The role of glutathione peroxidase-1 in health and disease.

Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.

Serum and milk concentrations of oxidant and anti-oxidant markers in dairy cows affected with bloody milk.

This study was conducted to determine the serum and milk levels of thiobarbturic acid-reac- tive substances (TBARS), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxi- dase (GSH-Px), vitamin E and selenium, IL-4 and IL-6 in lactating dairy cows affected with bloody milk using commercially available ELISA kits. Milk and whole blood samples were collected from 60 cows affected with bloody milk and 20 apparently healthy cows for control. In the serum, levels of GSH-Px and SOD were significantly (p˂0.05) higher in healthy cows compared to cows affected with bloody milk while the levels of TBARS and NO were significantly (p˂0.05) higher in affected cows. In the milk, levels of SOD, TBARS and NO were significantly (p˂0.05) higher in affected cows. In the serum, levels of vitamin E were significantly (p˂0.05) lower in affected cows compared to healthy cows, while no significant changes were observed in the levels of this vitamin in the milk between healthy and affected cows. In the serum, levels of selenium were significantly (p˂0.05) lower in affected cows while in milk, selenium levels were significantly (p˂0.05) higher in affected cows compared to healthy ones. Levels of IL-4 were significantly (p˂0.05) lower in the serum and milk of affected cows compared to healthy cows while levels of IL-6 were significantly (p˂0.05) higher in both serum and milk of affected cows. Results of this study suggest a possible role of oxidative stress in the pathogenesis of bloody milk in dairy cows.

Phytochemical Analysis and Antioxidant and Anti-Inflammatory Capacity of the Extracts of Fruits of the Sechium Hybrid.

In addition to their own antioxidants, human cells feed on external antioxidants, such as the phenolic compounds of fruits and vegetables, which work together to keep oxidative stress in check. Sechium edule, an edible species of chayote, has phenolic compounds with antioxidant activity and antineoplastic activity. A Sechium hybrid shows one thousand times greater antineoplastic activity than edible species, but its antioxidant and anti-inflammatory activities and the content of phenolic compounds are unknown. The aim of this study was to determine the antioxidant and anti-inflammatory capacity of the extract of fruits of the Sechium hybrid in vitro and in vivo. Phytochemical analysis using HPLC showed that the extract of the Sechium hybrid has at least 16 phenolic compounds; galangin, naringenin, phloretin and chlorogenic acid are the most abundant. In an in vitro assay, this extract inhibited 2,2-diphenyl-L-picrylhydrazyl (DPPH) activity and protected the dimyristoylphosphatidylethanolamine (DMPE) phospholipid model cell membrane from oxidation mediated by hypochlorous acid (HClO). In vivo, it was identified that the most abundant metabolites in the extract enter the bloodstream of the treated mice. On the other hand, the extract reduces the levels of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin-6 (IL-6) but increases interleukin-10 (IL-10) and glutathione peroxidase levels. Our findings indicate that intake of the fruits of the Sechium hybrid leads to antioxidant and anti-inflammatory effects in a mouse model. Therefore, these results support the possibility of exploring the clinical effect of this hybrid in humans.

In vivo and in vitro studies on inactivation of selenium containing protein- glutathione peroxidase 3 in mice nephrocytes caused by lead.

Glutathione peroxidases (Gpxs) play vital roles in elimination of hydroperoxide and other reactive oxygen species through catalyzing reduced glutathione to protect from oxidative stress caused by heavy metals such as lead. Among the family of Gpxs, Gpx3 is the only extracellular enzyme synthesized in the kidney and actively secreted into the plasma. This study investigated mechanisms of lead-induced GPx3 inactivation both at the animal and molecular levels. Six-week-old mice were randomly divided into 4 groups, and exposed to different lead concentrations (0, 1, 2 and 4 g/L) in their drinking water for 4 weeks. Contents of GPx3 in blood serum were tested by enzyme-linked immunosorbent assay (ELISA) and the mRNA levels of Gpx3 in mice nephrocytes were determined by quantitative real-time PCR (qPCR), both of which showed significantly inhibited at higher lead concentrations accompanied by the decreased Gpx3 activities and the elevated levels of malondialdehyde (MDA) in nephrocytes, which indicated that lead could induce strongly oxidative stress through affecting Gpx3 function. So we further investigated molecular mechanisms of GPx3 inactivation caused by lead with multiple spectroscopic techniques, isothermal titration calorimetry (ITC) and molecular docking studies in vitro. Results showed that lead statically quenched GPx3 fluorescence by tightly binding to the structural domain of GPx3 in a 3:1 ratio with high binding affinity (K = 3.1(±0.087) × 107 mol-1). Further investigation of the conformation of GPx3 by UV-visible spectroscopy and circular dichroism (CD) spectroscopy indicated that lead changed the secondary structure of GPx3 by loosening the GPx3 skeleton and decreasing the hydrophobicity around tryptophan residues. This work proved in vivo and in vitro experiments that lead could induce oxidative stress in mice nephrocytes by interacting with GPx3.

