The effect of natural dicarbonyls on activity of antioxidant enzymes in vitro and in vivo

Natural dicarbonyls, which may be accumulated during oxidative stress in atherosclerosis (e.g. malondialdehyde) or carbonyl stress in diabetes mellitus (glyoxal and methylglyoxal) effectively inhibited activities of commercial preparations of the antioxidant enzymes: Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and Se-contained glutathione peroxidase from human and bovine erythrocytes, and also rat liver glutathione-S-transferase. After incubation of human erythrocytes with 10 mM of each investigated dicarbonyls the decrease of intracellular Cu,Zn-SOD was observed. The decreased activity of erythrocyte Cu,Zn-SOD was also detected in patients with diabetes mellitus type 2 with carbohydrate metabolism impairments but effective sugar-lowered therapy was accompanied by the increase of this enzyme activity. The increase of erythrocytes Cu,Zn-SOD activity in diabetic patients treated with metformin (which may utilize methylgly-oxal) was higher than in erythrocytes of diabetic patients subjected to traditional therapy.     

Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED

In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.     

Free radical peroxidation of liver mitochondrial and microsomal phospholipids in rat postnatal development]

Activities of both non-enzymic (ascorbate-dependent) and enzymic NADPH-dependent) peroxidation of microsomal and mitochondrial phospholipids are found to be increased in rat liver during postnatal development. It is suggested, that microsomal NADPH-dependent phospholipid dioxygenase forming a chemical modification of membrane polyenic acyls, can be a factor regulating the activities of membrane-linked enzymes under normal physiological processes.     

Limited area of coronary-occlusion myocardial infarct in rats undergoing antioxidant therapy

The synthetic antioxidant dibunol, (ionol. 2,6-ditret-butyl-4-methylphenol) produces the limitation of the zone of the coronaro-occlusion myocardial infarction in rats by 15.8 and 24.2% on day 7 during daily oral administration in doses of 80 and 120 mg/kg, respectively. In the doses used, dibunol reduces the activity of glutathione peroxidase but does not change the activity of glutathione-S-transferase and superoxide dismutase in the infarction zone of the myocardium. It is concluded that free radical products play an important role in ischemic and infarction damage to the myocardium.     

Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins

The oxidative modification of low density lipoprotein (LDL) is thought to play an important role in atherogenesis. Drugs of -hydroxy--methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) family are usually used as a very effective lipid-lowering preparations but they simultaneously block biosynthesis of both cholesterol and ubiquinone Q₁₀ (coenzyme Q), which is an intermediate electron carrier in the mitochondrial respiratory chain. It is known that reduced form of ubiquinone Q₁₀ acts in the human LDL as very effective natural antioxidant. Daily per os administration of HMG-CoA reductase inhibitor simvastatin to rats for 30 day had no effect on high-energy phosphates (adenosin triphosphate, creatine phosphate) content in liver but decreased a level of these substances in myocardium. We study the Cu²⁺-mediated susceptibility of human LDL to oxidation and the levels of free radical products of LDL lipoperoxidation in LDL particles from patients with atherosclerosis after 3 months treatment with natural antioxidants vitamin E as well as during 6 months administration of HMG-CoA reductase inhibitors such as pravastatin and cerivastatin in monotherapy and in combination with natural antioxidant ubiquinone Q₁₀ or synthetic antioxidant probucol in a double-blind placebo-controlled trials. The 3 months of natural antioxidant vitamin E administration (400 mg daily) to patients did not increase the susceptibility of LDL to oxidation. On the other hand, synthetic antioxidant probucol during long-time period of treatment (3–6 months) in low-dose (250 mg daily) doesn't change the lipid metabolism parameters in the blood of patients but their high antioxidant activity was observed. Really, after oxidation of probucol-contained LDL by C-15 animal lipoxygenase in these particles we identified the electron spin resonance signal of probucol phenoxyl radical that suggests the interaction of LDL-associated probucol with lipid radicals in vivo. We observed that 6 months treatment of patients with pravastatine (40 mg daily) or cerivastatin (0.4 mg daily) was followed by sufficiently accumulation of LDL lipoperoxides in vivo. In contrast, the 6 months therapy with pravastatin in combination with ubiquinone Q₁₀ (60 mg daily) sharply decreased the LDL initial lipoperoxides level whereas during treatment with cerivastatin in combination with probucol (250 mg daily) the LDL lipoperoxides concentration was maintained on an invariable level. Therefore, antioxidants may be very effective in the prevention of atherogenic oxidative modification of LDL during HMG-CoA reductase inhibitors therapy.     

Effect of lipoxygenase metabolites of arachidonic acid on the surface charge of the erythrocyte membrane

The influence of metabolites of arachidonic acids on the electrophoretic mobility of the rat erythrocytes has been investigated. It is found that they can increase or decrease the surface charge of the erythrocyte membranes.     

Requirement of monohydroperoxy fatty acids for the oxygenation of 15LS-HETE by reticulocyte lipoxygenase

The lipoxygenase from reticulocytes oxygenates 15LS-HETE to 8-hydroperoxy-15-hydroxy-5,9,11,13-eicosatetraenoic acid and 5-hydroperoxy-15-hydroxy-6,8,11,13-eicosatetraenoic acid only in the presence of catalytic concentrations of monohydroperoxy fatty acids. During this reaction the hydroperoxy fatty acids are converted to more polar products including hydroxy fatty acids. From kinetic measurements of 15LS-HETE oxygenation it was calculated that 1 mol monohydroperoxy fatty acid is consumed during the oxygenation of about 9 mol 15LS-HETE.     

Genetic and Physiological Features of Reproduction in Prolific Animal

Genetic and physiological functional relationships between major reproductive parameters were studied in domestic prolific mammals with special reference to selection-induced changes in fertility and mothering ability in ten generations of pigs of sino-European Tiameslan composite line, which was first bred in France. Based on our hypothesis, balance equations were derived describing highly adaptive functional coadaptations of reproductive traits. Properties of these equations were examined with regard to artifical directional selection. Selection changes of secretory traits of mammary glands were shown to play a leading role in a correlated increase of biological fertility. Genetically determined regulatory relationships maintained by natural stabilizing selection were established between fertility, sow milk production, perinatal survival, and survival to weaning. Thus, a system of simple complementary equations characterizing an independent integrative reproductive physiological mother–young(s) system was obtained, which had not been previously published. The self-regulated homeostatic mother–young(s) system, studied for the first time ever, ensured homeostatic development of suckling piglets, compensatory regulation, and stabilization at the optimal level of biological (11.6 ± 0.17 piglets at birth) and actual (10.0 ± 0.08 piglets at weaning) fertility in the Tiameslan line.