Interplay between diabetes mellitus and atopic dermatitis.

Inflammatory dermatoses such as atopic dermatitis (AD) have long been linked to the pathogenesis of diabetes mellitus. Indeed, numerous studies show an increased risk of diabetes mellitus in individuals with AD although lower prevalence of diabetes mellitus is also observed in few studies. Though the underlying mechanisms accounting for the reciprocal influence between these two conditions are still unclear, the complex interplay between diabetes mellitus and AD is attributable, in part, to genetic and environmental factors, cytokines, epidermal dysfunction, as well as drugs used for the treatment of AD. Proper management of one condition can mitigate the other condition. In this review, we summarize the evidence of the interaction between diabetes mellitus and AD, and discuss the possible underlying mechanisms by which these two conditions influence each other.

MiRNA-224-5p regulates the defective permeability barrier in sensitive skin by targeting claudin-5.

BACKGROUND: Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression. MATERIALS AND METHODS: A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin. RESULTS: Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures. CONCLUSION: These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin.

Preventive and Therapeutic Benefits of Natural Ingredients in Photo-Induced Epidermal Dysfunction.

BACKGROUND: The skin, particularly the epidermis, is subjected to various external stresses, including ultraviolet (UV) irradiation. UV irradiation, mainly UVB at wavelength of 280-315 nm, can alter several epidermal functions, including cutaneous inflammation, epidermal hyperproliferation, DNA damage, disruption of epidermal permeability barrier and reduction in stratum corneum hydration levels. Because of the negative impacts of UVB irradiation on epidermal functions, great efforts have been made to develop regimens for the protection of alterations in epidermal function induced by UV irradiation. SUMMARY: While sunscreen can provide physical barrier to UV light, some natural ingredients can also effectively protect the skin from UVB irradiation-induced damages. Studies have demonstrated that either topical or oral administrations of some natural ingredients attenuate UVB irradiation-induced alterations in the epidermal function. The underlying mechanisms by which natural ingredients improve epidermal functions are attributable to antioxidation, stimulation of keratinocyte differentiation, increases in the content of epidermal natural moisturizers and inhibition of inflammation. KEY MESSAGE: Some natural ingredients exhibit protective and therapeutical benefits in photo-induced epidermal dysfunctions via divergent mechanisms.

Link between obesity and atopic dermatitis: Does obesity predispose to atopic dermatitis, or vice versa?

Two serious health conditions, obesity and atopic dermatitis (AD), share some pathological features such as insulin resistance, leptin resistance and inflammation, and a growing body of evidence suggests a link between obesity and AD. Obesity predisposes an individual to and/or worsens AD, whereas AD increases the risk of obesity. Obesity and AD's interactions are mediated by cytokines, chemokines and immune cells. Obese individuals with AD are more resistant to anti-inflammatory therapy, while weight loss can alleviate AD. In this review, we summarize the evidence linking AD and obesity. We also discuss the pathogenic role of obesity in AD, and vice versa. Because of the connection between these two conditions, mitigation of one could possibly prevent the development of or alleviate the other condition. Effective management of AD and weight loss can enhance the wellness of individuals with both of these conditions. However, proper clinical studies are warranted to validate this speculation.

Stratum corneum hydration inversely correlates with certain serum cytokine levels in the elderly, possibly contributing to inflammaging.

BACKGROUND: Chronic, low-grade inflammation, also termed 'inflammaging', has been linked to the development of some aging-associated disorders. Recent studies suggest that inflammaging is attributable to aging-associated epidermal dysfunction. However, abnormality in which epidermal function contributes to inflammaging is not clear. OBJECTIVE: We delineated the correlation of epidermal functions with circulating levels of proinflammatory cytokines in the elderly. METHODS: Blood sample was collected from a total of 255 participants aged ≥ 65 years. Epidermal biophysical properties were measured on the left forearm and the right shin. Serum cytokine levels were measured by Multiplex Luminex Assays. RESULTS: Neither skin surface pH nor transepidermal water loss rates (TEWL) correlated with serum cytokine levels except TEWL on the right shin for TNFa (p < 0.05). In contrast, stratum corneum hydration levels on both the forearm and the shin correlated negatively with serum cytokine levels (p < 0.05). CONCLUSION: Reduced stratum corneum hydration likely contributes to inflammaging.

