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关键词： carbon monoxide   diabetic cardiomyopathy   IL-33/ST2L axis   pyroptosis  

摘要： Objectives: This study aimed to investigate whether carbon monoxide (CO) can alleviate cardiomyocyte pyroptosis by downregulating the IL-33/ST2L axis in diabetic cardiomyopathy (DCM). Methods: The diabetic mouse model was established and treated with CO-releasing molecule-2 (CORM-2) or invalid CORM-2 (iCORM-2). For in vitro studies, cardiomyocytes were treated with high glucose (HG). Results: The HG-treated cardiomyocytes exhibited increased IL-33, ST2L, and pyroptosis-related protein expression compared with that in the control group (p < 0.05). Treatment with recombinant IL-33 further increased the expression of HG-induced pyroptosis-related proteins (p < 0.05). Compared with control mice, DCM mice showed reduced cardiac function and elevated expression of IL-33, ST2L, and pyroptosis-related proteins (p < 0.01). Intervention with CORM-2 ameliorated cardiac injury, and decreased the expression of IL-33, ST2L, and pyroptosis-related proteins in vivo and in vitro (p < 0.05). However, iCORM-2 had no effect both in vivo and in vitro. Conclusions: In conclusion, CO may inhibit cardiomyocyte pyroptosis by downregulating the IL-33/ST2L axis in DCM mice.

关键词： Tumor immune microenvironment   Advanced or recurrence NSCLC   EGFR mutations   HLA typing   EGFR TKIs  

摘要： Previously reported HLA class I correlated with the outcome of early-stage non-small cell lung cancer (NSCLC) in the Japanese population. The binding affinity capability of the EGFR mutation peptide and various HLA-A subtypes could explain this. We conducted a prospective cohort study to explore advanced EGFR-mutated NSCLC patients who received EGFR TKIs in various HLA-A subtypes, the outcomes of treatment, and tumor immune microenvironment (TIME). Eighty-four advanced NSCLC harboring EGFR exon 19 deletion and exon 21 L858R mutations were analyzed. Among these, the interested HLA-A subtypes of exon 19 deletion were composed of HLA-A*03:01 (7.1%), *30:01 (3.7%),*11:01 (82.1%), and *68:01 (7.1%). The interested HLA-A subtypes of exon 21 L858R were HLA-A*30:01 (28.5%), *33:03 (57.1%), and *34:01 (14.4%). Multivariate Cox-regression analysis revealed that the interested HLA-A subtypes were not an independent factor of progression-free or overall survival. No correlation was found between HLA-A subtypes and either inflammatory TIME or the presence of intra-tumoral CD8 TILs. HLA-A subtypes did not correlate with prognostic outcomes in sensitized EGFR mutations. The diverse binding affinity with EGFR peptides was not translated into the TIME patterns.

关键词： Acute coronary syndrome   Cytokines   Interleukins   Polymorphism   Meta-analysis  

摘要： Inflammatory cytokines are pivotal in the pathophysiology of acute coronary syndrome (ACS) and have been associated with major adverse cardiovascular events. In this study, we aimed to assess the association of eight polymorphisms in IL-10, IL-6, and TNF-alpha with the risk of ACS through a systematic review, meta-analysis, and trial sequential analysis. A comprehensive literature review was conducted across multiple databases, including PubMed/Medline, Web of Science, Scopus, and Cochrane Library, up until August 8, 2024. The Review Manager 5.3 software was utilized to compute the effect sizes such as the odds ratio accompanied by a 95% confidence interval. Out of 1499 records identified from databases, sources, or electronic searches, 51 articles were included in qualitative and quantitative syntheses (meta-analysis). For IL-6 -174G > C, the allelic and homozygous models showed significant associations with ACS risk. IL-6 -572G > C showed no significant association across all genetic models. IL-10 polymorphisms (-592C > A, -819C > T, and -1082A > G) generally showed no significant associations. TNF-alpha -308G > A polymorphism showed significant associations in all models. TNF-alpha -1031T > C and -238G > A showed no significant associations, with varying degrees of heterogeneity. Results suggest that certain cytokine polymorphisms, notably IL-6 -174G > C and TNF-alpha -308G > A, may play a crucial role in increasing susceptibility to ACS. These associations are especially pronounced in certain ethnic groups, such as Asians and Arabs, highlighting the importance of considering genetic diversity in clinical assessments.

