The Effect of Retinol Acetate on Liver Fibrosis Depends on the Temporal Features of the Development of Pathology.

Background: The effect of vitamin A on the manifestations of liver fibrosis is controversial and establishing the causes of its multidirectional influence is an urgent problem. In the work, the functional characteristics of the liver with Cu-induced fibrosis were determined after the restoration of vitamin A to the control level at the F0/F1 stage. Methods: In animals with liver fibrosis, classical indicators of physiology, functional activity of the liver, histological, and hematological characteristics were determined; the content of calcium and ROS was determined in bone marrow cells. Results: It was shown that in the liver with Cu-induced fibrosis, the restoration of vitamin A content to control values after per os injections of a retinol acetate solution at a dose of 0.10 mg (300 IU)/100 g of body weight in the early stages of this pathology development (Fо/F1) was accompanied by: a decrease in the number of immunocompetent cells in the bloodstream to control values; normalization of the amount of calcium ions and ROS in bone marrow cells; restoration to the control level of activity of alkaline phosphatase; an increase in the number of binuclear hepatocytes; and restoration of the dynamics of body weight growth in experimental animals, even against the background of the ongoing action of the hepatotoxic factor. Conclusion: We came to the conclusion that the multidirectional action of vitamin A, which occurs in liver fibrosis, depends not only on the concentration of vitamin A in the liver but also on temporal characteristics of cellular and metabolic links involved in the adaptive response formation. It was suggested that knowledge of the initial temporal metabolic characteristics and the amount of vitamin A in the liver, taking into account the stages of fibrosis development, can be an effective way to restore the altered homeostatic parameters of the body.

Vitamin A Reduces the Mortality of Animals with Induced Liver Fibrosis by Providing a Multi-level Body Defense System.

Background: Liver diseases remain the most important medical and biological problem. Works devoted to the study of the vitamin A role have shown conflicting results of its effect on the fibrosis development. We tested the hypothesis that an increase of the copper content in the liver, an example of which is Wilson's disease, shifts the balance in the redox system towards pro-oxidants, which leads to the antioxidant systems inhibition, including a decrease in the vitamin A content; this affects the levels of liver function regulation and the development of fibrosis. Methods: In animals with Cu-induced liver fibrosis, neutrophil activity, the immunocompetent cells content, the activity of alanine aminotransferase and γ-glutamylaminotransferase, the content of urea and creatinine in blood serum, as well as the vitamin A content in the liver, copper ions and its regenerative potential were determined. Results: It was found that three consecutive injections of copper sulfate to animals with an interval of 48 h between injections led to the death of 40% of the animals, and 60% showed resistance. The content of vitamin A in "resistant" animals at the beginning of the development of the fibrosis was reduced by 4 times compared to the control, the functional activity of the liver was somewhat reduced, and a connective tissue capsule was formed around the liver lobes in 75% of the animals. If animals with the initial stage of liver fibrosis received daily vitamin A at a dose of 300 IU/100 g of body weight, which was accompanied by its multiple increase in the liver (15 times on day 14), the mortality of animals decreased by almost 7 times, the functional activity of the liver did not differ from control. In the blood of these animals, the number of leukocytes, granulocytes, and monocytes was increased and phagocytic activity was increased. At the same time, the connective tissue capsule was developed more intensively than in animals receiving only copper sulfate, and was detected in 91% of the animals. Fragments of the liver, even more than in the case of fibrosis, lost the ability to regenerate in culture. Conclusion: We came to the conclusion that vitamin A leads to the connective tissue "specialization" formation of the liver and triggers vicious circles of metabolism and includes several levels of regulation systems. Further studies of the vitamin A effect mechanisms on the liver with fibrosis will allow the use of this antioxidant in the treatment.

CeO2 nanoparticles improve prooxidant/antioxidant balance, life quality and survival of old male rats.

