title: Curcumin protects human keratinocytes against inorganic arsenite-induced acute cytotoxicity through an NRF2-dependent mechanism.
abstract: Human exposure to inorganic arsenic leads to various dermal disorders, including hyperkeratosis and skin cancer. Curcumin is demonstrated to induce remarkable antioxidant activity in a variety of cells and tissues. The present study aimed at identifying curcumin as a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) and demonstrating its protective effect against inorganic arsenite- (iAs(3+)-) induced cytotoxicity in human keratinocytes. We found that curcumin led to nuclear accumulation of NRF2 protein and increased the expression of antioxidant response element- (ARE-) regulated genes in HaCaT keratinocytes in concentration- and time-dependent manners. High concentration of curcumin (20 μM) also increased protein expression of long isoforms of NRF1. Treatment with low concentrations of curcumin (2.5 or 5 μM) effectively increased the viability and survival of HaCaT cells against iAs(3+)-induced cytotoxicity as assessed by the MTT assay and flow cytometry and also attenuated iAs(3+)-induced expression of cleaved caspase-3 and cleaved PARP protein. Selective knockdown of NRF2 or KEAP1 by lentiviral shRNAs significantly diminished the cytoprotection conferred by curcumin, suggesting that the protection against iAs(3+)-induced cytotoxicity is dependent on the activation of NRF2. Our results provided a proof of the concept of using curcumin to activate the NRF2 pathway to alleviate arsenic-induced dermal damage.
authors.affiliation: Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Bei
authors.initials: B
authors.lastname: Yang
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Baocheng
authors.initials: B
authors.lastname: Deng
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhang
authors.forename: Shukun
authors.initials: S
authors.lastname: Jiang
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.forename: Dawei
authors.initials: D
authors.lastname: Guan
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D003474:Curcumin / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics
chemical_list: D000975:Antioxidants; D018053:Arsenites; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D012333:RNA, Messenger; D008156:Luciferases; D003474:Curcumin; C015001:arsenite