Trend of changes in epidermal biophysical properties in the Chinese aged 1 month to 17-year old.

BACKGROUND: Although it is known that epidermal biophysical properties vary with age and gender, the changes in epidermal biophysical properties over the time from baby to adolescence have not been elucidated yet. In the present study, we assessed the trend of changes in transepidermal water loss rates (TEWL), stratum corneum hydration, and skin surface pH in Chinese children. PARTICIPANTS AND METHODS: A total of 780 boys and 610 girls, aged 1 month to 17-year old, were enrolled in this study. TEWL and stratum corneum hydration on the forearm and the shin were measured with GPSkin Barrier, whereas skin surface pH was measured with portable skin pH meter. RESULTS: Overall, TEWL and stratum corneum hydration levels decreased, whereas skin surface pH increased in children from 1-month old to 17-year old. Significant decline in TEWL was observed on both the forearm and the shin of girls, and the shin of boys aged 13-17-year old. Similarly, marked decline in stratum corneum hydration levels started at ages of 6-12-year old. In contrast, decline in skin surface pH was observed in both girls and boys aged one to 12-month old except on the forearm of boys. Afterward, skin surface pH remained either stable or slight increase except on the shin of boys aged >12 months to 3-year old. CONCLUSIONS: These results demonstrate that both TEWL and stratum corneum hydration levels decrease, whereas skin surface pH increases in children aged 1 month to 17-year old. The changes in these biophysical properties vary with age, gender, and body site.

Association of Epidermal Biophysical Properties with Obesity and Its Implications.

BACKGROUND: Obesity is a condition defined by an excess amount of body fat, with body mass index (BMI) of 30 and higher. It is associated with a number of other medical conditions, including insulin resistance, diabetes mellitus, and cardiovascular diseases, as well as dyslipidemia, and it is also associated with several cutaneous disorders such as atopic dermatitis, psoriasis, intertriginous dermatitis, acanthosis nigricans and skin infections. SUMMARY: Evidence suggests a link between obesity and epidermal dysfunction. Generally, individuals with obesity display higher transepidermal water loss rate and lower stratum corneum hydration levels, although no association of obesity with epidermal dysfunction has been documented. Results of skin surface pH are controversial. But study demonstrated a positive correlation of BMI with skin surface pH on both the forearm and the shin in males, suggesting that the changes in epidermal function vary with gender in individuals with obesity. KEY MESSAGES: This review summarizes the association between obesity and epidermal function, and discusses possible underlying mechanisms. Individuals with obesity exhibit poor epidermal permeability barrier and lower stratum corneum hydration levels. Because of the pathogenic role of compromised epidermal function in inflammation, which is also linked to obesity, improvement in epidermal function could benefit individuals with obesity, particularly those with abnormalities in epidermal function.

Alterations in Epidermal Biophysical Properties in Autistic Children.

Autism is a neurodevelopmental disorder. Individuals with autism can exhibit multiple neurological symptoms such as deficit in social communication, restricted interests, and repetitive behaviors. Recent study showed that murine model of autism displays an increased transepidermal water loss (TEWL) and dry skin. But whether epidermal functions are also altered in children with autism is unknown. In the present study, TEWL, stratum corneum hydration, and skin surface pH were compared between children with autism (N = 56) and normal controls (N = 48). Our results showed that children with autism exhibited lower stratum corneum hydration levels, higher TEWL, and elevated skin surface pH in comparison to normal controls (p < 0.0001 for all). These results demonstrate that children with autism exhibit epidermal dysfunction.

Role of nitric oxide in regulating epidermal permeability barrier function.

Nitric oxide (NO), a free radical molecule synthesized by nitric oxide synthases (NOS), regulates multiple cellular functions in a variety of cell types. These NOS, including endothelial NOS (eNOS), inducible NOS (iNOS) and neural NOS (nNOS), are expressed in keratinocytes. Expression levels of both iNOS and nNOS decrease with ageing, and insufficient NO has been linked to the development of a number of disorders such as diabetes and hypertension, and to the severity of atherosclerosis. Conversely, excessive NO levels can induce cellular oxidative stress, but physiological levels of NO are required to maintain the normal functioning of cells, including keratinocytes. NO also regulates cutaneous functions, including epidermal permeability barrier homeostasis and wound healing, through its stimulation of keratinocyte proliferation, differentiation and lipid metabolism. Topical applications of a diverse group of agents which generate nitric oxide (called NO donors) such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) can delay permeability barrier recovery in barrier-disrupted skin, but iNOS is still required for epidermal permeability barrier homeostasis. This review summarizes the regulatory role that NO plays in epidermal permeability barrier functions and the underlying mechanisms involved.

