Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats
In comparison with the action of metformin — mimetic of the calorie restricted diet, which prolong the animals lifespan, it has been studied the effect of nanoparticles of cerium dioxide (CeO₂ NPs (1-2 nm)) on survival, physiological indices (the concentration of thyroxine, rectal temperature), as...
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| Zitieren: | Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats / Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov, S.L. Yefimova, V.P. Seminozhenko // Доповіді Національної академії наук України. — 2020. — № 10. — С. 35-44. — Бібліогр.: 15 назв. — англ. |
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Nikitchenko, Yu.V. Klochkov, V.K. Kavok, N.S. Karpenko, N.A. Sedyh, O.O. Nikitchenko, I.V. Bozhkov, A.I. Yefimova, S.L. Seminozhenko, V.P. 2020-12-19T16:13:13Z 2020-12-19T16:13:13Z 2020 Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats / Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov, S.L. Yefimova, V.P. Seminozhenko // Доповіді Національної академії наук України. — 2020. — № 10. — С. 35-44. — Бібліогр.: 15 назв. — англ. 1025-6415 DOI: doi.org/10.15407/dopovidi2020.10.035 https://nasplib.isofts.kiev.ua/handle/123456789/173762 612.67:577.24[546.65:66.-911.48] In comparison with the action of metformin — mimetic of the calorie restricted diet, which prolong the animals lifespan, it has been studied the effect of nanoparticles of cerium dioxide (CeO₂ NPs (1-2 nm)) on survival, physiological indices (the concentration of thyroxine, rectal temperature), as well as biochemical indices (content of lipid hydroperoxides, aconitase, glutathione peroxidase, glutaredoxin, glutathione reductase, NADP⁺ -dehydrogenase activities (glucose-6-phosphate-, malate- and isocitrate dehydrogenase)) in serum, liver mitochondrial and postmitochondrial fraction of ageing rats. It has been found that the prolonged use of CeO₂ NPs with drinking water (0.25-0.30 mg/kg of body weight per day) and metformin (100-110 mg/kg of body weight per day) from 670 days after the birth lead to a significant increase in survival (the median survival of control rats was 900, in animals treated with CeO₂ NPs — 960, and metformin — 990 days), a decrease in rectal temperature, a slowdown in the decrease in the level of thyroxine in blood, and normalization of the prooxidant/antioxidant balance in liver and blood tissues. Calculated integral index of reliability of prooxidant-antioxidant balance (reliability coefficient) in the studied tissues of rats in response to the application of the CeO₂ NPs increased 4.99 times, and metformin — 4.94 times compared to intact animals. The data obtained allow us concluding about the prospects of the CeO₂ NPs, as well as metformin for the development of geroprotector drugs, increasing the healthspan and survival of an ageing organism. У порівнянні з дією метформіну — міметика низькокалорійної дієти, що продовжує життя тварин, вивчається вплив наночастинок діоксиду церію (CeO₂ НЧ (1—2 нм)) на виживання, фізіологічні показники (концентрація тироксину, ректальна температура) та біохімічні показники (вміст ліпідних гідроперок сидів, активність ферментів аконітази, глутатіонпероксидази, глутаредоксину, глутатіонредуктази, НАДФ⁺-дегідрогеназ (глюкозо-6-фосфат дегідрогеназа, малат дегідрогеназа та ізоцитрат дегідрогеназа) у сироватці крові, мітохондріальної та постмітохондріальної фракцій печінки. Було встановлено, що тривале використання CeO₂ НЧ з питною водою (0,25—0,30 мг / кг маси тіла на добу) або метформіну (100—110 мг / кг маси тіла на добу) з 670 днів після народження призводило до значного збільшення виживання (медіана виживаності контрольних щурів становила 900 днів, у тварин, які отримували CeO₂ НЧ — 960 днів, і метформіну — 990 днів), зниження ректальної температури, уповільнення зниження тироксину в крові та нормалізації прооксидантно/антиоксидантного балансу в тканинах печінки та крові. Розрахований інтегральний показник надійності прооксидантно/антиоксидантного балансу (коефіцієнт надійності) у досліджуваних тканинах щурів у відповідь на використання CeO₂ НЧ зріс в 4,99 раза, а метформіну — у 4,94 раза порівняно з інтактними тваринами. Отримані дані дозволяють зробити висновки щодо перспектив наночастинок CeO₂, а також метформіну для розробки геропротекторних препаратів, що сприяють поліпшенню здоров’я та збільшують виживаність організму при старінні. en Видавничий дім "Академперіодика" НАН України Доповіді НАН України Матеріалознавство Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats Наночастинки діоксиду церію та метформін підвищують надійність прооксидантно/ антиоксидантного балансу та збільшують |виживаність щурів, що старіють Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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| title |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats |
| spellingShingle |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats Nikitchenko, Yu.V. Klochkov, V.K. Kavok, N.S. Karpenko, N.A. Sedyh, O.O. Nikitchenko, I.V. Bozhkov, A.I. Yefimova, S.L. Seminozhenko, V.P. Матеріалознавство |
