Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation.

The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI), which does not catalyze redox reactions, but instead is an ethanolamine phosphotransferase (Ept). In fact, the characteristic selenocysteine residue that defines selenoproteins lies far outside of the catalytic domain of SELENOI. Furthermore, data using recombinant SELENOI lacking the selenocysteine residue have suggested that the selenocysteine amino acid is not directly involved in the Ept reaction. SELENOI is involved in two different pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are constituents of cellular membranes. Ethanolamine phospholipid synthesis has emerged as an important process for metabolic reprogramming that occurs in pluripotent stem cells and proliferating tumor cells, and this review discusses roles for upregulation of SELENOI during T cell activation, proliferation, and differentiation. SELENOI deficiency lowers but does not completely diminish de novo synthesis of PE and plasmenyl PE during T cell activation. Interestingly, metabolic reprogramming in activated SELENOI deficient T cells is impaired and this reduces proliferative capacity while favoring tolerogenic to pathogenic phenotypes that arise from differentiation. The implications of these findings are discussed related to vaccine responses, autoimmunity, and cell-based therapeutic approaches.

Role for Selenium in Metabolic Homeostasis and Human Reproduction.

Selenium (Se) is a micronutrient essential for life. Dietary intake of Se within the physiological range is critical for human health and reproductive functions. Selenium levels outside the recommended range have been implicated in infertility and variety of other human diseases. However, presently it is not clear how different dietary Se sources are processed in our bodies, and in which form or how much dietary Se is optimum to maintain metabolic homeostasis and boost reproductive health. This uncertainty leads to imprecision in published dietary guidelines and advice for human daily intake of Se and in some cases generating controversies and even adverse outcomes including mortality. The chief aim for this review is to describe the sources of organic and inorganic Se, the metabolic pathways of selenoproteins synthesis, and the critical role of selenprotenis in the thyroid gland homeostasis and reproductive/fertility functions. Controversies on the use of Se in clinical practice and future directions to address these challenges are also described and discussed herein.

Selenium-dependent metabolic reprogramming during inflammation and resolution.

Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine, into selenoproteins through tRNA[Ser]Sec. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin lipopolysaccharide (LPS) activation of murine bone marrow-derived macrophages cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag-quantitative proteomics, metabolomics, and machine-learning approaches. Kinetic deltagram and clustering analysis indicated that addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing the pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation, to aid in the phenotypic transition toward alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation toward proresolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h after LPS stimulation that included succinate dehydrogenase complex, pyruvate kinase, and sedoheptulokinase. Se-dependent modulation of these pathways predisposed bone marrow-derived macrophages to preferentially increase oxidative phosphorylation to efficiently regulate inflammation and its timely resolution. The use of macrophages lacking selenoproteins indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of succinate dehydrogenase complex with dimethylmalonate affected the proresolving effects of Se by increasing the resolution interval in a murine peritonitis model. In summary, our studies provide novel insights into the role of cellular Se via metabolic reprograming to facilitate anti-inflammation and proresolution.

Selenium in Endocrinology-Selenoprotein-Related Diseases, Population Studies, and Epidemiological Evidence.

Selenium (Se), apart from iodine, iron, and calcium, is one of the nutrient-derived key elements strongly affecting the endocrine system. However, no specific hormonal "feedback" regulation for Se status has yet been identified, in contrast to the fine-tuned hormone network regulating Ca2+ and phosphate balance or hepcidin-related iron status. Since its discovery as an essential trace element, the effects of Se excess or deficiency on the endocrine system or components of the hypothalamic-pituitary-periphery feedback circuits, the thyroid hormone axis, glucoregulatory and adrenal hormones, male and female gonads, the musculoskeletal apparatus, and skin have been identified. Analysis of the Se status in the blood or via validated biomarkers such as the hepatically derived selenoprotein P provides valuable diagnostic insight and a rational basis for decision making on required therapeutic or preventive supplementation of risk groups or patients. Endocrine-related epidemiological and interventional evidence linking Se status to beneficial or potentially adverse actions of selected selenoproteins mediating most of the (patho-) physiological effects are discussed in this mini-review. Autoimmune thyroid disease, diabetes and obesity, male fertility, as well as osteoporosis are examples for which observational or interventional studies have indicated Se effects. The currently prevailing concept relating Se and selenoproteins to "oxidative stress," reactive oxygen species, radical hypotheses, and related strategies of pharmacological approaches based on various selenium compounds will not be the focus. The crucial biological function of several selenoproteins in cellular redox-regulation and specific enzyme reactions in endocrine pathways will be addressed and put in clinical perspective.

