Systematic analysis of molecular mechanisms of action of essential macro- and micronutrients on the neurotransmitter and vasodilator molecule nitric oxide (NO)
https://doi.org/10.17749/2077-8333/epi.par.con.2024.208
Abstract
Maintaining adequate levels of nitric oxide (NO) in the blood and other body tissues is necessary for the regulation of vascular tone, blood pressure, maintenance of oxygen metabolism and endothelial function. NO is also involved in regulating the balance of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmission. Nutritional factors profoundly affect NO metabolism. Systematic computer analysis of 26,103 publications by methods of topological approach to recognition allowed to identify the most crucial fields of clinical research assessing relationships between NO metabolism and nutrients: arginine-derived NO synthase-driven NO production, nitrate-containing products, folates and vitamin B12 in NO homeostasis (including the effects of modifications of the vitamin B12 molecule), other B vitamins (B1, B2, B7), antioxidant vitamins (C and E), hormone-like vitamins D3 and A, electrolytes magnesium and calcium, participation of the microbiome in NO production.
Keywords
Еndotheliopathy,
multiple organ pathology,
nitric oxide homeostasis,
nutraceuticals,
vitamin B12 derivatives,
nutrition
Supporting agencies: The work was supported by a grant from the Russian Science Foundation No. 20-12-00175-p on the basis of the Ivanovo State University of Chemical Technology
About the Authors
O. A. Gromova
Federal Research Center “Computer Science and Control”, Russian Academy of Sciences
Russian Federation
Russian Federation
Olga A. Gromova - Dr. Sci. Med., Prof.
44 corp. 2 Vavilov Str., Moscow, 119333
WoS ResearcherID J-4946-2017, Scopus Author ID 7003589812
I. Yu. Torshin
Federal Research Center “Computer Science and Control”, Russian Academy of Sciences
Russian Federation
Russian Federation
Ivan Yu. Torshin - PhD.
44 corp. 2 Vavilov Str., Moscow, 119333
WoS ResearcherID C-7683-2018, Scopus Author ID 7003300274
References
1. Cyr A.R., Huckaby L.V., Shiva S.S., Zuckerbraun B.S. Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020; 36 (2): 307–21. https://doi.org/10.1016/j.ccc.2019.12.009.
2. Bahadoran Z., Mirmiran P., Ghasemi A. Adipose organ dysfunction and type 2 diabetes: role of nitric oxide. Biochem Pharmacol. 2024; 221: 116043. https://doi.org/10.1016/j.bcp.2024.116043.
3. Ferraro G., Sardo P. Nitric oxide and brain hyperexcitability. In Vivo. 2004; 18 (3): 357–66.
4. Bonilla Ocampo D.A., Paipilla A.F., Marín E., et al. Dietary nitrate from beetroot juice for hypertension: a systematic review. Biomolecules. 2018; 8 (4): 134. https://doi.org/10.3390/biom8040134.
5. Gumanova N.G. Nitric oxide and its circulating NOx metabolites, their role in human body functioning and cardiovascular death risk prediction (part I). Russian Journal of Preventive Medicine. 2021; 24 (9): 102–9 (in Russ.). https://doi.org/10.17116/profmed202124091102.
6. Liu W., Hu B., Dehghan M., et al. Fruit, vegetable, and legume intake and the risk of all-cause, cardiovascular, and cancer mortality: a prospective study. Clin Nutr. 2021; 40 (6): 4316–23. https://doi.org/10.1016/j.clnu.2021.01.016.
7. Torshin I.Y. On solvability, regularity, and locality of the problem of genome annotation. Pattern Recognit Image Anal. 2010; 20: 386395. https://doi.org/10.1134/S1054661810030156.
8. Rudakov K.V., Torshin I.Yu. Questions of solvability of the problem of protein secondary structure recognition. Informatics and Applications. 2010; 4 (2): 25–35 (in Russ.).
9. Torshin I.Yu. On optimization problems arising fromthe application of topological data analysis to the search for forecasting algorithms with fixed correctors. Informatics and Applications. 2023; 17 (2): 2–10 (in Russ.). https://doi.org/10.14357/19922264230201.
10. Torshin I.Yu. On the formation of sets of precedents basedon tables of heterogeneous feature descriptions by methods of topological theory of data analysis. Informatics and Applications. 2023; 17 (3): 2–7 (in Russ.). https://doi.org/10.14357/19922264230301.
11. Torshin I.Yu., Gromova O.A., Stakhovskaya L.V., et al. Analysis of 19.9 million publications from the PubMed/MEDLINE database using artificial intelligence methods: approaches to the generalizations of accumulated data and the phenomenon of “fake news. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2020; 13 (2): 146–63 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.021.
