Cathodal bilateral transcranial direct-current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia-reperfusion injury.

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.

Ancient Loss of Catalytic Selenocysteine Spurred Convergent Adaptation in a Mammalian Oxidoreductase.

Selenocysteine, the 21st amino acid specified by the genetic code, is a rare selenium-containing residue found in the catalytic site of selenoprotein oxidoreductases. Selenocysteine is analogous to the common cysteine amino acid, but its selenium atom offers physical-chemical properties not provided by the corresponding sulfur atom in cysteine. Catalytic sites with selenocysteine in selenoproteins of vertebrates are under strong purifying selection, but one enzyme, glutathione peroxidase 6 (GPX6), independently exchanged selenocysteine for cysteine <100 million years ago in several mammalian lineages. We reconstructed and assayed these ancient enzymes before and after selenocysteine was lost and up to today and found them to have lost their classic ability to reduce hydroperoxides using glutathione. This loss of function, however, was accompanied by additional amino acid changes in the catalytic domain, with protein sites concertedly changing under positive selection across distant lineages abandoning selenocysteine in glutathione peroxidase 6. This demonstrates a narrow evolutionary range in maintaining fitness when sulfur in cysteine impairs the catalytic activity of this protein, with pleiotropy and epistasis likely driving the observed convergent evolution. We propose that the mutations shared across distinct lineages may trigger enzymatic properties beyond those in classic glutathione peroxidases, rather than simply recovering catalytic rate. These findings are an unusual example of adaptive convergence across mammalian selenoproteins, with the evolutionary signatures possibly representing the evolution of novel oxidoreductase functions.

Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker.

Selenium has been proven to influence several biological functions, showing to be an essential micronutrient. The functional studies demonstrated the benefits of a balanced selenium diet and how its deficiency is associated with diverse diseases, especially cancer and viral diseases. Selenium is an antioxidant, protecting the cells from damage, enhancing the immune system response, preventing cardiovascular diseases, and decreasing inflammation. Selenium can be found in its inorganic and organic forms, and its main form in the cells is the selenocysteine incorporated into selenoproteins. Twenty-five selenoproteins are currently known in the human genome: glutathione peroxidases, iodothyronine deiodinases, thioredoxin reductases, selenophosphate synthetase, and other selenoproteins. These proteins lead to the transport of selenium in the tissues, protect against oxidative damage, contribute to the stress of the endoplasmic reticulum, and control inflammation. Due to these functions, there has been growing interest in the influence of polymorphisms in selenoproteins in the last two decades. Selenoproteins' gene polymorphisms may influence protein structure and selenium concentration in plasma and its absorption and even impact the development and progression of certain diseases. This review aims to elucidate the role of selenoproteins and understand how their gene polymorphisms can influence the balance of physiological conditions. In this polymorphism review, we focused on the PubMed database, with only articles published in English between 2003 and 2023. The keywords used were "selenoprotein" and "polymorphism". Articles that did not approach the theme subject were excluded. Selenium and selenoproteins still have a long way to go in molecular studies, and several works demonstrated the importance of their polymorphisms as a risk biomarker for some diseases, especially cardiovascular and thyroid diseases, diabetes, and cancer.

The mechanism of selenium regulating the permeability of vascular endothelial cells through selenoprotein O.

Vascular diseases, a leading cause of death in human, are strongly associated with pathological damage to blood vessels. The selenoprotein (Sel) have been reported to play important roles in vascular disease. However, the role of SelO in vascular disease has not been conclusively investigated. The present experiment was to investigate the regulatory mechanism of the effect of SelO on the permeability of vascular endothelial. The H.E staining, FITC-Dextran staining, Dil-AC-LDL staining and FITC-WGA staining showed that vascular structure was damaged, and intercellular junctions were disrupted with selenium (Se)-deficient. Immunohistochemistry, qPCR and Western blot revealed decreased expression of the adhesion plaque proteins vinculin, talin and paxillin, decreased expression of the vascular connectivity effector molecules connexin, claudin-1 and E-cadherin and increased expression of JAM-A and N-cadherin, as well as decreased expression of the ZO-1 signaling pathways ZO-1, Rock, rhoGEF, cingulin and MLC-2. In a screening of 24 Sel present in mice, SelO showed the most pronounced changes in vascular tissues, and a possible association between SelO and vascular intercellular junction effectors was determined using IBM SPSS Statistics 25. Silencing of SelO, vascular endothelial intercellular junction adverse effects present. The regulatory relationship between SelO and vascular endothelial intercellular junctions was determined. The results showed that Se deficiency lead to increased vascular endothelial permeability and vascular tissue damage by decreasing SelO expression, suggesting a possible role for SelO in regulating vascular endothelial permeability.

SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aß phagocytosis.

Amyloid-beta (Aß) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we revealed that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborated that SELENOK deficiency inhibits microglial Aß phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aß phagocytosis. CD36 palmitoylation was reduced in the brains of patients and mice with AD. Se supplementation promoted SELENOK expression and CD36 palmitoylation, enhancing microglial Aß phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aß pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.

Effects of selenoprotein extracts from Cardamine hupingshanensis on growth, selenium metabolism, antioxidant capacity, immunity and intestinal health in largemouth bass Micropterus salmoides.

This study aimed to assess the impact of dietary selenoprotein extracts from Cardamine hupingshanensis (SePCH) on the growth, hematological parameters, selenium metabolism, immune responses, antioxidant capacities, inflammatory reactions and intestinal barrier functions in juvenile largemouth bass (Micropterus salmoides). The base diet was supplemented with four different concentrations of SePCH: 0.00, 0.30, 0.60 and 1.20 g/Kg (actual selenium contents: 0.37, 0.59, 0.84 and 1.30 mg/kg). These concentrations were used to formulate four isonitrogenous and isoenergetic diets for juvenile largemouth bass during a 60-day culture period. Adequate dietary SePCH (0.60 and 1.20 g/Kg) significantly increased weight gain and daily growth rate compared to the control groups (0.00 g/Kg). Furthermore, 0.60 and 1.20 g/Kg SePCH significantly enhanced amounts of white blood cells, red blood cells, platelets, lymphocytes and monocytes, and levels of hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin in the hemocytes. In addition, 0.60 and 1.20 g/Kg SePCH increased the mRNA expression levels of selenocysteine lyase, selenophosphate synthase 1, 15 kDa selenoprotein, selenoprotein T2, selenoprotein H, selenoprotein P and selenoprotein K in the fish liver and intestine compared to the controls. Adequate SePCH not only significantly elevated the activities of antioxidant enzymes (Total superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase), the levels of total antioxidant capacity and glutathione, while increased mRNA transcription levels of NF-E2-related factor 2, Cu/Zn-superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase. However, adequate SePCH significantly decreased levels of malondialdehyde and H2O2 and the mRNA expression levels of kelch-like ECH-associated protein 1a and kelch-like ECH-associated protein 1b in the fish liver and intestine compared to the controls. Meanwhile, adequate SePCH markedly enhanced the levels of immune factors (alkaline phosphatase, acid phosphatase, lysozyme, complement component 3, complement component 4 and immunoglobulin M) and innate immune-related genes (lysozyme, hepcidin, liver-expressed antimicrobial peptide 2, complement component 3 and complement component 4) in the fish liver and intestine compared to the controls. Adequate SePCH reduced the levels of pro-inflammatory cytokines (tumour necrosis factor-α, interleukin 8, interleukin 1ß and interferon γ), while increasing transforming growth factor ß1 levels at both transcriptional and protein levels in the liver and intestine. The mRNA expression levels of mitogen-activated protein kinase 13 (MAPK 13), MAPK14 and nuclear factor kappa B p65 were significantly reduced in the liver and intestine of fish fed with 0.60 and 1.20 g/Kg SePCH compared to the controls. Histological sections also demonstrated that 0.60 and 1.20 g/Kg SePCH significantly increased intestinal villus height and villus width compared to the controls. Furthermore, the mRNA expression levels of tight junction proteins (zonula occludens-1, zonula occludens-3, Claudin-1, Claudin-3, Claudin-5, Claudin-11, Claudin-23 and Claudin-34) and Mucin-17 were significantly upregulated in the intestinal epithelial cells of 0.60 and 1.20 g/Kg SePCH groups compared to the controls. In conclusion, these results found that 0.60 and 1.20 g/Kg dietary SePCH can not only improve growth, hematological parameters, selenium metabolism, antioxidant capacities, enhance immune responses and intestinal functions, but also alleviate inflammatory responses. This information can serve as a useful reference for formulating feeds for largemouth bass.

