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• Selenium deficiency has been linked to worse cognitive function in several populations, but no studies have been carried out in patients with heart failure. • SELENOP (selenoprotein P) is a transporter of selenium and plays a role in maintaining selenium levels in the brain, preventing neuronal damage and degeneration. • Higher levels of SELENOP were associated with better global cognitive function. • SELENOP deficiency (≤ 2.3 mg/L) was associated with cognitive impairment in the same tests. • SELENOP may play a role in preserving cognitive function in patients with heart failure, whereas SELENOP deficiency may contribute to cognitive impairment. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective To establish the association of the SEPP1 gene's (rs7579) polymorphism with enzymatic, metabolic and hormonal activity in patients with chronic pancreatitis (CP) and primary hypothyroidism. Materials and methods Eighty CP patients (40 with comorbid hypothyroidism) and 30 healthy controls participated in the case-control study. Pancreatic enzymes, Selenoprotein P, NO metabolites (NO2-+NO3-), glucose, total cholesterol (TC), triglycerides (TG) and low/high density lipoprotein cholesterol (LDL-, HDL-C), Atherogenicity Index (AI), thyroid-stimulating hormone (TSH), Thyroxine (T4), glomerular filtration rate (GFR) were studied. SEPP1 (rs7579) genotyping performed by PCR (FlexCycler BU). Results and discussion SEPP1 (rs7579) gene's A-allele increases the risk of hypothyroidism twice in CP [OR=2.0; OR 95%CI:1.09-3.66; p=0.023]. Pancreatic patients with hypothyroidism and SEPP1 gene's (rs7579) AA-genotype had 60.0% (pAA=0.013) lower elastase and 13.78% (p=0.003) higher α-amylase as well as TSH by 10.81% (pAA=0.009) and 15.64% (pAA=0.009), especially in women 14.55-45.18% (p<0.001) at a lower value of Selenoprotein P - by 28.65-48.08% (p≤0.048) regardless of the SEPP1 gene (rs7579) variants. Women have 17.43-18.14% (pW≤0.032) higher NO metabolites than men; A-allele women have free T4 value 2.62 times lower (pGG=0.01) than GG-women and 2.97 times lower (pW=0.011) than men. Comorbid patients with A-allele had elevated TC and LDL-C, by 11.77-26.45% (pAA≤0.01) and 18.06-26.21% (pAA≤0.019), respectively. Women have 54.50% (pW=0.002) higher AI with 39.30% lower (pW=0.034) Selenoprotein P and 21.96-24.56% (pW≤0.033) GFR than men. Conclusion SEPP1 (rs7579) gene polymorphism influences the risk of hypothyroidism in CP patients, changes of pancreatic enzymes, dyslipidaemia particular in AA-genotype carriers, mainly women. There was no dependence of SEPP1 and total NO metabolites values on the SEPP1 gene (rs7579) polymorphism. [ABSTRACT FROM AUTHOR]

Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). Selenoprotein P is a protein with antioxidant properties but has not been investigated in the context of DSPN. This study aimed to assess the associations between selenoprotein P and DSPN in people without and with type 2 diabetes (T2D). Cross-sectional and prospective analyses were based on 1053 (including 217 with T2D) and 513 participants (including 79 with T2D), respectively, aged 61–82 years from the population-based KORA F4 survey. DSPN at baseline (KORA F4) and in the follow-up survey KORA FF4 was defined based on the Michigan Neuropathy Screening Instrument. Serum levels of full-length selenoprotein P were quantified by ELISA. Associations between selenoprotein P and prevalent or incident DSPN were estimated using logistic regression analysis adjusting for multiple confounders. Selenoprotein P levels were not associated with prevalent DSPN in the total sample. However, there was a significant interaction by diabetes status. Higher levels of selenoprotein P were associated with lower odds of prevalent DSPN in individuals without T2D (fully adjusted model: OR 0.825 [95 % CI 0.682, 0.998], p = 0.0476), but not in those with T2D (OR [95 % CI] 1.098 [0.829, 1.454], p = 0.5132; p interaction = 0.0488). Selenoprotein P levels were not associated with incident DSPN over a follow-up of 6.5 years. In individuals without T2D from the older general population, lower selenoprotein P levels were associated with a higher prevalence of DSPN. Whether the antioxidant properties of selenoprotein P are responsible for the observed associations remains to be elucidated in future research. [Display omitted] • Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). • Selenoprotein P (SeP) has antioxidant properties but its association with DSPN is unknown. • Lower serum SeP levels were associated with a higher prevalence of DSPN in people without diabetes. • In people with type 2 diabetes, this inverse association was not seen. [ABSTRACT FROM AUTHOR]

Selenoprotein P (SELENOP) transports selenium to extrahepatic tissues and is a biomarker of selenium status. Low soil selenium leads to low dietary selenium intake. A consequence is an increased risk of cardiovascular disease. To investigate clinical aspects associated with SELENOP deficiency, including biomarkers of inflammation, quality of life, and mortality within 12 years, and the effect of dietary selenium and coenzyme Q 10 supplementation on SELENOP. SELENOP was determined at inclusion and after four years of supplementation in 403 elderly community-living participants low in selenium receiving selenium yeast (200 μg/day) and coenzyme Q 10 (200 mg/day), or placebo. Pre-intervention, the average serum selenium level was 67 μg/L. T-tests, repeated measures of variance, Cox proportional regressions analyses, Kaplan-Meier graphs and ANCOVA analyses were applied. Associations with biomarkers of inflammation, telomere length, quality of life and mortality were investigated. Benchmark modelling was used to determine the serum selenium concentration at which the saturation levels of SELENOP and GPx3 was achieved. Comparison with GPx3 and serum selenium to identify increased mortality risk was performed, and the effect of supplementation on SELENOP levels were evaluated. Inverse associations were observed between the level of SELENOP at inclusion and biomarkers for inflammation. At follow-up, shorter telomere lengths were seen in those with low levels of SELENOP at inclusion, whereas high levels of SELENOP were associated with better quality of life and decreased mortality. SELENOP had increased prognostic power compared to GPx3 and selenium. Saturation of SELENOP was achieved at a serum selenium level of 146 μg/L, and for GPx3 at 99 μg/L. Supplementation induced higher levels of SELENOP. Significant associations between SELENOP and inflammation, length of telomeres, quality of life, and mortality were observed. Thus, selenium supplementation improved SELENOP expression, thereby facilitating systemic selenium bioavailability and resulting in the observed positive health effects. [Display omitted] • Low and decreasing selenoprotein P (SELENOP) status in elderly subjects associated with all-cause and cardiovascular mortality. • Low SELENOP was associated with increased telomere attrition and impaired quality of life. • Randomized controlled intervention with selenium and coenzymeQ10 raised serum SELENOP. • Increased SELENOP associated with reduced telomere attrition, mortality, and improved quality of life. • SELENOP may translate the applied supplements into improved selenium transport, status and health benefits. [ABSTRACT FROM AUTHOR]

