[Effect of high selenium on insulin signaling pathway PI3K-AKT-mTOR in L02 cells].

OBJECTIVE: To observe the effect of high selenium on insulin signaling pathway PI3K-AKT-mTOR in L02 cells. METHODS: One group of L02 cell was treated with different concentrations of selenomethionine(SeMet, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075 and 0.1µmol/L) for 48 h, then cultured with serum-free medium for 4 h and stimulated with 1 µmol/L insulin for 15 min. The insulin signaling pathway(PI3K-AKT-mTOR) was detected by WB. Another group of L02 cell was treated with the same concentrations of SeMet as above for 48 h. The cell supernatant and lysates were collected for the analysis of SELENOP and GPX1, respectively by WB. RESULTS: The expressions of P-AKT-(Ser-473), P-AKT-(Thr-308), PI3K and mTOR in L02 cells under high-Se were decreased with the increase of SeMet concentration. The expressions of GPX1 and SELENOP were enhanced with the increase of SeMet. CONCLUSION: The insulin signaling pathway, PI3K-AKT-mTOR, was damaged in L02 cell under high-Se stress.

Matched analysis of circulating selenium with the breast cancer selenotranscriptome: a multicentre prospective study.

INTRODUCTION: Low serum selenium and altered tumour RNA expression of certain selenoproteins are associated with a poor breast cancer prognosis. Selenoprotein expression stringently depends on selenium availability, hence circulating selenium may interact with tumour selenoprotein expression. However, there is no matched analysis to date. METHODS: This study included 1453 patients with newly diagnosed breast cancer from the multicentric prospective Sweden Cancerome Analysis Network - Breast study. Total serum selenium, selenoprotein P and glutathione peroxidase 3 were analysed at time of diagnosis. Bulk RNA-sequencing was conducted in matched tumour tissues. Fully adjusted Cox regression models with an interaction term were employed to detect dose-dependent interactions of circulating selenium with the associations of tumour selenoprotein mRNA expression and mortality. RESULTS: 237 deaths were recorded within ~ 9 years follow-up. All three serum selenium biomarkers correlated positively (p < 0.001). All selenoproteins except for GPX6 were expressed in tumour tissues. Single cell RNA-sequencing revealed a heterogeneous expression pattern in the tumour microenvironment. Circulating selenium correlated positively with tumour SELENOW and SELENON expression (p < 0.001). In fully adjusted models, the associations of DIO1, DIO3 and SELENOM with mortality were dose-dependently modified by serum selenium (p < 0.001, p = 0.020, p = 0.038, respectively). With increasing selenium, DIO1 and SELENOM associated with lower, whereas DIO3 expression associated with higher mortality. Association of DIO1 with lower mortality was only apparent in patients with high selenium [above median (70.36 µg/L)], and the HR (95%CI) for one-unit increase in log(FPKM + 1) was 0.70 (0.50-0.98). CONCLUSIONS: This first unbiased analysis of serum selenium with the breast cancer selenotranscriptome identified an effect-modification of selenium on the associations of DIO1, SELENOM, and DIO3 with prognosis. Selenium substitution in patients with DIO1-expressing tumours merits consideration to improve survival.

Sex-specific associations of serum selenium and selenoprotein P with type 2 diabetes mellitus and hypertension in the Berlin Aging Study II.

