The molecular and cellular effect of homocysteine metabolism imbalance on human health

International Journal of Molecular Sciences

Volumn 17, Issue 10, 2016, Pages

  Škovierová, Henrieta ^a   Vidomanová, Eva ^a   Mahmood, Silvia ^a   Sopková, Janka ^a   Drgová, Anna ^a   Červeňová, Tatiana ^a   Halašová, Erika ^a   Lehotsky J ^a  

^a University Teaching Hospital in Martin   (Slovakia)

Author keywords

Cellular toxicity; Disease; Homocysteine metabolism; Hyperhomocysteimenia; Oxidative stress

Indexed keywords

HOMOCYSTEINE; MITOGEN ACTIVATED PROTEIN KINASE; NEUROTOXIN;

ALZHEIMER DISEASE; BONE REMODELING; BRAIN ISCHEMIA; CAPILLARY ELECTROPHORESIS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHRONIC KIDNEY DISEASE; CONGENITAL DISORDER; CYTOTOXICITY; DNA FRAGMENTATION; EXCITOTOXICITY; GASTROINTESTINAL DISEASE; GENETIC POLYMORPHISM; HEART INFARCTION; HYPERHOMOCYSTEINEMIA; MENTAL DISEASE; NEOPLASM; NEUROLOGIC DISEASE; OXIDATIVE STRESS; PROTEIN STRUCTURE; REVIEW; TISSUE INJURY; BLOOD; BONE DISEASE; CEREBROVASCULAR DISEASE; HEALTH STATUS; HUMAN; KIDNEY DISEASE; METABOLISM; OXIDATION REDUCTION REACTION; PATHOLOGY; PHYSIOLOGY; RISK FACTOR;

BONE DISEASES; CARDIOVASCULAR DISEASES; CEREBROVASCULAR DISORDERS; GASTROINTESTINAL DISEASES; HEALTH STATUS; HOMOCYSTEINE; HUMANS; HYPERHOMOCYSTEINEMIA; KIDNEY DISEASES; NEOPLASMS; OXIDATION-REDUCTION; OXIDATIVE STRESS; RISK FACTORS;

EID: 84992146088     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms17101733     Document Type: Review

References (112)

