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UNLABELLED: Selenium supplementation improves antioxidant status in critically ill patients with severe acute pancreatitis. It depends on quantum of dosage and supplementation time. The aim of this analysis is point out on benefit of antioxidant therapy by supplementing selenium. METHODS: Patient with severe acute pancreatitis and developing septic shock was admitted on anesthesiology and intensive care department. Adjuvant supplementation therapy with selenium was started in continual infusion 750 mg/24 h during next six days. Activity of antioxidant enzyme glutathione peroxidase and others inflammatory markers were decrease. A case report presents the possibility to affect on systemic inflammatory response syndrome pathogenesis in initial phase. It has to improve therapeutic progress in patients with severe acute pancreatitis.

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We investigated the effect of hydroxyl substituted chalcone (1a) and some chalcone analogues (1b-d) on isolated rat liver mitochondria to gain new insights into the cytotoxic mechanism of these compounds. We observed an inhibitory effect on phosphorylation and the partial uncoupling of compounds 1a and 1d. Increased radical generation and possible covalent interaction of the compounds with cellular thiols resulted in glutathione (GSH) depletion and modulation of the investigated mitochondrial activities. Disruption of interconnected mechanisms as electron transport chain and energetic metabolism, ROS production and insufficiency of antioxidant defensive system could lead to induction of cell death.

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In earlier studies, cytotoxity of chalcones (1) and cyclic chalcone analogues E-2-arylidene-tetralones (2) and -benzosuberones (3) towards various murine and human tumour cells has been tested. Preliminary biochemical investigations showed the compounds to inhibit protein and DNA syntheses. It was also found that the compounds affect the cellular thiol status of the treated cells. In order to gain new insights into the cytotoxic mechanism of the compounds effects of some previously investigated 2 and 3 derivatives on isolated rat liver mitochondria was investigated. It was found that the most cytotoxic compounds 2c and 3b significantly decreased the GSH level of the mitochondria. Incubation of the investigated chalcones with reduced GSH under cell-free conditions indicated spontaneous conjugation (non-redox) reaction at pH 7.4 and pH 9.0. Investigation of antioxidant capacity of the compounds by monitoring time course of the Fenton-reaction initiated in vitro degradation of 2-deoxyribose showed the compounds to display hydroxyl radical scavenger activity. Investigation of respiratory control ratio of 2c and 3b showed the compounds to display an inhibitory effect on respiration, compound 2b, however, displayed rather an uncoupling effect. The experiments provide further details of cytotoxic effects of the synthetic chalcones displaying dual - cytotoxic and cytoprotective - effects.

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Cancer therapy with daunorubicin is limited by its cardiotoxicity. It has been suggested that daunorubicin-induced free radical generation can be involved. The precise molecular mechanism of daunorubicin-induced cardiotoxicity is still not well understood but it is believed that mitochondria play an important role in this process. It has been reported that flavonoids with antioxidant properties may prevent anthracycline-induced cardiotoxicity. In this work, we investigated the effects of daunorubicin and quercetin on mitochondrial enzyme activities such as ATPase, glutathione peroxidase (GPx) and glutathione reductase (GR). Moreover, we also studied the changes of outer mitochondrial membrane using synchronous fluorescence spectra. The activity of ATPase and GR were significantly increased after daunorubicin application. Pretreatment with quercetin significantly alleviated this increase. On the other hand, GPx activity was significantly decreased and quercetin prevented this decrease. Treatment with quercetin alone had no significant effect on the enzyme activity studied. Quercetin also completely prevented daunorubicin-induced changes in fluorescence of the outer mitochondrial membrane. In conclusion, our data indicate that quercetin may be useful in mitigating daunorubicin-induced cardiotoxicity.

