Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Target engagement of ginsenosides in mild cognitive impairment using mass spectrometry-based drug affinity responsive target stability

  • Zhu, Zhu (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Li, Ruimei (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Qin, Wei (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Zhang, Hantao (Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Cheng, Yao (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Chen, Feiyan (Research and Innovation Center, College of Traditional Chinese Medicine & Integrated Chinese and Western Medicine College, Nanjing University of Chinese Medicine) ;
  • Chen, Cuihua (Research and Innovation Center, College of Traditional Chinese Medicine & Integrated Chinese and Western Medicine College, Nanjing University of Chinese Medicine) ;
  • Chen, Lin (Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Zhao, Yunan (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine)
  • Received : 2021.05.25
  • Accepted : 2021.12.14
  • Published : 2022.11.01
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Abstract

Background: Mild cognitive impairment (MCI) is a transitional condition between normality and dementia. Ginseng is known to have effects on attenuating cognitive deficits in neurogenerative diseases. Ginsenosides are the main bioactive component of ginseng, and their protein targets have not been fully understood. Furthermore, no thorough analysis is reported in ginsenoside-related protein targets in MCI. Methods: The candidate protein targets of ginsenosides in brain tissues were identified by drug affinity responsive target stability (DARTS) coupled with label-free liquid chromatography-mass spectrometry (LC-MS) analysis. Network pharmacology approach was used to collect the therapeutic targets for MCI. Based on the above-mentioned overlapping targets, we built up a proteineprotein interaction (PPI) network in STRING database and conducted gene ontology (GO) enrichment analysis. Finally, we assessed the effects of ginseng total saponins (GTS) and different ginsenosides on mitochondrial function by measuring the activity of the mitochondrial respiratory chain complex and performing molecular docking. Results: We screened 2526 MCI-related protein targets by databases and 349 ginsenoside-related protein targets by DARTS. On the basis of these 81 overlapping genes, enrichment analysis showed the mitochondria played an important role in GTS-mediated MCI pharmacological process. Mitochondrial function analysis showed GTS, protopanaxatriol (PPT), and Rd increased the activities of complex I in a dose-dependent manner. Molecular docking also predicted the docking pockets between PPT or Rd and mitochondrial respiratory chain complex I. Conclusion: This study indicated that ginsenosides might alleviate MCI by targeting respiratory chain complex I and regulating mitochondrial function, supporting ginseng's therapeutic application in cognitive deficits.

Keywords

Acknowledgement

The study was financially supported by the National Natural Science Foundation of China (Nos. 81873025, 82003970) and Jiangsu Provincial Natural Science Foundation of China (BK20181423).

