Selenoprotein P Research Articles

Selenium supplementation enhanced the expression of selenoproteins in hippocampus and played a neuroprotective role in LPS-induced neuroinflammation

Selenium (Se) is obtained from organic and inorganic selenium food content, which mainly depends on the regional soil selenium content. Selenium deficiency and decreased selenoprotein functions have been shown to associate with the progression of cognitive decline and neurodegenerations including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Selenoproteins are well recognized for their anti-oxidative activities. Given the high oxygen consumption, mammalian brains preferent@ially supplied with Se.Here, we propose a beneficiary role for dietary supplementation of sodium selenite (300 ng per gram of body weight) in ameliorating neuroinflammation induced by bilateral intracerebroventricular injection of 1 μL LPS (1 μg/μL), evidenced by the significantly reduced oxidative stress, downregulated pro-inflammatory cytokines expression, improved integrity of blood-brain barrier, as well as suppressed glial activation and shifted microglial MI/M2 polarization in Se-sup mouse brain. Se intake also reduced neural cell death and significantly improved the cognition in Se-sup mice following LPS challenge. The neuroprotective role for supplementary Se is likely to be ascribed to the overall elevated expression of selenoproteins, especially Selenoprotein P (SELENOP) and Glutathione peroxidase 4 (GPX4), ranking on top of the change in selenoprotein expression hierarchy. The regional hierarchy of Se induced elevation of SELENOP expression was further characterized. The SELENOP expression in the mediodorsal thalamic nucleus, dendric gyrus (DG) and cornu ammonis 3 (CA3) of hippocampus and lateral habenular nucleus was highly sensitive to dietary Se intake.

Stress-Related Immune Response and Selenium Status in Autoimmune Thyroid Disease Patients.

Autoimmune thyroid disease (AITD), including Graves' disease (GD) or Hashimoto's thyroiditis (HT), occurs due to genetic susceptibility and environmental factors, among which the role of stressful events remains controversial. This study investigated the relationship between the number and impact of stressful life events in AITD patients with selenium status, and the Th1/Th2/Th17 immune response. The study population included three groups: HT (n = 47), GD (n = 13), and a control group (n = 49). Thyroid function parameters, autoantibody levels, and the plasma levels of cytokines, selenium, selenoprotein P (SeP), and glutathione peroxidase 3 (GPx) activity were measured. Participants filled out the Life Experiences Survey. No significant differences in the number of stressful life events were found among the patients with HT, GD, and the controls. A higher (median (interquartile range)) negative stress level (8 (4-12)) than a positive stress level (3 (1-9)) was found in the HT group. The HT group showed a correlation between SeP and the positive stress level: rs = -0.296, p = 0.048, and the GD group between GPx and the negative stress level (rs = -0.702, p = 0.011). Significant positive correlations between thyroid peroxidase antibody level and the total number of major life events (p = 0.023), the number of major life events in the last 7-12 months, and the number of major life events with no impact and a negative stress level were found. We suggest that the measurements of Th2-related cytokines and selenoproteins could be used as biomarkers for the development of AITD in cases where stress is considered a component cause of the pathogenic mechanism of the disease.

Intervention study to inhibit the glucose metabolic remodeling in hepatocytes induced by high-selenium in vitro