Aged and young mice differentially respond to tape-stripping in epidermal gene expression.

Disruption of epidermal permeability barrier induces an increase in proinflammatory cytokine expression and release, stimulation of epidermal lipid and DNA synthesis, and expression of antimicrobial peptides. Although alterations in epidermal function in the aged skin are known, whether the epidermal transcriptomic responses to barrier disruption differ between aged and young mice remains unknown. Here, we performed RNA sequencing of the epidermis in 2-month- vs. 20-month-old mice following barrier disruption with repeated tape-stripping. At baseline condition, the epidermis of 20-month-old mice displayed an upregulation of inflammation-associated genes and down-regulation of epidermal structure- and development-related genes in comparison to 2-month-old mice. Barrier disruption upregulated expression levels of 327 genes and downregulated 209 genes in 2-month-old mice. In 20-month-old mice, the numbers of upregulated and down-regulated genes were 537 and 299, respectively. In comparison to young mice, the prominently upregulated genes in the 20-month-old mice were associated with the IL-17 signalling pathway, while downregulated genes were mainly involved in the cytokine-cytokine receptor interaction pathway. These results indicate that inflammation-associated signalling pathways are upregulated, while epidermal structure- and development-related genes are downregulated in the epidermis of aged mice, with further aggravation following barrier disruption, suggesting the importance of improving epidermal function in the elderly.

Correlation of Body Mass Index with Epidermal Biophysical Properties Varies with Gender in Chinese.

BACKGROUND: Epidermal function is associated with diabetes and renal disease. Whether obesity can reflect the changes in epidermal function is not clear yet. OBJECTIVE: We assessed here the correlation of epidermal functions with body mass index (BMI) in a large Chinese cohort. METHODS AND SUBJECTS: A total of 1,405 Chinese aged 21-98 years old were enrolled in this study. Epidermal functions, including transepidermal water loss (TEWL), stratum corneum hydration, and skin surface pH, were measured on the flexor forearm and the shin. Subjects' height and body weight were also measured. RESULTS: Age positively correlated with both TEWL and skin surface pH, while it negatively correlated with stratum corneum hydration on both the forearm and the shin of females. Similarly, age positively correlated with skin surface pH, while negatively correlating with stratum corneum hydration on both the forearm and the shin of males. In females, BMI positively correlated with skin surface pH, while it negatively correlated with stratum corneum hydration on both the forearm and the shin. However, BMI correlated neither with skin surface pH on both the forearm and the shin nor with stratum corneum hydration on the shin of males. CONCLUSION: These results demonstrate that correlations of BMI with age and epidermal functions vary with gender.

Efficacy and safety of 755 nm Q-switched Alexandrite Laser for Hori's nevus: a retrospective analysis of 482 Chinese women.

To evaluate the efficacy and safety of 755 nm Q-Switched alexandrite laser for Hori's nevus in a large cohort of Chinese women. We retrospectively analyzed the efficacy and safety of 755 nm Q-Switched alexandrite laser for Hori's nevus. Reduction in pigment was evaluated using a 4-score method. A total of 482 patients, aged 16 to 52 years, were included in this analysis. Patients were treated with 755 nm Q-Switched alexandrite laser at fluence levels of 5-8 J/cm2 for 2-4 treatment sessions. Following the treatments, 53% of patients showed over 75% reductions in pigment while 50-75% reductions in pigment were observed in 28% of patients. The rest displayed less than 50% improvements. Efficacy was positively correlated with the number of treatment sessions (p < 0.0001). Adverse reactions were temporary, mild erythema, and edema. A small portion of patients (15%) had hyperpigmentation, which disappeared within 2-6 months. 755 nm Q-Switched alexandrite laser is safe and has moderate benefits for Hori's nevus. Because its efficacy is positively correlated with the number of treatment sessions, increase in treatment sessions possibly could achieve a better outcome.

