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Abstract
Background: In Central Sulawesi, Indonesia, Syzygium polyanthum leaves (SPL) have been traditionally used by society to reduce high blood pressure. However, the molecular mechanism behind this effect still remains unclear.
Objective: This study aims to explore the antihypertensive molecular mechanisms of SPL using a network pharmacology approach.
Method: Previous studies have investigated some bioactive compounds contained in SPL. Those studies identified 57 bioactive compounds, of which 31 were filtered for further analysis. Target proteins from SPL and disease were identified using GeneCards. Then, 62 selected target proteins which overlapped through Venn diagrams would be analyzed using Cytoscape software to produce compounds-target proteins’ network. Protein-protein interactions were assessed using STRING and visualized by Cytoscape. GO Function and KEGG Pathways were obtained using ShinyGo.
Results: The results of this study revealed pathways associated with hypertension through the cellular senescence pathway with target proteins mTOR, ERK (also known as MAPK), p53, CycD, and IL6. The chemical constituents associated with these target proteins are hydroxychavicol, farnesol, naphthalene, phloretin, pyrogallol, and decanal, which were identified as compounds closely related to the target protein of hypertension.
Conclusion: The bioactive compounds in SPL play a significant role in regulating hypertension by influencing various target genes, particularly those associated with cellular senescence.
Keywords: Antihypertensive, bay leaf, cellular senescence, network pharmacology, Syzygium polyanthum
Keywords
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References
- Ahmed, W., White, I.R., Wilkinson, M., Johnson, C.F., Rattray, N., Kishore, A.K., Goodacre, R., Smith, C.J., & Fowler, S.J. (2021). Breath and Plasma Metabolomics To Assess Inflammation In Acute Stroke. Scientific Reports, 11(1), 1–14. https://doi.org/10.1038/s41598-021-01268-5
- Blowey, D.L. (2016). Diuretics In The Treatment of Hypertension. Pediatric Nephrology, 31(12), 2223–2233. https://doi.org/10.1007/s00467-016-3334-4
- Buckpitt, A., Kephalopoulos, S., Koistinen, K., Kotzias, D., Morawska, L., & Sagunski, H. (2010). Naphthalene. In: WHO Guidelines for Indoor Air Quality: Selected Pollutants, in: Geneva: World Health Organization. 4.
- Chamarthi, B., Williams, G.H., Ricchiuti, V., Srikumar, N., Hopkins, P.N., Luther, J.M., Jeunemaitre, X., & Thomas, A. (2011). Inflammation and Hypertension: The Interplay of Interleukin-6, Dietary Sodium, and the Renin–Angiotensin System in Humans. American Journal of Hypertension, 24(10), 1143–1148. https://doi.org/10.1038/ajh.2011.113
- Chang, M.C., Uang, B.J., Tsai, C.Y., Wu, H.L., Lin, B.R., Lee, C.S., Chen, Y.J., Chang, C.H., Tsai, Y.L., Kao, C.J., & Jeng, J.H. (2007). Hydroxychavicol, A Novel Betel Leaf Component, Inhibits Platelet Aggregation By Suppression of Cyclooxygenase, Thromboxane Production and Calcium Mobilization. British Journal of Pharmacology, 152, 73–82. https://doi.org/10.1038/sj.bjp.0707367
- Chaudhuri, J., Chowdhury, A.A., Biswas, N., Manna, A., Chatterjee, S., Mukherjee, T., Chaudhuri, U., Jaisankar, P., & Bandyopadhyay, S. (2014). Superoxide Activates mTOR-eIF4E-Bax Route To Induce Enhanced Apoptosis In Leukemic Cells. Apoptosis 19(1), 135–148. https://doi.org/10.1007/s10495-013-0904-9
