Selenoprotein P Levels Research Articles

ACCELERATED PACE OF BIOLOGICAL AGING IN PARTICIPANTS WITH LOW LEVELS OF SELENIUM BIOMARKERS IN BERLIN AGING STUDY II

Abstract Low levels of selenium in blood were shown to be associated with adverse health outcomes and are discussed as anti-aging interventions by some investigators. Inter-individual differences in the aging process can be quantified by epigenetic clocks (DNA methylation age, DNAmA). In this study, we analyzed 1,568 participants of the Berlin Aging Study II (BASE-II, mean age +/- SD: 68.8 +/- 3.7 years, 51% women). DNAmA, and its deviation from chronological age, DNAmA acceleration (DNAmAA), were measured from DNA methylation data derived from Illumina’s “MethylationEPIC” array via the Horvath, GrimAge, and DunedinPACE clock algorithms. Selenium was measured in serum samples via total reflection X-ray fluorescence (TXRF) spectroscopy. Selenoprotein P (SELENOP) was measured with ELISA. GPX3 was assessed as part of a larger set of proteins by mass spectrometry. A statistically significantly higher pace of ageing (using the DunedinPACE clock) was observed for participants with deficient selenium levels (< 90 μg/L). This association persisted after adjustment for age, sex, BMI, smoking, and genetic ancestry in linear regression (β=-0.02, SE=0.01, p= 0.012; n=757). Similarly, participants in the highest quartile of SELENOP levels showed a statistically significantly lower pace of ageing compared to the lowest quartile (DunedinPACE, β=-0.03, SE=0.01, p=0.007; n=740). Participants within the lowest quartile of GPX3 levels showed statistically significantly higher rates of biological ageing compared to the participants in the third quartile (HorvathDNAmAA, p=0.04), the fourth quartile (GrimAgeDNAmAA, p=0.003) or both quartiles combined (DunedinPACE, p=0.002). In conclusion, our findings support previous reports of potentially detrimental effects of low levels of selenium biomarkers.

Selenium biomarkers and miR‐7‐5p in overweight/obese women

IntroductionChronic low-grade inflammation and oxidative stress are pivotal contributors to the metabolic complications associated with obesity. Selenoprotein P (SELENOP) and glutathione peroxidase 1 (GPx1) are selenoproteins involved in the reduction of reactive oxygen species and pro-inflammatory cytokines levels. Nutritional epigenomics revealed the interaction of microRNAs and nutrients with an important impact on metabolic pathways involved in obesity. However, the knowledge regarding the influence of microRNA on selenium biomarkers and its impact on metabolic pathways related to obesity remains scarce. Thus, the aim of this study was to investigate the association of plasma miR‐7‐5p expression with selenium and inflammatory biomarkers in women with overweight/obesity. Material and methodsAnthropometric evaluations were performed and blood samples were collected for the analysis of fasting glucose, insulin, inflammatory and selenium biomarkers, and miR-7–5p expression in 54 women with overweight/obesity. Gene expression of SELENOP and GPX1 were evaluated in peripheral mononuclear blood cells. ResultsThis study observed a negative correlation between SELENOP levels and miR-7–5p (rho = −0.350; p = 0.018). Additionally, it was observed that body fat (OR = 0.737; p = 0.011), age (OR = 1.214; p = 0.007), and miR‐7‐5p (OR = 0.990; p = 0.015) emerged as significant predictors of SELENOP levels. ConclusionsIn conclusion, we observed a significant inverse association between miR‐7‐5p expression and SELENOP concentration in overweight/obese women, suggesting that age and percentage of body fat are also associated. Trial registration numberBrazilian Registry of Clinical Trials (ReBEC) number RBR-2nfy5q

Exploring Selenoprotein P in Liver Cancer: Advanced Statistical Analysis and Machine Learning Approaches.