To observe the effect of exogenous serine or glycine on the synthesis of selenoprotein and endogenous serine and the expression of metabolic enzymes in hepatocytes cultured with high-selenium in vitro and its dose-response relationship. The experiment was divided into two parts, namely a inhibition experiment and a dose-response experiment, using L02 cells as the intervention target. In the inhibition experiment, the blank control group, high-Se(SeMet) group, serine intervention group and high-Se+serine intervention group were set up. Both SeMet and serine were given at a level of 0.05 μmol/L, and the blank control group was given the same volumes of saline. In the dose-response experiment, the concentration of SeMet was 0.05 μmol/L, and the intervention concentration gradients of serine or glycine were 0, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100 and 500 μmol/L. The expression of phosphoglycerate dehydrogenase(PHGDH)、serine hydroxymethyltransferase 1(SHMT1)、methylenetetrahydrofolate reductase(MTHFR)、selenoprotein P(SELENOP) and glutathione peroxidase 1(GPX1)was detected by Western Blot(WB). (1)In the inhibition experiment, compared with the blank control group, the expression of selenium proteins(GPX1 and SELENOP) in L02 cells of the other three groups were significantly increased(P<0.05). Compared with the high expression of PHGDH in L02 cells of high-Se group, the expressions of PHGDH, SHMT1 and MTHFR in high-Se + serine group were significantly decreased(P<0.05). (2) In the dose-response experiment, the expression of PHGDH enzyme in L02 cells gradually decreased with the increase of the concentration of exogenous serine or glycine, showing an obvious dose-dependent effect. In contrast, none of the other metabolic enzymes(SHMT1 and MTHFR) showed similar trends in protein expression. The upregulated expression of PHGDH, the key enzyme in the de novo synthesis pathway of serine in hepatocytes cultured with high-selenium can be inhibited feedback by exogenous serine or endogenous serine transformed from exogenous glycine directly.

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

IntroductionSelenium (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. MethodsA 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. ResultsApplying 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. ConclusionThe 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.

Correlations of selenium and selenoprotein P with asymmetric dimethylarginine and lipid profile in patients with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular diseases (CVD). Accumulating evidence has suggested that selenium (Se) is of importance for optimal function of the cardiovascular system. This study aimed to investigate the associations of selenium and selenoprotein P (SePP) with asymmetric dimethylarginine (ADMA) and lipid profile in women with PCOS. MethodsIn this cross-sectional study, 125 females aged 18–45 years diagnosed with PCOS were recruited. An interviewer-administered questionnaire was applied to gather the relevant demographic characteristics, detailed clinical information, and lifestyle habits of participants. Fasting blood samples were obtained to measure biochemical parameters. Serum concentrations of total testosterone, sex hormone-binding globulin (SHBG), ADMA, and lipid profiles as well as anthropometric measurements were assessed across tertiles of serum Se and SePP concentrations. ResultsThere was a positive correlation between serum Se and SePP concentrations (r = 0.434, p < 0.001). Serum Se level was inversely correlated with ADMA (r = −0.21, p = 0.025) and TG (r = −0.17, p = 0.041) concentrations. There were also inverse correlations between SePP and ADMA (r = −0.34, p < 0.001), TG (r = −0.21, p = 0.019), and oxidized low density lipoprotein (ox-LDL) (r = −0.25, p = 0.007) levels. No significant relationship was found between serum Se and SePP concentrations with total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1), apolipoprotein-B (Apo-B100), total testosterone, SHBG, and free androgen index as well as anthropometric parameters (All p > 0.05). ConclusionThe present study found that Se and SePP levels were inversely correlated with ADMA and TG concentrations as well as ox-LDL levels.

Alleviating effects of selenium on fluoride-induced testosterone synthesis disorder and reproduction toxicity in rats

Fluoride (F) exists widely in food, water and other natural resources, and can cause damage to the reproductive system of human and animals. Studies have shown that selenium (Se) is a necessary trace element to maintain the normal male reproductive system. However, it is not clear whether it can alleviate the damage of reproductive system induced by F. Hence, sodium fluoride (NaF) was administered singly in drinking water at 100 mg L−1 alone and co-administered by drinking with sodium selenite (Na2SeO3) at 0.5, 1.0, 2.0 mg L−1 for 10 consecutive weeks. The results demonstrated that the sperm deformity rate were increased significantly by F, however, it was improved significantly after the addition of 2.0 mg L−1 Na2SeO3. The contents of glutathione peroxidase 4 (GPX-4), selenoprotein P (SePP), pregnenolone (PREG), androstenedione (ASD), and testosterone (T) were reduced obviously in the F group, however, it was increased significantly after adding 0.5, 1.0 and 2.0 mg L−1 Na2SeO3. F decreased noticeably the mRNA and protein expression levels of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side chain lyase (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), cytochrome P450 17α-hydroxylase (P450c17) and 17β-hydroxysteroid dehydrogenase (17β-HSD), which was increased obviously after the addition of 1.0 and 2.0 mg L−1 Na2SeO3. In summary, 2.0 mg L−1 Na2SeO3 can alleviate testosterone synthesis disorder induced by F via reducing oxidative stress, increasing the level of selenoprotein in testis and regulating the content of related hormones and enzyme activity during testosterone synthesis pathway.

