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关键词： Essential hypertension   Interleukin-33   interleukin-1receptor associated protein   Genetic polymorphisms   rs16865597  

摘要： BackgroundThe IL-33/ST2 pathway plays a crucial role in the development of essential hypertension (EH). This study aimed to investigate the relationship between EH and genetic variations in this pathway in the Chinese Han *** total of 1,151 EH patients and 1,135 healthy controls were included in the study. Sixteen single nucleotide polymorphisms (SNPs) in the interleukin-33 (IL-33) and interleukin-1receptor associated protein (IL-1RAcP) genes were genotyped using the Sequenom MassArray and TaqMan assays. Genotype and allele frequencies were compared between the EH patients and controls using logistic regression *** rs16865597 SNP in the IL-1RAcP gene was found to be associated with the risk of EH. Specifically, the presence of the C allele of rs16865597 was negatively correlated with EH susceptibility in both the additive model (P = 0.014, OR = 0.75, 95% CI = 0.59-0.94) and the recessive model (P = 0.011, OR = 0.72, 95% CI = 0.56-0.93). Additionally, rs16865597 was linked to a reduced risk of EH in specific subgroups, including males (OR add = 0.73, 95% CI = 0.56-0.94, P = 0.015), nonsmokers (OR add = 0.72, 95% CI = 0.54-0.96, P = 0.023), nondrinkers (OR add = 0.70, 95% CI = 0.53-0.93, P = 0.013), and individuals with low BMI (OR add = 0.69, 95% CI = 0.51-0.92, P = 0.013). Moreover, the C genotype of rs16865597 was strongly associated with higher interleukin-10 levels in *** rs16865597 SNP is significantly associated with a reduced risk of EH in the Chinese Han population, potentially due to its role in immune regulation.

关键词： cathepsin B   cathepsin L   human gingival fibroblast   interleukin-6   caveolin  

摘要： Aims Cathepsins are essential lysosomal enzymes that maintain organismal homeostasis by degrading extracellular substrates. The inflammatory cytokine interleukin-6 (IL-6) increases the production of cathepsins through the caveolin-1 (Cav-1) and c-Jun N-terminal kinase (JNK) signaling pathways, which have been implicated in the destruction of periodontal tissue. This study investigated the effect of the IL-6/soluble IL-6 receptor (sIL-6R) complex on the extracellular secretion of cathepsins in human gingival fibroblasts (HGFs) and examined the function of extracellularly secreted cathepsins B and L under acidic culture conditions in *** HGFs were isolated from healthy volunteer donors. The expression of Cav-1 was suppressed via transfection with small interfering RNA (siRNA) targeting Cav-1. The expression levels of cathepsins B and L induced by extracellular IL-6/sIL-6R were measured using western blotting and enzyme-linked immunosorbent assay. Extracellular cathepsin activity following IL-6/sIL-6R stimulation was assessed using a methylcoumarylamide substrate in a fluorescence-based assay. IL-6/sIL-6R-induced expression of cathepsins B and L in HGFs was quantified under inhibitory conditions for extracellular signal-regulated kinase (ERK) 1/2 and/or JNK signaling, both of which are transduction pathways activated by IL-6/sIL-6R. This quantification was also performed in HGFs with suppressed Cav-1 expression using western *** Cathepsins B and L were secreted in their precursor forms from HGFs, with significantly elevated protein levels observed at 24, 48, and 72 h post-IL-6/sIL-6R stimulation. Under acidic culture conditions, cathepsin B activity increased at 48 and 72 h. Cav-1 suppression inhibited the secretion of cathepsin B regardless of IL-6/sIL-6R stimulation, whereas the secretion of cathepsin L was reduced only after 48 h of IL-6/sIL-6R stimulation. Inhibition of ERK1/2 and JNK pathways decreased the secretion of cathepsin B after 48 h

关键词： IL-17RA   colon cancer   EMT   anti-tumor immunity   IL-17   CRC   mycobiome   immunotherapy   inflammation  