Selenoprotein P (SELENOP) acts as a crucial mediator, distributing selenium from the liver to other tissues within the body. Despite its established role in selenium metabolism, the specific functions of SELENOP in the development of liver cancer remain enigmatic. This study aims to unravel SELENOP's associations in hepatocellular carcinoma (HCC) by scrutinizing its expression in correlation with disease characteristics and investigating links to hormonal and lipid/triglyceride metabolism biomarkers as well as its potential as a prognosticator for overall survival and predictor of hypoxia. SELENOP mRNA expression was analyzed in 372 HCC patients sourced from The Cancer Genome Atlas (TCGA), utilizing statistical methodologies in R programming and machine learning techniques in Python. SELENOP expression significantly varied across HCC grades (p < 0.000001) and among racial groups (p = 0.0246), with lower levels in higher grades and Asian individuals, respectively. Gender significantly influenced SELENOP expression (p < 0.000001), with females showing lower altered expression compared to males. Notably, the Spearman correlation revealed strong positive connections of SELENOP with hormonal markers (AR, ESR1, THRB) and key lipid/triglyceride metabolism markers (PPARA, APOC3, APOA5). Regarding prognosis, SELENOP showed a significant association with overall survival (p = 0.0142) but explained only a limited proportion of variability (~10%). Machine learning suggested its potential as a predictive biomarker for hypoxia, explaining approximately 18.89% of the variance in hypoxia scores. Future directions include validating SELENOP's prognostic and diagnostic value in serum for personalized HCC treatment. Large-scale prospective studies correlating serum SELENOP levels with patient outcomes are essential, along with integrating them with clinical parameters for enhanced prognostic accuracy and tailored therapeutic strategies.

Diagnostic and prognostic values of serum Selenoprotein P and soluble St2 levels in pulmonary embolism

AimPulmonary Thromboembolism (PTE) occurs as a result of occlusion of one or more of the pulmonary artery branches by thrombus and is an important cause of right heart failure and pulmonary hypertension. Selenoprotein P (SePP) and soluble suppression of tumorigenicity 2 protein (sST2) are two new biomarkers that have previously been the subject of various studies in heart failure. The aim of this study was to determine the diagnostic and prognostic potential of SePP and soluble sST2 levels in patients with acute PTE. Materials and MethodsThe study included 135 patients diagnosed with acute non-massive PTE and 43 healthy volunteers. Clinical, laboratory, and radiological patient data were recorded. SePP and sST2 levels were measured in the patient and control groups. Patients were followed at 1, 3, and 6 months of treatment via the death notification system and telemedicine. ResultsSePP and sST2 levels were significantly lower in the patient group compared with the control group (SePP: 17.65 ng/ml vs. 43.06 ng/ml and sST2: 10.86 ng/ml vs. 16.20 ng/ml, both p < 0.001). No correlation was found at 1, 3, and 6 months of follow-up with prognosis and mortality. ConclusionSePP and sST2 values were significantly lower in patients with acute PTE compared with the control group. Low levels of these biomarkers may be diagnostically valuable.

Low Levels of Selenoprotein P Are Associated With Cognitive Impairment in Patients Hospitalized for Heart Failure

Selenoprotein P (SELENOP) is a transporter for selenium and has been shown to protect selenium-status maintenance in the brain against deficiency and to support neuronal development, neurogenesis and neurocognitive function. Selenium deficiency has previously been associated with cognitive impairment in various populations, but no studies have been carried out in subjects with heart failure (HF). To explore whether SELENOP deficiency in subjects with acute HF is associated with cognitive impairment. Plasma SELENOP, as measured by an immunoassay analysis, is a well-validated marker of plasma selenium status and has the benefit of providing information on the bioavailable fraction of selenium to preferentially supplied cells equipped with receptors for SELENOP uptake. SELENOP was measured in 320 subjects hospitalized for HF. Of the subjects, 187 also underwent 4 cognitive tests assessing global cognitive function: Montreal Cognitive Assessment (MoCA); information processing (Symbol Digit Modalities Test [SDMT]); visual attention and task switching (Trailmaking Test A [TMT-A]); and executive speed (A Quick Test of Cognitive Speed [AQT] form and color). Appropriate cutoffs were used for each cognitive test to define cognitive impairment. Cross-sectional associations between SELENOP concentrations and cognitive impairment, as defined by each cognitive test, were explored using multivariable logistic models. Further, multivariable logistic models exploring associations between selenium deficiency, defined as the lowest quartile of SELENOP levels, and cognitive impairment, defined by each cognitive test, were carried out. The 187 participants had a mean age of 73 (± 11.9) years; 31% were female and had a mean body mass index of 28.1 (± 5.6) kg/m2. Each 1 standard deviation increment in SELENOP concentrations was associated with lower odds of cognitive impairment, defined as a MoCA cut-off score < 23 (odds ratio [OR] 0.60; 95% CI 0.40-0.91; P = 0.017). Further, SELENOP concentrations in the lowest quartile (≤ 2.3 mg/L) were associated with cognitive impairment as measured by MoCA (OR 3.10; 95% CI 1.38-6.97; P = 0.006), SDMT (OR 2.26; 95% CI 1.10-4.67; P = 0.027) and TMT-A (OR 3.40; 95% CI 1.47-7.88; P = 0.004) but not by AQT form and color. In subjects admitted for HF, higher SELENOP concentrations were associated with better performance on the MoCA test, reflecting global cognition, and SELENOP deficiency was associated with cognitive impairment as defined by 3 cognitive tests.

