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BackgroundWhile numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.ObjectivesThis study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.MethodsAD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.ResultsGenetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).ConclusionsThis study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

BackgroundAtopic dermatitis (AD) disease activity and severity is highly variable during childhood. Early attempts to identify subtypes based on disease trajectory have assessed AD presence over time without incorporating severity.ObjectivesTo identify childhood AD subtypes from symptom severity and trajectories, and determine associations with genetic risk factors, comorbidities and demographic and environmental variables.MethodsWe split data from children in the Avon Longitudinal Study of Parents and Children birth cohort into development and validation sets. To identify subtypes, we ran latent class analyses in the development set on AD symptom reports up to age 14 years. We regressed identified subtypes on nongenetic variables in mutually adjusted, multiply imputed (genetic: unadjusted, complete case) multinomial regression analyses. We repeated analyses in the validation set and report confirmed results.ResultsThere were 11 866 children who contributed to analyses. We identified one Unaffected/Rare class (66% of children) and four AD subtypes: Severe-Frequent (4%), Moderate-Frequent (7%), Moderate-Declining (11%) and Mild-Intermittent (12%). Symptom patterns within the first two subtypes appeared more homogeneous than the last two. Filaggrin (FLG) null mutations, an AD polygenic risk score (PRS), being female, parental AD and comorbid asthma were associated with higher risk for some or all subtypes; FLG, AD-PRS and asthma associations were stronger along a subtype gradient arranged by increasing severity and frequency; FLG and AD-PRS further differentiated some phenotypes from each other.ConclusionsConsidering severity and AD trajectories leads to four well-defined and recognizable subtypes. The differential associations of risk factors among and between subtypes is novel and requires further research.

The outer layer of the epidermis composes the skin barrier, a sophisticated filter constituted by layers of corneocytes in a lipid matrix. The matrix lipids, especially the ceramide-generated sphingosine 1-phosphate, are the messengers that the skin barrier uses to communicate with the basal layer of the epidermis where replicating keratinocytes are located. Sphingosine 1-phosphate is a bioactive sphingolipid mediator involved in various cellular functions through S1PR1‒5, expressed by keratinocytes. We discovered that the S1pr2 absence is linked to an impairment in the skin barrier function. Although S1pr2-/- mouse skin has no difference in its phenotype and barrier function compared with that of wild-type mouse, after tape stripping, S1pr2-/- mouse showed significantly higher transepidermal water loss and required another 24 hours to normalize their transepidermal water loss levels. Moreover, after epicutaneous Staphylococcus aureus application, impaired S1pr2-/- mouse epidermal barrier function allowed deeper bacterial penetration and denser neutrophil infiltration in the dermis. Microarray and RNA sequence of S1pr2-/- mouse epidermis linked the barrier dysfunction with a decrease in FLG2 and tight junction components. In conclusion, S1pr2-/- mice have compromised skin barrier function and increased bacteria permeability, making them a suitable model for diseases that present similar characteristics, such as atopic dermatitis.

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

BackgroundAtopic eczema onset is described primarily in early childhood, and the frequency and characteristics of adult-onset disease remain controversial.ObjectiveWe sought to determine the proportion of subjects who report atopic eczema symptoms between birth and midadulthood and to examine demographic, immunologic, and genetic factors associated with period of symptom onset.MethodsWe conducted a longitudinal study using data from 2 nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Subjects were followed from birth through age 42 to 50 years. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave.ResultsThe annual period prevalence of atopic eczema ranged from 5% to 15% in 2 cohorts of more than 17,000 participants each followed from birth through middle age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with subjects whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socioeconomic group, smokers in adulthood, and less likely to have a history of asthma. In a subanalysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin-null mutations, and allergen-specific IgE were more common among those with childhood-onset disease.ConclusionRates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema.

We have generated an induced pluripotent stem cell (iPSC) line KCLi003-A (iOP101) from epidermal keratinocytes of a female donor, heterozygous for the loss-of-function mutation p.R501X in the filaggrin gene (FLG), using non-integrating Sendai virus vectors. Derivation and expansion of iPSCs were performed under xeno-free culture conditions. Characterization and validation of KCLi003-A line included molecular karyotyping, mutation screening using restriction enzyme digestion, next generation sequencing (NGS), while pluripotency and differentiation potential were confirmed by expression of associated markers in vitro and by in vivo teratoma assay.

We have generated an induced pluripotent stem cell (iPSC) line KCLi001-A (iOP118) from a female atopic dermatitis (AD) patient, heterozygous for the loss-of-function mutation c.2282del4 in the filaggrin gene (FLG). Epidermal keratinocytes were reprogrammed using non-integrating Sendai virus vectors. The entire process of derivation and expansion of AD-iPSCs were performed under xeno-free culture conditions. Characterization of KCLi001-A line included molecular karyotyping, mutation screening using restriction enzyme digestion and Sanger sequencing, while pluripotency and differentiation potential were confirmed by expression of associated markers in vitro and by in vivo teratoma assay.

This study aimed to evaluate the therapeutic efficacy of camellia oil on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in mice, as well as its effect on the expression of skin-barrier-related proteins. A mouse model of AD was created via topical application of DNCB; subsequently, the animals were randomly divided into four groups: the blank control (Control), model (Model), moisturizing cream (Moisturizer), and camellia oil (Camellia) groups. The Camellia group received camellia oil, whereas the Moisturizer group was treated with moisturizing cream, as a positive control. Skin lesions, ear and back tissue morphology, and the serum levels of IgE, IL-4, and IFN-γ were analyzed. Compared with the Control group, AD mice exhibited erythema, papules, dryness, peeling, and significantly higher serum IgE and IL-4 levels. Compared with the Model group, treatment with camellia oil and moisturizing cream considerably reduced skin inflammation, ear thickness, and scratching frequency. A histopathological analysis revealed that camellia oil reduced inflammatory-cell infiltration and edema in the AD-affected skin. Furthermore, camellia oil upregulated filaggrin (FLG), thus aiding in skin-barrier repair. These findings suggest that camellia oil significantly improves AD symptoms, enhances FLG expression, and restores the damaged skin barrier in AD mouse models.

