Age-Related Effects of Orthovanadate Nanoparticles Involve Activation of GSH-Dependent Antioxidant System in Liver Mitochondria

A Correction to this article was published on 05 June 2020

This article has been updated


Vanadium is an important ultra-trace element nowadays attracting attention with particular emphasis on medical application. But the therapeutic application of vanadium-based drugs is still questionable and restricted due to some toxic side effects. It was found that unique redox properties of vanadium in nanoform provided antioxidant activity and prevented oxidative disturbance in cells in vitro. Though, on the organism level, ambiguous effects of vanadium-based nanoparticles were observed. In this study, the age-related features of prooxidant/antioxidant balance in blood serum and liver mitochondrial and postmitochondrial fractions of 3 and 18-month-old Wistar male rats treated with orthovanadate nanoparticles (GdVO4/Eu3+, 8 × 25 nm) within 2 months have been investigated. Prooxidant potential-related indexes were the content of lipid hydroperoxides as well as aconitase activity. Activity of glutathione peroxidase, glutathione-S-transferase, glutaredoxin, glutathione reductase, glucose-6-phosphate dehydrogenase, and NADPH-dependent isocitrate dehydrogenase designated the tissue antioxidant potential. Based on the obtained values, the integral index of the prooxidant/antioxidant balance—the reliability coefficient (Kr) has been calculated. The data show that due to activation some chain links of GSH-dependent antioxidant system, GdVO4/Eu3+ nanoparticles increase the reliability of the prooxidant-antioxidant balance in tissues and especially in the liver mitochondria of old animals (Kr in mitochondria of young rats was 2.94, and in mitochondria of old ones—9.83 conventional units). Detected in vitro glutathione peroxidase-like activity of the GdVO4/Eu3+ nanoparticles is supposed to be among factors increasing the reliability of the system. So, for the first time, the beneficial effect of the long-term orthovanadate nanoparticle consumption in old males has been discovered.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Change history

  • 05 June 2020

    The original version of this article unfortunately contained a mistake.



Aconitase activity


Conventional units


Dynamic light scattering


Ethylenediaminetetraacetic acid


Glucose-6-phosphate dehydrogenase


Glutathione peroxidase


Glutathione reductase






Glutathione disulfide




Isocitrate dehydrogenase


The integral index of the prooxidant-antioxidant balance


Lipid hydroperoxide


Lipid peroxidation


Malonic dialdehyde


Mitochondrial fraction of liver


Nicotinamide adenine dinucleotide phosphate


Nicotinamide adenine dinucleotide phosphate+




Postmitochondrial fraction of liver


Reactive oxygen species


Standard error of mean


Thiobarbituric acid


(Oxymethyl) aminomethane


  1. 1.

    Hagen TM (2003) Oxidative stress, redox imbalance, and the aging process. Antioxid Redox Signal 5(5):503–506.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kregel KC, Zhang HJ (2007) An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Phys Regul Integr Comp Phys 292(1):R18–R36.

    CAS  Article  Google Scholar 

  3. 3.

    Sadowska-Bartosz I, Bartosz G (2014) Effect of antioxidants supplementation on aging and longevity. Biomed Res Int 2014:404680–404617.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Rzigalinski BA (2005) Nanoparticles and cell longevity. Technol Cancer Res Treat 4(6):651–659.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Narayanan KB, Park HH (2013) Pleiotropic functions of antioxidant nanoparticles for longevity and medicine. Adv Colloid Interf Sci 201:30–42.

    Article  Google Scholar 

  6. 6.

    Chen Z, Meng H, Xing G, Yuan H, Zhao F, Liu R, Ye C (2008) Age-related differences in pulmonary and cardiovascular responses to SiO2 nanoparticle inhalation: nanotoxicity has susceptible population Environmental science & technology 42(23):8985–8992.

  7. 7.

    Pessoa JC, Etcheverry S, Gambino D (2015) Vanadium compounds in medicine. Coord Chem Rev 301:24–48.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Tripathi D, Mani V, Pal RP (2018) Vanadium in biosphere and its role in biological processes. Biol Trace Elem Res 186(1):52–67.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Bishayee A, Oinam S, Basu M, Chatterjee M (2000) Vanadium chemoprevention of 7, 12-dimethylbenz (a) anthracene-induced rat mammary carcinogenesis: probable involvement of representative hepatic phase I and II xenobiotic metabolizing enzymes. Breast Cancer Res Treat 63(2):133–145.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Harati M, Ani M (2006) Low doses of vanadyl sulfate protect rats from lipid peroxidation and hypertriglyceridemic effects of fructose-enriched diet. Int J Diabet Metabol 14(3):134–137

    CAS  Article  Google Scholar 

  11. 11.

