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Prostaglandin (PG) D2 has been proposed to be essential for the initiation and maintenance of the physiological sleep of rats because intracerebroventricular administration of selenium tetrachloride (SeCl4), a selective inhibitor of PGD synthase (PGDS), was shown to reduce promptly and effectively the amounts of sleep during the period of infusion. However, gene knockout (KO) mice of PGDS and prostaglandin D receptor (DP1R) showed essentially the same circadian profiles and daily amounts of sleep as wild-type (WT) mice, raising questions about the involvement of PGD2 in regulating physiological sleep. Here we examined the effect of SeCl4 on the sleep of WT and KO mice for PGDS and DP1R and that of a DP1R antagonist, ONO-4127Na, on the sleep of rats. The i.p. injection of SeCl4 into WT mice decreased the PGD2 content in the brain without affecting the amounts of PGE2 and PGF(2alpha). It inhibited sleep dose-dependently and immediately after the administration during the light period when mice normally sleep, increasing the wake time; and the treatment with this compound resulted in a distinct sleep rebound during the following dark period. The SeCl4-induced insomnia was observed in hematopoietic PGDS KO mice but not at all in lipocalin-type PGDS KO, hematopoietic and lipocalin-type PGDS double KO or DP1R KO mice. Furthermore, the DP1R antagonist ONO-4127Na reduced sleep of rats by 30% during infusion into the subarachnoid space under the rostral basal forebrain at 200 pmol/min. These results clearly show that the lipocalin-type PGDS/PGD2/DP1R system plays pivotal roles in the regulation of physiological sleep.

Epidemiologic and experimental evidences indicate that selenium, an essential trace element, can reduce the risk of a variety of cancers. Protection against certain types of cancers, particularly colorectal cancers, is closely associated with pathways involving cyclooxygenase-2 (COX-2). We found that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, mediates critical anticancer effects of selenium via a COX-2/prostaglandin E(2) signaling pathway. Selenium activated AMPK in tumor xenografts as well as in colon cancer cell lines, and this activation seemed to be essential to the decrease in COX-2 expressions. Transduction with dominant-negative AMPK into colon cancer cells or application of cox-2(-/-)-negative cells supported the evidence that AMPK is an upstream signal of COX-2 and inhibits cell proliferation. In HT-29 colon cancer cells, carcinogenic agent 12-O-tetradecanoylphorbol-13-acetate (TPA) activated extracellular signal-regulated kinase (ERK) that led to COX-2 expression and selenium blocked the TPA-induced ERK and COX-2 activation via AMPK. We also showed the role of a reactive oxygen species as an AMPK activation signal in selenium-treated cells. We propose that AMPK is a novel and critical regulatory component in selenium-induced cancer cell death, further implying AMPK as a prime target of tumorigenesis.

With an approach to study the anti-tumor effects and mechanism of selenium compound, we investigated the anti-tumor activity and mechanism of Na5SeV5O18.H20 (NaSeVO) in K562 cells. The results showed that 0.625-20 mg/L NaSeVO could significantly inhibit the proliferation of K562 cells in vitro in a time- and concentration-dependent manner as determined by microculture tetrazolium (MTT) assay, the IC50 values were 14.41 (4.45-46.60) and 3.45 (2.29-5.22) mg/L after 48 h and 72 h treatment with NaSeVO respectively. In vivo experiments demonstrated that i.p. administration of 5, 10 mg/kg NaSeVO exhibited an significant inhibitory effect on the growth of transplantation tumor sarcoma 180 (S180) and hepatoma 22 (H22) in mice, with inhibition rate 26.8% and 58.4% on S180 and 31.3% and 47.4% on H22, respectively. Cell cycle studies indicated that the proportion of G0/G1 phase was increased at 2.5 mg/ L while decreased at 10 mg/L after treatment for 24, 48 h. Whereas S phase was decreased at 2.5-5 mg/L and markedly increased at 10 mg/L after treatment for 48 h. After treatment for 24 h, 10 mg/L NaSeVO also markedly increased S and G2/M phases. Take together, the result clearly showed that NaSeVO markedly increased S and G2/M phases at 10 mg/L. The study of immunocytochemistry showed that the expression bcl-2 is significantly inhibited by 10 mg/L NaSeVO, and bax increased. Morphology observation also revealed typical apoptotic features. NaSeVO also significantly caused the accumulation of Ca2+ and Mg2+, reactive oxygen species (ROS) and the reduction of pH value and mitochondrial membrane potential in K562 cells as compared with control by confocal laser scanning microscope. These results suggest that NaSeVO has anti-tumor effects and its mechanism is attributed partially to apoptosis induced by the elevation of intracellular Ca2+, Mg2+ and ROS concentration, and a reduction of pH value and mitochondria membrane potential (MMP).

Mesenchymal stem cells (MSCs) are capable of differentiating into multiple cell lineages and are useful for therapeutic applications. Labeling the MSCs with fluorescent probes is beneficial in tracing the fate of MSCs after implantation. We have introduced the CdSe/ZnS quantum dots (QDs) into the human bone marrow MSCs and examined the effects of QDs on the proliferation and chondrogenesis of the cells. The internalized QDs were found localized in perinuclear regions and remained there after a number of cell passages. The presence of QDs did not affect the proliferation of cells or the size of chondrospheres formed, when subjected to chondrogenesis induction. However, the expression of mRNA and protein of type II collagen and aggrecan in the chondrospheres was significantly inhibited in cells labeled with QDs, suggesting impaired chondrogenesis. Our results that the presence of QDs interferes with the chondrogenic differentiation of MSCs raise concerns in using the QDs as fluorescence tracers for stem cells.

Selenium is known to possess both genotoxic and antigenotoxic properties. In the present study, we have evaluated the genotoxicity and antigenotoxicity of three selenium compounds (sodium selenate, sodium selenite and selenous acid) by measuring in vitro micronucleus induction. Assays were conducted in whole blood lymphocytes and in the TK6 lymphoblastoid cell line, with and without co-treatment with potassium dichromate, a known genotoxic compound. In general, the compounds were more active in TK6 cells than they were in blood lymphocytes. Only 1 microM selenous acid increased the frequency of binucleated cells containing micronuclei (BNMN) in blood lymphocytes, while all three selenium compounds increased BNMN in TK6 cells. In addition, combinations of selenous acid and potassium dichromate resulted in lower frequencies of BNMN than potassium dichromate alone in blood lymphocytes, while combinations of sodium selenate and potassium dichromate produced lower frequencies of BNMN than potassium dichromate alone in TK6 cells. The concentrations of selenium compounds that were used, in combination with the medium components and the biological physiology of the whole blood lymphocytes and TK6 cells, could have affected the redox potential of the compounds, switching the chemicals from a pro-oxidant to antioxidant status and vice-versa. The lower activities of the compounds in blood lymphocytes may be due to the protective effects of blood components. The results indicate that the genotoxic and antigenotoxic properties of selenium compounds are highly dependent upon the conditions under which they are evaluated.