1. Warnecke, P.M.; Bestor, T.H. Cytosine methylation and human cancer. Curr. Opin. Oncol. 2000, 12, 68–73.
2. Stirzaker, C.; Song, J.Z.; Ng, W.; Du, Q.; Armstrong, N.J.; Locke, W.J.; Statham, A.L.; French, H.; Pidsley, R.; Valdes-Mora, F. et al. Methyl-CpG-binding protein MBD2 plays a key role in maintenance and spread of DNA methylation at CpG islands and shores in cancer. Oncogen 2016.
3. Mudd, S.H.; Ebert, M.H.; Scriver, C.R. Labile methyl group balances in the human: The role of sarcosine. Metabolism 1980, 29, 707–720.
4. Stead, L.M.; Au, K.P.; Jacobs, R.L.; Brosnan, M.E.; Brosnan, J.T. Methylation demand and homocysteine metabolism: Effects of dietary provision of creatine and guanidinoacetate. Am. J. Physiol. Endocrinol. Metab. 2001, 281, E1095–E1100.
5. Jacobs, R.L.; Stead, L.M.; Devlin, C.; Tabas, I.; Brosnan, M.E.; Brosnan, J.T.; Vance, D.E. Physiological regulation of phospholipid methylation alters plasma homocysteine in mice. J. Biol. Chem. 2005, 280, 28299–28305.
6. Wagner, C. Folate in Health and Disease; Bailey, L.B., Ed.; Marcel Dekker: New York, NY, USA, 1995; pp. 23–42.
7. Kerr, S.J. Competing methyltransferase systems. J. Biol. Chem. 1972, 247, 4248–4252.
8. Cantoni, G.L.; Chiang, P.K. Natural Sulfur Compounds; Cavallini, D., Gaull, G.E., Zappia, V., Eds.; Plenum Press: New York, NY, USA, 1980; pp. 67–80.
9. Jung, M.; Pfeifer, G.P. Aging and DNA methylation. BMC Biol. 2015, 13, 7.
10. Castro, R.; Rivera, I.; Blom, H.J.; Jakobs, C.; Tavares de Almeida, I. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: An overview. J. Inherit. Metab. Dis. 2006, 29, 3–20.
11. Wang, R. Gasotransmitters: Growing pains and joys. Trends Biochem. Sci. 2014, 39, 227–232.
12. Lee, M.; Schwab, C.; Yu, S.; McGeer, E.; McGeer, P.L. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol. Aging 2009, 30, 1523–1534.
13. Belalcázar, A.D.; Ball, J.G.; Frost, L.M.; Valentovic, M.A.; Wilkinson, J. Transsulfuration is a significant source of sulfur for glutathione production in human mammary epithelial cells. ISRN Biochem. 2013, 2013, 637897.
14. Brodek, P.; Olas, B. Biochemistry and therapeutic potential of hydrogen sulfide—Reality or fantasy? Postepy Hig. Med. Dosw. 2016, 70, 820–829.
15. Kožich, V.; Krijt, J.; Sokolová, J.; Melenovská, P.; Ješina, P.; Vozdek, R.; Majtán, T.; Kraus, J.P. Thioethers as markers of hydrogen sulfide production in homocystinurias. Biochimie 2016, 126, 14–20.
16. Sunden, S.L.; Renduchintala, M.S.; Park, E.I.; Miklasz, S.D.; Garrow, T.A. Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Arch. Biochem. Biophys. 1997, 345, 171–174.
17. Jakubowski, H. The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. J. Physiol. Pharmacol. 2008, 59, 155–167.
18. Jakubowski, H. Homocysteine is a protein amino acid in humans: Implications for homocysteine-linked disease. J. Biol. Chem. 2002, 277, 30425–30428.
19. Manolescu, B.N.; Oprea, E.; Farcasanu, I.C.; Berteanu, M.; Cercasov, C. Homocysteine and vitamin therapy in stroke prevention and treatment: A review. Acta Biochim. Pol. 2010, 57, 467–477.
20. Seshadri, S.; Beiser, A.; Selhub, J.; Jacques, P.F.; Rosenberg, I.H.; D’Agostino, R.B.; Wilson, P.W.; Wolf, P.A. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med. 2002, 346, 476–483.
21. Ji, C.; Kaplowitz, N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J. Gastroenterol. 2004, 10, 1699–1708.
22. Chen, Z.; Karaplis, A.C.; Ackerman, S.L.; Pogribny, I.P.; Melnyk, S.; Lussier-Cacan, S.; Chen, M.F.; Pai, A.; John, S.W.; Smith, R.S.; et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum. Mol. Genet. 2001, 10, 433–443.