    Francik R, Krośniak M, Barlik M, Kudła A, Gryboś R, Librowski T (2011) Impact of vanadium complexes treatment on the oxidative stress factors in wistar rats plasma. Bioinorg Chem Appl 2011:1–8.

    CAS  Article  Google Scholar 

  12. 12.

    Kim AD, Zhang R, Kang KA, You HJ, Hyun JW (2011) Increased glutathione synthesis following Nrf2 activation by vanadyl sulfate in human chang liver cells. Int J Mol Sci 12(12):8878–8894.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kim AD, Zhang R, Kang KA, You HJ, Kang KG, Hyun JW (2012) Jeju ground water containing vanadium enhances antioxidant systems in human liver cells. Biol Trace Elem Res 147(1–3):16–24.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Chandra AK, Ghosh R, Chatterjee A, Sarkar M (2007) Effects of vanadate on male rat reproductive tract histology, oxidative stress markers and androgenic enzyme activities. J Inorg Biochem 101(6):944–956.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J (2013) Toxicity of vanadium on isolated rat liver mitochondria: a new mechanistic approach. Metallomics 5(2):152–166.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Domingo JL (2000) Vanadium and diabetes. What about vanadium toxicity? Mol Cell Biochem 203(1):185–187.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Vernekar AA, Sinha D, Srivastava S, Paramasivam PU, D’Silva P, Mugesh G (2014) An antioxidant nanozyme that uncovers the cytoprotective potential of vanadia nanowires. Nat Commun 5:5301.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Ghosh S, Roy P, Karmodak N, Jemmis ED, Mugesh G (2018) Nanoisozymes: crystal-facet-dependent enzyme-mimetic activity of V2O5 nanomaterials. Angew Chem Int Ed Eng 130(17):4600–4605.

    CAS  Article  Google Scholar 

  19. 19.

    Kulkarni A, Kumar GS, Kaur J, Tikoo K (2014) A comparative study of the toxicological aspects of vanadium pentoxide and vanadium oxide nanoparticles. Inhal Toxicol 26(13):772–788.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Klochkov VK, Malyshenko AI, Sedykh OO, Malyukin YV (2011) Wet chemical synthesis and characterization of luminescent colloidal nanoparticles: ReVO4:Eu3+ (Re = La, Gd, Y) with rod-like and spindle-like shape. Funct Mater 18(1):111–115

    CAS  Google Scholar 

  21. 21.

    Klochkov VK, Grigorova AV, Sedyh OO, Malyukin YV (2012) The influence of agglomeration of nanoparticles on their superoxide dismutase-mimetic activity. Colloids Surf A Physicochem Eng Asp 409:176–182.

    CAS  Article  Google Scholar 

  22. 22.

    Yefimova SL, Maksimchuk PO, Seminko VV, Kavok NS, Klochkov VK, Hubenko KA, Sorokin AV, Kurilchenko IY, Malyukin YV (2019) Janus-faced redox activity of LnVO4: Eu3+ (Ln= Gd, Y, and La) nanoparticles. J Phys Chem C 123(24):15323–15329.

    CAS  Article  Google Scholar 

  23. 23.

    Kavok N, Grygorova G, Klochkov V, Yefimova S (2017) The role of serum proteins in the stabilization of colloidal LnVO4: Eu3+ (Ln= La, Gd, Y) and CeO2 nanoparticles. Colloids Surf A Physicochem Eng Asp 529:594–599.

    CAS  Article  Google Scholar 

  24. 24.

    Grygorova G, Klochkov V, Sedyh O, Malyukin Y (2014) Aggregative stability of colloidal ReVO4: Eu3+ (Re= La, Gd, Y) nanoparticles with different particle sizes. Colloids Surf A Physicochem Eng Asp 457:495–501.

    CAS  Article  Google Scholar 

  25. 25.

    Kavok NS, Averchenko KA, Klochkov VK, Yefimova SL, Malyukin YV (2014) Mitochondrial potential (ΔΨ m) changes in single rat hepatocytes: the effect of orthovanadate nanoparticles doped with rare-earth elements. Eur Phys J E Soft Matter 37(12):1–8.

    CAS  Article  Google Scholar 

  26. 26.

    Klochkov V, Kavok N, Grygorova G, Sedyh O, Malyukin Y (2013) Size and shape influence of luminescent orthovanadate nanoparticles on their accumulation in nuclear compartments of rat hepatocytes. Mater Sci Eng С Mater Biol Appl 33:2708–2712.

    CAS  Article  Google Scholar 

  27. 27.

    Tkachenko AS, Klochkov VK, Lesovoy VN, Myasoedov VV, Kavok NS, Onishchenko AI et al (2020) Orally administered gadolinium orthovanadate GdVO4: Eu3+ nanoparticles do not affect the hydrophobic region of cell membranes of leukocytes. Wiener Medizinische Wochenschrift:1–7.

