Potential role of lactoferrin in early diagnostics and treatment of Parkinson disease

Cover Page

Cite item

Full Text

Abstract

Incidence of Parkinson disease progressively grows with increasing age and percentage of elderly people in the global population. Clear understanding of the causes of dopaminergic neurons’ death in Substantia nigra and Parkinson disease pathogenesis are currently absent, not speaking of an efficient therapy. However, an early diagnosis of dopaminergic neurons’ degeneration and prescription of dopamine replacement therapy significantly slow down the rate of symptoms’ progression. An increased concentration of iron in Substantia nigra of Parkinson disease patients has been shown in several studies. In this review we summarized the data concerning a potential significance of lactoferrin, the iron-binding protein of exocrine secretions and neutrophils, for early diagnosis and treatment of Parkinson disease. Salivary and lacrimal lactoferrin levels in Parkinson disease patients were higher than those observed in the control group. Plasma levels of lactoferrin inversely correlated with Parkinson disease severity even after treatment with Levodopa, a dopamine agonist, and with monoaminooxidase inhibitors. Lactoferrin levels in cerebrospinal fluid of Parkinson disease patients negatively correlated with the tumor necrosis factor-alpha concentration. Lactoferrin treatment of rodents with several experimental models of Parkinson disease (induced by rotenone, MPTP) protected neurons and mitigated the symptoms of neurodegeneration. Some contradictions about the positive effects of lactoferrin as a remedy in Parkinson disease animal models and possible participation of lactoferrin in accumulation of iron in neurons are discussed.

About the authors

Alexey V. Sokolov

Institute of Experimental Medicine; Saint Petersburg State University; The Preclinical Translational Research Centre of the Almazov Centre

Author for correspondence.
Email: biochemsokolov@gmail.com
ORCID iD: 0000-0001-9033-0537
SPIN-code: 7427-7395

Doctor of Biological Sciences, Head of the Laboratory of Biochemical Genetics of the Department of Molecular Genetics; Professor of Chair of Fundamental Problems of Medicine and Medical Technology; Senior researcher of the Biochemical Research Department of the Preclinical Translational Research Centre

Russian Federation, Saint Petersburg

Irina V. Miliukhina

Institute of Experimental Medicine

Email: milyukhinaiv@yandex.ru
ORCID iD: 0000-0002-6433-542X
SPIN-code: 1767-2266

PhD, MD, Head of the Center of the Neurodegenerative Disorders

Russian Federation, Saint Petersburg

Yury P. Belsky

The Preclinical Translational Research Centre of the Almazov Centre

Email: belsky59@mail.ru

Doctor of Medical Sciences, Head of the Biochemical Research Department of the Preclinical Translational Research Centre

Russian Federation, Saint Petersburg

Nataly V. Belska

the Institute of Experimental Medicine of the Almazov Centre, Saint Petersburg

Email: natalybelska@yandex.ru

Doctor of Medical Sciences, Leading Researcher of the Toxicology Research Department of the Preclinical Translational Research Centre

