The redox-active defensive Selenoprotein T as a novel stress sensor protein playing a key role in the pathophysiology of heart failure.

Maladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute cardiac protection. However, its action in chronic settings of cardiac dysfunction is not understood. Here, we investigated the role of SELENOT in the pathophysiology of HF: (i) by designing a small peptide (PSELT), recapitulating SELENOT activity via the redox site, and assessed its beneficial action in a preclinical model of HF [aged spontaneously hypertensive heart failure (SHHF) rats] and against isoproterenol (ISO)-induced hypertrophy in rat ventricular H9c2 and adult human AC16 cardiomyocytes; (ii) by evaluating the SELENOT intra-cardiomyocyte production and secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, and the severe ultrastructural alterations, while counteracting key mediators of cardiac fibrosis, aging, and DNA damage and restoring desmin downregulation and SELENOT upregulation in the failing hearts. In the hemodynamic assessment, PSELT improved the contractile impairment at baseline and following ischemia/reperfusion injury, and reduced infarct size in normal and failing hearts. At cellular level, PSELT counteracted ISO-mediated hypertrophy and ultrastructural alterations through its redox motif, while mitigating ISO-triggered SELENOT intracellular production and secretion, a phenomenon that presumably reflects the extent of cell damage. Altogether, these results indicate that SELENOT could represent a novel sensor of hypertrophied cardiomyocytes and a potential PSELT-based new therapeutic approach in myocardial hypertrophy and HF.

The role of selenoprotein M in nickel-induced pyroptosis in mice spleen tissue via oxidative stress.

Nickel (Ni) is a heavy metal element and a pollutant that threatens the organism's health. Melatonin (Mel) is an antioxidant substance that can be secreted by the organism and has a protective effect against heavy metals. Selenoprotein M (SelM) is a selenoprotein widely distributed of the body, and its role is to protect these tissues from oxidative damage. To study the mechanism of Ni, Mel, and SelM in mouse spleen, 80 SelM+/+ wild-type and 80 SelM-/- homozygous mice were divided into 8 groups with 20 mice in each group. The Ni group was intragastric at a concentration of 10 mg/kg, while the Mel group was intragastric at 2 mg/kg. Mice were injected with 0.1 mL/10 g body weight for 21 days. Histopathological and ultrastructural observations showed the changes in Ni, such as the destruction of white and red pulp and the appearance of pyroptosomes. SelM knockout showed more severe injury, while Mel could effectively interfere with Ni-induced spleen toxicity. The results of antioxidant capacity determination showed that Ni could cause oxidative stress in the spleen, and Mel could also effectively reduce oxidative stress. Finally, Ni exposure increased the expression levels of the pyroptotic genes, including apoptosis-associated speck protein (ASC), absent in melanoma-2 (AIM2), NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), Caspase-1, interleukin- (IL-) 18, and IL-1ß (p < 0.05). Loss of SelM significantly increased these (p < 0.05), while Mel decreased the alleviated impact of Ni. In conclusion, the loss of SelM aggravated Ni-induced pyroptosis of the spleen via activating oxidative stress, which was alleviated by Mel, but the effect of Mel was not obvious in the absence of SelM, which reflected the important role of SelM in Ni-induced pyroptosis.

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation.

Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.

The relieving effect of sun-dried protein tonic on sports fatigue / O efeito calmante na fadiga esportiva da proteína tônica secada ao sol / El efecto calmante en la fatiga deportiva de la proteína tónica secada al sol

ABSTRACT Fatigue is a comprehensive process that involves many physiological and biochemical factors. It is a normal physiological reaction when human physical or mental activities reach a certain level. In recent years, it has been verified that free radicals are closely related to exercise-induced fatigue. Cardamine bursa purified selenoprotein has good oxygen-free radical scavenging ability and anti-lipid peroxide. It could protect mitochondria, liver, and red blood cells from peroxide injury. Therefore, it was speculated that the purification of selenoprotein Cardamine may play an active role in attenuating exercise-induced fatigue by scavenging free radicals. This study cleared the selenite protein Capsella bursa (SPC) as a research object, and evaluated its structural characteristics in relieving exercise-induced fatigue. The selenoprotein index system for exercise-induced fatigue was constructed by combining two AHP methods, principal component analysis and factor analysis. Purity, subunit composition, amino acid composition and RCM content were evaluated. The corresponding RCM protein was preliminarily predicted. The results showed that SPCH could significantly prolong the swimming time (P <0.01), improve the lactate clearance capacity (P <0.01), increase the glycogen content of the liver (P <0.01), and reduce the level of the BUN (P <0.05). SPCH has a good effect in relieving exercise-induced fatigue in mice, so it can be considered for development as a nutritional supplement to alleviate exercise-induced fatigue.

