S100A12 Protein

S100A12 蛋白质
  • 文章类型: Journal Article
    中性粒细胞是2019年严重冠状病毒病(COVID-19)中的关键免疫细胞。S100钙结合蛋白A12(S100A12)在急性炎症期间在中性粒细胞中高度表达。这项研究的目的是评估血清S100A12水平作为COVID-19的诊断和预后工具。在2020年至2024年期间收集了中度和重度COVID-19患者的血清样本。采用酶联免疫吸附法检测63例中度COVID-19患者、60例重症患者和33例健康对照者血清S100A12水平。与对照组相比,中度COVID-19的血清S100A12水平升高,严重病例甚至更高。在中度疾病中,血清S100A12水平与免疫细胞计数呈正相关。虽然C反应蛋白和降钙素原是确定的炎症标志物,在任一患者队列中,它们与血清S100A12水平均无相关性.严重COVID-19和万古霉素耐药肠球菌(VRE)感染患者S100A12水平升高。在单纯疱疹再激活的患者中也观察到S100A12水平升高。真菌超感染不会改变S100A12水平。这些数据表明,中度和重度COVID-19的血清S100A12增加,并因VRE血流感染和单纯疱疹再激活而进一步升高。因此,S100A12可能是严重COVID-19的新型生物标志物,也是细菌和病毒感染的早期诊断指标。
    Neutrophils are critical immune cells in severe coronavirus disease 2019 (COVID-19). S100 calcium-binding protein A12 (S100A12) is highly expressed in neutrophils during acute inflammation. The aim of this study was to evaluate serum S100A12 levels as a diagnostic and prognostic tool in COVID-19. Serum samples of patients with moderate and severe COVID-19 were collected during 2020 to 2024. Enzyme-linked immunosorbent assay was used to measure serum S100A12 levels in 63 patients with moderate COVID-19, 60 patients with severe disease and 33 healthy controls. Serum S100A12 levels were elevated in moderate COVID-19 compared to controls and were even higher in severe cases. In moderate disease, serum S100A12 levels positively correlated with immune cell counts. While C-reactive protein and procalcitonin are established inflammation markers, they did not correlate with serum S100A12 levels in either patient cohort. Patients with severe COVID-19 and vancomycin-resistant enterococcus (VRE) infection had increased S100A12 levels. Elevated S100A12 levels were also observed in patients with herpes simplex reactivation. Fungal superinfections did not alter S100A12 levels. These data show that serum S100A12 increases in moderate and severe COVID-19 and is further elevated by VRE bloodstream infection and herpes simplex reactivation. Therefore, S100A12 may serve as a novel biomarker for severe COVID-19 and an early diagnostic indicator for bacterial and viral infections.
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  • 文章类型: Journal Article
    牛皮癣,慢性炎症性皮肤病,与急性心肌梗死(AMI)等合并症有关。然而,连接这些条件的分子机制尚不清楚。在这项研究中,我们使用基因表达数据集进行了生物信息学分析,以鉴定与银屑病和AMI相关的差异表达基因和hub基因.我们的发现强调了免疫相关途径在这两种疾病的发病机理中的参与。此外,我们研究了hub基因在AMI患者和心肌梗死(MI)小鼠中的表达水平.ELISA测量显示CXCL8、IL1B、S100A9和S100A12在AMI患者血清中的表达与正常个体比拟。MI小鼠心脏组织的免疫组织化学染色显示,随着MI进展,CXCL8和IL-1B的表达逐渐增加,而S100A9在MI后第3天表现出高表达。mRNA表达分析验证了这些发现。此外,我们探讨了银屑病患者的皮肤病变,发现CXCL8,IL-1B的表达显着升高,与未受影响区域相比,受影响皮肤区域中的S100A9和S100A12。这些结果强调了在AMI和银屑病患者中hub基因的一致上调。以及在心肌梗塞小鼠中,强调它们作为疾病诊断可靠标志物的潜力。此外,分子对接模拟揭示了辛伐他汀与关键靶蛋白之间的潜在相互作用,建议一个潜在的治疗途径。总的来说,我们的研究揭示了共同的分子特征和潜在的治疗靶点,为针对银屑病和AMI常见途径的未来研究奠定基础。
