Free radicals and trace elements.
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Amino Acid Sequence↗
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Antioxidants in hereditary pancreatitis.
OBJECTIVE: The cause of hereditary pancreatitis (HP) remains unknown. This study evaluated the hypothesis that patients with HP have genetically determined low concentrations of antioxidants that may predispose them to repetitive pancreatic injury. METHODS: This cross-sectional analysis compared antioxidant levels in four groups of patients. Group 1 included 14 related people with chronic pancreatitis. Group 2 (11 individuals) belonged to the same kindred but did not have pancreatitis. Group 3 was a group of 65 unrelated control subjects, and Group 4 consisted of seven unrelated children with chronic pancreatitis from other causes. The antioxidant levels analyzed included glutathione peroxidase, superoxide dismutase, glutathione reductase, glutathione transferase, selenium, and vitamin E. Amylase levels were measured in all patients in groups 1, 2, and 4. RESULTS: People with chronic pancreatitis or relatives of people with hereditary pancreatitis (groups 1, 2, and 4) had significantly lower mean glutathione peroxidase values than controls (group 3, p < 0.001). Group 1 also had significantly lower selenium levels than groups 2 and 3 (p < 0.001) but greater levels than group 4 (p = 0.029). Vitamin E levels were lower in group 1 than in groups 2 and 4. The superoxide dismutase levels were significantly different between each group (p < 0.001), and group 1 had the highest level. The glutathione reductase, glutathione transferase, and amylase levels did not differ significantly between groups. However, group 1 had a significantly higher glutathione transferase level than group 4. CONCLUSION: We identified antioxidant deficiencies in a group of patients with hereditary pancreatitis. Higher selenium and vitamin E levels may have prevented their relatives in group 2 from having pancreatitis secondary to oxidant injury, despite low glutathione peroxidase levels. Supplementation with selenium or vitamin E or both may be a beneficial therapeutic option in these patients to decrease the frequency of pancreatitis.
Adolescent↗
Selenium deficiency as a model of experimental pre-eclampsia in rats.
Epidemiological studies and in vitro analysis demonstrate correlations between selenium status and human pre-eclampsia (PET). Selenium is an essential component in the anti-oxidant proteins glutathione peroxidase and thioredoxin reductase, which are produced in lower amounts in pre-eclamptic placenta. This study examined the effect of modulating dietary selenium content in pregnant rats. Rats were fed diets containing no selenium, 239 microg/kg selenium or 1000 microg/kg selenium, four weeks prior to and following conception. Significant pregnancy-specific increases in systolic blood pressure (116.4 +/- 5.2 mmHg vs 108 +/- 6.8 mmHg vs 111.4 +/- 4.7 mmHg) and proteinuria (9.68 +/- 2.12 microg/ml vs 5.93 +/- 1.59 microg/ml vs 4.43 +/- 0.96 microg/ml) were demonstrated in animals fed a selenium free-diet when compared with normal or high selenium diets. Placental weight and pup number were not affected by selenium deprivation, however a significant decrease in the pup weight was evident. Selenium deprivation caused dose-dependent decreases in liver glutathione peroxidase (28.55 +/- 3.82 mmoles/min/mg vs 34.68 +/- 8.64 mmoles/min/mg) and thioredoxin reductase (2.37 +/- 1.25 U/mg vs 6.68 +/- 1.82 U/mg) activity, whereas superoxide dismutase activity remained constant. Placental activity of these enzymes also decreased leading to oxidative stress as measured by increased lipid peroxides (17.92 +/- 1.78 micromoles/mg vs 8.30 +/- 5.52 micromoles/mg) and protein carbonyls in tissue extracts from selenium-free animals. These results suggest that selenium deficiency in pregnant rats leads to symptoms similar to those seen in human PET and may provide an experimental model for studying this complex disease.
Animals↗
Ebselen: prospective therapy for cerebral ischaemia.