RESUMO Fadiga é um processo abrangente envolvendo muitos fatores fisiológicos e bioquímicos. É uma reação fisiológica normal quando as atividades físicas ou mentais humanas atingem um certo nível. Nos últimos anos, verificou-se que os radicais livres estão intimamente relacionados com a fadiga induzida pelo exercício. A selenoproteina purificada de Cardamina bursa tem boa capacidade de depuração de radicais sem oxigénio e de peróxido anti-lípido. Poderia proteger as mitocôndrias, fígado e glóbulos vermelhos de lesões por peróxido. Por conseguinte, especulou-se que a purificação da selenoproteina de Cardamina pode desempenhar um papel activo na atenuação da fadiga induzida pelo exercício por meio de radicais livres de scavenging. Este estudo depurou a proteína selenita Capsella bursa (SPC) como objeto de pesquisa, e avaliou as suas características estruturais no alívio da fadiga induzida pelo exercício. O sistema de índice de selenoproteinas para a fadiga induzida pelo exercício foi construído por meio da combinação dos métodos de AHP, análise principal de componentes e a análise de fatores. Foram avaliados a pureza, a composição sub-unitária, a composição de aminoácidos e o conteúdo do RCM. A proteína correspondente do RCM foi prevista preliminarmente. Os resultados mostraram que o SPCH poderia prolongar significativamente o tempo de natação (P < 0.01), melhorar a capacidade de depuração do lactato (P< 0.01), aumentar o conteúdo do glicogênio do fígado (P < 0.01), e reduzir o nível do BUN (P< 0.05). o SPCH tem um bom efeito em aliviar a fadiga induzida pelo exercício em ratos, de modo que pode ser considerado para desenvolvê-lo como um suplemento nutricional para aliviar a fadiga induzida pelo exercício.

RESUMEN La fatiga es un proceso abarcador que envuelve muchos factores fisiológicos y bioquímicos. Es una reacción fisiológica normal cuando las actividades físicas o mentales humanas alcanzan un cierto nivel. En los últimos anos, se verificó que los radicales libres están íntimamente relacionados con la fatiga inducida por el ejercicio. La selenoproteína purificada de Cardamina bursa tiene buena capacidad de depuración de radicales sin oxígeno y de peróxido antilipídico. Podría proteger las mitocondrias, el hígado y los glóbulos rojos de lesiones por peróxido. Por consiguiente, se especuló que la purificación de la selenoproteína de Cardamina puede desempeñar un papel activo en la atenuación de la fatiga inducida por el ejercicio por medio de radicales libres de scavenging. Este estudio depuró la proteína selenita Capsella bursa (SPC) como objeto de investigación, y evaluó sus características estructurales en el alivio de la fatiga inducida por el ejercicio. El sistema de índice de selenoproteínas para a fatiga inducida por el ejercicio fue construido por medio de la combinación dos métodos de AHP, el análisis principal de componentes y el análisis de factores. Fueron evaluados la pureza, la composición sub-unitaria, la composición de aminoácidos y el contenido del RCM. La proteína correspondiente del RCM fue prevista preliminarmente. Los resultados mostraron que el SPCH podría prolongar significativamente el tiempo de natación (P < 0.01), mejorar la capacidad de depuración del lactato (P< 0.01), aumentar el contenido del glicógeno del hígado (P < 0.01), y reducir el nivel del BUN (P< 0.05). el SPCH tiene un buen efecto en aliviar la fatiga inducida por el ejercicio en ratones, de modo que puede ser considerado para desarrollarlo como un suplemento nutricional para aliviar la fatiga inducida por el ejercicio.

Biosynthesis of selenoproteins by Saccharomyces cerevisiae and characterization of its antioxidant activities.