Vitamin E and Selenium Reduce Prednisolone Side Effects in Rat Hearts.

Aim of this work was to determine the effects of dietary intake vitamin E and Se on lipid peroxidation (LPO) as Thiobarbituric acid reactive substances (TBARS) and on the antioxidative defense mechanisms in heart tissues of rats treated with high doses of prednisolone. 250 adult male Wistar rats were randomly divided into 5 groups and fed with normal diet. Additionally groups 3, 4, and 5 received a daily supplement in their drinking water of 20 mg vitamin E, 0.3 mg Se, and a combination of vitamin E and Se (20 mg/ 0.3 mg), respectively, for 30 days. For 3 d subsequently, control group was treated with placebo, and remaining four groups were injected intramuscularly with 100 mg/kg prednisolone. After last administration of prednisolone, 10 rats from each group were killed at 4, 8, 12, 24, and 48 h and the activities of antioxidant enzymes and the levels of GSH and TBARS were measured. GSH-Px, CAT activities and GSH levels decreased starting from 4th hour to 48% and 65% of control levels by 24th hour, respectively and it reincreased to control levels at 48th hour in the prednisolone group (p < 0.001, p < 0.001). In addition, prednisolone administration led 2-fold increase in heart TBARS levels at 24th hour (p < 0.001). E vitamins and Se inhibited the increase in heart TBARS and the decrease in antioxidative enzymes levels. Therefore, It is concluded that vitamin E and Se may have a preventive role in decreasing the increase of TBARS caused by prednisolone administration in our study.

Alpha lipoic acid supplementation improved antioxidant enzyme activities in hemodialysis patients.

Background: Cardiovascular disease (CVD) is the main cause of death in hemodialysis (HD) patients and oxidative stress is an important risk factor for CVD. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) are primary antioxidant enzymes in human cells acting against toxic reactive oxygen species (ROS) and their reduced activity may contribute to oxidative disorders in HD patients. Alpha lipoic acid (ALA) as a potent strong antioxidant may affect these enzymes. Objective: We examined the effects of ALA supplementation on antioxidant enzyme activities in HD patients. Method: In this double-blinded, randomized clinical trial, 63 HD patients (43 males and 20 females; age range: 22-79 years) were assigned into the ALA group (n: 31), receiving a daily dose of ALA (600 mg), or a control group (n: 32), receiving placebo for 8 weeks. Body mass index (BMI), antioxidant enzymes, albumin (Alb) and hemoglobin (Hb) were determined before and after intervention. Results: At baseline, the mean blood activities of SOD, GPx, and CAT in ALA group were 1032±366, 18.9±5.09 and 191±82.7 U/gHb which increased at the end of study to 1149±502, 19.1±7.19 and 208±86.6 U/gHb respectively. However, only the increase of SOD was statistically significant in comparison with placebo group (P = 0.04). The mean levels of Alb, Hb, weight and BMI were not significantly changed in study groups (P>0.05). Conclusion: ALA may be beneficial for HD patients by increasing the activity of antioxidant enzymes; however, further studies are needed to achieve precise results.

Response of a novel selenium-dependent glutathione peroxidase from thick shell mussel Mytilus coruscus exposed to lipopolysaccharide, copper and benzo[α]pyrene.