Stroke occurs due to haemorrhage or occlusive injury and results in ischaemia and reperfusion injury. A variety of destructive mechanisms are involved including oxygen radical generation, calcium overload, cytotoxicity and apoptosis as well as the generation of inflammatory mediators. Ebselen, 2-phenyl-1, 2-benzisoselenazol-3(2H)-one (PZ 51, DR3305), is a mimic of GSH peroxidase which also reacts with peroxynitrite and can inhibit enzymes such as lipoxygenases, NO synthases, NADPH oxidase, protein kinase C and H(+)/K(+)-ATPase. Ebselen is in a late stage of development for the treatment of stroke. The molecular actions of ebselen contribute to its anti-inflammatory and anti-oxidant properties, which have been demonstrated in a variety of in vivo models. Numerous in vitro experiments using isolated LDL, liposomes, microsomes, isolated cells and organs have established that ebselen protects against oxidative challenge. Unlike many inorganic and aliphatic selenium compounds, ebselen has low toxicity as metabolism of the compound does not liberate the selenium moiety, which remains within the ring structure. Subsequent metabolism involves methylation, glucuronidation and hydroxylation. Experimental studies in rats and dogs have revealed that ebselen is able to inhibit both vasospasm and tissue damage in stroke models, which correlates with its inhibitory effects on oxidative processes. Results from randomised, placebo-controlled, double-blind clinical studies on the neurological consequences of acute ischaemic stroke, subarachnoid haemorrhage and acute middle cerebral artery occlusion, have revealed that ebselen significantly enhances outcome in patients who have experienced occlusive cerebral ischaemia of limited duration. The benefit achieved with ebselen is closely related to the rapidity with which the treatment is initiated, following the onset of the stroke attack. Safety and tolerability are good and no adverse effects have become apparent. Ebselen is currently at the pre-registration stage for subarachnoid haemorrhage and stroke in Japan.
Animals↗
Novel implications of the potential role of selenium on antioxidant status in streptozotocin-induced diabetic mice.
Levels of blood glucose, lipid peroxidation, glutathione (GSH), glutathione peroxidase (GPx), glutathione S-transferase (GST) activities and blood selenium levels were determined in streptozotocin (STZ)-induced diabetic mice. The effect of oral administration of sodium selenite was studied on the above parameters. Diabetes caused hyperglycemia (2.8-fold increase) with a significant increase in the malondialdehyde levels (89% in liver and 83% in blood) and GST activity (55%) and marked decreases in GSH levels (approximately 73% in blood and 79% in liver) in the 5th week after STZ treatment as compared to normal control animals. Treatment of STZ-induced diabetic mice with sodium selenite changed these parameters to near control values in almost all cases. These results suggest that selenium plays a role in reducing the oxidative stress associated with diabetes.
Animals↗
[Effects of injury to endothelial cells on the binding of t-PA to cultured human umbilical vein endothelial cells].
Tissue plasminogen activator (t-PA) plays an important role in fibrinolysis. When t-PA is bound to endothelial cells (EC), its catalytic efficiency is increased and is prevented from being inhibited by its inhibitor PAI. In this paper, diamine was used to cause injury to cultured human umbilical vein endothelial cells by lipoperoxidation, and selenium was used as an anti-oxidant. Radioassay and autoradiography were used to detect the effects of injury on the binding ability of t-PA to EC. The results showed that the binding ability of t-PA to EC was reduced significantly after injury to EC by lipid peroxidation. Selenium could inhibit this reduction to a certain extent. It suggests that the decrease of fibrinolysis was related with the decrease of the binding ability of t-PA to EC after EC was injured.
Cells, Cultured↗
Diphenyl diselenide protects rat hippocampal slices submitted to oxygen-glucose deprivation and diminishes inducible nitric oxide synthase immunocontent.
Diphenyl diselenide (PhSe)2 is an organic selenium compound that has been little studied. In this study we investigated the effects of (PhSe)2 (0.1-3 microM) in a classical model of in vitro brain ischemia, which consists of exposing rat hippocampal slices to oxygen-glucose deprivation (OGD). Hippocampal slices were exposed for 60 min to OGD and the cellular viability (performed by MTT assay) as well as the immunocontent of nitric oxide synthase inducible (iNOS) were evaluated after 180 min of a recovery period. OGD decreased cellular viability by 50% and increased more than twice the immunocontent of iNOS of hippocampal slices. (PhSe)2 (1 and 3 microM) added during OGD and the recovery period abolished both effects. These results demonstrate for the first time the neuroprotective effects of (PhSe)2. Although the selenium analog--ebselen--has been widely used in ischemia models, our results suggest that other selenoorganic compounds could be investigated as pharmacological tools against brain disorders.
