The Role of Smad3 in the Realization of the Growth Potential of Different Types of Neural Progenitor Cells and the Secretory Function of Neuroglia.

The features of the participation of Smad3 in the functioning of neural stem cells (NSC), neuronal committed precursors (NCP), and neuroglial elements were studied in vitro. It was found that this intracellular signaling molecule enhances the clonogenic and proliferative activities of NCP and inhibits specialization of neuronal precursors. At the same time, Smad3 does not participate in the realization of the growth potential of NSC. With regard to the secretory function (production of neurotrophic growth factors) of neuroglial cells, the stimulating role of Smad3-mediated signaling was shown. These results indicate the promise of studying the possibility of using Smad3 as a fundamentally new target for neuroregenerative agents.

Effect of Xe/O2 Inhalation on Hemostasis in Experimental Thromboplastin Pneumonitis.

We studied the effectiveness of Xe/O2 mixture inhalation (30% Xe and 70% O2, 20 min for 5 days) in a model of experimental thromboplastin pneumonitis. Inhalation of the studied mixture decreased the intensity of the inflammatory process in the lung tissue assessed by the temperature response of animals, changed lung weight and lung weight coefficient. At acute stage of pneumonitis, an increase in xenon consumption was recorded due to its retention in the gas exchange zone and a natural decrease in oxygen consumption due to partial alveolar/capillary block. The formation of pneumonitis was accompanied by a pronounced procoagulant shift in the regulation system of the aggregate state of blood. The Xe/O2 inhalations ensured physiologically optimal levels of prothrombin and activated partial thromboplastin time against the background of a moderate decrease in fibrinogen level throughout the experiment. At the same time, the activity of the natural anticoagulant antithrombin III increased from day 5 to day 14.

Effect of Paclitaxel on the Hemostatic Potential of the Blood in the Experiment.

The duration and severity of prothrombotic effects of the maximum tolerated dose of paclitaxel (40 mg/kg) were evaluated in intact outbred mice. Hemostasis was assessed before and on days 1, 2, 5, 7, 10, 15, 20, and 30 after a single injection of paclitaxel using standard coagulation tests (activated partial thromboplastin time, prothrombin time, fibrinogen concentration, and antithrombin III) and a "global" method, low-frequency piezothromboelastography. A pronounced prothrombotic effect of paclitaxel was revealed starting from the first day postinjection that consisted in intensification of fibrinogenesis up to the 7th day in parallel with activation of the anticoagulant mechanisms. On days 7-30 after paclitaxel administration, decompensation of its anticoagulant activity due to paclitaxel-induced damage to the endothelium was observed with the formation of a procoagulant status of the hemostatic potential of the blood. A single administration of the maximum tolerated dose of paclitaxel forms a powerful thrombogenic stimulus during the first week and provides a long-term/trace procoagulant shift in the hemostasis system (days 10-30).

Prevention of the Genotoxic Effects of Doxorubicin with Anthocyanin-Containing Complex from Sorbus aucuparia L. Fruit.

We studied the effect of an anthocyanin-containing complex from the fruits of S. aucuparia L. on doxorubicin-induced genotoxicity in bone marrow cells of C57BL/6 mice. The complex reduced the genotoxic effect doxorubicin in metaphase plates of bone marrow cells in 24, 48 h, and 10 days after the administration of the cytostatic. The mean number of single fragments and the fraction of cells with gaps and aberrant metaphases also decreased.

Xenon-Induced Effects in Relieving Experimental Acute Respiratory Distress Syndrome.

The effects of inhalations of an oxygen-xenon (70%/30%) mixture were studied in two models of acute respiratory distress syndrome caused by intratracheal administration of 0.5 mg/kg LPS or 0.04 ml acidin-pepsin (pH 1.2). Inhalation of the oxygen-xenon mixture inhibited the development and reduced the intensity of the inflammatory process in the lung tissue, which was assessed by the dynamics of lung weight and body weight of animals: the therapeutic exposure decreased both parameters. It was found that the thrombogenic stimulus, pathognomonic for the development of acute respiratory distress syndrome, decreased under the effect of oxygen-xenon inhalations, while the level of natural anticoagulant antithrombin III increased.