摘要： Expression of interleukin (IL)-17 family cytokines is associated with tumor-promoting inflammation. We found that low expression of IL17RA associated with worse prognosis in late-stage colorectal cancer (CRC) patients. Deletion of Il17ra in intestinal epithelial cells (IECs) in a murine model of CRC enhanced epithelialto-mesenchymal transition (EMT) via increased expression of the epidermal growth factor receptor and subsequent activation of the kinase Src. Yet, these mice were protected from metastatic disease;Il17ra deletion impaired intestinal barrier function and enhanced systemic fungal invasion and associated immunity. However, in macrophages, IL-17RA was required for spleen tyrosine kinase (Syk) activation upon fungal-induced dectin-1 engagement, and Il17ra ablation impaired IL-18 release and protective CD8+ T cell-mediated antitumor immunity. Combining recombinant IL-17 and heat-killed Candida albicans rendered colorectal tumors sensitive to a-PD-1 treatment in a model of microsatellite stable (MSS) CRC. Thus, IL-17RA engages two distinct tumor-suppressive mechanisms in CRC, linking EMT and fungal-induced anti-tumor immunity during tumor progression.

关键词： Interleukin 8   Metastasis   EMT   Migration   Invasion   Angiogenesis   Therapy optimization   Immunotherapy improvement  

摘要： Tumors are structures of high complexity. Plurality of their structural and functional components- heterogeneity, diversity, directionality, interdependence and integration of signaling pathways- seem to follow isolated local rules, whereby a superordinate structure remains largely unknown. Understanding the complexity of cancer is the mainstay in finding determinants and developing effective therapies. Interleukin 8 (IL-8) is a potent proinflammatory chemokine that is significantly elevated in many different tumor entities. In contrast to its initially postulated anti-tumor properties, an increasing number of studies have been published in recent years linking this chemokine with tumor-promoting features and poor prognosis. This review summarizes the current state and diversity of the role of IL-8 in the development of cancer.

关键词： IL-17A   T cells   allergy   delayed-type hypersensitivity   extracellular vesicles   microRNA   rodent  

摘要： Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transporting functional molecules between donor cells and recipient cells, thereby regulating biological processes, such as immune responses. miR-451a, an immune regulatory microRNA, is highly abundant in circulating EVs; however, its precise physiological significance remains to be fully elucidated. Here, we demonstrate that miR-451a deficiency exacerbates delayed-type hypersensitivity (DTH) in mice. Notably, miR-451a knockout resulted in a significant increase in the number of interleukin (IL)-17A-expressing T helper 17 and γδ T cells infiltrating DTH-induced ear lesions. miR-451a deficiency also increased the number of γδ T cells in the secondary lymphoid tissues. Comprehensive analyses revealed that miR-451 deficiency promoted the expression of Rorc and γδ T cell-related genes following sensitization with allergens. Moreover, intravenous administration of wild-type EVs to miR-451a knockout mice increased cellular miR-451a levels in tissues and significantly attenuated the severity of DTH. Furthermore, synthetic lipid nanoparticles encapsulating miR-451a effectively mitigated DTH. Our findings indicate the importance of circulating miR-451a in the proliferation of γδ T cells and highlight the therapeutic potential of lipid nanoparticle-based microRNA delivery platforms for interventions in immune-related diseases.