The study investigated biosynthesis of selenoproteins by Saccharomyces. cerevisiae using inorganic selenium. Selenium supplement via two stages was carried out during fermentation and the physicochemical characteristics of selenoproteins and its antioxidant activities were examined through in vitro assessment procedures. After fermentation, dry cells weight (7.47 g/L) and selenium content (3079.60 µg/kg) in the yeast were achieved when fermentation time points at the 6th hour and the 9th hour were chosen to supplement 30% and 70% of 30 µg/mL Na2SeO3 respectively. A maximal yield of selenium content in selenoproteins reached 1013.07 µg/g under optimized culture conditions and was 133-fold higher than the control. One new band with molecular weight of 26.76 KDa appeared in conjugated selenoproteins of sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Surface structure of selenoproteins and the control was different by Scanning electron microscopy images. Infrared spectrometry analysis demonstrated that groups of HSe, SeO and C-Se-O involved in selenoproteins were important pieces of evidence showing presence of Se embedded in the protein molecule. Selenoproteins showed strong antioxidant activities on DPPH·, OH and ·O2-, which was much higher than the control proteins. Therefore, the study provided an efficient selenium-enriched culture method of inorganic selenite to organic selenium and basis for selenoproteins applications.

Neuroprotective effects of two selenium-containing peptides, TSeMMM and SeMDPGQQ, derived from selenium-enriched rice protein hydrolysates on Pb2+-induced oxidative stress in HT22 cells.

Immunomodulatory peptides with the sequences TSeMMM and SeMDPGQQ from selenium (Se)-enriched rice protein hydrolysates (SPHs) were identified in our previous study. We synthesized these two peptides to study whether they have neuroprotective effects on Pb2+-induced oxidative stress in mouse hippocampal HT22 cells, SPHs and a purified SPH fraction (SPHs-2) were used to compare the effects. Peptides pretreatments significantly suppressed Pb2+-induced cytotoxicity by increasing cell viability and decreasing cell apoptosis. TSeMMM and SeMDPGQQ reduced nitric oxide (NO) levels by 37.47% and 14.72% of Pb2+ group, as well as lactate dehydrogenase (LDH) release by 12.98% and 6.32% of Pb2+ group. TSeMMM and SeMDPGQQ could increase the activities of antioxidant enzymes; for example, the activity of superoxide dismutase (SOD) increased by 47.79% and 13.93%, respectively, and that of glutathione peroxidase (GSH-Px) increased by 94.7% and 78.73% of Pb2+ group. Additionally, nuclear factor erythroid 2-related factor (Nrf2) nuclear translocation and heme oxygenase 1 (HO-1) expression were triggered. These results suggest that TSeMMM and SeMDPGQQ can suppress oxidative damage caused by Pb2+; moreover, TSeMMM showed better neuroprotective potential than SeMDPGQQ.

Selenoprotein T as a new positive inotrope in the goldfish, Carassius auratus.

Selenoprotein T (SELENOT) is a thioredoxin-like protein, which mediates oxidoreductase functions via its redox active motif Cys-X-X-Sec. In mammals, SELENOT is expressed during ontogenesis and progressively decreases in adult tissues. In the heart, it is re-expressed after ischemia and induces cardioprotection against ischemia-reperfusion (IR) injury. SELENOT is present in teleost fish, including the goldfish Carassius auratus This study aimed to evaluate the cardiac expression of SELENOT, and the effects of exogenous PSELT (a 43-52 SELENOT-derived peptide) on the heart function of C. auratus, a hypoxia tolerance fish model. We found that SELENOT was expressed in cardiac extracts of juvenile and adult fish, located in the sarcoplasmic reticulum (SR) together with calsequestrin-2. Expression increased under acute hypoxia. On ex vivo isolated and perfused goldfish heart preparations, under normoxia, PSELT dose dependently increased stroke volume (VS), cardiac output [Formula: see text] and stroke work (SW), involving cAMP, PKA, L-type calcium channels, SERCA2a pumps and pAkt. Under hypoxia, PSELT did not affect myocardial contractility. Only at higher concentrations (10-8 to 10-7 mol l-1) was an increase of VS and [Formula: see text] observed. It also reduced the cardiac expression of 3-NT, a tissue marker of nitrosative stress, which increases under low oxygen availability. These data are the first to propose SELENOT 43-52 (PSELT) as a cardiac modulator in fish, with a potential protective role under hypoxia.