[The Role of Supersulfide in Methylmercury Detoxification].

Methylmercury is a ubiquitous neurotoxic substance present in the environment, and health concerns, especially through the consumption of seafood, remain. Glutathione (GSH)-mediated detoxification and the excretion of methylmercury are known metabolic detoxification pathways. We have also discovered a mechanism by which endogenous super-sulfides convert methylmercury to nontoxic metabolites such as bis-methylmercury sulfide. However, these metabolites are present in very small quantities, and the significance of the detoxification of methylmercury by super-sulfides is not well understood. Methylmercury binds to thiol groups in vivo but can also react with highly reactive selenols (selenocysteine residues). Such covalent bonds (S-mercuration and Se-mercuration) are broken by nucleophilic substitution reactions with other thiol and selenols, however, the contribution of super-sulfides to this substitution reaction is not well understood. Interestingly, a recent study suggested that selenoprotein P, the major selenium transport protein in plasma, binds to methylmercury, however, Se-mercuration was not determined. In this review, we introduce these series of reactions and discuss their involvement with super-sulfides in methylmercury toxicity.

Strong associations of serum selenoprotein P with all-cause mortality and mortality due to cancer, cardiovascular, respiratory and gastrointestinal diseases in older German adults.

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).

Association between low selenoprotein P concentrations and anaemia in hospitalized heart failure patients.

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.

Therapeutic Effects of Selenium on Alpha-Synuclein Accumulation in Substantia Nigra Pars Compacta in a Rat Model of Parkinson's Disease: Behavioral and Biochemical Outcomes.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 µg 6-OHDA/5 µl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.

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 (ß=0.42, P<0.001) and erythrocytes GPx activity (ß=0.28, P=0.002) as well as with lower serum TBARS levels (ß= -0.26, P=0.003). Similarly, higher serum levels of SELENOP were associated with higher TAC (ß=0.32, P<0.001) and erythrocyte GPx activity (ß=0.30, P=0.001). SELENOP also showed an inverse association with serum levels of TBARS (ß= -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.

Effects of different selenium sources and levels on the physiological state, selenoprotein expression, and production and preservation of selenium-enriched eggs in laying hens.

Selenium (i.e., Se) is a trace element that is vital in poultry nutrition, and optimal forms and levels of Se are critical for poultry productivity and health. This study aimed to compare the effects of sodium selenite (SS), yeast selenium (SY), and methionine selenium (SM) at selenium levels of 0.15 mg/kg and 0.30 mg/kg on production performance, egg quality, egg selenium content, antioxidant capacity, immunity and selenoprotein expression in laying hens. The trial was conducted in a 3 × 2 factorial arrangement, and a total of 576 forty-three-wk-old Hyland Brown laying hens were randomly assigned into 6 treatment groups, with diets supplemented with 0.15 mg Se/kg and 0.3 mg Se/kg of SS, SY and SM for 8 wk, respectively. Results revealed that SM increased the laying rate compared to SS and SY (P < 0.05), whereas different selenium levels had no effect. Organic selenium improved egg quality, preservation performance, and selenium deposition compared to SS (P < 0.05), while SY and SM had different preferences for Se deposition in the yolk and albumen. Also, organic selenium enhanced the antioxidant capacity and immune functions of laying hens at 0.15 mg Se/kg, whereas no obvious improvement was observed at 0.30 mg Se/kg. Moreover, SY and SM increased the mRNA expression of most selenoproteins compared to SS (P < 0.05), with SM exhibiting a more pronounced effect. Correlation analysis revealed a strong positive association between glutathione peroxidase 2 (GPx2), thioredoxin reductases (TrxRs), selenoprotein K (SelK), selenoprotein S (SelS), and antioxidant and immune properties. In conclusion, the use of low-dose organic selenium is recommended as a more effective alternative to inorganic selenium, and a dosage of 0.15 mg Se/kg from SM is recommended based on the trail conditions.

Selenium and selenoproteins role in Parkinson's disease: Is there a link between selenoproteins and accumulated alpha-synuclein?

