Selenoenzyme Activities Research Articles

Reversible Switch of Artificial Selenoenzyme Activity Modulated by Metal Ion-Induced Protein Nano-Assemblies

Reversible Switch of Artificial Selenoenzyme Activity Modulated by Metal Ion-Induced Protein Nano-Assemblies

#2716 Selenoprotein-P1 (SEPP-1) in human proximal tubule cells after ischemic-reperfusion injury: an in-vitro model

Abstract Background and Aims Novel biomarkers, anticipating serum creatinine rise, are eagerly needed to have a speedy diagnosis of acute kidney injury (AKI) and thus to mitigate and to preserve kidney function with well-timed therapeutic plans. Recently, in a pilot study on patients undergoing elective major cardiac surgery with cardiopulmonary bypass (CPB), selenoprotein-p1 (SEPP-1) has emerged as a promising candidate plasmatic biomarker for an early AKI risk stratification. SEPP-1 increased particularly between 4th to 8th hour after CPB and with a strict relation with ischemia duration (Bolignano et Al. Rev. Cardiovasc. Med. 2022). SEPP1 is primarily secreted from liver and acts as a selenium transporter supplying tissues and organs with this trace mineral which elicits the activity of specific glutathione peroxidase selenoenzymes. Additionally, renal tubular cells are able to synthetize this protein but remain unknown if, during AKI, SEPP1 increases as defeat answer to renal cells damage or if it's hepatic SEPP1 that accumulates for a reduced renal glomerular filtration rate. The primary aim of this study was to investigate the release of SEPP-1 by renal tubular cells in an experimental model of AKI induced by ischemia-reperfusion and secondarily evaluate the effect of selenium supplying on renal cells injury. Method Human proximal tubular cells (PTC), HK2 cells and human embryonic kidney 293 cells (HEK293) were cultured in Keratinocyte-SFM a complete serum-free medium supplemented with human recombinant Epidermal Growth Factor (rEGF) and Bovine Pituitary Extract (BPE) (LGC Standards s.r.l., Milan, Italy) and in Eagle's Minimum Essential Medium (E-MEM) (LGC Standards s.r.l., Milan, Italy) containing 10% fetal bovine serum, respectively. The cells were pre-incubated with medium containing Sodium Selenite 100 nM for 24 h and then were treated for 24 hours with CoCl2 (Sigma Aldrich S.r.l., Milan, Italy) a chemical hypoxia inducer (500 µM for HK-2 and 250 µM for HEK-293). After that cell viability was evaluated by MTT and trypan bleu dye exclusion assay, while, protein expression of HIF (hypoxia marker) and SEPP1 was analyzed by western blot analysis. Results Ischemia-reperfusion was simulated by the exposure of HK-2 and HEK-293 to CoCl2 and confirmed by HIF expression. The expression of SEPP-1 increased significantly in HK-2 and HEK-293 after hypoxia stress (Fig. 1). Furthermore, the treatment with CoCl2 determined a decrease of cell viability (about 50% less) and Sodium selenite alone increased cell proliferation (about 15% more) in both cell lines. Interestingly cell growth after hypoxia augmented significantly if cell lines were pre-treated with sodium-selenite, highly in HK-2 cells (p < 0.001). Conclusion These preliminary data evidenced, in vitro, that AKI is able to induce renal tubular expression of SEPP-1 and probably SEPP-1 release in human after renal injury is not only a result of a reduced filtration of the hepatic released protein. Furthermore, SEPP-1 showed a possible protective role in AKI. In fact, AKI induced by ischemia-reperfusion, in our in vitro cellular model, was able to induce an increased expression of SEPP-1 in renal tubular cells suggesting a shielding mechanism against injury related to selenium transport. This hypothesis was supported by an exalted SEPP-1 expression after Sodium-Selenite adding to cells’ culture. Supplementary experiments, including functional molecular assays in vitro and in vivo studies will allow to better characterize the role of SEPP-1 in AKI.

