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关键词： tumor necrosis factor alpha   interleukin 6   rheumatoid arthritis   depression  

摘要： Background/Aim: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, characterized by the production of numerous pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta), which lead to pathophysiological changes in innate and acquired immunity. The existing evidence shows that pro-inflammatory cytokines in rheumatoid arthritis impact monoaminergic neurotransmission, neurotropic factors, and synaptic activity, which may lead to the development of depression. Materials and Methods: In our study, we explored the association between TNF-alpha and IL-6, disease activity, and the degree of depression in patients with RA. The association between TNF-alpha and IL-6 and the Beck and Hamilton depression scales was analyzed in a group of 116 RA patients with depression. We investigated the same correlation in 45 patients with primary depression who represented the control group. Results: A Spearman test showed that IL-6 levels had a positive association with the Beck and Hamilton scales (p < 0.05) and that TNF-alpha had a positive association with the Hamilton scale (p < 0.05). Also, the Hamilton depression scale was the more sensitive scale in the detection of depressive symptoms. Conclusions: Our study indicates that elevated values of pro-inflammatory cytokines are associated with the degree of depression in patients with RA. Future preclinical and clinical studies will contribute to a better understanding of the pathophysiological mechanism of depression in patients with RA and may serve as the basis for new treatment modalities. By detecting depression promptly, with the help of the HAM-D as the more sensitive scale, we could influence the future modality of treatment, and with a multidisciplinary approach, we could ensure an improvement in the quality of life of patients with RA.

关键词： acute-on-chronic hepatitis B liver failure   glucocorticoid   prognosis prediction   SOCS3   IL-6  

摘要： Introduction: Early prediction is essential in hepatitis B virus-related acute-on-chronic liver failure (ACHBLF) patients receiving glucocorticoid therapy. Interleukin (IL)-6 is the main factor of cytokine storm that occurs in ACHBLF. IL-6 and suppressors of cytokine signaling 3 (SOCS3) may be associated with the prognosis of patients. Peripheral blood mononuclear cells (PBMCs), which are related to the immune response and inflammation of patients, are often used as materials for searching for biomarkers to predict ACHBLF. We aimed to determine serum cytokines levels and to evaluate the prediction value of SOCS3 and IL-6 mRNA levels in PBMC for ACHBLF patients with glucocorticoid therapy. Methods: Eighty-five patients with ACHBLF, fifty with pre-ACHBLF, fifty with CHB and thirty healthy controls (HCs) were enrolled. ACHBLF and pre-ACHBLF patients (n=135) received standard medical treatments (SMT) and 93 of them treated with glucocorticoids (SMT+GC). Serum cytokines levels, SOCS3 and IL-6 mRNA levels in peripheral blood mononuclear cells (PBMCs) were quantified. Results: Serum IL-6, IL-1 ss, IL-18 and TNF-alpha levels of non-survivors with glucocorticoid therapy were significantly higher than that of survivors. Serum IL-10 levels in the survivors with glucocorticoid therapy were significantly increased. The analysis of variable importance shows that IL-6 ranks first. SOCS3 and IL-6 mRNA levels in PBMCs were significantly higher in ACHBLF patients than those in pre-ACHBLF patients (p=0.0158;p=0.0421). Non-survivors showed significantly lower SOCS3 levels (p=0.0084) and higher IL-6 levels (p<0 .0001) than survivors in ACHBLF patients. Non-survivors in patients receiving GC therapy had significantly lower SOCS3 levels (p=0.0002) and higher IL-6 levels (p<0 .0001) than ***3 and IL-6 mRNA levels were predictors for 90-day prognosis of patients receiving GC therapy (p=0.003;p=0.002). AUC of MELD score+SOCS3+IL-6 was 0.887 (95%CI, 0.818-0.955) and the optimal cut

关键词： Colorectal cancer   Explosive tumor growth   Lynch syndrome   Immunotherapy  

摘要： BackgroundExplosive tumor growth is characterized by rapid tumor growth in a short time period. Currently, there is no precise scientific definition for the condition, which is often accompanied with a poor clinical prognosis. Herein, we presented a study of a young patient with colon cancer who experienced explosive tumor growth. A clinical multidisciplinary team (MDT) collaborated with bioinformaticians to provide precise treatment and elucidate the biological mechanisms underpinning this *** 28-year-old male patient diagnosed with colon cancer experienced explosive tumor growth. Peripheral bloods (PB) during immunotherapy were collected for immune cytokine analyses and flow cytometry assays on immune cell subsets. To further examine the underlying mechanisms of this explosive-growth, we conducted whole exome sequencing (WES) and RNA-sequencing (RNA-seq) of samples taken at different time *** patient was diagnosed with Lynch syndrome. We implemented an immunotherapy and performed PB immune cytokine assays before, during, and after this therapy. Our observations suggested that immunotherapy may remodel interferon-gamma (IFN-gamma) signaling and enhance T cell-mediated immune responses. By exploring explosive tumor growth mechanisms, we observed that tumors had significantly less insertion and deletion (INDEL) mutations and INDEL-derived neoantigens. Additionally, they had deficient antigen presentation functions as characterized by decreased IFN-gamma signaling *** loss and decreased IFN-gamma signaling activity contributed to explosive tumor growth in this patient. Recovered IFN-gamma signaling may lead to effective immunotherapy outcomes.

