Experimental Dermatology最新文献

The possibility of modulating the treatment regimen regarding dose reduction (de-escalation) or dose augmentation (escalation) in psoriasis biological treatment has been of increasing interest. De-escalation strategies include reducing the single therapeutic dose, the mg/kg ratio or the number of injections, or dose-spacing (D-S), that is, extending the interval between administrations. Data regarding dose de-escalation, in particular D-S, on IL-23, are lacking to date. The present pilot study is a cohort study with a retrospective analysis of the general characteristics and effectiveness outcomes of psoriatic patients undergoing therapeutic biologic D-S of risankizumab and guselkumab. Ninety-four patients, 32 (34.04%) treated with guselkumab and 62 (65.96%) treated with risankizumab, underwent dose modulation by D-S of 50% of the approved range. The mean PASI decreased from 12.15 (5.43 SD) to 0.15 (0.46 SD) at D-S time. Attainment of PASI100 was rapid: 88.3% at the D-S date, remaining stable over the following year, reaching 100% of patients observed 12 months after D-S. Similar is the trend for PASI 90 and PASI <=1 with 91.49% and 97.87% of achievement at D-S date, and all patients observed at 12 months post-D-S. The 12-month drug survival of the D-S regimen was 89.4%. Guselkumab showed a D-S drug survival of 93.3% versus 89.5% of risankizumab. No differences in mean PASIs at each time point were found between guselkumab and risankizumab. To conclude therapeutic modulation of IL-23 inhibitors in psoriatic patients who have achieved response stability seems a legitimate therapeutic strategy to maintain efficacy and safety.

In most cases, atopic dermatitis (AD) is induced by allergic inflammation, with antigen penetration into the epithelial tissues of the skin being the first step in AD development. Accordingly, inhibiting the skin penetration of antigens is effective in preventing AD. We evaluated the ability of the following four types of particles to adsorb ovalbumin (OVA): titanium dioxide (TiO₂), silicon dioxide (SiO₂), carbon, and SiO₂ coated with one-layer graphene (1LGCS). We found that metal oxide particles (TiO₂ and SiO₂) could adsorb OVA at pH 5.0, but their abilities decreased at pH 7.0 and 9.0. In contrast, the carbon-based particles (carbon and 1LGCS) adsorbed OVA regardless of pH changes. Epicutaneous treatment with OVA resulted in an increase in the proportion of OVA-positive Langerhans cells and dermal dendritic cells in the lymph nodes, along with elevated interleukin-4 mRNA expression, indicating that OVA penetrated the epidermis and underlying tissues. When OVA was applied together with the particles, these responses were significantly reduced by the carbon-based particles but were only partially or not inhibited by metal oxide particles. These findings indicated that antigen penetration was potently inhibited by the carbon-based particles. Additionally, when mice were epicutaneously sensitised and challenged with OVA in the presence of carbon, the increase in OVA-specific IgG1 and IgE levels was significantly inhibited. The efficiency of carbon-based particles may be attributed to their stable adsorption of proteins despite pH changes on the skin surface. These findings may lead to the development of new treatments for AD with fewer side effects.

Psoriasis is a common chronic inflammatory skin disease determined by genetic and environmental factors, resulting in the activation of IL-23/IL-17-mediated immune response, epidermal hyperproliferation, and keratinocyte activation. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts > 500 nucleotides with diverse regulatory functions; their role in epidermal dysfunction in psoriasis is poorly understood. To identify epidermal transcripts with potential roles in psoriasis, including lncRNAs, we performed RNA sequencing on keratinocytes from psoriasis and healthy skin. We identified 889 differentially expressed lncRNAs, many of which with yet unknown functions. RP11-295G20.2 was identified as a lncRNA significantly induced in psoriasis keratinocytes, and this was verified by qRT-PCR and by single-molecule in situ hybridisation. Analysis of subcellular fractions of epidermis revealed a cytoplasmic localisation in line with results of single molecule in situ hybridisation. We report that RP11-295G20.2 has a skin-enriched expression, and within skin it is mainly expressed in suprabasal epidermal layers. Moreover, RP11-295G20.2 is induced by the key psoriasis cytokine IL-17A and shows a dynamic regulation during keratinocyte differentiation with upregulation during early differentiation and downregulation in the late stage. Knockdown of RP11-295G20.2 in keratinocytes promotes terminal differentiation. Based on our findings, we named RP11-295G20.2 Cytoplasmic Differentiation-Associated Epidermal RNA, CYDAER. In summary, our study provides a comprehensive characterisation of the non-coding RNA landscape of psoriasis keratinocytes and identifies CYDAER as a skin-enriched lncRNA regulating keratinocyte differentiation. Our data suggest that overexpression of CYDAER may contribute to altered differentiation in psoriatic epidermis.

