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关键词： Endoplasmic reticulum stress   fibroblast-like synoviocytes   IL-21/IL-21R pathway   rheumatoid arthritis   USP18/GSDMD axis  

摘要： IntroductionThe persistent presence of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) contributes significantly to joint damage, yet the anti-apoptotic mechanisms involved are not well understood. This study investigates how the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) pathway affects RA-FLS survival during endoplasmic reticulum stress (ERS).MethodsClinical data, in vitro, and in vivo experiments were comprehensively *** patients with moderate-high disease activity and anti-CCP antibodies have high serum IL-21 levels. IL-21 enhances HFLS-RA cell survival and prevents apoptosis under ERS by upregulating IL-21R. It activates autophagy, shown by increased LC3II/I;ratio and p62 degradation, and inhibits ERS-mediated apoptosis by downregulating GRP78 and CHOP. Overexpressing IL-21R boosts autophagy and suppresses ERS. Transcriptome analysis identified USP18 as a key downstream effector of IL-21R. Silencing USP18 increased GSDMD expression and negated IL-21R's protective effects. In vivo, silencing IL-21R reduced joint inflammation and cartilage degradation in RA mouse models, reversing excessive autophagy and ERS marker expression in synovial *** study elucidates, for the first time, the mechanism by which IL-21/IL-21R synergistically modulates the survival of RA-FLS through the "autophagy-ERS balance" and the USP18/GSDMD axis.

关键词： Grass carp (Ctenopharyngodon idella)   Natural grass feeding mode   IFN-gamma 2   Muscle cell  

摘要： Grass carp (Ctenopharyngodon idella), as the highest-yielding freshwater species in China, has become a focus of muscle quality research. Previous studies have shown that natural grass feeding (GF) mode can improve the muscle quality of grass carp compared with artificial feeding (AF) mode, but its mechanism has not been revealed. In this study, we identified that interferon-gamma 2 (IFN-gamma 2) can be induced in the muscle tissues under GF mode. Therefore, recombinant IFN-gamma 2 protein was obtained to study its effect on grass carp muscle cells (GCMCs). We found that IFN-gamma 2 can facilitate the proliferation of GCMCs, and promote the myotube enlargement of GCMCs. Meanwhile, mRNA level investigations indicated that IFN-gamma 2 can regulate the expression of genes related to cell physiological processes. By transcriptome analysis, we screened a series of genes related to cell proliferation, differentiation, and migration. Using STAT1 inhibitor fludarabine in vitro, we confirmed that IFN-gamma 2 regulates the physiological development of GCMCs through JAK/STAT1. Finally, by knocking down IFN-gamma 2 in grass carp individuals, we verified that IFN-gamma 2 has an effective regulatory effect in vivo. This study provides novel target for improving the muscle quality of grass carp and provides inspiration for the development of aquaculture feeding *** grass feeding mode induces IFN-gamma 2 expression in grass carp ***-gamma 2 promotes the proliferation of grass carp muscle cells via JAK/***-gamma 2 regulates the expression of genes related to muscle proliferation in vivo.

关键词： 冠心病合并高血压   西药   血清因子   血压  

摘要： 本研究针对冠心病并发高血压个体,基于先前研究,明确中西医结合治疗的疗效,着重总结该治疗方式对机体血清炎症因子、血管内皮功能的作用。方法 纳入80例样本,均符合本研究纳入标准,均分为两组(n=40),分别予以单一西药治疗与中西医结合治疗,对比治疗后各组间相关指标,以达成研究目的。结果 治疗后,组间观察指标对比,相较于对照组,观察组血压改善幅度更大,症状发作时间更短且频次更少,组间治疗后的炎症因子水平均有降低,且观察组降幅更大,比较而言,观察组整体治疗有效率较对照组更高,数值对比有差异性,P<0.05。结论 针对冠心病并发高血压,结合中西医治疗方式的临床治疗效果更加理想,能够稳定降压的同时改善患者的炎症、血管内皮功能,以此减少症状的发作,减轻病情,治疗效果理想,值得推广应用。

关键词： BV2 microglia cells   caspase-3 (CASP3)   influenza-associated encephalopathy (IAE)   TNF signaling pathway  

摘要： Although patients infected with the avian influenza H7N9 virus primarily present flu-like symptoms, recent clinical studies have found that viral encephalopathy caused by avian influenza H7N9 virus infection is an essential factor in patient deaths. In this study, the H7N9 virus was used to infect mouse microglia cells (MGs) BV2, central nervous system (CNS)-resident macrophages, to determine the infectivity of the H7N9 virus in MGs. Besides, we investigated immune reactions in H7N9 virus-infected mouse MGs by comprehensively analyzing the transcriptome and proteome. Results revealed that the H7N9 virus could infect BV2 cells, inducing cytopathic effects (CPEs) and producing infectious progeny virus. Furthermore, infection activated the tumor necrosis factor (TNF) signaling pathway and cleaved caspase-3, leading to cell death. These findings provide insights into the mechanisms by which the H7N9 virus causes lesions in the central nervous system.

