Experimental Dermatology最新文献

The pemphigoid disease epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies against type VII collagen (COL7), immune cell infiltrates at the dermal–epidermal junction and subepidermal blistering. Proteases, particularly granzyme B (GzmB), have been established as therapeutic targets for the treatment of EBA and other pemphigoid diseases. We investigated the impact of the novel GzmB inhibitor SNT-6935 on anti-COL7 IgG-induced subepidermal blistering in a well-established EBA ex vivo model. Our findings demonstrate that pharmacological targeting of GzmB with its selective inhibitor SNT-6935 significantly reduced autoantibody-induced dermal–epidermal separation in human skin cryosections. Interestingly, treatment of skin cryosections with recombinant human GzmB alone did not cause dermal–epidermal separation, suggesting that additional mechanisms alongside GzmB are required for tissue damage in EBA. In conclusion, our study highlights the significant contribution of GzmB to the pathogenesis of EBA and supports the notion of GzmB as a therapeutic target in EBA and other pemphigoid diseases.

The diagnosis of Sézary syndrome (SS) relies on the identification of blood Sézary cells (SC) by different markers via flow cytometry. Treatment of SS is challenging since its pathogenesis is characterized by cell death resistance rather than hyperproliferation. In this study, we establish an integrated approach that considers both the expression of SC markers and sensitivity to cell death both spontaneously and upon in vitro treatment. Peripheral blood mononuclear cells were isolated from 20 SS patients and analysed for the SC markers CD7 and CD26 loss as well as CD158k and PD1 gain. The cells were then treated with different established and experimental therapies in vitro and cell death was measured. Spontaneous and therapeutically induced cell death were measured and correlated to cellular marker profiles. In the marker-positive cells, spontaneous cell death sensitivity was reduced. Different treatments in vitro managed to specifically induce cell death in the putative CTCL cell populations. Interestingly, a repeated analysis after 3 months of treatment revealed the CTCL cell death sensitivity to be restored by therapy. We propose this novel integrated approach comprising the evaluation of SC marker expression and analysis of cell death sensitivity upon treatment that can also enable a better therapy stratification.

Despite rising melanoma incidence in recent decades, there is a trend towards overall decreased mortality, reflecting multiple factors including improved treatment options for metastatic disease. While local treatments are the mainstay for early-stage melanoma, metastatic disease necessitates systemic treatment, with oncolytic virotherapy emerging as a promising option. For this review, articles were retrieved from PubMed from 1964 through 2024. We conducted title, abstract and full-text screening in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify articles describing the use of coxsackievirus A21 (V937), either as monotherapy or as part of combination therapy for malignant melanoma. Fifteen articles met inclusion criteria, offering preclinical and clinical data on V937's efficacy in reducing tumour burden. In addition to reporting manageable safety profiles, clinical trial data examining intratumoral V937 combination therapy with pembrolizumab and ipilimumab also endorsed favourable objective response rates compared to immune checkpoint inhibitor monotherapy (47% vs. 38% and 21% vs. 10%, respectively). In contrast, intravenous V937 monotherapy failed to yield additional benefit in a cohort of patients with Stage IIIC/IV melanoma (n = 3) despite achieving detectable levels in tumour tissue (1 × 10⁹ TCID₅₀). Although small subsets of patients experienced severe adverse effects and study design limitations imposed constraints on collected data, evidence for the efficacy of V937 remains encouraging. With few clinical trials evaluating V937 in melanoma, additional data is required before routine usage in standard treatment for metastatic lesions.

Prurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted-metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography-tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long-chain fatty acids, alpha-aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up-regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down-regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN.

Facial skin redness can be an indicator of skin inflammation, however the physiological connection between facial redness and inflammatory status, as well as its role in age-related skin changes, remains poorly understood. This study aims to investigate the association between the pattern of facial skin redness and biological inflammatory status, as well as age-related changes occurring in the skin. Four studies were conducted recruiting healthy Northern Asian females. Disordered spatial patterns of facial skin redness signals were assessed using image analysis, i.e., the a* gradient algorithm, which quantifies the disordered shape and pattern of localized redness signals on facial skin. This redness pattern was compared with (1) inflammatory protein markers (IL-1Ra/ IL-1α and IL-8) measured from stripped corneocyte samples, (2) gene expression profiles obtained through transcriptome analysis using skin biopsy samples, and (3) the distribution pattern of blood vessel measured using a photoacoustic microscope. The association between the skin redness pattern and current and future ageing-related skin changes was examined through a longitudinal study tracking the same subjects for 10 years. A significant correlation was observed between the a* gradient and the levels of inflammatory cytokines (IL-1Ra/IL-1α and IL-8). Transcriptome analysis revealed upregulation of genes related to acute inflammation, chronic inflammation, cellular senescence, and angiogenesis in subjects with higher a* gradients. The high a* gradient group exhibited an extension of blood vessel diameter and increased blood vessel density, while the medium a* gradient group only exhibited blood vessel extension. Lastly, the 10-year longitudinal study demonstrated that the a* gradient was associated with current and future skin ageing-related attributes, such as increased skin texture and wrinkle formation. The spatial pattern of localized redness on the skin reflects the biological inflammatory status, and this inflammatory condition helps predict current and future age-related skin changes.

