Impaired Skin Barrier Function Research Articles

Nuclear IL-33 Plays an Important Role in the Suppression of FLG, LOR, Keratin 1, and Keratin 10 by IL-4 and IL-13 in Human Keratinocytes

IL-33 is a chromatin-associated multifunctional cytokine implicated in the pathogenesis of atopic dermatitis (AD), an inflammatory skin disorder characterized by skin barrier dysfunction. The previous reports show that IL-33 is highly detected in the nucleus of epidermal keratinocytes in AD lesions compared with that in unaffected or normal skin. However, it is unclear whether intracellular IL-33 directly contributes to the pathogenesis of AD. T helper type 2 cytokines IL-4 and IL-13 that are elevated in AD lesions suppress keratinocyte differentiation to impair skin barrier function. We investigated whether intracellular IL-33 is involved in IL-4 and IL-13 function. In monolayer culture and living skin equivalent analyses, IL-4 and IL-13 increased the expression of full-length IL-33 in the nucleus of keratinocytes by activating the MAPK/extracellular signal‒regulated kinase kinase/extracellular signal‒regulated kinase signaling pathway, which is necessary for the inhibition of differentiation markers FLG, LOR, keratin 1, and keratin 10. The nuclear IL-33 functions as a transcription cofactor of signal transducer and activator of transcription 3, increasing the binding of phosphorylated signal transducer and activator of transcription 3 to FLG promoter, thereby inhibiting its transcription, and it inhibits the expression of transcription factor RUNX1 by signal transducer and activator of transcription 3 and signal transducer and activator of transcription 6, thereby downregulating LOR, keratin 1, and keratin 10. Thus, the elevated nuclear IL-33 in the epidermis of AD lesions may be involved in the pathogenesis of AD by inhibiting keratinocyte differentiation and skin barrier function.

Análise da Correlação Entre os Níveis Séricos de Vitamina D e a Gravidade da Dermatite Atópica

Introdução: A dermatite atópica (DA) é uma doença inflamatória crônica e multifatorial. Casos graves afetam a qualidade de vida. A patogénese é complexa, marcada por resposta imune celular defeituosa, exacerbação da resposta inflamatória Th2 e comprometimento da função de barreira da pele. Evidências sugerem que a vitamina D atua na regulação da resposta imune inata e adaptativa, na redução do processo inflamatório e na melhora da barreira cutânea. O nosso objectivo foi correlacionar os níveis séricos de vitamina D com a gravidade da DA.
 Material e Métodos: Foram analisados prontuários de 30 pacientes assistidos em um ambulatório de Dermatologia, entre 2015 e 2018. Os pacientes foram divididos em 2 grupos: doença leve (terapia tópica) e doença moderada a grave (usuários de imunossupressores).
 Resultados: Foram selecionados 10 casos com DA leve e 20 com DA moderada a grave. Entre os pacientes com doença leve, 20% apresentaram deficiência de vitamina D. Quanto aos pacientes com doença moderada a grave, 40% apresentaram vitamina D deficiente. Comparando a média de vitamina D nos dois grupos, não houve diferença estatística entre o valor médio.
 Conclusão: Estudos sobre associação entre os níveis de vitamina D e gravidade da DA permanecem controversos. Alguns trabalhos reforçam essa associação. Neste estudo, apesar da proporção de pacientes com deficiência de vitamina D ser duas vezes maior entre os pacientes com DA moderada a grave, não houve significância estatística entre os dois grupos, corroborando estudos já publicados. Mais estudos relacionando a dermatite atópica à vitamina D são desejáveis, tendo em vista a sua possível aplicabilidade como terapêutica auxiliar.

ARTICLE: Models to Study Skin Lipids in Relation to the Barrier Function: A Modern Update on Models and Methodologies Evaluating Skin Barrier Function.