    Psoriasis, a chronic inflammatory skin disorder, is associated with comorbidities such as acute myocardial infarction (AMI). However, the molecular mechanisms connecting these conditions are unclear. In this study, we conducted bioinformatics analyses using gene expression datasets to identify differentially expressed genes and hub genes associated with both psoriasis and AMI. Our findings emphasize the involvement of immune-related pathways in the pathogenesis of both conditions. Furthermore, we investigated the expression levels of hub genes in AMI patients and myocardial infarction (MI) mice. ELISA measurements revealed significantly higher levels of CXCL8, IL1B, S100A9, and S100A12 in the serum of AMI patients compared to normal individuals. Immunohistochemical staining of heart tissue from MI mice showed a progressive increase in the expression of CXCL8 and IL-1B as MI advanced, while S100A9 exhibited high expression at day 3 post-MI. mRNA expression analysis validated these findings. Additionally, we explored the skin lesions of psoriasis patients and found significantly higher expression of CXCL8, IL-1B, S100A9, and S100A12 in the affected skin areas compared to unaffected regions. These results highlight the consistent upregulation of hub genes in both AMI and psoriasis patients, as well as in myocardial infarction mice, underscoring their potential as reliable markers for disease diagnosis. Moreover, molecular docking simulations revealed potential interactions between simvastatin and key target proteins, suggesting a potential therapeutic avenue. Overall, our study uncovers shared molecular signatures and potential therapeutic targets, providing a foundation for future investigations targeting common pathways in psoriasis and AMI.
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    文章类型: Journal Article
    炎症性肠病是一种慢性免疫介导的疾病,具有复发和缓解的过程。它会导致胃肠道症状,生活质量低,以及医疗保健利用和相关成本的重大负担。因此,早期诊断和随访需要非侵入性生物标志物,以避免侵入性诊断程序的并发症.钙粒蛋白C是一种具有促炎特性的钙结合蛋白。这项研究的目的是评估血清钙粒蛋白C作为诊断和预测活性的非侵入性生物标志物的作用,与炎症性肠病中不同的生物标志物和内窥镜活性评分进行比较。该研究包括80例炎症性肠病患者(50例溃疡性结肠炎和30例Chron's患者)和20例正常对照。完整的血液照片,C反应蛋白,红细胞沉降率,测定粪便钙卫蛋白和血清钙粒蛋白C。进行了结肠镜检查和组织病理学检查,并评估了不同的活性评分系统。在溃疡性结肠炎组中,与对照组相比,血清钙粒蛋白C在统计学上显着升高[723.640±529.055ng/ml与80.850±24.416ng/ml]。根据美国胃肠病学会溃疡性结肠炎活动指数,在中度至重度溃疡性结肠炎中,粪便钙卫蛋白和血清钙粒蛋白C在统计学上显着高于轻度活动和缓解期的患者(两者均p<0.001)。关于克罗恩病的组,与对照组相比,血清钙粒蛋白C在统计学上显着升高[759.233±797.963ng/ml与80.850±24.416ng/mL]。根据克罗恩的疾病活动指数,在活动性疾病中,血清钙粒蛋白C和粪便钙卫蛋白在统计学上均显着高于缓解期(两者均p<0.001)。总之,血清钙粒蛋白C可作为一种非侵入性标志物来预测活动性和严重程度,并确保炎症性肠病患者的缓解。
    Inflammatory bowel disease is a chronic immune-mediated disorder with a relapsing and remitting course. It leads to disabling gastrointestinal symptoms, low quality of life, and a significant burden for healthcare utilization and associated costs. Therefore, non-invasive biomarkers are needed for early diagnosis and follow up to avoid the complications of invasive diagnostic procedures. Calgranulin C is a calcium binding protein with proinflammatory properties. The aim of this study was to evaluate the role of serum calgranulin C as a