  28. 28.

    Tkachenko, A. S., Klochkov, V. K., Onishchenko, A. O., Kavok, N. S., Tkachenko, V. L., & Nakonechna, O. A. (2019). In vivo evaluation of gadolinium orthovanadate GdVO4: Eu3+ nanoparticle toxicity.

  29. 29.

    Averchenko EA, Kavok NS, Klochkov VK, Malyukin YV (2014) Chemiluminescent diagnostics of free-radical processes in an abiotic system and in liver cells in the presence of nanoparticles based on rare-earth elements nReVO4: Eu3+(Re= Gd, Y, La) and CeO2. J Appl Spectrosc 81(5):827–833.

    CAS  Article  Google Scholar 

  30. 30.

    Karpenko NA, Malukin YuV, Koreneva EM, Klochkov VK, Kavok NS, Smolenko NP, Pochernyaeva SS (2013) The effects of chronic intake of cerium dioxide or gadolinium ortovanadate nanoparticles in aging male rats. Proc 3rd Int Conf Nanomaterials: applications and properties “2013” 2(4):04NAMB28-1-04NAMB28-4.

  31. 31.

    Karpenko NO, Korenieva YM, Chystiakova EY, Smolienko NP, Bielkina IO, Seliukova NY, Kustova SP, Boiko MO, Larianovska YB, Klochkov VK, Kavok NS (2016) The influence of the rare-earth metals nanoparticles on the rat's males reprductive function in the descending stage of ontogenesis. Ukr Biopharm J 4(45):75–80.

    Article  Google Scholar 

  32. 32.

    Klochkov VK, Grigorova AV, Sedyh OO, Malyukin YV (2012) Characteristics of nLnVO4: Eu3+(Ln= La, Gd, Y, Sm) sols with nanoparticles of different shapes and sizes. J Appl Spectrosc 79(5):726–730.

    CAS  Article  Google Scholar 

  33. 33.

    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358.

    CAS  Article  Google Scholar 

  34. 34.

    Asakawa T, Matsushita S (1980) Coloring conditions of thiobarbituric acid test for detecting lipid hydroperoxides. Lipids 15(3):137–140.

    CAS  Article  Google Scholar 

  35. 35.

    Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70(1):158–169

    CAS  Google Scholar 

  36. 36.

    Gallogly MM, Shelton MD, Qanungo S, Pai HV, Starke DQ, Cl H, Mieyal JJ (2010) Glutaredoxin regulates apoptosis in cardiomyocytes via NFkappaB targets Bcl-2 and Bcl-xL: implications for cardiac aging. Antioxid Redox Signal 12(12):1339–1353.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Younes M, Schlichting R, Siegers CP (1980) Glutathione S-transferase activities in rat liver: effect of some factors influencing the metabolism of xenobiotics. Pharmacol Res Commun 12(2):115–129.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Carlberg I, Mannervik B (1975) Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 250:5475–5480

    CAS  PubMed  Google Scholar 

  39. 39.

    Zaheer N, Tewari KK, Krishnan PS (1967) Mitochondrial forms of glucose 6-phosphate dehydrogenase and 6-phosphogluconic acid dehydrogenase in rat liver. Arch Biochem Biophys 120(1):22–34.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Bauman DE, Brown RE, Davis CL (1970) Pathways of fatty acid synthesis and reducing equivalent generation in mammary gland of rat, sow, and cow. Arch Biochem Biophys 140(1):237–244.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Varghese S, Tang Y, Imlay JA (2003) Contrasting sensitivities of Escherichia coli aconitases a and B to oxidation and iron depletion. J Bacteriol 185(1):221–230.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Bozhkov AI, Nikitchenko YV (2013) Caloric restriction diet induces specific epigenotypes associated with life span extension. J Nutr Therap 2(1):30–39

    Google Scholar 

  43. 43.

    Bozhkov AI, Nikitchenko Yu V, Al-Bahadly Ali MM (2016) Overeating in early postnatal ontogenesis forms metabolic memory and reduces lifespan. J Gerontol Geriatr Res 5:309

    Google Scholar 

  44. 44.

    Nikitchenko Yu. V. (2012) Prooxidant-antioxidant system in aging processes and experimental approaches to its correction. Dissertation, V. N. Karazin Kharkiv National University

  45. 45.