Maternal seafood consumption is associated with improved selenium status: Implications for child health

Selenium (Se) is required for synthesis of selenocysteine (Sec), an amino acid expressed in the active sites of Se-dependent enzymes (selenoenzymes), including forms with essential functions in fetal development, brain activities, thyroid hormone metabolism, calcium regulation, and to prevent or reverse oxidative damage. Homeostatic mechanisms normally ensure the brain is preferentially supplied with Se to maintain selenoenzymes, but high methylmercury (CH3Hg) exposures irreversibly inhibit their activities and impair Sec synthesis. Due to Hg’s high affinity for sulfur, CH3Hg initially binds with the cysteine (Cys) moieties of thiomolecules which are selenoenzyme substrates. These CH3Hg-Cys adducts enter selenoenzyme active sites and transfer CH3Hg to Sec, thus irreversibly inhibiting their activities. High CH3Hg exposures are uniquely able to induce a conditioned Se-deficiency that impairs synthesis of brain selenoenzymes. Since the fetal brain lacks Se reserves, it is far more vulnerable to CH3Hg exposures than adult brains. This prompted concerns that maternal exposures to CH3Hg present in seafood might impair child neurodevelopment. However, typical varieties of ocean fish contain far more Se than CH3Hg. Therefore, eating them should augment Se-status and thus prevent Hg-dependent loss of fetal selenoenzyme activities. To assess this hypothesis, umbilical cord blood and placental tissue samples were collected following delivery of a cohort of 100 babies born on Oahu, Hawaii. Dietary food frequency surveys of the mother’s last month of pregnancy identified groups with no (0 g/wk), low (0–12 g/wk), or high (12 + g/wk) levels of ocean fish consumption. Maternal seafood consumption increased Hg contents in fetal tissues and resulted in ∼34% of cord blood samples exceeding the EPA Hg reference level of 5.8 ppb (0.029 µM). However, Se concentrations in these tissues were orders of magnitude higher and ocean fish consumption caused cord blood Se to increase ∼9.4 times faster than Hg. Therefore, this study supports the hypothesis that maternal consumption of typical varieties of ocean fish provides substantial amounts of Se that protect against Hg-dependent losses in Se bioavailability. Recognizing the pivotal nature of the Hg:Se relationship provides a consilient perspective of seafood benefits vs. risks and clarifies the reasons for the contrasting findings of certain early studies.

The Influence of Long Carbon Chains on the Antioxidant and Anticancer Properties of N-Substituted Benzisoselenazolones and Corresponding Diselenides.

Organoselenium compounds are well-known for their numerous biocapacities, which result from the uniqueness of the selenium atom and the possibility of constructing heterorganic molecules that can mimic the activity of selenoenzymes, crucial for a multitude of important physiological processes. In this paper, we have synthesized a series of N-substituted benzisoselenazolones and corresponding diphenyl diselenides possessing lipophilic long carbon chains, solely or with additional polar insets: phenyl linkers and ester groups. Evaluation of their antioxidant and cytotoxic activity revealed an increased H2O2-reduction potential of diphenyl diselenides bearing N-octyl, ethyl N-(12-dodecanoate)- and N-(8-octanoate) groups, elevated radical scavenging activity of 2,2'-diselenobis(N-dodecylbenzamide) and a promising cytotoxic potential of N-(4-dodecyl)phenylbenzisoselenazol-3(2H)-one.

Selenomethionine Attenuated H2O2-Induced Oxidative Stress and Apoptosis by Nrf2 in Chicken Liver Cells.

Earlier studies have shown that selenomethionine (SM) supplements in broiler breeders had higher deposition in eggs, further reduced the mortality of chicken embryos, and exerted a stronger antioxidant ability in offspring than sodium selenite (SS). Since previous studies also confirmed that Se deposition in eggs was positively correlated with maternal supplementation, this study aimed to directly investigate the antioxidant activities and underlying mechanisms of SS and SM on the chicken hepatocellular carcinoma cell line (LMH). The cytotoxicity results showed that the safe concentration of SM was up to 1000 ng/mL, while SS was 100 ng/mL. In Se treatments, both SS and SM significantly elevated mRNA stability and the protein synthesis rate of glutathione peroxidase (GPx) and thioredoxin reductase (TrxR), two Se-containing antioxidant enzymes. Furthermore, SM exerted protective effects in the H2O2-induced oxidant stress model by reducing free radicals (including ROS, MDA, and NO) and elevating the activities of antioxidative enzymes, which performed better than SS. Furthermore, the results showed that cotreatment with SM significantly induced apoptosis induced by H2O2 on elevating the content of Bcl-2 and decreasing caspase-3. Moreover, investigations of the mechanism revealed that SM might exert antioxidant effects on H2O2-induced LMHs by activating the Nrf2 pathway and enhancing the activities of major antioxidant selenoenzymes downstream. These findings provide evidence for the effectiveness of SM on ameliorating H2O2-induced oxidative impairment and suggest SM has the potential to be used in the prevention or adjuvant treatment of oxidative-related impairment in poultry feeds.