Cold atmospheric plasma (CAP) has been utilized in various medical devices using its oxidative nature. Recent studies have provided evidence that CAP can facilitate the delivery of large, hydrophilic molecules through the epidermis to the dermis. On the other hand, a new approach called low-intensity CAP (LICAP) has been developed, allowing the plasma level to be controlled within a subtoxic range, thereby demonstrating various biological benefits without tissue damage. However, the ability of LICAP to enhance transepidermal delivery in sub-cytotoxic conditions has not been fully investigated. This study aims to determine the sub-cytotoxic range of exposure time for LICAP and, within the range, to investigate the effects of LICAP treatment on transepidermal drug delivery (TED) and mechanisms using human keratinocytes and a mouse model. For the in vitro studies, LICAP treatment was evaluated in human keratinocyte (HaCaT) cells by assessing reactive species production, DNA damage, and cytotoxicity profiles. Within the determined safety range, mechanistic analyses were conducted to examine LICAP-enhanced delivery pathways. mRNA expression and protein levels of tight and adherens junction genes were quantified, and changes in ultramicroscopic morphology of HaCaT monolayers were investigated. Intracellular delivery of fluorescein isothiocyanate (FITC)-dextran was also assessed. For the in vivo studies, E-cadherin expression and the transepidermal delivery (TED) of human epidermal growth factor (hEGF) were analyzed in LICAP-treated mouse dorsal skin. The upper safety range of LICAP exposure time, reducing cell viability by 70% (IC70 or LD30), was estimated at 34.3 s. Within the safety range, LICAP treatment downregulated multiple tight and adherens junction genes in HaCaT cells. Consistent with the in vitro results, the epidermal E-cadherin expression was reduced, and human epidermal growth factor (hEGF) was infiltrated in the dermis of the LICAP-treated mouse skin. Intercellular clefts were detected in the HaCaT cell monolayer immediately following LICAP treatment and intracellular delivery of FITC-dextran was confirmed after LICAP exposure. This study demonstrated that LICAP treatment enhances transepidermal permeation of hEGF, apparently via both paracellular and transcellular routes. Under our study conditions, LICAP treatment seems to be a novel approach to facilitate TED with low safety concerns in vitro. Further translational studies are needed for clinical evaluation., Competing Interests: Declarations. Competing interests: This work was supported by the Institute of Information and Communications Technology Planning and Evaluation (IITP) grant funded by the Korean government (MSIT) (No. 2021‐0‐01074, Development of Intelligent Plasma Medical Device Applying User Data Platform Technology Project) and Chung-Ang University Research Grants in 2024. One of the authors, Ga Ram Ahn, is a shareholder of the cooperation that provided the test device. All other authors declare no conflicts of interest., (© 2025. The Author(s).)

Adding of vegetable oils to skincare products or the use of plant oils for oil care is a current trend. Therefore, the safety and functionality of vegetable oils are of great concern to consumers and cosmetics manufacturers. This study focused on three types of vegetable oils: sunflower oil (SO), andiroba oil (AO) and hydrogenated olive oil (HOO). We conducted a comprehensive evaluation of the oils, which encompassed their ability to protect mouse skin keratinocytes (XB-2) and mouse fibroblasts (NIH 3T3) from damage caused by the surfactant sodium lauryl sulfate (SLS), their influence on the levels of filaggrin and collagen, their potential to aid in wound healing, and their effectiveness in anti-Staphylococcus aureus biofilm formation. The results showed that SO, AO and HOO at a concentration of 1.5 × 10 -4 % (v/v) have the ability to defend against SLS-induced cell damage, increase wound healing ability and the filaggrin and collagen content to XB-2 or NIH 3T3 cells. SO, AO and HOO at a concentration of 3.75 × 10 -3 % also have the anti-biofilm ability. Among the oils, AO can inhibit S. aureus biofilm composed of either polysaccharides or proteins. Therefore, the tested vegetable oils and can be applied to the cosmetics field as ingredients to repair damaged skin and preserve skin barrier stability.

Background: 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., Objective: To evaluate the association between the natural course of egg sensitization and FLG mutations., Methods: 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., Results: 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)., Conclusion: 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., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

In this review, we provide an overview of food allergy genetics and epigenetics aimed at clinicians and researchers. This includes a brief review of the current understanding of genetic and epigenetic mechanisms, inheritance of food allergy, as well as a discussion of advantages and limitations of the different types of studies in genetic research. We specifically focus on the results of genome-wide association studies in food allergy, which have identified 16 genetic variants that reach genome-wide significance, many of which overlap with other allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis. Identified genes for food allergy are mainly involved in epithelial barrier function (e.g., FLG, SERPINB7) and immune function (e.g., HLA, IL4). Epigenome-wide significant findings at 32 loci are also summarized as well as 14 additional loci with significance at a false discovery of < 1 × 10 -4 . Integration of epigenetic and genetic data is discussed in the context of disease mechanisms, many of which are shared with other allergic diseases. The potential utility of genetic and epigenetic discoveries is deliberated. In the future, genetic and epigenetic markers may offer ways to predict the presence or absence of clinical IgE-mediated food allergy among sensitized individuals, likelihood of development of natural tolerance, and response to immunotherapy., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

FLG is a well-known biomarker of atopic dermatitis and skin dryness. Its full proteolysis (or filaggrinolysis) produces the major constituents of the natural moisturizing factor. Some proteases/peptidases remain to be identified in this multistep process. Mining 16 omics analyses, we identified prolyl endopeptidase (PREP) as a candidate peptidase. Indirect immunofluorescence and confocal analysis demonstrated its localization in the granular and deep cornified layers, where it colocalized with FLG. Tandem mass spectroscopy and fluorescent quenching activity assays showed that PREP cleaved several synthetic peptides derived from the FLG sequence, at the carboxyl side of an internal proline. Deimination of these peptides increased PREP enzymatic efficiency. Specific inhibition of PREP in reconstructed human epidermis using benzyloxycarbonyl-pro-prolinal induced the accumulation of FLG monomers. Downregulation of PREP expression in reconstructed human epidermis using RNA interference confirmed the impact of PREP on FLG metabolism and highlighted a more general role of PREP in keratinocyte differentiation. Indeed, quantitative global proteomic, western blotting, and RT-qPCR analyses showed a strong reduction in the expression of bleomycin hydrolase, known to be involved in filaggrinolysis, and of several other actors of cornification such as loricrin. Consequently, at the functional level, the transepidermal electric resistance was drastically reduced., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of FLG and the tight junction protein ZO-1 in skin affected by moderate lymphedema or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to those in the controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that similar to the clinical scenario, the expression of skin barrier proteins was decreased relative to that in normal skin and that colonization with Staphylococcus epidermidis bacteria amplified this effect as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Author(s). BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Dictamnine and fraxinellone constitute the primary alkaloid and limonoid components in Cortex Dictamni, respectively. Both compounds exhibit anti-inflammatory properties. This study aims to assess the ability of dictamnine and fraxinellone in treating atopic dermatitis (AD) through in silico-, cell-, and animal-based experiments. The effects of these compounds on the coordinated activation of keratinocytes, macrophages, and basophils in AD development were investigated. A dinitrochlorobenzene (DNCB)-sensitized AD model in mice was employed to examine the in vivo anti-AD effects. Dictamnine and fraxinellone effectively reduced the release of proinflammatory effectors, including interleukin (IL)-4, IL-13, chemokine (C-C motif) ligand (CCL)5, and CCL17, by suppressing extracellular signal-regulated kinase (ERK) signaling in activated keratinocytes. The conditioned medium from dictamnine-treated macrophages reduced signal transducer and activator of transcription (STAT)3 in keratinocytes by 39 %, indicating the inhibition of keratinocytes-immune cell interaction. Both compounds comparably suppressed RBL-2H3 cell degranulation by decreasing histamine production. In vitro permeation test (IVPT) demonstrated three-fold greater skin absorption of topically applied dictamnine than fraxinellone. The in silico molecular docking manifested a preferable ceramide interaction with dictamnine over fraxinellone. Topical application of dictamnine decreased the mouse skin lesion development and the overexpressed cytokines/chemokines. This attenuation is comparable to the activity of tacrolimus ointment, a standard clinical treatment. Histological analysis revealed that dictamnine inhibited epidermal proliferation, reducing thickness from 220 to 97 μm. However, dictamnine did not restore the barrier function, as evidenced by the results of filaggrin and loricrin expression and in vivo transepidermal water loss (TEWL). The findings suggest that topical dictamnine can be a promising agent for alleviating AD inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Graphene and its various derivatives, known as graphene-based nanomaterials (GBNs), hold tremendous potential across many fields due to their exceptional properties. As with any novel material, concerns about their safety have emerged alongside their widespread production and use. Several studies have shown that GBNs can have diverse effects on various cell lines and organisms under different exposure conditions. This study intends to evaluate the potential toxicity of few-layer graphene (FLG) in human bronchial BEAS-2B. Cells were exposed to different concentrations of FLG for 24 h, and the cyto-genotoxic, oxidative, and inflammatory effects were evaluated. We found an increase in cytotoxicity in terms of cell death, cell apoptosis, and membrane damage at the highest concentration. We also detected a slight increase in direct DNA damage and the percentage of comets. Oxidative DNA damage was observed at the highest concentration. FLG exposure did not induce notable cytokine release. Overall, this study suggests that exposure to FLG can induce cytotoxicity, apoptosis, and DNA damage in BEAS-2B, particularly at high concentrations. These findings contribute to a better understanding of the potential health effects of FLG and highlight the importance of considering dose-dependent effects when assessing the safety of GBNs.