12. Abuzayan I., Turner S.W. Changes in exhaled nitric oxide after ingestion of L-arginine in children: a pilot study. Pediatr Pulmonol. 2010; 45 (3): 236–40. https://doi.org/10.1002/ppul.21110.
13. Mariotti F. Arginine supplementation and cardiometabolic risk. Curr Opin Clin Nutr Metab Care. 2020; 23 (1): 29–34. https://doi.org/10.1097/MCO.0000000000000612.
14. Zinellu A., Mangoni A.A. Arginine, transsulfuration, and folic acid pathway metabolomics in chronic obstructive pulmonary disease: a systematic review and meta-analysis. Cells. 2023; 12 (17): 2180. https://doi.org/10.3390/cells12172180.
15. Durante W., Johnson F.K., Johnson R.A. Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol. 2007; 34 (9): 906–11. https://doi.org/10.1111/j.1440-1681.2007.04638.x.
16. Tekwe C.D., Luan Y., Meininger C.J., et al. Dietary supplementation with L-leucine reduces nitric oxide synthesis by endothelial cells of rats. Exp Biol Med. 2023; 248 (18): 1537–49. https://doi.org/10.1177/15353702231199078.
17. Ivy J.L. Inorganic nitrate supplementation for cardiovascular health. Methodist Debakey Cardiovasc J. 2019; 15 (3): 200–6. https://doi.org/10.14797/mdcj-15-3-200.
18. Jones A.M., Vanhatalo A., Seals D.R., et al. Dietary nitrate and nitric oxide metabolism: mouth, circulation, skeletal muscle, and exercise performance. Med Sci Sports Exerc. 2021; 53 (2): 280–94. https://doi.org/10.1249/MSS.0000000000002470.
19. Raubenheimer K., Hickey D., Leveritt M., et al. Acute effects of nitrate-rich beetroot juice on blood pressure, hemostasis and vascular inflammation markers in healthy older adults: a randomized, placebo-controlled crossover study. Nutrients. 2017; 9 (11): 1270. https://doi.org/10.3390/nu9111270.
20. Zamani H., de Joode M.E.J.R., Hossein I.J., et al. The benefits and risks of beetroot juice consumption: a systematic review. Crit Rev Food Sci Nutr. 2021; 61 (5): 788–804. https://doi.org/10.1080/10408398.2020.1746629.
21. Bahrami L.S., Arabi S.M., Feizy Z., Rezvani R. The effect of beetroot inorganic nitrate supplementation on cardiovascular risk factors: a systematic review and meta-regression of randomized controlled trials. Nitric Oxide. 2021; 115: 8–22. https://doi.org/10.1016/j.niox.2021.06.002.
22. Gori T., Burstein J.M., Ahmed S., et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation. 2001; 104 (10): 1119–23. https://doi.org/10.1161/hc3501.095358.
23. Kolb A.F., Petrie L. Folate deficiency enhances the inflammatory response of macrophages. Mol Immunol. 2013; 54 (2): 164–72. https://doi.org/10.1016/j.molimm.2012.11.012.
24. Haloul M., Vinjamuri S.J., Naquiallah D., et al. Hyperhomocysteinemia and low folate and vitamin B12 are associated with vascular dysfunction and impaired nitric oxide sensitivity in morbidly obese patients. Nutrients. 2020; 12 (7): 2014. https://doi.org/10.3390/nu12072014.
25. Ozerol E., Ozerol I., Gökdeniz R., et al. Effect of smoking on serum concentrations of total homocysteine, folate, vitamin B12, and nitric oxide in pregnancy: a preliminary study. Fetal Diagn Ther. 2004; 19 (2): 145–8. https://doi.org/10.1159/000075139.
26. Stanger O., Weger M. Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium. Clin Chem Lab Med. 2003; 41 (11): 1444–54. https://doi.org/10.1515/CCLM.2003.222.
27. Sasaki K., Duan J., Murohara T., et al. Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation. J Am Coll Cardiol. 2003; 42 (2): 364–72. https://doi.org/10.1016/s0735-1097(03)00629-6.
28. Ahmed M.A., Kamal H.M., Taha A.M., Abd-Allateef S.F. Folic acid protects against experimental prenatal nicotine-induced cardiac injury by decreasing inflammatory changes, serum TNF and COX-2 expression. Pathophysiology. 2018; 25 (2): 151–6. https://doi.org/10.1016/j.pathophys.2018.04.001.
