Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by barrier dysfunction and immune dysregulation, often leading to increased allergen penetration, sensitization, and secondary infections. Colloidal oat emollients are widely used in adult AD management, but their role in pediatric AD treatment, prevention, and allergy modulation remains under investigation.

A comprehensive literature review evaluated clinical and preclinical studies on colloidal oat-containing emollients in pediatric AD treatment and prevention. Studies assessing skin barrier function, immune modulation, AD prevention, food allergy risk, and healthcare utilization were included.

Colloidal oat emollients improved skin hydration, reduced transepidermal water loss (TEWL), and supported barrier repair, leading to fewer AD flares and reduced reliance on steroid treatments. Studies suggest that early, consistent use of advanced emollient formulations may lower AD incidence in high-risk infants and reduce food sensitization rates. Real-world data indicate that patients using colloidal oat emollients have fewer clinic visits and lower overall healthcare costs. Concerns about oat sensitization remain unsubstantiated in most studies.

Colloidal oat emollients are effective, well-tolerated, and cost-efficient for pediatric AD management. Their barrier-restorative and anti-inflammatory properties may reduce AD and allergy risk. Future research should focus on head-to-head emollient comparisons to optimize treatment strategies.

In vitro permeation test (IVPT) is a critical part of the prescription screening and evaluation of topical/transdermal drug delivery systems, in which ex vivo human skin or animal skin are generally used as skin membranes. The development of skin equivalents to replace animal/ human skins has high scientific and industrial value owing to the issues such as ethical issues and large variability of real skin. Here, a double-layer skin equivalent (DSE) containing both dermal-simulating structure and epidermal barrier function was developed. The dermal structure was composed of photo-crosslinked glycosaminoglycan, calcium alginate and gelatin; while the epidermal barrier-simulating structure was an electrospun nano-polyurethane-membrane. Mainly contributed to the synergistic effect of polysaccharide and protein composites, the formed DSE had similar compression modulus to that of real full-layer skin. Most of all it exhibited high correlation and similar transdermal drug release behavior with mini-porcine skin for three model drugs with different Log P. The DSE also showed comparable kinetic model fitting results to mini-porcine skin and exhibited a closer resemblance to porcine skin than other skin equivalents reported. Moreover, the penetration resisting ability of the DSE can be adjusted by adjusting the formulation to simulate different types of skin.

Cyclodextrins (CDs) are efficient drug carriers for improving drug solubility, stability, and bioavailability. However, the mechanism underlying the interaction between cyclodextrin-drug inclusion complexes and skin remains unclear. In this work, molecular simulations were employed to study the release process of cyclodextrin-resveratrol inclusion complexes on the surface of the lipid bilayer. The results showed that structural orientation significantly influences release kinetics. Resveratrol (RES) is able to form inclusion complexes with β-CD in two possible orientations: M-form (Mono-hydroxyl group toward the primary rim of β-CD) and D-form (Di-hydroxyl group toward the secondary rim of β-CD). M-form inclusion structures facilitated RES release more efficiently than D-form configurations. Cavity-specific lipid interactions are the dominant driver of the release process. Meanwhile, it was determined that the β-CD/RES inclusion complex exhibited greater stability than γ-CD/RES and demonstrated superior release efficiency at the lipid membrane surface in comparison to α-CD/RES. This suggests that the cavity size of β-CD is more suitable for delivering resveratrol. Furthermore, umbrella sampling simulations reveal that hydroxypropyl-substituted β-CD could lessen the irritation to the lipid bilayer. The present study provides a theoretical foundation for the rational design of CD-based drug delivery systems.

The skin serves as an essential barrier against pathogens and external insults, preventing moisture loss. Chronic skin conditions such as atopic dermatitis stem from impairments in skin barrier function. Circadian rhythms affect skin blood flow and barrier characteristics, which are significant for understanding atopic dermatitis. Cinnamomum cassia bark, commonly known as cinnamon, is extensively utilized in both modern and Traditional Chinese Medicine for its therapeutic properties in managing chronic diseases. This study aimed to investigate the potential use of Cinnamomum cassia bark in enhancing skin barrier function. We examined the impact of Cinnamomum cassia bark extract (CCBE) on circadian clock-mediated enhancement of the skin barrier. CCBE enhanced the expression of keratinocyte differentiation markers, including keratin 10, filaggrin, caspase 14, and calpain-1. CCBE also increased the production of hyaluronic acid protein. Additionally, CCBE improved the circadian rhythm of period circadian regulator 2 (PER2). Notably, CCBE upregulated the expression of keratinocyte differentiation markers and PER2 specifically during the morning hours. Furthermore, we discovered that siRNA-mediated PER2 knockdown diminished the increase in keratinocyte differentiation markers induced by CCBE. These findings demonstrate that CCBE can regulate the differentiation of keratinocytes in a time-of-day-dependent manner via the circadian clock. CCBE augmented phosphorylation of p38 and JNK, while the CCBE-induced enhancement in FLG expression and PER2 circadian rhythm was reduced by p38 MAPK inhibitors. These results suggest that CCBE can strengthen the skin barrier diurnally via the p38 MAPK pathway, representing a novel and more effective method for enhancing skin barrier function that accommodates daily variations in skin barrier properties.

