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Skin microbiome can be altered in patients with atopic dermatitis (AD). An understanding of the changes from healthy to atopic skin can help develop new targets for treatment by identifying microbial and molecular biomarkers. This study investigates the skin microbiome and metabolome of healthy adult subjects and lesion (ADL) and non-lesion (ADNL) of AD patients by 16S rRNA gene sequencing and mass spectrometry, respectively. Samples from AD patients showed alterations in the diversity and composition of the skin microbiome, with ADL skin having the greatest divergence. Staphylococcus species, especially S. aureus, were significantly increased in AD patients. Metabolomic profiles were also different between the groups. Dipeptide derivatives are more abundant in ADL, which may be related to skin inflammation. Co-occurrence network analysis of the microbiome and metabolomics data revealed higher co-occurrence of metabolites and bacteria in healthy ADNL compared to ADL. S. aureus co-occurred with dipeptide derivatives in ADL, while phytosphingosine-derived compounds showed co-occurrences with commensal bacteria, for example, Paracoccus sp., Pseudomonas sp., Prevotella bivia, Lactobacillus iners, Anaerococcus sp., Micrococcus sp., Corynebacterium ureicelerivorans, Corynebacterium massiliense, Streptococcus thermophilus, and Roseomonas mucosa, in healthy and ADNL groups. Therefore, these findings provide valuable insights into how AD affects the human skin metabolome and microbiome.IMPORTANCEThis study provides valuable insight into changes in the skin microbiome and associated metabolomic profiles in an adult population with mild to moderate atopic dermatitis. It also identifies new therapeutic targets that may be useful for developing personalized treatments for individuals with atopic dermatitis based on their unique skin microbiome and metabolic profiles.

Transcription factor GATA3 is essential for the developmental processes of T cells. Recently, the silencer of a cytokine IFNγ gene was identified, the inhibitory activity of which requires GATA3. GATA3 has 2 Zn fingers and the commonly used GATA3 deficient mice lack both fingers (D2). We have established a mouse line that lacks only one Zn finger close to the C terminus (D1). The D1 mice line developed dermatitis, which was not observed in D2 mice. The expression of S100a8/S100a9 was elevated in D1 to a level higher than in D2, suggesting their roles in dermatitis development. CD8 T cells of both D1 and D2 lines expressed inhibitory receptors associated with the exhausted state. In the absence of MHC class II, the skin inflammation was exacerbated in both lines. The gene expression pattern of CD8 T cells became similar to that of effector T cells. Blocking Ab against LAG3 upregulated the expression of the effector molecules of T cells. These results suggest that the disfunction of GATA3 can lead to the spontaneous activation of CD8 T cells that causes skin inflammation, and that suppressive activity of MHC class II ‐ LAG3 interaction ameliorates dermatitis development. [ABSTRACT FROM AUTHOR]

Ferroptosis, a form of regulated cell death distinct from apoptosis, necrosis, and autophagy, is increasingly recognized for its role in skin disease pathology. Characterized by iron accumulation and lipid peroxidation, ferroptosis has been implicated in the progression of various skin conditions, including psoriasis, photosensitive dermatitis, and melanoma. This review provides an in-depth analysis of the molecular mechanisms underlying ferroptosis and compares its cellular effects with other forms of cell death in the context of skin health and disease. We systematically examine the role of ferroptosis in five specific skin diseases, including ichthyosis, psoriasis, polymorphous light eruption (PMLE), vitiligo, and melanoma, detailing its influence on disease pathogenesis and progression. Moreover, we explore the current clinical landscape of ferroptosis-targeted therapies, discussing their potential in managing and treating skin diseases. Our aim is to shed light on the therapeutic potential of modulating ferroptosis in skin disease research and practice. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light chain (NfL) has been identified as a biomarker in neuroaxonal injury. Cutaneous nerve injury resulting from inflammation and/or forced scratching may also potentially affect serum NfL (sNfL) levels. Objectives: We aimed to explore the relationship between sNfL levels and the severity of skin inflammation and scratch lesions in patients with pruritus. Methods: In this cross‐sectional pilot study, we measured the sNfL levels of 10 patients with pruritus of different aetiologies, and calculated age‐ and BMI‐adjusted sNfL percentiles based on a normative database consisting of 4532 control individuals. Next, we investigated the relationship between the levels of sNfL and the severity of skin inflammation and scratching injuries in these patients using a newly‐created Skin Inflammation and Scratch Lesions (SISL) score. Results: A positive correlation was observed between sNfL levels and the severity of skin inflammation and scratch lesions as measured by the SISL score (Spearman's rho = 0.70, p = 0.031). When correlated separately, both the "skin inflammation only" and "scratch lesions only" scores correlated positively with sNfL levels (Spearman's rho = 0.68, p = 0.031; Spearman's rho = 0.66, p = 0.041, respectively). Conclusions: sNfL may be a potential biomarker for cutaneous nerve injury associated with skin inflammation and/or scratching. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence suggests that particulate matter (PM) exposure can trigger or worsen atopic dermatitis (AD); however, the underlying mechanisms remain unclear. Recently, pregnane X receptor (PXR), a xenobiotic receptor, was reported to be related to skin inflammation in AD. Objectives: This study aimed to explore the effects of PM on AD and investigate the role of PXR in PM-exposed AD. Methods: In vivo and in vitro AD-like models were employed, using BALB/c mice, immortalized human keratinocytes (HaCaT), and mouse CD4+ T cells. Results: Topical application of PM significantly increased dermatitis score and skin thickness in AD-likemice. PM treatment increased themRNA and protein levels of type 17 inflammatorymediators, including interleukin (IL)-17A, IL-23A, IL-1b, andIL-6, in AD-like mice and human keratinocytes. PM also activated PXR signaling, and PXR knockdown exacerbated PM-induced type 17 inflammation in human keratinocytes and mouse CD4+ T cells. In contrast, PXR activation by rifampicin (a human PXR agonist) reduced PM-induced type 17 inflammation. Mechanistically, PXR activation led to a pronounced inhibition of the nuclear factor kappa B (NF-kB) pathway. Conclusion: In summary, PM exposure induces type 17 inflammation and PXR activation in AD. PXR activation reduces PM-induced type 17 inflammation by suppressing the NF-kB signaling pathway. Thus, PXR represents a promising therapeutic target for controlling the PM-induced AD aggravation. [ABSTRACT FROM AUTHOR]

