Advertisement

Chronic mild Hyperhomocysteinemia impairs energy metabolism, promotes DNA damage and induces a Nrf2 response to oxidative stress in rats brain

  • Tiago Marcon dos Santos
  • Cassiana Siebert
  • Micaela Federizzi de Oliveira
  • Vanusa Manfredini
  • Angela T. S. WyseEmail author
Original Research
  • 71 Downloads

Abstract

Homocysteine (HCY) has been linked to oxidative stress and varied metabolic changes that are dependent on its concentration and affected tissues. In the present study we evaluate parameters of energy metabolism [succinate dehydrogenase (SDH), complex II and IV (cytochrome c oxidase), and ATP levels] and oxidative stress [DCFH oxidation, nitrite levels, antioxidant enzymes and lipid, protein and DNA damages, as well as nuclear factor erythroid 2-related (Nrf2) protein abundance] in amygdala and prefrontal cortex of HCY-treated rats. Wistar male rats were treated with a subcutaneous injection of HCY (0.03 µmol/g of body weight) from the 30th to 60th post-natal day, twice a day, to induce mild hyperhomocysteinemia (HHCY). The rats were euthanatized without anesthesia at 12 h after the last injection, and amygdala and prefrontal cortex were dissected for biochemical analyses. In the amygdala, mild HHCY increased activities of SDH and complex II and decreased complex IV and ATP level, as well as increased antioxidant enzymes activities (glutathione peroxidase and superoxide dismutase), nitrite levels, DNA damage, and Nrf 2 protein abundance. In the prefrontal cortex, mild HHCY did not alter energy metabolism, but increased glutathione peroxidase, catalase and DNA damage. Other analyzed parameters were not altered by HCY-treatment. Our findings suggested that chronic mild HHCY changes each brain structure, particularly and specifically. These changes may be associated with the mechanisms by which chronic mild HHCY has been linked to the risk factor of fear, mood disorders and depression, as well as in neurodegenerative diseases.

Keywords

Homocysteine Mild hyperhomocysteinemia Nrf2 gene Antioxidant enzymes response Energy metabolism DNA damage 

Abbreviations

ATP

Adenosine triphosphate

CAT

Catalase

Complex II

Succinate dehydrogenase enzyme complexe

Complex IV

Cytochrome c oxidase enzyme

DCFH

2′,7′-dihydrodichlorofluorescein

DCF

2′,7′-dichlorofluorescein

DNA

Deoxyribonucleic acid

GPx

Glutathione peroxidase

GR

Glutathione reductase

GSH

Reduced glutathione

GSSG

Oxidized glutathione

HCY

Homocysteine

HHCY

Hyperhomocysteinemia

MDA

Malondialdehyde

MET

Methionine

NADPH

Nicotinamide adenine dinucleotide phosphate

NO

Nitric oxide

Nrf2

Nuclear factor erythroid 2-related

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

SDH

Succinate dehydrogenase enzyme

SOD

Superoxide dismutase

TBARS

Thiobarbituric acid reactive substances

Notes

Acknowledgments

This study was supported by Edital Universal/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), INCT (EN 465671/2014-4)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) – Brazil, and PRONEX(16/2551-0000465-0)/Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS) – Brazil.

Authors Contribution

T.M.S., C.S., and A.T S.W. were responsible for most of the experiments developed and the writing of the scientific article. The co-authors M.F.O. and V.M. contributed to the accomplishment of the comet experiment to evaluate DNA damage.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The experimental protocol was approved by the Ethics Committee of Universidade Federal do Rio Grande do Sul, in Porto Alegre (CEUA/UFRGS #33301). Every effort was made to minimize the number of animals and the distress caused throughout the experiment.

