Mediators of Inflammation最新文献_第9页

Pan-Cancer Analysis of the Cuproptosis-Related Gene DLD 铜臭相关基因DLD的泛癌分析

IF 4.6 3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-30 DOI: 10.1155/2023/5533444

Jiahui Lin, Guowei Wang, Sha Cheng, Yanan Hu, Huan Li, Wanjiang Feng, Xiaoming Liu, Canxia Xu

Background. Cancer affects millions of people each year and imposes a huge economic and social burden worldwide. Cuproptosis is a recently discovered novel mode of cell death. The exact function of the cuproptosis-related gene dihydrolipoamide dehydrogenase (DLD) and its role in pan-cancer is unknown. Methods. Data were retrieved from the GTEx, TCGA, and multiple online websites. These data were used to assess the expression, prognosis, and diagnostic value of DLD in various tumors. The relationship of DLD with immune microenvironment immunomodulators, immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI), and oncology drug sensitivity was explored by correlation analysis. Results. The mRNA and protein expression of DLD differs in most cancers. Survival analysis showed that DLD was associated with prognosis with KIRC, KIRP, KICH, and UCS. DLD had a strong diagnostic value in KIRC, GBM, PAAD, and LGG (AUC > 0.9). DLD promoter methylation affects the aberrant expression of LIHC, LUSC, PAAD, READ, and THCA. DLD was negatively correlated with stromal score, immune score, and ESTIMATE score in UCEC, TGCT, LUSC, and SARC. In UCS, resting memory CD4 T cells and activated NK cells were significantly correlated with DLD expression. Significant correlations were also observed between DLD expression and immunomodulators, immune checkpoints, TMB, and MSI in various cancers. Importantly, we also identified a number of potential drugs that may target DLD. Conclusion. DLD expression is associated with a variety of tumor prognoses and plays an integral role in tumorigenesis, tumor metabolism, and immunity.

背景。癌症每年影响数百万人，并在全世界造成巨大的经济和社会负担。铜细胞死亡是最近发现的一种新的细胞死亡方式。铜腐病相关基因二氢脂酰胺脱氢酶(DLD)的确切功能及其在泛癌中的作用尚不清楚。方法。数据从GTEx, TCGA和多个在线网站检索。这些数据被用来评估DLD在各种肿瘤中的表达、预后和诊断价值。通过相关分析探讨DLD与免疫微环境免疫调节剂、免疫检查点、肿瘤突变负荷(TMB)、微卫星不稳定性(MSI)、肿瘤药物敏感性的关系。结果。DLD的mRNA和蛋白表达在大多数癌症中是不同的。生存分析显示，DLD与KIRC、KIRP、KICH和UCS的预后相关。DLD对KIRC、GBM、PAAD和LGG有较强的诊断价值(AUC > 0.9)。DLD启动子甲基化影响LIHC、LUSC、PAAD、READ和THCA的异常表达。DLD与UCEC、TGCT、LUSC和SARC的基质评分、免疫评分和ESTIMATE评分呈负相关。在UCS中，静息记忆CD4 T细胞和活化NK细胞与DLD表达显著相关。在各种癌症中，DLD表达与免疫调节剂、免疫检查点、TMB和MSI之间也存在显著相关性。重要的是，我们还确定了一些可能针对DLD的潜在药物。结论。DLD表达与多种肿瘤预后相关，在肿瘤发生、肿瘤代谢和免疫中起着不可或缺的作用。

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引用次数: 0

Comparison of Inflammatory Cytokine Levels in Hepatic and Jugular Veins of Patients with Cirrhosis 肝硬化患者肝、颈静脉炎性细胞因子水平的比较

IF 4.6 3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-29 DOI: 10.1155/2023/9930902

Leonard Kaps, Carolina Medina-Montano, Matthias Bros, Stephan Grabbe, Simon Johannes Gairing, Eva M. Schleicher, Stephan Gehring, Jörn M. Schattenberg, Peter R. Galle, Marcus-Alexander Wörns, Michael Nagel, Christian Labenz