A selenoprotein T-derived peptide protects the heart against ischaemia/reperfusion injury through inhibition of apoptosis and oxidative stress.

AIM: Selenoprotein T (SelT or SELENOT) is a novel thioredoxin-like enzyme whose genetic ablation in mice results in early embryonic lethality. SelT exerts an essential cytoprotective action during development and after injury through its redox-active catalytic site. This study aimed to determine the expression and regulation of SelT in the mammalian heart in normal and pathological conditions and to evaluate the cardioprotective effect of a SelT-derived peptide, SelT43-52(PSELT) encompassing the redox motif which is key to its function, against ischaemia/reperfusion(I/R) injury. METHODS: We used the isolated Langendorff rat heart model and different analyses by immunohistochemistry, Western blot and ELISA. RESULTS: We found that SelT expression is very abundant in embryo but is undetectable in adult heart. However, SelT expression was tremendously increased after I/R. PSELT (5 nmol/L) was able to induce pharmacological post-conditioning cardioprotection as evidenced by a significant recovery of contractility (dLVP) and reduction of infarct size (IS), without changes in cardiac contracture (LVEDP). In contrast, a control peptide lacking the redox site did not confer cardioprotection. Immunoblot analysis showed that PSELT-dependent cardioprotection is accompanied by a significant increase in phosphorylated Akt, Erk-1/2 and Gsk3α-ß, and a decrement of p38MAPK. PSELT inhibited the pro-apoptotic factors Bax, caspase 3 and cytochrome c and stimulated the anti-apoptotic factor Bcl-2. Furthermore, PSELT significantly reduced several markers of I/R-induced oxidative and nitrosative stress. CONCLUSION: These results unravel the role of SelT as a cardiac modulator and identify PSELT as an effective pharmacological post-conditioning agent able to protect the heart after ischaemic injury.

Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology.

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-ß plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

Selenoglycoproteins attenuate adhesion of tumor cells to the brain microvascular endothelium via a process involving NF-κB activation.

Selenium-containing compounds and selenized yeast have anticancer properties. In order to address possible mechanisms involved in these effects, selenoglycoproteins (SGPs) were extracted from selenium-enriched yeast at pH 4.0 and 6.5 (the fractions are called SGP40 and SGP65, respectively), followed by evaluation of their impact on the interactions of lung and breast tumor cells with human brain microvascular endothelial cells (HBMECs). Extracted SGPs, especially SGP40, significantly inhibited adhesion of tumor cells to HBMECs and their transendothelial migration. Because the active components of SGPs are unknown, small selenium-containing compounds [leucyl-valyl-selenomethionyl-arginine (LVSe-MR) and methylselenoadenosine (M-Se-A)], which are normally present in selenized yeast, were introduced as additional treatment groups. Treatment of HBMECs with SGP40, LVSe-MR and M-Se-A induced changes in gene signatures, which suggested a central involvement of nuclear factor (NF)-κB-dependent pathway. These observations were confirmed in the subsequent analysis of NF-κB DNA binding activity, quantitative measurements of the expression of selected genes and proteins, and tumor cell adhesion assay with a specific NF-κB inhibitor as the additional treatment factor. These findings indicate that specific organic selenium-containing compounds have the ability to inhibit tumor cell adhesion to brain endothelial cells via down-regulation of NF-κB. SGPs appear to be more effective than small selenium-containing compounds, suggesting the role of not only selenium but also the glycoprotein component in the observed protective impact.