References

  1. Aebi H (1984) Catalase in vitro. Methods Enzym 105:121–126.  https://doi.org/10.1016/S0076-6879(84)05016-3 CrossRefGoogle Scholar
  2. Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145CrossRefPubMedGoogle Scholar
  3. Alberts B, Johnson A, Lewis J et al (2002) DNA repair. In: Molecular biology of the cell, 4th edn. Garland Science, New York, pp 1–6Google Scholar
  4. Araújo JRJMR, Martel F, Borges B et al (2015) Folates and aging: role in mild cognitive impairment, dementia and depression. Ageing Res Rev 22:9–19.  https://doi.org/10.1016/j.arr.2015.04.005 CrossRefPubMedGoogle Scholar
  5. Ashrafi G, Schwarz TL (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20:31–42.  https://doi.org/10.1038/cdd.2012.81 CrossRefPubMedGoogle Scholar
  6. Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272.  https://doi.org/10.1007/s00204-011-0674-5 CrossRefPubMedGoogle Scholar
  7. Beckhauser TF, Francis-Oliveira J, De Pasquale R (2016) Reactive oxygen species: physiological and physiopathological effects on synaptic plasticity. J Exp Neurosci 2016:23–48.  https://doi.org/10.4137/JEN.S39887 CrossRefGoogle Scholar
  8. Bhatia P, Singh N (2015) Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression. Fundam Clin Pharmacol 29:522–528.  https://doi.org/10.1111/fcp.12145 CrossRefPubMedGoogle Scholar
  9. Blanco G (2005) Na, K-ATPase subunit heterogeneity as a mechanism for tissue-specific ion regulation. Semin Nephrol 25:292–303.  https://doi.org/10.1016/j.semnephrol.2005.03.004 CrossRefPubMedGoogle Scholar
  10. Boers GH (2001) From gene to disease; from homocysteine to hyperhomocysteinemia. Ned Tijdschr Geneeskd 145:956–958PubMedGoogle Scholar
  11. Bonetti F, Brombo G, Zuliani G (2016) The relationship between hyperhomocysteinemia and neurodegeneration. Neurodegener Dis Manag 6:133–145.  https://doi.org/10.2217/nmt-2015-0008 CrossRefPubMedGoogle Scholar
  12. Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352PubMedGoogle Scholar
  13. Caudill MA, Wang JC, Melnyk S et al (2001) Biochemical and molecular action of nutrients intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine β-synthase heterozygous mice. Biochem Mol Action Nutr 131(11):2811–2818Google Scholar
  14. Chen S, Dong Z, Zhao Y et al (2017) Homocysteine induces mitochondrial dysfunction involving the crosstalk between oxidative stress and mitochondrial pSTAT3 in rat ischemic brain. Sci Rep 7:1–12.  https://doi.org/10.1038/s41598-017-07112-z CrossRefGoogle Scholar
  15. Chung YC, Kruyer A, Yao Y et al (2016) Hyperhomocysteinemia exacerbates Alzheimer’s disease pathology by way of the β-amyloid fibrinogen interaction. J Thromb Haemost 14:1442–1452.  https://doi.org/10.1111/jth.13340 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cobb CA, Cole MP (2015) Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 84:4–21.  https://doi.org/10.1016/j.nbd.2015.04.020 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cobley JN, Fiorello ML, Bailey DM (2018) Redox Biology 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503.  https://doi.org/10.1016/j.redox.2018.01.008 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Crema L, Schlabitz M, Tagliari B et al (2010) Na + , K + -ATPase activity is reduced in Amygdala of rats with chronic stress-induced anxiety-like behavior. Neurochem Res 35:1787–1795.  https://doi.org/10.1007/s11064-010-0245-9 CrossRefPubMedGoogle Scholar
