The interplay between selenoproteins, oxidative stress, and cell death pathways holds promise in unravelling novel therapeutic targets for Alzheimer’s disease (AD) in the future. Nonetheless, further comprehensive investigations are warranted to fully comprehend the precise contributions of selenoproteins in the aetiology and potential therapeutic strategies for Alzheimer’s disease. Previous work into gene expression networks in AD has included analysis of the entire transcriptome and, as of yet, has not yielded consistent insight into pathological pathways.1 Despite the comprehensive assessment of the transcriptome enabled by current technologies, one drawback of the whole transcriptome analysis is the risk of overlooking subtle yet significant variations in metabolic pathways.2 Thus, we aimed to assess gene expression of known selenoprotein and selenium-containing pathways in two different brain regions (dorsolateral prefrontal cortex (DPC) and posterior cingulate cortex (PCC)) across the AD spectrum. We used RNA sequencing data from The Rush University’s Religious Orders Study and Memory and Aging Project (ROSMAP) cohort available in the AD Knowledge Portal (https://www.synapse.org/).3 This study included data available for a total of 889 DPC and 647 PCC samples. Four pathological phenotypes were determined based on pathology (CERAD) and clinical (CDR) status: AD ([(+) pathology, (+) clinical], prodromal disease, corresponding to donors that have not received a clinical diagnosis despite the presence of pathological alterations ([(+) pathology, (−) clinical], controls ([(−) pathology, (−) clinical] and non-AD dementia [(+) pathology, (+) clinical]. This last group was excluded from the analysis as it is assumed they may have been misdiagnosed or presented with non-AD dementia. Six selenium or AD-related pathways were assessed, accounting for 421 unique genes. Group comparisons were performed using linear mixed modelling adjusted for age, sex, APOEe4 status and batch via DESeq2 package with Benjamini-Hochberg adjustment for multiple testing. A total of 18 genes significantly differed between AD and controls in both brain areas (same direction in both brain areas; P < 0.05), including eight selenoprotein genes or genes directly associated with selenoprotein synthesis. Fifteen of them were also different (same direction) in PCC (seven selenoprotein/selenoprotein synthesis genes), and four were different in DPC (four selenoprotein/selenoprotein synthesis genes) between AD and prodromal. Only three genes significantly differed between prodromal and control samples (DPC), including the selenoprotein DIO3 and the transcription factor SP3. Our findings indicate a progressive change in gene expression across the different stages of AD. These findings shed light on critical genes involved in selenoprotein synthesis that play a role in AD pathogenesis. Restricting the analysis to a subset of pathways enabled the detection of smaller alterations between groups, which is particularly appropriate in trace element homeostasis, where small alterations may have significant downstream effects.

Overexposure to Se is detrimental to glucose metabolism, mainly because of its pro-oxidant effects and the overexpression of selenoproteins. This systematic review evaluated the effects of Se supplementation on glycaemic control in healthy rodents. The methodology followed the PRISMA. We searched the databases for articles published up to May 2022. The risk of bias and the methodological quality were assessed using the SYRCLE and CAMARADES. The results are presented as meta-analytic estimates of the overall standardised mean difference (SMD) and 95 % CI. Of the 2359 records retrieved, thirteen studies were included, of which eleven used sodium selenite and two used zero-valent Se nanoparticles as supplement. Nine studies were included in the meta-analysis. Generally, the risk of bias was high, and 23·1 % of the studies were of high quality. Supplementation with sodium selenite significantly increased fasting blood glucose (SMD = 2·57 (95 % CI (1·07, 4·07)), I2 = 93·5 % (P = 0·001). Subgroup analyses showed effect size was larger for interventions lasting between 21 and 28 d (SMD = 25·74 (95 % CI (2·29, 9·18)), I2 = 96·1 % (P = 0·001)) and for a dose of 864·7 μg/kg/d of sodium selenite (SMD = 10·26 (95 % CI (2·42, 18·11), I2 = 97·1 % (P = 0·010)). However, it did not affect glutathione peroxidase activity (SMD = 0·60 (95 % CI (-0·71, 1·91)), I2 = 83·2 % (P = 0·37)). The current analysis demonstrated the adverse effects of sodium selenite supplementation on glycaemic control in healthy rodents.

