Oncoprotein stabilization in brain tumors.

Proteins involved in promoting cell proliferation and viability need to be timely expressed and carefully controlled for the proper development of the brain but also efficiently degraded in order to prevent cells from becoming brain cancer cells. A major pathway for targeted protein degradation in cells is the ubiquitin-proteasome system (UPS). Oncoproteins that drive tumor development and tumor maintenance are often deregulated and stabilized in malignant cells. This can occur when oncoproteins escape degradation by the UPS because of mutations in either the oncoprotein itself or in the UPS components responsible for recognition and ubiquitylation of the oncoprotein. As the pathogenic accumulation of an oncoprotein can lead to effectively sustained cell growth, viability and tumor progression, it is an indisputable target for cancer treatment. The most common types of malignant brain tumors in children and adults are medulloblastoma and glioma, respectively. Here, we review different ways of how deregulated proteolysis of oncoproteins involved in major signaling cancer pathways contributes to medulloblastoma and glioma development. We also describe means of targeting relevant oncoproteins in brain tumors with treatments affecting their stability or therapeutic strategies directed against the UPS itself.

Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex: a systematic meta-analysis of fMRI studies.

Functional Magnetic Resonance Imaging (fMRI) demonstrates that the subliminal presentation of arousing stimuli can activate subcortical brain regions independently of consciousness-generating top-down cortical modulation loops. Delineating these processes may elucidate mechanisms for arousal, aberration in which may underlie some psychiatric conditions. Here we are the first to review and discuss four Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies using subliminal paradigms. We find a maximum of 9 out of 12 studies using subliminal presentation of faces contributing to activation of the amygdala, and also a significantly high number of studies reporting activation in the bilateral anterior cingulate, bilateral insular cortex, hippocampus and primary visual cortex. Subliminal faces are the strongest modality, whereas lexical stimuli are the weakest. Meta-analyses independent of studies using Regions of Interest (ROI) revealed no biasing effect. Core neuronal arousal in the brain, which may be at first independent of conscious processing, potentially involves a network incorporating primary visual areas, somatosensory, implicit memory and conflict monitoring regions. These data could provide candidate brain regions for the study of psychiatric disorders associated with aberrant automatic emotional processing.

Oxidative stress in patients with beta-thalassemia major.

The aim of this work is to study the level of oxidative stress in blood of beta-thalassemia major patients with transfusional iron overload and chelation therapy as a central pathological process. Beta-thalassemia major results in an increase in the concentration of lipid peroxidation products in blood plasma of more than 100% and in the intensity of chemiluminescence - about 20% in comparison to healthy controls. The activity of the antioxidant enzyme superoxide dismutase in the blood of beta-thalassemia major patients is decreased by more than 30% and the total antioxidant activity is diminished by about 70% compared to controls. Experimental data confirm the progression of oxidative stress in patients with beta-thalassemia major: activation of free radical processes and lipid peroxidation, decreased antioxidant capacity. Strong oxidative damage and essential alternations define these parameters as sensitive markers of oxidative stress in patients with beta-thalassemia major. The combination of effective iron-chelatory agents with natural or synthetic antioxidants can be extremely helpful in clinical practice in the regulation of the antioxidant status of patients with beta-thalassemia major.

Chemiluminescent in vitro estimation of the inhibitory constants of antioxidants ascorbic and uric acids in Fenton's reaction in urine.

The goal of this research was to measure in vitro the inhibitory constants of the antioxidants ascorbic and uric acid in urine, with lucigenin enhanced chemiluminescence (CL) in Fenton's system. Maximum CL emission is registered in urine containing H2O2 (5.10(-4) M), Fe2+ (5.10(-5) M), EDTA (5.10(-5) M), and chemical enhancer lucigenin (10(-4) M) at pH 5.5 and 36 degrees C. Ascorbic acid exhibits up to 4-fold stronger antioxidant effect than uric acid. The constants of antioxidant inhibition in urine were measured at concentrations 10(-3) and 10(-4) M: for ascorbic acid, 5.92 +/- 0.04 and 24.05 +/- 1.82 micromol.sec(-1); for uric acid, 1.60 +/- 0.02 and 21.45 +/- 0.97 micromol.sec(-1), respectively. Three phases of CL kinetics of urine are well observed: spontaneous CL (0-10 sec), fast flash of CL (10-50 sec), and latent period (50-300 sec). The antioxidant efficiency of ascorbic and uric acids in the final stage of catabolic processes in the body is discussed.

Effect of vitamin E and vitamin C combination on experimental influenza virus infection.