Psoriasis is a chronic, relapsing, inflammatory skin disease that is caused by the immune system. Amygdalin possesses immune-modulating and anti-inflammatory effects. To explore the possible effects of amygdalin on psoriasis and its pathogenesis of action, we examined the effects of amygdalin on imiquimod-induced psoriasis, tape-stripping-induced skin barrier disruption, and investigated the potential mechanism of action in vitro. The fact that amygdalin could reduce the thickness of the epidermis and inflammatory cell infiltration in two animal models inhibited the production of IL-1β, IL-6, and TNF-a, and the expression of filaggrin, involucrin, and keratin10 was increased. Also, in IL-17 A and TNF-α induced HaCaT, amygdalin inhibits the expression of IL-6, IL-1β, and TNF-a, promoting the expression of skin barrier recovery-related proteins flaggrin, involucrin, and keratin10. Combined in vivo and in vitro experiments suggest that amygdalin modulates inflammation and the skin barrier in psoriasis. The same study also conducted a preliminary mechanistic exploration and found that amygdalin inhibited the phosphorylation of the p38MAPK signaling pathway. In conclusion, Amygdalin can alleviate psoriasis lesions and improve skin barrier impairment, and the research provides an experimental basis for its future development as a drug candidate for psoriasis therapy., Competing Interests: Declarations. Ethics statement: This animal experiment was reviewed and approved by the Animal Care and Use Committee of Guangzhou University of Traditional Chinese Medicine (2020038) and followed the ARRIVE guidelines. Competing interests: The authors declare no competing interests. Conflict of interest: The author declares no conflict of interest with this article., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In homeostatic conditions, the basal progenitor cells of the esophagus differentiate into a stratified squamous epithelium. However, in the setting of acid exposure or inflammation, there is a marked failure of basal cell differentiation, leading to basal cell hyperplasia. We have previously shown that lysyl oxidase (LOX), a collagen crosslinking enzyme, is upregulated in the setting of allergic inflammation of the esophagus; however, its role beyond collagen crosslinking is unknown. Herein, we propose a non-canonical epithelial-specific role of LOX in the maintenance of epithelial homeostasis using 3D organoid and murine models. We performed quantitative reverse transcriptase PCR, Western blot, histologic analysis, and RNA sequencing on immortalized non-transformed human esophageal epithelial cells (EPC2-hTERT) with short-hairpin RNA (shRNA) targeting LOX mRNA in both monolayer and 3D organoid culture. A novel murine model with a tamoxifen-induced Lox knockout specific to the stratified epithelium ( K5CreER ; Lox fl/fl ) was utilized to further define the role of epithelial LOX in vivo. We found that LOX knockdown decreased the proliferative capacity of the esophageal epithelial cells in monolayer culture, and dramatically reduced the organoid formation rate (OFR) in the shLOX organoids. LOX knockdown was associated with decreased expression of the differentiation markers filaggrin, loricrin, and involucrin, with RNA sequencing analysis revealing 1224 differentially expressed genes demonstrating downregulation of pathways involved in cell differentiation and epithelial development. Mice with Lox knockout in their stratified epithelium demonstrated increased basaloid content of their esophageal epithelium and decreased Ki-67 staining compared to the vehicle-treated mice, suggesting reduced differentiation and proliferation in the Lox-deficient epithelium in vivo. Our results demonstrate, both in vivo and in vitro, that LOX may regulate epithelial homeostasis in the esophagus through the modulation of epithelial proliferation and differentiation. Understanding the mechanisms of perturbation in epithelial proliferation and differentiation in an inflamed esophagus could lead to the development of novel treatments that could promote epithelial healing and restore homeostasis.