- Cheng, W.-H., Lu, P.-J., Hsiao, M., Hsiao, C.-H., Ho, W.-Y., Cheng, P.-W., Lin, C.-T., Hong, L.-Z., & Tseng, C.-J. (2012). Renin Activates PI3K-Akt-eNOS Signalling Through The Angiotensin AT 1 and Mas Receptors To Modulate Central Blood Pressure Control In The Nucleus Tractus Solitarii. British Journal of Pharmacology, 166, 2024–2035. https://doi.org/10.1111/j.1476-5381.2012.01832.x
- Di Palo, K.E., Barone, N.J. (2020). Hypertension and Heart Failure: Prevention, Targets, and Treatment. Heart Failure Clinics, 16(1), 99–106. https://doi.org/10.1016/j.hfc.2019.09.001
- Fan, H., Lu, F., Yang, A., Dong, Y., Liu, P., & Wang, Y. (2019). A Review on the Nonpharmacological Therapy of Traditional Chinese Medicine with Antihypertensive Effects. Evidence-based Complement. Evidence-based Complementary and Alternative Medicine, 2019, 1–7. https://doi.org/10.1155/2019/1317842
- Ge, S.X., Jung, D., Jung, D., & Yao, R. (2020). ShinyGO: A Graphical Gene-Set Enrichment Tool For Animals and Plants. Bioinformatics, 36(8), 2628–2629. https://doi.org/10.1093/bioinformatics/btz931
- Harun, N.H., Rasdi, N.A., Salleh, R.M., Safuan, S., Wan Ahmad, W.A.N., & Fuad, W.E.M. (2021). Subacute Toxicity Evaluation of Methanolic Extract of Syzygium polyanthum in Rats. Tropical Life Sciences Research, 32(2), 65–81. https://doi.org/10.21315/tlsr2021.32.2.5
- Ismail, A., & Wan Ahmad, W.A.N. (2019). Syzygium polyanthum (Wight) Walp: A Potential Phytomedicine. Pharmacognosy Journal, 11(2), 429–438. https://doi.org/10.5530/pj.2019.11.67
- Ismail, A., & Wan Ahmad, W.A.N. (2017). Autonomic Receptors and Nitric‑Oxide Involvements in Mediating Vasorelaxation Effect Induced by Syzygium polyanthum Leaves Extract. Pharmacognosy Research, 9, 9–14. https://doi.org/10.4103/pr.pr
- Ismail, A., & Wan Ahmad, W.A.N. (2016). Vasorelaxation Effect of Syzygium polyanthum (wight) walp. Leaves Extract On Isolated Thoracic Aorta Rings of Normal and Hypertensive Rats. IIUM Medical Journal Malaysia, 15, 102. https://doi.org/10.31436/imjm.v15i1.1264
- Jiménez, E., & Montiel, M. (2005). Activation of MAP Kinase by Muscarinic Cholinergic Receptors Induces Cell Proliferation and Protein Synthesis in Human Breast Cancer Cells. Journal of Cellular Physiology, 204(2), 678–686. https://doi.org/10.1002/jcp.20326
- Kanehisa, M., Furumichi, M., Sato, Y., Ishiguro-Watanabe, M., & Tanabe, M. (2021). KEGG: Integrating Viruses and Cellular Organisms. Nucleic Acids Research, 49, 545–551. https://doi.org/10.1093/nar/gkaa970
- Kearney, P.M., Whelton, M., Reynolds, K., Muntner, P., Whelton, P.K., & He, J. (2005). Global Burden of Hypertension: Analysis of Worldwide Data. Lancet, 365(9455), 217–223. https://doi.org/10.1016/s0140-6736(05)17741-1
- Luo, T. ting, Lu, Y., Yan, S. kai, Xiao, X., Rong, X. lu, & Guo, J. (2020). Network Pharmacology in Research of Chinese Medicine Formula: Methodology, Application and Prospective. Chinese Journal of Integrative Medicine, 26(1), 72–80. https://doi.org/10.1007/s11655-019-3064-0
- Luo, W., & Brouwer, C. (2013). Pathview: An R/Bioconductor Package For Pathway-Based Data Integration and Visualization. Bioinformatics, 29(14), 1830–1831. https://doi.org/10.1093/bioinformatics/btt285
- McCarthy, C.G., Wenceslau, C.F., Webb, R.C., & Joe, B. (2019). Novel Contributors and Mechanisms of Cellular Senescence in Hypertension-Associated Premature Vascular Aging. American Journal of Hypertension, 32(8), 709–719. https://doi.org/10.1093/ajh/hpz052
- Menezes, I.A.C., Barreto, C.M.N., Antoniolli, Â.R., Santos, M.R.V, & Sousa, D.P.D. (2010). Hypotensive Activity of Terpenes Found in Essential Oils. Z Naturforsch C J Biosci, 65(9-10), 562–566.
