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摘要： People living with HIV (PLWH) have an increased risk for developing tuberculosis after M. tuberculosis infection, despite anti-retroviral therapy (ART). To delineate the underlying mechanisms, we conducted single cell transcriptomics on bronchoalveolar lavage cells from PLWH on ART and HIV uninfected healthy controls infected with M. tuberculosis ex vivo. We identify an M1-like proinflammatory alveolar macrophage subset that sequentially acquires TNF signaling capacity in controls but not in PLWH. Cell-cell communication analyses reveal interactions between M1-like macrophages and effector memory T cells within TNF superfamily, chemokine, and costimulatory networks in the airways of controls. These interaction networks were lacking in PLWH infected with M. tuberculosis, where anti-inflammatory M2-like alveolar macrophages and T regulatory cells dominated along with dysregulated T cell signatures. Our data support a model in which impaired TNF-TNFR signaling, M2-like alveolar macrophages and aberrant macrophage-T cell crosstalk, lead to ineffective immunity to M. tuberculosis in PLWH on ART.

摘要： We have previously demonstrated that the circadian clock regulates the host response to influenza A virus (IAV) infection, conferring a time-of-day-specific protection -infection at dawn resulted in a threefold increase in survival and reduced immunopathology compared to infection at dusk. While IL10 is well-known for its immunoregulatory function, its role in IAV remains unclear, with studies reporting both protective and detrimental effects. Given the diurnal rhythmicity of IL-10 receptor ( ) expression in the lung, we investigated the contribution of IL-10 signaling to time-of-day-specific IAV protection. We found that blocking IL10 signaling abrogated the time of day protection, leading to increased immunopathology characterized by enhanced lymphocyte infiltration and global immune activation (transcriptomic analysis). Interestingly, while later, IL-10R blockade also eliminated the time-of-day difference in IAV outcomes, it improved the outcome of dusk-infected mice. Furthermore, natural killer (NK) cell depletion suppressed IL-10 levels in bronchoalveolar lavage, suggesting a role for NK cells in regulating IL-10 signaling. In conclusion, incorporating the circadian context has not only clarified the IL-10 role in IAV infection but also underscored the pivotal influence of circadian regulation on immune responses.

关键词： SARS-CoV-2   Single nucleotide polymorphism   Interleukin-27   IFITM3 protein   Egyptian people  

摘要： Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus disease 2019 (COVID-19), which is a huge global health threat. Interleukin27 (IL-27) gene is a cytokine that produces antiviral proteins in an IFN-independent manner and stimulates both pro- and anti-inflammatory responses. Interferon induced transmembrane protein 3 (IFITM3) inhibits SARS-CoV2 infection by blocking SARSCoV-2 spike proteins which facilitate viral entrance and cell-to-cell fusion. The association between genetic variants and COVID-19 in Egyptians is still unclear. Hence, we sought to investigate the impact of the single nucleotide polymorphism of IL-27P28 rs153109 and IFITM3 rs12252 on the susceptibility and severity of SARS-CoV-2 in Egyptian patients. Methods Our study included 242 SARS-CoV-2 patients were recruited from Main University Hospital, Alexandria University, Egypt, and 187 healthy controls. We subdivided the patient group into two subgroups: group A comprised mild/moderate cases (N = 42) (17.4%), and group B included severe/critical cases (N = 200) (82.6%). Genomic DNA was extracted from blood samples using the QIAamp DNA Blood Mini kit, then the PCR products of IL27 and IFITM3 were cut by FastDigest XhoI and MScI, respectively, for detection of SNPs of IL-27P28 rs153109 (-964A/G) and IFITM3 rs12252 (T>C). Results The present study found a significant association between IL27 rs153109 (-964A/G) and SARS-CoV-2 infection susceptibility after adjusting for the risk factor (advanced age), IL27 rs153109 (-964A/G) AG genotype (OR = 2.791, 95% CI: 1.237-6.295, P = 0.013), AA genotype (OR = 2.385, 95% CI: 1.075-5.291, P = 0.033), and (AG+AA vs. GG) genotypes (OR = 2.558, 95% CI: 1.186-5.517, P = 0.017). On the other hand, the IFITM3 rs12252(T>C) CT genotype (OR = 1.419, 95% CI: 0.843-2.391, P = 0.188), CC genotype (OR = 2.132, 95% CI: 0.436-10.415, P = 0.350), and (C/T+C/C vs. TT) genotypes (OR = 1.466, 95% CI: 0.884-2.432, P = 0.138) did not show a statisti

