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关键词： Health sciences   Medicine   Medical specialty   Immunology   Oncology   Pharmacology   Natural sciences   Biological sciences   Cancer systems biology  

摘要： T cell-redirecting bispecific antibodies (bsAbs) to treat advanced stage solid tumors are gaining interest after recent clinical successes. The immune checkpoint human leukocyte antigen G (HLA-G) is expressed in several tumor types while in normal tissues expression is limited. Here, we describe JNJ-78306358, a T cell-redirecting bispecific antibody (bsAb) to treat advanced stage solid tumors. JNJ-78306358 binds with high affinity to the a3 subunit of HLA-G on cancer cells and with purposely engineered weaker affinity to CD3 epsilon on T cells. JNJ-78306358 induced potent T cell-mediated cytotoxicity of HLA-G-expressing solid tumors in vitro and in vivo. JNJ-78306358 also blocked the interaction of HLA-G with its receptors in vitro, indicating that immune checkpoint blocking may contribute to its anti-tumor activity. These results suggest that T cell-redirection against HLA-G could be a potent and effective treatment for a wide range of solid tumor indications.

关键词： Rheumatoid arthritis   JAK inhibitors   STAT   IL-6   TNF-alpha  

摘要： Rheumatoid arthritis (RA) involves synovial tissue proliferation, inflammation, and angiogenesis, and contributes to joint destruction. Angiogenesis is a key therapeutic target for the treatment of RA, and Janus kinase (JAK) inhibitors have emerged as a promising therapy. In this study, we compared the inhibitory effects of five JAK inhibitors, including tofacitinib (TOF), baricitinib, peficitinib, upadacitinib, and filgotinib, on interleukin (IL)-6-induced inflammation in RA synovial tissues. All five inhibitors effectively suppressed IL-6-induced inflammatory and angiogenic factors, including vascular endothelial growth factor, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, by inhibiting the phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. Overall, the results suggest that while all five JAK inhibitors are effective in reducing IL-6-induced inflammatory and angiogenic factors, their efficacy may differ owing to specific molecular mechanisms and pharmacological properties.

关键词： 抗原特异性T细胞   细胞因子   活化诱导标志物   四聚体技术   T细胞抗原受体测序  

摘要： T细胞应答在抗病毒感染和抗肿瘤免疫中具有重要作用，对于T细胞应答的研究离不开抗原特异性T细胞检测技术。本文对抗原特异性T细胞检测技术的研究进展进行综述，涉及的实验方法包括经体外抗原刺激再活化后，检测特异性T细胞分泌细胞因子或活化分子的酶联免疫斑点（ELISPOT）技术，胞内细胞因子染色（ICS）技术和活化诱导标记（AIM）技术，以及基于已知表位——人类白细胞抗原（HLA）限制性的多聚体检测技术和最新发展的单细胞转录组和T细胞抗原受体（TCR）联合测序技术。利用上述方法，研究者能够全面和深入研究抗原特异性T细胞应答，包括：应答的强度、持续的时间、亚群信息、识别的表位及其HLA-限制性、TCR克隆信息及转录组特性等。

关键词： NSCLC   IL-37   IL-38   differential   precision medicine  

摘要： Lung cancer, a significant global health challenge, is primarily classified into non-small cell lung cancer (NSCLC) and small cell lung cancer. Despite advancements in targeted therapies and immunotherapies, NSCLC outcomes remain poor, with low five-year survival rates. Given the lung's constant exposure to the environment and the presence of mucosal-associated lymphoid tissues, immunity plays a crucial role in NSCLC development. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown promise. However, adverse immune events limit their efficacy. This review highlights the contrasting roles of IL-37 and IL-38 in NSCLC pathogenesis. IL-37, an anti-inflammatory cytokine, suppresses tumour growth. It achieves this by modulating macrophage polarization and dendritic cell maturation. Correlations between intra-tumoral IL-37 expression and improved survival suggest a protective role in NSCLC. This may be mediated through VEGF inhibition and immune regulation. Conversely, IL-38, while anti-inflammatory in certain contexts, exhibits a pro-tumorigenic role in NSCLC. IL-38 enhances tumour progression by increasing pro-inflammatory cytokine secretion and facilitating immune evasion, potentially through NF-kappa B signalling. Notably, IL-38 negatively regulates IL-37, further promoting tumorigenesis. Emerging data suggest that IL-37 has therapeutic potential in inhibiting NSCLC metastasis and supporting immune modulation. In contrast, IL-38 presents a potential target for mitigating pro-inflammatory microenvironment effects. The distinct roles of these cytokines emphasize the complex immune dynamics in NSCLC. Further exploration of their molecular mechanisms and therapeutic implications is warranted. Targeting IL-37 and IL-38 may offer novel strategies for enhancing NSCLC treatment outcomes