摘要： The contribution of interleukin-10 (IL-10), secreted by tumoral B cells, to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell-like (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knockout of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T-cell depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10-deficient lymphomas acquire a highly immunosuppressed and T-cell-exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, which is refractory to PD-1 immune checkpoint blockade. However, the response of IL-10-deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes the survival of malignant B cells, whereas the paracrine action of B-cell-derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies targeting the lymphoma microenvironment. Furthermore, IL-10-associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Thus, our work provides important functional and mechanistic insights into the role of B-cell-derived IL-10 in the biology of ABC-DLBCL.

关键词： Interleukin-37   Nuclear factor kappa B   Glycogen synthase kinase 3   Gestational diabetes mellitus  

摘要： PurposeTo investigate the role of IL-37 in gestational diabetes mellitus (GDM) and its potential *** GDM mouse model was constructed with a high-fat diet (HFD). The effects of IL-37 on glucose metabolism, insulin sensitivity, insulin resistance, and placental inflammation were examined using glucose and insulin tolerance tests, ELISA, western blot, HE staining, immunohistochemistry, immunofluorescence, and RT-qPCR. To further investigate the regulatory role of IL-37 in the GSK3/NF-kappa B pathway, experiments were repeated with the inclusion of DIF-3, a well-known activator of *** results indicated that the expression of IL-37 was decreased in mice with GDM. IL-37 overexpression could reduce placental inflammation, promote M2 polarization in macrophages, and decrease the mRNA levels of inflammation factors. In addition, the overexpression of IL-37 may improve abnormal glucose metabolism, enhance insulin sensitivity, and alleviate insulin resistance. Mechanistic studies have demonstrated that the anti-inflammatory and pro-glucose metabolism effects of IL-37 in GDM were reversed by the GSK activator DIF-3. After treatment with DIF-3, mice in the IL-37-treated group exhibited increased expression of GSK3 and p-NF-kappa B protein, along with decreased expression of IRS-1, p-Akt, and GLUT4 protein. These results consistently indicated that IL-37 may suppress inflammation to ameliorate GDM through the modulation of the GSK3/NF-kappa B ***-37 alleviated GDM by downregulating the activity of GSK-3/NF-kappa B. This modulation subsequently reduced inflammatory markers and improved insulin *** registrationNot applicable.

关键词： PUE   Chemotaxis   Macrophages   CD4(+)T cells   EAM  

摘要： Autoimmune myocarditis can result in dilated cardiomyopathy and heart failure, but effective drugs and clear therapeutic targets are still lacking. Experimental autoimmune myocarditis (EAM) serves as the primary animal model utilized for investigating human myocarditis. Puerarin (PUE), a compound derived from the root of Pueraria lobata, exhibits a broad spectrum of antioxidant and anti-inflammatory effects;nevertheless, its underlying mechanism remains elusive. The findings of this study suggested that PUE may attenuate the infiltration of inflammatory cells into the cardiac tissue by suppressing the secretion of chemokine CCL2 from endothelial cells and macrophages at the site of injury, as well as inhibiting the interaction between CCR2 and CCL2 in recruited inflammatory cells such as macrophages and Th1 cells. In this study, the focus was on investigating the impact of PUE on the chemotactic signal axis TNF-alpha/CCL2/CCR2. Through the utilization of Small Animal Ultrasound, Real-Time quantitative PCR, Co-Immunoprecipitation (Co-IP), and Immunofluorescence techniques on both cellular and animal models, it has been demonstrated that PUE effectively inhibits the production of CCL2 by disrupting the TNF-alpha/TNFR signaling pathway in macrophages and endothelial cells through its binding affinity with TNF-alpha. Additionally, PUE disrupts the transmission of chemotactic signals mediated by CCL2/CCR2 interaction through its binding to *** ultimately leads to a reduction in the infiltration of inflammatory cells into the heart. Moreover, the study highlights that PUE can effectively inhibit the transduction of the TNF alpha/CCL2/CCR2 chemotactic signal, resulting in decreased infiltration of macrophages and Th1 cells in the heart and subsequently reducing inflammatory damage to myocardial tissue in EAM mice.