Rapid developments in the field of organotypic cultures have generated a growing need for effective and non-invasive methods for quality control during tissue development. In this study, we correlate metabolic changes with epidermal differentiation and demonstrate that multiphoton microscopy with fluorescence lifetime imaging (MPM-FLIM) can be applied to monitor epidermal differentiation of keratinocytes with respect to proliferative and differentiated states. In a 2D keratinocyte tissue culture model, increased expression of differentiation markers keratin-1 and keratin-10 was induced with calcium supplementation. An accompanying shift from glycolysis to mitochondrial respiration was detected in metabolic flux assays. Analysis of MPM-FLIM images acquired at 750 nm and 900 nm excitation revealed a decreased relative fraction of intracellular NADH and FAD after high calcium treatment, consistent with increased oxidative phosphorylation. Epidermal differentiation could be monitored over a 96 h period. Discrimination analysis based on k-means clustering generated clusters that correlated well with the duration of high Ca2+ treatment, suggesting that MPM-FLIM can provide useful parameters for monitoring keratinocyte differentiation.

Reptiles, birds, mammals and amphibians, together forming the clade tetrapods, have a large diversity of cornified skin appendages, such as scales, feathers, hair and claws. The skin appendages consist of dead epithelial cells that are tightly packed with specific structural proteins. Here, we review the molecular diversity and expression patterns of major types of skin appendage proteins, namely keratin intermediate filament proteins, keratin-associated proteins (KRTAPs) and proteins encoded by genes of the epidermal differentiation complex (EDC), including corneous beta-proteins, also known as beta-keratins. We summarize the current knowledge about the components of skin appendages with a focus on keratins and EDC proteins that have recently been identified in reptiles and birds. We discuss gaps of knowledge and suggest directions of future research.

Terpenes are widely used in cosmetic formulations as chemical penetration enhancers (CPEs). However, the molecular mechanisms underlying the skin-penetration-enhancing effect have not been completely understood. In this work, molecular dynamics (MD) simulations were used to explore the influence of terpineol (TER), 1,8-cineole (CIN), and limonene (LIM) on the stratum corneum (SC) model. The results indicated that terpenes affected lipid membranes in a concentration-dependent manner and promoted skin permeation by disorganizing the cholesterol (CHOL) portion. The penetration of CPEs across the skin membrane also differed, with diffusion rates of limonene > 1,8-cineole > terpineol. The limonene molecules could penetrate the bilayer's center, forming a "triple layer" membrane structure. Furthermore, constrained simulations showed that the most favorable penetration pathway is via areas rich in CHOL. Terpineol could lower the energy barrier of the hydrophilic molecule (caffeic acid) across the cholesterol region. For the lipophilic molecule (osthole), limonene and 1,8-cineole could reduce the energy barrier across the cholesterol region. Each of the results provides novel insights into the mechanism of penetration of CPEs in the skin.

Exo70, a key exocyst complex component, is crucial for cell motility and extracellular matrix (ECM) remodeling in cancer metastasis. Despite its potential as a drug target, Exo70's post-translational modifications (PTMs) are poorly characterized. Here, we report that Exo70 is transamidated on Gln5 with Lys56 of cystatin A by transglutaminases TGM1 and TGM3, promoting tumor metastasis. This modification enhances Exo70's association with other exocyst subunits, essential for secreting matrix metalloproteinases, forming invadopodia, and delivering integrins to the leading edge. Tumor suppressor liver kinase B1 (LKB1), whose inactivation accelerates metastasis, phosphorylates TGM1 and TGM3 at Thr386 and Thr282, respectively, to inhibit their interaction with Exo70 and the following transamidation. Cantharidin, a US Food and Drug Administration (FDA)-approved drug, inhibits Exo70 transamidation to restrain tumor cell migration and invasion. Together, our findings highlight Exo70 transamidation as a key molecular mechanism and target and propose cantharidin as a therapeutic strategy with direct clinical translational value for metastatic cancers, especially those with LKB1 loss.

RNA therapeutics represent a rapidly expanding platform with game-changing prospects in personalized medicine. The disruptive potential of this technology will overhaul the standard of care with reference to both primary and specialty care. To date, RNA therapeutics have mostly been delivered parenterally via injection, but topical administration followed by intradermal or transdermal delivery represents an attractive method that is convenient to patients and minimally invasive. The skin barrier, particularly the lipid-rich stratum corneum, presents a significant hurdle to the uptake of large, charged oligonucleotide drugs. Therapeutic oligonucleotides need to be engineered for stability and specificity and formulated with state-of-the-art delivery strategies for efficient uptake. This review will cover various passive and active strategies deployed to enhance permeation through the stratum corneum and achieve effective delivery of RNA therapeutics to treat both local skin disorders and systemic diseases. Some strategies to achieve selectivity between local and systemic administration will also be discussed.

Physical trauma disrupts skin barrier function. How the skin barrier recovers is not fully understood. We evaluated in mice the mechanism of skin barrier recovery after mechanical injury inflicted by tape stripping. Tape stripping disrupted skin barrier function as evidenced by increased transepidermal water loss. We show that tape stripping induces IL-1-, IL-23-, and TCRγδ+-dependent upregulation of cutaneous Il17a and Il22 expression. We demonstrate that IL-17A and IL-22 induce epidermal hyperplasia, promote neutrophil recruitment, and delay skin barrier function recovery. Neutrophil depletion improved the recovery of skin barrier function and decreased epidermal hyperplasia. Single-cell RNA sequencing and flow cytometry analysis of skin cells revealed basophil infiltration into tape-stripped skin. Basophil depletion upregulated Il17a expression, increased neutrophil infiltration, and delayed skin barrier recovery. Comparative analysis of genes differentially expressed in tape-stripped skin of basophil-depleted mice and Il17a-/- mice indicated that basophils counteract the effects of IL-17A on the expression of epidermal and lipid metabolism genes important for skin barrier integrity. Our results demonstrate that basophils play a protective role by downregulating Il17a expression after mechanical skin injury, thereby counteracting the adverse effect of IL-17A on skin barrier function recovery, and suggest interventions to accelerate this recovery.