Several single nucleotide polymorphisms (SNPs) could indirectly, as well directly, influence metabolic parameters related to health effects in response to selenium (Se) supplementation. This study aimed to investigate whether the selenoprotein SNPs were associated with the response of Se status biomarkers to the Brazil nut consumption in patients using statins and if the variation in Se homoeostasis could affect antioxidant protection, lipid profile, muscle homoeostasis and selenoproteins mRNA. The study was performed in the Ribeirão Preto Medical School University Hospital. Thirty-two patients using statins received one unit of Brazil nut daily for 3 months. Body composition, blood Se concentrations, erythrocyte glutathione peroxidase (GPX) activity, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triacylglycerol (TAG), creatine kinase (CK) activity and gene expression of GPX1 and selenoprotein P (SELENOP) were evaluated before and after Brazil nut consumption. The volunteers were genotyped for SNP in GPX1 (rs1050450) and SELENOP (rs3877899 and rs7579). SNPs in selenoproteins were not associated with plasma and erythrocyte Se, but SNPs in SELENOP influenced the response of erythrocyte GPX activity and CK activity, TAG and LDL after Brazil nut consumption. Also, Brazil nut consumption increased GPX1 mRNA expression only in subjects with rs1050450 CC genotype. SELENOP mRNA expression was significantly lower in subjects with rs7579 GG genotype before and after the intervention. Thus, SNP in SELENOP could be associated with interindividual differences in Se homeostasis after Brazil nut consumption, emphasising the involvement of genetic variability in response to Se consumption towards health maintenance and disease prevention.

In recent years, nanoparticles have become a fashionable subject of research due to their sizes, shapes, and unique intrinsic physicochemical properties. In particular for the last 5 years, nano-Se has received tremendous attention in terms of its production, characteristic, and possible application for poultry/animal science and medical sciences. Indeed, Nano-Se is shown to be a potential source of Se for poultry/animal nutrition. However, there is an urgent need to address the questions related to nano-Se absorption, assimilation, and metabolism. It is not clear at present if major biological effects of nano-Se are due to Se-protein synthesis, direct antioxidant/prooxidant effects, or both. It is necessary to understand how metallic nano-Se can be converted into H2Se and further to SeCys to be incorporated into selenoproteins. The aforementioned issues must be resolved before nano-Se finds its way to animal/poultry production as a feed supplement and clearly this subject warrants further investigation.

Glutathione peroxidase (GSH-Px) was described as a selenoprotein in 1973 and, since then, a great body of information has been accumulated to validate its important role in the antioxidant defence network in all animals, including poultry. The GSH-Px family includes at least eight members, and four of them (GSH-Px1, GSH-Px2, GSH-Px3 and GSH-Px4) are shown to be selenoproteins in animals. They are characterised by species- and tissue-specificity in their expression and activity. An optimal Se status in tissues/body is key for maximum expression of GSH-Px and therefore, in avian research GSH-Px activity is widely used as a biomarker for determining Se status and requirements. On the other hand, GSH-Px is an inducible enzyme and its activity depends on the level of stress and can be used as an index of antioxidant defences. In poultry production two forms of Se-dependent GSH-Px (GSH-Px1 and GSH-Px4) have received most attention. The aim of this paper is to review GSH-Px properties and functions in relation to poultry biology with special emphasis to its role in chicken adaptation to various stress conditions. Recent advances in selenoprotein identification and characterisation in relation to poultry Se status, dietary sources of Se and stress conditions can shed light on the roles of GSH-Px in avian biology.

It is known that glutathione peroxidase (GSH-Px) belongs to the first and second levels of the antioxidant network and is involved in the regulation of many important cellular pathways including maintenance of the redox balance and signalling. In poultry the GSH-Px family includes four Se-dependent forms of the enzyme, however only GSH-Px1 and GSH-Px4 are well characterised and have received substantial attention as important enzymes participating in chicken adaptation to commercially-relevant stresses. The aim of this review is to analyse the current data on relationships between various stress conditions and the GSH-Px activity in poultry with special emphasis to selenium status and nutritional supplements. Indeed, the published literature indicates that there is a range of different nutritional (Se supplementation, antioxidants, plant extracts, probiotics, drugs, mycotoxins) and environmental (temperature stress, transportation, disease) factors modulating GSH-Px activity and/or expression in different tissues from poultry. These inducible enzymes are involved in adaptation to stress and Se supplementation in optimal concentrations whereby form is key for antioxidant system maintenance under stress conditions in commercial poultry production.

