Activation of Cholinergic Anti-Inflammatory Pathway in Peripheral Immune Cells Involved in Therapeutic Actions of α-Mangostin on Collagen-Induced Arthritis in Rats.

激活外周免疫细胞胆碱能抗炎通路参与 α-山竹素对大鼠胶原诱导性关节炎的治疗作用。

  • 影响因子:3.27
  • DOI:10.2147/DDDT.S249865
  • 作者列表:"Yin Q","Wu YJ","Pan S","Wang DD","Tao MQ","Pei WY","Zuo J
  • 发表时间:2020-05-22

Background:Studies have shown that α-mangostin (MG) could exert anti-rheumatic effects in vivo by restoring immunity homeostasis, and have indicated that activation of the choline anti-inflammatory pathway (CAP) may contribute to this immunomodulatory property. The current study was designed to further investigate the effects of MG on the CAP in peripheral immune cells and clarify its relevance to the potential anti-rheumatic actions. Methods:The catalytic activity of acetylcholinesterase (AChE) and expression of α7-nicotinic cholinergic receptor (α7nAChR) in peripheral blood mononuclear cells (PBMCs) from rats with collagen-induced arthritis (CIA) or human volunteers were evaluated after MG treatment. Consequent influences on the immune environment were assessed by flow cytometry and ELISA analyses. Indirect effects on joints resulting from these immune changes were studied in a co-culture system comprised of fibroblast-like synoviocytes (FLSs) and PBMCs. Results:MG promoted α7nAChR expression in PBMCs both in vivo and in vitro, and inhibited the enzymatic activity of AChE simultaneously. Activation of the CAP was accompanied by a significant decrease in Th17 cells (CD4+IL-17A+), while no obvious changes concerning the distribution of other T-cell subsets were noticed upon MG treatment. Meanwhile, MG decreased the secretion of TNF-α and IL-1β under inflammatory conditions. PBMCs from MG-treated CIA rats lost the potential to stimulate NF-κB activation and pro-inflammatory cytokine production of FLSs in the co-culture system. Conclusion:Overall, the evidence suggested that MG can improve the peripheral immune milieu in CIA rats by suppressing Th17-cell differentiation through CAP activation, and achieve remission of inflammation mediated by FLSs.


背景: 研究表明 α-山竹素 (α-mangostin,MG) 在体内可通过恢复免疫稳态发挥抗风湿作用,并提示激活胆碱抗炎通路 (CAP) 可能有助于这种免疫调节特性。本研究旨在进一步研究 MG 在外周免疫细胞中对 CAP 的影响,并阐明其与潜在抗风湿作用的相关性。 方法: 观察胶原诱导性关节炎 (CIA) 大鼠外周血单个核细胞 (pbmc) 乙酰胆碱酯酶 (AChE) 的催化活性及 α 7-烟碱胆碱能受体 (α 7nachr) 的表达。或人类志愿者在 MG 治疗后进行评估。通过流式细胞术和 ELISA 分析评估对免疫环境的影响。在由成纤维样滑膜细胞 (FLSs) 和 PBMCs 组成的共培养系统中研究了这些免疫变化对关节的间接影响。 结果: MG 促进体内和体外 PBMCs 中 α 7nachr 的表达,同时抑制 AChE 的酶活性。CAP 的激活伴随着 Th17 细胞 (CD4 + IL-17A +) 的显著减少,而在 MG 治疗时,其他 t 细胞亚群的分布没有明显变化。同时,MG 降低炎症状态下 TNF-α 和 il-1 β 的分泌。Mgc 处理的 CIA 大鼠 pbmc 在共培养体系中失去了刺激 NF-κ b 活化和促炎细胞因子产生 FLSs 的潜力。 结论: 总体上,有证据表明,MG 可通过 CAP 激活抑制 Th17 细胞分化,改善 CIA 大鼠的外周免疫环境,达到缓解 FLSs 介导的炎症反应。



作者列表:["Gomes da Silva IIF","Lima CAD","Monteiro MLA","Barboza DASP","Rushansky E","Mariano MHQA","Sandrin-Garcia P","de Souza PRE","Maia MMD"]

METHODS:Rheumatoid arthritis (RA) is an autoimmune disease which can lead to progressive and functional disability. Literature data suggest that some inflammatory proteins are dysregulated in RA patients and its genetic polymorphisms may contribute to the aetiology and pathogenesis of disease in different ethnic groups. Polymorphisms in and genes were studied in different populations with RA, but the analysis indicated contradictory results. Thereby, we hypothesised that polymorphisms in these genes could have a combined effect on susceptibility to and severity of disease. We evaluated the +3953 C/T (rs1143634), -137 G/C (rs187238), -94 ins/del ATTG (rs28362491) and +874 T/A (rs2430561) polymorphisms in the northeastern Brazilian population. Peripheral blood samples were collected and DNA extraction was conducted. The polymorphisms were evaluated by RFLP and ARMS-PCR. An association was observed in rs1143634 which showed a protective effect against development of RA in carriers of the T allele (OR = 0.58; 95% CI 0.36-0.92;  = .020). In addition, we found an association among genotypes of the rs1143634 with the HAQ index ( = .021) and rs2430561 with DAS28 ( = .029) and CDAI ( = .029). In relation to combined effects of these SNPs (C/C to rs1143634, G/G to rs187238, I/I to rs28362491 and AA to rs2430561) we found a significant association with decreased functional disability (HAQ index  < .001) and ESR ( = .034), indicating a lower disease activity in carriers of these genotypes. GLM analysis confirmed these associations (HAQ ( = 5.497;  < .001) and ESR ( = 2.727;  = .032)). Our analysis indicated that in the studied population +3953 C/T (rs1143634), -137 G/C (rs187238), -94 ins/del ATTG (rs28362491) and +874 T/A (rs2430561) polymorphisms can together contribute to RA severity although they do not individually influence the disease.

翻译标题与摘要 下载文献
作者列表:["Fattah SA","Abdel Fattah MA","Mesbah NM","Saleh SM","Abo-Elmatty DM","Mehanna ET"]

METHODS:ZNF804a and CDK1 genes code for proteins involved in inflammatory pathways. This study aimed to investigate the correlation of ZNF804a and CDK1 expression profiles in RA with the activity and the severity of the disease and to assess their association with inflammatory reactions in the Egyptian RA patients. ZNF804a and CDK1 expression profiles were assessed using quantitative PCR (qRT-PCR). Clinical and laboratory parameters were evaluated. ZNF804a expression was down-regulated by 0.177-fold while CDK1 expression was up-regulated to 3.29-fold in RA patients compared with healthy controls ( < .001). ZNF804a down-regulation was negatively correlated with CRP, RF, disease activity score of 28 joints (DAS) using CRP (DAS-CRP) and TNF-α. CDK1 overexpression was correlated with IFN-1 and ACPA in RA patients. ZNF804a and CDK1 genes are implicated in RA pathogenesis due to their influences on TNF-α and IFN-1 which contribute to inflammation in RA patients.

翻译标题与摘要 下载文献
作者列表:["Emery P","Horton S","Dumitru RB","Naraghi K","van der Heijde D","Wakefield RJ","Hensor EMA","Buch MH"]

METHODS:OBJECTIVES:We sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX. METHODS:Pragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/-anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints. RESULTS:We randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX. CONCLUSIONS:Compared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested.Trial registration numberNCT02433184.