关键词： inflammatory bowel diseases   Crohn's disease   ulcerative colitis   infliximab   adalimumab   polymorphisms   precision medicine  

摘要： Background/Objectives: Tumor necrosis factor alpha (TNF-alpha) is the key inflammatory cytokine involved in the pathogenesis of inflammatory bowel diseases (IBDs). Anti-TNF-alpha therapy has been successfully used for IBD treatment, although the therapeutic response differs among patients due to the genetic background. The aim of this study was to investigate whether the presence of single nucleotide polymorphisms (SNPs) on TNFA, TNFRSF1A, and TNFRSF1B genes could affect anti-TNF-alpha treatment effectiveness in IBD patients. Methods: In this prospective cohort study, 83 European IBD patients treated with infliximab or adalimumab (with or without steroid bridge therapy) as first-line therapy were enrolled. Genomic DNA was extracted from peripheral blood, and TNF-alpha (rs1800629, rs361525, rs1799724), TNFRSF1A (rs767455), and TNFRSF1B (rs1061622, rs1061624, rs3397, rs976881) SNPs were assessed. Steroid-free remission (SFR) (clinical remission together with steroid interruption) and anti-TNF-alpha therapy persistence after 12 months of follow-up were evaluated. Patients who stopped anti-TNF-alpha therapy before the end of follow-up, due to side effects or treatment failure, were defined as discontinuers. Results: A higher frequency of the G/G genotype in rs1800629 and the A/A genotype in rs1061624 was observed in the SFR group compared to non-SFR (97.7% vs. 82.8%;p = 0.025 and 32.6% vs. 10.3%;p = 0.029, respectively). Moreover, carriers of the A/A genotype in rs361525 and the C/C genotype in rs767455 had a lower probability of achieving SFR than wild-type patients (OR = 0.14;95% CI= 0.03-0.69;p = 0.016 and OR = 0.10;95% CI = 0.02-0.60;p = 0.012, respectively). Furthermore, an increased frequency of rs1800629 A allele was observed in patients who discontinued treatment compared to completers (27.3% vs. 6.9%;p = 0.033), as well as a high risk of interrupting therapy (HR = 6.47;95% CI = 1.15-36.38). Conclusions: These results suggest that the evaluation of SNPs in TNF-a

关键词： IL-19   Glioblastoma   Temozolomide  

摘要： BackgroundGlioblastoma multiforme (GBM) is an aggressive brain tumor with chemoresistant, immunosuppressive, and invasive properties. Despite standard therapies, including surgery, radiotherapy, and temozolomide (TMZ) chemotherapy, tumors inevitably recur in the peritumoral region. Targeting GBM-mediated immunosuppressive and invasive properties is a promising strategy to improve clinical *** utilized clinical and genomic data from the Taiwan GBM cohort and The Cancer Genome Atlas (TCGA) to analyze RNA sequencing data from patient tumor samples, determining the association of interleukin-19 (Il-19) expression with survival and immunosuppressive activity. Gene set enrichment analysis (GSEA) was performed to assess the relationship between the enrichment levels of immune subsets and Il-19 expression level, and Ingenuity Pathway Analysis (IPA) was used to predict immune responses. Cytokine array and single-cell RNA sequencing were used to examine the effects of IL-19 blockade on tumor immune microenvironment, including tumor-infiltrating leukocyte profiles, differentiation and immunosuppressive genes expression in tumor associated macrophages (TAM). CRISPR Il-19-/- cell lines and Il-19-/- mice were used to examine the role of IL-19 in tumor invasion and M2-like macrophage-mediated immunosuppression. Additionally, we developed novel cholesterol-polyethylene glycol-superparamagnetic iron oxide-IL-19 antibody nanoparticles (CHOL-PEG-SPIO-IL-19), characterized them using dynamic light scattering and transmission electron microscopy, Fourier-Transform Infrared spectroscopy, prussian blue assay, and conducted in vivo magnetic resonance imaging (MRI) in a human glioblastoma stem cell-derived GBM animal *** screening and IPA analysis identified IL-19 as a predicted immunosuppressive cytokine in the peritumoral region, associated with poor survival in patients with GBM. Blocking IL-19 significantly inhibited tumor progression of both TMZ-sensitive

关键词： Cyclophosphamide   Sakuranetin   Immunosuppression   Cytokines   Immunoglobulin   Interleukins  