| title_short |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats |
| title_full |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats |
| title_fullStr |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats |
| title_full_unstemmed |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats |
| title_sort |
cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats |
| author |
Nikitchenko, Yu.V. Klochkov, V.K. Kavok, N.S. Karpenko, N.A. Sedyh, O.O. Nikitchenko, I.V. Bozhkov, A.I. Yefimova, S.L. Seminozhenko, V.P. |
| author_facet |
Nikitchenko, Yu.V. Klochkov, V.K. Kavok, N.S. Karpenko, N.A. Sedyh, O.O. Nikitchenko, I.V. Bozhkov, A.I. Yefimova, S.L. Seminozhenko, V.P. |
| topic |
Матеріалознавство |
| topic_facet |
Матеріалознавство |
| publishDate |
2020 |
| language |
English |
| container_title |
Доповіді НАН України |
| publisher |
Видавничий дім "Академперіодика" НАН України |
| format |
Article |
| title_alt |
Наночастинки діоксиду церію та метформін підвищують надійність прооксидантно/ антиоксидантного балансу та збільшують |виживаність щурів, що старіють |
| description |
In comparison with the action of metformin — mimetic of the calorie restricted diet, which prolong the animals
lifespan, it has been studied the effect of nanoparticles of cerium dioxide (CeO₂ NPs (1-2 nm)) on survival,
physiological indices (the concentration of thyroxine, rectal temperature), as well as biochemical indices (content of
lipid hydroperoxides, aconitase, glutathione peroxidase, glutaredoxin, glutathione reductase, NADP⁺ -dehydrogenase
activities (glucose-6-phosphate-, malate- and isocitrate dehydrogenase)) in serum, liver mitochondrial and
postmitochondrial fraction of ageing rats.
It has been found that the prolonged use of CeO₂ NPs with drinking water (0.25-0.30 mg/kg of body weight
per day) and metformin (100-110 mg/kg of body weight per day) from 670 days after the birth lead to a significant
increase in survival (the median survival of control rats was 900, in animals treated with CeO₂ NPs — 960,
and metformin — 990 days), a decrease in rectal temperature, a slowdown in the decrease in the level of thyroxine
in blood, and normalization of the prooxidant/antioxidant balance in liver and blood tissues. Calculated integral
index of reliability of prooxidant-antioxidant balance (reliability coefficient) in the studied tissues of rats in
response to the application of the CeO₂ NPs increased 4.99 times, and metformin — 4.94 times compared to intact
animals. The data obtained allow us concluding about the prospects of the CeO₂ NPs, as well as metformin for
the development of geroprotector drugs, increasing the healthspan and survival of an ageing organism.
У порівнянні з дією метформіну — міметика низькокалорійної дієти, що продовжує життя тварин, вивчається вплив наночастинок діоксиду церію (CeO₂ НЧ (1—2 нм)) на виживання, фізіологічні показники (концентрація тироксину, ректальна температура) та біохімічні показники (вміст ліпідних гідроперок сидів, активність ферментів аконітази, глутатіонпероксидази, глутаредоксину, глутатіонредуктази,
НАДФ⁺-дегідрогеназ (глюкозо-6-фосфат дегідрогеназа, малат дегідрогеназа та ізоцитрат дегідрогеназа) у
сироватці крові, мітохондріальної та постмітохондріальної фракцій печінки.
Було встановлено, що тривале використання CeO₂ НЧ з питною водою (0,25—0,30 мг / кг маси тіла
на добу) або метформіну (100—110 мг / кг маси тіла на добу) з 670 днів після народження призводило до
значного збільшення виживання (медіана виживаності контрольних щурів становила 900 днів, у тварин,
які отримували CeO₂ НЧ — 960 днів, і метформіну — 990 днів), зниження ректальної температури, уповільнення зниження тироксину в крові та нормалізації прооксидантно/антиоксидантного балансу в тканинах печінки та крові. Розрахований інтегральний показник надійності прооксидантно/антиоксидантного балансу (коефіцієнт надійності) у досліджуваних тканинах щурів у відповідь на використання CeO₂
НЧ зріс в 4,99 раза, а метформіну — у 4,94 раза порівняно з інтактними тваринами.
Отримані дані дозволяють зробити висновки щодо перспектив наночастинок CeO₂, а також метформіну для розробки геропротекторних препаратів, що сприяють поліпшенню здоров’я та збільшують виживаність організму при старінні.
|
| issn |
1025-6415 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/173762 |
| citation_txt |
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/anti oxidant balance and the survival of ageing rats / Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov, S.L. Yefimova, V.P. Seminozhenko // Доповіді Національної академії наук України. — 2020. — № 10. — С. 35-44. — Бібліогр.: 15 назв. — англ. |
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35
ОПОВІДІ
НАЦІОНАЛЬНОЇ
АКАДЕМІЇ НАУК
УКРАЇНИ
ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 10: 35—44
Ц и т у в а н н я: Nikitchenko Yu.V., Klochkov V.K., Kavok N.S., Karpenko N.A., Sedyh O.O., Nikitchenko I.V.,
Bozhkov A.I., Yefimova S.L., Seminozhenko V.P. Cerium oxide nanoparticles and metformin increase the re liab-
ility of the prooxidant/antioxidant balance and the survival of ageing rats. Допов. Нац. акад. наук Укр. 2020.