  19. de S. Moreira D, Figueiró PW, Siebert C et al (2018) Chronic Mild Hyperhomocysteinemia Alters Inflammatory and Oxidative/Nitrative Status and Causes Protein/DNA Damage, as well as Ultrastructural Changes in Cerebral Cortex: Is Acetylsalicylic Acid Neuroprotective? Neurotox Res 33:580–592.  https://doi.org/10.1007/s12640-017-9847-1 CrossRefGoogle Scholar
  20. Di Meo S, Reed TT, Venditti P, Victor VM (2016) Role of ROS and RNS sources in physiological and pathological conditions. Oxid Med Cell Longev.  https://doi.org/10.1155/2016/1245049 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Emerit J, Edeas M, Bricaire F (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58:39–46.  https://doi.org/10.1016/j.biopha.2003.11.004 CrossRefPubMedGoogle Scholar
  22. Espinosa-Diez C, Miguel V, Mennerich D et al (2015) Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol 6:183–197.  https://doi.org/10.1016/j.redox.2015.07.008 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Familtseva A, Kalani A, Chaturvedi P et al (2014) Mitochondrial mitophagy in mesenteric artery remodelling in hyperhomocysteinemia. Physiol Rep 2:1–10.  https://doi.org/10.14814/phy2.283 CrossRefGoogle Scholar
  24. Ferreira FS, Biasibetti-brendler H, Pierozan P et al (2018) Kynurenic acid restores Nrf2 levels and prevents quinolinic acid-induced toxicity in rat striatal slices. Mol Neurobiol 55:8538–8549CrossRefPubMedGoogle Scholar
  25. Finkelstein JD (2007) Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine. Clin Chem Lab Med 45:1694–1699.  https://doi.org/10.1515/CCLM.2007.341 CrossRefPubMedGoogle Scholar
  26. Fischer JC, Ruitenbeek W, Berden JA et al (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36.  https://doi.org/10.1016/0009-8981(85)90135-4 CrossRefPubMedGoogle Scholar
  27. Folstein M, Liu T, Peter I et al (2007) The homocysteine hypothesis of depression. Am J Psychiatry 164:861–867.  https://doi.org/10.1176/ajp.2007.164.6.861 CrossRefPubMedGoogle Scholar
  28. Fujikawa K, Nakamichi N, Kato S et al (2012) Delayed mitochondrial membrane potential disruption by ATP in cultured rat hippocampal neurons exposed to N -Methyl- D - aspartate. 29:20–29.  https://doi.org/10.1254/jphs.12034FP CrossRefGoogle Scholar
  29. Gao L, Zeng XN, Guo HM et al (2012) Cognitive and neurochemical alterations in hyperhomocysteinemic rat. Neurol Sci 33:39–43.  https://doi.org/10.1007/s10072-011-0645-x CrossRefPubMedGoogle Scholar
  30. Gozzelino R, Arosio P (2016) Iron homeostasis in health and disease. Int J Mol Sci 17:1–14.  https://doi.org/10.3390/ijms17010130 CrossRefGoogle Scholar
  31. Green LC, Wagner DA, Glogowski J et al (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138.  https://doi.org/10.1016/0003-2697(82)90118-X CrossRefGoogle Scholar
  32. Grimm A, Eckert A (2017) Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem 143:418–431.  https://doi.org/10.1111/jnc.14037 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Hakem R (2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27:589–605.  https://doi.org/10.1038/emboj.2008.15 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Halliwell B (2012) Free radicals and antioxidants: updating a personal view. Nutr Rev 70:257–265.  https://doi.org/10.1111/j.1753-4887.2012.00476.x CrossRefPubMedGoogle Scholar
  35. Halliwell B, Gutteridge JMC (2007) Free Radicals in Biology and Medicine, 4th edn. Oxford University Press, OxfordGoogle Scholar
  36. Hannibal L, Blom HJ (2016) Homocysteine and disease: causal associations or epiphenomenons? Mol Aspects Med 53:36–42.  https://doi.org/10.1016/j.mam.2016.11.003 CrossRefPubMedGoogle Scholar