Selenoprotein-P deficiency is associated with higher risk of incident heart failure

Abstract Background Selenium deficiency has been associated with all-cause and cardiovascular mortality, incident cardiovascular disease (coronary artery disease, myocardial infarction and stroke), and with poor prognosis in patients with acute heart failure (HF). Furthermore, high selenium levels were recently shown to be associated with reduced mortality and reduced incidence of HF in non-smokers. Purpose To examine if selenoprotein-P (SELENOP), a main carrier protein of selenium, is associated with incident HF. Methods SELENOP concentrations were measured in 5060 randomly selected subjects from the population-based prospective cohort study “the Malmö Preventive Project” (n=18240) using a validated ELISA approach. After exclusion of subjects with prevalent HF (n=230), complete data on all co-variates was available in 4803 subjects (1400 women (29.1%), mean age 69.6±6.2 years, 885 (19.7%) current smokers). SELENOP was continously related to risk of incident HF using Cox regression models adjusted for age, sex, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking status, diabetes status, low-density lipoprotein cholesterol levels, and prevalent coronary events. Further, subjects within the lowest SELENOP quintile were compared to subjects in the remaining four quintiles in an adjusted model. Results Each 1 SD increment in SELENOP levels was associated with lower risk of incident HF (n=436) during a median follow-up period of 14.7 years (interquartile range 10.9–15.7 years, hazard ratio (HR) 0.92, 95% confidence interval (95% CI) 0.84–0.99; p=0.049 in a model adjusted for cardiovascular risk factors. Multivariate quintile analyses revealed that the subjects in the lowest SELENOP quintile were at the highest risk of incident HF in an adjusted model (HR 1.46; 95% CI: 1.17–1.83 for incident HF; p for trend 0.039) illustrated in a Kaplan-Meier survival analysis (Figure 1). No interaction effect was seen for sex or smoking. Conclusion Low SELENOP levels are associated with a higher risk of incident HF supporting recent studies, which further emphasizes the need for randomly controlled trials to examine if supplementation with selenium improves prognosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Medical Research CouncilSwedish Society of Medicine

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.

Hydroxy-Selenomethionine, an Organic Selenium Source, Increases Selenoprotein Expression and Positively Modulates the Inflammatory Response of LPS-Stimulated Macrophages.

The role of 2-hydroxy-(4-methylseleno)butanoic acid (OH-SeMet), a form of organic selenium (Se), in selenoprotein synthesis and inflammatory response of THP1-derived macrophages stimulated with lipopolysaccharide (LPS) has been investigated. Glutathione peroxidase (GPX) activity, GPX1 gene expression, selenoprotein P (SELENOP) protein and gene expression, and reactive oxygen species (ROS) production were studied in Se-deprived conditions (6 and 24 h). Then, macrophages were supplemented with OH-SeMet for 72 h and GPX1 and SELENOP gene expression were determined. The protective effect of OH-SeMet against oxidative stress was studied in H2O2-stimulated macrophages, as well as the effect on GPX1 gene expression, oxidative stress, cytokine production (TNFα, IL-1β and IL-10), and phagocytic and killing capacities after LPS stimulation. Se deprivation induced a reduction in GPX activity, GPX1 gene expression, and SELENOP protein and gene expression at 24 h. OH-SeMet upregulated GPX1 and SELENOP gene expression and decreased ROS production after H2O2 treatment. In LPS-stimulated macrophages, OH-SeMet upregulated GPX1 gene expression, enhanced phagocytic and killing capacities, and reduced ROS and cytokine production. Therefore, OH-SeMet supplementation supports selenoprotein expression and controls oxidative burst and cytokine production while enhancing phagocytic and killing capacities, modulating the inflammatory response, and avoiding the potentially toxic insult produced by highly activated macrophages.

