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关键词： myeloid cells   microglia   MHC   MR1   CD1d   neurodegenerative diseases  

摘要： In recent years, increasing evidence has highlighted the critical role of myeloid cells, specifically those that present antigen (APCs) in health and disease. These shape the progression and development of neurodegenerative disorders, where considerable interplay between the immune system and neurons influences the course of disease pathogenesis. Antigen-presenting myeloid cells display different classes of major histocompatibility complex (MHC) and MHC-like proteins on their surface for presenting various types of antigens to a wide variety of T cells. While most studies focus on the role of myeloid MHC class I and II molecules in health and disease, there is still much that remains unknown about non-polymorphic MHC-like molecules such as CD1d and MR1. Thus, in this review, we will summarize the recent findings regarding the contributions of both classical and non-classical MHC molecules, particularly on myeloid microglial APCs, in neurodegenerative diseases. This will offer a better understanding of altered mechanisms that may pave the way for the development of novel therapeutic strategies targeting immune cell-MHC interactions, to mitigate neurodegeneration and its associated pathology.

关键词： Bioinformatics   IL-33   Nomogram   Prognosis   Uterine corpus endometrial carcinoma  

摘要： Uterine corpus endometrial carcinoma (UCEC) is one of the most common malignant tumours of the female genital tract. In the occurrence, progression and prognosis of UCEC, chronic inflammation plays an important role, making it pivotal to identify inflammatory response-related endometrial diseases. The cytokine interleukin-33 (IL-33) plays significant roles in immune responses, and has been associated with inappropriate allergic reactions, autoimmune diseases, and cancer pathology. In the past decade, studies have begun to uncover the pivotal roles of IL-33 in shaping tumour microenvironment (TME), where it may promote or inhibit tumorigenesis and development depending on the specific tumour types. However, the association between IL-33 expression and UCEC remains unclear. Here we investigated the expression profiles of IL-33 in pan-cancer based on TCGA database. Then, differential gene expression analysis and correlation analysis of IL-33 was investigated in UCEC. In addition, functional enrichment analysis and Kaplan-Meier survival analysis were performed to predict the potential function of IL-33 and its role in the prognosis of UCEC patients. Also, a nomogram model was constructed to predict the prognosis of UCEC. The expression of the inflammatory factor NF-κB p65 and the IL-33, along with its receptor ST2, was analyzed in UCEC tumour tissues and normal tissues of clinical specimens through immunohistochemical staining. Meanwhile, we used toluidine blue staining and methanol Congo red staining to observe the infiltration of mast cells and eosinophils in the endometrial tissue. The results of Kaplan-Meier plotter data indicated that patients with lower IL-33 expression had poorer progression-free interval than those with higher expression. Based on the results of multifactor Cox regression, a nomogram was generated to predict UCEC occurrence risk and prognosis. Clinical specimen characteristics also confirmed a negative correlation between IL-33 expression and UC

关键词： AMPK/STAT3   DHA   EPA   Lipid metabolism   Myogenic IL-6   TRPV1/Ca(2+)  

摘要： Lipid metabolism disorder serve as a critical starting point for the development of chronic non-communicable diseases (NCDs). Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) are known for their lipid-lowering properties, but few studies have revealed their differences from the perspective of skeletal muscle endocrinology. Myogenic IL-6 has garnered significant attention for its role in energy distribution. The primary aim of this study was to investigate the effects and mechanisms of EPA and DHA on myogenic IL-6 and lipid metabolism disorders in mice, and to clarify the association between the alleviation of lipid metabolism disorders and myogenic IL-6 mediated by EPA/DHA. We found that EPA and DHA not only prevented high-fat diet-induced lipid metabolism disorders, but also up-regulated the expression of myogenic IL-6 by activating TRPV1/Ca signaling in skeletal muscle. However, the lipid metabolism prevention effect mediated by EPA was weakened after knockout gene of myogenic IL-6, with its body weight and body fat increased and a large amounts of lipid deposited in the blood, liver, and adipocytes. Meanwhile, there no significantly differences of AMPK/STAT3 signaling in adipose tissue between groups after knockout gene of myogenic IL-6. Based on the results above, we concluded that EPA and DHA can stimulate the production of myogenic IL-6 through TRPV1/Ca signaling in skeletal muscle. The prevention effect of lipid metabolism disorders by EPA, but not DHA, relies on myogenic IL-6, with the underlying mechanism may involving the enhancement of AMPK/STAT3 signaling mediated by myogenic IL-6 in adipose tissues.