№ 10. С. 35—44. https://doi.org/10.15407/dopovidi2020.10.035
https://doi.org/10.15407/dopovidi2020.10.035
УДК 612.67:577.24[546.65:66.-911.48]
Yu.V. Nikitchenko 1, V.K. Klochkov 2, N.S. Kavok 2,
N.A. Karpenko 2, O.O. Sedyh 2, I.V. Nikitchenko 1,
A.I. Bozhkov 1, S.L. Yefimova 2, V.P. Seminozhenko 2
1 V.N. Karazin Kharkiv National University
2 Institute for Scintillation Materials, SIC “IMK” of the NAS of Ukraine, Kharkiv
E-mail: kavok@isma.kharkov.ua
Cerium oxide nanoparticles and metformin increase
the reliability of the prooxidant/antioxidant balance
and the survival of ageing rats
Presented by Academician of the NAS of Ukraine V.P. Seminozhenko
In comparison with the action of metformin — mimetic of the calorie restricted diet, which prolong the animals
lifespan, it has been studied the effect of nanoparticles of cerium dioxide (CeO2 NPs (1-2 nm)) on survival,
physiological indices (the concentration of thyroxine, rectal temperature), as well as biochemical indices (content of
lipid hydroperoxides, aconitase, glutathione peroxidase, glutaredoxin, glutathione reductase, NADP+ -dehydro-
genase activities (glucose-6-phosphate-, malate- and isocitrate dehydrogenase)) in serum, liver mitochondrial and
postmitochondrial fraction of ageing rats.
It has been found that the prolonged use of CeO2 NPs with drinking water (0.25-0.30 mg/kg of body weight
per day) and metformin (100-110 mg/kg of body weight per day) from 670 days after the birth lead to a signi-
ficant increase in survival (the median survival of control rats was 900, in animals treated with CeO2 NPs — 960,
and metformin — 990 days), a decrease in rectal temperature, a slowdown in the decrease in the level of thyroxine
in blood, and normalization of the prooxidant/antioxidant balance in liver and blood tissues. Calculated integral
index of reliability of prooxidant-antioxidant balance (reliability coefficient) in the studied tissues of rats in
response to the application of the CeO2 NPs increased 4.99 times, and metformin — 4.94 times compared to intact
animals. The data obtained allow us concluding about the prospects of the CeO2 NPs, as well as metformin for
the development of geroprotector drugs, increasing the healthspan and survival of an ageing organism.
Keywords: CeO2 nanoparticles, metformin, prooxidant/antioxidant balance, thyroxine, body temperature, liver,
blood, survival of old male rats.
МАТЕРІАЛОЗНАВСТВО
36 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 10
Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov...
Introduction. It is now known that one of the effective non-genetic models, which lead to a sig-
nificant increase in life expectancy, is the calorie restriction (CR) [1, 2]. It should be noted that
the main mechanism of the effect of CR on the body is a slowdown in the development of oxi-
dative stress [2-5]. At the same time, it was shown that the effectiveness of CR on life expectancy
is manifested only when it is used from the early stages of ontogenesis. Therefore, a number of
authors believe that the CR cannot currently be used to increase the human lifespan [6]. In this
regard, recently, to increa se organism`s lifespan, a number of antidiabetic drugs imitating the ef-
fect of CR (CR-mimetics) are being considered. These drugs include biguanides (phen for min,
buformin, metformin), which also exhibit anti oxidant properties [7]. Currently, there is evidence
that these drugs increase the life span of nematodes, mice, and rats [7]. At the same time, there is
evidence of the absence of the effect of bi guanides on the lifespan of animals [8]. More over, de-
tected slight toxicity of metformin requires additional methods of correction during its long-term
use [9].
Therefore, the search for new antioxidant drugs capable of increasing the lifespan is rele-
vant. Of particular interest are the NPs of dioxide cerium (CeO2 NPs) which show SOD- and
catala se-like activity, preventing oxidative damage and increase survival of mice with impaired
SOD activity [10].
The aim of this work is to study the effect of CeO2 NPs, and metformin on the state of the
prooxidant/antioxidant balance and the survival rate of ageing rats.
