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The incidence of hypertension and cardiovascular disease (CVD) correlates with latitude and rises in winter. The molecular basis for this remains obscure. As nitric oxide (NO) metabolites are abundant in human skin, we hypothesized that exposure to UVA may mobilize NO bioactivity into the circulation to exert beneficial cardiovascular effects independently of vitamin D. In 24 healthy volunteers, irradiation of the skin with two standard erythemal doses of UVA lowered blood pressure (BP), with concomitant decreases in circulating nitrate and rises in nitrite concentrations. Unexpectedly, acute dietary intervention aimed at modulating systemic nitrate availability had no effect on UV-induced hemodynamic changes, indicating that cardiovascular effects were not mediated via direct utilization of circulating nitrate. UVA irradiation of the forearm caused increased blood flow independently of NO synthase (NOS) activity, suggesting involvement of pre-formed cutaneous NO stores. Confocal fluorescence microscopy studies of human skin pre-labeled with the NO-imaging probe diaminofluorescein 2 diacetate revealed that UVA-induced NO release occurs in a NOS-independent, dose-dependent manner, with the majority of the light-sensitive NO pool in the upper epidermis. Collectively, our data provide mechanistic insights into an important function of the skin in modulating systemic NO bioavailability, which may account for the latitudinal and seasonal variations of BP and CVD.

Apical extracellular matrices (aECMs) act as crucial barriers, and communicate with the epidermis to trigger protective responses following injury or infection. In Caenorhabditis elegans , the skin aECM, the cuticle, is produced by the epidermis and is decorated with periodic circumferential furrows. We previously showed that mutants lacking cuticle furrows exhibit persistent immune activation (PIA), providing a valuable model to study the link between cuticle damage and immune response. In a genetic suppressor screen, we identified spia-1 as a key gene downstream of furrow collagens and upstream of immune signalling. spia-1 expression oscillates during larval development, peaking between each moult together with patterning cuticular components. It encodes a secreted protein that localises to furrows. SPIA-1 shares a novel cysteine-cradle domain with other aECM proteins. SPIA - 1 mediates immune activation in response to furrow loss and is proposed to act as an extracellular signal activator of cuticle damage. This research provides a molecular insight into intricate interplay between cuticle integrity and epidermal immune activation in C. elegans .

Background Fatty acids increase ATP‐binding cassette ABC transporter A12 (ABCA12) levels via an increase in peroxisome proliferator‐activated receptor β/δ (PPAR β/δ). Promoting lipid transport to lamellar granules has been suggested to improve epidermal barrier function in patients with dry skin. Objective We investigated whether mevalonolactone (MVL) produced by Saccharomycopsis fibuligera improves dry skin by promoting ABCA12 expression and the amount of free fatty acids in epidermal keratinocytes. Methods We examined whether MVL increases ABCA12 mRNA and protein levels and the amount of Nile red‐positive lipids in cultured epidermal keratinocytes and in a three‐dimensional epidermal model by cell staining. Promotion of fatty acid production by MVL was analyzed by liquid chromatography‐mass spectrometry. We also evaluated whether MVL addition increases PPAR β/δ mRNA expression in cultured keratinocytes. Based on the results, a randomized controlled trial was conducted in which milky lotions containing MVL and placebo were applied to dry facial skin of healthy female volunteers in winter. Results MVL increased ABCA12 mRNA and protein levels and lamellar granule number and size. Fatty acid analysis revealed that MVL elevated myristic acid, palmitic acid, and palmitoleic acid levels as well as PPAR β/δ mRNA expression. In human tests, milky lotions containing MVL were shown to significantly improve transepidermal water loss (TEWL) in the stratum corneum compared to placebo. Conclusion The results suggest that MVL increases fatty acid uptake and ABCA12, promotes fatty acid transport to lamellar granules, and improves epidermal barrier function in dry skin through increased expression of PPAR β/δ.

Background A new, emollient‐rich moisturizing cream has been developed to support three critical elements of natural skin moisturization—hyaluronic acid, natural moisturizing factors, and lipids. Aims The aim of this study was to evaluate in vitro biomarkers associated with skin hydration and barrier support, followed by in vivo clinical hydration assessment and tolerability. Methods Using an in vitro epidermal skin model, tissues were treated with the study moisturizer or control (saline) for 24 h. Genes associated with hydration and barrier support were analyzed: claudin 4 (CLD4), aquaporin 3 (AQP3), hyaluronic acid synthase 2 (HAS2), and hyaluronidase 1 (HYAL1). The clinical study evaluated twice‐daily use of the study moisturizer in subjects with moderate‐to‐severe dry skin. Subject satisfaction and skin hydration measurements were captured at baseline, 2, 4, and 8 weeks. Results Increased expression of CLD4, AQP3, and HAS2 and reduced activity of HYAL1 were demonstrated after 24 h. In subjects applying the study moisturizer, significant mean percent improvements from baseline in skin hydration occurred at Weeks 2 (41%; p < 0.0001), 4 (38%; p < 0.0001), and 8 (116%; p < 0.0001). Ninety‐six percent of subjects reported their skin felt hydrated after 8 weeks. Conclusions An emollient‐rich moisturizing cream developed to support three critical elements of natural skin moisturization increased the expression of biomarkers associated with skin barrier support and hydration, and reduced the expression of HA‐degrading enzymes. Early, significant increases in skin hydration were observed.