Glutathione peroxidase (GPx) plays an important antioxidant role in cellular defense against environmental stress. In the present study, a novel selenium-dependent glutathione peroxidase termed McSeGPx firstly identified in thick shell mussel Mytilus coruscus. McSeGPx consists of 197 amino acid residues, characterized with one selenocysteine residue encoded by an opal stop codon TGA, one selenocysteine insertion sequence (SECIS) in the 3' untranslated region (UTR), two active site motifs and one signature sequence motif. McSeGPx transcripts were constitutively expressed in all examined tissues, and were significantly induced in gills and digestive glands with the stimulations of lipopolysaccharide (LPS), copper (Cu) and benzo[α]pyrene (B[α]P). Additionally, rough increases in McSeGPx activity were detected in both tissues under the challenge of LPS, Cu and B[α]P. Collectively, these results suggested that McSeGPx affiliate to selenocysteine dependent GPx (SeGPx) family and might play an important role in mediating the environmental stressors and antioxidant response in M. coruscus.

Direct biocatalysed synthesis of first sulfur-, selenium- and tellurium- containing l-ascorbyl hybrid derivatives with radical trapping and GPx-like properties.

6-O-l-Ascorbyl selenoesters, thioesters and telluroesters can be efficiently and directly prepared from l-ascorbic acid and suitable functionalised chalcogenoesters through lipase-catalysed transesterification reactions. Novel synthesised l-ascorbyl derivatives exhibited remarkable chain breaking and glutathione peroxidase-like activities.

Hepatoprotective Effects of Algerian Crataegus oxyacantha Leaves.

BACKGROUND: Hawthorn (C. oxyacantha), a common edible plant, is widely used for the preparation of a different foodstuff and is also used in traditional medicine to treat heart problems and gastrointestinal ailments. Recently, a few patents of Crataegus preparation for protective effects (prevention of cardiovascular and hepatic diseases) have been developed. OBJECTIVE: The current study aimed to explore the antioxidant and hepatoprotective effects of nbutanol extract of Crataegus oxyacantha leaves in acute liver damage induced by Doxorubicin (DOX). METHODS: Crataegus oxyacantha (100 mg/kg body weight) or vitamin E as a standard antioxidant (100 mg/kg body weight) were administered orally to female rats for 10 days, in the presence or absence of hepatotoxicity induced by a single intraperitoneal (i.p.) injection of DOX (15 mg/kg on the 8th day). On day 11, blood and liver samples were analyzed for biomarker levels and histopathological changes. Liver homogenates were used for determination of oxidative stress parameters that include Malondialdehyde (MDA), Glutathione (GSH) level and Glutathione Peroxidase (GPx) activity. RESULTS: Treatment with n-butanol extract of C. oxyacantha leaves significantly improved the altered liver enzyme activities and oxidative stress markers. The histopathological observations confirm the results of biochemical parameters. CONCLUSION: The obtained results support the traditional use of C. oxyacantha to cure gastrointestinal ailments and highlighted its possible use in the food and pharmaceutical industries as a source of natural antioxidant.

Kidney Toxicity and Response of Selenium Containing Protein-glutathione Peroxidase (Gpx3) to CdTe QDs on Different Levels.

The toxic mechanism of cadmium-quantum dots (Cd-QDs) to organisms is still debating. In this paper, it was found that Cd-QDs could induce adverse effects to kidney by entering into cells in a time and dose manner and disturbing the redox balance in vivo. As a selenium containing protein, glutathione peroxidase3 (Gpx3) plays a crucial role in maintaining the balance of redox system. The decrease in Gpx3 activity might be related to the imbalance of redox system. Similar to the animal results, it was demonstrated that Gpx3 activity is also inhibited by Cd-QDs in vitro. To investigate the underlying mechanism of Cd-QDs on conformational and functional changes of Gpx3, systematical measurements including calorimetric, multispectroscopic studies, and molecular model studies were carried out on molecular level. Results showed that Cd-QDs binds to Gpx3 via Van der Waals' force and hydrogen bonds, resulting in structural changes with increasing contents of α-helix. By interacting with Glu136 in the cavity of Gpx3 as well as Phe132, Pro130, and Van129 surrounded, Cd-QDs changes the microenvironment of fluorophore and further reduce the activity of Gpx3.

Oxidation of organic diselenides and ditellurides by H2O2 for bioinspired catalyst design.

The reactivity of diselenides and ditellurides of general formula (RX)2 (X = Se, Te; R = H, CH3, Ph) toward hydrogen peroxide was studied through a computational approach based on accurate Density Functional Theory (DFT) calculations. The aliphatic and aromatic dichalcogenides have been chosen in light of their activity in glutathione peroxidase (GPx)-like catalytic cycles and their promising features as efficient antioxidant compounds. The reaction products, the energetics and the mechanistic details of these oxidations are discussed. Analogous disulfides are included in our analysis for completeness. We find that the barrier for oxidation of dichalcogenides decreases from disulfides to diselenides to ditellurides. On the other hand, variation of the substituents at the chalcogen nucleus has relatively little effect on the reactivity.