BACKGROUND: While Parkinson's disease (PD) etiology is not clear yet, accumulated alpha-synuclein is proposed to induce neurodegeneration. Selenium (Se) and its functional proteins play a key role in aggregation of misfolded proteins. However, their implications in neurodegenerative process are unclear. AIM: Diagnosing Se and selenoprotein P (SelP), selenoprotein S (SelS) proportions in serum of PD patients to compare with healthy controls, whether the changes in their concentration could be a biomarker for PD. METHODS: Se concentration was investigated in 30 PD patients and 30 controls using atomic absorption spectrometry. Also, alpha-Synuclein, SelP, and SelS levels were evaluated by ELISA. The parameters were compared in PD patients and controls. Also, the variations within the case group according to their age, disorder stage, and drug administration were evaluated. RESULTS: PD subjects had higher Se concentration. The mean SelP in PD patients was lower from controls, whilst SelS levels were higher. Also, the concentration of alpha-synuclein was higher in PD patients. However, age, stage (except UPDRS III), and disorder duration had no influence on the Se and selenoproteins level, whilst there was a direct association between alpha-synuclein levels and disorder stage. Also, alpha-synuclein proportions in subjects using levodopa was significantly higher. CONCLUSION: Our results suggest that serum levels of Se and SelP could be a biomarker or risk factor for PD. Although SelS interferes to reduce aggregated proteins, its pathway in PD is not clearly understood. Future studies could focus on how SelS can reduce on alpha-synuclein aggregation. Thus, other studies should be performed on this issue to induce the selenoproteins in PD.

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

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

Selenomethionine alleviates environmental heat stress induced hepatic lipid accumulation and glycogen infiltration of broilers via maintaining mitochondrial and endoplasmic reticulum homeostasis.

With the increasing of global mean surface air temperature, heat stress (HS) induced by extreme high temperature has become a key factor restricting the poultry industry. Liver is the main metabolic organ of broilers, HS induces liver damage and metabolic disorders, which impairs the health of broilers and affects food safety. As an essential trace element for animals, selenium (Se) involves in the formation of antioxidant system, and its biological functions are generally mediated by selenoproteins. However, the mechanism of Se against HS induced liver damage and metabolic disorders in broilers is inadequate. Therefore, we developed the chronic heat stress (CHS) broiler model and investigated the potential protection mechanism of organic Se (selenomethionine, SeMet) on CHS induced liver damage and metabolic disorders. In present study, CHS caused liver oxidative damage, and induced hepatic lipid accumulation and glycogen infiltration of broilers, which are accompanied by mitochondrial dysfunction, abnormal mitochondrial tricarboxylic acid (TCA) cycle and endoplasmic reticulum (ER) stress. Dietary SeMet supplementation increased the hepatic Se concentration and exhibited protective effects via promoting the expression of selenotranscriptome and several key selenoproteins (GPX4, TXNRD2, SELENOK, SELENOM, SELENOS, SELENOT, GPX1, DIO1, SELENOH, SELENOU and SELENOW). These key selenoproteins synergistically improved the antioxidant capacity, and mitigated the mitochondrial dysfunction, abnormal mitochondrial TCA cycle and ER stress, thus recovered the hepatic triglyceride and glycogen concentration. What's more, SeMet supplementation suppressed lipid and glycogen biosynthesis and promoted lipid and glycogen breakdown in liver of broilers exposed to CHS though regulating the AMPK signals. Overall, our present study reveals a potential mechanism that Se alleviates environment HS induced liver damage and glycogen and lipid metabolism disorders in broilers, which provides a preventive and/or treatment measure for environment HS-dependent hepatic metabolic disorders in poultry industry.

α-lipoic acid ameliorates consequences of copper overload by up-regulating selenoproteins and decreasing redox misbalance.

α-lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuel production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/- cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with an improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of a Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease.

Selenium in Prostate Cancer: Prevention, Progression, and Treatment.

