Participation of Free-Radical Processes in Structural and Metabolic Disturbances in the Lung Tissues Caused by Exposure to Coal-Rock Dust and their Adaptogenic Correction.

Adaptive correction of structural and metabolic disturbances in the lungs caused by longterm exposure to coal-rock dust were studied in experiments on rats. It was shown that the complex antioxidant preparation containing dihydroquercetin compensated disturbances in the redox balance in the lung tissue, prevented the formation of dust granulomas, and reduced the severity of degenerative changes in the bronchopulmonary system.

Correction of Abnormalities Provoked by Long-Term Alcoholization with Hypoxic-Hyperoxic Training.

Free radical oxidation in the liver and skeletal muscles as well as stress behavior were examined in rats subjected to a gradual long-term alcoholization with elevated ethanol content from 10 to 40% followed by correction of alcohol-induced disturbances with hypoxic-hyperoxic training. The elevated plus-maze test revealed increased anxiety and appearance of risky behavior in alcoholized rats in the absence of changes in motor and orientation activity. In the liver and skeletal muscles of alcoholized rats, free radical oxidation processes were decompensated despite activation of antioxidant enzymes. Adaptation to intermittent hypoxia-hyperoxia during last two weeks of alcoholization exerted a protective effect against ethanol-induced oxidative stress: reduced anxious and risk behavior, normalized tissue tolerance of free radical oxidation processes, and restored the level of protective proteins.

Addition of Hyperoxic Component to Adaptation to Hypoxia Prevents Impairments Induced by Low Doses of Toxicants (Free Radical Oxidation and Proteins of HSP Family).

We studied the possibility of preventing disturbances caused by administration of low doses of toxicants by adaptation to interval hypoxia and hyperoxia. The preventive protective effect of adaptation to hypoxia-hyperoxia manifested in suppression of free radical oxidation, decrease in the levels of HIF-1α and inducible HOx-1, and improvement of tolerance to physical exercises.

[MAXIMUM SINGLE DOSE OF COLLOIDAL SILVER NEGATIVELY AFFECTS ERYTHROPOIESIS IN VITRO].

Erythroblastic islets (EI) of rat bone marrow were cultured for 24 h in the presence of silver nanoparticles (1.07 · 10(-4) mg/ml; 1.07 · 10(-3) mg/ml; and 1.07 · 10(-2) mg/mL). The colloidal silver at 1.07 · 10(-3) mg/ml concentration inhibited the formation of new Elby disrupting contacts of bone marrow macrophages with CFU-E (erythropoiesis de novo) by 65.3% (p < 0.05). Colloidal silver nanoparticles suppressed the reconstruction of erythropoiesis and inhibited the formation of new EI by disrupting contacts of CFU-E and central macrophages with matured erythroidal "crown" (erythropoiesis de repeto). The colloidal silver concentration of 1.07 · 10(-3) mg/ml in the culture medium also reduced the number of self-reconstructing EI by 67.5% (p <0.05), whereas 1.07 · 10(-2) mg/ml colloidal silver reduced this value by 93.7% (p < 0.05). Silver nanoparticles retarded maturation of erythroid cells at the stage of oxiphylic normoblast denucleation: 1.07 · 10(-3) mg/ml colloidal silver increased the number of mature El by 53% (p < 0.05). The retardation of erythropoiesis by colloidal silver in concentration equivalent to the maximum single dose is related to the effect of silver nanoparticles rather than glycerol present in the colloidal suspension.

Effects of fullerenol C60(OH)24 on erythropoiesis in vitro.

The effects of fullerenol C60(OH)24 in doses of 0.1-100 µg/ml on erythropoiesis were studied in the culture of erythroblastic islets of the bone marrow. Fullerenol in concentrations of 10 and 100 µg/ml had negative effects on the development of erythroid tissue: it inhibits proliferation of erythroid cells, delays erythroblast maturation, decelerates recruitment of erythroid CFU to differentiation, and suppresses repeated involvement of macrophages in erythroblastic islets.

Mechanisms of intracellular defense and activity of free radical oxidation in rat myocardium in the dynamics of chronic fluorine intoxication.

The mechanisms of intracellular defense and activity of free radical oxidation in the myocardium were studied in the dynamics of chronic fluorine intoxication. At the early stages of fluorine intoxication (day 3-week 3), the concentrations of defense proteins HIF-1α, HSC73, and HOx-2 and activity of the main metabolic enzymes increased, which promoted maintenance of cardiomyocyte structure and function at the normal physiological level. At late stages of fluorine intoxication (weeks 6 and 9), metabolic changes in the myocardium attest to high strain of the adaptive mechanisms.

[Dynamic changes in transcription factor HIF-1alpha, rapid response protein, and membrane structure resistance following acute hypoxia].