23. Zappacosta, B.; Mastroiacovo, P.; Persichilli, S.; Pounis, G.; Ruggeri, S.; Minucci, A.; Carnovale, E.; Andria, G.; Ricci, R.; Scala, I.; et al. Homocysteine lowering by folate-rich diet or pharmacological supplementations in subjects with moderate hyperhomocysteinemia. Nutrients 2013, 5, 1531–1543.
24. Fohr, I.P.; Prinz-Langenohl, R.; Brönstrup, A.; Bohlmann, A.M.; Nau, H.; Berthold, H.K.; Pietrzik, K. 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am. J. Clin. Nutr. 2002, 75, 275–282.
25. L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: A randomized placebo-controlled study. Am. J. Clin. Nutr. 2003, 77, 658–662.
26. Kim, S.J.; Lee, B.H.; Kim, Y.M.; Kim, G.H.; Yoo, H.W. Congenital MTHFR deficiency causing early-onset cerebral stroke in a case homozygous for MTHFR thermolabile variant. Metab. Brain. Dis. 2013, 28, 519–522.
27. Van der Put, N.M.; Gabreëls, F.; Stevens, E.M.; Smeitink, J.A.; Trijbels, F.J.; Eskes, T.K.; van den Heuvel, L.P.; Blom, H.J. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am. J. Hum. Genet. 1998, 62, 1044–1051.
28. Safarinejad, M.R.; Shafiei, N.; Safarinejad, S. Methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C and G1793A polymorphisms: Association with risk for clear cell renal cell carcinoma and tumour behaviour in men. Clin. Oncol. 2012, 24, 269–281.
29. Floyd, R.A.; Hensley, K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol. Aging 2002, 23, 795–807.
30. Perła-Kaján, J.; Twardowski, T.; Jakubowski, H. Mechanisms of homocysteine toxicity in humans. Amino Acids 2007, 32, 561–572.
31. Jakubowski, H. Protein homocysteinylation: Possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J. 1999, 13, 2277–2283.
32. 2+-ATPases in rats subjected to acute homocysteine and homocysteine thiolactone administration. Mol. Cell. Biochem. 2009, 327, 39–45.
33. Jakubowski, H.; Perla-Kaján, J.; Finnell, R.H.; Cabrera, R.M.; Wang, H.; Gupta, S.; Kruger, W.D.; Kraus, J.P.; Shih, D.M. Genetic or nutritional disorders in homocysteine or folate metabolism increase protein N-homocysteinylation in mice. FASEB J. 2009, 23, 1721–1727.
34. Petras, M.; Tatarkova, Z.; Kovalska, M.; Mokra, D.; Dobrota, D.; Lehotsky, J.; Drgova, A. Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J. Physiol. Pharmacol. 2014, 65, 15–23.
35. Sharma, G.S.; Kumar, T.; Dar, T.A.; Singh, L.R. Protein N-homocysteinylation: From cellular toxicity to neurodegeneration. Biochim. Biophys. Acta 2015, 1850, 2239–2245.
36. Undas, A.; Perła, J.; Lacinski, M.; Trzeciak, W.; Kaźmierski, R.; Jakubowski, H. Autoantibodies against N-homocysteinylated proteins in humans: Implications for atherosclerosis. Stroke 2004, 35, 1299–1304.
37. Raposo, B.; Rodríguez, C.; Martínez-González, J.; Badimon, L. High levels of homocysteine inhibit lysyl oxidase (LOX) and downregulate LOX expression in vascular endothelial cells. Atherosclerosis 2004, 177, 1–8.
38. Gurda, D.; Handschuh, L.; Kotkowiak, W.; Jakubowski, H. Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells. Amino Acids 2015, 47, 1319–1339.
39. Jacobsen, D.W. Hyperhomocysteinemia and oxidative stress: Time for a reality check? Arterioscler. Thromb. Vasc. Biol. 2000, 20, 1182–1184.
40. Dayal, S.; Arning, E.; Bottiglieri, T.; Böger, R.H.; Sigmund, C.D.; Faraci, F.M.; Lentz, S.R. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke 2004, 35, 1957–1962.