Due to its unique redox chemistry, nanoceria is considered as potent free radical scavenger and antioxidant. However, their protective capacity in aging organisms remains controversial. To detect the anti-aging effects associated with the redox activity of 2 and 10 nm nano-CeO2, different test systems were used, including in vitro analysis, in situ assay of mitochondria function and in vivo studies of suitable nano-CeO2 on aging of male Wistar rats from 22 months-old to the end of life. The 2 nm nanoparticles exhibited not only antioxidant (·OH scavenging; chemiluminescence assay; decomposition of H2O2, phosphatidylcholine autooxidation) but also prooxidant properties (reduced glutathione and reduced nicotinamide adenine dinucleotide phosphate oxidation) as well as affected mitochondria whereas in most test systems 10 nm nano-CeO2 showed less activity or was inert. Prolonged use of the more redox active 2 nm nano-CeO2 (0.25-0.3 mg/kg/day) in vivo with drinking water resulted in improvement in physiological parameters and normalization of the prooxidant/antioxidant balance in liver and blood of aging animals. Survival analysis using Kaplan-Meier curve and Gehan tests with Yates' correction showed that by the time the prooxidant-antioxidant balance was assessed (32 months), survival rates exceeded the control values most considerably. The apparent median survival for the control rats was 900 days, and for the experimental rats-960 days. In general, the data obtained indicate the ability of extra-small 2 nm nano-CeO2 to improve quality of life and increase the survival rate of an aging organism.

Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome.

We studied the role of cytotoxic components (DAMPs) formed in the body of patients with COVID-19 in ensuring the long-term preservation of post-COVID-19 manifestations and the possibility of creating an experimental model by transferring DAMPs to rats. In patients with post-COVID-19 syndrome (PCS) 2 months after SARS-CoV-2 infection we determined the presence of cytotoxic components in the blood serum (Terasaki test, Dunaliella viridis test and content of DAMPs). In post-COVID-19 syndrome patients with a high content of serum cytotoxic oligopeptide fraction (selective group, n = 16) we determined the number of leukocytes, lymphocytes, neutrophil granulocytes and monocytes in the blood, the content of C-reactive protein (CRP), the concentration of C3 and C4 complement components and circulating immune complexes, the serum content of IL-6, IL -10, IL-18, TNF-α, phagocytic activity of neutrophils, presence of neutrophil traps and autoantibodies ANA. It has been shown that in patients with PCS, there are components with cytotoxicity in the blood serum, form specific immunopathological patterns, which are characterized by: an increased content of CRP, complement system components C3 and C4 and cytokines (TNF-α, IL-6, IL-10, IL-18) activation, the formation of a wide range of autoantibodies ANA, the low efficiency of endocytosis in oxygen-independent phagocytosis; their phagocytic activity reaches its functional limit, and against this background, activation of neutrophil traps occurs, which can contribute to further induction of DAMPs. This self-sustaining cell-killing activation provided long-term preservation of PCS symptoms. The transfer of blood serum components from selective group patients with PCS to rats was accompanied by the appearance of cytotoxic components in them which induced sensitization and immunopathological reactions. Preventive administration of a biologically active substance with polyfunctional properties MF to experimental animals "corrected" the initial functional state of the body's immune-metabolic system and eliminated or facilitated immuno-inflammatory reactions.

Comparative Studies of Orthovanadate Nanoparticles and Metformin on Life Quality and Survival of Senile Wistar Rats.

