Antifungal nickel(II) complexes derived from amino sugars against pathogenic yeast, Candida albicans

The effects of substances able to reduce peroxidative processes on thyroid hormone-induced electrophysiological changes in ventricular muscle fibres were examined. For this study, 60 day old euthyroid and hyperthyroid rats were used. One group of hyperthyroid rats was untreated and the others were treated with vitamin E, N-acetylcysteine, and cholesterol, respectively. Hyperthyroidism was elicited by 10 day treatment with daily i.p. injections of triiodothyronine (10 microg/100 g body weight). Vitamin E and N-acetylcysteine were administered for 10 days by daily i.m. injections (20 mg/100 g body weight) and daily i.p. injections (100 mg/100 g body weight), respectively. Cholesterol was administered by cholesterol-supplemented diet (4%) from day 30. Hyperthyroidism induced a decrease in the whole antioxidant capacity and an increase in both lipid peroxidation and susceptibility to oxidative stress. Vitamin E and N-acetylcysteine administration to hyperthyroid rats led to reduction in lipid peroxidation and susceptibility to oxidative stress and to increase in antioxidant level, while the diet addition of cholesterol decreased lipid peroxidation but did not modify the other parameters. The hyperthyroid state was also associated with a decrease in the duration of the ventricular action potential recorded in vitro. The vitamin E and N-acetylcysteine administration attenuated the thyroid hormone-induced changes in action potential duration, which was however, significantly different from that of the euthyroid rats. In contrast, cholesterol supplementation did not modify the electrical activity of hyperthyroid heart. These results demonstrate that the triiodothyronine effects on ventricular electrophysiological properties are mediated, at least in part, through a membrane modification involving a free radical mechanism. Moreover, they indicate that the antioxidant-sensitive shortening of action potential duration induced by thyroid hormone is likely independent of enhanced peroxidative processes in sarcolemmal membrane.     

Influence of a melatonin implant on the free radical load in avian thyroid and its relation with thyroid hormonogenesis

The primary aim of this study was to evaluate the effect of melatonin on the oxiradical load in avian thyroid. The superoxide free radicals have been spin trapped by EPR spectroscopy in the thyroid gland of Indian rock pigeon Columbia livia following melatonin implantation for two weeks. Melatonin implantation resulted in augmentation in the levels of superoxide radical in the thyroid gland of pigeons with a concomitant decrease in the levels of the total superoxide dismutase activity. This was also associated with increased lipid peroxidation. Melatonin implantation caused a significant increase in plasma levels of glucose. Plasma levels of thyroxine (T4) and triiodothyronine (T3) were lower in the melatonin-treated pigeons. However, the T3/T4 ratio was higher following melatonin implantation. Since iodination of tyrosine is an H2O2-dependent phenomenon, the inhibition in the activity of SOD could lead to impaired thyroid hormone synthesis.     

Prevention of phorbol myristate acetate-induced acute lung injury by alpha-tocopherol liposomes

Phorbol-myristate acetate (PMA) is commonly used to produce experimental edema and other tissue injuries in the lung. Lung injuries induced by the administration of PMA has been shown to be mediated mainly by neutrophils. Neutrophils recruited to the lower respiratory tract may damage lung tissues by releasing reactive oxygen species, neutral proteases, and lysosomal enzymes. The present study was conducted to investigate whether alpha-tocopherol, entrapped in dipalmitoylphosphatidylcholine liposomes and delivered directly to the lung, could counteract some of the PMA-induced lung injuries. Plain liposomes or alpha-tocopherol containing liposomes (8 mg alpha-tocopherol/kg body weight) were intratracheally instilled into the lungs of rats 24 hr prior to PMA exposure (25 micrograms/kg) and treated rats were killed 3 hr later. Lungs of control animals exposed to PMA developed an increase in lung weight and lipid peroxidation as well as a decrease in lung angiotensin converting enzyme (ACE) and alkaline phosphatase (AKP) activities. PMA treatment also caused an increase in myeloperoxidase (MPO) activity in the lung, suggestive of neutrophil infiltration. Pretreatment of PMA-treated rats with plain liposomes had no effect on PMA-induced injuries. In contrast, pretreatment of rats with liposomal alpha-tocopherol, 24 hr prior to PMA administration, resulted in a significant elevation of pulmonary alpha-tocopherol concentration, accompanied by a concomitant reduction in MPO activity and reversal of PMA-induced changes in lung edema, lipid peroxidation, ACE and AKP activities. These results appear to demonstrate that the intratracheal administration of a liposome-associated lipophilic antioxidant, such as alpha-tocopherol, can significantly ameliorate the toxic effects of reactive oxygen species, putatively released from PMA-stimulated pulmonary target cells and infiltrating neutrophils.     

