[QSAR-modeling of desoxyuridine triphosphatase inhibitors in a series of some derivatives of uracil]. / QSAR-modelirovanie ingibitorov dezoksiuridintrifosfatazy v riadu nekotorykh proizvodnykh uratsila.

Due to the widespread prevalence, deoxyuridine triphosphatase (UTPase) is considered by modern biochemists and physicians as a promising target for the development of drugs with a wide range of activities. The therapeutic effect of these drugs will be due to suppression of DNA biosynthesis in various viruses, bacteria and protozoa. In order to rationalize the search for new dUTPase inhibitors, domestic and foreign researchers are actively using the QSAR methodology at the selection stage of hit compounds. However, the practical application of this methodology is impossible without existence of valid QSAR models. With the use of the GUSAR 2013 program, a quantitative analysis of the relationship between the structure and efficacy of 135 dUTPase inhibitors based on uracil derivatives was performed in the IC50 range of 30¸185000 nmol/L. Six statistically significant valid consensus models, characterized by high descriptive ability and moderate prognostic ability on the structures of training and test samples, are constructed. To build valid QSAR models for dUTPase inhibitors can use QNA or MNA descriptors and their combinations in a consensus approach.

[Express evaluation of antioxidant activity of uracil derivatives].

Using photometric methods the antioxidant activity of 19 uracil derivatives has been analyzed. The test using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals can be applied for the rapid assessment of antioxidant activity of uracils. Among uracil derivatives studied the compounds possesing a proton-donor group in C-5 position--free or alkylated amino group, as well as hydroxyl group were the most active: 5-aminouracil (IC50 3 mg/ml), 5-amino-6-methyluracil (IC50 of 5 mg/ml), 5-hydroxy-6-methyluracil (IC50 of 15 mg/ml), 5-hydroxy-1,3,6-trimethyluracil (IC50 of 15 mg/ml), 5-ethylamino-6-methyluracil (IC50 of 20 mg/ml), 5-methylamino-6-methyluracil (IC50 of 20 mg/ml), 5-allylaminouracil (IC50 of 20 mg/ml), 5-amino-1,3,6- trimethyluracil (IC50 of 25 mg/ml). These uracil derivatives were more active than the reference compounds ionol (IC50 of 30 mg/ml) and a-naphthylamine (IC50 of 45 mg/ml), but less active than ascorbic acid (IC50 0.8 mg/ml). There was a correlation between the results of DPPH test (IC50) and coupling constants of uracil derivatives with peroxide radicals of 1,4-dioxane (fk7). Uracil with proton-donor group at C-5 also showed high ferrum-reducing activity as determined by FRAP.

[Diurnal rhythm of sensitivity of nerve cell genome activity to changed motor regime]. / Sutochyi ritm chuvstvitel'nosti aktivnosti genoma nervnykh kletok k izmenennomu dvigatel'nomu rezhimu.

Diurnal variations in the incorporation of labelled precursors of RNA and proteins into the spinal, stem, and cerebral cell populations of the rat nervous system were studied on surviving brain slices under standard conditions and during exercise by swimming. Cosinor analysis of the relative level of 3H-uridine incorporation into spinal ganglia L5, superior cervical ganglia, spinal cord L5, hypothalamic suprachiasmatic nuclei and cerebellar cortex revealed that the arrangement of the calculated acrophases of these organs in the dark period of a day. The acrophases of visual and somatosensory cortical cells were observed in the light period of a day. The calculated maximum values of the rate of 3H-leucine incorporation into nerve cell proteins (the internal acrophases ranged from 3 to 9 hours) were seen at certain intervals. Thus, the processes providing the function of a protein-synthesizing apparatus of nerve cells are characterized by a definite time organization and these processes vary significantly in their activity during a diurnal cycle. Depending on the time of a day when exercise was performed, there were differences in the changing activity of genetic and protein-synthesizing apparatuses during nerve cell reactions. This is associated with the different time of the onset of a reaction, passage of its some stages, with the rate of processes, and with the periods of normalization. The curves of a phasic response are discussed.

