Antroquinonol Exerts Immunosuppressive Effect on CD8 +

Antroquinonol was investigated as antioxidant and inhibition of inflammatory responses. Our study was to evaluate its immunosuppressive effect on CD8+ T cells and protective effect on depigmentation. CD8+ T cells were treated with antroquinonol in vitro, and C57BL/6 mice were treated with antroquinonol with or without H2O2 in vivo for 50 consecutive days. We found antroquinonol could inhibit proliferation of CD8+ T cells and suppress the production of cytokines IL-2 and IFN-γ and T cell activation markers CD69 and CD137 in vitro. H2O2 treatment induced depigmentation and reduced hair follicle length, skin thickness, and tyrosinase expression in vivo. Whereas, antroquinonol obviously ameliorated depigmentation of mice skin and resisted the reduction of hair follicle length, skin thickness, and tyrosinase expression induced by H2O2. Antroquinonol decreased CD8+ T cell infiltration in mice skin, inhibited the production of IL-2 and IFN-γ, and decreased the expression of CXCL10 and CXCR3. Summarily, our data shows antroquinonol inhibits CD8+ T cell proliferation in vitro. It also reduces CD8+ T cell infiltration and proinflammatory cytokine secretion and suppresses the thinning of epidermal layer in vivo. Our findings suggest that antroquinonol exerts immunosuppressive effects on CD8+ T cell proliferation and activation to resist depigmentation induced by H2O2

Novel potential therapeutic targets of alopecia areata

Alopecia areata (AA) is a non-scarring hair loss disorder caused by autoimmunity. The immune collapse of the hair follicle, where interferon-gamma (IFN-γ) and CD8+ T cells accumulate, is a key factor in AA. However, the exact functional mechanism remains unclear. Therefore, AA treatment has poor efficacy maintenance and high relapse rate after drug withdrawal. Recent studies show that immune-related cells and molecules affect AA. These cells communicate through autocrine and paracrine signals. Various cytokines, chemokines and growth factors mediate this crosstalk. In addition, adipose-derived stem cells (ADSCs), gut microbiota, hair follicle melanocytes, non-coding RNAs and specific regulatory factors have crucial roles in intercellular communication without a clear cause, suggesting potential new targets for AA therapy. This review discusses the latest research on the possible pathogenesis and therapeutic targets of AA

Efficacy and safety of different JAK inhibitors in the treatment of alopecia areata: a network meta-analysis

BackgroundAlopecia areata (AA) is an immune disease characterized by non-scarring hair loss. With the widespread application of JAK inhibitors in immune-related diseases, attention is being given to their role in the treatment of AA. However, it is unclear which JAK inhibitors have a satisfactory or positive effect on AA. This network meta-analysis aimed to compare the efficacy and safety of different JAK inhibitors in the treatment of AA.MethodsThe network meta-analysis was performed according to the PRISMA guidelines. We included randomized controlled trials as well as a small number of cohort studies. The differences in efficacy and safety between the treatment and control groups were compared.ResultsFive randomized controlled trials, two retrospective studies, and two prospective studies involving 1689 patients were included in this network meta-analysis. In terms of efficacy, oral baricitinib and ruxolitinib significantly improved the response rate of patients compared to placebo [MD = 8.44, 95% CI (3.63, 19.63)] and [MD = 6.94, 95% CI, (1.72, 28.05)],respectively. Oral baricitinib treatment significantly improved the response rate compared to non-oral JAK inhibitor treatment [MD=7.56, 95% CI (1.32,43.36)]. Oral baricitinib, tofacitinib, and ruxolitinib treatments significantly improved the complete response rate compared to placebo [MD = 12.21, 95% CI (3.41, 43.79)], [MD = 10.16, 95% CI (1.02, 101.54)], and [MD = 9.79, 95% CI, (1.29, 74.27)], respectively. In terms of safety, oral baricitinib, tofacitinib, and ruxolitinib treatments significantly reduced treatment-emergent adverse event rates compared with conventional steroid treatment [MD = 0.08, 95% CI (0.02, 0.42)], [MD = 0.14, 95% CI (0.04, 0.55)], and [MD = 0.35, 95% CI, (0.14, 0.88)], respectively.ConclusionOral baricitinib and ruxolitinib are excellent options for the treatment of AA owing to their good efficacy and safety profiles. In contrast, non-oral JAK inhibitors do not appear to have satisfactory efficacy in treating AA. However, further studies are required to verify the optimal dose of JAK inhibitors for AA therapy

