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Benvitimod has been successfully used in the treatment of psoriasis and atopic dermatitis (AD). However, the mechanism remains to be clarified. We aim to assess the effects of benvitimod on MC903-induced dermatitis in mice and to investigate the effects of benvitimod on filaggrin (FLG), involucrin (IVL), and loricrin (LOR) expressions and possible mechanism. MC903-induced mouse AD model was used to evaluate the effects of benvitimod. Filaggrin, involucrin, and loricrin protein and mRNA expressions in lesions of mice dermatitis were measured by Western blot and quantitative real-time PCR. In vitro, normal human epidermal keratinocytes (NHEKs) were cultured and benvitimod was used to treat NHEKs primed with IL-4 and IL-13. Then AHR and OVOL1 in NHEKs were knocked down to evaluate the role of AHR and OVOL1 in the effects of benvitimod. Topical treatment of benvitimod repaired skin barrier and alleviated skin inflammation in mouse AD model. This effect was inhibited by pretreatment with an AHR antagonist. Benvitimod upregulated the filaggrin, involucrin, and loricrin expressions in lesions of mouse AD model. In addition, benvitimod upregulated the filaggrin, involucrin, and loricrin expressions in NHEKs. Knockdown of AHR or OVO-like (OVOL)1 abrogated the upregulation of filaggrin, involucrin, and loricrin induced by benvitimod. Benvitimod attenuated MC903-induced mouse dermatitis and upregulated filaggrin, involucrin, and loricrin expressions via AHR-OVOL1 axis. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) commonly reside on human skin in residents in long‐term care facilities, yet its colonization and impact on the skin of hemodialysis (HD) patients have yet to be studied. The aim of the present study was to investigate the colonization of S. aureus on the skin of pruritic and non‐pruritic HD patients, and the influence of S. aureus and S. aureus‐secreted α‐toxin on skin barrier function‐related protein expression. In this study, a higher relative S. aureus count in pruritic HD patients compared to non‐pruritic HD patients and healthy subjects were revealed by real‐time polymerase chain reaction. S. aureus and α‐toxin decreased mRNA and protein expression levels of aryl hydrocarbon receptor (AHR), ovo‐like transcriptional repressor 1 (OVOL1), and filaggrin (FLG) in keratinocytes. In addition, anti‐alpha‐hemolysin (anti‐hla) was used as an α‐toxin neutralizer, and it successfully abrogated S. aureus‐induced AHR, OVOL1, and FLG mRNA and protein expression downregulation. Mechanistically, α‐toxin could decrease FLG activity by preventing the recruitment of AHR to the FLG promoter region. In conclusion, pruritic HD patients had higher S. aureus colonization, with S. aureus‐secreted α‐toxin suppressing FLG expression through the AHR‐FLG axis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common and chronic inflammatory skin disease with frequent relapses. The genomics revolution has greatly contributed and revolutionised our knowledge of human AD; understanding the molecular skin fingerprint of AD and associated pathogenic immune pathways has led to preclinical assessments of several novel treatments. Initial studies using microarray analysis to analyse transcriptome (gene expression) changes provided relevant insight on the inflammatory and structural changes occurring at the time of acute or chronic AD skin lesions, or after immunomodulating treatments with drugs ciclosporin and dupilumab, a monoclonal antibody anti‐IL4 receptor. The studies revealed that human AD is characterised by the activation of multiple cytokine pathways (predominance of T helper cell [Th]2 with some activation of Th1, Th17 and Th22) as well as dysregulated expression of barrier components in the skin. There are several reports on the expression of different single molecular targets (e.g. interleukin [IL]‐13, CCL17 and periostin) in spontaneous canine AD (cAD). However, significant studies of the transcriptome have been limited to a single microarray study analysing chronic AD skin lesions in dogs. While revealing a large number of genes differentially expressed in cAD skin, the small sample size (n = 13 dogs) and the lack of changes in key epidermal barrier and inflammatory cytokine genes in the microarrays have inhibited discussion towards specific immunological changes. This review summarises the current literature regarding the molecular mechanisms of spontaneous cAD, including the recent data regarding RNA sequencing, and compares some pathogenic aspects to the previously published data from human AD. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) is a harmful air pollutant composed of chemicals and metals which affects human health by penetrating both the respiratory system and skin, causing oxidative stress and inflammation. This review investigates the association between PM and skin disease, focusing on the underlying molecular mechanisms and specific disease pathways involved. Studies have shown that PM exposure is positively associated with skin diseases such as atopic dermatitis, psoriasis, acne, and skin aging. PM-induced oxidative stress damages lipids, proteins, and DNA, impairing cellular functions and triggering inflammatory responses through pathways like aryl hydrocarbon receptor (AhR), NF-κB, and MAPK. This leads to increased production of inflammatory cytokines and exacerbates skin conditions. PM exposure exacerbates AD by triggering inflammation and barrier disruption. It disrupts keratinocyte differentiation and increases pro-inflammatory cytokines in psoriasis. In acne, it increases sebum production and inflammatory biomarkers. It accelerates skin aging by degrading ECM proteins and increasing MMP-1 and COX2. In conclusion, PM compromises skin health by penetrating skin barriers, inducing oxidative stress and inflammation through mechanisms like ROS generation and activation of key pathways, leading to cellular damage, apoptosis, and autophagy. This highlights the need for protective measures and targeted treatments to mitigate PM-induced skin damage. [ABSTRACT FROM AUTHOR]

Several microbiome studies have recently demonstrated microbial dysbiosis in various chronic inflammatory skin diseases, and it is considered an important role in the pathogenesis. Although the role of skin dysbiosis in inflammatory skin diseases is debatable, the local microenvironment is considered essential concerning compositional changes and functional alterations of the skin microbiota. Indeed, various local nutrients (e.g., lipids), pH values, water, oxygen, and antimicrobial peptides may affect the level of skin dysbiosis in these skin diseases. In particular, in atopic dermatitis and hidradenitis suppurativa, significant changes in skin dysbiosis have been associated with local aberrant host immune changes. In this review, the potential pathogenic crosstalk between the host and the microbiota is reviewed in relation to the physical, chemical, and biological microenvironments of various chronic inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

The human retroviral-like aspartic protease 1 (ASPRV1) is a retroviral-like protein that was first identified in the skin due to its expression in the stratum granulosum layer of the epidermis. Accordingly, it is also referred to as skin-specific aspartic protease. Similar to the retroviral polyproteins, the full-length ASPRV1 also undergoes self-proteolysis, the processing of the precursor is necessary for the autoactivation of the protease domain. ASPRV1’s functions are well-established at the level of the skin: it is part of the epidermal proteolytic network and has a significant contribution to skin moisturization via the limited proteolysis of filaggrin; it is only natural protein substrate identified so far. Filaggrin and ASPRV1 are also specific for mammalians, these proteins provide unique features for the skins of these species, and the importance of filaggrin processing in hydration is proved by the fact that some ASPRV1 mutations are associated with skin diseases such as ichthyosis. ASPRV1 was also found to be expressed in macrophage-like neutrophil cells, indicating that its functions are not limited to the skin. In addition, differential expression of ASPRV1 was detected in many diseases, with yet unknown significance. The currently known enzymatic characteristics—that had been revealed mainly by in vitro studies—and correlations with pathogenic phenotypes imply potentially important functions in multiple cell types, which makes the protein a promising target of functional studies. In this review we describe the currently available knowledge and future perspective in regard to ASPRV1. [ABSTRACT FROM AUTHOR]

