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High fat diet-induced brain damaging effects through autophagy-mediated senescence, inflammation and apoptosis mitigated by ginsenoside F1-enhanced mixture

  • Hou, Jingang (Kaist Institute for BioCentury, KAIST) ;
  • Jeon, Byeongmin (Department of Biological Sciences, KAIST) ;
  • Baek, Jongin (Department of Biological Sciences, KAIST) ;
  • Yun, Yeejin (Department of Biological Sciences, KAIST) ;
  • Kim, Daeun (Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University) ;
  • Chang, Boyoon (Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University) ;
  • Kim, Sungyeon (Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University) ;
  • Kim, Sunchang (Kaist Institute for BioCentury, KAIST)
  • Received : 2020.10.13
  • Accepted : 2021.04.11
  • Published : 2022.01.01

Abstract

Background: Herbal medicines are popular approaches to capably prevent and treat obesity and its related diseases. Excessive exposure to dietary lipids causes oxidative stress and inflammation, which possibly induces cellular senescence and contribute the damaging effects in brain. The potential roles of selective enhanced ginsenoside in regulating high fat diet (HFD)-induced brain damage remain unknown. Methods: The protection function of Ginsenoside F1-enhanced mixture (SGB121) was evaluated by in vivo and in vitro experiments. Human primary astrocytes and SH-SY5Y cells were treated with palmitic acid conjugated Bovine Serum Albumin, and the effects of SGB121 were determined by MTT and lipid uptake assays. For in vivo tests, C57BL/6J mice were fed with high fat diet for 3 months with or without SGB121 administration. Thereafter, immunohistochemistry, western blot, PCR and ELISA assays were conducted with brain tissues. Results and conclusion: SGB121 selectively suppressed HFD-induced oxidative stress and cellular senescence in brain, and reduced subsequent inflammation responses manifested by abrogated secretion of IL-6, IL-1β and TNFα via NF-κB signaling pathway. Interestingly, SGB121 protects against HFD-induced damage by improving mitophagy and endoplasmic reticulum-stress associated autophagy flux and inhibiting apoptosis. In addition, SGB121 regulates lipid uptake and accumulation by FATP4 and PPARα. SGB121 significantly abates excessively phosphorylated tau protein in the cortex and GFAP activation in corpus callosum. Together, our results suggest that SGB121 is able to favor the resistance of brain to HFD-induced damage, therefore provide explicit evidence of the potential to be a functional food.

Keywords

Acknowledgement

This work was supported by the Intelligent Synthetic Biology Center of the Global Frontier Project, funded by the Ministry of Education, Science and Technology (2011-0031955), Republic of Korea. Bio-Synergy Research Project (NRF-2021M3A9C4001028) of the Ministry of Science, ICT, Republic of Korea.

