[Potential cytostatic effect of the maleimide derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1-H-pyrrol-2,5-dione].

The cytostatic/cytotoxic effects of the maleimide derivative 1-(4-Cl-Benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrol-2,5-dione (MI-1) have been estimated on epithelial derived human cell cultures (Colo 205, MCF-7, and Hela). The anticancer and toxic effects of MI-1 have been investigated on DMH-induced cancer development and normal colon morphology in rats. The results showed that the compound studied has low cytotoxicity but produces a strong antiproliferative effect on cell cultures and partially suppresses colon cancer development in DMH-induced model. The MI-1 effect on normal colon mucosa is insignificant, and no destructive changes have been detected in the intestine of rats. This maleimide derivate can be considered as a promising anticancer drug.

[Effect of dihydropyrrol and maleimide derivatives on the state of the liver and colon in normal rats and those with colorectal carcinogenesis induced by dimethylhydrazine].

No liver and colon alterations in rats, caused by cytostatic compounds 5-amino-4-(1,3-benzothyazol-2-yl)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one (D1) and 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrol-2,5-dione (MI-1) when administered over a long time were found, as evidenced by the histopathological data and the data of activity of transaminases, alkaline phosphatase and lactate dehydrogenase in the blood serum. D1 and MI-1 in vivo decrease the total area of DMH-induced colon tumors in rats by 46-60%. Furthermore, D1 and MI-1 partially protect the liver and colon mucosa from toxic effects caused by 1,2-dimethylhydrazine (DMH) reducing DNA oxidative modifications, as evidenced by urine 8-hydroxydeoxyguanosine level. The effects of both compounds are similar, but MI-1 is less toxic for the liver and colon of intact animals possessing more pronounced antitumor activity and protective properties in the setting of chemically induced carcinogenesis.

[Mechanisms of nephrotoxicity of novel anticancer compound maleimide derivative MI-1].

The features of the impact of the maleimide derivative 1-(4-Cl-benzyl)-3-chloro-4-(CF3-fenilamino)-1H-pyrrole-2,5-dione (MI-1) on the viability and apoptosis-induced cell death of renal proximal and distal tubular epithelial cells and the amount of total and phosphorylated ERK1/2 were studied in order to establish possible mechanisms of nephrotoxicity induced by of MI-1. The viability and apoptosis of renal epithelial tubular cells after incubation with MI-1 were perfomed by 3,4,5-dymetyltiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT)-test and by flow cytometry after staining with specific antibodies to annexin V, respectively. The amount of ERK 1/2 was determined by Western blotting. The data indicate that MI-1 was more toxic with respect to the epithelial cells of distal than proximal tubule cells. The apoptosis-induced cell death pathway is involved in the mechanisms of MI-1 cytotoxicity. One of the possible mechanisms of MI-1 nephrotoxicity is increase in phosphorylation of ERK1/2 in the distal tubules. At the same time the increase amount of total ERK1/2 in proximal tubules under the influence of MI-1 may contribute to the survival of proximal tubular epithelial cells under the impact of a toxic factor or oxidative stress.

[Effects of ubiquitin gene silencing in anoxia-reoxygenation of cultured cardiomyocytes].

Ubiquitin-dependent proteasomal proteolysis is crucialin the turnover of cardiomyocytes functional proteins (actin, myosin, ion channels at. al.), therefore, investigation of cell death after ubiquitin (UBB) gene silencing using RNA interference and anoxia-reoxygenation (AR) modeling appears to be attractive. Cardiomyocytes were transfected by siRNA to ubiquitin gene using electroporation procedure, and then primary culture was treated by 30 min of anoxia and 60 min of reoxygenation. The number of living, necrotic and apoptotic cardiomyocytes was determined by fluorescence microscopy. The level of UBB and proteasome subunits beta5 (PSMB5) and beta9 (PSMB9) mRNA expression was estimated by real-time PCR. It was shown that UBB mRNA expression was increased by 2.1 times after AR modelling (P < 0.05). Small interference RNA injection in cell culture decreased ubiquitin, PSMB5 and PSMB9 expression by 2.4 (P < 0.05), 1.3 (P > 0.05) and 1.6 (P < 0.05) times, respectively, compared with control (scrambled siRNA introduction). At the same time, the number of living cardiomyocytes decreased to 70.26 +/- 1.54%, P<0.05, and the level of necrotic cells, apoptotic cells and cells with signs of autophagy augmented by 25.92 +/- 1.52%, (P = 0.38), 4.32 +/- 0.53% (P = 0.15) and 38.2 +/- 3.81% (P = 0.001), respectively. Ubiquitin silencing after AR (30 min/l h) increased the number of living cells by 3.7% and decreased the number of necrotic cells by 4.7% and did not alter the apoptotic and autophagic cells populations. The data obtained indicate that ubiquitin gene silencing, mRNA expression of which augmented during AR, induces necrotic and autophagic death of intact neonatal cardiomyocytes in culture, but enhances the AR resistance of these cells to some extent.