- Mohammed, T., Singh, M., Tiu, J.G., & Kim, A.S. (2022). Etiology and Management of Dyslipidemia in Patients With Cancer. Frontiers in Cardiovascular Medicine, 9, 1–13. https://doi.org/10.3389/fcvm.2022.892335
- Nakhate, K.T., Badwaik, H., Choudhary, R., Sakure, K., Agrawal, Y.O., Sharma, C., Ojha, S., & Goyal, S.N. (2022). Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin. Nutrients, 14, 1–24.
- Park, W.H. (2016). Pyrogallol Induces The Death of Human Pulmonary Fibroblast Cells Through ROS Increase and GSH Depletion. International Journal of Oncology, 49(2), 785–792. https://doi.org/10.3892/ijo.2016.3543
- Pistoia, F., Sacco, S., Degan, D., Tiseo, C., Ornello, R., & Carolei, A. (2016). Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation. High Blood Press. High Blood Pressure and Cardiovascular Prevention, 23(1), 1–10. https://doi.org/10.1007/s40292-015-0115-2
- Ramseyer, V.D., & Garvin, J.L. (2013). Tumor Necrosis Factor-α: Regulation of Renal Function and Blood Pressure. American Journal of Physiology - Renal Physiology, 304(10), 1231–1242. https://doi.org/10.1152/ajprenal.00557.2012
- Roger, I., Milara, J., Belhadj, N., & Cortijo, J. (2021). Senescence Alterations in Pulmonary Hypertension. Cells, 10(12), 1–24. https://doi.org/10.3390/cells10123456
- Rouzaud-Laborde, C., Lafitte, P., Balardy, L., Czosnyka, Z., & Schmidt, E.A. (2018). ICP and Antihypertensive Drugs. Acta Neurochirurgica, Supplementum, 126, 163–165. https://doi.org/10.1007/978-3-319-65798-1_34
- Silva, E.A.P., Carvalho, J.S., dos Santos, D.M., Oliveira, A.M.S., de Souza Araújo, A.A., Serafini, M.R., Oliveira Santos, L.A.B., Batista, M.V. d. A., Viana Santos, M.R., Siqueira Quintans, J. de S., Quintans-Júnior, L.J., & Barreto, A.S. (2021). Cardiovascular Effects of Farnesol and Its β-cyclodextrin Complex In Normotensive and Hypertensive Rats. European Journal of Pharmacology, 901, 1–11. https://doi.org/10.1016/j.ejphar.2021.174060
- Stannus, O., Jones, G., Cicuttini, F., Parameswaran, V., Quinn, S., Burgess, J., & Ding, C. (2010). Circulating Levels of IL-6 and TNF-α Are Associated With Knee Radiographic Osteoarthritis and Knee Cartilage Loss In Older Adults. Osteoarthritis and Cartilage, 18(11), 1441–1447. https://doi.org/10.1016/j.joca.2010.08.016
- Takase, H., Sugiura, T., Ohte, N., & Dohi, Y. (2015). Urinary Albumin as a Marker of Future Blood Pressure and Hypertension in the General Population. Medicine (United States), 94(6), 1–7. https://doi.org/10.1097/MD.0000000000000511
- Tan, R., Li, J., Peng, X., Zhu, L., Cai, L., Wang, T., Su, Y., Irani, K., & Hu, Q. (2013). GAPDH Is Critical For Superior Efficacy of Female Bone Marrow-Derived Mesenchymal Stem Cells On Pulmonary Hypertension. Cardiovascular Research, 100(1), 19–27. https://doi.org/10.1093/cvr/cvt165
- Ventura, H.O., & Lavie, C.J. (2019). Editorial: Epidemiology and Managing Aspects of Hypertension. Current Opinion in Cardiology, 34(4), 329–330. https://doi.org/10.1097/HCO.0000000000000631
