title: Oxidative Damage Control in a Human (Mini-) Organ: Nrf2 Activation Protects against Oxidative Stress-Induced Hair Growth Inhibition.
abstract: The in situ control of redox insult in human organs is of major clinical relevance, yet remains incompletely understood. Activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the "master regulator" of genes controlling cellular redox homeostasis, is advocated as a therapeutic strategy for diseases with severely impaired redox balance. It remains to be shown whether this strategy is effective in human organs, rather than only in isolated human cell types. We have therefore explored the role of Nrf2 in a uniquely accessible human (mini-) organ: scalp hair follicles. Microarray and qRT-PCR analysis of human hair follicles after Nrf2 activation using sulforaphane identified the modulation of phase II metabolism, reactive oxygen species clearance, the pentose phosphate pathway, and glutathione homeostasis. Nrf2 knockdown (small interfering RNA) in cultured human hair follicles confirmed the regulation of key Nrf2 target genes (i.e., heme oxygenase-1, NAD(P)H dehydrogenase, quinone 1, glutathione reductase, glutamate-cysteine ligase catalytic subunit, ABCC1, peroxiredoxin 1). Importantly, Nrf2 activation significantly reduced reactive oxygen species levels and associated lipid peroxidation. Nrf2 preactivation reduced premature catagen and hair growth inhibition induced by oxidative stress (H2O2or menadione), significantly ameliorated the H2O2-dependent increase in matrix keratinocyte apoptosis and reversed the reactive oxygen species-induced reduction in hair matrix proliferation. This study thus provides direct evidence for the crucial role of Nrf2 in protecting human organ function (i.e., scalp hair follicles) against redox insult.
authors.affiliation: The Centre for Dermatology Research, School of Biological Sciences, University of Manchester, Manchester, UK; Department of Biological Sciences, School of Applied Sciences, University of Huddersfield, Huddersfield, UK. Electronic address: i.haslam@hud.ac.uk.
authors.forename: Iain S
authors.initials: IS
authors.lastname: Haslam
authors.affiliation: The Centre for Dermatology Research, School of Biological Sciences, University of Manchester, Manchester, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Jadkauskaite
authors.affiliation: DE-MTA "Lendület" Cellular Physiology Research Group, Departments of Immunology and Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Imre Lőrinc
authors.initials: IL
authors.lastname: Szabó
authors.affiliation: The Centre for Dermatology Research, School of Biological Sciences, University of Manchester, Manchester, UK.
authors.forename: Selma
authors.initials: S
authors.lastname: Staege
authors.affiliation: The Centre for Dermatology Research, School of Biological Sciences, University of Manchester, Manchester, UK.
authors.forename: Jasper
authors.initials: J
authors.lastname: Hesebeck-Brinckmann
authors.affiliation: Unilever R&D, Colworth Discover, Sharnbrook, UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Jenkins
authors.affiliation: Unilever R&D, Colworth Discover, Sharnbrook, UK.
authors.forename: Ranjit K
authors.initials: RK
authors.lastname: Bhogal
authors.affiliation: Unilever R&D, Colworth Discover, Sharnbrook, UK.
authors.forename: Fei-Ling
authors.initials: FL
authors.lastname: Lim
authors.affiliation: Farjo Medical Centre, Manchester, UK.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Farjo
authors.affiliation: Farjo Medical Centre, Manchester, UK.
authors.forename: Bessam
authors.initials: B
authors.lastname: Farjo
authors.affiliation: DE-MTA "Lendület" Cellular Physiology Research Group, Departments of Immunology and Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bíró
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Institute of Technology (ETH), Zürich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: The Centre for Dermatology Research, School of Biological Sciences, University of Manchester, Manchester, UK. Electronic address: ralf.paus@manchester.ac.uk.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D018859:Hair Follicle / Q000254:growth & development*; D051547:Heme Oxygenase-1 / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1