Although vitamin D (VD) is known to have multiple effects on the skin and immunity, its effects on atopic dermatitis (AD) severity remain unclear. We investigated whether oral cholecalciferol (VD3) supplementation changes stratum corneum expression of the vitamin D receptor ( vdr ), and the epidermal alarmins Cathelicidin Antimicrobial Peptide ( camp /LL-37) and Thymic Stromal Lymphopoietin ( tslp ) in children with AD. We conducted an open-label supplementation study with weekly oral VD3 for six weeks in children with AD. Serum 25-hydroxyvitamin D (25OHD), lesional Staphylococcus aureus colonization, and AD severity evaluated by SCORAD index were evaluated before and after supplementation. Tape stripping (TS) was performed on non-lesional and lesional skin to measure mRNA expression of vdr , camp , and tslp through RT-qPCR and LL-37 peptide by ELISA. Twenty-two children with moderate–severe AD received weekly oral VD3 for six weeks. Total serum 25OHD increased from 45.1 ± 23 to 93.5 ± 24.3 nmoL/L ( p  < 0.0001), while SCORAD decreased from 41.4 ± 13.5 to 31.5 ± 15.8 ( p  < 0.0001). After treatment, epidermal gene expression of camp increased significantly in non-lesional ( p  = 0.014) and lesional ( p  = 0.0007) tape stripping samples, while vdr only increased in lesional skin samples ( p  < 0.0001) . LL-37 peptide increased significantly only in lesional skin samples ( p  = 0.008). Gene expression of tslp did not change after oral VD3 treatment. In children with AD, oral VD3 supplementation was associated with improved VD status and AD severity, as well as increased VDR and Cathelicidin expression in lesional skin, which provide mechanistic clues on its effects.

The influence of a topically applied formulation containing components of natural moisturizing factor (NMF) on barrier-related parameters of the stratum corneum (SC) was investigated in vivo using confocal Raman microspectroscopy in a randomized, placebo-controlled double-blind study on 12 volunteers for 14 days. This method allowed for the elucidation of subtle differences between the verum and the placebo even though the components of the verum naturally occur in the SC. This differentiation is not possible non-invasively by conventional methods. In this study, we found that the applied verum and placebo formulations disrupted the equilibrium of water, NMF and lipids in the SC. The adverse effects of the formulation could be mitigated by incorporating it into a simplified supplementation of NMF molecules. As a long-term effect, the amount of strongly bound water increases at 30–40% SC depth (p < 0.05) and the amount of weakly bound water decreases at 30–40% SC depth (p < 0.05) for the verum. This supplement was also unexpectedly able to prevent intercellular lipids (ICL) disorganization in selected depths. In the long term, the verum treatment limited the lateral disorganization of the ICL to the upper 20% SC depth. Further research is required to elucidate the interplay of these factors in the SC, to better understand their contribution to the equilibrium and barrier function of the skin. This understanding of the interaction of these naturally occurring components could help in the future to develop and optimize topical treatments for diseases like psoriasis, atopic dermatitis, ichthyosis where the skin barrier is disrupted.

The stratum corneum (SC) is the outermost layer of the epidermis and plays an important role in maintaining skin moisture and protecting the skin from the external environment. Ceramide and natural moisturizing factor (NMF) are the major SC components that maintain skin moisture. In this study, we investigated whether the oral intake of enzymatically decomposed AP collagen peptides (APCPs) can improve skin moisture and barrier function by assessing changes in the ceramide and NMF contents in the SC after APCP ingestion with the aim to develop a skin functional food. Fifty participants orally ingested APCP (1000 mg) or placebo for 12 weeks, and then, skin hydration and skin texture were evaluated. SC samples were collected to analyze skin scaling, ceramide, and NMF contents. Participants in the APCP group exhibited improved skin moisture content by 7.33% (p = 0.031) and roughness by −4.09% (p = 0.036) when compared with those in the placebo group. NMF content; the amounts of amino acids (AA), including glycine and proline; and AA derivatives were significantly increased in the APCP group (31.98 μg/mg protein) compared to those in the placebo group (−16.01 μg/mg protein) (p = 0.006). The amounts of total ceramides and ceramide subclasses were significantly higher in the APCP group than in the placebo group (p = 0.014). In conclusion, our results demonstrate that APCP intake improves skin moisture and increase the ceramide and NMF contents in the SC, thereby enhancing the skin barrier function.