Different Effects and Mechanisms of Selenium Compounds in Improving Pathology in Alzheimer’s Disease

Owing to the strong antioxidant capacity of selenium (Se) in vivo, a variety of Se compounds have been shown to have great potential for improving the main pathologies and cognitive impairment in Alzheimer's disease (AD) models. However, the differences in the anti-AD effects and mechanisms of different Se compounds are still unclear. Theoretically, the absorption and metabolism of different forms of Se in the body vary, which directly determines the diversification of downstream regulatory pathways. In this study, low doses of Se-methylselenocysteine (SMC), selenomethionine (SeM), or sodium selenate (SeNa) were administered to triple transgenic AD (3× Tg-AD) mice for short time periods. AD pathology, activities of selenoenzymes, and metabolic profiles in the brain were studied to explore the similarities and differences in the anti-AD effects and mechanisms of the three Se compounds. We found that all of these Se compounds significantly increased Se levels and antioxidant capacity, regulated amino acid metabolism, and ameliorated synaptic deficits, thus improving the cognitive capacity of AD mice. Importantly, SMC preferentially increased the expression and activity of thioredoxin reductase and reduced tau phosphorylation by inhibiting glycogen synthase kinase-3 beta (GSK-3β) activity. Glutathione peroxidase 1 (GPx1), the selenoenzyme most affected by SeM, decreased amyloid beta production and improved mitochondrial function. SeNa improved methionine sulfoxide reductase B1 (MsrB1) expression, reflected in AD pathology as promoting the expression of synaptic proteins and restoring synaptic deficits. Herein, we reveal the differences and mechanisms by which different Se compounds improve multiple pathologies of AD and provide novel insights into the targeted administration of Se-containing drugs in the treatment of AD.

Concomitant selenoenzyme inhibitor exposures as etiologic contributors to disease: Implications for preventative medicine

The physiological activities of selenium (Se) occur through enzymes that incorporate selenocysteine (Sec), a rare but important amino acid. The human genome includes 25 genes coding for Sec that employ it to catalyze challenging reactions. Selenoenzymes control thyroid hormones, calcium activities, immune responses, and perform other vital roles, but most are devoted to preventing and reversing oxidative damage. As the most potent intracellular nucleophile (pKa 5.2), Sec is vulnerable to binding by metallic and organic soft electrophiles (E*). These electron poor reactants initially form covalent bonds with nucleophiles such as cysteine (Cys) whose thiol (pKa 8.3) forms adducts which function as suicide substrates for selenoenzymes. These adducts orient E* to interact with Sec and since Se has a higher affinity for E* than sulfur, the E* transfers to Sec and irreversibly inhibits the enzyme's activity. Organic electrophiles have lower Se-binding affinities than metallic E*, but exposure sources are more abundant. Individuals with poor Se status are more vulnerable to the toxic effects of high E* exposures. The relative E*:Se stoichiometries remain undefined, but the aggregate effects of multiple E* exposures are predicted to be additive and possibly synergistic under certain conditions. The potential for the combined Se-binding effects of common pharmaceutical, dietary, or environmental E* require study, but even temporary loss of selenoenzyme activities would accentuate oxidative damage to tissues. As various degenerative diseases are associated with accumulating DNA damage, defining the effects of complementary E* exposures on selenoenzyme activities may enhance the ability of preventative medicine to support healthy aging.

Selenium Status in Diet Affects Nephrotoxicity Induced by Cisplatin in Mice.