Identification of SLC40A1, LCN2, CREB5, and SLC7A11 as ferroptosis-related biomarkers in alopecia areata through machine learning

Abstract Alopecia areata (AA) is a common non-scarring hair loss condition driven by the collapse of immune privilege and oxidative stress. The role of ferroptosis, a type of cell death linked to oxidative stress, in AA is yet to be explored, even though it's implicated in various diseases. Using transcriptome data from AA patients and controls from datasets GSE68801 and GSE80342, we aimed to identify AA diagnostic marker genes linked to ferroptosis. We employed Single-sample gene set enrichment analysis (ssGSEA) for immune cell infiltration evaluation. Correlations between ferroptosis-related differentially expressed genes (FRDEGs) and immune cells/functions were identified using Spearman analysis. Feature selection was done through Support vector machine-recursive feature elimination (SVM-RFE) and LASSO regression models. Validation was performed using the GSE80342 dataset, followed by hierarchical internal validation. We also constructed a nomogram to assess the predictive ability of FRDEGs in AA. Furthermore, the expression and distribution of these molecules were confirmed through immunofluorescence. Four genes, namely SLC40A1, LCN2, CREB5, and SLC7A11, were identified as markers for AA. A prediction model based on these genes showed high accuracy (AUC = 0.9052). Immunofluorescence revealed reduced expression of these molecules in AA patients compared to normal controls (NC), with SLC40A1 and CREB5 showing significant differences. Notably, they were primarily localized to the outer root sheath and in proximity to the sebaceous glands. Our study identified several ferroptosis-related genes associated with AA. These findings, emerging from the integration of immune cell infiltration analysis and machine learning, contribute to the evolving understanding of diagnostic and therapeutic strategies in AA. Importantly, this research lays a solid foundation for subsequent studies exploring the intricate relationship between AA and ferroptosis

Analysis of the effect of the Chinese herbal pair, Semen Persicae–Carthami Flos, on psoriasis using network pharmacology

Purpose: To investigate the underlying effect of the Chinese herbal pair, Semen Persicae–Carthami Flos (PC), on psoriasis using network pharmacology. Method: The core components and targets of the Chinese herbal pair were screened using TCMSP and BATMAN databases. Psoriasis disease targets were searched in OMIM and GeneCards databases. The common targets of the herbal pair and psoriasis were identified using a Venn diagram. The component–psoriasis-target network map was constructed using Cytoscape software. Protein interaction analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed on STRING website, R Project, and DAVID 6.8 database. Molecular docking was performed using AutoDock Vina software to predict the binding of herbal pair PC to psoriasis targets. Results: A total of 45 components and 105 potential targets of PC, as well as 3729 psoriasis-related genes, were screened from the databases. Venn diagram shows that there were 62 common targets of PC and psoriasis. These common targets involved biological processes such as DNA transcription factor receptor binding, cytokine receptor binding, and regulation of molecular function. The targets also involved apoptosis and the advanced glycation end-products (AGE)-receptor for AGEs (RAGE), tumor necrosis factor, and phosphatidylinositol 3-kinase/protein kinase B signaling pathways. In addition, the main active components of PC spontaneously bound to the targets. Conclusion: The Chinese herbal pair PC provides an alternative clinical therapeutic strategy for patients with psoriasis

Efficacy and safety of JAK inhibitors in the treatment of alopecia areata in children: a systematic review and meta-analysis

Background Alopecia areata (AA) is a non-scarring hair loss mediated by T lymphocytes. Recently, a growing number of studies have shown that Janus kinase inhibitors are effective in the treatment of AA in children. Methods A systematic review and meta-analysis were performed according to the PRISMA guidelines. Good response was defined as more than 50% decrease in Severity of Alopecia Tool (SALT) score or complete regrowth or more than 50% regrowth. Partial response was defined as 5–50% decrease in SALT score. Any response to treatment was defined as more than 5% in SALT score decrease. Results There were 81.9% responders, 68.5% good responders, and 7.7% partial responders among the 10 included studies. The treatment duration was longer in good responders than in partial responders (p = .009). Oral route was linked to a better response to topical medication, with an odds ratio of 7.8 (95%CI 1.655–36.76). In terms of toxicity, reported adverse events included only mild symptoms. Liver transaminase elevation, upper respiratory tract infection, and eosinophilia were the most common adverse events. Conclusions Janus kinase inhibitors demonstrated promise in the treatment of AA in children, with the most common side effects being minor and reversible