Bioaccessible selenium sourced from Se-rich mustard cake facilitates protection from TBHP induced cytotoxicity in melanoma cells.

Selenium (Se) is an essential dietary supplement that resolves inflammatory responses and offers antioxidant cytoprotection. In this study, we present the data on the cytoprotective effect of Se-rich mustard protein isolated from mustard cultivated in seleniferous soils in Punjab, India. The concentrations of total Se in mustard seed, oil-free mustard cake, and mustard protein were 110.0 ± 3.04, 143.0 ± 5.18, and 582.3 ± 6.23 µg g-1, respectively. The cytoprotective effect of Se-rich mustard protein was studied on tert-butyl hydroperoxide (TBHP)-induced cytotoxicity in a mouse melanoma cell line (B16-F10). When compared with TBHP treated cells (where no viable cells were found), Se-rich protein made bioaccessible through simulated gastrointestinal digestion protected melanoma cells from cytotoxicity with decreased levels of oxidative stress resulting in 73% cell viability. Such an effect was associated with a significant increase in glutathione peroxidase activity as a function of bioaccessible Se and its response towards cytoprotection.

Attenuating effects of caffeic acid phenethyl ester and betaine on abamectin-induced hepatotoxicity and nephrotoxicity.

Abamectin (ABM) is a widely utilized potent anthelmintic and insecticidal agent. In this study, we investigated the protective effects of caffeic acid phenethyl ester (CAPE) and betaine (BET) against ABM-induced hepatotoxicity and nephrotoxicity in rats. Forty rats were divided into five groups, receiving either oral saline solution (normal control), oral ABM at a dose of 2 mg/kg BW (1/5 LD50), CAPE (10 µmol/kg BW intraperitoneally) followed by ABM, or BET supplementation at a dose of 250 mg/kg BW followed by ABM administration, while group V rats received a combination of i.p. CAPE and oral BET in the same doses before receiving ABM. Biochemical analysis showed that ABM administration significantly (p < 0.05) increased serum levels of aminotransferases, alkaline phosphatase, lactate dehydrogenase, and cholesterol, as well as serum creatinine and urea. Compared to the control group, ABM-intoxicated rats had significantly (p < 0.05) higher tissue concentrations of nitric oxide and malondialdehyde, as well as lower tissue glutathione concentration, total antioxidant capacity, and antioxidant enzymatic activity (glutathione peroxidase, superoxide dismutase, and catalase). Histopathological examination of hepatic and renal tissues of ABM-intoxicated rats showed acute inflammatory and necrotic changes. Pretreatment with CAPE and/or BET reversed the biochemical and histopathological alterations of ABM on the liver and kidneys. Therefore, CAPE and BET (alone or in combination) could be promising protective agents against ABM-induced hepatotoxicity and nephrotoxicity. Future studies should confirm our findings and evaluate the other molecular effects are involved in the combination chemoprotection of CAPE and BET.

A novel 76-mer peptide mimic with the synergism of superoxide dismutase and glutathione peroxidase.

The balance of oxidation and reduction in the body requires the synergistic effect of various antioxidant enzymes. Therefore, the construction of enzyme mimics with multiple antioxidant activities is important and beneficial for further research on the synergistic effects of antioxidant enzymes and their mechanism of action. To explore the synergistic effect of superoxide dismutase (SOD) and glutathione peroxidase (GPx), a 76-mer selenium-containing peptide (Se-76P) mimic containing the active SOD and GPx centers was designed. Moreover, a cell-penetrating peptide was introduced into Se-76P by structure modeling, and then, Se-76P was expressed by a single-protein production combined with the cysteine auxotrophic double-expression system of Escherichia coli. The results suggest that Se-76P exhibits SOD and GPx activities, following the GPx activity of 109 U/mg protein and the SOD activity of 1218 U/mg protein. The labeled Se-76P with FITC fluorescence was verified to enter the L02 cells successfully; it improved the antioxidant activity in cells and promoted the consumption of glucose and synthesis of glycogen. The injection of Se-76P subcutaneously decreased the levels of blood glucose and malondialdehyde of lipid peroxidation produced in mice, indicating that Se-76P had antioxidative properties and a certain regulatory role of glucose metabolism. The data analysis provides further clarification that Se-76P can regulate insulin signal transduction to play an insulin-like role, which not only has a greater significance for further elucidating the catalytic mechanism of the enzyme and their synergistic effects on each other but also has enormous medicinal potential.

