.

Zhuang S ，Yu R ，Zhong J ，Liu P ，Liu Z ... -  《-》