- Wenzel, U.O., Bode, M., Köhl, J., & Ehmke, H. (2017). A Pathogenic Role of Complement In Arterial Hypertension and Hypertensive End Organ Damage. American Journal of Physiology - Heart and Circulatory Physiology, 312(3), 349–354. https://doi.org/10.1152/ajpheart.00759.2016
- Widyawati, T., Yusoff, N.A., Bello, I., Asmawi, M.Z., & Ahmad, M. (2022). Bioactivity-Guided Fractionation and Identification of Antidiabetic Compound of Syzygium polyanthum (Wight.)’s Leaf Extract in Streptozotocin-Induced Diabetic Rat Model. Molecules, 27(20), 1–15. https://doi.org/10.3390/molecules27206814
References
Ahmed, W., White, I.R., Wilkinson, M., Johnson, C.F., Rattray, N., Kishore, A.K., Goodacre, R., Smith, C.J., & Fowler, S.J. (2021). Breath and Plasma Metabolomics To Assess Inflammation In Acute Stroke. Scientific Reports, 11(1), 1–14. https://doi.org/10.1038/s41598-021-01268-5
Blowey, D.L. (2016). Diuretics In The Treatment of Hypertension. Pediatric Nephrology, 31(12), 2223–2233. https://doi.org/10.1007/s00467-016-3334-4
Buckpitt, A., Kephalopoulos, S., Koistinen, K., Kotzias, D., Morawska, L., & Sagunski, H. (2010). Naphthalene. In: WHO Guidelines for Indoor Air Quality: Selected Pollutants, in: Geneva: World Health Organization. 4.
Chamarthi, B., Williams, G.H., Ricchiuti, V., Srikumar, N., Hopkins, P.N., Luther, J.M., Jeunemaitre, X., & Thomas, A. (2011). Inflammation and Hypertension: The Interplay of Interleukin-6, Dietary Sodium, and the Renin–Angiotensin System in Humans. American Journal of Hypertension, 24(10), 1143–1148. https://doi.org/10.1038/ajh.2011.113
Chang, M.C., Uang, B.J., Tsai, C.Y., Wu, H.L., Lin, B.R., Lee, C.S., Chen, Y.J., Chang, C.H., Tsai, Y.L., Kao, C.J., & Jeng, J.H. (2007). Hydroxychavicol, A Novel Betel Leaf Component, Inhibits Platelet Aggregation By Suppression of Cyclooxygenase, Thromboxane Production and Calcium Mobilization. British Journal of Pharmacology, 152, 73–82. https://doi.org/10.1038/sj.bjp.0707367
Chaudhuri, J., Chowdhury, A.A., Biswas, N., Manna, A., Chatterjee, S., Mukherjee, T., Chaudhuri, U., Jaisankar, P., & Bandyopadhyay, S. (2014). Superoxide Activates mTOR-eIF4E-Bax Route To Induce Enhanced Apoptosis In Leukemic Cells. Apoptosis 19(1), 135–148. https://doi.org/10.1007/s10495-013-0904-9
Cheng, W.-H., Lu, P.-J., Hsiao, M., Hsiao, C.-H., Ho, W.-Y., Cheng, P.-W., Lin, C.-T., Hong, L.-Z., & Tseng, C.-J. (2012). Renin Activates PI3K-Akt-eNOS Signalling Through The Angiotensin AT 1 and Mas Receptors To Modulate Central Blood Pressure Control In The Nucleus Tractus Solitarii. British Journal of Pharmacology, 166, 2024–2035. https://doi.org/10.1111/j.1476-5381.2012.01832.x
Di Palo, K.E., Barone, N.J. (2020). Hypertension and Heart Failure: Prevention, Targets, and Treatment. Heart Failure Clinics, 16(1), 99–106. https://doi.org/10.1016/j.hfc.2019.09.001
Fan, H., Lu, F., Yang, A., Dong, Y., Liu, P., & Wang, Y. (2019). A Review on the Nonpharmacological Therapy of Traditional Chinese Medicine with Antihypertensive Effects. Evidence-based Complement. Evidence-based Complementary and Alternative Medicine, 2019, 1–7. https://doi.org/10.1155/2019/1317842