[State of the liver antioxidant system and content of matrix metalloproteinase-2 of the large intestine under the effect of maleimide derivative in experimental colorectal carcinogenesis in rats].

The maleimide derivative--1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrol-2.5-dione (MI-1) with cytostatic activity did not cause substantial changes of liver antioxidant system and level of matrix metalloproteinase-2 in intestinal mucosa after chronic treatment (for 20 weeks). MI-1 did not cause significant changes in the content of thiobarbituric-active products and plasma membrane protein carbonyl groups in the rat liver. However activities of superoxide dismutase, glutathione peroxidase, and content of reduced glutathione were decreased in both doses--0.027 and 2.7 mg/kg. The level of matrix metalloproteinase-2 in intestinal mucosa was decreased just in maximum dose--2.7 mg/kg. The contents of thiobarbituric-active products, protein carbonyl groups, reduced glutathione, matrix metalloproteinase-2, activities of glutathione peroxidase and glutathione-S-transferase in the liver cells have increased in 1.2-dimethylhydrazine-induced colon cancer in rats. The activities of enzymes of the first line of antioxidant defense--superoxide dismutase and catalase were decreased to 40%. The maleimide derivative prevents development of oxidation stress and partially reduce them to control level.

[Effect of maleimide derivative on the morpho-functional state of the kidney in experimental colon carcinogenesis in rats].

The effect of long-term administration of the novel maleimide derivative with antiproliferative activity on kidney morpho-functional state in experimental (1,2-dimethylhydrazine-induced) colon carcinogenesis has been investigated on 60 male rats. 1,2-Dimethylhydrazine was injected subcutaneously in dose 20 mg/kg one time per week during 20 weeks. Maleimide derivative in dose of 0,027 and 2,7 mg/kg was given per os daily during the same time. The state of kidneys was evaluated after morphometrical investigation and measurement of urea, creatinine and chlorides levels in blood serum. It hasn't been revealed significant structure-functional changes in kidneys after daily administration during 20 weeks. The induction of proliferate activity of distal tubules epithelial cells and reducing of epithelial layer thickness in proximal tubules in kidneys in rats with experimental carcinogenesis has been observed. In experimental colon carcinogenesis, maleimide derivative displays some protective action to tubular apparatus of rat's kidney cortical nephrons and reduces the frequency of preneoplastic changes in tubules epithelial cells.

[Ecto-nucleotidases of ectonucleoside triphosphate diphosphohydrolase family: structure, localization and functional significance].

Ecto-nucleotidases are enzymes of hydrolase class. They split extracellular nucleoside tri- and diphosphate. In this review a short history of these enzymes investigation, classification, structure, and functional significance of ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDase) has been presented. These enzymes are glycoproteins anchored in membranes. They do not form phosphorylated enzyme's form during catalytic circle, and (by analogy with membrane-bound ATPases) form homooligomeric ensembles. Activity of these enzymes depends on bivalent ions, in particular Ca2+ and Mg2+. E-NTPDases function in the composition of ecto-nucleotidase cascade that contains other nucleotide-hydrolyzing enzymes. They regulate P2-receptors by hydrolyzing its ligand specifically ATP. Both modern information and results of our investigation about influence of different endo- and exogenous factors on activity of these enzymes has been presented.

[Evaluation of hepatotoxicity of novel maleimide derivative with cytostatic activity and its effect on peroxidation process and antioxidant system in the liver].