Selenoglutathione Diselenide: Unique Redox Reactions in the GPx-Like Catalytic Cycle and Repairing of Disulfide Bonds in Scrambled Protein.

Selenoglutathione (GSeH) is a selenium analogue of naturally abundant glutathione (GSH). In this study, this water-soluble small tripeptide was synthesized in a high yield (up to 98%) as an oxidized diselenide form, i.e., GSeSeG (1), by liquid-phase peptide synthesis (LPPS). Obtained 1 was applied to the investigation of the glutathione peroxidase (GPx)-like catalytic cycle. The important intermediates, i.e., GSe- and GSeSG, besides GSeO2H were characterized by 77Se NMR spectroscopy. Thiol exchange of GSeSG with various thiols, such as cysteine and dithiothreitol, was found to promote the conversion to GSe- significantly. In addition, disproportionation of GSeSR to 1 and RSSR, which would be initiated by heterolytic cleavage of the Se-S bond and catalyzed by the generated selenolate, was observed. On the basis of these redox behaviors, it was proposed that the heterolytic cleavage of the Se-S bond can be facilitated by the interaction between the Se atom and an amino or aromatic group, which is present at the GPx active site. On the other hand, when a catalytic amount of 1 was reacted with scrambled 4S species of RNase A in the presence of NADPH and glutathione reductase, native protein was efficiently regenerated, suggesting a potential use of 1 to repair misfolded proteins through reduction of the non-native SS bonds.

[Human selenium-containing single-chain variable fragment with glutathione peroxidase activity protects NIH3T3 fibroblast against oxidative damage].

Ultraviolet B (UVB medium wave, 280-315 nm) induces cellular oxidative damage and apoptosis by producing reactive oxygen species (ROS). Glutathione peroxidase functions as an antioxidant by catalyzing the reduction of hydrogen peroxide, the more important member of reactive oxygen species. A human selenium-containing single-chain variable fragment (se-scFv-B3) with glutathione peroxidase activity of 1288 U/µmol was generated and investigated for its antioxidant effects in UVB-induced oxidative damage model. In particular, cell viability, lipid peroxidation extent, cell apoptosis, the change of mitochondrial membrane potential, caspase-3 activity and the levels of intracellular reactive oxygen species were assayed. Human se-scFv-B3 protects NIH3T3 cells against ultraviolet B-induced oxidative damage and subsequent apoptosis by prevention of lipid peroxidation, inhibition of the collapse of mitochondrial membrane potential as well as the suppression of the caspase-3 activity and the level of intracellular ROS. It seems that antioxidant effects of human se-scFv-B3 are mainly associated with its capability to scavenge reactive oxygen species, which is similar to that of the natural glutathione peroxidase.

Selenium Enrichment of Horticultural Crops.

The ability of some crops to accumulate selenium (Se) is crucial for human nutrition and health. Selenium has been identified as a cofactor of the enzyme glutathione peroxidase, which is a catalyzer in the reduction of peroxides that can damage cells and tissues, and can act as an antioxidant. Plants are the first link in the food chain, which ends with humans. Increasing the Se quantity in plant products, including leafy and fruity vegetables, and fruit crops, without exceeding the toxic threshold, is thus a good way to increase animal and human Se intake, with positive effects on long-term health. In many Se-enriched plants, most Se is in its major organic form. Given that this form is more available to humans and more efficient in increasing the selenium content than inorganic forms, the consumption of Se-enriched plants appears to be beneficial. An antioxidant effect of Se has been detected in Se-enriched vegetables and fruit crops due to an improved antioxidative status and to a reduced biosynthesis of ethylene, which is the hormone with a primary role in plant senescence and fruit ripening. This thus highlights the possible positive effect of Se in preserving a longer shelf-life and longer-lasting quality.

Glutathione peroxidase 4 inhibits Wnt/ß-catenin signaling and regulates dorsal organizer formation in zebrafish embryos.