The deficiency of Se, an essential micronutrient, has been implicated in adverse pregnancy outcomes. Our study was designed to determine total serum Se, selenoproteins (extracellular glutathione peroxidase (GPx-3), selenoprotein P (SeP)), selenoalbumin (SeAlb) and selenometabolites in healthy women and their newborns at delivery. This cross-sectional study included eighty-three healthy mother–baby couples. Total Se and Se species concentrations were measured in maternal and umbilical cord sera by an in-series coupling of two-dimensional size-exclusion and affinity HPLC. Additional measurements of serum SeP concentration and of serum GPx-3 enzyme activity were carried out using ELISA. Total Se concentration was significantly higher in maternal serum than in cord serum (68·9 (sd 15·2) and 56·1 (sd 14·6) µg/l, respectively; P<0·01). There were significant correlations between selenoprotein and SeAlb concentrations in mothers and newborns, although they also showed significant differences in GPx-3 (11·2 (sd 3·7) v. 10·5 (sd 3·5) µg/l; P<0·01), SeP (42·5 (sd 9·5) v. 28·1 (sd 7·7) µg/l; P<0·01) and SeAlb (11·6 (sd 3·6) v. 14·1 (sd 4·3) µg/l; P<0·01) concentrations in maternal and cord sera, respectively. Serum GPx-3 activity and concentration were positively correlated in mothers (r 0·33; P=0·038) but not in newborns. GPx-3 activity in cord serum was significantly correlated with gestational age (r 0·44; P=0·009). SeAlb concentration was significantly higher in babies, whereas SeP and GPx-3 concentrations were significantly higher in mothers. The differences cannot be explained by simple diffusion; specific transfer mechanisms are probably involved. GPx-3 concentrations in mothers, at delivery, are related to maternal Se status, whereas the GPx-3 activity in cord serum depends on gestational age.

Infectious diseases impair Se metabolism, and low Se status is associated with mortality risk in adults with critical disease. The Se status of neonates is poorly characterised, and a potential impact of connatal infection is unknown. We hypothesised that an infection negatively affects the Se status of neonates. We conducted an observational case–control study at three intensive care units at the Charité-Universitätsmedizin Berlin, Germany. Plasma samples were collected from forty-four neonates. On the basis of clinical signs for bacterial infection and concentrations of IL-6 or C-reactive protein, neonates were classified into control (n 23) and infected (n 21) groups. Plasma Se and selenoprotein P (SePP) concentrations were determined by X-ray fluorescence and ELISA, respectively, at day of birth (day 1) and 48 h later (day 3). Se and SePP showed a positive correlation in both groups of neonates. Se concentrations indicative of Se deficit in adults (<20 µg/l) were observed in four infected neonates and one control subject, and three infected neonates had very low SePP concentrations (<0·5 mg/l). The univariate analysis revealed a significant difference in Se and SePP concentrations between the groups. Both parameters correlated inversely to IL-6 in neonates with severe inflammation (IL-6>500 ng/l). During antibiotic therapy, SePP increased significantly from day 1 (1·03 (sd 0·10) mg/l) to day 3 (1·34 (sd 0·10) mg/l), indicative of improved hepatic Se metabolism. We conclude that both Se and SePP are suitable biomarkers for assessing Se status in neonates and for identifying subjects at risk of deficiency.

Increased substitution of marine ingredients by terrestrial plant products in aquafeeds has been proven to be suitable for Atlantic salmon farming. However, a reduction in n-3 long-chain PUFA is a consequence of this substitution. In contrast, relatively little attention has been paid to the effects of fishmeal and oil substitution on levels of micronutrients such as Se, considering fish are major sources of this mineral for human consumers. To evaluate the effects of dietary marine ingredient substitution on tissue Se distribution and the expression of Se metabolism and antioxidant enzyme genes, Atlantic salmons were fed three feeds based on commercial formulations with increasing levels of plant proteins (PP) and vegetable oil. Lipid content in flesh did not vary at any sampling point, but it was higher in the liver of 1 kg of fish fed higher PP. Fatty acid content reflected dietary input and was related to oxidation levels (thiobarbituric acid-reactive substances). Liver had the highest Se levels, followed by head kidney, whereas the lowest contents were found in brain and gill. The Se concentration of flesh decreased considerably with high levels of substitution, reducing the added value of fish consumption. Only the brain showed significant differences in glutathione peroxidase, transfer RNA selenocysteine 1-associated protein 1b and superoxide dismutase expression, whereas no significant regulation of Se-related genes was found in liver. Although Se levels in the diets satisfied the essential requirements of salmon, high PP levels led to a reduction in the supply of this essential micronutrient.