Invasive growth and metastatic dissemination represent the primary cause of death in cancer patients. In order to successfully detach from the primary tumour and establish metastases in distant tissues, cancer cells need to dynamically rewire their cell adhesion machinery. Here we revisit the potential association of MCAM, a member of the immunoglobulin superfamily that was initially identified as a melanoma antigen, with disease progression. Using immunohistochemical stainings and bioinformatic analyses of published datasets, we find abundant MCAM expression both in primary and metastatic human melanomas. In additional bioinformatic analyses, we show that MCAM is highly expressed in foetal melanocytes and subsequently downregulated during melanocyte maturation. Bioinformatic inference of cellular communication networks reveals that melanoma cells with high MCAM expression more actively engage in signalling crosstalk with endothelial cells. Experimental investigations demonstrate that disruption of MCAM in melanoma cells inhibits their migration on endothelial cell surfaces in vitro and decreases their ability to develop spontaneous lung metastases in vivo. Taken together, our results could not confirm the notion that MCAM expression represents a useful biomarker for disease progression but provide evidence that MCAM expression might represent part of a reactivated embryonal transcriptional program that facilitates melanoma–endothelial cell interactions during metastatic progression.

Hidradenitis suppurativa (HS) is a relatively common and highly morbid inflammatory skin disease. Due to the relatively limited understanding of HS's pathogenesis, there are currently insufficient treatment options available, and many patients' medical needs are not being met. This is partly due to the historical scarcity of ex vivo assays and animal models that accurately recapitulate the disease. Thus, we have developed a standardised whole-tissue explant model of HS to examine its pathogenic mechanisms and the efficacy of potential treatments within intact human tissue. We measured cytokine protein and RNA within whole tissue maintained in an agar-media solution, finding that IL-6 and IL-8 concentrations trended upwards in both HS explants and healthy controls, while IL-17A, IL-1β, and TNF-α exhibited increases in HS tissue alone. We also show that the explants were responsive to treatment with both dexamethasone and IL-2. Not only do our results show that this model effectively delivers treatments throughout the explants, but they also elucidate which cytokines are related to the explant process regardless of tissue state and which are related to HS tissue specifically, laying the groundwork for future implementations of this model.

Ceramide has transitioned from an incidental discovery to a vital element in skincare, becoming a thoroughly studied compound in the quest to treat skin conditions. Creating a moisture barrier, preserving hydration, regulating pH, controlling inflammation, and enhancing skin functions and appearance are among its established benefits. It is often used medically to repair skin barrier defects, as observed in inflammatory skin conditions like atopic dermatitis (AD) and dry skin types. Furthermore, ceramide and its metabolites are commonly used as predictors before disease manifestation and for prognostication processes, thus can be used as biomarker for clinical diagnosis as well. In the last couple of decades, momentum was also seen in the pre-clinical studies involving anti-cancer and nanotechnology field, whereby ceramide was also used as a drug, a carrier, or even adjunct formulation to increase efficacy of treatment such as chemotherapy. Approaches to increase ceramide levels include directly replenishing lost ceramides with natural extracts, synthetic pseudo-ceramides, or ceramide-like analogues, as well as using supplements that stimulate the body's natural ceramide production. Although ceramide is a well-known treatment in skincare and for common skin conditions like AD and psoriasis, its development and related pharmacology for severe skin conditions, such as skin cancer, remain in pre-clinical stages. Hence, the purpose of this research is to explore the role of ceramide in skin health and its application in common skin diseases.