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关键词： Crimean-Congo haemorrhagic fever virus   Kosovo Hoti   sheep   virus shedding   RNA persistence   HUMAN ENDOTHELIAL-CELLS   NECROSIS-FACTOR-ALPHA   SEROEPIDEMIOLOGICAL SURVEY   PERMEABILITY   PATHOGENESIS   INCREASES   CATTLE   TNF   HYPERPERMEABILITY   EPIDEMIOLOGY  

摘要： Crimean-Congo haemorrhagic fever orthonairovirus (CCHFV) is a tick-borne, risk group 4 pathogen that often causes a severe haemorrhagic disease in humans (CCHF) with high case fatality rates. The virus is believed to be maintained in a tick-vertebrate-tick ecological cycle involving numerous wild and domestic animal species; however the biology of CCHFV infection in these animals remains poorly understood. Here, we experimentally infect domestic sheep with CCHFV Kosovo Hoti, a clinical isolate representing high pathogenicity to humans and increasingly utilized in current research. In the absence of prominent clinical signs, the infection leads to an acute viremia and coinciding viral shedding, fever and markers for potential impairment in liver and kidney functions. A number of host responses distinguish the subclinical infection in sheep versus fatal infection in humans. These include an early reduction of neutrophil recruitment and its chemoattractant, IL-8, in the blood stream of infected sheep, whereas neutrophil infiltration and elevated IL-8 are features of fatal CCHFV infections reported in immunodeficient mice and humans. Several inflammatory cytokines that correlate with poor disease outcomes in humans and have potential to cause vascular dysfunction, a primary hallmark of severe CCHF, are down-regulated or restricted from increasing in sheep. Of particular interest, the detection of CCHFV RNA (including full-length genome) in a variety of sheep tissues long after the acute phase of infection indicates a widespread viral dissemination in the host and suggests a potentially long-term persisting impact of CCHFV infection. These findings reveal previously unrecognized aspects of CCHFV biology in animals.

关键词： Gastric cancer   PD-L1   IL-10   microbiome   butyrate   avatar model   Faecalibacterium prausnitzii   EXPRESSION  

摘要： Early detection and surgical treatment are essential to achieve a good outcome in gastric cancer (GC). Stage IV and recurrent GC have a poor prognosis. Therefore, new treatments for GC are needed. We investigated the intestinal microbiome of GC patients and attempted to reverse the immunosuppression of the immune and cancer cells of GC patients through the modulation of microbiome metabolites. We evaluated the levels of programmed death-ligand 1 (PD-L1) and interleukin (IL)-10 in the peripheral blood immunocytes of GC patients. Cancer tissues were obtained from patients who underwent surgical resection of GC, and stained sections of cancer tissues were visualized via confocal microscopy. The intestinal microbiome was analyzed using stool samples of healthy individuals and GC patients. Patient-derived avatar model was developed by injecting peripheral blood mononuclear cells (PBMCs) from advanced GC (AGC) patients into NSG mice, followed by injection of AGS cells. PD-L1 and IL-10 had higher expression levels in immune cells of GC patients than in those of healthy controls. The levels of immunosuppressive factors were increased in the immune and tumor cells of tumor tissues of GC patients. The abundances of Faecalibacterium and Bifidobacterium in the intestinal flora were lower in GC patients than in healthy individuals. Butyrate, a representative microbiome metabolite, suppressed the expression levels of PD-L1 and IL-10 in immune cells. In addition, the PBMCs of AGC patients showed increased levels of immunosuppressive factors in the avatar mouse model. Butyrate inhibited tumor growth in mice. Restoration of the intestinal microbiome and its metabolic functions inhibit tumor growth and reverse the immunosuppression due to increased PD-L1 and IL-10 levels in PBMCs and tumor cells of GC patients.

关键词： covid-19   acute kidney injury   IL-8   IP-10   biomarker   HOSPITALIZED-PATIENTS   COVID-19   AKI  

摘要： Objectives: Persistent severe acute kidney injury (PS-AKI) is associated with poor clinical outcomes. Our study attempted to evaluate the diagnostic value of chemokines for early-stage PS-AKI prediction. Methods: According to the KDIGO criteria, 115 COVID-19 patients diagnosed with stage 2/3 AKI were recruited from the intensive care unit between December 2022 and February 2023. Primary clinical outcomes included detecting PS-AKI in the first week (>= KDIGO stage 2 >= 72 h). Cytometric Bead Array was used to detect patient plasma levels (interleukin-8 (IL-8), C-C chemokine ligand 5 (CCL5), chemokine (C-X-C Motif) ligand 9 (CXCL9), and interferon-inducible protein 10 (IP-10)) of chemokines within 24 h of enrollment. Results: Of the 115 COVID-19 patients with stage 2/3 AKI, 27 were diagnosed with PS-AKI. Among the four measured chemokines, only the IL-8 level was significantly elevated in the PS-AKI group than in the Non-PS-AKI group. IL-8 was more effective as a biomarker while predicting PS-AKI with an area under the curve of 0.769 (0.675-0.863). This was superior to other biomarkers related to AKI, including serum creatinine. Moreover, plasma IL-8 levels of >32.2 pg/ml on admission could predict PS-AKI risk (sensitivity = 92.6%, specificity = 51.1%). Additionally, the IL-8 level was associated with total protein and IL-6 levels. Conclusion: Plasma IL-8 is a promising marker for the early identification of PS-AKI among COVID-19 patients. These findings should be validated in further studies with a larger sample size.