  37. Hartmann A, Agurell E, Beevers C et al (2003) Recommendations for conducting the in vivo alkaline Comet assay. 18:45–51Google Scholar
  38. Hiemstra S, Niemeijer M, Koedoot E et al (2017) Comprehensive landscape of Nrf2 and p53 pathway activation dynamics by oxidative stress and DNA damage. Chem Res Toxicol 30:923–933.  https://doi.org/10.1021/acs.chemrestox.6b00322 CrossRefPubMedGoogle Scholar
  39. Holmström KM, Kostov RV, Dinkova-Kostova AT (2017) The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol 2:80–91.  https://doi.org/10.1016/j.cotox.2016.10.002 CrossRefGoogle Scholar
  40. Ikeda K, Onaka T, Yamakado M et al (2003) Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-deficient mice. J Neurosci 23:4667–4676CrossRefPubMedGoogle Scholar
  41. Islam T (2016) Oxidative stress and mitochondrial dysfunction- linked neurodegenerative disorders. Neurol Res 6412:1–10.  https://doi.org/10.1080/01616412.2016.1251711 CrossRefGoogle Scholar
  42. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461:1071–1078.  https://doi.org/10.1038/nature08467 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Jakubowski H (2003) Incorporation of homocysteine into protein in humans. 41:1462–1466Google Scholar
  44. Jakubowski H (2017) Homocysteine editing, thioester chemistry, coenzyme A, and the origin of coded peptide synthesis †. Life 7:6.  https://doi.org/10.3390/life7010006 CrossRefPubMedCentralGoogle Scholar
  45. Juel C (2016) Nitric oxide and Na, K-ATPase activity in rat skeletal muscle. Acta Physiol 216:447–453.  https://doi.org/10.1111/apha.12617 CrossRefGoogle Scholar
  46. Keyer K, Imlay JA (1996) Superoxide accelerates DNA damage by elevating free-iron levels. Proc Natl Acad Sci 93:13635–13640.  https://doi.org/10.1073/pnas.93.24.13635 CrossRefPubMedGoogle Scholar
  47. Khatun S, Chaube SK, Bhattacharyya CN (2013) Generation of hydrogen peroxide mediates hanging death-induced neuronal cell apoptosis in the dentate gyrus of the rat brain. Brain Res Bull 95:54–60.  https://doi.org/10.1016/j.brainresbull.2013.03.002 CrossRefPubMedGoogle Scholar
  48. Kocer B, Guven H, Conkbayir I et al (2016) The effect of hyperhomocysteinemia on motor symptoms, cognitive status, and vascular risk in patients with parkinson’s disease. Parkinsons Dis 2016:1589747.  https://doi.org/10.1155/2016/1589747 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kruman I, Culmsee C (2000) Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 20:6920–6926CrossRefPubMedGoogle Scholar
  50. Kubera M, Obuchowicz E, Goehler L et al (2011) In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuro-Psychopharmacology Biol Psychiatry 35:744–759.  https://doi.org/10.1016/j.pnpbp.2010.08.026 CrossRefGoogle Scholar
  51. Kumagai A, Sasaki T, Matsuoka K et al (2019) Monitoring of glutamate-induced excitotoxicity by mitochondrial oxygen consumption. Synapse 73:e22067.  https://doi.org/10.1002/syn.22067 CrossRefPubMedGoogle Scholar
  52. Kumar A, Chanana P (2017) Role of nitric oxide in stress-induced anxiety: from pathophysiology to therapeutic target. Vitam Horm 103:147–167CrossRefPubMedGoogle Scholar
  53. Lebel CP, Ischiropoulos H, Bondys SC (1992) Evaluation of the Probe 2′,7′-Dichiorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231CrossRefPubMedGoogle Scholar
  54. Lei XG, Cheng W-H, McClung JP (2007) Metabolic regulation and function of glutathione peroxidase-1. Annu Rev Nutr 27:41–61.  https://doi.org/10.1146/annurev.nutr.27.061406.093716 CrossRefPubMedGoogle Scholar
