Modulation of function and structure of stratum corneum in sphingomyelin synthase 2-deficient mice.

Sphingomyelin synthase (SMS) synthesizes sphingomyelin (SM) from ceramide (Cer), a precursor of Cer. The effects of SMS deficiency on stratum corneum (SC) barrier function and SC lamellar structure are unknown. In this report, permeation of hydrophilic and lipophilic compounds through full-thickness skin or stripped skin of SMS2-knockout (KO) and wild-type (WT) mice was examined. Furthermore, small-angle and wide-angle X-ray scattering (SAXS and WAXS) measurements of the SC were performed as a function of temperature to analyze the lamellar structure and hydrocarbon chain packing, where a SC sample was changed from 10 °C to 120 °C at 2 °C/min and the X-ray diffraction profile in the small-angle region and the wide-angle region was observed. Skin permeability of the hydrophilic compound increased significantly for SMS2-KO mice when compared with that of WT mice. In contrast, no difference was observed in the penetration of lipophilic compounds in the skin of both SMS2-KO and WT mice. In SC of SMS2-KO mice, two sharp SAXS peaks were observed due to the lamellar structure with a repetition period of 4.8 nm. The WAXS revealed that the intensity ratio R0.42/0.37 of the 0.42 nm peak at 2.4 nm-1 to the 0.37 nm peak at 2.7 nm-1 was smaller in the SMS2-KO mouse than in the WT mouse. Due to the temperature dependence of the WAXS, the peaks of 2.4 and 2.7 nm-1 remained until the higher temperatures in SMS2-KO mouse SC than those in WT mouse SC. The results of X-ray diffraction suggest that deficiency of SMS2 may cause the appearance of highly ordered structures of SC, which in turn may reduce the barrier function of SC.

DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.

DNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis-specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune response and infiltration of immune cells. Mechanistically, DNA hypomethylation in keratinocytes triggered transposon derepression, mitotic defects, and formation of micronuclei. DNA release into the cytosol of DNMT1-deficient keratinocytes activated signaling through cGAS and STING, thus triggering inflammation. Our findings show that disruption of a key epigenetic mark directly impacts immune and tissue homeostasis, and potentially impacts our understanding of autoinflammatory diseases and cancer immunotherapy.

Impaired Skin Barrier Function Due to Reduced ω-O-Acylceramide Levels in a Mouse Model of Sjögren-Larsson Syndrome.

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.

Impact of Gloves and Mask Use on Epidermal Barrier Function in Health Care Workers.

BACKGROUND: Coronavirus disease 2019 has rapidly spread all over the world. Personal protective equipment (PPE) including masks and gloves is needed to avoid transmission. Adverse skin reactions associated with PPE have been described, but there is no information regarding objective measures to assess skin impairment related to PPE. OBJECTIVE: The aim of the study was to evaluate the impact of using facial mask and nitrile gloves on epidermal barrier function and skin homeostasis. METHODS: A cross-sectional study was designed. Thirty-four health care workers wearing nitrile gloves and a mask for 2 hours were included. Transepidermal water loss, stratum corneum hydration, erythema, and temperature were measured. RESULTS: Transepidermal water loss (31.11 vs 14.24 g·m-2·h-1), temperature (33.29°C vs 32.57°C), and erythema were significantly greater at the area covered by gloves compared with the noncovered area. Transepidermal water loss (22.82 vs 13.69 g·m-2·h-1), temperature, and erythema (411.43 vs 335.52 arbitrary units) were significantly increased at the area covered by mask, whereas stratum corneum hydration was lower. Transepidermal water loss was greater at the area covered by a surgical mask than at a filtering respirator mask coded filtering facepiece 2 (27.09 vs 18.02 g·m-2·h-1, P = 0.034). CONCLUSIONS: Skin homeostasis and epidermal barrier function may be impaired by gloves and mask use. High-quality PPE should be provided, and adequate skin prevention measures should be implemented to reduce epidermal barrier damage.

Crocodile-like sensory scales in a Late Jurassic theropod dinosaur.

Early in amniote evolution, epidermal scales evolved in stem reptiles as an efficient barrier against water loss and ultraviolet radiation, making them a key development in the transition to a fully terrestrial existence [1]. Accordingly, epidermal scales are not simple inert structures but highly-evolved organs suited to perform a broad suite of functions. Here, we provide new data on the epidermal complexity of a non-avian theropod, Juravenator starki, from the Torleite Formation (upper Kimmeridgian), Bavaria, Germany [2]. Although epidermal scales have been noted previously on the tail of Juravenator, we report a unique scale type with distinctive circular nodes that we identify as integumentary sense organs, analogous to those in modern crocodylians. The surprising presence of such structures suggests the tail had a sensory function, which is nevertheless congruent with the inferred ecology of Juravenator and the evolution of integumentary sense organs among archosaurs.