BACKGROUND: Selenium is essential for expression and proper function of a set of redox active selenoproteins implicated in aging-relevant diseases, e.g. type 2 diabetes mellitus (T2D) and hypertension. However, data in cohorts of older adults, particularly with respect to different Se biomarkers and sex-specific analyses are sparse. OBJECTIVE: To assess associations of serum Se and selenoprotein P (SELENOP) concentrations with T2D and hypertension in a cohort of older females and males. METHODS: This study included 1500 participants from the Berlin Aging Study II. Diagnosis of T2D was made in case of antidiabetic medication, self-reported T2D, or laboratory parameters. Diagnosis of hypertension was based on self-report, blood pressure measurement, or anti-hypertensive medication. Se was measured by spectroscopy, and SELENOP by ELISA. Multiple adjusted regression models quantified dose-dependent associations. RESULTS: Participants had a median(IQR) age of 68 (65,71) years, and 767 (51%) were women. 191 (13%) participants had T2D and 1126 (75%) had hypertension. Se and SELENOP correlated significantly (r = 0.59, p < 0.001), and were elevated in those with self-reported Se supplementation. Serum Se and SELENOP were not associated with T2D in the whole cohort. In men, SELENOP was positively associated with T2D, OR (95%CI) for one mg/L increase in SELENOP was 1.22 (1.00,1.48). Se was non-linearly associated with hypertension, comparing to the lowest quartile (Q1), and participants with higher Se levels (Q3) had a lower OR (95%CI) of 0.66 (0.45,0.96), which was specific for men. SELENOP positively associated with hypertension, and OR (95%CI) per one mg/L increase was 1.15 (1.01,1.32). CONCLUSIONS: The data suggest a sex-specific interrelationship of Se status with T2D and hypertension, with apparent biomarker-specific associations.

Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone.

Chronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination. Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) µg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3. We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.

SELENOP rs3877899 Variant Affects the Risk of Developing Advanced Stages of Retinopathy of Prematurity (ROP).

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.

SARS-CoV-2 Main Protease Targets Host Selenoproteins and Glutathione Biosynthesis for Knockdown via Proteolysis, Potentially Disrupting the Thioredoxin and Glutaredoxin Redox Cycles.

Associations between dietary selenium status and the clinical outcome of many viral infections, including SARS-CoV-2, are well established. Multiple independent studies have documented a significant inverse correlation between selenium status and the incidence and mortality of COVID-19. At the molecular level, SARS-CoV-2 infection has been shown to decrease the expression of certain selenoproteins, both in vitro and in COVID-19 patients. Using computational methods, our group previously identified a set of six host proteins that contain potential SARS-CoV-2 main protease (Mpro) cleavage sites. Here we show experimentally that Mpro can cleave four of the six predicted target sites, including those from three selenoproteins: thioredoxin reductase 1 (TXNRD1), selenoprotein F, and selenoprotein P, as well as the rate-limiting enzyme in glutathione synthesis, glutamate-cysteine ligase catalytic subunit (GCLC). Cleavage was assessed by incubating recombinant SARS-CoV-2 Mpro with synthetic peptides spanning the proposed cleavage sites, and analyzing the products via UPLC-MS. Furthermore, upon incubation of a recombinant Sec498Ser mutant of the full TXNRD1 protein with SARS-CoV-2 Mpro, the predicted cleavage was observed, destroying the TXNRD1 C-terminal redox center. Mechanistically, proteolytic knockdown of both TXNRD1 and GCLC is consistent with a viral strategy to inhibit DNA synthesis, conserving the pool of ribonucleotides for increased virion production. Viral infectivity could also be enhanced by GCLC knockdown, given the ability of glutathione to disrupt the structure of the viral spike protein via disulfide bond reduction. These findings shed new light on the importance of dietary factors like selenium and glutathione in COVID-19 prevention and treatment.

Selenium, Iodine and Iron-Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism.

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H2O2-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus-pituitary-thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as 'thyroxisome' at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

Effects of insufficient serine on health and selenoprotein expression in rats and their offspring.