non-invasive biomarker for diagnosis and prediction of activity in comparison to different biomarkers and endoscopic activity scores in inflammatory bowel disease. The study included 80 inflammatory bowel disease patients (50 Ulcerative colitis and 30 Chron\'s patients) and 20 normal controls. Complete blood picture, C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin and serum calgranulin C were measured. Colonoscopies with histopathological examination were done and different activity scoring systems assessed. Among ulcerative colitis group, serum calgranulin C was statistically significantly higher in comparison to control group [723.640±529.055 ng/ml versus 80.850±24.416 ng/ml]. Depending on the American college of gastroenterology ulcerative colitis activity index, fecal calprotectin and serum calgranulin C were statistically significantly higher among moderate to severe ulcerative colitis than those with mild activity and those in remission (p < 0.001, for both). Regarding Crohn\'s disease group, serum calgranulin C was statistically significantly higher in comparison to control group [759.233±797.963 ng/ml versus 80.850±24.416 ng/mL]. Depending on Crohn\'s disease activity index, both serum calgranulin C and fecal calprotectin were statistically significantly higher among active disease than those in remission (p < 0.001, for both). In conclusion, serum calgranulin C could be used as a non-invasive marker to predict activity and severity and to ensure remission among inflammatory bowel disease patients.
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  • 文章类型: Journal Article
    背景:幼年特发性关节炎(JIA)包括一组异质性疾病,可导致明显的残疾和生活质量下降。关于临床反应预测因子的数据不足以指导为个体患者选择合适的生物制剂。这项研究旨在调查S100A8/9和S100A12作为多关节病程幼年特发性关节炎(pJIA)中abatacept反应的预测生物标志物的倾向。
    方法:本探索性分析使用了一项针对活动性pJIA患者(n=219)皮下abatacept的3期试验(NCT01844518)的数据。评估了基线生物标志物水平与JIA-American风湿病学会(ACR)标准反应或基线疾病活动(通过使用C反应蛋白[JADAS27-CRP]在27个关节中的青少年关节炎疾病活动评分测量)的改善之间的关联。评估从基线到第4个月的生物标志物水平变化,以预测长达21个月的疾病结果。
    结果:在基线时,158名患者有可用的生物标志物样本。较低的基线S100A8/9水平(≤3295ng/mL)与达到JIA-ACR90的更大几率相关(优势比[OR]:2.54[95%置信区间(CI):1.25-5.18]),JIA-ACR100(OR:3.72[95%CI:1.48-9.37]),JIA-ACR非活动性疾病(ID;OR:4.25[95%CI:2.03-8.92]),第4个月JADAS27-CRPID(OR:2.34[95%CI:1.02-5.39]),第16个月JIA-ACRID(OR:3.01[95%CI:1.57-5.78])。较低的基线S100A12水平(≤176ng/mL)与达到JIA-ACR90的几率更大相关(OR:2.52[95%CI:1.23-5.13]),JIA-ACR100(OR:3.68[95%CI:1.46-9.28]),JIA-ACRID(OR:3.66[95%CI:1.76-7.61]),JIA-ACR90(OR:2.03[95%CI:1.07-3.87]),JIA-ACR100(OR:2.14[95%CI:1.10-4.17]),和JIA-ACRID(OR:4.22[95%CI:2.15-8.29]),在16个月。从基线到第4个月,在JIA-ACR90/100/ID应答者中,S100A8/9和S100A12的下降通常超过50%。
    结论:较低的S100A8/9和S100A12蛋白基线水平预测对abatacept治疗的反应优于较高水平,并且可能作为pJIA的早期预测生物标志物。这些生物标志物水平的降低也可以预测pJIA对abatacept的长期反应。
    BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA).
    METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months.
    RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders.
