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The role of cellular senescence in the pathogenesis of Rheumatoid Arthritis: Focus on IL-6 as a target gene 细胞衰老在类风湿关节炎发病机制中的作用:关注作为靶基因的 IL-6
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1016/j.cyto.2024.156762
Fengxia Xu , Zhen Li , Tao Liu , Xue Pang , Chang Fan , Hui Jiang

Background

Rheumatoid arthritis is a chronic autoimmune disease. However, the specific role of senescence in rheumatoid arthritis (RA) is unknown. This study aimed to identify potential aging-related genes that have diagnostic and therapeutic value for RA.

Methods

The GSE89408 dataset was downloaded from the Gene Expression Omnibus (GEO). Aging-related genes were downloaded from the HAGR database. Differentially expressed genes (DEGs) were subsequently identified with the “edgeR” tool. Next, hub genes were identified with a PPI network and CytoHubba analysis. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of these hub genes. Immune infiltration analysis was performed with the CIBERSORT algorithm. Additionally, molecular docking was performed with CB-Dock2. Finally, correlation experiments were performed to validate the bioinformatics and molecular docking results.

Results

A total of 22 ADEGs were identified. Combined PPI network and CytoHubba analyses identified a total of 7 hub genes, including IL-6, IL7R, IL2RG, CDK1, PTGS2, and LEP, which are associated mainly with inflammation and immune responses. ROC analysis revealed that the hub genes were highly predictive of RA. Analysis of immune infiltration revealed that the 6 hub genes were positively associated with M1 macrophages. Validation experiments revealed that the inhibition of IL-6 significantly decreased the degree of synovial fibroblast (FLS) senescence. Furthermore, molecular docking and validation experiments revealed that IL-6 is a potential target for drug therapy.

Conclusion

This study demonstrated that RA-FLS senescence may promote the development of RA via inflammatory and immune mechanisms. Seven hub genes were identified, of which IL-6 is a reliable biomarker for the diagnosis and treatment of RA.
背景类风湿性关节炎是一种慢性自身免疫性疾病。然而,衰老在类风湿性关节炎(RA)中的具体作用尚不清楚。本研究旨在鉴定对类风湿关节炎有诊断和治疗价值的潜在衰老相关基因。方法从基因表达总库(GEO)下载 GSE89408 数据集。衰老相关基因从 HAGR 数据库下载。随后使用 "edgeR "工具鉴定了差异表达基因(DEGs)。接着,通过 PPI 网络和 CytoHubba 分析确定了枢纽基因。接收者操作特征曲线(ROC)用于评估这些中心基因的诊断价值。利用 CIBERSORT 算法进行了免疫浸润分析。此外,还使用 CB-Dock2 进行了分子对接。最后,进行了相关实验来验证生物信息学和分子对接的结果。结合 PPI 网络和 CytoHubba 分析,共发现了 7 个枢纽基因,包括 IL-6、IL7R、IL2RG、CDK1、PTGS2 和 LEP,它们主要与炎症和免疫反应有关。ROC分析显示,这些中枢基因对RA具有高度预测性。免疫浸润分析显示,6个中心基因与M1巨噬细胞呈正相关。验证实验显示,抑制IL-6可显著降低滑膜成纤维细胞(FLS)的衰老程度。此外,分子对接和验证实验显示,IL-6是药物治疗的潜在靶点。本研究发现了七个枢纽基因,其中 IL-6 是诊断和治疗 RA 的可靠生物标志物。
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引用次数: 0
The assessment of usefulness of cytokines and other soluble mediators as the predictors of sequalae development in various forms of tick-borne encephalitis (TBE) 评估细胞因子和其他可溶性介质作为各种蜱传脑炎(TBE)后遗症发展预测因子的作用
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1016/j.cyto.2024.156767
Piotr Czupryna , Anna Moniuszko-Malinowska , Gabriela Trojan , Justyna Adamczuk , Diana Martonik , Anna Parfieniuk-Kowerda , Ewelina Kruszewska , Maciej Giecko , Sambor Grygorczuk

Aim

The aim of the study was to assess the usefulness of cytokines and other soluble mediators in differentiation between severe and mild course of tick-borne encephalitis (TBE) as well as the predictor of sequalae development.

Material and methods

122 patients (mean age 47.66 ± 14.77 years, 43 females, 79 males) with TBE were included in the study.
Concentrations of 82 cytokines, growth factors, selectins, matrix metalloproteinases and other soluble mediators were measured in serum and CSF samples according to the manufacturer’s instruction on a Bio-Plex 200 System using the custom made Luminex assays. Enzyme-linked immunosorbent assays for the quantitative detection of human IL-26, IL-29 IL-22, CXCL12 were performed.

Results

No significant differences between serum concentrations of examined factors between group with sequelae and group with complete recovery were observed.
In the CSF the concentrations of GM-CSF, Il-1α, Il-2, Il-4, Il-6, Il-12p70, Il-17A, CXCL1, CXCL6, Il-8, CCL4, CCL20, TRAIL, CD40L, MMP8 were significantly higher in patients who developed sequelae than in patients with complete recovery.
For TRAIL concentration over 26.65 pg/ml in CSF the probability of sequalae development was 10.5 higher. In case of CCL20 – the concentration over 21.38 pg/ml in CSF the odds ratio was 6.429 times. For MMP-8 over 4210.54 pg/ml, the odds ratio was 11.222 times.