Successful antioxidant treatment of the so-called "free radical diseases" has been reported in the literature. In this study we examined the preventive effect of vitamin E and vitamin C, alone and in combination, on the damage caused by influenza virus infection (IVI). Male mice (ICR), infected with influenza virus A/2/68/(H3N2) (1.5 of LD(50)), were administered single once-daily doses of vitamin E (60 mg/kg b.w.) and vitamin C (80 mg/kg b.w.) intraperitoneally (3 days before virus inoculation). On the 5th and 7th day, respectively, after virus inoculation, animals were decapitated. Monooxygenase enzyme activity (ethylmorphine N-demethylase, amidopyrin N-demethylase, analgin N-demethylase, aniline hydroxylase, cytochrome P-450 content and NADPH-cytochrome C reductase [CCR]) was determined in liver 9000 x g supernatant. Primary and secondary products of lipid peroxidation (LPO; conjugated dienes [CD] and TBA-reactive substances) were measured in blood plasma, lung and liver 9000 x g supernatant. Vitamin E effectively restored LPO-levels increased by IVI. The effect of vitamin C was similar, but slighter. The combination (vitamin E + C) had greater effect on LPO levels than their separate administration. P-450-dependent monooxygenase activity was significantly restored and more pronounced cytochrome P-450 content and NADPH-CCR activity was noted. The preventive effect of vitamin E was stronger than the effect of vitamin C, but the combination (vitamin E + C) had the strongest effect. The superior protective effect of the combination is probably due to vitamin C's repairing effect on vitamin E's tocopheroxyl radical.

Antioxidant properties of rimantadine in influenza virus infected mice and in some model systems.

Influenza virus infection is associated with development of oxidative stress in lung and blood plasma, viz. increase of primary and secondary lipid peroxidation products. It was established that rimantadine treatment led to a decrease of the products of lipid peroxidation in tissues of mice experimentally infected with influenza virus A/Aichi/2/68 (H3N2). The effect is strongest in blood plasma (a decrease of about 50%) and weaker in the lung (about 20%). To elucidate the mechanism of this action of rimantadine, experiments were carried out with some model systems. The capability of rimantadine to scavenge superoxide radicals (scavenging properties) was studied in a system of xanthine-xanthine oxidase to generate superoxide. The amount of superoxide was measured spectrophotometrically by the NBT-test and chemiluminesce. Rimantadine does not show scavenging properties and its antioxidant effect observed in vivo, is not a result of its direct action on the processes of lipid peroxidation and/or interaction with antioxidant enzymes. The antioxidant properties of rimantadine were investigated by measurement of induced lipid peroxidation in a Fe2+ and (Fe2+ - EDTA) system with an egg liposomal suspension. Our findings with model systems do not prove an antioxidant or prooxidant effect of the drug on the processes of lipid peroxidation. Apparently, the observed antioxidant effect of rimantadine in vivo is not connected directly with free radical processes in the organism.

Effect of vitamin E on lipid peroxidation and liver monooxigenase activity in experimental influenza virus infection.

Influenza virus infection was associated with development of oxidative stress in liver of mice, viz. increase in amount of lipid peroxidation products, decrease in cytochrome P-450 and NADP. H-cytochrome c-reductase activity, and inhibition of liver monooxygenases (aniline hydroxylase, ethylmorphine-N-demethylase, amidopyrine-N-demethylase and analgin-N-demethylase). These effects were most pronounced on the 7th day after virus inoculation as compared to the 5th one. Supplementation of mice with vitamin E before virus inoculation leads to liver protection against oxidative stress and toxicosis. A marked decrease of lipid peroxidation products and an increase of cytochrome P-450 and activities of monooxygenases was established. The stabilizing effect of vitamin E was dose-dependent and was most pronounced on the 5th day after virus inoculation as compared to the 7th one.

Screening of thermotolerant yeasts as producers of superoxide dismutase.

A screening procedure for highly thermostable yeast superoxide dismutase was developed. Growth yields at various temperatures were estimated for ten mesophilic and thermotolerant strains, belonging to the genera Saccharomyces, Kluyveromyces and Pichia. Higher yields at 45 degrees C were obtained for K. lactis 90-3 and 90-4. A correlation between the ability to grow at higher temperature and the thermostability of the superoxide dismutase enzyme synthesized was observed. A comparison of the operational stability of the superoxide dismutase of all tested strains suggests that the enzyme of K. lactis strains was more thermostable than that of the other tested microorganisms.

Role of superoxide dismutase in the oxidation of N-alkanes by yeasts.

Yeast microorganisms from Candida genus are investigated for their superoxide dismutase (SOD) and catalase activity during cultivation on N-alkanes. The later caused a considerable increase of Cu/Zn SOD activity of yeast cells in comparison with glucose. A correlation between SOD and catalase activity existed. It is further observed that cells of Candida lipolytica 68-72 which contain a high level of Cu/Zn SOD were more resistant to lethality of exogenous O2-. An over-production of Cu/Zn SOD during the assimilation of N-alkanes by yeasts is also connected to their considerable resistance to increased concentrations of Cu2+ and Zn2+ ions in the nutrient medium. The results are consistent with the assumption that the enhanced resistance of yeast cells to O2- and high concentrations of Cu2+ and Zn(2+)-ions are due to the increased activity of Cu/Zn SOD and that SOD is involved in the protection of some cellular components. Polyacrylamide gel electrophoresis of Candida lipolytica cell-free extracts revealed the same chromatic bands of SOD activity under growth on glucose and N-alkanes. The type of the carbon source used from yeast cells as a single source of carbon and energy had no influence on the SOD profile of the cell.