A childhood cancer sibling''s oral history

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent. In this communication, we show the modulatory effect of DL-alpha-tocopherol (Vitamin-E) on ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative stress, toxicity and hyperproliferative response in rats. Fe-NTA-treatment enhances the susceptibility of renal microsomal membrane for iron-ascorbate-induced lipid peroxidation and hydrogen peroxide generation which are accompanied by a decrease in the activities of renal antioxidant enzymes, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and depletion in the level of renal glutathione. Parallel to these changes, a sharp increase in blood urea nitrogen and serum creatinine has been observed. In addition, Fe-NTA-treatment also enhances renal ornithine decarboxylase activity (ODC) and increases [3H]thymidine incorporation in renal DNA. Prophylactic treatment of animals with Vit.E daily for 1 week prior to the administration of Fe-NTA resulted in the diminution of Fe-NTA-mediated damage. Enhanced susceptibility of renal microsomal membrane for lipid peroxidation induced by iron-ascorbate and hydrogen peroxide generation were significantly reduced (P < 0.05). In addition, the depleted level of glutathione and inhibited activities of antioxidant enzymes recovered to significant levels (P < 0.05). Similarly, the enhanced blood urea nitrogen and serum creatinine levels which are indicative of renal injury showed a reduction of about 50% at a higher dose of Vit.E. The pretreatment of rats with Vit.E reduced the Fe-NTA-mediated induction in ODC activity and enhancement in [3H]thymidine incorporation in DNA. The protective effect of Vit.E was dose dependent. In summary, our data suggest that Vit.E is an effective chemopreventive agent in kidney and may suppress Fe-NTA-induced renal toxicity.     

Regulating for pharmaceutical care outcomes

Change in cellular reduced glutathione (GSH) level was examined after the addition of 1-10 mM potassium sorbate (SA-K) to cultured rat hepatocytes. The cellular GSH content was decreased to the lowest level at 6 h after the addition of SA-K, and then gradually returned to the normal level except for hepatocytes exposed to 10 mM SA-K. Although the decrease in GSH level was not associated with lactate dehydrogenase (LDH) leakage in hepatocytes exposed to SA-K up to the concentration of 5 mM, cell injury was caused in cells exposed to 10 mM SA-K. When eicosapentaenoic acid was added in conjunction with various concentrations of SA-K to hepatocytes, peroxidation of the fatty acid was accelerated in parallel with the decrease in cellular GSH level. The enhanced lipid peroxidation in the hepatocytes co-exposed to SA-K and eicosapentaenoic acid (EPA) induced the development of cell injury. These results suggest that hepatocytes exposed to SA-K become susceptible to oxidative stress such as lipid peroxidation.     

Direct cytotoxicity of hypoxia-reoxygenation towards sinusoidal endothelial cells in the rat