Background. Systemic inflammation with elevated inflammatory cytokines is a hallmark in patients with cirrhosis and the main driver of decompensation. There is insufficient data on whether inflammatory cytokine levels differ between hepatic and jugular veins, which may have implications for further immunological studies. Methods. Blood from the hepatic and jugular veins of 40 patients with cirrhosis was collected during hepatic venous pressure gradient (HVPG) measurements. Serum levels of 13 inflammatory cytokines (IL-1β, Int-α2, Int-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33) were quantified by cytometric bead array. Results. Cytokine levels of IFN-α2, IFN-γ, TNF-α, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-23, and IL-33 were significantly elevated in patients with decompensated cirrhosis compared to patients with compensated cirrhosis. When comparing patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) to patients without CSPH, there were significantly enhanced serum levels of IL-6 and IL-18 in the former group. There was no significant difference between cytokine serum levels between blood obtained from the jugular versus hepatic veins. Even in subgroup analyses stratified for an early cirrhosis stage (Child-Pugh (CP) A) or more decompensated stages (CP B/C), cytokine levels were similar. Conclusion. Cytokine levels increase with decompensation and increasing portal hypertension in patients with cirrhosis. There is no relevant difference in cytokine levels between hepatic and jugular blood in patients with cirrhosis.

背景。炎症细胞因子升高的全身性炎症是肝硬化患者的标志，也是代偿失代偿的主要驱动因素。关于肝静脉和颈静脉之间炎症细胞因子水平是否不同的数据不足，这可能对进一步的免疫学研究有影响。方法。采集40例肝硬化患者的肝静脉和颈静脉血液，测量肝静脉压梯度(HVPG)。采用细胞头阵列法测定血清中13种炎症因子(IL-1β、Int-α2、Int-γ、TNF-α、MCP-1、IL-6、IL-8、IL-10、IL-12p70、IL-17A、IL-18、IL-23、IL-33)的水平。结果。与代偿性肝硬化患者相比，失代偿性肝硬化患者的IFN-α2、IFN-γ、TNF-α、IL-6、IL-8、IL-10、IL-17A、IL-18、IL-23和IL-33的细胞因子水平显著升高。将有临床意义的门脉高压(CSPH, HVPG≥10 mmHg)患者与无CSPH患者进行比较，前者血清IL-6、IL-18水平显著升高。颈静脉与肝静脉的血清细胞因子水平无显著差异。即使在早期肝硬化阶段(Child-Pugh (CP) A)或更多失代偿期(CP B/C)的亚组分析中，细胞因子水平也相似。结论。细胞因子水平随着肝硬化患者失代偿和门静脉高压的增加而升高。肝硬化患者肝血和颈血细胞因子水平无相关差异。

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引用次数: 0

Abdominal Aortic Occlusion and the Inflammatory Effects in Heart and Brain 腹主动脉闭塞与心脑炎症作用

IF 4.6 3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-28 DOI: 10.1155/2023/2730841

Jun Xu, Sijie Li, Alexandra Wehbe, Xunming Ji, Yong Yang, Yu Yang, Linhui Qin, Feng-Yong Liu, Yuchuan Ding, Changhong Ren

Background. Abdominal aortic occlusion (AAO) occurs frequently and causes ischemia/reperfusion (I/R) injury to distant organs. In this study, we aimed to investigate whether AAO induced I/R injury and subsequent damage in cardiac and neurologic tissue. We also aimed to investigate the how length of ischemic time in AAO influences reactive oxygen species (ROS) production and inflammatory marker levels in the heart, brain, and serum. Methods. Sixty male C57BL/6 mice were used in this study. The mice were randomly divided into either sham group or AAO group. The AAO group was further subdivided into 1–4 hr groups of aortic occlusion times. The infrarenal abdominal aorta was clamped for 1–4 hr depending on the AAO group and was then reperfused for 24 hr after clamp removal. Serum, hippocampus, and left ventricle tissue samples were then subjected to biochemical and histopathological analyses. Results. AAO-induced I/R injury had no effect on cell necrosis, cell apoptosis, or ROS production. However, serum and hippocampus levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH) increased in AAO groups when compared to sham group. Superoxide dismutase and total antioxidant capacity decreased in the serum, hippocampus, and left ventricle. In the serum, AAO increased the level of inducible nitric oxide synthase (iNOS) and decreased the levels of anti-inflammatory factors (such as arginase-1), transforming growth factor- β1 (TGF-β1), interleukin 4 (IL-4), and interleukin 10 (IL-10). In the hippocampus, AAO increased the levels of tumor necrosis factor (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), IL-4, and IL-6, and decreased the level of TGF-β1. In the left ventricle, AAO increased the level of iNOS and decreased the levels of TGF-β1, IL-4, and IL-10. Conclusions. AAO did not induce cell necrosis or apoptosis in cardiac or neurologic tissue, but it can cause inflammation in the serum, brain, and heart.