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The aim of this pilot study was to assess a humoral response to influenza vaccine in 9 women with breast cancer. In the epidemic season 1998/1999 the patients received a single 0.5-ml dose of split influenza vaccine (Vaxigrip, Pasteur Merieux). Humoral response was measured by the hemagglutinin inhibition test in sera collected before vaccination and 1 month after vaccination. All results were compared with a control group of 19 healthy vaccinated women. The mean 'fold' increases ranged from 12.0 to 22.2 in patients with breast cancer and from 10.5 to 29.2 in healthy women. After vaccination, protection rates ranged from 44.4% to 88.9% and 63.2% to 94.7%, respectively. Response rates were between 44.4% and 88.9% in women with cancer and between 63.2% and 78.9% in the control group. After vaccination, antihaemagglutinin antibody titers were significantly higher than the prevaccination titers. During the whole study there were no statistically significant differences in humoral response between patients with breast cancer and healthy women. The results of the present study clearly show that women with breast cancer, including those undergoing chemotherapy, were able to develop a good serological response to influenza vaccine.

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The authors have studied the susceptibility of two key protective enzymes, glutathione peroxidase (GPX) and glutathione reductase (GR) to the reactive oxygen species (ROS) known to induce oxidative damage in vitro system containing Fe2+/EDTA. The ability of ROS scavanger stobadine to prevent oxidative damage was also studied. Incubation of GPX with Fe2+/EDTA resulted in the significant decrease in its enzyme activity while under the same condition the activity of GR was not changed. The presence of stobadine was effective in protecting GPX from the loss of its activity by in vitro oxidizing agents. The monitoring of the mitochondrial outer membrane dynamics by the method of synchronous fluorescence fingerprint showed that the membrane is involved in these processes. (Fig. 3, Ref. 35.)

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The study investigated the prooxidative in vitro effect of various Fe(2+)-EDTA concentrations on biochemical parameters of the energetic metabolism of rat liver mitochondria. Fe(2+)-EDTA was added in concentrations 150, 300 and 400 mmol/mg of mitochondrial protein. The study included the investigation of consumption of oxygen in state 4 (without ADP addition) and in state 3 (with ADP addition), and the activities of ATP-ase, superoxide dismutase (SOD) and glutathione reductase. The mitochondrial outer membrane dynamics were simultaneously monitored by the method of synchronous fluorescence fingerprint. When compared with the control group, the results imply that in state 4, the addition of 150 mmol of Fe2+/mg of mitochondrial protein caused an insignificant increase in respiration to 104%, whereas in state 3, the oxygen consumption was insignificantly inhibited to 82%. The activity of ATPase was insignificantly raised to 105%, whereas the superoxide dismutase activity has decreased significantly to 77%. The activity of glutathione reductase increased significantly to 124%. The addition of 300 mmol of Fe2+/mg of mitochondrial protein has caused a significant inhibition of oxygen consumption to 67% in state 4 and to 31% in state 3. The activity of ATPase showed an insignificant elevation to 104%. The activity of superoxide dismutase was significantly reduced to 52% and that of glutathione reductase dropped to 72%. The addition of 400 Fe2+/mg of mitochondrial protein strongly diminished the oxygen consumption to 36% in state 4, and similarly to 37% in state 3. The activity of ATP-ase was significantly decreased to 39%, the superoxide dismutase activity diminished to 17% and glutathione reductase activity dropped to 37%. The monitoring of the mitochondrial outer membrane by the analysis of synchronous fluorescence fingerprint showed that the membrane is involved in these processes. (Fig. 5, Ref. 12.)

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Previous work has shown, that stobadine-hydrochloride (-)cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-14-pyrido(4,3b) indole administered in a single dose 2 mg/kg of body weight reduces cardiotoxic effect of isoproterenol (1 mg/kg) as shown by lowered serum enzyme activities of AST, CPK, LDH and ALT. We studied the effect of stobadine in vivo on respiration, the level of ATP, malondialdehyde (MDA) and superoxiddismutase (SOD) in heart mitochondria. Serum enzyme activities of AST, CPK and LDH after stobadine application were significantly decreased. In mitochondria, respiration and activity of SOD were inhibited, level of MDA was increased and level of ATP was unchanged. The cardioprotective effect of stobadine is not linked to preservation of mitochondrial function. This effect is probably more complex and mediated on the level of the whole organism.