The skin barrier is a multifaceted microenvironment, comprised not only of structural and molecular components that maintain its integrity, but also a lipid matrix comprising an equimolar ratio of cholesterol, free fatty acids, and ceramides. Lipid abnormalities induced by environmental or pathological stimuli are often associated with impaired skin barrier function and integrity. Incorporation of skin lipids in skincare formulations to help fortify barrier function has become widespread. While there are resources available to study the barrier, a comprehensive evaluation of skin models, from in situ to in vivo, that focus on alterations of the lipid content, seems to be lacking. This article reviews current methods to evaluate the skin lipid barrier and touches upon the significance of using such models within the cosmetic field to study formulations that incorporate barrier lipids. J Drugs Dermatol. 20(4 Suppl):s10-16. doi:10.36849/JDD.S589B.

Evidence of Barrier Deficiency in Rosacea and the Importance of Integrating OTC Skincare Products into Treatment Regimens.

Rosacea, an inflammatory skin disease that leads to an impaired skin barrier function commonly involves the face. Symptoms of rosacea can be bothersome and include pain, stinging, burning, itching, and facial flushing. This review explored skin barrier impairment in rosacea and reduced symptomatology when using over the counter (OTC) skincare products. Nine dermatologists (the panel) completed a survey on OTC products they recommend for rosacea. The survey results were summarized, presented, and discussed during the online meeting, together with the results of a literature review. The outcome of these discussions, coupled with the panel's expert opinion and experience, is shown in the current review. Addressing barrier dysfunction by use of moisturizer and cleanser formulations that restore skin hydration, normalize skin pH, restore the microbiome, and skin lipids can assist in improving rosacea signs and symptoms. The panel's consensus was that in addition to the use of prescription medications, skincare recommendations are a crucial part of successful rosacea therapy. In addition to occlusives and humectants, barrier restoring ingredients such as ceramides, hyaluronic acid, and niacinamide were considered beneficial. Equally important was the absence of potentially irritating substances. The use of OTC products can improve rosacea symptomatology and signs. As adjuncts, these products are recommended before and during prescription therapy and as part of a maintenance regimen. J Drugs Dermatol. 20(4):384-392. doi:10.36849/JDD.5861 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL fTEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Sargassum horneri (Turner) C. Agardh ethanol extract attenuates fine dust-induced inflammatory responses and impaired skin barrier functions in HaCaT keratinocytes

Ethnopharmacological relevanceSargassum horneri (Turner) C. Agardh is well known in East Asia as an edible brown alga rich in bioactive compounds. It has an ethnopharmacological significance in traditional Chinese medicine to treat inflammatory disorders varying from edema, furuncles, dysuria to cardiovascular diseases. Aim of the studySurge of fine dust (FD), in densely populated areas, have been reported to cause adverse health conditions ranging from respiratory diseases to inflammatory skin disorders. The current study investigates the protective effects of an ethanol extract from S. horneri (SHE) on FD-induced inflammatory responses and impaired skin hydration in HaCaT keratinocytes. Materials and methodsIntracellular reactive oxygen species (ROS) generation was evaluated with the 2′,7′-Dichlorofluorescin diacetate (DCFH-DA) stain. Anti-inflammatory properties of SHE in FD-stimulated HaCaT keratinocytes were investigated for the suppression of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways and downregulation of pro-inflammatory cytokines. As a means of studying FD-induced skin barrier disruption and the effects of SHE on stratum corneum hydration-controlling factors, tight junction regulatory mediators, and hyaluronic acid (HA) production were evaluated using keratinocytes. ResultsSHE suppressed the intracellular ROS production, simultaneously improving cell viability in FD-stimulated keratinocytes. Also, SHE upregulated anti-inflammatory cytokine interleukin (IL)-4 while downregulating inflammatory cytokines IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α; epidermal and epithelial cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP); thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and regulated upon activation, normally T-expressed, and presumably secreted expression and suppressed (RANTES) chemokine, MAPK and NF-κB mediators in a dose-dependent manner. Furthermore, SHE ameliorated filaggrin, involucrin, lymphoepithelial Kazal-type-related inhibitor (LEKTI), signifying its beneficial effects on deteriorated skin hydration caused by FD-induced inflammation. SHE further exhibited its skin protective effects regulating the tight junction proteins; Occludin, zonula occludens (ZO)-1, claudin-1, claudin-4, claudin-7, and claudin-23 while increasing the production of HA minimizing skin damage. ConclusionsAnti-inflammatory effects of, SHE against FD-induced keratinocyte inflammation is attributable to the suppression of upstream MAPK and NF-κB mediators. SHE indicated potential anti-inflammatory properties attenuating deteriorated skin barrier function in HaCaT keratinocytes. The effects are attributable to the polyphenols and other antioxidant compounds in SHE. Further studies could envisage the use of SHE for developing rejuvenating cosmetics.