Conclusions

TRAIL, CCL-20 and MMP-8 are promising biomarkers of prediction of the sequalae development of TBE.
Pro-inflammatory cytokines IL-8, IL-1, IL-2, IL-12, IL-17A also associate well with the risk of sequelae and could be further evaluated as prognostic markers in TBE, individually or as elements of a larger model.
研究旨在评估细胞因子和其他可溶性介质在区分蜱传脑炎(TBE)重度和轻度病程中的作用,以及预测后遗症发展的作用。血清和脑脊液样本中 82 种细胞因子、生长因子、选择素、基质金属蛋白酶和其他可溶性介质的浓度均按照制造商的说明在 Bio-Plex 200 系统上使用定制的 Luminex 分析方法进行了测定。结果后遗症组和完全康复组血清中被检因子的浓度无明显差异。在脑脊液中,后遗症患者的 GM-CSF、Il-1α、Il-2、Il-4、Il-6、Il-12p70、Il-17A、CXCL1、CXCL6、Il-8、CCL4、CCL20、TRAIL、CD40L、MMP8 的浓度明显高于完全康复患者。CCL20--CSF中浓度超过21.38 pg/ml的几率比为6.429倍。结论TRAIL、CCL-20 和 MMP-8 是预测肺结核后遗症发生的有希望的生物标志物。前炎症细胞因子 IL-8、IL-1、IL-2、IL-12、IL-17A 也与后遗症风险密切相关,可作为肺结核的预后标志物单独或作为更大模型的元素进行进一步评估。
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引用次数: 0
Skin wound repairing effects of adipose mesenchymal stem cells is promoted by the combined application of insulin-like growth factor 1: The key role of miR-21-5p-mediated signaling transduction 联合应用胰岛素样生长因子1促进脂肪间充质干细胞的皮肤伤口修复效应:miR-21-5p介导的信号转导的关键作用
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1016/j.cyto.2024.156760
Shuo Cui , Linlei Wang , Huafei Zhao , Fei Lu , Yuhua Chen , Yadong Gu
Mesenchymal stem cells (ADMSCs) have been applied to the treatment of skin injuries and the co-administration of cytokines can enhance the effects. In the current study, the promoting effects of insulin-like growth factor 1 (IGF-1) on the skin wound healing effects of adipose-derived MSCs (ADMSCs) were assessed and the associated mechanism was explored by focusing on miR-21-5p mediated pathways. ADMSCs were isolated from epididymis rats, and skin wounded rats were employed as the in vivo model for evaluating the effect of ADMCs on skin healing and secretion of cytokines. Then a microarray assay was employed to select potential miR target of IGF-1 on ADMSCs. The level of the selected miR was modulated in ADMSCs, and the effects on skin injuries were also assessed. Administration of ADMSCs promoted skin wound healing and induced the production of bFGF, IL-1β, PDGF, SDF-1, IGF-1, and TNF-α. The co-administration of IGF-1 and ADMSCs strengthened the effect of ADMSCs on skin wound by suppressing activity of matrix metalloproteinase-1 (MMP-1). At molecular level, the treatment of IGF-1 up-regulated miR-21-5p level in ADMSCs, which then suppressed the expression of KLF6 in injured skin tissues and promoted wound healing. The inhibition of miR-21-5p counteracted the promoting effects of IGF-1 on the skin healing effects of ADMSCs. Findings outlined in the current study indicated that IGF-1 could promote the wound healing effects of ADMSCs by up-regulating miR-21-5p level.
间充质干细胞(ADMSCs)已被应用于治疗皮肤损伤,联合使用细胞因子可增强其效果。本研究评估了胰岛素样生长因子1(IGF-1)对脂肪间充质干细胞(ADMSCs)皮肤伤口愈合效果的促进作用,并通过关注miR-21-5p介导的途径探讨了相关机制。研究人员从附睾大鼠体内分离出 ADMSCs,并以皮肤损伤大鼠为体内模型,评估 ADMCs 对皮肤愈合和细胞因子分泌的影响。然后用芯片分析法筛选出 IGF-1 在 ADMSCs 上的潜在 miR 靶标。研究人员调节了所选 miR 在 ADMSCs 中的水平,并评估了其对皮肤损伤的影响。给予 ADMSCs 可促进皮肤伤口愈合,并诱导产生 bFGF、IL-1β、PDGF、SDF-1、IGF-1 和 TNF-α。通过抑制基质金属蛋白酶-1(MMP-1)的活性,IGF-1 和 ADMSCs 的联合应用加强了 ADMSCs 对皮肤伤口的作用。在分子水平上,IGF-1能上调ADMSCs中的miR-21-5p水平,进而抑制KLF6在受伤皮肤组织中的表达,促进伤口愈合。抑制 miR-21-5p 可抵消 IGF-1 对 ADMSCs 皮肤愈合作用的促进作用。本研究概述的结果表明,IGF-1 可通过上调 miR-21-5p 水平促进 ADMSCs 的伤口愈合作用。
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引用次数: 0
Zinc pathogenic importance in correcting immunity and restoring public health in the post-COVID period: An overview 锌致病剂在后 COVID 时期纠正免疫和恢复公众健康方面的重要性:概述
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-21 DOI: 10.1016/j.cyto.2024.156761
Maria Sankova , Vladimir Nikolenko , Marine Oganesyan , Yurii Vinnik , Liliya Gavryushova , Sofya Redina , Negorya Rizaeva , Aleksey Sankov , Kirill Bulygin , Andzhela Vovkogon , André Pontes-Silva , Yury Zharikov

