Combining network pharmacology and bioinformatics to identify bioactive compounds and potential mechanisms of action of Sedum aizoon L in the treatment of atherosclerosis

Main Article Content

Bo Jie Zhu
Guan Ye Nai
Tian Xiao Pan
Zhuo Fei Ma
Wei Jie Zhou

Keywords

Sedum aizoon L, atherosclerosis, network pharmacology

Abstract

Sedum aizoon L (SL) is a medicinal plant containing several active components with anti-inflammatory, hemostatic, and blood pressure lowering effects. The aim of this research was to investigate the main pathways, mechanisms, and active components of SL to treat atherosclerosis (AS) through network pharmacology. The active ingredients and their targets of action were obtained by setting the active ingredient-screening conditions using SL as a keyword in the Traditional Chinese Medicine (TCM) System Pharmacology Database and Analysis Platform. The differentially expressed genes related to AS were obtained from the Gene Expression Omnibus database, and the targets related to the treatment of AS were retrieved from databases, such as DisGeNet and GENECARDs, and the targets of AS and SL were intersected using the Cytoscape software platform and applied to construct a drug–compound–target–pathway network map. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and protein–protein interaction were performed to explore the mechanisms of action of SL against AS. In all, 12 active ingredients were screened from the chemical composition of SL, among which myricetin, oleanolic acid, ursolic acid, sitosterol, and beta-sitosterol were the major active ingredients for the anti-atherosclerotic effect of SL. Combining the active ingredient–target network and disease–target protein–protein interaction (PPI) network, GO and KEGG analysis, tumor necrosis factor signaling pathway, and interleukin-17 signaling pathway were the key pathways of action. SL acts as an anti-atherosclerotic agent through multiple chemical components, targets, and pathways. The active ingredients of SL mainly play the role of prevention and treatment of AS by inhibiting inflammatory response, as an antioxidant, and by lowering blood lipids, thereby providing the theoretical basis for its clinical use.

Abstract 217 | PDF Downloads 176 HTML Downloads 7 XML Downloads 7

References

Ali, M., Ibrahim, S., Jalil, S., et al., 2007. Ursolic acid: a potent inhibitor of superoxides produced in the cellular system. Phytotherapy Research: PTR 21: 558–561. 10.1002/ptr.2108

Allahverdian, S., Chehroudi, A., McManus, B., et al., 2014. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 129: 1551–1559. 10.1161/CIRCULATIONAHA.113.005015

Bakhshian, Nik A., Hutcheson, J., Aikawa, E., 2017. Extracellular vesicles as mediators of cardiovascular calcification. Frontiers in Cardiovascular Medicine 4: 78. 10.3389/fcvm.2017.00078

Chen, G. and Goeddel, D., 2002. TNF-R1 signaling: a beautiful pathway. Science (New York, NY) 296: 1634–1635. 10.1126/science.1071924

Chen, G., Xu, H., Wu, Y., et al., 2021. Myricetin suppresses the proliferation and migration of vascular smooth muscle cells and inhibits neointimal hyperplasia via suppressing TGFBR1 signaling pathways. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology 92: 153719. 10.1016/j.phymed.2021.153719

Fereydouni, Z., Amirinezhad, Fard E., Mansouri, K., et al., 2020. Saponins from Tribulus terrestris L. extract down-regulate the expression of ICAM-1, VCAM-1 and E-selectin in human endothelial cell lines. International Journal of Molecular and Cellular Medicine 9: 73–83.

Gao, W., Liu, H., Yuan, J., et al., 2016. Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. Journal of Cellular and Molecular Medicine 20: 2318–2327. 10.1111/jcmm.12923

Hafiane, A., 2019. Vulnerable plaque, characteristics, detection, and potential therapies. Journal of Cardiovascular Development and Disease 6. 10.3390/jcdd6030026

He, S., He, S., Chen, Y., et al., 2022. Beta-sitosterol modulates the migration of vascular smooth muscle cells via the PPARG/AMPK/mTOR pathway. Pharmacology 1–15. 10.1159/000525218

Humphries, S., Cooper, J., Seed, M., et al., 2018. Coronary heart disease mortality in treated familial hypercholesterolaemia: update of the UK Simon Broome FH register. Atherosclerosis 274: 41–46. 10.1016/j.atherosclerosis.2018.04.040

Ikeda, Y., Murakami, A. and Ohigashi, H., 2008. Ursolic acid: an anti-and pro-inflammatory triterpenoid. Molecular Nutrition & Food Research 52: 26–42. 10.1002/mnfr.200700389

Keeter, W., Ma, S., Stahr, N., et al., 2022. Atherosclerosis and multi-organ-associated pathologies. Seminars in Immunopathology 44: 363–374. 10.1007/s00281-022-00914-y

