Open Access Peer-reviewed Research Article

Main Article Content

Minjun Wang corresponding author


Background: Atherosclerosis (AS) is one of the leading causes of cardiovascular diseases. The traditional China herb pairs such as Huanglian-Gualou, Honghua-Taoren, and Suhexiang-Bingpian showed therapeutic effects on AS by clearing heat and resolving phlegm, invigorating blood and removing blood stasis, as well as aromatic resuscitation, respectively. However, the common and specific mechanisms of these pairs against the same disease are elusive.
Objective: This study aimed to explore the molecular mechanisms of 3 herb pairs treating AS by network pharmacology, molecular modeling and mechanism experiments.
Methods: The components and their corresponding targets of 3 herb pairs, as well as AS-related targets, were collected from multiple databases and literature. Then the protein-protein interaction network was built to identify the key components and targets associated with AS. The pathway enrichment analysis using KEGG was carried out for analyzing the common mechanisms of 3 herb pairs against AS. Finally, the binding modes of the key components and targets were analyzed by molecular docking and molecular dynamic simulation.
Results: The PPI network indicated that the common targets of 3 herb pairs focused on four pathways, including regulated vascular shear stress, TNF, ARE-RAGE, and IL-17 pathways. The molecular docking analysis indicated that the key component quercetin showed highest docking score with PTGS2 in comparison to other targets. Molecular dynamics simulations revealed that quercetin stably anchored to the active pocket of PTGS2 by forming hydrogen bonds with Thr175, Asn351, and Trp356.
Conclusion: The molecular mechanism of Huanglian-Gualou, Honghua-Taoren, and Suhexiang-Bingpian against AS was preliminarily expounded, and we wish to provide a theoretical instruction for clinical treatment of AS.

atherosclerosis, network pharmacology, molecular docking, molecular dynamics

Article Details

How to Cite
Wang, M. (2023). Exploring the mechanism of three herb pairs for the treatment of atherosclerosis through network pharmacology and molecular modeling. Journal of Pharmaceutical and Biopharmaceutical Research, 5(1), 349-365.