Cisplatin is one of the most active chemotherapy drugs to treat solid tumors. However, it also causes various side effects, especially nephrotoxicity, in which oxidative stress plays critical roles. Our previous studies found that cisplatin selectively inhibited selenoenzyme thioredoxin reductase1 (TrxR1) in the kidney at an early stage and, subsequently, induced the activation of Nrf2. However, the effects of selenium on cisplatin-induced nephrotoxicity are still unclear. In this study, we established mice models with different selenium intake levels to explore the effects of selenoenzyme activity changes on cisplatin-induced nephrotoxicity. Results showed that feeding with a selenium-deficient diet sensitize the mice to cisplatin-induced damage, whereas selenium supplementation increased the activities of selenoenzymes TrxR and glutathione peroxidase (GPx), changed the renal cellular redox environment to a reduced state, and exhibited protective effects. These results demonstrated the correlation of selenoenzymes with cisplatin-induced side effects and provided a basis for the potential approach to alleviate cisplatin-induced renal injury.

Improving selenium accumulation in broilers using Escherichia coli Nissle 1917 with surface-displayed selenite reductase SerV01

Cell surface display of selenite reductase SerV01 in EcN enhanced Se(iv) reduction to achieve better selenium supplementation, selenoenzyme activity and intestinal flora in broilers.

Selenium Status Affects Hypertrophic Growth of Skeletal Muscle in Growing Zebrafish by Mediating Protein Turnover.

Selenium (Se) status is closely related to skeletal muscle physiological status. However, its influence on skeletal muscle growth has not been well studied. This study aimed to analyze the impacts of overall Se status (deficient, adequate, and high) on skeletal muscle growth using a growing zebrafish model. Zebrafish (1.5-mo-old) were fed graded levels of Se (deficient: 0.10mg Se/kg; marginally deficient: 0.22mg Se/kg; adequate: 0.34mg Se/kg; high: 0.44, 0.57, and 0.69mg Se/kg) as Se-enriched yeast for 30 d. Zebrafish growth, and Se accumulation, selenoenzyme activity, selenotranscriptome profiles, and oxidative status in the whole body, and selenotranscriptome profiles, histological characteristics, biochemicals, and gene and protein expression profiles related to muscle growth in the skeletal muscle were analyzed by model fitting and/or 1-factor ANOVA. Se status biomarkers within the whole body and skeletal muscle indicated that 0.34mg Se/kg was adequate for growing zebrafish. For biomarkers related to skeletal muscle growth, compared with 0.34mg Se/kg, 0.10mg Se/kg decreased the white muscle cross-sectional area (WMCSA) and the mean diameter of white muscle fibers (MDWMF) by 14.4%-15.1%, inhibited protein kinase B-target of rapamycin complex 1 signaling by 63.7%-68.5%, and stimulated the autophagy-lysosome pathway by 1.07 times and the ubiquitin-proteasome pathway (UPP) by 96.0% (P <0.05), whereas 0.22mg Se/kg only decreased the WMCSA by 7.8% (P <0.05); furthermore, 0.44mg Se/kg had no clear effects on skeletal muscle biomarkers, whereas 0.57-0.69mg Se/kg decreased the WMCSA and MDWMF by 6.3%-25.9% and 5.1%-21.3%, respectively, and stimulated the UPP by 2.23 times (P <0.05). A level of 0.34mg Se/kg is adequate for the growth of zebrafish skeletal muscle, whereas ≤0.10 and ≥0.57mg Se/kg are too low or too high, respectively, for maintaining efficient protein accretion and normal hypertrophic growth.

