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Exploration on "Efficacy-toxicity" Association Mechanisms of
增强出版Tripterygium wilfordii Polyglycoside Tablets Against Rheumatoid Arthritis Based on Multi-omics Integrated Regulatory Network- Chinese Journal of Experimental Traditional Medical Formulae Vol. 29, Issue 5, Pages: 49-57(2023)
- 作者机构：
1.中国中医科学院 中药研究所，北京 100700
2.安徽中医药大学 第一附属医院，合肥 230031
- 作者简介：
- 基金信息：
DOI：10.13422/j.cnki.syfjx.20221545
CLC： R2-0;R33;R593.22Published：05 March 2023，
Published Online：07 July 2022，
Received：24 April 2022，
- 稿件说明：
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王晓月,张依,陈文佳等.从临床多组学整合调控网络探究雷公藤多苷片治疗类风湿关节炎的“效-毒”关联机制[J].中国实验方剂学杂志,2023,29(05):49-57.
WANG Xiaoyue,ZHANG Yi,CHEN Wenjia,et al.Exploration on "Efficacy-toxicity" Association Mechanisms of Tripterygium wilfordii Polyglycoside Tablets Against Rheumatoid Arthritis Based on Multi-omics Integrated Regulatory Network[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(05):49-57.
王晓月,张依,陈文佳等.从临床多组学整合调控网络探究雷公藤多苷片治疗类风湿关节炎的“效-毒”关联机制[J].中国实验方剂学杂志,2023,29(05):49-57. DOI： 10.13422/j.cnki.syfjx.20221545.
WANG Xiaoyue,ZHANG Yi,CHEN Wenjia,et al.Exploration on "Efficacy-toxicity" Association Mechanisms of Tripterygium wilfordii Polyglycoside Tablets Against Rheumatoid Arthritis Based on Multi-omics Integrated Regulatory Network[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(05):49-57. DOI： 10.13422/j.cnki.syfjx.20221545.
摘要
目的
2
通过雷公藤多苷片治疗类风湿关节炎疗效应答和诱发药源性肝损伤相关分子互作网络挖掘，揭示雷公藤多苷片的“效-毒”关联机制。
方法
2
利用前期已获得临床来源的雷公藤多苷片疗效应答相关基因表达谱和诱发药源性肝损伤相关蛋白质表达谱数据，根据生物分子间的相互作用信息，构建雷公藤多苷片“效-毒”关联网络，并通过计算网络节点的拓扑特征值，筛选关键网络靶标和挖掘其生物学功能。
结果
2
经临床转录组学检测，获得雷公藤多苷片治疗类风湿关节炎疗效相关差异表达基因119个。经临床蛋白质组学检测，获得雷公藤多苷片诱发药源性肝损伤相关差异表达蛋白质49个。进一步的临床症状富集分析表明，雷公藤多苷片治疗类风湿关节炎的效应基因与痹症相关中医症状和医学临床表型紧密相关，雷公藤多苷片诱发药源性肝损伤相关的差异蛋白质最显著富集于消化系统异常的临床症状，可见，上述多组学数据能够表征雷公藤多苷片治疗类风湿关节炎和诱发药源性肝损伤的主要临床症状。进而，“效-毒”关联网络挖掘表明，雷公藤多苷片治疗类风湿关节炎的关键效应靶标和诱发药源性肝损伤核心致毒蛋白质均参与机体“免疫-炎症”失衡的调节，特别在中性粒细胞脱颗粒、补体级联反应、蛋白质翻译后修饰介导的免疫炎症反应等方面发挥着重要作用；二者还显著富集于肾素-血管紧张素系统（RAS）和丝裂原活化蛋白激酶（MAPK）信号通路等与细胞增殖和细胞周期调控密切相关的信号通路，以及参与糖原代谢和氧化还原反应等肝脏功能直接相关的生物学通路。
结论
2
本研究采用临床表型组学、临床转录组学和蛋白质组学整合的研究策略，系统阐释了雷公藤多苷片“效-毒”的关联特征和分子机制，为探索雷公藤多苷片“增效减毒”机制奠定良好的数据基础。
Abstract
Objective
2
To explore the "efficacy-toxicity" association mechanisms of
Tripterygium wilfordii
polyglycoside tablets （TWPT） by establishing and analyzing an interaction network associated with the clinical efficacy of TWPT in the treatment of rheumatoid arthritis （RA） and TWPT-induced liver injury.
Method
2
On the basis of the TWPT efficacy-related gene expression profile and TWPT-induced liver injury-related protein expression profile which were both obtained from our clinical cohorts， the "efficacy-toxicity" association network of TWPT was constructed， and the key network targets were identified by calculating the topological values of the nodes， including the degree， closeness and betweenness. After that， the biological functions and pathways of the key network targets were investigated by enrichment analysis.
Result
2
A total of 119 differentially expressed genes （58 up-regulated and 61 down-regulated） between RA patients with TWPT well and weak response were identified as TWPT efficacy-related genes by clinical transcriptomics， and 49 differentially expressed proteins （36 up-regulated and 13 down-regulated） were demonstrated to be TWPT-induced liver injury-related proteins by clinical proteomics. In addition， the clinical symptom enrichment analysis indicated that the TWPT efficacy-related genes were significantly associated with various clinical symptoms of arthralgia in traditional Chinese medicine and clinical phenotypes of modern medicine， and most of the TWPT-induced liver injury-related proteins were involved in digestive system abnormalities. Therefore， the aforementioned multi-omics data represented the main clinical symptoms of TWPT treating RA and inducing liver injury. Mechanically， the "efficacy-toxicity" association network revealed that both TWPT efficacy-related genes and TWPT-induced liver injury-related core proteins were involved in the "immune-inflammatory" imbalance， especially playing an important role in neutrophil degranulation， complement cascade reaction， and immune-inflammatory response mediated by protein post-translational modification. Notably， the above genes and proteins were also enriched in various signaling pathways related to cell proliferation and cell cycle regulation， such as RAS and mitogen-activated protein kinase （MAPK） signaling pathway， and in several liver functional processes， such as glycogen metabolism and redox reaction.
Conclusion
2
This study systematically explained the "efficacy-toxicity" association characteristics and molecular mechanisms of TWPT by applying a research strategy integrating clinical phenomics， transcriptomics and proteomics， laying a good data foundation for exploring the "efficacy enhancing and toxicity-reducing" mechanisms of TWPT.
关键词
雷公藤多苷片类风湿关节炎药源性肝损伤多组学整合“效-毒”关联网络
Keywords
Tripterygium wilfordii polyglycoside tabletsrheumatoid arthritisdrug-induced liver injurymulti-omics integration"efficacy-toxicity" association network
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