背景。腹主动脉阻塞(AAO)是一种常见的腹主动脉阻塞，可引起远端器官缺血/再灌注(I/R)损伤。在这项研究中，我们旨在研究AAO是否会引起心脏和神经组织的I/R损伤和随后的损伤。我们还旨在研究AAO缺血时间的长短对心脏、大脑和血清中活性氧(ROS)产生和炎症标志物水平的影响。方法。本研究选用60只雄性C57BL/6小鼠。将小鼠随机分为假手术组和AAO组。AAO组按主动脉阻塞时间进一步细分为1 ~ 4小时组。根据AAO组的不同，夹住腹主动脉1-4小时，然后在取下夹后再灌注24小时。然后对血清、海马和左心室组织样本进行生化和组织病理学分析。结果。aao诱导的I/R损伤对细胞坏死、细胞凋亡或ROS的产生没有影响。然而，与假手术组相比，AAO组血清和海马中丙二醛(MDA)和乳酸脱氢酶(LDH)水平升高。血清、海马和左心室超氧化物歧化酶和总抗氧化能力下降。在血清中，AAO提高了诱导型一氧化氮合酶(iNOS)水平，降低了抗炎因子(如精氨酸酶-1)、转化生长因子-β1 (TGF-β1)、白细胞介素4 (IL-4)、白细胞介素10 (IL-10)水平。AAO使海马组织中肿瘤坏死因子(TNF-α)、白细胞介素1β (IL-1β)、白细胞介素6 (IL-6)、IL-4、IL-6水平升高，TGF-β1水平降低。在左心室，AAO升高iNOS水平，降低TGF-β1、IL-4、IL-10水平。结论。AAO不会引起心脏或神经组织的细胞坏死或凋亡，但会引起血清、脑和心脏的炎症。

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引用次数: 0

Cell-Specific Regulation of Inflammatory Cytokines and Acute-Phase Proteins by the Glucocorticoid Receptor 糖皮质激素受体对炎症细胞因子和急性期蛋白的细胞特异性调节

IF 4.6 3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-28 DOI: 10.1155/2023/4399998

Rebecca Winkler, Hong Lu

Background. Literature and data mining found abnormal induction of chemokine (C-X-C motif) ligand 1 (CXCL1) and CXCL8 and down-regulation of CXCL2 in inflammatory liver diseases. This study was performed to understand the glucocorticoid receptor’s (GR’s) effects on chemokine and acute-phase protein expression in human liver, in settings of bacterial infection (modeled using LPS) or inflammation (modeled using TNFα). Methods. Primary human hepatocytes (PHH) were treated with combinations of tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), and dexamethasone (DEX) for 24 h, following which chemokine mRNA and protein expression were analyzed using qPCR and enzyme-linked immunosorbent assay assays. Dual luciferase assays were performed on transfected cell lines. Mutant CXCL2 promoters were used in dual luciferase assays to identify specific regions of the CXCL2 promoter affected by GR, TNFα, or hepatocyte nuclear factor 4α (HNF4α, a liver-enriched transcription factor). Results. In PHH from donor 1, GR strongly inhibited LPS-induced CXCL1 and CXCL8 translation and transcription, whereas CXCL2 transcription tended to increase with DEX treatment. In PHH from donor 2, DEX treatment inhibited protein expression and secretion of CXCL1 and CXCL8 induced by TNFα and/or LPS, whereas CXCL2 upregulation was largely unaffected by DEX treatment. In nonliver HEK293T cells GR activity inhibited CXCL2 promoter activity. However, in liver-derived HEPG2 cells, GR induced CXCL2 promoter activity. A 407-base pair region upstream of CXCL2 promoter is necessary for full GR functionality in HEPG2 cells. TNFα synergized with HNF4α in inducing CXCL2 promoter activity in HEPG2 cells. Conclusions. GR’s effects on chemokine expression are cell-type specific and chemokine specific. GR down-regulated CXCL1 and CXCL8 in different cell types, whereas the specific activation of CXCL2 in hepatocytes and down-regulation of CXCL2 in nonhepatocytes by GR appears due to cell-specific utilization of CXCL2 promoter. By specifically increasing GR activity in the liver, we may normalize chemokine imbalances and prevent sepsis in inflammatory liver diseases.