Wistar rats were fed Se-deficient (0.017 +/- 0.002 mg Se/kg) and Seadequate (0.32 +/- 0.045 Se mg/kg) diets for 12 mo and then were given 5 mg/kg of cholestane-3beta,5alpha,6beta-triol (3-triol), intravenously. Se compounds (Na(2)SeO(3) and ebselen) were supplemented in different doses and times to the Se-deficient rats. Twenty-four hours after 3-triol infusion, the changes in ultrastructures of rat aorta were examined by scanning electron micrography (SEM) and transmission electron micrography (TEM). SEM examinations showed that 3-triol induced diffused injuries on arterial endothelial urfaces of long-term Se-deficient rat, and a large number of holes or craterlike defects were observed. TEM examinations further showed that 3-triol induced swelling, necrosis, and shedding of endothelial cells, which resulted in the destruction of endothelial integrity. Meanwhile, smooth muscle cells proliferated and migrated toward intimae; the breakage of internal elastic lamina benefited the migration of smooth muscle cells. Supplemented with Na(2)SeO(3) (40 microg/kg, 10 d per continuum) and ebselen (20 mg/kg), respectively, exhibited significant protection from damages induced by 3-triol. It seems that protecting mechanisms were different between Na(2)SeO(3) and ebselen. The present investigation gave visual evidence that both injuries induced by cholesterol oxides and the Se nutritional status contributed to the development of atherosclerosis.

Selenium is an essential trace metal element, whereas large doses of selenium exert adverse effects to the human body. We examined the effects of selenium compounds, sodium selenite (Na2SeO3) and sodium selenate (Na2SeO4), on catecholamine secretion from cultured bovine adrenal chromaffin cells. Treatment of chromaffin cells with sodium selenite for 72, 48, and 24 h caused decreases in protein and catecholamine contents, in association with cell damage, at concentrations over 30, 300, and 300 microM, respectively. The cells treated with subtoxic conditions (<100 microM, 48 h) of sodium selenite were used for further experiments. Sodium selenite treatment for 48 h inhibited carbachol (CCh)-induced catecholamine secretion in a concentration-dependent and non-competitive manner, while it did not affect high K+- and veratridine-induced catecholamine secretion. Sodium selenite (100 microM) did not affect CCh- and veratridine-induced 22Na+ influx, while the compound inhibited 45Ca2+ influx induced only by CCh, but not high K+ and veratridine. Sodium selenate even at higher concentrations (1000 microM) did not affect any stimulus-induced catecholamine secretion and 45Ca2+ influx. Thus, sodium selenite may specifically exert adverse effects, such as inhibition of physiological stimulus-induced catecholamine secretion from adrenal chromaffin cells due to inhibition of Ca2+ influx.

Garlic (Allium sativum) and onion (Allium cepa) are widely known for their biological properties but are far from having revealed all of their secrets even if the compounds involved in the biological mechanisms, flavenols, sulphur and seleno compounds have been identified. The beneficial effect of garlic on health including protection against cardiovascular diseases and cancers results from all of these compounds although their individual involvement is complex. Garlic and onion, broccoli, wild leek, have the ability to accumulate the selenium (Se) from soil. These Se-enriched plants present a greater protection against carcinogenesis than the common plants and two Se-compounds possessing anti-cancer activity have been identified: Se-methyl selenocysteine and gamma-glutamyl-Se-methyl selenocysteine. However, several Se-compounds from Se-enriched garlic or onion remain unidentified. The techniques for the detection of Se-species are numerous but few methods are able to identify the detected compounds. The very small quantities of Se-compounds present and the clear lack of standards do not make their analysis straightforward, particularly for non-enriched samples. Over the last 10 or so years development of the synthesis of Se-compounds and the use of GC-AED or EC/HPLC-ICP-MS have shown considerable possibilities. These techniques have allowed advances in the identification of Se-compounds, some of which are analogues of S-compounds in plants and yeasts. When these techniques are coupled to EC/HPLC-APCI-MS-MS, they provide a lot of information about the Se-biosynthesis in garlic. This has allowed the preferential formation of methylated compounds in Se-biochemistry to be identified, in contrast to the sulphur biochemistry of the Allium spp. in which compounds containing propenylic groups predominate. This review focuses on the recent advances in the analytical methods of Se-compounds in garlic and onion and particular attention is given to the biological properties of Se-species identified in Se-enriched plants.

CdSe/ZnS quantum dots (QDs) have recently been used as cell tracers for long term imaging of live cells. A number of studies indicate that introduction of quantum dots to cells have no apparent deleterious effects on the morphology or growth of cells. In the present study, the human bone marrow mesenchymal stem cells (hBMSCs) were used as a model to examine the effects of QDs on the growth and osteogenic differentiation of the cells. The CdSe/ZnS QDs were delivered into hBMSCs by liposome-mediated transfection with high efficiency; analysis by transmission electron microscopy revealed that the internalized QDs could be located in the endosome-like vesicles. Uptake of QDs into hBMSCs did not affect the proliferation and cell cycle distribution of the cells. When induced to differentiate along the osteogenic lineage, the QD-containing-hBMSCs were shown to have mineral deposition on the extracellular matrix. However, the cells displayed lower alkaline phosphatase activity as compared to those without QDs. Analysis by reverse transcriptase polymerase chain reaction further demonstrated that the expression of two osteogenic markers, osteopontin and osteocalcin, was significantly inhibited. Together our results show that the presence of QDs in hBMSCs prevents the full response of the cells to induced osteogenic differentiation.

Fluorescent quantum dots (semiconductor nanocrystals) have the potential to revolutionize biological imaging, but their use has been limited by difficulties in obtaining quantum dots that are water soluble and biocompatible. The objectives of our research were to develop a methodology for encapsulation of cadnium-selenium (CdSe) quantum dots (QDs) in phospholipid nanoemulsion that mimics the natural lipoprotein core and to study their interactions with cultured non-small cell lung cancer cells (NSCLC). We found that CdSe QDs can be efficiently encapsulated in the phospholipid nanoemulsion. The QD nanoemulsion has a particle size approximately 80 nm and appears physically stable. The QD nanoemulsion interacts well with cells. The intensity of cellular fluorescence imaging increases with the cell incubation time, indicating more QDs were taken up by the cells, respectively. Two types of fluorescence microscopies confirm that QDs are primarily localized in the cytoplasm but not in the nucleus of the cells.

Twenty-seven selenium compounds and sixteen structurally related organosulfur compounds were tested for quinone reductase (QR) and glutathione-S-transferase (GST) inducing activity in murine hepatoma (Hepa 1c1c7) cells. Sixteen selenium compounds were able to double QR activity, and seven of them also doubled GST activity. The nine most potent compounds, dimethyl diselenide, 2,5-diphenyl- selenophene, dibenzyl diselenide, methylseleninic acid, diphenyl diselenide, benzeneseleninic acid, benzene selenol, triphenylselenonium chloride, and ebselen (2-phenyl- 1,2-benzisoselenazol-3(2H)-one), doubled QR-specific activity at levels lower than 7 microM. The concentration-dependence of QR induction and cell growth inhibition were linearly correlated (P < 0.001, r2 = 0.96) among the group of organoselenium compounds with putative selenol-generating potential, implying that both responses of Hepa 1c1c7 cells were based on these selenol metabolites.