41. Timkova, V.; Tatarkova, Z.; Lehotsky, J.; Racay, P.; Dobrota, D.; Kaplan, P. Effects of mild hyperhomocysteinemia on electron transport chain complexes, oxidative stress, and protein expression in rat cardiac mitochondria. Mol. Cell. Biochem. 2016, 411, 261–270.
42. Faraci, F.M.; Lentz, S.R. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 2004, 35, 345–347.
43. Boldyrev, A.A.; Bryushkova, E.; Mashkina, A.; Vladychenskaya, E. Why is homocysteine toxic for the nervous and immune systems? Curr. Aging Sci. 2013, 6, 29–36.
44. Lehotsky, J.; Petras, M.; Kovalska, M.; Tothova, B.; Drgova, A.; Kaplan, P. Mechanisms involved in the ischemic tolerance in brain: Effect of the homocysteine. Cell. Mol. Neurobiol. 2015, 35, 7–15.
45. Postea, O.; Krotz, F.; Henger, A.; Keller, C.; Weiss, N. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 508–513.
46. Mattson, M.P.; Shea, T.B. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 2003, 26, 137–146.
47. Poddar, R.; Paul, S. Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. J. Neurochem. 2013, 124, 558–570.
48. Kovalska, M.; Kovalska, L.; Tothova, B.; Mahmood, S.; Adamkov, M.; Lehotsky, J. Combination of hyperhomocysteinemia and ischemic tolerance in experimental model of global ischemia in rats. J. Physiol. Pharmacol. 2015, 66, 887–897.
49. Škovierová, H.; Mahmood, S.; Blahovcová, E.; Hatok, J.; Lehotský, J.; Murín, R. Effect of homocysteine on survival of human glial cells. Physiol. Res. 2015, 64, 747–754.
50. Verkhratsky, A.; Toescu, E.C. Neuronal-glial networks as substrate for CNS integration. J. Cell. Mol. Med. 2006, 10, 826–836.
51. Blahovcova, E.; Richterova, R.; Kolarovszki, B.; Dobrota, D.; Racay, P.; Hatok, J. Apoptosis-related gene expression in tumor tissue samples obtained from patients diagnosed with glioblastoma multiforme. Int. J. Mol. Med. 2015, 36, 1677–1684.
52. Huang, R.F.; Huang, S.M.; Lin, B.S.; Wei, J.S.; Liu, T.Z. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life Sci. 2001, 68, 2799–2811.
53. Kamath, A.F.; Chauhan, A.K.; Kisucka, J.; Dole, V.S.; Loscalzo, J.; Handy, D.E.; Wagner, D.D. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 2006, 107, 591–593.
54. Tyagi, N.; Gillespie, W.; Vacek, J.C.; Sen, U.; Tyagi, S.C.; Lominadze, D. Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway. J. Cell. Physiol. 2009, 220, 257–266.
55. Tyagi, N.; Moshal, K.S.; Tyagi, S.C.; Lominadze, D. γ-Aminbuturic acid A receptor mitigates homocysteine-induced endothelial cell permeability. Endothelium 2007, 14, 315–323.
56. Betzen, C.; White, R.; Zehendner, C.M.; Pietrowski, E.; Bender, B.; Luhmann, H.J.; Kuhlmann, C.R. Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium. Free Radic. Biol. Med. 2009, 47, 1212–1220.
57. Kamat, P.K.; Vacek, J.C.; Kalani, A.; Tyagi, N. Homocysteine induced cerebrovascular dysfunction: A link to Alzheimer’s disease etiology. Open Neurol. J. 2015, 9, 9–14.
58. Klein, T.; Bischoff, R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids 2011, 41, 271–290.
59. Carson, N.A.; Neil, D.W. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch. Dis. Child. 1962, 37, 505–513.
60. McCully, K.S. Vascular pathology of homocysteine: Implications for pathogenesis of arteriosclerosis. Am. J. Pathol. 1969, 56, 111–128.
61. Givvimani, S.; Munjal, C.; Narayanan, N.; Aqil, F.; Tyagi, G.; Metreveli, N.; Tyagi, S.C. Hyperhomocysteinemia decreases intestinal motility leading to constipation. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G281–G290.
