Experimental Evaluation of the Effectiveness of Isobornylphenols in the Model of Pathospermia and Their Effect on the Antioxidant-Prooxidant Balance of Male Germ Cells.

We studied the effect of antioxidants dibornol (2,6-diisobornyl-4-methylphenol) and its derivative (4-hydroxymethyl-2,6-diisobornylphenol), members of the alkylated phenols group, on the redox potential of male germ cells and their morphological and functional state in the rat model of pathospermia. Pharmacological effect was observed in animals treated with dibornol. The studied compounds led to the normalization of the antioxidant-prooxidant balance. However, the value of this indicator against the background of treatment with dibornol derivative attested to a shift in the redox balance of cells towards reduction reactions.

The New Data on the Serotonin and FMRFamide Localization in the Nervous System of Opisthorchis felineus Metacercaria.

BACKGROUND: Trematoda Opisthorchis felineus Rivolta, 1884 is the causative agent of dangerous parasite disease-opisthorchiasis, widespread in the Russian Federation. The details of the neuroanatomical localization of the serotoninergic and FMRFamidergic neurotransmitter elements as well as their functional roles remain not studied enough in both adult and larval forms of O. felineus. The studies in this area are important in term of the development of a new pharmacological strategy of the struggle with the causative agent of opisthorchiasis affecting the neuronal signal substances and the function of its nervous system. PURPOSE: The aim of this work was the immunocytochemical study of the neurotransmitters serotonin (5-HT, 5-Hydroxitryptamine) and neuropeptide FMRFamide localization in the nervous system of the opisthorchiasis causative agent-O. felineus metacercaria. To study the relationship between the detected neurotransmitters and the muscular elements of the parasite, the muscle staining was carried out simultaneously using fluorophore-conjugated phalloidin. METHODS: The localization of 5-HTergic and FMRFamidergic nerve structures was determined by immunocytochemical method. The staining samples were analyzed using a fluorescent and confocal laser scanning microscopies. RESULTS: The new data on the presence and distribution of the serotonin-immunopositive (IP)- and FMRFa-IP components in the central and peripheral departments of the nervous system of  O. felineus metacercaria has been obtained. Besides that a number of the new anatomical details of the nervous system organization and of the innervation of the organs and tissues in the investigated parasite have been revealed. CONCLUSION: The data obtained on the presence and localization of the 5-HTergic and peptidergic (FMRFamide) components in central and peripheral departments of the nervous system of O. felineus metacercaria elaborated and expanded the existing information about the nervous system as well as the innervations of the tissues and organs in the causative agent of opistchorchiasis.

Effectiveness of Phenolic Antioxidants in Experimental Model of Benign Prostatic Hyperplasia.

Experimental model of sulpiride-provoked benign prostatic hyperplasia was employed to comparatively assess the effect of phenolic antioxidants (dihydroquercetin, p-thyrozol, dibornol, and prostagenin) on prostate morphology. All examined agents decreased the degree of hyperplasia in acinar epithelium; the greatest efficacy was demonstrated by prostagenin. Moreover, dihydroquercetin and p-thyrozol increased the cross-section area of acinar lumina and prostate volume, which is inadmissible in this pathology. These results suggest that the use of phenolic antioxidants in the therapy of benign prostatic hyperplasia should be strictly controlled.

Glucose causes primary necrosis in exponentially grown yeast Saccharomyces cerevisiae.

In this paper, we present data on sugar-induced cell death (SICD) in the yeast Saccharomyces cerevisiae in the exponential phase of growth. We suggest that the nature of SICD in exponentially grown yeast is primary necrosis, in contrast to cells in the stationary growth phase, which exhibit apoptotic SICD. The following findings confirm this conclusion: (i) the process rate; (ii) the impairments of plasma membrane integrity; (iii) the drastic morphological changes in the intracellular content; (iv) the absence of chromatin condensation; (v) the absence of externalization of phosphotidylserine (PS) on the outer leaflet of plasma membrane and (vi) the insensitivity of the SICD process to cycloheximide (CHX). Research shows that SICD occurs in a subpopulation of cells in the S-phase.

