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

Abstract

This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity of heme oxygenase-1 (HO-1), an enzyme with potent antioxidant properties, as well as the molecular mechanisms involved. DHF markedly upregulated HO-1 mRNA and protein expression in human keratinocytes (HaCaT cells), resulting in increased HO-1 activity. DHF also increased the protein level of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates HO-1 expression by binding to the antioxidant response element (ARE) within the HO-1 gene promoter, in a time-dependent manner. Moreover, DHF decreased the expression of Kelch-like ECH-associated protein 1, a repressor of Nrf2 activity, and induced the translocation of Nrf2 from the cytosol into the nucleus, thereby allowing its association with the ARE site. DHF activated extracellular-regulated kinase (ERK) and protein kinase B (PKB, Akt) in keratinocytes, while the ERK and Akt inhibitors attenuated DHF-enhanced Nrf2 and HO-1 expression. DHF also protected the keratinocytes against hydrogen peroxide- and ultraviolet B-induced oxidative damage, while HO-1, ERK and Akt inhibitors markedly suppressed DHF-mediated cytoprotection. Taken together, the results suggested that DHF activates ERK- and Akt-Nrf2 signaling cascades in HaCaT cells, leading to the upregulation of HO-1 and cytoprotection against oxidative stress.

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

“…It is well known that activation of PI3K/AKT signaling functions as a cytoprotective mechanism against oxidative stress (Mo et al 2012, Ryu et al 2014, Yang et al 2013. In this sense, our results demonstrated that, in addition to stimulating Hmox1 gene expression, treatment of Y1 cells with either ACTH or 8Br-cAMP also leads to an increase in Akt phosphorylation levels.…”

The protective effects of endogenous hydrogen sulfide modulator, S-propargyl-cysteine, on high glucose-induced apoptosis in cardiomyocytes: A novel mechanism mediated by the activation of Nrf2

“…Besides the oxidant stress, it was reported that Nrf2 could be activated by extracellular-regulated kinase (ERK 1/2) and protein kinase B (PKB, Akt) (Niture et al, 2014;Ryu et al, 2014). In a separate set of experiments, we further proved that SRPC could activate Akt pathways, but not Erk 1/2 pathway.…”

Edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia injury: heme oxygenase-1 and PI3K/Akt pathway may be involved

“…PI3K/Akt may stimulate Nrf2, a key transcriptional factor in the regulation the expression of phase-II detoxification and antioxidant response element (ARE) under oxidative stress, including HO-1. Ryu et al suggested that PI3K/Akt phosphorylate Nrf2 and facilitate its release from the Keap1-Nrf2 complex, allowing activated Nrf2 to translocate into the nucleus, then induces phase II defense enzymes, such as HO-1 [40]. Peroxynitrite, which contributes to the activation of Nrf2 and Nrf2 binding to ARE may also be involved [41].…”