Animals↗
Effects of molybdate, tungstate, and selenium compounds on formate dehydrogenase and other enzyme systems in Escherichia coli.
The role of selenium and molybdenum in the metabolism of Escherichia coli was explored by growing cells in a simple salts medium and examining the metabolic consequences of altering the concentration of molybdenum and selenium compounds in the medium. The addition of tungstate increased the molybdate deficiency of this medium, as reflected by lowered levels of enzyme systems previously recognized to require compounds of molybdenum and selenium for their formation [formate-dependent oxygen reduction, formate dehydrogenase (FDH) (EC 1.2.2.1), and nitrate reductase (EC 1.9.6.1)]. The requirement for selenium and molybdenum appears to be unique to the enzymes of formate and nitrate metabolism since molybdate- and selenite-deficient medium had no effect on the level of several dehydrogenase and oxidase systems, for which the electron donors were reduced nicotinamide adenine dinucleotide, succinate, d- or l-lactate, and glycerol. In addition, no effect was observed on the growth rate or cell yield with any carbon source tested (glucose, glycerol, dl-lactate, acetate, succinate, and l-malate) when the medium was deficient in molybdenum and selenium. dl-Selenocystine was about as effective as selenite in stimulating the formation of formate dehydrogenase, whereas dl-selenomethionine was only 1% as effective. In aerobic cells, an amount of FDH was formed such that 3,200 or 3,800 moles of formate were oxidized per min per mole of added selenium (added as dl-selenocystine or selenite, respectively).
Aerobiosis↗
Induction of apoptosis by sodium selenite in human acute promyelocytic leukemia NB4 cells: involvement of oxidative stress and mitochondria.
The mechanisms involved in the anti-carcinogenic activity of selenium remained to be elucidated. In the present study, we examined sodium selenite induced apoptosis and oxidative stress in human acute promyelocytic leukemia cell lines (NB4). Cell growth and viability were assessed by trypan blue exclusion and cell counting; apoptosis by DNA electrophoresis and analysis of intracellular DNA contents; reactive oxygen species and reduced glutathione in the cell were measured by lucigenin dependent chemoluminescent (CL) test and spectrophotometer; mitochondrial transmembrane potential was measured by flow cytometry. Sodium selenite could inhibit the growth and induce apoptosis of NB4 cells. Sodium selenite could increase the production of reactive oxygen species (ROS) in NB4 cells and decrease the level of intracellular reduced glutathione, but caused no change in the activity of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx). Sodium selenite enhanced the collapse of mitochondrial transmembrane potential (MTP), in parallel with the production of ROS. Finally antioxidant N-acetylcysteine (NAC) could inhibit the ROS production, MTP collapse and apoptosis in NB4 cells. Our results suggested that sodium selenite could induce apoptosis of NB4 cells through mitochondrial change mediated by production of reactive oxygen species within the cells.
Acetylcysteine↗
[Retrospective biochemical study of the preventive property of antioxidants in retinopathy of prematurity].
Oxygen radical injury may be one of the factors leading to Retinopathy of Prematurity. It occurs when the body's natural antioxidant capacity is overwhelmed by the free oxygen radicals produced during the perinatal period. Supposing, that premature infants may have defects in their antioxidant systems which can be detected later, even in childhood, a retrospective study of 36 patients of different ages (born prematurely) suffering from different stages of Retinopathy of Prematurity was carried out. According to our results, the signs of an acute oxidative stress could only be seen in the 3 month-old patients' erythrocyte glutathione redox system which was independent of the clinical severity of retinopathy. However, following an in vitro oxidative stress an increased susceptibility of erythrocytes was found in all our patient groups, which means, that the ratio of residual and original amounts of reduced glutathione was decreased and the amount of oxidated derivates of haemoglobin was increased. As selenium is an integral part of glutathione peroxidase enzyme, the very low selenium levels measured in all of our patient groups indicate a reduced glutathione peroxidase activity. The present study suggests, that selenium depletion even in Hungary might play an important role in the pathogenesis of Retinopathy of Prematurity.