ARTICLE: Models to Study Skin Lipids in Relation to the Barrier Function: A Modern Update on Models and Methodologies Evaluating Skin Barrier Function

The skin barrier is a multifaceted microenvironment, comprised not only of structural and molecular components that maintain its integrity, but also a lipid matrix comprising an equimolar ratio of cholesterol, free fatty acids, and ceramides. Lipid abnormalities induced by environmental or pathological stimuli are often associated with impaired skin barrier function and integrity. Incorporation of skin lipids in skincare formulations to help fortify barrier function has become widespread. While there are resources available to study the barrier, a comprehensive evaluation of skin models, from in situ to in vivo, that focus on alterations of the lipid content, seems to be lacking. This article reviews current methods to evaluate the skin lipid barrier and touches upon the significance of using such models within the cosmetic field to study formulations that incorporate barrier lipids. J Drugs Dermatol. 20(4 Suppl):s10-16. doi:10.36849/JDD.S589B

Stress Impairs Skin Barrier Function and Induces α2-3 Linked N-Acetylneuraminic Acid and Core 1 O-Glycans on Skin Mucins in Atlantic Salmon, Salmo salar.

The skin barrier consists of mucus, primarily comprising highly glycosylated mucins, and the epithelium. Host mucin glycosylation governs interactions with pathogens and stress is associated with impaired epithelial barrier function. We characterized Atlantic salmon skin barrier function during chronic stress (high density) and mucin O-glycosylation changes in response to acute and chronic stress. Fish held at low (LD: 14–30 kg/m3) and high densities (HD: 50-80 kg/m3) were subjected to acute stress 24 h before sampling at 17 and 21 weeks after start of the experiment. Blood parameters indicated primary and secondary stress responses at both sampling points. At the second sampling, skin barrier function towards molecules was reduced in the HD compared to the LD group (Papp mannitol; p < 0.01). Liquid chromatography–mass spectrometry revealed 81 O-glycan structures from the skin. Fish subjected to both chronic and acute stress had an increased proportion of large O-glycan structures. Overall, four of the O-glycan changes have potential as indicators of stress, especially for the combined chronic and acute stress. Stress thus impairs skin barrier function and induces glycosylation changes, which have potential to both affect interactions with pathogens and serve as stress indicators.

Prebiotics in atopic dermatitis prevention and management

Atopic dermatitis (AD) is a common, chronic inflammatory skin disease that is highly prevalent, especially among children. In addition to impaired skin barrier functions, AD is characterized by dysfunctional immunity and altered skin and gut microbiome. On the skin, there is an increased S. aureus colonization and reduced microbiome diversity while in the gut there is a diminution of short-chain fatty acid-producing bacteria, such as Bifidobacterium. There is no cure for AD, but symptoms can be managed by appropriate therapies aimed at minimizing exacerbations, and duration and degree of the AD flares. Functional foods, including probiotics and prebiotics, are being used to relieve AD symptoms. While probiotics supplement the gut with “good bacteria”, prebiotics promote the growth of “good bacteria” on the skin and in the gut. Here, we review immune dysfunction and microbiome association in AD and potential use of prebiotics in the prevention and management of AD.

