Lrp8 knockout mice fed a selenium-replete diet display subtle deficits in their spatial learning and memory function.

Selenium is an essential trace element that is delivered to the brain by the selenium transport protein selenoprotein P (SEPP1), primarily by binding to its receptor low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), at the blood-brain barrier. Selenium transport is required for several important brain functions, with transgenic deletion of either Sepp1 or Lrp8 resulting in severe neurological dysfunction and death in mice fed a selenium-deficient diet. Previous studies have reported that although feeding a standard chow diet can prevent these severe deficits, some motor coordination and cognitive dysfunction remain. Importantly, no single study has directly compared the motor and cognitive performance of the Sepp1 and Lrp8 knockout (KO) lines. Here, we report the results of a comprehensive parallel analysis of the motor and spatial learning and memory function of Sepp1 and Lrp8 knockout mice fed a standard mouse chow diet. Our results revealed that Sepp1 knockout mice raised on a selenium-replete diet displayed motor and cognitive function that was indistinguishable from their wild-type littermates. In contrast, we found that although Lrp8-knockout mice fed a selenium-replete diet had normal motor function, their spatial learning and memory showed subtle deficits. We also found that the deficit in baseline adult hippocampal neurogenesis exhibited by Lrp8-deficit mice could not be rescued by dietary selenium supplementation. Taken together, these findings further highlight the importance of selenium transport in maintaining healthy brain function. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Prediagnostic selenium status, selenoprotein gene variants and association with breast cancer risk in a European cohort study.

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30-0.98, Ptrend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.

The selenoprotein P-LRP5/6-WNT3A complex promotes tumorigenesis in sporadic colorectal cancer.

Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In this issue of the JCI, Pilat et al. demonstrate that increased SELENOP expression promoted the progression of conventional adenomas to carcinoma. SELENOP functioned as a modulator of canonical WNT signaling activity through interactions with WNT3A and its coreceptor LDL receptor-related protein 5/6 (LRP5/6). Secreted SELENOP formed a concentration gradient along the gut crypt axis, which might amplify WNT signaling activity by binding to LRPL5/6. The mechanism for WNT control via SELENOP may affect colorectal tumorigenesis and provide therapeutic targets for CRC.

An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase.

Selenoprotein P (SeP, encoded by the SELENOP gene) is a plasma protein that contains selenium in the form of selenocysteine residues (Sec, a cysteine analog containing selenium instead of sulfur). SeP functions for the transport of selenium to specific tissues in a receptor-dependent manner. Apolipoprotein E receptor 2 (ApoER2) has been identified as a SeP receptor. However, diverse variants of ApoER2 have been reported, and the details of its tissue specificity and the molecular mechanism of its efficiency remain unclear. In the present study, we found that human T lymphoma Jurkat cells have a high ability to utilize selenium via SeP, while this ability was low in human rhabdomyosarcoma cells. We identified an ApoER2 variant with a high affinity for SeP in Jurkat cells. This variant had a dissociation constant value of 0.67 nM and a highly glycosylated O-linked sugar domain. Moreover, the acidification of intracellular vesicles was necessary for selenium transport via SeP in both cell types. In rhabdomyosarcoma cells, SeP underwent proteolytic degradation in lysosomes and transported selenium in a Sec lyase-dependent manner. However, in Jurkat cells, SeP transported selenium in Sec lyase-independent manner. These findings indicate a preferential selenium transport pathway involving SeP and high-affinity ApoER2 in a Sec lyase-independent manner. Herein, we provide a novel dynamic transport pathway for selenium via SeP.

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions.

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.

High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression.