Background: The epidermal barrier acts as a defense against external agents as well as helps to maintain body homeostasis. Polynucleotides (PN), exogenous DNA fragments, promote wound repair through their stimulatory and anti‐inflammatory effects. Recent findings indicate a synergistic effect of PN and hyaluronic acid (HA) combinations in regulating inflammation and promoting cell proliferation. This study aims to elucidate the effects of PN and HA on repairing the epidermal barrier following its disruption by tape stripping (TS) in a mouse model. Materials and Methods: After disrupting the epidermal barrier using TS, a formulation containing PN (14 mg/mL) and HA (6 mg/mL) was applied. Trans‐epidermal water loss (TEWL) was measured at 0, 3, 6, 24, 48, and 72 h. Mice were euthanized after the final application at 72 h, and tissue samples were analyzed for epidermal/dermal thickness, neutrophil infiltration, and filaggrin expression. Results: We observed a significant reduction in TEWL in the PN+HA group compared to that in the control group (20.8 ± 0.5 vs. 43.7 ± 0.5 g/m2h at 72 h, p < 0.05), indicating an improvement in barrier function. Histological evaluation showed decreased epidermal and dermal thickening in the PN+HA group compared to that in the control group (epidermal: 29.4 ± 2.2 vs. 57.9 ± 3.5 μm; dermal: 464.8 ± 25.9 vs. 825.9 ± 44.8 μm, both p < 0.05). Additionally, neutrophil infiltration in the dermis was significantly reduced, and filaggrin protein levels were significantly higher in the PN+HA group compared to those in the control group (4.8 ± 0.4 vs. 21.1 ± 3.3 for neutrophils; 0.84 ± 0.04 vs. 0.42 ± 0.03 for filaggrin, both p < 0.05). Conclusion: These results suggest that PN+HA may be an effective therapeutic strategy for repairing skin barrier damage. [ABSTRACT FROM AUTHOR]

Filaggrin (FLG) is an essential structural protein expressed in differentiated keratinocytes. Insufficient FLG expression contributes to the pathogenesis of chronic inflammatory skin diseases. Saikosaponin A (SSA), a bioactive oleanane-type triterpenoid, exerts anti-inflammatory activity. However, the effects of topically applied SSA on FLG expression in inflamed skin remain unclear. This study aimed to evaluate the biological activity of SSA in restoring reduced FLG expression. The effect of SSA on FLG expression in HaCaT cells was assessed through various biological methods, including reverse transcription PCR, quantitative real-time PCR, immunoblotting, and immunofluorescence staining. TNFα and IFNγ decreased FLG mRNA, cytoplasmic FLG protein levels, and FLG gene promoter–reporter activity compared to the control groups. However, the presence of SSA restored these effects. A series of FLG promoter–reporter constructs were generated to investigate the underlying mechanism of the effect of SSA on FLG expression. Mutation of the AP1-binding site (mtAP1) in the −343/+25 FLG promoter–reporter abrogated the decrease in reporter activities caused by TNFα + IFNγ, suggesting the importance of the AP1-binding site in reducing FLG expression. The SSA treatment restored FLG expression by inhibiting the expression and nuclear localization of FRA1 and c-Jun, components of AP1, triggered by TNFα + IFNγ stimulation. The ERK1/2 mitogen-activated protein kinase signaling pathway upregulates FRA1 and c-Jun expression, thereby reducing FLG levels. The SSA treatment inhibited ERK1/2 activation caused by TNFα + IFNγ stimulation and reduced the levels of FRA1 and c-Jun proteins in the nucleus, leading to a decrease in the binding of FRA1, c-Jun, p-STAT1, and HDAC1 to the AP1-binding site in the FLG promoter. The effect of SSA was evaluated in an animal study using a BALB/c mouse model, which induces human atopic-dermatitis-like skin lesions via the topical application of dinitrochlorobenzene. Topically applied SSA significantly reduced skin thickening, immune cell infiltration, and the expression of FRA1, c-Jun, and p-ERK1/2 compared to the vehicle-treated group. These results suggest that SSA can effectively recover impaired FLG levels in inflamed skin by preventing the formation of the repressor complex consisting of FRA1, c-Jun, HDAC1, and STAT1. [ABSTRACT FROM AUTHOR]

The integrity of the reconstructed human epidermis generated in vitro can be assessed using histological analyses combined with immunohistochemical staining of keratinocyte differentiation markers. Technical differences during the preparation and capture of stained images may influence the outcome of computational methods. Due to the specific nature of the analyzed material, no annotated datasets or dedicated methods are publicly available. Using a dataset with 598 unannotated images showing cross-sections of in vitro reconstructed human epidermis stained with DAB-based immunohistochemistry reaction to visualize four different keratinocyte differentiation marker proteins (filaggrin, keratin 10, Ki67, HSPA2) and counterstained with hematoxylin, we developed an unsupervised method for the detection and quantification of immunohistochemical staining. The pipeline consists of the following steps: (i) color normalization; (ii) color deconvolution; (iii) morphological operations; (iv) automatic image rotation; and (v) clustering. The most effective combination of methods includes (i) Reinhard's normalization; (ii) Ruifrok and Johnston color-deconvolution method; (iii) proposed image-rotation method based on boundary distribution of image intensity; and (iv) k-means clustering. The results of the work should enhance the performance of quantitative analyses of protein markers in reconstructed human epidermis samples and enable the comparison of their spatial distribution between different experimental conditions. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Glucocerebrosidase 1 (GBA1) mutations are associated with reduced survival in Parkinson's disease but their effect on survival in dementia with Lewy bodies (DLB) is unclear.To assess the impact of GBA1 mutations on survival among Ashkenazi Jews with DLB, while controlling for APOE status.One hundred and forty participants from Tel Aviv Medical Center, Israel were genotyped for GBA1 mutations and APOE polymorphisms. Survival rates and follow‐up cognitive screening scores were analyzed.GBA1 mutation carriers had a two‐fold increased risk of death (HR = 1.999), while APOE status did not independently affect survival. In a subset of patients with available clinical data (N = 63), carriers of the APOE ε4 allele showed faster cognitive deterioration, while GBA1 mutation carriers also declined more rapidly albeit not significantly.Understanding the genetic effects on survival and progression is crucial for patient counseling and inclusion in clinical trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Propolis is a natural resinous substance made by bees through mixing various plant sources. Propolis has been widely recognized as a functional food due to its diverse range of beneficial bioactivities. However, the therapeutic effects of consuming propolis against atopic dermatitis (AD) remain largely unknown. The current study aimed to investigate the potential efficacy of propolis against AD and explore the active compound as well as the direct molecular target. In HaCaT keratinocytes, propolis inhibited TNF‐α‐induced interleukin (IL)‐6 and IL‐8 secretion. It also led to a reduction in chemokines such as monocyte chemoattractant protein‐1 (MCP‐1) and macrophage‐derived chemokine (MDC), while restoring the levels of barrier proteins, filaggrin and involucrin. Propolis exhibited similar effects in AD‐like human skin, leading to the suppression of AD markers and the restoration of barrier proteins. In DNCB‐induced mice, oral administration of propolis attenuated AD symptoms, improved barrier function, and reduced scratching frequency and transepidermal water loss (TEWL). In addition, propolis reversed the mRNA levels of AD‐related markers in mouse dorsal skin. These effects were attributed to caffeic acid phenethyl ester (CAPE), the active compound identified by comparing major components of propolis. Mechanistic studies revealed that CAPE as well as propolis could directly and selectively target MKK4. Collectively, these findings demonstrate that propolis may be used as a functional food agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