Many selenoorganic compounds play an important role in biochemical processes and act as antioxidants, enzyme inhibitors or drugs. The effects of a new selenocompound--bis(2-aminophenyl)-diselenide on oxidative/nitrative changes in human plasma proteins induced by peroxynitrite (ONOO(-)) were studied in vitro and compared with the those of ebselen, a well-known antioxidant. We also studied the role of the tested selenocompounds in peroxynitrite-induced plasma lipid peroxidation. Exposure of the plasma to peroxynitrite (0.1 mM) resulted in an increase in the level of carbonyl groups and nitrotyrosine residues in plasma proteins (estimated using the ELISA method and Western blot analysis). In the presence of different concentrations (0.025-0.1 mM) of the tested selenocompounds, 0.1 mM peroxynitrite caused a distinct decrease in the level of carbonyl group formation and tyrosine nitration in plasma proteins. Moreover, these selenocompounds also inhibited plasma lipid peroxidation induced by ONOO(-1) (0.1 mM). The obtained results indicate that in vitro bis(2-aminophenyl)-diselenide and ebselen have very similar protective effects against peroxynitrite-induced oxidative/nitrative damage to human plasma proteins and lipids.

Selenium protects cells and inhibits many inflammatory cell mechanisms through antioxidant seleno-enzymes. Immunity improvement is illustrated by the study of Berger and colleagues, with reduction of nosocomial pneumonia in burnt patients under multi-trace-element supplementation. As seleno-compounds (especially sodium selenite) are pro-oxidant, however, administration above 800 microg/day may be dangerous in septic shock. Paradoxically, direct reversible pro-oxidative effects of seleno-compounds may also be beneficial for reduction of inflammation (genomic action, apoptosis), and may even be bactericidal or virucidal. These facts need to be further examined, as well as the possible dramatic drop of plasma selenoprotein P in septic shock and its role in endothelium protection.

The micronutrient element selenium (Se) has been shown to be effective in reducing the incidence of cancer in animal models and human clinical trials. Selenoproteins and low molecular weight Se compounds were implicated in the chemopreventive effect, but specific mechanisms are not clear. We examined the role of Se and selenoproteins in liver tumor formation in TGFalpha/c-Myc transgenic mice, which are characterized by disrupted redox homeostasis and develop liver cancer by 6 months of age. In these mice, both Se deficiency and high levels of Se compounds suppressed hepatocarcinogenesis. In addition, both treatments induced expression of detoxification genes, increased apoptosis and inhibited cell proliferation. Within low-to-optimal levels of dietary Se, tumor formation correlated with expression of most selenoproteins. These data suggest that changes in selenoprotein expression may either suppress or promote tumorigenesis depending on cell type and genotype. Since dietary Se may have opposing effects on cancer, it is important to identify the subjects who will benefit from Se supplementation as well as those who will not.

Syntheses and characterization of the selenium analogue (MSeI) of anti-thyroid drug methimazole and a series of organoselenium compounds bearing N-methylimidazole pharmacophore are described. In contrast to the sulfur compound that exists predominantly in its thione form, the selenium analogue exists in a selenol form, which spontaneously oxidizes in air to produce the corresponding diselenide. The reduction of the diselenide by GSH or NaBH(4) affords the biologically active selenol, which effectively inhibits the lactoperoxidase (LPO) activity in vitro. The monoselenides having N-methylimidazole moiety are found to be much less active than the selenol, suggesting that the presence of a selenol moiety is important for the LPO inhibition. The kinetic and mechanistic studies reveal that MSeI inhibits the LPO activity by reducing the H(2)O(2), providing a novel method to reversibly inhibit the enzyme. Although MSeI strongly inhibits LPO, the enzyme's activity can be completely recovered by increasing the H(2)O(2) concentration. On the other hand, the inhibition by methimazole (MMI), the sulfur analogue, cannot be reversed by increasing the H(2)O(2) concentration, leading to a complete inactivation of the enzyme. The reversible inhibition of LPO by some of the selenium derivatives is correlated with their glutathione peroxidase (GPx) activity, and the high GPx activity of the selenium compounds as compared with their sulfur analogues suggests that the selenium derivatives may protect the thyroid gland from oxidative damage.

Six novel selenium-containing polyphenolic acid esters were synthesized and evaluated as antioxidants and 5-lipoxygenase inhibitors. Synthesis of the title compounds involved the Mitsunobu reaction of polyphenolic acids with 2-phenylselenoethanol. Compounds and were found to be very effective antioxidants and 5-lipoxygenase inhibitors with activity comparable to or better than caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE).

Although selenium, an essential trace element and a component of glutathione peroxidase, is known to protect the heart from ischemia-reperfusion (I/R)-induced injury, the mechanisms of this protection are not fully understood. For this purpose, isolated rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion; sodium selenite (25-1,000 nM) was added in the perfusion medium 10 min prior to ischemia, as well as during reperfusion. Selenium caused a dose-dependent improvement in cardiac performance and attenuated the decrease in the ratio of reduced glutathione to oxidized glutathione, as well as the increased level of malondialdehyde in I/R heart. Elevated ratios of nuclear factor-kappaB (NF-kappaB) in particulate and cytosolic fraction and of phosphorylated NF-kappaB and total NF-kappaB in I/R hearts were reduced by selenium. Cardiac dysfunction in hearts perfused with xanthine plus xanthine oxidase mixture, as well as hydrogen peroxide, or subjected to Ca2+ paradox was also attenuated by selenium. These data suggest that selenium protects the heart against I/R injury due to its action on the redox state and deactivation of NF-kappaB in I/R hearts.

HIV protease inhibitors (PIs) have been implicated to cause cardiovascular complications. Previous studies demonstrated that the PI ritonavir (RTV) caused endothelial dysfunction in porcine arteries. This study investigated and compared the effects of 5 commonly used PIs on vasomotor function, endothelial nitric oxide synthase (eNOS) expression, and oxidative stress in porcine coronary arteries. Vessel rings were incubated with 15 microM of RTV, amprenavir (APV), saquinavir (SQV), indinavir (IDV), or nelfinavir (NFV) for 24 hours. Vasomotor function was studied using a myograph system. The contractility of the rings was significantly reduced for RTV and SQV. In response to bradykinin at 10(-5) M, the endothelium-dependent relaxation was significantly reduced for RTV, APV, and SQV. The eNOS mRNA levels were significantly reduced for RTV, APV, and SQV. Furthermore, the superoxide anion (O(2)(-)) levels of the vessels were significantly increased for RTV and APV. It was found that nitric oxide production was decreased, whereas the level of nitrotyrosine proteins was increased in RTV-treated vessels. Furthermore, antioxidant seleno-L-methionine (SeMet) reversed RTV-induced O(2)(-) production and vasomotor dysfunction. Thus, the HIV PIs RTV, APV, and SQV at 15 microM have more potent in vitro effects on vasomotor dysfunction, eNOS downregulation, and O(2)(-) production than IDV and NFV. The antioxidant SeMet can block these adverse effects of RTV. The results suggest that antioxidant therapy may have applications for controlling PI-associated cardiovascular complications.