The extracellular lipid matrix in the stratum corneum (SC) plays a critical role in skin barrier functionality, comprising three primary components: ceramides, cholesterol, and free fatty acids. The diverse ceramides, differentiated by molecular structures such as hydroxylations and varying chain lengths, are essential for the lipid matrix's structural integrity. Recently, a new subclass of ceramide, 1-O-acylceramide NP (CerENP), has been identified; however, its precise role in the lipid matrix of the SC is still elusive. Herein, we investigate the role of CerENP on the structure and permeability of the SC using molecular dynamics simulations. Our findings indicate that CerENP contributes to a compact lipid matrix in the lateral dimension of our SC model with a repeat distance of about 13 nm. Additionally, ethanol permeability assessments show that CerENP effectively reduces molecular penetration through the lipid matrix. This study provides an insight into the role of a new subclass of ceramide in the SC, enhancing our understanding of skin structure and the mechanisms behind barrier dysfunction in skin diseases.

In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism.

Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis.

Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes.

Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

This review provides a comprehensive summary of the skin penetration pathways of xenobiotics, including metals, organic pollutants, and nanoparticles (NPs), with a particular focus on the methodologies employed to elucidate these penetration routes. The impacts of the physicochemical properties of exogenous substances and the properties of solvent carriers on the penetration efficiencies were discussed. Furthermore, the review outlines the steady-state and transient models for predicting the skin permeability of xenobiotics, emphasizing the models which enable realistic visualization of pharmaco-kinetic phenomena via detailed geometric representations of the skin microstructure, such as stratum corneum (SC) (bricks and mortar) and skin appendages (hair follicles and sebaceous gland units). Limitations of published research, gaps in current knowledge, and recommendations for future research are highlighted, providing insight for a better understanding of the skin penetration behavior of xenobiotics and associated health risks in practical application contexts.

The stratum corneum is the outermost skin layer with a vital role in skin barrier function. It is comprised of dead keratinocytes (corneocytes) and is known to maintain its thickness by shedding cells, although, the precise mechanisms that safeguard stratum corneum maturation and homeostasis remain unclear. Previous ex vivo studies have suggested a neutral-to-acidic pH gradient in the stratum corneum. Here, we use intravital pH imaging at single-corneocyte resolution to demonstrate that corneocytes actually undergo differentiation to develop three distinct zones in the stratum corneum, each with a distinct pH value. We identified a moderately acidic lower, an acidic middle, and a pH-neutral upper layer in the stratum corneum, with tight junctions playing a key role in their development. The upper pH neutral zone can adjust its pH according to the external environment and has a neutral pH under steady-state conditions owing to the influence of skin microbiota. The middle acidic pH zone provides a defensive barrier against pathogens. With mathematical modeling, we demonstrate the controlled protease activation of kallikrein-related peptidases on the stratum corneum surface that results in proper corneocyte shedding in desquamation. This work adds crucial information to our understanding of how stratum corneum homeostasis is maintained.

The skin wound healing process consists of hemostatic, inflammatory, proliferative, and maturation phases, with a complex cellular response by multiple cell types in the epidermis, dermis, and immune system. Magnesium is a mineral essential for life, and although magnesium treatment promotes cutaneous wound healing, the molecular mechanism and timing of action of the healing process are unknown. This study, using human epidermal-derived HaCaT cells and human normal epidermal keratinocyte cells, was performed to investigate the mechanism involved in the effect of magnesium on wound healing. The expression levels of epidermal differentiation-promoting factors were reduced by MgCl2, suggesting an inhibitory effect on epidermal differentiation in the remodeling stage of the late wound healing process. On the other hand, MgCl2 treatment increased the expression of matrix metalloproteinase-7 (MMP7), a cell migration-promoting factor, and enhanced cell migration via the MEK/ERK pathway activation. The enhancement of cell migration by MgCl2 was inhibited by MMP7 knockdown, suggesting that MgCl2 enhances cell migration which is mediated by increased MMP7 expression. Our results revealed that MgCl2 inhibits epidermal differentiation but promotes cell migration, suggesting that applying magnesium to the early wound healing process could be beneficial.

Staphylococcus aureus is a leading cause of skin and soft tissue infections. Colonization by this bacterium is increased in individuals with chronic cutaneous diseases such as atopic dermatitis, psoriasis, and bullous pemphigoid. The greater abundance of S. aureus on the skin of subjects with atopic dermatitis in particular has been linked to recurrent cutaneous infections. The primary cell type of the epidermal layer of the skin is the keratinocyte, and it is thought that S. aureus internalized in keratinocytes associates with an increased incidence of skin infections. This study addresses whether keratinocyte differentiation and/or inflammation, two important characteristics altered in cutaneous diseases, influence bacterial internalization. To do this, S. aureus internalization was measured in immortalized and primary keratinocytes that were differentiated using high Ca2+-containing media and/or exposed to cytokines characteristic of atopic dermatitis (IL-4 and IL-13) or psoriasis (IL-17A and IL-22) skin. Our results indicate that S. aureus internalization is uniquely decreased upon keratinocyte differentiation, since this was not observed with another skin-resident bacterium, S. epidermidis. Additionally, treatment with IL-4 + IL-13 diminished bacterial internalization. We interpret this decrease as a mechanism of keratinocyte-based bacterial killing since a similar number of bacterial genomes were detected in cytokine-treated cells, but less viable internalized S. aureus was recovered. Finally, of the receptors reported for S. aureus binding/internalizing into keratinocytes, expression of the α5 component of the α5β1 integrin was in greatest accordance with the number of internalized bacteria in the context of keratinocyte differentiation.IMPORTANCEIndividuals with chronic cutaneous diseases demonstrate heightened susceptibility for severe and recurrent infections from Staphylococcus aureus. What drives this altered susceptibility remains poorly understood. Previous publications have detected S. aureus as deep as the dermal layer of skin in subjects with atopic dermatitis, suggesting that the cutaneous environment of this disease enables deeper bacterial infiltration than occurs in healthy individuals. This observation indicates that S. aureus has greater opportunity to interact with multiple skin cell types in individuals with chronic inflammatory skin diseases. Identifying the characteristics of the skin that influence bacterial internalization, a common method to establish reservoirs and evade the immune response, is critical for our understanding of S. aureus pathogenesis. The significance of this research is the novel identification of epidermal characteristics that influence S. aureus internalization. With this knowledge, methods can be developed to identify patient populations at greater risk for cutaneous infections.

