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Microbiology and Biotechnology Letters

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Food Microbiology (FM)  |  Probiotics in Nutrition and Health

Microbiol. Biotechnol. Lett. 2021; 49(2): 138-147

https://doi.org/10.48022/mbl.2009.09006

Received: September 9, 2020; Accepted: January 8, 2021

Apigenin Ameliorates Oxidative Stress-induced Neuronal Apoptosis in SH-SY5Y Cells

Yeo Jin Kim1, Eun Ju Cho1, Ah Young Lee2* and Weon Taek Seo2*

1Department of Food Science and Nutrition and Kimchi Research Institute, Pusan National University, Busan 46241, Republic of Korea 2Department of Food Science, Gyeongnam National University of Science and Technology, Jinju 52725, Republic of Korea

Correspondence to :
Ah Young Lee,   aylee@gntech.ac.kr
Weon Taek Seo,   wtseo@gntech.ac.kr

The overproduction of reactive nitrogen species (RNS) and reactive oxygen species (ROS) causes oxidative damage to neuronal cells, leading to the progression of neurodegenerative diseases. In this study, we determined the nitric oxide radical (NO), hydroxyl radical (·OH), and superoxide anion radical (O2) scavenging activities of apigenin. Our results showed that apigenin exhibited remarkable, concentration-dependent ·OH, O2, and NO radical scavenging activities. Particularly, apigenin indicated the strongest ·OH radical scavenging activity with 93.38% in the concentration of 100 μM. Furthermore, we also investigated the protective effects of apigenin against hydrogen peroxide (H2O2)-induced oxidative stress in SH-SY5Y cells. The H2O2 treatment resulted in a significant decrease in cell viability, as well as an increase in lactate dehydrogenase (LDH) release and ROS production compared with the H2O2-nontreated SH-SY5Y cells. However, the cell viability significantly increased in the apigenin-treated group, as well as inhibited ROS generation and LDH release compared with the H2O2-induced control group. To elucidate the protective mechanisms of apigenin against oxidative stress in SH-SY5Y, we analyzed the apoptosis-related protein expression. The apigenin treatment resulted in the downregulated expression of apoptosis-related protein markers, such as cytochrome C, cleaved caspase-3, poly (ADP)-ribose polymerase (PARP), and B-cell lymphoma 2-associated X (Bax), as well as the upregulated expression of anti-apoptosis markers such as B-cell lymphoma 2 (Bcl-2). In this study, we report that apigenin exhibits a neuroprotective effect against oxidative stress in SH-SY5Y cells. These results suggest that apigenin may be considered as a potential agent for neurodegenerative disease prevention.

Keywords: Hydrogen peroxide, neuronal, neurodegenerative diseases, neuroprotection, oxidative stress