INTRODUCTION: Selenium (Se) is an essential trace element that exerts its effects mainly as the proteinogenic amino acid selenocysteine within a small set of selenoproteins. Among all family members, selenoprotein P (SELENOP) constitutes a particularly interesting protein as it serves as a biomarker and serum Se transporter from liver to privileged tissues. SELENOP expression is tightly regulated by dietary Se intake, inflammation, hypoxia and certain substances, but a systematic drug screening has hitherto not been performed. METHODS: A compound library of 1861 FDA approved clinically relevant drugs was systematically screened for interfering effects on SELENOP expression in HepG2 cells using a validated ELISA method. Dilution experiments were conducted to characterize dose-responses. A most potent SELENOP inhibitor was further characterized by RNA-seq analysis to assess effect-associated biochemical pathways. RESULTS: Applying a 2-fold change threshold, 236 modulators of SELENOP expression were identified. All initial hits were replicated as biological triplicates and analyzed for effects on cell viability. A set of 38 drugs suppressed SELENOP expression more than three-fold, among which were cancer drugs, immunosuppressants, anti-infectious drugs, nutritional supplements and others. Considering a 90% cell viability threshold, resveratrol, vidofludimus, and antimony potassium-tartrate were the most potent substances with suppressive effects on extracellular SELENOP concentrations. Resveratrol suppressed SELENOP levels dose-dependently in a concentration range from 0.8 µM to 50.0 µM, without affecting cell viability, along with strong effects on key genes controlling metabolic pathways and vesicle trafficking. CONCLUSION: The results highlight an unexpected direct effect of the plant stilbenoid resveratrol, known for its antioxidative and health-promoting effects, on the central Se transport protein. The suppressive effects on SELENOP may increase liver Se levels and intracellular selenoprotein expression, thereby conferring additional protection to hepatocytes at the expense of systemic Se transport. Further physiological effects from this interaction require analyses in vivo and by clinical studies.

Selenoprotein P - Selenium transport protein, enzyme and biomarker of selenium status.

The habitual intake of selenium (Se) varies strongly around the world, and many people are at risk of inadequate supply and health risks from Se deficiency. Within the human organism, efficient transport mechanisms ensure that organs with a high demand and relevance for reproduction and survival are preferentially supplied. To this end, selenoprotein P (SELENOP) is synthesized in the liver and mediates Se transport to essential tissues such as the endocrine glands and the brain, where the "SELENOP cycle" maintains a privileged Se status. Mouse models indicate that SELENOP is not essential for life, as supplemental Se supply was capable of preventing the development of severe symptoms. However, knockout mice died under limiting supply, arguing for an essential role of SELENOP in Se deficiency. Many clinical studies support this notion, pointing to close links between health risks and low SELENOP levels. Accordingly, circulating SELENOP concentrations serve as a functional biomarker of Se supply, at least until a saturated status is achieved and SELENOP levels reach a plateau. Upon toxic intake, a further increase in SELENOP is observed, i.e., SELENOP provides information about possible selenosis. The SELENOP transcripts predict an insertion of ten selenocysteine residues. However, the decoding is imperfect, and not all these positions are ultimately occupied by selenocysteine. In addition to the selenocysteine residues near the C-terminus, one selenocysteine resides central within an enzyme-like environment. SELENOP proved capable of catalyzing peroxide degradation in vitro and protecting e.g. LDL particles from oxidation. An enzymatic activity in the intact organism is unclear, but an increasing number of clinical studies provides evidence for a direct involvement of SELENOP-dependent Se transport as an important and modifiable risk factor of disease. This interaction is particularly strong for cardiovascular and critical disease including COVID-19, cancer at various sites and autoimmune thyroiditis. This review briefly highlights the links between the growing knowledge of Se in health and disease over the last 50 years and the specific advances that have been made in our understanding of the physiological and clinical contribution of SELENOP to the current picture.

The selenoprotein P 3' untranslated region is an RNA binding protein platform that fine tunes selenocysteine incorporation.