Effect of Sodium Lauryl Sulfate (SLS) Applied as a Patch on Human Skin Physiology and Its Microbiota

In this study, we assessed the change in skin microbiota composition, relative abundance, and diversity with skin physiology disruption induced by SLS patch. Healthy women declaring to have a reactive skin were submitted to a 0.5% aqueous sodium lauryl sulfate solution application under occlusive patch condition for 24 h. Skin properties were characterized by tewametry, corneometry, and colorimetry and bacterial diversity was assessed by 16S rRNA sequencing. Analysis before and one day after SLS patch removal revealed an increase of skin redness and a decrease of stratum corneum hydration and skin barrier function. The relative abundance of taxa containing potential pathogens increase (Firmicutes: Staphylococcaceae; Proteobacteria: Enterobacteriaceae, Pantoea) while some of the most occurring Actinobacteria with valuable skin protection and repair capacities decreased (Micrococcus, Kocuria, and Corynebacterium). We observed an impaired skin barrier function and dehydration induced by SLS patch disturb the subtle balance of skin microbiota towards skin bacterial community dysbiosis. This study provides new insights on the skin bacterial composition and skin physiology simultaneously impaired by a SLS patch.

Research Institute of Pediatrics and Children’s Health in “Central Clinical Hospital of the Russian Academy of Sciences”

Federation Skin lesions with development of erosive-ulcerative defects and impaired skin barrier function are common for large number of diseases. Successful epithelization of skin defects depends on the wound process, body’s compensatory functions, environmental factors and correctly selected treatment. Comprehensive treatment should include systemic and local therapy as well as current dressings. The article shows current dressings possibilities the treatment of various skin diseases, outlines all pros and cons of the major current dressings.

Role of YAP-related T cell imbalance and epidermal keratinocyte dysfunction in the pathogenesis of atopic dermatitis

BackgroundAtopic dermatitis (AD) is characterized by impaired skin barrier function and immune system dysfunction. The expression and role of Yes-associated protein (YAP) in AD are unclear. ObjectiveTo characterize the role of the YAP in T cell imbalance and epidermal keratinocyte dysfunction in the pathogenesis of AD. MethodsWe included 35 patients with AD (21 acute and 14 chronic). An AD mouse model was constructed using 2,4-dinitrofluorobenzene, and AD-like inflammatory cell model was constructed using TNF-α/IFN-γ-activated HaCaT cells. The proportion of Th1/Th2/Th17/Treg cells was detected using flow cytometry. After mononuclear cells were obtained from human peripheral blood or mouse spleen and induced to differentiate into different T cell subsets, YAP mRNA and protein expression were analyzed. Up-regulation of YAP was induced by lentivirus and down-regulation of YAP was induced by its specific inhibitor verteporfin (VP). The expression of YAP in skin lesions and infiltrating T cell subsets was detected using immunohistochemistry and double immunofluorescence staining, respectively. ResultsWe found differing degrees of Th1/Th2/Th17/Treg imbalance in acute and chronic AD. YAP expression was downregulated in Treg cells and upregulated in Th17 cells; YAP expression was downregulated in the AD epidermis. After YAP overexpression, the proportion of both Th17 and the Treg cells differentiated from mouse spleen mononuclear cells increased. There was an opposite trend after YAP inhibition. The proliferation and migration decreased and apoptosis increased after YAP inhibition in HaCaT cells. ConclusionChange of YAP expression may cause T cell imbalance and hamper the healing of the epidermis in AD.

Elaeagnus L gum polysaccharides alleviate the impairment of barrier function in the dry skin model mice.