    CONCLUSIONS: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
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  • 文章类型: Journal Article
    免疫-炎症途径在心肌梗死的发展中起关键作用。然而,很少有研究使用生物信息学分析系统探讨免疫相关基因与心肌梗死预后的关系。我们的研究旨在鉴定ST段抬高型心肌梗死(STEMI)患者中差异表达的免疫相关基因(DEIRG),并探讨其与临床预后的关系。
    我们对基因表达综合数据集进行了系统评价,选择GSE49925、GSE60993和GSE61144进行分析。使用GEO2R鉴定DEIRG,并在所选数据集中重叠。功能富集分析阐明了DEIRGs的生物学功能和途径。我们使用LASSO惩罚Cox比例风险回归建立了最佳预后预测模型。通过生存分析评估签名的临床效用,ROC曲线评估,和决策曲线分析。此外,我们构建了预测生存率的预后列线图.使用我们自己的血浆样品进行外部验证。
    所得到的预后特征整合了两个失调的DEIRG(S100A12和IL2RB)和两个临床变量(血清肌酐水平和Gensini评分)。这种特征有效地将患者分为低风险和高风险组。生存分析,ROC曲线分析,和决策曲线分析在疾病发作后的头两年内证明了其强大的预测性能和临床实用性。外部验证证实了风险组之间的显著结果差异。
    我们的研究为STEMI患者建立了结合DEIRGs和临床变量的预后特征。该特征显示了对患者分层和生存风险评估的有希望的预测能力。
    UNASSIGNED: The immune-inflammatory pathway plays a critical role in myocardial infarction development. However, few studies have systematically explored immune-related genes in relation to myocardial infarction prognosis using bioinformatic analysis. Our study aims to identify differentially expressed immune-related genes(DEIRGs) in ST-segment elevation myocardial infarction (STEMI) patients and investigate their association with clinical outcomes.
    UNASSIGNED: We conducted a systematic review of Gene Expression Omnibus datasets, selecting GSE49925, GSE60993, and GSE61144 for analysis. DEIRGs were identified using GEO2R and overlapped across the chosen datasets. Functional enrichment analysis elucidated the DEIRGs\' biological functions and pathways. We established an optimal prognostic prediction model using LASSO penalized Cox proportional hazards regression. The signature\'s clinical utility was evaluated through survival analysis, ROC curve assessment, and decision curve analysis. Additionally, we constructed a prognostic nomogram for survival rate prediction. External validation was performed using our own plasma samples.
    UNASSIGNED: The resulting prognostic signature integrated two dysregulated DEIRGs (S100A12 and IL2RB) and two clinical variables (serum creatinine level and Gensini score). This signature effectively stratified patients into low- and high-risk groups. Survival analysis, ROC curve analysis, and decision curve analysis demonstrated its robust predictive performance and clinical utility within the first two years post-disease onset. External validation confirmed significant outcome differences between risk groups.
    UNASSIGNED: Our study establishes a prognostic signature that combines DEIRGs and clinical variables for STEMI patients. The signature exhibits promising predictive capabilities for patient stratification and survival risk assessment.
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  • 文章类型: Journal Article
    尽管静脉内免疫球蛋白(IVIG)抵抗的川崎病(KD)表现出持续的血管炎症刺激和冠状动脉扩张的风险增加。然而,该病的发病机制尚不清楚,没有确定的生物标志物来预测其发生。本研究拟探讨S100A12/TLR2相关信号分子和临床指标在IVIG耐药KD预测建模中的实用性。根据IVIG治疗反应对受试者进行分类:IVIG敏感KD组206例,IVIG耐药KD组49例。采用Real-timePCR检测患者外周血单个核细胞中S100A12、TLR2、MYD88和NF-κB的表达,在收集人口特征的同时,临床表现,和KD儿童的实验室测试结果。多因素二元logistic回归分析确定降钙素原(PCT)水平(≥0.845ng/mL),Na水平(≤136.55mmol/L),和S100A12的相对表达水平(≥10.224)作为IVIG耐药KD的独立危险因素,并建立了具有良好预测能力的新评分模型来预测IVIG耐药KD的发生。
    Although intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) presents with persistent inflammatory stimulation of the blood vessels and an increased risk of coronary artery dilatation. However, the pathogenesis of this disease is unclear, with no established biomarkers to predict its occurrence. This study intends to explore the utility of S100A12/TLR2-related signaling molecules and clinical indicators in the predictive modeling of IVIG-resistant KD. The subjects were classified according to IVIG treatment response: 206 patients in an IVIG-sensitive KD group and 49 in an IVIG-resistant KD group. Real-time PCR was used to measure the expression of S100A12, TLR2, MYD88, and NF-κB in peripheral blood mononuclear cells of patients, while collecting demographic characteristics, clinical manifestations, and laboratory test results of KD children. Multi-factor binary logistic regression analysis identified procalcitonin (PCT) level (≥ 0.845 ng/mL), Na level (≤ 136.55 mmol/L), and the relative expression level of S100A12 (≥ 10.224) as independent risk factors for IVIG-resistant KD and developed a new scoring model with good predictive ability to predict the occurrence of IVIG-resistant KD.