We previously reported that a pathogenic abnormality in the barrier and water-holding functions of the stratum corneum (SC) in the skin of patients with atopic dermatitis (AD) is mainly attributable to significantly decreased levels of total ceramides in the SC. That decrease is mediated by the abnormal expression of a novel ceramide-reducing enzyme, sphingomyelin/glucosylceramide deacylase (SGDase), which is the β-subunit (ASAH1b) of acid ceramidase. In this study, we determined whether mice overexpressing ASAH1b in their epidermis develop AD-like skin symptoms. We generated transgenic (TG) mice overexpressing ASAH1b, regulated by the involucrin promoter, to localize its expression in the upper epidermis. After hair removal using a depilatory cream containing glycolic acid, the TG mice without any visible skin inflammation at 8 weeks of age had increased levels of ASAH1b and decreased levels of SC ceramide, with disrupted barrier functions measured by trans-epidermal water loss compared to the wild-type (WT) mice. Interestingly, enzymatic assays revealed that SGDase activity was not detectable in the skin of the TG mice compared to WT mice. Immunological staining revealed that there was an increased expression level of IL-33 in the epidermis and an accumulation of macrophages in the dermis of TG mice compared to WT mice, which are phenotypic characteristics of AD, that were exacerbated by tape-stripping of the skin. In the skin of the TG mice, the mRNA levels of IL-5, CCL11, IL-22, CXCL10, and IFNγ were significantly upregulated compared to the WT mice, and tape-stripping significantly increased the mRNA levels of IL-4, IL-33, CXCL1, CXCL12, TLR9, and CD163 compared to WT mice. These findings strongly indicate that the skin of the depilatory cream-treated TG mice exists in an atopic dry skin condition that is highly sensitive to various environmental stimuli. The sum of our results suggests that ASAH1b itself, even in the absence of its enzymatic activity, is a major etiologic factor for atopic dry skin symptoms via an unknown mechanism. [ABSTRACT FROM AUTHOR]

Introduction: The pathogenesis of atopic dermatitis (AD) involves complex interactions between environmental factors, the skin microbiome, epidermal barrier defects, and altered immune responses that develop on a not fully understood specific genetic background. Aim: We aimed to evaluate the contribution of single nucleotide polymorphisms (SNPs) in the IL-35 genes (IL-12A and EBI3) towards AD susceptibility and clinical characteristics of AD in the Polish population. Two SNPs (rs568408, rs582054) in IL-12A and one SNP (rs428253) in EBI3 were selected. Material and methods: Blood samples were collected from 202 AD patients and 178 healthy individuals. SNPs in IL-35 genes were analysed by the polymerase chain reaction with sequence-specific primers (SSP-PCR) method. Results: For IL-12A rs568408, the AA genotype was significantly linked to increased odds of AD (OR = 34.61; 95% CI: 2.06-579.97, p = 0.0137) and marginally associated with normal total serum IgE levels (OR = 2.82; 95% CI: 0.97-8.16; p = 0.05), while the GA genotype showed significantly reduced odds of AD (OR = 0.53; 95% CI: 0.34-0.81; p = 0.0035). In the context of IL-12A rs582054, TT genotype carriers had increased odds of AD (OR = 2.05; 95% CI: 1.08-3.85; p = 0.03). Patients with the GG genotype of EBI3 rs428253 had decreased odds of high total serum IgE levels (OR = 0.42; 95% CI: 0.20-0.86; p = 0.02) and milder pruritus severity compared to CC genotype carriers (4.12 vs. 7.50; p = 0.02). Conclusions: IL-35 genetic variations appear to play a role in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: The integrity of the stratum corneum (SC) is crucial for the skin's barrier function, protecting against environmental stressors and minimizing transepidermal water loss. Advances in skincare formulations have introduced multilamellar systems designed to emulate the SC's lipid composition and organization. This study hypothesizes that the application of a multilamellar cream will significantly impact the SC's lipid content and lamellar structure, thereby enhancing the epidermal barrier. Methods: A saturated phosphatidylcholine‐based multilamellar cream was applied to a cohort of adult subjects with very dry skin. Electron microscopy was utilized to analyse the micro‐morphology of the cream and its integration into the lipid‐depleted SC. Lipid analysis was conducted to quantify changes in the intercellular lipid matrix. Results: Transmission‐electron microscopy (TEM) imaging demonstrated that the multilamellar cream possesses a structured arrangement comparable to the natural SC architecture. Short‐term application revealed a time‐dependent restoration of lipid bilayers, while a 14‐day regimen showed a marked increase in lipid lamellae density and length within the SC. Lipid analysis indicated a significant increase in total lipid content, with notable enhancements in ceramide and free fatty acid levels, without altering cholesterol levels. Lipid ratio analysis further confirmed the rebalancing of the SC's lipid composition. Discussion: The multilamellar cream selectively increased specific lipids critical for barrier function, suggesting an action mechanism that aligns with the skin's natural regulatory processes. This selective augmentation indicates the potential of the formulation to not only restore but also enhance the epidermal barrier, with the maintenance of physiological lipid ratios suggesting compatibility with intrinsic repair mechanisms. Conclusion: The study confirms that a multilamellar cream can significantly improve the SC's lipid composition and structural integrity, indicating enhanced barrier function. They are pivotal for skincare professionals, dermatologists, and product developers, enriching the understanding of multilamellar creams' benefits and applications in improving epidermal barrier function. [ABSTRACT FROM AUTHOR]

Objective: Atopic dermatitis (AD) is characterized by compositional and structural changes to the skin at lesional sites. Alteration to the levels and organization of both protein and lipid components are associated with disease status and lead to impaired barrier and hydration. Corneodesmosin (CDSN) and the arrangement and length of the intercellular lipid lamellae (ICLL) are altered in disrupted skin states. The aim of this research was to profile the distribution of CDSN and the ICLL in the stratum corneum (SC) at lesional and non‐lesional sites in AD‐prone skin and to investigate the impact of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. Methods: An IRB‐approved study was conducted with participants with active AD. From a small subset of participants, tape strips were collected from lesional and non‐lesional sites on the arm, prior to and after twice daily application, over 4 weeks of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. Fluorescent antibody staining was used to investigate the distribution of CDSN. Transmission electron microscopy (TEM) was used to characterize the ICLL. Results: The distribution/coverage of CDSN was similar between lesional and non‐lesional sites at baseline; application of the lotion resulted in a more defined honeycomb/peripheral distribution. Normalized ICLL (nICLL) was lower in baseline samples from lesional sites relative to non‐lesional sites. Application of the lotion increased this parameter by the end of the study at all sites. Conclusion: The eczema calming lotion containing petroleum jelly, fatty acids and colloidal oatmeal provided changes in corneodesmosomal proteins distribution and ICLL, consistent with improvements in corneocyte maturation and improved barrier function in the skin of individuals with atopic dermatitis. [ABSTRACT FROM AUTHOR]

The stratum corneum (SC), the outermost epidermal layer, plays a pivotal role in skin barrier function. This review delves into the intricate process of protein degradation within the stratum corneum, elucidating the roles of specific enzymes, regulatory mechanisms and the consequent impact on various skin conditions. Protein degradation is a finely tuned process, orchestrated by a suite of proteolytic enzymes like kallikreins. These enzymes are responsible for the breakdown of corneodesmosomes and the orderly desquamation of corneocytes, a process essential for skin homeostasis. Another critical enzymatic process is the breakdown of proteins like filaggrin and the generation of amino acids and their derivatives, required in the physiological water‐handling properties of the SC. Regulation of these proteolytic activities is complex, involving a balance between endogenous inhibitors and other factors like pH, hydration and environmental stressors. Dysregulation of protease activity is linked to a spectrum of skin conditions, ranging from xerosis to inflammatory diseases like atopic dermatitis and psoriasis. Aberrant protein degradation can lead to compromised skin barrier function, increased tissue water loss and heightened susceptibility to infections and allergens. Understanding the factors affecting protein degradation can inform the development of targeted skincare products. Advances in biochemistry and dermatology have paved the way for the search for active ingredients designed to modulate protease activity. Such innovations may offer promising therapeutic avenues for enhancing skin barrier function and treating skin disorders. This review underscores the significance of enzymatic protein degradation in the SC and its regulatory mechanisms. It provides insights into the pathophysiology of skin diseases and outlines the potential for novel skincare interventions. By bridging the gap between fundamental research and practical applications, this article aims to inspire further investigation for better understanding of skin physiology and innovation in the realm of skincare product development. [ABSTRACT FROM AUTHOR]

