Impact of Age and Body Site on Adult Female Skin Surface pH

Background: pH is known as an important parameter in epidermal barrier function and homeostasis. Aim: The impact of age and body site on skin surface pH (pH(SS)) of women was evaluated in vivo. Methods: Time domain dual lifetime referencing with luminescent sensor foils was used for pH(SS) measurements. pH(SS) was measured on the forehead, the temple, and the volar forearm of adult females (n = 97, 52.87 +/- 18.58 years, 20-97 years). Every single measurement contained 2,500 pH values due to the luminescence imaging technique used. Results: pH(SS) slightly increases with age on all three investigated body sites. There are no significant differences in pH(SS) between the three investigated body sites. Conclusion: Adult pH(SS) on the forehead, the temple and the volar forearm increases slightly with age. This knowledge is crucial for adapting medical skin care products. Copyright (C) 2012 S. Karger AG, Base

Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan

Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results We have detected mutations in all families in five different genes: TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3. Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1, a splice site variant in NIPAL4, and missense variants in ABCA12 and CYP4F22. We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI

A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.

Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI(-/-) and KtyII(-/-)(K8) mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell-intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation

Self-consistent field theory for the interactions between keratin intermediate filaments

Background: Keratins are important structural proteins found in skin, hair and nails. Keratin Intermediate Filaments are major components of corneocytes, nonviable horny cells of the Stratum Corneum, the outermost layer of skin. It is considered that interactions between unstructured domains of Keratin Intermediate Filaments are the key factor in maintaining the elasticity of the skin. Results: We have developed a model for the interactions between keratin intermediate filaments based on self-consistent field theory. The intermediate filaments are represented by charged surfaces, and the disordered terminal domains of the keratins are represented by charged heteropolymers grafted to these surfaces. We estimate the system is close to a charge compensation point where the heteropolymer grafting density is matched to the surface charge density. Using a protein model with amino acid resolution for the terminal domains, we find that the terminal chains can mediate a weak attraction between the keratin surfaces. The origin of the attraction is a combination of bridging and electrostatics. The attraction disappears when the system moves away from the charge compensation point, or when excess small ions and/or NMF-representing free amino acids are added. Conclusions: These results are in concordance with experimental observations, and support the idea that the interaction between keratin filaments, and ultimately in part the elastic properties of the keratin-containing tissue, is controlled by a combination of the physico-chemical properties of the disordered terminal domains and the composition of the medium in the inter-filament region. Keywords: Stratum corneum, Skin keratins, Intermediate filaments, Unstructured terminal domains, Bridging attractio

hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers

Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients

Induced pluripotent stem cell line heterozygous for p.R501X mutation in filaggrin: KCLi003-A

We have generated an induced pluripotent stem cell (iPSC) line KCLi003-A (iOP101) from epidermal keratinocytes of a female donor, heterozygous for the loss-of-function mutation p.R501X in the filaggrin gene (FLG), using non-integrating Sendai virus vectors. Derivation and expansion of iPSCs were performed under xeno-free culture conditions. Characterization and validation of KCLi003-A line included molecular karyotyping, mutation screening using restriction enzyme digestion, next generation sequencing (NGS), while pluripotency and differentiation potential were confirmed by expression of associated markers in vitro and by in vivo teratoma assay

Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V

Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD

Enhanced expression of genes related to xenobiotic metabolism in the skin of patients with atopic dermatitis but not with ichthyosis vulgaris

Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to xenobiotic metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to xenobiotic metabolism

Pseudoceramide-Containing Physiological Lipid Mixture Reduces Adverse Effects of Topical Steroids