Dry skin is a common skin condition caused by reduction of water-holding capacity, which is regulated by skin barrier function. Dry skin can also be a symptom that indicates a more serious diagnosis. There are a number of moisturizers on the market, which play an important role in dermatologic and cosmetic therapies. However, the demand for these products with good and therapeutic efficiency is still growing. It remains necessary to investigate the effects of Elaeagnus L gum polysaccharides (EAP), which are prepared from gum of Elaeagnus angustifolia L. on the epidermal permeability barrier function and their possible underlying mechanisms. EAP were purified, analyzed, and tested on human keratinocyte cell line (HaCaT) and then on the skin in vivo to evaluate their antiinflammatory activities and their impacts on impaired skin barrier function. Histological analyses revealed that topical administration with EAP effectively attenuated dryness-like skin condition, including less percutaneous water loss rate, less infiltrate inflammation cells, and less epidermal thickening. Moreover, EAP inhibited the production of various inflammatory mediators and increased AQP-3, FLG, and LOR expression. Our results indicated that EAP enhances epidermal permeability barrier function, and they can be used as a promising adjuvant agent in skin care cosmetics and in treating some skin disorders characterized by cutaneous inflammation and abnormal barrier function.

Anticancer activity of topical ointments with histone deacetylase inhibitor, trichostatin A

Trichostatin A (TSA), being a strong specific histone deacetylase (HDAC) inhibitor, may lead to the inhibition of growth, differentiation and/or apoptosis of cells in a number of tumors. Semisolid drug formulations for topical release of anticancer agents may be an alternative strategy or a supplement of the systemic therapy. To prepare semisolid formulations with TSA to be used directly on the skin and to assess the anticancer effect in vivo on a mouse model with L1 neoplastic tumors. Twenty-four formulations were prepared in the form of semisolid systems containing TSA as the active ingredient. Then, an in vitro study was performed concerning the release of the active substance from the prepared formulations. Four formulations were selected for in vivo studies: oil-in-water cream, hydrogel, w/o emulsion ointment on the absorptive hydrophobic medium, and o/w emulsion gel. The tumor size and mouse body weight were measured during the experiment. The tumors and healthy skin of the mice were assessed regarding the skin barrier function with the Corneometer and Tewameter probes. The semisolid formulation with TSA applied on the skin reduced the growth of neoplastic tumors as compared with the control group. This is especially pronounced in the case of w/o emulsion ointment and o/w emulsion gel. The Corneometer shows that neoplastic tumor growth and formulations on the skin have no effect on the skin condition in comparison with the mouse skin without tumor. The measurement performed with the Tewameter has revealed impaired skin barrier function of neoplastic tumors. Semisolid formulations with TSA fit well in the mainstream of research into topical medicines applied directly on neoplastic tumors, which may support and supplement current oncological treatment.

The use of probiotics and bacteria-derived preparations in topical treatment of atopic dermatitis—A systematic review

Atopic dermatitis (AD) is a highly widespread inflammatory skin disease affecting 5% to 20% of the population, associated with reduced quality of life, increased health care expenditures, and increased risk of developing other allergic diseases. The pathologic chain of phenomena in AD starts with (1) impaired skin barrier function, through (2) decreased bacterial diversity of the skin, and (3) susceptibility to skin infections (including Staphylococcus aureus predomination and colonization), toward (4) immune dysregulation.

The Suppressive Effect of Leucine-Rich Glioma Inactivated 3 (LGI3) Peptide on Impaired Skin Barrier Function in a Murine Model Atopic Dermatitis.

This study aimed to restore the skin barrier function from atopic dermatitis (AD) via treatment with leucine-rich glioma inactivated 3 (LGI3) peptide. Male NC/Nga mice (7 weeks, 20 g) were randomly allocated into three groups (control, AD, and LGI3 group). After induction of AD skin lesions with Dermatophagoides farinae ointment, mice were treated with LGI3. The clinical score of AD was the highest and the dorsal skin thickness was the thickest in the AD group. In contrast, LGI3 treatment improved the clinical score and the dorsal skin thickness compared to the AD model. LGI3 treatment suppressed histopathological thickness of the epithelial cell layer of the dorsal skin. LGI3 treatment could indirectly reduce mast cell infiltration through restoring the barrier function of the skin. Additionally, the filaggrin expression was increased in immunohistochemical evaluation. In conclusion, the ameliorating effect and maintaining skin barrier homeostasis in the AD murine model treated with LGI3 could be attributed to complete re-epithelialization of keratinocytes. Hence, LGI3 might be considered as a new potential therapeutic target for restoring skin barrier function in AD.