Psychopharmacological Effects of Stimulation of the Functions of Neural Stem Cells by STAT3 Inhibitor under Conditions of Modeled Ethanol-Induced Encephalopathy.

The psychopharmacological effects of a stimulator of functions of progenitor cells of the nervous tissue STAT3 inhibitor (STAT3 Inhibitor XIV, LLL12) were studied under conditions of modeled alcoholic encephalopathy in C57BL/6 mice. The pharmacological agent corrected the parameters of exploratory behavior (characterizing predominantly cognitive activity) in the experimental animals at the late terms of observation. At the same time, the reproducibility of the conditioned passive avoidance response developed at the beginning of the course STAT3 inhibitor administration decreased. These effects developed against the background of a significant increase in the content of neural stem cells and their proliferative activity in the paraventricular zone of the brain.

The Role of JAK and STAT3 in Regulation of Secretory Function of Neuroglial Cells of Different Types in Ethanol-Induced Neurodegenerationt.

The effects of JAK and STAT3 inhibitors on the production of neurotrophic growth factors by different types of neuroglial cells were studied under conditions of in vitro and in vivo models of ethanol-induced neurodegeneration. It was shown that these signaling molecules do not participate in the secretion of neurotrophins by intact astrocytes and oligodendrocytes. The inhibitory role of JAK in the regulation of this function of microglial cells was revealed. We also revealed significant changes in the role of JAK and the presence of STAT3 specifics within the framework of JAK/STAT signaling in the production of growth factors by various glial elements under the influence of ethanol. Neurodegeneration modeled in vitro led to the appearance of a "negative" effect of STAT3 on the production of neurogenesis stimulants by all types of glial cells. Moreover, the role of STAT3 in oligodendrocytes and microglial cells generally corresponded to that of JAK/STAT signaling. In astrocytes, only selective blockade of STAT3 (but not JAK) led to stimulation of their function. In mice subjected to prolonged peroral alcoholization, the neuroglial responses to the pharmacological regulation of JAK/STAT signaling were different. An inversion of the role of JAK and STAT3 in the production of neurotrophins by oligodendrocytes was noted. In addition, JAK inhibitor did not stimulate secretory function of microglial cells under conditions of prolonged exposure to ethanol in vivo.

Role of MAPK ERK1/2 and p38 in the Regulation of Secretory Functions of Different Populations of Neuroglia in Ethanol-Induced Neurodegeneration.

We studied the participation of ERK1/2 and p38 in secretion of neurotrophic growth factors by various types of neuroglia under conditions of in vitro and in vivo modeled ethanol-induced neurodegeneration. The inhibitory role of these protein kinases in the production of neurotrophins by intact astrocytes and the absence of their participation in the regulation of functions of oligodendrocytes and microglial cells were shown. Under conditions of ethanol neurotoxicity, the role of ERK1/2 and p38 in the production of growth factors by glial elements was significantly changed. Neurodegeneration modeled in vitro led to inversion of the role of both protein kinases in the secretion of neurotrophins by astroglia and inhibition of the cytokine-synthesizing function of oligodendrocytes and microglial cells by ERK1/2 and p38. In mice receiving ethanol per os for a long time (as well as in cells in vitro exposed to ethanol), mitogen-activated kinases stimulated the function of astrocytes and inhibited the production of growth factors by microglial cells. At the same time, chronic alcoholization was accompanied by the appearance of the stimulating role of ERK1/2 and p38 in the implementation of the secretory function by oligodendrocytes.

Pharmacological Correction of Cisplatin-Induced Hemostatic Disorders.

A single intraperitoneal administration of cisplatin in the MTD to outbred female mice disturbed hemostasis and formed the procoagulant phenotype of hemostatic potential on days 7-10 culminating in a pronounced hypocoagulation on day 15. Hemostasis was corrected with warfarin and an extract containing furocoumarins composed of isopimpinellin (42.97%), bergapten (35.18%), and xanthotoxin (15.41%). The extract was standardized with gas chromatography-mass spectrometry, thin-layer chromatography, and HPLC. Furocoumarins and reference drug warfarin were administered intragastrically during 4 days starting on day 6 after the administration of cisplatin. Both furocoumarins and warfarin corrected hypercoagulation on days 7-10. On day 10, furocoumarins normalized coagulation, whereas warfarin resulted in hypocoagulation. On days 15-30, no effects of warfarin were observed. furocoumarins corrected hypocoagulation on days 15-20 with prolongation of this effect up to experimental day 30.