62. Iacobazzi, V.; Infantino, V.; Castegna, A.; Andria, G. Hyperhomocysteinemia: Related genetic diseases and congenital defects, abnormal DNA methylation and newborn screening issues. Mol. Genet. Metab. 2014, 113, 27–33.
63. Perna, A.F.; Ingrosso, D. Atherosclerosis determinants in renal disease: How much is homocysteine involved? Nephrol. Dial. Transplant. 2015, 31, 860–863.
64. Schalinske, K.L.; Smazal, A.L. Homocysteine imbalance: A pathological metabolic marker. Adv. Nutr. 2012, 3, 755–762.
65. Clarke, R.; Daly, L.; Robinson, K.; Naughten, E.; Cahalane, S.; Fowler, B.; Graham, I. Hyperhomocysteinemia: An independent risk factor for vascular disease. N. Engl. J. Med. 1991, 324, 1149–1155.
66. Williams, K.T.; Schalinske, K.L. Homocysteine metabolism and its relation to health and disease. Biofactors 2010, 36, 19–24.
67. Woodward, M.; Rumley, A.; Rumley, A.; Rumley, C.; Lewington, S.; Morrison, C.E.; Lowe, G.D. The association between homocysteine and myocardial infarction is independent of age, sex, blood pressure, cholesterol, smoking and markers of inflammation: The Glasgow Myocardial Infarction Study. Blood Coagul. Fibrinolysis 2006, 17, 1–5.
68. Refsum, H.; Ueland, P.M.; Nygård, O.; Vollset, S.E. Homocysteine and cardiovascular disease. Annu. Rev. Med. 1998, 49, 31–62.
69. De Chiara, B.; Sedda, V.; Parolini, M.; Campolo, J.; De Maria, R.; Caruso, R.; Pizzi, G.; Disoteo, O.; Dellanoce, C.; Corno, A.R. et al. Plasma total cysteine and cardiovascular risk burden: Action and interaction. Sci. World J. 2012, 2012, 303654.
70. Clarke, R.; Halsey, J.; Lewington, S.; Lonn, E.; Armitage, J.; Manson, J.E.; Bønaa, K.H.; Spence, J.D.; Nygård, O.; Jamison, R.; et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37,485 individuals. Arch. Intern. Med. 2010, 170, 1622–1631.
71. He, L.; Zeng, H.; Li, F.; Feng, J.; Liu, S.; Liu, J.; Yu, J.; Mao, J.; Hong, T.; Chen, A.F.; et al. Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia. Am. J. Physiol. Endocrinol. Metab. 2010, 299, E1061–E1065.
72. Antoniades, C.; Shirodaria, C.; Leeson, P.; Baarholm, O.A.; Van-Assche, T.; Cunnington, C.; Pillai, R.; Ratnatunga, C.; Tousoulis, D.; Stefanadis, C. MTHFR 677C > T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis. Circulation 2009, 119, 2507–2515.
73. Kim, B.J.; Seo, M.; Huh, J.K.; Kwon, C.H.; Kim, J.T.; Sung, K.C.; Kim, B.S.; Kang, J.H. Associations of plasma homocysteine levels with arterial stiffness in prehypertensive individuals. Clin. Exp. Hypertens. 2011, 33, 411–417.
74. Zhang, H.; Liu, Z.; Ma, S.; Zhang, H.; Kong, F.; He, Y.; Yang, X.; Wang, Y.; Xu, H.; Yang, A. Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis. Mol. Med. Rep. 2016, 14, 289–300.
75. −/− mice. FEBS Lett. 2015, 589, 3998–4009.
76. Gu, P.; DeFina, L.F.; Leonard, D.; John, S.; Weiner, M.F.; Brown, E.S. Relationship between serum homocysteine levels and depressive symptoms: The Cooper Center Longitudinal Study. J. Clin. Psychiatry 2012, 73, 691–695.
77. Gariballa, S. Testing homocysteine-induced neurotransmitter deficiency, and depression of mood hypothesis in clinical practice. Age Ageing 2011, 40, 702–705.
78. Pacheco-Quinto, J.; Rodriguez de Turco, E.B.; DeRosa, S.; Howard, A.; Cruz-Sanchez, F.; Sambamurti, K.; Refolo, L.; Petanceska, S.; Pappolla, M.A. Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid β peptide levels. Neurobiol. Dis. 2006, 22, 651–656.
79. Vafai, S.B.; Stock, J.B. Protein phosphatase 2A methylation: A link between elevated plasma homocysteine and Alzheimer’s disease. FEBS Lett. 2002, 518, 1–4.