  55. Liu XF, Hao JL, Xie T et al (2017) Nrf2 as a target for prevention of age-related and diabetic cataracts by against oxidative stress. Aging Cell 16:934–942.  https://doi.org/10.1111/acel.12645 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Liu XL, Di WY, Yu XM et al (2018) Mitochondria-mediated damage to dopaminergic neurons in Parkinson’s disease (Review). Int J Mol Med 41:615–623.  https://doi.org/10.3892/ijmm.2017.3255 CrossRefPubMedGoogle Scholar
  57. Lowry O, Rosebrough N, Farr A, Randall R (1951) Protein measurement with the Folin phenol reagent. Readings 193:265–275.  https://doi.org/10.1016/0304-3894(92)87011-4 CrossRefGoogle Scholar
  58. Ma Q (2013) Role of Nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426.  https://doi.org/10.1146/annurev-pharmtox-011112-140320 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Maluf SW, Erdtmann B (2000) Follow-up study of the genetic damage in lymphocytes of pharmacists and nurses handling antineoplastic drugs evaluated by cytokinesis-block micronuclei analysis and single cell gel electrophoresis assay. Mutat Res 471:21–27CrossRefPubMedGoogle Scholar
  60. Mandaviya PR, Stolk L, Heil SG (2014) Homocysteine and DNA methylation: a review of animal and human literature. Mol Genet Metab 113:243–252.  https://doi.org/10.1016/j.ymgme.2014.10.006 CrossRefPubMedGoogle Scholar
  61. Marklund S (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) Handbook of methods for oxygen radical research, 4th edn. CRC Press, Boca RatonGoogle Scholar
  62. Martin LJ (2008) DNA damage and repair: relevance to mechanisms of neurodegeneration. J Neuropathol Exp Neurol 67:377–387.  https://doi.org/10.1097/NEN.0b013e31816ff780 CrossRefPubMedPubMedCentralGoogle Scholar
  63. McCully KS (2015) Homocysteine metabolism, atherosclerosis, and diseases of aging. Compr Physiol 6:471–505.  https://doi.org/10.1002/cphy.c150021 CrossRefPubMedGoogle Scholar
  64. Miller AL (2003) The methionine-homocysteine cycle and its effects on cognitive diseases. 8:7–19Google Scholar
  65. Minagawa H, Watanabe A, Akatsu H et al (2010) Homocysteine, another Risk factor for alzheimer disease, impairs apolipoprotein E3 function. J Biol Chem 285:38382–38388.  https://doi.org/10.1074/jbc.M110.146258 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Morris G, Berk M (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 13:1–24.  https://doi.org/10.1186/s12916-015-0310-y CrossRefGoogle Scholar
  67. Moseley AE, Williams MT, Schaefer TL et al (2007) Deficiency in Na+, K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice. J Neurosci 27:616–626.  https://doi.org/10.1523/JNEUROSCI.4464-06.2007 CrossRefPubMedGoogle Scholar
  68. Moustafa AA, Hewedi DH, Eissa AM et al (2014) Homocysteine levels in schizophrenia and affective disorders — focus on cognition. Front Behav Neurosci 8:1–10.  https://doi.org/10.3389/fnbeh.2014.00343 CrossRefGoogle Scholar
  69. Mudd SH (2011) Hypermethioninemias of genetic and non-genetic origin: a review. Am J Med Genet Part C Semin Med Genet 157:3–32.  https://doi.org/10.1002/ajmg.c.30293 CrossRefGoogle Scholar
  70. Nadin SB, Roig LMV, Ciocca DR (2001) A silver staining method for single-cell gel assay. 49:1183–1186Google Scholar
  71. Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580:2994–3005.  https://doi.org/10.1016/j.febslet.2006.04.088 CrossRefPubMedGoogle Scholar
  72. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefGoogle Scholar
  73. Permoda-Osip A, Dorszewska J (2013) Hyperhomocysteinemia in bipolar depression: clinical and biochemical correlates. Neuropsychobiology 68(4):193–196.  https://doi.org/10.1159/000355292 CrossRefPubMedGoogle Scholar