Chemical Forms of Mercury in Blue Marlin Billfish: Implications for Human Exposure

Although fish is an important source of nutrients, including some of the healthiest proteins, long-chain fatty acids, and essential selenium, species at the top of the food chain frequently contain large amounts of toxic mercury (Hg). The provisional tolerable weekly intake (PTWI) of Hg from fish consumption is calculated from the total concentration of Hg and assuming that all Hg is speciated as organic methylmercury (MeHg). Using high energy-resolution X-ray absorption near-edge structure (HR-XANES) spectroscopy, we show that blue marlin (Makaira sp.), a common top predator consumed by humans, contains high concentrations of inorganic Hg(II) complexed as 57 ± 10% Hg-tetraselenolate [Hg(Sec)4] and 43 ± 10% tiemannite (HgSe). The stable Hg–Se chemical bond likely attenuates the bioavailability of Hg and counteracts some of its health hazards to consumers. Thus, monitoring the concentration of MeHg, rather than total Hg, in top predators such as marlin would provide a more robust measure of potential Hg exposure and may be sufficient for food safety controls. The bonding of Hg atoms to four selenocysteine (Sec) residues in the Hg(Sec)4 complex severely depletes the stock of bioavailable Se, and quantification shows that blue marlin is not a chief source of dietary Se essential to selenoenzyme synthesis and activity.

Neonatal Selenoenzyme Expression Is Variably Susceptible to Duration of Maternal Selenium Deficiency.

Maternal selenium (Se) deficiency is associated with decreased neonatal Se levels, which increases the risk for neonatal morbidities. There is a hierarchy to selenoprotein expression after Se deficiency in adult rodents, depending on the particular protein and organ evaluated. However, it is unknown how limited Se supply during pregnancy impacts neonatal selenoprotein expression. We used an Se-deficient diet to induce perinatal Se deficiency (SeD), initiated 2–4 weeks before onset of breeding and continuing through gestation. Neonatal plasma, liver, heart, kidney, and lung were collected on the day of birth and assessed for selenoproteins, factors required for Se processing, and non-Se containing antioxidant enzymes (AOE). Maternal SeD reduced neonatal circulating and hepatic glutathione peroxidase (GPx) activity, as well as hepatic expression of Gpx1 and selenophosphate synthetase 2 (Sps2). In contrast, the impact of maternal SeD on hepatic thioredoxin reductase 1, hepatic non-Se containing AOEs, as well as cardiac, renal, and pulmonary GPx activity, varied based on duration of maternal exposure to SeD diet. We conclude that the neonatal liver and circulation demonstrate earlier depletion in selenoenzyme activity after maternal SeD. Our data indicate that prolonged maternal SeD may escalate risk to the neonate by progressively diminishing Se-containing AOE across multiple organs.

Evaluation of the effect of silver and silver nanoparticles on the function of selenoproteins using an in-vitro model of the fish intestine: The cell line RTgutGC

Emerging research in mammalian cells suggests that ionic (AgNO3) and nano silver (AgNP) can disrupt the metabolism of selenium which plays a vital role in oxidative stress control. However, the effect of silver (Ag) on selenoprotein function in fish is poorly understood. Here we evaluate the effects of AgNO3 and citrate coated AgNP (cit-AgNP) on selenoprotein function and oxidative stress using a fish cell line derived from the rainbow trout (Oncorhynchus mykiss) intestine (RTgutGC). Cell viability was evaluated using a cytotoxicity assay which measures simultaneously metabolic activity, membrane integrity and lysosome integrity. Cells exposed to equimolar amounts of AgNO3 and cit-AgNP accumulated the same amount of silver intracellularly, however AgNO3 was more toxic than cit-AgNP. Selenoenzymes glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) mRNA levels and enzyme activity were measured. While mRNA levels remained unaffected by AgNO3 or cit-AgNP, the enzyme activity of GPx was inhibited by AgNO3 (1 µM) and cit-AgNP (5 µM) and TrxR activity was inhibited by AgNO3 (0.4 µM) and cit-AgNP (1, 5 µM). Moreover, cells exposed to 1 µM of AgNO3 and cit-AgNP showed an increase in metallothionein b (MTb) mRNA levels at 24 h of exposure, confirming the uptake of silver, but returned to control levels at 72 h suggesting silver scavenging by MTb. Oxidative stress was not observed at any of the doses of AgNO3 or cit-AgNP tested. Overall, this study shows that AgNO3 or cit-AgNP can inhibit the activity of selenoenzymes but do not induce oxidative stress in RTgutGC cells.