Background: Traditional topical drug delivery for treating inflammatory skin diseases suffers from poor skin penetration and long-term side effects. Metal nanoparticles show promising application in topical drug delivery for inflammatory skin diseases. Methods: Here, we synthesized a new type of nanoparticles, azelamide monoethanolamine-functionalized gold nanoparticles (Au-MEA NPs), based on citrate-capped gold nanoparticles (Au-CA NPs) via the ligand exchange method. The physical and chemical properties of Au-CA NPs and Au-MEA NPs were characterized. In vivo studies were performed using imiquimod-induced psoriasis and LL37-induced rosacea animal models, respectively. For in vitro studies, a model of cellular inflammation was established using HaCaT cells stimulated with TNF-α. In addition, proteomics, gelatin zymography, and other techniques were used to investigate the possible therapeutic mechanisms of the Au-MEA NPs. Results: We found that Au-MEA NPs exhibited better stability and permeation properties compared to conventional Au-CA NPs. Transcutaneously administered Au-MEA NPs exerted potent therapeutic efficacy against both rosacea-like and psoriasiform skin dermatitis in vivo without overt signs of toxicity. Mechanistically, Au-MEA NPs reduced the production of pro-inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting the activity of MMP9. Conclusion: Au-MEA NPs have the potential to be a topical nanomedicine for the effective and safe treatment of inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Background: Baricitinib, commonly used for autoimmune diseases, is typically administered orally, which can lead to systemic adverse effects. A topical formulation could potentially offer localized therapeutic effects while minimizing these side effects. Objectives: This study focuses on developing a lipid-based topical formulation of baricitinib (BCT-OS) for treating psoriasis. Methods: The optimized formulation was then assessed for physical, chemical, and biopharmaceutical characterization. Furthermore, the anti-inflammatory efficacy of the formulation was tested in a model of psoriasis induced by imiquimod in mice, and its tolerance was determined by the evaluation of biomechanical skin properties and an inflammation test model induced by xylol in mice. Results: BCT-OS presented appropriate characteristics for skin administration in terms of pH, rheology, extensibility, and stability. The formulation also demonstrated a notable reduction in skin inflammation in the mouse model, and high tolerability without affecting the skin integrity. Conclusions: BCT-OS shows promise as an alternative treatment for psoriasis, offering localized therapeutic benefits with a potentially improved safety profile compared to systemic administration. [ABSTRACT FROM AUTHOR]

Objectives: Cold plasma has shown efficacy in various dermatological applications by reduces inflammatory responses and modulating cytokine expression. Therefore, this study aimed to investigate the therapeutic effects of cold plasma on psoriasis. Methods: In psoriasis HaCaT cells with cold plasma, we confirmed the expression of inflammatory cytokines involved in psoriasis formation and MAPK pathway, cell cycle, and apoptosis‐related factors. In psoriasis‐like BALB/c mice model, the effects of cold plasma treatment on skin were visually assessed. The expression of psoriasis‐related factors was confirmed through qPCR, Western blotting, and Immunohistochemistry. Results: Cold plasma led to a reduction in inflammatory cytokines including IL‐17A, IL‐23A, IL‐24, IL‐1β, and TNF‐α in the psoriasis cell line. It also modulated factors involved in the MAPK pathway and the cell cycle. In the psoriasis‐like mice model, cold plasma resulted in improvements in skin thickness, erythema, scaling, and PASI. Additionally, decreases in inflammatory cytokines like INF‐γ, IL‐23, and S100a7 were observed, along with improvements in MAPK pathway activation, apoptosis, and other psoriasis‐related factors. Conclusion: Through in vitro and in vivo studies, our research highlights the potential of cold plasma as a novel therapeutic approach for psoriasis. Furthermore, cold plasma could serve as an adjunctive treatment for skin immunological diseases. [ABSTRACT FROM AUTHOR]

Skin inflammation and immune regulation have been suggested to be associated with allergic contact dermatitis (ACD) progression, but whether the system's immune regulation is a cause or a potential mechanism is still unknown. This study aims to assess the upstream and downstream of systemic immune factors on ACD within a bidirectional Mendelian-randomization design. A bidirectional two-sample MR analysis was employed to implement the results from genome-wide association studies for 52 system immune factors and ACD. Genetic associations with systemic immune factors and ACD were obtained from the IEU Open GWAS project database. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis, MR-Egger, weighted median, MR-pleiotropy residual sum, and outlier (MR-PRESSO) was also used as the sensitivity analyses. Only Tumor necrosis factor ligand superfamily member 11 (TNFS11) from among 52 systemic immune factors was associated with a protective effect of ACD. However, ACD was associated with a decrease in Interleukin-9 (IL9) and an increase in C-X-C motif chemokine 1 (GROα), Tumor necrosis factor ligand superfamily member 10 (TRAIL), C4, and complement factor B of the assessed systemic immune factors. This study identified TNFS11 as the upstream regulator and IL9, GROα, TRAIL, C4, and complement factor B as the downstream regulator of ACD, providing opportunities for new therapeutic exploitation of ACD. Nonetheless, these associations of systemic immune factors need to be verified in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Brachytherapy is a form of internal radiation therapy where radioactive sources are placed directly in or near tumors. This paper shows how brachytherapy can be personalized using new technologies like 3D-printed applicators, advanced imaging techniques, and artificial intelligence to make treatment more precise and effective. The authors also explore the role of genetic tests and biomarkers for choosing the best treatments for each patient, as well as future approaches such as combining brachytherapy with immunotherapy and developing new ways to shape radiation doses using shielding. By tailoring treatments to individual patients, personalized brachytherapy aims to effectively treat cancer while reducing treatment-related side effects. Brachytherapy offers a highly conformal and adaptive approach to radiation therapy for various oncologic conditions. This review explores the rationale, applications, technological advances, and future directions of personalized brachytherapy. Integration of advanced imaging techniques, 3D-printed applicators, and artificial intelligence are rapidly enhancing brachytherapy delivery and efficiency, while genomic tests and molecular biomarkers are refining patient and dose selection. Emerging research on combining brachytherapy with immunotherapy offers unique synergistic potential, and technologies such as intensity-modulated and shielded brachytherapy applicators present novel opportunities to further optimize dose distributions. Despite these promising advances, the field faces challenges including a need to train more practitioners and develop new approaches to treating a broader range of malignancies. As personalized medicine evolves, brachytherapy's ability to deliver highly targeted, individualized treatments positions it as a critical component in future cancer care. [ABSTRACT FROM AUTHOR]