Ge, S.X., Jung, D., Jung, D., & Yao, R. (2020). ShinyGO: A Graphical Gene-Set Enrichment Tool For Animals and Plants. Bioinformatics, 36(8), 2628–2629. https://doi.org/10.1093/bioinformatics/btz931
Harun, N.H., Rasdi, N.A., Salleh, R.M., Safuan, S., Wan Ahmad, W.A.N., & Fuad, W.E.M. (2021). Subacute Toxicity Evaluation of Methanolic Extract of Syzygium polyanthum in Rats. Tropical Life Sciences Research, 32(2), 65–81. https://doi.org/10.21315/tlsr2021.32.2.5
Ismail, A., & Wan Ahmad, W.A.N. (2019). Syzygium polyanthum (Wight) Walp: A Potential Phytomedicine. Pharmacognosy Journal, 11(2), 429–438. https://doi.org/10.5530/pj.2019.11.67
Ismail, A., & Wan Ahmad, W.A.N. (2017). Autonomic Receptors and Nitric‑Oxide Involvements in Mediating Vasorelaxation Effect Induced by Syzygium polyanthum Leaves Extract. Pharmacognosy Research, 9, 9–14. https://doi.org/10.4103/pr.pr
Ismail, A., & Wan Ahmad, W.A.N. (2016). Vasorelaxation Effect of Syzygium polyanthum (wight) walp. Leaves Extract On Isolated Thoracic Aorta Rings of Normal and Hypertensive Rats. IIUM Medical Journal Malaysia, 15, 102. https://doi.org/10.31436/imjm.v15i1.1264
Jiménez, E., & Montiel, M. (2005). Activation of MAP Kinase by Muscarinic Cholinergic Receptors Induces Cell Proliferation and Protein Synthesis in Human Breast Cancer Cells. Journal of Cellular Physiology, 204(2), 678–686. https://doi.org/10.1002/jcp.20326
Kanehisa, M., Furumichi, M., Sato, Y., Ishiguro-Watanabe, M., & Tanabe, M. (2021). KEGG: Integrating Viruses and Cellular Organisms. Nucleic Acids Research, 49, 545–551. https://doi.org/10.1093/nar/gkaa970
Kearney, P.M., Whelton, M., Reynolds, K., Muntner, P., Whelton, P.K., & He, J. (2005). Global Burden of Hypertension: Analysis of Worldwide Data. Lancet, 365(9455), 217–223. https://doi.org/10.1016/s0140-6736(05)17741-1
Luo, T. ting, Lu, Y., Yan, S. kai, Xiao, X., Rong, X. lu, & Guo, J. (2020). Network Pharmacology in Research of Chinese Medicine Formula: Methodology, Application and Prospective. Chinese Journal of Integrative Medicine, 26(1), 72–80. https://doi.org/10.1007/s11655-019-3064-0
Luo, W., & Brouwer, C. (2013). Pathview: An R/Bioconductor Package For Pathway-Based Data Integration and Visualization. Bioinformatics, 29(14), 1830–1831. https://doi.org/10.1093/bioinformatics/btt285
McCarthy, C.G., Wenceslau, C.F., Webb, R.C., & Joe, B. (2019). Novel Contributors and Mechanisms of Cellular Senescence in Hypertension-Associated Premature Vascular Aging. American Journal of Hypertension, 32(8), 709–719. https://doi.org/10.1093/ajh/hpz052
Menezes, I.A.C., Barreto, C.M.N., Antoniolli, Â.R., Santos, M.R.V, & Sousa, D.P.D. (2010). Hypotensive Activity of Terpenes Found in Essential Oils. Z Naturforsch C J Biosci, 65(9-10), 562–566.
Mohammed, T., Singh, M., Tiu, J.G., & Kim, A.S. (2022). Etiology and Management of Dyslipidemia in Patients With Cancer. Frontiers in Cardiovascular Medicine, 9, 1–13. https://doi.org/10.3389/fcvm.2022.892335
Nakhate, K.T., Badwaik, H., Choudhary, R., Sakure, K., Agrawal, Y.O., Sharma, C., Ojha, S., & Goyal, S.N. (2022). Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin. Nutrients, 14, 1–24.