  74. Potts MB, Rola R, Claus CP et al (2009) Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain. J Neurosci Res 87:1848–1857.  https://doi.org/10.1002/jnr.21996 CrossRefPubMedPubMedCentralGoogle Scholar
  75. Rahman I, Kode A, Biswas SK (2007) Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 1:3159–3165.  https://doi.org/10.1038/nprot.2006.378 CrossRefGoogle Scholar
  76. Ramdial K, Franco MC, Estevez AG (2017) Cellular mechanisms of peroxynitrite-induced neuronal death. Brain Res Bull 133:4–11.  https://doi.org/10.1016/j.brainresbull.2017.05.008 CrossRefPubMedGoogle Scholar
  77. Roy B, Guittet O, Beuneu C et al (2004) Depletion of deoxyribonucleoside triphosphate. Free Radic Biol Med 36:507–516.  https://doi.org/10.1016/j.freeradbiomed.2003.11.028 CrossRefPubMedGoogle Scholar
  78. Rueda CB, Llorente-Folch I, Traba J et al (2016) Glutamate excitotoxicity and Ca2 + -regulation of respiration: role of the Ca2 + activated mitochondrial transporters (CaMCs). BBA - Bioenerg 1857:1158–1166.  https://doi.org/10.1016/j.bbabio.2016.04.003 CrossRefGoogle Scholar
  79. Rustin P, Chretien D, Bourgeron T et al (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51.  https://doi.org/10.1016/0009-8981(94)90055-8 CrossRefPubMedGoogle Scholar
  80. Sabouny R, Fraunberger E, Geoffrion M et al (2017) The Keap1–Nrf2 stress response pathway promotes mitochondrial hyperfusion through degradation of the mitochondrial fission protein Drp1. Antioxid Redox Signal 27(18):1447–1459.  https://doi.org/10.1089/ars.2016.6855 CrossRefPubMedGoogle Scholar
  81. Samavarchi Tehrani S, Mahmoodzadeh Hosseini H, Yousefi T et al (2018) The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer. J Cell Biochem.  https://doi.org/10.1002/jcb.27617 CrossRefPubMedGoogle Scholar
  82. Scherer EBS, da Cunha AA, Kolling J et al (2011) Development of an animal model for chronic mild hyperhomocysteinemia and its response to oxidative damage. Int J Dev Neurosci 29:693–699.  https://doi.org/10.1016/j.ijdevneu.2011.06.004 CrossRefPubMedGoogle Scholar
  83. Scherer EBS, Loureiro SO, Vuaden FC et al (2013) Mild hyperhomocysteinemia reduces the activity and immunocontent, but does not alter the gene expression, of catalytic α subunits of cerebral Na +, K + -ATPase. Mol Cell Biochem 378:91–97.  https://doi.org/10.1007/s11010-013-1598-6 CrossRefPubMedGoogle Scholar
  84. Scherer EBS, Loureiro SO, Vuaden FC et al (2014) Mild hyperhomocysteinemia increases brain acetylcholinesterase and proinflammatory cytokine levels in different tissues. Mol Neurobiol 50:589–596.  https://doi.org/10.1007/s12035-014-8660-6 CrossRefPubMedGoogle Scholar
  85. Scherer EBS, Savio LEB, Vuaden FC et al (2012a) Chronic mild hyperhomocysteinemia alters ectonucleotidase activities and gene expression of ecto-5′-nucleotidase/CD73 in rat lymphocytes. Mol Cell Biochem 361:187–194.  https://doi.org/10.1007/s11010-011-1141-6 CrossRefGoogle Scholar
  86. Scherer EBS, Schmitz F, Vuaden FC et al (2012b) Mild hyperhomocysteinemia alters extracellular adenine metabolism in rat brain. Neuroscience 223:28–34.  https://doi.org/10.1016/j.neuroscience.2012.07.035 CrossRefPubMedGoogle Scholar
  87. Sharma M, Tiwari M, Tiwari RK (2015) Hyperhomocysteinemia: impact on neurodegenerative diseases. Basic Clin Pharmacol Toxicol 117:287–296.  https://doi.org/10.1111/bcpt.12424 CrossRefPubMedGoogle Scholar
  88. Singh NP, Mccoy MT, Tice RR, Schneider EL (1988) Technique for quantitation damage in individual of low levels of DNA cells. Exp Cell Res 175(175):184–191CrossRefPubMedGoogle Scholar