Antioxidants↗
The efficacy of trypsin: chymotrypsin preparation in the reduction of oxidative damage during burn injury.
This study was mainly aimed to investigate the efficacy of trypsin:chymotrypsin to elicit anti-oxidant properties. In our earlier studies it was observed that the enzyme preparation exhibited an anti-inflammatory action as there was a remarkable reduction in oedema formation and tissue destruction. This led to further study on the amount of lipid peroxidation products formed and the levels of enzymatic and non-enzymatic anti-oxidants and relative trace element contents of copper, selenium, iron and zinc during administration of the enzyme preparation. Decreased formation of lipid peroxidation products was observed in treated group in comparison with the untreated group. Higher levels of enzymatic anti-oxidants mainly super oxide dismutase, catalase, glutathione peroxidase and glutathione-s-transferase and non-enzymatic antioxidant namely ceruloplasmin persisted for a longer period of time in the treated group than in the untreated group. No statistical significance was observed in non-enzymatic antioxidants viz. ascorbic acid and tocopherol levels in both the groups. Increased serum copper and selenium levels in the treated group could be related to higher levels of the ceruloplasmin and glutathione peroxidase observed in the treated group. The above studies support the finding that treatment with the enzyme preparation reduced tissue destruction leading to decreased formation of free radicals and subsequent effective scavenging of free radicals by the higher levels of enzymatic and non-enzymatic anti-oxidants.
Adult↗
Correlation between prevention of cataract development by disulfiram and fates of selenium in selenite-treated rats.
PURPOSE: We found a new pharmacological effect of disulfiram (DSF) against rat pups with cataract induced by selenite injection. The possible reactive mechanism is discussed in this present paper. METHODS: Wistar male and female rats aged 13 and 30 days, and male rats aged 7 weeks were used this present study. Cataract was induced by injection of selenite (19 micromol/kg, s.c.) to 13-day old rats. The lens opacification was monitored by using the slit lamp equipped with an anterior eye segment analysis system (EAS-1000, Nidek). The selenium contents in rat organs were detected fluorimetrically. Liposomes containing DSF (DSF-liposomes) were prepared by the reverse-phase evaporation method. Rat pups were instilled 5 microl of DSF-liposomes into both eyes 4 times per day. Adult rats were administered with DSF suspensions (100 mg/kg) by nasal cannulation. The changes of plasma concentration of diethyldithiocarbamate (DDC), which was a metabolite of disulfiram, were determined by HPLC method. RESULTS: Intraocular treatment with DSF-liposomes prevented the onset of cataract development in rat pups injected with sodium selenite. Treatment with DSF also significantly reduced the selenium contents in plasma at 1 h post-treatment and in the eye at 96 h post-treatment. No significant differences of selenium content in liver and kidney were observed in 13-day old rats instilled with DSF-liposomes or DSF free liposomes. Cataract could not be induced in the 30-days-old rats with the same dose of selenite (19 micromol/kg) and the liver, kidney, and especially eye of the older rats had lower levels of selenium than 13-day old rats. Diethyldithiocarbamate (DDC), an active metabolite of DSF, was decreased in the plasma following a subcutaneous injection of sodium selenite. The selenium concentration in the plasma was decreased by the intranasal administration of DSF suspensions. CONCLUSIONS: Instillation of DSF-liposomes into the eyes of rat pups given a subcutaneous injection of sodium selenite to induce cataracts prevented the formation of cataracts. The mechanism of inhibition may have resulted from a decreased level of selenium in the eyes following the treatment with DSF. On the other hand, as it is known that the cataracts may result from selenite-induced oxidative stress in the lens, DSF and DDC may react as anti-oxidants.
Administration, Intranasal↗
Serum selenium predicts levels of F2-isoprostanes and prostaglandin F2alpha in a 27 year follow-up study of Swedish men.