Neuroprotective Activity of D-HES in Transient Global Cerebral Ischemia in Rats.

We studied the effect of O-((((4-hydroxy-3,5-di(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl) benzyl)oxy)ethyl)-O-(2-hydroxyethyl)-(1→4)-α-D-glucan (D-HES, 80 mg/kg, intravenously) and reference preparation ethylmethylhydroxypyridine succinate (EMHP-S, 50 mg/kg, intravenously) on rat survival and neurological deficit in 24 h after transient global cerebral ischemia in Wistar rats. Intravenous administration of D-HES and EMHP-S significantly increased the number of survivors by 68 and 78%, respectively, in comparison with the control group. In groups treated with D-HES and EMHP-S, the number of animals with severe neurological deficit was significantly lower and the number of animals moderate or mild neurological deficit was significantly higher than in the control group.

Cardioprotective Activity of 2,6-Diisobornyl-4-Methylphenol in Acute Myocardial Ischemia/Reperfusion in Rats.

We studied the cardioprotective effect of 2,6-diisobornyl-4-methylphenol under conditions of myocardial ischemia/reperfusion in rats. Daily administration of 2,6-diisobornyl-4-methylphenol (100 mg/kg intragastrically) over 3 days before and 5 days after modeling of myocardial ischemia/reperfusion prevented the increase in the infarction area by almost 2 times in comparison with the control by day 5 after recirculation. The type and severity of pathological changes in ECG parameters reflecting necrotic changes in the myocardium under the action of the compound significantly decreased by day 35 of the experiment. Animal survival rate during the first 24 h after ischemia/reperfusion modeling in the experimental group was by 29% higher than in the control group.

[The application of the emulsified turpentine baths for the correction of the functional state of the cross-country skiers].

The baths with emulsified turpentine find the wide application in balneotherapy. They produce especially pronounced beneficial prophylactic effects in the patients presenting with microtrombosis and microvascular stasis. Moreover, these baths may be prescribed to improve microcirculation, increase the functional reserves and physical capacity in the athletes. At the same time, the current literature appears to contain no scientific publications on the application of emulsified turpentine baths for the restoration of the physical capacity of the professional ski runners. The lack of relevant information motivated the study reported in the present article. The main objective of the study involving 10 subjects was to evaluate the effectiveness of the modified emulsified turpentine baths as a method by which to restore and enhance the physical capacity of the professional cross-country skiers. The physical capacity of the athletes was evaluated from the results of the bicycle ergometer exercise test with the use of the «Oxycon Pro¼ system. The data obtained suggest that a course of the emulsified turpentine baths increases the activity of the cardiorespiratory system, improves the physical capacity, and enhances the functional reserves of the body in the anaerobic zone.

Fluorescent analysis for bioindication of ozone on unicellular models.

Unicellular model plant systems (vegetative microspores of horsetail Equisetum arvense and pollen of six plant species Corylus avellana, Dolichothele albescens Populus balsamifera, Salix caprea, Saintpaulia ionantha, Tulipa hybridum, on which autofluorescence and fluorescence after histochemical treatment studied, have been represented as bioindicators of ozone. It has found that low doses of ozone 0.005 or 0.008 µl/l did not affect or stimulate the autofluorescence of the samples with the ability to germinate in an artificial medium. In higher ozone concentrations (0.032 µl/l) either the decrease in the intensity of the emission or changing in the position of the maxima in the fluorescence spectrum (new 515-520 nm maximum characteristic for the green-and yellow area has appeared) were observed. In dose of 0.2 µl/l, higher than above the threshold of danger to human health, autofluorescence in all samples fell down to up to zero, and there was no the ability to germinate. In this case the formation of lipofuscin-like compounds fluoresced in blue with maxima from 440 to 485 nm was observed. Stress metabolites, known as neurotransmitters biogenic amines, were found in treated cells as determined on the characteristic fluorescence at 460-480 nm in the samples after a specific histochemical reactions for catecholamines (with glyoxylic acid) or for histamine (with o-phthalic aldehyde). Increased intensity of the emission under the treatment with ozone (total doses from 0.012 to 0.032 µl/l) was associated with an increase in the concentrations of catecholamines and histamine. The fluorescent analysis on undamaged cells-possible bioindicators of ozone can be useful in ecomonitoring for earlier warning about health hazardous concentrations of this compound in the air.