Role of Selenium in Viral Infections with a Major Focus on SARS-CoV-2.

Viral infections have afflicted human health and despite great advancements in scientific knowledge and technologies, continue to affect our society today. The current coronavirus (COVID-19) pandemic has put a spotlight on the need to review the evidence on the impact of nutritional strategies to maintain a healthy immune system, particularly in instances where there are limited therapeutic treatments. Selenium, an essential trace element in humans, has a long history of lowering the occurrence and severity of viral infections. Much of the benefits derived from selenium are due to its incorporation into selenocysteine, an important component of proteins known as selenoproteins. Viral infections are associated with an increase in reactive oxygen species and may result in oxidative stress. Studies suggest that selenium deficiency alters immune response and viral infection by increasing oxidative stress and the rate of mutations in the viral genome, leading to an increase in pathogenicity and damage to the host. This review examines viral infections, including the novel SARS-CoV-2, in the context of selenium, in order to inform potential nutritional strategies to maintain a healthy immune system.

Thyroxine binding to type III iodothyronine deiodinase.

Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop's N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I⋯Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I⋯O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.

Knockout of Selenoprotein V Affects Regulation of Selenoprotein Expression by Dietary Selenium and Fat Intakes in Mice.

BACKGROUND: The metabolic function of selenoprotein V (SELENOV) remains unknown. OBJECTIVES: Two experiments were conducted to determine effects of the Selenov knockout (KO) on selenium concentration and mRNA, protein, and/or activity of 4 major selenoproteins [glutathione peroxidase (GPX) 1, GPX4, thioredoxin reductase-1 (TXNRD1), and selenoprotein P (SELENOP)] in the serum, liver, testis, and/or white adipose tissue (WAT) of mice fed different dietary selenium and fat concentrations. METHODS: In Experiment (Expt) 1, 40 KO and 40 wild-type (WT) mice (males, 8 wk old) were fed (n = 10/genotype) a casein-sucrose basal diet plus 0, 0.3, 1, or 3 mg Se/kg (as sodium selenite) for 32 wk . In Expt 2, 20 KO and 20 WT mice (males, 8 wk old) were fed (n  = 10/genotype) a normal-fat diet (NF; 10% calories from fat) or a high-fat diet (HF; 60% calories from fat) for 19 wk. RESULTS: In Expt 1, the KO caused consistent or substantial decreases (P < 0.05) of mRNA amounts of Gpx1, Txnrd1, and Selenop in the testis (≤52%), but selenium concentrations (19-29%) and GPX activities (≤ 50%) were decreased in the liver across different dietary selenium concentrations . Hepatic and testis GPX1 protein was elevated (≤31%) and decreased (≤45%) by the KO, respectively. In Expt 2, the genotype and dietary fat intake exerted interaction effects ( P < 0.05) on Gpx1 mRNA amounts in the WAT; Gpx1, Txnrd1, and Selenop mRNA amounts and TXNRD activities in the testis; and selenium concentrations in the serum and liver. However, these 2 treatments produced largely independent or additive effects (P < 0.05) on the GPX1 and SELENOP protein amounts in the liver and testis (up to ± 50% changes). CONCLUSIONS: The KO-mediated changes in the tissue selenium concentrations and functional expression of 3 major selenoproteins implied potential for SELENOV in regulating body selenium metabolism in the mouse.

Selenium and selenoproteins: from endothelial cytoprotection to clinical outcomes.

The role of the vascular endothelium in inflammation was demonstrated experimentally through biomarkers of endothelial dysfunction and cytoprotection. Selenium is a trace element essential for cell protection against oxidative lesions triggered by reactive oxygen species or inflammatory responses. Preclinical studies have demonstrated a relationship between adhesion molecules as biomarkers of endothelial dysfunction and selenoproteins as biomarkers of selenium status under conditions that mimic different diseases. Most studies in humans indicate an association between selenium deficiency and increased risk of morbidity and mortality, yet the pathophysiology of selenium in endothelial activation remains unknown. Here, we summarize selenium-dependent endothelial function evaluation techniques and focus on the role of selenium in endothelial cytoprotection according to current scientific knowledge. Most studies on the role of selenium in endothelial processes show selenium-dependent endothelial functions and explain how cells and tissues adapt to inflammatory insults. Taken together, these studies show an increase in adhesion molecules and a decrease in the expression of selenoproteins following a decreased exposure to selenium. Few clinical trials have enough methodological quality to be included in meta-analysis on the benefits of selenium supplementation. Furthermore, the methodology adopted in many studies does not consider the relevant findings on the pathophysiology of endothelial dysfunction. Preclinical studies should be more frequently integrated into clinical studies to provide clearer views on the role of selenium status in endothelial cytoprotection.