In this study, the ultraviolet B (UVB)-induced skin photoaging inhibitory activity of pomegranate peel extract with increased ellagic acid content through enzymatic hydrolysis was evaluated in HaCaT cells. Among various enzymes, Viscozyme with high tannase and β-glucosidase activities was used, and 1.0 % Viscozyme was added to hydrolyze pomegranate peel for 2 h at 40°C to establish the optimal reaction conditions for high ellagic acid content. Subsequently, when cells were treated with enzyme extracted pomegranate peels (40 μg/mL), the gene expression of matrix metalloproteinases (MMP)-2 and 13, which play key role in skin elasticity and moisture, and the protein expression of MMP13 were downregulated compared to the UVB-control group (UVB-C). In addition, the protein expression levels of tissue inhibitors, metalloproteinase-1 and 2, and collagen type I alpha 1 were upregulated, the gene expression of hyaluronic acid synthase-1, and filaggrin significantly increased, and interleukin-1β increased by photoaging was decreased. Furthermore, compared to the UVB-C, there was a significant increase in the gene expression of superoxide dismutase-1 and glutathione peroxidase, which resulted in a decrease in reactive oxygen species and malondialdehyde levels. These results were confirmed to be due to the inhibition of the mitogen-activated protein kinase pathway and downregulation of the protein expression of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase, and P38. In conclusion, pomegranate peel, from which ellagic acid was extracted using Viscozyme, showed a reactive oxygen species inhibitory effect in UVB-irradiated HaCaT cells and thus may have a significant potential as a cosmetic ingredient with anti-aging effects., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hyung Joo Suh reports financial support was provided by Korea Ministry of Small and Medium Enterprises and Startups. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: In vitro methods have been widely used to assess adverse effects. Reconstructed Human Epidermis (RHE) poses as a fascinating test system employed to assess the dermal irritation hazard potential of chemicals. Although several RHE models are reported in the OECD Test Guideline No. 439, the OECD Document No. 220 encourages the scientific community to develop and validate new RHE test systems due to its relevance for socio-economic advancement., Methods: Following the criteria documented in the OECD No. 220, a blind study for skin irritation (OECD 439) was conducted employing the Minimum List of Reference Chemicals for Determination of Reproducibility and Predictive Capacity using ES®-RHE. Structural and functional characteristics were assessed alongside the prediction model., Results: The model has shown reproducibility of optical density and barrier function, similarly to internationally validated methods. Furthermore, it shows the cell layers' development and differentiation ability due to Cytokeratin14, Cytokeratin10, and filaggrin expression. The prediction model resulted in sensitivity, specificity and accuracy rates of 100, 70, and 77 %, respectively., Conclusions: The ES®-RHE demonstrated reliability and relevance, with similar structural and functional characteristics comparable to internationally validated models, in addition to the accepted predictive capacity according to OECD required minimum criteria, thus confirming the suitability of the national ES®-RHE in the hazard prediction of dermal irritation based on OECD Test Guideline No. 439., Competing Interests: Conflict of Interest The authors are collaborators of Eleve Science Pesquisa e Desenvolvimento Ltda, a start-up, located in SUPERA Parque Tecnológico de Ribeirão Preto - University of São Paulo/Brazil that has received financial support from FINEP and FAPESP in Brazil. However, the authors declare that there are no conflicts of interest related to the content of this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ultraviolet (UV) exposure triggers skin aging primarily by disrupting skin barrier function, resulting in dry skin and wrinkle formation. Oyster hydrolysate (OH), as a functional food, has been reported for anti-cancer, anti-oxidant and anti-apoptotic effects. This study investigated the underlying mechanism of OH effect on UVB-induced skin aging in SKH1 hairless mice. Mice were exposed to UVB three times per week while they were fed with a normal diet or diet containing OH for 10 weeks. Additionally, a randomized, double-blind, and placebo-controlled clinical trial was performed to investigate the OH effect on human skin moisturizing to evaluate its efficacy and safety. UVB exposure increased parameters of skin aging; dehydration, transepidermal water loss, and macroscopic dorsal skin lesions. OH significantly reduced these features of skin aging. Histological analysis demonstrated that OH decreased skin epidermal and dermal thickness and collagen degradation induced by UVB. OH significantly reduced ROS production, suppressed macrophage activation and neutrophil infiltration, and downregulated pro-inflammatory cytokine production. OH improved skin barrier function by increasing the expression of filaggrin, aquaporin-3, and hyaluronic acid synthesis enzymes and promoting recovery from skin damage. Importantly, the results from a human clinical trial demonstrated that OH improved skin moisturization and integrity with no side effects. Taken together, OH supplementation ameliorates skin damage via anti-oxidant and anti-inflammatory properties and enhances skin hydration and barrier function. OH has a therapeutic potential for skin photoaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the repairing and anti-wrinkle efficacy of the facial cream enriched with C-xyloside, aiming at comprehensively evaluating its skin anti- aging effect and clarify its potential mechanism of action., Methods: The repairing efficacy was studied on 3D epidermis skin model and the antiaging efficacy was studied on ex-vivo human skin. Two clinical studies were conducted with Chinese females. In the first study, 49 subjects aged between 30 and 50 with wrinkle concerns were recruited and instructed to apply the investigational cream containing C-xyloside for 8 weeks. Wrinkles attributes were assessed by dermatologist. Instrumental measurements on skin hydration, trans-epidermal water loss (TEWL), and skin elasticity were also conducted. In the second study, 30 subjects aged between 25 and 60 with self-declared sensitive skin and facial redness were recruited and instructed to apply the cream for 4 weeks. Biomarker analysis of the stratum corneum was conducted through facial tape strips., Results: The cream improved the histomorphology of the 3D epidermis skin model after SLS stimulation, and significantly increase the expression of LOR and FLG. On human skin, the cream improved the histopathology induced by UV, and significantly increased the protein content of COL I and COL III, collagen density and the number of Ki-67 positive cell of skin compared with model group (n = 3, p < 0.01). The results from the first clinical study demonstrate a significant increased the skin hydration and elasticity by 21.90%, 13.08% (R2) and 12.30% (R5), respectively (n = 49, p < 0.05), and the TEWL values decreased by 33.94% (n = 49, p < 0.05), after 8 weeks application of the cream. In addition, the scores for nasolabial folds, glabellar wrinkle, underneath eye wrinkles, crow's feet wrinkle and forehead wrinkle in the volunteers exhibited a significant reduction of 34.02%, 43.34%, 50.03%, 33.64% and 55.81% respectively (n = 49, p < 0.05). The (rCE)/(fCE) ratio of volunteers based on tape stripping significant increased after using the sample cream (n = 30, p < 0.05)., Conclusion: The cream containing C-xyloside showed improvement of skin wrinkles and enhancement of skin barrier function. These efficacies may be attributed to the fact that the sample cream can increase the expression of skin barrier related proteins LOR and FLG, promote the maturation of cornified envelope, enhance collagen I and III protein expression and stimulate skin cell proliferation, to provide sufficient evidence supporting its antiaging efficacy of skin., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Sodium lauryl sulfate (SLS) is used as a control irritant in patch testing for allergic contact dermatitis (ACD). However, up to 20% of those tested react to SLS, whereby the pathophysiological basis of this reaction is still unclear. To mimic patch test reactions, we repeatedly applied SLS to the skin of wild-type mice. Reactions were compared with those in a classical ACD model induced by oxazolone and an irritant contact dermatitis (ICD) model induced by croton oil. Skin inflammation was assessed with ear thickness measurements, immunohistochemistry, qRT-PCR, and flow cytometry. Topical SLS treatment was further investigated in Flg/Hrnr -/- , Myd88/Tlr3 -/- , and Rag1 -/- mouse models. All three compounds caused ear swelling with different courses. Oxazolone treatment, compared with the ICD model, resulted in a greater influx of immune cells (CD4 + , MHCII + , CD11b + ). Similarly, SLS did not induce immune cell infiltration or expression of selected inflammatory and regulatory cytokines. SLS induced the most pronounced keratinocyte proliferation. Compared with wild-type mice, topical SLS application did not increase ear swelling in skin barrier deficient Flg/Hrnr -/- mice, but led to significantly delayed swelling in mice with defects in innate or adaptive immune functions (Myd88/Tlr3 -/- , Rag1 -/- ). SLS-induced contact dermatitis differed from classical ACD and ICD, as it elicited less pronounced immune alterations. Skin barrier impairment does not affect SLS-induced contact dermatitis, whereas both innate and adaptive components are involved in SLS skin reactions., (© 2024 Wiley‐VCH GmbH.)

Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum (ER) Ca2+ - ATPase (SERCA2). Mutations of this gene result in alterations of calcium homoeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, was then applied to this ATP2A2-silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+ ]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the ER, the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene-silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin 10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signalling and may be used as a potential strategy for improving aspects of DD.