Introduction: Stratum corneum (SC) is essential for skin barrier function, mitigating water loss and shielding against potentially harmful substances and allergens. The SC's lipid matrix, arranged in a lamellar structure, is integral to its protective role. Our study explores the restoration effects of a multilamellar cream with an acidic pH compared to a basic placebo cream on skin physiology and its interaction with the skin microbiome after stress induction via tape stripping (TS). Materials and Methods: In this double‐blind study, 14 healthy participants aged 21–58 years were assessed pre‐ and post‐tape stripping, followed by a 14 days application of a multilamellar test cream and a placebo cream with evaluations on days 7, 14 and 17 for sustained effects. Skin physiology was analysed in terms of epidermal barrier function, SC hydration and surface pH. The microbiome was analysed by 16S rRNA amplicon sequencing the 16S rRNA gene using Illumina MiSeq, with subsequent species identification. Results: Our study showed significant improvements in skin barrier repair and SC hydration with verum, particularly after 14 days of application, while both creams initially enhanced stratum corneum hydration. No significant changes in surface‐pH were detected. The skin microbiome analysis revealed that TS slightly decreased alpha diversity, a trend that verum significantly reversed, enhancing diversity beyond baseline levels after 14 days. Overall, while both creams contributed to a broader microbial phyla diversity over time, no significant changes in the abundance of specific genera or species were noted between treatments. Discussion and Conclusion: Our study delineates the efficacy of a pH‐optimized multilamellar cream in enhancing epidermal barrier recovery and SC hydration post‐sequential TS, in contrast to an unstructured basic placebo. Verum cream significantly improved skin barrier function and SC hydration at day 14, with sustained effects evident beyond the treatment period. Furthermore, the multilamellar formulation facilitated the restitution of cutaneous microbiome diversity, a key indicator of healthy skin ecology, underscoring the symbiotic relationship between barrier integrity and microbial composition. These findings underscore the importance of multilamellar emollient structures in dermatological therapeutics, with potential implications for the design of advanced skincare interventions that holistically support cutaneous resilience and homeostasis. [ABSTRACT FROM AUTHOR]

Previous observational studies have linked inflammatory skin diseases with mental health issues and neuroticism. However, the specific impact of neuroticism and its subclusters (i.e. worry, depressed affect, and sensitivity to environmental stress and adversity) on these conditions remains underexplored. In this work, we explored causal associations between common inflammatory skin diseases and neuroticism. We conducted a two-sample, bidirectional Mendelian randomization (MR) analysis using data from genome-wide association studies in psoriasis, atopic dermatitis, neuroticism and relevant genetic subclusters conducted on participants of European ancestry. Corrections for sample overlap were applied where necessary. We found that psoriasis was causally associated with increased levels of worry (odds ratio, 95% confidence intervals: 1.011, 1.006–1.016, P = 3.84 × 10–6) while none of the neuroticism subclusters showed significant association with psoriasis. Sensitivity analyses revealed considerable evidence of directional pleiotropy between psoriasis and neuroticism traits. Conversely, genetic liability to atopic dermatitis did not exhibit any significant association with neuroticism traits. Notably, genetically predicted worry was linked to an elevated risk of atopic dermatitis (odds ratio, 95% confidence intervals: 1.227, 1.067–1.41, P = 3.97 × 10–3). Correction for overlapping samples confirmed the robustness of these results. These findings suggest potential avenues for future interventions aimed at reducing stress and worry among patients with inflammatory skin conditions. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Hen's egg exposure through impaired skin barrier is considered a major mechanism of sensitization to eggs. However, the impact of filaggrin (FLG) gene loss‐of‐function mutations on the natural history of egg sensitization lacks consensus among studies.To evaluate the association between the natural course of egg sensitization and FLG mutations.We used Japanese and the UK birth cohorts (CHIBA and MAAS) to identify the longitudinal patterns of egg sensitization until mid‐school age and examined the relationship between the identified patterns and FLG mutations. Sensitization was assessed using egg white‐specific IgE levels or skin prick tests (SPTs). Egg allergy was confirmed by parental reports and sensitization. Latent class growth analysis identified longitudinal patterns.Three similar patterns of egg sensitization (persistent, early‐onset remitting, and no/low grade classes) were identified in both cohorts, with differing prevalence estimates. The proportion of children with egg allergy in the persistent class at 7 or 8 years of age was 23% (CHIBA) and 20% (MAAS). Consistently in both cohorts, FLG mutations were significantly associated only with the persistent class. Children with FLG mutations had an approximately four‐fold increased risk of being in the persistent sensitization class (RRRs: 4.3, 95%C.I. (1.2–16.0), p = .03 in CHIBA; 4.3 (1.3–14.7), p = .02 in MAAS).FLG loss‐of‐function mutations are associated with persistent egg sensitization in both Japanese and European ethnicities, and the mutations might be a potential biomarker for identifying the risk of persistent egg sensitization/allergy in early infancy. Future studies should incorporate oral food challenges to confirm this relationship. [ABSTRACT FROM AUTHOR]

Background and Objectives: Atopic dermatitis is a chronic inflammatory skin disorder with a significant burden on patients' quality of life. This systematic review aims to evaluate the restoration of skin barrier abnormalities with interleukin-4/interleukin-13 (IL-4/IL-13) inhibitors and Janus kinase (JAK) inhibitors in atopic dermatitis. Materials and Methods: A comprehensive review of the literature was conducted, focusing on studies that assess the use of IL-4/IL-13 inhibitors and JAK inhibitors for atopic dermatitis. We identified eligible studies by searching Medline via PubMed with a special focus on their effect on the restoration of the epidermal barrier. Included studies evaluated the transepidermal water loss (TEWL), the reduction in epidermal thickness (ET), the improvement in ceramide synthesis, and the increase in stratum corneum hydration (SCH) with IL-4/IL-13 inhibitors and JAK inhibitors. The quality of included studies was assessed using the ROBINS-I and the RoB 2.0 tool for assessing the risk of bias. Results: Ten of the included studies concern dupilumab, while two concern JAK inhibitors. Ten were observational studies and two were randomized controlled trials (RCTs). The total number of included participants was 378 concerning dupilumab and 38 concerning JAK inhibitors. Five studies did not include any comparison group, three included healthy volunteers, two were conducted versus placebo, and two compared dupilumab with other treatments. The follow-up period ranged between 29 days and 32 weeks. The results demonstrated a significant decrease in transepidermal water loss (TEWL) and an increase in SCH on eczematous lesions for patients with sustained response to dupilumab treatment and observed improvements in ET and filaggrin (FLG) staining, which further support the efficacy of JAK inhibitors in enhancing skin barrier function. Conclusions: This review underscores the efficacy of IL-4/IL-13 inhibitors in improving skin barrier function. However, the limited number of studies focusing on JAK inhibitors and the overall lack of RCTs highlight the need for further research to establish the definitive role of IL-4/IL-13 inhibitors and JAK inhibitors in the restoration of the skin barrier. [ABSTRACT FROM AUTHOR]

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Background: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear. Methods: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association. Results: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1–5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45–0.77) and at 6 months (RR = 0.49, 95 % CI 0.36–0.68). , Reduced risks of eczema were also observed at 2–5 (RR = 0.52, 95 % CI 0.37–0.73) and 3–5 years of age (RR = 0.50 95 % CI 0.35–0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations. Conclusions: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts.