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  • 文章类型: Journal Article
    S100蛋白的结构和功能由两个不同的钙结合EF手基序调节。在这项工作中,我们使用溶液状态NMR光谱研究了两个钙结合位点之间的协同性,并绘制了靶结合位点的变构变化图.为了解析各个钙结合事件的贡献,S100A12的变体被设计为选择性地将钙与EF-I(N63A)或EF-II(E31A)环结合,分别。对野生型蛋白及其突变体的主链化学位移的详细分析表明,钙与规范的EF-II环的结合是“封闭的”apo与“开放的”Ca2结合的构象之间构象转换的主要触发因素。蛋白质的构象。消除S100特异性EF-I环中的结合对EF-II环的钙结合亲和力和伴随的结构重排具有有限的影响。相比之下,EF-II环中结合的缺失显着减弱了EF-I环中的钙亲和力,并且该结构采用“闭合”apo样构象。实验酰胺氮(15N)弛豫率的分析(R1,R2,和15N-{1H}NOE)和分子动力学(MD)模拟表明,钙结合态相对松弛,在负责靶标识别的功能相关域(例如铰链域和C-末端残基)中诱导了皮纳秒运动。与MD模拟相结合的实验松弛研究表明,尽管EF-I环中的钙结合单独不会诱导多肽链中的显着运动,EF-I在EF-II环中结合钙的存在下调节多肽的波动。这些结果为钙结合对靶标识别的动态调节提供了新的见解,并揭示了S100A12中两个钙结合事件之间的协同作用。
    Structure and functions of S100 proteins are regulated by two distinct calcium binding EF hand motifs. In this work, we used solution-state NMR spectroscopy to investigate the cooperativity between the two calcium binding sites and map the allosteric changes at the target binding site. To parse the contribution of the individual calcium binding events, variants of S100A12 were designed to selectively bind calcium to either the EF-I (N63A) or EF-II (E31A) loop, respectively. Detailed analysis of the backbone chemical shifts for wildtype protein and its mutants indicates that calcium binding to the canonical EF-II loop is the principal trigger for the conformational switch between \'closed\' apo to the \'open\' Ca2+ -bound conformation of the protein. Elimination of binding in S100-specific EF-I loop has limited impact on the calcium binding affinity of the EF-II loop and the concomitant structural rearrangement. In contrast, deletion of binding in the EF-II loop significantly attenuates calcium affinity in the EF-I loop and the structure adopts a \'closed\' apo-like conformation. Analysis of experimental amide nitrogen (15 N) relaxation rates (R1 , R2 , and 15 N-{1 H} NOE) and molecular dynamics (MD) simulations demonstrate that the calcium bound state is relatively floppy with pico-nanosecond motions induced in functionally relevant domains responsible for target recognition such as the hinge domain and the C-terminal residues. Experimental relaxation studies combined with MD simulations show that while calcium binding in the EF-I loop alone does not induce significant motions in the polypeptide chain, EF-I regulates fluctuations in the polypeptide in the presence of bound calcium in the EF-II loop. These results offer novel insights into the dynamic regulation of target recognition by calcium binding and unravels the role of cooperativity between the two calcium binding events in S100A12.