Lipidomics profiling of skin surface lipids in senile pruritus

BackgroundSenile pruritus is common, yet its etiology remains unknown. Aging-associated skin barrier defects and skin surface lipid (SSL) alterations have been postulated to play important roles in its occurrence. In the present study, the lipidomic profiles of SSLs in elderly patients were examined to better understand the potential causes of senile pruritus.MethodsTransepidermal water loss (TEWL) was evaluated to assess the skin barrier function. The Ameliorated Kawashima Itch Scale score was used to measure the pruritus severity. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis were employed to investigate SSL alterations.ResultsThe results showed that senile pruritus patients had higher TEWL values than control subjects (13.13 ± 4.28 versus 6.71 ± 2.45, p < 0.01). LC-MS/MS revealed significant differences in the lipidomic profiles and identified 81 species of SSLs that differed between the two groups. Compared with control subjects, senile pruritus patients had increased levels of ceramides (Cers), diacylglycerols, fatty acids, phosphatidylcholines, phosphatidylethanolamines, phytosphingosines, sphingosines, diacylceryl-3-O-carboxyhydroxymethylcholine, diacylglyceryl trimethylhomoserine, and unsaturated free fatty acids, but decreased levels of triacylglycerol. Cer-EOS, Cer-NDS, and Cer-NS were positively correlated with TEWL value (p < 0.05). Pruritus severity score was positively correlated with sphingomyelin, Cer-NP, Cer-AS, Cer-NDS, and Cer-NS, but negatively correlated with Cer-BS, Cer-EODS, Cer-EOS, and Cer-AP.ConclusionsThe present study indicated that patients with senile pruritus have impaired skin barrier function and altered SSL composition. Certain SSL species identified in this study may be potential targets for future studies on the pathogenesis of senile pruritus.Trial registrationPeking University International Hospital (Number: YN2018QN04; date: January 2019).

263 First in human use of a novel in vivo gene therapy for the treatment of autosomal recessive congenital ichthyosis: Results of a phase I/II placebo controlled trial

Autosomal recessive congenital ichthyosis (ARCI) is a rare, monogenic cornification disorder with erythema, epidermal scaling, ectropion, and impaired skin barrier function. Mutations in TGM1 encoding transglutaminase 1 are the predominant cause of ARCI, affecting >55% of US ARCI patients. Current therapeutic options for treating ARCI provide only symptomatic relief, necessitating the development of targeted therapeutics. KB105 is a novel, convenient, first in class, off-the-shelf disease correcting topical gene therapy for the treatment of TGM1-deficient ARCI.

413 Wildfire-associated air pollution impacts clinic visits for itch and atopic dermatitis

With climate change, the frequency and intensity of wildfires are expected to increase, leading to episodes of poor air quality that could exacerbate patients’ pre-existing dermatoses. To assess the effects of exposure to wildfire-associated air pollution on skin, we investigated if the 2018 California Camp Fire led to detectable increases in clinic visits for atopic dermatitis (AD) or itch at dermatology clinics 175 miles from the origin of the fire. We collected data from 2015-2019 on particulate matter (PM2.5) concentration and smoke plume density in San Francisco and the number of outpatient dermatology visits for AD or itch symptoms at an academic medical center. Data were analyzed using Poisson regression with empirical standard errors, and the models included exposure lags and covariates: patient age and sex, temperature, and humidity. We found that the rates of weekly pediatric AD clinic visits, adult AD clinic visits, and pediatric itch symptoms during the Camp Fire were respectively 1.75 (95% CI: 1.21, 2.50), 1.28 (1.08, 1.51), and 2.10 (1.44, 3.00) times the rate for non-fire weeks for a 0-week lag, adjusted for time of year and confounders. Every 10 μg/m3 increase in average weekly PM2.5 concentration was associated with an adjusted rate ratio of 1.08 (95% CI: 1.04, 1.12) for weekly pediatric AD clinic visits. Thus, there was increased use of dermatology services for AD associated with exposure to air pollution from the Camp Fire, particularly for the pediatric population. With an impaired skin barrier function, AD patients may be at increased risk of adverse skin reactions following pollution exposure, which can negatively impact quality of life. Understanding the effects of air pollution on patients’ skin health can inform how dermatologists counsel patients and expand comprehension of the broader health effects of climate change.