Methylmercury exposure during the vulnerable window of the cerebrum in postnatal developing rats

The developing brain is known to be sensitive to the toxic effects of methylmercury (MeHg). The effects of toxic levels of MeHg exposure during the most seemingly vulnerable window of the cerebrum are not well studied. In this study, we aimed to examine the specific effects of toxic levels of MeHg on neurobehavior, neurodegeneration, and selenoenzyme activity in the cerebrum of infant rats. Male Wistar rats (n = 8/group) were orally treated with MeHg at an acute toxic dose (8 mg Hg/kg/day) for 10 consecutive days starting on postnatal day 14 (P14). The MeHg-exposed rats showed a significant reduction in body weight after day 8 and severe neurological symptoms similar to dystonia on day 12 (P25). Motor coordination deficits determined using the rotarod performance test and short-term memory impairment determined using the Y-maze task were observed in the MeHg-exposed rats on day 11 (P24). The MeHg-exposed rats sacrificed on day 12 showed severe cerebral neuronal degeneration, reactive astrocytosis, and TUNEL-positive apoptotic nuclei, with the cerebral Hg concentration of 15.0 ± 1.6 μg/g. Furthermore, the activities of glutathione peroxidase and thioredoxin reductase in the cerebrum in MeHg-exposed rats were lower than those in control. These results indicate that MeHg exposure to infant rats will be useful to predict the effects of MeHg at the cerebral growth spurt in humans.

Targeted Metabolomics Analysis Reveals that Dietary Supranutritional Selenium Regulates Sugar and Acylcarnitine Metabolism Homeostasis in Pig Liver

The association between high selenium (Se) intake and metabolic disorders such as type 2 diabetes has raised great concern, but the underlying mechanism remains unclear. Through targeted metabolomics analysis, we examined the liver sugar and acylcarnitine metabolism responses to supranutritional selenomethionine (SeMet) supplementation in pigs. Thirty-six castrated male pigs (Duroc-Landrace-Yorkshire, 62.0±3.3kg) were fed SeMet adequate (Se-A, 0.25mg Se/kg) or SeMet supranutritional (Se-S, 2.5mg Se/kg) diets for 60 d. The Se concentration, biochemical, gene expression, enzyme activity, and energy-targeted metabolite profiles were analyzed. The Se-S group had greater fasting serum concentrations of glucose (1.9-fold), insulin (1.4-fold), and free fatty acids (FFAs,1.3-fold) relative to the Se-A group (P <0.05). The liver total Se concentration was 4.2-fold that of the Se-A group in the Se-S group (P <0.05), but expression of most selenoprotein genes and selenoenzyme activity did not differ between the 2 groups. Seven of 27 targeted sugar metabolites and 4 of 21 acylcarnitine metabolites significantly changed in response to high SeMet (P <0.05). High SeMet supplementation significantly upregulated phosphoenolpyruvate carboxy kinase (PEPCK) activity by 64.4% and decreased hexokinase and succinate dehydrogenase (SDH) activity by 46.5-56.7% (P <0.05). The relative contents of glucose, dihydroxyacetone phosphate, α-ketoglutarate, fumarate, malate, erythrose-4-phosphate, and sedoheptulose-7-phosphate in the Se-S group were 21.1-360% greater than those in the Se-A group (P <0.05). The expression of fatty acid synthase (FASN) and the relative contents of carnitine, hexanoyl-carnitine, decanoyl-carnitine, and tetradecanoyl-carnitine in the Se-S group were 35-97% higher than those in the Se-A group (P <0.05). Dietary high SeMet-induced hyperglycemia and hyperinsulinemia were associated with suppression of sugar metabolism and elevation of lipid synthesis in pig livers. Our research provides novel insights into high SeMet intake-induced type 2 diabetes.

