title: Can nitroxides evoke the Keap1-Nrf2-ARE pathway in skin?
abstract: Nitroxides are stable cyclic radicals of diverse size, charge, and lipophilicity. They are cell-permeative, which effectively protects cells, tissues, isolated organs, and laboratory animals from radical-induced damage. The mechanisms of activity through which nitroxides operate are diverse, including superoxide dismutase-mimetic activity, oxidation of semiquinone radicals, oxidation of reduced metal ions, procatalase-mimetic activity, interruption of radical chain reactions, and indirect modulation of NO levels. Nitroxides possess both a nucleophilic (reducing properties) and an electrophilic (oxidizing properties) nature and, therefore, they may affect different cellular pathways. In the current study, a novel mechanism of action by which nitroxides provide skin protection based on their electrophilic nature is suggested. This study shows that nitroxides may act as electrophiles, directly or indirectly, capable of activating the Keap1-Nrf2-ARE pathway in human keratinocytes (HaCaT) and in human skin (human organ culture model). The high potency of oxoammonium cations versus hydroxylamines in activating the system is demonstrated. The mechanism of action by which nitroxides activate the Keap1-Nrf2-ARE pathway is discussed. Understanding the mechanism of activity may expand the usage of nitroxides as a skin protection strategy against oxidative stress-related conditions.
authors.affiliation: The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; Department of Chemical Engineering and Technion-Israel Institute of Technology, Haifa 32000, Israel; The Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa 32000, Israel; Department of Developmental Biology and Cancer Research, The Hebrew University Medical School, Ein-Karem Campus, Jerusalem 91120, Israel.
authors.forename: Maya Ben Yehuda
authors.initials: MB
authors.lastname: Greenwald
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University Medical School, Ein-Karem Campus, Jerusalem 91120, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Anzi
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University Medical School, Ein-Karem Campus, Jerusalem 91120, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Ben Sasson
authors.affiliation: Department of Chemical Engineering and Technion-Israel Institute of Technology, Haifa 32000, Israel; The Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Havazelet
authors.initials: H
authors.lastname: Bianco-Peled
authors.affiliation: The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. Electronic address: ronk@ekmd.huji.ac.il.
authors.forename: Ron
authors.initials: R
authors.lastname: Kohen
mesh_terms: D000328:Adult; D061745:Antioxidant Response Elements; D002460:Cell Line; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D015603:Keratinocytes / Q000378:metabolism*; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: 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; D009589:Nitrogen Oxides
keywords: Free radicals; HO-1; Keap1–Nrf2–ARE; Nitroxides; Skin