Background Changes in the level or profile of ceramides are associated with decreased stratum corneum (SC) barrier function. Topical application of a pseudo‐ceramide (pCer)‐containing moisturizer can improve barrier function. Additionally, pCer that absorbs into the SC may improve ceramide profiles. Aim We investigated the relationship between pCer absorption into the SC and SC properties and determined the efficacy of a pCer‐containing spray compared with that of a commercial spray without pCer. Patients/Methods Patients with self‐perceived dry and sensitive skin and decreased barrier function (transepidermal water loss [TEWL] > 10 g/m2h) were randomized into two groups to topically apply a pCer‐containing spray (test group; N = 33) or commercial spray without pCer (control group; N = 19) twice daily as a single‐blind study. SC function and ceramide properties were investigated before and after 4 weeks of application. Results In the test group, the ceramide (NP)/(NS) ratio proportionally increased with the pCer application level after 4 weeks of pCer‐containing spray application. In the control group, there were no changes in SC function after topical application of the commercially available spray without pCer; however, the SC water content, TEWL, SC cell area, and scaling score improved in the test group. Furthermore, the changes in TEWL in the test group were significantly negatively correlated with the pCer application level. Conclusions The efficacy of pCer‐containing sprays for those who have sensitive skin with impaired barrier function was demonstrated. Furthermore, the improvement in SC barrier function induced by pCer may contribute to normalizing the SC ceramide profile.

Background Sensitive skin requires targeted care to improve barrier function, reduce inflammation, and manage neurovascular reactivity. Objective Encorelane, a novel ingredient blend of saccharide isomerate, ribose, and fructooligosaccharides, was evaluated for its efficacy in addressing sensitive skin and visible aging signs. Methods In vitro: A 3D epidermal model (EpiKutis) with Sodium Lauryl Sulfate (SLS) induction was used to assess cytokines (interleukin 1α [IL‐1α], interleukin 6 [IL‐6], interleukin 8 [IL‐8], tumor necrosis factor α [TNF‐α], prostaglandin E2 [PGE2]) and barrier markers (filaggrin [FLG], loricrin [LOR], transglutaminase 1 [TGM1]). Hydration was examined via aquaporin 3 (AQP3) expression levels. Anti‐wrinkle efficacy was tested against UVA/UVB exposure, evaluating collagen synthesis and skin matrix components (Collagen types I, III, IV, VII, XVII, Laminin 5, hyaluronic acid [HA], Chondroitin sulfate [CS]). In vivo: A 6‐week double‐blind, half‐face study in 23 sensitive‐skin subjects evaluated the clinical effects of Encorelane versus placebo on repair, redness, firmness, and wrinkles. Results In vitro: Compared to the control group, Encorelane significantly reduced the levels of IL‐1α, TNF‐α, IL‐6, IL‐8, and PGE2 (p < 0.05), and significantly increased the levels of AQP3, FLG, LOR, TGM1, collagen types I, III, IV, VII, XVII, and laminin 5 (p < 0.05). In vivo: Compared to the placebo, Encorelane significantly improved TEWL, R2, F4, and crow's feet wrinkles (p < 0.05). Conclusion Encorelane effectively targets both inflammation and aging signs, supporting its use as a dermocosmetic solution for sensitive, aging‐prone skin.

Xerosis affects up to 75% of older people and develops as a result of a skin barrier defect. Emollients are widely used to treat xerosis; however, there is limited understanding of the differences between them and their effects on the skin barrier in older people. This study aimed to compare the effect of a commercially available emollient containing 5% urea, ceramide NP and lactate (test emollient) to an alternative emollient without these additives (control emollient) on the properties of the skin barrier in older people. Two cohorts of 21 volunteers aged >60 years with dry skin were recruited. The first applied the test emollient to one forearm and no treatment to the other for 28 days. The second compared the test emollient to the control emollient observing the same parameters. Effects on the skin barrier were determined by measuring skin barrier function, hydration, skin surface pH and by analysing Fourier transform infrared spectra before and after treatment. A third cohort of 6 young adults was recruited to investigate the effect of a single treatment with the test emollient on the molecular structure of the skin barrier at greater depths by employing the tape-stripping technique. The test emollient hydrated the skin to a significantly greater extent and for a longer period of time compared to the control emollient, an effect associated with a significant elevation of carboxylate groups (a marker of natural moisturizing factor content) within the stratum corneum. Furthermore, the test emollient imparted additional benefits to the structure and function of the skin barrier not exhibited by the control emollient. In conclusion, the test emollient addressed the pathological features of xerotic aged skin, supporting its use as first-line therapy for xerotic skin conditions in this population.