AIMS/BACKGROUND: Sinusoidal endothelial cells are the primary target of ischemia-reperfusion injury following liver preservation. The present study was undertaken to examine the susceptibility of sinusoidal endothelial cells to hypoxia-reoxygenation and the potential role of oxygen free radicals in the induction of cell injury. METHODS: Sinusoidal endothelial cells were isolated from rat liver. After 2 3 days of primary culture, the cells were exposed to hypoxia (N2/CO2 95/5) for 120 min and reoxygenation (O2/CO2 95/5) for 90 min. Control cells were exposed to hypoxia alone, to 95% O2 alone or were maintained under normoxic conditions. Human umbilical vein endothelial cells were used as a model of vascular endothelial cells and submitted to the same protocol. Cell viability and lipid peroxidation were assessed by LDH leakage and malondialdehyde production, respectively. In order to test the potential role of xanthine oxidase and mitochondrial dysfunction in cell injury, the cells were treated with allopurinol and potassium cyanide (KCN) respectively. RESULTS: The different gaseous treatments did not affect LDH leakage in human umbilical vein endothelial cells. In sinusoidal endothelial cells, the sequential hypoxia-reoxygenation caused a significant increase in LDH release, malondialdehyde production and xanthine oxidase activity while hypoxia alone had no effect except on xanthine oxidase activity. Allopurinol inhibited xanthine oxidase without preventing cell injury or lipid peroxidation in this latter cell type. CONCLUSIONS: The results suggest that sinusoidal endothelial cells, as opposed to vascular endothelial cells, are susceptible to a direct cytotoxic effect of hypoxia-reoxygenation. This effect occurs in combination with an increase in xanthine oxidase activity and lipid peroxidation, although cell injury is mediated at least in part by mechanisms independent of xanthine oxidase such as mitochondrial dysfunction.     

Time-level relationship for lipid peroxidation and the protective effect of alpha-tocopherol in experimental mild and severe brain injury

OBJECTIVE: Oxygen free radical-mediated lipid peroxidation has been proposed to be one of the major mechanisms of secondary damage in traumatic brain injury. The first purpose of this study was to establish the time-level relationship for lipid peroxidation in injured brain tissue. The second purpose was to examine the protective effect of alpha-tocopherol against lipid peroxidation. METHODS: For this study, 65 guinea pigs in five groups were studied. Five of the animals were identified as a control group, and the remaining 60 animals were divided equally into four groups (Groups A, B, C, and D). Mild injury (200 g x cm) (Groups A and C) and severe injury (1000 g x cm) (Groups B and D) were produced by the method of Feeney et al. Alpha-tocopherol (100 mg/kg) was administered intraperitoneally before brain injury in Groups C and D. Five animals from each group were killed immediately after trauma, five after 1 hour, and the remaining five animals after 36 hours. Lipid peroxidation in traumatized brain tissues was assessed using the thiobarbituric acid method. RESULTS: In all groups with traumatic brain injuries, levels of malondialdehyde, a lipid peroxidation product, were higher than in the control group. The amount of lipid peroxidation was increased by the severity of the trauma. Alpha-tocopherol significantly suppressed the rise in lipid peroxide levels in traumatized brain tissues. CONCLUSION: This study demonstrates that lipid peroxidation is increased by the severity of trauma and that alpha-tocopherol has a protective effect against oxygen free radical-mediated lipid peroxidation in mild and severe brain injury.     

Dehydroepiandrosterone-induced lipid peroxidation in rat liver mitochondria

Administration of dehydroepiandrosterone (DHEA), a steroid hormone of the adrenal cortex which acts as a peroxisome proliferator and hepatocarcinogen in the rat, caused an increase in NADPH-dependent lipid peroxidation in mitochondria isolated from the liver, kidney and heart, but not from the brain. The effect of DHEA on rat liver mitochondrial lipid peroxidation became discernible after feeding steroid-containing diet (0.6% w/w) for 3 days, and reached maximal levels between 1 and 2 weeks. DHEA in the concentration range 0.001-0.02% did not significantly increase lipid peroxidation compared to the control. Lipid peroxidation was significantly enhanced in animals given a diet containing > or = 0.05% DHEA. The addition of DHEA in the concentration range 0.1-100 microM to mitochondria isolated from control rats had no effect on lipid peroxidation. It seems, therefore, that the steroid effect is mediated by an intracellular process. Our data indicate that induction of mitochondrial membrane lipid peroxidation is an early effect of DHEA administration at pharmacological doses.     

