Exploring the potential mechanism of drug pair Salviae Miltiorrhizae Radix et Rhizoma and Notoginseng Radix et Rhizoma in the treatment of thrombosis after polycythemia vera by network pharmacology

Abstract

Thrombosis is a leading cause of mortality and morbidity in patients suffering from polycythemia vera (PV). Drug pair Salviae Miltiorrhizae Radix et Rhizoma (Danshen, DS) and Notoginseng Radix et Rhizoma (Sanqi, SQ) is common traditional Chinese medicine (TCM) used in clinical practice to promote blood circulation and eliminate blood stasis. In this study, network pharmacology and molecular docking were used to analyze the potentially active ingredients and underlying mechanisms of drug pair DS-SQ against thrombosis after PV. These results show that 54 targets are related to both disease and the drug pair. Nineteen core targets, including IL-6 and AKT1, were screened. Luteolin and tanshinone IIa from DS as well as quercetin from SQ might be the major substances in the treatment of thrombosis after PV. KEGG enrichment analysis demonstrated that the lipid and atherosclerosis signaling pathway might play a significant role. These results provide valuable insights and a reference for the use of drug pair DS-SQ in management of thrombosis after PV and lay a foundation for further exploration of pharmacological effects.

Keywords

thrombosis / polycythemia vera / Salviae Miltiorrhizae Radix et Rhizoma / Notoginseng Radix et Rhizoma / network pharmacology / mechanism

Acknowledgment

This work was supported by grant from the Project of the National Natural Science Foundation of China (Grant No. 82060028). The study wasalso funded by the Yunnan Blood Disease Clinical Medical Center (Grant No. 2023YJZX-XY05), the Yunnan Health Commission (L2019003) to TS, the Yunnan Provincial Key Laboratory of Clinical Virology (Grant No. 202205AG070005), and the Yunnan Provincial Key Laboratory of Innovative Application of Traditional Chinese Medicine.

A statement that all authors have seen and approved the manuscript

All the authors were involved in the manuscript writing process and approved it for publication.

Appendix A. Supplementary data

Supplementary data to this article can be found online.

References

[1] Patel AB, Masarova L, Mesa RA, et al. Polycythemia vera: past, present and future. Leuk Lymphoma, 2024, 65: 1552-1564.

[2] Krecak I, Lekovic D, Arsenovic I, et al. Systemic Inflammatory Index in Polycythemia Vera and Its Prognostic Implications. J Clin Med, 2024, 13: 4459.

[3] Rocca B, Tosetto A, Petrucci G, et al. Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial. Am J Hematol, 2024, 99: 1462-1474.

[4] Chia YC, Siti Asmaa MJ, Ramli M, et al. Molecular Genetics of Thrombotic Myeloproliferative Neoplasms: Implications in Precision Oncology. Diagnostics (Basel), 2023, 13: 163.

[5] Zhang J, Liu SL, Wang H, et al. The effects of borneol on the pharmacokinetics and brain distribution of tanshinone IIA, salvianolic acid B and ginsenoside Rg(1) in Fufang Danshen preparation in rats. Chin J Nat Med, 2021, 19: 153-160.

[6] Yin SJ, Luo YQ, Zhao CP, et al. Antithrombotic effect and action mechanism of Salvia miltiorrhiza and Panax notoginseng herbal pair on the zebrafish. Chin Med, 2020, 15: 35.

[7] Jiao S, Tang B, Wang Y, et al. Pro-angiogenic Role of Danqi Pill Through Activating Fatty Acids Oxidation Pathway Against Coronary Artery Disease. Front Pharmacol, 2018, 9: 1414.

[8] Sheng S, Wang J, Wang L, et al. Network pharmacology analyses of the antithrombotic pharmacological mechanism of Fufang Xueshuantong Capsule with experimental support using disseminated intravascular coagulation rats. J Ethnopharmacol, 2014, 154: 735-744.

[9] Kasimu R, Wang XL, Wang XM, et al. Antithrombotic effects and related mechanisms of Salvia deserta Schang root EtOAc extracts. Sci Rep, 2018, 8: 17753.

[10] Wang X, Wang Y, Chen J, et al. On the mechanism of wogonin against acute monocytic leukemia using network pharmacology and experimental validation. Sci Rep, 2024, 14: 10114.

[11] Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res, 2019, 47: 357-364.

[12] Safran M, Chalifa-caspi V, Shmueli O, et al. Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE. Nucleic Acids Res, 2003, 31: 142-146.

[13] Amberger JS, Hamosh A. Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes. Curr Protoc Bioinformatics, 2017, 58: 1.2.1-1.2.12.

[14] Liu X, Zhu F, Ma XH, et al. The Therapeutic Target Database: an internet resource for the primary targets of approved, clinical trial and experimental drugs. Expert Opin Ther Targets, 2011, 15: 903-912.

[15] Piñero J, Bravo À, Queralt-ROSINACH N, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res, 2017, 45: 833-839.

[16] Barbarino JM, Whirl-carrillo M, Altman RB, et al. PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med, 2018, 10: 1417.

[17] Sherman BT, 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: 216-221.

[18] Lai HR, Tu YS, Zhang S, et al. Association of inflammation and abnormal lipid metabolism with risk of thrombosis and thrombosis progression in patients with polycythemia vera: a retrospective study. Ann Hematol, 2023, 102: 3413-3426.

[19] Todor SB, Ichim C, Boicean A, et al. Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications-A Narrative Review. Curr Issues Mol Biol, 2024, 46: 8407-8423.