Russian Federation

Vadim B. Vasilyev

Institute of Experimental Medicine; Saint Petersburg State University

Email: vadim@biokemis.ru
ORCID iD: 0000-0002-9707-262X
SPIN-code: 6699-6350

Doctor of Medical Sciences, Head of the Department of Molecular Genetics

Russian Federation, Saint Petersburg

References

  1. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5(6):525-535. https://doi.org/10.1016/S1474-4422(06)70471-9.
  2. Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinson’s disease. Revue Neurologique. 2016;172(1):14-26. https://doi.org/10.1016/j.neurol.2015.09.012.
  3. Fahn S. Description of Parkinson’s disease as a clinical syndrome. Ann NY Acad Sci. 2006;991(1):1-14. https://doi.org/ 10.1111/j.1749-6632.2003.tb07458.x.
  4. Larsen JP, Beiske AG, Bekkelund SI, et al. Motor symptoms in Parkinson disease. Tidsskr Nor Laegeforen. 2008;128(18):2068-2071.
  5. Jiang H, Song N, Jiao Q, et al. Iron Pathophysiology in Parkinson Diseases. Adv Exp Med Biol. 2019;1173:45-66. https://doi.org/10.1007/978-981-13-9589-5_4.
  6. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 1991;114(Pt 5):2283-2301. https://doi.org/10.1093/brain/114.5.2283.
  7. Morris CM, Edwardson JA. Iron histochemistry of the substantia nigra in Parkinson’s disease. Neurodegeneration. 1994;3(4):277-282.
  8. Sian-Hülsmann J, Mandel S, Youdim MB, Riederer P. The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem. 2011;118(6):939-957. https://doi.org/10.1111/j.1471-4159.2010.07132.x.
  9. Wypijewska A, Galazka-Friedman J, Bauminger ER, et al. Iron and reactive oxygen species activity in parkinsonian Substantia nigra. Parkinsonism Relat Disord. 2010;16(5):329-333. https://doi.org/10.1016/j.parkreldis.2010.02.007.
  10. Huddleston DE, Langley J, Sedlacik J, et al. In vivo detection of lateral-ventral tier nigral degeneration in Parkinson’s disease. Hum Brain Mapp. 2017;38(5):2627-2634. https://doi.org/10.1002/hbm.23547.
  11. Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol. 2006;59:559-562. https://doi.org/10.1002/ana.20789.
  12. Aminoff MJ. Treatment should not be initiated too soon in Parkinson’s disease. Ann Neurol. 2006;59:562-564. https://doi.org/10.1002/ana.20814.
  13. Hare DJ, Double KL. Iron and dopamine: a toxic couple. Brain. 2016;139(Pt4):1026-1035. https://doi.org/10.1093/brain/aww022.
  14. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis. 2013;3(4):461-491. https://doi.org/10.3233/JPD-130230.
  15. Olivieri S, Conti A, Iannaccone S, et al. Ceruloplasmin oxidation, a feature of Parkinson’s disease CSF, inhibits ferroxidase activity and promotes cellular iron retention. J Neurosci. 2011;31(50):18568-18577. https://doi.org/10.1523/JNEUROSCI.3768-11.2011.
  16. Wang J, Jiang H, Xie JX. Time dependent effects of 6-OHDA lesions on iron level and neuronal loss in rat nigrostriatal system. Neurochem Res. 2004;29(12):2239-2243. https://doi.org/10.1007/s11064-004-7031-5.
  17. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273-285. https://doi.org/10.1016/j.cell.2017.09.021.
  18. Castellani RJ, Siedlak SL, Perry G, Smith MA. Sequestration of iron by Lewy bodies in Parkinson’s disease. Acta Neuropathol. 2000;100(2):111-114. https://doi.org/10.1007/s004010050001.
  19. Adamczyk A, Solecka J, Strosznajder JB. Expression of alpha-synuclein in different brain parts of adult and aged rats. J Physiol Pharmacol. 2005;56 (1):29-37.
  20. Allen Reish HE, Standaert DG. Role of alpha-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis. 2015;5(1):1-19. https://doi.org/10.3233/JPD-140491.