关键词： 脓毒症   急性肾损伤   预后   降钙素原   白细胞介素6   半胱氨酸蛋白酶抑制物C  

摘要： 目的 探讨降钙素原（PCT）、白细胞介素6(IL-6)、胱抑素（CysC）联合检测在脓毒症急性肾损伤（AKI）诊断及预后评估中的价值。方法 100例脓毒症患者根据AKI发生情况分为AKI组（n=56）和无AKI组（n=44）;AKI患者分为存活组（n=32）和死亡组（n=24）。收集患者临床资料，采用酶联免疫吸附试验检测PCT、IL-6、CysC水平；急性生理功能和慢性健康状况评分（APACHEⅡ）评估病情；采用受试者工作特征（ROC）曲线评估PCT、IL-6、CysC对脓毒症合并AKI诊断及死亡的预测价值。结果 AKI组男性比例、年龄、高血压并糖尿病比例、APACHEⅡ评分、血肌酐（Scr）、PCT、IL-6、CysC水平高于非AKI组，合并症比例、发病时间低于非AKI组（P<0.05）。ROC曲线结果显示，PCT、IL-6、CysC联合诊断脓毒症合并AKI的曲线下面积（AUC）为0.859，敏感度为91.07%，特异度为90.91%，联合诊断效能优于单一指标。死亡组APACHEⅡ评分、PCT、IL-6、CysC水平高于存活组（P<0.05）。ROC曲线结果显示，PCT、IL-6、CysC联合预测脓毒症合并AKI患者死亡的AUC为0.847，敏感度为91.67%，特异度为87.50%，联合预测效能优于单一指标。结论 联合PCT、CysC、IL-6指标对脓毒症合并AKI诊断以及预后预测的价值更高。

关键词： ICIs   IL-6/JAK/STAT3   Osimertinib   irAEs   macrophages  

摘要： OBJECTIVE:The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. METHODS:An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. RESULTS:Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. CONCLUSIONS:An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.

关键词： Aerocyte   Alarmin   Alveolar   COVID-19   IL-33   viral LRTD  

摘要： Interleukin (IL)-33 is released following tissue damage, causing airway inflammation and remodelling via reduced IL-33 (IL-33)/serum stimulation-2 (ST2) and oxidised IL-33 (IL-33)/receptor for advanced glycation end products (RAGE)/epidermal growth factor receptor (EGFR) pathways. This study aimed to identify associations of IL-33 with clinical outcomes and pathological mechanisms during viral lower respiratory tract disease (LRTD). Ultra-sensitive immunoassays were developed to measure IL-33, IL-33 and IL-33/sST2 complexes in samples from patients hospitalised with COVID-19. Immunohistochemistry and multiomics were used to characterise lung samples. Elevated IL-33 in the airway and IL-33/sST2 complex in the circulation correlated with poor clinical outcomes (death, need for intensive care or mechanical ventilation). IL-33 was localised to airway epithelial and endothelial barriers, whereas IL1RL1 was expressed on aerocytes, alveolar endothelial cells specialised for gaseous exchange. IL-33 increased expression of mediators of neutrophilic inflammation, immune cell infiltration, interferon signalling and coagulation in endothelial cell cultures. Endothelial IL-33 signatures were strongly related with signatures associated with viral LRTD. Increased IL-33 release following respiratory viral infections is associated with poor clinical outcomes and might contribute to alveolar dysfunction. Although this does not show a causal relationship with disease, these results provide a rationale to evaluate pathological roles for IL-33 in viral LRTD.