Low concentrations of selenium (Se) predict mortality and cardiovascular diseases in some populations. The effect of Se on in vivo indicators of oxidative stress and inflammation, two important features of atherosclerosis, in human populations is largely unexplored. This study investigated the longitudinal association between serum selenium (s-Se) and a golden standard indicator of oxidative stress in vivo (8-iso-prostaglandin F2alpha, a major F2-isoprostane), an indicator of cyclooxygenase (COX)-mediated inflammation (prostaglandin F2alpha), high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and serum amyloid A protein (SAA) in a follow-up study of 27 years. The s-Se was measured in 615 Swedish men at 50 years of age in a health investigation. The status of oxidative stress and inflammation was evaluated in a re-investigation 27 years later by quantification of urinary 8-iso-PGF2alpha and 15-keto-dihydro-PGF2alpha (a major metabolite of PGF2alpha) and serum hsCRP, SAA and IL-6. Men in the highest quartile of s-Se at age 50 had decreased levels of 8-iso-PGF2alpha compared to all lower quartiles and decreased levels of PGF2alpha compared to all lower quartiles at follow-up. These associations were independent of BMI, diabetes, hyperlipidemia, hypertension, smoking, alpha-tocopherol and beta-carotene at baseline. The s-Se was not associated with hsCRP, SAA or IL-6 at follow-up. In conclusion, high concentrations of s-Se predict reduced levels of oxidative stress and subclinical COX-mediated (but not cytokine-mediated) inflammation in a male population. The associations between Se, oxidative stress and inflammation, respectively, might be related to the proposed cardiovascular protective property of Se.
Aged↗
Diphenyl diselenide reverses cadmium-induced oxidative damage on mice tissues.
The concept that selenium-containing molecules may be better antioxidants than classical antioxidants, has led to the design of synthetic organoselenium compounds. In the present investigation subchronic deleterious effects of cadmium-intoxication in mice and a possible protective effect of diphenyl diselenide (PhSe)2 (5 micromol/kg) were studied. Male adult Swiss albino mice (25-35 g) received CdCl2 (10 micromol/kg, subcutaneously), five times/week, for 4 weeks. A number of toxicological parameters in blood, liver, kidney, spleen and brain of mice were examined including delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation and ascorbic acid content, the parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and lactate dehydrogenase (LDH) were also determined. The results demonstrated that cadmium caused inhibition of delta-ALA-D activity in liver (24%), kidney (33%) and spleen (73%) and (PhSe)2 therapy was effective in restoring enzyme activity in all tissues. A reduction in ascorbic acid content was observed in kidney (11%) and spleen (10.7%) of cadmium-treated mice and (PhSe)2 was only effective in improving this reduction in kidney. An increase of lipid peroxidation induced by cadmium was noted in liver (29%) and brain (28%) tissues and (PhSe)2 therapy was effective in restoring TBARS levels in both tissues. We also observed an increase on plasma LDH (1.99-times), AST (1.93-times) and ALT (4.24-times) activities. (PhSe)2 therapy was effective in restoring AST activity at control level. (PhSe)2 did not present toxic effects when plasma parameters were evaluated. The results suggest that the administration of an antioxidant (PhSe)2, during cadmium intoxication may provide beneficial effects by reducing oxidative stress in tissues.
Alanine Transaminase↗
Selenium toxicity: cause and effects in aquatic birds.
There are several manners in which selenium may express its toxicity: (1) an important mechanism appears to involve the formation of CH(3)Se(minus sign) which either enters a redox cycle and generates superoxide and oxidative stress, or forms free radicals that bind to and inhibit important enzymes and proteins. (2) Excess selenium as selenocysteine results in inhibition of selenium methylation metabolism. As a consequence, concentrations of hydrogen selenide, an intermediate metabolite, accumulate in animals and are hepatotoxic, possibly causing other selenium-related adverse effects. (3) It is also possible that the presence of excess selenium analogs of sulfur-containing enzymes and structural proteins play a role in avian teratogenesis. L-selenomethionine is the most likely major dietary form of selenium encountered by aquatic birds, with lesser amounts of L-selenocysteine ingested from aquatic animal foods. The literature is suggestive that L-selenomethionine is not any more toxic to adult birds than other animals. L-Selenomethionine accumulates in tissue protein of adult birds and in the protein of egg white as would be expected to occur in animals. There is no suggestion from the literature that the levels of L-selenomethionine that would be expected to accumulate in eggs in the absence of environmental concentration of selenium pose harm to the developing embryo. For several species of aquatic birds, levels of Se as selenomethionine in the egg above 3 ppm on a wet weight basis result in reduced hatchability and deformed embryos. The toxicity of L-selenomethionine injected directly into eggs is greater than that found from the entry of L-selenomethionine into the egg from the normal adult diet. This suggests that there is unusual if not abnormal metabolism of L-selenomethionine in the embryo not seen when L-selenomethionine is present in egg white protein where it likely serves as a source of selenium for glutathione peroxidase synthesis in the developing aquatic chick.
