Modern aspects of regulatory, pathophysiological and toxic effects of cobalt ions during oral intake in the human body

View or download the full article: 

S.I. Dolomatov1, T.P. Sataeva1, W. Zukow2


1Medical Academy named after S.I. Georgievsky of Vernadsky Crimea Federal University, 5/7 Lenin Boulevard, Simferopol, 295006, Russian Federation jurisdiction
2Universitas Nicolai Copernici, 1 Lwowska Str., 87–100 Toruń, Poland


Cobalt is an essential microelement which is an indispensable part of several enzymes and co-enzymes. Cobalt ions may occur in the environment from both natural sources and due to human activities. This metal is very widespread in the natural environment and can be formed due to anthropogenic activity. Toxic effects produced by cobalt and its compounds depend on the physical and chemical properties of these complexes, including their electronic structure, ion parameters (charge-size relations) and kinetics. Cobalt has both beneficial and harmful effects on human health. Cobalt is beneficial for humans because it is a part of vitamin B12, which is essential to maintain human health. If humans and animals are exposed to levels of cobalt normally found in the environment, it is not harmful. When excessive cobalt amounts enter a human body, multiple and chronic harmful health effects can occur and the longer the cobalt ions are stored in the body, the more changes they cause in cells. Cobalt gets into a body via several ways: mainly with food, via the respiratory system, through the skin or as a component of various biomaterials. Despite this metal being abundant, much of our knowledge on cobalt toxicity is based mainly on studies performed on animals. Undoubtedly, inorganic forms of cobalt are toxic as they accumulate in various tissues and can evoke a chain of pathological cascade changes in cells. Although some cobalt effects might be beneficial for medicine. Therefore, the purpose of our review is to provide the current analysis about the most significant regulatory, pathophysiological and epigenetic effects of Co2+ in a human body.

cobalt, Co2+ salts, Co2+ kinetics, heavy metal, cobalt toxicology, pathophysiology, epigenetics
Dolomatov S.I., Sataeva T.P., Zukow W. Modern aspects of regulatory, pathophysiological and toxic effects of cobalt ions during oral intake in the human body. Health Risk Analysis, 2019, no. 3, pp. 161–174. DOI: 10.21668/health.risk/2019.3.19.eng
  1. Hokin B., Adams M., Ashton J., Louie H. Comparison of the dietary cobalt intake in three different Australian diets. Asia. Pac. J. Clin. Nutr., 2004, vol. 13, no. 3, pp. 289–291.
  2. Gál J., Hursthouse A., Tatner P., Stewart F., Welton R. Cobalt and secondary poisoning in the terrestrial food chain: Data review and research gaps to support risk assessment. Environment International, 2008, no. 34, pp. 821–838. DOI: 10.1016/j.envint.2007.10.006
  3. Scientific Opinion on the use of cobalt compounds as additives in animal nutrition. EFSA Panel on Additives and Prod-ucts or Substances used in Animal Feed (FEEDAP). EFSA Journal, 2009, vol. 7, no. 12: 1383, 45 p. DOI: 10.2903/j.efsa.2009.1383