关键词： CT-26 tumor   cytokines   natural killer cells   SAR-444245   T cells  

摘要： Anti-tumoral immunity requires coordination of diverse responses leading to durable tumor clearance. Immunotherapy leverages specific mechanisms of the immune system to improve effector cell-mediated attack of tumors. We engineered SAR-444245 [SAR'245, formerly known as THOR-707] as a not-alpha interleukin-2 (IL-2) designed for increased half-life and selective targeting of CD8+ T and natural killer (NK) cells while reducing targeting of immune-suppressive CD4+ regulatory T cells (Tregs). The anti-tumoral efficacy of SAR'245 was investigated using the syngeneic CT-26 mouse model characterized by high infiltration with Tregs and responsiveness to programmed cell-death protein-1 (PD-1) checkpoint inhibitory antibodies. We evaluated SAR'245 pharmacokinetics and peripheral and intra-tumoral pharmacodynamics employing cytometry, histochemistry, RNAseq and secreted cytokine readouts, and in vivo efficacy as single-agent and in combination with an anti-mouse PD-1 antibody. In CT-26 tumor-bearing mice, SAR'245 administration induced peripheral expansion of CD8+ T and NK cells, including T cell memory subpopulations, without significant Treg expansion. SAR'245 stimulated anti-tumor activity that was enhanced in combination with an anti-PD-1 checkpoint inhibitory antibody, promoting both long-term survival and rejection of tumor cells on re-challenge. This agent elevated lymphocytic infiltration of tumors and T cell clonal diversity, eliciting multiple intra-tumoral gene signatures reporting on enhanced effector cell activity and persistence in the tumor microenvironment. Overall, we demonstrate that the IL-2 not-alpha agent SAR'245 induces immune responses that promote infiltration of CD8+ T and NK cells with enhanced effector function, leading to durable antitumoral response. These findings suggest SAR'245 potential for the treatment of solid tumors, particularly in combination with inhibitors of PD-1.

关键词： rheumatoid arthritis   body composition   TNF inhibitors   sarcopenia   inflammation   inflammatory activity   cytokines  

摘要： Rheumatoid arthritis (RA) is a chronic inflammatory disease frequently associated with alterations in body composition, including reduced lean mass and increased fat mass. These alterations are thought to be driven by persistent systemic inflammation, which may be influenced by inflammatory activity and by therapeutic interventions. Objectives: This pilot study aimed to provide preliminary data on changes in body composition and inflammatory activity in biologic-naive patients with active RA during the initial 6 months of TNF inhibitor treatment, and to compare baseline body composition with healthy controls. We conducted a single-center, observational, 24-week pilot study of 70 biologic-naive RA patients with moderate-to-severe disease activity and 70 matched healthy controls. Lean mass, fat mass, and lean mass index (LMI) were measured using dual-energy X-ray absorptiometry at baseline for both groups, and after 6 months only in the RA group. Clinical, laboratory, adipokines, and cytokine parameters were also recorded. At baseline, RA patients had lower lean mass and LMI than controls. Over 6 months, RA patients showed significant clinical and laboratory improvement, with a corresponding increase in lean mass and LMI. No statistically significant change was observed in fat mass. The increase in lean mass was paralleled by a reduction in inflammatory markers. The LMI was inversely associated with female sex (beta = -0.562) and C-reactive protein (beta = -0.432) and directly associated with body mass index (beta = 0.570). Similar associations were observed for total lean mass and change in lean mass, as well as for DAS28 (beta = -0.333). This pilot study provides preliminary evidence that TNF inhibitor therapy may be associated with increased lean mass and decreased inflammation in RA patients. Owing to the absence of a comparator RA group not receiving TNF inhibitors, these findings should be interpreted as hypothesis-generating.