关键词： histidine-rich glycoprotein   tumor necrosis factor-alpha   integrin   tube formation   angiogenesis   factor erythroid 2-related factor 2  

摘要： Introduction Tumor necrosis factor-alpha (TNF-alpha)-induced angiogenesis plays a critical role in tumor progression and metastasis, making it an important therapeutic target in cancer treatment. Suppressing angiogenesis can effectively limit tumor growth and metastasis. However, despite advancements in understanding angiogenic pathways, effective strategies to inhibit TNF-alpha-mediated angiogenesis remain *** This study investigates the antiangiogenic effects of histidine-rich glycoprotein (HRG), a multifunctional plasma protein with potent antiangiogenic properties, on TNF-alpha-stimulated human endothelial cells (***926). Tube formation assays were performed to assess angiogenesis, and gene/protein expression analyses were conducted to evaluate HRG's effects on integrins alpha V and beta 8. The role of nuclear factor erythroid 2-related factor 2 (NRF2) in HRG-mediated antiangiogenic activity was also examined through nuclear translocation assays and NRF2 activation *** At physiological concentrations, HRG effectively suppressed TNF-alpha-induced tube formation in vitro and downregulated TNF-alpha-induced expression of integrins alpha V and beta 8 at both the mRNA and protein levels. HRG treatment promoted NRF2 nuclear translocation in a time-dependent manner. Furthermore, activation of NRF2 significantly reduced TNF-alpha-induced tube formation and integrin expression, suggesting that NRF2 plays a key role in HRG-mediated antiangiogenic *** and Conclusion Our findings indicate that HRG suppresses TNF-alpha-induced angiogenesis by promoting NRF2 nuclear translocation and transcriptional activation, which in turn inhibits integrin alpha V and beta 8 expression. Given the essential role of angiogenesis in tumor progression, HRG's ability to regulate this process presents a promising therapeutic strategy for cancer treatment.

关键词： 毛蕊异黄酮   骨关节炎   软骨分化   软骨细胞   骨髓间充质干细胞  

摘要： 目的：探究毛蕊异黄酮在软骨细胞炎症损伤和软骨分化进程中的作用，以期为软骨损伤相关疾病的治疗提供理论基础和可用药物证据。方法：碘乙酸用于骨关节炎（osteoarthritis,OA）小鼠模型的制备并从构建的OA模型小鼠中分离骨髓间充质干细胞（bone marrow mesenchymal stem cells,BMSCs）；白介素1β(interleukin-1β,IL-1β)用于诱导ATDC5软骨细胞炎性损伤；酶联免疫吸附实验（enzyme-linked immunosorbent assay,ELISA）检测细胞中炎性因子白介素6(interleukin-6,IL-6)和肿瘤坏死因子-α(tumor necrosis factor α,TNF-α)的水平；商业试剂盒检测细胞中活性氧（eactive oxygen species,ROS）水平；流式细胞术检测细胞凋亡水平；细胞计数试剂盒（cell counting Kit-8,CCK8）检测细胞活力；实时荧光定量PCR(quantitative real-time polymerase chain reaction,qRT-PCR)和Western blot检测细胞中成软骨标志物、肥大型软骨标志物、纤维化软骨标志物和成骨标志物的表达。结果：与对照组相比，毛蕊异黄酮干预组细胞活力和细胞凋亡水平无显著差异（P>0.05）。IL-1β处理后细胞活力显著降低（P<0.05）,IL-6和TNF-α的含量显著上调（P<0.05）,ROS水平显著升高（P<0.05）。经毛蕊异黄酮处理后，细胞活力显著升高（P<0.05）,IL-6和TNF-α的含量显著降低（P<0.05）,ROS水平显著降低，且呈浓度依赖性（P<0.05）。IL-1β处理后CollagenⅡ、SOX9和Aggrecan的表达降低（P<0.05）,Collagen X和MMP-13和CollagenⅠ和CollagenⅢ表达升高（P<0.05）。毛蕊异黄酮进一步处理后，CollagenⅡ、SOX9和Aggrecan的表达显著升高（P<0.05）,Collagen X和MMP-13和CollagenⅠ和CollagenⅢ表达显著降低。与对照组相比，OA组小鼠BMSCs中ALP和RUNX2表达显著下调（P<0.05），肥大型软骨标志物表达显著升高（P<0.05）。毛蕊异黄酮处理后，病理学改变有所缓解，且BMSCs中成软骨化标志物和成骨标志物表达显著上调（P<0.05），肥大型软骨标志物表达显著降低（P<0.05）。结论：毛蕊异黄酮减轻了IL-1β引起的软骨细胞炎症反应，降低了纤维化表型的表达，并促进BMSCs的成软骨分化，抑制成骨分化。