Materials and Methods. Aqueous solutions of CeO2 NPs were obtained by the following
method [11]: 100 ml of a solution of CeCl3 (0.002 mol/L) were mixed with 100 ml of a solution
of hexamethylenetetramine (0.004 mol/L) and stirred by using a magnetic stirrer for 3 h at room
temperature. After that, 1.8 ml NH4 OH and 0.6 ml of H2 O2 were added into the solution. Then
the solution was put in round-bottom flask and was refluxed for 5 h. As a result, transparent co-
lorless solutions were obtained. The solution was evaporated in a rotary evaporator flask under
vacuum at the bath temperature of 70 °C to 30 ml. A solution of 1 M CaCl2 was added to the
obtained solution until the resulting solution became turbid. Then coagulated ceria nanoparticles
were isolated by centrifugation and redispersed in a solution of 1 M CaCl2 again. The procedure
of precipitate cleaning was repeated three times. After the last stage of centrifugation, a solution
of sodium citrate with a molar ratio CeO2/NaCt of 1: 1 was added to the precipitate. The solu-
tions were additionally dialyzed for 24 h against deionized water to remove the excess of ions and
organics species. Dialysis membrane tubing with a molecular weight cutoff of “Cellu Sep H1”
3.5 KDa was used, and water was renewed each 6 h (the water / colloid volume ratio is 40).
Thus, the impurity-free solution was found to be transparent in transmitted light at a concent-
ration CeO2 of 1 g/L with a poorly yellow color. As evident from Fig. 1, the particles are spherical
and well-dispersed with the average particle size of about 2 nm.
Investigations were performed on male Wistar rats maintained under standard vivarium
conditions in accordance with the guidelines of the European Convention for the Protection
of the Vertebrata using for the Experimental and Scientific Purposes (1986). In the experi-
ment, 12 months old (6 rats) and 23 months old animals (61 rats) were used. The manipula-
tions with the animals were carried out in accordance with the European Convention for the
Pro tec tion of Vertebrate Animals used for Experimental and Scientific Purposes (Strasbourg,
1986).
37ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 10
Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/antioxidant balance...
CeO2 NPs were given to the experimental 23-
months rats (31 individual) with drinking water at a
final dose of 0.25-0.3 mg /kg body weight per day for
the end of life, metformin was given with drinking wa-
ter at a final dose at 100-110 mg /kg body weight [8].
Animals that received standard drinking water and we-
re kept under the same conditions constituted the Cont-
rol group (30 animals). Rectal temperature mea su re-
ments were performed using ThermoWorks Mic rother-
ma 2T (USA). The concentration of thyroxine (T4) was
determined by the enzyme immunoassay using the Total
T4 RIA kit from IMMUNOTECH (Czech Republic).
At the age of 33-month- old, 6 animals from each
group were scarified, and the state of prooxidant/an-
tioxidant balance was investigated. Mitochondrial
(MC), postmitochondrial (PMC) fractions of liver were obtained by differential centrifugation
immediately after necropsy. These samples, as well as serum (S), were either analyzed immedi-
ately (lipid hydroperoxide, LHPO) or stored in liquid nitrogen till the analysis.
The parameters of the prooxidant/antioxidant balance were measured using the methods
described by us earlier [4, 5, 12]. LHPO content in liver was determined by the method of
Ohkawa et al. (1979), and in serum - by the method of Asakawa et al. (1980) spectrophoto met-
rially (UV VIS, Germany). Aconitase activity (Aco) (EC 4.2.1.3) was determined in MC with
spectrophotometry at 240 nm, as described by Varghese (2003) with minor changes. Glutathione
peroxidase (GPx) activity in liver fractions was measured in a reaction coupled with exogenous
glutathione reductase spectrophotometrially at 340 nm by the method of Paglia and Valentine
(1967). Determination of glutaredoxin activity (Grx) (EC 1.20.4.1) in liver MC was measured
with spectrophotometry at 340 nm (Gallogly et al. 2010) Glutathione reductase (GR) activity in
MC and PMC was determined by oxidation of NADPH spectrophotometry at 340 nm according
to the method of Carlberg (1975). Glucose-6-phosphate dehydrogenase (G-6-PDG) activity,
NADP-dependent isocitrate dehydrogenase (ICDG) activity, and NADP-dependent malate de-
hydrogenase (MDG) activity were investigated by the restoration of NADP+ according to the
methods of Zaheer (1967), Bauman (1970), Usatenko (1974). Protein content was determined by
the Lowry method in the modification by Miller (1959).
The integral index of the prooxidant/antioxidant balance in liver mitochondria of young and
old animals as reliability coefficient (Kr) was calculated using the formula [12]:
⎛ ⎞ ⎛ ⎞ ⎛ ⎞× ×⎜ ⎟ ⎜ ⎟ ⎜ ⎟⎝ ⎠ ⎝ ⎠ ⎝ ⎠
=
⎛ ⎞ ⎛ ⎞ ⎛ ⎞ ⎛ ⎞ ⎛ ⎞ ⎛ ⎞× × × × ×⎜ ⎟ ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ ⎜⎝ ⎠ ⎝ ⎠ ⎝ ⎠ ⎝ ⎠ ⎝ ⎠ ⎝
LHPO S ) LHPO MC LHPO PMC
LHPO S ) LHPO MC LHPO PMC
GPx S GPx MC GPx PMC GRx C GR MC GR PMC
GPx S GPx MC GPx PMC GRx MC GR MC GR PMC
Kr
c c
exp exp t exp t
c c c c c c
exp t exp t exp t exp t exp t exp t ⎟⎠
where the values with the indices exp t correspond to the ones obtained for animals treated with
NPs CeO2, and the values with the indices c — to control rats. The values in the formula are taken
from tables 1 and 2 of the present work.