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The acute toxic effect of the herbicide chloridazone and mitochondrial respiration were investigated and typical clinical signs of intoxication were described in rats (Wistar), pheasants (Phasianus colchicus) and sheep (Slovak Merino). The LD50 of chloridazone was calculated to be for rats 800 mg/kg bw (range 552 to 1160 mg/kg bw) and for pheasants 3684 mg/kg bw (range 1768 to 7677 mg/kg bw). According to WHO chloridazone is moderately toxic for rats and slightly toxic for pheasants. The LD50 for sheep is 161 mg/kg bw (range 76 to 340 mg/kg bw). Chloridazone thus presents an acute risk for ruminants, which is in coincidence with the WHO classification characterising it as a very toxic compound. The following clinical features of intoxication were observed after p.o. administration of chloridazone: apathy, dyspnoea, hyperventilation, hypersalivation (sheep - foam hypersalivation), paralysis, tonic-clonic convulsions and death in clonic convulsions. Very quick rigor mortis. Chloridazone interfered with mitochondrial respiration in the liver of rats yet its mode of action was different from that of succinate substrate or glutamate-malate. Succinate dependent respiration was significantly decreased in both states (3 and 4) of respiration. Glutamate-malate respiration was not changed in state 4, though it significantly increased in state 3 after ADP administration. RCP (respiration control proportion) value was increased on using either of the substances.

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Our previous study showed that stobadine is effective against ischemia/reperfusion-induced gastric mucosal injury. The present study examined the ability of stobadine to protect erythrocyte membrane against free radical injury after long-term carbon tetrachloride (CCl4) application. The erythrocyte membrane changes were established using colloid-osmotic hemolysis. The significant increase of colloid-osmotic hemolysis was found in animals treated with CCl4. CCl4 also increased formation of thiobarbituric acid-reactive substances (TBARs) and decreased thiol group content. Stobadine in both doses (10.0 and 20.0 mg.kg-1) protected erythrocyte membrane against CCl4-induced injury. The membrane lipid bilayer is the most affected part of the erythrocyte membrane. In presence of stobadine, CCl4-induced lipid peroxidation was partially or totally prevented whereas the level of total membrane thiols was increased. Based on these results, it can be concluded that protective effect of stobadine on CCl4-induced erythrocyte membrane changes should be related to its antioxidant properties.

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After six-day administration of rolitetracycline (RTC) in the cardiac mitochondria of old rabbits the rate of oxygen consumption (glutamate-malate as well as 2-oxoglutarate) declines, while the malonic dialdehyde (MDA) rises. This provides evidence of more intense lipoperoxidation due to rolitetracycline. However, the ATP-ase activity increases and therefore this parameter is unsuitable in this experimental set-up (presence of tetracycline antibiotic) as an indicator of impaired integrity of mitochondrial membranes. After administration of RTC the activity of superoxide dismutase (SOD) increases markedly, but in case of concurrent administration of vitamin E it declines which is evidence of the prooxidative action of tetracyclines. Tetracycline itself and its metabolites which are formed during the biotransformation and degradation of epianhydrotetracycline (ETC) do not alter significantly the oxygen consumption nor the ATP-ase activity in cardiac mitochondria of old rabbits in vitro. Of these metabolites only anhydrotetracycline (ATC) and in particular epianhydrotetracycline (EATC) inhibit both parameters. From experiments in vitro ensues the relationship between the action and structure of the antibiotic and its metabolites the structure of cycle C and the nature of the substituents in positions C6 and C1 of this tetracycline cycle, as prerequisites are created for the formation of prooxidative structures.

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The possibility of eliminating adverse effects of tetracycline and isoproterenol pretreatment on energy generation of myocardial mitochondria by vitamin E administration was investigated in old rabbits. Vitamin E administered in doses of 1.5 mg per kg body weight over 6 days was found to improve energy metabolism in old rabbits whose metabolism had been deranged by isoproterenol pretreatment in the dose of 1.5 mg per kg body weight. Subsequent administration of vitamin E to rabbits pretreated with isoproterenol and tetracycline in doses of 15 mg per kg body weight daily over 6 days also resulted in improvement of energy metabolism parameters studied. Under the given conditions vitamin E was found to exert a protective effect on oxidative phosphorylation of the myocardium damaged by isoproterenol and tetracycline.

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