关键词： IL-1 beta   antibody   inflammation   antibody engineering   inflammatory disease   autoimmune diseases  

摘要： Interleukin-1 beta (IL-1 beta) is a key mediator of innate immunity against pathogen infections. However, dysregulated IL-1 beta activity is associated with various autoinflammatory, autoimmune, degenerative, atherosclerotic diseases, and cancers. Biologic drugs that neutralize excess IL-1 beta activity, such as canakinumab, have been effective in treating IL-1 beta-mediated diseases. This article reports the discovery and development of a novel humanized anti-IL-1 beta antibody, designated as TAVO103A, which exhibited potent binding affinities to human and monkey IL-1 beta. TAVO103A demonstrated more potent neutralization of IL-1 beta activities compared to canakinumab in multiple assays, including tests on the IL-1 beta-driven signal transduction cascade, inflammatory cytokine release from MRC-5 cells, chemokine release from A549 cells, and the proliferation of D10.G4.1 helper T cells. Ex vivo studies showed that TAVO103A effectively neutralized IL-1 beta-mediated release of pro-inflammatory cytokines from peripheral blood mononuclear cells. In addition, TAVO103A exhibited dose-dependent efficacy in a knee joint inflammation mouse model. TAVO103A underwent Fc engineering to reduce binding to Fc gamma receptors, increase affinity to FcRn receptors, and enhance its resistance to proteolytic degradation. In a Phase 1 study, TAVO103A was found to be safe, well tolerated, and demonstrated a median half-life of 63 days in healthy subjects. By recognizing a different epitope, TAVO103A provided more potent neutralization of IL-1 beta activities, a longer circulating half-life, and improved safety profiles compared to canakinumab, positioning it to be a potential best-in-class therapeutic option for various IL-1 beta-mediated diseases. This article reports the discovery and development of a novel humanized anti-IL-1 ss antibody, designated as TAVO103A, which exhibited potent binding affinities to human and monkey IL-1 ss. TAVO103A demonstrated more potent neutralization of

关键词： Rheumatoid arthritis   herbal compounds   interleukin-1   interleukin-6   inflammation   density functional theory   molecular dynamics  

摘要： Background Rheumatoid arthritis (RA) remains a significant therapeutic challenge due to its chronic inflammatory nature. Consequently, many patients turn to alternative therapies, such as herbal compounds and supplements, when conventional treatments prove relatively ineffective or cause adverse side effects. Some compounds are being investigated for their potential to alleviate RA symptoms or manage disease. This study aimed to evaluate the anti-inflammatory effects of selected herbal compounds targeting the Interleukin-1 (IL-1) and Interleukin-6 (IL-6) pathways, key inflammatory regulators in RA. Specifically, the study assessed the binding affinity, stability, and dynamics of IL-1 and IL-6 inhibitory compounds as potential therapeutic agents for *** In silico experiments were conducted with herbal compounds to modulate IL-1 and IL-6 signaling. Computational techniques, including molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations, Absorption, Distribution, Metabolism, and Excretion (ADME) analysis, toxicity predictions, and Density Functional Theory (DFT) analysis, were employed to investigate these interactions *** Neoglucobrassicin demonstrated the strongest binding affinity for IL-6 (Total score: -349.00 kJ/mol), followed by Galbelgin (-338.00 kJ/mol). For IL-1 beta, CID21722980 exhibited the highest binding affinity (-273.14 kJ/mol), with Eupaformosanin ranking second (-264.29 kJ/mol). Neoglucobrassicin formed interactions with multiple IL-6 residues, indicating a stable binding complex, while CID21722980 similarly interacted with key IL-1 beta residues, forming stable complexes. Both the Neoglucobrassicin-IL-6 and CID21722980-IL1 beta complexes demonstrated structural stability, as evidenced by Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) stabilizing towards the end of the 100 ns molecular dynamics (MD) simulation. MM-GBSA anal