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  1. Davalli P, Mitic T, Caporali A, Lauriola A, D'Arca D. 2016. ROS, cell senescence, and novel molecular mechanisms in aging and agerelated diseases. Oxid. Med. Cell. Longev. 2016: 3565127.
    Pubmed KoreaMed
  2. Del Rio LA. 2015. ROS and RNS in plant physiology: an overview. J. Exp. Bot. 66: 2827-2837.
    Pubmed
  3. Phaniendra A, Jestadi DB, Periyasamy L. 2015. Free radicals: properties, sources, targets, and their implication in various diseases. Indian J. Clin. Biochem. 30: 11-26.
    Pubmed KoreaMed
  4. Islam MT. 2017. Oxidative stress and mitochondrial dysfunctionlinked neurodegenerative disorders. Neurol. Res. 39: 73-82.
    Pubmed
  5. Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, et al. 2015. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed. Pharmacother. 74: 101-110.
    Pubmed
  6. Niu X, Zheng S, Liu H, Li S. 2018. Protective effects of taurine against inflammation, apoptosis, and oxidative stress in brain injury. Mol. Med. Rep. 18: 4516-4522.
  7. Cobley JN, Fiorello ML, Bailey DM. 2018. 13 Reasons why the brain is susceptible to oxidative stress. Redox Biol. 15: 490-503.
    Pubmed KoreaMed
  8. Forster JI, Köglsberger S, Trefois C, Boyd O, Baumuratov AS, Buck L, et al. 2016. Characterization of differentiated SH-SY5Y as neuronal screening model reveals increased oxidative vulnerability. J. Biomol. Screen 21: 496-509.
    Pubmed KoreaMed
  9. Park HR, Lee H, Park H, Jeon JW, Cho WK, Ma JY. 2015. Neuroprotective effects of Liripope platyphylla extract against hydrogen peroxide-induced cytotoxicity in human neuroblastoma SHSY5Y cells. BMC Complement. Med. Ther. 15: 171.
    Pubmed KoreaMed
  10. Zhang B, Cui Y, Wang L, Zhao L, Hou C, Zeng Q, et al. 2018. Autophagy regulates high concentrations of iodide-induced apoptosis in SH-SY5Y cells. Toxicol. Lett. 284: 129-135.
    Pubmed
  11. Nirmaladevi D, Venkataramana M, Chandranayaka S, Ramesha A, Jameel NM, Srinivas C. 2014. Neuroprotective effects of bikaverin on H2O2-induced oxidative stress mediated neuronal damage in SH-SY5Y cell line. Cell. Mol. Neurobiol. 34: 973-985.
    Pubmed
  12. Yang R, Wei L, Fu QQ, Wang H, You H, Yu HR. 2016. SOD3 ameliorates H2O2 induced oxidative damage in SH-SY5Y cells by inhibiting the mitochondrial pathway. Neurochem. Res. 41: 1818-1830.
    Pubmed
  13. Shi MD, Shiao CK, Lee YC, Shih YW. 2015. Apigenin, a dietary flavonoid, inhibits proliferation of human bladder cancer T-24 cells via blocking cell cycle progression and inducing apoptosis. Cancer Cell Int. 15: 33.
    Pubmed KoreaMed
  14. Chen XJ, Wu MY, Li DH, You J. 2016. Apigenin inhibits glioma cell growth through promoting microRNA-16 and suppression of Bcl-2 and nuclear factor-kappaB/MMP9. Mol. Med. Rep. 14: 23522358.
    Pubmed
  15. Kowalska I, Adach W, Stochmal A, Olas B. 2020. A comparison of the effects of apigenin and seven of its derivatives on selected biomarkers of oxidative stress and coagulation in vitro. Food. Chem. Toxicol. 136: 111016.
    Pubmed
  16. Amini R, Yazdanparast R, Ghaffari SH. 2015. Apigenin modulates the expression levels of pro-inflammatory mediators to reduce the human insulin amyloid-induced oxidant damages in SK-NMC cells. Hum. Exp. Toxicol. 34: 642-653.
    Pubmed
  17. Sun X, Min D, Wang Y, Hao L. 2015. Potassium aspartate inhibits SH-SY5Y cell damage and apoptosis induced by ouabain and H2O2. Mol. Med. Rep. 12: 2842-2848.
    Pubmed
  18. Sharma A, Ghani A, Sak K, Tuli HS, Sharma AK, Setzer WN, et al. 2019. Probing into therapeutic anti-cancer potential of apigenin:recent trends and future directions. Recent. Pat. Inflamm. Allergy Drug. Discov. 13: 124-133.
    Pubmed
  19. Zhao L, Wang JL, Liu R, Li XX, Li JF, Zhang L. 2013. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer's disease mouse model. Molecules 18: 9949-9965.
    Pubmed KoreaMed
  20. Li F, Lang F, Zhang H, Xu L, Wang Y, Zhai C, et al. 2017. Apigenin alleviates endotoxin-induced myocardial toxicity by modulating inflammation, oxidative stress, and autophagy. Oxid. Med. Cell. Longev. 2017: 2302896.