Selenium-enriched Cardamine violifolia improves growth performance with potential regulation of intestinal health and antioxidant function in weaned pigs.

This study was conducted to evaluate the effects of different Selenium (Se) sources on growth performance, intestinal function and antioxidant status of weaned piglets. A total of 300 weaned pigs were randomly allocated to 5 treatment groups with 5 replicates of 12 pigs/pen. The control group was corn-soybean basal diet without any additional Se supplement. The experimental diets were supplemented with 0.3 mg/kg of Se from sodium selenite (SS), Se-enriched yeast (SEY), Se-enriched Cardamine violifolia (SEC) and 0.3+0.3 mg/kg of Se from SEY and SEC, respectively. The trial lasted for 4 weeks. The results showed that diets supplementation with SEY, SEC or SEY+SEC could improve average daily gain and reduce feed/gain ratio during the entire study. Compared with the control group, SEC or SEY+SEC improved intestinal morphology, indicated by greater villus height and villus height/ crypt depth ratio. In addition, SEC or SEY+SEC also increased maltase and lactase activities as well as tight junction protein expression. Different Se sources decreased malondialdehyde (MDA) concentration and improved superoxide dismutase (SOD) activity in serum. In the jejunum, SEY or SEC reduced MDA concentration and increased total antioxidant capacity (T-AOC) compared with the control group. Moreover, SEY+SEC increased the antioxidant parameters including SOD and T-AOC in the jejunum. Dietary SEY or SEC supplementation significantly increased the mRNA expression of selenoproteins including thioredoxin reductase 1 (TXNRD1), selenoprotein I (SELENOI), selenoprotein S (SELENOS), and selenoprotein P (SELENOP) in the jejunum. In conclusion, organic Se sources, especially Cardamine violifolia, improve growth performance, potentially by regulating intestinal function, antioxidant capacity and selenoprotein expression in piglets.

Selenium Status and Supplementation Effects in Pregnancy-A Study on Mother-Child Pairs from a Single-Center Cohort.

The demand for selenium (Se) increases during pregnancy since this element supports child growth, proper neuronal development and maternal thyroid function. The issue is particularly relevant for populations living in areas with a limited selenium supply, where many pregnant women opt for Se supplementation. The efficiency of this measure is unknown, although it seems vital in the prevention of severe Se deficiency. In order to evaluate this hypothesis, an observational study was conducted in Poland, where Se deficiency is prevalent. Pregnant women were invited to participate in the study and provided serum samples at the end of pregnancy (n = 115). Information on the supplemental intake of micronutrients was recorded in a face-to-face interview. In addition, serum samples were isolated from the cord blood of newborns at delivery (n = 112) and included in the analyses. Thyroid hormone status was evaluated by routine laboratory tests, and Se status was determined by total Se and selenoprotein P (SELENOP) concentrations and extracellular glutathione peroxidase (GPX3) activity. The three parameters of Se status correlated strongly within the group of mothers and within the group of newborns, with an additional significant correlation found among mother–child pairs. One-third of mothers reported additional Se intake, mainly as a component of multi-micronutrient supplements, at a mean (±SD) dosage of 42 ± 14 µg Se/day. Despite this regime, most of the women presented an insufficient Se status, with 79% of mothers displaying serum Se concentrations below 70 µg/L (indicating Se deficiency) and 22% showing levels below 45.9 µg/L (severe Se deficiency). The inadequate Se supply was also reflected in relatively low SELENOP concentrations and GPX3 activity. Neither total Se nor SELENOP or GPX3 levels were significantly higher in the group of mothers reporting the intake of supplements than in the non-supplementing group. Nevertheless, elevated SELENOP concentrations were observed in the subgroup receiving supplements with more than 55 µg/day. We conclude that the self-administered supplementation of small Se dosages was not sufficient to achieve replete Se status in the micronutrient scant area. However, the maternal Se deficit measured by either Se, SELENOP or GPX3 was transferred from mothers to the newborns, as the parameters correlated strongly in the mother–newborn pairs of samples. It is vital to re-evaluate the guidelines concerning pregnancy care and monitoring of micronutrient status during pregnancy, in particular in areas where deficiencies are present.