213 Increased 11β-hydroxysteroid dehydrogenase type 1 contributes to the impaired barrier in aged skin

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone, an inactive form of glucocorticoid (GC) into cortisol, the active form in human. It is expressed by several tissues including the skin. Excessive active GC deteriorates skin barrier function. Aged skin presents skin barrier impairment. This study was conducted in human and mice to determine if 11β-HSD1 affects the impaired barrier function of aged skin. For human study, elderly and young peoples were enrolled. Mice were divided into the wild aged mice, wild aged mice treated by topical 11β-HSD1 inhibitor, 11β-HSD1 knockout (KO) mice, wild young mice, and wild young mice treated by 11β-HSD1 inhibitor. Cortisol levels were elevated in the stratum corneum (SC) and oral epithelium of the elderly rather than the young. The 11β-HSD1 expression was increased in immunohistochemistry staining of aged mouse skin. Aged mice showed higher transepidermal water loss (TEWL) and lower SC hydration than young ones. Serum inflammatory cytokines such as interleukin-1α, -4, -31 and tumor necrosis factor-α were significantly increased in aged mice than in young mice. SC corticosterone was suppressed in aged 11β-HSD1 KO mice and topical 11β-HSD1 inhibitor applied wild-type mice. Horneodesmosome density was suppressed in aged wild mice, but elevated in aged 11β-HSD1 KO mice and in aged wild mice treated by topical 11β-HSD1 inhibitor. The number of lamellar bodies was increased in topical 11β-HSD1 inhibitor applied mice compared to wild aged mice. The amounts of SC lipids including ceramides, cholesterol, and fatty acids were increased in topical 11β-HSD1 inhibitor applied mice compared to wild aged mice. Expressions of mRNA of lipid synthesis related enzymes were increased in aged 11β-HSD1 KO mice and topical 11β-HSD1 inhibitor applied wild mice. Conclusively, 11β-HSD1 expression is elevated in the aged skin, that increases active GC and then deteriorates skin barrier function.

DRM02, a novel phosphodiesterase-4 inhibitor with cutaneous anti-inflammatory activity

ABSTRACT Chronic inflammatory skin disorders are frequently associated with impaired skin barrier function. Selective phosphodiesterase-4 (PDE4) inhibition constitutes an effective therapeutic strategy for the treatment of inflammatory skin diseases. We now report the pharmacological anti-inflammatory profile of DRM02, a novel pyrazolylbenzothiazole derivative with selective in vitro inhibitory activity toward PDE4 isoforms A, B and D. DRM02 treatment of cultured primary human and mouse epidermal keratinocytes interfered with pro-inflammatory cytokine production elicited by interleukin-1α and tumor necrosis factor-α. Similarly, DRM02 inhibited the production of pro-inflammatory cytokines by human peripheral blood mononuclear cells ex vivo and cultured THP-1 monocyte-like cells, with IC50 values of 0.6–14 µM. These anti-inflammatory properties of DRM02 were associated with dose-dependent repression of nuclear factor-κB (NF-κB) transcriptional activity. In skin inflammation in vivo mouse models, topically applied DRM02 inhibited the acute response to phorbol ester and induced Th2-type contact hypersensitivity reactivity. Further, DRM02 also decreased cutaneous clinical changes and expression of Th17 immune pathway cytokines in a mouse model of psoriasis evoked by repeated topical imiquimod application. Thus, the overall pharmacological profiling of the PDE4 inhibitor DRM02 has revealed its potential as a topical therapy for inflammatory skin disorders and restoration of skin homeostasis.