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付佳琪,蔡治国,于漫亚,郭志江,张云晓,崔兴.基于网络药理学及全转录组测序对当归四逆汤干预外泌体抑制多发性骨髓瘤血管新生的机制研究[J].湖南中医药大学学报英文版,2022,42(1):120-128.[Click to copy
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| 基于网络药理学及全转录组测序对当归四逆汤干预外泌体抑制多发性骨髓瘤血管新生的机制研究 |
| 付佳琪,蔡治国,于漫亚,郭志江,张云晓,崔兴 |
| (山东中医药大学中医学院, 山东 济南 250013;山东中医药大学附属医院质控办, 山东 济南 250013;山东中医药大学附属医院血液科, 山东 济南 250013) |
| 摘要: |
| 目的 基于骨髓瘤细胞株外泌体测序及网络药理学研究当归四逆汤抑制多发性骨髓瘤血管新生的机制，为后续研究提供有针对性的指导。方法 利用TCMSP在线平台及SwissTargetPrediction网站获取当归四逆汤主要化学成分及对应靶点，借助GeneCards获取多发性骨髓瘤血管新生相关靶点基因，经与当归四逆汤作用靶点匹配后，获得当归四逆汤抑制多发性骨髓瘤血管新生的作用靶点，并筛选出相应作用成分。取正常人（n=5）和骨髓瘤患者（n=6）外周血清提取外泌体进行测序，获得差异表达基因。对骨髓瘤细胞外泌体进行全转录组测序，取交集后获得骨髓瘤来源外泌体差异表达基因。进而与当归四逆汤抑制多发性骨髓瘤血管新生的作用靶点匹配，获得当归四逆汤干预外泌体抑制多发性骨髓瘤的作用靶点。借助STRING平台与Cytoscape 3.8.2软件对靶点间相互作用网络进行分析，并利用Metascape网站进行GO功能和KEGG通路富集分析。运用R语言对结果进行可视化处理。最后对主要有效成分和作用靶点进行分子对接验证。结果 当归四逆汤作用于多发性骨髓瘤血管新生的有效成分有117种，干预外泌体发挥作用的相关靶点39个，包括CCND1、EGF等。GO分析结果显示，当归四逆汤作用于多发性骨髓瘤血管新生潜在靶点的生物功能涉及血管新生、血管系统发育、细胞周期调节等。KEGG通路富集显示，当归四逆汤作用于多发性骨髓瘤血管新生潜在靶点的通路主要涉及PI3K-AKT、HIF-1等与VEGF相关的信号通路等。分子对接结果表明主要有效成分槲皮素、桦木酸与关键作用靶点AKT1之间具有良好的对接活性。结论 本研究初步揭示了当归四逆汤能够通过PI3K-AKT、HIF-1通路干预外泌体抑制多发性骨髓瘤血管新生，为进一步的实验研究提供基础。 |
| 关键词: 外泌体 全转录组测序 当归四逆汤 多发性骨髓瘤 血管新生 网络药理学 |
| DOI：10.3969/j.issn.1674-070X.2022.01.024 |
| Received:September 24, 2021 |
| 基金项目:国家自然科学基金面上项目（82074348）；泰山学者青年专家人才项目（tsqn201812145）；山东省重点研发计划（公益类）（2019GSF108162）；山东省自然科学基金项目（ZR2020MH354）。 |
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| Study on the mechanism of Danggui Sini Decoction intervening exosomes inhibiting angiogenesis of multiple myeloma based on network pharmacology and whole transcriptome sequencing |
| FU Jiaqi,CAI Zhiguo,YU Manya,GUO Zhijiang,ZHANG Yunxiao,CUI Xing |
| (School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, China;Quality Control Office, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, China;Department of Hematology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, China) |
| Abstract: |
| Objective To explore the mechanism of Danggui Sini Decoction in inhibition of angiogenesis in multiple myeloma based on exosome sequencing of myeloma cells and network pharmacology, in order to provide targeted guidance for further studies. Methods The main chemical components and corresponding targets of Danggui Sini Decoction were obtained by TCMSP online platform and SwissTargetPrediction website. GeneCards was used to obtain the target genes related to angiogenesis of multiple myeloma. After matching with the targets of Danggui Sini Decoction, the targets of Danggui Sini Decoction inhibiting angiogenesis of multiple myeloma was obtained, and the corresponding action components were screened. Exosomes were extracted from peripheral blood serum of normal persons (n=5) and myeloma patients (n=6) and sequenced to obtain differentially expressed genes. Whole transcriptome sequencing of myeloma exosomes was performed, and the differentially expressed genes of myeloma-derived exosomes were obtained after intersection. Then, the targets of Danggui Sini Decoction in inhibiting angiogenesis of multiple myeloma were matched, and the targets of Danggui Sini Decoction intervening exosomes in inhibiting multiple myeloma were obtained. The interaction network between targets was analyzed by STRING platform and Cytoscape 3.8.2 software, and GO function and KEGG pathway enrichment analysis were performed by Metascape website. R language was used to visualize the results. Finally, molecular docking verification was performed on the main effective components and targets. Results There were 117 effective components of Danggui Sini Decoction on angiogenesis in multiple myeloma, and 39 related targets for intervention of exosomes, including CCND1, EGF, etc. GO analysis showed that the biological functions of potential targets of Danggui Sini Decoction on angiogenesis in multiple myeloma were related to angiogenesis, vascular system development and cell cycle regulation. KEGG pathway enrichment showed that the pathways of Danggui Sini Decoction acting on potential targets of multiple myeloma angiogenesis mainly involved PI3K-AKT, HIF-1 and other VEGF-related signaling pathways. Molecular docking results showed that quercetin and betulinic acid had good docking activity with key target AKT1. Conclusion This study preliminarily revealed Danggui Sini Decoction can intervene exosomes to inhibit multiple myeloma angiogenesis through PI3K-Akt and HIF-1 pathways, providing a basis for further research. |
| Key words: exosome whole transcriptome sequencing Danggui Sini Decoction multiple myeloma angiogenesis network pharmacology |
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