Altered Epidermal Permeability Barrier Function in the Uninvolved Skin Supports a Role of Epidermal Dysfunction in the Pathogenesis of Occupational Hand Eczema.

Although a compromised epidermal permeability barrier can contribute to the development of contact dermatitis, whether subjects with hand eczema display abnormalities in baseline epidermal permeability barrier function in their uninvolved skin remains unknown. The aim of the present study was to assess epidermal permeability barrier function in subjects with and without hand eczema in clothing manufacturers. Upon approval by the institutional review board, volunteers were recruited from clothing manufacturers in Guangzhou City, China. An 11-item questionnaire was used to collect general data from the volunteers. The diagnoses of self-proclaimed hand eczema were further confirmed by a dermatologist. Epidermal biophysical properties, including transepidermal water loss (TEWL) rates, stratum corneum hydration and skin surface pH were measured on the flexural surface of the left forearm in all volunteers. Epidermal biophysical properties were compared among cohorts of subjects with active hand eczema, a prior history of hand eczema and without any history of hand eczema. A total of 650 questionnaires were collected from 462 females and 188 males, with a mean age of 36.7 ± 0.46 years (range 16-69 years; 95% CI 35.8-37.59). Thirty-five subjects (5.4%) currently had hand eczema, while 28 subjects (4.3%) reported a prior history of hand eczema that was inactive currently. The prevalence of hand eczema did not differ significantly between genders. Neither a prior personal nor a family history of allergies was associated with the prevalence of hand eczema, but certain occupations and frequent contact with disinfectants were independently associated with the prevalence of hand eczema. In the overall cohort, males displayed higher TEWL rates and stratum corneum hydration levels than did females. Both skin surface pH and TEWL rates differed significantly among normal controls and subjects with active hand eczema or a prior history of hand eczema (p < 0.05). In conclusion, the uninvolved skin site of subjects with hand eczema exhibits abnormalities in epidermal perme-ability barrier, supporting a pathogenic role of epidermal dysfunction in hand eczema. Whether subjects with hand eczema in other occupations also display altered epidermal function on uninvolved skin remains to be explored.

Aging-associated alterations in epidermal function and their clinical significance.

Chronologically-aged skin displays multiple functional changes in both the dermis and the epidermis. It appears that epidermal dysfunction, compromised permeability homeostasis, reduced stratum corneum hydration and elevated skin surface pH predispose to the development of aging-associated cutaneous and extracutaneous disorders. Improvements in epidermal function have been shown to be an effective alternative therapy in the prevention and treatment of some aging-associated cutaneous disorders, including eczematous dermatitis, pruritus, and xerosis. Recent studies demonstrated that epidermal dysfunction leads to the development of chronic, low-grade systemic inflammation, termed 'inflammaging,' which is linked to the development of aging-associated systemic disorders. Thus, correction of epidermal dysfunction could comprise a novel strategy in the prevention and treatment of aging-associated systemic disorders as well. In this review, we summarize aging-associated alterations in epidermal function, their underlying mechanisms, and their clinical significance. Regimens to improve epidermal function in the elderly are also discussed.

Ichthyosis: A Road Model for Skin Research.

The understanding of monogenetic disorders of cornification, including the group of diseases called ichthyoses, has expanded greatly in recent years. Studies of the aetiology of more than 50 types of ichthyosis have almost invariably uncovered errors in the biosynthesis of epidermal lipids or structural proteins essential for normal skin barrier function. The barrier abnormality per se may elicit epidermal inflammation, hyperproliferation and hyperkeratosis, potentially contributing to the patient's skin symptoms. Despite this and other new knowledge about pathomechanisms, treatment of ichthyosis often remains unsatisfactory. This review highlights a series of approaches used to elucidate the pathobiology and clinical consequences of different types of ichthyosis, and related diseases with the ultimate goal of finding new and better treatments.

The Role of the Skin Barrier in Periorificial Dermatitis.

Periorificial dermatitis, mostly known as perioral dermatitis, is a benign inflammatory facial dermatosis which can be a severe burden and even disfiguring and psychologically disturbing. The disease still presents a challenge for physicians when it comes to etiology and appropriate therapy. Although a variety of extrinsic and intrinsic factors have been proposed as etiopathogenetic factors, none of these fully explain complex pathogenesis of the disease. There is more evidence that supports beliefs that the epidermal barrier dysfunction is an underlying main pathogenic factor that contributes to persistent cutaneous inflammation in typical facial localizations. Patients with periorificial dermatitis are considered hyper-reactors who have impaired essential function of the skin barrier, especially the skin barrier of the perioral region, characterized by thin permeable stratum corneum and imbalance of intercellular lipids, which makes them more susceptible to various internal and external irritants that contribute to the development of the disease. The verification of this connection reinforces the need for clinicians to address this issue when approaching their patients and formulating the best treatment plan. Treatment should emphasize repairing the impaired skin barrier function to minimize associated skin inflammation and sensitivity, which results in resolution of the objective and subjective symptoms.