[Distribution of 4-methyl-2,6-diisobornylphenol in rat tissues].

We have studied the distribution of the new compound 4-methyl-2,6-diisobornylphenol in rats after a single oral administration in a dose of 20 mg/kg. The pharmacokinetic parameters have been estimated by the noncompartmental method. It is established that the drug is nonuniformly distributed in the body and has a high affinity for liver and heart. A low penetration of 4-methyl-2,6-diisobornilphenol has been found in brain tissue. The accumulation of 4-methyl-2,6-diisobornilphenol in adipose tissues has not been found. It been showed that the drug is slowly eliminated from the body, especially from the heart tissues for which the mean retention time is MRT = 45 h.

Hemorheologic effects of dibornol in a model of myocardial ischemia/reperfusion.

We studied the effects of novel sterically hindered phenol, 4-methyl-2,6-diisobornyl phenol (dibornol) on the rheological properties of the blood in the model of myocardial ischemia/reperfusion. Dibornol (100 mg/kg intraperitoneally for 3 days before and 5 days after ischemia/reperfusion) decreased blood viscosity by 9-25% in comparison with that in sham-operatedanimals by modulating cellular (erythrocyte deformability and aggregation) and plasma (plasma viscosity) rheological parameters. Normalization of blood rheology under the influence of dibornol increased the availability of oxygen to tissues at high shear rates by 9-18% after acute ischemia/reperfusion in rats.

[Evaluation of the linearity of pharmacokinetics of the phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intragastric administration].

The linearity of pharmacokinetics of 4-methyl-2,6-diisobornylphenol after single intragastric administration in doses within 10 - 200 mg/kg has been studied in rats. It has been established that pharmacokinetics of 4-methyl-2,6-diisobornilphenol in the indicated dose range is not linear due to a limited absorption of the drug from the intestine.

[Antioxidant properties of conjugates of polyethylene glycols, having a terpenophenolic fragments].

A series of water-soluble conjugates has been synthesized from polyethylene glycols of various lengths and 4-bromomethyl-2,6-diisobornylphenol. Evaluation of membrane protective and antioxidant activity of synthesized products on the model of H2O2-induced hemolysis of blood erythrocytes showed that conjugates have considerable antioxidant activity. A significant membrane protective effect was showed in conjugates with 0.2 and 0.8 mass. % of 2,6-diisobornyl-4-methylene fragments.

[Pharmacological effects of Abies polyprenols and carsil on alcohol-induced hepatitis].

The introduction of polyprenols isolated from fir (Abies) tree in male rats weighing 170 - 180 g with alcohol-induced hepatitis favored reduction in hepatocyte cytolysis and cholestasis and led to an improvement of the protein- and glycogen-synthesizing function of liver. A clear tendency to normalization of the maintenance of total lipids, triglycerides and phospholipids and the inhibition of lipid peroxidization processes in the damaged organ was observed. The introduction of Abies polyprenols also improved the process of bile secretion and its chemical composition.

[Synthesis of novel terpenophenol-chlorin conjugates and evaluation of their membranotropic and membrane protective properties].

A series of terpenophenol-chlorin conjugates where terpenophenolic fragment has amide bond with macrocycle of methylpheophorbide a, formed by amidation of 13(2)-ester group were obtained by interaction of methylpheophorbide a and ortho-aminomethyl derivatives of 2-isobornyl-4-methylphenol. The substances investigated ability to interact with the cell membrane was shown in blood erythrocytes surface structure with scanning electron microscope. The conjugates studied were established to have antioxidant and membrane protective properties resulted from inhibiting H2O2-induced erythrocytes hemolysis and decrease of lipid peroxidation secondary product accumulation.

[Surface active properties of isobornylphenols in systems with different degrees of complexity].