关键词： Piezocision   Corticotomy   IL-1 beta   Gingival crevicular fluid   Orthodontic acceleration   Bone remodelling  

摘要： BackgroundAccelerating orthodontic treatment is crucial in reducing complications such as root resorption, caries, and oral hygiene compromise, especially in adults. Piezocision and corticotomy are surgical techniques that accelerate tooth movement by causing bone remodelling. This study compares and evaluates changes in Interleukin-1 beta (IL-1 beta) levels in gingival crevicular fluid (GCF) following piezocision and corticotomy-facilitated orthodontics in adults. AimTo assess and compare IL-1 beta fluctuations in GCF of adult patients undergoing corticotomy and piezocision-assisted orthodontic treatment. Materials & methodsThis split-mouth study consisted of 16 adult patients (18-25 years) who needed premolar extractions. One half of the maxilla was randomly assigned for piezocision and the other half for corticotomy. GCF samples were taken from maxillary canines at varying time intervals: pre-treatment (T0), before surgery (T1), and 24 h (T2), 7 days (T3), and 21 days (T4) following surgery. IL-1 beta concentrations were quantified using an ELISA kit, and statistical analysis was done. ResultsIL-1 beta concentrations were highest at 24 h after surgery (T2) in both groups and decreased steadily by day 21 (T4), but were still elevated above pre-treatment levels. IL-1 beta concentrations were significantly greater in the piezocision group at all time points after surgery than in the corticotomy group (p < 0.001), reflecting a more intense inflammatory reaction and greater bone cell metabolism. ConclusionThis study suggests that piezocision elicits a more intense biological response than corticotomy, as reflected by higher IL-1 beta levels in gingival crevicular fluid. While this may indicate a potential for enhanced bone remodelling and accelerated tooth movement, further research is needed to directly correlate cytokine expression with the rate of orthodontic tooth movement.

摘要： During the resolution of inflammation, Ly6C+F4/80- monocytes differentiate to Ly6C-F4/80+ macrophages that exert apoptotic cell engulfment (efferocytosis) properties and consequently convert to interferon (IFN)-beta-producing macrophages. Here, we report that exposure to IFN-beta, or transforming growth factor (TGF)-beta, or a deficiency in the pro-apoptotic protein ARTS, results in the conversion of mature macrophages to an Ly6C+F4/80+CCR2+ phenotype in vivo and ex vivo. Deficiency in ARTS or caspase inhibition results in enhanced conversion of macrophages to the Ly6C+ phenotype. Moreover, IFN-beta-triggered Ly6C+ macrophages are hyper-efferocytic and express higher levels of the efferocytic receptor CD36. Inhibition of CD36 ligation results in complete abrogation of efferocytosis ex vivo in both Ly6C+ and Ly6C- macrophages. Notably, IFN-beta also promotes the emergence of Ly6C+ macrophages during the resolution of liver fibrosis, while transcriptomic analysis further links this rejuvenated phenotype to macrophage subsets found in human inflammatory liver disease. Altogether, our findings indicate IFN-beta promotes macrophage conversion to a distinct hyper-efferocytic phenotype that is limited by ARTS and apoptosis during the resolution of inflammation.

关键词： Antisynthetase syndrome   Anti-TNF-alpha   Autoimmunity   Myositis   Interstitial lung disease  

关键词： genetic phenomena   genetic variation   inbreeding   KIR receptors   maternal-foetal histocompatibility   molecular epidemiology   pre-eclampsia   pregnancy   pregnancy-induced hypertension  

摘要： In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (FROH 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4+ T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive d

关键词： Single nucleotide polymorphisms   Proteinuria   Genetic loci   Immunosuppressives   Medical risk factors   Creatinine   Serum albumin   Variant genotypes  