关键词： MUC1   lung adenocarcinoma   cancer cell stemness   paclitaxel resistance   NF-kappa B   MAPK   DRUG-RESISTANCE   CANCER   MUC1   CHEMORESISTANCE   EXPRESSION   CAPACITY   CELLS  

摘要： Background: The chemotherapy resistance often leads to chemotherapy failure. This study aims to explore the molecular mechanism by which MUC1 regulates paclitaxel resistance in lung adenocarcinoma (LUAD), providing scientific basis for future target selection. Methods: The bioinformatics method was used to analyse the mRNA and protein expression characteristics of MUC1 in LUAD. RT-qPCR and ELISA were used to detect the mRNA and protein expression, flow cytometry was used to detect CD133(+) cells, and cell viability was detected by CCK-8 assay. The mRNA-seq was performed to analyse the changes in expression profile, GO and KEGG analysis were used to explore the potential biological functions. Results: MUC1 is highly expressed in LUAD patients and is associated with a higher tumour infiltration. In paclitaxel resistance LUAD cells (A549/TAX cells), the expression of MUC1, EGFR/p-EGFR and IL-6 were higher than that of A549 cells, the proportion of CD133(+) cells was significantly increased, and the expression of cancer stem cell (CSCs) transcription factors (NANOG, OCT4 and SOX2) were significantly up-regulated. After knocking down MUC1 in A549/Tax cells, the activity of A549/Tax cells was significantly decreased. Correspondingly, the expression of EGFR, IL-6, OCT4, NANOG, and SOX2 were significantly down-regulated. The mRNA-seq showed that knocking down MUC1 affected the gene expression, DEGs mainly enriched in NF-kappa B and MAPK signalling pathway. Conclusion: MUC1 was highly expressed in A549/TAX cells, and MUC1-EGFR crosstalk with IL-6 may be due to the activation of NF-kappa B and MAPK pathways, which promote the enrichment of CSCs and lead to paclitaxel resistance.

关键词： Organic dust   therapy   immunology   inflammation   lung disease   DOSE-RESPONSE RELATIONSHIPS   ENVIRONMENTAL EXPOSURES   RESPIRATORY HEALTH   TNF-ALPHA   WORKERS   MACROPHAGES   ENDOTOXIN   INTERLEUKIN-10   FIBROSIS   INJURY  

摘要： Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 mu g) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 treatment reduced ODE (25%, 50%)-induced lung levels of TNF alpha (-76%, -83% [reduction], respectively), neutrophil chemoattractant CXCL1 (-51%, -60%), and lavage fluid IL-6 (-84%, -89%). IL-10 treatment reduced ODE (25%, 50%)-induced lung neutrophils (-49%, -70%) and recruited CD11cintCD11b+ monocyte-macrophages (-49%, -70%). IL-10 therapy reduced ODE-associated expression of antigen presentation (MHC Class II, CD80, CD86) and inflammatory (Ly6C) markers and increased anti-inflammatory CD206 expression on CD11cintCD11b+ cells. ODE (12.5%, 25%)-induced lung pathology was also reduced with IL-10 therapy. In conclusion, the studies here showed that short-term, lung-delivered IL-10 treatment induced a beneficial response in reducing inflammatory consequences (that were also associated with striking reduction in recruited monocyte-macrophages) following acute complex organic dust exposure.