Incompressible limit of a continuum model of tissue growth with segregation for two cell populations.

This paper proposes a model for the growth of two interacting populations of cells that do not mix. The dynamics is driven by pressure and cohesion forces on the one hand and proliferation on the other hand. Contrasting with earlier works which assume that the two populations are initially segregated, our model can deal with initially mixed populations as it explicitly incorporates a repul-sion force that enforces segregation. To balance segregation instabilities potentially triggered by the repulsion force, our model also incorporates a fourth order diffusion. In this paper, we study the influ-ence of the model parameters thanks to one-dimensional simulations using a finite-volume method for a relaxation approximation of the fourth order diffusion. Then, following earlier works on the single population case, we provide formal arguments that the model approximates a free boundary Hele Shaw type model that we characterise using both analytical and numerical arguments.

A quantitative study of transepidermal water loss (TEWL) on conventional and microclimate management capable mattresses and hospital beds.

BACKGROUND: Transepidermal water loss (TEWL) is regarded as one of the most important parameters characterizing skin barrier integrity and has found to be higher in impaired skin barrier function. Reduced or low TEWL instead indicates skin barrier integrity or improvement. We evaluated if different mattresses/hospital beds can influence this skin barrier function by measuring TEWL before and after subjects lying in conventional and microclimate management capable mattresses/hospital beds. METHODS: We included 25 healthy subjects in our study. Measurements were made using Courage & Khazaka Multi Probe Adapter MPA with Tewameter TM300 to determine TEWL before and after the subjects were lying in conventional (Viskolastic® Plus, Wulff Med Tec GmbH, Fedderingen, Germany and Duo™ 2 mattress, Hill-Rom GmbH Essen, Germany) or microclimate management capable mattresses/hospital beds (ClinActiv + MCM™ and PEARLS AFT, Hill-Rom GmbH Essen, Germany). RESULTS: While there was no statistically significant difference in standard mattresses/hospital beds (22.19 ±â€¯12.99 and 19.80 ±â€¯11.48 g/hm2), the decrease of TEWL was statistically significant in both microclimate management capable mattresses/hospital beds we investigated (16.89 ±â€¯8.586 g/hm2 and 17.41 ±â€¯7.203 g/hm2) compared to baseline values (35.85 ±â€¯24.51 g/hm2). CONCLUSION: As higher TEWL announces impaired skin barrier function these findings indicate that the choice of the mattress/hospital bed is important for skin barrier function and microclimate management systems improve skin barrier function of the skin.

Assessing Biophysical and Physiological Profiles of Scalp Seborrheic Dermatitis in the Thai Population.

BACKGROUND: Scalp seborrheic dermatitis (SD) is a common and chronic inflammatory skin disease which tends to recur over time. By measuring biophysical properties of the stratum corneum, many studies report abnormal biophysical profiles and their association in various dermatologic diseases. The aim of the study is to analyze the biophysical properties and skin barrier defects of scalp SD compared to healthy controls. MATERIALS AND METHODS: This study is a cross-sectional study assessing the correlation of various biophysical and physiological profiles in scalp SD. Forty-two Thai participants with scalp SD were enrolled in the study and 40 healthy participants were also enrolled as the control group. Both SD and control group were subjected to a one-time biophysical and physiological properties' measurement of transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin surface pH, skin surface lipid, and skin roughness. RESULTS: The mean TEWL of lesional skin of SD cases were significantly higher than those of control group (P<0.05). Relating to high mean TEWL, the mean SCH was found to be significantly lower in SD cases (P<0.05). Skin surface lipid was also found to be significantly higher in SD group (P<0.05). However, there were no differences in skin surface pH (P=0.104) and roughness (P=0.308) between the two groups. Pairwise comparison of each subgroup found that moderate and severe SD demonstrated significantly higher mean skin surface lipid than that of control group (P<0.05). CONCLUSION: Scalp SD may be associated with seborrhea in Thai population. Monitoring of SCH, TEWL, and skin surface lipid could be helpful in assessing severity and evaluating the treatment outcome in patients with scalp SD.

Mechanical modeling of pimple growth.

Pimple is one of the most common skin diseases for humans, whose growth cause pain yet the corresponding mechanical analysis is lacking. A finite element model is developed to quantify the deformation field with the expansion of follicle, and then the mechanical stimulus is related to the sensation of pain during the development of pimple. Parametric studies show the dependence of mechanical stimulus and pain level on the pimple-surrounded structures, follicle depth and mechanical properties of the epidermis. The findings in this paper may provide useful insights on prevention or pain mitigation of pimples, as well as those related to other tissue growth and respective cosmetic concerns.