AP1 transcription factors are important controllers of gene expression in the epidermis, and altered AP1 factor function can perturb keratinocyte proliferation and differentiation. However, our understanding of how AP1 signaling changes may underlie or exacerbate skin disease is limited. We have shown that inhibiting AP1 factor function in suprabasal adult epidermis leads to reduced filaggrin levels and to a phenotype that resembles the genetic disorder ichthyosis vulgaris. We now show that inhibiting AP1 factor function during development in embryonic epidermis produces marked phenotypic changes including reduced filaggrin mRNA and protein levels, compromised barrier function, marked ultrastructural change, and enhanced dehydration susceptibility that resembles the phenotype observed in the flaky tail mouse, a model for ichthyosis vulgaris. In addition, the AP1 factor-deficient newborn mice display a collodion membrane phenotype that is not observed in flaky tail mice or in newborn individuals with ichthyosis vulgaris but is present in other forms of ichthyosis. This mixed phenotype suggests the need for a better understanding of the possible role of filaggrin loss and AP1 transcription factor deficiency in ichthyoses and collodion membrane formation.

Loss-of-function mutations in the FLG gene cause ichthyosis vulgaris (IV) and represent the major predisposing genetic risk factor for atopic dermatitis (AD). Although both conditions are characterized by epidermal barrier impairment, AD also exhibits signs of inflammation. This work was aimed at delineating the role of FLG loss-of-function mutations on eicosanoid metabolism in IV and AD. Using human epidermal equivalents (HEEs) generated with keratinocytes isolated from nonlesional skin of patients with FLG wild-type AD (WT/WT), FLG-mutated AD (FLG/WT), IV (FLG/FLG), or FLG WT control skin, we assessed the potential autocrine role of epidermal-derived eicosanoids in FLG-associated versus FLG-WT AD pathogenesis. Ultrastructural analyses demonstrated abnormal stratum corneum lipid architecture in AD and IV HEEs, independent of FLG genotype. Both AD (FLG/WT) and IV (FLG/FLG) HEEs showed impaired late epidermal differentiation. Only AD (FLG/WT) HEEs exhibited significantly increased levels of inflammatory cytokines. Analyses of lipid mediators revealed increased arachidonic acid and 12-lipoxygenase metabolites. Whereas treatment of control HEEs with arachidonic acid increased expression of inflammatory cytokines, 12-hydroxy-eicosatetraenoic acid attenuated expression of late differentiation markers. Thus, FLG mutations lead to alterations in epidermal eicosanoid metabolism that could serve as an autocrine trigger of inflammation and impaired late epidermal differentiation in AD.

Bacteria that reside on the skin can influence the behavior of the cutaneous immune system, but the mechanisms responsible for these effects are incompletely understood. Colonization of the skin by Staphylococcus aureus (S. aureus) is increased in atopic dermatitis and can result in increased severity of the disease. In this study, we show that S. aureus stimulates human keratinocytes to increase their endogenous protease activity, including specific increases in trypsin activity. This increased protease activity coincided with increased expression of mRNA for kallikreins (KLKs), with KLK6, 13, and 14 showing the greatest induction after exposure to S. aureus. Suppression of mRNA for these KLKs in keratinocytes by targeted small interfering RNA silencing before S. aureus exposure blocked the increase in protease activity. Keratinocytes exposed to S. aureus showed enhanced degradation of desmoglein-1 and filaggrin, whereas small interfering RNA for KLK6, KLK13, and KLK14 partially blocked this degradation. These data illustrate how S. aureus directly influences the skin barrier integrity by stimulating endogenous proteolytic activity and defines a previously unknown mechanism by which S. aureus may influence skin diseases.

BackgroundHypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives.MethodsWe evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications.ResultsAverage age was 51 and 69% were women. Mean SBP was 119 ± 18 and DBP was 74 ± 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for ≥1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 ± 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 ± 0.3 mm Hg (p = 0.04) higher. Anti-cit-fibrinogen A (211-230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit-clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7-8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first-degree relatives had 16.4± (p = 0.03) higher SBP and 12.1± mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives.ConclusionIn first-degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset.

Patients with atopic dermatitis (AD) have an abnormal skin barrier and are frequently colonized by S. aureus. In this study we investigated if S. aureus penetrates the epidermal barrier of subjects with AD and sought to understand the mechanism and functional significance of this entry. S. aureus was observed to be more abundant in the dermis of lesional skin from AD patients. Bacterial entry past the epidermis was observed in cultured human skin equivalents and in mice but was found to be increased in the skin of cathelicidin knockout and ovalbumin-sensitized filaggrin mutant mice. S. aureus penetration through the epidermis was dependent on bacterial viability and protease activity, because killed bacteria and a protease-null mutant strain of S. aureus were unable to penetrate. Entry of S. aureus directly correlated with increased expression of IL-4, IL-13, IL-22, thymic stromal lymphopoietin, and other cytokines associated with AD and with decreased expression of cathelicidin. These data illustrate how abnormalities of the epidermal barrier in AD can alter the balance of S. aureus entry into the dermis and provide an explanation for how such dermal dysbiosis results in increased inflammatory cytokines and exacerbation of disease.

The crosslinked envelope of the mammalian epidermal corneocyte serves as a scaffold for assembly of the lipid barrier of the epidermis. Thus, deficient envelope crosslinking by keratinocyte transglutaminase (TGM1) is a major cause of the human autosomal recessive congenital ichthyoses characterized by barrier defects. Expectations that loss of some envelope protein components would also confer an ichthyosis phenotype have been difficult to demonstrate. To help rationalize this observation, the protein profile of epidermis from loricrin knockout mice has been compared to that of wild type. Despite the mild phenotype of the knockout, some 40 proteins were incorporated into envelope material to significantly different extents compared to those of wild type. Nearly half were also incorporated to similarly altered extents into the disulfide bonded keratin network of the corneocyte. The results suggest that loss of loricrin alters their incorporation into envelopes as a consequence of protein-protein interactions during cell maturation. Mass spectrometric protein profiling revealed that keratin 1, keratin 10, and loricrin are prominent envelope components and that dozens of other proteins are also components. This finding helps rationalize the potential formation of functional envelopes, despite loss of a single component, due to the availability of many alternative transglutaminase substrates.

Genes related to the parathyroid hormone (PTH) influence cutaneous immune defense and development, but the full functions of the PTH family in cutaneous biology remain incompletely understood. In this study, we examined the expression and potential functions of the PTH second receptor (PTH2R) and its ligand, the tuberoinfundibular peptide of 39 residues (TIP39), in the skin. TIP39 and PTH2R mRNA and protein were detectable in both human and mouse skin, and in cultured keratinocytes and adipocytes. TIP39 was observed in the basal layer of human skin, whereas PTH2R was detected in the spinous to granular layer. The subcellular localization of TIP39 in keratinocytes changed during calcium-induced differentiation and shifted to colocalize with PTH2R at the membrane. The addition of recombinant TIP39 to normal human keratinocytes in culture induced an increase in intercellular calcium and triggered aspects of terminal differentiation including decreased keratin-14 and increased involucrin expression. Consistent with these observations, PTH2R(-/-) mice were observed to have increased epidermal thickness. In summary, identification of TIP39 and its receptor in the epidermis reveals an additional PTH family member that is expressed in the skin and may influence keratinocyte function.