PURPOSE: Various therapeutic approaches have been suggested for preventing or reducing the adverse effects of topical glucocorticoids, including skin barrier impairment. Previously, we have shown that impairment of skin barrier function by the highest potency topical glucocorticoid, clobetasol 17-propinate (CP), can be partially prevented by co-application of a physiological lipid mixture containing pseudoceramide, free fatty acids, and cholesterol (multi-lamellar emulsion [MLE]). Skin atrophic effects of CP were also partially reduced by MLE. In this study, the preventive effects of MLE on the lowest potency topical glucocorticoid, hydrocortisone (HC), were investigated using animal models. METHODS: Anti-inflammatory activity of topical HC was evaluated using a 12-O-tetradecanoylphobol-13-acetate-induced skin edema model. Topical steroid induced adverse effects were evaluated using hairless mouse. RESULTS: The results showed that the anti-inflammatory activity was not altered by co-application of either MLE or hydrobase. However, co-application of MLE and 1.0% HC showed less impairment in the epidermal permeability barrier function, skin hydration, and skin surface pH compared with hydrobase. Stratum corneum integrity, evaluated by measuring trans-epidermal water loss after repeated tape stripping, showed less damage with MLE co-application. Long-term application of topical HC induced skin atrophy, measured by a reduction in skinfold and epidermal thickness and in the number of epidermal proliferating cell nucleus antigen (PCNA)-positive keratinocytes. Co-application of MLE did not affect the skinfold or epidermal thickness, but the number of PCNA-positive keratinocytes was less decreased with MLE use. CONCLUSIONS: These results suggest that co-application of MLE is effective in reducing the local adverse effects of low-potency topical glucocorticoids and supports the therapeutic efficacy of physiological lipid mixtures on skin barrier function.ope

Prevention of skin reactions due to teletherapy in women with breast cancer: a comprehensive review

One of the possible courses of cancer treatment is teletherapy, and one of the most important adverse side effects are skin reactions, an ailment more commonly called radiodermatitis. The main purpose of this study is to analyze knowledge of the evidence about topical products used in the prevention of radiodermatitis, to support care delivery to women with breast cancer during teletherapy. The research method used here is the comprehensive literature review. Four databases were used to select the bibliography. The sample consists of 15 articles. The data shows that, among the topical products analyzed here, Calendula, corticosteroids and Xclair have shown significant protective effects, underlining their actions. The lack of articles published in Brazil highlights the need for further research in this area, seeking better care quality through the use of products with scientifically proven efficiency.Teleterapia está entre las modalidades de tratamiento para el cáncer y uno de sus principales efectos adversos son reacciones de la piel, comúnmente llamado radiodermatitis. Este estudio objetivó analizar el conocimiento acerca de los productos tópicos utilizados para la prevención de la radiodermatitis que justifiquen la atención en teleterapia en mujeres con cáncer de mama. Se adoptó como método de investigación la revisión integradora de la literatura. Para la selección de los artículos se utilizaron cuatro bases de datos. La muestra fue constituida por 15 artículos. Los datos muestran que entre los productos tópicos analizados la caléndula, esteroides y Clair X tuvo un efecto protector significativo, destacando así por sus acciones. La ausencia de artículos publicados en Brasil se centra en la necesidad de seguir investigando para mejorar la calidad de la atención mediante el uso de productos con una eficacia científicamente probada.Dentre as modalidades de tratamento para o câncer está a teleterapia, e um dos principais efeitos adversos dessa modalidade são as reações de pele, comumente chamadas radiodermatites. O presente estudo teve como objetivo analisar o conhecimento sobre as evidências acerca de produtos tópicos, utilizados na prevenção de radiodermatite, que fundamente o cuidado em teleterapia direcionado a mulheres com câncer de mama. Adotou-se como método de pesquisa a revisão integrativa da literatura. Para a seleção da bibliografia utilizaram-se quatro bases de dados. A amostra constitui-se de 15 artigos. Os dados demonstram que, dentre os produtos tópicos analisados, a calêndula, os corticoesteroides e o Xclair tiveram efeito protetor significante, destacando-se, assim, pelas suas ações. A ausência de artigos publicados no Brasil mostra a necessidade de mais pesquisas nessa área, visando a melhor qualidade na assistência a mulheres com câncer de mama, por meio da utilização de produtos com eficácia comprovada cientificamente