DataSheet_1_Efficacy and safety of different JAK inhibitors in the treatment of alopecia areata: a network meta-analysis.docx

BackgroundAlopecia areata (AA) is an immune disease characterized by non-scarring hair loss. With the widespread application of JAK inhibitors in immune-related diseases, attention is being given to their role in the treatment of AA. However, it is unclear which JAK inhibitors have a satisfactory or positive effect on AA. This network meta-analysis aimed to compare the efficacy and safety of different JAK inhibitors in the treatment of AA.MethodsThe network meta-analysis was performed according to the PRISMA guidelines. We included randomized controlled trials as well as a small number of cohort studies. The differences in efficacy and safety between the treatment and control groups were compared.ResultsFive randomized controlled trials, two retrospective studies, and two prospective studies involving 1689 patients were included in this network meta-analysis. In terms of efficacy, oral baricitinib and ruxolitinib significantly improved the response rate of patients compared to placebo [MD = 8.44, 95% CI (3.63, 19.63)] and [MD = 6.94, 95% CI, (1.72, 28.05)],respectively. Oral baricitinib treatment significantly improved the response rate compared to non-oral JAK inhibitor treatment [MD=7.56, 95% CI (1.32,43.36)]. Oral baricitinib, tofacitinib, and ruxolitinib treatments significantly improved the complete response rate compared to placebo [MD = 12.21, 95% CI (3.41, 43.79)], [MD = 10.16, 95% CI (1.02, 101.54)], and [MD = 9.79, 95% CI, (1.29, 74.27)], respectively. In terms of safety, oral baricitinib, tofacitinib, and ruxolitinib treatments significantly reduced treatment-emergent adverse event rates compared with conventional steroid treatment [MD = 0.08, 95% CI (0.02, 0.42)], [MD = 0.14, 95% CI (0.04, 0.55)], and [MD = 0.35, 95% CI, (0.14, 0.88)], respectively.ConclusionOral baricitinib and ruxolitinib are excellent options for the treatment of AA owing to their good efficacy and safety profiles. In contrast, non-oral JAK inhibitors do not appear to have satisfactory efficacy in treating AA. However, further studies are required to verify the optimal dose of JAK inhibitors for AA therapy.</p

Redox Biology / Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

Autophagy allows cells fundamental adaptations to metabolic needs and to stress. Using autophagic bulk degradation cells can clear crosslinked macromolecules and damaged organelles that arise under redox stress. Accumulation of such debris results in cellular dysfunction and is observed in aged tissue and senescent cells. Conversely, promising anti-aging strategies aim at inhibiting the mTOR pathway and thereby activating autophagy, to counteract aging associated damage. We have inactivated autophagy related 7 (Atg7), an essential autophagy gene, in murine keratinocytes (KC) and have found in an earlier study that this resulted in increased baseline oxidative stress and reduced capacity to degrade crosslinked proteins after oxidative ultraviolet stress. To investigate whether autophagy deficiency would promote cellular aging, we studied how Atg7 deficient (KO) and Atg7 bearing cells (WT) would respond to stress induced by paraquat (PQ), an oxidant drug commonly used to induce cellular senescence. Atg7 deficient KC displayed increased prostanoid signaling and a pro- mitotic gene expression signature as compared to the WT. After exposure to PQ, both WT and KO cells showed an inflammatory and stress-related transcriptomic response. However, the Atg7 deficient cells additionally showed drastic DNA damage- and cell cycle arrest signaling. Indeed, DNA fragmentation and oxidation were strongly increased in the stressed Atg7 deficient cells upon PQ stress but also after oxidizing ultraviolet A irradiation. Damage associated phosphorylated histone H2AX (H2AX) foci were increased in the nuclei, whereas expression of the nuclear lamina protein lamin B1 was strongly decreased. Similarly, in both, PQ treated mouse tail skin explants and in UVA irradiated mouse tail skin, we found a strong increase in H2AX positive nuclei within the basal layer of Atg7 deficient epidermis. Atg7 deficiency significantly affected expression of lipid metabolic genes. Therefore we performed lipid profiling of keratinocytes which demonstrated a major dysregulation of cellular lipid metabolism. We found accumulation of autophagy agonisitic free fatty acids, whereas triglyceride levels were strongly decreased. Together, our data show that in absence of Atg7/autophagy the resistance of keratinocytes to intrinsic and environmental oxidative stress was severely impaired and resulted in DNA damage, cell cycle arrest and a disturbed lipid phenotype, all typical for premature cell aging.(VLID)485638