The skin hydration level is a key factor that influences the physical and mechanical properties of the skin. The stratum corneum (SC), the outermost layer of the epidermis, is responsible for the skin's barrier function. In this study, we investigated the role of a unique composition of Viola yedoensis extract for its ability to activate CD44, a cell-surface receptor of hyaluronic acid, and aquaporin-3, a water-transporting protein, in human keratinocytes (HaCaT). An ELISA assay evaluating the protein expression levels of CD44, aquaporin-3 (AQP3), filaggrin, and keratin-10 revealed that V. yedoensis extract upregulated the levels of CD44 and AQP3 by 15% and 78%, respectively. Additionally, V. yedoensis extract demonstrated a comparative effect on water vapor flux in TEWL and lipid perturbation in DSC versus the reference, glycerin. In light of this new biological efficacy, a detailed phytochemical characterization was undertaken using an integrated LC-HRMS/MS-based metabolomics approach, which provided further insights on the chemistry of V. yedoensis . This led to the identification of 29 secondary metabolites, 14 of which are reported here for the first time, including esculetin, aesculin, apigenin and kaempferol C-glycosides, megastigmane glycosides, roseoside, platanionoside B, and an eriojaposide B isomer, along with the rare, calenduloside F and esculetin diglucoside, which are reported for the first time from the genus, Viola . Notably, two active components identified in the V. yedoensis extract, namely, aesculin and schaftoside, showed an upregulation of the protein expression of CD44 in HaCaT cells by 123% and 193% within 24 h of treatment, respectively, while aesculin increased AQP3 levels by 46%. Aesculin and schaftoside also significantly upregulated the expression of K-10 levels by 299% and 116%, which was considerably higher than sodium hyaluronate, the positive control. The rationale used to characterize the new structures is outlined along with the related biosynthetic pathways envisioned to generate roseoside and Eriojaposide B. These findings provide new molecular insights to deepen the understanding of how V. yedoensis extract, along with the biomarkers aesculin and schaftoside, restores the skin barrier and skin hydration benefits.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with rising prevalence, marked by eczematous lesions, itching, and a weakened skin barrier often tied to filaggrin gene mutations. This breakdown allows allergen and microbe entry, with thymic stromal lymphopoietin (TSLP) playing a crucial role by activating immune pathways that amplify the allergic response. TSLP's central role in AD pathogenesis makes it a promising therapeutic target. Consequently, in this study, we used the virtual drug screening, molecular dynamics simulation, and binding free energies calculation approaches to explore the African Natural Product Database against the TSLP protein. The molecular screening identified four compounds with high docking scores, namely SA&#95;0090 (-7.37), EA&#95;0131 (-7.10), NA&#95;0018 (-7.03), and WA&#95;0006 (-6.99 kcal/mol). Furthermore, the KD analysis showed a strong binding affinity of these compounds with TSLP, with values of -5.36, -5.36, -5.34, and -5.32 kcal/mol, respectively. Moreover, the strong binding affinity of these compounds was further validated by molecular dynamic simulation analysis, which revealed that the WA&#95;0006-TSLP is the most stable complex with the lowest average RMSD. However, the total binding free energies were -40.5602, -41.0967, -27.3293, and -51.3496 kcal/mol, respectively, showing the strong interaction between the selected compounds and TSLP. Likewise, these compounds showed excellent pharmacokinetics characteristics. In conclusion, this integrative approach provides a foundation for the development of safe and effective treatments for AD, potentially offering relief to millions of patients worldwide.

Background: Acne vulgaris (AV) is the eighth most common nonfatal disease globally. Previous work identified an association between AV and increased filaggrin (FLG) protein expression in the follicular epidermis, but further work did not find a clear link between loss-of-function (LoF) FLG gene mutations and protection from AV., Objectives: To explore any association between AV and FLG LoF mutations in a cohort of genotyped patients of Bangladeshi ancestry with atopic eczema (AE) in East London., Methods: A retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone -clinical assessment. A χ2-test or Fisher's exact test was used to determine differences in AV history between FLG LoF genotype groups., Results: We found a significant reduction in history of AV in patients with AE with FLG LoF mutations (19 of 82) relative to those without FLG mutations (47 of 129) (23% vs. 36.4%; P = 0.02). We showed a nonsignificant reduction in AV diagnosis in patients with impaired barrier function (measured by transepidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (P = 0.02)., Conclusions: In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Atopic dermatitis (AD) is characterized by chronic inflammation, barrier dysfunction, and pruritus, exacerbated by external stimuli, such as scratching. This study investigates the role of extracellular adenosine triphosphate (ATP) in the pathophysiology of AD and assesses the therapeutic potential of clodronate, an ATP release inhibitor. Our research demonstrates that extracellular ATP impairs skin barrier function by reducing the filaggrin expression in the keratinocytes, a critical protein for barrier integrity. Furthermore, ATP release, triggered by IL-4 and mechanical stimuli, amplifies inflammation by promoting cytokine and chemokine production by the immune cells. Clodronate, by inhibiting ATP release, restores the filaggrin levels in the keratinocytes, reduces TARC production in the dendritic cells, and alleviates AD symptoms in a mouse model. These findings suggest that targeting extracellular ATP could offer a novel therapeutic approach to improving skin barrier function and reducing inflammation in AD. Future studies should explore the long-term efficacy and safety of ATP-targeted therapies in clinical settings.

Haliotis discus , an abalone, is a marine gastropod mollusk that has been cultivated globally owing to its nutritional value and high market demand. However, the visceral parts of H. discus are typically discarded as by-products, highlighting the need to explore their potential value in developing cosmeceuticals and pharmaceuticals. This study investigated the potential moisturizing effects of H. discus visceral tissues. Various hydrolysates from H. discus viscera tissue were evaluated for proximate composition, radical scavenging, and hyaluronidase inhibition activities. Alcalase hydrolysate was isolated using gel filtration chromatography (GFC), and its moisturizing effects were tested on human dermal fibroblasts (HDF), HaCaT keratinocytes, and reconstructed human skin tissue. The Alcalase hydrolysate showed the highest extraction yield, radical scavenging, and hyaluronidase inhibition activities. The Alcalase hydrolysate GFC fraction 1 increased collagen synthesis-related molecules, including procollagen type 1 in HDF and hyaluronic acid-related molecules in HaCaT cells. These moisturizing effects were confirmed in reconstructed human skin tissues by increased levels of aquaporin 3 and filaggrin. Fraction 1 consisted of two main peptides: DNPLLPGPPF and SADNPLLPGPPF. In conclusion, H. discus Alcalase hydrolysate and its fractions have potential moisturizing properties and can be used as cosmeceuticals.

