Journal of Ginseng Research

  • 제48권4호
  • /
  • Pages.395-404
  • /
  • 2024
  • /
  • 1226-8453(pISSN)
  • /
  • 2093-4947(eISSN)
고려인삼학회 (The Korean Society of Ginseng)
권호 표지
DOI QR코드

DOI QR Code

Integration of virtual screening and proteomics reveals potential targets and pathways for ginsenoside Rg1 against myocardial ischemia

  • Rongfang Xie (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University) ;
  • Chenlu Li (Department of Hyperbaric Oxygen, The First Affiliated Hospital, Fujian Medical University) ;
  • Chenhui Zhong (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University) ;
  • Zuan Lin (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University) ;
  • Shaoguang Li (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University) ;
  • Bing Chen (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University) ;
  • Youjia Wu (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University) ;
  • Fen Hu (Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Department of Etiology, School of Basic Medical Sciences, Fujian Medical University) ;
  • Peiying Shi (Department of Traditional Chinese Medicine Resources and Development, College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University) ;
  • Hong Yao (Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University)
  • 투고 : 2022.11.25
  • 심사 : 2024.02.08
  • 발행 : 2024.07.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: Ginsenoside Rg1 (Rg1) is one of the main active components in Chinese medicines, Panax ginseng and Panax notoginseng. Research has shown that Rg1 has a protective effect on the cardiovascular system, including anti-myocardial ischemia-reperfusion injury, anti-apoptosis, and promotion of myocardial angiogenesis, suggesting it a potential cardiovascular agent. However, the protective mechanism involved is still not fully understood. Methods: Based on network pharmacology, ligand-based protein docking, proteomics, Western blot, protein recombination and spectroscopic analysis (UV-Vis and fluorescence spectra) techniques, potential targets and pathways for Rg1 against myocardial ischemia (MI) were screened and explored. Results: An important target set containing 19 proteins was constructed. Two target proteins with more favorable binding activity for Rg1 against MI were further identified by molecular docking, including mitogen-activated protein kinase 1 (MAPK1) and adenosine kinase (ADK). Meanwhile, Rg1 intervention on H9c2 cells injured by H2O2 showed an inhibitory oxidative phosphorylation (OXPHOS) pathway. The inhibition of Rg1 on MAPK1 and OXPHOS pathway was confirmed by Western blot assay. By protein recombination and spectroscopic analysis, the binding reaction between ADK and Rg1 was also evaluated. Conclusion: Rg1 can effectively alleviate cardiomyocytes oxidative stress injury via targeting MAPK1 and ADK, and inhibiting oxidative phosphorylation (OXPHOS) pathway. The present study provides scientific basis for the clinical application of the natural active ingredient, Rg1, and also gives rise to a methodological reference to the searching of action targets and pathways of other natural active ingredients.

키워드

과제정보

This work was supported by National Natural Science Foundation of China (81973558), key project supported by the Natural Science Foundation of Fujian province, China (2021J02033), and the Funds of Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, China (FKLDSR202104).