Changes in Hemostasis System in Outbred Female Mice with Cisplatin-Induced Procoagulant Status.

Procoagulant status was modeled in outbred female mice by single injection of cisplatin in a maximum tolerated dose and hemostasis parameters monitored over 30 days by methods of coagulogram and low-frequency piezothromboelastography (global test). Monitoring revealed waveform changes in the hemostatic potential: the structural and chronometric hypercoagulation recorded starting from the first day and attaining its maximum on days 5-7 was followed by hypocoagulation and returned to normocoagulation on day 30. This pattern reflects prolonged effect of cisplatin: formation of severe dysfunction of the endothelium providing the main anticoagulant pool of hemostasis (day 1) aggravated by disturbances of the plastic functions of the liver (days 15-20), and recovery (days 20-30).

Dalayed Effects of Antitumor Drug Paclitaxel on the Hereditary Material and Hemopoietic System of CBA Mice.

Paclitaxel in a single MTD of 40 mg/kg caused chromosome aberrations and genome changes (polyploidy) in the bone marrow cells of mice early and 3 months after the injection. The quantity of early precursors of erythropoiesis in the bone marrow decreased, as did their proliferative potential irrespective of the animal gender. Injection of paclitaxel in the MTD caused the development of bone marrow hypoplasia during the early period of observation (up to 14 days) and 3 months after injection.

Studying the General Toxicity and Cumulative Properties of a Radiopharmaceutical Nanocolloid, (99m)Tc-Al2O3.

We studied toxicity of a new Russian radiopharmaceutical Nanocolloid, (99m)Tc-Al2O3. Tests for acute toxicity showed that this agent belongs to a class of moderate-toxicity substances and does not have cumulative properties. The evaluation of subchronic toxicity after subcutaneous injection of this product to rats (0.04, 0.2, and 0.4 ml/kg) and rabbits (0.02 and 0.2 ml/kg) for 7 days did not reveal changes in the general state, temperature, body weight, indices of the peripheral blood and bone marrow, functions of the heart, liver, kidneys, and nervous system, and morphological characteristics of the internal organs in animals. The drug does not produce a local irritant effect.

The efficiency of non-photochemical fluorescence quenching by cation radicals in photosystem II reaction centers.

In a direct experiment, the rate constants of photochemical k p and non-photochemical k p+ quenching of the chlorophyll fluorescence have been determined in spinach photosystem II (PS II) membrane fragments, oxygen-evolving PS II core, as well as manganese-depleted PS II particles using pulse fluorimetry. In the dark-adapted reaction center(s) (RC), the fluorescence decay kinetics of the antenna were measured at low-intensity picosecond pulsed excitation. To create a "closed" P680+Q A- state, RCs were illuminated by high-intensity actinic flash 8 ns prior to the measuring flash. The obtained data were approximated by the sum of two decaying exponents. It was found that the antennae fluorescence quenching efficiency by the oxidized photoactive pigment of RC P680+ was about 1.5 times higher than that of the neutral P680 state. These results were confirmed by a single-photon counting technique, which allowed to resolve the additional slow component of the fluorescence decay. Slow component was assigned to the charge recombination of P680+Pheo- in PS II RC. Thus, for the first time, the ratio k p+ /k p â‰… 1.5 was found directly. The mechanism of the higher efficiency of non-photochemical quenching comparing to photochemical quenching is discussed.

Study of Subchronic Toxicity of Relatox on Sexually Immature Animals.

Intramuscular injections of Relatox in therapeutic and toxic doses to young outbred laboratory rats for 14 days caused no changes in the peripheral blood and bone marrow parameters, serum biochemical parameters, and morphology of the major viscera. In the toxic dose, the drug caused local irritation (inflammation, atrophy, and sclerosis in muscle tissue). Regeneration processes started in muscle tissue 7 days after Relatox withdrawal.