Background/objectives: Diesel Particulate Matter (DPM) is a very small particulate matter originating from cities, factories, and the use of fossil fuels in diesel vehicles. When DPM permeates the skin, it causes inflammation, leading to severe atopic dermatitis. Hibiscus cannabinus L. (Kenaf) seeds and leaves possess various beneficial properties, including anti-coagulation, antioxidant, and anti-inflammation effects. In this study, we investigated the anti-inflammatory effects of an ethanol extract of Hibiscus cannabinus L. flower (HCFE) in HaCaT cells stimulated with 100 μg/mL of DPM., Methods: The anthocyanin content of HCFE was analyzed, and its antioxidant capacity was investigated using the DPPH assay. After inducing inflammation with 100 ug/mL of DPM, the cytotoxicity of HCFE 25, 50, and 100 ug/mL was measured, and the inhibitory effect of HCFE on inflammatory mediators was evaluated., Results: Anthocyanin and myricetin-3- O -glucoside were present in HCFE and showed high antioxidant capacity. In addition, HCFE decreased the mRNA expression of inflammatory cytokines and chemokines such as IL-1β, IL-4, IL-6, IL-8, IL-13, and MCP-1, and significantly reduced the gene expression of CXCL10, CCL5, CCL17, and CCL22, which are known to increase in atopic dermatitis lesions. Furthermore, HCFE reduced intracellular reactive oxygen species (ROS) production, and down-regulated the activation of NF-κB, MAPKs. Inhibition of the NLRP-3 inflammasome was observed in DPM-stimulated HaCaT cells. In addition, the restoration of filaggrin and involucrin, skin barrier proteins destroyed by DPM exposure, was confirmed., Conclusions: These data suggest that HCFE could be used to prevent and improve skin inflammation and atopic dermatitis through the regulation of inflammatory mediators and the inhibition of skin water loss.

Objective: Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression., Methods: Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥3 years or until clinical arthritis diagnosis. Blood samples from inclusion were analysed for nine ACPA reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model., Results: Two hundred and sixty-seven individuals were included with median follow-up of 49 months (interquartile range [IQR]: 22-60); 101 (38%) developed arthritis after a median of 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (hazard ratio [HR] 8.0; 95% CI: 2.9, 22), ultrasound-detected tenosynovitis (HR 3.4; 95% CI: 2.0, 6.0), IL-6 levels (HR 1.5; 95% CI: 1.2, 1.8) and IL-15 receptor α (IL-15Rα) levels (HR 0.6; 95% CI: 0.4, 0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [s.e. 0.02], AUC 0.82 [95% CI: 0.76, 0.89], cross-validated AUC 0.70 [95% CI: 0.56, 0.85])., Conclusion: We propose a high RA risk phase characterized by presence of ACPA reactivity, tenosynovitis, IL-6 and IL-15Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES., Methods: Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study., Results: Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon)., Conclusions: This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients., (© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

The integrity of the skin barrier is essential for maintaining skin health, with the stratum corneum and filaggrin 2 (FLG-2) playing a key role. FLG-2 deficiency or mutation has been linked to diseases such as atopic dermatitis, while external stressors such as ultraviolet B (UVB) radiation further damage the epidermal barrier. This study investigated the effects of recombinant filaggrin (rFLG) on skin barrier function and UVB induced epidermal destruction. Cell experiments showed that 10 μg/mL of rFLG could increase the mobility of HaCaT cells from 20 % to 42 %, increase the epithelial resistance (TEER) value by about 2 times, and up-regulate the tight junction associated protein by about 2 times. In mouse models of UVB-induced epidermal barrier destruction, rFLG at concentrations of 0.5, 1, and 2 mg/mL showed effective cell uptake and skin penetration, alleviating erythema, and reducing skin thickness in mice by 1.5-3 times. Among them, 2 mg/mL of rFLG treatment restored the expression of tight junction proteins (LOR, ZO-1, and caspase-14), reduced collagen degradation, and reduced oxidative stress by normalizing serum hydroxyproline and superoxide dismutase levels. In addition, 2 mg/mL of rFLG inhibited UVB-induced upregulation of matrix metalloproteinases (MMP-3 and MMP-9) and reduced pro-inflammatory factors (IL-10, IL-1α, IL-6, and TNF-α) and apoptotic markers (P38, Bax, and Bcl-2) to normal levels. These findings suggested that rFLG effectively enhanced skin barrier integrity and mitigated UVB-induced epidermal barrier destruction, highlighting its potential as a therapeutic agent for diseases associated with skin barrier dysfunction., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Three-dimensional human epidermal equivalents (HEEs) are a state-of-the-art organotypic culture model in preclinical investigative dermatology and regulatory toxicology. In this study, we investigated the utility of electrical impedance spectroscopy (EIS) for noninvasive measurement of HEE epidermal barrier function. Our setup comprised a custom-made lid fit with 12 electrode pairs aligned on the standard 24-transwell cell culture system. Serial EIS measurements for 7 consecutive days did not impact epidermal morphology, and readouts showed comparable trends with HEEs measured only once. We determined 2 frequency ranges in the resulting impedance spectra: a lower frequency range termed EIS diff correlated with keratinocyte terminal differentiation independent of epidermal thickness and a higher frequency range termed EIS SC correlated with stratum corneum thickness. HEEs generated from CRISPR/Cas9-engineered keratinocytes that lack key differentiation genes FLG, TFAP2A, AHR, or CLDN1 confirmed that keratinocyte terminal differentiation is the major parameter defining EIS diff . Exposure to proinflammatory psoriasis- or atopic dermatitis-associated cytokine cocktails lowered the expression of keratinocyte differentiation markers and reduced EIS diff . This cytokine-associated decrease in EIS diff was normalized after stimulation with therapeutic molecules. In conclusion, EIS provides a noninvasive system to consecutively and quantitatively assess HEE barrier function and to sensitively and objectively measure barrier development, defects, and repair., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD), a chronic inflammatory disease, severely interferes with patient life. Human placenta extract (HPH; also known as human placenta hydrolysate) is a rich source of various bioactive substances and has widely been used to dampen inflammation, improve fatigue, exert anti-aging effects, and promote wound healing. However, information regarding HPH's incorporation in AD therapies is limited. Therefore, this study aimed to evaluate HPH's effective potential in treating AD using tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT), immunized splenocytes, and a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. In TNF-α /IFN-γ-stimulated HaCaT cells, HPH markedly reduced the production of reactive oxygen species (ROS) and restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 1(SOD1), catalase, and filaggrin (FLG). HPH reduced interleukin (IL)-6; thymus- and activation-regulated chemokine (TARC); thymic stromal lymphopoietin (TSLP); and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) levels and inhibited nuclear factor kappa B phosphorylation. Additionally, HPH suppressed the T helper 2 (Th2) immune response in immunized splenocytes. In the AD-like mouse model, it significantly mitigated the DNCB-induced elevation in infiltrating mast cells and macrophages, epidermal thickness, and AD symptoms. HPH also reduced TSLP levels and prevented FLG downregulation. Furthermore, it decreased the expression levels of IL-4, IL-5, IL-13, TARC, RANTES, and immunoglobulin E (IgE) in serum and AD-like skin lesion. Overall, our findings demonstrate that HPH effectively inhibits AD development and is a potentially useful therapeutic agent for AD-like skin disease.