关键词： 骨关节炎   单髁置换术   美国特种外科医院评分   白细胞介素1   白细胞介素6   肿瘤坏死因子α  

摘要： 背景:单髁置换因其创伤小、失血少、并发症少、康复快、膝关节功能优、假体生存率高等优点,越来越受到重视,相关报道多集中于其临床疗效,而单髁置换后患者体内相关炎性细胞因子的水平变化罕见报道。目的:探讨膝关节内侧间室骨关节炎患者单髁置换后的疗效及关节滑液白细胞介素1、白细胞介素6、肿瘤坏死因子α水平变化。方法:以2021年9月至2023年3月因膝内侧间室骨关节炎行单髁置换治疗并符合纳入标准的30例患者作为研究对象。比较术前、术后胫骨近端内侧角、股胫角、疼痛目测类比评分、美国特种外科医院膝关节评分、膝关节活动度及关节滑液白细胞介素1、白细胞介素6、肿瘤坏死因子α水平,并进行统计学分析。结果与结论:①30例患者术后切口均Ⅰ级愈合,术后均获6个月以上随访,所有患者均未出现假体松动、假体衬垫脱位等并发症;②术后1个月测量胫骨近端内侧角、股胫角均较术前明显改善(P<0.05);③术后1,3,6个月测量疼痛目测类比评分、美国特种外科医院膝关节评分、膝关节活动度均优于术前(P<0.05),术后各时间点呈逐渐好转趋势(P<0.05);④术后3,6个月测量关节滑液白细胞介素1、白细胞介素6、肿瘤坏死因子α水平均较术前逐渐下降(P<0.05),术后各时间点呈逐渐下降趋势;⑤提示单髁置换可有效治疗膝关节内侧间室骨关节炎,显著缓解患者疼痛,恢复膝关节功能,改善膝内翻畸形及下肢力线,并能在一定程度上降低关节内炎性细胞因子白细胞介素1、白细胞介素6、肿瘤坏死因子α的表达水平。

关键词： 类风湿关节炎   免疫复合物   骨转换标志物   骨质疏松症   骨免疫学  

摘要： 背景:类风湿关节炎患者骨质疏松症的发生率明显增高,患者血清中存在的大量免疫复合物是否促进了骨质疏松症的发生与发展仍不明确。目的:探讨类风湿关节炎患者血清总免疫复合物与骨质疏松症的关系。方法:(1)临床试验:选择50名健康体检者(健康对照组)与50例初治型类风湿关节炎患者(类风湿关节炎组),回顾性分析两组患者的临床资料与实验室检查,比较两组血清总免疫复合物水平。将类风湿关节炎患者血清总免疫复合物与骨密度、骨转换标志物及其他临床指标进行相关性分析。(2)细胞实验:分离培养健康志愿者外周血单核细胞,分4组处理:类风湿关节炎组加入类风湿关节炎患者血清总免疫复合物悬液,正常对照组加入健康体检者血清总免疫复合物悬液,阳性对照组加入含巨噬细胞集落刺激因子与核因子κB受体活化因子配体的α-MEM培养基,阴性对照组加入α-MEM培养基。处理7 d后进行抗酒石酸酸性磷酸酶染色,观察破骨细胞形成情况。结果与结论:(1)临床试验:类风湿关节炎组患者血清总免疫复合物、血清碱性磷酸酶水平均明显高于健康体检者(P<0.01,P<0.05);Pearson相关分析结果显示,类风湿关节炎患者血清总免疫复合物与血沉(r=0.330,P=0.019)、血清碱性磷酸酶(r=0.545,P=0.001)、抗环瓜氨酸肽抗体(r=0.377,P=0.007)和Ⅰ型胶原C端肽(r=0.738,P=0.001)呈正相关关系,与腰椎骨密度(r=-0.595,P=0.001)呈负相关关系;二元Logistic回归分析结果显示,年龄[OR=1.086,95%CI(1.022,1.154),P=0.008]、抗环瓜氨酸肽抗体[OR=1.002,95%CI(0.999,1.005),P=0.035]、Ⅰ型胶原C端肽[OR=0.141,95%CI(0.015,8.900),P=0.008]和血清总免疫复合物[OR=2.895,95%CI(1.228,6.827),P=0.001]是类风湿关节炎患者骨量异常(骨量减少或骨质疏松)的影响因素;(2)细胞实验:阳性对照组、正常对照组、类风湿关节炎组可见抗酒石酸酸性磷酸酶染色阳性的破骨细胞,并且与正常对照组相比,类风湿关节炎组破骨细胞形成更多(P<0.01);(3)结果表明,血清总免疫复合物可作为预测类风湿关节炎并发骨质疏松症的潜在血清学指标,清除血清中的免疫复合物或者干预免疫复合物与其受体的结合可能成为临床预防和治疗类风湿关节炎并发骨质疏松症的有效手段。

关键词： Sam68   Inflammation   Inflammatory bowel disease   Arthritis   Cardiovascular disease   TNF   TLR   TCR   BCR   TUMOR-NECROSIS-FACTOR   RNA-BINDING PROTEIN   KAPPA-B ACTIVATION   BRUTONS TYROSINE KINASE   INSULIN-RECEPTOR   CELL-RECEPTOR   EPITHELIAL-CELLS   APOPTOSIS   LEPTIN   DOMAIN  

摘要： Sam68 is a ubiquitously expressed KH-domain containing RNA-binding protein highly studied for its involvement in regulating multiple steps of RNA metabolism. Sam68 also contains multiple protein-protein interaction regions such as proline-rich regions, tyrosine phosphorylation sites, and arginine methylation sites, all of which facilitate its participation as an adaptor protein in multiple signaling pathways, likely independent of its RNA-binding role. This review focuses on providing a comprehensive report on the adaptor roles of Sam68 in inflammatory signaling and inflammatory diseases. The insights presented here have the potential to open new avenues in inflammation research and justify targeting Sam68 to control aberrant inflammatory responses.