Selenium (Se) is a very effective anti-cancer agent. We studied the effects of inorganic Se compounds on induction of apoptosis by which Se compounds exert cancer chemopreventive activity. With the use of HSC-3 human oral squamous cell carcinoma cells, the present study showed that treatment with Se for 72 h, in the form of SeO2 and Na2SeO3, but not Na2SeO4, markedly induced apoptosis in a dose-dependent manner. Treatment of HSC-3 cells with 100 microM SeO2 resulted in the caspase-3-like and -9-like activation. Se compounds induced a loss of mitochondrial membrane potential (DeltaPsim), but did not induce the generation of reactive oxygen species. Treatment with SeO2 for 18 h resulted in 80% loss of reduced glutathione (GSH), which is known to be involved in the metabolism of Se. Treatment with N-acetyl-L-cysteine, or exogenous GSH, prevented the SeO2-induced apoptosis. Treatment with GSH led to the partial reverse in reduction of DeltaPsim caused by SeO2, while buthionine sulfoximine augmented the SeO2- or Na2SeO3-induced apoptosis. These results suggest that modulation of the mitochondrial redox equilibrium by Se contributes to the mitochondrial pathway, regulating caspase-9-mediated apoptosis without a concurrent increase in ROS.

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic compound found in grapes and wine, has been shown to have anti-inflammatory, anti-oxidant, anti-tumor and anti-platelet activities. Using different methods, we show that resveratrol reduces oxidative stress induced by cisplatin (cis-diamminedichloroplatinum II) and selenium-cisplatin conjugate ([NH(3)](2)Pt(SeO(3)), Se-Pt) in human blood platelets, lymphocytes and plasma. Resveratrol decreased the production of 8-epi-prostaglandin F(2) (a biomarker of lipid peroxidation) in control blood platelets and platelets treated with platinum compounds (10 microg/ml), and markedly reduced activities of different anti-oxidative enzymes (glutathione peroxidase, superoxide dismutase and catalase) in these cells. A combined action of resveratrol and Se-Pt evoked a significant decrease of DNA damage (measured by comet assay) in lymphocytes compared with cells treated with Se-Pt only. Resveratrol also caused a distinct reduction of total anti-oxidant level in plasma after incubation with platinum compounds. Therefore, anti-oxidative activity of resveratrol may diminish oxidative stress and damage to cellular biomolecules (lipids, proteins and DNA) induced by platinum compounds.

Background and Aims: The cancer-protective properties of vegetable consumption are most likely mediated through 'bioactive compounds' that induce a variety of physiologic functions including acting as direct or indirect antioxidants, regulating enzymes and controlling apoptosis and the cell cycle. The 'functional food' industry has produced and marketed foods enriched with bioactive compounds, but there are no universally accepted criteria for judging efficacy of the compounds or enriched foods., Scope: Carotenoids, glucosinolates, polyphenols and selenocompounds are families of bioactive compounds common to vegetables. Although numerous studies have investigated the agricultural and human health implications of enriching foods with one or more of these compounds, inadequate chemical identification of compounds, lack of relevant endpoints and inconsistencies in mechanistic hypotheses and experimental methodologies leave many critical gaps in our understanding of the benefits of such compounds. This review proposes a decision-making process for determining whether there is reasonable evidence of efficacy for the both the compound and the enriched food. These criteria have been used to judge the evidence of efficacy for cancer prevention by carotenoids, polyphenols, glucosinolates and selenocompounds., Conclusions: The evidence of efficacy is weak for carotenoids and polyphenols; the evidence is stronger for glucosinolates and lycopene, but production of enriched foods still is premature. Additionally there is unacceptable variability in the amount and chemical form of these compounds in plants. The evidence of efficacy for selenocompounds is strong, but the clinical study that is potentially the most convincing is still in progress; also the variability in amount and chemical form of Se in plants is a problem. These gaps in understanding bioactive compounds and their health benefits should not serve to reduce research interest but should, instead, encourage plant and nutritional scientists to work together to develop strategies for improvement of health through food.

The effect of dietary selenium yeast, a source of organic selenium, on heat shock protein 70 (hsp70) responses, redox status, growth and feed utilization were evaluated either in enteropathogenic Escherichia coli-challenged (EPEC) or in heat-stressed (HS) male broiler chickens grown to 42 days of age. One day-old chicks in experiment 1 were challenged orally with EPEC (10(6) cfu/chicken on day 1 and boosted by water application on days 2, 3, and 4) and fed diets with or without selenium yeast. Body weight (BW), feed conversion ratio (FCR), and total mortality were determined at 42 days of age, and this was followed by collection of ileal tissue for the quantification of total glutathione (TGSH), reduced glutathione (GSH), oxidized glutathione (GSSG), and hsp70 in randomly selected chickens from each treatment. In experiment 2, male broiler chickens were fed diets with or without selenium yeast under a thermoneutral rearing condition. At four weeks of age, blood and hepatic tissue were collected from chickens maintained in the thermoneutral environment and from chickens subjected to HS (40 degrees C for 1 h) and analyzed for TGSH, GSH, GSSG, and hsp70. Selenium yeast improved BW, FCR, and decreased mortality in both control and EPEC-challenged chicks. Selenium yeast significantly attenuated hsp70 expression in EPEC-challenged chickens and in those subjected to HS. The EPEC challenge increased TGSH and GSSG levels and decreased GSH/GSSG ratio. However, GSSG level accumulated in chickens fed diets without selenium supplementation resulting in a lower GSH/GSSG ratio in the selenium yeast-fed group. Heat stress increased GSSG level and decreased GSH/GSSG ratio. Selenium yeast-fed groups maintained higher levels of GSSG before and after HS with a resultant lower GSH/GSSG ratio. The hsp70 response was significantly less in those chickens fed selenium yeast and challenged with either EPEC or HS than in those chickens given no supplemental selenium. The results of this study suggest that selenium yeast supplementation had imparted resistance to oxidative stress associated with enteric bacteria infection and to high temperature exposure. It is believed that the resistance to the stressors was due to an improved redox status of the selenium yeast-fed chickens.