Pattern formation of skin cancers: Effects of cancer proliferation and hydrodynamic interactions.

We study pattern formation of skin cancers by means of numerical simulation of a binary system consisting of cancer and healthy cells. We extend the conventional model H for macrophase separations by considering a logistic growth of cancer cells and also a mechanical friction between dermis and epidermis. Importantly, our model exhibits a microphase separation due to the proliferation of cancer cells. By numerically solving the time evolution equations of the cancer composition and its velocity, we show that the phase separation kinetics strongly depends on the cell proliferation rate as well as on the strength of hydrodynamic interactions. A steady-state diagram of cancer patterns is established in terms of these two dynamical parameters and some of the patterns correspond to clinically observed cancer patterns. Furthermore, we examine in detail the time evolution of the average composition of cancer cells and the characteristic length of the microstructures. Our results demonstrate that different sequence of cancer patterns can be obtained by changing the proliferation rate and/or hydrodynamic interactions.

A lethal fungal pathogen directly alters tight junction proteins in the skin of a susceptible amphibian.

Bacterial and viral pathogens can weaken epithelial barriers by targeting and disrupting tight junction (TJ) proteins. However, comparatively little is known about the direct effects of fungal pathogens on TJ proteins and their expression. The disease chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is threatening amphibian populations worldwide. Bd is known to infect amphibian skin and disrupt cutaneous osmoregulation. However, exactly how this occurs is poorly understood. This study considered the impact of Bd infection on the barrier properties of the Australian green tree frog (Litoria caerulea) epidermis by examining how inoculation of animals with Bd influenced the paracellular movement of FITC-dextran (4 kDa, FD-4) across the skin in association with alterations in the mRNA and protein abundance of select TJ proteins of the epidermal TJ complex. It was observed that Bd infection increased paracellular movement of FD-4 across the skin linearly with fungal infection load. In addition, Bd infection increased transcript abundance of the tricellular TJ (tTJ) protein tricellulin (Tric) as well as the bicellular TJ (bTJ) proteins occludin (Ocln), claudin (Cldn)-1, Cldn-4 and the scaffolding TJ protein zonula occludens 1 (ZO-1). However, while Tric protein abundance increased in accord with changes in transcript abundance, protein abundance of Cldn-1 was significantly reduced and Ocln protein abundance was unchanged. Data indicate that disruption of cutaneous osmoregulation in L. caerulea following Bd infection occurs, at least in part, by an increase in epidermal paracellular permeability in association with compromised integrity of the epidermal TJ complex.

Could Inflammaging and Its Sequelae Be Prevented or Mitigated?

Aged humans display a chronic and low-grade inflammation, termed "inflammaging", which has been potentially linked to the subsequent development of some aging-associated systemic disorders, including type 2 diabetes, atherosclerotic cardiovascular disease, Alzheimer's disease and obesity. Though the origin of aging-associated systemic inflammation is uncertain, epidemiological studies show that inflammatory dermatoses (psoriasis and eczema) are risk factors for some aging-associated systemic disorders, such as type 2 diabetes and atherosclerotic cardiovascular disease. Moreover, recent studies demonstrate that epidermal dysfunction in aged skin not only causes cutaneous inflammation, but also a subsequent increase in circulating levels of proinflammatory cytokines, suggesting that the skin could be a major contributor to inflammaging. This hypothesis is further supported by reductions in circulating levels of proinflammatory cytokines in both aged humans and murine, following improvements in epidermal function with topical emollients. Therefore, correction of epidermal dysfunction could be a novel approach for the prevention and mitigation of certain inflammation-associated chronic disorders in aged humans.

Gerontodermatology: the fragility of the epidermis in older adults.

The proportion of adults over 60 years of age is rapidly increasing and is estimated to reach approximately one-sixth of the global population by 2030. An ageing population is a real challenge for healthcare resources, including dermatologists and geriatricians, as age-related changes in skin integrity and barrier function make older adults more susceptible to developing skin pathologies such as pruritus, dermatitis and infections. Fragile skin arises from several interlinked causes, including age-related changes in skin barrier integrity, previous and current lifestyle choices, skin pathologies and medical interventions. Dermo-cosmetics can play a key role in enhancing skin care regimens and preventing pathologies in this age group. In vitro studies, clinical, and in-daily clinical practice studies of dermo-cosmetics have shown them to be effective in many skin conditions in older adults, like xerosis and pruritus. Incontinence-associated dermatitis (IAD), a common condition arising from contact with irritants such as urine and faeces which can significantly impact the quality of life of sufferers, can also be improved with a barrier cream in incontinent patients aged 70 years and older. This supplement focuses on the increased fragility of older skin, the development of common skin pathologies and the efficacy and tolerance of dermo-cosmetic products in older adults.