  89. Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87:1157–1180.  https://doi.org/10.1007/s00204-013-1034-4 CrossRefPubMedGoogle Scholar
  90. Sipkens JA, Krijnen PAJ, Meischl C et al (2007) Homocysteine affects cardiomyocyte viability: concentration-dependent effects on reversible flip-flop, apoptosis and necrosis. Apoptosis 12:1407–1418.  https://doi.org/10.1007/s10495-007-0077-5 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Skovierová H, Vidomanová E, Mahmood S et al (2016) The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 17:1–18.  https://doi.org/10.3390/ijms17101733 CrossRefGoogle Scholar
  92. Tagliari B, Scherer EB, MacHado FR et al (2011) Antioxidants prevent memory deficits provoked by chronic variable Stress in rats. Neurochem Res 36:2373–2380.  https://doi.org/10.1007/s11064-011-0563-6 CrossRefPubMedGoogle Scholar
  93. Tice RR, Agurell E, Anderson D et al (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 221:206–221CrossRefGoogle Scholar
  94. Tonelli C, Chio IIC, Tuveson DA (2017) Transcriptional regulation by Nrf2. Antioxid Redox Signal 29:1727–1745.  https://doi.org/10.1089/ars.2017.7342 CrossRefPubMedGoogle Scholar
  95. Upchurch GR, Welch GN, Fabian AJ et al (1997) Stimulation of endothelial nitric oxide production by homocyst(e)ine. Atherosclerosis 132:177–185.  https://doi.org/10.1016/S0021-9150(97)00090-7 CrossRefPubMedGoogle Scholar
  96. Uribe P, Treulen F, Boguen R et al (2016) Nitrosative stress by peroxynitrite impairs ATP production in human spermatozoa. Andrologia 49:1–8.  https://doi.org/10.1111/and.12615 CrossRefGoogle Scholar
  97. Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333CrossRefPubMedGoogle Scholar
  98. Williams KT, Schalinske KL (2010) Homocysteine metabolism and its relation to health and disease. BioFactors 36:19–24.  https://doi.org/10.1002/biof.71 CrossRefPubMedGoogle Scholar
  99. Winterbourn CC (2013) The biological chemistry of hydrogen peroxide. Methods Enzymol 528:3–25CrossRefPubMedGoogle Scholar
  100. Witt KA, Mark KS, Hom S, Davis TP (2003) Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Circ Physiol 285:H2820–H2831.  https://doi.org/10.1152/ajpheart.00589.2003 CrossRefGoogle Scholar
  101. Zhang H, Davies KJA, Forman HJ (2015) Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med 88:314–336.  https://doi.org/10.1016/j.freeradbiomed.2015.05.036.Oxidative CrossRefPubMedPubMedCentralGoogle Scholar
  102. Zhang J, Zheng YG (2016) SAM/SAH analogs as versatile tools for SAM-dependent methyltransferases. ACS Chem Biol 11:583–597.  https://doi.org/10.1021/acschembio.5b00812 CrossRefPubMedGoogle Scholar
  103. Zhao K, Whiteman M, Spencer JPE, Halliwell B (2001) DNA damage by nitrite and peroxynitrite: protection by dietary phenols. Methods Enzymol 335:296–307.  https://doi.org/10.1016/S0076-6879(01)35252-7 CrossRefPubMedGoogle Scholar
  104. Zhu Y, Carvey PM, Ling Z (2006) Age-related changes in glutathione and glutathione-related enzymes in rat brain. Brain Res 1090:35–44.  https://doi.org/10.1016/j.brainres.2006.03.063 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Tiago Marcon dos Santos
    • 1
  • Cassiana Siebert
    • 1
  • Micaela Federizzi de Oliveira
    • 2
  • Vanusa Manfredini
    • 2
  • Angela T. S. Wyse
    • 1
    Email author
  1. 1.Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Laboratório de Hematologia e Citologia ClínicaUniversidade Federal do PampaUruguaianaBrazil

Personalised recommendations