背景。文献和数据挖掘发现，趋化因子(C-X-C基序)配体1 (CXCL1)和CXCL8在炎症性肝病中的异常诱导以及CXCL2的下调。本研究旨在了解糖皮质激素受体(GR)在细菌感染(用LPS模拟)或炎症(用TNFα模拟)环境下对人肝脏趋化因子和急性期蛋白表达的影响。方法。采用肿瘤坏死因子α (TNFα)、脂多糖(LPS)和地塞米松(DEX)联合治疗原代人肝细胞(PHH) 24 h，采用qPCR和酶联免疫吸附法分析趋化因子mRNA和蛋白的表达。对转染细胞系进行双荧光素酶测定。突变型CXCL2启动子用于双荧光素酶测定，以确定CXCL2启动子受GR、TNFα或肝细胞核因子4α (HNF4α，一种肝脏富集转录因子)影响的特定区域。结果。在供体1的PHH中，GR强烈抑制lps诱导的CXCL1和CXCL8的翻译和转录，而CXCL2的转录则随着DEX的处理而增加。在供体2的PHH中，DEX抑制了TNFα和/或LPS诱导的CXCL1和CXCL8的蛋白表达和分泌，而CXCL2的上调在很大程度上不受DEX的影响。在非肝脏HEK293T细胞中，GR活性抑制CXCL2启动子活性。然而，在肝源性HEPG2细胞中，GR诱导CXCL2启动子活性。在HEPG2细胞中，CXCL2启动子上游的一个407碱基对区域是完全GR功能所必需的。TNFα与HNF4α协同诱导HEPG2细胞CXCL2启动子活性。结论。GR对趋化因子表达的影响具有细胞类型特异性和趋化因子特异性。GR在不同细胞类型中下调CXCL1和CXCL8，而GR在肝细胞中特异性激活CXCL2和在非肝细胞中下调CXCL2是由于细胞特异性利用CXCL2启动子。通过特异性地增加肝脏中的GR活性，我们可以使趋化因子失衡正常化，并预防炎症性肝病中的败血症。

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引用次数: 1

Association between the Systemic Immune-Inflammation Index and Thyroid Function in U.S. Adults. 美国成年人全身免疫炎症指数与甲状腺功能之间的关系

IF 4.6 3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-16 eCollection Date: 2023-01-01 DOI: 10.1155/2023/5831858

Xin-Yu Hu, Ying-Chao Liang, Huan-Huan Zhang, Hui-Lin Li, De-Liang Liu

Background: The systemic immune-inflammation index (SII) is used as an indicator of prognosis for a wide range of diseases. Thyroid function has been found to be strongly associated with inflammation. The purpose of this investigation was to analyze the correlation between SII and various thyroid functions.

Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2007-2012. The association between SII and thyroid function was analyzed using weighted univariate and multivariate linear regression analyses. Subgroup analyses, interaction tests, and weighted restricted cubic spline (RCS) regression analyses were also employed to test this correlation.

Results: Of the 6,875 participants (age ≥ 20 years), the mean age was 46.87 ± 0.40 years. The adjusted model showed that lnSII was negatively correlated with FT3 (β = -0.0559, 95% CI -0.1060 to -0.0059,) and FT3/FT4 (β = -0.0920, 95% CI -0.1667 to -0.0173,). There was a positive correlation between lnSII and TT4 (β = 0.1499, 95% CI 0.0722-0.2276,). In subgroup analyses, lnSII still independently affected a wide range of thyroid functions. Weighted RCS analysis showed a nonlinear relationship between FT3 and lnSII.