  21. Binolfi A, Rasia RM, Bertoncini CW, et al. Interaction of α-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement. J Am Chem Soc. 2006;128(30):9893-9901. https://doi.org/10.1021/ja0618649.
  22. Bharathi SS, Indi, Rao KSJ. Copper- and iron-induced differential fibril formation in α-synuclein: TEM study. Neuroscience Letters. 2007;424(2):78-82. https://doi.org/ 10.1016/j.neulet.2007.06.052.
  23. Fujiwara H, Hasegawa M, Dohmae N, et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160-164. https://doi.org/10.1038/ncb748.
  24. Liu LL, Franz KJ. Phosphorylation-dependent metal binding by α-synuclein peptide fragments. J Biol Inorg Chem. 2007;12:234-247. https://doi.org/10.1007/s00775-006-0181-y.
  25. Santner A, Uversky VN. Metalloproteomics and metal toxicology of α-synuclein. Metallomics. 2010;2(6):378-392. https://doi.org/10.1039/b926659c.
  26. Friedlich AL, Tanzi RE, Rogers JT. The 5’-untranslated region of Parkinson’s disease α-synuclein messenger RNA contains a predicted iron responsive element. Mol Psychiatry. 2007;12(3):222-223. https://doi.org/10.1038/sj.mp.4001937.
  27. Li W., Jiang H, Song N, Xie J. Oxidative stress partially contributes to iron-induced α-synuclein aggregation in SK-N-SH cells. Neurotox Res. 2011;19(3):435-442. https://doi.org/10.1007/s12640-010-9187-x.
  28. Febbraro F, Giorgi M, Caldarola S, et al. α-Synuclein expression is modulated at the translational level by iron. NeuroReport. 2012;23(9):576-580. https://doi.org/10.1097/WNR.0b013e328354a1f0.
  29. Davies P, Moualla D, Brown DR. Alpha-synuclein is a cellular ferrireductase. PLoS One. 2011;6(1):e15814. https://doi.org/10.1371/journal.pone.0015814.
  30. Yu S, Zuo X, Li Y, et al. Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells. Neurosci Lett. 2004;367(1):34-39. https://doi.org/10.1016/j.neulet.2004.05.118.
  31. Logroscino G, Marder K, Graziano J, et al. Altered systemic iron metabolism in Parkinson’s disease. Neurology. 1997;49(3):714-717. https://doi.org/10.1212/wnl.49. 3.714.
  32. Abbott RA, Cox M, Markus H, Tomkins A. Diet, body size and micronutrient status in Parkinson’s disease. Eur J Clin Nutr. 1992;46(12):879-884.
  33. Xu W, Zhi Y, Yuan Y, et al. Correlations between abnormal iron metabolism and non-motor symptoms in Parkinson’s disease. J Neural Transm (Vienna). 2018;125(7):1027-1032. https://doi.org/10.1007/s00702-018-1889-x.
  34. Si QQ, Yuan YS, Zhi Y, et al. Plasma transferrin level correlates with the tremor-dominant phenotype of Parkinson’s disease. Neurosci Lett. 2018;684:42-46. https://doi.org/10.1016/j.neulet.2018.07.004.
  35. Faucheux BA, Nillesse N, Damier P, et al. Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. Proc Natl Acad Sci U S A. 1995;92(21):9603-9607. https://doi.org/10.1073/pnas.92.21.9603.
  36. Bonn D. Pumping iron in Parkinson’s disease. Lancet. 1996;347(9015):1614. https://doi.org/10.1016/s0140-6736 (96)91094-6.
  37. Aisen P, Leibman A. Lactoferrin and transferrin: a comparative study. Biochim Biophys Acta. 1972;257(2):314-323. https://doi.org/10.1016/0005-2795(72)90283-8.
  38. Leveugle B, Faucheux BA, Bouras C, et al. Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol. 1996;91(6):566-572. https://doi.org/10.1007/s004010050468.
  39. Mochizuki H, Imai H, Endo K, et al. Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Neuroscience Letters. 1994;168(1-2):251-253. https://doi.org/10.1016/0304-3940(94)90462-6.
  40. Fillebeen C, Dexter D, Mitchell V, et al. Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. Adv Exp Med Biol. 1998;443:293-300. https://doi.org/10.1007/978-1-4757-9068-9_36.
  41. Fillebeen C, Mitchell V, Dexter D, et al. Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. Brain Res Mol Brain Res. 1999;72(2):183-194. https://doi.org/10.1016/s0169-328x (99)00221-1.