Fig. 1. TEM image of synthesized CeO2 NPs
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Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov...
The obtained results were processed with the Student’s t-test using the “Statistica v.6” com-
puter software package. Analysis for survival was performed using the Kaplan—Meyer test.
Survival curves were compared using the Gehan method with Yates correction. All data were
expressed as mean ± SEM. Significance level was set at p < 0.05.
Results and Discussion. From the literature, it is known that an experimental decrease in
body temperature of animals can lead to an increase in life expectancy [13]. In particular, it has
been shown that the long-term use of a calorie-limited life-prolonging diet is accompanied by a
decrease in rectal temperature in experimental mice and rats. Also shown is a decrease in rectal
temperature in experimental animals with the long-term use of biguanides (phenformin, buform-
in, metformin), which increase life expectancy [7].
In our studies, we have found that CeO2 NPs or metformin applications within 100-110 days
significantly reduce rectal temperature compared to control animals. So, in particular, when using
CeO2 NPs, the rectal temperature decreased by 0.58 °C and when using metformin — by 0.78 °C
(p < 0.05; n = 24-31).
In this regard, it can be concluded that CeO2 NPs affect rectal temperature in very old
animals in the same way as metformin (CR-mimetic) and just like the calorie-restricted life-pro-
longing diet itself.
Important indicator, which characterizes the rate of ageing, can be the level of thyroid hor-
mones in the blood. Numerous data indicate that the content of thyroid hormones decreases
significantly with the age of mammals [13].
In our studies, it is found that thyroxine (T4) content in 32-month-old (975 days after
birth) control rats is significantly, by 27.2 %, lower as compared with the level of hormone in
adults 12-months (365 days after birthday) control animals. Prolonged use of CeO2 NPs sig-
ni ficantly slowed a decrease in the concentration of this hormone in blood serum. Thus, in
32-month-old experimental rats, the T4 level does not significantly differ from this indicator in
12-month-old control animals (data not shown).
A significant slowdown in the decrease in serum T4 in very old, 32-month-old rats is also
found with a long-term use of metformin. In this regard, it should be noted that the deceleration
in reduction of blood T4 concentrations is characteristic of the action of CR, which prolongs the
lifespan of animals [4, 5]. Thus, it can be concluded that the NPs CeO2 slow the age-dependent
declining of T4 level as a CR-mimetic — metformin and just the CR.
It has been shown that, at the late stages of ontogenesis in rats, during natural ageing, the
content of products of free radical oxidation of biomolecules in liver and blood significantly
increases, and the activity of a number of antioxidant enzymes decreases [5]. Therefore, it was
of interest to investigate the prooxidant/antioxidant balance in liver and blood of experimental
animals at the long-last use of CeO2 NPs or metformin. It has been shown that, in very old —
32-month-old control rats, LHPO content in blood serum, liver PMC and MC fractions was
by 23.5 %, 28.0 % and 36.2 % higher, than in 12-months control animals (Table 1).
In response to the CeO2 NPs application, the level LHPO in serum, liver PMC and MC of
32-month-old animals is significantly reduced as compared to the control values and leveled
with ones in the tissues of 12-month-old rats (Table 1). Similar changes of lipid peroxidation
products in serum, liver MC and PMC of experimental animals are detected in response to
the long-term use of metformin (see Table 1). In this connection, it should be noted that the de-
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Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/antioxidant balance...
celeration of the LHPO accumulation have been identified earlier in the study of long-last use
of CR, which prolongs the life of animals [4, 5].
Another indicator of the state of the prooxidant potential is the value of aconitase acti-
vity (Aco) in liver mitochondria. Aco is the only enzyme in the liver MC which activity is con-
siderably reduced, proportionally to oxidative stress intensity and ageing. Our studies reveal
that, in old control rats (32 months old), Aco activity is reliably lower than in adults 12 months
animals (see Table 1). In experimental old rats, which received CeO2 NPs, this activity remains at
the level of adult 12-months rats. Similar changes of Aco activity are also observed at the pro-
longed administration of metform.
Thus, the data obtained indicate that the long-term use of CeO2 NPs maintains the pro-
oxidant potential of liver and blood of 32-month-old experimental animals at the reduced level
of adult 12-month-old control rats. A decrease in the prooxidant potential of very old 32-month-
old rats also occurred with long-term use of metformin.