Conclusion: Close relationships exist between SII and a variety of thyroid functions. SII can be used as an indicator to predict thyroid dysfunction. Control of inflammatory activity may be a protective measure against thyroid dysfunction. More large-scale prospective studies are necessary to further explore the correlation between SII and thyroid function and the role of obesity in this.

背景:全身免疫炎症指数(SII)被广泛用作疾病预后的指标。甲状腺功能已被发现与炎症密切相关。本研究的目的是分析SII与各种甲状腺功能之间的相关性。方法:本研究利用2007-2012年国家健康与营养检查调查(NHANES)的数据。采用加权单变量和多变量线性回归分析SII与甲状腺功能之间的关系。亚组分析、相互作用检验和加权限制性三次样条(RCS)回归分析也被用来检验这种相关性。结果:6875名参与者(年龄≥20岁)，平均年龄46.87±0.40岁。调整后的模型显示，lnSII与FT3 (β = -0.0559, 95% CI -0.1060 ~ -0.0059，)和FT3/FT4 (β = -0.0920, 95% CI -0.1667 ~ -0.0173，)呈负相关。lnSII与TT4呈正相关(β = 0.1499, 95% CI 0.0722-0.2276，)。在亚组分析中，lnSII仍然独立影响广泛的甲状腺功能。加权RCS分析显示FT3与lnSII之间存在非线性关系。结论:SII与多种甲状腺功能有密切关系。SII可作为预测甲状腺功能障碍的指标。控制炎症活动可能是预防甲状腺功能障碍的一种保护措施。需要更多的大规模前瞻性研究来进一步探讨SII与甲状腺功能的相关性以及肥胖在其中的作用。

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引用次数: 0

Integrative Analysis of Clinical and Bioinformatics Databases to Reveal the Role of Peripheral Innate Immunity in Kawasaki Disease 临床和生物信息学数据库的综合分析揭示外周先天免疫在川崎病中的作用

3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-14 DOI: 10.1155/2023/6699050

Hongjun Ba, Lili Zhang, Huimin Peng, Jixun Lin, Youzhen Qin, Yao Wang

Kawasaki disease (KD) is an immune-response disorder with unknown etiology. KD is an acute systemic immune vasculitis caused by infectious factors that can be complicated by coronary artery lesions. Innate immune cells are closely associated with KD onset, but we know little regarding the expression of immunity-related genes (IRGs) and the possible immune regulatory mechanisms involved in KD. In this study, we analyzed public single-cell RNA sequencing (scRNA-seq) and microarray data of peripheral blood mononuclear cells from normal controls and KD patients. The results of scRNA-seq revealed myeloid cells, T cells, B cells, NK cells, erythrocytes, platelets, plasma cells, hematopoietic stem cells, and progenitor cells in the peripheral blood of patients with KD. In particular, myeloid cells were expanded and heterogeneous. Further analysis of the myeloid cell population revealed that monocytes in KD exhibited higher expression of the inflammatory genes S100A8, S100A9, and S100A12; furthermore, CD14+CD16+ monocyte clusters were associated with inflammatory responses. Microarray data revealed that activation of the innate immune response contributed to KD development and progression. Differential expression and weighted gene coexpression network analysis identified 48 differentially expressed IRGs associated with response to intravenous immunoglobulin, currently the most effective treatment of KD, although numerous patients are resistant. Protein–protein interaction analysis identified ten hub genes (IL1R1, SOCS3, IL1R2, TLR8, IL1RN, CCR1, IL1B, IL4R, IL10RB, and IFNGR1) among the IRGs. In addition, the expressions of IL1R1, SOCS3, CCR1, IL1B, and IL10RB were validated in Chinese KD patients using the real-time reverse transcriptase-polymerase chain reaction. Finally, we found that the neutrophil/lymphocyte ratio could be used as a biomarker to predict responsiveness to intravenous immunoglobulin in KD. In conclusion, our data highlight the importance of innate immunity in KD pathogenesis and its potential in predicting treatment response.