The present study was performed to examine the mechanism by which selenate ameliorates the insulin sensitivity in type II diabetic dbdb mice. Therefore, 21-adult female dbdb mice were randomly assigned to three experimental groups (0Se, SeIV and SeVI) with seven animals per group. Mice of group 0Se were fed with a selenium-deficient diet (<0.02 mg Se/kg) based on wheat and torula yeast for 8 weeks whereas the mice of groups SeIV (selenite) and SeVI (selenate) were fed with sodium selenite and sodium selenate (up to 35% of the LD(50) for mice in eighth week), in addition to the diet by daily tube feeding. Eight weeks of selenate application led to significantly elevated insulin sensitivity in comparison with selenium deficiency and selenite application. The activity of cytosolic protein tyrosine phosphatases (PTPs) as important negative regulators of insulin signalling was reduced from 53.8% to 22.5% in the liver and skeletal muscle of selenate-treated mice in comparison with the selenium deficient and selenite-treated controls, suggesting an inhibition of PTPs by intermediary selenate metabolites. In an additional in vitro inhibition study, selenate (oxidation state +VI) did not inhibit PTP activity. Selenium metabolites in the oxidation state +IV were found to be the actual inhibitors of PTP activity. In conclusion, the results of the present study show that one possible mechanism by which supranutritional selenate doses enhance insulin sensitivity in type II diabetic dbdb mice is based on the inhibition of PTPS as negative regulators of insulin signalling. Moreover the cellular metabolism of selenate including its intermediary reduction to the oxidation state +IV seems to play a crucial role during this process.

Among the substances that attracted the attention of oncologists in recent years are selenium-containing compounds, both inorganic and organic. Several epidemiological studies have shown an inverse correlation between selenium intake and cancer incidence. In the experiments reported here, we compared the effects of 2 inorganic selenium-containing salts that differed in the level of selenium oxidation, selenite IV and selenate VI. We tested the effects of these 2 compounds on cell survival and growth, cell cycle processing, cell morphology, cytoskeleton, and lipid peroxidation in 3 human skin cell types: normal keratinocytes, melanocytes, and human melanoma cell line HTB140. The different effects of selenite and selenate on the viability, growth, and morphology of normal cells and tumor cells are reported and provide a base for future research and treatment of some neoplastic diseases. The attention is paid to cell apoptosis induced by selenite and not by selenate, and the effects of tested substances on thioredoxin reductase system are postulated.

Epidemiological, clinical and experimental evidence collectively suggests that Se in different inorganic and organic forms provides a potential cancer chemopreventive agent, active against several types of cancer. It can exert preventive activity in all the three stages of cancer: initiation, promotion and progression. Literature reports revealed that organoselenocyanates have more potential as chemopreventive agents than inorganic forms due to their lower toxicity. In our previous report we showed chemopreventive efficacy of diphenylmethyl selenocyanate during the initiation and pre- plus post-initiation phases of skin and colon carcinogenesis process. The present study was undertaken to explore the anti-tumour promoting activity of diphenylmethyl selenocyanate in a 7,12-dimethylbenz (a) anthracene (DMBA)-croton oil two-stage skin carcinogenesis model. The results obtained showed significant (p<0.01) reduction of the incidence and number of skin papillomas, precancerous skin lesions, along with significant (p<0.01) elevation of phase II detoxifying enzymes (GST, Catalase and SOD) and inhibition of lipid peroxidation in liver and skin. Thus, the present data strongly suggest that diphenylmethyl selenocyanate also has the potential to act as anti-tumour promoter agent in a two-stage skin carcinogenesis mouse model, pointing to possible general efficacy.

Cationic porphyrins are known to bind to and stabilize different types of G-quadruplexes. Recent studies have shown the biological relevance of the intramolecular parallel G-quadruplex as a transcriptional silencer in the c-MYC promoter. TMPyP4 also binds to this G-quadruplex and most likely converts it to a mixed parallel/antiparallel G-quadruplex with two external lateral loops and one internal propeller loop, suppressing c-MYC transcriptional activation. To achieve therapeutic selectivity by targeting G-quadruplexes, it is necessary to synthesize drugs that can differentiate among the different types of G-quadruplexes. We have designed and synthesized a core-modified expanded porphyrin analogue, 5,10,15,20-[tetra(N-methyl-3-pyridyl)]-26,28-diselenasapphyrin chloride (Se2SAP). Se2SAP converts the parallel c-MYC G-quadruplex into a mixed parallel/antiparallel G-quadruplex with one external lateral loop and two internal propeller loops, resulting in strong and selective binding to this G-quadruplex. A Taq polymerase stop assay was used to evaluate the binding of TMPyP4 and Se2SAP to G-quadruplex DNA. Compared to TMPyP4, Se2SAP shows a greater selectivity for and a 40-fold increase in stabilization of the single lateral-loop hybrid. Surface plasmon resonance and competition experiments with duplex DNA and other G-quadruplexes further confirmed the selectivity of Se2SAP for the c-MYC G-quadruplex. Significantly, Se2SAP was found to be less photoactive and noncytotoxic in comparison to TMPyP4. From this study, we have identified an expanded porphyrin that selectively binds with the c-MYC G-quadruplex in the presence of duplex DNA and other G-quadruplexes.

We investigated the superoxide anion-scavenging effects of six selenocarbamates and four thiocarbamates, using a highly sensitive quantitative chemiluminescence method. At 333 nM, six selenocarbamates and four thiocarbamates scavenged in the range of 2.9-68.7% of O(2)*-. Se-methyl N-phenylselenocarbamate and Se-methyl N-(4-methylphenyl)selenocarbamate exhibited the strongest superoxide anion-scavenging activity among the Se-selenocarbamates. In contrast, the corresponding S-thiocarbamates had moderate inhibitory effect. The 50% inhibitory concentrations (IC(50)) of Se-methyl-N-phenylselenocarbamate and Se-methyl-N-(4-methylphenyl)selenocarbamate were determined to be 140 nM and 162 nM, respectively. Thus, these compounds acted in vitro as effective and potentially useful O(2)*- scavengers.

Changes of lipid peroxidation reaction and NK cell activity in spleen of CCl4-induced liver injury mice with adding orgnoselenium from Se-enriched lactobacillus were studied to discuss the protective effect of orgnoselenium and its mechanism. Sixty healthy mice (female: male=1:1) were chosen and divided randomly into four groups: control group (group C), orgnoselenium group (group Se), CCl4-injection group (group CCl4) and CCl4-injection plus orgnoselenium group (group CCl4-Se). The liver injury was induced by abdominal injection of CCl4 (0.07ml/100g body weight) on every other day over four weeks. The spleens were collected at the 2nd and 4th week, and spleen NK cell activity, spleen homogenate GSH-Px, SOD, CAT activities and MDA concentration were determined. The results showed that during the entire experimental period, spleen homogenate GSH-Px, SOD and CAT activities in groups C, Se and CCl4-Se were higher or significantly higher than that in group CCl4, and three antioxidant enzyme activities in groups Se and CCl4-Se had no apparent differences from that in group C except that there were significant increases of SOD activity at the 4th week. Spleen homogenate MDA content of group CCl4 increased markedly compared with that of groups C, Se and CCl4-Se, MDA level of group CCl4-Se was close to that of group C, and that of group Se was lower. During the entire experimental period, NK cell activity of group Se was the highest and significantly higher than that of group C at the 4th week, a lowest value was observed in group CCl4, which was lower or markedly lower than that of groups C, Se and CCl4-Se, there were no significant differences between group CCl4-Se and group C. It is suggested that orgnoselenium from Se-enriched lactobacillus can enhance antioxidation ability in normal mice and play an effective role by means of improving and enhancing the spleen antioxidation enzymes and NK cell activities in the process of intervening liver injury.