Context: The problem of correcting immune system function and compensating for co-morbidities becomes particularly clinically significant in the post-COVID period. There is evidence that certain trace elements in the human body, particularly zinc ions, play a critical role in restoring the function of the immune system and internal organs. Objective: To analyze the mechanisms of zinc action maintaining the body homeostasis in order to justify pathogenetically the inclusion of zinc drugs in the therapy of patients in the post-COVID period. Methods: Data from Elsevier, Global Health, PubMed-NCBI, Embase, MEDLINE, Scopus, Research gate, RSCI Scopus, Cochrane Library, Google Academy, e-LIBRARY.RU and CyberLeninka were used. Results: This review showed that the importance of zinc in maintaining body homeostasis in the post-COVID period is determined by its multifaceted effect on all parts of the immune system, its anti-inflammatory activity, antimicrobial properties and participation in the restoration of internal organ function. Elimination of zinc deficiency in the post-COVID period is essential to support immunity, compensate for comorbidities and reduce the risk of complications. The impossibility of synthesizing zinc in the body requires its constant intake in sufficient quantities. Zinc levels are significantly reduced after infectious diseases, as this element is specifically distributed to organs and tissues to maintain immunological and metabolic functions. The degree of zinc deficiency is associated with the severity of COVID-19 and the post-COVID period. It is pathogenetically justified to prescribe zinc drugs in the post-COVID period, the choice of which should take into account comorbidities and severity of hypozincemia. Conclusion: Regularly administered therapy with zinc drugs in the post-COVID period will help correct the population immunity and restore public health.

背景:在后 COVID 期,纠正免疫系统功能和补偿并发症的问题在临床上变得尤为重要。有证据表明,人体内的某些微量元素,尤其是锌离子,在恢复免疫系统和内脏器官功能方面发挥着至关重要的作用。研究目的分析锌在维持机体平衡方面的作用机制,以便从病理学角度证明将锌药物纳入后 COVID 期患者的治疗中是合理的。研究方法数据来源:Elsevier、Global Health、PubMed-NCBI、Embase、MEDLINE、Scopus、Research gate、RSCI Scopus、Cochrane Library、Google Academy、e-LIBRARY.RU 和 CyberLeninka。结果综述显示,锌对免疫系统各部分的多方面影响、抗炎活性、抗菌特性以及参与内脏器官功能的恢复,决定了锌在 COVID 后时期维持机体平衡的重要性。在后 COVID 期间消除锌缺乏症对于支持免疫力、补偿并发症和降低并发症风险至关重要。由于体内无法合成锌,因此需要不断摄入足量的锌。感染性疾病后,体内的锌含量会明显降低,因为这种元素专门分布在器官和组织中,以维持免疫和新陈代谢功能。缺锌的程度与 COVID-19 的严重程度和 COVID 后的时期有关。从病理学角度来看,在 COVID 后时期处方锌药物是合理的,但在选择药物时应考虑到合并症和低锌血症的严重程度。结论在禽流感后时期定期使用锌药物治疗将有助于纠正人群免疫力和恢复公众健康。
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引用次数: 0
Associations between per- and poly-fluoroalkyl substance (PFAS) exposure and immune responses among women in the California Teachers study: A cross-sectional evaluation 加利福尼亚教师研究中女性接触全氟和多氟烷基物质 (PFAS) 与免疫反应之间的关系:横断面评估
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1016/j.cyto.2024.156753
Emily L. Cauble , Peggy Reynolds , Marta Epeldegui , Syam S. Andra , Larry Magpantay , Srinivasan Narasimhan , Divya Pulivarthi , Julie Von Behren , Otoniel Martinez-Maza , Debbie Goldberg , Emma S. Spielfogel , James V. Lacey Jr. , Sophia S. Wang

Introduction

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that have been linked to a number of health outcomes, including those related to immune dysfunction. However, there are limited numbers of epidemiological-based studies that directly examine the association between PFAS exposure and immune responses.

Methods

In this cross-sectional study nested in the California Teachers Study cohort, we measured nine PFAS analytes in serum. Of the 9 analytes, we further evaluated four (PFHxS [perfluorohexane sulfonate], PFNA [perfluorononanoic acid], PFOA [perfluorooctanoic acid], PFOS [perfluorooctanesulfonic acid]) that had detection levels of > 80 %, in relation to 16 systemic inflammatory/immune markers and corresponding immune pathways (Th1 [pro-inflammatory/macrophage activation], B-cell activation, and T-cell activation). Study participants (n = 722) were female, completed a questionnaire regarding various health measures and behaviors, and donated a blood sample between 2013–2016. The association between PFAS analytes and individual immune markers and pathways were evaluated by calculating odds ratios (OR) and 95 % confidence intervals (CI) in a logistic regression model. PFAS analytes were evaluated both as a dichotomous exposure (above or below the respective median) and as a continuous variable (per 1 unit increase [ng/mL]).

Results

The prevalence of detecting any PFAS analyte rose with increasing age, with the highest PFAS prevalence observed among those aged 75 + years and the lowest PFAS prevalence observed among those aged 40–49 years (study participant age range: 40–95 years). Significant associations with BAFF (B-cell activating factor) levels above the median were observed among participants with elevated (defined as above the median) levels of PFHxS (OR=1.53), PFOA (OR=1.43), and PFOS (OR=1.40). Similarly, there were statistically significant associations between elevated levels of PFHxS and TNFRII (tumor necrosis factor receptor 2) levels (OR=1.78) and IL2Rα (interleukin 2 receptor subunit alpha) levels (OR=1.48). We also observed significant inverse associations between elevated PFNA and sCD14 (soluble cluster of differentiation 14) (OR=0.73). No significant associations were observed between elevated PFNA and any immune marker. Evaluation of PFAS exposures as continuous exposures in association with dichotomized cytokines were generally consistent with the dichotomized associations.

