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Diabetic foot ulcers (DFUs) are a serious complication of diabetes, characterized by impaired wound healing and high morbidity and mortality risks. While ETS1 is known to influence fibroblast pathological remodeling, its specific role in DFU and fibroblast wound healing remains unclear. Methods: Skin tissue samples from DFU patients were categorized by Wagner grades to analyze ETS1 expression. Primary fibroblasts derived from diabetes mellitus wound (DMFBs) were collected from wound margins to test migration ability and analyze cell phenotype by immunofluorescence; they were further treated with siETS1 and the ETS1 inhibitor YK-4-279. Techniques including Western blotting, quantitative Real-Time PCR (qRT-PCR), and immunofluorescence were used to assess the expressionof ETS1, Collagen I, and phenotype in DMFBs. Additionally, the binding sites between human ETS1 and the PP2A promoter were predicted by the UCSC and JASPAR databases. It intended to explore the negative transcriptional regulation of PP2A by ETS1 and its implications in fibroblast function and wound healing. Results: Fibroblasts derived from Wagner Grades II–IV exhibit differences in cell morphology, migratory ability, and phenotype. Our findings indicate a significant upregulation of ETS1 in Wagner III and IV. The downregulation of ETS1 was observed to enhance DMFB migration and increase the expression of Collagen I and α-SMA. These changes suggest a potential mechanism by which PP2A regulates the YAP/Hippo pathway in diabetic wound healing. Conclusion: ETS1 appears to impede the repair processes in DFUs, likely through the negative regulation of PP2A, affecting fibroblast function and wound healing. [ABSTRACT FROM AUTHOR]

Background: Diabetes impairs wound healing, notably in diabetic foot ulcers (DFU). Stress, marked by the accumulation of lipoylated mitochondrial enzymes and the depletion of Fe–S cluster proteins, triggers cuproptosis—a distinct form of cell death. The involvement of copper in the pathophysiology of DFU has been recognized, and currently, a copper-based therapeutic strategy is emerging as a viable option for enhancing ulcer healing. This study investigates genes linked to copper metabolism in DFU, aiming to uncover potential targets for therapeutic intervention. Methods: Two diabetic wound Gene Expression Omnibus (GEO) datasets were analyzed to study immune cell dysregulation in diabetic wounds. Differentially expressed genes related to copper metabolism were identified and analyzed using machine learning methods. Gene ontology, pathway enrichment, and immune infiltration analyses were performed using DFU samples. The expression of identified genes was validated using qRT-PCR and single-cell RNA sequencing. Results: Ten genes associated with copper metabolism were identified. Among these, SLC31A1 and ADNP were found to be significantly differentially expressed in DFU. Notably, SLC31A1 exhibited higher expression in macrophages, whereas ADNP was found to be highly expressed in fibroblasts and chondrocytes. Conclusion: The study indicates a close link between copper metabolism, the infiltration of immune cells, and DFU. It proposes that copper metabolism could influence the progression of DFU through the activation of immune responses. These observations offer fresh perspectives on the underlying mechanisms of DFU and identify potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Psoriasis is a global health problem and one of the most frequent chronic, relapsing inflammatory skin diseases. With a prevalence of 1-3% worldwide, it is typically observed in patients 20-30 years old, with a second peak occurring at 55 to 60. Its pathogenesis is unclear but there is strong genetic influence associated. Several genes have been found to be linked with an altered immune system resulting in the development of psoriasis. This literature review is aimed at the current knowledge and the role of inflammasomes in psoriasis with regard to the NLRP1 and NLRP3 gene polymorphism associated with the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a common, chronic, and multifactorial inflammatory cutaneous disorder that involves genetic and epigenetic factors. N6-methyladenosine methylation (m 6 A) is the most prevalent RNA modification implicated in various diseases; however, its role in psoriasis still needs to be further explored. We aimed to explore the mechanisms underlying the effects of m 6 A in psoriasis pathogenesis, prompting new therapeutic targets., Methods: Three psoriasis-related datasets, including GSE155702, GSE109248, and GSE142582, were collected. Differentially m 6 A methylated genes (DMGs) between psoriasis lesions of psoriasis patients and healthy skin controls were identified from the GSE155702 dataset, and corresponding Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Differentially expressed genes (DEGs) and the common DEGs between the two groups were screened from the GSE109248 and GSE142582 datasets; the expression and interactions of the m 6 A regulators were analyzed. The m 6 A levels of total RNAs and the protein expression levels of METTL3, WTAP, ALKBH5, FTO, and METTL14 in imiquimod (IMQ)-induced psoriasiform lesions were evaluated., Results: 66 significantly upregulated and 381 significantly downregulated m 6 A peaks were identified, corresponding to 414 genes which were particularly associated with cell and tissue development processes and cell cycle related items. 271 common DEGs were identified, associating with keratinocyte differentiation, epidermis development, cytokine-cytokine receptor interaction, and fatty acid metabolic processes. 15 crucial m 6 A related differentially expressed genes were obtained after the intersection of the DMGs and common DEGs, including NEU2, GALNT6, MTCL1, DOC2B, CAMK2N1, SNTB1, RNF150, CGNL1, CCDC102A, MEOX2, EEF2K, OBSCN, SLC46A2, CCDC85A, and DACH1 . In addition, we found that m 6 A methylation and these five m 6 A regulators were both upregulated in psoriatic lesions., Conclusions: It revealed that psoriasis pathophysiological processes encompass m 6 A epigenetic alterations, and that m 6 A alterations may specifically influence cell proliferation and neural regulation, and closely associated with osteoarticular involvement and metabolic syndrome in psoriasis., (© 2024 The Author(s). Published by IMR Press.)