  4. Tvermoes B.E., Paustenbach D.J., Kerger B.D., Finley B.L., Unice K.M. Review of cobalt toxicokinetics following oral dosing: Implications for health risk assessments and metal-on-metal hip implant patients. Crit. Rev. Toxicol., 2015, vol. 45, no. 5, pp. 367–387. DOI: 10.3109/10408444.2014.985818
  5. Tvermoes B.E., Unice K.M., Paustenbach D.J., Finley B.L., Otani J.M., Galbraith D.A. Effects and blood concentrations of cobalt after ingestion of 1 mg/d by human volunteers for 90 d. Am. J. Clin. Nutr., 2014, no. 99, pp. 632–646. DOI: 10.3945/ajcn.113.071449
  6. Unice K.M., Monnot A.D., Gaffney S.H., Tvermoes B.E., Thuett K.A., Paustenbach D.J., Finley B.L. Inorganic cobalt supplementation: Prediction of cobalt levels in whole blood and urine using a biokinetic model. Food and Chemical Toxicology, 2012, vol. 50, no. 7, pp. 2456–2461. DOI: 10.1016/j.fct.2012.04.009
  7. Wei B., Yu J., Wang J., Li H., Yang L., Kong C. Trace Metals in the Urine and Hair of a Population in an Endemic Ar-senism Area. Biol. Trace. Elem. Res., 2018, vol. 182, no. 2, pp. 209–216. DOI: 10.1007/s12011-017-1108-x
  8. Simonsen L.O., Harbak H., Bennekou P. Cobalt metabolism and toxicology – a brief update. Sci. Total. Environ., 2012, vol. 432, pp. 210–215. DOI: 10.1016/j.scitotenv.2012.06.009
  9. Ryuko S., Ma Y., Ma N., Sakaue M., Kuno T. Genome-wide screen reveals novel mechanisms for regulating cobalt up-take and detoxification in fission yeast. Mol. Genet. Genomics, 2012, vol. 287, no. 8, pp. 651–662. DOI: 10.1007/s00438-012-0705-9
  10. Leyssens L., Vinck B., Van Der Straeten C., Wuyts F., Maes L. Cobalt toxicity in humans – a review of the potential sources and systemic health effects. Toxicology, 2017, no. 387, pp. 43–56. DOI: 10.1016/j.tox.2017.05.015
  11. De Boeck M., Kirsch-Volders M., Lison D. Cobalt and antimony: genotoxicity and carcinogenicity. Mutat. Res., 2003, vol. 533, no. 1, 2, pp. 135–152. DOI: 10.1016/j.mrfmmm.2003.07.012
  12. Paustenbach D.J., Tvermoes B.E., Unice K.M., Finley B.L., Kerger B.D. A review of the health hazards posed by cobalt. Crit. Rev. Toxicol., 2013, vol. 43, no. 4, pp. 316–362. DOI: 10.3109/10408444.2013.779633
  13. Liang Y., Zhen X., Wang K., Ma J. Folic acid attenuates cobalt chloride-induced PGE2 production in HUVECs via the NO/HIF-1alpha/COX-2 pathway. Biochem. Biophys. Res. Commun., 2017, vol. 490, no. 2, pp. 567–573. DOI: 10.1016/j.bbrc.2017.06.079
  14. Yorita C.K.L. Metals in blood and urine, and thyroid function among adults in the United States 2007–2008. Int J. Hyg. Environ. Health, 2013, vol. 216, no. 6, pp. 624–632. DOI: 10.1016/j.ijheh.2012.08.005
  15. Catalani S., Rizzetti M.C., Padovani A., Apostoli P. Neurotoxicity of cobalt. Hum. Exp. Toxicol., 2012, vol. 31, no. 5, pp. 421–437. DOI: 10.1177/0960327111414280
  16. Dai Y., Li W., Zhong M., Chen J., Liu Y., Cheng Q., Li T. Preconditioning and post-treatment with cobalt chloride in rat model of perinatal hypoxic–ischemic encephalopathy. Brain Dev., 2014, vol. 36, no. 3, pp. 228–240. DOI: 10.1016/j.braindev.2013.04.007