Conclusions

PFAS exposure was associated with altered levels of circulating inflammatory/immune markers; the associations were specific to PFAS analyte and immune marker. If validated, our results may suggest potential immune mechanisms underlying associations between the different PFAS analytes and adverse health outcomes.

引言 全氟和多氟烷基物质(PFAS)是一种持久性环境污染物,与许多健康结果有关,包括与免疫功能障碍有关的健康结果。方法 在这项嵌套于加州教师研究队列的横断面研究中,我们测量了血清中的九种全氟辛烷磺酸分析物。在这 9 种分析物中,我们进一步评估了 4 种(PFHxS [全氟己烷磺酸]、PFNA [全氟壬酸]、PFOA [全氟辛酸]、PFOS [全氟辛烷磺酸])与 16 种全身炎症/免疫标记物和相应免疫途径(Th1 [促炎症/巨噬细胞活化]、B 细胞活化和 T 细胞活化)的关系,这些标记物的检测水平为 80%。研究参与者(n = 722)均为女性,填写了有关各种健康措施和行为的问卷,并在 2013-2016 年间捐献了血液样本。通过在逻辑回归模型中计算几率比(OR)和 95 % 置信区间(CI),评估了 PFAS 分析物与单个免疫标记物和免疫途径之间的关联。PFAS分析物既作为二分暴露量(高于或低于各自的中位数),也作为连续变量(每增加1个单位[纳克/毫升])进行评估。结果检测到任何PFAS分析物的流行率随着年龄的增加而上升,75岁以上人群的PFAS流行率最高,40-49岁人群的PFAS流行率最低(研究参与者年龄范围:40-95岁)。在 PFHxS(OR=1.53)、PFOA(OR=1.43)和 PFOS(OR=1.40)水平升高(定义为高于中位数)的参与者中,观察到与 BAFF(B 细胞活化因子)水平高于中位数有显著关联。同样,PFHxS 水平升高与 TNFRII(肿瘤坏死因子受体 2)水平(OR=1.78)和 IL2Rα(白细胞介素 2 受体亚基 alpha)水平(OR=1.48)之间也存在统计学意义上的显著关联。我们还观察到 PFNA 升高与 sCD14(可溶性分化簇 14)之间存在明显的反向关系(OR=0.73)。未观察到 PFNA 升高与任何免疫标记物之间存在明显关联。结论 PFAS 暴露与循环炎症/免疫标记物水平的改变有关;这种关联与 PFAS 分析物和免疫标记物有关。如果得到验证,我们的研究结果可能表明不同的全氟辛烷磺酸分析物与不良健康结果之间存在潜在的免疫机制。
{"title":"Associations between per- and poly-fluoroalkyl substance (PFAS) exposure and immune responses among women in the California Teachers study: A cross-sectional evaluation","authors":"Emily L. Cauble ,&nbsp;Peggy Reynolds ,&nbsp;Marta Epeldegui ,&nbsp;Syam S. Andra ,&nbsp;Larry Magpantay ,&nbsp;Srinivasan Narasimhan ,&nbsp;Divya Pulivarthi ,&nbsp;Julie Von Behren ,&nbsp;Otoniel Martinez-Maza ,&nbsp;Debbie Goldberg ,&nbsp;Emma S. Spielfogel ,&nbsp;James V. Lacey Jr. ,&nbsp;Sophia S. Wang","doi":"10.1016/j.cyto.2024.156753","DOIUrl":"10.1016/j.cyto.2024.156753","url":null,"abstract":"<div><h3>Introduction</h3><p>Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that have been linked to a number of health outcomes, including those related to immune dysfunction. However, there are limited numbers of epidemiological-based studies that directly examine the association between PFAS exposure and immune responses.</p></div><div><h3>Methods</h3><p>In this cross-sectional study nested in the California Teachers Study cohort, we measured nine PFAS analytes in serum. Of the 9 analytes, we further evaluated four (PFHxS [perfluorohexane sulfonate], PFNA [perfluorononanoic acid], PFOA [perfluorooctanoic acid], PFOS [perfluorooctanesulfonic acid]) that had detection levels of &gt; 80 %, in relation to 16 systemic inflammatory/immune markers and corresponding immune pathways (Th1 [pro-inflammatory/macrophage activation], B-cell activation, and T-cell activation). Study participants (n = 722) were female, completed a questionnaire regarding various health measures and behaviors, and donated a blood sample between 2013–2016. The association between PFAS analytes and individual immune markers and pathways were evaluated by calculating odds ratios (OR) and 95 % confidence intervals (CI) in a logistic regression model. PFAS analytes were evaluated both as a dichotomous exposure (above or below the respective median) and as a continuous variable (per 1 unit increase [ng/mL]).</p></div><div><h3>Results</h3><p>The prevalence of detecting any PFAS analyte rose with increasing age, with the highest PFAS prevalence observed among those aged 75 + years and the lowest PFAS prevalence observed among those aged 40–49 years (study participant age range: 40–95 years). Significant associations with BAFF (B-cell activating factor) levels above the median were observed among participants with elevated (defined as above the median) levels of PFHxS (OR=1.53), PFOA (OR=1.43), and PFOS (OR=1.40). Similarly, there were statistically significant associations between elevated levels of PFHxS and TNFRII (tumor necrosis factor receptor 2) levels (OR=1.78) and IL2Rα (interleukin 2 receptor subunit alpha) levels (OR=1.48). We also observed significant inverse associations between elevated PFNA and sCD14 (soluble cluster of differentiation 14) (OR=0.73). No significant associations were observed between elevated PFNA and any immune marker. Evaluation of PFAS exposures as continuous exposures in association with dichotomized cytokines were generally consistent with the dichotomized associations.</p></div><div><h3>Conclusions</h3><p>PFAS exposure was associated with altered levels of circulating inflammatory/immune markers; the associations were specific to PFAS analyte and immune marker. If validated, our results may suggest potential immune mechanisms underlying associations between the different PFAS analytes and adverse health outcomes.</p></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"184 ","pages":"Article 156753"},"PeriodicalIF":3.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043466624002576/pdfft?md5=8df70d8434ceffdffcbc9b3c792bf5e5&pid=1-s2.0-S1043466624002576-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142238976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Old drug, new use: Recent advances for G-CSF 老药新用:G-CSF 的最新进展
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1016/j.cyto.2024.156759
Lun Yan , Jing Li , Yang Yang , Xi Zhang , Cheng Zhang

Granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3 (CSF3), is a proinflammatory cytokine that primarily stimulates the survival, proliferation, differentiation and function of neutrophil granulocyte progenitor cells and mature neutrophils. Over the past years, G-CSF has mainly been used to cure patients with neutropenia and as a part of chemotherapy to induct the remission for refractory/relapse leukemia. Recent studies showed that C-CSF can been used as condition regimens and as a part of preventive methods after allogeneic transplantation to improve the survival of patients and also has immunoregulation, and has promote or inhibit the proliferation of solid tumors. Therefore, in this review, we firstly describe the structure for G-CSF. Then its functions and mechanism were reviewed including the neutrophil mobilization, differentiation, migration, and inhibiting apoptosis of neutrophils, and its immunoregulation. Finally, the clinical applications were further discussed.

粒细胞集落刺激因子(G-CSF)又称集落刺激因子 3(CSF3),是一种促炎细胞因子,主要刺激中性粒细胞祖细胞和成熟中性粒细胞的存活、增殖、分化和功能。多年来,G-CSF 主要用于治疗中性粒细胞减少症患者,并作为化疗的一部分,诱导难治性/复发性白血病患者病情缓解。最近的研究表明,C-CSF 可作为同种异体移植后的条件疗法和预防方法的一部分,以提高患者的生存率,同时还具有免疫调节作用,并能促进或抑制实体瘤的增殖。因此,在这篇综述中,我们首先描述了 G-CSF 的结构。然后综述了其功能和机制,包括中性粒细胞动员、分化、迁移、抑制中性粒细胞凋亡以及免疫调节。最后,进一步讨论了其临床应用。
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引用次数: 0
IL-33/ST2 enhances MMP-12 expression by macrophages to mediate inflammatory and immune response in IgG4-Related Ophthalmic Disease IL-33/ST2 可增强巨噬细胞 MMP-12 的表达,从而介导 IgG4 相关眼病的炎症和免疫反应
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1016/j.cyto.2024.156754
Xia Ding , Yu Yu , Dai Su , Ming Lin , Mingjiao Chen , Yue Xing , Jin Li

IgG4-Related Ophthalmic Disease (IgG4-ROD) is a chronic autoimmune-mediated fibrotic disease that predominantly affects the lacrimal glands, often leading to loss of function in the involved tissues or organs. Recent studies have demonstrated that MMP-12 is highly expressed in IgG4-ROD and plays a significant role in regulating immune responses. In this study, we reviewed nine patients diagnosed with IgG4-ROD based on clinical manifestations and histological analysis, and we investigated the expression of IL-33/ST2 and MMP-12 in IgG4-ROD lacrimal gland tissues using IHC. We found that IL-33 interacts with its specific receptor ST2, both of which are significantly overexpressed in IgG4-ROD tissues. Additionally, we successfully constructed a mouse model by introducing the LatY136F mutation into C57BL/6 mice to mimic IgG4-ROD lacrimal gland involvement, which helped elucidate the mechanisms involved in the induction of MMP-12. Furthermore, immunofluorescence staining confirmed that most MMP-12+ cells were derived from M2 macrophages, and an ELISA assay demonstrated that IL-33 upregulates MMP-12 in IgG4-ROD. Collectively, these data suggest that the IL-33/ST2/MMP-12 signaling pathway is activated in IgG4-ROD, with IL-33/ST2 potentially promoting M2 macrophage polarization and activation to produce MMP-12, which may serve as a novel therapeutic target for IgG4-ROD.