9-Fluorenemethyl H-phosphonoselenoate monoester has been used to produce thymidine 3'-O-phosphoroselenoate monoester from which various P(V) derivatives containing multiple modifications at phosphorus were obtained; e.g., thymidine 3'-O-phosphoroselenofluoridate, 3'-O-phosphoroselenothioate, or 3'-O-phosphorodiselenoate monoesters.

By a combination of trace techniques and various biochemical methods, information about the characteristics of a 15-kDa selenoprotein was obtained. After labeling of rats in vivo with [(75)Se]selenite, subcellular fractionation of the homogenates of the prostate, lung, brain, thyroid gland, and large intestine, and gel electrophoretic separation of the proteins and subcellular fractionation, 15-kDa (75)Se was found in the cytosols of the tissues prostate > brain > lung > thyroid gland > large intestine after autoradiography. After coelectrophoresis of the separated 15-kDa labeled band obtained from each cytosolic fraction, the 15-kDa (75)Se band migrated in the same way as the combined bands isolated from the five tissue cytosols. After proteolytic cleavage in the gel of the 15-kDa labeled band obtained from the cytosol of each tissue and re-electrophoresis, the same labeled peptide pattern was found in each gel slice after autoradiography. By means of reversed-phase HPLC, we characterized a selenocysteine-containing protein that has enzymatic activity like that of glutathione peroxidase.

Objective: To investigate the mechanisms underlying the effect of selenium dioxide (SeO(2)) on the proliferation, apoptosis, and apoptosis-related gene expressions of Bcl-2 and p53 in 3 leukemia cell lines NB4, K562 and HL-60., Methods: The three leukemia cell lines were treated with 3, 10 and 30 mmol/L SeO(2) and apoptosis detected by flow cytometry and analysis of p53 and Bcl-2 expressions., Results: SeO(2) at 10 and 30 mmol/L could inhibit the proliferation of three leukemia cell lines. SeO(2) treatment at 30 mmol/L for 48 h induced an apoptosis rate of 54.0 %, 46.5 %, 49.6 % in NB4, K562, and HL-60 cells respectively, and down-regulated Bcl-2 expression in NB4 and K562 but not in HL-60 cells., Conclusion: SeO(2) can induce apoptosis in NB4, K562 and HL-60 leukemia cells, involving the down-regulation of Bcl-2 and up-regulation of p53.

Human exposure to alkylating agents metabolized from tobacco- and food-borne carcinogens occurs regularly. Dietary inorganic compounds such as selenium and vanadium have been shown previously to provide chemoprotective benefits in rat and human trials. Here, we present biochemical data on the ability of inorganic compounds to protect DNA from alkylation damage. An enzyme cleavage assay is used to observe alkylated DNA. Simple salts (e.g., NaCl or NiCl(2)) did not prevent DNA alkylation, whereas anionic oxo species (e.g., Na(2)SeO(4) or Na(3)VO(4)) did inhibit alkylation. We propose that these oxo species behave as nucleophilic targets for the electrophilic alkylating agents, thereby preventing DNA damage.

The syntheses of two ammonium salts of 1,4-dideoxy-1,4-imino-d-galactitol containing erythritol sulfate side chains are described. The parent compound is a known inhibitor of the enzyme UDP-galactopyranose mutase (UDP-galactopyranose furanomutase, E.C. 5.4.99.9), which is responsible for the conversion of UDP-galactopyranose into UDP-galactofuranose and is presumably protonated in its active form. The side chain was chosen because it is present in a known sulfonium ion alpha-glucosidase inhibitor, salacinol. The syntheses of the selenonium analogues derived from 1,4-dideoxy-1,4-seleno-d-galactitol are also described. The synthetic strategy in the syntheses of all four salts involved the nucleophilic attack of a protected derivative of the alditol at the least hindered carbon of 2,4-O-benzylidene d- or l-erythritol-1,3-cyclic sulfate to give adducts that were subsequently deprotected. The importance of different protecting groups used in the various syntheses is also highlighted. Enzyme inhibition assays carried out on these compounds, and the corresponding sulfonium ions synthesized previously, show that they are poor inhibitors of UDP-galactopyranose mutase.

Hydrophobic-interaction chromatography coupled on-line with chemical-vapor-generation atomic-fluorescence spectrometry (HIC-CVGAFS), optimized recently for the analysis of thiol-containing proteins under denaturing conditions, has been used to study the chemical reduction of denatured proteins. Four proteins chosen as models (human serum albumin (HSA), bovine serum albumin (BSA), alpha-lactalbumin (alpha-Lac) from bovine milk, and lysozyme from chicken egg (Lys)) were denatured with urea and reduced with dithiothreitol (DTT), with selenol as catalyst. The method is based on derivatization of the -SH groups of proteins with p-hydroxymercurybenzoate (PHMB), followed by HIC separation and post-column on-line reaction of the derivatized reduced, denatured proteins with bromine generated in situ. HgII, derived from rapid conversion of uncomplexed and protein-complexed PHMB, is selectively detected by AFS in an Ar/H2 miniaturized flame after sodium borohydride (NaBH4) reduction to Hg degrees . The yield of the reduction was studied as a function of reductant concentration, reduction time (tred), and urea concentration. Results showed that the optimum values for DTT and selenol concentrations and for tred were between 1 and 100 mmol L(-1) and between 1 and 20 min, respectively, depending on the protein studied. The percentage disulfide bond reduction increases as the urea concentration used for protein denaturation increases, giving a single-step sigmoid increment for single-domain, low-MW proteins (alpha-Lac and Lys), and a two-step sigmoid increment for multi-domain, high MW proteins (HSA and BSA). The shapes of plots of percentage reduced disulfide against urea concentration are characteristic of each protein and are correlated with the location of S-S in the protein. Under the adopted conditions complete protein denaturation is the conditio sine qua non for obtaining 100% S-S reduction. The detection limit for denatured, reduced proteins examined under the optimized conditions was found to be in the range 1-5 x 10(-12) mol L(-1) (10-30 pg), depending on the protein considered.

As an essential element, selenium is present in enzymes from several families, including glutathione peroxidases, and is thought to exert anticarcinogenic properties. A remarkable feature of selenium consists of its ability to oxidize thiols under reducing conditions. Thus, one mode of action recently suggested is the oxidation of thiol groups of metallothionein, thereby providing zinc for essential reactions. However, tetrahedral zinc ion complexation to four thiolates, similar to that found in metallothionein, is present in one of the major classes of transcription factors and other so-called zinc finger proteins. Within this study we investigated the effect of selenium compounds on the activity of the formamidopyrimidine-DNA glycosylase (Fpg), a zinc finger protein involved in base excision repair, and on the DNA-binding capacity and integrity of xeroderma pigmentosum group A protein (XPA), a zinc finger protein essential for nucleotide excision repair. The reducible selenium compounds phenylseleninic acid, phenylselenyl chloride, selenocystine, ebselen, and 2-nitrophenylselenocyanate caused a concentration-dependent decrease of Fpg activity, while no inhibition was detected with fully reduced selenomethionine, methylselenocysteine or some sulfur-containing analogs. Furthermore, reducible selenium compounds interfered with XPA-DNA binding and released zinc from the zinc finger motif, XPAzf. Zinc release was even evident at high glutathione/oxidised glutathine ratios prevailing under cellular conditions. Finally, comparative studies with metallothionein and XPAzf revealed similar or even accelerated zinc release from XPAzf. Altogether, the results indicate that zinc finger motifs are highly reactive towards oxidizing selenium compounds. This could affect gene expression, DNA repair and, thus, genomic stability.