    Pubmed KoreaMed
  21. Zhao L, Wang JL, Wang YR, Fa XZ. 2013. Apigenin attenuates coppermediated beta-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res. 1492: 33-45.
    Pubmed
  22. Chung SK, Osawa T, Kawakishi S. 1997. Hydroxyl radical-scavenging effects of spices and scavengers from brown mustard (Brassica nigra). J. Biosci. Biotechnol. Biochem. 61: 118-123.
  23. Nishikimi M, Appaji N, Yagi K. 1972. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem. Biophys. Res. Commun. 46: 849854.
  24. Marcocci L, Packer L, Droy-Lefaix MT, Sekaki A, Gardes-Albert M. 1994. Antioxidant action of Ginkgo biloba extract EGb 761. Methods Enzymol. 234: 462-475.
  25. Cathcart R, Schwiers E, Ames BN. 1984. Detection of picomole levels of lipid hydroperoxides using a dichlorofluorescein fluorescent assay. Methods Enzymol. 105: 352-358.
  26. Niedzielska E, Smaga I, Gawlik M, Moniczewski A, Stankowicz P, Pera J, et al. 2016. Oxidative stress in neurodegenerative diseases. Mol. Neurobiol. 53: 4094-4125.
    Pubmed KoreaMed
  27. Cai L, Wang LF, Pan JP, Mi XN, Zhang Z, Geng HJ, et al. 2016. Neuroprotective effects of methyl 3,4-dihydroxybenzoate against TBHP-induced oxidative damage in SH-SY5Y cells. Molecules 21:1071.
    Pubmed KoreaMed
  28. Valko M, Jomova K, Rhodes CJ, Kuca K, Musilek K. 2016. Redoxand non-redox-metal-induced formation of free radicals and their role in human disease. Arch. Toxicol. 90: 1-37.
    Pubmed
  29. Enogieru AB, Haylett W, Hiss DC, Bardien S, Ekpo OE. 2018. Rutin as a potent antioxidant: implications for neurodegenerative disorders. Oxid. Med. Cell. Longev. 2018: 6241017.
    Pubmed KoreaMed
  30. Achete de Souza G, de Marqui SV, Matias JN, Guiguer EL, Barbalho SM. 2020. Effects of Ginkgo biloba on diseases related to oxidative stress. Planta. Med. 86: 376-386.
    Pubmed
  31. Pezeshki-Nia S, Asle-Rousta M, Mahmazi S. 2020. Spinacia oleracea L. extract attenuates hippocampal expression of TNF-alpha and IL-1beta in rats exposed to chronic restraint stress. Med. J. Islam. Repub. Iran 34: 10.
  32. Salehi B, Venditti A, Sharifi-Rad M, Kregiel D, Sharifi-Rad J, Durazzo A, et al. 2019. The therapeutic potential of apigenin. Int. J. Mol. Sci. 20: 1305.
    Pubmed KoreaMed
  33. Balez R, Steiner N, Engel M, Muñoz SS, Lum JS, Wu Y, et al. 2016. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease. Sci. Rep. 12: 31450.
    Pubmed KoreaMed
  34. Kang SS, Lee JY, Choi YK, Kim GS, Han BH. 2004. Neuroprotective effects of flavones on hydrogen peroxide-induced apoptosis in SH-SY5Y neuroblostoma cells. Bioorg. Med. Chem. Lett. 3: 22612264.
    Pubmed
  35. Castelli V, Benedetti E, Antonosante A, Catanesi M, Pitari G, Ippoliti R, et al. 2019. Neuronal cells rearrangement during aging and neurodegenerative disease: metabolism, oxidative stress and organelles dynamic. Front. Mol. Neurosci. 28: 132.
    Pubmed KoreaMed
  36. Wang X, Michaelis EK. 2010. Selective neuronal vulnerability to oxidative stress in the brain. Front. Aging. Neurosci. 2: 12.
    Pubmed KoreaMed
  37. Zhang L, Yu H, Sun Y, Lin X, Chen B, Tan C, et al. 2007. Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur. J. Pharmacol. 564:18-25.
    Pubmed
  38. Mattson MP, Pedersen WA, Duan W, Culmsee C, Camandola S. 1999. Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases. Ann. NY Acad. Sci. 893: 154-175.
    Pubmed
  39. Lee DZ, Chung JM, Chung K, Kang MG. 2012. Reactive oxygen species (ROS) modulate AMPA receptor phosphorylation and cell-surface localization in concert with pain-related behavior. Pain. 153: 1905-1915.
    Pubmed KoreaMed
  40. AbdulSalam SF, Gurjar PN, Zhu H, Liu J, Johnson ES, Kadekaro AL, et al. 2017. Self-cyclizing antioxidants to prevent DNA damage caused by hydroxyl radical. Chembiochem. 18: 2007-2011.
    Pubmed
  41. Chiste RC, Freitas M, Mercadante AZ, Fernandes E. 2015. Superoxide anion radical: generation and detection in cellular and non-cellular systems. Curr. Med. Chem. 22: 4234-4256.
    Pubmed
