1. 广西中医药大学, 基础医学院生理教研室, 广西南宁 530222
2. 广西中医药大学, 赛恩斯新医药学院医学系, 广西南宁 530222
| 摘 要: | 目的:运用网络药理学和分子对接探究丹参基于血管新生防治肝纤维化的作用机制。方法:通过TCMSP数据库明晰丹参的活性药理成分以及其作用靶点,利用TTD、GeneCards、CTD等数据库获得肝纤维化、血管新生相关靶点,采用Venn图对丹参活性成分作用靶点和肝纤维化及血管新生相关靶点进行交互处理;使用Cytoscape3.9.0软件构建药物-成分-靶点-疾病网络;利用String数据库构建交互靶点互作网络;利用Metascape平台对交互靶点进行GO(Gene Ontology)富集分析和KEGG(Kyoto Encyclopedia of Genes and Genomes)信号通路分析,明确丹参基于血管新生防治肝纤维化的分子机制。结果:通过TCSMP数据库筛选出丹参活性成分65个,作用潜在靶点132个,通过GeneCards、TTD、CTD数据库分别筛选出肝纤维化和血管新生靶点4841、1200个,映射取交集得到丹参影响血管新生防治肝纤维化的共同靶点50个,构建丹参-成分-靶点-疾病网络图,并对共同靶点蛋白进行PPI网络分析,得到关键靶点。对共同靶点在Metascape平台进行GO和KEGG信号通路富集分析,显示PI3K-Akt信号通路、糖尿病并发症中的AGE-RAGE信号通路、MAPK信号通路、VEGF信号通路等信号通路可能参与丹参调节血管新生防治肝纤维化的不同环节。分子对接结果显示良好。结论:丹参的多种主要活性成分通过多通路发挥抗血管新生的作用,从而防治肝纤维化。 |
| 关 键 词: | 肝纤维化; 血管新生; 丹参; 网络药理学 |
| DOI: | 10.57237/j.mrf.2023.04.006 |
1. Department of Physiology, School of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530222, China
2. Department of Medicine, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning 530222, China
| Abstract: | Objective: Network pharmacology and molecular docking were used to explore the mechanism of Salvia miltiorrhiza in the prevention and treatment of liver fibrosis based on angiogenesis. Method: The active pharmacological components and their action targets of Salvia miltiorrhiza were clarified by TCMSP database, and the targets related to hepatic fibrosis and angiogenesis were obtained by TTD, GeneCards, CTD and other databases. The active components of Salvia miltiorrhiza and the targets related to liver fibrosis and angiogenesis were interactively processed by Venn map. The drug-component-target-disease network was constructed by Cytoscape3.9.0 software, and the interaction target network was constructed by using String database. The interaction targets were analyzed by GO (Gene Ontology) enrichment analysis and KEGG (Kyoto Encyclopedia of Genesand Genomes) signal pathway analysis using Metascape platform to clarify the molecular mechanism of Salvia miltiorrhiza in the prevention and treatment of liver fibrosis based on angiogenesis. Result: 65 active components and 132potential targets of Salvia miltiorrhiza were screened from TCSMP database, 4841 and 1200 targets of hepatic fibrosis and angiogenesis were screened by GeneCards, TTD and CTD database respectively, 50 common targets of Salvia miltiorrhiza affecting angiogenesis and prevention and treatment of liver fibrosis were obtained by mapping, and the Salvia miltiorrhiza-component-target-disease network map was constructed. The common target proteins were analyzed by PPI network, and the key targets were obtained. The enrichment analysis