Objective: To observe the impact of insufficient exogenous and/or endogenous serine on selenoprotein expression and health of pregnant rats and their offspring. Method: Experiment 1 was conducted in male rats, in which the dose-dependent effects of serine on selenoprotein expression and thyroid hormones (T3, T4 and TSH) were investigated by feeding either a serine adequate diet (20C), serine-deprived diet (20CSD) or 20CSD with different serine levels (0.5, 1.0, and 2.0 times the amount of serine in 20C). In experiment 2, a PHGDH inhibitor was administrated to pregnant rats fed either 20C or 20CSD. Blood and organ tissues of pregnant rats and offspring were subjected to the analyses of thyroid hormone, serine and homocysteine and GPx3 and SELENOP in plasma and expression of GPx1 and DIO1, 2 in tissues respectively. Result: In experiment 1, plasma SELENOP and GPx3 levels in adult male rats increased with the increasing dose of serine. Immunohistochemical results showed that GPx1 expression in liver and kidney of male rats also increased with increasing serine supplementation. Amongst all diet groups, only male rats fed 20CSD had significantly lower plasma TSH and T4 levels (P < 0.05). In experiment 2, GPx1 and DIO2 expression in the liver and kidney were suppressed in pregnant rats administered with a PHGDH compared to those who were not (P < 0.05). There were no significant differences in plasma T4 and T3 amongst all diet groups (P > 0.05). Also, offspring born to pregnant rats administered with a PHGDH inhibitor exhibited slower growth rates and hyperhomocysteinemia compared to offspring from mothers not administered with the inhibitor (P < 0.05). Conclusions: Insufficient exogenous serine through the diet decreased selenoprotein synthesis in adult male rats. However, this was not observed in pregnant rats, whereby exogenous or endogenous serine deficiency had no effect on the selenoprotein levels. A possible explanation is that dams may have an adaptive mechanism to limit maternal serine utilization and ensure adequate supply to the fetus.

Autoimmunity to selenoprotein P predicts breast cancer recurrence.

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

EGCG-derived polymeric oxidation products enhance insulin sensitivity in db/db mice.

The present study investigated the influence of epigallocatechin-3-gallate (EGCG) and its autoxidation products on insulin sensitivity in db/db mice. Compared to EGCG, autoxidation products of EGCG alleviated diabetic symptoms by suppressing the deleterious renal axis of the renin-angiotensin system (RAS), activating the beneficial hepatic axis of RAS, and downregulating hepatic and renal SELENOP and TXNIP. A molecular weight fraction study demonstrated that polymeric oxidation products were of essential importance. The mechanism of action involved coating polymeric oxidation products on the cell surface to protect against cholesterol loading, which induces abnormal RAS. Moreover, polymeric oxidation products could regulate RAS and SELENOP at doses that were far below cytotoxicity. The proof-of-principal demonstrations of EGCG-derived polymeric oxidation products open a new avenue for discovering highly active polymeric oxidation products based on the oxidation of naturally occurring polyphenols to manage diabetes and other diseases involving abnormal RAS.

Estado nutricional de indivíduos com Comprometimento Cognitivo Leve e Doença de Alzheimer em relação ao Selênio e sua associação com parâmetros que predispõem ao declínio cognitivo / Nutritional status of subjects with mild cognitive impairment and Alzheimer's disease in relation to selenium and its association with paramenters that predispose to cognitive decline