Introduction: fertility is necessary for hatchability of broiler breeder eggs. Roosters as half part of the fertility have a great role and with increasing age fertility is declined. It has been revealed that phospholipid fraction of the avian spermatozoa membranes has high proportion of polyunsaturated fatty acids (PUFA) and it is the reason why the spermatozoa are susceptible to free radical damages. To maintain sperm fertilizing ability, an antioxidant defense system is a crucial point. In avian semen the antioxidant system consists of natural antioxidants together with enzymes that have antioxidant characteristics such as glutathione peroxidase (GPx) and selenoprotein P (SEPP1) protects sperm against free radicals and their destructive metabolites. Antioxidants such as vitamin E and selenium (Se) have remarkable roles in avian reproduction. To gain great reproductive performances in breeders, optimum level of antioxidant in diet is thought to be necessary. By using additives such as selenium (Se) we can help delaying this reduction through antioxidant properties of Se. Replacing inorganic Se by new source of Se like the nano form in poultry diets can improve the fertility of broiler breeder eggs. This research was conducted to investigate the effect of Nano-Selenium (NanoSe) in comparison with sodium selenite on serum selenoprotein p (SEPP1) and glutathione peroxidase (GPx) content in broiler breeder roosters. Material and Method: A total of thirty Arbor Acres broiler breeder roosters (40 wks.) were randomly divided into five experimental groups. Each of which included 3 replicates of 2 birds. According to the arbor acres broiler breeder manual, the amount of 160 grams of diet was allocated daily for each rooster which had 12% crude protein and 2800 kcal/kg metabolizable energy. After one-week adaptation, birds were fed the corn-soybean meal-based basal diet (T1) supplemented with 0.3 mg/kg Sodium Selenite (T2), 0.15 mg/kg nano-Se (T3), 0.3 mg/kg nano-Se (T4) and 0.6 mg/kg nano-Se (T5). The duration of feeding experiment was four weeks. After the adaptation period, a 2.5 ml of blood sample was taken from each rooster. Two weeks later, in the middle of the research, blood sampling was done again from each bird. Four weeks after the treatment was done at the end of experiment, the roosters were humanely euthanized by cervical dislocation, the 3rd and last sampling was implemented at the end of experiment that as in the previous sampling was done, the blood samples were centrifuged and separated serum was stored in -20°C . Then serum concentration of the antioxidant “SEPP1” was measured by ELISA method and “GPx” was analyzed using a spectrophotometry kit. Results and discussion: By increasing the level of nanoselenium in diet, the serum concentration of SEPP1 and GPx also increases (P < 0.05) and using 0.6 mg/kg nano-Se in the diet reached the highest value. Based on a consideration of all experiment indexes, in this research, 0.6 mg/kg is suggested to be the best level of supplementation of nano-Se, and nano-Se showed higher contents of serum SEPP1 and GPx at the same amounts of nano-Se and sodium selenite supplementation. In conclusion, dietary supplementation of nano-Se was more effective than sodium selenite on serum SEPP1 and GPx concentration of tested selenoproteins in broiler breeder males. [ABSTRACT FROM AUTHOR]

Simple Summary: This research explores the role of selenoprotein P, a protein crucial for transporting selenium in the body, in liver cancer. The study aims to understand how selenoprotein P levels relate to the severity of hepatocellular carcinoma and its impact on patient outcomes. Findings indicate that selenoprotein P expression varies significantly with cancer stage and patient demographics like race and gender. It also correlates strongly with hormone and lipid metabolism markers. Importantly, selenoprotein P shows potential as a predictor of patient survival and as a biomarker for hypoxia, a condition affecting cancer progression. These insights may lead to better diagnostic tools and personalized treatments for liver cancer, emphasizing the need for further studies to validate selenoprotein P's clinical utility in real-world settings. 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. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG). Methods: We recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). Results: Changes in LECT2 were correlated with the percentage of total weight loss (ρ = − 0.499, P = 0.024) and the decrease in total fat area (ρ = 0.559, P = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P = 0.043) and the insulinogenic index (ρ = 0.638, P = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601). Conclusions: SeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications. [ABSTRACT FROM AUTHOR]

Abstract Aims Heart failure (HF) patients with anaemia tend to have a worse outcome, with increased hospitalization rates, decreased exercise tolerance, and higher mortality compared to those without anaemia. Limited research exists on the association between selenium deficiency and anaemia specifically in HF patients, despite previous findings of a correlation in different populations. The BIOSTAT‐CHF study demonstrated that higher selenium levels in HF patients were associated to a lower risk of anaemia and iron deficiency. This study investigates the relationship between selenoprotein P (SELENOP) concentrations, a major contributor and functional biomarker of selenium transport, and anaemia, Hb levels, and iron status in hospitalized HF patients. Methods and results SELENOP was analysed in 320 hospitalized HF subjects, with complete data available for 310 subjects. The relationships between continuous SELENOP concentrations and 1) Hb concentrations, 2) anaemia (Hb