The role of selenoprotein P in the determining the sensitivity of cervical cancer patients to concurrent chemoradiotherapy: A metabonomics-based analysis

BackgroundThe effect of selenoprotein P (SELENOP) levels on the sensitivity of cervical cancer patients to concurrent chemoradiotherapy (CCRT) has not been reported. In this study, the effects of the variations in plasma SELENOP levels on the sensitivity of cervical cancer patients to CCRT were investigated using metabonomics. MethodsTwo patient groups were evaluated, i.e., the case group: 11 patients with intermediate to advanced primary squamous cervical cancer, who developed resistance against CCRT, and the sensitivity group: 11 patients who did not develop resistance were matched in a 1:1 ratio (controls). Blood samples were collected before and after CCRT, and the plasma SELENOP levels were measured by ELISA. The different metabolites present in the plasma were analyzed by UPLC-MS-MS. ResultsSELENOP levels exhibited a significant reduction in both the resistant and sensitive groups after CCRT (F = 50.705, P < 0.001), and interaction effects between sensitivity and pre-and post-treatment on SELENOP levels were observed (F = 7.414, P = 0.013). Further, a more significant reduction in the SELENOP levels was observed in the CCRT-resistant group (mean reduction, 0.028 µg/mL; P < 0.001) than in the sensitive group (mean reduction, 0.013 µg/mL; P = 0.006). Four metabolic biomarkers, i.e., C18, C19, C20 sphingomyelin, and phosphatidylcholine 20:2/22:6, were shown to be differentially expressed between the resistant and sensitive groups pre-and post-treatment. C20 sphingomyelin levels exhibited a significant correlation with SELENOP levels (r = −0.326, P = 0.031). ConclusionThe levels of plasma SELENOP in the CCRT-resistant group decreased significantly, suggesting that SELENOP might affect the sensitivity by modulating lipid synthesis and metabolism.

Elevated Selenoprotein P Levels in Thalassemia Major Patients

Previous studies have measured selenium levels and glutathione peroxidase 3 (GPX3) activity in patients with thalassemia major (TM). However, Selenoprotein P (SEPP), which is responsible for the storage and transport of selenium, has not been studied in thalassemia patients. This study aims to correlate thyroid functions of TM patients with their SEPP and GPX3 levels. Eighty subjects (40 controls, 40 TM patients) were included in this study. GPX3 and SEPP concentrations were measured in all subjects using sandwich ELISA. Iron, ferritin, urinary iodine, thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), anti-thyroid peroxidase (anti-TPO), and anti-human thyroglobulin (anti-hTG) concentrations were also measured. Mean SEPP concentration was higher in the TM group compared to the control group. A slight elevation in GPX3 levels was also observed in thalassemia patients, yet it was not statistically significant. In both TM patients and controls, ferritin was inversely correlated with free T4 concentration and GPX3 was inversely correlated with free T4 and T3 concentrations. There was also a negative correlation between SEPP and TSH concentrations in healthy subjects. This is the first study, which has measured SEPP concentrations in thalassemia patients. SEPP levels were higher in TM patients compared to controls. Correlations between thyroid hormones and selenoproteins may indicate that selenium is necessary for thyroid function. Detailed studies are required to elaborate the role of SEPP in thyroid metabolism in thalassemia patients.

