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首页 » 基金与期刊 » Arthritis and Rheumatology:绿茶中的化合物能够阻断类风湿性关节炎

Arthritis and Rheumatology:绿茶中的化合物能够阻断类风湿性关节炎

来源:生物谷 2016-02-18 14:26

2016年2月18日 讯 /生物谷BIOON/ --华盛顿州立大学研究人员识别出一种潜在新方法,抗击因类风湿性关节炎导致的关节疼痛、炎症和组织损伤。

他们的发现最新发表于《Arthritis and Rheumatology》,并登上该期刊的封面。

类风湿性关节炎是一种使人衰弱的自身免疫性疾病,主要影响手部和足部的小关节。会导致肿痛并发展成软骨损伤、骨侵蚀和关节畸形。

"现有的类风湿性关节炎药物由于价格昂贵和免疫抑制问题,有时不适合长期使用"该研究领导者Salah-uddin Ahmed说道。

他的团队评估了一个叫做epigallocatechin-3-gallate(EGCG)的植物化学成分,该分子存在于绿茶中,具有抗炎作用。他们的研究表明,EGCG能够有效阻断类风湿性关节炎的影响而不阻断其他的细胞功能,因而在作为该病疗法方面具有较大的潜力。

"这项研究开启了使用EGCG来作用于TAK1的研究领域。TAK1是一种重要的信号蛋白质,在类风湿性关节炎中,前炎性细胞活素会通过这种蛋白质传输信号引起炎症和组织破坏"Ahmed说道。

研究人员在人类类风湿性关节炎临床前动物模型中证实了他们的发现。在为期10天的EGGG治疗中,他们观察到动物的脚踝肿胀显着减少。

在过去15年里,Ahmed一直专注于类风湿性关节炎的相关研究。(生物谷Bioon.com)

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DOI:10.1002/art.39447

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

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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