摘要： Background Primary membranous nephropathy is a widely recognized autoimmune disease associated with podocyte antigens;the most important autoantigen is PLA2R1. PLA2R1 and HLA-DQA1 play important roles in the production of pathogenic antibodies. The purpose of this study was to observe the relationship between gene polymorphisms and primary membranous nephropathy and explore the clinical functional clues of PLA2R1 and HLA-DQA1 genes affecting treatment *** The study enrolled 89 patients with primary membranous nephropathy and 91 healthy people as a control. Single-nucleotide polymorphism loci (seven on PLA2R1 and two on HLA-DQA1) were identified using the PCR-Sanger technique. The patients were followed up until the 12th month, and relevant clinical data were collected. The relationship between these single-nucleotide polymorphism loci and primary membranous nephropathy remission was *** Genotypic and allelic frequency distributions for six single-nucleotide polymorphisms within PLA2R1 (rs4664308, rs3792189, rs3792192, rs1870102, rs17831251, and rs35771982) and one in HLA-DQA1 (rs2187668) were associated with morbidity of primary membranous nephropathy. Single-nucleotide polymorphisms rs1870102, rs17831251, and rs2187668 were statistically significant in the genetic model analysis. The odds ratio for primary membranous nephropathy in patients carrying rs2187668 GG and rs1870102 AA was 52.875. We found that PLA2R1 single-nucleotide polymorphism rs36771982 was related to proteinuria remission at the 12th month, and found in further analysis that PLA2R1 single-nucleotide polymorphisms rs3792189, rs3792192, rs17831251, and rs35771982 were related to treatment response in the RTX *** In this study, we found several PLA2R1 and HLA-DQA1 single-nucleotide polymorphism loci associated with primary membranous nephropathy morbidity and that some PLA2R1 single-nucleotide polymorphism loci were related to the treatment response of patien

关键词： Cancer immunotherapy   Immunology   Oncology  

摘要： We assessed the therapeutic efficacy of a semiallogeneic dendritic cell (DC) vaccine in comparison to a syngeneic one for suppression of B16-F10 and TC-1 tumors. Syngeneic bone marrow-derived DCs (BMDCs) were generated from C57BL/6J mice and semiallogeneic BMDCs with a mutation in either MHC class I or II were generated from B6.C-H2-K-bm1/ByJ or B6(C)-H2-Ab1(bm12)/KhEgJ mice, respectively. We demonstrated in vivo and in vitro that the MHC class II semiallogeneic BMDC vaccine had superior efficacy over the syngeneic and the MHC class I semiallogeneic BMDC vaccine, providing allogeneic CD4(+) T cell help to enhance the antitumor CD8(+) T cell response through allogeneic stimulation by the mutant MHC class II molecules. We discovered that this help was induced only at an early stage of tumor growth and at a later stage of tumor growth;combining our BMDC vaccine with Treg depletion enhanced tumor suppression. We demonstrated the improved efficacy of a semiallogeneic BMDC vaccine that kept tumor-peptide presentation intact on syngeneic MHC class I molecules so that mutant MHC class II could provide allogeneic help. This strategy should enable promising new DC-based cancer immunotherapies, offering an alternative to autologous DC vaccines by incorporating allogenicity as an adjuvant.

关键词： italic>TNFTLR2   Schizophrenia   Inflammation   Immune   Association study  

摘要： BackgroundClinical and genetic studies have suggested that immune dysregulation and neuroinflammation are involved in the pathogenesis of schizophrenia. Peripheral laboratory markers are accessible indicators linked to systemic inflammation and immune function. Genetic studies have demonstrated that blood parameters are highly heritable. Therefore, the aim of this study was to analyze the association between blood parameters and IL10, TNF, TLR2, and TLR6 gene polymorphisms in Mexican patients with *** included 236 Mexican patients with schizophrenia. Peripheral blood samples were obtained in the early morning, prior the breakfast, from each participant. Complete blood count was analyzed. Genomic DNA was extracted, and genotyping was performed using TaqMan Discrimination assay of IL10 (rs1554286), TNF (rs1800629), TLR2 (rs7656411), and TLR6 (rs5743827). Association analyses between blood parameters and genotypes of the four genetic variants were performed using chi-square tests and ANOVA with Tukey's post-hoc multiple *** observed higher monocyte levels (F = 5.57;p = 0.004) and monocyte-lymphocyte ratio (F = 5.49;p = 0.004) in patients carrying the GG genotype of rs7656411/TLR2 compared with TT or TG genotype carriers. Additionally, we observed a high frequency of the G allele of rs1800629/TNF, showing a low platelet count compared with carriers of the A allele (chi 2 = 8.6, p = 0.003;OR = 3.82;CI, 1.46-9.96). Furthermore, we were unable to detect any gene-gene interaction in the analysis of MPV and platelet count after 1000-fold permutation *** findings indicate that blood parameter levels may be affected by genetic variants of TNF and TLR2 genes, indicating a potential role for innate immune response activation in schizophrenia in the Mexican population. Further studies with larger cohorts and comprehensive genetic analyses are essential to validate these findings and clarify the role of innate immune genes i