Selenium compounds, such as sodium selenite and Ebselen were shown to increase high affinity ryanodine binding to the skeletal muscle type ryanodine receptor (RyR1) at nanomolar concentrations, and inhibit the receptor at low micromolar concentrations. This biphasic response was observed in both concentration and time-dependent assays. Extensive washing did not reverse either the stimulation or suppression of receptor binding, but both were prevented or reversed by addition of reduced glutathione, GSH. Selenium compounds were also shown to induce Ca(2+) release from the isolated sarcoplasmic reticulum vesicles. Sodium selenite and Ebselen stimulated the skeletal muscle ryanodine receptor by oxidizing 14 of 47 free thiols per monomer on RyR1 (as detected with the alkylating agent 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin) (CPM). Oxidation of the remaining thiols by these selenium compounds resulted in inhibition of the ryanodine receptor.

2-Phenylselenenyl-1,8-cineole (PSC) increased both the pentobarbital-induced sleeping time and the reaction time (up to 2 h) in the tail immersion method. PSC also caused dose-dependent inhibition of acetic acid induced writhing with maximum inhibition of 93.4% and was approximately 8.5-fold more potent than 1,8-cineole. These findings show that PSC presents sedative effect and significant antinociceptive activity.

In this study, the effect of ascorbic acid (vitamin C), DL-alpha-tocopherol acetate (vitamin E), and sodium selenate (selenium) on ethanol-induced gastric mucosal injury in rats was investigated morphologically and biochemically. The gastric mucosal injury was produced by administration of 1 mL of absolute ethanol to each rat. Animals received vitamin C (250 mg/kg), vitamin E (250 mg/kg), and selenium (0.5 mg/kg) for 3 d 1 h prior to the administration of absolute ethanol. In gastric mucosa of rats given ethanol according to control groups, neuronal nitric oxide expression decreased. This immunoreactivity was much lower in the group given ethanol+vitamin C+vitamin E+selenium than the control group and the ethanol-induced group. Scanning electron microscopic evaluation of the ethanol-induced group, when compared to control groups, revealed degenerative changes in gastric mucosa, whereas a good arrangement in surface topography of gastric mucosa in the group given ethanol + vitamin C+vitamin E + selenium was observed. In the group administered ethanol, a reduction of the stomach glutathione (GSH) and serum total protein levels and increases in serum sialic acid, triglycerides, and stomach lipid peroxidation (LPO) levels were observed. Vitamin C+vitamin E+Se administration to alcohol-treated rats significantly increased the serum total protein, triglyceride levels, and stomach GSH levels and significantly lowered the levels of serum sialic acid and stomach LPO compared to untreated alcohol-supplemented rats. As a result of these findings, we can say that the combination of vitamin C, vitamin E, and selenium has a protective effect on ethanol-induced gastric mucosal injury of rats.

Thio and seleno analogues of tetramethylrosamine were prepared by the directed-metalation/cyclization of the corresponding N,N-diethyl 2-(3-dimethylaminophenylchalcogeno)-4-dimethylaminobenzamide to the 2,7-bis-(N,N-dimethylamino)-9H-chalcogenoxanthen-9-one followed by the addition of phenylmagnesium bromide, dehydration, and ion exchange to the chloride salt. The thio and seleno tetramethylrosamines had longer wavelengths of absorption and higher quantum yields for the generation of singlet oxygen than tetramethylrosamine. Both the thio and selenoanalogues of tetramethylrosamine were efficient photosensitizers against R3230AC rat mammary adenocarcinoma cells in vitro.

Neem, Azadirachta indica, is a plant from the family Meliaceae, known as "Pokok Semambu" in Malay community. It has been extensively used in India as traditional Ayurvedic and folklore minedicine for the treatment of various diseases. This study aimed to determine the distribution of selenium in the liver of rats during hepatocarcinogenesis when neem aqueous extract and dietary selenium was supplemented.

Selenium, an essential micronutrient, plays important roles against different diseases, including several types of cancer. In the present study, antioxidative and chemopreventive properties of a synthetic organoselenium compound, diphenylmethyl selenocyanate, were evaluated with a 7,12-dimethylbenz (a) anthracene - croton oil induced two-stage mouse skin carcinogenesis model. The compound was administered orally to carcinogen-treated mice at two different non-toxic doses, 2mg/kg. b.w. and 3mg/kg. b.w. Significant inhibition in the incidence of papilloma formation (53-80%) as well as in the cumulative numbers of papillomas per papilloma bearing mouse were observed in the treated groups as compared to the carcinogen control group. The compound was also found to upregulate significantly different phase II detoxifying enzymes such as glutathione-S-transferase (p<0.01) and superoxide dismutase (p<0.01) in skin cytosol when measured after 15 days and also after 12 weeks of the first 7,12-dimethylbenz (a) anthracene treatment. Lipid peroxidation measured with reference to thiobarbituric acid reactive substances in skin microsomes was significantly inhibited (p<0.05) in a dose dependent manner by diphenylmethyl selenocyanate. Considerable inhibition of the level of nitric oxide production in peritoneal macrophages was observed after 12 weeks (p<0.05). Thus the compound appears to exert chemopreventive activity in terms of papilloma formation, which may be through modulation of cutaneous lipid peroxidation, the phase II detoxifying enzyme system and nitric oxide production.

Epidemiologic evidence in humans suggests a role for selenium in reducing cancer incidence and mortality. The aim of the present study was that to assess the ability of selenium dioxide (SeO2) to enhance the lymphocyte progression through the cell cycle in patients with advanced (stage IV) cancer. Ten patients (mean age 51.9 years, range: 32-74; M/F ratio: 3/7) with tumors at different sites were included in the study. The addition into culture of SeO2 1.5 microM enhanced significantly the progression into S phase of PBMCs isolated from cancer patients, whilst no significant effect was observed on PBMCs isolated from controls. ROS levels were significantly higher, whereas GPx activity was significantly lower in cancer patients than controls. Serum levels of IL-6 and TNFalpha were significantly higher in cancer patients than controls. Our results show the ability of selenium to induce a progression of PBMCs from cancer patients into the cell cycle, which is an essential prerequisite for the physiological functioning of the immune system and thus positively influence the immune status of advanced cancer patients. The mechanism of action of selenium could be to downregulate the production and release of proinflammatory cytokines, which have a role in cancer progression and particularly in the onset of cachexia.