Background: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment., Objectives: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment., Methods: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment., Results: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment., Conclusion: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment., (© 2020 S. Karger AG, Basel.)

Pollutants such as PM2.5 are polluting the environment seriously, causing numerous health problems. However, the skin toxicity caused by PM2.5 has been little reported so far. CCK-8 was used to test the effects of PM2.5 on melanin cell proliferation. The effect of PM2.5 on melanocyte apoptosis was detected by flow cytometry. ELISA was used to detect the expression of oxidative stress-related factors, including reactive oxygen species (ROS). The expression of autophagosomes was detected by MDC immunohistochemical staining, and Western blot was used to detect the expression of autophagy marker LC3II/I. With the increasing concentrations of PM2.5, the proliferation rate and apoptosis rate of melanocytes decreased significantly, meanwhile the expression of oxidative stress-related factors ROS, was obviously increased. The expression of LC3II/I induced by PM2.5 venom was higher than that of the control group in a concentration-dependent manner. However, there was no statistically significant difference between the water-soluble components of PM2.5 and the water-insoluble ones. PM2.5 can inhibit the proliferation of melanocytes and induce their apoptosis, which may be related to the oxidative damage of PM2.5. PM2.5 also induced autophagy in melanocytes, which is obviously correlated with its concentration. The mechanism may be a self-protective response of cells to oxidative stress injury and apoptosis.

Gorlin syndrome, a rare autosomal dominant disease, is characterized by numerous basal cell carcinomas, multiple jaw cysts, palmar and plantar pits and embryological deformities. Mutations in the PTCH1 gene are the most common molecular defects associated with Gorlin syndrome. We detected a duplication of thymine after nucleotide position 2927 in exon 18 of the PTCH1 gene (c.2927 dupT) in a fifty-year-old male proband with peri-anal basal cell carcinoma and his brother. The mutation creates a frameshift and leads to a premature stop codon (p.Tyr977 Leufs* 16) lacking 5 of the 12 transmembrane-spanning domains. However, the functional significance of truncation of the N terminal regions remains currently unknown and to be further investigated. The current findings indicate that genetic testing of PTCH1 gene mutational status may aid in the early diagnosis of Gorlin syndrome in which multiple complex abnormalities are present, hampering prompt diagnosis and treatment., Competing Interests: None., (IJCEP Copyright © 2017.)

BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance. Here we showed that overexpression of HDAC6 confers resistance to vemurafenib in BRAF-mutant A375 cells. ACY-1215, a selective HDAC6 inhibitor, inhibits the proliferation and induces the apoptosis of A375 cells. Moreover, ACY-1215 sensitizes A375 cells to vemurafenib induced cell proliferation inhibition and apoptosis induction, which occur partly through induction of endoplasmic reticulum (ER) stress and inactivation of extracellular signal-regulated kinase (ERK). Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of melanoma and overcoming resistance to vemurafenib.