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Arth & Rheumatol:绿茶儿茶素有效阻断风湿性关节炎

来源:生物谷 2016-02-18 14:24

图片来源:medicalxpress.com

2016年2月18日 讯 /生物谷BIOON/ --来自华盛顿州立大学的研究者近日鉴别出了一种新方法来抵御由风湿性关节炎引发的关节痛、炎症及组织损伤,相关研究刊登于国际杂志Arthritis and Rheumatology上。风湿性关节炎是一种严重的自身免疫障碍,其会影响手脚小关节的功能,经常会引发关节出现疼痛性的隆起进而发展为软骨损伤、骨糜烂及关节畸形等。

研究者Salah-uddin Ahmed指出,当前治疗风湿性关节炎的药物非常昂贵,而且具有一定的免疫抑制性,有时候并不适合长期使用。本文中研究者评估了一种名为儿茶素(表没食子儿茶素没食子酸酯,EGCG)的植物化学成分,儿茶素是一种绿茶中的抗炎性分子,研究发现儿茶素在治疗风湿性关节炎上具有较大的潜力,因为该分子可以在不阻断其它细胞功能的前体下有效阻断疾病的效应。

本文研究为利用EGCG分子来靶向作用TAK1分子提供了一定的见解,TAK1分子是一种重要的靶向性蛋白信号,促炎细胞因子可以释放该蛋白信号从而引发风湿性关节炎患者机体出现炎症及组织破坏。此前研究人员在患人类风湿性关节炎的动物模型中证实了上述发现,即给予模式动物EGCG分子进行为期10天的治疗可以有效降低动物的疾病表现。

目前研究人员已经进行15年同风湿性关节炎相关的研究,Ahmed表示他们后期还将投入大量精力来进一步深入研究EGCG治疗风湿性关节炎的机制,并进行相关的临床试验,早日开发出有效治疗风湿性关节炎的新型靶向性疗法。(生物谷Bioon.com)

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Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin-3-Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K63-Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

Anil K. Singh1, Sadiq Umar1, Sharayah Riegsecker2, Mukesh Chourasia3 andSalahuddin Ahmed1,*

Objective Transforming growth factor β–activated kinase 1 (TAK1) is a key MAPKKK family protein in interleukin-1β (IL-1β), tumor necrosis factor (TNF), and Toll-like receptor signaling. This study was undertaken to examine the posttranslational modification of TAK1 and its therapeutic regulation in rheumatoid arthritis (RA). Methods The effect of TAK1, IL-1 receptor–associated kinase 1 (IRAK-1), and TNF receptor–associated factor 6 (TRAF6) inhibition was evaluated in IL-1β–stimulated human RA synovial fibroblasts (RASFs). Western blotting, immunoprecipitation, and 20S proteasome assay were used to study the ubiquitination process in RASFs. The efficacy of epigallocatechin-3-gallate (EGCG), a potent antiinflammatory molecule, in regulating these processes in RASFs was evaluated. Molecular docking was performed to examine the interaction of EGCG with human TAK1, IRAK-1, and TRAF6. These findings were confirmed using a rat model of adjuvant-induced arthritis (AIA). Results Inhibition of TAK1, but not IRAK-1 or TRAF6, completely abrogated IL-1β–induced IL-6 and IL-8 synthesis in RASFs. EGCG inhibited TAK1 phosphorylation at Thr184/187 and occupied the C174 position, an ATP-binding site, to inhibit its kinase activity. EGCG pretreatment also inhibited K63-linked autoubiquitination of TRAF6, a posttranslational modification essential for TAK1 autophosphorylation, by forming a stable H bond at the K124 position on TRAF6. Furthermore, EGCG enhanced proteasome-associated deubiquitinase expression to rescue proteins from proteasomal degradation. Western blot analyses of joint homogenates from rats with AIA showed a significant increase in K48-linked polyubiquitination, TAK1 phosphorylation, and TRAF6 expression when compared to naive rats. Administration of EGCG (50 mg/kg/day) for 10 days ameliorated AIA in rats by reducing TAK1 phosphorylation and K48-linked polyubiquitination. Conclusion Our findings provide a rationale for targeting TAK1 for the treatment of RA with EGCG.

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