摘要： Cyclophosphamide is a widely used chemotherapeutic agent known for its effectiveness in treating various cancers;however, it is associated with significant immunosuppressive side effects. This study investigates the potential of sakuranetin, a natural flavonoid, in mice under cyclophosphamide-induced immunosuppressive conditions. Mice were grouped into four groups: one control group, two treated with cyclophosphamide and two sakuranetin-treated groups receiving different doses (10 and 20 mg/kg). Immune organ indices, lymphocyte proliferation, hematological parameters, nitric oxide levels, cytokines (tumor necrosis factor alpha-TNF-alpha, interferon gamma-IFN-gamma), interleukins (interleukin-1 beta-IL-1 beta, IL-4, IL-6), immunoglobulin G (IgG), IgM levels, plague-forming cells quantification, qualitative hemolysis, and delayed-type hypersensitivity were assessed. Cyclophosphamide significantly (P < 0.05) reduced immune organ indices, lymphocyte proliferation, changes in hematological parameters, and nitric oxide levels. Treatment with both sakuranetin doses restored these parameters and normalized cytokine, IgG, and IgM levels (P < 0.05). Sakuranetin significantly (P < 0.05) improved the immunomodulatory action with elevated immune response with downregulation in immune response mediated by cells. Sakuranetin effectively counteracts cyclophosphamide-induced immunosuppression by modulating the IFN-gamma, TNF-alpha, IgG, and interleukin pathway, suggesting its potential as a protective agent.

关键词： Preterm prelabor rupture of fetal membranes   Interleukin-1 beta   ADAMTS9   NF-kappa B   Protein O-fucosyltransferase 2  

摘要： Background Preterm prelabor rupture of membranes (pPROM) is a leading cause of neonatal morbidity and mortality. While intra-amniotic infection is a well-established driver of pPROM, the role of sterile intra-amniotic inflammation remains unclear. Recent evidence suggests that interleukin-1 beta (IL-1 beta) promotes extracellular matrix (ECM) remodeling via downstream effectors, a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9), while protein O-fucosyltransferase 2 (POFUT2) facilitates its O-fucosylation and secretion, amplifying ECM degradation. This study investigates how IL-1 beta-triggered nuclear factor kappa-B (NF-kappa B) activation promotes ADAMTS9 and POFUT2 expression, ultimately driving fetal membrane ECM remodeling and weakening in pPROM without signs of intra-amniotic infection. Methods A nested case-control study included maternal serum and fetal membrane samples from 60 pregnant women (34 pPROM, 26 full-term births [FTB]). ELISA measured serum levels of IL-1 beta and ADAMTS9, and their correlations were analyzed. Mechanistic studies utilized primary human amniotic epithelial cells (hAECs) and fetal membrane-decidua explants with IL-1 beta treatment. The role of NF-kappa B was explored using chromatin immunoprecipitation (ChIP) and luciferase assays to assess NF-kappa B binding to the promoters of ADAMTS9 and POFUT2. A murine model of sterile intra-amniotic inflammation under ultrasound-guided IL-1 beta injection was used to validate in vitro findings and assess pregnancy outcomes. Results Serum IL-1 beta and ADAMTS9 levels at 16 weeks of gestation were significantly higher in pPROM cases compared to FTB controls (P < 0.001). A combined model of these biomarkers demonstrated high predictive accuracy for pPROM (AUC = 0.83). Mechanistically, IL-1 beta activated NF-kappa B, leading to its binding to the promoters of ADAMTS9 and POFUT2. NF-kappa B activation promoted ADAMTS9 expression, while POFUT2 enhanced its s

关键词： 猪δ冠状病毒   S蛋白   真核表达   多克隆抗体  

摘要： 【背景】猪δ冠状病毒(porcine deltacoronavirus，PDCoV)是2012年首次报道的一种猪肠道冠状病毒，主要引起猪以腹泻、呕吐和脱水为特征的胃肠道疾病，与猪流行性腹泻、猪传染性胃肠炎等的临床症状类似，难以区别。PDCoV具有4种结构蛋白，棘突蛋白(Spike，S)位于PDCoV病毒粒子表面，由S1和S2两个亚基组成，是病毒中和抗体的主要靶标。【目的】应用真核系统表达PDCoV S1蛋白并进行纯化，制备该蛋白的多克隆抗体。【方法】通过RT-PCR技术扩增PDCoV CHN-JS-2018株的S1基因，连接到pCAGGS真核表达载体中，构建pCAGGS-PDCoV-S1-mFc和pCAGGS-PDCoV-S1-hFc真核表达质粒，经测序正确后转染HEK293T细胞，采用IFA和Western blot检测重组蛋白表达。以纯化的PDCoV-S1-mFc重组蛋白免疫BALB/c小鼠，制备多克隆抗体，IFA检验多抗血清的反应原性，间接ELISA测定多抗血清效价。【结果】构建的pCAGGS-PDCoV-S1-mFc和pCAGGS-PDCoV-S1-hFc真核表达质粒能够在HEK293T细胞中表达，并与PDCoV阳性小鼠血清特异性结合，制备的PDCoV S1重组蛋白的多克隆抗体效价达到1:64 000以上，中和抗体效价为1:185，可用于猪δ冠状病毒检测的间接免疫荧光试验、Western-blot检测。【结论】本研究真核表达的PDCoV S1重组蛋白具有较强的免疫原性，可诱导小鼠产生较高效价的抗体，制备的多克隆抗体具有良好的反应性和中和活性，为后续开展PDCoV诊断、S1单克隆抗体制备、疫苗研制等奠定基础。