참고문헌

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, De Ferranti SD, Floyd J, Fornage M, Gillespie C. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 2017;135(10):e146-603.
  2. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, De Ferranti S, Despr'es J-P, Fullerton HJ. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133(4):e38-360.
  3. Marzilli M, Crea F, Morrone D, Bonow RO, Brown DL, Camici PG, Chilian WM, DeMaria A, Guarini G, Huqi A. Myocardial ischemia: from disease to syndrome. Int J Cardiol 2020;314:32-5.
  4. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357(11):1121-35.
  5. Forman MB, Virmani R, Puett DW. Mechanisms and therapy of myocardial reperfusion injury. Circulation 1990;81(3 Suppl):69-78.
  6. Chen K, Li G, Geng F, Zhang Z, Li J, Yang M, Dong L, Gao F. Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats. Apoptosis 2014;19(6):946-57.
  7. Li L, Pan C-S, Yan L, Cui Y-C, Liu Y-Y, Mu H-N, He K, Hu B-H, Chang X, Sun K. Ginsenoside Rg1 ameliorates rat myocardial ischemia-reperfusion injury by modulating energy metabolism pathways. Front Physiol 2018;9:78.
  8. Wang X-d, Gu T-x, Shi E-y, Lu C-m, Wang C. Effect and mechanism of panaxoside Rg1 on neovascularization in myocardial infarction rats. Chin J Integr Med 2010;16(2):162-6.
  9. Zhao F, Lu ML, Wang HX. Ginsenoside Rg1 ameliorates chronic intermittent hypoxia-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway. J Gin Res 2023;47(1):144-54.
  10. Zhu HM, Yan CY, Yao P, Li P, Li Y, Yang H. Ginsenoside Rg1 protects cardiac mitochondrial function via targeting GSTP1 to block S-glutathionylation of optic atrophy 1. Free Radical Biol Med 2023;204:54-67.
  11. Lu ML, Wang J, Sun Y, Li C, Sun TR, Hou XW, Wang HX. Ginsenoside Rg1 attenuates mechanical stress-induced cardiac injury via calcium sensing receptorrelated pathway. J Gin Res 2021;45(6):683-94.
  12. Tian G, Li J, Zhou LN. Ginsenoside Rg1 regulates autophagy and endoplasmic reticulum stress via the AMPK/mTOR and PERK/ATF4/CHOP pathways to alleviate alcohol-induced myocardial injury. Int J Mol Med 2023;51(1):56.
  13. Guan SB, Xin YF, Ding YG, Zhang QL, Han W. Ginsenoside Rg1 protects against cardiac remodeling in heart failure via SIRT1/PINK1/Parkin-mediated mitophagy. Chem Biodivers 2023;20(2):e202200730.
  14. Cheung CHY, Juan H-F. Quantitative proteomics in lung cancer. J Biomed Sci 2017;24(1):1-11.
  15. Xu M, Deng J, Xu K, Zhu T, Han L, Yan Y, Yao D, Deng H, Wang D, Sun Y. In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine. Theranostics 2019;9(9):2475.
  16. Lam MP, Ping P, Murphy E. Proteomics research in cardiovascular medicine and biomarker discovery. J Am Coll Cardiol 2016;68(25):2819-30.
  17. Klebe G. Virtual ligand screening: strategies, perspectives and limitations. Drug Discov Today 2006;11(13-14):580-94.
  18. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13(11):2498-504.
  19. Yu G, Wang L-G, Han Y, He Q-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012;16(5):284-7.
  20. Yu G, Wang L-G, Yan G-R, He Q-Y. DOSE: an R/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics 2015;31(4):608-9.
  21. Carlson M, Falcon S, Pages H, Li N. org. Hs. eg. db: genome wide annotation for Human. R package version 2019;2(0). 2018.
  22. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31(2):455-61.
  23. Schrodinger L. The PyMOL molecular graphics system. 2015. Google Scholar There is no corresponding record for this reference 2018, Version 1.8.
  24. Murr C, Grammer TB, Meinitzer A, Kleber ME, Marz W, Fuchs D. Immune activation and inflammation in patients with cardiovascular disease are associated with higher phenylalanine to tyrosine ratios: the ludwigshafen risk and cardiovascular health study, vol. 2014. Amino Acids; 2014.
  25. Tual-Chalot S, Stellos K. Therapeutic potential of adenosine kinase inhibition in vascular disease. Cardiovasc Res 2021;117(2):354-6.
  26. Wang W, Wang B, Sun S, Cao S, Zhai X, Zhang C, Zhang Q, Yuan Q, Sun Y, Xue M. Inhibition of adenosine kinase attenuates myocardial ischaemia/reperfusion injury. J Cell Mol Med 2021;25(6):2931-43.
  27. Guo W, Liu X, Li J, Shen Y, Zhou Z, Wang M, Xie Y, Feng X, Wang L, Wu X. Prdx1 alleviates cardiomyocyte apoptosis through ROS-activated MAPK pathway during myocardial ischemia/reperfusion injury. Int J Biol Macromol 2018;112:608-15.
  28. Hu H, Nan J, Sun Y, Zhu D, Xiao C, Wang Y, Zhu L, Wu Y, Zhao J, Wu R. Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemiareperfusion injury via dimerized STAT3. Proc Natl Acad Sci USA 2017;114(45):11908-13.
  29. Jiang L, Yin X, Chen Y-H, Chen Y, Jiang W, Zheng H, Huang F-Q, Liu B, Zhou W, Qi L-W. Proteomic analysis reveals ginsenoside Rb1 attenuates myocardial ischemia/reperfusion injury through inhibiting ROS production from mitochondrial complex I. Theranostics 2021;11(4):1703.
  30. Kussmaul L, Hirst J. The mechanism of superoxide production by NADH: ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci USA 2006;103(20):7607-12.
  31. Liu Y, Fiskum G, Schubert D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 2002;80(5):780-7.
  32. Lu X, Jin Y, Wang Y, Chen Y, Fan X. Multimodal integrated strategy for the discovery and identification of quality markers in traditional Chinese medicine. J Pharm Anal 2022;12(5):701-10.
  33. Peart J, Paul Matherne G, Cerniway RJ, Headrick JP. Cardioprotection with adenosine metabolism inhibitors in ischemic-reperfused mouse heart. Cardiovasc Res 2001;52(1):120-9.
  34. Peart JN, Gross GJ. Cardioprotection following adenosine kinase inhibition in rat hearts. Basic Res Cardiol 2005;100(4):328-36.