[Fast transport of proteins in the axons of spinal cord motor neurons in rats adapted and unadapted to physical loading]. / Bystryi transport belkov aksonami motoneironov spinnogo mozga krys, predvaritel'no adaptirovannykh i neadaptirovannykh k vozdeistviiu fizicheskoi nagruzki.

The prolonged nonintensive swimming without load (12+ +2 h) provoked a decrease of the rate of fast axonal transport in the motor fibres of the sciatic nerve by 18% and of the overall amount of transported proteins 2-fold as compared with control. The relatively short-term but more intensive activity (swimming with the load 1/11 of body weight during 60+ +10 min.) results in an increase of the rate by 10% and the overall amount of fast transported proteins 2-fold. Daily swimming (3 h. without load and 10-15 min. with load) during 20 days returns the above parametres to the controls. The compensative-adaptive changes of fast anterograde transport are the fact that may be involved in trophic communication between neuron and target cell.

[Immunogenesis and axoplasmic transport in Wistar rats]. / Immunogenez i aksoplazmaticheskii transport u krys Vistar.

Immunization of Wistar rats with thymus dependent antigens (sheep red blood cells-SRBC) is accompanied by a reliable increase in the synthesis of RNA and proteins in thalamic cerebral cortex and spinal marrow (48 hrs after antigen injection) and also in an increase in the intensity of rapid axoplasmic transport (RAT) along motor fibers of sciatic nerve (5,48,72 hrs following the beginning of immunization). There was a consecutive augmentation in AFC number in mesenteric and partly in inguinal lymph nodes (96 hrs after SRBC injection). Thus, time dependence between immunogenesis and axoplasmic transport in experimental animals (Wistar rats) was determined for the first time. It identifies another, previously unstudied, channel in interactions of immune and nervous systems.

[Cosinor analysis of the circadian dynamics of transcription in populations of neurocytes from a number of sections of the rat nervous system]. / Kosinor-analiz tsirkadnoi dinamiki transkriptsii v populiatsiiakh nevrotsitov riada otdelov nervnoi sistemy krys.

Diurnal fluctuations of endogenous RNA polymerases activity were studied in the cell nucleus of the cerebral stem and spinal nervous system populations (neurocytes of the hypothalamic suprachiasmatic nuclei, superior cervical ganglia, spinal ganglia L5, motoneurones of the spinal cord and Purkinje cells) were revealed. The acrophases of the visual cortex neurones were observed just before light reception.

[Changes in the axonal protein transport under conditions of elevated functional activity of the neurons]. / Izmeneniia aksonal'nogo transporta belkov v usloviiakh povyshennoi funktsional'noi aktivnosti neironov.

The prolonged nonintensive physical activity by swimming without load (12 +/- 2 h.) has no effect on the overall amount of fast and slow transported proteins of transport velocity in rat central and peripheral sensory fibres of the sciatic nerve. However, the rate of fast axonal transport in the motor fibres decreases by 18% and the amount of proteins by a factor of 2 as compared with control. The rate of slow axonal transport does not change, but the mean level of transported labeled proteins decreases by 1.9 times. The relatively short-term but more intensive activity (swimming with the load during 60 +/- 10 min.) provokes an increase of the rate by 10% and the overall amount of fast transported proteins by 2 times. The rest of the animals during 6 h. returns the above parameters to control values. A suggestion is made that the rate and the amount of transported proteins depend on the variations in functional state of the neurons and their axons.

[Changes in the rate of axonal flow of proteins through the branches of motor and sensory neurocytes during the period of intense growth of the sciatic nerve in rats]. / Izmenenie skorosti aksonal'nogo toka belkov po otrostkam motornykh i chuvstvitel'nykh nevrotsitov v period intensivnogo rosta sedalishchnogo nerva krysy.

