沉香中2-苯乙基色酮衍生物GYF-17和GYF-7抗类风湿关节炎的药效作用及分子机制研究

Rheumatoid arthritis (RA) is an autoimmune disease with high morbidity and disability and a serious threat to human health. The present therapeutic drugs are associated with poor curative effect, multiple adverse effects and high cost, then severely restricted therapy of RA. Our preliminary study purified two 2-(phenethyl)-chromone derivatives from Agarwood, GYF-17 and GYF-7, which showed intensive inhibitory effects on innate and adaptive immune in vitro and in vivo experiments. In addition, we found that these two compounds mainly exerted their immunosuppressive effects via inhibiting activation of STAT signaling pathways. These results suggest that GYF-17 and GYF-7 have great potential to be developed into therapeutic agent of RA. In this study, we will investigate the therapeutic effects of GYF-17 and GYF-7 on RA, and reveal the underlying targets that GYF-17 and GYF-7 regulate cytokine-JAK-STAT signaling pathways and then exert immunosuppressive effects. Then provide prospect for discovering lead compounds and new drug targets for RA therapy, reveal the mechanism that Agarwood exerts effect in RA therapy and promote clinical application of Agarwood.

类风湿关节炎（Rheumatoid arthritis, RA）是一种发病率和死亡率都很高的严重威胁人类健康的自身免疫性疾病。目前临床常用治疗RA的药物存在疗效不理想、副作用大和价格昂贵等诸多缺陷，严重制约了RA的治疗。本课题前期研究发现沉香中提取分离的2-苯乙基色酮衍生物GYF-17和GYF-7对天然免疫和适应性免疫具有良好的体外体内抑制作用，初步机制研究发现GYF-17和GYF-7主要通过抑制STAT信号通路发挥免疫抑制作用，显示这2个化合物具有良好的治疗RA的潜力。本课题拟采用模型动物深入研究GYF-17和GYF-7对RA的治疗作用，并通过系统的机制研究阐明GYF-17和GYF-7在细胞因子-JAK-STAT信号通路中的作用靶点及对靶点蛋白家族的选择性作用，为治疗RA活性先导化合物和药物新靶点的发现奠定基础，同时也为中药沉香抗风湿作用的阐释和临床应用提供科学依据。

类风湿性关节炎（Rheumatoid arthritis, RA）是一种发病率和死亡率都很高的严重威胁人类健康的自身免疫性疾病。目前临床常用治疗RA的药物存在疗效不理想、副作用大和价格昂贵等诸多缺陷，严重制约了RA的治疗。本课题发现沉香中提取分离的2-苯乙基色酮衍生物GYF-17对CD4+ T细胞向Th2细胞分化和B细胞的多种重要功能具有选择性抑制作用，发挥显著的体液免疫抑制作用。利用胶原诱导RA模型，揭示了GYF-17对RA具有良好治疗作用，能够显著改善RA评分、关节损伤和抗原特异性免疫反应。通过深入的免疫细胞信号通路和激酶筛选研究，最终证实了GYF-17发挥药效的主要作用机制是抑制GSK-α和GSK-β激酶活性。本课题为将沉香中2-苯乙基色酮衍生物GYF-17开发为全新RA治疗药物奠定了基础。