Selenoproteins contain the 21st amino acid, selenocysteine (Sec), which is incorporated at select UGA codons when a specialized hairpin sequence, the Sec insertion sequence (SECIS) element, is present in the 3' UTR. Aside from the SECIS, selenoprotein mRNA 3' UTRs are not conserved between different selenoproteins within a species. In contrast, the 3'-UTR of a given selenoprotein is often conserved across species, which supports the hypothesis that cis-acting elements in the 3'-UTR other than the SECIS exert post-transcriptional control on selenoprotein expression. In order to determine the function of one such SECIS context, we chose to focus on the plasma selenoprotein, SELENOP, which is required to maintain selenium homeostasis as a selenium transport protein that contains 10 Sec residues. It is unique in that its mRNA contains two SECIS elements in the context of a highly conserved 843-nucleotide 3' UTR. Here we have used RNA affinity chromatography and identified PTBP1 as the major RNA binding protein that specifically interacts with the sequence between the two SECIS elements. We then used CRISPR/Cas9 genome editing to delete two regions surrounding the first SECIS element. We found that these sequences are involved in regulating SELENOP mRNA and protein levels, which are inversely altered as a function of selenium concentrations.

Role of selenoprotein P expression in the function of pancreatic ß cells: Prevention of ferroptosis-like cell death and stress-induced nascent granule degradation.

Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic ß cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic ß cells and Selenop small interfering (si)RNA, we found that Selenop gene knockdown (KD) resulted in decreased cell viability, cellular pro/insulin levels, insulin secretion, and levels of several cellular selenoproteins, including glutathione peroxidase 4 (Gpx4) and selenoprotein K (Selenok). These dysfunctions induced by Selenop siRNA were recovered by the addition of Se. Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD, while stress-induced nascent granule degradation (SINGD), regulated by Selenok, was responsible for the decrease in proinsulin. SINGD was also observed in the pancreatic ß cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic ß cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK.

Genetically determined variations of selenoprotein P are associated with antioxidant, muscular, and lipid biomarkers in response to Brazil nut consumption by patients using statins.

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.

The Effect of tRNA[Ser]Sec Isopentenylation on Selenoprotein Expression.

Transfer RNA[Ser]Sec carries multiple post-transcriptional modifications. The A37G mutation in tRNA[Ser]Sec abrogates isopentenylation of base 37 and has a profound effect on selenoprotein expression in mice. Patients with a homozygous pathogenic p.R323Q variant in tRNA-isopentenyl-transferase (TRIT1) show a severe neurological disorder, and hence we wondered whether selenoprotein expression was impaired. Patient fibroblasts with the homozygous p.R323Q variant did not show a general decrease in selenoprotein expression. However, recombinant human TRIT1R323Q had significantly diminished activities towards several tRNA substrates in vitro. We thus engineered mice conditionally deficient in Trit1 in hepatocytes and neurons. Mass-spectrometry revealed that hypermodification of U34 to mcm5Um occurs independently of isopentenylation of A37 in tRNA[Ser]Sec. Western blotting and 75Se metabolic labeling showed only moderate effects on selenoprotein levels and 75Se incorporation. A detailed analysis of Trit1-deficient liver using ribosomal profiling demonstrated that UGA/Sec re-coding was moderately affected in Selenop, Txnrd1, and Sephs2, but not in Gpx1. 2'O-methylation of U34 in tRNA[Ser]Sec depends on FTSJ1, but does not affect UGA/Sec re-coding in selenoprotein translation. Taken together, our results show that a lack of isopentenylation of tRNA[Ser]Sec affects UGA/Sec read-through but differs from a A37G mutation.

Toenail selenium, plasma selenoprotein P and risk of advanced prostate cancer: A nested case-control study.

Low selenium status may be associated with increased risk of prostate cancer (PC), particularly aggressive PC, and variation in selenoprotein genes may constitute an important modifying factor. We aimed to investigate the association between two selenium status biomarkers [toenail selenium, plasma selenoprotein P (SELENOP)] and risk of advanced, high-grade and advanced-stage PC. We further studied whether variations in selenoprotein genes were associated with PC risk and selenium biomarker concentrations. In the "Diet, Cancer and Health" cohort, 27 178 men aged 50 to 65 years were enrolled from 1993 to 1997. Between baseline and 2012, 1160 cohort participants were diagnosed with advanced PC; among these 462 had high-grade and 281 had advanced-stage disease at diagnosis. Each case was risk set-matched to one control. Toenail selenium and plasma SELENOP concentrations were measured by neutron activation analysis and a SELENOP-ELISA, respectively, and genotyping was performed for 27 selected single nucleotide polymorphisms (SNPs) in 12 selenium pathway genes (including seven selenoproteins) by allele-specific PCR. Toenail selenium and circulating SELENOP concentrations were not associated with advanced, high-grade or advanced-stage PC. After adjustment for multiple testing, none of the genes were associated with PC risk. Neither toenail selenium nor plasma SELENOP was associated with advanced, high-grade or advanced-stage PC.