  17. Mendy A., Gasana J., Vieira E.R. Urinary heavy metals and associated medical conditions in the US adult population. Int. J. Environ. Health Res., 2012, vol. 22, no. 2, pp. 105–118. DOI: 10.1080/09603123.2011.605877
  18. Yuan Y., Hilliard G., Ferguson T., Millhorn D.E. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J. Biol. Chem., 2003, vol. 278, no. 18, pp. 15911–15916. DOI: 10.74/jbc.M300463200
  19. Maxwell P., Salnikow K. HIF-1: an oxygen and metal responsive transcription factor. Cancer Biol. Ther., 2004, vol. 3, no. 1, pp. 29–35. DOI: 10.4161/cbt.3.1.547
  20. Jelkmann W. The Disparate Roles of Cobalt in Erythropoiesis, and Doping Relevance. Open Journal of Hematology, 2012, vol. 3, no. 1, pp. 3–6. DOI: 10.13055/ojhmt_3_1_6.121211
  21. Muñoz‐Sánchez J., Chánez‐Cárdenas M.E. The use of cobalt chloride as a chemical hypoxia model. J. Appl. Toxicol., 2018, vol. 39, no. 4, pp. 1–15. DOI: 10.1002/jat.3749
  22. Catalani S., Leone R., Rizzetti M.C., Padovani A., Apostoli P. The Role of Albumin in Human Toxicology of Cobalt: Contribution from a Clinical Case. ISRN Hematology, 2011, vol. 2011, 6 p. DOI: 10.5402/2011/690620
  23. Jomova K., Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology, 2011, vol. 283, no. 2, 3, pp. 65–87. DOI: 10.1016/j.tox.2011.03.001
  24. Zadnipryany I.V., Tretiakova O.S., Sataieva T.P., Zukow W. Experimental review of cobalt induced cardiomyopathy. Russian Open Medical Journal, 2017, vol. 6, no. 1, pp. 1–4. DOI: 10.15275/rusomj.2017.0103
  25. Wang G., Hazra T.K., Mitra S., Lee H.M., Englander E.W. Mitochondrial DNA damage and a hypoxic response are induced by CoCl(2) in rat neuronal PC12 cells. Nucleic. Acids. Res., 2000, vol. 28, no. 10, pp. 2135–2140. DOI: 10.1093/nar/28.10.2135
  26. Lee J.-H., Choi S.-H., Baek M.-W., Kim M.-H., Kim H.-J., Kim S.-H., Oh S.-J., Park H.-J. [et al.]. CoCl2 induces apoptosis through the mitochondria- and death receptor-mediated pathway in the mouse embryonic stem cells. Mol. Cell. Biochem., 2013, vol. 379, pp. 133–140. DOI: 10.1007/s11010-013-1635-5
  27. K. Chamaon, P. Schönfeld, F. Awiszus, J. Bertrand, C.H. Lohmann. Ionic cobalt but not metal particles induces ROS generation in immune cells in vitro. J. Biomed. Mater. Res. B. Appl. Biomater., 2019, vol. 107, no. 4, pp. 1246–1253. DOI: 10.1002/jbm.b.34217
  28. Lawrence H., Deeha D.J., Holland J.P., Anjum S.A., Mawdesley A.E., Kirby J.A., Tyson-Cappera A.J. Cobalt ions re-cruit inflammatory cells in vitro through human Toll-like receptor-4. Biochem. Biophys. Rep., 2016, vol. 7, pp. 374–378. DOI: 10.1016/j.bbrep.2016.07.003
  29. S.A. Anjum, H. Lawrence, J.P. Holland, J.A. Kirby, D.J. Deehan, A.J. Tyson Effect of cobalt-mediated Toll-like re-ceptor 4 activation on inflammatory responses in endothelial cells. Oncotarget, 2016, vol. 7, no. 47, pp. 76471–76478. DOI: 10.18632/oncotarget.13260
  30. Shweta, Mishra K.P., Chanda S., Singh S.B., Ganju L. A comparative immunological analysis of CoCl2 treated cells with in vitro hypoxic exposure. Biometals, 2015, vol. 28, no. 1, pp. 175–185. DOI: 10.1007/s10534-014-9813-9 31. Shrivas-tava K., Bansal A., Singh B., Sairam M., Ilavazhagan G. Sub-chronic oral toxicity study in Sprague-Dawley rats with hypoxia mimetic cobalt chloride towards the development of promising neutraceutical for oxygen deprivation. Exp. Toxicol. Pathol., 2010, vol. 62, no. 5, pp. 489–496. DOI: 10.1016/j.etp.2009.06.012