Park, W.H. (2016). Pyrogallol Induces The Death of Human Pulmonary Fibroblast Cells Through ROS Increase and GSH Depletion. International Journal of Oncology, 49(2), 785–792. https://doi.org/10.3892/ijo.2016.3543
Pistoia, F., Sacco, S., Degan, D., Tiseo, C., Ornello, R., & Carolei, A. (2016). Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation. High Blood Press. High Blood Pressure and Cardiovascular Prevention, 23(1), 1–10. https://doi.org/10.1007/s40292-015-0115-2
Ramseyer, V.D., & Garvin, J.L. (2013). Tumor Necrosis Factor-α: Regulation of Renal Function and Blood Pressure. American Journal of Physiology - Renal Physiology, 304(10), 1231–1242. https://doi.org/10.1152/ajprenal.00557.2012
Roger, I., Milara, J., Belhadj, N., & Cortijo, J. (2021). Senescence Alterations in Pulmonary Hypertension. Cells, 10(12), 1–24. https://doi.org/10.3390/cells10123456
Rouzaud-Laborde, C., Lafitte, P., Balardy, L., Czosnyka, Z., & Schmidt, E.A. (2018). ICP and Antihypertensive Drugs. Acta Neurochirurgica, Supplementum, 126, 163–165. https://doi.org/10.1007/978-3-319-65798-1_34
Silva, E.A.P., Carvalho, J.S., dos Santos, D.M., Oliveira, A.M.S., de Souza Araújo, A.A., Serafini, M.R., Oliveira Santos, L.A.B., Batista, M.V. d. A., Viana Santos, M.R., Siqueira Quintans, J. de S., Quintans-Júnior, L.J., & Barreto, A.S. (2021). Cardiovascular Effects of Farnesol and Its β-cyclodextrin Complex In Normotensive and Hypertensive Rats. European Journal of Pharmacology, 901, 1–11. https://doi.org/10.1016/j.ejphar.2021.174060
Stannus, O., Jones, G., Cicuttini, F., Parameswaran, V., Quinn, S., Burgess, J., & Ding, C. (2010). Circulating Levels of IL-6 and TNF-α Are Associated With Knee Radiographic Osteoarthritis and Knee Cartilage Loss In Older Adults. Osteoarthritis and Cartilage, 18(11), 1441–1447. https://doi.org/10.1016/j.joca.2010.08.016
Takase, H., Sugiura, T., Ohte, N., & Dohi, Y. (2015). Urinary Albumin as a Marker of Future Blood Pressure and Hypertension in the General Population. Medicine (United States), 94(6), 1–7. https://doi.org/10.1097/MD.0000000000000511
Tan, R., Li, J., Peng, X., Zhu, L., Cai, L., Wang, T., Su, Y., Irani, K., & Hu, Q. (2013). GAPDH Is Critical For Superior Efficacy of Female Bone Marrow-Derived Mesenchymal Stem Cells On Pulmonary Hypertension. Cardiovascular Research, 100(1), 19–27. https://doi.org/10.1093/cvr/cvt165
Ventura, H.O., & Lavie, C.J. (2019). Editorial: Epidemiology and Managing Aspects of Hypertension. Current Opinion in Cardiology, 34(4), 329–330. https://doi.org/10.1097/HCO.0000000000000631
Wenzel, U.O., Bode, M., Köhl, J., & Ehmke, H. (2017). A Pathogenic Role of Complement In Arterial Hypertension and Hypertensive End Organ Damage. American Journal of Physiology - Heart and Circulatory Physiology, 312(3), 349–354. https://doi.org/10.1152/ajpheart.00759.2016
Widyawati, T., Yusoff, N.A., Bello, I., Asmawi, M.Z., & Ahmad, M. (2022). Bioactivity-Guided Fractionation and Identification of Antidiabetic Compound of Syzygium polyanthum (Wight.)’s Leaf Extract in Streptozotocin-Induced Diabetic Rat Model. Molecules, 27(20), 1–15. https://doi.org/10.3390/molecules27206814