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) patients with anaemia tend to have a worse outcome, with increased hospitalization rates, decreased exercise tolerance, and higher mortality compared to those without anaemia. Limited research exists on the association between selenium deficiency and anaemia specifically in HF patients, despite previous findings of a correlation in different populations. The BIOSTAT‐CHF study demonstrated that higher selenium levels in HF patients were associated to a lower risk of anaemia and iron deficiency. This study investigates the relationship between selenoprotein P (SELENOP) concentrations, a major contributor and functional biomarker of selenium transport, and anaemia, Hb levels, and iron status in hospitalized HF patients. Methods and results: SELENOP was analysed in 320 hospitalized HF subjects, with complete data available for 310 subjects. The relationships between continuous SELENOP concentrations and 1) Hb concentrations, 2) anaemia (Hb < 115 g/L (women), <130 g/L (men)), and 3) iron status (as measured by transferrin receptor 1 (TfR1) which increases in iron deficiency) were evaluated using multivariable logistic and linear regression models. Additionally, SELENOP concentrations in the lowest quartile were related to anaemia, haemoglobin, and iron state in multivariable logistic and linear models. The mean age of the study population was 75.0 ± 11.6 years, and 30% were women. Anaemia was present in 133 subjects (42.9%). SELENOP concentrations were positively correlated with haemoglobin concentrations (0.238; P < 0.001) and negatively with TfR1 concentrations (−0.238, P < 0.001). In multivariable regression models, higher SELENOP concentrations were associated with higher Hb concentrations (B = 3.23; P = 0.002) and lower TfR1 concentrations (B = −0.20; P < 0.001). Furthermore, SELENOP deficiency was associated with lower Hb concentrations (B = −7.64: P = 0.001), higher TfR1 concentrations (B = 0.31; P = 0.003), and higher odds of anaemia in HF patients (odds ratio 2.17; 95% confidence interval 1.23–3.82; P = 0.008). Conclusions: In hospitalized heart failure patients, lower concentrations of SELENOP were associated with higher prevalence of anaemia. [ABSTRACT FROM AUTHOR]

Non‐invasive transcranial direct‐current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se‐dependent signalling in rat cerebral ischaemia–reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct‐current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen‐glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R‐insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R‐insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality‐control signalling, vesicle‐associated membrane protein 2 (VAMP2) and syntaxin‐4 (STX4), in OGD/R‐insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS‐ and BtDCS‐induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. Key points: Cathodal bilateral transcranial direct‐current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra.Se plays a crucial role in cerebral ischaemia injury.Direct‐current stimulation reduces mitochondria injury and blocks the reduction of vesicle‐associated membrane protein 2 (VAMP2) and syntaxin‐4 (STX4) in oxygen‐glucose deprivation reoxygenation‐insulted neurons following coculturing with astrocytes.Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the relationship between selenoprotein P, peroxiredoxin-5, renalase, total antioxidant status (TAS), mean blood pressure (mBP), and apnea-hypopnea index (AHI). Methods: The study group consisted of 112 patients hospitalized to verify the diagnosis of obstructive sleep apnea (OSA). The inclusion criteria were consent to participate in the study and age ≥ 18 years. Patients with active proliferative disease, severe systemic diseases, or mental diseases were excluded from the study. Each patient underwent full polysomnography and had blood pressure measured. Blood samples were collected and laboratory test was performed. Results: Among 112 patients enrolled, there was a statistically significant negative linear correlation between blood pressure values (sBP, dBP, mBP) and selenoprotein P, renalase, and TAS levels. Similarly, there was a negative linear correlation between AHI and selenoprotein P, renalase, and TAS levels, but none between AHI and peroxiredoxin-5. Based on the obtained regression models, higher selenoprotein P, peroxiredoxin-5, and renalase levels were independently associated with higher TAS. Lower mBP values were independently associated with the use of antihypertensive drugs, higher TAS, and younger age. Male gender, higher BMI, and higher mBP were independently associated with higher AHI. Conclusions: Higher concentrations of selenoprotein P, peroxiredoxin-5, and renalase were associated with higher TAS, which confirms their antioxidant properties. There was an indirect connection between tested antioxidants and blood pressure values. [ABSTRACT FROM AUTHOR]

Galanin-like peptide (GALP) is a neuropeptide that was first isolated and identified from the porcine hypothalamus. Studies have described an anti-obesity effect of GALP. We previously found that intracerebroventricular administration of GALP in mice resulted in an increase in respiratory exchange rate 12 to 16 h later. GALP may also affect glucose metabolism, but the detailed mechanism has not been elucidated. In this study, we investigated the effects of GALP on glucose and lipid metabolism in the liver. Nine-week-old male C57BL / 6 J mice were administered a single intracerebroventricular dose of saline or GALP and dissected 16 h later. There were no significant between-group differences in body weight and blood glucose levels. With regard to gene and protein expression, G6Pase associated with hepatic gluconeogenesis was significantly reduced in the GALP group. In addition, the hepatokines selenoprotein P and fetuin-A, which induce insulin resistance in the liver, were significantly decreased in the GALP group. These results suggest that intracerebroventricular administration of GALP decreases the expression of key hepatokines, thereby enhancing glucose metabolism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Selenium is an essential trace mineral. The main function of selenoprotein P (SELENOP) is to transport selenium but it has also been ascribed anti-oxidative effects. Methods: To assess the association of repeated measurements of serum SELENOP concentration with all-cause and cause-specific mortality serum SELENOP was measured at baseline and 5-year follow-up in 7,186 and 4,164 participants of the ESTHER study, a German population-based cohort aged 50–74 years at baseline. Results: During 17.3 years of follow-up, 2,126 study participants (30%) died. The relationship of serum SELENOP concentration with all-cause mortality was L-shaped, with mortality being significantly higher at SELENOP concentrations < 4.1 mg/L, which is near the bottom tertile's cut-off (4.2 mg/L). All-cause mortality of participants in the bottom SELENOP tertile was significantly increased compared to subjects in the top tertile (hazard ratio [95% confidence interval]: 1.35 [1.21–1.50]). SELENOP in the bottom tertile was further associated with increased cardiovascular mortality (1.24 [1.04–1.49]), cancer mortality (1.31 [1.09–1.58]), respiratory disease mortality (2.06 [1.28–3.32]) and gastrointestinal disease mortality (2.04 [1.25–3.32]). The excess risk of all-cause mortality for those in the bottom SELENOP tertile was more than twice as strong in men as in women (interaction of SELENOP and sex; p = 0.008). Conclusions: In this large cohort study, serum SELENOP concentration was inversely associated with all-cause and cause-specific mortality. Consistent inverse associations with multiple mortality outcomes might be explained by an impaired selenium transport and selenium deficiency in multiple organs. Trials testing the efficacy of selenium supplements in subjects with low baseline SELENOP concentration are needed. Trial registration: Retrospectively registered in the German Clinical Trials Register on Feb 14, 2018 (ID: DRKS00014028). [ABSTRACT FROM AUTHOR]