References

  1. Sachdev PS, Blacker D, Blazer DG, Ganguli M, Jeste DV, Paulsen JS, et al. Classifying neurocognitive disorders: the DSM-5 approach. Nat Rev Neurol 2014 Nov;10(11):634-42. https://doi.org/10.1038/nrneurol.2014.181
  2. Andrade C, Radhakrishnan R. The prevention and treatment of cognitive decline and dementia: an overview of recent research on experimental treatments. Indian J Psychiatr 2009 Jan;51(1):12-25. https://doi.org/10.4103/0019-5545.44900
  3. Attems J, Jellinger KA. Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 2006 Nov-Dec;25(6):265-71.
  4. Jongsiriyanyong S, Limpawattana P. Mild cognitive impairment in clinical practice: a review article. Am J Alzheimers Dis Other Demen 2018 Dec;33(8): 500-7. https://doi.org/10.1177/1533317518791401
  5. Petersen RC. Mild cognitive impairment: transition between aging and Alzheimer's disease. Neurologia 2000 Mar;15(3):93-101.
  6. Nocerino E, Amato M, Izzo AA. The aphrodisiac and adaptogenic properties of ginseng. Fitoterapia 2000 Aug;71(Suppl 1):S1-5. https://doi.org/10.1016/S0367-326X(00)00170-2
  7. Smith I, Williamson EM, Putnam S, Farrimond J, Whalley BJ. Effects and mechanisms of ginseng and ginsenosides on cognition. Nutr Rev 2014 May;72(5):319-33. https://doi.org/10.1111/nure.12099
  8. Mook-Jung I, Hong HS, Boo JH, Lee KH, Yun SH, Cheong MY, et al. Ginsenoside Rb1 and Rg1 improve spatial learning and increase hippocampal synaptophysin level in mice. J Neurosci Res 2001 Mar 15;63(6):509-15. https://doi.org/10.1002/jnr.1045
  9. DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002 Feb;51(2):145-55. https://doi.org/10.1002/ana.10069
  10. Ye R, Han J, Kong X, Zhao L, Cao R, Rao Z, et al. Protective effects of ginsenoside Rd on PC12 cells against hydrogen peroxide. Biol Pharm Bull 2008 Oct;31(10): 1923-7. https://doi.org/10.1248/bpb.31.1923
  11. Zhang G, Liu A, Zhou Y, San X, Jin T, Jin Y. Panax ginseng ginsenoside-Rg2 protects memory impairment via anti-apoptosis in a rat model with vascular dementia. J Ethnopharmacol 2008 Feb 12;115(3):441-8. https://doi.org/10.1016/j.jep.2007.10.026
  12. Zhao HF, Li Q, Li Y. Long-term ginsenoside administration prevents memory loss in aged female C57BL/6J mice by modulating the redox status and upregulating the plasticity-related proteins in hippocampus. Neuroscience 2011 Jun 2;183:189-202. https://doi.org/10.1016/j.neuroscience.2011.03.048
  13. Lomenick B, Hao R, Jonai N, Chin RM, Aghajan M, Warburton S, et al. Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci U S A 2009 Dec 22;106(51):21984-9. https://doi.org/10.1073/pnas.0910040106
  14. Zhao YN, Wang ZL, Dai JG, Chen L, Huang YF. Preparation and quality assessment of high-purity ginseng total saponins by ion exchange resin combined with macroporous adsorption resin separation. Chin J Nat Med 2014 May;12(5):382-92.
  15. Ouyang LF, Wang ZL, Dai JG, Chen L, Zhao YN. Determination of total ginsenosides in ginseng extracts using charged aerosol detection with post-column compensation of the gradient. Chin J Nat Med 2014 Nov;12(11):857-68.
  16. Pai MY, Lomenick B, Hwang H, Schiestl R, McBride W, Loo JA, et al. Drug affinity responsive target stability (DARTS) for small-molecule target identification. Methods Mol Biol 2015;1263:287-98. https://doi.org/10.1007/978-1-4939-2269-7_22
  17. Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D. GeneCards: integrating information about genes, proteins and diseases. Trends Genet 1997 Apr;13(4):163. https://doi.org/10.1016/S0168-9525(97)01103-7
  18. Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: online Mendelian Inheritance in Man (OMIM(R)), an online catalog of human genes and genetic disorders. Nucleic Acids Res 2015 Jan;43(Database issue): D789-98. https://doi.org/10.1093/nar/gku1205
  19. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 2017 Jan 4;45(D1): D362-8.
  20. Lomenick B, Jung G, Wohlschlegel JA, Huang J. Target identification using drug affinity responsive target stability (DARTS). Curr Protoc Chem Biol 2011 Dec 1;3(4):163-80. https://doi.org/10.1002/9780470559277.ch110180
  21. Chang J, Kim Y, Kwon HJ. Advances in identification and validation of protein targets of natural products without chemical modification. Nat Prod Rep 2016 May 4;33(5):719-30. https://doi.org/10.1039/C5NP00107B
  22. Sun J, Prabhu N, Tang J, Yang F, Jia L, Guo J, et al. Recent advances in proteomewide label-free target deconvolution for bioactive small molecules. Med Res Rev 2021 Feb 3;41(6):2893-926. https://doi.org/10.1002/med.21788
  23. Sengupta B, Stemmler M, Laughlin SB, Niven JE. Action potential energy efficiency varies among neuron types in vertebrates and invertebrates. PLoS Comput Biol 2010 Jul 1;6:e1000840.
  24. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006 Oct 19;443(7113):787-95. https://doi.org/10.1038/nature05292
  25. Pollard AK, Craig EL, Chakrabarti L. Mitochondrial complex 1 activity measured by spectrophotometry is reduced across all brain regions in ageing and more specifically in neurodegeneration. PLoS One 2016;11(6):e0157405. https://doi.org/10.1371/journal.pone.0157405
  26. Peralta S, Torraco A, Wenz T, Garcia S, Diaz F, Moraes CT. Partial complex I deficiency due to the CNS conditional ablation of Ndufa5 results in a mild chronic encephalopathy but no increase in oxidative damage. Hum Mol Genet 2014 Mar 15;23(6):1399-412. https://doi.org/10.1093/hmg/ddt526
  27. Huang T, Fang F, Chen L, Zhu Y, Zhang J, Chen X, et al. Ginsenoside Rg1 attenuates oligomeric Abeta(1-42)-induced mitochondrial dysfunction. Curr Alzheimer Res 2012 Mar;9(3):388-95. https://doi.org/10.2174/156720512800107636
  28. Sun M, Huang C, Wang C, Zheng J, Zhang P, Xu Y, et al. Ginsenoside Rg3 improves cardiac mitochondrial population quality: mimetic exercise training. Biochem Biophys Res Commun 2013 Nov 8;441(1):169-74. https://doi.org/10.1016/j.bbrc.2013.10.039
  29. Zhou JS, Wang JF, He BR, Cui YS, Fang XY, Ni JL, et al. Ginsenoside Rd attenuates mitochondrial permeability transition and cytochrome C release in isolated spinal cord mitochondria: involvement of kinase-mediated pathways. Int J Mol Sci 2014 Jun 3;15(6):9859-77. https://doi.org/10.3390/ijms15069859
  30. Gonzalez-Burgos E, Fernandez-Moriano C, Lozano R, Iglesias I, GomezSerranillos MP. Ginsenosides Rd and Re co-treatments improve rotenoneinduced oxidative stress and mitochondrial impairment in SH-SY5Y neuroblastoma cells. Food Chem Toxicol 2017 Nov;109(Pt 1):38-47. https://doi.org/10.1016/j.fct.2017.08.013
  31. Yang LX, Zhang X, Zhao G. Ginsenoside Rd attenuates DNA damage by increasing expression of DNA glycosylase endonuclease VIII-like proteins after focal cerebral ischemia. Chin Med J (Engl) 2016 Aug 20;129(16):1955-62. https://doi.org/10.4103/0366-6999.187851
  32. Ye R, Kong X, Yang Q, Zhang Y, Han J, Zhao G. Ginsenoside Rd attenuates redox imbalance and improves stroke outcome after focal cerebral ischemia in aged mice. Neuropharmacology 2011 Sep;61(4):815-24. https://doi.org/10.1016/j.neuropharm.2011.05.029