Skin-mediated drug delivery methods currently are receiving significant attention as a promising approach for the enhanced delivery of drugs through the skin. Skin-mediated drug delivery offers the potential to overcome the limitations of traditional drug delivery methods, including oral administration and intravenous injection. The challenges associated with drug permeation through layers of skin, which act as a major barrier, are explored, and strategies to overcome these limitations are discussed in detail. This review categorizes skin-mediated drug delivery methods based on the means of increasing drug permeation, and it provides a comprehensive overview of the mechanisms and techniques associated with these methods. In addition, recent advancements in the application of skin-mediated drug delivery are presented. The review also outlines the limitations of ongoing research and suggests future perspectives of studies regarding the skin-mediated delivery of drugs.

The epidermal differentiation complex (EDC) is a cluster of genes that encode protein components of the outermost layers of the epidermis in mammals, reptiles and birds. The development of the stratified epidermis from a single-layered ectoderm involves an embryo-specific superficial cell layer, the periderm. An additional layer, the subperiderm, develops in crocodilians and over scutate scales of birds. Here, we review the expression of EDC genes during embryonic development. Several EDC genes are expressed predominantly or exclusively in embryo-specific cell layers, whereas others are confined to the epidermal layers that are maintained in postnatal skin. The S100 fused-type proteins scaffoldin and trichohyalin are expressed in the avian and mammalian periderm, respectively. Scaffoldin forms the so-called periderm granules, which are histological markers of the periderm in birds. Epidermal differentiation cysteine-rich protein (EDCRP) and epidermal differentiation protein containing DPCC motifs (EDDM) are expressed in the avian subperiderm where they are supposed to undergo cross-linking via disulfide bonds. Furthermore, a histidine-rich epidermal differentiation protein and feather-type corneous beta-proteins, also known as beta-keratins, are expressed in the subperiderm. The accumulating evidence for roles of EDC genes in the development of the epidermis has implications on the evolutionary diversification of the skin in amniotes.

Inert interactions between randomly moving entities and spatial disorder play a crucial role in quantifying the diffusive properties of a system, with examples ranging from molecules advancing along dendritic spines to antipredator displacements of animals due to sparse vegetation. Despite the ubiquity of such phenomena, a general framework to model the movement explicitly in the presence of spatial heterogeneities is missing. Here, we tackle this challenge and develop an analytic theory to model inert particle-environment interactions in domains of arbitrary shape and dimensions. We use a discrete space formulation, which allows us to model the interactions between an agent and the environment as perturbed dynamics between lattice sites. Interactions from spatial disorder, such as impenetrable and permeable obstacles or regions of increased or decreased diffusivity, as well as many others, can be modelled using our framework. We provide exact expressions for the generating function of the occupation probability of the diffusing particle and related transport quantities such as first-passage, return, and exit probabilities and their respective means. We uncover a surprising property, the disorder indifference phenomenon of the mean first-passage time in the presence of a permeable barrier in quasi-1D systems. We demonstrate the widespread applicability of our formalism by considering three examples that span across scales and disciplines. (1) We explore an enhancement strategy of transdermal drug delivery. (2) We represent the movement decisions of an animal undergoing thigomotaxis, the tendency to remain at the peripheries of its enclosure, using a spatially disordered environment. (3) We illustrate the use of spatial heterogeneities to model inert interactions between particles by modeling the search for a promoter region on the DNA by transcription factors during gene transcription.

Oats (Avena sativa L.) are used as therapeutic plants, particularly in dermatology. Despite numerous studies on their skin moisturization, anti-inflammation, and antioxidation effects, the precise molecular mechanisms of these effects are only partially understood. In this study, the efficacy of oat sprouts in the treatment of allergic contact dermatitis (ACD) was investigated, and their specific phytoconstituents and exact mechanisms of action were identified. In the in vivo ACD model, by stimulating the mitogen-activated protein kinase signaling pathway, oat sprouts increased the expression levels of proteins associated with skin barrier formation, which are produced during the differentiation of keratinocytes. In addition, in a lipopolysaccharide-induced skin irritation model using HaCaT, steroidal saponins (avenacoside B and 26-deglucoavenacoside B) and a flavonoid (isovitexin-2-o-arabinoside) of oat sprouts regulated the genetic expression of the same proteins located on the adjacent locus of human chromosomes known as the epidermal differentiation complex (EDC). Furthermore, oat sprouts showed immunomodulatory functions. These findings suggest the potential for expanding the use of oat sprouts as a treatment option for various diseases characterized by skin barrier disruption.

The aim of this research was to investigate the role of the cornified epithelium, the outermost layer of the oral mucosa, engineered to prevent water loss and microorganism invasion, in severe forms of periodontitis (stage III or IV, grade C).