摘要： gamma delta T cells represent key players in immune surveillance after T-cell receptor alpha/beta (alpha beta)/CD19depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Although encouraging data are available on the impact of V delta 2-targeting therapy in improving HSCT clinical outcomes, their role in providing antimicrobial immunity is largely unexplored. This study aimed to investigate the antiviral protective profile of V delta 2 T cells in pediatric patients given haplo-HSCT. The characterization of gamma delta T cells was performed in pediatric recipients (n = 26) in the donor graft and at 30, 60, and 120 days after haplo-HSCT. The antiviral activity of V delta 2 T cells and the cytomegalovirus (CMV)-specific alpha beta T-cell immunity was analyzed. Early after HSCT, V delta 2 T cells was significantly higher in patients who did not experience viral reactivation (No-VR) than in patients with CMV reactivation. Interestingly, this difference was already present in the grafts. Clustering analysis identified a protective subset of V delta 2 T cells in patients with No-VR, expressing CD16, NKG2D, and CD107a, and producing Th1 cytokines. This subset directly correlated with interleukin-15 and inversely with the CMV DNA level. Stimulated V delta 2 T cells inhibit CMV replication, acquired CD86/HLA-DR molecules, induced HLA-DR on monocytes, and improved the alpha beta CMV-specific T-cell response. Altogether, these results identify an antiviral protective profile displayed by V delta 2 T cells early after HSCT, and define their ability to inhibit CMV replication, to induce antigen-presenting cell maturation and to improve alpha beta virus-specific T-cell response, opening a new application of V delta 2-targeting immunotherapy after HSCT, adding the antiviral to the antitumor potential.

关键词： anti-TNF drug levels   transcriptomics   microRNA   Crohn's disease   gene regulation  

摘要： Background MicroRNAs (miRNAs) play a key role in regulating gene expression in Crohn's disease (CD). Although several studies have identified miRNAs with biomarker potential, an exhaustive characterization of the miRNAome in CD is still lacking. We performed the largest miRNA profiling effort to date to analyze miRNA variability across intestinal tissues, disease activity status, and infliximab treatment in *** We generated 119 transcriptomic profiles from the terminal ileum and left colon biopsies of 30 individuals (10 with active CD, 10 with quiescent CD, and 10 healthy controls). Half of the samples were cultured ex vivo with infliximab, and the remaining half with basal medium. Using variance analyses and linear mixed differential expression models, we explored the determinants of miRNAome variability in CD. We also generated infliximab response signatures to identify candidates and examine interactions between miRNAs and the coding *** Tissue location, and patient-specific effects, were the main factors in miRNA variability in CD, with some differentially expressed miRNAs involved in epithelial-mesenchymal transition (miR-200s, miR-429). We identified 9 miRNAs with treatment-responsive behaviour, particularly to the terminal ileum of active CD cases. Although the changes observed in active CD cases suggest that many alterations are not offset by infliximab incubation, we described 13 miRNAs-mRNA pairs with potential involvement in the anti-tumor necrosis factor (TNF) treatment, 7 of which have been already *** A comprehensive miRNA profiling revealed significant intestinal tissue-specific variability and identified key alterations in the miRNA-mRNA interactome that might be involved in therapeutic response to anti-TNF in CD. This article provides an extensive characterization of the miRNA variability in Crohn's Disease biopsies incubated ex vivo with infliximab, revealing tissue-specific regulatory programs and identif

关键词： Ionic liquids   Microwave Irradiation   Solvents   Additives   Nanomaterials  

摘要： The synergy between ionic liquids (ILs) and microwave (MW) irradiation has sparked a significant interest in material synthesis in general and nanomaterials in particular, revolutionizing the field of materials science. This review explores the fundamental properties and unique attributes of ILs, emphasizing their role as solvents, additives, templates, making them ideal for synthesizing materials, particularly nanomaterials like metals, metal oxides, and doped nanoparticles. The microwave assisted synthesis approach is discussed next vis-& agrave;-vis their advantages such as volumetric heating, reduced reaction times, enhanced yields and facile scalability. A new synthetic approach is also expounded on, where in very small quantity of an ionic liquid (IL), as an additive, can be coupled with low heating microwave solvents (non-polar solvents) and subjected to microwave-irradiation. The new strategy of Ionic-liquid (IL) Mediated Microwave Synthesis (ILMMAS), can be particularly important in nanomaterial synthesis, as the non-polar solvents can be heated very quickly under microwave irradiation. This review emphasizes the crucial role of ILs in advancing nanomaterial synthesis and highlights their synergy with microwave irradiation for sustainable and efficient material synthesis processes.