The Thioredoxin-Like Family of Selenoproteins: Implications in Aging and Age-Related Degeneration.

The thioredoxin-like (Rdx) family proteins contain four selenoproteins (selenoprotein H, SELENOH; selenoprotein T, SELENOT; selenoprotein V, SELENOV; selenoprotein W, SELENOW) and a nonselenoprotein Rdx12. They share a CxxU or a CxxC (C, cysteine; x, any amino acid; U, selenocysteine) motif and a stretch of eGxFEI(V) sequence. From the evolutionary perspective, SELENOW and SELENOV are clustered together and SELENOH and SELENOT are in another branch. Selenoproteins in the Rdx family exhibit tissue- and organelle-specific distribution and are differentially influenced in response to selenium deficiency. While SELENOH is nucleus-exclusive, SELENOT resides mainly in endoplasmic reticulum and SELENOW in cytosol. SELENOV is expressed essentially only in the testes with unknown cellular localization. SELENOH and SELENOW are more sensitive than SELENOT and SELENOV to selenium deficiency. While physiological functions of the Rdx family of selenoproteins are not fully understand, results from animal models demonstrated that (1) brain-specific SELENOT knockout mice are susceptible to 1-methyl-4-phenylpyridinium-induced Parkinson's disease in association with redox imbalance and (2) adult zebrafishes with heterozygous SELENOH knockout are prone to dimethylbenzanthracene-induced tumorigenesis together with increased DNA damage and oxidative stress. Further animal and human studies are needed to fully understand physiological roles of the Rdx family of selenoproteins in redox regulation, genome maintenance, aging, and age-related degeneration.

Amblyomma maculatum SECIS binding protein 2 and putative selenoprotein P are indispensable for pathogen replication and tick fecundity.

Selenium, a vital trace element, is incorporated into selenoproteins to produce selenocysteine. Our previous studies have revealed an adaptive co-evolutionary process that has enabled the spotted fever-causing tick-borne pathogen Rickettsia parkeri to survive by manipulating an antioxidant defense system associated with selenium, which includes a full set of selenoproteins and other antioxidants in ticks. Here, we conducted a systemic investigation of SECIS binding protein 2 (SBP2) and putative selenoprotein P (SELENOP) by transcript silencing in adult female Gulf-coast ticks (Amblyomma maculatum). Knockdown of the SBP2 and SELENOP genes depleted the respective transcript levels of these tick selenogenes, and caused differential regulation of other antioxidants. Importantly, the selenium level in the immature and mature tick stages increased significantly after a blood meal, but the selenium level decreased in ticks after the SBP2 and SELENOP knockdowns. Moreover, the SBP2 knockdown significantly impaired both transovarial transmission of R. parkeri to tick eggs and egg hatching. Overall, our data offer new insight into the relationship between the SBP2 selenoprotein synthesis gene and the putative tick SELENOP gene. It also augments our understanding of selenoprotein synthesis, selenium maintenance and utilization, and bacterial colonization of a tick vector.

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex.

Calcium (Ca(2+)) is a secondary messenger in cells and Ca(2+) flux initiated from endoplasmic reticulum (ER) stores via inositol 1,4,5-triphosphate (IP3) binding to the IP3 receptor (IP3R) is particularly important for the activation and function of immune cells. Previous studies demonstrated that genetic deletion of selenoprotein K (Selk) led to decreased Ca(2+) flux in a variety of immune cells and impaired immunity, but the mechanism was unclear. Here we show that Selk deficiency does not affect receptor-induced IP3 production, but Selk deficiency through genetic deletion or low selenium in culture media leads to low expression of the IP3R due to a defect in IP3R palmitoylation. Bioinformatic analysis of the DHHC (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) family of enzymes that catalyze protein palmitoylation revealed that one member, DHHC6, contains a predicted Src-homology 3 (SH3) domain and DHHC6 is localized to the ER membrane. Because Selk is also an ER membrane protein and contains an SH3 binding domain, immunofluorescence and coimmunoprecipitation experiments were conducted and revealed DHHC6/Selk interactions in the ER membrane that depended on SH3/SH3 binding domain interactions. DHHC6 knockdown using shRNA in stably transfected cell lines led to decreased expression of the IP3R and impaired IP3R-dependent Ca(2+) flux. Mass spectrophotometric and bioinformatic analyses of the IP3R protein identified two palmitoylated cysteine residues and another potentially palmitoylated cysteine, and mutation of these three cysteines to alanines resulted in decreased IP3R palmitoylation and function. These findings reveal IP3R palmitoylation as a critical regulator of Ca(2+) flux in immune cells and define a previously unidentified DHHC/Selk complex responsible for this process.