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, P trend = 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. [Display omitted] • Largest prospective analysis of the association of Se status biomarkers and Se pathway genetic variation with BC risk. • Higher Se status does not appear to be associated with BC risk overall. • Higher activity of the GPX3 selenoenzyme may reduce risk of BC in premenopausal women. • Inherited SNPs in several selenoprotein and Se related genes could impact BC risk alone or in combination with Se status. Significance/what's new : Higher selenium (Se) status may not markedly help prevent breast cancer development, though higher activity of the glutathione peroxidase 3 selenoenzyme (GPX3; that contains Se in the form of selenocysteine) may reduce risk of breast cancer in premenopausal women. Additionally, inherited common genetic variants in several selenoprotein and Se-related genes could impact breast cancer risk alone or in combination with Se status. [ABSTRACT FROM AUTHOR]

Deficiency of essential trace element, Se, has been implicated in adverse birth outcomes and in child linear growth because of its important role in redox biology and associated antioxidant effects. We used data from a randomised controlled trial conducted among a cohort of pregnant and lactating women in Dhaka, Bangladesh to examine associations between Se biomarkers in whole blood (WBSe), serum and selenoprotein P (SEPP1) in maternal delivery and venous cord (VC) blood. Associations between Se biomarkers, birth weight and infant growth outcomes (age-adjusted length, weight, head circumference and weight-for-length z-scores) at birth, 1 and 2 years of age were examined using regression analyses. WB and serum Se were negatively associated with birth weight (adjusted β , 95 % CI, WBSe delivery: −26·6 (–44·3, −8·9); WBSe VC: −19·6 (–33·0, −6·1)); however, delivery SEPP1 levels (adjusted β : −37·5 (–73·0, −2·0)) and VC blood (adjusted β : 82·3 (30·0, 134·7)) showed inconsistent and opposite associations with birth weight. Positive associations for SEPP1 VC suggest preferential transfer from mother to fetus. We found small associations between infant growth and WBSe VC (length-for-age z-score β , 95 % CI, at birth: −0·05 (–0·1, −0·01)); 12 months (β : −0·05 (–0·08, −0·007)). Weight-for-age z-score also showed weak negative associations with delivery WBSe (at birth: −0·07 (–0·1, −0·02); 12 -months: −0·05 (–0·1, −0·005)) and in WBSe VC (at birth: −0·05 (–0·08, −0·02); 12 months: −0·05 (–0·09, −0·004)). Given the fine balance between essential nutritional and toxic properties of Se, it is possible that WB and serum Se may negatively impact growth outcomes, both in utero and postpartum. [ABSTRACT FROM AUTHOR]

Selenium 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. SELENOP 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. Each 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). Low selenoprotein P levels are associated with a higher risk of incident HF in a general population. Further studies are warranted. [Display omitted] • Selenium levels have previously been associated to incidence of heart failure. • The association was observed only in non-smokers. • Selenoprotein P is a main carrier of selenium, reflective of selenium status. • Selenoprotein P was associated with a lower risk of incident HF irrespective of smoking status. • Selenium-deficient subjects had the highest risk of incident HF compared to all other subjects. [ABSTRACT FROM AUTHOR]

Background: Studies have established the association between blood β-amyloid (Aβ) levels and Alzheimer's disease, but population-based studies concerning the association between selenium (Se) and Aβ levels in blood samples are very limited. Therefore, we explored the association in an elderly population with Se status and serum Aβ measures. Methods: A cross-sectional study on 469 elderly individuals from four rural counties with diverse soil Se levels was carried out. Fasting blood Se, serum selenoprotein P (SELENOP), and glutathione peroxidase (GPX), serum Aβ42, and Aβ40 were measured. Quantile regression models were used to determine the associations of blood Se, serum GPX, and SELENOP with Aβ levels. Results: Significant negative associations were observed between blood Se and serum Aβ42 and Aβ40 levels at all percentiles (P < 0.05). The associations were generally stronger at higher Aβ42 and Aβ40 percentiles than lower Aβ42 and Aβ40 percentiles. Blood Se was positively associated with serum Aβ42/Aβ40 ratio at 25th, 50th, and 75th percentiles. Significant positive associations were observed between serum GPX and Aβ42 and Aβ40 levels at all percentiles (P < 0.05). The positive associations were generally stronger at higher Aβ42 and Aβ40 percentiles than at lower percentiles. Serum GPX was negatively associated with Aβ42/Aβ40 ratio at 25th, 50th, 75th, and 95th percentiles. No associations with serum SELENOP and Aβ levels were observed. Conclusions: Our results suggest that higher Se levels are associated with lower serum Aβ42 and Aβ40 levels and with higher Aβ42/Aβ40 ratio, and the results are specific for different selenoproteins. [ABSTRACT FROM AUTHOR]

(1) In this study we determined the effect of long-term selenomethionine administration on the oxidative stress level and changes in antioxidant protein/enzyme activity; mRNA expression; and the levels of iron, zinc, and copper. (2) Experiments were performed on 4–6-week-old BALB/c mice, which were given selenomethionine (0.4 mg Se/kg b.w.) solution for 8 weeks. The element concentration was determined via inductively coupled plasma mass spectrometry. mRNA expression of SelenoP, Cat, and Sod1 was quantified using real-time quantitative reverse transcription. Malondialdehyde content and catalase activity were determined spectrophotometrically. (3) After long-term SeMet administration, the amount of Se increased by 12-fold in mouse blood, 15-fold in the liver, and 42-fold in the brain, as compared to that in the control. Exposure to SeMet decreased amounts of Fe and Cu in blood, but increased Fe and Zn levels in the liver and increased the levels of all examined elements in the brain. Se increased malondialdehyde content in the blood and brain but decreased it in liver. SeMet administration increased the mRNA expression of selenoprotein P, dismutase, and catalase, but decreased catalase activity in brain and liver. (4) Eight-week-long selenomethionine consumption elevated Se levels in the blood, liver, and especially in the brain and disturbed the homeostasis of Fe, Zn, and Cu. Moreover, Se induced lipid peroxidation in the blood and brain, but not in the liver. In response to SeMet exposure, significant up-regulation of the mRNA expression of catalase, superoxide dismutase 1, and selenoprotein P in the brain, and especially in the liver, was determined. [ABSTRACT FROM AUTHOR]