The content of LHPO in body tissues is controlled mainly by the glutathione peroxidase
antioxidant system (glutathione peroxidase, a number of isoenzymes of glutathione- S- trans-
ferase and glutaredoxin). In our earlier studies, it was found that, at the later stages of ontogenesis,
the activity of glutathione peroxidase (GPx) in the liver and blood significantly decreases [5].
In the present work, we have shown a decrease in the GPx activity in serum, liver PMC and
MC in 32-months control rats to 19.1 %, 20.3 %, and 25.8 %, respectively, as compared to the ac-
tivity in 12-month-old control animals (p < 0.05, Table 1). Prolonged use of CeO2 NPs signi-
ficantly retards the lowering of GPx activity. The use of metformin also resulted in a significant
reduction in a deceleration of the GPx activity in serum, liver PMC and MC of 32-months ex-
perimental animals (Table 1). In this connection, it should be noted that a slowdown of a decrease
in the GPx activity in liver and blood was also revealed by us in response to CR [4, 5].
Table 1. Lipid hydroperoxides content and activities of aconitase,
glutathione peroxidase, and glutaredoxin in liver and blood
of ageing rats received nanoparticles CeO2 or metformin (n = 6)
Parameter
Tissue/
Liver
fraction
12-months 32-months
Control Control CeO2 NPs Metformin
LHPO nmol MDA / ml Serum 2.51± 0.09 3.10 ± 0.12* 2.36 ± 0.09** 2.39** ± 0.06**
LHPO, nmol MDA / mg
protein
PMC 0.250 ± 0.012 0.320 ± 0.070* 0.242 ± 0.012** 0.246 ± 0.009**
MC 0.403 ± 0.025 0.549 ± 0.045* 0.422 ± 0.031** 0.373 ± 0.027**
Aco, nmol aconitate / min ⋅ mg
protein MC 31.0 ± 8.0 24.9 ± 0.8* 29.9 ± 1.0** 29.7 ± 1.7**
GPx, μmol NADPH / min ⋅ ml Serum 5.77 ± 0.27 4.67 ± 0.12* 5.34 ± 0.30 5.69 ± 0.38**
GPx, nmol NADPH / min ⋅ mg
protein
PMC 604.4 ± 29.4 481.7 ± 27.4* 623.5 ± 55.6 606.5 ± 44.0
MC 394.5 ± 31.0 292.9 ± 21.7* 352.7 ± 18.3 330.9 ± 14.7
Grx, nmol NADPH / min ⋅ mg
protein MC 4.31 ± 0.19 3.46*± 0.22 4.27± 0.27 4,00± 0.13
Notes: * — p < 0.05 compared with control 12-months animals; ** — p < 0.05 in comparison with the control
32-months animals
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Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov...
The study of another enzyme, utilizing lipid hydroperoxides and hydrogen peroxide — glu-
taredoxin (Grx), shows that the enzyme activity in old control rats is significantly lower than
the activity in 12-months control animals. Prolonged use of CeO2 NPs and metformin prevents a
decline of the Grx activity (Table 1).
Investigation of the activity of glutathione reductase (GR), an enzyme that provides GPx
and Grx with reduced glutathione reveals no significant changes in this activity in the liver
MC of control animals ,as well as of rats long-last receiving CeO2 NPs and metformin (Table 2).
In the study of enzyme activities providing mitochondrial GR with reduced NADPH —
NADP-dehydrogenases (G-6-PDG, MDH and ICDG), significant changes in 32-month-old
control animals compared to the controls 12-months are not detected (Table 2). In experimental
animals, only a tendency to increase the G-6-PDG activity in response to the prolonged use of
CeO2 NPs is observed.
When studying the activity of the same enzymes in the liver PMC, it has been found that
the GR activity in control 32-month old rats is significantly lower than in adult 12 months of
age (Table 2). These data are consistent with our earlier results, which indicate a decrease in the
GR activity in rat liver PMC with ageing [5].
Long-term use of CeO2 NPs significantly slows down the decrease in the studied activity
in the PMC of the liver fraction. A similar effect on the GR activity of the liver PMC was found
with a long-term use of metformin (Table 2).
The study of the NADP-dependent dehydrogenases activity in the liver PMC established
that only the ICDH activity decreases significantly in 32-month-old control rats (as compared
to the 12-month control animals) (Table 2). The prolonged use of CeO2 NPs significantly retards
the reduction of the activity. A significant slowdown in the decrease in the ICDH activity in
the liver PMC was also found with a long-term use of metformin.