  31. Liu Y., Xu H., Liu F., Tao R., Yin J. Effects of serum cobalt ion concentration on the liver, kidney and heart in mice. Orthopaedic Surgery, 2010, vol. 2, no. 2, pp. 134–140. DOI: 10.1111/j.1757-7861.2010.00076.x
  32. Akinrinde A.S., Oyagbemi A.A., Omobowale T.O., Asenuga E.R., Ajibade T.O. Alterations in blood pressure, antiox-idant status and caspase 8 expression in cobalt chloride-induced cardio-renal dysfunction are reversed by Ocimum gratissimum and gallic acid in Wistar rats. J. Trace. Elem. Med. Biol., 2016, no. 36, pp. 27–37. DOI: 10.1016/j.jtemb.2016.03.015
  33. Feng W., Zhang Y., Deng H., Li S.J. Interaction of divalent metal ions with human translocase of inner membrane of mitochondria TIM23. Biochem. Biophys. Res. Commun., 2016, vol. 475, no. 1, pp. 76–80. DOI: 10.1016/j.bbrc.2016.05.039
  34. Niu N., Li Z., Zhu M., Sun H., Yang J., Xu S., Zhao W., Song R. Effects of nuclear respiratory factor-1 on apoptosis and mitochondrial dysfunction induced by cobalt chloride in H9C2 cells. Molecular medicine reports, 2019, vol. 19, no. 3, pp. 2153–2163. DOI: 10.3892/mmr.2019.9839
  35. Hantson P. Mechanisms of toxic cardiomyopathy. Clin. Toxicol., 2019, vol. 57, no. 1, pp. 1–9. DOI: 10.1080/15563650.2018.1497172
  36. Kurhaluk N., Lukash O., Nosar V., Portnychenko A.G., Portnychenko V., Wszedybyl-Winklewska M., Winklewski P.J. Liver mitochondrial respiratory plasticity and oxygen uptake evoked by cobalt chloride in rats with low and high resistance to extreme hypobaric hypoxia. Can. J. Physiol. Pharmacol., 2019, vol. 97, no. 5, pp. 392–399. DOI: 10.1139/cjpp-2018-0642
  37. He Y., Gan X., Zhang L., Liu B., Zhu Z., Li T., Zhu J., Chen J., Yu H. CoCl2 induces apoptosis via a ROS-dependent pathway and Drp1-mediated mitochondria fission in periodontal ligament stem cells. Am. J. Physiol. Cell. Physiol., 2018, vol. 315, no. 3, pp. C389–C397. DOI: 10.1152/ajpcell.00248.2017
  38. Saxena S., Shukla D., Bansal A. Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride. Toxicol. Appl. Pharmacol., 2012, vol. 264, no. 3, pp. 324–334. DOI: 10.1016/j.taap.2012.08.033
  39. Liu Y., Hong H., Lu X., Wang W., Liu F., Yang H.L. L-Ascorbic Acid Protected Against Extrinsic and Intrinsic Apoptosis Induced by Cobalt Nanoparticles Through ROS Attenuation. Biol. Trace. Elem. Res., 2017, vol. 175, no. 2, pp. 428–439. DOI: 10.1007/s12011-016-0789-x
  40. Ebert B., Jelkmann W. Intolerability of cobalt salt as erythropoietic agent. Drug. Test. Anal., 2014, vol. 6, no. 3, pp. 185–189. DOI: 10.1002/dta.1528
  41. Hoffmeister T., Schwenke D., Wachsmuth N., Krug O., Thevis M., Byrnes W.C., Schmidt W.F.J. Erythropoietic effects of low-dose cobalt application. Drug. Test. Anal., 2019, vol. 11, no. 2, pp. 200–207. DOI: 10.1002/dta.2478
  42. Karaczyn A., Ivanov S., Reynolds M., Zhitkovich A., Kasprzak K.S., Salnikow K. Ascorbate depletion mediates up-regulation of hypoxia-associated proteins by cell density and nickel. J. Cell. Biochem., 2006, vol. 97, no. 5, pp. 1025–1035. DOI: 10.1002/jcb.20705