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 (28 days 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%.

Association between creatine kinase activity, oxidative stress and selenoproteins mRNA expression changes after Brazil nut consumption of patients using statins.

BACKGROUND & AIMS: Although the mechanisms by which statins promote muscle disorders remain unclear, supplementation with dietary antioxidants may mitigate statins' side effects. This study aimed to investigate whether the consumption of Brazil nuts modulates serum creatine kinase (CK) activity in patients regularly using statins. METHODS: The study was performed in the Ribeirão Preto Medical School University Hospital. Thirty-two patients in regular use of statins were divided according to CK activity levels (G1: increased or G2: normal) and received one unit of Brazil nut daily for 3 months. Body composition, blood selenium (Se) concentrations, erythrocyte glutathione peroxidase (GPX) activity, oxidative stress parameters, and CK activity were evaluated before and after supplementation. RESULTS: In both groups, supplementation with one Brazil nut daily for 3 months contributed to achieve decreased levels of CK activity in serum, with positive changes in plasma and erythrocyte Se concentrations (p < 0.0001), and increased levels of GPX activity. Among the parameters related to curbing of oxidative stress, we observed reduced levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in both groups after supplementation. We also found a moderately negative association between CK and GPX activity (r = -41; p < 0.02). Expression of selenoproteins GPX1, SELENOP, and SELENON after Brazil nut supplementation was unchanged. CONCLUSION: Brazil nut consumption enhanced the control of CK activity by improving oxidative stress biomarkers in patients using statins but did not modulate mRNA expression of selenoproteins.

Selenoprotein P and its potential role in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease associated with cognitive decline, loss of memory, and progressive cerebral atrophy. The trace element selenium (Se) is known to be involved in brain pathology. Selenoprotein P (SELENOP), as the main Se transport protein, is, to a great extent, responsible for maintaining Se homeostasis and the hierarchy of selenoprotein expression in the body. Adequate Se supply through SELENOP is vital for proper brain development and function. Additionally, SELENOP may be implicated in pathological processes in the central nervous system, including those in AD. The current review summarizes recent findings on the possible role of SELENOP in AD, with a focus on probable mechanisms: Se delivery to neurons, antioxidant activity, cytoskeleton assembly, interaction with redox-active metals (e.g., copper and iron), and misfolded proteins (amyloid beta and tau protein). The use of SELENOP as a biomarker of Se status is also briefly discussed. Epidemiological studies on Se supplementation are beyond the scope of the current review.

Processive Recoding and Metazoan Evolution of Selenoprotein P: Up to 132 UGAs in Molluscs.

Selenoproteins typically contain a single selenocysteine, the 21st amino acid, encoded by a context-redefined UGA. However, human selenoprotein P (SelenoP) has a redox-functioning selenocysteine in its N-terminal domain and nine selenium transporter-functioning selenocysteines in its C-terminal domain. Here we show that diverse SelenoP genes are present across metazoa with highly variable numbers of Sec-UGAs, ranging from a single UGA in certain insects, to 9 in common spider, and up to 132 in bivalve molluscs. SelenoP genes were shaped by a dynamic evolutionary process linked to selenium usage. Gene evolution featured modular expansions of an ancestral multi-Sec domain, which led to particularly Sec-rich SelenoP proteins in many aquatic organisms. We focused on molluscs, and chose Pacific oyster Magallana gigas as experimental model. We show that oyster SelenoP mRNA with 46 UGAs is translated full-length in vivo. Ribosome profiling indicates that selenocysteine specification occurs with ∼5% efficiency at UGA1 and approaches 100% efficiency at distal 3' UGAs. We report genetic elements relevant to its expression, including a leader open reading frame and an RNA structure overlapping the initiation codon that modulates ribosome progression in a selenium-dependent manner. Unlike their mammalian counterparts, the two SECIS elements in oyster SelenoP (3'UTR recoding elements) do not show functional differentiation in vitro. Oysters can increase their tissue selenium level up to 50-fold upon supplementation, which also results in extensive changes in selenoprotein expression.