G-6-PDG activity in the liver PMC of control 32-month-old rats practically does not differ
from the activity of 12-month-old control animals. With prolonged use of CeO2 NPs, the stud-
Table 2. Glutathione- and NADP-reductase activities
in liver mitochondrial and postmitochondrial fractions of rats
at the prolonged use of CeO2 nanoparticles or metformin (n = 6)
Parameter
Liver
fraction
12- months 32-months
Control Control CeO2 NPs Metformin
GR, nmol NADPH /
min ⋅ mg protein
MC 40.3 ± 3.4 34.1 ± 2.0 36.4 ± 2.6 38.5 ± 2.0
PMC 52.3 ± 3.7 43.1 ± 1.3* 60.0 ± 7.2** 54.1 ± 4.4**
ICDH, nmol NADPH /
min ⋅ mg protein
MC 247.9 ± 16.1 206.9 ± 31.9 243.2 ± 18.9 235.0 ± 30.0
PMC 304.4 ± 19.7 233.7 ± 10.0* 314.8 ± 34.6** 288.4 ± 13.2**
G-6-PDG, nmol NADPH /
min ⋅ mg protein
MC 23.0 ± 1.4 20.1 ± 2.6 27.2 ± 2.5• 22.9 ± 3.2
PMC 52.1 ± 5.8 49.6 ± 6.5 115.2 ± 17.3*,** 93.6 ± 23.0•
MDH, nmol NADPH /
min ⋅ mg protein
MC 4.38 ± 0.45 3.32 ± 0.44 3.29 ± 0.42 3.44 ± 0.35
PMC 37.9 ± 4.8 30.2 ± 4.5 45.9 ± 3.6** 28.9 ± 3.3
Notes: * — p < 0.05 compared to the control of 12-month-old animals; ** — p < 0.05 compared to the control of
32-month-old animals; • —0.05 < p < 0.1 in comparison with the control 32-months animals
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Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/antioxidant balance...
ied activity is significantly increased (by 121.1 % compared to control 12-months animals and
by 132.3 % in comparison with the control 32-months rats). In this connection, it should be
noted that, in the liver MC of rats received CeO2 NPs, the G-6-PDG activity is somewhat high-
er (by 35.3 %) than in the control 32-month old animals (Table 2).
In the case of prolonged use of metformin, G-6-PDG activity increases less remarkably
than at the CeO2 NPs use.
When studying the activity of NADP- dependent MDH in the PMC of the liver, it has been
found that, in old 32-month-old rats, the studied activity is slightly lower (by 20.3 % ) than in
control 12-month-old animals (Table 2). Long-term use of CeO2 NPs increases the activity by
52.0 % in comparison with the old control animals. At the same time, long-term use of met-
formin did not significantly affect the NADP- dependent MDH activity in the liver PMC.
In our studies, for an integrated assessment of prooxidant/antioxidant balance changes in
liver and blood of rats at CeO2 NPs or metformin action, the coefficient reliability (Kr) of the
balance has been used, which is calculated according to the formula described in the section
“Materials and Methods” with the data given in tables 1 and 2. In the absence of significant chan-
ges under the any influence, the coefficient would amount to ~ 1 c.u.
In our work, the calculated Kr value is 4.99 c.u. in rats received CeO2 NPs, while at met-
formin using — 4.94 c.u. These data indicate that the reliability of prooxidant/antioxidant ba-
lance in response to the application of the CeO2 NPs or metformin increases almost 5 times in
comparison to the intact animals.
Based on the analysis of physiological (rectal temperature and T4 level) and biochemical
parameters (the content of LPO products and the activity of enzymes of the glutathione-depen-
dent antioxidant system), as well as based on the calculation of the reliability coefficient of
the prooxidant/antioxidant balance, we can assume the geroprotective activity of NPs CeO2
and metformin in ageing rats.
The study of the survival of control and experimental rats was carried out from 670 days
after birth to the end of the life of the last animal. Presented in Fig. 2 survival data, which were
calculated by the Kaplan-Meier method, suggest that indicators of survival in experimental
animals are significantly higher than in the control rats. The degree of slowing down of mortality
in experimental animals is especially pronounced at the initial stages of the experiment. Thus,
the survival rate of control rats was less than 0.9 conventional units by 730 days after birth,
with the use of CeO2 NPs — by 800 days, and with the use of metformin — by 810 days of the
expe riment (Fig. 2). Reduced survival rate lesser than 0.8 c.u. in the control rats is observed by
780 day after birth, and in experimental animals only to the 860 Day — for the received CeO2
group NPs, and by the 870 Day — for the group received metformin. Reduced survival rate less
than 0.6 c.u. in the control is occurred by 850 days after birth, and in rats treated with CeO2
NPs — only by 920 days, for the metformin group — 950 days. The median survival of animals was
in control rats — 900 days, animals receiving CeO2 NPs — 960 days, in animals treated with met-
formin — 990 days. In the later stages of ontogeny, the effect of the CeO2 NPs is less pronounced.
So, the decrease in survival is less than 0.4 c. u. in the control animals occurred at 950 day,
while the experimental animals treated with CeO2 NPs — to 990 day, while metformin — at 1030
day. Survival decrease lesser than 0.2 c.u. in the control animals occurred at 1040 day; the expe-
rimental animals received NPs CeO2 — to 1050 day, and metformin — 1080.
42 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 10
Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov...