[20] Tang H, Qin N, Rao C, et al. Screening of Potential Anti-Thrombotic Ingredients from Salvia miltiorrhiza in Zebrafish and by Molecular Docking. Molecules, 2021, 26: 6807.

[21] Wang H, Zhong L, Mi S, et al. Tanshinone IIA prevents platelet activation and down-regulates CD36 and MKK4/JNK 2 signaling pathway. BMC Cardiovasc Disord, 2020, 20: 81.

[22] Gogoi D, Chattopadhyay P, Dolui SK, et al. Studies on in vivo antithrombotic activity of quercetin, a natural flavonoid isolated from a traditional medicinal plant, African eggplant (Solanum indicum). J Ethnopharmacol, 2024, 335: 118686.

[23] Saviano A, De Vita S, Chini MG, et al. In Silico, In Vitro, and In Vivo Analysis of Tanshinone IIA and Cryptotanshinone from Salvia miltiorrhiza as Modulators of Cyclooxygenase-2/mPGES-1/Endothelial Prostaglandin EP3 Pathway. Biomolecules, 2022, 12: 99.

[24] Zaragozá C, Monserrat J, Mantecón C, et al. Binding and antiplatelet activity of quercetin, rutin, diosmetin, and diosmin flavonoids. Biomed Pharmacother, 2021, 141: 111867.

[25] Zhang Q, Guo D, Wang Y, et al. Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction via HIF-1α/PGC-1α Mediated Glucose Metabolism Pathway. Front Pharmacol, 2020, 11: 458.

[26] Liu Z, Gao J, Ban Y, et al. Synergistic effect of paeoniflorin combined with luteolin in alleviating Lipopolysaccharides-induced acute lung injury. J Ethnopharmacol, 2024, 327: 118022.

[27] Schrottmaier WC, Assinger A. The Concept of Thromboinflammation. Hamostaseologie, 2024, 44: 21-30.

[28] Wang JC, Shi G, Chen C, et al. TLR2 Derangements Likely Play a Significant Role in the Inflammatory Response and Thrombosis in Patients with Ph(-) Classical Myeloproliferative Neoplasm. Mediators Inflamm, 2024, 2024: 1827127.

[29] Zogorean R, Wirtz S. The yin and yang of B cells in a constant state of battle: intestinal inflammation and inflammatory bowel disease. Front Immunol, 2023, 14: 1260266.

[30] Kim J, Zhang S, Zhu Y, et al. Amelioration of colitis progression by ginseng-derived exosome-like nanoparticles through suppression of inflammatory cytokines. J Ginseng Res, 2023, 47: 627-637.

[31] Yang R, Yang H, Wei J, et al. Mechanisms Underlying the Effects of Lianhua Qingwen on Sepsis-Induced Acute Lung Injury: A Network Pharmacology Approach. Front Pharmacol, 2021, 12: 717652.

[32] Li Y, Wu X, Pan J, et al. Hepatocyte steatosis activates macrophage inflammatory response accelerating atherosclerosis development. Zhejiang Da Xue Xue Bao Yi Xue Ban, 2023, 52: 751-765.

[33] Wang H, Tian Q, Zhang R, et al. Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD 36 pathway. Lipids Health Dis, 2024, 23: 76.

[34] Kökény G, Calvier L, Hansmann G. PPARγ and TGFβ- Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys. Int J Mol Sci, 2021, 22: 10431.

[35] Zhou X, Razmovski-naumovski V, Chang D, et al. Synergistic Effects of Danshen (Salvia Miltiorrhiza Radix et Rhizoma) and Sanqi (Notoginseng Radix et Rhizoma) Combination in Inhibiting Inflammation Mediators in RAW264.7 Cells. Biomed Res Int, 2016, 2016: 5758195.

[36] Li W, Xu F, Huang R, et al. Xueshuantong Injection in Treating Deep Venous Thrombosis: A Systematic Review and Trial Sequential Analysis. Evid Based Complement Alternat Med, 2021, 2021: 6622925.

[37] Hur JY, Choi N, Choi JH, et al. Risk of thrombosis, hemorrhage and leukemic transformation in patients with myeloproliferative neoplasms: A nationwide longitudinal cohort study. Thromb Res, 2024, 236: 209-219.

[38] Ghim M, Yang SW, David KRZ, et al. NO Synthesis but Not Apoptosis, Mitosis or Inflammation Can Explain Correlations between Flow Directionality and Paracellular Permeability of Cultured Endothelium. Int J Mol Sci, 2022, 23: 8076.

[39] Cominal JG, Cacemiro MDC, Berzoti-coelho MG, et al. Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms. Front Oncol, 2021, 11: 665037.

[40] Xu Y, Ye H. Progress in understanding the mechanisms of resistance to BCL-2 inhibitors. Exp Hematol Oncol, 2022, 11: 31.

[41] Wang X, Khalil RA. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Adv Pharmacol, 2018, 81: 241-330.

[42] Zhang X, Li S, Chen Z, et al. Tanshinone ⅡA participates in the treatment of endometriosis by regulating adhesion, invasion, angiogenesis and inhibition of PI3K/Akt/ mTOR signaling pathway. Mol Med Rep, 2023, 28: 221.

[43] Kang H, Yang J, Zhang W, et al. Effect of endothelial glycocalyx on water and LDL transport through the rat abdominal aorta. Am J Physiol Heart Circ Physiol, 2021, 320: 1724-1737.