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关键词： aging   intestinal stem cells   ERK/MAPK signaling pathway   IFN-γ signaling pathway  

摘要： While the intestinal epithelium has the highest cellular turnover rates in the mammalian body, it is also considered one of the tissues most resilient to aging-related disorders. Here, we reveal an innate protective mechanism that safeguards intestinal stem cells (ISCs) from environmental conditions in the aged intestine. Using in vivo phenotypic analysis, transcriptomics, and in vitro intestinal organoid studies, we show that age- dependent activation of interferon-g (IFN-g) signaling and inactivation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling are responsible for establishing an equilibrium of Lgr5+ ISCs-between active and quiescent states-to preserve the ISC pool during aging. Furthermore, we show that differentiated cells have different sensitivities to each of the two signaling pathways, which may induce aging-related, functional, and metabolic changes in the body. Thus, our findings reveal an exquisitely balanced, age-dependent signaling mechanism that preserves stem cells at the expense of differentiated cells.

关键词： 血钠   肝素结合蛋白与白蛋白比值   白细胞介素-10   川崎病   川崎病休克综合征   冠状动脉损害   免疫球蛋白   预测价值  

摘要： 目的 探讨联合检测血钠、肝素结合蛋白与白蛋白比值（HBP/ALB）、白细胞介素-10(IL-10)对儿童川崎病所致川崎病休克综合征（KDSS）的早期预测价值。方法 选取105例儿童川崎病所致KDSS患者（KDSS组）及105例儿童川崎病（对照组）为研究对象。比较2组临床资料以及血钠、HBP/ALB、IL-10。采用多因素Logistic回归分析筛选血钠、HBP/ALB、IL-10对儿童川崎病所致KDSS的影响因素。采用受试者工作特征曲线（ROC）分析传统预测方案（冠状动脉损害、IVIG抵抗）及新型预测方案（血钠、HBP/ALB、IL-10）预测儿童川崎病所致KDSS的价值。结果 KDSS组冠状动脉损害和IVIG抵抗患者占比高于对照组，差异有统计学意义（P<0.05）。KDSS组血钠低于对照组，HBP/ALB、IL-10高于对照组，差异有统计学意义（P<0.05）。多因素Logistic回归分析显示，血钠、HBP/ALB、IL-10是儿童川崎病所致KDSS的影响因素（P<0.05）。传统预测方案：冠状动脉损害、IVIG抵抗及其联合预测儿童川崎病所致KDSS的曲线下面积（AUC）依次为0.795、0.676、0.873(P<0.05)；新型预测方案：血钠、HBP/ALB、IL-10及其联合预测儿童川崎病所致KDSS的AUC依次为0.767、0.824、0.760、0.945(P<0.05)。血钠、HBP/ALB、IL-10联合预测的AUC大于冠状动脉损害、IVIG抵抗联合预测（P<0.05）。结论 血钠降低、HBP/ALB升高、IL-10升高与儿童川崎病所致KDSS有关。血钠、HBP/ALB、IL-10联合预测儿童川崎病所致KDSS的价值较高。

关键词： chondrocyte   cigarette smoke extract   TNF-alpha inhibitor   osteoarthritis   apoptosis   caspase 3/7   mitochondrial transmembrane potential   ROS  

摘要： Smoking has been associated, among other factors, with musculoskeletal disorders. Although there is no consensus about the effects of smoking on osteoarthritis (OA), the increase in TNF-alpha in smokers has been considered an important factor in OA induction or progression. However, studies on the effects of smoking on chondrocytes are lacking. Here we aimed to study the effects of cigarette smoke extract (CSE) associated with a TNF-alpha inhibitor on cell death of primary human chondrocytes derived from osteoarthritic patients. CSE at 10% led to cell death by apoptosis after 48 h of incubation, together with caspase 3/7 activation, decrease in mitochondrial transmembrane potential, ROS production, and improvement in syndercan-1, perlecan, and RUNX2 gene expression. All these effects promoted by CSE were reversed by TNF-alpha inhibitor. Collagen II, F-actin, and SOX9 were also analyzed, and CSE promoted alteration in the expression of these proteins. In conclusion, our results support the clinical impact of smoking on OA development by showing the detrimental action of CSE on osteoarthritis-derived chondrocytes and the protective effects of TNF-alpha inhibitors, reinforcing the importance of this cytokine in the cartilage injury process.

关键词： Mesothelioma   HLA-C   DNA methylation   Mendelian randomization   Tumor microenvironment  

摘要： BackgroundMalignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underpinning mesothelioma's progression remain insufficiently understood. HLA-C, a class I major histocompatibility complex (MHC) molecule, has been implicated in immune modulation and cancer progression, but its specific role in mesothelioma has yet to be thoroughly investigated. MethodsThis study employed a comprehensive multi-omics approach, integrating single-cell RNA sequencing, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR), to elucidate the role of HLA-C in mesothelioma progression. We first analyzed HLA-C expression within the TME, with particular focus on immune cells, especially macrophages. Survival analysis was conducted using data from the TCGA mesothelioma cohort to assess the clinical relevance of HLA-C expression. We utilized mediated MR analysis to investigate the impact of DNA methylation on HLA-C expression, identifying key mediators such as inflammatory cytokines, immune cell populations, blood cell types, and metabolites that could potentially influence patient prognosis. ResultsHLA-C was predominantly expressed in macrophages, T cells, and NK cells within the TME, and higher expression levels were associated with improved patient survival. MR analysis revealed that DNA methylation regulates HLA-C expression, which in turn impacts mesothelioma outcomes. Mediated MR analysis, encompassing 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types, and 1400 metabolites, highlighted several critical mediators of HLA-C's effect on prognosis, including IL-10, CD33 expression on CD33dim HLA DR- myeloid cells, the reticulocyte perturbation response, and the ADP-to-citrate ratio. Gene set enrichment analysis (GSEA) showe

关键词： psoriasis   keratinocytes stem cells (KSC)   early transit amplifying (ETA) cells   late transit amplifying cells (LTA)   IL-17 variants   IL-17 receptors  

摘要： Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the interleukin 17 (IL-17) signaling axis. Given that psoriasis development depends on keratinocyte stem cells and early progenitors' sensitivity to differentiation, we analyzed IL-17 ligands and the expression and function of in a novel subset of keratinocyte subpopulations: keratinocyte stem cells (KSC) and early and late Transit Amplifying (ETA or LTA, respectively) cells. We found that all subpopulations expressed all IL-17 variants, predominantly in ETA and LTA. Conversely, IL-17 receptor expression resulted in more heterogeneity, with IL-17RA, -C, and -E being the most differentially regulated. Stimulus with IL-17A, IL-17-F, IL-17-A/F, and IL-17C promotes the upregulation of CXCL1, CXCL8, and DEFB4 mRNAs expression in both KSC and ETA. Moreover, IL-17A and IL-17A/F mainly decrease KSC proliferation and promote cell cycle block. Globally, IL-17A and IL-17A/F modulated the expression of proliferation, differentiation, and psoriasis-associated markers. Furthermore, KSC- and ETA-derived 3D reconstructions displayed increased epidermal thickness and upregulated KRT16 expression after treatment with IL-17A or IL-17A/F. Therefore, our data demonstrated that IL-17 family members perform distinctive functions in a specific keratinocyte subpopulation and define IL-17 signaling as a critical modulator of KSC behavior, proving its role in epidermal homeostasis dysregulation of psoriasis.