Proposal of a study protocol of a preliminary double-blind randomized controlled trial. Verifying effects of selenium supplementation on selenoprotein p and s genes expression in protein and mRNA levels in subjects with coronary artery disease: selenegene.

BACKGROUND: Selenium is the component of selenocystein amino acid, which itself is the building block of selenoproteins having diverse effects on various aspects of the human health. Among these proteins, selenoprotein P is the central to the distribution and homeostasis of selenium, and selenoprotein S as a transmembrane protein is associated with a range of inflammatory markers, particularly in the context of cardiovascular disease. It is known that selenium status outside of the normal range is considered to confer different benefits or adverse cardiovascular risk factors. Therefore, for the first time, we aimed to verify effects of Selenium supplementation on Selenoprotein P and S Genes Expression in Protein and mRNA Levels in Subjects with Coronary Artery Disease (CAD). METHODS: This is the study protocol of a double blinded randomized clinical trial on 130 subjects with angiographically documented stenosis of more than 75% in one or more coronary artery vessels. In this 60-day study, 65 patients in each group received either a 200mg selenium yeast or placebo tablets once daily. During the study, subjects were followed by phone calls and visited our clinic twice to repeat baseline measurements. We hypothesized that our finding would enable a more basic and confirmed understanding for the effect of selenium supplementation by investigating its effect on gene expression levels in people with CAD. DISCUSSION: Upon confirmation of this hypothesis, the beneficial effect of inflammation regulation by supplementation with micronutrients could be considered for subjects with CVD.

Genetic variants in selenoprotein genes modulate biomarkers of selenium status in response to Brazil nut supplementation (the SU.BRA.NUT study).

BACKGROUND: The beneficial effects of selenium (Se) to human health are exerted by selenoproteins, which can be quantified in blood and used as biomarkers of Se status. Different responses of Se biomarkers after supplementation with selenomethionine and sodium selenite have been observed and some of them could be due to genetic polymorphisms, mainly single nucleotide polymorphisms (SNPs). Brazil nuts are known to be the richest natural source of Se. OBJECTIVE: Investigate how genetic variations in selenoprotein genes modulate biomarkers of Se status in response to Brazil nut supplementation. METHODS: The SU.BRA.NUT study was a four month interventional trial which involved healthy volunteers of both genders, selected in University of Sao Paulo. The supplementation was done with one Brazil nut a day for 8 weeks, followed by 8 weeks of washout. Blood samples were collected at 5 time points: baseline, 4 and 8 weeks of supplementation and 4 and 8 weeks of washout for analysis of five biomarkers of Se status - erythrocyte GPx1 (Glutathione Peroxidase 1) activity, plasma GPx3 activity, plasma Se, erythrocyte Se, and plasma selenoprotein P. The gene expression of GPX1, SELENOP, SELENOF and SELENOS was done before and after 8 weeks of supplementation. The volunteers were genotyped for SNPs in GPX1 (rs1050450, rs3811699 and rs1800699), GPX4 (rs713041), SELENOP (rs3877899 and rs7579), SELENOF (rs5845) and SELENOS (rs34713741). RESULTS: A total of 130 volunteers finished the protocol. The concentrations of four biomarkers of Se status increased significantly after 4 and 8 weeks of supplementation, being modulated by gender. In addition, erythrocyte GPx1 activity was associated with rs1050450, rs713041 and rs5845. Plasma Se was associated with rs7579 and selenoprotein P with plasma Se at baseline. Nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450. SELENOP mRNA expression was significantly lower in subjects with GG genotype at rs7579 before and after supplementation. CONCLUSION: Genetic variations in GPX1 and SELENOP genes are associated with different responses of molecular and biochemical biomarkers of Se status after Brazil nut supplementation in healthy Brazilians. The SU.BRA.NUT study was registred at www.clinicaltrials.gov as NCT 03111355.