Uncontrolled inflammation is a contributing factor to many leading causes of human morbidity and mortality including atherosclerosis, cancer and diabetes. Se is an essential nutrient in the mammalian diet that has some anti-inflammatory properties and, at sufficient amounts in the diet, has been shown to be protective in various inflammatory-based disease models. More recently, Se has been shown to alter the expression of eicosanoids that orchestrate the initiation, magnitude and resolution of inflammation. Many of the health benefits of Se are thought to be due to antioxidant and redox-regulating properties of certain selenoproteins. The present review will discuss the existing evidence that supports the concept that optimal Se intake can mitigate dysfunctional inflammatory responses, in part, through the regulation of eicosanoid metabolism. The ability of selenoproteins to alter the biosynthesis of eicosanoids by reducing oxidative stress and/or by modifying redox-regulated signalling pathways also will be discussed. Based on the current literature, however, it is clear that more research is necessary to uncover the specific beneficial mechanisms behind the anti-inflammatory properties of selenoproteins and other Se metabolites, especially as related to eicosanoid biosynthesis. A better understanding of the mechanisms involved in Se-mediated regulation of host inflammatory responses may lead to the development of dietary intervention strategies that take optimal advantage of its biological potency.

There is evidence from epidemiological studies suggesting that increased consumption of cruciferous vegetables may protect against specific cancers more effectively than total fruit and vegetable intake. These beneficial effects are attributed to the glucosinolate breakdown products, isothiocyanates (ITC). Similarly, selenium (Se) consumption has also been inversely associated with cancer risk and as an integral part of many selenoproteins may influence multiple pathways in the development of cancer. This paper will briefly review the current state of knowledge concerning the effect of Se and ITC in cancer development with a particular emphasis on its antioxidant properties, and will also address whether alterations in DNA methylation may be a potential mechanism whereby these dietary constituents protect against the carcinogenic process. Furthermore, we will discuss the advantages of combining ITC and Se to benefit from their complementary mechanisms of action to potentially protect against the alterations leading to neoplasia. Based on this review it may be concluded that an understanding of the impact of ITC and Se on aberrant DNA methylation in relation to factors modulating gene-specific and global methylation patterns, in addition to the effect of these food constituents as modulators of key selenoenzymes, such as gastrointestinal glutathione peroxidase-2 (GPx2) and thioredoxin reductase-1 (TrxR1), may provide insights into the potential synergy among various components of a plant-based diet that may counteract the genetic and epigenetic alterations that initiate and sustain neoplasia.

Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk.

Certain forms of dietary Se may have advantages for improving human Se status and regulating the risk for disease, such as cancers, including colorectal cancer (CRC). The present study compared the effects of a Se-enriched milk protein (dairy-Se) with a Se-rich yeast (yeast-Se) on plasma Se levels and rectal selenoprotein gene expression since we reasoned that if these genes were not regulated, there was little potential for regulating the risk for CRC in this organ. A total of twenty-three healthy volunteers with plasma Se in the lower half of the population range were supplemented with dairy-Se (150 μg/d) or yeast-Se (150 μg/d) for 6 weeks, followed by 6 weeks of washout period. Blood was sampled every 2 weeks, and rectal biopsies were obtained before and after Se supplementation and after the washout period. Plasma Se levels and glutathione peroxidase (GPx) activity, and rectal mRNA of selenoprotein P (SeP), cytosolic GPx-1 (GPx-1), gastrointestinal GPx-2 (GPx-2) and thioredoxin reductase-1 (TrxR-1) were measured. Plasma Se levels increased rapidly in both Se groups (P < 0·001); plasma GPx activity was not significantly changed. Rectal SeP mRNA increased at 6 weeks compared with baseline in both Se groups (P < 0·05); only dairy-Se resulted in a sustained elevation of SeP after the washout period (P < 0·05). Rectal GPx-1 and GPx-2 mRNA were higher with dairy-Se (P < 0·05) than with yeast-Se at 6 weeks. In conclusion, three rectal selenoprotein mRNA were differentially regulated by dairy-Se and yeast-Se. Changes in rectal selenoproteins are not predicted by changes in plasma Se; dairy-Se effectively regulates the expression of several rectal selenoproteins of relevance to the risk for CRC.