Phenylalanine is a crucial amino acid in the process of melanogenesis. However, the exact mechanism by which it is transported into melanocytes has not been disclosed. The aim of this study was to identify and examine the key transporters that are responsible for phenylalanine transportation and evaluate their significance in melanogenesis. The amino acid transporter SLC16A10 was found to be up-regulated in both melasma (GSE72140) and sun-exposed skin (GSE67098). The protein levels of SLC16A10 were proportional to the melanin content in melanocytic nevi, indicating that SLC16A10 was related to melanogenesis. After SLC16A10 overexpression, melanin increased significantly in MNT1 cells. Meanwhile, the expression of melanogenesis-related proteins such as TYR and TYRP1 increased, while their RNA levels did not change. Transcriptomics data indicated that SLC16A10 can enhance the function of ribosome. Furthermore, targeted metabolomics data and ELISA results demonstrated SLC16A10 mainly affected the transport of phenylalanine into the cells. Then, phenylalanine was added to the cell culture medium after SLC16A10 overexpression, melanin synthesis in cells furtherly increased, which verified that SLC16A10 enhances melanogenesis by promoting the uptake of phenylalanine. Finally, we found that SLC16A10 expression increased after UVB irradiation. Knockdown SLC16A10 reduced UVB-induced melanin production and phenylalanine uptake by cells. In summary, SLC16A10 enhances melanogenesis by promoting the uptake of phenylalanine, and upregulation SLC16A10 is likely responsible for the UVB-induced hyperpigmentation as well.

Psoriasis is considered to be multifactorial, with both genetic and environmental factors contributing to its development. Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment, originating from sources such as cigarette smoke, exhaust emissions, grilled foods, smoked foods and urban air. Researchs have established a link between PAHs exposure and autoimmune disorders; however, specific effects of PAHs on psoriasis remain underexplored. This study aims to evaluate the correlation between PAHs exposure and susceptibility to psoriasis. We analysed eight monohydroxy PAHs (1-Hydroxynaphthalene (1-NAP), 2-Hydroxynaphthalene (2-NAP), 3-Hydroxyfluorene (3-FLU), 2-Hydroxyfluorene (2-FLU), 1-Hydroxyphenanthrene (1-PHE), 1-Hydroxypyrene (1-PYR), 2-Hydroxyphenanthrene (2-PHE) and 3-Hydroxyphenanthrene (3-PHE)) in 5996 participants from the National Health and Nutrition Examination Survey (NHANES). We employed multivariate logistic regression, trend analysis, weighted quantile sum (WQS) regression and restricted cubic spline (RCS) analysis to investigate the relationship between PAHs exposure and psoriasis risk. Multivariate logistic regression and trend analysis revealed that monohydroxy PAHs, including 2-NAP, 3-FLU, 2-FLU and the mixture of 2-PHE and 3-PHE, are associated with an increased risk of psoriasis. Additionally, WQS regression showed a significant positive correlation between combined exposure to monohydroxy PAHs and psoriasis risk, with the mixture of 2-PHE and 3-PHE (47.3%) being the most influential factor. RCS regression further corroborated these findings. Specifically, 2-FLU can increase the expression of psoriasis-related inflammatory factors in HaCaT cells. In conclusion, PAHs exposure increases the risk of developing psoriasis. Efforts to reduce PAHs levels in the environment and minimise exposure are crucial for public health strategies aimed at preventing psoriasis.

In a double-blind, randomized controlled trial, we investigated the effectiveness of adding antiplatelet drugs to up-dosing antihistamines for the treatment of chronic spontaneous urticaria (CSU) in patients with elevated D-dimer levels who had an inadequate response to conventional antihistamine doses. Twenty patients with Urticaria Activity Score over 7 days (UAS7) ≥16 and D-dimer >500 ng/mL were randomized to receive either antiplatelet therapy (cilostazol 150 mg/day + dipyridamole 50 mg/day) with antihistamine (desloratadine 20 mg/day) or antihistamine alone for 4 weeks. The antiplatelet group demonstrated a greater decrease in UAS7 compared to the control group (28.10 to 8.90 vs. 22.90 to 16.40, p < 0.001 vs. p = 0.054). Both groups experienced improved quality of life (DLQI), but the improvement was greater in the antiplatelet group (p = 0.046). D-dimer levels decreased only in the antiplatelet group (1133.67 ng/mL to 581.89 ng/mL, p = 0.013) with no significant change observed in the control group. This suggests that combining dipyridamole and cilostazol with up-dosing antihistamines may be more effective for CSU patients with high D-dimer levels compared to up-dosing antihistamines alone. This could be due to a reduction in platelet activation, as evidenced by the decrease in D-dimer levels observed in the antiplatelet group.