Ethnopharmacological Relevance: Volatile oil is widely used in traditional Chinese medicine owing to its unique hydrophobic and lipophilic properties and rapid skin absorption. Artemisia annua L. (A.annua) essential oil (AAEO), a volatile oil extracted from A. annua, exhibits anti-inflammatory properties. However, few studies have investigated its effects on skin inflammation., Aim of the Study: To investigate and elucidate the mechanisms of action of AAEO in the treatment of atopic dermatitis (AD)., Materials and Methods: Network pharmacology was used to predict the targets and pathways of AAEO for the treatment of AD. The AD mouse model was established by topical application of 2,4-dintrochlorobenzene (DNCB), AAEO, and the positive control drug hydrocortisone butyrate cream (HBC). We evaluated the symptoms of AD, SCORAD scores, histological analysis, and serum IgE and TNF-α levels in mice. Immunofluorescence, western blotting, and qPCR were used to investigate the signaling pathways., Results: Network pharmacology analysis indicated that AAEO may exert its effects via the MAPK/NF-κB signaling pathway. Animal experiments demonstrated that topical application of AAEO and HBC significantly ameliorated skin lesions, reduced dermatitis score, and decreased spleen weight compared to DNCB treatment. AAEO reduced skin epidermal thickness and mast cell infiltration. DNCB markedly reduced the protein levels of filaggrin (FLG) and loricrin (LOR), whereas AAEO reversed these changes. Notably, the 5% concentration of AAEO demonstrated substantial improvement in skin barrier function. Compared to the DNCB group, the levels of FLG and LOR remained almost unchanged following HBC treatment. DNCB markedly elevated IgE and TNF-α levels, which were reversed by AAEO and HBC treatment. Among the inflammatory cytokines, DNCB increased mRNA expression of TNF-α, IL-1β, and IL-6, however, it reduced IL-10, with AAEO and HBC reversing these changes to various degrees. Additionally, DNCB-induced ERK, JNK, and P38 phosphorylation, associated with the upregulation of phosphorylation of NF-κB, whereas, AAEO and HBC exhibited potent inhibition of the MAPK/NF-κB signaling pathway., Conclusions: This study systematically demonstrated the possible therapeutic effects and mechanisms of AAEO in AD via network pharmacological analysis and experimental confirmation. These results revealed that topical application of AAEO can suppress skin inflammation and restore skin barrier function. These findings provide the potential application of AAEO in synthesizing external preparations for both pharmacological and cosmetic industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies, and practices in allergy prevention., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear., Objectives: To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge., Methods: Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence., Results: Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge., Conclusions: Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair., Competing Interests: Conflicts of interest M.B. and V.L.N. are employees of No7 Beauty Company. O.K., R.B., R.E.B.W., A.K.L., C.C., C.E.M.G. and S.B.-P. declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Substances that can efficiently enhance skin penetration while exerting no adverse effect are useful for drug and cosmetics formulation., Objective: To investigate the safety and enhance skin penetration efficacy of Putocrin®, a combination containing 2% isosorbide dimethyl ether, 1% pentanediol, and 0.5% inositol., Methods: An in vitro keratinocyte cell assay using 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide (MTT), and an in vitro EpiKutis® skin study adopted hematoxylin and eosin staining, immunostaining, and liquid chromatography-mass spectrometry (LC-MS) analysis were carried out to investigate the safety of Putocrin®. A pigskin-Franz cell system experiment applied high-performance liquid chromatography (HPLC) to compare the skin penetration efficiency of fluorescein isothiocyanate (Fitc)-labeled tranexamic acid with or without the assistance of Putocrin®. The safety and efficacy of Putocrin® was further evaluated on zebrafish embryos., Results: The MTT assay showed that Putocrin® at concentration ≤2.5% did not significantly affect cell viability. The in vitro EpiKutis® skin study revealed that 2.5% Putocrin® did not affect skin morphology, filaggrin content, ceramide/protein, or fatty acid/protein ratios, but significantly increased loricrin content by 86.00% (p < 0.001). The pigskin-Franz cell penetration experiment demonstrated that Fitc-labeled tranexamic acid could barely penetrate the skin (with penetration rate of 1.121%), while Putocrin® significantly enhanced the penetration rate up to 83.983%, which was close to unlabeled tranexamic acid (90.013%). The zebrafish embryo study showed that 2.5% Putocrin® did not exert observable toxicity and obviously assisted the skin penetration of Fitc-labeled tranexamic acid into fish embryos. These results indicate the strong enhancing skin penetration potency of Putocrin®., Conclusion: This study demonstrated the safety as well as the strong enhancing skin penetration potency of Putocrin® for cosmetics formulation use., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

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., (© 2024 Japanese Dermatological Association.)

Bifidobacteria are the most prevalent members of the intestinal microbiota in mammals and other animals, and they play a significant role in promoting gut health through their probiotic effects. Recently, the potential applications of Bifidobacteria have been extended to skin health. However, the beneficial mechanism of Bifidobacteria on the skin barrier remains unclear. In this study, keratinocyte HaCaT cells were used as models to evaluate the protective effects of the cell-free supernatant (CFS), heat-inactivated bacteria, and bacterial lysate of Bifidobacterium animalis CGMCC25262 on the skin barrier and inflammatory cytokines. The results showed that all the tested samples were able to upregulate the transcription levels of biomarker genes associated with the skin barrier, such as hyaluronic acid synthetase (HAS) and aquaporins (AQPs). Notably, the transcription of the hyaluronic acid synthetase gene-2 (HAS-2) is upregulated by 3~4 times, and AQP3 increased by 2.5 times when the keratinocyte HaCaT cells were co-incubated with 0.8 to 1% CFS. In particular, the expression level of Filaggrin (FLG) in HaCaT cells increased by 1.7 to 2.7 times when incubated with Bifidobacterial samples, reaching its peak at a concentration of 0.8% CFS. Moreover, B. animalis CGMCC25262 also decreased the expression of the proinflammatory cytokine RANTES to one-tenth compared to the levels observed in HaCaT cells induced with tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). These results demonstrate the potential of B. animalis CGMCC25262 in protecting the skin barrier and reducing inflammatory response., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose of Review: This review summarizes recent advances in identifying genetic risk factors for atopic dermatitis and how these genetic associations are being used to explore the causal relationships between atopic dermatitis and potential risk factors and downstream outcomes., Recent Findings: A recent large-scale GWAS meta-analysis has identified 91 genetic loci associated with atopic dermatitis. Rare variant studies have also identified new gain-of-function or loss-of-function variants implicated in atopic dermatitis, particularly for FLG and STAT6/JAK1 . Finally, there has been a surge in utilizing genetic association data to investigate the causal relationships between atopic dermatitis and other traits. Mendelian randomization studies have found that various metabolites and gut microbiota are causal for atopic dermatitis and have causally implicate atopic dermatitis in the development of alopecia areata, diabetes, vascular dementia and some cancers., Summary: The past year has seen a huge increase in the genes implicated for atopic dermatitis and in the use of genetics to explore causal relationships. The latter requires caution in implementation and interpretation, but is a promising area of research. In the coming years, increasing the ethnic diversity of atopic dermatitis genetic studies would be very welcome and the translation of current genetic findings into new drugs will be an exciting area of development., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)