Novel maleimide derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrol-2.5-dione (MI-1) with cytostatic activity does not damage rat liver cells after intragastric administration. It is confirmed by alanine- and aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase activities in blood serum. Preliminary treatment with MI-1 partially prevents from liver cell damage caused by CoCl2. the content of thiobarbituric-active products, protein carbonyl groups, reduced glutathione and activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in the liver cell after one- and ten-days treatment with novel maleimide derivative have been studied. It has been determined that one-day administration of MI-1 has not caused significant changes of peroxidation process and antioxidant system in the liver cells. After ten days treatment the activity of glutathione-S-transferase has been increased, superoxide dismutase--two times decreased, but other parameters have not been significantly changed. Ten days injection of CoCl2 provokes some manifestations of oxidative stress in the liver cells that has been partially leveled by preliminary treatment with maleimide derivative.

[Disorders in lipid composition and properties of plasma membrane in epithelial cells of the placental villous chorion in chlamydial infection].

Lipid composition of plasma membranes of placental epithelial cells of villous chorion of healthy women and those with chlamydiosis has been studied. Lipid composition of plasma membranes of ill women differs from that of healthy women by reduction of total phospholipids quantity, by the increase of the level of free cholesterol and free fatty acids. A disturbance in the ratio between certain lipid fractions and increasing quantity of lysophospholipids is observed. Two-fold oppression of plasma membranes Na+, K+ -ATPase activity of placental epithelial cells of villous chorion in ill women has been detected but Mg2+, Ca2+ -ATPase activity has not changed. Thus chlamydial infection causes significant disorders in lipid composition and functioning of epithelial cells membranes of chorion.

[Effect of heavy metal mixture on the main functions of the central nervous system].

The influence of heavy metals salts mix, the most widespread pollutants of Prydnieprovsky region natural reservoirs on animal behavioral reactions, memory processes and total bioelectric activity of various brain departments has been investigated. It was revealed that heavy metals consumption with drinking water results in the development of the neurotization processes, at that due to animals hyperactivity there is an exhaustion of nervous centers that is reflected by prolongation of immobility periods in animals. Increase of the latent period of conditioned reflex formation in the 8th radial labyrinth together with decrease of task fulfillment efficiency indicate deterioration of the training ability of these animals and impairment of their short-term memory. Meaningful changes in total neocortex bioelectric activity (strengthening in specters of theta- and beta-ranges and weakening in alpha-waves area), dorsal hyppocampus (strengthening of spectral capacity in theta- and its weakening in at-range) and fore-part hypothalamus (decrease of spectral capacity in the high-frequency area) are shown. It allows us to make the conclusion about significant changes in the brain cortex and in the cortical-subcortical interactions under the influence of heavy metal salts. Reaction of the hind hypothalamus differed from the reaction described above and came to strengthening of the spectrum capacity in high-frequency ranges and to weakening in low-frequency ones, that testifies the raised sensitivity of this brain department to the heavy metals action.

[The weak acids as proton carriers through bilayer lipid membranes].

The ability of the weak inorganic acids (H2S, HCN) and lower carboxylic acids to interact with bilayer lipid membranes (BLMs), change their conductivity, act as the protonophores were investigated. The mechanism of the BLM conductivity change was studied. The factors affecting the acids interaction with model lipid membranes were determined. Maximum conductivity change observes at pH equal dissociation constant of weak acids and depends on the distribution coefficient "octanol(membrane)-water".

[Effect of ecopathogenic environmental factors on the system of antioxidant defense in different parts of the rat brain].

Influence ofecopathogenic environmental (radiation-chemical) factors on activities of superoxiddismutase, catalase and total antioxidative activity (TAA) has been investigated in morphologically and functionally different parts of rat brain. It has been found that reaction of cells in brain cortex, subcortical structures and cerebellum to these factors in all cases is revealed through the antioxidant enzyme activities decrease in all studied brain structures but in various degrees. In brain cortex, which is characterized by higher metabolic level, functional complexity and specialization, the higher level of antioxidation defense is marked both in normal state and under the action of negative factors, that allows to maintain the prooxidation-antioxidation balance. Subcortical structures were more sensitive to the heavy metal impact. Compared to the action of single factors at chronic combined influence of radiation and heavy metals on the separate antioxidative enzymes a summation effect can be observed and at aforesaid joint impact on multi-component system of antioxidation defense a partial mutual evening-out of effects of radiation and chemical agents can be marked.