Selenoproteins: molecular pathways and physiological roles.

Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

Farmaconutrición parenteral con selenio en la sepsis / Pharmaconutrition with parenteral selenium in sepsis

La enfermedad crítica se caracteriza por estrés oxidativo, el cual conduce a una disfunción orgánica múltiple, siendo dicha disfunción secundaria a sepsis la causa más frecuente de mortalidad en la unidad de cuidados intensivos. Durante las últimas 2 décadas, se ha acumulado una evidencia creciente a favor del uso de los micronutrientes antioxidantes en los pacientes críticos. De acuerdo con la evidencia reciente, la terapéutica con selenio puede ser considerada como la piedra angular dentro de las estrategias antioxidantes en la sepsis. El selenio, administrado como selenito de sodio o ácido selenioso, se comporta como un fármaco o nutrofármaco con efecto citotóxico y prooxidante cuando una dosis de carga en forma de bolo intravenoso es administrada en la fase precoz de la sepsis grave y el shock séptico. Hasta el momento, diversos estudios fase ii sobre suplementación de selenio han demostrado que esta estrategia es capaz de disminuir la mortalidad, la severidad de la disfunción orgánica y las infecciones. En el futuro próximo, nuevos estudios fase iii deberán confirmar los efectos de la farmaconutrición parenteral con selenio en la sepsis. En la presente revisión se discute la evidencia actual sobre la farmaconutrición con selenio en la sepsis

Critical illness is characterized by oxidative stress which leads to multiple organ failure, and sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit. Over the last 2 decades, different antioxidant therapies have been developed o improve outcomes in septic patients. According to recent evidence, selenium therapy should be considered the cornerstone of the antioxidant strategies. Selenium given as selenious acid or sodium selenite should be considered as a drug or pharmaconutrient with prooxidant and cytotoxic effects when a loading dose in intravenous bolus form is administered, particularly in the early stage of severe sepsis/septic shock. To date, several phaseiitrials have demonstrated that selenium therapy may be able to decrease mortality, improve organ dysfunction and reduceinfections in critically ill septic patients. The effect of selenium therapy in sepsis syndrome must be confirmed by large, well designed phaseiiiclinical trials. The purpose of this review is to discuss current evidence on selenium pharmaconutrition in sepsis síndrome

Selenium biochemistry and its role for human health.

Despite its very low level in humans, selenium plays an important and unique role among the (semi)metal trace essential elements because it is the only one for which incorporation into proteins is genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five selenoproteins have been identified so far in the human proteome. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic effect for human diseases. This review summarizes the most recent findings on the biochemistry of active selenium species in humans, and addresses the latest evidence on the link between selenium intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the interpretation of biochemical mechanisms rather than epidemiological/observational data. In this context, the review includes the following sections: (1) brief introduction; (2) general nutritional aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of human diseases.

High selenium impairs hepatic insulin sensitivity through opposite regulation of ROS.

Insulin resistance is the hallmark of type 2 diabetes. As an essential trace element, selenium (Se) is recommended worldwide for supplementation to prevent Se-deficient pathological conditions, including diabetes and insulin resistance. However, recent evidence has shown that supra-nutritional Se intake is positively associated with the prevalence of diabetes. In the present research, we examined the effect of high Se on insulin sensitivity, and studied possible mechanisms in rats and in rat hepatocytes. Insulin sensitivity and glucose/lipid metabolism were determined by glucose/insulin tolerance test, western blot, immunofluorescence, specific probes and other biochemical assays. We show that high Se activates selenoproteins, including glutathione peroxidase and selenoprotein P, and depletes chromium, leading to a common metabolic intersection-lipolysis in adipose tissue and influx of fatty acids in liver. Fatty acid ß-oxidation generates acetyl-CoA, which is metabolized in trichloroacetic acid cycle, supplying excessive electrons for mitochondrial oxidative phosphorylation and leading to increased "bad" reactive oxygen species (ROS) production in mitochondria and final disturbance of insulin signaling. Furthermore, high Se-activated selenoproteins also weaken insulin-stimulated "good" ROS signal generated by NAD(P)H oxidase, leading to attenuation of insulin signaling. Taken together, these data suggest that excessive intake of Se induces hepatic insulin resistance through opposite regulation of ROS.