Within the last decade, a great number of reports have discussed cellular redox signalization depending on the levels of oxygen and reactive oxygen species (ROS). Experiments have proven that ROS can not only be damaging, but are also able to induce the synthesis of cell defense systems. The initiation of redox signal system results in the induction of various transcription factors which response to hypoxia and hyperoxia, an increase in ROS, oxidants etc. The most significant of them is HIF-1alpha, transcription factor playing an important role in the regulation of oxygen homeostasis in the cell as well as in resistance of the heart and the brain to ischemic and reperfusion injury. About 60 genes activated by HIF-1 are known today; among these are genes that code defense systems: cellular antioxidant system, peroxiredoxines, prostaglandins, heme oxygenase, and heat shock proteins. However, despite numerous data on HIF-lalpha expression stimulation or suppression in exposure to ischemia or hypoxia, they are rather contradictory. In this study, changes in HIF-la induction three, six, and twelve hours after acute hypoxia (8% O2 during one hour) were evaluated, and the dynamics of HIF-1alpha level following hypoxia was compared with the dynamics of the levels of rapid response protein, such as inducible heme oxygenase form, HSP70 stress inducible protein, and antioxidant defense enzymes. The findings indicate a nonlinear dynamics of changes in the levels of transcription factors and rapid response proteins with protective function, tissue specificity of their induction, a direct correlation between HIF-1alpha and superoxide dismutase levels in the heart and HIF-1alpha and HSP70 levels in the liver. The stability of membrane structures of different organs and cardiac sarcoplasmatic reticulum Ca pump are maintained by activation of redox signalization and compensatory synthesis of defense proteins.

[Effects of adaptation to periodic hypoxia on Ca2+ pump of the cardiac sarcoplasmic reticulum and its resistance to endogenous damaging factors]. / Vliianie adaptatsii k periodicheskoi gipoksii na Ca2+-nasos sarkoplazmaticheskogo retikuluma serdsa i ego ustoichivost' k éndogennym povrezhdaiushchim faktoram.

The adaptation of rats to periodic "altitude" hypoxia in the altitude chamber (6 hour daily at an altitude of 5000 m during a month) led to increased activity of the Ca2+ pump in the myocardial sarcoplasmic reticulum, which was associated with lower Kd values and higher calcium transport Vmax. When a cardiac homogenate was kept at 4 degrees C, autolysis resulted in a decrease in Ca2+ pump activity (which was more rapid in adapted animals than in the controls) and an equal increase in the levels of free calcium in the homogenates in the two series of experiments. The approximate data were obtained when a homogenate was incubated at 37 degrees C, but when it was incubated at 4 degrees C, the rate of Ca(2+)-pump inactivation decreased 20-fold. Incubation in the presence of free radical oxidative inductors (Fe2+ ascorbate) led to high resistance of myocardial Ca(2+)-pump in the adapted rats. The paper discusses the causes of myocardial Ca(2+)-pump activation in periodic hypoxic adaptation and the mechanisms for its increased resistance to active oxygen, as well as their role in the cardioprotective effect of the adaptation.

[Adaptation to short-term stressor factors increases calcium pump activity in sarcoplasmic reticulum and decreases the rate of its inactivation during autolysis]. / Adaptatsiia k kratkovremennym stressornym vozdeistviiam uvelichivaet aktivnost' kal'tsievogo nasosa sarkoplazmaticheskogo retikuluma i snizhaet skorost' ego inaktivatsii pri avtolize.

Effects of long-term immobilization stress and adaptation to short-term stressory actions on Ca2(+)-transport system were studied in sarcoplasmic reticulum (SR) of rat myocardium. The stress inhibited the rate of Ca2+ transport in SR, while adaptation not only optimized the Ca2(+)-pump functions but prevented the stress-induced impairments of its functions. After stress resistance of Ca2(+)-pump to endogenous impairing factors (in autolysis) was decreased 2-3-fold, whereas adaptation increased the SR membrane stability so distinctly that after simultaneous stress the membrane stability was maintained at the level which-was 2.5-times higher as compared with controls. Long-term stress caused also the higher output of Ca+2 from intracellular stores as compared with controls, while during adaptation and simultaneous stress and adaptation the loss of Ca2+ was practically absent. Protective effects of adaptation to short-term stressory actions on the Ca2(+)-transport system of cardiomyocytes are discussed.

[Analysis of thermodenaturation of Na,K-ATPase in the rat myocardial sarcolemma and possible role of damage of this enzyme in the pathogenesis of arrhythmias]. / Analiz termodenaturatsii Na,K-ATFazy sarkolemmy miokarda krys pri stresse i vozmozhnaia rol' povrezhdeniia étogo fermenta v patogeneze aritmii.