Porphyromonas gingivalis, a major periodontal disease pathogen, can affect cornified epithelial protein expression through chronic activation of signal transducer and activator of transcription 6 (Stat6). We used a mouse model, Stat6VT, that mimics this to determine the effects of barrier defect on P gingivalis-induced inflammation, bone loss, and cornified epithelial protein expression, and compared histologic and immunohistologic findings with tissues obtained from human controls and patients with stage III and IV, grade C disease. Alveolar bone loss in mice was assessed using micro-computerised tomography, and soft tissue morphology was qualitatively and semi-quantitatively assessed by histologic examination for several proteins, including loricrin, filaggrin, cytokeratin 1, cytokeratin 14, a proliferation marker, a pan-leukocyte marker, as well as morphologic signs of inflammation. Relative cytokine levels were measured in mouse plasma by cytokine array.

In the tissues from patients with periodontal disease, there were greater signs of inflammation (rete pegs, clear cells, inflammatory infiltrates) and a decrease and broadening of expression of loricrin and cytokeratin 1. Cytokeratin 14 expression was also broader and decreased in stage IV. P gingivalis-infected Stat6VT mice showed greater alveolar bone loss in 9 out of 16 examined sites, and similar patterns of disruption to human patients in expression of loricrin and cytokeratins 1 and 14. There were also increased numbers of leukocytes, decreased proliferation, and greater signs of inflammation compared with P gingivalis-infected control mice.

Our study provides evidence that changes in epithelial organisation can exacerbate the effects of P gingivalis infection, with similarities to the most severe forms of human periodontitis.

The potential of low-frequency ultrasound (LFU) combined with nanotechnology-based formulations in improving skin tumors topical treatment was investigated. The impact of solid lipid nanoparticles (SLN) and hydrophilic nanogels as coupling media on LFU-induced skin localized transport regions (LTR) and the penetration of doxorubicin (DOX) in LFU-pretreated skin was evaluated. SLN were prepared by the microemulsion technique and liquid crystalline nanogels using Poloxamer. In vitro, the skin was pretreated with LFU until skin resistivity of ∼1 KΩ.cm2 using the various coupling media followed by evaluation of DOX penetration from DOX-nanogel and SLN-DOX in skin layers. Squamous cell carcinoma (SCC) induced in mice was LFU-treated using the nanogel with the LFU tip placed 5 mm or 10 mm from the tumor surface, followed by DOX-nanogel application. LFU with nanogel coupling achieved larger LTR areas than LFU with SLN coupling. In LFU-pretreated skin, DOX-nanogel significantly improved drug penetration to the viable epidermis, while SLN-DOX hindered drug transport through LTR. In vivo, LFU-nanogel pretreatment with the 10 mm tip distance induced significant tumor inhibition and reduced tumor cell numbers and necrosis. These findings suggest the importance of optimizing nanoparticle-based formulations and LFU parameters for the clinical application of LFU technology in skin tumor treatment.

Improvement of skin barrier strength could lead to healthy and youthful appearance. "Beauty inside-out" approach using nutraceuticals such as tomato derived carotenoids to support skin barrier strength could be of benefit to the ageing population.

A panel of 60 female subjects were provided with the Lumenato capsules (containing carotenoids) or placebo capsules as nutritional supplements for 3 months. Skin health and barrier function were observed using evaporimeter which measures trans epidermal water loss (TEWL). Barrier strength was determined by study of the number of strippings required to disrupt skin barrier and barrier repair was observed in terms of TEWL a few hours after barrier disruption. Cutometer was used to observe skin firmness and elasticity. Measurements were obtained before treatment and after 4 and 12 weeks of use.

Results indicated a statistically significant improvement (p < 0.05) in skin barrier strength; a higher number of strippings were required to disrupt skin barrier after 12 weeks of supplement use. There was also a significant improvement in skin firmness and elasticity as observed with a cutometer.

Based on the confines and conditions of this study, oral supplementation with Lumenato resulted in significant improvement in skin barrier as well as skin firmness and elasticity.

Psoriasis, one of the most common skin diseases affecting roughly 2%-3% of the world population, is associated with a reduced skin barrier function (SBF) that might play an important role in its pathophysiology. The SBF is provided primarily by the stratum corneum (SC) of the skin. Previous studies have revealed a higher trans-epidermal water loss, lower hydration, abnormal concentration and composition of intercellular lipids, as well as alterations in secondary keratin structure in the psoriatic SC. We compared on molecular level lesional psoriatic skin (LPS) with non-lesional psoriatic skin (nLPS) from 19 patients non-invasively in vivo, using confocal Raman micro-spectroscopy. By analysing the corresponding Raman spectra, we determined SBF-defining parameters of the SC depth-dependently. Our results revealed a lower total lipid concentration, a shift of lamellar lipid organisation towards more gauche-conformers and an increase of the less dense hexagonal lateral packing of the intercellular lipids in LPS. Furthermore, we observed lower natural moisturising factor concentration, lower total water as well as a strong tendency towards less strongly bound and more weakly bound water molecules in LPS. Finally, we detected a less stable secondary keratin structure with increased β-sheets, in contrast to the tertiary structure, showing a higher degree of folded keratin in LPS. These findings clearly suggest structural differences indicating a reduced SBF in LPS, and are discussed in juxtaposition to preceding outcomes for psoriatic and healthy skin. Understanding the alterations of the psoriatic SC provides insights into the exact pathophysiology of psoriasis and paves the way for optimal future treatments.