    Delaval E, Perichon M, Friguet B (2004) Age-related impairment of mitochondrial matrix aconitase and ATP-stimulated protease in rat liver and heart. Eur J Biochem 271(22):4559–4564.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Lushchak OV, Piroddi M, Galli F, Lushchak VI (2014) Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species. Redox Rep 19(1):8–15.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Sharma RK, Pasqualotto FF, Nelson DR, Thomas JJ, Agarwal A (1999) The reactive oxygen species—total antioxidant capacity score is a new measure of oxidative stress to predict male infertility. Hum Reprod 14(11):2801–2807.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Golikov AP, Davydov BV, Rudnev DV, Klychnikova EV, Bykova NS, Riabinin VA, Polumiskov VI, Nikolaeva NI, Golikov PP (2005) Effect of mexicor on oxidative stress in acute myocardial infarction. Kardiologiia 45(7):21–26

    CAS  PubMed  Google Scholar 

  49. 49.

    Park EJ, Lee GH, Yoon C, Kim DW (2016) Comparison of distribution and toxicity following repeated oral dosing of different vanadium oxide nanoparticles in mice. Environ Res 150:154–165.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Klochkov VK, Kaliman VP, Karpenko NA, Kavok NS, Malyukina MY, Yefimova SL, Malyukin YV (2016) In vivo effects of rare-earth based nanoparticles on oxidative balance in rats. Biotechnologia Acta 9(6):72–81.

    Article  Google Scholar 

  51. 51.

    Nikitchenko YV, Klochkov VK, Kavok NS, Karpenko NA, Sedyh OO, Bozhkov AI, Malyukin YV, Semynozhenko VP (2020) Gadolinium orthovanadate nanoparticles increase survival of old rats (In Russ.). Dopov. Nac. Akad. Nauk Ukr 2:29–36.

    CAS  Article  Google Scholar 

  52. 52.

    Wörle-Knirsch JM, Kern K, Schleh C, Adelhelm C, Feldmann C, Krug HF (2007) Nanoparticulate vanadium oxide potentiated vanadium toxicity in human lung cells. Environ Sci Technol 41(1):331–336.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Treviño S, Díaz A, Sánchez-Lara E, Sanchez-Gaytan BL, Perez-Aguilar JM, González-Vergara E (2019) Vanadium in biological action: chemical, pharmacological aspects, and metabolic implications in diabetes mellitus. Biol Trace Elem Res 188(1):68–98.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Rehder D (2015) The role of vanadium in biology. Metallomics 7(5):730–742.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Xu M, Fujita D, Kajiwara S, Minowa T, Li X, Takemura T, Iwai H, Hanagata N (2010) Contribution of physicochemical characteristics of nano-oxides to cytotoxicity. Biomaterials 31(31):8022–8031.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Yefimova SL, Maksimchuk PO, Hubenko KA, Klochkov VK, Borovoy IA, Sorokin AV, Malyukin YV (2019) Untangling the mechanisms of GdYVO4: Eu3+ nanoparticle Photocatalytic activity. Colloids Surf A Physicochem Eng Asp 577:630–636.

    CAS  Article  Google Scholar 

  57. 57.

    Fricker SP (2006) The therapeutic application of lanthanides. Chem Soc Rev 35(6):524–533.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Dong H, Du SR, Zheng XY, Lyu GM, Sun LD, Li LD et al (2015) Lanthanide nanoparticles: from design toward bioimaging and therapy. Chem Rev 115(19):10725–10815.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Gai S, Li C, Yang P, Lin J (2014) Recent progress in rare earth micro/nanocrystals: soft chemical synthesis, luminescent properties, and biomedical applications. Chem Rev 114(4):2343–2389.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Bouzigues C, Gacoin T, Alexandrou A (2011) Biological applications of rare-earth based nanoparticles. ACS Nano 5(11):8488–8505.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Abdesselem M, Schoeffel M, Maurin I, Ramodiharilafy R, Autret G, Clément O, Tharaux PL, Boilot JP, Gacoin T, Bouzigues C, Alexandrou A (2014) Multifunctional rare-earth vanadate nanoparticles: luminescent labels, oxidant sensors, and MRI contrast agents. ACS Nano 8(11):11126–11137.

    CAS  Article  PubMed  Google Scholar 

Download references


This work was supported by the State Fund For Fundamental Research (project no. Ф64/29-2016).

Author information



Corresponding author

Correspondence to Nataliya S. Kavok.

Ethics declarations

All manipulations with animals were carried out in accordance with The International Convention of working with animals and Ukraine Law “On animals protection from cruel treatment.”

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original version of this article unfortunately contained an error in the equation. The original article has been corrected.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nikitchenko, Y.V., Klochkov, V.K., Kavok, N.S. et al. Age-Related Effects of Orthovanadate Nanoparticles Involve Activation of GSH-Dependent Antioxidant System in Liver Mitochondria. Biol Trace Elem Res 199, 649–659 (2021).

Download citation


  • Vanadium
  • GdVO4/Eu3+ nanoparticles
  • Prooxidant/antioxidant balance
  • Mitochondria
  • Male rats