  43. Kaczmarek M., Cachau R.E., Topol I.A., Kasprzak K.S., Ghio A., Salnikow K. Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein. Toxicol. Sci., 2009, vol. 107, no. 2, pp. 394–403. DOI: 10.1093/toxsci/kfn251
  44. Yuan Y., Hilliard G., Ferguson T., Millhorn D.E. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J. Biol. Chem., 2003, vol. 278, no. 18, pp. 15911–15916. DOI: 10.74/jbc.M300463200
  45. Shrivastava K., Ram M.S., Bansal A., Singh S.S., Ilavazhagan G. Cobalt supplementation promotes hypoxic tolerance and facilitates acclimatization to hypobaric hypoxia in rat brain. High. Alt. Med. Biol., 2008, vol. 9, no. 1, pp. 63–75. DOI: 10.1089/ham.2008.1046
  46. Jeon E.S., Shin J.H., Hwang S.J., Moon G.J., Bang O.Y., Kim H.H. Cobalt chloride induces neuronal differentiation of human mesenchymal stem cells through upregulation of microRNA-124a. Biochem. Biophys. Res. Commun., 2014, vol. 444, no. 4, pp. 581–587. DOI: 10.1016/j.bbrc.2014.01.114
  47. Chai Y.C., Mendes L.F., Van Gastel N., Carmeliet G., Luyten F.P. Fine-tuning pro-angiogenic effects of cobalt for simultaneous enhancement of vascular endothelial growth factor secretion and implant neovascularization. Acta Biomater., 2018, no. 72, pp. 447–460. DOI: 10.1016/j.actbio.2018.03.048
  48. Chen Y., Zhao Q., Yang X., Yu X., Yu D., Zhao W. Effects of cobalt chloride on the stem cell marker expression and osteogenic differentiation of stem cells from human exfoliated deciduous teeth. Cell. Stress. Chaperones., 2019, vol. 24, no. 3, pp. 527–538. DOI: 10.1007/s12192-019-00981-5
  49. Matsumoto M., Makino Y., Tanaka T., Tanaka H., Ishizaka N., Noiri E., Fujita T., Nangaku M. Induction of Renopro-tective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats. J. Am. Soc. Nephrol., 2003, no. 14, pp. 1825–1832.
  50. Tanaka T., Kojima I., Ohse T., Ingelfinger J.R., Adler S., Fujita T., Nangaku M. Cobalt promotes angiogenesis via hy-poxia-inducible factor and protects tubulointerstitium in the remnant kidney model. Laboratory Investigation, 2005, no. 85, pp. 1292–1307. DOI: 10.1038/labinvest.3700328
  51. Oyagbemi A.A., Omobowale T.O., Awoyomi O.V., Ajibade T.O., Falayi O.O., Ogunpolu B.S., Okotie U.J., Asenuga E.R. [et al.]. Cobalt chloride toxicity elicited hypertension and cardiac complication via induction of oxidative stress and upregula-tion of COX-2/Bax signaling pathway. Hum. Exp. Toxicol., 2019, vol. 38, no. 5, pp. 519–532. DOI: 10.1177/0960327118812158
  52. Kong D., Zhang F., Shao J., Wu L., Zhang X., Chen L., Lu Y., Zheng S. Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes. Lab. Invest., 2015, vol. 95, no. 11, pp. 1234–1245. DOI: 10.1038/labinvest.2015.107
  53. Czarnek K., Terpiłowska S., Siwicki A.K. Selected aspects of the action of cobalt ions in the human body. Cent. Eur. J. Immunol., 2015, vol. 40, no. 2, pp. 236–242. DOI: 10.5114/ceji.2015.52837
  54. Nagasawa H. Pathophysiological response to hypoxia – from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment. J. Pharmacol. Sci., 2011, vol. 115, no. 4, pp. 446–452.