Background: Acne vulgaris, a common chronic dermatological condition worldwide, is associated with inflammatory response and Cutibacterium acnes. Individuals with acne vulgaris and sensitive skin have limited suitable treatments due to the skin irritation and side effects exhibited by current hydroxy acidic medications. Aims: This study aimed to evaluate the synergistic effects of Guaiacum officinale (GO) and Rhodomyrtus Tomentosa (RT) extracts for treating acne vulgaris on sensitive skin by inhibiting inflammation. Methods: The phytochemical constituents and antioxidant activity of GO and RT extracts were determined in vitro. The anti‐inflammatory effects were investigated in peptidoglycan (PGN)‐induced HaCaT cells. Further, a 28‐day clinical trial was conducted involving 30 subjects with both sensitive skin and acne to evaluate the efficacy and subjects' satisfaction. Results: Total phenolics and flavonoids were detected in GO and RT extracts, the IC50 values for DPPH radical scavenging were 6.15 wt% and 0.76 wt%, respectively. The combination of GO and RT extracts at a 1:1 (v/v) ratio significantly decreased the expression of TLR‐2 and TLR‐4, as well as the secretion of IL‐1α, IL‐8, and TNF‐α in PGN‐induced HaCaT cells, by 2.30–7.93 times compared to GO extract alone (p < 0.05). Moreover, the cream containing 5 wt% the combination significantly improved facial acne and redness (p < 0.05). The number of comedones decreased by 50.00% and papules by 30.65% after 28 days of application. No adverse events were reported and 96.67% of the subjects were satisfied with the treatment. Conclusion: The efficacy of the GO and RT extracts in synergistically suppressing inflammation, improving acne vulgaris, and reducing redness. The study offers an effective and non‐irritant treatment for acne vulgaris in individuals with sensitive skin. [ABSTRACT FROM AUTHOR]

The cutaneous microbiome represents a highly dynamic community of bacteria, fungi and viruses. Scientific evidence, particularly from the last two decades, has revealed that these organisms are far from being inconsequential microscopic hitchhikers on the human body, nor are they all opportunistic pathogens waiting for the chance to penetrate the skin barrier and cause infection. In this review, we will describe how dermatological diseases have been found to be associated with disruptions and imbalances in the skin microbiome and how this new evidence had shaped the diagnosis and clinical practice relating to these disorders. We will identify the microbial agents which have been found to directly exacerbate skin diseases, as well as those which can ameliorate many of the symptoms associated with dermatological disorders. Furthermore, we will discuss the studies which suggest that bacteriotherapy, either by topical use of probiotics or by bacteria‐derived compounds, can rectify skin microbial imbalances, thereby offering a promising alternative to antibiotic treatment and reducing the risks of antibiotic resistance. [ABSTRACT FROM AUTHOR]

Background and rationale: Ultraviolet-B (UVB) light induces dermal inflammation, although it is mostly absorbed in the epidermis. Recent reports suggest extracellular vesicles (EVs) act as a mediator of photodamage signaling. Melatonin is reported to be a protective factor against UV-induced damage. We hypothesized that EVs derived from UVB-irradiated keratinocytes might trigger proinflammatory responses in dermal cells and tested whether melatonin can ameliorate UVB-induced inflammation. Methods: We used UVB-irradiated HaCaT cells, primary keratinocytes and STING knock-out mice to model production of EVs under photodamaging conditions and performed immunoblotting and ELISA to measure their effect on dermal macrophages. Results: UVB-irradiated keratinocytes produce an increased number of EVs that contain higher concentrations of DNA and protein compared with controls. KC-derived EVs (KEVs) induced a STING- and inflammasome-mediated proinflammatory response in macrophages in vitro, and a pronounced inflammatory infiltrate in mouse dermis in vivo. Melatonin ameliorated KEVs inflammatory effect both in vitro and in vivo. Conclusions: This data suggests EVs are mediators in a crosstalk that takes place between keratinocytes and their neighboring cells as a result of photodamage. Further studies exploring EVs induced by damaging doses of UVB, and their impact on other cells will provide insight into photodamage and may help develop targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Abrocitinib, an oral small-molecule Janus kinase 1 (JAK1) inhibitor, has been widely accepted for the treatment of moderate-to-severe atopic dermatitis (AD). Currently there is a paucity of data on the adverse events (AEs) after abrocitinib treatment, especially on rare events such as exacerbation of facial dermatitis, and their causal relationship and subsequent management remains poorly elucidated. Case presentation: A 43-year-old female patient with moderate AD received dupilumab after failure of topical treatments. Facial dermatitis persisted and became refractory after dupilumab treatment, and the patient changed treatment to oral abrocitinib. Fifteen hours after the first dose of abrocitinib, she developed exacerbation of facial dermatitis with swelling. The patient was initially diagnosed as abrocitinib-induced hypersensitivity. However, a score of 3 of the Naranjo adverse drug reaction assessment indicates week correlation between abrocitinib therapy and exacerbation of facial dermatitis, and negative results from subsequent drug provocation test further suggests no causal relationship. Conclusions: The present case report highlights the necessity of careful determination of abrocitinib-induced hypersensitivity, which should not be diagnosed simply based on the time sequence between drug exposure and symptom occurrence. In addition, caution should be exercised for drug withdrawal, especially when confirmative evidence is absent. Drug provocation test can be helpful and effective treatments could be continued unless severe AEs occur. [ABSTRACT FROM AUTHOR]

Despite its long history as a preferential cyclooxygenase-2 inhibitor, the topical application of etodolac in inflammatory disorders does not achieve the desired clinical efficiency because of its poor water solubility and poor skin permeation. In the ongoing study, phosalosomes were designed to mitigate the etodolac drawbacks and to enhance its skin localization. Hyaluronic acid was utilized to prepare a dermal gel for the alleviation of skin inflammation. Etodolac loaded hyaluronic acid phosalosomal gel had a sustainable release profile and 10.59-fold enhanced skin retention compared to free etodolac, with boosted skin tolerability on histopathological examination after acute and chronic applications. Confocal laser microscopy imaging indicated that the etodolac amounts accumulated in the liver and kidney following dermal application were 29 and 5.7-fold lower than those following the systemic dose, respectively. For in vivo studies, etodolac loaded hyaluronic acid phosalosomal gel presented superior anti-oedemic and significant anti-nociception potential. The promising homogenous localization highlighted its potential for the delivery of lipophilic drugs for the targeted treatment of other localized skin disorders. [ABSTRACT FROM AUTHOR]

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019–2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease. [ABSTRACT FROM AUTHOR]

Torreya grandis (T. grandis, Taxaceae) is a well-known nut tree species. Its fruit aril and leaves possess a unique aroma, making it an ideal natural raw material for extracting essential oils (EOs). This study aims to comprehensively compare the composition, biological activities, and pharmacological mechanism of EOs extracted from the arils (AEO) and leaves (LEO) of T. grandis. The results revealed that the chemical composition of the two EOs was highly consistent, with α-pinene and D-limonene as the main components. Both EOs significantly reduced cellular melanin production and inhibited tyrosinase activity in α-MSH-stimulated B16 cells (p < 0.05). AEO and LEO suppressed inflammatory responses in LPS-stimulated RAW 264.7 macrophages, significantly inhibiting cellular NO production and proinflammatory cytokines such as TNF-α and IL-6 (p < 0.05). A network pharmacology analysis reveals that AEO and LEO share similar molecular mechanisms and pharmacological pathways for treating skin pigmentation and inflammation. Regulating inflammatory cytokines may be a critical pathway for AEO and LEO in treating skin pigmentation. These findings suggest that AEO and LEO have potential for cosmetic applications. The leaves of T. grandis could be a valuable source of supplementary materials for producing T. grandis aril EO. [ABSTRACT FROM AUTHOR]