of GO and KEGG signal pathways on the Metascape platform showed that PI3K-Akt signal pathway, AGE-RAGE signal pathway in diabetic complications, MAPK signal pathway, VEGF signal pathway and other signal pathways may be involved in different aspects of Salvia miltiorrhiza regulating angiogenesis and preventing liver fibrosis. The results of molecular docking are good. Conclusion: A variety of main active components of Salvia miltiorrhiza play the role of anti-angiogenesis through multiple pathways, so as to prevent and treat liver fibrosis. |
| Keywords: | Liver Fibrosis; Angiogenesis; Salvia; Network Pharmacology |
| 1. | 国家自然科学基金项目 (82204755, 81960751) |
| 2. | 广西自然科学基金青年基金项目 (2023GXNSFBA297094) |
| 3. | 广西中医药大学赛恩斯新医药学院国家级大学生创新创业训练项目 (202313643012) |
| 4. | 广西中医药大学国家级大学生创新创业训练项目 (202310600020) |
| 5. | 广西中医药大学青年基金项目 (2022QN008; 2022MS024) |
| 6. | 广西中医药大学赛恩斯新医药学院科研项目 (2022MS002; 2022MS008; 2022QJ001) |
| [1] | Wang FD, Zhou J, Chen EQ. Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis [J]. Front Pharmacol. 2022; 13: 787748. |
| [2] | Tai Y, Zhao C, Lan T, Zhang L, Xiao Y, Tong H, Liu R, Tang C, Gao J. Integrated Analysis of Hepatic miRNA and mRNA Expression Profiles in the Spontaneous Reversal Process of Liver Fibrosis [J]. Front Genet. 2021; 12: 706341. |
| [3] | Zadorozhna M, Di Gioia S, Conese M, Mangieri D. Neovascularization is a key feature of liver fibrosis progression: anti-angiogenesis as an innovative way of liver fibrosis treatment [J]. Mol Biol Rep. 2020; 47(3): 2279-2288. |
| [4] | 高俪原; 梁宝瑜; 金春; 李余佳; 王桭屹; 张峰; 郑仕中, 血管新生在肝脏疾病发生与发展中作用的研究进展 [J]. 生理科学进展, 2020, 35-39, 35-39. |
| [5] | 罗丹, 王宏艳. 丹参及其化合物对血管新生中血管内皮生长因子/血管内皮生长因子受体通路调控作用研究进展[J].国际中医中药杂志, 2021, 43(10): 1054-1057. |
| [6] | 原景; 杜韩; 万梅绪; 李智; 张燕欣; 李德坤; 庄朋伟; 鞠爱春, 丹参有效成分及丹参类制剂抗炎药理作用的研究进展[J].药物评价研究, 2021, 39-49, 39-49. |
| [7] | 郑洋; 王佳慧; 彭岳; 原鲜玲; 汪磊; 赵铁建, 莪术醇对小鼠肝窦内皮细胞结构的影响及其对肝内血管新生的抑制作用 [J]. 吉林大学学报(医学版), 2021, 55-61, 55-61. |
| [8] | 单晓晓, 洪帮振, 刘洁, 王国凯, 陈卫东, 俞年军, 彭代银, 王雷, 张彩云. 丹参化学成分、药理作用、临床应用的研究进展及质量标志物的预测分析 [J]. 中国中药杂志, 2021, 46(21): 5496-5511. |
| [9] | 朱婷婷, 程紫薇, 邢东炜, 张闽光.缺氧微环境调控肝细胞癌血管新生的研究进展 [J]. 医学研究杂志, 2021, 50(09): 19-22. |
| [10] | Wu W, Li W, Wei J, Wang C, Yao Y, Zhu W, He W, Zhou W, Liu J. Chronic intermittent hypoxia accelerates liver fibrosis in rats with combined hypoxia and nonalcoholic steatohepatitis via angiogenesis rather than endoplasmic reticulum stress [J]. Acta Biochim Biophys Sin (Shanghai). 2019; 51(2): 159-167. |
| [11] | 辜群利, 李晖, 陈婧.抗血管生成疗法在肝纤维化肝硬化和肝细胞癌中的应用进展 [J]. 医药导报, 2022, 41(1): 92-98. |