This study aimed to assess the relationship between chosen antioxidants, namely selenoprotein P (SELENOP), peroxiredoxin-5 (Prdx-5), renalase and selected cardiovascular consequences tested in ambulatory blood pressure monitoring (ABPM) and echocardiography (ECHO). In our work, cardiovascular consequences refer to higher mean blood pressure (MBP) and pulse pressure (PP) on ABPM, as well as to left atrial enlargement (LAE), left ventricular hypertrophy (LVH) and lower left ventricular ejection fraction (LVEF%) on ECHO. The study group consisted of 101 consecutive patients admitted to the Department of Internal Medicine, Occupational Diseases and Hypertension to verify the diagnosis of Obstructive Sleep Apnoea (OSA). Each patient underwent full polysomnography, blood tests, ABPM and ECHO. Both selenoprotein-P and renalase levels correlated with different ABPM and ECHO parameters. We found no correlation between the peroxiredoxin-5 level and none of the tested parameters. We point to the possible application of SELENOP plasma-level testing in the initial selection of high cardiovascular-risk patients, especially if access to more advanced examinations is limited. We further suggest SELENOP measurement as a possible indicator of patients at increased left ventricular hypertrophy risk who should be of particular interest and may benefit from ECHO testing. [ABSTRACT FROM AUTHOR]

Abstract Aims/Introduction Selenoprotein P (SeP; encoded by SEPP1 in humans) is a hepatokine that causes impaired insulin secretion and insulin resistance. Metformin downregulates SELENOP promoter activity through an adenosine monophosphate‐activated kinase–forkhead box protein O3a pathway in hepatocytes. This study aimed to test our hypothesis that circulating SeP levels are associated with the glucose‐lowering effect of metformin in humans. Materials and Methods A total of 84 participants with poorly controlled type 2 diabetes were randomly assigned to receive metformin (1,000 mg, twice daily) or a dipeptidyl peptidase‐4 inhibitor, alogliptin (25 mg, once daily) for 12 weeks. We tested metformin and alogliptin on SeP levels and factors associated therewith as a post‐hoc analysis. Results Both metformin and aloglipitin did not change the SeP levels. Although metformin significantly increased the insulin secretory index secretory units of islets in transplantation only in participants with higher baseline SeP (>3.87), both agents similarly reduced fasting plasma glucose and glycated hemoglobin. SeP levels at baseline were correlated negatively with changes in SeP (r = −0.484, P = 0.004) and fasting plasma glucose (r = −0.433, P = 0.011), and positively with changes in C‐peptide immunoreactivity (r = 0.420, P = 0.017) and secretory units of islets in transplantation (r = 0.388, P = 0.028) in the metformin, but not alogliptin, group. Conclusions Higher baseline levels of SeP significantly predicted metformin‐mediated, but not alogliptin‐mediated, glucose‐lowering and insulinotropic effects. Serum SeP levels might be a novel biomarker for predicting the outcomes of metformin therapy, which might be helpful in tailoring diabetes medication.

The significance of selenoproteins for the incidence of prematurity and oxidative-damage-related diseases in premature newborns is poorly understood. The latter are at risk for ROP as well as BPD, IVH, PDA, RDS, and NEC, which is particularly high for newborns with extremely low gestational age (ELGA) and extremely low birth weight (ELBW). This study evaluates the hypothesis that variation in the selenoprotein-encoding genes SELENOP, SELENOS, and GPX4 affects the risk of ROP and other comorbidities. The study included infants born ≤ 32 GA, matched for onset and progression of ROP into three groups: no ROP, spontaneously remitting ROP, and ROP requiring treatment. SNPs were determined with predesigned TaqMan SNP genotyping assays. We found the association of the SELENOP rs3877899A allele with ELGA (defined as <28 GA), ROP requiring treatment, and ROP not responsive to treatment. The number of RBC transfusions, ELGA, surfactant treatment, and coexistence of the rs3877899A allele with ELGA were independent predictors of ROP onset and progression, accounting for 43.1% of the risk variation. In conclusion, the SELENOP rs3877899A allele associated with reduced selenium bioavailability may contribute to the risk of ROP and visual impairment in extremely preterm infants. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Selenoprotein P (SeP; encoded by SEPP1 in humans) is a hepatokine that causes impaired insulin secretion and insulin resistance. Metformin downregulates SELENOP promoter activity through an adenosine monophosphate‐activated kinase–forkhead box protein O3a pathway in hepatocytes. This study aimed to test our hypothesis that circulating SeP levels are associated with the glucose‐lowering effect of metformin in humans. Materials and Methods: A total of 84 participants with poorly controlled type 2 diabetes were randomly assigned to receive metformin (1,000 mg, twice daily) or a dipeptidyl peptidase‐4 inhibitor, alogliptin (25 mg, once daily) for 12 weeks. We tested metformin and alogliptin on SeP levels and factors associated therewith as a post‐hoc analysis. Results: Both metformin and aloglipitin did not change the SeP levels. Although metformin significantly increased the insulin secretory index secretory units of islets in transplantation only in participants with higher baseline SeP (>3.87), both agents similarly reduced fasting plasma glucose and glycated hemoglobin. SeP levels at baseline were correlated negatively with changes in SeP (r = −0.484, P = 0.004) and fasting plasma glucose (r = −0.433, P = 0.011), and positively with changes in C‐peptide immunoreactivity (r = 0.420, P = 0.017) and secretory units of islets in transplantation (r = 0.388, P = 0.028) in the metformin, but not alogliptin, group. Conclusions: Higher baseline levels of SeP significantly predicted metformin‐mediated, but not alogliptin‐mediated, glucose‐lowering and insulinotropic effects. Serum SeP levels might be a novel biomarker for predicting the outcomes of metformin therapy, which might be helpful in tailoring diabetes medication. [ABSTRACT FROM AUTHOR]