Effect of prolong use of orthovanadate nanoparticles (GdVO4/Eu3+ NPs (8 × 25 nm)) on life quality and survival of male Wistar rats on the late stage of ontogenesis (from 23 months to the end of life) has been investigated. Multi-parametric assessment of orthovanadate NPs influences against metformin (Met) which is a well-known calorie restriction mimetic (CR-mimetic) has been completed. The quality of life was assessed by taking into account age-related hallmarks-phenotype and some physiological parameters (condition of the coat, body weight, concentration of thyroxine, rectal temperature) as well as indicators of the pro-oxidant/antioxidant balance of blood and liver (the content of lipid hydroperoxides; aconitase, glutathione peroxidase, glutathione reductase, glutaredoxin activity, and activity of NADP+-dehydrogenases (DG) (glucose-6-phosphate DG, malate DG, and isocitrate DG)) in aging animals. Kaplan-Meier curve and Gehan tests with Yates' correction were performed for the survival analysis. It has been found that long-term use of GdVO4/Eu3+ NPs (0.25-0.30 mg/kg/day), as well as Met (100-110 mg/kg/day) with drinking water led to reliable improvement of physiological parameters and normalization of the pro-oxidant/antioxidant balance in the liver and blood of experimental animals. A significant increase in the survival rate of aging rats was observed; the apparent median survival for control rats was 900 days, while for experimental rats, 1010 and 990 days for GdVO4/Eu3+ NPs and Met, respectively. In general, the data obtained demonstrate the ability of GdVO4/Eu3+ NPs and CR-mimetic-Met to improve the quality of life and increase the survival of an elderly organism.

Anti-aging Effects of Antioxidant Rare-Earth Orthovanadate Nanoparticles in Wistar Rats.

Biomedical application of rare-earth-based nanoparticles attracts much attention due to their unique optical and redox properties and quite low toxicity. Earlier, we found age-related beneficial effects of rare-earth-based orthovanadate nanoparticles (OV NPs) on the prooxidant/antioxidant balance in liver and blood of Wistar rats, as reported by Nikitchenko et al. (Biol Trace Elem Res (2020). https://doi.org/10.1007/s12011-020-02196-7 ). However, the question remained unclear whether OV NPs' redox activity directly defines the protection ability. In the present work, antiradical, antioxidant, and membrane-protective properties of GdYVO4/Eu3+ NPs (1-2 nm), GdVO4/Eu3+ NPs (8 × 25 nm), LaVO4/Eu3+ (57 × 8 nm) were assayed in a comparative manner in various model systems. All OV NPs demonstrated the protective properties, but extra-small GdYVO4/Eu3+ NPs revealed the weakest antioxidant efficacy. In isolated mitochondria, OV NPs lowered (most evidently-extra-small NPs) respiration and oxidative phosphorylation, as well as ATP concentration. We conclude that not only the direct antioxidant effect but also slight suppression of bioenergetic processes by the OV NPs as well as the triggering of GSH-dependent antioxidant system may represent the principal mechanisms of their beneficial influences in an aged organism. This statement is consistent with improvement of the oxidative balance of 33-month-old rats due to prolonged administration of GdVO4 /Eu3+ NPs (for 11 months) accompanied by retention of the GSH signaling of the old rats at the level of 12 months mature animals. Consequently, an increase of antioxidant defense upon prolonged usage of OV NPs will lead to oxidative balance stabilization increasing the health span and survival of an organism.

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

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.

Possible role of alteration of aldehyde's scavenger enzymes during aging.

Apoptosis in tissues is induced by different kind of signals including endogenous aldehydes, such as 4-hydroxy-2, 3-nonenal. The accumulation rate of aldehydes in the cell is affected by conditions of oxidative stress. In the cell, aldehydes can be metabolized by various isoforms of aldehyde dehydrogenase, aldehyde reductase, and glutathione-S-transferase. There is evidence suggesting that the catalytic properties of these enzymes change during ontogenesis, and that aging is accompanied by their reduced activities. These functional changes may contribute substantially to the alteration in the organism sensitivity to damaging action of stress factors during aging, to age-related modulation of the action of endogenous aldehydes as a signal for apoptosis, and finally, to the origin of diseases associated with aging. In this context, the stimulation of enzymes' expression, and the activation of the catalytic properties of enzymes responsible for catabolism of endogenous aldehydes could become a perspective direction in increasing the organism resistance to the action of damaging factors during aging.