Facial redness in atopic dermatitis (AD) is often intractable due to factors like chronic inflammation, steroid-induced telangiectasia, and rosacea-like dermatitis from topical treatments. Pulsed-dye laser (PDL) effectively treats both vascular and non-vascular inflammatory conditions, but its use in adult AD is limited. This study presents three cases of refractory AD with significant facial erythema treated with PDL. Two women and one man had undergone five to thirteen PDL treatments at 3 weeks to 3-month intervals. Clinical response was evaluated using the Eczema Severity Score, which showed significant improvement after PDL treatments. Our cases explore the efficacy of PDL in treating refractory facial erythema in adult AD patients. Patients tolerated the procedures well without severe complications such as hyperpigmentation, hypopigmentation, or blister formation. These findings suggest that PDL effectively reduces facial redness and alleviates associated AD symptoms. PDL is expected to address both vasodilation and cutaneous inflammation as an adjunctive therapy to manage refractory facial redness in adult AD. Further cases and research are needed to fully understand PDL's immunomodulatory effects. [ABSTRACT FROM AUTHOR]

The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Canine atopic dermatitis (AD) closely mimics human AD and is recognized as a beneficial animal model. House dust mites (HDM) are a common allergen for both species. The effects of chronic exposure to HDM on the skin have not been studied in this animal model, and it is not known how changes in gene expression correlate to the severity of dermatitis. Methods: We used an established canine model of AD and took biopsies before HDM exposure (D0) and five times during repeated allergen challenges (on Days 1, 2, 8, 15, and 29, hereafter referred to as D1, D2, D8, D15, and D29). The severity of dermatitis was scored on the same days. Results: Trichohyalin (TCHH) gene expression decreased the most (15-fold decrease on D29 vs. D0) and negatively correlated with the severity of dermatitis. Gap-junction protein gene expression increased over 3-fold on D1, D8, and D29 and positively correlated with the severity of dermatitis. Compared to D0, IL-31 gene expression significantly increased on D8 (p = 0.0098), D15 (p = 0.0068), and D29 (p = 0.0187), but the correlation with the severity of dermatitis did not reach significance. Discussion: This is the first report on trichohyalin, a protein belonging to the S100 family, and gap-junction protein gene expression in the context of the clinical severity of AD. We propose that these proteins should be further investigated to better understand their role in this complex disease. [ABSTRACT FROM AUTHOR]

Skin inflammation associated with chronic diseases involves a direct role of keratinocytes in its immunopathogenesis, triggering a cascade of immune responses. Despite this, highly targeted treatments remain elusive, highlighting the need for more specific therapeutic strategies. In this study, nanocapsules containing quinizarin (QZ/NC) were developed and evaluated in an in vitro model of keratinocyte-mediated inflammation, incorporating the action of photodynamic therapy (PDT) and analyzing permeation in a 3D skin model. Comprehensive physicochemical, stability, cytotoxicity, and permeation analyses of the nanomaterials were conducted. The nanocapsules demonstrated desirable physicochemical properties, remained stable throughout the analysis period, and exhibited no spectroscopic alterations. Cytotoxicity tests revealed no toxicity at the lowest concentrations of QZ/NC. Permeation and cellular uptake studies confirmed QZ/NC permeation in 3D skin models, along with intracellular incorporation and internalization of the drug, thereby enhancing its efficacy in drug delivery. The developed model for inducing the inflammatory process in vitro yielded promising results, particularly when the synthesized nanomaterial was combined with PDT, showing a reduction in cytokine levels. These findings suggest a potential new therapeutic approach for treating inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

In recent years, a wide variety of high-performance and versatile nanofiber membranes have been successfully created using different electrospinning methods. As vehicles for medication, they have been receiving more attention because of their exceptional antibacterial characteristics and ability to heal wounds, resulting in improved drug delivery and release. This quality makes them an appealing choice for treating various skin conditions like wounds, fungal infections, skin discoloration disorders, dermatitis, and skin cancer. This article offers comprehensive information on the electrospinning procedure, the categorization of nanofiber membranes, and their use in dermatology. Additionally, it delves into successful case studies, showcasing the utilization of nanofiber membranes in the field of skin diseases to promote their substantial advancement. [ABSTRACT FROM AUTHOR]