A Doença de Alzheimer (DA) é a principal forma de demência e um dos grandes desafios no sistema de saúde do século 21. O Comprometimento Cognitvo Leve (CCL) é um estágio que antecede a DA e que compartilha algumas vias metabólicas em comum. A fisiopatologia da DA é caracterizada pela ampla morte neuronal e pela presença de placas neuríticas e emaranhados neurofibrilares, respectivamente relacionadas ao acúmulo de peptídeo beta amiloide (Aß) em tecidos cerebrais e alterações no citoesqueleto que se originam da hiperfosforilação da proteína tau nos neurônios. Algumas linhas de evidência sustentam a hipótese de que o estresse oxidativo, nitrosativo e a inflamação tenham um papel importante na patogênese tanto do DA como do CCL. O selênio, mineral essencial ao ser humano, encontra-se incorporado ao sítio ativo de 25 selenoproteínas, das quais pelo menos um terço apresenta papel antioxidante, além de potencialmente modularem o sistema inflamatório. Deste modo, o estado nutricional adequado dos indivíduos relativo ao selênio, parece exercer efeito neuroprotetor, reduzindo o risco para o CCL e DA e retardando a progressão destas doenças. A entrega de selênio para o cérebro se dá pela interação da selenoproteína P (SELENOP) com o receptor de apolipoproteína E2 (ApoER2). A apolipoproteína E (ApoE) também interage com o ApoER2 no metabolismo de lipídeos. Assim, pode-se pensar que indivíduos portadores do polimorfismo do gene da apolipoproteína E ε4 (APOE ε4), o principal polimorfismo genético para o aumento no risco de desenvolvimento de DA, possam ter essa entrega de selênio prejudicada para o cérebro uma vez que os receptores ApoER2 dos portadores do polimorfismo de APOE ε4 são sequestrados para compartimentos intracelulares, sendo menos expressos na membrana plasmática e portanto diminuindo a interação com a SELENOP. Este trabalho teve por objetivo avaliar se a distribuição do selênio no plasma e líquor de indivíduos portadores de CCL e DA é afetada pelo alelo APOE ε4, avaliar se o estado nutricional do indivíduo em relação ao selênio afeta marcadores de assinatura biológica para DA (peptídeo beta amilóide, proteína tau e proteína tau fosforilada) e concentrações de citocinas inflamatórias. Para tanto, foram selecionadas amostras de plasma e líquor do banco de material biológico do Instituto de Psiquiatria da FMUSP, sendo 14 indivíduos do grupo CCL, 28 indivíduos do grupo DA e 28 indivíduos controles, de ambos os gêneros, com idade acima de 60 anos e residentes na cidade de São Paulo. Foram avaliados os seguintes marcadores: concentrações de selênio no plasma e líquor, concentrações SELENOP no plasma e líquor, citocinas inflamatórias, fator neurotrófico derivado do cérebro (BDNF) e marcadores de assinatura biológica para DA. Não foi evidenciada diferença entre os três diferentes grupos em relação ao selênio e a SELENOP da mesma forma que não houve influência do genótipo APOE ε4 nas concentrações de selênio e SELENOP, porém houve uma tendência de menores concentrações de selênio plasmático nos carreadores do alelo APOE ε4. Também houve uma tendência a uma menor pontuação nos testes MMSE e CAMCOG em indivíduos com menores concentrações plasmáticas de selênio. Não se evidenciou que o estado nutricional dos indivíduos em relação ao selênio influencie as concentrações de marcadores para assinatura biológica para DA e de citocinas inflamatórias, com exceção da IL-10 que apresentou correlação positiva com SELENOP plasmática. A partir desses resultados, conclui-se que o estado nutricional dos indivíduos relativo ao selênio parece não ter influencia significativa em aspectos do CCL e DA e que sua distribuição não é alterada pelo genótipo APOE ε4

Alzheimer's disease (AD) is the main form of dementia and one of the major challenges in the healthcare system of the 21st century. Mild Cognitive Impairment (MCI) is a stage that precedes AD and shares common metabolic pathways. The pathophysiology of AD is characterized by extensive neuronal death, presence of neuritic plaques and neurofibrillary tangles, respectively related to the accumulation of amyloid beta peptide (Aß) in brain tissues and changes in the cytoskeleton that originate from hyperphosphorylation of the Tau protein in neurons. Some lines of evidence support the hypothesis that oxidative, nitrosative stress and inflammation play an important role in the pathogenesis of both AD and MCI. Selenium, an essential mineral to humans, is incorporated into the active site of 25 selenoproteins, of which at least one third has an antioxidant role, in addition to its potential in modulating the inflammatory system. Therefore, the appropriate nutritional status related to selenium seems to exert a neuroprotective effect, reducing the risk for MCI and AD and decreasing the progression of these diseases. Selenium is delivered to the brain by the interaction of selenoprotein P (SELENOP) with the ApoE2 receptor (ApoER2). Apolipoprotein E (ApoE) also interacts with ApoER2 in lipid metabolism. Thus, it can be speculated that individuals that carry apolipoprotein E ε4 gene (APOE ε4), the main genetic polymorphism that increases the risk of AD, may have impaired selenium delivery to the brain since ApoER2 receptors of the APOE ε4 carriers are sequestered to intracellular compartments, being less expressed in the plasma membrane decreasing its interaction with SELENOP. This study aimed to assess whether the distribution of selenium in the plasma and CSF of subjects with MCI and AD is affected by the APOE ε4 allele, evaluate whether the nutritional status of selenium affects biological signature markers for AD (amyloid beta peptide, tau protein and phosphorylated tau protein) and to asses the concentrations of inflammatory cytokines. For this purpose, plasma and cerebrospinal fluid (CSF) samples were selected from the biological material bank of the Institute of Psychiatry of FMUSP, with 14 subjects from the MCI group, 28 from the DA group and 28 from control subjects, both genders, aged over 60 years and São Paulo residents. The following markers were evaluated: selenium concentrations in plasma and CSF, SELENOP concentrations in plasma and CSF, inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and biological signature for AD. There was no difference between the three different groups in relation to selenium and SELENOP; in addition, there was no influence of the APOE ε4 genotype on selenium and SELENOP concentrations, but there was a tendency towards lower plasma selenium concentrations in the APOE ε4 carriers. There was also a tendency for lower scores on the MMSE and CAMCOG tests in subjects with lower plasma selenium concentrations. It was not shown that selenium nutritional status influences the concentrations of biological signature for AD and inflammatory cytokines, with the exception of IL-10 which showed a positive correlation with plasma SELENOP. From these results, we concluded that selenium nutritional status does not seem to have a significant influence in aspects of MCI and DA and that its distribution is not altered by the APOE genotype ε4