  42. Grau AJ, Willig V, Fogel W, Werle E. Assessment of plasma lactoferrin in Parkinson’s disease. Mov Disord. 2001;16(1):131-134. https://doi.org/10.1002/1531-8257 (200101)16:1<131::AID-MDS1008>3.0.CO;2-O
  43. Zakharova ET, Sokolov AV, Pavlichenko NN, et al. Erythropoietin and Nrf2: key factors in the neuroprotection provided by apo-lactoferrin. Biometals. 2018;31(3):425-443. https://doi.org/10.1007/s10534-018-0111-9.
  44. Mohamed WA, Schaalan MF. Antidiabetic efficacy of lactoferrin in type 2 diabetic pediatrics; controlling impact on PPAR-γ, SIRT-1, and TLR4 downstream signaling pathway. Diabetol Metab Syndr. 2018;10:89. https://doi.org/10.1186/s13098-018-0390-x.
  45. Fillebeen C, Descamps L, Dehouck MP, et al. Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem. 1999;274(11):7011-7017. https://doi.org/10.1074/jbc.274.11.7011.
  46. Harada E, Araki Y, Furumura E, et al. Characteristic transfer of colostrum-derived biologically active substances into cerebrospinal fluid via blood in natural suckling neonatal pigs. J Vet Med A Physiol Pathol Clin Med. 2002;49(7):358-364. https://doi.org/10.1046/j.1439-0442.2002.00457.x.
  47. Talukder MJ, Takeuchi T, Harada E. Receptor-mediated transport of lactoferrin into the cerebrospinal fluid via plasma in young calves. J Vet Med Sci. 2003;65(9):957-964. https://doi.org/10.1292/jvms.65.957.
  48. Ji B, Maeda J, Higuchi M, et al. Pharmacokinetics and brain uptake of lactoferrin in rats. Life Sci. 2006;78(8):851-855. https://doi.org/10.1016/j.lfs.2005.05.085.
  49. Huang R, Ke W, Liu Y, et al. Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model. J Neurol Sci. 2010;290(1-2):123-130. https://doi.org/10.1016/j.jns.2009.09.032.
  50. Hu K, Shi Y, Jiang W, et al. Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: preparation, characterization and efficacy in Parkinson’s disease. Int J Pharm. 2011;415(1-2):273-83. https://doi.org/10.1016/ j.ijpharm.2011.05.062.
  51. Bi C, Wang A, Chu Y, et al. Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson’s disease treatment. Int J Nanomedicine. 2016;11:6547-6559. https://doi.org/10.2147/IJN.S120939.
  52. Yan X, Xu L, Bi C, et al. Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects. Int J Nanomedicine. 2018;13:273-281. https://doi.org/10.2147/IJN.S151475.
  53. Tang S, Wang A, Yan X, et al. Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease. Drug Deliv. 2019;26(1):700-707. https://doi.org/10.1080/10717544.2019.1636420.
  54. Takeuchi T, Hayashida Ki, Inagaki H, et al. Opioid mediated suppressive effect of milk-derived lactoferrin on distress induced by maternal separation in rat pups. Brain Res. 2003;979(1-2):216-224. https://doi.org/10.1016/s0006-8993(03)02941-x.
  55. Kamemori N, Takeuchi T, Hayashida K, Harada E. Suppressive effects of milk-derived lactoferrin on psychological stress in adult rats. Brain Res. 2004;1029(1):34-40. https://doi.org/10.1016/j.brainres.2004.09.015.
  56. McManus B, Korpela R, O’Connor P, et al. Compared to casein, bovine lactoferrin reduces plasma leptin and corticosterone and affects hypothalamic gene expression without altering weight gain or fat mass in high fat diet fed C57/BL6J mice. Nutrition & Metabolism. 2015;12:53. https://doi.org/10.1186/s12986-015-0049-7.
  57. Aleshina GM, Yankelevich IA, Zakharova ET, et al. Stress-protective effect of human lactoferrin. Ross Fiziol Zh Im I M Sechenova. 2016;102(7):846-851.
  58. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811-7819. https://doi.org/10.1074/jbc.M008923200.
  59. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037-1044. https://doi.org/10.1172/JCI15686.