IgG4 相关眼病(IgG4-ROD)是一种由自身免疫介导的慢性纤维化疾病,主要影响泪腺,往往导致受累组织或器官功能丧失。最近的研究表明,MMP-12 在 IgG4-ROD 中高度表达,并在调节免疫反应中发挥重要作用。在本研究中,我们回顾了根据临床表现和组织学分析确诊的9例IgG4-ROD患者,并使用IHC检测了IgG4-ROD泪腺组织中IL-33/ST2和MMP-12的表达。我们发现,IL-33与其特异性受体ST2相互作用,两者在IgG4-ROD组织中均显著过表达。此外,我们还通过在 C57BL/6 小鼠中引入 LatY136F 突变成功构建了一个小鼠模型,以模拟 IgG4-ROD 泪腺受累,这有助于阐明诱导 MMP-12 的相关机制。此外,免疫荧光染色证实,大多数MMP-12+细胞来自M2巨噬细胞,ELISA测定证明,IL-33能上调IgG4-ROD的MMP-12。总之,这些数据表明,IL-33/ST2/MMP-12信号通路在IgG4-ROD中被激活,IL-33/ST2可能促进M2巨噬细胞极化和活化以产生MMP-12,这可能成为IgG4-ROD的一个新的治疗靶点。
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引用次数: 0
Optimizing CAR-T cell Culture: Differential effects of IL-2, IL-12, and IL-21 on CAR-T cells 优化 CAR-T 细胞培养:IL-2、IL-12 和 IL-21 对 CAR-T 细胞的不同影响
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1016/j.cyto.2024.156758
Mengmeng Zhang , JingJing Kong , Fanxiang Yin , Jianxiang Shi , Jin Li , Zan Qiu , Baohong Yue , Shuya Wang , Nannan Sun , Quande Lin , Liyan Fu , Xiaoqian Wang , Xianlei Sun , Yanxia Gao , Yong Jiang , Rongqun Guo

Background

Chimeric antigen receptor (CAR)-T therapy has demonstrated sustained clinical remission in numerous hematologic malignancies and has expanded to encompass solid tumors and autoimmune diseases. While progress is being made in establishing optimal culture conditions for CAR-T cells, the identification of the most effective cytokine for promoting their persistence in vitro remains elusive.

Methods

Here, we employed scRNA-seq (single-cell RNA sequencing) analysis to investigate the potential alterations in biological processes within CAR-T cells following exposure to cytokines (IL-2, IL-12, and IL-21) and antigens. Transcriptomic changes in diverse CAR-T groups were compared following various treatments, with a focus on epigenetic modifications, metabolic shifts, cellular senescence, and exhaustion.

Results

Our study reveals that CAR-T cells treated with antigen, IL-2, and IL-12 exhibit signs of exhaustion and senescence, whereas those treated with IL-21 do not display these characteristics. The activities of glycolysis and epigenetic changes were significantly increased by treatments with antigens, IL-2, and IL-12, while IL-21 treatment maintained the oxidative phosphorylation (OXPHOS) of CAR-T cells.

Conclusions

Our findings suggest that IL-21 may play a role in preventing senescence and could be utilized in combination with other strategies, such as IL-2 and IL-12, for CAR-T culture.

背景嵌合抗原受体(CAR)-T疗法已在多种血液系统恶性肿瘤中显示出持续的临床缓解效果,并已扩展到实体瘤和自身免疫性疾病。虽然在建立 CAR-T 细胞的最佳培养条件方面取得了进展,但确定促进其体外持续存在的最有效细胞因子的工作仍遥遥无期。方法在此,我们采用了 scRNA-seq(单细胞 RNA 测序)分析来研究暴露于细胞因子(IL-2、IL-12 和 IL-21)和抗原后 CAR-T 细胞内生物过程的潜在变化。结果我们的研究发现,接受抗原、IL-2 和 IL-12 处理的 CAR-T 细胞表现出衰竭和衰老的迹象,而接受 IL-21 处理的细胞则没有这些特征。糖酵解活性和表观遗传变化在抗原、IL-2 和 IL-12 的处理下显著增加,而 IL-21 处理则维持了 CAR-T 细胞的氧化磷酸化(OXPHOS)。
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引用次数: 0
Lupeol stimulates iNOS, TNF-α, and IL-10 expression in the U937 cell line infected with old-world Leishmania donovani 羽扇豆醇能刺激感染了旧世界利什曼原虫的 U937 细胞系中 iNOS、TNF-α 和 IL-10 的表达
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.cyto.2024.156757
Talib Fadhil Abbas , Hayder Z. Ali

Objective

Visceral leishmaniasis is a neglected tropical disease that can be lethal if not treated. The available medicines have severe side effects, such as toxicity and drug resistance. Various investigations are looking into new anti-leishmanial compounds from natural products that have little impact on host cells. Lupeol, a triterpenoid present in the flora of many edible plants, has been shown to have antimicrobial properties. The present study investigated the immunomodulatory effects of lupeol on U937 macrophages infected with Leishmania donovani, focusing on the expression of key cytokines and enzymes involved in the immune response.

Methods

U937 macrophages were infected with Leishmania donovani amastigotes and treated with varying concentrations of lupeol throughout three days. The expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10) were measured using real-time polymerase chain reaction (RT-PCR). A positive simulation of gene expression was estimated using ΔΔCT to assess relative expression.

Results

The results demonstrated that lupeol significantly upregulated iNOS and TNF-α expression, especially at higher concentrations, indicating enhanced pro-inflammatory and anti-leishmanial activity. Interestingly, IL-10 expression also increased, suggesting a complex immunomodulatory role of lupeol that involves both pro-inflammatory and anti-inflammatory pathways. Pearson correlation analysis revealed a strong association between iNOS and TNF-α (0.97692), as well as a moderate correlation between iNOS and IL-10 (0.51603).