lncRNA DLEU2 acts as a miR-181a sponge to regulate SEPP1 and inhibit skeletal muscle differentiation and regeneration.

Sarcopenia is a serious public health problem associated with the loss of muscle mass and function. The purpose of this study was to identify molecular markers and construct a ceRNA pathway as a significant predictor of sarcopenia. We designed a prediction model to select important differentially expressed mRNAs (DEMs), and constructed a sarcopenia associated ceRNA network. After correlation analysis of each element in the ceRNA network based on clinical samples and GTEX database, C2C12 mouse myoblasts were used as a model to verify the identified ceRNA pathways. A new model for predicting sarcopenia based on four molecular markers SEPP1, SV2A, GOT1, and GFOD1 was developed. The model was used to construct a ceRNA network and showed high accuracy. Correlation analysis showed that the expression levels of lncDLEU2, SEPP1, and miR-181a were closely associated with a high risk of sarcopenia. lncDLEU2 inhibits muscle differentiation and regeneration by acting as a miR-181a sponge regulating SEPP1 expression. In this study, a highly accurate prediction tool was developed to improve the prediction outcomes of sarcopenia. These findings suggest that the lncDLEU2-miR-181a-SEPP1 pathway inhibits muscle differentiation and regeneration. This pathway may be a new therapeutic target for the treatment of sarcopenia.

His-Rich Domain of Selenoprotein P Ameliorates Neuropathology and Cognitive Deficits by Regulating TrkB Pathway and Zinc Homeostasis in an Alzheimer Model of Mice.

Selenoproteins are a family of special proteins that contain the 21st amino acid, selenocysteine (Sec), in their sequence. Selenoprotein P has 10 Sec residues and modulates selenium homeostasis and redox balance in the brain. Previously, we found that the Sec-devoid His-rich motif of selenoprotein P (Selenop-H) suppressed metal-induced aggregation and neurotoxicities of both Aß and tau in vitro. To investigate the intervening capacity of Selenop-H on the neuropathology and cognitive deficits of triple transgenic AD (3 × Tg-AD) mice, the Selenop-H gene packaged in rAAV9 was delivered into the hippocampal CA3 regions of mice via stereotaxic injection. Four months later, we demonstrated that Selenop-H (1) improved the spatial learning and memory deficits, (2) alleviated neuron damage and synaptic protein loss, (3) inhibited both tau pathology and amyloid beta protein (Aß) aggregation, (4) activated both BDNF- and Src-mediated TrkB signaling, and (5) increased MT3 and ZnT3 levels and restored Zn2+ homeostasis in the mice model of AD. The study revealed that Selenop-H is potent in ameliorating AD-related neuropathology and cognitive deficits by modulating TrkB signaling and Zn2+ homeostasis.

Selenium deficiency is linearly associated with hypoglycemia in healthy adults.

