Investigation of the mechanism of action and identification of candidate traditional Chinese medicines for the treatment of ischemic stroke in the Danshen-Jiangxiang pair based on drug-target-disease association network_Journal of Biomedical Engineering

Authors：

GAO Jiaxuan ,  DING Yanrui

School of Science, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China;

Corresponding author：

DING Yanrui, Email: yr_ding@jiangnan.edu.cn

Keywords：

Drug-target-symptom-disease association network; Danshen-Jiangxiang; Ischemic stroke; Mechanism of action; Candidate traditional Chinese medicine

DOI：

10.7507/1001-5515.202303005

Video：

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The therapeutic efficacy of Danshen and Jiangxiang in the treatment of ischemic stroke (IS) is relatively significant. Studying the mechanism of action of Danshen and Jiangxiang in the treatment of IS can effectively identify candidate traditional Chinese medicines (TCM) with efficacy. However, it is challenging to analyze the effector substances and explain the mechanism of action of Danshen-Jiangxiang from a systematic perspective using traditional pharmacological approaches. In this study, a systematic study was conducted based on the drug-target-symptom-disease association network using complex network theory. On the basis of the association information about Danshen, Jiangxiang and IS, the protein-protein interaction (PPI) network and the “drug pair-pharmacodynamic ingredient-target-IS” network were constructed. The different topological features of the networks were analyzed to identify the core pharmacodynamic ingredients including formononetin in Jiangxiang, cryptotanshinone and tanshinone IIA in Danshen as well as core target proteins such as prostaglandin G/H synthase 2, retinoic acid receptor RXR-alpha, sodium channel protein type 5 subunit alpha, prostaglandin G/H synthase 1 and beta-2 adrenergic receptor. Further, a method for screening IS candidates based on TCM symptoms was proposed to identify key TCM symptoms and syndromes using the “drug pair-TCM symptom-syndrome-IS” network. The results showed that three TCMs, namely Puhuang, Sanleng and Zelan, might be potential therapeutic candidates for IS, which provided a theoretical reference for the development of drugs for the treatment of IS.

Citation： GAO Jiaxuan, DING Yanrui. Investigation of the mechanism of action and identification of candidate traditional Chinese medicines for the treatment of ischemic stroke in the Danshen-Jiangxiang pair based on drug-target-disease association network. Journal of Biomedical Engineering, 2023, 40(4): 762-769. doi: 10.7507/1001-5515.202303005 Copy

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33.	马建福, 王豆, 李涛, 等. 郁金治疗卒中后抑郁的药理机制研究进展. 中国实验方剂学杂志, 2022, 28(7): 276-282.

