Zerumbone protects human skin keratinocytes against UVA-irradiated damages through Nrf2 induction

Hsin-Ling Yang; Chin-Ling Lee; Mallikarjuna Korivi; Jiunn-Wang Liao; Peramaiyan Rajendran; Jia-Jiuan Wu; You-Cheng Hseu

doi:10.1016/j.bcp.2017.12.014

Zerumbone protects human skin keratinocytes against UVA-irradiated damages through Nrf2 induction

Biochem Pharmacol. 2018 Feb:148:130-146. doi: 10.1016/j.bcp.2017.12.014. Epub 2017 Dec 20.

Authors

Hsin-Ling Yang¹, Chin-Ling Lee¹, Mallikarjuna Korivi¹, Jiunn-Wang Liao², Peramaiyan Rajendran³, Jia-Jiuan Wu¹, You-Cheng Hseu⁴

Affiliations

¹ Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
² Graduate Institute of Veterinary Pathology, National Chung-Hsing University, Taichung 402, Taiwan.
³ Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
⁴ Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: ychseu@mail.cmu.edu.tw.

PMID: 29273513
DOI: 10.1016/j.bcp.2017.12.014

Abstract

Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2-10 μM) substantially suppressed UVA (15 J/cm²)-induced HaCaT cell death and lactate dehydrogenase release in a dose-dependent manner. UVA-induced excessive ROS production, DNA single-strand breaks, apoptotic DNA fragmentation and a dysregulated Bax/Bcl-2 ratio were remarkably reversed by zerumbone in keratinocytes. Zerumbone-mediated cytoprotective properties were associated with increased nuclear translocation of nuclear factor-E2-related factor-2 (Nrf2) and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by induction of heme oxygenase-1 (HO-1) and γ-glutamyl cysteine ligase (γ-GCLC) genes in zerumbone-treated keratinocytes. Zerumbone-induced Nrf2 transcriptional activation was mediated by the p38 MAPK, PI3K/AKT and PKC signaling cascades. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished zerumbone-mediated cytoprotective effects, as evidenced by impaired antioxidant genes, uncontrolled ROS/apoptotic DNA fragmentation and keratinocytes death, following UVA irradiation. In vivo evidence demonstrated that zerumbone treatment to nude mice (55 and 110 μg/day) significantly ameliorated UVA (15 J/cm²/every 2-day/14-day) cytotoxicity via increased nuclear localization of Nrf2 and Nrf2-dependent antioxidant genes (HO-1 and γ-GCLC) in UVA-treated skin tissues. Our findings emphasized the significance of Nrf2/ARE-signaling in zerumbone-mediated induction of antioxidant genes against UVA-toxicity. The molecular evidence suggests zerumbone can be a natural medicine to treat/prevent UVA-induced skin damage/photoaging.

Keywords: Apoptosis; HaCaT cells; Nrf2; ROS; UVA irradiation; Zerumbone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line
DNA Damage / radiation effects
Gene Expression Regulation / drug effects*
Humans
Keratinocytes / drug effects*
Keratinocytes / radiation effects*
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Protein Transport / drug effects
RNA Interference
Reactive Oxygen Species
Sesquiterpenes / pharmacology*
Ultraviolet Rays

Substances

NF-E2-Related Factor 2
NFE2L2 protein, human
Reactive Oxygen Species
Sesquiterpenes
zerumbone