[Effect of N-oxidized pyridine derivatives on lipid peroxidation in the livers of rats]. / Vplyv N-okysnenykh pokhidnykh pirydynu na kysnezalezhni protsesi v tkanyni pechinky shchuriv.

Effects of N-oxide 2,6-dimetilpyridine (ivin) on the intensity of lipid peroxidation (in vivo and in vitro), microsomal hydroxylation and secretion of the bile (in vivo) were investigated. It has been shown that the preparation did not act significantly on the rate of lipid peroxidation in the liver homogenates both in vivo (5 mg/100 g, 4 weeks) and in vitro (10(-6)-10(-2) mol, incubation). Ivin did not change the activity of the microsomal hydroxylation (hexenal), but stimulated the excretion of biliary organic and inorganic components. The role of NO as a transmitter for effects of N-oxide 2,6-dimetilpyridine and the possibility of its influence on the processes under exploration via the modification of the structure of a biomembrane have being discussed to be one of the basic mechanisms.

[Platelet membrane Ca(2+) and Na(+), K(+)-ATPase activity and aggregation in myelodysplastic syndrome]. / Ca(2+) ta Na(+), K(+)-ATP-azna aktyvnist' membran trombotsytiv i ïkhnia agregatsiia za miielodysplastychnoho syndromu.

Platelet aggregation was decreased under action of ADP and collagen in patients with myelodysplastic syndrome. The decrease in aggregation started from 3-rd minutes and decreased in 4 and 5 minutes after action of ADP. The study of Ca(2+)-ATPase and Na+, K(+)-ATPase membrane activities showed the decrease in Ca(2+)-ATPase and increase in Na+, K(+)-ATPase activity in the patients with myelodysplastic syndrome.

[Mechanisms of generating calcium signals in exocrine acinar cells]. / Mekhanizmy heneratsiï kal'tsiievykh syhnaliv v ekzokrynnykh atsynarnykh klitynakh.

Review. Modern data about mechanisms of generation of the calcium signals in the exocrine acinar cells are presented. The mechanisms of inositol-1,4,5-trisphosphate- and Ca(2+)-induced Ca2+ release from intracellular stores of the acinar cells and mechanisms their influx from extracellular medium are described. The mechanisms which initiate Ca2+ oscillations and their role in the secretion of the fluid and enzymes by acinar cells are discussed.

[The effect of dimethylethanolamine on the summation capacity of the central nervous system and on the work capacity of animals in a chronic experiment]. / Vplyv dymetyletanolaminu na sumatsiinu zdatnist' tsentral'noï nervovoï systemy ta pratsezdatnist' tvaryn u khronichnomu eksperymenti.

The effects of inhaling action of dimethylethanolamine (twenty-four-hour for four months (on summarizing liminal index, SLI) and efficiency of white rats in dependence on various concentrations of amino alcohol were studied in chronic experiments. The obtained results allowed to conclude, that high (2.76 mg/m3) concentration of dimethylethanolamine influenced on functional state of central nervous system. SLI changes pointed to disturbance of dynamic equilibrium between processes of inhibition and excitation with prevalence of latter. In the same time the sufficient grounds for the attribution of dimethylethanolamine to myorelaxants were absent, since in our experiments we used only very high concentrations of this agent.

[A theoretical approach to determining the membranotrophic activities of regulatory peptides]. / Teoreticheskii podkhod k opredeleniiu membranotropnoi aktivnosti reguliatornykh peptidov.

The theoretical approach of the determination of the regulatory peptides (RP) membrane activity is developed. The realised calculations are evidence of possibility of the theoretical determination of the RP characteristics, which indicate their membrane active properties and allow to determine their probable location in the membrane matrix.

[A pharmacological analysis of the effect of angiotensin on stimulated gastric secretion]. / Farmakolohichnyi analiz vplyvu anhiotenzynu na stymul'ovanu shlunkovu sekretsiiu.

Chronic experiments on dogs with gastric fistulas were carried out to study the influence of angiotensin 1 and angiotensin 2 on pentagastrin- and histamine-induced gastric acid secretion. It was established that both angiotensins inhibited gastric acid secretion stimulated by pentagastrin but not by histamine. Comparative analysis of the effects of stimulation and inhibition of cholino- and adrenoreceptors on this inhibitory action of angiotensins suggested the mediation of angiotensin influence through the modulation of cholinergic reactions of parietal cells in the stomach.