1. Ojaghihaghighi S, Vahdati S S, Mikaeilpour A, et al. Comparison of neurological clinical manifestation in patients with hemorrhagic and ischemic stroke. World J Emerg Med, 2017, 8(1): 34-38.
2. Kanazawa M, Takahashi T, Ishikawa M, et al. Angiogenesis in the ischemic core: a potential treatment target?. J Cereb Blood Flow Metab, 2019, 39(5): 753-769.
3. Hansson G K. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 2005, 352(16): 1685-1695.
4. Xiong X, White R E, Xu L, et al. Mitigation of murine focal cerebral ischemia by the hypocretin/orexin system is associated with reduced inflammation. Stroke, 2013, 44(3): 764-770.
5. Qiu J. Traditional medicine: a culture in the balance. Nature, 2007, 448(7150): 126-129.
6. Libby P, Ridker P M, Hansson G K, et al. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol, 2009, 54(23): 2129-2138.
7. 寿斌耀, 陈兰英, 张妮, 等. 降香不同提取物通过调控能量代谢抑制大鼠急性心肌缺血损伤. 中成药, 2021, 43(2): 374-380.
8. 谢丽华, 赵毅锦, 林兴丽, 等. 中药治疗脑缺血的用药规律研究. 中医药导报, 2017, 23(17): 38-40.
9. Wang S, Luo K, Liang J, et al. Metabolomics study on the synergistic interaction between Salvia miltiorrhiza and Lignum dalbergiae odoriferae used as 'J un-Shi' herbs in a S. miltiorrhiza recipe. Med Res Rev, 2011, 20(1): 16-22.
10. Zheng X, Zhao X, Wang S, et al. Co-administration of Dalbergia odorifera increased bioavailability of Salvia miltiorrhizae in rabbits. Am J Chin Med, 2007, 35(5): 831-840.
11. 李斐, 孟运莲. 香丹注射液对大鼠脑缺血再灌注损伤的保护作用. 中国现代药物应用, 2010, 4(1): 25-27.
12. 李斐, 张岳. 香丹注射液对脑缺血再灌注大鼠细胞凋亡与FADD mRNA表达的影响. 中国老年学杂志, 2013, 33(16): 3899-3900.
13. Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform, 2014, 6: 1-6.
14. Kim S, Chen J, Cheng T, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res, 2021, 49(1): 1388-1395.
15. Consortium T U. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res, 2021, 49(1): 480-489.
16. Stelzer G, Rosen N, Plaschkes I, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics, 2016, 54(1): 1-33.
17. Amberger J S, Bocchini C A, Scott A F, et al. OMIM.org: leveraging knowledge across phenotype–gene relationships. Nucleic Acids Res, 2019, 47(1): 1038-1043.
18. Zhou Y, Zhang Y, Lian X, et al. Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents. Nucleic Acids Res, 2022, 50(1): 1398-1407.
19. Szklarczyk D, Gable A L, Nastou K C, et al. The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res, 2021, 49(1): 605-612.
20. Wu Y, Zhang F, Yang K, et al. SymMap: an integrative database of traditional Chinese medicine enhanced by symptom mapping. Nucleic Acids Res, 2019, 47(1): 1110-1117.
21. Sherman B T, Hao M, Qiu J, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res, 2022, 50(1): 216-221.
22. Hers I, Vincent E E, Tavaré J M. Akt signalling in health and disease. Cell Signal, 2011, 23(10): 1515-1527.
23. Boldin M P, Goncharov T M, Goltseve Y V, et al Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor–induced cell death. Cell, 1996, 85(6): 803-815.
24. Lalaoui N, Boyden S E, Oda HM, et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature, 2020, 577(7788): 103-108.
25. Owaki H, Makar R, Boulton T G, et al. Extracellular signal-regulated kinases in T cells: characterization of human ERK1 and ERK2 cDNAs. Biochem Biophys Res Commun, 1992, 182(3): 1416-1422.
26. Beinke S, Robinson M J, Hugunin M, et al. Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105. Mol Cell Biol, 2004, 24(21): 9658-9667.
27. Yokoyama C, Tanabe T. Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem Biophys Res Commun, 1989, 165(2): 888-894.
28. Gellens M E, George Jr A L, Chen L, et al. Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci U S A, 1992, 89(2): 554-558.
29. Lee D, Lin T, Lee C, et al. MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases. Proc Natl Acad Sci U S A, 2017, 114(8): 2072-2077.
30. Chung F Z, Wang C D, Potter P C, et al. Site-directed mutagenesis and continuous expression of human b-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation. J Biol Chem, 1988, 263(9): 4052-4055.
31. Sugimoto M, Ko R, Goshima H, et al. Formononetin attenuates H₂O₂-induced cell death through decreasing ROS level by PI3K/Akt-Nrf2-activated antioxidant gene expression and suppressing MAPK-regulated apoptosis in neuronal SH-SY5Y cell. Neurotoxicology, 2021, 85: 186-200.
32. Mao Y, Qu Y, Wang Q. Cryptotanshinone reduces neurotoxicity induced by cerebral ischemia-reperfusion injury involving modulation of microglial polarization. Restor Neurol Neurosci, 2021, 39(3): 209-220.
33. 马建福, 王豆, 李涛, 等. 郁金治疗卒中后抑郁的药理机制研究进展. 中国实验方剂学杂志, 2022, 28(7): 276-282.

Journal of Biomedical Engineering

Investigation of the mechanism of action and identification of candidate traditional Chinese medicines for the treatment of ischemic stroke in the Danshen-Jiangxiang pair based on drug-target-disease association network

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