Daily nutrition varies considerably among individuals. The number of vegetarians is increasing continuously due to ethical, environmental, religious or other reasons. There is growing concern over their nutritional status with respect to micronutrient deficiencies. Among the essential trace elements, Se is of prime importance as it is part of the active site in selenoproteins. European soil and plants are relatively poor sources of Se, while farm animals are generally supplemented with Se in order to improve their health and avoid deficiency syndromes. We therefore wondered whether German vegetarians display a measurable Se deficiency. To this end, we compared young vegetarians (n 54) and omnivores (n 53). We assessed their Se status by measuring extracellular glutathione peroxidase 3 (GPX3) activity, and concentrations of total serum Se and circulating Se-transport protein selenoprotein P (SEPP). GPX3 activities were not different between the groups, whereas both total Se and SEPP concentrations were reduced to 79·5 and 71·2 % in vegetarians compared with omnivores. When splitting the group of vegetarians into vegans (n 26) and vegetarians consuming egg and milk products (n 28), analyses of the Se-dependent biomarkers did not reveal significant differences. We conclude that low serum Se is mirrored by circulating SEPP concentrations, but not by GPX3 activities in marginally supplied individuals. The specific dietary Se sources, divergent metabolic routes of selenomethionine v. selenocysteine and the different saturation kinetics of GPX3 and SEPP probably underlie our contradictory findings. Whether German vegetarians and vegans need to be considered as a Se-deficient group depends on the biomarker chosen.

Certain forms of dietary Se may have an advantage in improving Se status and reducing cancer risk. The present study compared the effects of an Se-enriched milk protein product (dairy-Se) with an Se yeast (yeast-Se) on selenoprotein activity and expression in the mouse colon. Mice were fed four diets for 4 weeks: a control milk protein diet (Se at 0·068 parts per million (ppm)), dairy-Se diets with Se at 0·5 and 1 ppm, and a yeast-Se diet with Se at 1 ppm. Cytosolic glutathione peroxidase-1 (GPx-1) activity, mRNA of selenoprotein P (SeP), GPx-1, gastrointestinal glutathione peroxidase-2 (GPx-2) and thioredoxin reductase-1 (TrxR-1) were examined in the mouse colon. Dairy-Se diets did not significantly affect GPx-1 mRNA and GPx-1 activity but produced a dose-dependent increase in SeP and GPx-2 mRNA, with a significantly higher level achieved at 1 ppm Se (P < 0·05). Yeast-Se at 1 ppm significantly increased GPx-1 mRNA and GPx-1 activity (P < 0·01) but not GPx-2 mRNA. Neither Se supplement had any effect on TrxR-1. The present study indicates that selenoprotein levels in the mouse colon are regulated differently depending on the Se supplement. As we have previously shown that dairy-Se at 1 ppm was protective against colorectal cancer (CRC) in an azoxymethane-induced CRC mouse model, this up-regulation of colonic GPx-2 and SeP with Se supplementation may be crucial to its chemopreventive action.

In eukaryotes, the specific cotranslational insertion of selenocysteine at UGA codons requires the presence of a secondary structural motif in the 3′ untranslated region of the selenoprotein mRNA. This selenocysteine insertion sequence (SECIS) element is predicted to form a hairpin and contains three regions of sequence invariance that are thought to interact with a specific protein or proteins. Specificity of RNA-binding protein recognition of cognate RNAs is usually characterized by the ability of the protein to recognize and distinguish between a consensus binding site and sequences containing mutations to highly conserved positions in the consensus sequence. Using a functional assay for the ability of wild-type and mutant SECIS elements to direct cotranslational selenocysteine incorporation, we have investigated the relative contributions of individual invariant nucleotides to SECIS element function. We report the novel finding that, for this consensus RNA motif, mutations at the invariant nucleotides are tolerated to different degrees in different elements, depending on the identity of a single nonconserved nucleotide. Further, we demonstrate that the sequences adjacent to the minimal element, although not required for function, can affect function through their propensity to base pair. These findings shed light on the specific structure these conserved sequences may form within the element. This information is crucial to the design of strategies for the identification of SECIS-binding proteins, and hence the elucidation of the mechanism of selenocysteine incorporation in eukaryotes.