Extended exposure to UVB (280–315 nm) radiation results in oxidative damage and inflammation of the skin. Previous research has demonstrated that pilose antler extracts have strong anti-inflammatory properties and possess antioxidant effects. This study aimed to elucidate the mechanism of pilose antler protein in repairing photodamage caused by UVB radiation in HaCaT cells and ICR mice. Pilose antler protein (PAP) was found to increase the expression of type I collagen and hyaluronic acid in HaCaT cells under UVB irradiation while also inhibiting reactive oxygen species (ROS) production and oxidative stress in vitro. In vivo, the topical application of pilose antler protein effectively attenuated UVB-induced skin damage in ICR mice by reducing interleukin-1β (IL-β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and inhibiting skin inflammation while alleviating UVB-induced oxidative stress. It was shown that pilose antler protein repaired UVB-induced photodamage through the MAPK and TGF-β/Smad pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are a common and growing type of cancer treatment, but they can cause side effects. This study aims to understand these side effects in patients with kidney cancer and bladder cancer. We compared the types and severity of side effects between these two groups to determine if there are differences. We also compared them to other tumor types to see if there is a unique pattern. The findings will help doctors better predict and manage side effects. This will hopefully lead to improving patient care for those receiving ICI treatment. Background: Immune checkpoint inhibitors (ICIs) have become common lines of therapy for genitourinary cancers (GUcs). Given their widespread use, understanding the risk factors, comparative profiles, and timing of immune-related adverse events (irAEs) is essential. Methods: We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 1 February 2011 and 7 April 2022 at a comprehensive cancer center and its outreach clinics. Dichotomous outcomes were modeled using multivariable logistic regression. Survival outcomes were compared using multivariable Cox regression. Results: Among 3101 patients, 196 had renal cell carcinoma (RCC) and 170 had urothelial tumors. RCC patients were more likely to experience irAEs (OR 1.78; 95% CI 1.32–2.39), whereas urothelial carcinoma patients were not (OR 1.22; 95% CI 0.88–1.67). RCC patients were more prone to dermatitis, thyroiditis, acute kidney injury, and myocarditis, compared to other tumors, while urothelial carcinoma patients were not. The impact of irAEs on survival was not significantly different for GUcs compared to other tumors. Conclusions: RCC primaries have a significantly different irAE profile than most tumors, as opposed to urothelial primaries. Further, RCC was more likely to experience any irAEs. Heterogeneity of survival benefits by irAEs was not seen. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focused on understanding how radiation therapy, a common treatment for cancer, affects the skin of dogs. While radiation is effective at destroying cancer cells, it can also cause damage to healthy skin, leading to various side effects like redness, peeling, changes in skin color, and sores. Over nine weeks, we monitored these skin changes in dogs, observing that radiation led to increased inflammation and stress in the skin cells, as well as significant disruptions in how skin cells grow and heal. We also noticed changes in specific proteins and genes related to skin inflammation, healing, and cell death. These findings help us better understand how radiation therapy impacts the skin and provide valuable information for managing these side effects in dogs. Radiation therapy is a crucial cancer treatment, but it can damage healthy tissues, leading to side effects like skin injuries and molecular alterations. This study aimed to elucidate histological and molecular changes in canine skin post-radiation therapy (post-RT) over nine weeks, focusing on inflammation, stem cell activity, angiogenesis, keratinocyte regeneration, and apoptosis. Four male beagles received a cumulative radiation dose of 48 Gy, followed by clinical observations, histological examinations, and an RT-qPCR analysis of skin biopsies. Histological changes correlated with clinical recovery from inflammation. A post-RT analysis revealed a notable decrease in the mRNA levels of Oct4, Sox2, and Nanog from weeks 1 to 9. VEGF 188 levels initially saw a slight increase at week 1, but they had significantly declined by week 9. Both mRNA and protein levels of COX–2 and Keratin 10 significantly decreased over the 9 weeks following RT, although COX–2 expression surged in the first 2 weeks, and Keratin 10 levels increased at weeks 4 to 5 compared to normal skin. Apoptosis peaked at 2 weeks and diminished, nearing normal by 9 weeks. These findings offer insights into the mechanisms of radiation-induced skin injury and provide guidance for managing side effects in canine radiation therapy. [ABSTRACT FROM AUTHOR]

Among the occupational skin diseases, bird mite dermatitis (gamasoidosis) is an infrequent and under-reported condition. A report is presented of a group of workers employed in a habitat restoration centre who developed episodes of pruritus and skin rashes associated with bird mites. The mite bites resolved approximately two weeks after each episode, without specific medical intervention and despite ongoing work activities. A workplace health-risk assessment and microscopic analysis of 'swabs' of the work environment aided the identification of bird mite as the causative agent. The source of the bird mites was infested red-winged starlings nesting in the roof of the workplace facility. Incidents of gamasoidosis as described are considered occupational dermatoses since they were acquired in the workplace and the diagnosis was based on clinical--parasitological analysis. When diagnosing gamasoidosis, the clinical history and physical examination provide useful clues, but the clinical features of skin lesions of arthropod or other insect bites are very similar. Microscopic detection of the mite is confirmatory. [ABSTRACT FROM AUTHOR]

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The increasing use of hyaluronic acid (HA) implants has made adverse effects more apparent. Here, we present a rare case of massive allergic dermatitis due to HA injections. We performed dermoscopy and color ultrasound, which clarified that this was an allergic dermatitis caused by fillers, and analyzed the possible causes of the allergy. Common treatments were compared, and the advantages of 5-FU-based treatment regimens and their associated mechanisms were noted. A low dose of 5-fluorouracil and triamcinolone acetonide was administered to the patient's entire face and neck, and significant efficacy was achieved. We aimed to gather evidence on extensive dermatitis caused by HA injection, provide new perspectives and solutions for subsequent HA injections, and promote further research on the potential mechanisms of extensive skin inflammation and allergies caused by local HA injections. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune system-mediated skin disease identified by the appearance of erythematous as a central symptom. As a recurrent and chronic inflammatory disease, psoriasis is influenced by both genetic and environmental factors and is known to be with no effective cure. Considering a multifaceted etiology of psoriasis, synergistic therapy exhibits great benefits over monotherapy, which becomes common for the treatment of various diseases. Herein, we present the nanozyme microspheres with structural color-coding labels for synergistic therapy of psoriasis. In particular, microsphere hydrogel is fabricated by the edible hydroxypropyl cellulose (HPC), which can generate a photonic liquid crystalline mesophase under lyotropic conditions in solution. Through adjustment of hydrogel components, microspheres endow with different functions, including moisturizing (paraffin), cfDNA scavenging (chitosan), and anti-inflammation (cerium oxide nanozyme). To improve patient convenience, hydrogel drops with different properties are tailored with different vivid structural colors by exploiting the lyotropic behavior of HPC. Of particular note, both in vitro and in vivo experiments have demonstrated the significant therapeutic effects of the encoded structural color microspheres. Green moisturizing microspheres facilitate to relieve dry, flaky skin patches; blue cfDNA scavenging and red anti-inflammatory microspheres significantly reduce skin inflammation. More importantly, combination therapy with encoded microspheres exerted the synergistic effects, including the increased body weight, thicker epidermal layer, and reduced immune activation. Overall, this synergistic treatment offers a promising platform for personalized management of psoriasis and various inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Traditional topical drug delivery for treating inflammatory skin diseases suffers from poor skin penetration and long-term side effects. Metal nanoparticles show promising application in topical drug delivery for inflammatory skin diseases. Methods Here, we synthesized a new type of nanoparticles, azelamide monoethanolamine-functionalized gold nanoparticles (Au-MEA NPs), based on citrate-capped gold nanoparticles (Au-CA NPs) via the ligand exchange method. The physical and chemical properties of Au-CA NPs and Au-MEA NPs were characterized. In vivo studies were performed using imiquimod-induced psoriasis and LL37-induced rosacea animal models, respectively. For in vitro studies, a model of cellular inflammation was established using HaCaT cells stimulated with TNF-α. In addition, proteomics, gelatin zymography, and other techniques were used to investigate the possible therapeutic mechanisms of the Au-MEA NPs. Results We found that Au-MEA NPs exhibited better stability and permeation properties compared to conventional Au-CA NPs. Transcutaneously administered Au-MEA NPs exerted potent therapeutic efficacy against both rosacea-like and psoriasiform skin dermatitis in vivo without overt signs of toxicity. Mechanistically, Au-MEA NPs reduced the production of pro-inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting the activity of MMP9. Conclusion Au-MEA NPs have the potential to be a topical nanomedicine for the effective and safe treatment of inflammatory skin diseases.

Abstract The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.