Simultaneous detection of the enzyme activities of GPx1 and GPx4 guide optimization of selenium in cell biological experiments

Selenium is a metalloid trace element essential for maintaining the optimal redox environment in cells and tissues. It is structurally incorporated into over 25 selenoproteins and enzymes. The glutathione peroxidase (GPx) family of enzymes has a critical role in human health because of its antioxidant function. The recommended daily allowance (RDA) for selenium intake in humans was established to maximize the activity of GPx in plasma. Suboptimal availability of selenium can limit the expression and activities of GPxs leading to a compromised redox environment. This can cause detrimental oxidative distress that could be prevented by increasing the availability of selenium. In cell culture studies, the medium is typically deficient in selenium; supplementation with selenium can increase selenoenzyme activities. However, the optimal level of supplementation in cell culture media has not been well characterized. We performed dose-response experiments for the activities of GPx1 and GPx4 vs. the level of selenium supplementation in cell culture medium. For this, we advanced an assay to determine the activities of both GPx1 and GPx4 efficiently in a single run. During the optimization process, we found that the observed activities of GPx1 and GPx4 depend greatly on the pH of the assay buffer; the observed activities increase with increasing pH, with pH 8 being optimal. Using the combination assay, we also found that the expression and activities for both GPx1 and GPx4 can be maximized in exponentially growing cells by supplementing cell culture media with ≈ 200 nM seleno-l-methionine, without concerns for toxicity. Optimizing the availability of selenium in cell culture to maximize the expression and activities GPx1 and GPx4 may allow for better translation of information from cell culture work to in vivo settings.

Dietary Serine Supplementation Regulates Selenoprotein Transcription and Selenoenzyme Activity in Pigs.

The synthesis of selenocysteine and its incorporation into selenoproteins require serine during the action of seryl-tRNA synthetase. In view of this, we conducted this study to explore the effects of dietary serine supplementation on selenoprotein transcription and selenoenzyme activity in pigs. A total of 35 crossbred barrows (28days old) were randomly assigned to five treatment groups. During the 42-day growth experiment, pigs were fed either a basal diet with no supplemented serine or diets supplemented with 0.25%, 0.5%, 0.75%, or 1% serine. The results showed that serine supplementation had no effect on the selenium content in the serum, skeletal muscle, and kidney of pigs. However, dietary supplementation with 0.5% serine significantly increased the selenium content in the liver. Diets supplemented with different levels of serine significantly increased the gene expression of glutathione peroxidase 1 (Gpx1), Gpx2, thioredoxin reductase 1 (Txnrd1), Txnrd2, and selenoprotein P (Sepp1) in the skeletal muscle and liver of pigs. Moreover, pigs supplemented with 0.5% serine had the highest selenoprotein P concentration and glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) activities in the skeletal muscle, which were significantly higher than those in the control pigs. Additionally, pigs supplemented with 0.25% serine had the highest GPx and TrxR activities in the liver, which were significantly higher than those in the control pigs. In conclusion, dietary serine supplementation could improve selenoprotein transcription and selenoenzyme activity in pigs, with the appropriate concentrations of serine to be included in the diet being 0.25% or 0.5%.

Selenium prevent cadmium-induced hepatotoxicity through modulation of endoplasmic reticulum-resident selenoproteins and attenuation of endoplasmic reticulum stress

Cadmium (Cd), a heavy metal contaminant, exists in humans and animals throughout life and closely associate with severe hepatotoxicity. Selenium (Se) has been recognized as an effective chemo-protectant of Cd, but the underlying mechanisms remain unclear. The objective of the present study is to illustrate the antagonistic effect of Se against Cd-induced hepatotoxicity. Primary hepatocytes were cultured in the presence of 5 μM Cd, 1 μM Se and the mixture of 1 μM Se and 5 μM Cd for 24 h. Cell viability and morphology, antioxidant status, endoplasmic reticulum (ER) stress response and selenotranscriptome were assessed. It was observed that Se treatment dramatically alleviated Cd-induced hepatocytes death and morphological change. Simultaneously, Se mitigated Cd-induced oxidative stress by reducing ROS production, increasing reduced glutathione (GSH) level and increasing selenoenzyme (glutathione peroxidase, GPX) activity. Cd induced hepatotoxicity via disordering ER-resident selenoproteins transcription and triggering ER stress and unfolded protein response. Supplementary Se evidently relieved hepatocytes injury via modulating ER-resident selenoproteins transcription to inhibit ER stress. Collectively, our findings showed a potential protection of Se against Cd-induced hepatotoxicity via suppressing ER stress response.