Abstract Background Psoriasis is a disease of overactive immune system. OVOL1 and Filaggrin have been associated with many inflammatory skin lesions. To the best of our knowledge, the correlation between OVOL1 and Filaggrin in psoriasis was not previously investigated. This work aims to search the immunohistochemical expression and correlation between OVOL1 and Filaggrin in psoriasis. Materials and methods Slides cut from paraffin blocks of 30 psoriasis cases and 30 control subjects were stained with OVOL1 and Filaggrin. Clinicopathological data were correlated with the results of staining. Results OVOL1 and Filaggrin expression in epidermis showed a significant gradual reduction from normal skin to peri-lesional and psoriasis biopsies (P

Abstract Background Loss of function mutations in the filaggrin gene (FLG) play an important role in the pathogenesis of atopic dermatitis (AD). However, FLG is structurally challenging to sequence using conventional high‐throughput techniques. Genome‐wide association studies (GWAS) chips and imputation panels are also not designed to detect most of these mutations. Furthermore, bioinformatics tools have variable sensitivity for identification of loss of function variants. Targeted sequencing is often performed for AD but requires a comprehensive list of potential variants. Objectives This study sought to compile all published FLG single nucleotide polymorphisms (SNPs) in AD and characterize the methods for assessing the associated phenotype. Methods We searched nine electronic databases for studies that reported measures of association between FLG and AD. Data regarding FLG SNPs and participant demographics were extracted. The identified SNPs were compared to those available in the National Human Genome Research Institute‐European Bioinformatics Institute (NHGRI‐EBI) GWAS Catalogue and the 1000Genomes reference panel. Results We identified 168 SNPs in FLG that have been associated with AD, with the most studied being R501X, 2282del4, R2447X, 3321delA, S3247X and p.S2554 in European and Asian ancestries. A total of 153 of these SNPs are not available from GWAS studies, and 78 are not included in the 1000Genomes reference panel. Conclusions Because FLG is a complex gene, current GWAS chips do not capture most of the polymorphisms that have been associated with AD.

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting both children and adults. The clinical picture of AD manifests in typical skin lesions, such as localized eczema and dry skin, with dominant, persistent itching that leads to sleep disturbances. The pathophysiology of AD has been extensively investigated with respect to epigenetic and genetic factors, skin barrier defects, as well as immunological and microbial disorders. However, to date, the involvement of extracellular matrix (ECM) elements has received limited attention. Collagen, a major component of the ECM, may serve as a therapeutic target for the future treatment of AD. This paper summarizes the role of collagens, which are the most abundant components of the extracellular matrix in AD. [ABSTRACT FROM AUTHOR]

The article explores the potential of vinpocetine, a phosphodiesterase 1 inhibitor, in treating atopic dermatitis (AD). The study used a mouse model of AD and found that vinpocetine improved symptoms such as skin inflammation and barrier function. It also reduced the infiltration of inflammatory cells and levels of certain cytokines in the skin. The findings suggest that vinpocetine could be a promising therapeutic option for AD, but further research is needed to understand its mechanisms and long-term effects. The research was supported by the Chung-Ang University Research Scholarship Grants in 2022. [Extracted from the article]

The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear. This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association. Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1–5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45–0.77) and at 6 months (RR = 0.49, 95 % CI 0.36–0.68). , Reduced risks of eczema were also observed at 2–5 (RR = 0.52, 95 % CI 0.37–0.73) and 3–5 years of age (RR = 0.50 95 % CI 0.35–0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations. Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts. [ABSTRACT FROM AUTHOR]

Background In the general population randomized controlled trial PreventADALL, frequent emollient bath additives from 2 weeks of age did not prevent atopic dermatitis, while the effect on skin barrier function throughout infancy is not established. Objectives The primary aim of this exploratory substudy was to assess the effect of mineral-based oil baths on transepidermal water loss (TEWL) and dry skin through infancy, and secondarily to explore if filaggrin (FLG) mutations modified the effect. Methods Overall, 2153 infants were included and randomized to either the 'Skin intervention' (SI) group (n = 995) (oil bath 4 times weekly from 2 weeks through 8 months) or 'No skin intervention' (NSI) group (n = 1158), with TEWL measurements at 3, 6 and/or 12 months of age. Information on FLG mutation status was available for 1683 of these infants. Effects of the skin intervention on TEWL and dry skin through infancy were assessed by mixed-effects regression modelling. Background characteristics and protocol adherence were collected from electronic questionnaires, birth records and weekly diaries. Results The TEWL (95% confidence interval) was on average 0.42 g m–2 h–1 (0.13–0.70, P = 0.004) higher in the SI group compared with the NSI group through the first year of life, with significantly higher levels at 3 months [8.6 (8.3–9.0) vs. 7.6 (7.3–7.9)], but similar at 6 and 12 months. Dry skin was observed significantly more often in the NSI group compared with the SI group at 3 months (59% vs. 51%) and at 6 months of age (63% vs. 53%), while at 12 months of age, the difference was no longer significant. At 3 months, the TEWL of FLG mutation carriers was similar to the TEWL in the SI group. No interaction between SI and FLG mutation was found in the first year of life. Conclusions Infants given frequent oil baths from 2 weeks of age had reduced skin barrier function through infancy compared with controls, largely attributed to higher TEWL at 3 months of age, while the skin at 3 and 6 months appeared less dry in infants subjected to the skin intervention. [ABSTRACT FROM AUTHOR]

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891). There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward. [ABSTRACT FROM AUTHOR]

Loss‐of‐function (LoF) mutations in the filaggrin gene (FLG) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude‐dependent difference in the prevalence of LoF FLG mutations was systematically evaluated. A systematic review and meta‐analysis were performed to estimate the prevalence of LoF FLG mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle‐Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9th December 2021. Studies were included if they contained data on the prevalence of LoF FLG mutations in AD patients or from the general population or associations between AD and LoF FLG mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF FLG mutations was 19.1% (95% CI, 17.3–21.0) in AD patients and 5.8% (95% CI, 5.3–6.2) in the general population. There was a significant positive association between AD and LoF FLG mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF FLG mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. FLG LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from FLG LoF mutations remains unknown. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15%‐30% of children and 10% of adults globally, with its incidence being influenced by genetic, environmental, and various other factors. While the immune plays a crucial role in the development, the composition of gut microbiota and serum metabolites also contribute to its pathogenesis. Subject: Study the characteristics of gut microbiota and serum metabolites in patients with atopic dermatitis Method: In this study, we collected stool and serum samples from 28 AD patients and 23 healthy individuals (NC) for metagenomic sequencing of gut microbiota and non‐targeted metabolomic sequencing of serum. Result: Our results revealed a lower diversity of gut microbiota in the AD group compared to the NC group. The predominant Phylum in AD patients were Bacteroidetes, Pseudomonas, and Verrucomicrobia, with the most dominant bacterial genus being Faecalibacterium. At the species level, Prevotella copri and Faecalibacterium prausnitzii were found to be the most abundant bacteria. Significant differences in serum metabolite profiles were observed between NC and AD patients, with noticeable variations in metabolite expression levels. The majority of metabolites in the serum of AD patients exhibited low expression, while a few showed high expression levels. Notably, metabolites such as Cholesterol glucuronide, Styrene, Lutein, Betaine, Phosphorylcholine, Taurine, and Creatinine displayed the most pronounced alterations. Conclusion: These findings contribute to a further understanding of the complexities underlying this disease. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify the heterogeneity of atopic dermatitis and to identify key genetic factors. This can lead to new approaches and personalized treatment strategies. I conducted a literature review of three scientific publication platforms (i.e., PubMed, Cochrane Library, Scopus) for records published between July 2011 and July 2023 using key words related to the genetics of atopic dermatitis. The high heritability and genetic pleiotropia of atopic dermatitis emphasize the importance of its genetic predisposition and interaction with concomitant diseases. The study also shows the role of various genes associated with immunity and inflammatory reactions, as well as the high heritability of atopic dermatitis, particularly among twins. Genetic mutations, specifically polymorphisms of genes encoding immune factors and inflammatory responses, determine an individual's predisposition to atopic dermatitis. Research findings also point to genetic aspects associated with other skin conditions such as psoriasis and vitiligo, confirming the existence of common genetic mechanisms between these diseases. Specifically, polymorphisms of the filaggrin gene have been found to be key genetic determinants of atopic dermatitis. I analyzed the genetic basis of atopic dermatitis, emphasizing the importance of genetic determinants and their interaction with the immune system and extracellular matrix. This study contributes to the understanding of the mechanisms of atopic dermatitis and opens new perspectives for individualized treatments. [ABSTRACT FROM AUTHOR]