川崎病是一种病因不明的免疫反应性疾病。KD是一种由感染因素引起的急性全身性免疫性血管炎，可并发冠状动脉病变。先天性免疫细胞与KD发病密切相关，但我们对免疫相关基因(IRGs)的表达和KD可能涉及的免疫调节机制知之甚少。在这项研究中，我们分析了来自正常对照和KD患者外周血单个核细胞的公开单细胞RNA测序(scRNA-seq)和微阵列数据。scRNA-seq结果显示，KD患者外周血中存在髓系细胞、T细胞、B细胞、NK细胞、红细胞、血小板、浆细胞、造血干细胞和祖细胞。特别是骨髓细胞扩增且呈异质性。对骨髓细胞群的进一步分析显示，KD中的单核细胞表现出更高的炎症基因S100A8、S100A9和S100A12的表达;此外，CD14+CD16+单核细胞簇与炎症反应相关。微阵列数据显示，先天免疫反应的激活有助于KD的发展和进展。差异表达和加权基因共表达网络分析确定了48个与静脉注射免疫球蛋白反应相关的差异表达IRGs，静脉注射免疫球蛋白是目前治疗KD最有效的方法，尽管许多患者具有耐药性。蛋白-蛋白互作分析鉴定出IRGs中的10个枢纽基因(IL1R1、SOCS3、IL1R2、TLR8、IL1RN、CCR1、IL1B、IL4R、IL10RB和IFNGR1)。此外，采用实时逆转录聚合酶链反应验证了中国KD患者中IL1R1、SOCS3、CCR1、IL1B和IL10RB的表达。最后，我们发现中性粒细胞/淋巴细胞比率可以作为预测KD患者静脉注射免疫球蛋白反应性的生物标志物。总之，我们的数据强调了先天免疫在KD发病机制中的重要性及其在预测治疗反应方面的潜力。

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引用次数: 0

Contribution of m5C RNA Modification-Related Genes to Prognosis and Immunotherapy Prediction in Patients with Ovarian Cancer m5C RNA修饰相关基因对卵巢癌患者预后和免疫治疗预测的贡献

3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-13 DOI: 10.1155/2023/1400267

Yibin Liu, Shouze Liu, Lu Yan, Qianqian Zhang, Wenhua Liu, Xianghua Huang, Shikai Liu

Background. 5-Methylcytosine (m5C) RNA modification is closely implicated in the occurrence of a variety of cancers. Here, we established a novel prognostic signature for ovarian cancer (OC) patients based on m5C RNA modification-related genes and explored the correlation between these genes with the tumor immune microenvironment. Methods. Methylated-RNA immunoprecipitation sequencing helped us to identify candidate genes related to m5C RNA modification at first. Based on TCGA database, we screened the differentially expressed candidate genes related to the prognosis and constructed a prognostic model using LASSO Cox regression analyses. Notably, the accuracy of the model was evaluated by Kaplan–Meier analysis and receiver operator characteristic curves. Independent prognostic risk factors were investigated by Cox proportional hazard model. Furthermore, we also analyzed the biological functions and pathways involved in the signature. Finally, the immune response of the model was visualized in great detail. Results. Totally, 2,493 candidate genes proved to be involved in m5C modification of RNA for OC. We developed a signature with prognostic value consisting of six m5C RNA modification-related genes. Specially, samples have been split into two cohorts with low- and high-risk scores according to the model, in which the low-risk OC patients exhibited dramatically better overall survival time than those with high-risk scores. Besides, not only was this model a prognostic factor independent of other clinical characteristics but it predicted the intensity of the immune response in OC. Significantly, the accuracy and availability of the signature were verified by ICGC database. Conclusions. Our study bridged the gap between m5C RNA modification and the prognosis of OC and was expected to provide an effective breakthrough for immunotherapy in OC patients.