Atopic dermatitis (AD)/atopic eczema is a chronic relapsing inflammatory skin disease affecting nearly 14% of the adult population. An important pathogenetic pillar in AD is the disrupted skin barrier function (SBF). The atopic stratum corneum (SC) has been examined using several methods, including Raman microspectroscopy, yet so far, there is no depth-dependent analysis over the entire SC thickness. Therefore, we recruited 21 AD patients (9 female, 12 male) and compared the lesional (LAS) with non-lesional atopic skin (nLAS) in vivo with confocal Raman microspectroscopy. Our results demonstrated decreased total intercellular lipid and carotenoid concentrations, as well as a shift towards decreased orthorhombic lateral lipid organisation in LAS. Further, we observed a lower concentration of natural moisturising factor (NMF) and a trend towards increased strongly bound and decreased weakly bound water in LAS. Finally, LAS showed an altered secondary and tertiary keratin structure, demonstrating a more folded keratin state than nLAS. The obtained results are discussed in comparison with healthy skin and yield detailed insights into the atopic SC structure. LAS clearly shows molecular alterations at certain SC depths compared with nLAS which imply a reduced SBF. A thorough understanding of these alterations provides useful information on the aetiology of AD and for the development/control of targeted topical therapies.

The anatomic layers of the skin are well-defined, and a functional model of the skin barrier has recently been described. Barrier disruption plays a key role in several skin conditions, and moisturization is recommended as an initial treatment in conditions such as atopic dermatitis. This review aimed to analyze the skin barrier in the context of the function model, with a focus on the mechanisms by which moisturizers support each of the functional layers of the skin barrier to promote homeostasis and repair.

The skin barrier is comprised of four interdependent layers - physical, chemical, microbiologic, and immunologic - which maintain barrier structure and function. Moisturizers target disruption affecting each of these four layers through several mechanisms and were shown to improve transepidermal water loss in several studies. Occlusives, humectants, and emollients occlude the surface of the stratum corneum (SC), draw water from the dermis into the epidermis, and assimilate into the SC, respectively, in order to strengthen the physical skin barrier. Acidic moisturizers bolster the chemical skin barrier by supporting optimal enzymatic function, increasing ceramide production, and facilitating ideal conditions for commensal microorganisms. Regular moisturization may strengthen the immunologic skin barrier by reducing permeability and subsequent allergen penetration and sensitization.

The physical, chemical, microbiologic, and immunologic layers of the skin barrier are each uniquely impacted in states of skin barrier disruption. Moisturizers target each of the layers of the skin barrier to maintain homeostasis and facilitate repair.

The use of cosmetics has become a habit for women. However, their influence on the microbial diversity of the skin has rarely been studied.

Herein, the effect of cosmetics containing complex polysaccharides on the skin bacterial microbiota of female forehead and cheek areas was analyzed. Eighty volunteers were recruited and split into two groups (40 people each); one group was treated with cosmetics containing complex polysaccharides and the other with basic cream for 28 days. Skin samples were collected using sterilized cotton swabs, and 16S rDNA high-throughput sequencing was used to analyze the changes in skin bacterial microbiota composition before and after the intervention.

A total of twenty-four phyla were detected in the forehead and cheek skin samples of 80 volunteers, the top three of which were Proteobacteria, Firmicutes, and Actinobacteria. The main genera of the forehead skin bacterial microbiota were Cutibacterium (11.1%), Acinetobacter (10.4%), Enterococcus (8.9%), Ralstonia (8.8%), and Staphylococcus (8.7%), while those of the cheek skin bacterial microbiota were Staphylococcus (20.0%), Ralstonia (8.7%), Propionibacterium (7.9%), Acinetobacter (7.2%), and Bifidobacterium (6.0%). Compared with basic cream, the use of cosmetics containing complex polysaccharides significantly increased the relative abundance of Staphylococcus and Bacillus in the forehead and cheek and reduced the relative abundance of Propionibacterium and Bifidobacterium. Thus, cosmetics containing complex polysaccharides could modify the composition of skin bacterial microbiota, which may help to maintain stable conditions of the skin.

The application of a far-ultraviolet C (UVC) light emitting diode (LED) of 233 nm showed significant bactericidal efficacy at an applied dose between 20 and 80 mJ cm-2 as reported recently. In addition, only minor epidermal DNA lesions were observed in ex vivo human skin and in vitro epidermal models <10% of the minimal erythema dose of UVB radiation. To broaden the potential range of applications of such systems, e.g. to include postoperative application on wounds for the purpose of decontamination, we assessed how a disruption of normal anatomic skin structure and function influences the skin damage induced by light from 233 nm far-UVC LEDs. Thus, we induced superficial skin wounds by mechanical detachment of the stratum corneum in ex vivo human skin. Barrier-disruption of the skin could be successfully determined by measuring an increase in the transepidermal water loss (TEWL) and the stratum corneum loss could be determined morphologically by 2-photon microscopy (2-PM). After far-UVC irradiation of the skin, we screened the tissue for the development of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). The abundance of DNA lesions was elevated in wound skin in comparison to intact skin after irradiation with far-UVC. However, no increase in DNA lesions was detected when artificial wound exudate consisting of cell culture medium and serum was applied to the disrupted skin surface prior to irradiation. This effect agrees with the results of ray tracing simulations of the absorption of far-UVC light incident on a superficial skin wound. Interestingly, no significant deviations in radical formation between intact skin and superficially wounded skin were detected after far-UVC irradiation as analyzed by electron paramagnetic resonance (EPR) spectroscopy. In conclusion, 233 nm LED light at a dose of 60 mJ/cm2 could be applied safely on superficial wounds for the purpose of skin antisepsis as long as the wounds are covered with wound fluid.