关键词： Nailfold videocapillaroscopy   Idiopathic Inflammatory myopathy   Type I interferon   Myositis-specific antibody  

摘要： Objective This study aimed to characterize nailfold videocapillaroscopy (NVC) features in patients with different subtypes of Idiopathic inflammatory myopathy (IIM) and to investigate the correlations between NVC findings, myositis-specific antibody (MSA) subtypes, disease activity, cytokine profiles, and interferon-stimulated gene (ISG) expression levels. Methods This cross-sectional observational single-center study included 55 IIM patients, categorized into MDA5 (+), anti-aminoacyl-tRNA-synthetase antibodies (ARS) (+), and MSA(-) groups based on their MSA profiles. Demographic data, laboratory tests, and NVC assessments were systematically collected and analyzed. The relative expression of type I ISGs in whole blood, as well as serum cytokine and chemokine profiles, were measured. Statistical analyses were performed to explore correlations between NVC scores and clinical parameters, including serum biomarkers. Results NVC abnormalities were observed in most IIM patients, with significant differences in NVC features among the MSA subgroups. The MDA5(+) group exhibited significantly higher scores for capillary dilation (P < 0.01), giant capillaries (P < 0.05), microhemorrhages (P < 0.01), and abnormal capillary morphology (P < 0.05) compared to the ARS (+) group. ISG expression and cytokine levels were upregulated in IIM patients, with active disease patients showing significantly higher levels of certain ISGs and cytokines compared to clinically stable patients. Notably, specific NVC score dimensions were positively correlated with the levels of certain ISGs and cytokines. For example, microhemorrhage, capillary dilation, and capillary density all had significantly positive correlations with MX1, IFI27, IP-10, RANTES, and GRO alpha (P < 0.05). And giant capillary is also related to levels of IFI27, SDF-1 alpha, IP-10, RANTES, and GRO alpha (P < 0.05). Conclusion IIM patients exhibit distinct NVC abnormalities, which vary across different MSA subtypes. NVC findings

关键词： 沙棘   沙棘油   麦卢卡蜂蜜   抗氧化   抑菌圈   细胞因子  

摘要： 为探究沙棘油质量分数及添加麦卢卡蜂蜜对沙棘原浆功能活性的影响，该文测定了含不同质量分数沙棘油的醇见沙棘原浆和醇见麦卢卡沙棘原浆的体外抗氧化、抑菌及免疫调节作用。抗氧化实验采用DPPH和ABTS法测定；抑菌实验选取大肠杆菌、金黄色葡萄球菌和枯草芽孢杆菌作为受试菌，采用牛津杯法测定抑菌圈直径、琼脂扩散法测定最低抑菌浓度、微量肉汤稀释法测定最低杀菌浓度；免疫调节实验选取小鼠巨噬细胞株系RAW 264.7作为靶细胞，测定IL-1β、TNF-α和IL-6三种免疫因子的含量。结果表明含不同质量分数沙棘油的醇见沙棘原浆和醇见麦卢卡沙棘原浆的ABTS自由基清除率约为10 100 μmol/L Vc当量，对大肠杆菌、金黄色葡萄球菌和枯草芽孢杆菌的抑菌圈直径均在9.00 mm以上，含6.0 g/100 mL沙棘油的醇见麦卢卡沙棘原浆能够抑制LPS诱导的IL-1β和IL-6水平上升。另外，随着沙棘油质量分数的增高，其抗氧化能力和抑菌能力均增强。增高沙棘油质量分数可提高沙棘原浆体外抗氧化及抑菌作用，添加麦卢卡蜂蜜使沙棘原浆具有免疫调节作用。