背景:5-甲基胞嘧啶(m5C) RNA修饰与多种癌症的发生密切相关。在此，我们基于m5C RNA修饰相关基因建立了卵巢癌(OC)患者预后的新特征，并探讨了这些基因与肿瘤免疫微环境的相关性。方法。甲基化RNA免疫沉淀测序帮助我们首先确定了与m5C RNA修饰相关的候选基因。基于TCGA数据库，筛选与预后相关的差异表达候选基因，采用LASSO Cox回归分析构建预后模型。值得注意的是，通过Kaplan-Meier分析和接收算子特征曲线来评估模型的准确性。采用Cox比例风险模型调查独立预后危险因素。此外，我们还分析了该信号的生物学功能和信号通路。最后，对模型的免疫反应进行了详细的可视化。结果。总共有2493个候选基因被证明参与了OC RNA的m5C修饰。我们开发了一个由六个m5C RNA修饰相关基因组成的具有预后价值的标记。特别的是，根据该模型，样本被分为低风险和高风险两组，其中低风险OC患者的总生存时间明显优于高风险OC患者。此外，该模型不仅是一个独立于其他临床特征的预后因素，而且可以预测OC的免疫反应强度。重要的是，ICGC数据库验证了签名的准确性和可用性。结论。我们的研究填补了m5C RNA修饰与OC预后之间的空白，有望为OC患者的免疫治疗提供有效的突破。

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引用次数: 0

Jia-Wei-Kai-Xin-San Treatment Alleviated Mild Cognitive Impairment through Anti-Inflammatory and Antiapoptotic Mechanisms in SAMP8 Mice. 加味开心散治疗通过抗炎和抗凋亡机制减轻SAMP8小鼠轻度认知障碍。

IF 4.6 3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-02 eCollection Date: 2023-01-01 DOI: 10.1155/2023/7807302

Xiaolu Zhang, Yingxin Sun, Qun Yu, Wenyun Zeng, Yue Zhang, Miao Zeng, Kexin Pang, Yifei Yu, Jiali Gan, Huhu Li, Lin Yang, Xijuan Jiang

Background: Alleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer's disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI.

Methods: MCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl's/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells.

Results: It was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus.

Conclusion: JWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

背景:减轻轻度认知障碍(MCI)对于延缓阿尔茨海默病(AD)的进展至关重要。加味凯心散(JWKXS)应用于MCI治疗AD。然而，JWKXS治疗MCI的机制尚不清楚。因此，本研究旨在探讨JWKXS在SAMP8小鼠MCI模型中的作用及其机制。方法:建立MCI模型，检测SAMP8小鼠在4、6、8月龄时的学习记忆能力，探讨其脑内病理机制。小鼠治疗8周后，采用Morris水迷宫法、HE/尼氏/免疫组化染色法观察JWKXS对MCI的影响。结合UPLC-Q-TOF/MS和系统药理学分析预测其作用机制，并在SAMP8小鼠、BV2小胶质细胞和PC12细胞上进一步验证。结果:发现4月龄SAMP8小鼠出现轻度认知损伤。JWKXS治疗2个月后，大鼠学习记忆能力提高，海马组织和神经元损伤减轻。通过网络药理学研究发现JWKXS治疗MCI涉及TLR4/NF-κB通路、NLRP3炎性小体激活、内源性和外源性凋亡四个关键信号通路。体外和体内实验表明，JWKXS通过抑制小胶质细胞活化，抑制TLR4/NF-κB和NLRP3炎性小体通路，阻断外源性和内源性凋亡通路，从而抑制海马神经元凋亡，从而减轻神经炎症。结论:JWKXS治疗可提高MCI大鼠的学习记忆能力，并通过诱导抗炎症和抗细胞凋亡发挥神经保护作用。的局限性。干预的样本量小，持续时间短，限制了对机制的深入研究。未来的前景。这为进一步明确抗ad机制提供了方向，并为该制剂走向临床提供了一定的数据支持。

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引用次数: 0

RhoA Promotes Synovial Proliferation and Bone Erosion in Rheumatoid Arthritis through Wnt/PCP Pathway RhoA通过Wnt/PCP通路促进类风湿关节炎滑膜增生和骨侵蚀

3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-11-01 DOI: 10.1155/2023/5057009

Ning Chen, Chao-Yue Diao, Xin Huang, Wei-Xing Tan, Ya-Bing Chen, Xin-Yu Qian, Jie Gao, Dong-Bao Zhao

Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.

