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Gallic acid (GA), a natural small molecule found in Radix Paeoniae Rubra, has a variety of favorable biological activities. However, the anti-psoriasis effect of GA has never been explored up to now. This study evaluates the protective effect of GA on psoriasis-like skin disease both in vitro and in vivo and explores the underlying mechanism. The results show that GA significantly decreases the mRNA and protein expression of keratin 16 and keratin 17 which are the markers of psoriasis. Additionally, GA obviously ameliorates psoriasis area and severity index scores and decreases the epidermal hyperplasia of psoriasis-like disease mice. The activity of Nrf2 which targets keratin 16 and keratin 17 is significantly downregulated by GA. Furthermore, the downregulation of keratin 16 and keratin 17 induced by GA was abolished by the Nrf2-overexpression in vitro. This study initially elucidates the anti-psoriasis effect and mechanism of GA which hints that GA would be a potential candidate for the treatment of psoriasis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation of epidermis. Although hyperproliferation-associated keratins K6, K16, and K17 are considered to be the hallmarks of psoriasis, the molecular basis underlying the overexpression of these keratins remains unclear. Nrf2 regulates cell proliferation. Therefore, we investigated whether Nrf2 regulates keratinocyte proliferation via promoting expression of K6, K16, and K17 in psoriasis. We initially found that psoriatic epidermis exhibited elevated expression of Nrf2. Furthermore, Nrf2 promoted expression of K6, K16, and K17 in both HaCaT cells and primary human keratinocytes by binding to the ARE domains located in the promoter of these genes. Additionally, upon stimulation with IL-17 or IL-22, Nrf2 translocated to the nucleus and initiated expression of targeted keratins. In mice of imiquimod-induced psoriasis-like dermatitis, topical application of Nrf2 small interfering RNA alleviated the epidermal hyperplasia with reduced expression of these keratins. More importantly, Nrf2 promoted the proliferation of human keratinocytes through up-regulation of K6, K16, or K17. These data suggested that inflammatory cytokines promoted Nrf2 nuclear translocation in psoriatic epidermis, which led to elevated expression of K6, K16, and K17, thus promoting keratinocyte proliferation and contributing to the pathogenesis of psoriasis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from case series and case reports. Most patients in these reports were not genetically tested for PC., Objective: We sought to clarify the prevalence of clinical features associated with PC., Methods: We surveyed 254 individuals with confirmed keratin mutations regarding their experience with clinical findings associated with PC. Statistical comparison of the groups by keratin mutation was performed using logistic regression analysis., Results: Although the onset of clinical symptoms varied considerably among our patients, a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years. Plantar pain had the most profound impact on quality of life. Other clinical findings reported by our patients included fingernail dystrophy, oral leukokeratosis, palmar keratoderma, follicular hyperkeratosis, hyperhidrosis, cysts, hoarseness, and natal teeth. We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation. Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2., Limitations: Data were obtained through questionnaires, not by direct examination. Patients were self- or physician-referred., Conclusions: We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC.

Treatment with the natural chemical sulforaphane (SF) ameliorates skin blistering in keratin 14 (K14)-deficient mice, correlating with the induction of K16 and K17 in the basal layer of epidermis (Kerns et al., PNAS 104:14460, 2007). Here we address the basis for the SF-mediated K16 and K17 induction in mouse epidermis in vivo. As expected, induction of K16 partly depends on the transcription factor Nrf2, which is activated by SF exposure. Strikingly, K17 induction occurs independently of Nrf2 activity and parallels the decrease in glutathione occurring shortly after epidermal exposure to SF. Pharmacological manipulation of glutathione levels in mouse epidermis in vivo alters K17 and K16 expression in the expected manner. We present findings suggesting that select MAP kinases participate in mediating the Nrf2- and glutathione-dependent alterations in K16 and K17 levels in SF-treated epidermis. These findings advance our understanding of the effect of SF on gene expression in epidermis, point to a role for glutathione in mediating some of these effects, and establish that SF induces the expression of two contiguous and highly related genes, K16 and K17, via distinct mechanisms.

Background: Beta-catenin exerts its crucial role in hair follicle development and hair growth cycle. Although the importance of Wnt/beta-catenin is well recognized, the downstream effectors of beta-catenin have not been clearly elucidated yet., Objective: The aim of this study is to identify the beta-catenin-regulated genes in cultured human hair outer root sheath (ORS) cells., Methods: We transduced ORS cells with adenovirus harboring the expression cassette for constitutive active form of beta-catenin, then performed cDNA microarray., Results: Overexpression of beta-catenin led to the upregulation of hair cell differentiation markers such as keratin 16 and 17. In addition, the expression of Pitx2, a bicoid-type homeodomain transcription factor, was also increased by overexpression of beta-catenin in ORS cells cultured in vitro. To investigate the potential role of Pitx2, we made the recombinant adenovirus expressing Pitx2, then transduced into the cultured ORS cells. Interestingly, Pitx2 induced the expression of keratin 16 and 17, indicating that Pitx2 activates ORS cells towards the follicular differentiation pathway preferentially., Conclusion: Our results implicate the potential importance of Pitx2 as a beta-catenin downstream modulator in hair growth control.

Background: Pachyonychia congenita (PC) is a rare autosomal dominant keratin disorder, subdivided into two major variants, PC-1 and PC-2. Predominant characteristics include hypertrophic nail dystrophy, focal palmoplantar keratoderma and oral leukokeratosis. Multiple steatocystomas that develop during puberty are a useful feature distinguishing PC-2 from PC-1. At the molecular level it has been shown that mutations in keratin K6a or K16 cause PC-1 whereas those in K6b or K17 lead to PC-2., Objective: To identify mutations in 22 families presenting with clinical symptoms of either PC-1/focal non-epidermolytic palmoplantar keratoderma (FNEPPK) or PC-2., Methods: Mutation analysis was performed on genomic DNA from PC patients by direct sequencing., Results: Here, we report four new missense and five known mutations in K6a; one new deletion and three previously identified missense mutations in K16; plus one known mutation in K17., Conclusion: With one exception, all these heterozygous mutations are within the highly conserved helix boundary motif regions at either end of the keratin rod domain. In one sporadic case, a unique mutation in K16 resulting in deletion of 24bp was found within the central rod domain, in a child with a phenotype predominantly consisting of focal plantar keratoderma. The identification of mutations in cases of PC is prerequisite for future development of gene-specific and/or mutation-specific therapies.