Background: One of the key obstacles to the healing of diabetic wound is the persistence of active inflammation. We previously demonstrated the potential of cell-free fat extract (CEFFE) to promote the healing of diabetic wounds, and annexin A5 (A5) is a crucial anti-inflammatory protein within CEFFE. This study aimed to evaluate the therapeutic potential of A5 in diabetic wounds. Methods: A5 was loaded into GelMA hydrogels and applied to skin wounds of diabetic mice in vivo. The diabetic wounds with the treatment of GelMA-A5 were observed for 14 days and evaluated by histological analysis. Accessment of inflammation regulation were conducted through anti-CD68 staining, anti-CD86 and anti-CD206 staining, and qRT-PCR of wound tissue. In presence of A5, macrophages stimulated by lipopolysaccharide (LPS) in vitro, and detected through qRT-PCR, flow cytometry, and immunocytofluorescence staining. Besides, epithelial cells were co-cultured with A5 for epithelialization regulation by CCK-8 assay and cell migration assay. Results: A5 could promote diabetic wound healing and regulate inflammations by promoting the transition of macrophages from M1 to M2 phenotype. In vitro experiments demonstrated that A5 exerted a significant effect on reducing pro-inflammatory factors and inhibiting the polarization of macrophages from M0 toward M1 phenotype. A5 significantly promoted the migration of epithelial cells. Conclusion: Annexin A5 has a significant impact on the regulation of macrophage inflammation and promotion of epithelialization.

A dual-responsive hydrogel drug reservoir responding to body temperature and electrical stimulation achieves high drug release efficiency at 37 °C and efficient transdermal delivery. The Zn battery-driven iontophoresis results in an effective treatment of atopic dermatitis with the release of dexamethasone. This work provides a non-invasive treatment modality for chronic epidermal diseases that require precise drug delivery. [Display omitted] • Polyelectrolyte hydrogel shows thermal-electrochemical dual-responsive drug release. • Wearable Zn battery-powered iontophoresis for transdermal delivery with enhanced efficacy. • Effective treatment of atopic dermatitis in mice is achieved. Atopic dermatitis is a chronic, inflammation skin disease that remains a major public health challenge. The current drug-loading hydrogel dressings offer numerous benefits with enhanced loading capacity and a moist-rich environment. However, their development is still limited by the accessibility of a suitable driven source outside the clinical environment for precise control over transdermal delivery kinetics. Here, we prepare a sulfonated poly(3,4-ethylenedioxythiophene) (PEDOT) polyelectrolyte hydrogel drug reservoir that responds to different stimuli-both endogenous cue (body temperature) and exogenous cue (electrical stimulation), for wearable on-demand transdermal delivery with enhanced efficacy. Functioned as both the drug reservoir and cathode in a Zn battery-powered iontophoresis patch, this dual-responsive hydrogel achieves high drug release efficiency (68.4 %) at 37 °C. Evaluation in hairless mouse skin demonstrates the efficacy of this technology by facilitating transdermal transport of 12.2 μg cm−2 dexamethasone phosphate when discharged with a 103 Ω external resistor for 3 h. The Zn battery-driven iontophoresis results in an effective treatment of atopic dermatitis, displaying reductions in epidermal thickness, mast cell infiltration inhibition, and a decrease in IgE levels. This work provides a new treatment modality for chronic epidermal diseases that require precise drug delivery in a non-invasive way. [ABSTRACT FROM AUTHOR]

We described the first case of rhinofacial pythiosis with dissemination in an adult horse in Uruguay. The affected horse presented a partially circumscribed mass measuring 30 x 23 x 9 cm affecting the right side of the face with involvement of cutaneous, subcutaneous, and muscular tissues, the right nasal cavity, and adjacent structures. At postmortem examination, the main lesions were “kunkers” characterized by pyogranulomatous and eosinophilic dermatitis, Splendore-Hoeppli reaction and numerous intralesional hyphae immunolabeling with polyclonal anti-Pythium insidiosum antibody. Similar lesions were observed in the lung and submandibular lymph nodes. The diagnosis was made by the characteristic histological lesions and the strong immunolabelling by anti-P. insidiosum antibody. [ABSTRACT FROM AUTHOR]

In dry skin (DS), skin-barrier function is easily disturbed and moisturizing factors in the stratum corneum are reduced. Despite being a common condition, DS is often overlooked in patients with advanced age or comorbid diseases. In September 2022, specialists in dermatology and skin care met to discuss unmet needs and management of patients with DS with existing medical conditions or DS induced by ongoing pharmacological treatments. There was consensus about the need to improve the current understanding and management of DS in patients with comorbidities, including type 2 diabetes, chronic kidney disease, radiodermatitis, and photodamaged skin. Clinical guidance related to optimal treatment of DS in patients with advanced age or comorbid diseases is needed. Dexpanthenol-containing emollients have been shown to provide rapid relief from the symptoms and clinical signs of skin inflammation and are well-tolerated and effective in terms of moisturizing and soothing DS and maintaining skin-barrier function. Thus, dexpanthenol-containing emollients may play an important role in future management of DS. Further research is needed to elucidate the efficacy of dexpanthenol across the spectrum of DS, irrespective of comorbidity status or age. [ABSTRACT FROM AUTHOR]

Yun Zhong,1– 3 Yufei Zhao,4 Xin Meng,2 Fan Wang,2 Lei Zhou1 1Department of Dermatology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Gastrointestinal Surgery, Laboratory of Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Lei Zhou, Department of Dermatology, the Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, People’s Republic of China, Tel +020-85253333, Fax +020-85253336, Email zhoulei53@mail.sysu.edu.cnBackground: Rosacea, a recurring dermatological disorder, demands effective therapeutic approaches. Traditional Chinese medicine, particularly Liangxue Siwu Decoction (LXSWD), has shown promise in managing inflammatory skin diseases, such as rosacea. This study focuses on uncovering LXSWD’s specific effects on the inflammatory symptoms of rosacea.Objective: Our research investigates LXSWD’s therapeutic effectiveness in rosacea treatment and delves into its underlying mechanisms.Methods: Network pharmacology was utilized to identify LXSWD’s key components and their targets in rosacea management, which were then validated by molecular docking. An in vivo rosacea-like model in LL-37-induced mice was developed, subdividing them into control, model, and LXSWD groups. The LXSWD group received oral administration (25.0 g/kg/day) for six days before model induction. Post-treatment evaluations included skin tissue analyses to verify our network pharmacology predictions.Results: Key active ingredients in LXSWD, such as quercetin, kaempferol, and luteolin, were identified alongside central target proteins like TNF and MMPs. Our molecular docking study confirmed the interactions between these ingredients and targets. Analyses through GO and KEGG pathways indicated LXSWD’s role in mitigating inflammation, particularly influencing the TNF and IL-17 pathways. LXSWD treatment in vivo markedly alleviated LL-37-induced symptoms in mice, showing a marked reduction in inflammatory cytokines (p < 0.05) and modulation of crucial genes (p < 0.05). These results, supported by immunofluorescence analysis and Western blot, underline the modulatory effects of LXSWD on MMPs, offering significant protection against rosacea’s inflammation alterations (p < 0.05).Conclusion: Integrating network pharmacology, molecular docking, and in vivo experiments, this study elucidates LXSWD’s potential mechanisms in rosacea treatment. It offers a novel theoretical framework for its clinical use in managing rosacea.Keywords: Liangxue siwu decoction, molecular docking, network pharmacology, rosacea, skin inflammation