Mutations in 3ß-hydroxysteroid-δ8, δ7-isomerase paradoxically benefit epidermal permeability barrier homeostasis in mice.

Inherited or acquired blockade of distal steps in the cholesterol synthetic pathway results in ichthyosis, due to reduced cholesterol production and/or the accumulation of toxic metabolic precursors, while inhibition of epidermal cholesterol synthesis compromises epidermal permeability barrier homeostasis. We showed here that 3ß-hydroxysteroid-δ8, δ7-isomerase-deficient mice (TD), an analog for CHILD syndrome in humans, exhibited not only lower basal transepidermal water loss rates, but also accelerated permeability barrier recovery despite the lower expression levels of mRNA for epidermal differentiation marker-related proteins and lipid synthetic enzymes. Moreover, TD mice displayed low skin surface pH, paralleled by increased expression levels of mRNA for sodium/hydrogen exchanger 1 (NHE1) and increased antimicrobial peptide expression, compared with wild-type (WT) mice, which may compensate for the decreased differentiation and lipid synthesis. Additionally, in comparison with WT controls, TD mice showed a significant reduction in ear thickness following challenges with either phorbol ester or oxazolone. However, TD mice exhibited growth retardation. Together, these results demonstrate that 3ß-hydroxysteroid-δ8, δ7-isomerase deficiency does not compromise epidermal permeability barrier in mice, suggesting that alterations in epidermal function depend on which step of the cholesterol synthetic pathway is interrupted. But whether these findings in mice could be mirrored in humans remains to be determined.

Topical Applications of a Heparinoid-Containing Product Attenuate Glucocorticoid-Induced Alterations in Epidermal Permeability Barrier in Mice.

INTRODUCTION: Either systemic or topical glucocorticoids (GCs) can cause significant adverse effects on cutaneous structure and function. Although some products and ingredients can improve GC-induced abnormalities in epidermal permeability barrier, the efficacy is moderate. Prior studies in normal mice showed that topical applications of a heparinoid-containing product, Hirudoid® cream, improve epidermal barrier function by upregulation of epidermal proliferation, expression of mRNA for epidermal differentiation, and lipid production. OBJECTIVE: The objective of this study was to assess whether topical applications of this product could prevent GC-induced changes in epidermal function in murine skin. MATERIALS AND METHODS: One group of C57BL/6J mice was treated topically with 0.05% clobetasol propionate twice daily for 6 days, while another group was treated topically with Hirudoid® cream 30 min after each application of clobetasol propionate. Untreated mice served as normal controls. Transepidermal water loss (TEWL) rates, stratum corneum hydration, and skin surface pH were measured using respective probes connected to an MPA5 physiology monitor. qPCR was used to measure the expression levels of mRNA for keratinocyte differentiation-related proteins and lipid synthetic enzymes. RESULTS: Co-applications of Hirudoid® cream with GC minimally, but significantly, increased skin thickness in comparison to GC treatment alone (p < 0.05), in parallel with increased expression levels of mRNA for PCNA in both the dermis and the epidermis. Moreover, Hirudoid® cream largely prevented GC-induced elevation in basal TEWL (p < 0.001) and delay in barrier recovery (p < 0.05), accompanied by upregulation in the expression levels of mRNA for epidermal involucrin, HMGCoA, and SPT1. However, both stratum corneum hydration and skin surface pH were comparable in the skin treated with GC alone versus GC + Hirudoid® cream. CONCLUSION: Topical heparinoid-containing product can partially prevent GC-induced alterations in some epidermal functions.

Inducible nitric oxide synthase is required for epidermal permeability barrier homeostasis in mice.

Nitric oxide (NO) regulates a variety of epidermal functions, including epidermal proliferation, differentiation and cutaneous wound healing. However, whether nitric oxide (NO) and its synthetic enzymes regulate epidermal permeability barrier homeostasis is not clear. In the present study, we employed inducible nitric oxide synthase (iNOS) KO mice to explore the role of iNOS in epidermal permeability barrier homeostasis. Our results showed that iNOS mice displayed a comparable levels of basal transepidermal water loss rates, stratum corneum hydration and skin surface pH to their wild-type mice, but epidermal permeability barrier recovery was significantly delayed both 2 and 4 hours after acute barrier disruption by tape stripping. In parallel, expression levels of mRNA for epidermal differentiation-related proteins and lipid synthetic enzymes were lower in iNOS KO mice versus wild-type controls. Topical applications of two structurally unrelated NO donors to iNOS KO mice improved permeability barrier recovery kinetics and upregulated expression levels of mRNA for epidermal differentiation-related proteins and lipid synthetic enzymes. Together, these results indicate that iNOS and its product regulate epidermal permeability barrier homeostasis in mice.