Ras同源基因家族成员A (RhoA)在Wnt/平面细胞极性(PCP)通路中起重要作用，该通路在类风湿关节炎(RA)患者中显著激活。RhoA在RA滑膜炎和骨侵蚀中的作用尚不清楚。在这里，我们不仅探讨了RhoA对RA成纤维细胞样滑膜细胞(FLSs)增殖和侵袭的影响，还阐明了其对小鼠破骨细胞和小鼠胶原诱导关节炎(CIA)模型的影响。结果显示RhoA在RA和CIA滑膜组织中过表达。慢病毒介导的RhoA沉默增加了ra - fls的凋亡，减弱了侵袭，并显著上调了骨保护素/核因子-κB受体激活物配体(OPG/RANKL)比率。此外，RhoA沉默抑制小鼠体外破骨细胞分化，减轻CIA小鼠滑膜增生和骨侵蚀。这些作用在RA-FLSs和破骨细胞中均受RhoA/ RhoA相关蛋白激酶2 (ROCK2)调控，并可能与Janus激酶/信号转导和转录激活因子(JAK/STAT)通路相互作用。

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引用次数: 0

Identifying Macrophage-Related Genes in Ulcerative Colitis Using Weighted Coexpression Network Analysis and Machine Learning 利用加权共表达网络分析和机器学习识别溃疡性结肠炎中巨噬细胞相关基因

3区医学 Q2 CELL BIOLOGY

Mediators of Inflammation

Pub Date : 2023-10-25 DOI: 10.1155/2023/4373840

Shaocheng Hong, Hongqian Wang, Shixin Chan, Jiayi Zhang, Bangjie Chen, Xiaohan Ma, Xi Chen

Ulcerative colitis (UC) is an inflammatory bowel disease of unknown cause that typically affects the colon and rectum. Innate intestinal immunity, including macrophages, plays a significant role in the pathological development of UC. Using the CIBERSORT algorithm, we observed elevated levels of 22 types of immune cell infiltrates, as well as increased M1 and decreased M2 macrophages in UC compared to normal colonic mucosa. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with macrophages and UC, resulting in the identification of 52 macrophage-related genes (MRGs) that were enriched in macrophages at single-cell resolution. Consensus clustering based on these 52 MRGs divided the integrated UC cohorts into three subtypes. Machine learning algorithms were used to identify ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14), and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the training set, and their diagnostic value was validated in independent validation sets. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) revealed the main biological effects, and that interleukin-17 was one of several signaling pathways enriched by the three genes. We also constructed a competitive endogenous RNA (CeRNA) network reflecting a potential posttranscriptional regulatory mechanism. Expression of diagnostic markers was validated in vivo and in biospecimens, and our immunohistochemistry (IHC) results confirmed that HMGCS2 gradually decreased during the transformation of UC to colorectal cancer. In conclusion, ENPP1, SLC6A14, and HMGCS2 are associated with macrophages and the progression of UC pathogenesis and have good diagnostic value for patients with UC.

溃疡性结肠炎(UC)是一种病因不明的炎症性肠病，通常影响结肠和直肠。包括巨噬细胞在内的先天肠道免疫在UC的病理发展中起着重要作用。使用CIBERSORT算法，我们观察到与正常结肠粘膜相比，UC中22种免疫细胞浸润水平升高，M1巨噬细胞增加，M2巨噬细胞减少。加权基因共表达网络分析(WGCNA)用于鉴定与巨噬细胞和UC相关的模块，鉴定出52个巨噬细胞相关基因(MRGs)，这些基因在单细胞分辨率下富集于巨噬细胞中。基于这52个mrg的共识聚类将UC队列分为三个亚型。利用机器学习算法识别训练集中的外核苷酸焦磷酸酶/磷酸二酯酶1 (ENPP1)、钠和氯依赖的中性和碱性氨基酸转运蛋白B(0+) (SLC6A14)和3-羟基-3-甲基戊二酰辅酶a合成酶2 (HMGCS2)，并在独立验证集中验证其诊断价值。基因集富集分析(GSEA)和基因集变异分析(GSVA)揭示了主要的生物学效应，白介素-17是这三个基因富集的几种信号通路之一。我们还构建了一个竞争性内源性RNA (CeRNA)网络，反映了潜在的转录后调控机制。在体内和生物标本中验证了诊断标志物的表达，我们的免疫组织化学(IHC)结果证实了HMGCS2在UC向结直肠癌的转化过程中逐渐减少。综上所述，ENPP1、SLC6A14、HMGCS2与巨噬细胞及UC发病进展相关，对UC患者具有良好的诊断价值。

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引用次数: 0