  42. Sies H, Jones DP. 2020. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell. Biol. 21: 363383.
    Pubmed
  43. Bagheri M, Nair RR, Singh KK, Saini DK. 2017. ATM-ROS-iNOS axis regulates nitric oxide mediated cellular senescence. Biochim. Biophys. Acta. Mol. Cell. Res. 1864: 177-190.
    Pubmed
  44. Singh D, Khan MA, Siddique HR. 2019. Apigenin, a plant flavone playing noble roles in cancer prevention via modulation of key cell signaling networks. Recent. Pat. Anticancer. Drug Discov. 14:298-311.
    Pubmed
  45. Wang M, Firrman J, Liu L, Yam K. 2019. A review on flavonoid apigenin: dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. Biomed. Res. Int. 2019:7010467.
    Pubmed KoreaMed
  46. Zhang L, Yu H, Sun Y, Lin X, Chen B, Tan C, et al. 2007. Protective effect of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur. J. Pharmacol. 564: 1825.
    Pubmed
  47. Tian X, Gao L, An L, Jiang X, Bai J, Huang J, et al. 2016. Pretreatment of MQA, a caffeoylquinic acid derivative compound, protects against H2O2-induced oxidative stress in SH-SY5Y cells. Neurol. Res. 38: 1079-1087.
    Pubmed
  48. Kale J, Osterlund EJ, Andrews DW. 2018. BCL-2 family proteins:changing partners in the dance towards death. Cell. Death. Differ. 25: 65-80.
    Pubmed KoreaMed
  49. Opferman JT, Kothari A. 2018. Anti-apoptotic BCL-2 family members in development. Cell. Death. Differ. 25: 37-45.
    Pubmed KoreaMed
  50. Siddiqui WA, Ahad A, Ahsan H. 2015. The mystery of BCL2 family:Bcl-2 proteins and apoptosis: an update. Arch. Toxicol. 89: 289317.
    Pubmed
  51. Garner TP, Reyna DE, Priyadarshi A, Chen HC, Li S, Wu Y, et al. 2016. An autoinhibited dimeric form of BAX regulates the BAX activation pathway. Mol. Cell. 63: 485-497.
    Pubmed KoreaMed
  52. Zare MFR, Rakhshan K, Aboutaleb N, Nikbakht F, Naderi N, Bakhshesh M, et al. 2019. Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats. Life. Sci. 232: 116623.
    Pubmed
  53. Zhong Y, Jin C, Gan J, Wang X, Shi Z, Xia X, et al. 2017. Apigenin attenuates patulin-induced apoptosis in HEK293 cells by modulating ROS-mediated mitochondrial dysfunction and caspase signal pathway Toxicon. 137: 106-113.
    Pubmed
  54. Qi H, Shuai J. 2016. Alzheimer's disease via enhanced calcium signaling caused by the decrease of endoplasmic reticulummitochondrial distance. Med. Hypotheses 89: 28-31.
    Pubmed
  55. Xu P, Cai X, Zhang W, Li Y, Qiu P, Lu D, et al. 2016. Flavonoids of Rosa roxburghii Tratt exhibit radioprotection and anti-apoptosis properties via the Bcl-2(Ca2+)/Caspase-3/PARP-1 pathway. Apoptosis 21: 1125-1143.
    Pubmed
  56. Kim A, Nam YJ, Lee MS, Shin YK, Sohn DS, Lee CS. 2016. Apigenin reduces proteasome inhibition-induced neuronal apoptosis by suppressing the cell death process. Neurochem. Res. 41: 29692980.
    Pubmed
  57. Han Y, Zhang T, Su J, Zhao Y, Chenchen Wang, Li X. 2017. Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage. J. Clin. Neurosci. 40: 157-162.
    Pubmed
  58. Huang J, May JM. 2006. Ascorbic acid protects SH-SY5Y neuroblastoma cells from apoptosis and death induced by betaamyloid. Brain Res. 1097: 52-58.
    Pubmed
  59. Guillemain I, Fontès G, Privat A, Chaudieu I. 2003. Early programmed cell death in human NT2 cell cultures during differentiation induced by all-trans-retinoic acid. J. Neurosci. Res. 71: 38-45.
    Pubmed
  60. Ross ME. 1996. Cell division and the nervous system: regulating the cycle from neural differentiation to death. Trends Neurosci. 19: 62-68.
  61. Li P, Zhao QL, Wu LH, Jawaid P, Jiao YF, Kadowaki M, et al. 2014. Isofraxidin, a potent reactive oxygen species (ROS) scavenger, protects human leukemia cells from radiation-induced apoptosis via ROS/mitochondria pathway in p53-independent manner. Apoptosis 19: 1043-1053.
    Pubmed
  62. Guo H, Kong S, Chen W, Dai Z, Lin T, Su J, et al. 2014. Apigenin mediated protection of OGD-evoked neuron-like injury in differentiated PC12 cells. Neurochem. Res. 39: 2197-2210.
    Pubmed

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