  1. Falk E. Pathogenesis of atherosclerosis. Journal of the American College of Cardiology, 2006, 47: 7-12.
  2. Gisterå A and Hansson GK. The immunology of atherosclerosis. Nature reviews nephrology, 2017, 13(6): 368-380.
  3. Raggi P, Genest J, Giles JT, et al. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions. Atherosclerosis, 2018, 276: 98-108.
  4. Okuyama H, Langsjoen PH, Hamazaki T, et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert review of clinical pharmacology, 2015, 8(2): 189-199.
  5. Ting-Ting LI, Zhi-Bin W, Yang LI, et al. The mechanisms of traditional Chinese medicine underlying the prevention and treatment of atherosclerosis. Chinese Journal of Natural Medicines, 2019, 17(6): 401-412.
  6. Rui R, Yang H, Liu Y, et al. Effects of Berberine on Atherosclerosis. Frontiers in pharmacology, 2021, 12: 764175.
  7. Lei X, Li N, Bai Z, et al. Chemical constituent from the peel of Trichosanthes kirilowii Maxim and their NF-$kappa$B inhibitory activity. Natural Product Research, 2021, 35(23): 5132-5137.
  8. Fu N, Li H, Sun J, et al. Trichosanthes pericarpium aqueous extract enhances the mobilization of endothelial progenitor cells and up-regulates the expression of VEGF, eNOS, NO, and MMP-9 in acute myocardial ischemic rats. Frontiers in Physiology, 2018, 8: 1132.
  9. Jiagang D, Li C, Wang H, et al. Amygdalin mediates relieved atherosclerosis in apolipoprotein E deficient mice through the induction of regulatory T cells. Biochemical and Biophysical Research Communications, 2011, 411(3): 523-529.
  10. Xue X, Deng Y, Wang J, et al. Hydroxysafflor yellow A, a natural compound from Carthamus tinctorius L with good effect of alleviating atherosclerosis. Phytomedicine, 2021, 91: 153694.
  11. Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. Journal of cheminformatics, 2014, 6: 1-6.
  12. Meng FC, Wu ZF, Yin ZQ, et al. Coptidis rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity. Chinese medicine, 2018, 13: 13.
  13. Yu X, Tang L, Wu H, et al. Trichosanthis Fructus: botany, traditional uses, phytochemistry and pharmacology. Journal of ethnopharmacology, 2018, 224: 177-194.
  14. Zhang LL, Tian K, Tang ZH, et al. Phytochemistry and Pharmacology of Carthamus tinctorius L. The American journal of Chinese medicine, 2016, 44(2): 197-226.
  15. Zou L, Zhang Y, Li W, et al. Comparison of chemical profiles, anti-inflammatory activity, and UPLC-Q-TOF/MS-based metabolomics in endotoxic fever rats between synthetic borneol and natural borneol. Molecules, 2017, 22(9): 1446.
  16. Hovaneissian M, Archier P, Mathe C, et al. Analytical investigation of styrax and benzoin balsams by HPLC‐PAD‐fluorimetry and GC-MS. Phytochemical Analysis, 2008, 19(4): 301-310.
  17. Tanaka R, Nitta A and Nagatsu A. Application of a quantitative 1 H-NMR method for the determination of amygdalin in Persicae semen, Armeniacae semen, and Mume fructus. Journal of natural medicines, 2014, 68:225-230.
  18. Gfeller D, Grosdidier A, Wirth M, et al. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic acids research, 2014, 42(W1): W32-W38.
  19. Keiser MJ, Roth BL, Armbruster BN, et al. Relating protein pharmacology by ligand chemistry. Nature biotechnology, 2007, 25(2): 197-206.
  20. Amberger JS, Bocchini CA, Schiettecatte F, et al. OMIM. org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic acids research, 2015, 43(D1): D789-D798.
  21. Piñero J, Bravo À, Queralt-Rosinach N, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic acids research, 2017, 45: D833-d839.
  22. Rebhan M, Chalifa-Caspi V, Prilusky J, et al. GeneCards: integrating information about genes, proteins and diseases. Trends in genetics: TIG, 1997, 13(4): 163-163.
  23. Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research, 2003, 13(11): 2498-2504.
  24. Szklarczyk D, Gable A L, Lyon D, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic acids research, 2019, 47(D1): D607-D613.
  25. Louis S. Sybyl.Tripos, Inc. 1699 South Hanley Road, MO 63144-62913.
  26. Lucido MJ, Orlando BJ, Vecchio AJ, et al. Crystal structure of aspirin-acetylated human cyclooxygenase-2: insight into the formation of products with reversed stereochemistry. Biochemistry, 2016, 55(8): 1226-1238.
  27. Aertgeerts K, Skene R, Yano J, et al. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. Journal of Biological Chemistry, 2011, 286(21): 18756-18765.
  28. Du JQ, Wu J, Zhang HJ, et al. Isoquinoline-1, 3, 4-trione derivatives inactivate caspase-3 by generation of reactive oxygen species. Journal of Biological Chemistry, 2008, 283(44): 30205-30215.
  29. Bruning JB, Chalmers MJ, Prasad S, et al. Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure (London, England : 1993), 2007, 15: 1258-1271.
  30. Abraham MJ, Murtola T, Schulz R, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2015, 1: 19-25.
  31. Lindorff-Larsen K, Piana S, Palmo K, et al. Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins: Structure, Function, and Bioinformatics, 2010, 78(8): 1950-1958.
  32. AMBER14. University of California, San Francisco, 2014.
  33. Bussi G, Donadio D and Parrinello M. Canonical sampling through velocity rescaling. The Journal of chemical physics, 2007, 126(1): 014101.
  34. Nosé S and Klein ML. Constant pressure molecular dynamics for molecular systems. Molecular Physics, 1983, 50: 1055-1076.