OBJECTIVE: The trace element selenium (Se) is needed for regular biosynthesis of selenoproteins, which contribute to antioxidative defense systems and affect redox-regulated signaling. Elevated Se intake and selenoprotein expression levels have been associated with impaired hydrogen peroxide-dependent signaling by insulin, leading to hyperglycemia and insulin resistance. The relation of low Se intake with glucose status and carbohydrate metabolism is poorly known. RESEARCH DESIGN AND METHODS: A cross sectional analysis among healthy subjects residing in two Chinese counties with different habitual Se intakes was conducted. Fasted glucose levels were related to Se concentrations of 5686 adults by linear regression analysis with Se, body mass index, age, thyroid status, insulin and sex as independent variables. RESULTS: Serum Se correlated strongly and positively with glucose in the Se-deficient population. There was no strong relationship of Se and glucose in the non-deficient population. Overt hypoglycemia (serum glucose < 2.8 mM) was observed in 19.2% of this random sample of subjects in the Se-deficient and in 1.4% of the moderately supplied population, respectively. CONCLUSIONS: An adequate Se supply constitutes an important factor for glucose homeostasis in human subjects. The interaction between Se status and glucose control is not limited to hyperglycemia, but apparently extends to hypoglycemia risk in Se deficiency. This newly identified relationship may be of relevance for the course of severe disease including major trauma, sepsis and COVID-19, where Se deficiency has been associated with mortality risk.

Metabolomics signature associated with circulating serum selenoprotein P levels.

PURPOSE: Selenoprotein P (SELENOP) has been previously related to various metabolic traits with partially conflicting results. The identification of SELENOP-associated metabolites, using an untargeted metabolomics approach, may provide novel biological insights relevant to disentangle the role of SELENOP in human health. METHODS: In this cross-sectional study, 572 serum metabolites were identified by comparing the obtained LC-MS/MS spectra with spectra stored in Metabolon's spectra library. Serum SELENOP levels were measured in 832 men and women using an ELISA kit. RESULTS: Circulating SELENOP levels were associated with 24 out of 572 metabolites after accounting for the number of independent dimensions in the metabolomics data, including inverse associations with alanine, glutamate, leucine, isoleucine and valine, an unknown compound X-12063, urate and the peptides gamma-glutamyl-leucine, and N-acetylcarnosine. Positive associations were observed between SELENOP and several lipid compounds. Of the identified metabolites, each standard deviation increase in the branched-chain amino acids (isoleucine, leucine, valine), alanine and gamma-glutamyl-leucine was related to higher odds of having T2DM [OR (95% CI): 1.96 (1.41-2.73); 1.62 (1.15-2.28); 1.94 (1.45-2.60), 1.57 (1.17-2.11), and 1.52 (1.13-2.05), respectively]. CONCLUSIONS: Higher serum SELENOP levels were associated with an overall healthy metabolomics profile, which may provide further insights into potential mechanisms of SELENOP-associated metabolic disorders.

The Selenium Transport Protein, Selenoprotein P, Requires Coding Sequence Determinants to Promote Efficient Selenocysteine Incorporation.

Selenoproteins are an essential and unique group of proteins in which selenocysteine (Sec) is incorporated in response to a stop codon (UGA). Reprograming of UGA for Sec insertion in eukaryotes requires a cis-acting stem-loop structure in the 3' untranslated region of selenoprotein mRNA and several trans-acting factors. Together these factors are sufficient for Sec incorporation in vitro, but the process is highly inefficient. An additional challenge is the synthesis of selenoprotein P (SELENOP), which uniquely contains multiple UGA codons. Full-length SELENOP expression requires processive Sec incorporation, the mechanism for which is not understood. In this study, we identify core coding region sequence determinants within the SELENOP mRNA that govern SELENOP synthesis. Using 75Se labeling in cells, we determined that the N-terminal coding sequence (upstream of the second UGA) and C-terminal coding sequence context are two independent determinants for efficient synthesis of full-length SELENOP. In addition, the distance between the first UGA and the consensus signal peptide is also critical for efficiency.

Genetic polymorphism in selenoprotein P modifies the response to selenium-rich foods on blood levels of selenium and selenoprotein P in a randomized dietary intervention study in Danes.