  55. Eskandani M., Vandghanooni S., Barar J., Nazemiyeh H., Omidi Y. Cell physiology regulation by hypoxia inducible factor-1: Targeting oxygen-related nanomachineries of hypoxic cells. Int J. Biol. Macromol., 2017, no. 99, pp. 46–62. DOI: 10.1016/j.ijbiomac.2016.10.113
  56. Liang Y., Zhen X., Wang K., Ma J. Folic acid attenuates cobalt chloride-induced PGE2 production in HUVECs via the NO/HIF-1alpha/COX-2 pathway. Biochem. Biophys. Res. Commun., 2017, vol. 490, no. 2, pp. 567–573. DOI: 10.1016/j.bbrc.2017.06.079
  57. Schmidt M., Raghavan B., Müller V., Vogl T., Fejer G., Tchaptchet S., Keck S., Kalis C. [et al.]. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat. Immunol., 2010, vol. 11, no. 9, pp. 814–819. DOI: 10.1038/ni.1919
  58. Samelko L., Landgraeber S., McAllister K., Jacobs J., Hallab N.J. Cobalt Alloy Implant Debris Induces Inflammation and Bone Loss Primarily through Danger Signaling, Not TLR4 Activation: Implications for DAMP-ening Implant Related In-flammation. PLoS ONE, 2016, vol. 11, no. 7, pp. e0160141. DOI: 10.1371/journal.pone.0160141
  59. Kwak J., Choi S.J., Oh W., Yang Y.S., Jeon H.B., Jeon E.S. Cobalt Chloride Enhances the Anti-Inflammatory Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells through the ERK-HIF-1α-MicroRNA-146a-Mediated Sig-naling Pathway. Stem. Cells International, 2018, vol. 2018, 12 p. DOI: 10.1155/2018/4978763
  60. Xu J., Nyga A., Li W., Zhang X., Gavara N., Knight M.M., Shelton J.C. Cobalt ions stimulate a fibrotic response through matrix remodelling, fibroblast contraction and release of pro-fibrotic signals from macrophages. European Cells and Materials, 2018, no. 36, pp. 142–155. DOI: 10.22203/eCM.v036a11
  61. Ratha S., Dasa L., Kokatea S., Ghosha N., Dixita P., Routb N., Singhc S.P., Chattopadhyaya S. [et al.]. Inhibition of histone/lysine acetyltransferase activity kills CoCl2-treated and hypoxia-exposed gastric cancer cells and reduces their invasiveness. Int J. Biochem. Cell. Biol., 2017, no. 82, pp. 28–40. DOI: 10.1016/j.biocel.2016.11.014
  62. Li C.-L., Xu Z.-B., Fan X.-L., Chen H.-X., Yu Q.-N., Fang S.-B., Wang S.-Y., Lin Y.-D., Fu Q.-L. MicroRNA-21 Mediates the Protective Effects of Mesenchymal Stem Cells Derived from iPSCs to Human Bronchial Epithelial Cell Injury Under Hypoxia. Cell. Transplantation., 2018, vol. 27, no. 3, pp. 571–583. DOI: 10.1177/0963689718767159
  63. Permenter M.G., Dennis W.E., Sutto T.E., Jackson D.A., Lewis J.A. [et al.]. Exposure to Cobalt Causes Transcriptomic and Proteomic Changes in Two Rat Liver Derived Cell Lines. PLoS ONE, 2013, vol. 8, no. 12, pp. e83751. DOI: 10.1371/journal.pone.0083751
  64. Salnikow K., Zhitkovich A. Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic and Chromium. Chem. Res. Toxicol., 2008, vol. 21, no. 1, pp. 28–44. DOI: 10.1021/tx700198a
  65. Salnikow K., Aprelikova O., Ivanov S., Tackett S., Kaczmarek M., Karaczyn A., Yee H., Kasprzak K.S., Niederhuber J. Regulation of hypoxia-inducible genes by ETS1 transcription factor. Carcinogenesis, 2008, vol. 29, no. 8, pp. 1493–1499. DOI: 10.1093/carcin/bgn088
