title: Induction of activation of the antioxidant response element and stabilization of Nrf2 by 3-(3-pyridylmethylidene)-2-indolinone (PMID) confers protection against oxidative stress-induced cell death.
abstract: The antioxidant response elements (ARE) are a cis-acting enhancer sequence located in regulatory regions of antioxidant and detoxifying genes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a member of the Cap 'n' Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE-containing genes. Under oxidative stress, Nrf2/ARE induction is fundamental to defense against reactive oxygen species (ROS) and serves as a key factor in the protection against toxic xenobiotics. 3-(3-Pyridylmethylidene)-2-Indolinone (PMID) is a derivative of 2-indolinone compounds which act as protein kinase inhibitors and show anti-tumor activity. However, the role of PMID in the oxidative stress remains unknown. In the present study, we showed that PMID induced the activation of ARE-mediated transcription, increased the DNA-binding activity of Nrf2 and then up-regulated the expression of antioxidant genes such as HO-1, SOD, and NQO1. The level of Nrf2 protein was increased in cells treated with PMID by a post-transcriptional mechanism. Under CHX treatment, the stability of Nrf2 protein was enhanced by PMID with decreased turnover rate. We showed that PMID reduced the ubiquitination of Nrf2 and disrupted the Cullin3 (Cul3)-Keap1 interaction. Furthermore, cells treated with PMID showed resistance to cytotoxicity by H(2)O(2) and pro-oxidant 6-OHDA. PMID also up-regulated the antioxidant level in BALB/c mice. Taken together, the compound PMID induces the ARE-mediated gene expression through stabilization of Nrf2 protein and activation of Nrf2/ARE pathway and protects against oxidative stress-mediated cell death.
authors.affiliation: Tianjin University, School of Chemical Engineering and Technology, Department of pharmaceutical engineering, Tianjin, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Yao
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Xiang-Zhen
authors.initials: XZ
authors.lastname: Kong
authors.forename: Shou-Guo
authors.initials: SG
authors.lastname: Zhang
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Wang
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Zhan
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Wang-Xiang
authors.initials: WX
authors.lastname: Xu
authors.forename: Liu-Jun
authors.initials: LJ
authors.lastname: Tang
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Ge
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Li
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology*; D020218:Response Elements; D013482:Superoxide Dismutase / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000603440:3-(3-pyridylmethylidene)-2-indolinone; D000975:Antioxidants; D007211:Indoles; D051267:NF-E2-Related Factor 2; D011725:Pyridines; D013482:Superoxide Dismutase; D005978:Glutathione