Essential trace element selenium and redox regulation: its metabolism, physiological function, and related diseases

Graphical abstract Abstract The essential trace element selenium plays a significant role in redox homeostasis in the human body. Selenium is very reactive and has a potent toxicity; however, the living body cleverly utilizes its reactivity for redox reactions. The biological function of selenium is mainly mediated by selenoproteins, which contain selenocysteine, a cysteine analogue that possesses selenium instead of sulphur. Twenty-five types of human selenoproteins have been identified, including glutathione peroxidase (GPX; for the reduction of hydrogen peroxide and lipid hydroperoxide) and thioredoxin reductase (for redox regulation). Selenoprotein P (SELENOP), which is a major selenoprotein in the plasma, is mainly synthesized in the liver and secreted into the plasma. As a multifunctional protein with selenium-transporting activity, GPX-like activity, and metal-binding properties, SELENOP plays a vital role in selenium metabolism and redox regulation. This review focuses on the relationship between selenium metabolism and redox regulation, particularly on the physiological role of selenoproteins and the pathophysiological implications of its disorder. Furthermore, the significant roles of selenium in infectious diseases and its utility for phylaxis are discussed.

Associations between Circulating SELENOP Level and Disorders of Glucose and Lipid Metabolism: A Meta-Analysis.

Selenoprotein P (SELENOP) is an extracellular antioxidant, selenium transporter, and hepatokine interfering with glucose and lipid metabolism. To study the association between the circulating SELENOP concentration and glucose and lipid metabolic diseases (GLMDs), including gestational diabetes (GD), metabolic syndrome (MetS), non-alcoholic fatty liver disease, obesity, and type 2 diabetes, as well as the individual markers, a meta-analysis was conducted by searching multiple databases from their establishment through March 2022 and including 27 articles published between October 2010 and May 2021, involving 4033 participants. Participants with GLMDs had higher levels of SELENOP than those without GLMDs (standardized mean difference = 0.84, 95% CI: 0.16 to 1.51), and the SELENOP levels were positively correlated with the markers of GLMDs (pooled effect size = 0.09, 95% CI: 0.02 to 0.15). Subgroup analyses showed that the SELENOP concentrations were higher in women with GD and lower in individuals with MetS than their counterparts, respectively. Moreover, SELENOP was positively correlated with low-density lipoprotein cholesterol, but not with the other markers of GLMDs. Thus, the heterogenicity derived from diseases or disease markers should be carefully considered while interpreting the overall positive association between SELENOP and GLMDs. Studies with a larger sample size and advanced design are warranted to confirm these findings.

Selenium Status in Paediatric Patients with Neurodevelopmental Diseases.

Neurodevelopmental diseases are often associated with other comorbidities, especially inflammatory processes. The disease may affect the trace element (TE) status, which in turn may affect disease severity and progression. Selenium (Se) is an essential TE required for the biosynthesis of selenoproteins including the transporter selenoprotein P (SELENOP) and extracellular glutathione peroxidase (GPX3). SELENOP deficiency in transgenic mice resulted in a Se status-dependent phenotype characterized by impaired growth and disturbed neuronal development, with epileptic seizures on a Se-deficient diet. Therefore, we hypothesized that Se and SELENOP deficiencies may be prevalent in paediatric patients with a neurodevelopmental disease. In an exploratory cross-sectional study, serum samples from children with neurodevelopmental diseases (n = 147) were analysed for total serum Se, copper (Cu), and zinc (Zn) concentrations as well as for the TE biomarkers SELENOP, ceruloplasmin (CP), and GPX3 activity. Children with epilepsy displayed elevated Cu and Zn concentrations but no dysregulation of serum Se status. Significantly reduced SELENOP concentrations were found in association with intellectual disability (mean ± SD (standard deviation); 3.9 ± 0.9 mg/L vs. 4.4 ± 1.2 mg/L, p = 0.015). A particularly low GPX3 activity (mean ± SD; 172.4 ± 36.5 vs. 192.6 ± 46.8 U/L, p = 0.012) was observed in phacomatoses. Autoantibodies to SELENOP, known to impair Se transport, were not detected in any of the children. In conclusion, there was no general association between Se deficiency and epilepsy in this observational analysis, which does not exclude its relevance to individual cases. Sufficiently high SELENOP concentrations seem to be of relevance to the support of normal mental development. Decreased GPX3 activity in phacomatoses may be relevant to the characteristic skin lesions and merits further analysis. Longitudinal studies are needed to determine whether the observed differences are relevant to disease progression and whether correcting a diagnosed TE deficiency may confer health benefits to affected children.