29. van Oostrom O., de Kleijn D.P., Fledderus J.O., et al. Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study. Cardiovasc Diabetol. 2009; 8: 47. https://doi.org/10.1186/1475-2840-8-47.
30. Xia X.S., Li X., Wang L., et al. Supplementation of folic acid and vitamin B12 reduces plasma levels of asymmetric dimethylarginine in patients with acute ischemic stroke. J Clin Neurosci. 2014; 21 (9): 1586–90. https://doi.org/10.1016/j.jocn.2013.11.043.
31. Holven K.B., Holm T., Aukrust P., et al. Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects. Am J Med. 2001; 110 (7): 536–42. https://doi.org/10.1016/s0002-9343(01)00696-9.
32. Schneider M.P., Schlaich M.P., Harazny J.M., et al. Folic acid treatment normalizes NOS-dependence of vascular tone in the metabolic syndrome. Obesity. 2011; 19 (5): 960–7. https://doi.org/10.1038/oby.2010.210.
33. Doshi S., McDowell I., Moat S., et al. Folate improves endothelial function in patients with coronary heart disease. Clin Chem Lab Med. 2003; 41 (11): 1505–12. https://doi.org/10.1515/CCLM.2003.231.
34. Sharma V.S., Pilz R.B., Boss G.R., Magde D. Reactions of nitric oxide with vitamin B12 and its precursor, cobinamide. Biochemistry. 2003; 42 (29): 8900–8. https://doi.org/10.1021/bi034469t.
35. Manzanares W., Hardy G. Vitamin B12: the forgotten micronutrient for critical care. Curr Opin Clin Nutr Metab Care. 2010; 13 (6): 662–8. https://doi.org/10.1097/MCO.0b013e32833dfaec.
36. Mukherjee S., Das D., Mukherjee M., et al. Synergistic effect of folic acid and vitamin B12 in ameliorating arsenic-induced oxidative damage in pancreatic tissue of rat. J Nutr Biochem. 2006; 17 (5): 319–27. https://doi.org/10.1016/j.jnutbio.2005.08.003.
37. Torshin I.Yu., Gromova O.A., Maiorova L.A. Chemoreactomic analysis of the antioxidant properties of vitamin B12 derivatives. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2024; 17 (3): 358–67 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2024.239.
38. Torshin I.Yu., Gromova O.A., Dereven’kov I.A., Maiorova L.A. Chemoproteomic analysis of the pharmacological properties of vitamin В12 derivatives. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2024; 17 (3): 345–57 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2024.214.
39. Gromova O.A., Frolova D.E., Torshin I.Yu., et al. Antitumor effects of vitamin B12 in vitro, in vivo, in silico. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. https://doi.org/10.17749/2070-4909/farmakoekonomika.2024.231.
40. Akaike A., Tamura Y., Sato Y., Yokota T. Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharmacol. 1993; 241 (1): 1–6. https://doi.org/10.1016/0014-2999(93)90925-8.
41. Wacker J., Frühauf J., Schulz M., et al. Riboflavin deficiency and preeclampsia. Obstet Gynecol. 2000; 96 (1): 38–44. https://doi.org/10.1016/s0029-7844(00)00847-4.
42. Alcázar-Leyva S., Alvarado-Vásquez N. Could thiamine pyrophosphate be a regulator of the nitric oxide synthesis in the endothelial cell of diabetic patients? Med Hypotheses. 2011; 76 (5): 629–31. https://doi.org/10.1016/j.mehy.2011.01.015.
43. McCarty M.F., DiNicolantonio J.J. Neuroprotective potential of high-dose biotin. Med Hypotheses. 2017; 109: 145–9. https://doi.org/10.1016/j.mehy.2017.10.012.
44. Belardinelli R., Tiano L., Littarru G.P. Oxidative stress, endothelial function and coenzyme Q10. Biofactors. 2008; 32 (1-4): 129–33. https://doi.org/10.1002/biof.5520320115.
45. McCarty M.F. Coping with endothelial superoxide: potential complementarity of arginine and high-dose folate. Med Hypotheses. 2004; 63 (4): 709–18. https://doi.org/10.1016/j.mehy.2002.11.006.
46. Kuzkaya N., Weissmann N., Harrison D.G., Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003; 278 (25): 22546–54. https://doi.org/10.1074/jbc.M302227200.
47. Muller-Delp J.M. Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability. Cardiovasc Res. 2009; 84 (2): 178–9. https://doi.org/10.1093/cvr/cvp307.