A tale of two toxicities: malformed selenoproteins and oxidative stress both contribute to selenium stress in plants.

BACKGROUND: Despite selenium's toxicity in plants at higher levels, crops supply most of the essential dietary selenium in humans. In plants, inorganic selenium can be assimilated into selenocysteine, which can replace cysteine in proteins. Selenium toxicity in plants has been attributed to the formation of non-specific selenoproteins. However, this paradigm can be challenged now that there is increasingly abundant evidence suggesting that selenium-induced oxidative stress also contributes to toxicity in plants. SCOPE: This Botanical Briefing summarizes the evidence indicating that selenium toxicity in plants is attributable to both the accumulation of non-specific selenoproteins and selenium-induced oxidative stress. Evidence is also presented to substantiate the claim that inadvertent selenocysteine replacement probably impairs or misfolds proteins, which supports the malformed selenoprotein hypothesis. The possible physiological ramifications of selenoproteins and selenium-induced oxidative stress are discussed. CONCLUSIONS: Malformed selenoproteins and oxidative stress are two distinct types of stress that drive selenium toxicity in plants and could impact cellular processes in plants that have yet to be thoroughly explored. Although challenging, deciphering whether the extent of selenium toxicity in plants is imparted by selenoproteins or oxidative stress could be helpful in the development of crops with fortified levels of selenium.

Selenium and the thyroid.

PURPOSE OF REVIEW: To provide information on the role of the essential trace element selenium, which enables appropriate thyroid hormone synthesis, secretion, and metabolism, and to discuss supplementation with various selenium compounds, which prevent thyroid diseases such as goiter and exert beneficial effects in thyroid autoimmune diseases. RECENT FINDINGS: Selenium administration in both autoimmune thyroiditis (M. Hashimoto) and mild Graves' disease improves clinical scores and well-being of patients and reduces autoimmune antibody titres in several prospective, placebo-controlled supplementation studies. SUMMARY: Adequate nutritional supply of selenium, together with the two other essential trace elements iodine and iron, is required for a healthy thyroid during development and adolescence, as well as in the adult and aging populations.

Selenium in the redox regulation of the Nrf2 and the Wnt pathway.

Selenium deficiency is known to increase cancer risk by so far unclear mechanisms. Selenium exerts its biological effects via selenocysteine as an integral part of selenoproteins. Certain selenoproteins have redox properties, thereby providing a tool to regulate hydroperoxide-mediated signaling. Selenium deficiency does not only reduce synthesis of selenoproteins but also affects the expression of other proteins and even pathways. A moderate Se deficiency activates the Nrf2 and the Wnt pathways. The link between both pathways appears to be GSK3ß which in the active state prepares Nrf2 as well as ß-catenin, the key player in Wnt signaling, for ubiquitination and proteasomal degradation, thus silencing their transcriptional activity. Upon stimulation by Wnt signals, GSK3ß becomes inactivated and transcription factors are stabilized. Many intermediate steps in both pathways can be modulated by hydroperoxides, making them predestined to be regulated by selenoproteins. Oxidation sensors are (i) Keap1 which keeps Nrf2 in the cytosol unless it is modified by hydroperoxides/electrophiles and (ii) nucleoredoxin (Nrx) which is associated with disheveled (Dvl). NOX1-derived H2O2 oxidizes Nrx leading to the liberation of Dvl and the activation of Wnt signaling. Selenium deficiency can support oxidation of both sensors and activate both pathways. The consequences are dual: while the Keap1/Nrf2 system is generally believed to protect against oxidative stress, diverse xenobiotics, inflammation, and carcinogenesis, the Wnt response is considered rather a risky one in these respects. However, not only healthy cells but also malignant ones benefit from intact Keap1/Nrf2 signaling, making a dysregulated hydroperoxide signaling a plausible explanation for the increased cancer risk in selenium deficiency.

Selenium in bone health: roles in antioxidant protection and cell proliferation.

Selenium (Se) is an essential trace element for humans and animals, and several findings suggest that dietary Se intake may be necessary for bone health. Such findings may relate to roles of Se in antioxidant protection, enhanced immune surveillance and modulation of cell proliferation. Elucidation of the mechanisms by which Se supports these cellular processes can lead to a better understanding of the role of this nutrient in normal bone metabolism. This article reviews the current knowledge concerning the molecular functions of Se relevant to bone health.