Background: Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway. Methods: We utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran's Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings. Results: The Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929–0.972, p = 6.65 × 10− 6), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906–0.971, p = 2.79 × 10− 4), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906–0.969, p = 1.48 × 10− 4) and TAG (56:8) (OR: 0.918, 95% CI: 0.876–0.961, p = 2.72 × 10− 4) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028–1.079, p = 2.11 × 10− 5) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039–1.135, p = 2.47 × 10− 4) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%. Conclusion: Our research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a disease of overactive immune system. OVOL1 and Filaggrin have been associated with many inflammatory skin lesions. To the best of our knowledge, the correlation between OVOL1 and Filaggrin in psoriasis was not previously investigated. This work aims to search the immunohistochemical expression and correlation between OVOL1 and Filaggrin in psoriasis. Materials and methods: Slides cut from paraffin blocks of 30 psoriasis cases and 30 control subjects were stained with OVOL1 and Filaggrin. Clinicopathological data were correlated with the results of staining. Results: OVOL1 and Filaggrin expression in epidermis showed a significant gradual reduction from normal skin to peri-lesional and psoriasis biopsies (P < 0.001). In contrast, psoriasis dermis showed a significant overexpression of OVOL1 in inflammatory cells in relation to peri-lesional biopsies (P < 0.002). OVOL1 demonstrated a significant direct correlation with Filaggrin expression in psoriasis (r = 0.568, P < 0.004). OVOL1 and Filaggrin expression in psoriasis skin epidermis demonstrated a statistically significant negative correlation with PASI score. Conclusion: OVOL1 and Filaggrin might be involved in psoriasis-associated inflammation and skin hyperproliferation. OVOL1 might have a protective barrier function in the skin and could be used to stratify progressive disease. Filaggrin may play a role in progression of psoriasis. OVOL1 inhibition could be considered in suppression of Filaggrin function. OVOL1 agonists may be beneficial in psoriasis treatment. [ABSTRACT FROM AUTHOR]

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP. [ABSTRACT FROM AUTHOR]

Cannabis contains numerous natural components and has several effects such as anticancer, anti-inflammatory and antioxidant. Cheungsam is a variety of non-drug-type hemp, developed in Korea and is used for fiber (stem) and oil (seed). The efficacy of Cheungsam on skin is not yet known, and although there are previous studies on Cheungsam seed oil, there are no studies on Cheungsam seed husk. In this study, we investigated the potential of Cheungsam seed husk ethanol extract (CSSH) to alleviate skin inflammation through evaluating the gene and protein expression levels of inflammatory mediators. The results showed that CSSH reduced pro-inflammatory cytokines (IL-1β, IL-6, IL-8, MCP-1 and CXCL10) and atopic dermatitis-related cytokines (IL-4, CCL17, MDC and RANTES) in TNF-α/IFN-γ-induced HaCaT cells. Furthermore, ERK, JNK and p38 phosphorylation were decreased and p-p65, p-IκBα, NLRP3, caspase-1, p-JAK1 and p-STAT6 were suppressed after CSSH treatment. CSSH significantly increased the level of the skin barrier factors filaggrin and involucrin. These results suggest that Cheungsam seed husk ethanol extract regulates the mechanism of skin inflammation and can be used as a new treatment for skin inflammatory diseases. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a chronic complex inflammatory skin disorder that requires sustainable treatment methods due to the limited efficacy of conventional therapies. Sargassum serratifolium, an algal species with diverse bioactive substances, is investigated in this study for its potential benefits as a therapeutic agent for atopic dermatitis. RNA sequencing of LPS-stimulated macrophages treated with ethanolic extract of Sargassum serratifolium (ESS) revealed its ability to inhibit a broad range of inflammation-related signaling, which was proven in RAW 264.7 and HaCaT cells. In DNCB-induced BALB/c or HR-1 mice, ESS treatment improved symptoms of atopic dermatitis within the skin, along with histological improvements such as reduced epidermal thickness and infiltration of mast cells. ESS showed a tendency to improve serum IgE levels and inflammation-related cytokine changes, while also improving the mRNA expression levels of Chi3l3, Ccr1, and Fcεr1a genes in the skin. Additionally, ESS compounds (sargachromanol (SCM), sargaquinoic acid (SQA), and sargahydroquinoic acid (SHQA)) mitigated inflammatory responses in LPS-treated RAW264.7 macrophages. In summary, ESS has an anti-inflammatory effect and improves atopic dermatitis, ESS may be applied as a therapeutics for atopic dermatitis. [ABSTRACT FROM AUTHOR]

Background: Filaggrin (FLG) is an essential protein that plays a vital role in maintaining skin barrier function and moisture levels, allowing the skin to adapt to dry environments. However, the precise temporal dynamics of FLG metabolism in the human epidermis remain poorly understood, and suitable tools to study these time‐dependent effects are currently lacking. Objective: To investigate the molecular mechanisms and time course of FLG metabolism and skin barrier function under high‐ and low‐humidity conditions, utilizing a reconstructed epidermis model. Methods: EpiSkin specimens cultured under humid or dry conditions for varying durations (2–48 h) were compared by assessing FLG degradation and skin barrier formation using immunofluorescence staining and western blotting. Results: Under conditions of low humidity, the proteolysis of FLG in EpiSkin increased between 4 and 12 h and was accompanied by elevated levels of cysteine–aspartic protease (caspase)‐14. The expression of peptidyl arginine deiminase 1 and calpain 1 also increased at 4 h. However, after 24 h, the expression of these three FLG‐degrading proteins significantly decreased. Conversely, the levels of pyrrolidone‐5‐carboxylic acid and urocanic acid initially decreased at 2 h and then increased between 12 and 24 h. Additionally, the expression of skin barrier proteins, such as FLG, transglutaminase 5, loricrin and zonula occludens‐1, decreased starting from 12 h. Notably, epidermal cell viability and activity were also inhibited. Conclusion: We propose a reliable and ethical model to study the temporal dynamics of FLG metabolism and its role in skin barrier function. Using a commercially reconstructed epidermis to mimic dry skin formation obviates the need for animal and human testing. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis has a marked economic impact and affects the quality of life. A cosmetic compound with an innovative strategy is proposed here as a small chemical neutraligand, GPN279 (previously identified as a theophylline derivative), that binds and potently neutralizes the TARC/CCL17 chemokine, activating the Th2 cell‐expressed CCR4 receptor. Objective: Our objective was to evaluate the safety and activity of topically applied GPN279 in mild‐to‐moderate atopic dermatitis patients in a randomized, double‐blind, placebo‐controlled, parallel group trial. Such cosmetic active ingredient targeting dry skin with an atopic tendency would open a parallel strategy to the pharmaceutical approach, in particular for mild to moderate subjects, as an alternative to reduce the evolution towards severe forms of atopy. Methods: This 4‐week trial included adults with mild‐to‐moderate atopic dermatitis, according to the SCORAD index. Patients were randomized into two groups treated by topical applications of either an emulsion containing 0.44% GPN279 in placebo on skin lesions or the placebo (4.56% glycerin). Clinical activity was evaluated with the SCORAD as the primary objective. As secondary objectives, POEM, erythema, skin moisturization, its barrier function (TEWL) and safety were evaluated. Results: Twenty‐one patients in each group completed the study. SCORAD was significantly improved in the GPN279 group vs. placebo. GPN279 also significantly improved POEM, induced a rapid and significant decrease of erythema, and improved skin moisture. GPN279 and placebo were well tolerated throughout the study. Conclusion: A cosmetic cream comprising the CCL17 neutraligand GPN279 improved the skin barrier and physiology criteria in patients with mild‐to‐moderate atopic dermatitis. [ABSTRACT FROM AUTHOR]