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  • 文章类型: Journal Article
    骨关节炎(OA)是一种退行性关节疾病,影响全球数百万人。滑膜炎和巨噬细胞极化是OA发展的重要身分。然而,滑液(SF)中促进巨噬细胞极化的具体成分尚不清楚.
    半定量抗体阵列用于概述SF的蛋白质组。对获得的数据进行差异表达分析和GO/KEGG。采用免疫组织化学和ELISA检测临床标本中SFS100A12水平与滑膜炎水平的关系。进行体外细胞实验以研究S100A12对巨噬细胞极化的影响。公共数据库用于预测和构建以S100A12为中心的lncRNA-miRNA-mRNA竞争内源性RNA网络,使用GEO数据集进行了初步验证。
    该研究概述了OA和非OASF中的蛋白质谱。成果显示S100A12水平在OASF和炎性软骨细胞中显著增高。与非OA滑膜相比,OA滑膜具有更严重的滑膜炎和更高水平的S100A12。外源性S100A12上调M1标记和磷酸化p65的水平,促进p65核易位,而用BAY11-7082预处理逆转了这些变化。还发现LINC00894在OA中上调并且与S100A12显著相关,潜在地通过充当miRNA海绵来调节S100A12表达。
    这项研究表明,S100A12通过NF-κB途径促进M1巨噬细胞极化,并发现LINC00894有潜力调控S100A12的表达作为治疗途径。
    Osteoarthritis (OA) is a degenerative joint disease that affects millions worldwide. Synovitis and macrophage polarization are important factors in the development of OA. However, the specific components of synovial fluid (SF) responsible for promoting macrophage polarization remain unclear.
    Semi-quantitative antibody arrays were used to outline the proteome of SF. Differential expression analysis and GO/KEGG were performed on the obtained data. Immunohistochemistry and ELISA were used to investigate the relationship between SF S100A12 levels and synovitis levels in clinalclinical samples. In vitro cell experiments were conducted to investigate the effect of S100A12 on macrophage polarization. Public databases were utilized to predict and construct an S100A12-centered lncRNA-miRNA-mRNA competing endogenous RNA network, which was preliminarily validated using GEO datasets.
    The study outlines the protein profile in OA and non-OA SF. The results showed that the S100A12 level was significantly increased in OA SF and inflammatory chondrocytes. The OA synovium had more severe synovitis and higher levels of S100A12 than non-OA synovium. Exogenous S100A12 upregulated the levels of M1 markers and phosphorylated p65 and promoted p65 nuclear translocation, while pretreatment with BAY 11-7082 reversed these changes. It was also discovered that LINC00894 was upregulated in OA and significantly correlated with S100A12, potentially regulating S100A12 expression by acting as a miRNA sponge.
    This study demonstrated that S100A12 promotes M1 macrophage polarization through the NF-κB pathway, and found that LINC00894 has the potential to regulate the expression of S100A12 as a therapeutic approach.