  60. Urrutia P, Aguirre P, Esparza A, et al. Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. J Neurochem. 2013;126(4):541-549. https://doi.org/10.1111/jnc.12244.
  61. Paesano R, Berlutti F, Pietropaoli M, et al. Lactoferrin efficacy versus ferrous sulfate in curing iron deficiency and iron deficiency anemia in pregnant women. Biometals. 2010;23(3):411-417. https://doi.org/10.1007/s10534-010-9335-z.
  62. Pulina MO, Sokolov AV, Zakharova ET, et al. Effect of lactoferrin on consequences of acute experimental hemorrhagic anemia in rats. Bull Exp Biol Med. 2010; 149:219-222. https://doi.org/10.1007/s10517-010-0911-6.
  63. Cutone A, Frioni A, Berlutti F, et al. Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages. Biometals. 2014;27(5):807-813. https://doi.org/10.1007/s10534-014-9742-7.
  64. De Domenico I, Ward DMcV, Bonaccorsi di Patti MC, et al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823-2831. https://doi.org/10.1038/sj.emboj.7601735.
  65. Zakharova ET, Kostevich VA, Sokolov AV, Vasilyev VB. Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha. Biometals. 2012;25(6):1247-1259. https://doi.org/10.1007/s10534-012-9586-y.
  66. Kostevich VA, Sokolov AV, Kozlov SO, et al. Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet. Biometals. 2016;29(4):691-704. https://doi.org/10.1007/s10534-016-9944-2.
  67. Xue YQ, Zhao LR, Guo WP, Duan WM. Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson’s disease. Neuroscience. 2007;146(3):1245-1258. https://doi.org/10.1016/j.neuroscience.2007.02.004.
  68. Rousseau E, Michel PP, Hirsch EC. The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis. Mol Pharmacol. 2013;84(6):888-898. https://doi.org/10.1124/mol.113.087965.
  69. Xu SF, Zhang YH, Wang S, et al. Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice. Redox Biol. 2019;21:101090. https://doi.org/10.1016/j.redox.2018.101090.
  70. Liu H, Wu H, Zhu N, et al. Lactoferrin protects against iron dysregulation, oxidative stress, and apoptosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson‘s disease in mice. J Neurochem. 2020;152(3):397-415. https://doi.org/10.1111/jnc.14857.
  71. Yu SY, Sun L, Liu Z, et al. Sleep disorders in Parkinson‘s disease: clinical features, iron metabolism and related mechanism. PLoS One. 2013;8(12):e82924. https://doi.org/10.1371/journal.pone.0082924.
  72. Carro E, Bartolomé F, Bermejo-Pareja F, et al. Early diagnosis of mild cognitive impairment and Alzheimer’s disease based on salivary lactoferrin. Alzheimers Dement (Amst). 2017;8:131-138. https://doi.org/10.1016/j.dadm.2017.04.002.
  73. Hamm-Alvarez SF, Janga SR, Edman MC, et al. Levels of oligomeric α-Synuclein in reflex tears distinguish Parkinson’s disease patients from healthy controls. Biomark Med. 2019;13(17): 1447-1457. https://doi.org/10.2217/bmm-2019-0315.
  74. Bougea A, Koros C, Stefanis L. Salivary alpha-synuclein as a biomarker for Parkinson’s disease: a systematic review. J Neural Transm (Vienna). 2019;126(11):1373-1382. https://doi.org/10.1007/s00702-019-02062-4.
  75. Bougea A, Stefanis L, Paraskevas GP, et al. Plasma alpha-synuclein levels in patients with Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci. 2019;40(5):929-938. https://doi.org/10.1007/s10072-019-03738-1.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Effects of lactoferrin treatment on the pathogenesis of Parkinson disease modeled in animals: DA — dopamine

Download (214KB)
Indexing metadata

Copyright (c) 2020 Sokolov A.V., Miliukhina I.V., Belsky Y.P., Belska N.V., Vasilyev V.B.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».