Long-term inflammatory skin disease atopic dermatitis is characterized by dry skin, itching, and eczematous lesions. During inflammation skin barrier protein impairment promotes S. aureus colonisation in the inflamed skin, worsening AD patient's clinical condition. Proteomic analysis revealed the presence of several immune evasion proteins and virulence factors in S. aureus extracellular vesicles (EVs), suggesting a possible role for these proteins in the pathophysiology of atopic dermatitis. The objective of this study is to assess the efficacy of a wall fragment obtained from a patented strain of C. acnes DSM28251 (c40) and its combination with a mucopolysaccharide carrier (HAc40) in counteract the pathogenic potential of EVs produced by S. aureus ATCC 14458. Results obtained from in vitro studies on HaCaT keratinocyte cells showed that HAc40 and c40 treatment significantly altered the size and pathogenicity of S. aureus EVs. Specifically, EVs grew larger, potentially reducing their ability to interact with the target cells and decreasing cytotoxicity. Additionally, the overexpression of the tight junctions mRNA zona occludens 1 (ZO1) and claudin 1 (CLDN1) following EVs exposure was decreased by HAc40 and c40 treatment, indicating a protective effect on the epidermal barrier's function. These findings demonstrate how Hac40 and c40 may mitigate the harmful effects of S. aureus EVs. Further investigation is needed to elucidate the exact mechanisms underlying this interaction and explore the potential clinical utility of c40 and its mucopolysaccharide carrier conjugate HAc40 in managing atopic dermatitis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by itching and skin barrier dysfunction. Moderate to severe AD is often refractory to first-line topical treatments, and systemic immunosuppressants have been shown to be effective but have significant adverse effects. The paucity of basic treatments has contributed to the development of targeted topical and systemic immunotherapies based on the use of small molecules and biologic drugs which can directly interact with AD pathogenetic pathways. They represent a new era of therapeutic innovation. Additional new treatments are desirable since AD is a heterogeneous disease marked by different immunological phenotypes. This manuscript will review the mechanism of action, safety profile, and efficacy of promising new systemic immunological treatments for AD. Since moderate to severe AD can result in poor quality of life, the development of targeted and well-tolerated immunomodulators is a crucial purpose. The introduction of new pharmacological agents may offer new therapeutic options. However, there is the need to evaluate how "narrow-acting" agents, such as individual interleukin inhibitors, will perform under the safety and efficacy profiles compared with "broad-acting" agents, such as JAK inhibitors. [ABSTRACT FROM AUTHOR]

Glycolic acid (GA) is extensively used in cosmetic formulations and skin peeling treatments but its adverse effects, notably severe disruption of epidermal structure, limit its clinical utility. However, the detailed impact of GA on epidermal homeostasis, including changes in structure and protein expression over time, is not fully understood. This study employed a reconstructed human epidermis (RHE) model to assess the effects of varying GA concentrations on epidermal proliferation, differentiation, and desquamation at different time points. Through histology, immunofluorescence, and immunohistochemistry, we observed that 35% GA concentration adversely caused abnormal epidermal homeostasis by affecting epidermal proliferation, differentiation and desquamation. Our findings reveal time-specific responses of key proteins to GA: Filaggrin, Involucrin, Loricrin, and Ki67 showed very early responses; KLK10 an early response; and AQP3 and K10 late responses. This research provides a detailed characterization of GA's effects in an RHE model, mimicking clinical superficial peeling and identifying optimal times for detecting GA-induced changes. Our results offer insights for designing interventions to mitigate GA's adverse effects on skin, enhancing the safety and efficacy of GA peeling treatments. • GA induced-RHE model can simulate the clinical superficial peeling. • Epidermal homeostasis-related proteins show time-specific responses to GA stimulation. • 35% GA affects epidermal homeostasis by inhibiting proliferation. • 35% GA affects epidermal homeostasis by disturbing differentiation and desquamation. • 35% GA induced the expression of desquamation-related protein KLK10. [ABSTRACT FROM AUTHOR]

Background: Myeloid cells play critical roles in the regulation of myocardial injury and repair. Clonal hematopoiesis (CH)‐related mutations in genes, such as Ten‐eleven Translocation 2 (TET2), can impair myeloid cells and are associated with increased risk of cardiovascular disease (CVD). How Tet2 loss‐of‐function (LOF) impacts myeloid cells and disrupts normal myocardial repair remains unclear. Methods: We established ischemia‐induced myocardial infarction (MI) in a myeloid‐specific Tet2‐deficient mouse model. The echocardiographic assessment was conducted to evaluate the cardiac function. Histological analysis was performed to evaluate morphological changes in infarcted areas and fibrosis. To monitor the dynamic changes of myeloid cells in cardiac tissues during cardiac remodeling after MI, we performed longitudinal analysis on subsets of myeloid cells using flow cytometry. We performed immunofluorescence (IF) staining to examine the DNA damage and genome instability caused by Tet2 LOF. Gene expression was assessed by real‐time qRT‐PCR. Stimulator of Interferon Genes (STING) pathway activation was assessed using various methods, including Western blotting, flow cytometry, ELISA and IF staining of key signaling proteins involved in this pathway. Additionally, H‐151 was used as a pharmacological tool to antagonize augmented STING activation in the murine MI model. Results: We observed a substantial increase of neutrophils in the post‐MI mice, which contributes to adverse outcomes during heart repair. Mechanistically, Tet2‐deficient myeloid cells exhibited increased genome instability, accompanied with augmented activation of the STING pathway. Furthermore, the use of H‐151 a covalent STING binder that targets the cysteine residue at position 91 and functions as a potent STING antagonist, led to a substantial decrease in neutrophil populations in Tet2‐deficient mice following myocardial infarction, thereby reversing adverse cardiac outcomes. Conclusion: Our novel findings establish the rationale for targeting the cGAS‐STING pathway as a promising therapeutic strategy to mitigate cardiovascular disease risk in individuals with clonal hematopoiesis harboring TET2 loss‐of‐function mutations. Highlights: Myeloid‐specific Tet2 depletion promotes neutrophil expansion upon myocardium infarction (MI);Tet2‐deficient myeloid cells exhibit increased genome instability and cGAS‐STING overactivation;STING antagonist H‐151 treatment reduces neutrophil expansion in Tet2‐deficient mice after MI and mitigates deleterious cardiac outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Microalgae biotechnology utilizes species like Porphyridium cruentum for their valuable phycobiliproteins and exopolysaccharides, which have potential industrial applications and health benefits, particularly in skin condition improvement. Methods: A mutant of P. cruentum LIMS-PS-1061 was developed through ethyl methanesulfonate mutagenesis and subsequent colony screening to study changes in its biomass production and pigment composition under different lighting conditions. Results and discussion: The mutant exhibited a 33.9% increase in dry weight under white light compared to the wild type. Despite maintaining the total pigment content, specific components changed significantly: chlorophyll content decreased 2.20- and 3.61-fold under white and blue light respectively, while phycobiliproteins increased 1.59- and 1.23-fold under the same conditions. These alterations suggest a compensatory mechanism for maintaining photosynthetic capacity. Furthermore, the exopolysaccharides of P. cruentum upregulated genes related to skin moisturization, barrier enhancement, and elasticity, and promoted wound healing through fibroblast migration. This supports the proposed mechanism of action for P. cruentum’s exopolysaccharides in improving human skin conditions by integrating the effects of aquaporin 3, filaggrin, involucrin, loricrin, elastin, and fibrillin-1. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a frequent inflammatory condition that usually begins during early childhood, but it increasingly starts to debut, even in the elderly. Based on immunoglobulin E (IgE) levels and clinical features, two subsets of this disease have been recognized: intrinsic and extrinsic. When speaking about AD, most specialists think about filaggrin (FLG) mutations resulting in epidermal barrier defects, which is the case in most atopic patients, but some have a normal barrier, as seen by imaging, and still have specific clinical lesions along with metal allergies. Specific molecules (IL-10, IFN-γ, and HBD-3) have been shown to greatly impact the interactions between internal and external factors in this peculiar form of AD. A less-known protein, suprabasin, has been highlighted as a promising explanation for nickel anomalies in intrinsic AD. [ABSTRACT FROM AUTHOR]