Conclusion

These findings suggest that lupeol may promote a balanced immune response, enhancing the body’s ability to combat L. donovani while potentially mitigating excessive inflammation. Lupeol can potentially serve as a novel therapeutic agent against visceral leishmaniasis.

目的:皮损利什曼病是一种被忽视的热带疾病,如果不加以治疗,可能会导致死亡。现有药物具有严重的副作用,如毒性和耐药性。各种研究正在从对宿主细胞影响较小的天然产品中寻找新的抗利什曼病化合物。羽扇豆醇是一种存在于许多可食用植物中的三萜类化合物,已被证明具有抗菌特性。本研究调查了羽扇豆醇对感染唐氏利什曼病的 U937 巨噬细胞的免疫调节作用,重点研究了参与免疫反应的关键细胞因子和酶的表达。使用实时聚合酶链反应(RT-PCR)测量诱导型一氧化氮合酶(iNOS)、肿瘤坏死因子-α(TNF-α)和白细胞介素-10(IL-10)的表达水平。结果结果表明,露贝醇能显著上调 iNOS 和 TNF-α 的表达,尤其是在较高浓度时,这表明露贝醇具有更强的促炎和抗利什曼病活性。有趣的是,IL-10 的表达也增加了,这表明羽扇豆醇的免疫调节作用很复杂,既涉及促炎途径,也涉及抗炎途径。皮尔逊相关性分析表明,iNOS 与 TNF-α 之间存在很强的相关性(0.97692),iNOS 与 IL-10 之间也存在中等程度的相关性(0.51603)。羽扇豆醇有可能成为一种新型的内脏利什曼病治疗剂。
{"title":"Lupeol stimulates iNOS, TNF-α, and IL-10 expression in the U937 cell line infected with old-world Leishmania donovani","authors":"Talib Fadhil Abbas ,&nbsp;Hayder Z. Ali","doi":"10.1016/j.cyto.2024.156757","DOIUrl":"10.1016/j.cyto.2024.156757","url":null,"abstract":"<div><h3>Objective</h3><p>Visceral leishmaniasis is a neglected tropical disease that can be lethal if not treated. The available medicines have severe side effects, such as toxicity and drug resistance. Various investigations are looking into new anti-leishmanial compounds from natural products that have little impact on host cells. Lupeol, a triterpenoid present in the flora of many edible plants, has been shown to have antimicrobial properties. The present study investigated the immunomodulatory effects of lupeol on U937 macrophages infected with <em>Leishmania donovani</em>, focusing on the expression of key cytokines and enzymes involved in the immune response.</p></div><div><h3>Methods</h3><p>U937 macrophages were infected with <em>Leishmania donovani</em> amastigotes and treated with varying concentrations of lupeol throughout three days. The expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10) were measured using real-time polymerase chain reaction (RT-PCR). A positive simulation of gene expression was estimated using ΔΔCT to assess relative expression.</p></div><div><h3>Results</h3><p>The results demonstrated that lupeol significantly upregulated iNOS and TNF-α expression, especially at higher concentrations, indicating enhanced pro-inflammatory and anti-leishmanial activity. Interestingly, IL-10 expression also increased, suggesting a complex immunomodulatory role of lupeol that involves both pro-inflammatory and anti-inflammatory pathways. Pearson correlation analysis revealed a strong association between iNOS and TNF-α (0.97692), as well as a moderate correlation between iNOS and IL-10 (0.51603).</p></div><div><h3>Conclusion</h3><p>These findings suggest that lupeol may promote a balanced immune response, enhancing the body’s ability to combat <em>L. donovani</em> while potentially mitigating excessive inflammation. Lupeol can potentially serve as a novel therapeutic agent against visceral leishmaniasis.</p></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"183 ","pages":"Article 156757"},"PeriodicalIF":3.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
COVID 19: Prevention and treatment through the Indian perspective COVID 19:从印度角度看预防和治疗问题
IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-15 DOI: 10.1016/j.cyto.2024.156756
Harish Chandra , Archana Yadav , Rajendra Prasad , Kalpana Sagar , Nitin Bhardwaj , Kartikey Kumar Gupta , Ghanshyam Singh Thakur , Manisha Nigam , Raffaele Pezzani , João Paulo Martins de Lima , Henrique Douglas Melo Coutinho , Abhay Prakash Mishra

The most destructive period the world has experienced seems to be behind us. Not a single nation was spared by this disease, and many continue to struggle today. Even after recovering from COVID, patient may continue to experience some post-COVID effects, such as heart irregularities or a decline in lung vitality. In the past three years (2019–2022), the world has witnessed the power of a small entity, a single peculiar virus. Science initially appeared to be helpless in this regard, but due to the emergence of disease, pharmaceutics (the development of anti-covid drugs), immunology (the rapid antigen test), microbiology (the isolation of viruses from infected people), biotechnology (the development of recombinant vaccines), biochemistry (the blood profile, the D-dimer test), and biochemistry (blood profile, D-dimer test), biophysics (PCR, RT-PCR, CT Scan, MRI) had worked together to fight the disease. The results of these efforts are the development of new diagnostic techniques, possible treatment and finally the availability of vaccines against COVID-19. However, it is not proven that the treatment through the traditional medical system is directly active on SARS-CoV-2 but is instead indirectly acting on SARS-CoV-2 effects by improving symptoms derived from the viral disease. In India, the traditional system of medicine and tradition knowledge together worked in the pandemic and proved effective strategies in prevention and treatment of SARS-CoV-2. The use of effective masks, PPE kits, plasma therapy, yoga, lockdowns and social seclusion, use of modern antiviral drugs, monoclonal antibodies, herbal remedies, homoeopathy, hygienic practice, as well as the willpower of people, are all contributing to the fight against COVID. Which methods or practices will be effective against COVID nobody is aware since medical professionals who wear PPE kits do not live longer, and some people in India who remained unprotected and roamed freely were not susceptible to infection. The focus of this review is on the mode of transmission, diagnosis, preventive measures, vaccines currently under development, modern medicine developed against SARS-CoV-2, ayurvedic medicine used during pandemic, homoeopathic medicine used during pandemic, and specific yoga poses that can be used to lessen COVID-related symptoms.