Kishimoto, Y., Sasaki, K., Saita, E., et al., 2018. Plasma heme oxygenase-1 levels and carotid atherosclerosis. Stroke 49: 2230–2232. 10.1161/STROKEAHA.118.022256

Kobiyama, K. and Ley, K., 2018. Atherosclerosis. Circulation Research 123: 1118–1120. 10.1161/CIRCRESAHA.118.313816

Kumbhani, D., Marso, S., Alvarez, C., et al., 2015. State-of-the-art: hypo-responsiveness to oral antiplatelet therapy in patients with type 2 diabetes mellitus. Current Cardiovascular Risk Reports 9: 4. 10.1007/s12170-014-0430-5

Lee, Y., Cho, Y., Kim, E., et al., 2019. Reduced expression of pyruvate kinase in kidney proximal tubule cells is a potential mechanism of pravastatin altered glucose metabolism. Scientific Reports 9: 5318. 10.1038/s41598-019-39461-2

Li, M., Qi, Z., Hao, Y., et al., 2017. New adducts of iriflophene and flavonoids isolated from Sedum aizoon L. with potential antitumor activity. Molecules (Basel, Switzerland) 22. 10.3390/molecules22111859

Li, L., Wei, L., Shen, A., et al., 2015. Oleanolic acid modulates multiple intracellular targets to inhibit colorectal cancer growth. International Journal of Oncology 47: 2247–2254. 10.3892/ijo.2015.3198

Li, Q., Zhao, W., Zeng, X., et al., 2018. Ursolic acid attenuates atherosclerosis in ApoE mice: role of LOX-1 mediated by ROS/NF-κB pathway. Molecules (Basel, Switzerland) 23. 10.3390/molecules23051101

Liao, P., Lai, M., Hsu, K., et al., 2018. Identification of β-sitosterol as in vitro anti-inflammatory constituent in Moringa oleifera. Journal of Agricultural and Food Chemistry 66: 10748–10759. 10.1021/acs.jafc.8b04555

Liu, H., Guo, L., Xing, J., et al., 2020. The protective role of DPP4 inhibitors in atherosclerosis. European Journal of Pharmacology 875: 173037. 10.1016/j.ejphar.2020.173037

Liu, M., Li, X., Lu, L., et al., 2014. Cardiovascular disease and its relationship with chronic kidney disease. European Review for Medical and Pharmacological Sciences 18: 2918–2926.

Liu, S., Li, Y., Zeng, X., et al., 2019. Burden of cardiovascular diseases in China, 1990–2016: Findings from the 2016 Global Burden of Disease Study. JAMA Cardiology 4: 342–352. 10.1001/jamacardio.2019.0295

Love, K. and Liu, Z., 2021. DPP4 activity, hyperinsulinemia, and atherosclerosis. Journal of Clinical Endocrinology and Metabolism 106: 1553–1565. 10.1210/clinem/dgab078

Meng, Z., Wang, M., Xing, J., et al., 2019. Myricetin ameliorates atherosclerosis in the low-density-lipoprotein receptor knockout mice by suppression of cholesterol accumulation in macrophage foam cells. Nutrition & Metabolism 16: 25. 10.1186/s12986-019-0354-7

Mundi, S., Massaro, M., Scoditti, E., et al., 2018, Endothelial permeability, LDL deposition, and cardiovascular risk factors-a review. Cardiovascular Research 114: 35–52. 10.1093/cvr/cvx226

Ott, B., Daiello, L., Dahabreh, I., et al., 2015. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. Journal of General Internal Medicine 30: 348–58. 10.1007/s11606-014-3115-3

Pan, Y., Zhou, F., Song, Z., et al., 2018. Oleanolic acid protects against pathogenesis of atherosclerosis, possibly via FXR-mediated angiotensin (Ang)-(1–7) upregulation. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 97: 1694–1700. 10.1016/j.biopha.2017.11.151

Panes, O., González, C., Hidalgo, P., et al., 2017. Platelet tissue factor activity and membrane cholesterol are increased in hypercholesterolemia and normalized by rosuvastatin, but not by atorvastatin. Atherosclerosis 257: 164–71. 10.1016/j.atherosclerosis.2016.12.019

Pollier, J. and Goossens, A., 2012. Oleanolic acid. Phytochemistry 77: 10–15. 10.1016/j.phytochem.2011.12.022

Rossano, R., Larocca, M., Riviello, L., et al., 2014. Heterogeneity of serum gelatinases MMP-2 and MMP-9 isoforms and charge variants. Journal of Cellular and Molecular Medicine 18: 242–252. 10.1111/jcmm.12181

Schraml, B., Hildner, K., Ise, W., et al., 2009. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460: 405–409. 10.1038/nature08114