To unravel the diffusion mechanisms of percutaneous drug delivery, suitable numerical analysis of stratum corneum structure is essential. In this research paper, we accounted for the permeable envelope layer in the brick-and-mortar finite element models of human stratum corneum. Both penetration and desorption experiments for tritiated water were simulated by transient finite element analysis. Rivet-shaped corneodesmosomes were included in the brick and mortar model. Results showed that cornified lipid permeability (Penv) is a determinant in desorption of the solute, while lipid transverse diffusion coefficient (Dlip-trans) is prominent during penetration. These two major unknowns (Penv and Dlip-trans) were obtained by extensive fitting of the finite element model to the experimental water data. Penv and Dlip-trans were determined to be 1×10-2 cm/s and 5.7×10-10 cm2/s, respectively.

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug-in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades-results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

Fibrosis is a pathological repair process common among organs, that responds to damage by replacement of tissue with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may enable a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.

As a keratolytic, salicylic acid (SA) can be topically applied in various formulations and doses in dermatology. Supramolecular SA hydrogel, a new SA formulation with higher bioavailability, is developed and commercially available nowadays. However, there still remain concerns that the long-term and continual application of SA at low concentrations may jeopardize the cutaneous barrier properties.

To reveal the long-term effects of 0.5-5% supramolecular SA hydrogel on the skin barrier in normal mice models.

The 0.5%, 1%, 2%, and 5% supramolecular SA hydrogel or hydrogel vehicle without SA was applied to mice's shaved dorsal skin once per day respectively. Tissue samples of the dorsal skin were harvested on day 14 and 28 of the serial application of SA for histopathological observation and transcriptomic analysis.

Following topical supramolecular SA hydrogel therapy with various concentrations of SA (0.5%, 1%, 2%, and 5%) for 14 days and 28 days, there were no obvious macroscopic signs of impaired cutaneous health and no inflammatory or degenerative abnormalities were observed in histological results. Additionally, the transcriptomic analysis revealed that on day 14, SA dramatically altered the expression of genes related to the extracellular matrix structural constituent. And on day 28, SA regulated gene expression profiles of keratinization, cornified envelope, and lipid metabolism remarkably. Furthermore, the expression of skin barrier related genes was significantly elevated after the application of SA based on RNA-seq results, and this is likely to be associated with the PPAR signaling pathway according to the enrichment analysis.

Our findings demonstrated that the sustained topical administration of the 0.5-5% supramolecular SA hydrogel for up to 28 days did no harm to normal murine skin and upregulated the expression of genes related to the epidermal barrier.

Skin is considered one of the most convenient sites for drug administration. The present study evaluated the effect of gold nanoparticles stabilized by chitosan (CS-AuNPs) and citrate ions (Ci-AuNPs) on skin permeation of sodium fluorescein (NaFI) and rhodamine b base (RhB) as small model hydrophilic and lipophilic permeants, respectively. CS-AuNPs and Ci-AuNPs were characterized by transmitted electron microscopy (TEM) and dynamic light scattering (DLS). Skin permeation was investigated using porcine skin with diffusion cells and confocal laser scanning microscopy (CLSM). The CS-AuNPs and Ci-AuNPs were spherical-shaped nanosized particles (38.4±0.7 and 32.2±0.7 nm, respectively). The zeta potential of CS-AuNPs was positive (+30.7±1.2 mV) whereas that of Ci-AuNPs was negative (-60.2±0.4 mV). The skin permeation study revealed that CS-AuNPs could enhance the permeation of NaFI with enhancement ratio (ER) of 38.2±7.5, and the effect was superior to that of Ci-AuNPs. CLSM visualization suggested that skin permeation was enhanced by improving the delivery through the transepidermal pathway. However, the permeability of RhB, a lipophilic molecule, was not significantly affected by CS-AuNPs and Ci-AuNPs. Moreover, CS-AuNPs had no cytotoxic toward human skin fibroblast cells. Therefore, CS-AuNPs are a promising skin permeation enhancer of small polar compounds.

Our skin has a unique barrier function, which is imperative for the body's protection against external pathogens and environmental insults. Although interacting closely and sharing many similarities with key mucosal barrier sites, such as the gut and the lung, the skin also provides protection for internal tissues and organs and has a distinct lipid and chemical composition. Skin immunity develops over time and is influenced by a multiplicity of different factors, including lifestyle, genetics, and environmental exposures. Alterations in early life skin immune and structural development may have long-term consequences for skin health. In this review, we summarize the current knowledge on cutaneous barrier and immune development from early life to adulthood, with an overview of skin physiology and immune responses. We specifically highlight the influence of the skin microenvironment and other host intrinsic, host extrinsic (e.g. skin microbiome), and environmental factors on early life cutaneous immunity.

Hypertrophic scars (HTS) result from injury to the skin and represent a clinical burden with limited treatment options. Previously, we demonstrated that statin drugs could attenuate HTS formation, but convenient topical delivery and retention of these drugs at the wound site remains a challenge.

Here, we aimed to develop a topical cream formulation that can deliver statin drugs simply and conveniently to reduce scar hypertrophy.

We formulated creams containing 10% pravastatin, 2% simvastatin, and 10% simvastatin. We tested these creams for their ability to reduce scar hypertrophy and attenuate dermal fibrosis in a clinically relevant HTS wound model performed in rabbit ear skin. We also monitored trans-epidermal water loss (TEWL) over the course of wound healing in order to understand the effects of statin treatment on epidermal barrier recovery.

Of the three creams formulated, only application of 10% simvastatin cream significantly attenuated hypertrophy of resultant scars compared with vehicle cream application. Application of 10% simvastatin cream resulted in a decrease in macrophage and myofibroblast density at post-operative day 28 (POD28) harvest. Application of 10% simvastatin cream resulted in visible symptoms of dryness and increased TEWL at POD28, but subsequent withdrawal of statin cream treatment resulted in rapid alleviation of dryness and decrease in TEWL back to normal levels.

