PMID- 29277538
OWN - NLM
STAT- MEDLINE
DCOM- 20190513
LR  - 20220105
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Print)
IS  - 0022-202X (Linking)
VI  - 138
IP  - 5
DP  - 2018 May
TI  - Sexual Dimorphism in Response to an NRF2 Inducer in a Model for 
      Pachyonychia Congenita.
PG  - 1094-1100
LID - S0022-202X(17)33234-7 [pii]
LID - 10.1016/j.jid.2017.09.054 [doi]
AB  - Sex is an influential factor regarding pathophysiology and therapeutic response 
      in human disease. Pachyonychia congenita is caused by mutations in keratin genes 
      and typified by dystrophic lesions affecting nails, glands, oral mucosa, and 
      palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK) severely 
      impairs mobility in pachyonychia congenita. Mice genetically null for keratin 16 
      (Krt16), one of the genes mutated in pachyonychia congenita, develop pachyonychia 
      congenita-like PPK. In male Krt16(-/-) mice, oxidative stress associated with 
      impaired glutathione synthesis and nuclear factor erythroid-derived 2 related 
      factor 2 (NRF2)-dependent gene expression precedes PPK onset, which can be 
      prevented by topical sulforaphane-mediated activation of NRF2. We report here 
      that sulforaphane treatment fails to activate NRF2 and prevent PPK in female 
      Krt16(-/-) mice despite a similar set of molecular circumstances. Follow-up 
      studies reveal a temporal shift in PPK onset in Krt16(-/-) females, coinciding 
      with sex-specific fluctuations in footpad skin glutathione levels. Dual treatment 
      with sulforaphane and diarylpropionitrile, an estrogen receptor beta selective 
      agonist, results in NRF2 activation, normalization of glutathione levels, and 
      prevention of PPK in female Krt16(-/-) mice. These findings point to a sex 
      difference in NRF2 responsiveness that needs be considered when exploring NRF2 as 
      a therapeutic target in skin disorders.
CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Kerns, Michelle L
AU  - Kerns ML
AD  - Department of Biochemistry and Molecular Biology, Bloomberg School of Public 
      Health, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Hakim, Jill M C
AU  - Hakim JMC
AD  - Department of Biochemistry and Molecular Biology, Bloomberg School of Public 
      Health, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Zieman, Abigail
AU  - Zieman A
AD  - Department of Biochemistry and Molecular Biology, Bloomberg School of Public 
      Health, Johns Hopkins University, Baltimore, Maryland, USA; Department of Cell 
      and Developmental Biology, University of Michigan Medical School, Ann Arbor, 
      Michigan, USA.
FAU - Lu, Rosemary G
AU  - Lu RG
AD  - Department of Biochemistry and Molecular Biology, Bloomberg School of Public 
      Health, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Coulombe, Pierre A
AU  - Coulombe PA
AD  - Department of Biochemistry and Molecular Biology, Bloomberg School of Public 
      Health, Johns Hopkins University, Baltimore, Maryland, USA; Department of Cell 
      and Developmental Biology, University of Michigan Medical School, Ann Arbor, 
      Michigan, USA; Department of Biological Chemistry, Johns Hopkins University, 
      Baltimore, Maryland, USA; Department of Dermatology, Johns Hopkins University, 
      Baltimore, Maryland, USA; Department of Oncology, School of Medicine, Johns 
      Hopkins University, Baltimore, Maryland, USA; Sidney Kimmel Comprehensive Cancer 
      Center, Johns Hopkins University, Baltimore, Maryland, USA. Electronic address: 
      coulombe@umich.edu.
LA  - eng
GR  - R01 AR044232/AR/NIAMS NIH HHS/United States
GR  - T32 CA009110/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20171224
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (2,3-bis(4-hydroxyphenyl)-propionitrile)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Isothiocyanates)
RN  - 0 (Keratin-16)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nitriles)
RN  - 0 (Propionates)
RN  - 0 (Sulfoxides)
RN  - GA49J4310U (sulforaphane)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
CIN - J Invest Dermatol. 2018 May;138(5):1019-1022. PMID: 29681388
MH  - Animals
MH  - Disease Models, Animal
MH  - Estrogen Receptor alpha/genetics/physiology
MH  - Female
MH  - Glutathione/metabolism
MH  - Humans
MH  - Isothiocyanates/pharmacology/therapeutic use
MH  - Keratin-16/physiology
MH  - Keratoderma, Palmoplantar/*drug therapy/etiology
MH  - Male
MH  - Mice
MH  - NF-E2-Related Factor 2/*physiology
MH  - Nitriles/therapeutic use
MH  - Pachyonychia Congenita/*drug therapy/etiology
MH  - Propionates/therapeutic use
MH  - Sex Characteristics
MH  - Sulfoxides
PMC - PMC5912985
MID - NIHMS942860
EDAT- 2017/12/27 06:00
MHDA- 2019/05/14 06:00
PMCR- 2018/06/01
CRDT- 2017/12/27 06:00
PHST- 2017/05/30 00:00 [received]
PHST- 2017/09/25 00:00 [revised]
PHST- 2017/09/28 00:00 [accepted]
PHST- 2017/12/27 06:00 [pubmed]
PHST- 2019/05/14 06:00 [medline]
PHST- 2017/12/27 06:00 [entrez]
PHST- 2018/06/01 00:00 [pmc-release]
AID - S0022-202X(17)33234-7 [pii]
AID - 10.1016/j.jid.2017.09.054 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2018 May;138(5):1094-1100. doi: 10.1016/j.jid.2017.09.054. 
      Epub 2017 Dec 24.