Surgical treatment of chronic pulmonary thromboembolism

It has become increasingly obvious that free radicals and lipid peroxidation contribute to brain damage from trauma by mediating edema formation and ischemia. It should, therefore, be expected that the actual level of endogenous antioxidants, as for example, vitamin C and E in plasma, has an influence on the extent of free radical-induced injury. In this communication we investigate the effect of dietary changes in the free radical scavenger alpha-tocopherol on posttraumatic cerebral swelling in Sprague-Dawley rats. Low, normal, and high plasma levels of alpha-tocopherol were established by respective diets supplied over 2 weeks. Animals of all groups received the same food without alpha-tocopherol. One group was fed a vitamin E-free diet. The pellet-food for the other animals was supplemented either with 5-mg alpha-tocopherol/100 g or 250-mg alpha-tocopherol/100 g dry mass, respectively. The vitamin E-free diet lowered the alpha-tocopherol level in plasma to 30% of control, whereas supplementation with 250 mg/100 g led to a plasma concentration of 200% of control. The animals were then subjected to a focal cold injury of the left cerebral hemisphere. Twenty-four hours after trauma the brain was removed and the water content of each hemisphere was determined by the wet-dry weight method. Swelling of the traumatized hemisphere was calculated as the difference in weight between the traumatized and contralateral control hemisphere. The 2-week alpha-tocopherol supplementation or -deletion diet, respectively, did not either afford significant reduction or lead to an enhancement of traumatic brain swelling. Likewise, the increase in brain water content of the traumatized hemisphere was not affected. It is concluded that supplementation or depletion of alpha-tocopherol for 2 weeks, resulting in a marked increase or decrease of the vitamin E plasma level, does not influence formation of posttraumatic vasogenic brain edema.     

Dietary fish oil inhibits human erythrocyte Mg,NaK-ATPase

The effects of long-term treatment with a high dose (7.7 g/day) of n-3 polyunsaturated fatty acids (PUFA) were studied for human red blood cells (RBCs). RBCs isolated from healthy subjects treated for 30 and 180 days with n-3 PUFA showed the following modifications: (1) a time dependent modification of membrane fatty acid composition with a concomitant increase in membrane lipid unsaturation; (2) an increase in lipid peroxidation, expressed as malondialdehyde release, induced in vitro by t-butyl hydroperoxide (t-BOOH); (3) a time-dependent decrease in susceptibility to hemolysis, expressed as K+ leakage, induced in vitro by t-BOOH; (4) a time-dependent decrease in total and ouabain-insensitive Mg,NaK-ATPase activity. These results suggest that long term dietary supplementation with high doses of n-3 PUFA significantly modifies RBC structure and function that might lead to harmful side effects.     

Effects of rebamipide, a novel anti-ulcer agent, on gastric mucosal injury induced by platelet-activating factor in rats

We examined the role of gastric mucosal blood flow, lipid peroxidation, and neutrophil accumulation mediated by platelet-activating factor in the protective effect of rebamipide against gastric mucosal injury in rats. The intravenous injection of platelet-activating factor induced hyperemia and hemorrhagic erosions in rat stomachs. Rebamipide did not affect the decrease in the gastric mucosal blood flow induced by platelet-activating factor. The increase in gastric injury score after platelet-activating factor injection and the increase in thiobarbituric acid-reactive substances were significantly inhibited by the administration of rebamipide. The gastric injury score was closely correlated with the accumulation of lipid peroxides. Tissue-associated myeloperoxidase activity in the gastric mucosa significantly increased after platelet activating factor injection; this increase was not influenced by rebamipide treatment. The protective effect of rebamipide against the platelet-activiting factor-induced gastric mucosal injury may be due to direct inhibition of lipid peroxidation or scavenging of oxygen radicals that initiate lipid peroxidation.     

Thyroid hormones and cytogenetic outcomes in backpack sprayers using ethylenebis(dithiocarbamate) (EBDC) fungicides in Mexico

Ethylenebis(dithiocarbamate) (EBDC) fungicides are used heavily in the United States. EBDCs (e.g., mancozeb, maneb) are metabolized to ethylene thiourea (ETU). The EPA classifies ETU as a carcinogen, based on thyroid and other cancers in rodents, and has restricted the use of EBDCs, while requiring workers to use protective equipment. There are no data on the potential carcinogenicity of EBDCs in humans, and there is only one study on human genotoxicity. ETU is known to cause decreases of thyroxine (T4) and increases in thyroid-stimulating hormone (TSH) in rodents. We have studied cytogenetic outcomes and serum thyroid hormone levels among 49 heavily exposed workers without protective equipment spraying EBDC on tomatoes in Mexico. We also studied 14 lightly exposed landowners and 31 nonexposed controls. Urinary ETU was used to compare exposure between groups. We found an increase in TSH (p = 0.05) among applicators compared to controls, but no decrease in thyroid hormone (T4). We found increases in sister chromatid exchange (p = 0.03) and in chromosome translocations (chromosome aberrations that persist through cell division) for applicators compared to controls (p = 0.05). However, the subset of reciprocal translocations showed a lesser increase (p = 0.24). Our data suggest that EBDCs affect the thyroid gland and the lymphocyte genome among heavily exposed workers. However, our data are limited to subclinical outcomes, are of borderline statistical significance, and should be interpreted with caution.     