世界经历的最具破坏性的时期似乎已经过去。没有一个国家能幸免于这一疾病,许多国家至今仍在与之抗争。即使从 COVID 中康复,患者也可能继续经历一些后 COVID 影响,如心律不齐或肺活量下降。在过去的三年里(2019-2022年),世界见证了一个小实体、一种单一奇特病毒的力量。科学最初在这方面似乎束手无策,但由于疾病的出现,制药学(抗病毒药物的开发)、免疫学(快速抗原检测)、微生物学(从感染者身上分离病毒)、生物技术(重组疫苗的开发)、生物化学(血液图谱、D-二聚体检测)和生物物理学(PCR、RT-PCR、CT 扫描、核磁共振成像)曾共同努力与疾病作斗争。这些努力的结果是开发出了新的诊断技术和可能的治疗方法,并最终推出了针对 COVID-19 的疫苗。然而,通过传统医学系统进行的治疗并没有证明对 SARS-CoV-2 有直接作用,而是通过改善病毒性疾病引起的症状间接地对 SARS-CoV-2 起作用。在印度,传统医学系统和传统知识在这次大流行中发挥了作用,并被证明是预防和治疗 SARS-CoV-2 的有效策略。使用有效的口罩、个人防护装备包、血浆疗法、瑜伽、封锁和社会隔离、使用现代抗病毒药物、单克隆抗体、草药疗法、同种疗法、卫生习惯以及人们的意志力,这些都有助于抗击 COVID。由于穿戴个人防护装备包的医务人员并不长寿,而且印度一些没有防护措施、自由活动的人也不容易感染,因此没有人知道哪些方法或做法能够有效防治 COVID。本综述的重点是传播方式、诊断、预防措施、目前正在开发的疫苗、针对 SARS-CoV-2 开发的现代药物、大流行期间使用的阿育吠陀医学、大流行期间使用的同种疗法药物,以及可用于减轻 COVID 相关症状的特定瑜伽姿势。
{"title":"COVID 19: Prevention and treatment through the Indian perspective","authors":"Harish Chandra ,&nbsp;Archana Yadav ,&nbsp;Rajendra Prasad ,&nbsp;Kalpana Sagar ,&nbsp;Nitin Bhardwaj ,&nbsp;Kartikey Kumar Gupta ,&nbsp;Ghanshyam Singh Thakur ,&nbsp;Manisha Nigam ,&nbsp;Raffaele Pezzani ,&nbsp;João Paulo Martins de Lima ,&nbsp;Henrique Douglas Melo Coutinho ,&nbsp;Abhay Prakash Mishra","doi":"10.1016/j.cyto.2024.156756","DOIUrl":"10.1016/j.cyto.2024.156756","url":null,"abstract":"<div><p>The most destructive period the world has experienced seems to be behind us. Not a single nation was spared by this disease, and many continue to struggle today. Even after recovering from COVID, patient may continue to experience some post-COVID effects, such as heart irregularities or a decline in lung vitality. In the past three years (2019–2022), the world has witnessed the power of a small entity, a single peculiar virus. Science initially appeared to be helpless in this regard, but due to the emergence of disease, pharmaceutics (the development of anti-covid drugs), immunology (the rapid antigen test), microbiology (the isolation of viruses from infected people), biotechnology (the development of recombinant vaccines), biochemistry (the blood profile, the D-dimer test), and biochemistry (blood profile, D-dimer test), biophysics (PCR, RT-PCR, CT Scan, MRI) had worked together to fight the disease. The results of these efforts are the development of new diagnostic techniques, possible treatment and finally the availability of vaccines against COVID-19. However, it is not proven that the treatment through the traditional medical system is directly active on SARS-CoV-2 but is instead indirectly acting on SARS-CoV-2 effects by improving symptoms derived from the viral disease. In India, the traditional system of medicine and tradition knowledge together worked in the pandemic and proved effective strategies in prevention and treatment of SARS-CoV-2. The use of effective masks, PPE kits, plasma therapy, yoga, lockdowns and social seclusion, use of modern antiviral drugs, monoclonal antibodies, herbal remedies, homoeopathy, hygienic practice, as well as the willpower of people, are all contributing to the fight against COVID. Which methods or practices will be effective against COVID nobody is aware since medical professionals who wear PPE kits do not live longer, and some people in India who remained unprotected and roamed freely were not susceptible to infection. The focus of this review is on the mode of transmission, diagnosis, preventive measures, vaccines currently under development, modern medicine developed against SARS-CoV-2, ayurvedic medicine used during pandemic, homoeopathic medicine used during pandemic, and specific yoga poses that can be used to lessen COVID-related symptoms.</p></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"183 ","pages":"Article 156756"},"PeriodicalIF":3.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cytokine
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