[The mechanisms of the antioxidant action of shielded phenols in biological membranes. The effects of 4-methyl-2,6-di-tert-butylphenol (ionol) and its derivatives]. / Mekhanizmy antioksidantnogo deistviia ékranirovannykh fenolov v biologicheskikh membranakh. Effekty 4-metil-2,6-ditretbutil-fenola (ionola) i ego proizvodnykh.

According to Bulgarian-Soviet program "Biostab" we studied characteristics of different phenol compounds (ionol derivatives). The aim of the present study is to determine antiradical and antioxidant activity of a number of ionol derivatives in pure chemical systems and in different membrane fractions of a natural origin.

[Mechanisms of the effects of Ca2+ ions on lipid peroxidation]. / Mekhanizmy deistviia ionov Ca2+ na protsess perekisnogo okisleniia lipidov.

Mechanisms underlying Ca2+ effects on lipid peroxidation (LPO) induced in liposomes (from egg yolk lecithin) and UFsomes (from linolenic acid, methyl linolenate) with the aid of O2- -system (Fe2+ + ascorbate) were studied. It was shown that stimulation of lipid peroxidation by low Ca2+ concentrations (10(-6)-10(-5) M) was due to its ability to release Fe2+-ions bound to negatively charged (phosphate, carboxylic) lipid groups (of licethin, linolenic acid), thus increasing the concentration of catalytically active Fe2+. The inhibitory effect of high Ca2+ concentrations was caused by its interaction with superoxide anion-radicals and was not observed in LPO-systems, independent of O2- generation (e. g. Fe2+ + cumol hydroperoxide).

[Study of the mechanism of initiation of enzymatic NADPH-dependent lipid peroxidation in membranes of the endoplasmic reticulum]. / Izuchenie mekhanizma initsiirovaniia fermentativnogo NADPH-zavisimogo perekisnogo okisleniia lipidov v membranakh éndoplazmaticheskogo retikuluma.

The localization and mechanism of generation of active oxygen species in the enzymatic NADPH-dependent lipid peroxidation system in liver microsomes were studied. Using the spin-trapping method, the key role of active oxygen species in the initiation of NADPH-dependent enzymatic lipid peroxidation was confirmed. It was shown that active oxygen species are generated via consecutive one-electron reduction of the oxygen molecule by NADPH-cytochrome P-450 reductase.

[Initiation of nonenzymatic lipid peroxidation in a Fe2+-ascorbate-linolenate system]. / Initsiirovanie nefermentativnogo perekisnogo okisleniialipidov v sisteme Fe2+-askorbat-linolenat.

Using spin trapping method there were discovered and identified the radicals of linolenic acid formed when initiating its peroxidation by the system Fe2+-ascorbate. Mechanism of formation of linolenic acid radicals and their role in initiation of peroxidation were studied. A scheme of reactions of peroxidation initiation in the system Fe2+-ascorbate. linolenic acid is proposed.

[Lipid peroxidation in the myocardium in experimental infarct]. / Perekisnoe okislenie lipidov v miokarde pri éksperimental'nom infarkte.

Changes in the content of lipid peroxidation (LP) products and activities of antioxidant enzymes--superoxide dismutase, glutathione peroxidase and catalase in myocardium of rats after experimental infarction as well as after pretreatment with antioxidant ionol, beta-adrenoblocker inderal and verapamil, an inhibitor of slow Ca2+-channels have been studied. In the left ventricles of the control animals decreased levels of LP-products (Schiff bases and lipid hydroperoxides) have been registered as compared with right ventricles, accompanied by increased activity of antioxidant enzymes in the left ventricles. In experimental infarction the level of LP products increases and activity of antioxidant enzymes decreases both in ischemic and nonischemic regions of the heart. In nonischemic zone these changes can be prevented by pretreatment with inderal and ionol but not with verapamil.

[Lipid peroxidation in experimental myocardial infarct: the action of hyperbaric oxygenation]. / Perekisnoe okislenie lipidov pri éksperimental'nom infarkte miokarda: deistvie giperbaricheskoi oksigenatsii.

Rats with experimental myocardial infarction demonstrated decrease in the activity of superoxide dismutase and catalase and increase in the content of lipid peroxidation (LPO) products and Schiff bases both in and outside the area of necrosis. The combined ischemic damage and hyperbaric oxygenation resulted in the over additive effect of accumulation of LPO products in and outside the area of infarction. The data suggest that it is desirable to use antioxidants during hyperbaric oxygenation.

[Study of radicals formed in the interaction of organic hydroperoxides with ferric ions using the spin trap method]. / Issledovanie radikalov, obrazuiushchikhsia pri vzaimodeistvii organicheskikh gidroperekisei s ionami zheleza, metodom spinovykh lovushek.

The mechanism of free radical generation in the reaction of ferrous ion with t-butyl and linolenic acid hydroperoxide was investigated by spin trapping method. The t-butoxyl, methyl, linolenic acid alkoxyl and alkyl radical spin adducts EPR spectra were observed and identified.