Cardiac hepatopathy refers to acute or chronic liver damage caused by cardiac dysfunction in the absence of any other possible causative reasons of liver injury. There is a large number of evidence of the fact that cardiac hepatopathy is associated with poor clinical outcomes in patients with acute or actually decompensated heart failure (HF). However, the currently dominated pathophysiological background does not explain a role of metabolic regulative proteins secreted by hepatocytes in progression of HF, including adverse cardiac remodeling, kidney injury, skeletal muscle dysfunction, osteopenia, sarcopenia and cardiac cachexia. The aim of this narrative review was to accumulate knowledge of hepatokines (adropin; fetuin-A, selenoprotein P, fibroblast growth factor-21, and alpha-1-microglobulin) as adaptive regulators of metabolic homeostasis in patients with HF. It is suggested that hepatokines play a crucial, causative role in inter-organ interactions and mediate tissue protective effects counteracting oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and necrosis. The discriminative potencies of hepatokines for HF and damage of target organs in patients with known HF is under on-going scientific discussion and requires more investigations in the future. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Selenoprotein P (SeP, encoded by SELENOP in humans) is a hepatokine that causes insulin resistance in the liver and skeletal muscle. It was found that polyunsaturated fatty acid eicosapentaenoic acid (EPA) downregulates Selenop expression by inactivating SREBP‐1c. The present study aimed to examine the effect of EPA for 12 weeks on circulating SeP levels and insulin sensitivity in humans with type 2 diabetes. Methods A total of 20 participants with dyslipidemia and type 2 diabetes were randomly assigned to an EPA (900 mg, twice daily) group and a control group. The primary endpoint was a change in serum SeP levels. Organ‐specific insulin sensitivity in the liver (HGP and %HGP), skeletal muscle (Rd), and adipose tissue (FFA and %FFA) were assessed using a hyperinsulinemic‐euglycemic clamp study with stable isotope‐labeled glucose infusion. Results Serum SeP levels were not changed in either group at the end of the study. In the EPA group, the changes in SeP levels were positively correlated with the change in serum EPA levels (r = 0.709, P = 0.022). Treatment with EPA significantly enhanced %FFA but not %HGP and Rd. The change in serum EPA levels was significantly positively correlated with the change in %HGP, and negatively correlated with changes in Rd. Conclusions The change in serum EPA levels was positively correlated with serum SeP levels, hepatic insulin sensitivity, and negatively with skeletal muscle insulin sensitivity in humans with type 2 diabetes. The EPA‐induced enhancement of hepatic insulin sensitivity might be associated with a mechanism independent of serum SeP levels.

Background: Selenium has an anti-diabetic action as it an insulin-mimetic and antioxidant nutrient. Selenoprotein P (SeP) is an extracellular glycoprotein, that was linked to insulin resistance (IR). Aim: To validate of serum SeP as a measure for insulin resistance in patients with type 1 diabetes mellitus (T1DM). Methods: This prospective case-control study included 45 children and adolescents with T1DM and 45 healthy children and adolescents. Serum SeP was measured by ELISA and compared to estimated glucose disposal rate (eGDR) as a measure of insulin resistance. Results: Mean ± SD of SeP level was higher in T1DM patients than control group (59.78 ± 59.38 ng/ml, 55.57 ± 7.6 ng/ml,respectively), this difference was statistically insignificant (p= 0.642). SeP demonstrated significant positive correlations with duration of diabetes (r=0.413, p=0.005), high density lipoproteins (r=0.496, p=0.001) and glycosylated hemoglobin (r=0.357, p=0.016). There were statistically significant differences in eGDR between cases and controls (7.78±3.08 mg/kg/min, 12.53±0.91mg/kg/min, respectively, (p= 0.001). There was no correlation between SeP level and eGDR values (IR indicator). Conclusion: Serum SeP level in T1DM patients was not indicative of IR. Higher serum SeP level are associated with longer duration and poor control of T1DM.

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.

Aims: Increasing evidence has shown that selenoprotein P levels are elevated in type 2 diabetes mellitus and are associated with insulin resistance and release. This study aimed to determine if there was a connection between selenoprotein P levels and metabolic parameters in patients with diabetes with microvascular complications. Methods: Serum selenoprotein P concentrations were measured by ELISA in 44 patients with diabetes with complications and 36 patients with diabetes without complications. Results: There was no statistically significant difference in selenoprotein P levels between the groups [1.9 (0.9–2.6) and 1.9 (0.8–2.4) ng/mL, respectively, p = 0.565]. Selenoprotein P, glucose, glycosylated hemoglobin, C-reactive protein, triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were not statistically significantly correlated in patients with complications. However, there was a significant correlation with high-density lipoprotein cholesterol (r = − 0.401, p = 0.042). Conclusions: We did not find high selenoprotein P levels in patients with complications, but its inverse association with high-density lipoprotein cholesterol indicates that it may play a role in developing cardiovascular disease in this community of patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Fifty years have passed since the discovery of the first selenoprotein by Rotruck and colleagues. In that time, the essential nature of selenium has come to light including the dependence of the brain on selenium to function properly. Animal models have shown that a lack of certain selenoproteins in the brain is detrimental for neuronal health, sometimes leading to neurodegeneration. There is also potential for selenoprotein-mediated redox balance to impact neuronal activity, including neurotransmission. Important insights on these topics have been gained over the past several years. This review briefly summarizes the known roles of specific selenoproteins in the brain while highlighting recent advancements regarding selenoproteins in neuronal function. Hypothetical models of selenoprotein function and emerging topics in the field are also provided. [Display omitted] • After 50 years of research, the mechanisms of action of several selenoproteins have been uncovered. • Selenoproteins regulate neuronal activity through redox signaling. • These actions may have implications for humans disease and therapy. [ABSTRACT FROM AUTHOR]

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case–control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status. [ABSTRACT FROM AUTHOR]

Selenoprotein P (SeP), encoded by the SELENOP gene, is the major selenium-containing protein in human plasma. SeP has 10 residues of selenocysteine (Sec, cysteine analog in which the sulfur is replaced by selenium), and Sec plays a significant role in the multifunctional properties of SeP. The one Sec residue on the N-terminal side functions for the redox reaction that reduces lipid hydroperoxides, while the 9 Sec residues on the C-terminal side are responsible for the selenium supplying activity. In the middle of SeP, the domain rich in basic amino acids containing consecutive histidine is present. SeP has been reported to have multiple metal-binding abilities such as Hg, Cd, Cu, Ni, Zn, and Co; however, its physiological significance and the effects on SeP functions remain unclear. In this review, the findings to date on the metal-binding properties of SeP and its structural relevance are summarized, particularly for methylmercury. The binding of other selenoproteins to metals is also described. Finally, the interactions of selenoproteins with various metals and its significance for biological defense are discussed. [ABSTRACT FROM AUTHOR]