References

  1. Seidell JC. Obesity, insulin resistance and diabetes-a worldwide epidemic. Br J Nutr 2000;83:S5-8. https://doi.org/10.1017/s000711450000088x
  2. Flegal KM. Body mass index of healthy men compared with healthy women in the United States. Int J Obes 2006;30:374-9. https://doi.org/10.1038/sj.ijo.0803117
  3. Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 2004;89:2595-600. https://doi.org/10.1210/jc.2004-0372
  4. Klein R, Klein BE, Moss SE. Is obesity related to microvascular and macrovascular complications in diabetes?: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. JAMA Intern Med 1997;157:650-6. https://doi.org/10.1001/archinte.1997.00440270094008
  5. Kyle TK, Dhurandhar EJ, Allison DB. Regarding obesity as a disease: evolving policies and their implications. Endocrinol Metab Clin North Am 2016;45:511-20. https://doi.org/10.1016/j.ecl.2016.04.004
  6. Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res 2004;59:207-24. https://doi.org/10.1210/rp.59.1.207
  7. Calle EE, Thun MJ. Obesity and cancer. Oncogene 2004;23:6365-78. https://doi.org/10.1038/sj.onc.1207751
  8. Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. Eur J Pharmacol 2013;719:170-9. https://doi.org/10.1016/j.ejphar.2013.08.008
  9. Alzoubi KH, Khabour OF, Salah HA, Hasan Z. Vitamin E prevents high-fat high-carbohydrates diet-induced memory impairment: the role of oxidative stress. Physiol Behav 2013;119:72-8. https://doi.org/10.1016/j.physbeh.2013.06.011
  10. Dalvi PS, Chalmers JA, Luo V, Han DY, Wellhauser L, Liu Y, et al. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. Int J Obes 2017;41:149-58. https://doi.org/10.1038/ijo.2016.183
  11. Baker DJ, Petersen RC. Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest 2018;128:1208-16. https://doi.org/10.1172/jci95145
  12. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK. Cellular senescence and the aging brain. Exp Gerontol 2015;68:3-7. https://doi.org/10.1016/j.exger.2014.09.018
  13. DiBattista AM, Sierra F, Masliah E. NIA workshop on senescence in brain aging and Alzheimer's disease and its related dementias. GeroScience 2020;42:389-96. https://doi.org/10.1007/s11357-020-00153-9
  14. Graves SI, Baker DJ. Implicating endothelial cell senescence to dysfunction in the ageing and diseased brain. Basic Clin Pharmacol Toxicol 2020;127:102-10. https://doi.org/10.1111/bcpt.13403
  15. Kim JE, Lee Wh, Yang Sm, Cho SH, Baek MC, Song GY, Bae JS. Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses. Food Chem Toxicol 2019;124:45-53. https://doi.org/10.1016/j.fct.2018.11.057
  16. Hou JG, Yun YJ, Xue JJ, Jeon BM, Kim SC. Doxorubicin-induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2. Phytother Res 2020;34:1659-69. https://doi.org/10.1002/ptr.6636
  17. Fang F, Chen Xc, Huang Tw, Lue LF, Luddy JS, Yan SS. Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta-Mol Basis Dis 2012;1822:286-92. https://doi.org/10.1016/j.bbadis.2011.10.004
  18. Xu L, Chen WF, Wong MS. Ginsenoside Rg1 protects dopaminergic neurons in a rat model of Parkinson's disease through the IGF-I receptor signalling pathway. Br J Pharmacol 2009;158:738-48. https://doi.org/10.1111/j.1476-5381.2009.00361.x
  19. Li ZP, Ji GE. Ginseng and obesity. J Ginseng Res 2018;42:1-8. https://doi.org/10.1016/j.jgr.2016.12.005
  20. Cui CH, Jeon BM, Fu Yy, Im W, Kim SC. High-density immobilization of a ginsenoside-transforming β-glucosidase for enhanced food-grade production of minor ginsenosides. Appl Microbiol Biotechnol 2019;103:7003-15. https://doi.org/10.1007/s00253-019-09951-4
  21. Park CH, Park SK, Seung TW, Jin DE, Guo TJ, Heo HJ. Effect of ginseng (Panax ginseng) berry EtOAc fraction on cognitive impairment in C57BL/6 mice under high-fat diet inducement. Evid Based Complement Alternat Med 2015;2015.
  22. Kim JM, Park CH, Park SK, Seung TW, Kang JY, Ha JS, et al. Ginsenoside re ameliorates brain insulin resistance and cognitive dysfunction in high fat diet-induced C57BL/6 mice. J Agric Food Chem 2017;65:2719-29. https://doi.org/10.1021/acs.jafc.7b00297
  23. Wanders RJA, Ruiter JPN, Ijlst L, Waterham HR, Houten SM. The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J Inherit Metab Dis 2010;33:479-94. https://doi.org/10.1007/s10545-010-9104-8
  24. Okada LSDR, Oliveira CP, Stefano JT, Nogueira MA, da Silva IDCG, Cordeiro FB, et al. Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - proteomic and lipidomic insight. Clin Nutr 2018;37:1474-84. https://doi.org/10.1016/j.clnu.2017.08.031
  25. Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta-Bioenergetics 2011;1807:726-34. https://doi.org/10.1016/j.bbabio.2010.10.022
  26. Burton GJ, Yung HW, Murray AJ. Mitochondrial-endoplasmic reticulum interactions in the trophoblast: stress and senescence. Placenta 2017;52:146-55. https://doi.org/10.1016/j.placenta.2016.04.001
  27. Liu J, Wang Lh, Wang Zg, Liu JP. Roles of telomere biology in cell senescence, replicative and chronological ageing. Cells 2019;8:54. https://doi.org/10.3390/cells8010054
  28. Doherty J, Baehrecke EH. Life, death and autophagy. Nat Cell Biol 2018;20:1110-7. https://doi.org/10.1038/s41556-018-0201-5