Interaction of NKX3.1 and SELENOP genotype with prostate cancer recurrence.

BACKGROUND: NKX3.1 is a tumor suppressor frequently lost in prostate cancer. Previous studies by others indicated that the risks associated with reduced NKX3.1 levels can be enhanced by anti-oxidant supplementation. Selenium is an essential component of several proteins with anti-oxidant functions and lower levels of selenium have been associated with greater risk of prostate cancer. In contrast, participants of the select prostate cancer prevention trial were at increased risk of prostate cancer when supplemented with selenium when their baseline selenium levels were high. METHODS: In order to investigate whether there was an interaction between a functional polymorphism in NKX3.1 that results in less protein and selenium status with prostate cancer grade or outcome, plasma selenium levels and the genotypes of NKX3.1 and the selenium carrier protein SELENOP were determined from a cohort of men who underwent radical protatectomy. RESULTS: NKX3.1 and SELENOP genotypes were associated with a more aggressive prostate tumor grade at the time of prostatectomy, but there were no significant interactions of NKX3.1 genotype with either selenium status or SELENOP genotype. There was also a significant association between NKX3.1 genotype and prostate cancer recurrence, however this association was modified by SELENOP genotype, but not with plasma selenium levels. CONCLUSIONS: These data indicate that the impact of selenium status on prostate cancer may be influenced by factors other than the amount of selenium in circulation.

Four selenoprotein P genes exist in salmonids: Analysis of their origin and expression following Se supplementation and bacterial infection.

The following research was conducted to elucidate the evolution and expression of salmonid selenoprotein P (SelP), a selenoprotein that is unique in having multiple selenocysteine (Sec) residues, following supranutritional selenium supplementation and infection in rainbow trout. We show that in salmonids SelP is present as four paralogues and that the diversification of SelP genes during vertebrate evolution relates to whole genome duplication events. With 17 and 16 selenocysteine residues for rainbow trout (Oncorhynchus mykiss)/Atlantic salmon (Salmo salar) SelPa1 and SelPa2 proteins respectively and 1 or 2 (trout or salmon) and 4 or 3 (trout or salmon) selenocysteine residues for salmonid SelPb1 and SelPb2 proteins respectively, this is the highest number of (predicted) multiple selenocysteine containing SelP proteins reported for any vertebrate species to date. To investigate the effects of selenium form on SelP expression we added different concentrations (1 nM- 10 µM) of organic or inorganic selenium to a trout cell line (RTG-2 cells) and analysed changes in mRNA abundance. We next studied the impact of supplementation on the potential modulation of these transcripts by PAMPs and proinflammatory cytokines in RTG-2 and RTS-11 cells. These experiments revealed that selenium type influenced the responses, and that SelP gene subfunctionalisation was apparent. To get an insight into the expression patterns in vivo we conducted a feeding trial with 2 diets differing in selenium content and 5 weeks later challenged the trout with a bacterial pathogen (Aeromonas salmonicida). Four tissues were analysed for SelP paralogue expression. The results show a significant induction of SelPa1 in gills and intestine following infection in selenium supplemented fish and for SelPa2 in gills. SelPb1 was significantly reduced in head kidney of both diet groups following infection, whilst SelPb2 was significantly upregulated in skin of both diet groups post infection. Overall these findings reveal differential expression profiles for the SelPa/SelPb paralogues in trout, influenced by selenium supply, cell type/tissue and stimulant. The increase of multiple Sec containing SelP proteins in salmonids could indicate an enhanced requirement for selenium in this lineage.