Abstract Human immortal keratinocyte cells (HaCaT) are induced with UVB to establish an injury model. This model is utilized to investigate whether oat bran fermentation broth (OBF) has a reparative effect on skin inflammation and damage to the skin barrier caused by UVB irradiation. The results show that compared with unfermented oat bran (OB), OBF exhibits higher structural homogeneity, increased molecular weight size, active substances content, and in vitro antioxidant activity. OBF has a scavenging effect on excess reactive oxygen species (ROS) and increases the intracellular levels of antioxidant enzymes. It was found that OBF has a stronger inhibitory effect on the release of inflammatory factors than OB. It increases the synthesis of AQP3 and FLG proteins while decreasing the secretion of KLK-7. OBF can inhibit the transcription level of inflammatory factors by suppressing the JAK/STAT signaling pathway. Safety experiments demonstrate that OBF has a high safety profile. Graphical Abstract

Skin inflammation with the potential sequel of moist epitheliolysis and edema constitute the most frequent breast radiotherapy (RT) acute side effects. The aim of this study was to compare the predictive value of tissue-derived radiomics features to the total breast volume (TBV) for the moist cells epitheliolysis as a surrogate for skin inflammation, and edema. Radiomics features were extracted from computed tomography (CT) scans of 252 breast cancer patients from two volumes of interest: TBV and glandular tissue (GT). Machine learning classifiers were trained on radiomics and clinical features, which were evaluated for both side effects. The best radiomics model was a least absolute shrinkage and selection operator (LASSO) classifier, using TBV features, predicting moist cells epitheliolysis, achieving an area under the receiver operating characteristic (AUROC) of 0.74. This was comparable to TBV breast volume (AUROC of 0.75). Combined models of radiomics and clinical features did not improve performance. Exclusion of volume-correlated features slightly reduced the predictive performance (AUROC 0.71). We could demonstrate the general propensity of planning CT-based radiomics models to predict breast RT-dependent side effects. Mammary tissue was more predictive than glandular tissue. The radiomics features performance was influenced by their high correlation to TBV volume. [ABSTRACT FROM AUTHOR]

Psoriasis is characterized by keratinocyte (KC) hyperproliferation and inflammatory cell infiltration, but the mechanisms remain unclear. In an imiquimod-induced mouse psoriasiform model, p38 activity is significantly elevated in KCs and p38α specific deletion in KCs ameliorates skin inflammation. p38α signaling promotes KC proliferation and psoriasis-related proinflammatory gene expression during psoriasis development. Mechanistically, p38α enhances KC proliferation and production of inflammatory cytokines and chemokines by activating STAT3. While p38α signaling in KCs does not affect the expression of IL-23 and IL-17, it substantially amplifies the IL-23/IL-17 pathogenic axis in psoriasis. The therapeutic effect of IL-17 neutralization is associated with decreased p38 and STAT3 activities in KCs and targeting the p38α-STAT3 axis in KCs ameliorates the severity of psoriasis. As IL-17 also highly activates p38 and STAT3 in KCs, our findings reveal a sustained signaling circuit important for psoriasis development, highlighting p38α-STAT3 axis as an important target for psoriasis treatment. p38α signaling promotes keratinocyte proliferation and psoriasis-related proinflammatory gene expression in psoriasis by activating STAT3, and further amplifies the IL-23/IL-17 pathogenic axis. [ABSTRACT FROM AUTHOR]

Natural caffeic acid (CA) and its analogues have been studied for their potential applications in the treatment of various inflammatory and infectious skin diseases. However, the molecular mechanism underlying the effects of the CA remains largely unknown. Here, we report that CA and its two analogues, caffeic acid phenethyl ester (CAPE) and caffeic acid methyl caffeate (CAMC), inhibit TRPV3 currents in their concentration- and structure-dependent manners with IC50 values ranging from 102 to 410 μM. At the single-channel level, CA reduces the channel open probability and open frequency without alteration of unitary conductance. CA selectively inhibits TRPV3 relative to other subtypes of thermo-TRPs, such as TRPA1, TRPV1, TRPV4, and TRPM8. Molecular docking combined with site-specific mutagenesis reveals that a residue T636 in the Pore-loop is critical for CA binding to TRPV3. Further in vivo evaluation shows that CA significantly reverses TRPV3-mediated skin inflammation induced by skin sensitizer carvacrol. Altogether, our findings demonstrate that CA exerts its anti-inflammatory effects by selectively inhibiting TRPV3 through binding to the pocket formed by the Pore-loop and the S6. CA may serve as a lead for further modification and identification of specific TRPV3 channel inhibitors. [ABSTRACT FROM AUTHOR]

The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member ABCC1 as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the ABCC1 gene locus. In cutaneous SCC and during the activation of the keratinocyte differentiation program, ∆Np63 and ABCC1 levels are positively correlated raising the possibility that ABCC1 might be involved in the regulation of the proliferative/differentiative capabilities of squamous tissue. However, we did not find any gross alteration in the structure and morphology of the epidermis in humanized hABCC1 knock-out mice. Conversely, we found that the genetic ablation of ABCC1 led to a marked reduction in inflammation-mediated proliferation of keratinocytes, suggesting that ABCC1 might be involved in the regulation of keratinocyte proliferation upon inflammatory/proliferative signals. In line with these observations, we found a significant increase in ABCC1 expression in squamous cell carcinomas (SCCs), a tumor type characterized by keratinocyte hyper-proliferation and a pro-inflammatory tumor microenvironment. Collectively, these data uncover ABCC1 as an additional ∆Np63 target gene potentially involved in those skin diseases characterized by dysregulation of proliferation/differentiation balance. [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]