| [12] | Pan J, Cai X, Zheng X, Zhu X, Feng J, Wang X. Luteolin inhibits viability, migration, angiogenesis and invasion of non-small cell lung cancer vascular endothelial cells via miR-133a-3p/purine rich element binding protein B-mediated MAPK and PI3K/Akt signaling pathways [J]. Tissue Cell. 2022; 75: 101740. |
| [13] | 胡泽香, 佟雷, 耿艳萌, 杨琦, 侯甲福. 木犀草素的药理活性及其制剂研究进展 [J]. 中医临床研究, 2022, 14(10): 141-145. |
| [14] | 郝雪莲, 亢泽峰, 陈水龄, 刘健.丹参酮IIA对BN大鼠脉络膜新生血管HIF-1α和VEGF表达的影响 [J]. 中国中医眼科杂志, 2020, 30(3): 166-170+184. |
| [15] | Gu Y, Liu W, Liu G, Li X, Lu P. Assessing the protective effects of cryptotanshinone on CoCl2 induced hypoxia in RPE cells [J]. Mol Med Rep. 2021; 24(4): 739. |
| [16] | Wu JS, Meng QY, Shi XH, Liu LX, Zhang ZK, Guan HS, Shao CL, Wang CY. The oxygenated products of cryptotanshinone by biotransformation with Cunninghamella elegans exerting anti-neuroinflammatory effects by inhibiting TLR 4-mediated MAPK signaling pathway [J]. Bioorg Chem. 2020; 104: 104246. |
| [17] | Fei E, Chen P, Zhang Q, Zhong Y, Zhou T. Protein Kinase B/Akt1 Phosphorylates Dysbindin-1A at Serine 10 to Regulate Neuronal Development [J]. Neuroscience. 2022; 490: 66-78. |
| [18] | 濮雪华, 李飞, 缪小莉, 叶纪录, 陆伦根.转化生长因子β通过PI3K/AKT/mTOR/p70S6K通路调节肝祖细胞的迁移 [J].中华肝脏病杂志, 2018, 26(9): 680-685. |
| [19] | 李玮浩. CD105、MMP9和VEGF在肝细胞肝癌组织的表达 [D]. 郑州大学, 2006. |
| [20] | 曹自, 孙保存, 赵秀兰, 张艳辉, 古强, 梁晓辉, 董学易, 赵楠. Runx2通过促进MMP9的表达增强肝细胞肝癌迁移侵袭能力 [J]. 中国肿瘤临床, 2017, 44(9): 424-428. |
| [21] | Ai F, Chen M, Li W, Yang Y, Xu G, Gui F, Liu Z, Bai X, Chen Z. Danshen improves damaged cardiac angiogenesis and cardiac function induced by myocardial infarction by modulating HIF1α/VEGFA signaling pathway [J]. Int J Clin Exp Med. 2015; 8(10): 18311-18318. |
| [22] | 牛艳邦, 王晓玲, 陈晨, 任益凡, 张海利, 董胜利. 二甲双胍抑制PI3K-AKT-mTOR信号通路对四氯化碳诱导的小鼠急性肝损伤的影响[J].中国生物制品学杂志, 2021, 34(9): 1062-1068+1075. |
| [23] | Nasirzadeh M, Rasmi Y, Rahbarghazi R, Kheradmand F, Karimipour M, Aramwit P, Astinfeshan M, Gholinejad Z, Daeihasani B, Saboory E, Shirpoor A, Rezabakhsh A, Zolali E, Khalaji N. Crocetin promotes angiogenesis in human endothelial cells through PI3K-Akt-eNOS signaling pathway [J]. EXCLI J. 2019; 18: 936-949. |
| [24] | Wang XL, Qi J, Shi YQ, Lu ZY, Li RL, Huang GJ, Ning BB, Hao LS, Wang H, Hao CN, Li Y, Zhou HS, Duan JL. Atorvastatin plus therapeutic ultrasound improve postnatal neovascularization in response to hindlimb ischemia via the PI3K-Akt pathway [J]. Am J Transl Res. 2019; 11(5): 2877-2886. |
| [25] | 郑洋, 梁天坚, 王佳慧, 赵铁建, 汪磊.莪术醇对肝窦内皮细胞MAPK信号通路作用的实验研究 [J]. 中华中医药学刊, 2021, 39(1): 57-61. |
| [26] | 宋丽. 加味补阳还五汤通过MAPK/ERK信号通路干预肺纤维化血管新生机制的实验研究及临床分析 [D]. 山东中医药大学, 2021. |
| [27] | 朱婷婷, 程紫薇, 邢东炜, 张闽光. 基于HIF-1α/VEGF/NF-κB信号通路探讨天冬多糖调控COMMD3抑制肝癌血管生成的作用机制 [J]. 中华中医药杂志, 2022, 37(5): 2836-2841. |