关键词： Coronary artery disease   Epigenetics   Pyrosequencing   DNA methylation   Epigenome-wide association study   Human leucocyte antigen (HLA) gene   DNA METHYLATION   ATHEROSCLEROTIC PLAQUE   HEART-DISEASE   WIDE ANALYSIS   SUSCEPTIBILITY   MECHANISMS   EXPRESSION   SITES   CELLS  

摘要： Background DNA methylation, one of the most stable forms of epigenetic modification is associated with the development and progression of coronary artery disease (CAD). Our previously reported study on epigenome-wide microarray analysis showed significantly methylated CpG sites. Top 5 significant CpGs from HLA gene were selected and analysed by Pyrosequencing (PSQ) to determine their association with severity of CAD.Methods Blood samples of 50-age matched angiographically CAD positive male cases with 50 angiographically CAD negative male controls were subjected to lipid profile estimation and PSQ for methylation level analysis. Findings and subgroup analysis were evaluated by Mann-Whitney U; Kruskal-Wallis' rank test and two-way ANOVA by MedCalc (v19.6).Results Methylation levels in HLA-DQA1 for cg10217052 was 78.5 (37-85) and 76.5 (24-84); cg09411910 was 81 (72.0 to 93.0) and 81.5 (50.0 to 89.0) in cases and controls respectively. Levels in HLA-DQB1-cg03344051, were 28.88 + 9.41 for cases and 30.36 + 9.37 in controls. For HLA-DRB1-cg07889003, levels in cases and controls were 15.5 (5.00-39.00) and 10.5 (5.00-29.0); while in cg08269402 were 52 (16-65) and 42.5 (17-61) respectively. No association was observed between methylation levels and lipid profile. cg03344051, cg07889003 and cg08269402 were significantly differentiated in double or triple vessel disease (DVD or TVD) as compared to single vessel disease (SVD) suggesting an increase in the extent of methylation with the increase in CAD severity.Conclusion The present study shows significant increase in the extent of methylation in 3 CpG sites in DVD/TVD cases as compared to SVD cases. Additionally, a novel site, cg07889003 identified in our discovery phase has shown association with the severity of CAD.

关键词： iRhom2   ADAM17   Secretome   Macrophages   MHC class I molecules   SUBSTRATE SELECTIVITY   PHORBOL ESTER   ADAM17   METALLOPROTEINASE   DIFFERENTIATION   TRAFFICKING   DISINTEGRIN   CONTRIBUTE   CLEAVAGE   BRAIN  

摘要： Proteolytic release of transmembrane proteins from the cell surface, the so called ectodomain shedding, is a key process in inflammation. Inactive rhomboid 2 (iRhom2) plays a crucial role in this context, in that it guides maturation and function of the sheddase ADAM17 (a disintegrin and metalloproteinase 17) in immune cells, and, ultimately, its ability to release inflammatory mediators such as tumor necrosis factor alpha (TNF alpha). Yet, the macrophage sheddome of iRhom2/ADAM17, which is the collection of substrates that are released by the proteolytic complex, is only partly known. In this study, we applied high-resolution proteomics to murine and human iRhom2-deficient macrophages for a systematic identification of substrates, and therefore functions, of the iRhom2/ADAM17 proteolytic complex. We found that iRhom2 loss suppressed the release of a group of transmembrane proteins, including known (e.g. CSF1R) and putative novel ADAM17 substrates. In the latter group, shedding of major histocompatibility complex class I molecules (MHC-I) was consistently reduced in both murine and human macrophages when iRhom2 was ablated. Intriguingly, it emerged that in addition to its shedding, iRhom2 could also control surface expression of MHC-I by an undefined mechanism. We have demonstrated the biological significance of this process by using an in vitro model of CD8+ T-cell (CTL) activation. In this model, iRhom2 loss and consequent reduction of MHC-I expression on the cell surface of an Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line dampened activation of autologous CTLs and their cell-mediated cytotoxicity. Taken together, this study uncovers a new role for iRhom2 in controlling cell surface levels of MHC-I by a dual mechanism that involves regulation of their surface expression and ectodomain shedding.