Animals↗
Effects of dietary selenium on glutathione peroxidase and thioredoxin reductase activity and recovery from cardiac ischemia-reperfusion.
Glutathione peroxidase and thioredoxin reductase are selenocysteine-dependent enzymes that protect against oxidative injury. This study examined the effects of dietary selenium on the activity of these two enzymes in rats, and investigated the ability of selenium to modulate myocardial function post ischemia-reperfusion. Male wistar rats were fed diets containing 0, 50, 240 and 1000 microg/kg sodium selenite for 5 weeks. Langendorff perfused hearts isolated from these rats were subjected to 22.5 min global ischemia and 45 min reperfusion, with functional recovery assessed. Liver samples were collected at the time of sacrifice, and heart and liver tissues assayed for thioredoxin reductase and glutathione peroxidase activity. Selenium deficiency reduced the activity of both glutathione peroxidase and thioredoxin reductase systemically. Hearts from selenium deficient animals were more susceptible to ischemia-reperfusion injury when compared to normal controls (38% recovery of rate pressure product (RPP) vs. 47% recovery of RPP). Selenium supplementation increased the endogenous activity of thioredoxin reductase and glutathione peroxidase and resulted in improved recovery of cardiac function post ischemia reperfusion (57% recovery of RPP). Endogenous activity of glutathione peroxidase and thioredoxin reductase is dependent on an adequate supply of the micronutrient selenium. Reduced activity of these antioxidant enzymes is associated with significant reductions in myocardial function post ischemia-reperfusion.
Animals↗
Adsorption mechanisms of selenium oxyanions at the aluminum oxide/water interface.
Sorption processes at the mineral/water interface typically control the mobility and bioaccessibility of many inorganic contaminants such as oxyanions. Selenium is an important micronutrient for human and animal health, but at elevated concentrations selenium toxicity is a concern. The objective of this study was to determine the bonding mechanisms of selenate (SeO4(2-) and selenite (SeO3(2-) on hydrous aluminum oxide (HAO) over a wide range of reaction pH using extended X-ray absorption fine structure (EXAFS) spectroscopy. Additionally, selenate adsorption on corundum (alpha-Al2O3) was studied to determine if adsorption mechanisms change as the aluminum oxide surface structure changes. The overall findings were that selenite forms a mixture of outer-sphere and inner-sphere bidentate-binuclear (corner-sharing) surface complexes on HAO, selenate forms primarily outer-sphere surface complexes on HAO, and on corundum selenate forms outer-sphere surface complexes at pH 3.5 but inner-sphere monodentate surface complexes at pH 4.5 and above. It is possible that the lack of inner-sphere complex formation at pH 3.5 is caused by changes in the corundum surface at low pH or secondary precipitate formation. The results are consistent with a structure-based reactivity for metal oxides, wherein hydrous metal oxides form outer-sphere complexes with sulfate and selenate, but inner-sphere monodentate surface complexes are formed between sulfate and selenate and alpha-Me2O3.
Adsorption↗
[Effect of aluminum poisoning and gamma-irradiation on the antioxidant system of the body and study of possibilities for correction].
The influence of selenium and rutin on the antioxidant protection system of the organisms in connection with Al-intoxication and gamma-irradiation was investigated. It has been determined that selenium increases the antioxidant protection caused by aluminium. Under simultaneous action of aluminium and gamma-irradiation upon the organism selenium stimulated accumulation of toxic lipids peroxide oxidation products. Rutin action in the situations under investigation caused weakening of antioxidant protection.
Aluminum↗