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,Min Ju; Kang,Kyoung Ah; Piao,Mei Jing; Kim,Ki Cheon; Zheng,Jian; Yao,Cheng Wen; Cha,Ji Won; Chung,Ha Sook; Kim,Sang Cheol; Jung,Eunsun; Park,Deokhoon; Chae,Sungwook; Hyun,Jin Won

doi:10.3892/ijmm.2014.1643

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

Authors:
- Min Ju Ryu
- Kyoung Ah Kang
- Mei Jing Piao
- Ki Cheon Kim
- Jian Zheng
- Cheng Wen Yao
- Ji Won Cha
- Ha Sook Chung
- Sang Cheol Kim
- Eunsun Jung
- Deokhoon Park
- Sungwook Chae
- Jin Won Hyun
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Affiliations: Food and Nutrition, Duksung Women's University, Seoul 132-714, Republic of Korea, School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea, Biospectrum Life Science Institute, Seongnam, Gyunggi Do 442‑13, Republic of Korea, Aging Research Center, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea
Published online on: February 4, 2014 https://doi.org/10.3892/ijmm.2014.1643
Pages: 964-970

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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.

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