14C-glycin was microinjected into the ventral horns of the spinal cord or spinal ganglions. The rate of fast and slow axoplasmic transport of proteins in the axons of motor and sensory neurons was studied by liquid scintillation. Motor fibers of the sciatic nerve manifested a marked decrease (P less than 0.05) in the rate of slow axoplasmatic transport of the labeled protein from 5.25 +/- 0,31 in 2-week-old rats to 3.45 +/- +/- 0.23 mm/day in 4-week-old animals and a significant increase in the rate of fast axoplasmic transport (P less than 0.05) from 99 +/- 13.2 (2-week-old rats) up to 198 +/- 18.9 mm/day (in 4-week-old rats). The two-week-old rats had higher rates (4.5 +/- 0.3 mm/day) of slow axoplasmic transport of the labeled protein in the central and peripheral axons of sensory neurocytes and lower rates of fast axoplasmic transport (126 +/- 14.7 mm/day) as compared with 4-week-old animals (3.75--4.1 +/- 0.25 -- slow transport; 144 +/- 23.34 mm/day -- fast transport). However, the differences described are not significant.

[Duration of the mitotic cyle of mouse liver cells at different stages of carcinogenesis induced by ortho-aminoazotoluene]. / Prodolzhitel'nost' mitoticheskogo tsikla kletok pecheni myshei na razlichnykh stadiiakh kantserogeneza, indutsirovannogo ortoaminoazotoluolom.

Orthoaminoazotoluol was administered to mice for a period of 9 months. The duration of the G2-and S-periods of the mitotic cycle determined by the autoradiographic method, and mitotic duration--by the stathmokinetics technique with the use of colchicine in the intact liver, the cells of the adenoma nodes, and primary hepatomas. The duration of the S-period of the intact hepatocytes and adenoma nodes proved to be equal (13.8 hours, respectively). As to the primary hepatoma cells--it decreased to 12.8 hours. The duration of the G2-period showed no essential change during the carcinogenesis, and was equal to 2.2--2.7 hours. An average mitotic duration in the course of 24 hours was also constant and was approximately equal to 1 hour. A rise in the number of mitoses and PNA-synthesizing cells in the hepatomas occurred as a result of entering in mitosis and the S-period of a greater number of cells, but not as a result to prolongation of the duration of the S-and M-periods of the mitotic cycle.

[Diurnal rhythm of cell proliferation at the late stages of precancerous changes in the liver induced by ortho-aminoazo-toluene]. / Sutochnye ritmy kletochnoi proliferatsii na pozdnykh stadiiakh predrakovykh izmenenii pecheni, indutsirovannykh ortoaminoazotoluolom.

Orthoaminoazotoluol was administered to mice for a period of nine months. Circadian rhythms of mitotic activity and the number of the DNA-synthesizing cells were determined by autoradiography (with the use of 3H-thymidine) at the second (adenomatous nodes) and the third (primary hepatoma) stages of carcinogenesis in the developing tumours and the surrounding liver parenchyma. The listed structures proved to have a single-peak rhythm of mitotic activity with the maximum of mitoses at 4-7 a. m.; the labeled nuclei circadian rhythm was double-peaked with the maximum at 7 p. m. and 4 a. m. The mean 24-hour values of both indices at the second and third stages of hepatocarcinogenesis were much greater than in the surrounding non-tumour tissue of the liver.

[Circadian rhythms of cell proliferation in mice during the early stages of hepatocarcinogenesis induced by ortho-aminoazotoluol]. / O sutochnykh ritmakh kletochnoi proliferatsii na rannikh stadiiakh gepatokantserogeneza myshei, indutsirovannogo ortoaminoazotoluolom

The 24-hour rhythms of the mitotic activity and the changes in the number of DNA-synthesising cells were studied in mouse hepatocytes at the early stages of carcinogenesis of the liver induced with orthoaminoazotoluol in these animals; the autoradiographic method with thymidin-3H was used. During the first stage (that of diffuse irregular hyperplasia) and the second stage (that of focal proliferation) the rhythms of of the changes in the mitotic activity of test animals as incontrols had a distinct monophasic character with the maximum number of mitoses at the early morning hours and the minimum at the evening-night hours. Under normal conditions and during the first stage of carcinogenesis of the liver the DNA-synthesizing cell rhythms had a distinct monophasic character with the maximum during the day and evening hours, respectively; during the second stage of carcinogenesis the rhythm was characterized by the appearance of the second maximum at the early morning hours. The mean 24-hour values of both indices increased during the carcinogenesis.