[EFFECT OF SYNTHETIC ANTIOXIADNT THIOPHAN AND SCUTELLARIA BAICALENSIS ROOT EXTRACT ON DRUG-INDUCED MUTAGENESIS].

Gene protective properties of synthetic antioxidant thiophane and the extract of in vitro cultivated roots of Scutellaria baicalensis were studied on the model of Dr. melanogaster larvae genetic structure damage by drugs cisplatin and cyclophosphan (cyclophosphamide). It is established that adding thiophane or Scutellaria baicalensis root extract to a nutrient medium leads to a decrease in amount of Dr. melanogaster recombinants (females bearing recessive yellow and/or singed marker mutations).

Changes in the state of hemoglobin in patients with coronary heart disease and patients with circulatory failure.

Morphology of erythrocytes and conformation of hemoglobin-derived hematoporphyrin were studied in patients with coronary heart disease (CHD) and patients with circulatory failure using laser interference microscopy and Raman spectroscopy. Correlation was revealed (r=0.81) between hemoglobin oxygen saturation and oxyhemoglobin fraction in erythrocytes evaluated by Raman spectroscopy. Patients with CHD and patients with circulatory failure showed reduced oxygen-releasing capacity of hemoglobin and hemoglobin content and increased oxygen-binding capacity of hemoglobin, and hemoglobin affinity for oxygen. Significant differences from the control were observed only in patients with circulatory failure. It was found that hemoglobin content, hematocrit, and the shape of erythrocytes during CHD and circulatory failure did not differ from the control, whereas the area of erythrocytes was increased.

[Evaluation of manganese-trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetate complex (Cyclomang) as paramagnetic contrast agent for magnetic resonance imaging].

Preclinical evaluation of a 0.5 M solution of the manganese(II)- trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetate complex (Mn-DCTA, Cyclomang) has been carried out with a view to substitution of potentially toxic gadolinium-containing paramagnetic contrast agents for clinical MRI routines. The toxicological tests of Mn(II)-DCTA were performed on mice and rats. Liquid phantoms were used for evaluating the relaxivity of Mn(II)-DCTA in comparison to that of Gd(III)-DTPA and Mn-DTPA. The diagnostic imaging properties of Mn(II)-DCTA were quantitatively assessed on dogs with cerebral meningeomas (n = 10). The LD50 upon single administration in rats was above 17 ml/kg, thus slightly exceeding the corresponding values for of Gd(III)-DTPA and Mn-DTPA. The relaxivity of Mn(II)-DCTA amounted to R1 = 3.68 (mM(-1) x s(-1)) and did not differ significantly from the values known for Gd-DTPA and Mn-DTPA. Mn(II)-DCTA ensured high-intensity contrast of tumor areas in brain of dogs. It is concluded that Mn(II)-DCTA can be employed as a paramagnetic contrast agent in routine MRI studies and is worth further clinical evaluation.

[Effect of Scutellaria baicalensis root extract on cytogenetic damage induced by paclitaxel and cisplatin in mice].

The effect of root extract of Baikal skullcap (Scutellaria baicalensis) cultivated in vitro, on the gene structure of CBA/CaLac mice bone marrow cells damaged by anticancer drugs paclitaxel and cisplatin has been studied. It is established that the root extract exhibits gene protective property upon both single and chronic administration.

Pharmacology of somatrotropin pegylated by electron-beam synthesis nanotechnology.

Pharmacological characteristics of somatotropin pegylated using electron-beam synthesis nanotechnology (PEG-STH) were studied. Oral PEG-STH stimulated the intensity of protein and lipid metabolism and endochondral bone growth without modifying the processes of periosteal and endosteal bone formation. Specific activity of this substance administered orally significantly surpassed that of parenteral non-modified growth hormone.

Evaluation of anti-inflammatory effects of Trombovazim in the model of liver ischemia-reperfusion.

Administration of enzyme preparation Trombovazim as a corrector of ischemic damage to animals with experimental liver ischemia-reperfusion reduces neutrophilic infiltration of liver parenchyma and decreases hyperfermentemia, which attests to a decrease in the intensity of destructive changes in hepatocytes.