Efeitos do consumo de castanha-do-brasil ( Bertholetia excelsa H. B. K. ) sobre o estresse oxidativo em pacientes com comprometimento cognitivo leve e a relação com variações em genes de selenoproteínas / Effects of the intake of Brazil nut (Bertholetia excels H. B. K) on the oxidative stress in patients with mild cognitive impairment and its relation with polymorphisms in selenoprotein genes

Visto que o estresse oxidativo está intimamente relacionado com a progressão da demência, este se apresenta como um possível alvo terapêutico a fim de preservar as funções cognitivas. No mesmo sentido, estudos mostram o papel antioxidante do selênio, mineral que atua por meio das selenoproteínas, com destaque para a família de enzimas antioxidantes glutationa peroxidase (GPx) e a selenoproteína responsável pelo transporte de selênio, a selenoproteína P (SePP). Entretanto, diferentes genótipos dos genes que codificam essas selenoproteínas podem refletir em diferentes respostas diante de intervenções alimentares. Assim, este trabalho teve como objetivo verificar os efeitos da suplementação com castanha-do-brasil sobre o estresse oxidativo em pacientes com comprometimento cognitivo leve (CCL) e verificar sua relação com os polimorfismos rs1050450 (Pro198Leu) no gene da GPx1, rs3877899 e rs7579 no gene da selenoproteína P. Participaram do estudo 31 indivíduos com CCL, voluntários, de ambos os sexos, frequentadores do Ambulatório de Memória do Idoso do Serviço de Geriatria da Faculdade de Medicina da Universidade de São Paulo, com idade igual ou superior a 60 anos, que foram distribuídos aleatoriamente entre os grupos Castanha e Controle. O grupo Castanha recebeu uma unidade de castanha-do-brasil por dia durante seis meses. Foram avaliados os seguintes marcadores: determinação de selênio no plasma e nos eritrócitos, atividade da GPx eritrocitária, avaliação dos níveis de oxygen radical absorbance capacity (ORAC) e de malondialdeído (MDA) plasmáticos, perfil lipídico sérico e expressão gênica de GPx1 e SePP. Além disso, os participantes foram submetidos à avaliação cognitiva e genotipados quanto aos polimorfismos rs1050450, rs3877899 e rs7579. Cada unidade de castanha-do-brasil forneceu 288,75µg de selênio. Dentre os 31 participantes selecionados, apenas 20 concluíram o estudo, e observou-se que, antes da intervenção, os grupos de estudo não apresentavam diferença quanto aos níveis de selênio no plasma e no eritrócito, bem como na atividade da GPx e nos níveis plasmáticos de ORAC e de MDA. Porém, após a suplementação, verificou-se aumento significativo no selênio plasmático (290,6±74,6) e eritrocitário (574,6±181,4) e na atividade da GPx (59,55±20,79) no grupo Castanha, diferente do grupo Controle (47,48±11,7 no plasma; 33,5±16,1 no eritrócito; 42,54±13,05 atividade da GPx). Em relação ao MDA, verificou-se que ambos os grupos apresentaram aumento após a intervenção, porém não significativo. No caso do ORAC, não se verificou alteração entre os grupos após os seis meses. O escore CERAD, que avalia desempenho cognitivo, não foi diferente entre os grupos após o tratamento, entretanto as mudanças observadas na fluência verbal e na praxia construtiva ao longo do acompanhamento foram mais favoráveis no grupo Castanha. A frequência dos genótipos de referência foram 40% para Pro198Leu, 55% para rs7579 e 60% para rs3877899. Não foram identificadas diferenças entre os níveis de selênio, de atividade da GPx, de MDA e de ORAC entre os genótipos, porém em análise multivariada verificou-se que o alelo variante do Pro198Leu se relacionou com aumento de 0,613 dp na concentração de selênio no plasma no baseline. A influência dos polimorfismos na resposta à intervenção com castanha-do-brasil foi avaliada nos 11 participantes do grupo Castanha, e observou-se que os genótipos não influenciaram na resposta quanto os níveis de selênio plasmático e eritrocitário, bem como de MDA. Entretanto, quanto à atividade da GPx, embora todos os genótipos tenham apresentado aumento após a intervenção, isso não foi significativo para o genótipo dominante do rs7579 e para o variante do rs3877899. A expressão de GPx1 e de SePP também foi diferente entre os genótipos: indivíduos com alelo variante do Pro198Leu apresentaram redução da expressão da GPx1, enquanto carreadores do genótipo homozigoto dominante tiveram aumento. Também percebeu-se que a expressão da SePP foi reduzida em todos os genótipos, entretanto essa mudança foi mais relevante para os genótipos variantes do Pro198Leu e rs7579 e para o genótipo GG do rs3877899. A partir desses resultados, concluiu-se que o consumo de apenas uma castanha-do-brasil diariamente, durante seis meses, é suficiente para recuperar o estado nutricional relativo ao selênio, e isso parece ter efeitos positivos sobre a cognição em idosos com CCL. Além disso, observou-se que o polimorfismo Pro198Leu no gene da GPx1 parece influenciar o estado nutricional quanto ao selênio, bem como a expressão de GPx, enquanto que os polimorfismos rs7579 e rs3877899 parecem não influenciar, de maneira significativa, o metabolismo de selênio frente ao consumo de castanha-do-brasil

