title: Cytoprotection against beta-amyloid (Aβ) peptide-mediated oxidative damage and autophagy by Keap1 RNAi in human glioma U87mg cells.
abstract: Extensive oxidative stress has been considered a primary pathological factor for many neurodegenerative disorders (NDDs). We speculated that the oxidative damage to brain cells can be managed by promoting the endogenous cellular antioxidants through the RNA interference (RNAi) against Keap1 (kelch-like ECH-associated protein). Keap1 acts as a negative regulator of Nrf2 (NF-E2-related factor 2) that represses the activation of the antioxidant responsive element (ARE). Here, we investigated whether Keap1 knockdown enhances the cellular antioxidant capacity and provides the neuroprotection against oxidative stress from hydrogen peroxide and beta-amyloid (Aβ) peptide in U87mg cells. We found that the Keap1 siRNA pre-treated group displayed higher expression of diverse antioxidant genes and an increased antioxidant capacity compared to the control group. Moreover, the Keap1 RNAi exerted a cytoprotective effect against H2O2 treatment. In Aβ peptide treatment experiments, the Keap1 siRNA pre-treated groups maintained acceptable cell viability, relatively intact cellular morphology, and controlled oxidative damage levels while the control groups suffered from Aβ peptide-mediated neurotoxicity. Keap1 RNAi also attenuated the oxidative stress-mediated autophagy as well. These findings suggest that Keap1 RNAi can serve as a therapeutic strategy for relieving oxidative stress-associated symptoms in many NDDs.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, United States.
authors.forename: Pilju
authors.initials: P
authors.lastname: Youn
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, United States.
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, United States. Electronic address: darin.furgeson@gmail.com.
authors.forename: Darin Y
authors.initials: DY
authors.lastname: Furgeson
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D005910:Glioma / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008315:Malondialdehyde / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D034622:RNA Interference / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012844:Sincalide / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; C075222:amyloid beta-protein (1-42); D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D012844:Sincalide
keywords: Autophagy; Beta-amyloid (Aβ) peptide; Keap1–Nrf2 pathway; Neurodegenerative disorders (NDD); Oxidative stress; RNA interference (RNAi)