Antagonistic Interaction of Selenium and Cadmium in Human Hepatic Cells Through Selenoproteins.

Cadmium (Cd) is a highly toxic heavy metal for humans and animals, which is associated with acute hepatotoxicity. Selenium (Se) confers protection against Cd-induced toxicity in cells, diminishing the levels of ROS and increasing the activity of antioxidant selenoproteins such as glutathione peroxidase (GPx). The aim of this study was to evaluate the antagonistic effect of selenomethionine (SeMet) against Cd toxicity in HepG2 cells, through the modulation of selenoproteins. To this end, the cells were cultured in the presence of 100 µM SeMet and 5 μM, 15 µM, and 25 µM CdCl2 and a combination of both species for 24 h. At the end of the experiment, cell viability was determined by MTT assay. The total metal content of Cd and Se was analyzed by triple-quadrupole inductively coupled plasma–mass spectrometry (ICP-QqQ-MS). To quantify the concentration of three selenoproteins [GPx, selenoprotein P (SELENOP), and selenoalbumin (SeAlb)] and selenometabolites, an analytical methodology based on column switching and a species-unspecific isotopic dilution approach using two-dimensional size exclusion and affinity chromatography coupled to ICP-QqQ-MS was applied. The co-exposure of SeMet and Cd in HepG2 cells enhanced the cell viability and diminished the Cd accumulation in cells. Se supplementation increased the levels of selenometabolites, GPx, SELENOP, and SeAlb; however, the presence of Cd resulted in a significant diminution of selenometabolites and SELENOP. These results suggested that SeMet may affect the accumulation of Cd in cells, as well as the suppression of selenoprotein synthesis induced by Cd.

Autoimmunity to selenoprotein P predicts breast cancer recurrence

BackgroundLow concentrations of serum selenium (Se) and its main transporter selenoprotein P (SELENOP) are associated with a poor prognosis following breast cancer diagnosis. Recently, natural autoantibodies (aAb) with antagonistic properties to SELENOP uptake have been identified in healthy subjects, and in patients with thyroid disease. Given the potential transport disrupting properties, we hypothesized that breast cancer patients with SELENOP-aAb may have a poor prognosis. MethodsSELENOP-aAb along with serum Se, SELENOP and GPX3 activity were determined in serum samples of 1988 patients with a new diagnosis of breast cancer enrolled in the multicentre SCAN-B study. Patients were followed for ∼9 years and multivariate Cox regression models were applied to assess hazard ratios. ResultsApplying a cut-off based on outlier detection, we identified 7.65% of patients with SELENOP-aAb. Autoantibody titres correlated positively to total Se and SELENOP concentrations, but not to GPX3 activity, supporting a negative role of SELENOP-aAb on Se transport. SELENOP-aAb were associated with age, but independent of tumor characteristics. After fully adjusting for potential confounders, SELENOP-aAb were associated with higher recurrence, HR(95%CI) = 1.87(1.17–2.99), particularly in patients with low Se concentrations, HR(95%CI) = 2.16(1.20–3.88). Associations of SELENOP-aAb with recurrence and mortality were linear and dose-dependent, with fully adjusted HR(95%CI) per log increase of 1.25(1.01–1.55) and 1.31(1.13–1.51), respectively. ConclusionOur results indicate a prognostic and pathophysiological relevance of SELENOP-aAb in breast cancer, with potential relevance for other malignancies. Assessment of SELENOP-aAb at time of diagnosis identifies patients with a distinctly elevated risk for a poor prognosis, independent of established prognostic factors, who may respond favourably to Se supplementation.

Role of selenoprotein P expression in the function of pancreatic β 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 β cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic β 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 β cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic β cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK.

Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species.

Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the α8β1 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4+ T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4+ T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.