关键词： systemic sclerosis   microvasculopathy   fibrosis   immune dysregulation   avenciguat   inflammation   interferon  

摘要： Objectives The soluble guanylate cyclase (sGC) stimulator riociguat is approved for the treatment of pulmonary arterial hypertension and may have antifibrotic effects. However, in fibrotic tissues, oxidative stress and hypoxia can render sGC insensitive to sGC stimulators. sGC activators overcome this limitation. Here, we characterize the novel sGC activator, avenciguat, in preclinical models of *** Human microvascular endothelial cells-dermal (HMVEC-d) cultured in hypoxic conditions and activated human platelet-rich plasma were incubated with varying doses of avenciguat, and the levels of TGF-beta 2 and human CXC chemokine family ligand 4 (CXCL4) were measured, respectively. Treatment with avenciguat was analysed in mice with bleomycin-induced dermal and pulmonary *** Avenciguat reduced hypoxia-induced synthesis of TGF-beta 2 by HMVEC-d and inhibited CXCL4 release by platelets. Moreover, avenciguat demonstrated antifibrotic effects on bleomycin-induced dermal and pulmonary fibrosis. RNA sequencing of affected skin uncovered a unique profile distinguishing avenciguat from riociguat. Avenciguat treatment resulted in deeper regulation of IFN-1 signalling and genes associated with immune response vs riociguat *** In preclinical studies, avenciguat shows the potential to influence vascular, fibrotic and immune-related processes in murine models of SSc. These studies suggest that it may offer therapeutic benefit across multiple aspects of SSc pathophysiology and support the rationale for further investigation in a Phase II clinical trial (VITALISScE (TM);NCT05559580) of avenciguat in SSc.

关键词： CARHSP1   Prostate cancer   IL-17RA   RNA binding protein   JAK-STAT3 signaling pathway   NF-kappa B signaling pathway   PD-L1  

摘要： BackgroundCalcium-regulated heat-stable protein 1 (CARHSP1) has been identified as a cold shock domain (CSD) protein family member, participating in the regulation of ribosomal translation, mRNA degradation, and the rate of transcription termination. However, there is an extremely limited understanding of the function of CARHSP1 as an RNA binding protein (RBP) in prostate cancer (PCa).MethodsThe expression pattern of CARHSP1 and the correlation between the CARHSP1 expression and clinical prognosis in PCa patients were analyzed by using multiple public databases. In vitro and in vivo functional assays were conducted to assess the role of CARHSP1. The mechanisms of CARHSP1 function on IL-17RA were identified by RNA pull-down and RNA stability assays. A co-culture model of Jurkat cells and PCa cells was established to investigate the potential role of CARHSP1 in tumor immunity of ***1 was highly expressed in PCa, and correlated with advanced characteristics of PCa and unfavorable prognosis in PCa patients. Moreover, knockdown of CARHSP1 significantly dampened the capacity of proliferation, migration, invasion, and immune evasion of PCa cells in vitro and in vivo. Mechanistically, the RNA-binding protein CARHSP1 selectively bound to the mRNA of IL-17RA, resulting in the increased expression of both IL-17RA mRNA and protein. Downregulating expression of CARHSP1 shortened the half-life of IL-17RA mRNA and reduced its expression. Subsequently, the downstream pathways of IL-17RA, JAK-STAT3 signaling pathway and NF-kappa B signaling pathway, were activated by CARHSP1 and contributed to the malignant phenotype of PCa *** conclusion, our results demonstrated that the increased expression of CARHSP1 in PCa is correlated with advanced clinical characteristics and unfavorable prognosis, and CARHSP1 may promote the progression of PCa through enhancing the mRNA stability of IL-17RA and activating its downstream pathways. These results suggest that CARH