Seasonal variations of epidermal biophysical properties in Kunming, China: A self-controlled cohort study.

BACKGROUND: Epidermal biophysical properties can be affected by many factors, including body site, age, gender, ethnicity, disease, temperature, humidity, and ultraviolet (UV) radiation. Information about variation of epidermal biophysical properties with seasons is still limited. In the present study, we determined seasonal variation of epidermal biophysical properties of women in Kunming, China. MATERIALS AND METHODS: A total of 72 women, aged 22.96 ± 2.11 years, were enrolled in this study. Transepidermal water loss rates (TEWL), stratum corneum (SC) hydration, sebum content, melanin index (MI), erythema index (EI), and L*a* values were measured on the right cheek and the right forearm, using a non-invasive skin physiological instrument in the spring, summer, autumn, and winter in Kunming, China. RESULTS: On the cheek, TEWL, SC hydration, sebum, MI, and L*a* values varied greatly with seasons (P < .05). SC hydration, sebum, MI, and a*value peaked in the summer, but went lowest in winter. In contrast, TEWL and L*value went lowest in summer but peaked in winter. Similarly, SC hydration, MI, and L*value also varied with seasons on the forearm (P < .05). In addition, SC hydration, sebum, MI, EI, and a*value of the cheek were higher than that of the forearm (P < .001), but L*values of the cheek were lower than that of the forearm (P < .001). There were no correlations among TEWL and MI, EI, and L*a*values in any season (P > .05). CONCLUSIONS: Both epidermal permeability barrier function, sebum, and skin pigment in healthy women vary seasons in Kunming, China.

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.

A topical heparinoid-containing product improves epidermal permeability barrier homeostasis in mice.

Because of the importance of epidermal functions, including stratum corneum hydration and maintenance of permeability barrier homeostasis, in the pathogenesis of a variety of cutaneous and systemic disorders, a wide range of products has been developed to improve epidermal functions. However, the underlying mechanisms whereby certain products, including heparinoid-containing product, are far little understood. In the present study, we assessed the impact of a heparinoid-containing product, Hirudoid® cream, on epidermal permeability barrier function and expression levels of a panel of epidermal mRNA related to the formation/maintenance of the permeability barrier in mouse skin. Our results showed that while the baseline levels of transepidermal water rates remained unchanged, treatment with Hirudoid® cream twice daily for 7 days significantly accelerated permeability barrier recovery and increased stratum corneum hydration. In parallel, expression levels of epidermal mRNA for certain differentiation marker-related proteins, lipid synthetic enzymes, keratinocyte proliferation and antimicrobial peptides also increased significantly. Together, these results provide the underlying mechanisms by which topical Hirudoid® cream improves epidermal permeability barrier and antimicrobial function. Because of its benefits for epidermal functions, heparinoid-containing product could be more useful in the management of skin conditions, characterized by abnormal permeability barrier and antimicrobial function.

Moisturizers versus Current and Next-Generation Barrier Repair Therapy for the Management of Atopic Dermatitis.

We compare here the principal characteristics of over-the-counter moisturizers with physiologic lipid-based barrier repair therapy. Moisturizers are standard ancillary therapy for anti-inflammatory skin disorders, like atopic dermatitis (AD), and can attenuate the emergence of AD, the initial step in the "atopic march." But not all moisturizers are beneficial; some can make skin function worse, and can even induce inflammation, possibly accounting for the frequent occurrence of "sensitive skin" in women. In contrast, physiologic lipid-based barrier repair therapy, if comprised of the 3 key stratum corneum lipids, in sufficient quantities and at an appropriate molar ratio, can correct the barrier abnormality and reduce inflammation in AD, and perhaps in other inflammatory dermatoses.