Age and urban-rural disparities in cutaneous melanoma mortality rates in the United States during the COVID-19 pandemic.

Most recent studies on the coronavirus disease 2019 (COVID-19) pandemic and cutaneous melanoma (CM) focused more on delayed diagnosis or advanced presentation. We aimed to ascertain mortality trends of CM between 2012 and 2022, focusing on the effects of the COVID-19 pandemic. In this serial population-based study, the National Vital Statistics System dataset was queried for mortality data. Excess CM-related mortality rates were estimated by calculating the difference between observed and projected mortality rates during the pandemic. Totally there were 108,853 CM-associated deaths in 2012-2022. CM-associated mortality saw a declining trend from 2012 to 2019 overall. However, it increased sharply in 2020 (ASMR 3.73 per 100,000 persons, 5.95% excess mortality), and remained high in 2021 and 2022, with the ASMRs of 3.82 and 3.81, corresponding to 11.17% and 13.20% excess mortality, respectively. The nonmetro areas had the most pronounced rise in mortality with 12.20% excess death in 2020, 15.33% in 2021 and 20.52% in 2022, corresponding to a 4-6 times excess mortality risk compared to large metro areas during the pandemic. The elderly had the most pronounced rise in mortality, but the mortality in the younger population was reduced.

Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.

Introduction: The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib. Methods: hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS. Results: Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis. Conclusion: Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

Serine deficiency exacerbates psoriatic skin inflammation by regulating S-adenosyl methionine-dependent DNA methylation and NF-κB signalling activation in keratinocytes.

BACKGROUND: Serine metabolism is crucial for tumour oncogenesis and immune responses. S-adenosyl methionine (SAM), a methyl donor, is typically derived from serine-driven one-carbon metabolism. However, the involvement of serine metabolism in psoriatic skin inflammation remains unclear. OBJECTIVES: To investigate the association between serine metabolism and psoriatic skin inflammation. METHODS: Clinical samples were collected from patients with psoriasis and the expression of serine biosynthesis enzymes was evaluated. The HaCaT human keratinocyte cell line was transfected with small interfering RNA (siRNA) of key enzyme or treated with inhibitors. RNA sequencing and DNA methylation assays were performed to elucidate the mechanisms underlying serine metabolism-regulated psoriatic keratinocyte inflammation. An imiquimod (IMQ)-induced psoriasis mouse model was established to determine the effect of the SAM administration on psoriatic skin inflammation. RESULTS: The expression of serine synthesis pathway enzymes, including the first rate-limiting enzyme in serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), was downregulated in the epidermal lesions of patients with psoriasis compared with that in healthy controls. Suppressing PHGDH in keratinocytes promoted the production of proinflammatory cytokines and enrichment of psoriatic-related signalling pathways, including the tumour necrosis factor-alpha (TNF-α) signalling pathway, interleukin (IL)-17 signalling pathway and NF-κB signalling pathway. In particular, PHGDH inhibition markedly promoted the secretion of IL-6 in keratinocytes with or without IL-17A, IL-22, IL-1α, oncostatin M and TNF-α (mix) stimulation. Mechanistically, PHGDH inhibition upregulated the expression of IL-6 by inhibiting SAM-dependent DNA methylation at the promoter and increasing the binding of myocyte enhancer factor 2A. Furthermore, PHGDH inhibition increased the secretion of IL-6 by increasing the activation of NF-κB via SAM inhibition. SAM treatment effectively alleviated IMQ-induced psoriasis-like skin inflammation in mice. CONCLUSIONS: Our study revealed the crucial role of PHGDH in antagonising psoriatic skin inflammation and indicated that targeting serine metabolism may represent a novel therapeutic strategy for treating psoriasis.