Oxidative Damage Control in a Human (Mini-) Organ: Nrf2 Activation Protects against Oxidative Stress-Induced Hair Growth Inhibition

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• 作者：Iain S. Haslam¹ ; ² ; ^{i.haslam@hud.ac.uk} ; Laura Jadkauskaite¹ ; Imre Lőrinc Szabó ; ³ ; Selma Staege¹ ; Jasper Hesebeck-Brinckmann¹ ; Gail Jenkins⁴ ; Ranjit K. Bhogal⁴ ; Fei-Ling Lim⁴ ; Nilofer Farjo⁵ ; Bessam Farjo⁵ ; Tamá ; s Bí ; ró ; ³ ; Matthias Schä ; fer⁶ ; Ralf Paus¹ ; ^{ralf.paus@manchester.ac.uk}
• 关键词：DP ; dermal papilla ; GSR ; glutathione reductase ; HF ; hair follicle ; HO-1 ; heme oxygenase-1 ; NQO1 ; NAD(P)H dehydrogenase ; quinone 1 ; Nrf2 ; nuclear factor (erythroid-derived 2)-like 2 ; ORS ; outer root sheath ; ORSK ; outer root sheath keratinocyte ; PRDX1 ; peroxiredoxin 1 ; ROS ; reactive oxygen species ; SFN ; sulforaphane ; siRNA ; small interfering RNA
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：137
• 期：2
• 页码：295-304
• 全文大小：2795 K
• 卷排序：137

文摘

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 (H2O2 or 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.