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
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.
References
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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
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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
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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
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
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Aug 31, 2023
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Zhu, B. J., Nai, G. Y., Pan, T. X., Ma, Z. F., & Zhou, W. J. (2023). Combining network pharmacology and bioinformatics to identify bioactive compounds and potential mechanisms of action of Sedum aizoon L in the treatment of atherosclerosis. Quality Assurance and Safety of Crops & Foods, 15(3), 104-116. https://doi.org/10.15586/qas.v15i3.1333
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How to Cite
Zhu, B. J., Nai, G. Y., Pan, T. X., Ma, Z. F., & Zhou, W. J. (2023). Combining network pharmacology and bioinformatics to identify bioactive compounds and potential mechanisms of action of Sedum aizoon L in the treatment of atherosclerosis. Quality Assurance and Safety of Crops & Foods, 15(3), 104-116. https://doi.org/10.15586/qas.v15i3.1333