中文摘要
类风湿关节炎患者体内炎症因子升高是其重要特征,并导致机体转运蛋白表达及活性改变。雷公藤是中医辨证论治该病的首选中药,其主要活性毒性成分雷公藤甲素疗效明确、但治疗窗窄、毒性较大,临床应用受限。本研究以雷公藤甲素为研究对象,采用大鼠原代细胞和胶原诱导类风湿关节炎模型,以SLC主要转运蛋白变化为研究主线,考察生理/病理状态下雷公藤甲素暴露量、药效、毒性、转运蛋白活性和基因表达变化之间相关性,探讨转运蛋白和雷公藤甲素的交互影响,阐明其对毒、效的重要作用和药物治疗对其的影响。遵循中医辩证论治和中药药性理论,多学科结合,从整体、细胞和分子水平深入探讨SLC转运蛋白在雷公藤甲素治疗类风湿关节炎中的重要作用。阐明雷公藤甲素药效和肝肾毒性的本质及机理,为临床合理应用雷公藤甲素提供实验数据。以中医理论为指导,雷公藤为例揭示有毒中药毒效相关的作用原理和应用规律,为中医药控制有毒中药的毒性而合理应用提供科学参考。
英文摘要
The increasing amount of inflammatory factors is an important feature of rheumatoid arthritis, which consequently influences the expressions and activities of the transporters. In the differential system in traditional Chinese medical science, Tripterygium is the TCM of first choice for the treatment of rheumatoid arthritis. Triptolide, which has good efficacy but narrow therapeutic window, is recognized as the main active and toxic ingredient of Tripterygium. Its clinical application is limited because of the common and serious toxicity. Taking Triptolide as the research object, this study uses rat primary cells and collagen-induced rheumatoid arthritis model to investigate the relationship of changes in Triptolide exposure, efficacy, toxicity, SLC transporter proteins and gene expression in physiological /pathological condition with the transformation of transporter proteins as the leading clue. Then the interaction of Triptolide and transporters will be explored to clarify its role in the correlation of toxicity and effect, also the impact of drug treatment to transporters. Following the theory of TCM syndrome differentiation and Chinese medicine herbs, the study tries to combine the multidisciplinary to explore the important role of SLC transporters in Triptolide treatment of rheumatoid arthritis on the whole, cell and molecular level. The experimental data will be used to elucidate the essence and mechanism of the efficacy and hepatotoxicity-nephrotoxicity of Triptolide and for the clinical application of Triptolide and Tripterygium. Under the guidance of traditional Chinese theory, the study of Tripterygium as an example will be used to reveal the mechanism and regularity of correlations between toxicity and efficacy of toxic herbs and provide scientific basis for the control of toxicity and reasonable applications of toxic herbs.