  29. Dou Zx, Ivanov A, Adams PD, Berger SL. Mammalian autophagy degrades nuclear constituents in response to tumorigenic stress. Autophagy 2016;12:1416-7. https://doi.org/10.1080/15548627.2015.1127465
  30. Korolchuk VI, Miwa S, Carroll B, Von Zglinicki T. Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine 2017;21:7-13. https://doi.org/10.1016/j.ebiom.2017.03.020
  31. Nopparat C, Sinjanakhom P, Govitrapong P. Melatonin reverses H2O2-induced senescence in SH-SY 5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB. J Pineal Res 2017;63:e12407. https://doi.org/10.1111/jpi.12407
  32. Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev 2010;29:273-83. https://doi.org/10.1007/s10555-010-9220-9
  33. Glabinski AR, Tani M, Aras S, Stoler MH, Tuohy VK, Ransohoff RM. Regulation and function of central nervous system chemokines. Int J Dev Neurosci 1995;13:153-65. https://doi.org/10.1016/0736-5748(95)00017-B
  34. Ravindran J, Agrawal M, Gupta N, Rao PL. Alteration of blood brain barrier permeability by T-2 toxin: role of MMP-9 and inflammatory cytokines. Toxicology 2011;280:44-52. https://doi.org/10.1016/j.tox.2010.11.006
  35. Rensink AA, Gellekink H, Otte-Holler I, Hans J, de Waal RM, Verbeek MM, Kremer B. Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease. Acta Neuropathol 2002;104:525-33. https://doi.org/10.1007/s00401-002-0585-x
  36. Merson TD, Binder MD, Kilpatrick TJ. Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular Med 2010;12:99-132. https://doi.org/10.1007/s12017-010-8112-z
  37. Stout MB, Justice JN, Nicklas BJ, Kirkland JL. Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology 2017;32:9-19. https://doi.org/10.1152/physiol.00012.2016
  38. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 2008;7:83-105. https://doi.org/10.1016/j.arr.2007.09.002
  39. Hou JG, Yun YJ, Xue JJ, Sun MQ, Kim SC. D-galactose induces astrocytic aging and contributes to astrocytoma progression and chemoresistance via cellular senescence. Mol Med Report 2019;20:4111-8.
  40. Maubach G, Schmadicke AC, Naumann M. NEMO links nuclear factor-κB to human diseases. Trends Mol Med 2017;23:1138-55. https://doi.org/10.1016/j.molmed.2017.10.004
  41. Sun B, Dwivedi N, Bechtel TJ, Paulsen JL, Muth A, Bawadekar M, et al. Citrullination of NF-kB p65 enhances its nuclear localization and TLR-induced expression of IL-1β and TNFα. Sci Immunol 2017;2.
  42. Whitley SK, Balasubramani A, Zindl CL, Sen R, Shibata Y, Crawford GE, Weathington NM, Hatton RD, Weaver CT. IL-1R signaling promotes STAT3 and NF-κB factor recruitment to distal cis-regulatory elements that regulate Il17a/f transcription. J Biol Chem 2018;293:15790-800. https://doi.org/10.1074/jbc.RA118.002721
  43. Hao S, Dey A, Yu XL, Stranahan AM. Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain, Behav, Immun 2016;51:230-9. https://doi.org/10.1016/j.bbi.2015.08.023
  44. Maciejczyk M, Zebrowska E, Zalewska A, Chabowski A. Redox balance, antioxidant defense, and oxidative damage in the hypothalamus and cerebral cortex of rats with high fat diet-induced insulin resistance. Oxid Med Cell Longev 2018;2018.
  45. Zhang Xc, Dong F, Ren J, Driscoll MJ, Culver B. High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol 2005;191:318-25. https://doi.org/10.1016/j.expneurol.2004.10.011
  46. Franklin TB, Krueger-Naug AM, Clarke DB, Arrigo AP, Currie RW. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperthermia 2005;21:379-92. https://doi.org/10.1080/02656730500069955
  47. Sharp FR, Zhan XH, Liu DZ. Heat shock proteins in the brain: role of Hsp70, hsp 27, and HO-1 (Hsp32) and their therapeutic potential. Transl Stroke Res 2013;4:685-92. https://doi.org/10.1007/s12975-013-0271-4
  48. Li Yh, Zhang R, Hou Xl, Zhang Ym, Ding Fj, Li F, Yao Y, Wang Y. Microglia activation triggers oligodendrocyte precursor cells apoptosis via HSP60. Mol Med Report 2017;16:603-8. https://doi.org/10.3892/mmr.2017.6673
  49. Alford KA, Glennie S, Turrell BR, Rawlinson L, Saklatvala J, Dean JL. Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-β-activated kinase-1 (TAK1)-mediated signaling. J Biol Chem 2007;282:6232-41. https://doi.org/10.1074/jbc.M610987200
  50. Jin Ch, Cleveland JC, Ao Lh, Li Jl, Zeng Qc, Fullerton DA, Meng Xz. Human myocardium releases heat shock protein 27 (HSP27) after global ischemia: the proinflammatory effect of extracellular HSP27 through toll-like receptor (TLR)-2 and TLR4. Mol Med 2014;20:280-9. https://doi.org/10.2119/molmed.2014.00058
  51. Wu F, Echeverry R, Wu J, An J, Haile WB, Cooper DS, Catano M, Yepes M. Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK 1/2-CREB-ATF3 signaling pathway. Mol Cell Neurosci 2013;52:9-19. https://doi.org/10.1016/j.mcn.2012.10.001
  52. Han Jh, Oh JP, Yoo M, Cui CH, Jeon BM, Kim SC, Han JH. Minor ginsenoside F1 improves memory in APP/PS1 mice. Mol Brain 2019;12:1-8. https://doi.org/10.1186/s13041-018-0417-0
  53. Stremmel W, Pohl J, Ring A, Herrmann T. A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids. Lipids 2001;36:981-9. https://doi.org/10.1007/s11745-001-0809-2