80. Rhodehouse, B.C.; Mayo, J.N.; Beard, R.S., Jr.; Chen, C.H.; Bearden, S.E. Opening of the blood-brain barrier before cerebral pathology in mild hyperhomocysteinemia. PLoS ONE 2013, 8, e63951.
81. Oulhaj, A.; Refsum, H.; Beaumont, H.; Williams, J.; King, E.; Jacoby, R.; Smith, A.D. Homocysteine as a predictor of cognitive decline in Alzheimer’s disease. Int. J. Geriatr. Psychiatry 2010, 25, 82–90.
82. Chen, C.S.; Chou, M.C.; Yeh, Y.C.; Yang, Y.H.; Lai, C.L.; Yen, C.F.; Liu, C.K.; Liao, Y.C. Plasma homocysteine levels and major depressive disorders in Alzheimer disease. Am. J. Geriatr. Psychiatry 2010, 18, 1045–1048.
83. Chung, Y.C.; Kruyer, A.; Yao, Y.; Feierman, E.; Richards, A.; Strickland, S.; Norris, E.H. Hyperhomocysteinemia exacerbates Alzheimer’s disease pathology by way of the β-amyloid fibrinogen interaction. J. Thromb. Haemost. 2016, 14, 1442–1452.
84. Guo, T.; Chen, H.; Liu, B.; Ji, W.; Yang, C. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genet. Test. Mol. Biomark. 2012, 16, 968–973.
85. Park, J.W.; Ro, M.J.; Pyun, J.A.; Kwack, K.B.; Nam, M.; Bang, H.J.; Yang, J.W.; Choi, K.S.; Kim, S.K.; Chung, J.H. MTHFR 1298A > C is a risk factor for autism spectrum disorder in the Korean population. Psychiatry Res. 2014, 215, 258–259.
86. Rai, V. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: Evidence of genetic susceptibility. Metab. Brain Dis. 2016, 31, 727–735.
87. Matsushita, K.; Coresh, J.; Sang, Y.; Chalmers, J.; Fox, C.; Guallar, E.; Jafar, T.; Jassal, S.K.; Landman, G.W.; Muntner, P.; et al. CKD Prognosis Consortium: Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: A collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015, 3, 514–525.
88. Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.; Das, S.R.; de Ferranti, S.; Després, J.P.; Fullerton, H.J. et al. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation 2016, 133, e38–e360.
89. Kumar, T.; Sharma, G.S.; Singh, L.R. Homocystinuria: Therapeutic approach. Clin. Chim. Acta 2016, 458, 55–62.
90. Huo, Y.; Li, J.; Qin, X.; Huang, Y.; Wang, X.; Gottesman, R.F.; Tang, G.; Wang, B.; Chen, D.; He, M.; et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: The CSPPT randomized clinical trial. JAMA 2015, 313, 1325–1335.
91. Smith, D.E.; Hornstra, J.M.; Kok, R.M.; Blom, H.J.; Smulders, Y.M. Folic acid supplementation does not reduce intracellular homocysteine, and may disturb intracellular one-carbon metabolism. Clin. Chem. Lab. Med. 2013, 51, 1643–1650.
92. Perna, A.F.; Lanza, D.; Sepe, I.; Conzo, G.; Altucci, L.; Ingrosso, D. Altered folate receptor 2 expression in uraemic patients on haemodialysis: Implications for folate resistance. Nephrol. Dial. Transplant. 2013, 28, 1214–1224.
93. Kim, D.J.; Koh, J.M.; Lee, O.; Kim, N.J.; Lee, Y.S.; Kim, Y.S.; Park, J.Y.; Lee, K.U.; Kim, G.S. Homocysteine enhances apoptosis in human bone marrow stromal cells. Bone 2006, 39, 582–590.
94. Herrmann, M.; Tami, A.; Wildemann, B.; Wolny, M.; Wagner, A.; Schorr, H.; Taban-Shomal, O.; Umanskaya, N.; Ross, S.; Garcia, P.; et al. Hyperhomocysteinemia induces a tissue specific accumulation of homocysteine in bone by collagen binding and adversely affects bone. Bone 2009, 44, 467–475.
95. Thaler, R.; Spitzer, S.; Rumpler, M.; Fratzl-Zelman, N.; Klaushofer, K.; Paschalis, E.P.; Varga, F. Differential effects of homocysteine and β aminopropionitrile on preosteoblastic MC3T3-E1 cells. Bone 2010, 46, 703–709.