Interrelations between the structure of the semi-synthetic phenolic antioxidants -- isobornylphenols and their surface active properties were studied in the chemical (the lecithin aggregation in hexane) and biological (the incubation with the blood erythrocytes) model systems. It has been shown that all studied compounds are able to affect the lecithin aggregation in hexane: the share of the main fraction of the L micelles decreases with increasing the share of particles of greater size. The effect substantially depends on hindered OH group and the presence of the intramolecular hydrogen bond in molecule. The cytotoxic properties of isobornylphenols (the concentration is 100 M) are predominantly due to the molecule structure. The interrelation between the aggregate size of the main fraction of L in the presence of the studied compounds and the discocyte share during mice blood erythrocyte incubation in their presence for 4 h is revealed. Thus, this provides the possibility to assume that the ability of the different biological active substances to affect the lecithin aggregation in non-polar solvent could be used as a model system for the initial assessment of their surface active properties.

[Pharmacokinetics of phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intravenous injection].

The pharmacokinetics of 4-methyl-2,6-diisobornylphenol (MDIBP) in rat blood plasma has been studied after intravenous injection. The drug concentration in the plasma was determined using a reverse-phase HPLC procedure. It is shown that MDIBP rapidly penetrates into intensively perfused organs, but is slowly eliminated from the organism (MRT value amounting to 9 h).

[Structural changes of eye chorioretinal complex after total cerebral ischemia and their correction].

Structural changes of eye chorioretinal complex were investigated in 40 adult male outbred albino rats after total transient cerebral ischemia using electron microscopy and morphometric analysis. Furthermore, the influence of a new sterically hindered phenolic antioxidant dibornol on these processes was estimated. Our studies demonstrated that total transient cerebral ischemia in rats resulted in the capillary thrombosis of the choriocapillary lamina of the uvea, structural disturbances of the blood-retinal barrier, degeneration of the retinal neurons and radial glia. Course administration of dibornol was shown to improve the microcirculation and to protect the retinal neuronal structures, pigment epithelium, and radial glia.

[Resolution of racemic ortho-isobornylphenol into enantiomers and evaluation of their antioxidant activity].

The resolution of the racemic ortho-isobornylphenol into enantiomers via diastereomeric camphanates was carried out. The absolute configuration ofchiral centers of synthesized compounds was established by the single crystal X-ray diffraction method. Antioxidant activity and membrane protective properties of individual enantiomers were studied on the model of H2O2-induced hemolysis of red blood cells.

Hemorheological effects of ortho-isobornyl phenol derivative under conditions of brain ischemia in rats.

Hemorheological activity of 4-methyl-2,6-di-isobornyl phenol, a new o-isobornyl phenol derivative, was studied under conditions of experimental prolonged partial cerebral ischemia. Brain ischemia is associated with hemorheological disorders which can be characterized as blood hyperviscosity syndrome: increased viscosity of the whole blood (within a wide range of shear rates), plasma viscosity, fibrinogen content in blood plasma, and platelet aggregation; deterioration of platelet deformability and reduced availability of oxygen for tissues. A course (5 days) of intragastric 4-methyl-2,6-di-isobornyl phenol (100 mg/kg) prevented the development of blood hyperviscosity syndrome by modulating blood macrorheology (reduction of plasma viscosity and fibrinogen content) and microrheology (reduction of erythrocyte aggregation and improvement of their deformability).

Morphological changes in retinal neurons in streptozotocin-induced diabetes mellitus and their correction with an isobornylphenol derivative.

Along with microangiopathy, one of the main causes of blindness in diabetic retinopathy consists of degeneration of retinal neurons. Electron microscopy and morphometric analysis were used to study structural changes in neurosensory cells, associative, and ganglion neurons in the retina in 30 while mongrel male rats with streptozotocin diabetes for two months and the effects of a new semisynthetic antioxidant 4-methyl-2,6-diisobornylphenol, a screened phenol, were evaluated. Destructive changes were found to affect the outer segments of neurosensory cells and ganglion neurons. The number density of neurosensory and ganglion cells decreased, and the proportion of these cells with pyknotic nuclei increased. 4-Methyl-2,6-diisobornylphenol had neuroprotective actions, preventing destructive changes to neurosensory cells and ganglion neurons.