Background: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Due to its high prevalence, considerable morbidity, and chronicity, there is a need for the accurate in vivo evaluation of treatment efficacy. Line-field confocal optical coherence tomography (LC-OCT) is a new emerging imaging technique able to perform a non-invasive, real-time examination of the epidermis and the upper dermis. LC-OCT may represent a promising tool in the diagnosis and treatment follow-up of chronic eczematous skin diseases with barrier defects. Objectives: We aimed to investigate the role of LC-OCT in the non-invasive monitoring of the treatment effect on five patients with severe atopic dermatitis during dupilumab treatment. Materials and Methods: LC-OCT imaging was performed on five patients (three women and two men) aged between 14 and 85 years old at the baseline and at 2, 4, and 6 weeks of treatment with dupilumab. The LC-OCT scans were performed at two sites, the lesional skin in the antecubital fossa and the extensor part of the arm, considered a control site on each patient for comparison. The captured images were later evaluated. Descriptive statistics and a t-test were used to compare the analyzed parameters over time and between involved atopic skin and clinically healthy skin. Results: The LC-OCT imaging was able to detect the difference in stratum corneum (SC) thickness and quality and epidermal thickness (ET) and the changes before and after treatment with high accuracy. The main findings include a significant reduction in the epidermal and stratum corneum thickness and decreased epidermal spongiosis and inflammation, with better quality of the stratum corneum indicating restoration of its tightness at both lesional and control sites. Conclusions: This study demonstrates that clinical improvement of affected and unaffected atopic skin under dupilumab treatment correlates with the LC-OCT findings. LC-OCT represents a novel, non-invasive tool examining the in vivo skin barrier and inflammation and can help to monitor the treatment efficacy among patients with atopic dermatitis in daily practice. [ABSTRACT FROM AUTHOR]

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs. [ABSTRACT FROM AUTHOR]

Immune-mediated comorbidities in patients with psoriasiform eczema are common. It can be challenging to manage multiple immune-mediated diseases, especially considering that biologic treatments are prone to causing paradoxical effects. The aim of this retrospective observational case series was to describe the course of both psoriasiform eczema and immune-mediated comorbidities in five patients treated with upadacitinib for psoriasiform dermatitis. Five patients, all male, were included. All the patients suffered from psoriasiform eczema. Moreover, two of the patients suffered from alopecia areata, two from vitiligo, one from ulcerative colitis and one from hidradenitis suppurativa. In all cases, the treatment with upadacitinib was rapidly effective on the eczema. The effectiveness on alopecia areata was good in both cases, while the results on vitiligo were only partial. The only case of ulcerative colitis achieved complete remission, while the case of hidradenitis suppurativa experience partial improvement. In conclusion, upadacitinib was effective in treating not only psoriasiform eczema, but also several immune mediated comorbidities. Additional studies are necessary to determine the efficacy of upadacitinib in alopecia areata, vitiligo and hidradenitis suppurativa. [ABSTRACT FROM AUTHOR]

Eyelid dermatitis (ED) affects a cosmetically significant area and leads to patients' distress. Despite ongoing and recent research efforts, ED remains a multidisciplinary problem that needs further characterization. We aimed to evaluate the atopic eyelid dermatitis (AED) frequency in ED patients and to perform their clinical profiling. PubMed databases were searched from 01.01.1980 till 01.02.2024 to PRISMA guidelines using a search strategy: (eyelid OR periorbital OR periocular) AND (dermatitis or eczema). Studies with patch-tested ED patients were included. Proportional meta-analysis was performed using JBI SUMARI software. We included 65 studies across Europe, North America, Asia and Australia, with a total of 21,793 patch-tested ED patients. AED was reported in 27.5% (95% CI 0.177, 0.384) of patch-tested ED patients. Isolated ED was noted in 51.6% (95% CI 0.408, 0.623) of 8453 ED patients with reported lesion distribution, including 430 patients with isolated AED. Our meta-analysis demonstrated that the AED frequency in patch-tested ED patients exceeded the previous estimate of 10%. Isolated AED was noted in adult patients, attending contact allergy clinics. Future studies are needed to elucidate the global prevalence and natural history of isolated AED in adults. [ABSTRACT FROM AUTHOR]

Psoriasis is a common chronic inflammatory skin disease that significantly impacts the patients' quality of life. Recent studies highlighted the function of the interleukin (IL)-1 family member IL-38 in skin homeostasis and suggested an anti-inflammatory role for this cytokine in psoriasis. In this study, we generated mice specifically overexpressing the IL-38 protein in epidermal keratinocytes. We confirmed IL-38 overexpression in the skin by Western blotting. We further detected the protein by ELISA in the plasma, as well as in conditioned media of skin explants isolated from IL-38 overexpressing mice, indicating that IL-38 produced in the epidermis is released from keratinocytes and can be found in the circulation. Unexpectedly, epidermal IL-38 overexpression did not impact the global severity of imiquimod (IMQ)-induced skin inflammation, Similarly, keratinocyte activation and differentiation in IMQ-treated skin were not affected by increased IL-38 expression and there was no global effect on local or systemic inflammatory responses. Nevertheless, we observed a selective inhibition of CXCL1 and IL-6 production in response to IMQ in IL-38 overexpressing skin, as well as reduced Ly6g mRNA levels, suggesting decreased neutrophil infiltration. Epidermal IL-38 overexpression also selectively affected the desquamation process during IMQ-induced psoriasis, as illustrated by reduced plaque formation. Taken together, our results validate the generation of a new mouse line allowing for tissue-specific IL-38 overexpression. Interestingly, epidermal IL-38 overexpression selectively affected specific disease-associated readouts during IMQ-induced psoriasis, suggesting a more complex role of IL-38 in the inflamed skin than previously recognized. In particular, our data highlight a potential involvement of IL-38 in the regulation of skin desquamation. [ABSTRACT FROM AUTHOR]

Graphene oxide (GO), a carbon-based material with oxygen-containing functional groups, can be applied in biomedicine for drug delivery, cancer therapy, and tissue regeneration. We have previously shown that nanoscale-sized graphene oxide (NGO), an oxidized graphene derivative, exhibits effective anti-inflammatory activity in a murine model of sepsis mediated by T helper (Th)1-promoting cytokines such as IFNγ and TNFα. However, whether NGO influences Th2-induced skin inflammation remains unclear. To address this issue, we employed an ovalbumin (OVA) plus aluminum hydroxide (Alum)-induced Th2-mediated skin inflammation model in conjunction with OVA-specific DO11.10 T cell receptor transgenic Balb/c mice. In vivo NGO injection upon OVA/Alum sensitization down-regulated OVA-elicited antigen-specific Th2 cells and GATA3-expressing Th2-type regulatory T cells. Next, we examined the effect of NGO injection on OVA/Alum-induced atopic dermatitis (AD)-like skin inflammation. NGO-injected mice exhibited significantly decreased Th2 disease phenotypes (e.g., a lower clinical score, decreased epidermal thickness and Th2 cell differentiation, and fewer infiltrated mast cells and basophils in skin lesions) compared with vehicle-injected control mice. Overall, our results suggest that NGOs are promising therapeutic materials for treating allergic diseases such as AD. [ABSTRACT FROM AUTHOR]