Dual role of betel leaf extract on thyroid function in male mice

The effects of betel leaf extract (0.10, 0.40, 0.80 and 2.0 g kg-1 day-1 for 15 days) on the alterations in thyroid hormone concentrations. lipid peroxidation (LPO) and on the activities of superoxide dismutase (SOD) and catalase (CAT) were investigated in male Swiss mice. Administration of betel leaf extract exhibited a dual role, depending on the different doses. While the lowest dose decreased thyroxine (T4) and increased serum triiodothyronine (T3) concentrations, reverse effects were observed at two higher doses. Higher doses also increased LPO with a concomitant decrease in SOD and CAT activities. However, with the lowest dose most of these effects were reversed. These findings suggest that betel leaf can be both stimulatory and inhibitory to thyroid function, particularly for T3 generation and lipid peroxidation in male mice, depending on the amount consumed.     

In vivo salicylate hydroxylation: a potential biomarker for assessing acute ozone exposure and effects in humans

Ozone is known to yield hydroxyl radical, which may contribute to ozone-mediated lung injury. In the presence of hydroxyl radical, salicylate is hydroxylated to form 2,3-dihydroxybenzoic acid (2,3-DHBA). There is no evidence of enzymatic formation of 2,3-DHBA. We hypothesized that salicylate hydroxylation might be used as a biomarker indicating human exposure to ozone. Healthy, nonsmoking volunteers, 18 to 34 yr of age, were given acetylsalicylic acid (975 mg) or placebo orally 0.5 h before an exposure. Subjects were exposed to ozone (0.12 or 0.4 ppm) or filtered air in an environmental chamber for 2 h, while performing intermittent exercise. Results indicate significant decrements in FVC, FEV1.0, forced expiratory flows at 50% and 75% of FVC, and peak expiratory flow rate, and an increase in airway resistance, after exposure to 0.4 ppm ozone in comparison with air control (p < 0.05). Exposure to 0.4 ppm ozone also resulted in increased symptom numbers and severity (p < 0.05). When subjects were exposed to 0.12 ppm ozone, changes of pulmonary function and symptoms reported were minimal. Plasma concentration of 2,3-DHBA was significantly increased after exposure to 0.12 and 0.4 ppm ozone in comparison with air control (p < 0.05). There was a significant correlation between ozone-induced changes of pulmonary function and normalized salicylate hydroxylation (p < 0.05). The results indicate that exposure to ozone can initiate in vivo production of hydroxyl radical, a potent reactive agent. Salicylate hydroxylation may then serve as a sensitive dosimetric biomarker for ozone exposure, even at subclinical ozone exposure levels.     

Effect of selenium and lodine supplementation on growth rate and on thyroid and somatotropic function in dairy calves at pasture

The effects of Se and I supplementation on growth rate and on thyroid and somatotropic function were examined for heifer calves from two herds fed pasture. Supplementation of calves with intraruminal Se pellets increased the basal plasma concentration of 3,5,3'-triiodothyronine and reduced the basal plasma concentration of thyroxine for both herds. For one herd, supplementation with Se increased the triiodothyronine response to challenge with thyrotropin-releasing hormone, increased BW gain, and tended to increase the plasma concentration of IGF-I. The plasma concentration of growth hormone was unaffected by Se supplementation. Supplementation with I increased the response of thyroid hormones to thyrotropin-releasing hormone but did not increase BW gain. Interaction between Se and I treatment within the herds was not apparent for any outcome variable. These data suggest that the effects of Se deficiency in grazing calves may be mediated by alterations in thyroid hormone metabolism but apparently are not mediated through modulation of the peripheral concentration of growth hormone.     