关键词： bipolar disorder   DEGs (differentially expressed genes)   IL-17 pathway   immunoinflammatory response   immune infiltration analysis  

摘要： Objective Bipolar Disorder (BD) is a complex psychiatric condition influenced by genetic and environmental factors. This study aims to explore global mRNA expression in Peripheral blood white cells (PBMC) of BD patients. Methods We analyzed whole-genome gene expression profiles from PBMC of 12 BD states-manic (BD-M), 12 BD states-depressive (BD-D), and 12 matched healthy controls (HC) using microarrays. Validation of differentially expressed genes within the IL-17 pathway was conducted through qRT-PCR, while ELISA measured specific protein levels. GO and KEGG pathway enrichment analyses were performed, alongside PPI analysis and Gene Set Variation Analysis (GSVA) to assess immune cell infiltration. Results In the comparison between BD and HC, a total of 304 differentially expressed genes (DEGs) were identified, of which 217 genes were upregulated and 87 genes were downregulated. In the comparisons between BD and HC, BD-M and HC, and BD-D and HC, 91 DEGs were found. Enrichment analysis suggested that biological processes and signaling pathways related to extracellular matrix, stress response, heparin binding, and immune inflammation were upregulated in the BD group. KEGG analysis and PPI results indicate that the IL-17 signaling pathway plays an important role in BD and its subtypes. In the IL-17 signaling pathway, compared to HC, the expression of Jun, Fosb, Fosl1, TNFAIP3, NFKBIA, CXCL2, CXCL8, IL6 and IL17 genes was upregulated in BD patients. RT-qPCR analysis showed that the expression of Jun, Fosb, Fosl1, NFKBIA, TNFAIP3, CXCL2, and CXCL8 genes was significantly upregulated in BD, ELISA results indicated that the protein levels of CXCL8/IL-8, IL-6 and IL-17 in the BD group were significantly higher than those in the HC group (all P < 0.05). Immune infiltration analysis showed that central memory CD4+ T cells (P=0.010), eosinophils (P=0.038), and mast cells (P=0.029) were increased in infiltration in the BD group. Conclusion This study integrates transcriptomics

关键词： CBP/EP300   epigenetics   bromodomain inhibitors   TNF-alpha   NF kappa B   inflammation  

摘要： Tumor necrosis factor alpha (TNF-alpha) is a central driver of inflammation in autoimmune conditions such as Crohn's disease and rheumatoid arthritis (RA). Targeting epigenetic regulators involved in cytokine expression holds therapeutic promise, yet the precise role of the CBP/EP300 bromodomains (BRDs) in modulating immune responses remains poorly understood. Here, we introduce a distinct class of selective CBP/EP300-BRD inhibitors based on a unique 3-methylcinnoline acetyl-lysine mimic, identified through high-throughput fragment docking. These inhibitors significantly reduce TNF-alpha-driven cytokine expression in vitro by blocking NF kappa B signaling in immune cells. In vivo, BRD inhibition led to a robust anti-inflammatory effect, decreasing cytokine secretion (including IL-1 beta, MCP-1, IL-1 alpha, and IL-6) and preventing immune cell migration to inflamed lymph nodes in a TNF-alpha-stimulated murine model. Our findings highlight CBP/EP300-BRDs as promising targets for autoimmune therapy, with these non-cytotoxic inhibitors offering a potential complementary approach for RA and other TNF-alpha-mediated inflammatory conditions.

关键词： luminex testing   HLA antibodies   non-HLA antibodies   AT1RAbs   assay standardization  

摘要： Evidence for the contribution of non-HLA antibodies on long-term allograft outcome was suggested in early studies by Paul Terasaki and colleagues who showed worse 10-year allograft outcome in HLA identical kidney transplant recipients with a positive panel reactive antibody (PRA) as determined by the micro cytotoxicity assay, in which cells express other targets beside HLA. More recent reports have shown worse graft outcome when antibodies against non-HLA antigens were detected with HLA-donor specific antibodies (HLA-DSA), and even suggest that non-HLA antibodies may serve as precursor to development of HLA antibodies. Unfortunately, the recent studies lack reproducibility, which then leads to skepticism as to the relevance of non-HLA antibody in transplantation outcome. Consequently, routine testing for non-HLA antibody along with monitoring of HLA-DSA as part of a post-transplant immune surveillance protocol is not standard practice. The Sensitization in Transplantation: Assessment of Risk (STAR) workgroup summarized the current literature on this topic, citing differences in cohort characteristics, variability in study design, selection of sample and timepoints for testing and variability in the assays used to detect non-HLA antibodies, as reasons that impact the accurate assessment on the relevance of non-HLA antibodies. However, correlation between test results and outcome can only be determined if the assay in question is detecting the correct analyte. Therefore, here we will make the case for a plan that requires a systematic validation of high-throughput bead-based assays, to include appropriate sequence selection for non-HLA antigenic targets and quality control metrics as a first step to solving this puzzle.