Activity of Na+, K+-ATPase and kinetics of the enzyme thermodenaturation were estimated in preparations of heavy sarcolemma isolated from rat myocardium. Emotional-painful stress (EPS) decreased the enzymatic activity by 20%, whereas the rate of the enzyme thermodenaturation was increased 2-3-fold. A thermodynamic analysis enabled to find a decrease in the energy of activation of the process after the stressory effects as well as alterations in entalpy and entropy under conditions of practically constant changes in free energy; this suggests the possible conformational transformations in the Na+, K+-ATPase molecules in EPS, resembling the state of denaturation. Lipid peroxidation was essential for the decrease in the enzyme thermostability. Activation of lipid peroxidation in the sarcolemma native membranes was accompanied by impairments typical for EPS. Preadministration of an antioxidant ionol before stress protected both the activity and thermostability of Na+, K+-ATPase. Adaptation to EPS by means of multiple short-term stressory actions prevented also the enzyme impairment. Mechanisms of the stress arrhythmogenic effect are discussed.

[The tissue specificity of the protective action of cytoplasmic factors on the membrane-bound system of Ca2+ transport in the sarcoplasmic reticulum of the heart and the skeletal muscles]. / Tkanespetsifichnost' protektornogo deistviia tsitoplazmaticheskikh faktorov na membranno-sviazannuiu sistemy transporta Ca2+ v sarkoplazmaticheskom retikulume serdtsa i skeletnykh myshts.

Whether soluble cytoplasmic factors (SCF) can protect the membrane-associated Ca2+ transport system in sarcoplasmic reticulum (SR) was studied in controls, stress and adaptation to it. Ca-transport was damaged in stress much more in the skeletal muscles compared to the heart. Initial performance of Ca-pump in the skeletal muscles was decreased by 43%, in the heart--no change. After stress, thermoresistance of the enzyme in the skeletal muscles was 3-5 times less than in the myocardium. The enzyme reaction on adaptation and stress in both tissues is the same--a significant rise in Ca-pump thermoresistance. When preadapted animals are exposed to stress, deceleration of the initial speed and resistance of the enzyme in the myocardium are fully prevented while in the skeletal muscles Ca-pump resistance is higher than in the controls. In the heart, SCF have a protective effect on thermoresistance. In the skeletal muscles, SCF protect initial speed of the enzyme in the control, in stress and adaptation to it. A cross-over protective SCF (from adapted animals) effect was found on the stress-impaired membrane system of Ca-transport. Adapted SCF elevate 2.5-fold thermoresistance of the enzyme. Correlation between cytoplasmic and membrane protective mechanisms in stress and adaptation to it is considered.

[Adaptation to hypoxia and hyperoxia improves physical endurance: the role of reactive oxygen species and redox-signaling].

We have conducted theoretical foundation, experimental analysis and a pilot study of a new method of adaptation to hypoxia and hyperoxia in the prevention of hypoxic and stress-induced disorders and improving the body's tolerance to physical stress. It has been shown in the experimental part that a combination of physical exercise with adaptation to hypoxia-hyperoxia significantly increased tolerance to acute physical load (APL) and its active phase. Analysis of lipid peroxidation processes, antioxidant enzymes and HSPs showed that short-term training for physical exercise by itself compensates the stressor, but not the hypoxic component of the APL, the combination of training with adaptation to hypoxia-hyperoxia completely normalizes the stressor and hypoxic components of APL. The pilot study has been performed to evaluate the effectiveness of hypoxic-hyperoxic training course in qualified young athletes with over-training syndrome. After completing the course of hypoxia-hyperoxia adaptation, 14 sessions, accompanied by light mode sports training, the athletes set the normalization of autonomic balance, increased resistance to acute hypoxia in hypoxic test, increased physical performance--increased PWC170, maximal oxygen consumption (VO2max) parameters, their relative values to body mass, diminished shift of rate pressure product in the load. Thus, we confirmed experimental findings that hypoxic-hyperoxic training optimizes hypoxic (increased athletes resistance to proper hypoxia) and stress (myocardium economy in acute physical stress testing) components in systemic adaptation and restoration of athletes' with over-training syndrome.

[Particularities of adrenergic regulation and the function of cardiovascular system at remote periods after myocardial infarction in rats of different strains].