  66. Chervona Y., Costa M. The control of histone methylation and gene expression by oxidative stress, hypoxia and metals. Free Radic. Biol. Med., 2012, vol. 53, no. 5, pp. 1041–1047. DOI: 10.1016/j.freeradbiomed.2012.07.020
  67. Brocato J., Costa M. Basic Mechanics of DNA Methylation and the Unique Landscape of the DNA Methylome in Metal-Induced Carcinogenesis. Crit. Rev. Toxicol., 2013, vol. 43, no. 6, pp. 493–514. DOI: 10.3109/10408444.2013.794769
  68. Bae S., Jeong H.-J., Cha H.J., Kim K., Choi Y.M., An I.-S., Koh H.J., Lim D.J. [et al.]. The hypoxia-mimetic agent cobalt chloride induces cell cycle arrest and alters gene expression in U266 multiple myeloma cells. International journal of molecular medicine, 2012, no. 30, pp. 1180–1186. DOI: 10.3892/ijmm.2012.1115
  69. Hattori S., Kamiya T., Hara H., Ninomiya M., Koketsu M., Adach T. CoCl2 Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells. Biol. Pharm. Bull., 2016, vol. 39, no. 12, pp. 2036–2041. DOI: 10.1248/bpb.b16-00551
  70. Chen R., Jiang T., She Y., Xu J., Li C., Zhou S., Shen H., Shi H., Liu S. Effects of Cobalt Chloride, a Hypoxia-Mimetic Agent, on Autophagy and Atrophy in Skeletal C2C12 Myotubes. Biomed. Res. Int., 2017, no. 7097580. DOI: 10.1155/2017/7097580
  71. Tan L., Lai X., Zhang M., Zeng T., Liu Y., Deng X., Qiu M., Li J. [et al.]. A stimuli-responsive drug release nanoplat-form for kidney-specific anti-fibrosis treatment. Biomater. Sci., 2019, vol. 7, no. 4, pp. 1554–1564. DOI: 10.1039/c8bm01297k
  72. Stenger C., Naves T., Verdier M., Ratinaud M.H. The cell death response to the ROS inducer, cobalt chloride, in neu-roblastoma cell lines according to p53 status. Int J. Oncol., 2011, vol. 39, no. 3, pp. 601–609. DOI: 10.3892/ijo.2011.1083
  73. Chimeh U., Zimmerman M.A., Gilyazova N., Li P.A. B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Au-tophagy Induction. Int J. Med. Sci., 2018, vol. 15, no. 12, pp. 1384–1396. DOI: 10.7150/ijms.24702
  74. Kumanto M., Paukkeri E.-L., Nieminen R., Moilanen E. Cobalt (II) Chloride Modifies the Phenotype of Macrophage Activation. Basic & Clinical Pharmacology & Toxicology, 2017, no. 121, pp. 98–105. DOI: 10.1111/bcpt.12773
  75. Luo H.-M., Du M.-H., Lin Z.-L., Zhang L., Ma L. [et al.]. Valproic Acid Treatment Inhibits Hypoxia-Inducible Factor 1α Accumulation and Protects against Burn-Induced Gut Barrier Dysfunction in a Rodent Model. PLoS ONE, 2013, vol. 8, no. 10, pp. e77523. DOI: 10.1371/journal.pone.0077523
  76. Kim Y.J., Park S.J., Kim N.R., Chin H.S. Effects of Histone Deacetylase Inhibitor (Valproic Acid) on the Expression of Hypoxia-inducibleFactor-1 Alpha in Human Retinal Müller Cells. Korean J. Ophthalmol., 2017, vol. 31, no. 1, pp. 80–85. DOI: 10.3341/kjo.2017.31.1.80
  77. Ho J.J., Metcalf J.L., Yan M.S., Turgeon P.J., Wang J.J., Chalsev M., Petruzziello-Pellegrini T.N., Tsui A.K. [et al.]. Functional importance of Dicer protein in the adaptive cellular response to hypoxia. J. Biol. Chem., 2012, vol. 287, no. 34, pp. 29003–29020. DOI: 10.1074/jbc.M112.373365

You are here