Based on the analysis of survival curves, it should be noted that the action of CeO2 NPs,
in the used concentration (0.25-0.30 mg / kg body weight, with drinking water) is most effec-
tive only in the initial stage of the experiment.
CR-mimetic metformin affects the survival of experimental animals significantly greater than
CeO2 NPs at the initial stage of the experiment, and especially — in the later stages of the study.
The data obtained allow us to conclude about the prospects of the CeO2 NPs and metformin
for the development of geroprotector drugs, increasing the survival of ageing animals. Howe-
ver, taking into account certain contradictions about the effect of metformin on life expectancy
[8], as well as data on its certain toxicity [9], from our point of view, cerium dioxide nanopar-
ticles could be more promising to increase the reliability of prooxidant / antioxidant balance and
the survival of aging rats.
Conclusions. Published earlier data on the beneficial effect of orthovanadate NPs during
normal and accelerated ageing on physiological and biochemical indices of ageing organism
[12, 14, 15] are consistent with those of the present work on the possibility of a correction of age-
related changes and an increase in the survival of ageing animals with NPs. Accounting for the
survival curves and the stabilizing effect of the investigated compounds on the prooxidant/anti-
oxidant balance, we can conclude that they are promising for the development of geroprotective
drugs that slow down the ageing process.
Fig. 2. Effect of a long-term use of CeO2 nanoparticles or metformin on the survival rate of old rats: 1 — con-
trol (- -); 2 — CeO2 nanoparticles (…...); 3—metformin (..- -. .) (n = 30-31)
Notes: Median of survival in control animals is 900 days; in rats received CeO2 nanoparticles — 960 days, and in
rats received metformin, — 990 days.
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Cerium oxide nanoparticles and metformin increase the reliability of the prooxidant/antioxidant balance...
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dopovidi2020.07.043
Received 30.08.2020
44 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 10
Yu.V. Nikitchenko, V.K. Klochkov, N.S. Kavok, N.A. Karpenko, O.O. Sedyh, I.V. Nikitchenko, A.I. Bozhkov...
Ю.В. Нікітченко 1, В.К. Клочков 2, Н.С. Кавок 2,
Н.О. Карпенко 2, О.О. Сєдих 2, І.В. Нікітченко, |
А.І. Божков 1, С.Л. Єфімова 2, В.П. Семіноженко 2
1 Харківський національний університет ім. В.Н. Каразіна
2 Інститут сцинтиляційних матеріалів, НТК “ІМК” НАН України, Харків
E-mail: kavok@isma.kharkov.ua
НАНОЧАСТИНКИ ДІОКСИДУ ЦЕРІЮ ТА МЕТФОРМІН
ПІДВИЩУЮТЬ НАДІЙНІСТЬ ПРООКСИДАНТНО/
АНТИОКСИДАНТНОГО БАЛАНСУ ТА ЗБІЛЬШУЮТЬ
|ВИЖИВАНІСТЬ ЩУРІВ, ЩО СТАРІЮТЬ
У порівнянні з дією метформіну — міметика низькокалорійної дієти, що продовжує життя тварин, вив-
чається вплив наночастинок діоксиду церію (CeO2 НЧ (1—2 нм)) на виживання, фізіологічні показ-
ники (концентрація тироксину, ректальна температура) та біохімічні показники (вміст ліпідних гідро-
перок сидів, активність ферментів аконітази, глутатіонпероксидази, глутаредоксину, глутатіонредуктази,
НАДФ+-дегідрогеназ (глюкозо-6-фосфат дегідрогеназа, малат дегідрогеназа та ізоцитрат дегідрогеназа) у
сироватці крові, мітохондріальної та постмітохондріальної фракцій печінки.
Було встановлено, що тривале використання CeO2 НЧ з питною водою (0,25—0,30 мг / кг маси тіла
на добу) або метформіну (100—110 мг / кг маси тіла на добу) з 670 днів після народження призводило до
значного збільшення виживання (медіана виживаності контрольних щурів становила 900 днів, у тварин,
які отримували CeO2 НЧ — 960 днів, і метформіну — 990 днів), зниження ректальної температури, упо-
вільнення зниження тироксину в крові та нормалізації прооксидантно/антиоксидантного балансу в тка-
нинах печінки та крові. Розрахований інтегральний показник надійності прооксидантно/антиоксидант-
ного балансу (коефіцієнт надійності) у досліджуваних тканинах щурів у відповідь на використання CeO2
НЧ зріс в 4,99 раза, а метформіну — у 4,94 раза порівняно з інтактними тваринами.
Отримані дані дозволяють зробити висновки щодо перспектив наночастинок CeO2, а також мет-
форміну для розробки геропротекторних препаратів, що сприяють поліпшенню здоров’я та збільшують
виживаність організму при старінні.
Ключові слова: наночастинки CeO2, метформін, прооксидантно/антиоксидантний баланс, тироксин,
температура тіла, печінка, кров, виживання старих щурів-самців.
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