Selenium, a trace mineral with various biological functions, has become a focal point in prostate cancer research. This review aims to present a comprehensive overview of selenium's involvement in prostate cancer, covering its impact on prevention, development, treatment, and underlying mechanisms. Observational studies have revealed a link between selenium levels and selenoproteins with prostate cancer progression. However, randomized controlled studies have shown that selenium supplementation does not prevent prostate cancer (HR: 0.95; 95% CI 0.80-1.13). This discrepancy might be attributed to selenoprotein single nucleotide polymorphisms. In the context of combinatorial therapy, selenium has demonstrated promising synergistic potential in the treatment of prostate cancer. Emerging evidence highlights the significant role of selenium and selenoproteins in prostate cancer, encompassing AR signaling, antioxidative properties, cell death, cell cycle regulation, angiogenesis, epigenetic regulation, immunoregulation, epithelial-mesenchymal transformation, and redox signal. In conclusion, selenium's diverse properties make it a promising trace mineral in prostate cancer prevention, development, and treatment and as a platform for exploring novel agents.

Association of Selenium Levels with Neurodegenerative Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Neurodegenerative diseases (NDs) have posed significant challenges to public health, and it is crucial to understand their mechanisms in order to develop effective therapeutic strategies. Recent studies have highlighted the potential role of selenium in ND pathogenesis, as it plays a vital role in maintaining cellular homeostasis and preventing oxidative damage. However, a comprehensive analysis of the association between selenium and NDs is still lacking. METHOD: Five public databases, namely PubMed, Web of Science, EMBASE, Cochrane and Clinical Trials, were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I2), Cochrane's Q test and Tau2 were calculated to evaluate the heterogeneity. RESULT: The association of selenium in ND patients with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) was studied. A statistically significant relationship was only found for AD patients (SMD = -0.41, 95% CI (-0.64, -0.17), p < 0.001), especially for erythrocytes. However, no significant relationship was observed in the analysis of the other four diseases. CONCLUSION: Generally, this meta-analysis indicated that AD patients are strongly associated with lower selenium concentrations compared with healthy people, which may provide a clinical reference in the future. However, more studies are urgently needed for further study and treatment of neurodegenerative diseases.

Selenoproteins and tRNA-Sec: regulators of cancer redox homeostasis.

In the past two decades significant progress has been made in uncovering the biological function of selenium. Selenium, an essential trace element, is required for the biogenesis of selenocysteine which is then incorporated into selenoproteins. These selenoproteins have emerged as central regulators of cellular antioxidant capacity and maintenance of redox homeostasis. This review provides a comprehensive examination of the multifaceted functions of selenoproteins with a particular emphasis on their contributions to cellular antioxidant capacity. Additionally, we highlight the promising potential of targeting selenoproteins and the biogenesis of selenocysteine as avenues for therapeutic intervention in cancer. By understanding the intricate relationship between selenium, selenoproteins, and reactive oxygen species (ROS), insights can be gained to develop therapies that exploit the inherent vulnerabilities of cancer cells.

Selenium, Selenoproteins and 10-year Cardiovascular Risk: Results from the ATTICA Study.

BACKGROUND: Selenium (Se) is an essential trace element that is involved in several pathophysiological functions. The relationship of Se with cardiovascular disease remains inconclusive, especially regarding the role of different selenospecies. OBJECTIVE: The present study assessed the levels of Se distribution in plasma selenoproteins, namely glutathione peroxidase 3 (GPx3), selenoprotein P (SelP) and selenoalbumin (SeAlb) and total Se in selenoproteins in relation to 10-year cardiovascular risk in the ATTICA prospective study. METHODS: A sub-sample from the ATTICA Study's database, consisting of 278 subjects (114 women and 164 men) with data on Se and selenoproteins levels, was considered. SeGPx3, SelP, and SeAlb in human plasma were simultaneously determined by high-performance liquid chromatography (HPLC) coupled with inductively coupled plasma mass spectrometry (ICP-MS) at baseline. The duration of the follow-up was 8.74 ±2.36 years (mean± standard deviation) and cardiovascular outcomes were recorded. Cox proportional hazards models were applied with total Se or selenoprotein Se as independent variables adjusted for several covariates. RESULTS: Total Se in selenoproteins was positively related to 10-year relative risk of cardiovascular disease (Hazard Ratios of 3rd vs 2nd tertile 10.02, 95% CI:1.15, 92.34). Subjects with high Se but low SeGPx3, as identified by discordant percentiles in the distribution of SeGPx3 and Se, had a higher cardiovascular risk. CONCLUSION: The differentiated effects of circulating selenoproteins on cardiovascular disease risk in the present study, suggest the importance of redox regulation by specific selenoproteins.