UNLABELLED: Heart function was studied in the August rats with innate raised sympathetic-adrenal system and in the Wistar rats through the period of 3 month after myocardial infarction. The sizes of the postinfarction scars were similar in the rats under comparison (56-62%) but end-diastolic pressure in Wistar rats and in August rats was 18.7 +/- 2.2 mm Hg and 11.8 +/- 0.7 mm Hg. Under the maximum isometric load induced by the aorta coarctation, the work efficiency of the heart in the August rats was greater than in the Wistar rats. During the postinfarction period, plasma catecholamine (CA) in August rats was higher than in Wistar rats. In the adrenal glands, the CA contents in August rats increased and in Wistar rats decreased. The activity of CA resynthes in the adrenal glands and in the hypothalamus in August rats did not change and in Wistar rats increased. The blood contents of nitrate and nitrite and hemine oxygenase-1 level in the myocardium of August rats were increased in contrast to Wistar rats. THE CONCLUSION: the higher viability of the myocardium in August rats with long existing postinfarction cardiasclerosis is to a considerable extent associated with lowered activation of the sympathetic-adrenal system under more expressing activation of NO-system and antioxidant protection.

[Reactive oxygen species and redox-signaling during adaptation to changes of oxygen level].

Review of last 15 years literature and own experimental data on role of reactive oxygen species (ROS) and redox signalization in induction of cell protective systems and development of adaptive resistance. Modem ideas of ROS involvement in redox signalization, induction of transcription factors and protective proteins, ways of cell response to ROS, essential limitations of exogenic antioxidants are shown. Concept of ROS involvement in non-specific component of increase resistance is introduced. Peculiarities of author's method of adaptation to change oxygen level are discussed. Experimental data on efficacy of adaptation to periodic hypoxiahyperoxia from ROS-induced stresses are presented.

Induction of HSPs and antioxidant defense enzymes during activation of free radical oxidation at the early stage of hypokinesia.

We studied the stress component of the early stage of hypokinesia during hindlimb unloading. The intensity of free radical processes was evaluated and the content of protective proteins (antioxidant defense enzymes and proteins of the HSP family) was measured in the heart and liver. Three-hour hypokinesia increased the content of constitutive protective proteins, including hemoxygenase-2 and antioxidant defense enzymes, in the heart. Hypokinesia for 72 h was accompanied by more potent activation of antioxidant defense enzymes and increase in the content of inducible hemoxygenase-1, which leads to partial compensation of activated free radical oxidation. In the liver, hypokinesia of different duration suppressed the protective systems: the synthesis of inducible and constitutive hemoxygenases and antioxidant defense enzymes decreased, while the sensitivity of liver membrane structures to reactive oxygen species increased. We revealed a tissue-specific response to hypokinesia: pronounced damaging effect predominated in the liver and partial compensation of elevated production of reactive oxygen species was observed in the heart due to activation of protective systems.

[Variability of hemodynamic parameters and resistance to stress damage in rats of different strains].

Total power of heart rate variability and baroreflex sensitivity were significantly smaller in the August rats than in the Wistar rats, but adrenal and plasma catecholamine contents were considerably higher in the former ones. 1 hour after stress (30 min in cold water), plasma catecholamine was increased 2-fold in Wistar rats, while in August rats the adrenaline concentration increased only by 58% and the were no changes in noradrenaline content. At the same time, activation of catecholamine metabolism in the adrenal glands was similar in both groups. The oxidative stress induced by hydrogen peroxide depressed the contractile function of isolated heart in the August rats to a smaller extent as compared to Wistar rats, control ones and after the cold-water stress. This effect correlated with more pronounced stability ofantioxidant enzymes in the August rats. It seems that the greater resistance to stress damage in the August rats is mediated by enhanced power of defense mechanisms both at systemic and cellular levels.

[The role of free radical processes and redox-signalization in adaptation of the organism to changes in oxygen level].

Data are presented on participation of free-radical oxygenation in development of the organism adaptation. The redox-signalization concept is discussed in the aspect of its responsibility for the initial stage of external signal transmission to the cell genetic apparatus. The pro- and antioxidant system ratio is noted as important for assessment of formation of the cell structure and the tissue resistance. A protective effect of periodic hyperoxia was shown as well as regularities of its development similar formation of adaptation to the periodic hyperoxia.

Adaptation to periodic hypoxia and hyperoxia improves resistance of membrane structures in heart, liver, and brain.

A novel principle of short-term periodic adaptive training by varying the oxygen level from hypo- to hyperoxia is substantiated both theoretically and experimentally. Short-term adaptation to hypoxia-normoxia produced a membrane-protective effect in the heart and cerebral cortex, but increased the sensitivity to free radical oxidation and decreased the level of components of the antioxidant defense system in the liver. Hypo-hyperoxia adaptation produced a membrane-stabilizing effect in the heart, brain, and liver, which was more pronounced compared to the effect of hypoxia-normoxia training. In contrast to hypoxia-normoxia adaptation, in case of hypo-hyperoxia training the adaptive defense developed as early as 15 days after the start of training.