The effect of lactoferrin on skin was simulated using a recombinant human epidermal model. The anti-inflammatory and soothing effect of lactoferrin was verified using IL-1α and TSLP Elisa assay. The effects of lactoferrin on the expression of related genes and proteins were detected using qPCR and immunofluorescence staining. The results showed that lactoferrin can effectively enhance the Transepidermal Electrical Resistance (TEER) and inhibit the secretion of inflammatory cytokine IL-1α and TSLP. In addition, it was confirmed using qPCR that lactoferrin had high expression levels on AQP3, FLG, IVL, CLDN1 and HAS1 genes. Immunofluorescence staining confirmed that lactoferrin had high fluorescence intensity and expression in AQP3, Filaggrin and Involucrin. The results showed that lactoferrin improved the skin barrier at higher than 1.5 mg/mL. At the same time, it can have anti-inflammatory and moisturizing effects. This study provides a strong basis for the application of lactoferrin in cosmetics and daily chemical products. [ABSTRACT FROM AUTHOR]

Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is involved in pruritus in inflammatory skin diseases such as atopic dermatitis (AD) and dry skin. We previously reported that tapinarof, a stilbene molecule, upregulates SEMA3A in human keratinocytes. We also showed that this mechanism is mediated via the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and the nuclear factor erythroid 2-related factor 2 (NRF2) axis. Since some stilbenes activate AHR and NRF2, we attempted to identify other stilbenes that upregulate SEMA3A. We analyzed normal human epidermal keratinocytes (NHEKs) treated with 11 types of stilbenes and examined SEMA3A expression. We found that resveratrol and pinostilbene, antioxidant polyphenols, upregulated SEMA3A and increased nuclear AHR and NRF2 expression. In addition, AHR knockdown by small interfering RNA (siRNA) transfection abolished the NRF2 nuclear expression. Furthermore, AHR and NRF2 knockdown by siRNA transfection abrogated resveratrol- and pinostilbene-induced SEMA3A upregulation. Finally, we confirmed that resveratrol and pinostilbene increased SEMA3A promoter activity through NRF2 binding using ChIP-qPCR analysis. These results suggest that resveratrol and pinostilbene upregulate SEMA3A via the AHR–NRF2 axis in human keratinocytes. [ABSTRACT FROM AUTHOR]

Background: There is a significant imbalance of mitochondrial activity and oxidative stress (OS) status in patients with atopic dermatitis (AD). This study aims to screen skin and peripheral mitochondria-related biomarkers, providing insights into the underlying mechanisms of mitochondrial dysfunction in AD. Methods: Public data were obtained from MitoCarta 3.0 and GEO database. We screened mitochondria-related differentially expressed genes (MitoDEGs) using R language and then performed GO and KEGG pathway analysis on MitoDEGs. PPI and machine learning algorithms were also used to select hub MitoDEGs. Meanwhile, the expression of hub MitoDEGs in clinical samples were verified. Using ROC curve analysis, the diagnostic performance of risk model constructed from these hub MitoDEGs was evaluated in the training and validation sets. Further computer-aided algorithm analyses included gene set enrichment analysis (GSEA), immune infiltration and mitochondrial metabolism, centered on these hub MitoDEGs. We also used real-time PCR and Spearman method to evaluate the relationship between plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) levels and disease severity in AD patients. Results: MitoDEGs in AD were significantly enriched in pathways involved in mitochondrial respiration, mitochondrial metabolism, and mitochondrial membrane transport. Four hub genes (BAX, IDH3A, MRPS6, and GPT2) were selected to take part in the creation of a novel mitochondrial-based risk model for AD prediction. The risk score demonstrated excellent diagnostic performance in both the training cohort (AUC = 1.000) and the validation cohort (AUC = 0.810). Four hub MitoDEGs were also clearly associated with the innate immune cells' infiltration and the molecular modifications of mitochondrial hypermetabolism in AD. We further discovered that AD patients had considerably greater plasma ccf-mtDNA levels than controls (U = 92.0, p<0.001). Besides, there was a significant relationship between the up-regulation of plasma mtDNA and the severity of AD symptoms. Conclusions: The study highlights BAX, IDH3A, MRPS6 and GPT2 as crucial MitoDEGs and demonstrates their efficiency in identifying AD. Moderate to severe AD is associated with increased markers of mitochondrial damage and cellular stress (ccf=mtDNA). Our study provides data support for the variation in mitochondria-related functional characteristics of AD patients. [ABSTRACT FROM AUTHOR]

Eczema (atopic dermatitis, AD) is a skin disease characterized by skin barrier dysfunction due to various factors, including genetics, immune system abnormalities, and environmental triggers. Application of emollients and topical drugs such as corticosteroids and calcineurin inhibitors form the mainstay of treatments for this challenging condition. This review aims to summarize the recent advances made in phytochemical-based topical applications to treat AD and the different carriers that are being used. In this review, the clinical efficacy of several plant extracts and bioactive phytochemical compounds in treating AD are discussed. The anti-atopic effects of the herbs are evident through improvements in the Scoring Atopic Dermatitis (SCORAD) index, reduced epidermal thickness, decreased transepidermal water loss, and alleviated itching and dryness in individuals affected by AD as well as in AD mouse models. Histopathological studies and serum analyses conducted in AD mouse models demonstrated a reduction in key inflammatory factors, including thymic stromal lymphopoietin (TSLP), serum immunoglobulin E (IgE), and interleukins (IL). Additionally, there was an observed upregulation of the filaggrin (FLG) gene, which regulates the proteins constituting the stratum corneum, the outermost layer of the epidermis. Carriers play a crucial role in topical drug applications, influencing dose delivery, retention, and bioavailability. This discussion delves into the efficacy of various nanocarriers, including liposomes, ethosomes, nanoemulsions, micelles, nanocrystals, solid-lipid nanoparticles, and polymeric nanoparticles. Consequently, the potential long-term side effects such as atrophy, eruptions, lymphoma, pain, and allergic reactions that are associated with current topical treatments, including emollients, topical corticosteroids, topical calcineurin inhibitors, and crisaborole, can potentially be mitigated through the use of phytochemical-based natural topical treatments. [ABSTRACT FROM AUTHOR]

Introduction: The effects of fructo-oligosaccharides (FOS) on atopic dermatitis (AD) have not been determined. Methods: In a randomized, double-blind, placebo-controlled trial, children with AD aged 24 months to 17 years received either advanced FOS containing 4.25 g of 1-kestose or a placebo (maltose) for 12 weeks. Results: The SCORAD and itching scores were reduced in patients treated with both FOS (all p < 0.01) and maltose (p < 0.05 and p < 0.01). Sleep disturbance was improved only in the FOS group (p < 0.01). The FOS group revealed a decreased proportion of linoleic acid (18:2) esterified omega-hydroxy-ceramides (EOS-CERs) with amide-linked shorter chain fatty acids (C28 and C30, all p < 0.05), along with an increased proportion of EOS-CERs with longer chain fatty acids (C32, p < 0.01). Discussion: FOS may be beneficial in alleviating itching and sleep disturbance, as well as improving skin barrier function in children with AD. [ABSTRACT FROM AUTHOR]