Our data demonstrate that topical administration of 10% simvastatin cream antagonizes dermal fibrosis and reduces hypertrophy in an HTS model, and withdrawal of the cream enables recovery of epidermal barrier and resolution of skin dryness.

The ichthyoses are a large, heterogeneous group of skin cornification disorders. They can be inherited or acquired, and result in defective keratinocyte differentiation and abnormal epidermal barrier formation. The resultant skin barrier dysfunction leads to increased transepidermal water loss and inflammation. Disordered cornification is clinically characterized by skin scaling with various degrees of thickening, desquamation (peeling) and erythema (redness). Regardless of the type of ichthyosis, many patients suffer from itching, recurrent infections, sweating impairment (hypohidrosis) with heat intolerance, and diverse ocular, hearing and nutritional complications that should be monitored periodically. The characteristic clinical features are considered to be a homeostatic attempt to repair the skin barrier, but heterogeneous clinical presentation and imperfect phenotype-genotype correlation hinder diagnosis. An accurate molecular diagnosis is, however, crucial for predicting prognosis and providing appropriate genetic counselling. Most ichthyoses severely affect patient quality of life and, in severe forms, may cause considerable disability and even death. So far, treatment provides only symptomatic relief. It is lifelong, expensive, time-consuming, and often provides disappointing results. A better understanding of the molecular mechanisms that underlie these conditions is essential for designing pathogenesis-driven and patient-tailored innovative therapeutic solutions.

Vernix caseosa is a complex proteolipid material synthesized partly by fetal sebaceous glands during the last trimester of pregnancy. Understanding the structure and function of newborn skin is crucial for determining optimal thermal support, infection control, and skin moisturization. So far, in Ethiopia, there is no research done related to the distribution of vernix caseosa and associated factors on newborn skin. Doing such research could give awareness about factors associated with the distribution of vernix caseosa on newborns' skin and to take necessary protective measures for those that may be affected.

The objective of this study is to assess the distribution of vernix caseosa and associated factors among newborns delivered at Adama Comprehensive Specialized Hospital Medical College from November to December 1, 2021.

Hospital-based cross-sectional study design was conducted from November to December 1, 2021 at Adama Comprehensive Specialized Hospital Medical College (ACSHMC). Four hundred twenty-two eligible newborns were selected by a systematic sampling method. Data were collected by four data collectors by using a pretested questionnaire. The distribution of vernix caseosa on the different regions of the neonate was assessed, by exposing their whole body for a minute. Data entry was done by EPI data version 4.6 and analyzed by using SPSS version 25. A logistic regression of P-value of <0.25 during bivariate and P < 0.05 during multivariate analysis at a 95% confidence level was considered statistically significant.

Out of 422 study participants 231 (54.7%) with 95% CI (49.8, 59.8) babies had vernix caseosa. Being primiparous with (AOR = 1.9, PV = 0.013, 95% CI: 1.141, 2.92), being multiparous with (AOR = 1.98, PV = 0.04, CI: 1.29, 3.225), being females with (AOR = 2.1, PV = 0.001, CI: 1.39, 3.18), being preterm with (AOR = 2.98, PV = 0.036, 95% CI: 1.08, 10.72), non-diseased newborns with (AOR = 1.6, PV = 0.046, 95% CI: 1.07, 2.7) were identified as associated factors for the distribution of vernix caseosa on the newborn skin.

This study showed that the distribution of vernix caseosa on the skin of the newborns was associated with parity, sex, gestational age, and absence of disease.

Multiphoton fluorescence lifetime imaging microscopy (MPM-FLIM) is extensively proposed as a non-invasive optical method to study tissue metabolism. The approach is based on recording changes in the fluorescence lifetime attributed to metabolic co-enzymes, of which nicotinamide adenine dinucleotide (NADH) is of major importance. However, intrinsic tissue fluorescence is complex. Particularly when utilizing two-photon excitation, as conventionally employed in MPM. This increases the possibility for spectral crosstalk and incorrect assignment of the origin of the FLIM signal. Here we demonstrate that in keratinocytes, proteins such as keratin may interfere with the signal usually assigned to NADH in MPM-FLIM by contributing to the lifetime component at 1.5 ns. This is supported by a change in fluorescence lifetime distribution in KRT5- and KRT14-silenced cells. Altogether, our results suggest that the MPM-FLIM data originating from cellular autofluorescence is far more complex than previously suggested and that the contribution from other tissue constituents should not be neglected-changing the paradigm for data interpretation in this context.

In this work using Coherent anti-Stokes Raman Scattering microscopy, it was possible to directly measure the time dependent, spatially resolved change in concentration of water (D₂ O) in intact skin tissue with a spatial resolution of under 1 μm, and combined with a multilayer diffusion model, diffusion coefficients at different depths in the tissue were extracted. The results show that the diffusion varies at different layers throughout the Stratum Corneum (SC), indicating that the SC is not a homogeneous barrier but a complicated heterogeneous structure. Interestingly, averaging over the diffusion at the different depths and samples gave a relatively constant value of 0.047 ± 0.01 μm² /second. Treating the skin with acetone or tape stripping led to an increased diffusion coefficient of 0.064 ± 0.02 μm² /second and 0.079 ± 0.03 μm² /second, respectively. The combined method and model presented here shows potential for wide applications for measuring spatially resolved diffusion of different substances in a variety of different samples.

Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found that KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we established KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage-defining factor across tissue types.