In this study, the effect of a combination of vitamin C (ascorbic acid), vitamin E (dl-alpha-tocopherol acetate), and selenium (sodium selenate) on ethanol-induced liver damage in rats was investigated, morphologically and biochemically. The ethanol-induced injury was produced by the administration of 1 mL of absolute ethanol to each rat. Animals received vitamin C (250 mg/kg), vitamin E (250 mg/kg), and selenium (0.5 mg/kg) (ViCESe) for 3 d 1 h prior to the administration of absolute ethanol. In the liver of the animals given ethanol, the degenerative changes such as extreme hyperemia, vacuolization in cells of portal areas, a dilation in sinusoids, mononuclear cell infiltration, a swelling in cisternae of granular endoplasmic reticulum and in mitochondrial cristae, an increase in smooth endoplasmic reticulum, many lipid vacuoles were observed both light and electron microscopically. A similar structure was usually distinguished when compared with control animals, in rats given ethanol + ViCESe. In this group, the findings indicating cellular damage were either not observed at all or were decreased. In the group administered ethanol, a reduction of the blood glutathione (GSH) level and increases in serum values of alanine aminotranserase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activities were observed, whereas in the control group, the reverse was found to occur. On the other hand, in the group in which ethanol + ViCESe was administered, it was observed that the blood GSH value and serum ALP and ALT activities increased and serum AST, LDH, and GGT activities decreased. As a result, the present study indicates that ViCESe because of their antioxidant activity against ethanol damage have a protective effect on the liver.

We investigated the effect of selenium form and dose on the total glutathione and non-protein -SH group contents in the edible spinach (Spinacia oleracea L.) and ground tomato (Lycopersicon esculentum Mill.) plants. Our experiments were carried out in a hydroponic culture. Selenium was added to the culture medium in its selenite (Na2SeO3 x 5H2O) and selenate (Na2SeO4) forms. Regardless of the selenium form, we observed an increase in the non-protein thiol content. The non-protein -SH group content depended on the form and dose of selenium as well as on the organ and plant species. Regardless of the selenium form, a higher content of non-protein -SH groups were found in the spinach biomass than in the tomato biomass. Selenite contributed to a larger accumulation of non-protein -SH groups in the roots, whereas selenate contributed to their accumulation in the shoots

Blood content of MDA in rats increased 1 and 2 weeks after mandibular bone fracture at stages of cellular fibrous and chondroid callus and decreased 4 weeks after fracture at the stage of primary bone callus. Treatment with Se (intragastrically and electrophoretically) reduced this increase by activating selenium-containing glutathione peroxidase. In order to clear out the relationship between Se and carbohydrate metabolism in different ages, the distribution of Se between the blood and mandibular bone, diaphysis and metaepiphyseal zone of the femoral bone was studied using the bone/blood relative radioactivity coefficient after intraperitoneal injection of [(75)Se]selenate. In control 1-month-old rats the radioactivity had 2 peaks corresponding to 6 and 48 h. The first peak was presumably caused by Se adsorption on hydroxyapatite, the second by chemosorption on hydroxyapatite and protein binding. Only one peak of relative radioactivity (after 12-48 h) was observed in 3-month-old control rats, and it could be increased by sucrose diet. The relative radioactivity was higher in rats receiving sucrose ration for 2 months starting from the age of 1 month in comparison with the control.

Selenium is an essential trace element that up-regulates a major component of the antioxidant defense mechanism by controlling the body's glutathione (GSH) pool and its major Se-containing antioxidant enzyme, glutathione peroxidase (GPX). Evidence has emerged suggesting that organic selenium, natural seleno-amino acids found in plants, grains and selenized yeast, maintains the antioxidant defense system more efficiently than inorganic selenium. Inorganic selenium is a pro-oxidant, whereas organic selenium possesses antioxidant properties itself. As a pro-oxidant, inorganic selenium is not suitable for animals or humans. Therefore, we examined the GSH-GPX system in broiler chickens and determined that organic selenium was indeed more beneficial than inorganic selenium. Chickens fed the organic selenium as Sel-Plex, a selenized yeast, had elevated GPX activity in both blood and liver in a thermoneutral environment and after heat distress. More importantly, the ability to reduce the oxidized glutathione (GSSG to 2 GSH) was enhanced and facilitated by maintenance of glutathione reductase activity. Organic selenium-fed chickens were less affected by mild heat distress than inorganic selenium-fed chickens, and this assessment was based upon less induction of heat shock protein 70 (hsp70) in organic selenium-fed chickens. Our results clearly show that heat distress, a potent inducer of oxidative stress and hsp70, can be partially ameliorated by feeding organic selenium. We attribute this observation to an enhanced GSH-GPX antioxidant system in organic selenium-fed chickens.

Nickel, cadmium, cobalt and arsenic compounds are well known carcinogens to humans and experimental animals. In addition to the induction of mainly oxidative DNA damage, they interfere with nucleotide and base excision repair (BER) at low, non-cytotoxic concentrations. In case of arsenic, an inactivation of DNA repair has also been observed for the trivalent and pentavalent methylated metabolites, with the strongest effects exerted by MMA(III) and DMA(III). As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling have been identified. For example, arsenite suppresses poly(ADP-ribosyl)ation at extremely low, environmentally relevant concentrations. Also, Fpg and XPA involved in BER and NER, respectively, are inactivated by arsenite, MMA(III) and DMA(III). Nevertheless, an interaction with the zinc finger structures of DNA repair proteins may also occur by essential trace elements such as certain selenium compounds, which appear to exert anticarcinogenic properties at low concentrations but may compromise genetic stability at higher concentrations.

A growing body of evidence indicates that the powerful oxidant peroxynitrite (ONOO(-)) may function as an intracellular signal for production of proinflammatory cytokines, such as interleukin-8 (IL-8) in human leukocytes. In this study, we investigated whether selenomethionine, selenocysteine, and the synthetic organoselenium compound ebselen (2-phenyl-1,2-benzisoselenazol-3(2h)-one) could inhibit ONOO(-)-mediated IL-8 gene expression in human leukocytes in whole blood. At micromolar concentrations, ebselen, selenomethionine, and selenocysteine effectively prevented nuclear accumulation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) evoked by exogenous ONOO(-), in both polymorphonuclear and mononuclear leukocytes, and inhibited IL-8 gene and protein expression. The inhibitory actions of selenium-containing molecules were concentration-dependent (EC(50) values: 8.0-13.2 muM) and were not shared by their sulphur analogs methionine and cystine. Furthermore, ebselen, selenomethionine, and selenocysteine markedly reduced LPS-evoked intracellular ONOO(-) formation in leukocytes, resulting in 36-66% decreases in nuclear accumulation of AP-1 and NF-kappaB in both polymorphonuclear and mononuclear leukocytes and inhibition of IL-8 mRNA expression and IL-8 release. These findings indicate that selenium-containing compounds can effectively oppose ONOO(-) signaling in leukocytes and suggest a role for selenium-containing molecules as potential modifiers of inappropriate leukocyte trafficking under pathological conditions associated with enhanced ONOO(-) formation.