关键词： 多种细胞因子   急性胰腺炎   继发感染   诊断价值  

摘要： 探讨IL-6、TNF-α、IL-8、PCT及CRP在急性胰腺炎继发感染中的诊断效能,并分析其与临床结局之间的联系。方法 纳入2024年2月至2025年2月期间收治的50例急性胰腺炎患者,分为实验组和对照组,各25例。采集外周血清样本,利用酶联免疫吸附法测定IL-6、TNF-α、IL-8、PCT与CRP水平。运用ROC曲线评估各指标的诊断准确性。对两组住院时间和抗生素使用时长进行对比分析,以揭示炎性因子水平变化与临床恢复之间的潜在关系。结果 实验组IL-6、TNF-α及PCT水平均显著升高,差异具有统计学意义。IL-6平均浓度为135.2±28.4pg/mL,对照组为62.3±15.1pg/mL。TNF-α分别为45.6±9.8与18.7±4.2pg/mL。PCT水平则为2.1±0.6ng/mL对比0.3±0.1ng/mL。ROC分析显示,PCT单独诊断价值最强(AUC=0.93),多指标联合检测诊断效能更高(AUC=0.96)。值得注意的是,对照组住院时长为14.2±3.1天,而实验组仅为9.8±2.5天。抗生素使用天数缩短,死亡率随之降低。结论 IL-6、TNF-α及PCT在急性胰腺炎继发感染中表现出较高的敏感性与特异性。PCT作为单一指标,其诊断效力最为突出。多因子联合检测提供更具参考价值的判断依据。炎症因子的动态变化与治疗反应密切相关,提前干预或可缩短住院周期,优化抗菌治疗路径。未来可尝试构建基于这些生物标志物的风险评分模型,用以早期识别感染倾向,辅助临床决策。

关键词： nanoparticles   Saussurea costus   NF-kappa B   TNF-alpha   inflammation  

摘要： Objectives Porphyromonas gingivalis is a major contributing pathogen in periodontitis and triggers an inflammatory response that leads to tissue damage, primarily through the activation of proinflammatory cytokines such as nuclear factor kappa B (NF-kappa B) and tumor necrosis factor-alpha (TNF-alpha). Saussurea costus , a medicinal plant known for its anti-inflammatory properties, offers a potential alternative to prevent inflammation. This study explores the effects of S. costus nanoparticles on inflammation in periodontitis, specifically examining their ability to reduce the expression of NF-kappa B and TNF-alpha. Materials and Methods Twenty male Wistar rats were injected with P. gingivalis into the central incisor region of the mandible to induce periodontitis. The rats were then treated with S. costus nanoparticles, alongside a control group. Immunohistochemical staining was performed to assess the expression of NF-kappa B and TNF-alpha at two time points: 2 and 5 days posttreatment. Bone and lower anterior gingival sulcus tissues were analyzed for immunohistochemical expression of these markers. Statistical Analysis Statistical analysis was performed using the Kruskal-Wallis and Mann-Whitney U tests. Results Treatment with S. costus nanoparticles resulted in significantly lower expressions of NF-kappa B and TNF-alpha compared with the control group at both 2 and 5 days posttreatment ( p < 0.05). Conclusion The S. costus nanoparticles effectively reduced NF-kappa B and TNF-alpha expression in periodontitis, with a more pronounced effect observed on day 5 compared with day 2, suggesting its potential as a therapeutic agent in managing periodontal inflammation.

关键词： acute lung injury   lung delivery   nanomedicine   siRNA   TNF-alpha  

摘要： This study investigates the potential of pulmonary delivery of siRNA as an emergency therapy for acute lung injury (ALI). To obtain a quick anti-inflammatory response, TNF-alpha, a critical pro-inflammatory cytokine, is knocked down for its early involvement in inflammatory responses. Therefore, TNF-alpha siRNA-lipid nanoparticles (LNPs) are designed and characterized for cellular uptake in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophages, primary alveolar macrophages, and neutrophils from a murine ALI model. Intracellular trafficking and siRNA cytoplasmic release are evaluated in untreated and LPS-activated RAW264.7 cells. LPS-activated cells exhibit a fast and strong uptake of LNPs, including in primary cells. In RAW264.7 cells, significant endosomal escape and siRNA cytoplasmic release are observed after 16 h. In vitro efficacy studies reveal consistent TNF-alpha inhibition across pre-, co-, and post-incubation protocols, confirming the versatility of siRNA-LNPs in preventive or curative conditions. After intratracheal administration of TNF-alpha siRNA-LNPs in a murine ALI model, the distribution of LNPs demonstrates an accumulation in immune cells, including macrophages and neutrophils, reducing TNF-alpha and IL-6 levels, indicating a rapid anti-inflammatory effect. This work underscores the efficacy of TNF-alpha siRNA-LNPs in treating lung inflammatory diseases like ALI and highlights the importance of optimizing LNP distribution and delivery timing to enhance therapeutic outcomes.

关键词： genomics   GWAS   HLA   phenome-wide   biobank   summary statistics   UKBB   FinnGen  

摘要： The human leukocyte antigen (HLA) region plays an important role in human health through its involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome wide for 412,181 Finnish individuals and 2,459 diseases. Across the 1,035 diseases with a genome-wide association study association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 diseases, including 1,750 associations uncovered by haplotype analysis. We found that some haplotypes show both risk-increasing and protective associations across different diseases, while others consistently increase risk across diseases, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk and underscores the importance of classical and non-classical genes as well as non-coding variation.