The Wnt/ß-catenin signaling pathway plays pivotal roles in axis formation during embryogenesis and in adult tissue homeostasis. Glutathione peroxidase 4 (GPX4) is a selenoenzyme and participates in the reduction of peroxides. Its synthesis depends on the availability of the element selenium. However, the roles of GPX4 in vertebrate embryonic development and underlying mechanisms are largely unknown. Here, we show that maternal loss of zebrafish gpx4b promotes embryonic dorsal organizer formation, whereas overexpression of gpx4b inhibits the development of the dorsal organizer. Depletion of human GPX4 and zebrafish gpx4b (GPX4/gpx4b) increases, while GPX4/gpx4b overexpression decreases, Wnt/ß-catenin signaling in vivo and in vitro Functional and epistatic studies showed that GPX4 functions at the Tcf/Lef level, independently of selenocysteine activation. Mechanistically, GPX4 interacts with Tcf/Lefs and inhibits Wnt activity by preventing the binding of Tcf/Lefs to the promoters of Wnt target genes, resulting in inhibitory action in the presence of Wnt/ß-catenin signaling. Our findings unravel GPX4 as a suppressor of Wnt/ß-catenin signals, suggesting a possible relationship between the Wnt/ß-catenin pathway and selenium via the association of Tcf/Lef family proteins with GPX4.

Hepatoprotective efficacy of Nigella sativa seeds dietary supplementation against lead acetate-induced oxidative damage in rabbit - Purification and characterization of glutathione peroxidase.

Lead (Pb) is a toxic ubiquitous environmental pollutant that induces hepatotoxicity in both animals and humans. The ability of Nigella saliva seeds (NSS) in ameliorating lead acetate (PbAc)-induced hepatic oxidative damage was investigated using a rabbit model. Forty New Zealand rabbits were given feed and water ad libitum. They were allocated randomly into four groups: control; PbAc (5g/L drinking water); NSS (20g/kg diet) and NSS+PbAc groups. After two months, liver samples were collected and analyzed for malondialdehyde (MDA), glutathione (GSH), glutathione S-transferase (GST) and glutathione peroxidase (GPx) contents. Purification and characterization of GPx were also evaluated. PbAc exposure significantly (p<0.05) increased MDA (lipid peroxidation biomarker) and reduced the GSH levels and the GST and GPx activities. Concurrently supplemented NSS significantly (p<0.05) decreased MDA levels and restored the GSH, GST, and GPx contents successfully. Electrophoretically, the homogeneous GPx preparation from the liver had a specific activity of 30.44 U/mg protein and a yield of 1.31%. The Km values for cumene hydroperoxide were 4.76µM in control, PbAc and NSS+PbAc groups, and 4.09µM in NSS group. The GPx reaction had a temperature optimum 40°C, pH optimum 8 and molecular weight 21 kDa. The obtained data indicated the potent efficacy of NSS against PbAc-induced oxidative stress; that was mediated through induction and activation of antioxidants, particularly GPx and scavenging free radicals. Moreover, the purified hepatic GPx is characterized as a selenoprotein (Se-GPx).

Selenium and redox signaling.

Selenium compounds that contain selenol functions or can be metabolized to selenols are toxic via superoxide and H2O2 generation, when ingested at dosages beyond requirement. At supra-nutritional dosages various forms of programmed cell death are observed. At physiological intakes, selenium exerts its function as constituent of selenoproteins, which overwhelmingly are oxidoreductases. Out of those, the glutathione peroxidases counteract hydroperoxide-stimulated signaling cascades comprising inflammation triggered by cytokines or lipid mediators, insulin signaling and different forms of programmed cell death. Similar events are exerted by peroxiredoxins, which functionally depend on the selenoproteins of the thioredoxin reductase family. The thiol peroxidases of both families can, however, also act as sensors for hydroperoxides, thereby initiating signaling cascades. Although the interaction of selenoproteins with signaling events has been established by genetic techniques, the in vivo relevance of these findings is still hard to delineate for several reasons: The biosynthesis of individual selenoproteins responds differently to variations of selenium intakes; selenium is preferentially delivered to privileged tissues via inter-organ trafficking and receptor-mediated uptake, and only half of the selenoproteins known by sequence have been functionally characterized. The fragmentary insights do not allow any uncritical use of selenium for optimizing human health.