Effect of thyroid status on lipid composition and peroxidation in the mouse liver

In order to analyze the possible relationship between metabolic rate and oxidative stress, OF1 female mice were rendered hyper- or hypothyroid for 4-5 weeks by administration of 0.0012% L-thyroxine (T4) or 0.05% 6-n-propyl-2-thiouracil (PTU), respectively, in their drinking water. Treatment with T4 resulted in increased basal metabolic rate measured by oxygen consumption and liver cytochrome oxidase activity without altering the glutathione redox system. Endogenous lipid peroxidation, sensitivity to lipid peroxidation and fatty acid unsaturation were decreased in the hyperthyroid group. Hypothyroidism also decreased phosphatidylcholine and cardiolipin fatty acid unsaturation but not in total lipids, and thus lipid peroxidation was not altered. Cardiolipin, a mainly mitochondrial lipid, was the most profoundly altered fraction by both hyper- and hypothyroidism. It is suggested that the lipid changes observed in hyperthyroid animals can protect them against an increased oxidative attack to tissue lipids due to their increased mitochondrial activities.     

Effects of vitamins A and E on the antioxidative metabolism of weaning pigs given dietary fats of different qualities

Early weaned piglets were divided into eight groups of 6 animals each. The animals were fed diets differing in fat quality (4% soybean oil, POZ 5 or 176) and in the content of the vitamins A (5,000 or 20,000 I.U./kg) and E (25 or 125 I.U./kg) over a period of 7 weeks. At the beginning, on day 25 and 47 blood samples were taken and analysed for vitamin A and E. In liver, heart, M. longissimus dorsi and M. semitendinosus vitamin A, E and the TBA-reactive substances were analysed. Induced lipid peroxidation was assessed by the ethane and pentane production rate in the skeletal muscle. During the weaning period a decrease in the alpha-tocopherol level was observed. In groups with the lower doses of vitamin E this effect was more pronounced. After 47 days the alpha-tocopherol concentrations in plasma and heart and skeletal muscle fell about 25-30% by offering high doses of vitamin A compared to those groups fed low doses. Oxidized fats also led to lower tocopherol concentrations in muscle tissues. Hydrocarbon production in M. longissimus dorsi and M. semitendinosus was significantly reduced in groups with the high supplement of vitamin E. A tendentially opposite effect was seen in groups supplied with high levels of vitamin A or oxidized fat. Although retinyl esters in plasma are a minor fraction of the vitamin A activity, they present 99% of the vitamin A in the liver. The distribution pattern of the different retinyl esters was independent of the amount of supplementary vitamin A. In the present experiment 20,000 U of Vitamin A reduced plasma and tissue vitamin E levels. This effect led to an increase of lipid peroxidation indicated by the higher production of hydrocarbons. The results raise concerns about further increases of vitamin A supplementation in piglet feed.     

Prenatal care utilization in New York City: comparison of measures and assessment of their significance for urban health

Short-term exposure to the air pollutant ozone results in severe injury to the nares, trachea, and centriacinus. Long-term exposure however, leads to a state of tolerance that is characterized by remodeling in the centriacinar airways and markedly reduced cell necrosis and inflammation. This remodeling consists of hypertrophy and hyperplasia of Clara cells with a 2- to 5-fold increase in the intracellular content of the major protein synthesized by the Clara cell, Clara cell secretory protein (CCSP). Previous in vitro studies suggest that CCSP may moderate inflammation and bind reactive cytotoxicants. This study tested whether acute and chronic exposure to ozone alters the normal level of expression of the CCSP gene. Rats were exposed to ozone, 1 ppm 8 h nightly, for up to 90 days. Immunohistochemistry demonstrated repopulation of the alveolar ducts with CCSP positive Clara cells and an increase in the intensity of immunoreactive CCSP within Clara cells. The results showed that (1) CCSP mRNA expression, GAPDH, and beta-actin do not change as a result of ozone injury, (2) mRNA levels are more variable as a result of ozone injury and (3) CCSP mRNA expression increases with age.