96. Cao, H.X.; Gao, C.M.; Takezaki, T.; Wu, J.Z.; Ding, J.H.; Liu, Y.T.; Li, S.P.; Su, P.; Cao, J.; Hamajima, N.; et al. Genetic polymorphisms of methylenetetrahydrofolate reductase and susceptibility to colorectal cancer. Asian Pac. J. Cancer Prev. 2008, 9, 203–208.
97. Munjal, C.; Givvimani, S.; Qipshidze, N.; Tyagi, N.; Falcone, J.C.; Tyagi, S.C. Mesenteric vascular remodeling in hyperhomocysteinemia. Mol. Cell. Biochem. 2011, 348, 99–108.
98. Hierholzer, C.; Kalff, J.C.; Billiar, T.R.; Bauer, A.J.; Tweardy, D.J.; Harbrecht, B.G. Induced nitric oxide promotes intestinal inflammation following hemorrhagic shock. Am. J. Physiol. Gastrointest. Liver Physiol. 2004, 286, G225–G233.
99. Garg, P.; Vijay-Kumar, M.; Wang, L.; Gewirtz, A.T.; Merlin, D.; Sitaraman, S.V. Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2009, 296, G175–G184.
100. Almadori, G.; Bussu, F.; Galli, J.; Cadoni, G.; Zappacosta, B.; Persichilli, S.; Minucci, A.; Giardina, B.; Maurizi, M. Serum levels of folate, homocysteine, and vitamin B12 in head and neck squamous cell carcinoma and in laryngeal leukoplakia. Cancer 2005, 103, 284–292.
101. Kato, I.; Dnistrian, A.M.; Schwartz, M.; Toniolo, P.; Koenig, K.; Shore, R.E.; Akhmedkhanov, A.; Zeleniuch-Jacquotte, A.; Riboli, E. Serum folate, homocysteine and colorectal cancer risk in women: A nested case-control study. Br. J. Cancer 1999, 79, 1917–1922.
102. Sun, C.F.; Haven, T.R.; Wu, T.L.; Tsao, K.C.; Wu, J.T. Serum total homocysteine increases with the rapid proliferation rate of tumor cells and decline upon cell death: A potential new tumor marker. Clin. Chim. Acta 2002, 321, 55–62.
103. Naushad, S.M.; Reddy, C.A.; Kumaraswami, K.; Divyya, S.; Kotamraju, S.; Gottumukkala, S.R.; Digumarti, R.R.; Kutala, V.K. Impact of hyperhomocysteinemia on breast cancer initiation and progression: Epigenetic perspective. Cell Biochem. Biophys. 2014, 68, 397–406.
104. Fryer, A.A.; Emes, R.D.; Ismail, K.M.; Haworth, K.E.; Mein, C.; Carroll, W.D.; Farrell, W.E. Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans. Epigenetics 2011, 6, 86–94.
105. Jayanthi Bai, N.; Jayakrishnan, S. Homocysteine: A Biomarker in neurodegenetrative diseases. Int. J. Biol. Med. Res. 2015, 6, 5272–5274.
106. Fonseca, V.; Guba, S.C.; Fink, L.M. Hyperhomocysteinemia and the endocrine system: Implications for atherosclerosis and thrombosis. Endocr. Rev. 1999, 20, 738–759.
107. Refsum, H.; Wesenberg, F.; Ueland, P.M. Plasma homocysteine in children with acute lymphoblastic leukemia: Changes during a chemotherapeutic regimen including methotrexate. Cancer Res. 1991, 51, 828–835.
108. Ozkan, Y.; Yardim-Akaydin, S.; Firat, H.; Calişkan-Can, E.; Ardiç, S.; Simşek, B. Usefulness of homocysteine as a cancer marker: Total thiol compounds and folate levels in untreated lung cancer patients. Anticancer Res. 2007, 27, 1185–1189.
109. Iacobazzi, V.; Castegna, A.; Infantino, V.; Andria, G. Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Mol. Genet. Metab. 2013, 110, 25–34.
110. Zhang, C.; Feng, Y.; Qu, S.; Wei, X.; Zhu, H.; Luo, Q.; Liu, M.; Chen, G.; Xiao, X. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovasc. Res. 2011, 90, 538–545.
111. Perła-Kaján, J.; Jakubowski, H. Paraoxonase 1 and homocysteine metabolism. Amino Acids 2012, 43, 1405–1417.
112. Tyagi, N.; Qipshidze, N.; Munjal, C.; Vacek, J.C.; Metreveli, N.; Givvimani, S.; Tyagi, S.C. Tetrahydrocurcumin ameliorates homocysteinylated cytochrome-c mediated autophagy in hyperhomocysteinemia mice after cerebral ischemia. J. Mol. Neurosci. 2012, 47, 128–138.