  35. Gómez-Hernández A, Martín-Ventura J L, Sánchez-Galán E, et al. Overexpression of COX-2, prostaglandin E synthase-1 and prostaglandin E receptors in blood mononuclear cells and plaque of patients with carotid atherosclerosis: regulation by nuclear factor-$kappa$B. Atherosclerosis, 2006, 187(1): 139-149.
  36. Maleki SJ, Crespo JF annd Cabanillas B. Anti-inflammatory effects of flavonoids. Food chemistry, 2019, 299: 125124.
  37. Zeboudj L, Maître M, Guyonnet L, et al. Selective EGF-receptor inhibition in CD4+ T cells induces anergy and limits atherosclerosis. Journal of the American College of Cardiology, 2018, 71(2): 160-172.
  38. Lee S, Lim HJ, Park HY, et al. Berberine inhibits rat vascular smooth muscle cell proliferation and migration in vitro and improves neointima formation after balloon injury in vivo: berberine improves neointima formation in a rat model. Atherosclerosis, 2006, 186(1): 29-37.
  39. Bian W, Jing X, Yang Z, et al. Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis. Aging (Albany NY), 2020, 12(7): 6385.
  40. Haftcheshmeh SM, Abedi M, Mashayekhi K, et al. Berberine as a natural modulator of inflammatory signaling pathways in the immune system: Focus on NF-$kappa$B, JAK/STAT, and MAPK signaling pathways. Phytotherapy Research, 2022, 36(3): 1216-1230.
  41. Al-Shali KZ, House AA, Hanley AJG, et al. Genetic variation in PPARG encoding peroxisome proliferator-activated receptor $gamma$ associated with carotid atherosclerosis. Stroke, 2004, 35(9): 2036-2040.
  42. Yang N, Tang Q, Qin W, et al. Treatment of obesity-related inflammation with a novel synthetic pentacyclic oleanane triterpenoids via modulation of macrophage polarization. EBioMedicine, 2019, 45: 473-486.
  43. Huang Z, Wang L, Meng S, et al. Berberine reduces both MMP-9 and EMMPRIN expression through prevention of p38 pathway activation in PMA-induced macrophages. International journal of cardiology, 2011, 146(2): 153-158.
  44. Hedayati-Moghadam M, Hosseinian S, Paseban M, et al. The role of chemokines in cardiovascular diseases and the therapeutic effect of curcumin on CXCL8 and CCL2 as pathological chemokines in atherosclerosis. Natural Products and Human Diseases: Pharmacology, Molecular Targets, and Therapeutic Benefits, 2021, 1328: 155-170.
  45. Wang Y, Jia Q, Zhang Y, et al. Amygdalin attenuates atherosclerosis and plays an anti-inflammatory role in ApoE knock-out mice and bone marrow-derived macrophages. Frontiers in Pharmacology, 2020, 11: 590929.
  46. Guo XD, Zhang DY, Gao XJ, et al. Quercetin and quercetin-3-O-glucuronide are equally effective in ameliorating endothelial insulin resistance through inhibition of reactive oxygen species-associated inflammation. Molecular nutrition & food research, 2013, 57(6): 1037-1045.
  47. Guo J, Qin Z, He Q, et al. Shexiang baoxin pill for acute myocardial infarction: Clinical evidence and molecular mechanism of antioxidative stress. Oxidative Medicine and Cellular Longevity, 2021, 2021: 7644648.
  48. Wang YH and Zhang YR. Variations in compositions and antioxidant activities of essential oils from leaves of Luodian Blumea balsamifera from different harvest times in China. PLoS One, 2020, 15(6): e0234661.
  49. Yang S, Li R, Tang L, et al. TLR4-mediated anti-atherosclerosis mechanisms of angiotensin-converting enzyme inhibitor–fosinopril. Cellular immunology, 2013, 285(1-2): 38-41.
  50. Zhang L, Wang F, Zhang Q, et al. Anti-inflammatory and anti-apoptotic effects of stybenpropol A on human umbilical vein endothelial cells. International Journal of Molecular Sciences, 2019, 20(21): 5383.
  51. Sbarsi I, Falcone C, Boiocchi C, et al. Inflammation and atherosclerosis: the role of TNF and TNF receptors polymorphisms in coronary artery disease. International Journal of Immunopathology and Pharmacology, 2007, 20(1): 145-154.
  52. Chen G and Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science, 2002, 296(5573): 1634-1635.
  53. Van Quickelberghe E, De Sutter D, van Loo G, et al. A protein-protein interaction map of the TNF-induced NF-$kappa$B signal transduction pathway. Scientific data, 2018, 5(1): 1-9.
  54. Li CL, Tan LH, Wang YF, et al. Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo. Phytomedicine, 2019, 52: 272-283.
  55. Cao H, Jia Q, Yan L, et al. Quercetin suppresses the progression of atherosclerosis by regulating MST1-mediated autophagy in ox-LDL-induced RAW264. 7 macrophage foam cells. International journal of molecular sciences, 2019, 20(23): 6093.
  56. Rosenblat M, Volkova N and Aviram M. Pomegranate phytosterol ($beta$-sitosterol) and polyphenolic antioxidant (punicalagin) addition to statin, significantly protected against macrophage foam cells formation. Atherosclerosis, 2013, 226(1): 110-117.
  57. Hao X, Sun W, Ke C, et al. Anti-inflammatory activities of leaf oil from Cinnamomum subavenium in vitro and in vivo. BioMed Research International, 2019, 2019: 1823149.
  58. Cheng Y, Chu Y, Su X, et al. Pharmacokinetic–pharmacodynamic modeling to study the anti-dysmenorrhea effect of Guizhi Fuling capsule on primary dysmenorrhea rats. Phytomedicine, 2018, 48: 141-151.
  59. Al-Khayri JM, Sahana GR, Nagella P, et al. Flavonoids as potential anti-inflammatory molecules: A review. Molecules, 2022, 27(9): 2901.
  60. Zhu Y, Xian X, Wang Z, et al. Research progress on the relationship between atherosclerosis and inflammation. Biomolecules, 2018, 8(3): 80.
  61. Chen J, Ye Z, Wang X, et al. Nitric oxide bioavailability dysfunction involves in atherosclerosis. Biomedicine & Pharmacotherapy, 2018, 97: 423-428.