Shi, S., Ji, X., Shi, J., et al., 2022. Andrographolide in atherosclerosis: integrating network pharmacology and in vitro pharmacological evaluation. Bioscience Reports 42. 10.1042/BSR20212812

Sierra, S., Luquin, N. and Navarro-Otano, J., 2018. The endocannabinoid system in cardiovascular function: novel insights and clinical implications. Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society 28: 35–52. 10.1007/s10286-017-0488-5

Somova, L., Nadar, A., Rammanan, P., et al., 2003. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology 10: 115–121. 10.1078/094471103321659807

Song, L., Zhang, J., Lai, R., et al., 2021. Chinese herbal medicines and active metabolites: potential antioxidant treatments for atherosclerosis. Frontiers in Pharmacology 12: 675999. 10.3389/fphar.2021.675999

Stary, H., Chandler, A., Glagov, S., et al., 1994. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 89: 2462–2478. 10.1161/01.CIR.89.5.2462

Sun, J., Yin, X., Liu, H., et al., 2018. Rapamycin inhibits ox-LDL--induced inflammation in human endothelial cells in vitro by inhibiting the mTORC2/PKC/c-Fos pathway. Acta Pharmacologica Sinica 39: 336–344. 10.1038/aps.2017.102

Troidl, K., Schubert, C., Vlacil, A., et al., 2020. The lipopeptide MALP-2 promotes collateral growth. Cells 9. 10.3390/cells9040997

Tsoref, O., Tyomkin, D., Amit, U., et al., 2018. E-selectin-targeted copolymer reduces atherosclerotic lesions, adverse cardiac remodeling, and dysfunction. Journal of Controlled Release: Official Journal of the Controlled Release Society 288: 136–147. 10.1016/j.jconrel.2018.08.029

Varatharajalu, R., Garige, M., Leckey, L., et al., 2016. Protective role of dietary curcumin in the prevention of the oxidative stress induced by chronic alcohol with respect to hepatic injury and antiatherogenic markers. Oxidative Medicine and Cellular Longevity 2016: 5017460. 10.1155/2016/5017460

Veldhoen, M., Hocking, R., Atkins, C., et al., 2006. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179–189. 10.1016/j.immuni.2006.01.001

Wang, X., Liu, R., Zhang, W., et al., 2013. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Molecular and Cellular Endocrinology 376: 70–80. 10.1016/j.mce.2013.06.014

Wang, H., Xu, F., Zhang, X., et al., 2021. Transcriptomic analysis reveals antibacterial mechanism of flavonoids from Sedum aizoon L. against Pseudomonas fragi. 10.1016/j.foodcont.2021.108755

Wu, D., Hu, Q., Wang, Y., et al. 2022. Identification of HMOX1 as a critical ferroptosis-related gene in atherosclerosis. Frontiers in Cardiovascular Medicine 9: 833642. 10.3389/fcvm.2022.833642

Wu, Z., Li, W., Liu, G., et al., 2018. Network-based methods for prediction of drug-target interactions. Frontiers in Pharmacology 9: 1134. 10.3389/fphar.2018.01134

Wu, M., Xu, K., Guo, Y., et al., 2019. Lipoprotein(a) and-atherosclerotic cardiovascular disease: current understanding and future perspectives. Cardiovascular Drugs and Therapy 33: 739–48. 10.1007/s10557-019-06906-9

Xi, J., Rong, Y., Zhao, Z., et al., 2021. Scutellarin ameliorates high-glucose-induced vascular endothelial cells injury by activating PINK1/Parkin-mediated mitophagy. Journal of Ethnophar-macology 271: 113855. 10.1016/j.jep.2021.113855

Xie, X., Ma, X., Zeng, S., et al., 2020. Mechanisms of berberine for the treatment of atherosclerosis based on network pharmacology. Evidence-Based Complementary and Alternative Medicine: eCAM 2020: 3568756. 10.1155/2020/3568756

Xu, T., Wang, Z., Lei, T., et al., 2015. New flavonoid glycosides from Sedum aizoon L. Fitoterapia 101: 125–132. 10.1016/j.fitote.2014.12.014

Zhang, W., Feng, J., Cheng, B., et al., 2018. Oleanolic acid protects against oxidative stress-induced human umbilical vein endothelial cell injury by activating AKT/eNOS signaling. Molecular Medicine Reports 18: 3641–3648. 10.3892/mmr.2018.9354

Zhao, C. and Herrington, D., 2016. The function of cathepsins B, D, and X in atherosclerosis. American Journal of Cardiovascular Disease 6: 163–170.

Zhou, S., Ai, Z., Li, W., et al., 2020. In vitro deciphering the pharmacological mechanisms of taohe-chengqi decoction extract against renal fibrosis through integrating network pharmacology and experimental validation. Frontiers in Pharmacology 11: 425. 10.3389/fphar.2020.00425