Physiologically Oriented Interactions of Nutrients and Toxicants (POINT) Model of Mercury-Selenium Interactions During Fetal Development (FS08-08-19)

ObjectivesThis study used POINT models to assess the effects of differing levels of MeHg exposures on selenium (Se) distributions in adolescent rat brain tissues and the effects of maternal rat MeHg exposures on Se distribution and functions in their brains and those of their offspring as a means of predicting interactive effects of MeHg and Se in human epidemiological studies. The effects of dietary MeHg and Se intakes on activities of thioredoxin reductase (TXNRD) and glutathione peroxidase (GPX1) in brain tissues in adult and fetal rats are known to be indicative of Hg-dependent disruptions of Se homeostasis and physiology. MethodsUsing the previously developed Physiologically Oriented Interactions of Nutrients and Toxicants (POINT) model, the toxicokinetic and toxicodynamics of MeHg that had previously been observed in laboratory rat feeding studies were reanalyzed to create a predictive model of how dietary MeHg exposures accumulate and distribute into adult as well as maternal/fetal tissues and use inhibition of selenoenzyme activities to indirectly assess Se availability. ResultsApplying retention coefficients to predict tissue Hg and Se concentrations provided toxicokinetic and toxicodymanic influences of MeHg on Se distributions and functions as well as Se effects on MeHg distributions. In adolescent rats, brain Se was significantly related to dietary Se (F = 42.0; P < 0.0001) and but not to MeHg in the diet. Brain Hg was strongly related to dietary MeHg (F = 248.9; P < 0.0001), but not dietary Se. Brain Se availability was strongly related to dietary MeHg (F = 111.6; P < 0.0001), but not to diet Se. Brain GPx activity was significantly associated with brain Se availability (F = 13.8; P < 0.001) and brain Se contents (F = 7.4; P = 0.01), but not to brain Hg. Brain TRx activity was significantly associated with brain Se availability (F = 48.2; P < 0.00001) and brain Hg contents (F = 25.8; P < 0.0001). Fetal brain was particularly sensitive to maternal MeHg and Se intakes, providing a highly consistent relationship between calculated [HgSe] and [Hg][Se] (F = 652; P < 0.000001). ConclusionsPOINT Models provide reliable predictions of tissue Hg and Se relationships that reflect associated risks vs. benefits Funding SourcesThis work was funded by the United States Environmental Protection Agency (U.S. E.P.A.) and the National Oceanic and Atmospheric Administration (NOAA).

Selenium health benefit values provide a reliable index of seafood benefits vs. risks

BackgroundMethylmercury (CH3Hg) toxicity causes irreversible inhibition of selenium (Se)-dependent enzymes, including those that are required to prevent and reverse oxidative damage in the brain. Fish consumption provides numerous essential nutrients required for optimal health, but is also associated with CH3Hg exposure risks, especially during fetal development. Therefore, it is necessary to assess the amounts of both elements in seafood to evaluate relative risks or benefits. Consumption of ocean fish containing Se in molar excess of CH3Hg will prevent interruption of selenoenzyme activities, thereby alleviating Hg-exposure risks. Because dietary Se is a pivotal determinant of CH3Hg’s effects, the Selenium Health Benefit Value (HBV) criterion was developed to predict risks or benefits as a result of seafood consumption. A negative HBV indicates Hg is present in molar excess of Se and may impair Se availability while a positive HBV indicates consumption will improve the Se status of the consumer, thus negating risks of Hg toxicity. ObjectiveThis study examined the Hg and Se contents of varieties of seafood to establish those with positive HBV’s offering benefits and those having negative HBVs indicating potential consumption risks. MethodsThe Hg and Se molar concentrations in samples of meat from pilot whale, mako shark, thresher shark, swordfish, bigeye tuna, and skipjack tuna were used to determine their HBV’s in relation to body weight. ResultsThe HBVs of pilot whale, mako shark, and swordfish were typically negative and inversely related to body weight, indicating their consumption may impair Se availability. However, the HBV’s of thresher shark, bigeye tuna, and skipjack tuna were uniformly positive regardless of body weights, indicating their consumption counteracts Hg-dependent risks of selenoenzyme impairment. ConclusionsThe HBV criterion provides a reliable basis for differentiating seafoods whose intake should be limited during pregnancy from those that should be consumed to obtain health benefits.