BACKGROUND: Selenium is an essential trace element and is suggested to play a role in the etiology of a number of chronic diseases. Genetic variation in genes encoding selenoproteins, such as selenoprotein P and the glutathione peroxidases, may affect selenium status and, thus, individual susceptibility to some chronic diseases. In the present study, we aimed to (1) investigate the effect of mussel and fish intake on glutathione peroxidase enzyme activity and (2) examine whether single nucleotide polymorphisms in the GPX1, GPX4, and SELENOP genes modify the effect of mussel and fish intake for 26 weeks on whole blood selenium, plasma selenoprotein P concentrations, and erythrocyte GPX enzyme activity in a randomized intervention trial in Denmark. RESULTS: CC homozygotes of the SELENOP/rs3877899 polymorphism who consumed 1000 g fish and mussels per week for 26 consecutive weeks had higher levels of both selenoprotein P (difference between means - 4.68 ng/mL (95% CI - 8.49, - 0.871)) and whole blood selenium (difference between means - 5.76 (95% CI - 12.5, 1.01)) compared to fish and mussel consuming T-allele carriers although the effect in whole blood selenium concentration was not statistically significant. CONCLUSIONS: Our study indicates that genetically determined variation in SELENOP leads to different responses in expression of selenoproteins following consumption of selenium-rich foods. This study also emphasizes the importance of taking individual aspects such as genotypes into consideration when assessing risk in public health recommendations.

Up-regulation of selenoprotein P and HIP/PAP mRNAs in hepatocytes by intermittent hypoxia via down-regulation of miR-203.

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human hepatocytes (JHH5, JHH7, and HepG2) to experimental IH or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction (RT-PCR), and found that IH significantly increased the mRNA levels of selenoprotein P (SELENOP) - a hepatokine - and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) - one of REG (Regenerating gene) family. We next investigated promoter activities of both genes and discovered that they were not increased by IH. On the other hand, a target mRNA search of micro RNA (miRNA) revealed that both mRNAs have a potential target sequence for miR-203. The miR-203 level of IH-treated cells was significantly lower than that of normoxia-treated cells. Thus, we introduced miR-203 inhibitor and a non-specific control RNA (miR-203 inhibitor NC) into HepG2 cells and measured the mRNA levels of SELENOP and HIP/PAP. The IH-induced expression of SELENOP and HIP/PAP was abolished by the introduction of miR-203 inhibitor but not by miR-203 inhibitor NC. These results demonstrate that IH stress up-regulates the levels of SELENOP in human hepatocytes to accelerate insulin resistance and up-regulates the levels of HIP/PAP mRNAs to proliferate such hepatocytes, via the miR-203 mediated mechanism.

A case-control study of selenoprotein genes polymorphisms and autoimmune thyroid diseases in a Chinese population.

BACKGROUND: Selenium is an essential trace and there is a high selenium concentration in the thyroid gland. Selenium deficiency may impair the thyroid function. The aim of this study was to investigate the association between three selenoprotein genes polymorphisms and autoimmune thyroid diseases. METHODS: We genotyped six single-nucleotide polymorphisms (SNPs), rs6865453 in selenoprotein P gene (SELENOP), rs713041 rs2074451 rs3746165 in glutathione peroxidase 4 gene (GPX4) and rs28665122 and rs7178239 in selenoprotein S gene (SELENOS) by MassARRAY system using the chip-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry technology in 1060 patients with autoimmune thyroid diseases and 938 healthy controls. RESULTS: Major alleles in rs6865453 of SELENOP, rs713041, rs2074451, rs3746165 of GPX4 decreased while the major allele C in rs28665122 of SELENOS increased in AITD patients than in the control. The allele C and genotype CC in rs7178239 of SELENOS showed different trend in GD and HT patients when compared with the control. All the distribution difference showed nonsignificant. Analysis according to clinical features including ophthalmopathy, hypothyroidism and family history came out to be negative either. CONCLUSIONS: Our findings suggest non-association between three selenoprotein genes and AITD, conflicting to the positive result in another population. Different selenium nutrition status in different populations may contribute to conflicting results, the contribution of genetic variants in AITD mechanism may be another reason.