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  • 文章类型: Observational Study
    背景:乳腺癌是全球女性癌症死亡的第二大常见原因。反直觉,基于大型人群的回顾性试验报告,与乳房切除术相比,保乳手术(BCS)后的生存率更高,校正肿瘤和患者变量。更广泛的手术组织损伤和伤害性刺激对交感神经系统的激活与免疫抑制有关。我们假设乳房切除术会导致血浆损伤相关分子模式(DAMPs)的表达更高,且术中交感神经激活更多,从而引起术后免疫失调。免疫抑制可导致术后并发症并影响无瘤生存。
    方法:在这项前瞻性观察研究中,血浆DAMPs(HMGB1,HSP70,S100A8/A9和S100A12),术中交感神经激活(疼痛水平(NOL)指数从0到100),在接受选择性BCS(n=20)和乳房切除术(n=20)的患者中,比较了术后免疫功能(血浆细胞因子浓度和离体细胞因子产生能力)。
    结果:TNF的离体细胞因子生产能力,两组在手术后1小时几乎没有IL-6和IL-1β。水平在术后第3天(POD3)出现恢复,与乳房切除术相比,BCS后IL-1β的离体生产能力显着提高(p=0.041)。乳房切除术后1小时,IL-6的血浆浓度更高(p=.045)。乳房切除术后POD3的血浆警报S100A8/A9和S100A12的浓度显着升高(分别为p=.003和p=.041)。回归分析显示,当校正去甲肾上腺素当量时,乳房切除术期间NOL测量值≤8(没有伤害感受)的百分比显着降低(分别为36%和45%,p=.038)。所有患者中NOL测量值≤8的百分比与POD3上IL-1β和TNF的离体细胞因子产生能力相关(r=.408;p=.011和r=.500;p=.001,分别)。
    结论:这项初步研究显示,在BCS和乳房切除术后早期出现实质性的免疫抑制,并在随后的几天内恢复。BCS和乳房切除术在DAMPs释放和术中交感神经激活方面的差异可能会影响术后免疫稳态,从而有助于在先前基于人群的大型回顾性试验中BCS后报告的更好的生存率。这些结果支持进一步探索(1)S100警报作为乳腺癌手术的潜在治疗靶标,以及(2)抑制术中交感神经激活以证实观察到的与术后免疫失调的关联。
    BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival.
    METHODS: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20).
    RESULTS: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1β was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1β after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1β and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively).
    CONCLUSIONS: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.
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  • 文章类型: Journal Article
    背景:脓毒症,以全身炎症反应综合征和危及生命的器官功能障碍为特征,仍然是全球残疾和死亡的重要原因。尽管有影响,脓毒症诊断的可靠生物标志物尚待确定.
    目的:本研究旨在通过对多个微阵列数据集的分析来调查和鉴定脓毒症中的关键基因和途径,为未来的临床试验提供潜在的治疗目标。
    方法:从基因表达综合(GEO)数据库下载两个独立的基因表达谱(GSE54514和GSE69528)。合并和批量规范化后,使用“limma”软件包获得差异表达基因(DEGs)。使用“R”软件进行基因本体论(GO)和基因集富集分析(GSEA)。使用用于检索相互作用基因(STRING)的搜索工具构建蛋白质-蛋白质相互作用(PPI)网络。使用Cytoscape鉴定了前10个hub基因。构建并评估了预测脓毒症发生的列线图模型。
    结果:210例败血症和91例对照血液样本的生物信息学分析鉴定出72DEGs。GO分析揭示了与免疫反应过程的关联。GSEA表明参与关键信号通路。S100A12、MMP9和PRTN3是脓毒症的独立危险因素。
    结论:本研究通过生物信息学方法揭示了脓毒症的关键基因和途径。S100A12、MMP9和PRTN3可能在对感染的免疫反应中发挥重要作用。影响脓毒症预后。
    BACKGROUND: Sepsis, characterized by systemic inflammatory response syndrome and life-threatening organ dysfunction, remains a significant global cause of disability and death. Despite its impact, reliable biomarkers for sepsis diagnosis are yet to be identified.
    OBJECTIVE: This study aims to investigate and identify key genes and pathways in sepsis through the analysis of multiple microarray datasets, providing potential treatment targets for future clinical trials.
    METHODS: Two independent gene expression profiles (GSE54514 and GSE69528) were downloaded from the Gene Expression Omnibus (GEO) database. After merging and batch normalization, differentially expressed genes (DEGs) were obtained using the \"limma\" package. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were performed using \"R\" software. A Protein-Protein Interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING). The top 10 hub genes were identified using Cytoscape. A Nomogram model for predicting sepsis occurrence was constructed and evaluated.
    RESULTS: Bioinformatic analysis of 210 sepsis and 91 control blood samples identified 72 DEGs. GO analyses revealed associations with immune response processes. GSEA indicated involvement in key signaling pathways. S100A12, MMP9, and PRTN3 were identified as independent risk factors for sepsis.
    CONCLUSIONS: This study unveils critical genes and pathways in sepsis through bioinformatic methods. S100A12, MMP9, and PRTN3 may play essential roles in the immune response to infection, influencing sepsis prognosis.
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