关键词： 远距离运输   应激   西门塔尔牛   临床指标   细胞因子   肠道菌群  

摘要： 【目的】旨在探究远距离运输对西门塔尔牛主要临床和血液相关指标及肠道菌群的影响。【方法】试验选取70头8月龄临床检查健康、体况相近的西门塔尔牛，采用上下层有篷运输车，密度约为1.04 m2/头，从内蒙古自治区通辽市运往四川省泸定县，随机选取上层12头为研究对象并标记。运输装车当天和到达目的地以及到达后第2 d至第7 d分别标记为Tb、Ta和T2d-T7d。测定并记录Tb至T7d主要临床指标，统计发病率和死亡率。分别采用ELISA法和16S rDNA检测牛Tb和Ta血清炎性、免疫、氧化、应激等因子水平和肠道粪便菌群变化。【结果】远距离运输后较运输前，西门塔尔牛脱水程度、体温、心率、呼吸频率和发病率均极显著升高（P<0.01），而体重和单次反刍咀嚼次数极显著下降（P<0.01），主要以呼吸道疾病（13头，发病率为19%）和消化道疾病（11头，发病率为16%）为主；血清IL-1β、TNF-α、IL-4、IL-10和CRP水平极显著下降（P<0.01），而IgA、IgG和CAT水平极显著上升（P<0.01），IL-6和SAA水平均显著下降（P<0.05），而IgM水平显著上升（P<0.05）；肠道菌群在门水平上，拟杆菌门、Spirochaetota菌门丰度显著下降（P<0.05），放线菌门（Actinobacteria）、蓝细菌门（Cyanobacteria）丰度显著上升（P<0.05），脱硫弧菌门（Desulfobacterota）丰度极显著上升（P<0.01）。在属水平上，Rikenellaceae＿RC9＿gut＿group、Alistipes、Monoglobus和Prevotellaceae＿UCG-004丰度显著下降（P<0.05），NK4A214＿group丰度显著上升（P<0.05）。【结论】远距离运输易造成西门塔尔牛严重脱水，体重下降，体温、心率和呼吸频率显著上升，并影响反刍，导致呼吸道和消化道疾病发病率升高；引起免疫力降低，发生炎症反应和氧化应激；肠道菌群多样性和丰富度显著下降，且有益菌丰度显著下降，而有害菌丰度显著上升。

关键词： COVID-19   Mortality   Adult intensive & critical care   SARS-CoV-2 Infection   ACCIDENT & EMERGENCY MEDICINE  

摘要： Objectives To investigate the serum IL-6 levels and their rate of change in predicting the mortality of critically ill patients with COVID-19 in Vietnam. Design A single-centre, cross-sectional study. Setting An Intensive Care Centre for the Treatment of Critically Ill Patients with COVID-19 in Ho Chi Minh City, Vietnam. Participants We included patients aged 18 years or older who were critically ill with COVID-19 and presented to the study centre from 30 July 2021 to 15 October 2021. We excluded patients who did not have serum IL-6 measurements between admission and the end of the first day. Primary outcome measures The primary outcome was hospital all-cause mortality. Results Of 90 patients, 41.1% were men, the median age was 60.5 years (Q1-Q3: 52.0-71.0), and 76.7% of patients died in the hospital. Elevated IL-6 levels were observed on admission (41.79 pg/mL;Q1-Q3: 20.68-106.27) and on the third day after admission (72.00 pg/mL;Q1-Q3: 26.98-186.50), along with a significant rate of change in IL-6 during that period (839.5%;SD: 2753.2). While admission IL-6 level (areas under the receiver operator characteristic curve (AUROC): 0.610 (95% CI: 0.459 to 0.761);cut-off value >= 15.8 pg/mL) and rate of change in IL-6 on the third day of admission (AUROC: 0.586 (95% CI: 0.420 to 0.751);cut-off value >=-58.7%) demonstrated poor discriminatory ability in predicting hospital mortality, the third day IL-6 rate of change from admission >=-58.7% (adjusted OR: 12.812;95% CI: 2.104 to 78.005) emerged as an independent predictor of hospital mortality. Conclusions This study focused on a highly selected cohort of critically ill COVID-19 patients with a high IL-6 level and mortality rate. Despite the poor discriminatory value of admission IL-6 levels, the rate of change in IL-6 proved valuable in predicting mortality. To identify critically ill COVID-19 patients with the highest risk for mortality, monitoring the serial serum IL-6 measurements and observing the rate of change in s

关键词： Interleukin-2   T cells   allostery   conformational exchange   molecular dynamics simulations   nuclear magnetic resonance spectroscopy   receptor binding  

摘要： Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.