48. Frei B. On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction. Proc Soc Exp Biol Med. 1999; 222 (3): 196–204. https://doi.org/10.1046/j.1525-1373.1999.d01-136.x.
49. Mortensen A., Lykkesfeldt J. Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin-dependent manner? In vitro, in vivo and clinical studies. Nitric Oxide. 2014; 36: 51–7. https://doi.org/10.1016/j.niox.2013.12.001.
50. Pullin C.H., Bonham J.R., McDowell I.F., et al. Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria. J Inherit Metab Dis. 2002; 25 (2): 107–18. https://doi.org/10.1023/a:1015672625913.
51. Saremi A., Arora R. Vitamin E and cardiovascular disease. Am J Ther. 2010; 17 (3): e56–65. https://doi.org/10.1097/MJT.0b013e31819cdc9a.
52. Boshtam M., Rafiei M., Sadeghi K., Sarraf-Zadegan N. Vitamin E can reduce blood pressure in mild hypertensives. Int J Vitam Nutr Res. 2002; 72 (5): 309–14. https://doi.org/10.1024/0300-9831.72.5.309.
53. Conde C.M., Cyrino F.Z., Bottino D.A., et al. Longchain n-3 polyunsaturated fatty acids and microvascular reactivity: observation in the hamster cheek pouch. Microvasc Res. 2007; 73 (3): 237–47. https://doi.org/10.1016/j.mvr.2006.11.002.
54. Martin S., Giannone G., Andriantsitohaina R., Martinez M.C. Delphinidin, an active compound of red wine, inhibits endothelial cell apoptosis via nitric oxide pathway and regulation of calcium homeostasis. Br J Pharmacol. 2003; 139 (6): 1095–102. https://doi.org/10.1038/sj.bjp.0705347.
55. de la Guía-Galipienso F., Martínez-Ferran M., Vallecillo N., et al. Vitamin D and cardiovascular health. Clin Nutr. 2021; 40 (5): 2946–57. https://doi.org/10.1016/j.clnu.2020.12.025.
56. Kim D.H., Meza C.A., Clarke H., et al. Vitamin D and endothelial function. Nutrients. 2020; 12 (2): 575. https://doi.org/.3390/nu12020575.
57. Wiedermann U., Chen X.J., Enerbäck L., et al. Vitamin A deficiency increases inflammatory responses. Scand J Immunol. 1996; 44 (6): 578–84. https://doi.org/10.1046/j.1365-3083.1996.d01-351.x.
58. Gadhia M.M., Cutter G.R., Abman S.H., Kinsella J.P. Effects of early inhaled nitric oxide therapy and vitamin A supplementation on the risk for bronchopulmonary dysplasia in premature newborns with respiratory failure. J Pediatr. 2014; 164 (4): 744–8. https://doi.org/10.1016/j.jpeds.2013.11.040.
59. Banjanin N., Belojevic G. Relationship of dietary magnesium intake and serum magnesium with hypertension: a review. Magnes Res. 2021; 34 (4): 166–71. https://doi.org/10.1684/mrh.2021.0492.
60. Gromova O.A., Torshin I.Yu. Magnesium and “diseases of civilization.” Moscow: GEOTAR-Media; 2018: 800 pp. (in Russ.).
61. Ye M., Li Q., Xiao L., Zheng Z. Serum magnesium and fractional exhaled nitric oxide in relation to the severity in asthma-chronic obstructive pulmonary disease overlap. Biol Trace Elem Res. 2021; 199 (5): 1771–7. https://doi.org/10.1007/s12011-020-02314-5.
62. López-Jaramillo P. Calcium, nitric oxide, and preeclampsia. Semin Perinatol. 2000; 24 (1): 33–6. https://doi.org/10.1016/s0146-0005(00)80052-x.
63. Vanhatalo A., Blackwell J.R., L'Heureux J.E., et al. Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans. Free Radic Biol Med. 2018; 124: 21–30. https://doi.org/10.1016/j.freeradbiomed.2018.05.078.
64. Zhou L., Ding C., Wu J., et al. Probiotics and synbiotics show clinical efficacy in treating gestational diabetes mellitus: a meta-analysis. Prim Care Diabetes. 2021; 15 (6): 937–47. https://doi.org/10.1016/j.pcd.2021.08.005.
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Gromova O.A., Torshin I.Yu. Systematic analysis of molecular mechanisms of action of essential macro- and micronutrients on the neurotransmitter and vasodilator molecule nitric oxide (NO). Epilepsy and paroxysmal conditions. 2024;16(4):385-401. (In Russ.) https://doi.org/10.17749/2077-8333/epi.par.con.2024.208
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