Selenium speciation studies in cancer patients to evaluate the responses of biomarkers of selenium status to different selenium compounds

This work presents the first systematic comparison of selenium (Se) speciation in plasma from cancer patients treated orally with three Se compounds (sodium selenite, SS; L-selenomethionine, SeMet; or Se-methylselenocysteine, MSC) at 400 µg/day for 28 days. The primary goal was to investigate how these chemical forms of Se affect the plasma Se distribution, aiming to identify the most effective Se compound for optimal selenoprotein expression. This was achieved using methodology based on HPLC-ICP-MS after sample preparation/fractionation approaches. Measurements of total Se in plasma samples collected before and after 4 weeks of treatment showed that median total Se levels increased significantly from 89.6 to 126.4 µg kg−1 Se (p < 0.001), particularly when SeMet was administered (190.4 µg kg−1 Se). Speciation studies showed that the most critical differences between treated and baseline samples were seen for selenoprotein P (SELENOP) and selenoalbumin after administration with MSC (p = 5.8 × 10−4) and SeMet (p = 6.8 × 10−5), respectively. Notably, selenosugar-1 was detected in all low-molecular-weight plasma fractions following treatment, particularly with MSC. Two different chromatographic approaches and spiking experiments demonstrated that about 45% of that increase in SELENOP levels (to ~ 8.8 mg L−1) with SeMet is likely due to the non-specific incorporation of SeMet into the SELENOP affinity fraction. To the authors’ knowledge, this has not been reported to date. Therefore, SELENOP is probably part of both the regulated (55%) and non-regulated (45%) Se pools after SeMet administration, whereas SS and MSC mainly contribute to the regulated one.Graphical abstract

Selenium deficiency is associated with anemia in heart failure patients - The HARVEST Study

Abstract Background Heart failure (HF) patients with anemia have worse clinical outcomes with increased hospitalization rates, decreased exercise tolerance, and higher mortality compared to those without anemia. Previous studies have indicated a correlation between selenium deficiency and anemia in healthy elderly individuals and in pregnant women. The BIOSTAT-CHF study reported that HF patients with higher selenium levels were less likely to have anemia or iron deficiency. These studies suggest that selenium deficiency can lead to the development of anemia. However, studies regarding this association in HF patients are limited. Purpose The purpose of this study was to examine the relationship between selenium deficiency, measured by selenoprotein P (SELENOP) levels, and anemia, hemoglobin levels, and iron state in subjects with acute HF. Methods SELENOP, a well-validated plasma marker of selenium status, was measured in 320 subjects hospitalized for HF in the Swedish HeArt and bRain failure inVESTigation trial (the HARVEST study). Of these subjects, 310 had complete data on all covariates. Prior to analyses, skewed variables were ln-transformed. The relationships between continuous SELENOP levels and 1) Hb levels, 2) anemia (Hb &amp;lt; 115 g/L (women), &amp;lt; 130 g/L (men)), and 3) iron status (as measured by transferrin receptor 1 (TfR1) which increase in iron deficiency) were evaluated using multivariable logistic and linear regression models adjusting for age, sex and renal function (cystatin C). Additionally, selenium deficiency was defined as SELENOP levels in the lowest quartile and its association with anemia, hemoglobin, and iron state was explored in multivariable logistic and linear models. Results Anemia was present in 133 subjects (42.9%). SELENOP levels were positively correlated with hemoglobin levels (0.238; p = 2.3x10-5) and negatively associated with TfR1 levels (-0.238, p = 2.0x10-6). In multivariable linear regression models, each 1 standard deviation increase in SELENOP was linked to higher Hb levels and lower TfR1 levels (Table 1). Furthermore, selenium deficiency was associated with lower Hb levels, higher TfR1 levels, and higher odds of anemia in HF patients (Table 1). Conclusions In acute heart failure patients, lower levels of selenoprotein P were associated with lower hemoglobin levels, higher transferrin receptor 1 levels, and a higher prevalence of anemia.

Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2

Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.

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

IntroductionSelenium deficiency has been associated with mortality, cardiovascular disease and worsened prognosis in heart failure (HF). In a recent population-based study, high selenium levels were shown to be associated with reduced mortality and reduced incidence of HF, but only in non-smokers. Here, we aimed to examine if selenoprotein P (SELENOP), a main selenium carrier protein, is associated with incident HF. Materials and methodsSELENOP concentrations were measured in plasma of 5060 randomly selected subjects from the population-based prospective cohort “Malmö Preventive Project” (n = 18240) using an ELISA approach. Exclusion of subjects with prevalent HF (n = 230) and subjects with missing data on co-variates included in the regression analysis (n = 27) resulted in complete data for 4803 subjects (29.1% women, mean age 69.6 ± 6.2 years, 19.7% smokers). Cox regression models adjusted for traditional risk factors were used to analyse SELENOP's association with incident HF. Further, subjects within the quintile with the lowest SELENOP concentrations were compared to subjects in the remaining quintiles. ResultsEach 1 standard deviation increment in SELENOP levels was associated with lower risk of incident HF (n = 436) during a median follow-up period of 14.7 years (hazard ratio (HR) 0.90; CI95% 0.82–0.99; p = 0.043). Further analyses showed that subjects in the lowest SELENOP quintile were at the highest risk of incident HF when compared to quintiles 2–5 (HR 1.52; CI95% 1.21–1.89; p = 2.5 × 10−4). ConclusionLow selenoprotein P levels are associated with a higher risk of incident HF in a general population. Further studies are warranted.

Association of Serum Selenium and Selenoprotein P with Oxidative Stress Biomarkers in Patients with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age which is characterized by various reproductive and metabolic disorders. Oxidative stress (OS) is now recognized to be involved in the pathogenesis of PCOS which could be targeted in the management of PCOS-related complications. Selenium (Se), as an antioxidant trace element, has been shown to decrease in PCOS patients. This study aimed to investigate the relationship between the Se and selenoprotein P (SELENOP) levels with OS markers in women with PCOS. In this cross-sectional study, 125 females aged 18-45 years diagnosed with PCOS were included. Demographic, clinical, and lifestyle information of participants were obtained using the relevant questionnaires. Fasting blood samples were collected to measure biochemical parameters. Serum levels of thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities as well as anthropometric measurements were assessed across tertiles of serum concentrations of Se and SELENOP. Higher serum levels of Se were associated with higher serum TAC levels (β=0.42, P<0.001) and erythrocytes GPx activity (β=0.28, P=0.002) as well as with lower serum TBARS levels (β= -0.26, P=0.003). Similarly, higher serum levels of SELENOP were associated with higher TAC (β=0.32, P<0.001) and erythrocyte GPx activity (β=0.30, P=0.001). SELENOP also showed an inverse association with serum levels of TBARS (β= -0.40, P<0.001). Nevertheless, erythrocytes SOD and CAT activities showed no significant relationships with serum Se and SELENOP concentrations (all P>0.05). The present study found that serum Se and SELENOP levels were inversely associated with TBARS levels and positively associated with TAC levels and erythrocytes GPx activity.

Excessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P

Selenium homeostasis depends on hepatic biosynthesis of selenoprotein P (SELENOP) and SELENOP-mediated transport from the liver to e.g. the brain. In addition, the liver maintains copper homeostasis. Selenium and copper metabolism are inversely regulated, as increasing copper and decreasing selenium levels are observed in blood during aging and inflammation. Here we show that copper treatment increased intracellular selenium and SELENOP in hepatocytes and decreased extracellular SELENOP levels. Hepatic accumulation of copper is a characteristic of Wilson’s disease. Accordingly, SELENOP levels were low in serum of Wilson’s disease patients and Wilson’s rats. Mechanistically, drugs targeting protein transport in the Golgi complex mimicked some of the effects observed, indicating a disrupting effect of excessive copper on intracellular SELENOP transport resulting in its accumulation in the late Golgi. Our data suggest that hepatic copper levels determine SELENOP release from the liver and may affect selenium transport to peripheral organs such as the brain.

Selenium level correlates negatively with antibodies but positively with thyroid function in children with down syndrome: an Indonesian study.

Children with Down syndrome (DS) are prone to developing autoimmune thyroid disease (AITD). Previous studies found lower selenium (Se) levels in children with AITD. Glutathione peroxidase-3 (GPx3) and selenoprotein-P (SePP) are widely used to measure Se levels. DS children tend to have lower Se levels, the main contributor to hypothyroidism in this population. This study aimed to analyze the Se's role in AITD in Indonesian children with DS. This cross-sectional study was conducted between February 2021-June 2022 at the Pediatric Outpatient Clinic of Dr Soetomo Hospital. DS children aged 1 month to 18 years were enrolled using consecutive sampling. Thyroid-stimulating hormone, free thyroxine, thyroid peroxidase (TPO-Ab) and thyroglobulin (Tg-Ab) autoantibody, GPx3, and SePP levels were measured in plasma samples using enzyme-linked immunosorbent assays. Statistical analyses used Chi-square, Mann-Whitney, and Spearman's rank correlation (r s). All results with p<0.05 were considered statistically significant. Among 62 children with DS, SePP and GPx3 levels were significantly lower in those with AITD than those without AITD (p=0.013 and p=0.018, respectively). SePP and GPx3 levels correlated significantly with lower TPO-Ab (r s=-0.439 with p=1×10-5 and r s=-0.396 with p=0.001, respectively) and Tg-Ab (r s=-0.474 with p=1×10-5 and r s=-0.410 with p=0.001, respectively) levels. SePP levels correlated significantly with lower thyroid dysfunction incidence (r s=-0.252, p=0.048) in the AITD group. Selenium deficiency contributes to autoimmune process in the thyroid and to thyroid dysfunction in children with Down syndrome. Our findings recommend increasing Se levels through Se-containing foods to reduce the risks of AITD and thyroid dysfunction in DS children with AITD.

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.

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.

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.

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.

A County-Level Spatial Study of Serum Selenoprotein P and Keshan Disease.

BackgroundKeshan disease (KD) is strongly associated with selenium deficiency. Selenoprotein P (SELENOP) is a recognized molecular biomarker of selenoproteins and an important indicator of selenium nutrition. This study was aimed at providing geographically precisely visualized evidence of selenium nutrition at molecular level for assessing KD prevention, control, and elimination on the etiological perspective.MethodsWe used spatial ecological design for this study. The serum SELENOP levels of the residents were measured by ELISA. ArcGIS version 9.0 was used for spatial description, spatial autocorrelation analysis of SELENOP levels and spatial regression with per capita disposable income.ResultsThe mean serum SELENOP levels of the 6,382 residents in 1,688 counties were 4.62 ± 1.82 μg/mL. The mean serum SELENOP levels of the residents living in the townships and rural areas of KD endemic counties were not statistically significantly lower than those of the KD non-endemic counties. The mean serum SELENOP levels were globally clustered (Moran's I = 0.03, z = 6.37, and P < 0.0001), and 99.3% (553/557) of the cold spots, identified by local autocorrelation analysis (Getis-Ord-Gi* analysis), were located in the KD endemic provinces of Shaanxi, Shanxi, Henan, Hebei, Shandong, Inner Mongolia, Gansu, Hubei, Chongqing, Yunnan, and Sichuan. The serum SELENOP level was positively correlated with per capita disposable income (t = 3.52, P = 0.0004).ConclusionsThe results of this study were the geographically precisely visualized evidence of selenium nutrition at molecular level for assessing KD elimination on the etiological perspective. The cold spot counties found by Getis-Ord-Gi* analysis in the KD endemic provinces should be the high priority of KD precision prevention and control.