Introduction: Severely burned patients exhibit increased nutritional requirements and are at high risk of developing sepsis. Selenium is an essential trace element supporting antioxidant and anti-inflammatory pathways, mediated by incorporation into selenoproteins. The selenium status may affect sepsis risk in burn injury., Methods: This prospective cohort study included 90 adult patients admitted to Zurich Burn Center, Switzerland. All patients received a continuous intravenous infusion of 1000 μg sodium selenite per day during the first week as part of local standard of care. Three complementary biomarkers of serum selenium status were determined at nine time-points up to six months postburn, namely total selenium, selenoprotein P, and glutathione peroxidase 3. The resulting data were correlated to clinical parameters and outcomes, with sepsis as the primary end point., Results: A high fraction of the patients displayed selenium deficiency already at admission, and developed sepsis during hospitalization (n = 55; 61 %). Selenium status at admission was inversely related to burn severity. Low baseline selenoprotein P was associated with sepsis incidence, irrespective of trauma severity (adjusted HR, 1.94; 95 % CI, 1.05-3.63; p = 0.035). Burn severity and baseline concentrations of selenoprotein P and white blood cells together predicted sepsis with an area under the curve of 0.84 (95 % CI, 0.75-0.93; p < 0.0001). Supplemental selenium was associated with a transient normalization of selenium status., Conclusion: Considering its rapid decline following severe burn injury, the assessment of serum selenoprotein P upon admission may contribute to an early prediction of sepsis risk., Competing Interests: Competing interests LS holds shares of selenOmed GmbH, a company involved in Se status assessment; no other relationships or activities that could appear to have influenced the submitted work are indicated., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Selenium has potential safeguarding properties against cognitive decline, because of its role in protecting DNA, proteins, and lipids in the brain from oxidative damage. However, acute and chronic overexposure to selenium can be neurotoxic., Objective: The aim of this analysis was to explore the association between selenium status [serum selenium and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity] and cognitive function in 85-y olds living in Northeast England at baseline and ≤5 y of follow-up., Methods: Global cognitive performance was assessed in 755 participants from the Newcastle 85+ study using the standardized Mini-Mental State Examination and attention-specific cognition was assessed using composite scores derived from the Cognitive Drug Research System. Serum selenium, SELENOP, and GPx3 activity were measured at baseline by total reflection X-ray fluorescence, enzyme-linked immunosorbent assay, and coupled-enzyme reaction, respectively. Regression analyses explored linear and nonlinear associations between continuous values and tertiles of selenium status biomarkers, respectively, and cognitive function at baseline. Generalized linear mixed models explored associations between continuous values and tertiles of selenium status biomarkers, and global cognitive decline over 5 y, and attention-specific cognitive decline over 3 y., Results: Over 3 and 5 y, none of the selenium biomarkers were associated with the rate of cognitive decline. At baseline, in fully adjusted models, higher serum selenium was nonlinearly associated with global cognition (β = 0.05 ± 0.01, P = 0.387 linear, β = 0.04 ± 0.01, P = 0.002 nonlinear). SELENOP and GPx3 activity were not associated with any cognitive outcomes., Conclusions: There were no associations between selenium status and cognitive decline. However, serum selenium, but not SELENOP or GPx3 activity, was positively associated nonlinearly with global cognition at baseline. Furthermore, these associations were not evident during follow-up, potentially because of residual confounding and reverse causation., Competing Interests: Conflict of interest LS holds shares on selenOmed GmbH, a company involved in selenium status assessment. All other authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: Pulmonary 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 Methods: The 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., Results: SePP 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., Conclusion: SePP 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., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Selenoprotein P (SeP) is synthesized in the liver and plays a vital role in maintaining selenium homeostasis via transport throughout the body. Previous studies have shown that SeP-deficient mice have severely reduced expression of selenoproteins essential for testicular function, leading to male infertility. We previously reported that the high expression of Ccdc152 in hepatocytes acts as a lncRNA, suppressing SeP expression in the liver. Ccdc152 reduces SeP translation by binding to SeP mRNA and decreasing its interaction with SECIS-binding protein 2. Although Ccdc152 is highly expressed in testes, its function remains unclear. Therefore, this study aimed to elucidate the role of Ccdc152 in the testes. Using the CRISPR/Cas9 system, we generated mice lacking all exons of Ccdc152 and found that SeP expression levels in the liver and plasma, as well as overall selenium homeostasis, remained unchanged. No significant differences were observed in the expression of glutathione peroxidase 1/4 or level of selenium in the testes. Subsequent investigation of the impact on male reproductive function revealed no abnormalities in sperm motility or Mendelian ratios of the offspring. However, a slight decrease in testicular weight and an increased rate of sperm malformations in the epididymis were observed. RNA-seq and pathway analyses identified the reduced expression of multiple genes related to kinesin and reproductive pathways. Based on these findings, Ccdc152 may not be essential for male reproductive function, but it may enhance reproductive capabilities by maintaining the expression of genes necessary for reproduction.

Selenium is a potent nucleophile essential for selenoenzymes, such as glutathione peroxidase (also known as GSH-Px; GPX; GPx) and selenoprotein P (also known as SelP; SEPP1; SELENOP; SeP). SeP is predominantly secreted from the liver and functions as a selenium carrier in plasma. We previously found that sulforaphane (SFN), an electrophilic phytochemical, reduces SeP production in cultured hepatocytes and mouse liver, however, the effect of electrophilic modification of SeP by SFN on selenium transport and metabolism remains unclear. In the present study, we demonstrate that sulforaphane covalently modifies selenocysteine/cysteine residues of SeP using an acidic biotin PAEC 5 maleimide labeling assay, which allows for focused-labeling of selenocysteine residues. Although the SFN-SeP adduct can be taken up by HepG2 cells and degraded by the lysosome, it was less effective in inducing GPx expression. Our findings indicate that SFN disrupts the selenium supply pathway through the formation of the SeP-SFN adduct., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takashi Tyama reports financial support was provided by Japan Society for the Promotion of Science. Yoshiro Saito reports financial support was provided by japan society for the promotion of science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Drinking alcohol is considered one of the risk factors for development of diabetes mellitus. Recently, it was reported that selenoprotein P levels in blood are increased by ethanol intake. However, the mechanism by which ethanol increases selenoprotein P has not been elucidated. The expression of selenoprotein P protein and its mRNA were increased in a concentration- and time-dependent manner when human liver-derived HepG2 cells were treated with ethanol. Levels of AMPK and JNK proteins, which have been known to regulate selenoprotein P transcription, were unchanged by ethanol treatment. However, the amount of nuclear FoxO3a, a transcription factor of SeP, was increased. This was associated with dephosphorylation of ERK1 but not ERK2. It was found that ERK1 was dephosphorylated by activation of dual-specific phosphatase 5 and dual-specific phosphatase 6. However, the phosphorylation of MEK by ERK phosphokinase was not affected by ethanol treatment. These results suggest that the ethanol-induced increase in SeP levels occurs by enhanced transcription of SeP mRNA via the DUSP5/6-ERK1-FoxO3a pathway., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

Yanni Yang,1– 3,&ast; Daning Li,1,&ast; Wentao Wu,1 Dingxing Huang,1 Haishi Zheng,3 Yirixiati Aihaiti3 1School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 3Department of Joint Surgery, Xi’an Jiaotong University Affiliated HongHui Hospital, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wentao WuSchool of Public Health, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of ChinaTel +86 156 80833716Email 15680833716@163.comBackground: Selenium (Se) exhibits its anti-carcinogenic properties by regulating the redox system. However, the relationship between selenoprotein P (SeP), mRNA (SELENOP mRNA) and tumorigenesis remains unclear. Plasma SeP transports Se to various target tissues and has antioxidant characteristics. The present study aimed to explore the multifaceted pan-cancer properties of SELENOP in terms of its tissue-specific expression, prognostic value, immune function, and signaling pathway enrichment.Patients and Methods: The expression profile of SELENOP was determined in 33 tumor types and survival, pathway enrichment, and correlation analyses were conducted based on TCGA database. The relationship between SELENOP expression and immune infiltration and macrophage subtype gene markers was investigated using the TIMER and GEPIA.Results: SELENOP gene expression was decreased in many cancer tissues, but was upregulated in brain lower grade glioma (LGG). Furthermore, SELENOP expression was associated with a better prognosis in most cancers, but a poorer prognosis in LGG and uterine corpus endometrioid carcinoma (UCEC). Our results showed that SELENOP was correlated with infiltration level of six immune cell types, where SELENOP also showed a strong correlation with macrophages in some cancer types. However, we failed to determine macrophage polarization in 33 tumor types. SELENOP negatively regulated vascular endothelial cell proliferation in LGG and UCEC and epidermal cell differentiation in six tumor types. In contrast, upregulation was related to immune function, including T cell activation, B cell-mediated immunity, adaptive immune response and immune response regulation cell surface receptor signaling pathways in another six tumor types.Conclusion: These findings highlighted the tissue-specific expression, prognostic value and immune characteristics of SELENOP in pan-cancer, and provided insights for illustrating the role of SELENOP in tumorigenesis.Keywords: selenoprotein P, pan-cancer, immune infiltration, prognosis, tissue-specific expression

Objectives Few spatial studies on Keshan disease (KD) prevalence and serum selenoprotein P (SELENOP) levels have been reported in the Heilongjiang Province, China. This study aimed to investigate the spatial relationships between KD prevalence, SELENOP levels, and the socio-economic status for the precise prevention and control of KD. Material and Methods The study was carried out in all the 66 KD endemic counties in the Heilongjiang Province using a non-probability sampling method of a key village survey based on county-wide case-searching. The participants completed a questionnaire and had their serum SELENOP levels measured using enzyme-linked immunosorbent assay. Thematic maps were created, and spatial regression analysis was performed by ordinary least squares using ArcGIS 9.0. Results Overall, 53 676 residents were surveyed based on case-searching, and blood samples were collected from 409 residents. In total, 50 chronic KD cases were identified with a total prevalence of 9.3/10 000 population. The prevalence in the Tangyuan County was the highest (250/10 000 population). The mean serum SELENOP level was 13.96 mg/l. The spatial regression analysis showed that KD prevalence positively correlated with SELENOP levels and negatively with per capita disposable income among rural residents. Conclusions The Tangyuan County should be considered for the precise prevention and control of KD. Further research is necessary to verify the reliability of SELENOP for estimating body selenium levels, and to better understand the relationship between selenium intake and KD in the investigated area. Int J Occup Med Environ Health. 2021;34(5):659–66

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. [ABSTRACT FROM AUTHOR]

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 (T 4), triiodothyronine (T 3), 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 T 4 concentration and GPX3 was inversely correlated with free T 4 and T 3 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. [ABSTRACT FROM AUTHOR]

Selenoproteins and selenium (Se) are essential for thyroid hormone synthesis, metabolism and thyroid gland functions. The human thyroid gland is one of the organs vulnerable to tissue- -specific autoimmune diseases. The aim of this study was to investigate roles of Se and several selenoproteins, including selenoprotein P (SePP), glutathione peroxidase-3 (GPx3), thioredoxin reductase (TrxR), type 1 iodothyronine deiodinase (DI1), selenoprotein W (SelW), selenoprotein H (SelH), and oxidative stress in etiopathogenesis of Hashimoto thyroiditis. A total of 40 patients with Hashimoto thyroiditis and 42 healthy controls were included in the study. Serum Se levels were measured by inductively coupled plasma optical emission spectrometry (ICP-OES). 8-hydroxydeoxyguanosine (8-OHdG), SePP, SelW, SelH, GPx-3, TrxR, and DI1 levels were determined by enzyme-linked immunosorbent assay (ELISA) kits. Se levels were significantly decreased, but plasma SelH, 8-OHdG levels, and TrxR activities were significantly increased in the Hashimoto thyroiditis group. Plasma SePP levels, GPx3and DI1 activities did not significantly changed in Hashimoto thyroiditis patients. Changes in circulating Se and selenoprotein levels/activities, together with increased oxidative stress, might have important impact on the etiopathogenesis of Hashimoto thyroiditis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Selenoprotein P (SeP; encoded by SELENOP in humans, Selenop in rodents) is a hepatokine that is upregulated in the liver of humans with type 2 diabetes. Excess SeP contributes to the onset of insulin resistance and various type 2 diabetes-related complications. We have previously reported that the long-chain saturated fatty acid, palmitic acid, upregulates Selenop expression, whereas the polyunsaturated fatty acids (PUFAs) downregulate it in hepatocytes. However, the effect of medium-chain fatty acids (MCFAs) on Selenop is unknown. Here, we report novel mechanisms that underlie the lauric acid-mediated Selenop gene regulation in hepatocytes. Lauric acid upregulated Selenop expression in Hepa1-6 hepatocytes and mice liver. A luciferase promoter assay and computational analysis of transcription factor-binding sites identified the hepatic nuclear factor 4α (HNF4α) binding site in the SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay showed that lauric acid increased the binding of HNF4α to the SELENOP promoter. The knockdown of Hnf4αusing siRNA canceled the upregulation of lauric acid-induced Selenop. The lauric acid-induced impairment of Akt phosphorylation brought about by insulin was rescued by the knockdown of either Hnf4α or Selenop. These results provide new insights into the regulation of SeP by fatty acids and suggest that SeP may mediate MCFA-induced hepatic insulin signal reduction. [ABSTRACT FROM AUTHOR]