Since oxidative stress is closely related to progression of dementia, the antioxidant system may be a potential therapeutic target to preserve cognitive function. In this way, studies show the antioxidant role of selenium, which plays as selenoproteins especially glutathione peroxidase (GPx) family and selenoprotein P (SePP). However, different genotypes of selenoprotein genes may result in different response to dietary intake. Therefore, this work aimed to verify the effects of Brazil nuts intake on oxidative stress and the role of the polymorphisms rs1050450 (Pro198Leu) in GPx1 gene and rs7579 and rs3877899 in SePP gene in mild cognitive impairment (MCI) patients. Study subjects comprised 31 voluntary patients with MCI who attended the Memory and Aging Unit of the Geriatrics Division, University of São Paulo Medical School (Brazil). They were randomly assigned to ingestion of Brazil nuts or to the control group. Brazil nuts group received one nut daily during six months. The following parameters were analysed: selenium concentration in plasma and erythrocyte, GPx activity in erythrocyte, plasmatic levels of oxygen radical absorbance capacity (ORAC) and of malondialdedyde (MDA), serum lipid profile. Besides, we evaluated cognitive performance and the patients were genotyped to rs1050450, rs3877899 e rs7579 polymorphisms. Each Brazil nut provided 288.75µg of selenium. Among 31 enrolled participants, only 20 finished the study. No differences regarding selenium levels, GPx activity, ORAC and MDA levels were observed at baseline between groups. However, after treatment, we observed significant increase in selenium in plasma (290.6±74.6) and in erythrocyte (574.6±181.4) and in GPx activity (59.55±20.79) in treated group, unlike control group (47.48±11.70 selenium in plasma; 33.5±16.1 selenium in erythrocyte; 42.54±13.05 GPx activity). Although not significant, MDA level increased after 6 months in both groups and ORAC levels were not different across time. CERAD total score was not different across time between groups, however changes in verbal fluency and constructional praxis subtests across time were significantly more favorable on the supplemented group when compared with control group. The frequency of dominant genotypes for Pro198Leu, rs7579 and rs3877899 were 40%, 55% and 60%, respectively. We did not observe differences regarding to selenium ORAC and MDA levels and GPx activity among genotypes, however after linear regression analysis the presence of variant allele of Pro198Leu was associated with an increase of 0.613 SD in selenium plasma level at baseline. The effect of polymorphisms in response to Brazil nut intake was analysed in Brazil nut group, and we observed that sele nium and MDA levels were not affected by polymorphisms. However although GPx activity increased in all genotype groups, this was not significant in dominant genotype of rs7579 and variant genotypes of rs3877899. GPx1 and SePP expression was also different among groups across time: variant allele of Pro198Leu presented decreased expression of GPx1 while dominant homozygous presented increase of expression. We also observed that SePP expression was reduced in all genotypes, but his was more important in variant genotypes of Pro198Leu and rs7579 and in GG genotype of rs3877899. From these results, we can conclude that consumption of only one Brazil nut is enough to restore selenium status, and this may be positive effects on cognition performance. Furthermore we observed that Pro198Leu polymorphism may influence selenium nutritional status and GPx activity whereas rs7579 and rs3877899 polymorphisms did not have an effect on selenium metabolism after Brazil nut intake

Expanding chemical diversity of conotoxins: peptoid-peptide chimeras of the sodium channel blocker µ-KIIIA and its selenopeptide analogues.

The µ-conotoxin KIIIA is a three disulfide-bridged blocker of voltage-gated sodium channels (VGSCs). The Lys(7) residue in KIIIA is an attractive target for manipulating the selectivity and efficacy of this peptide. Here, we report the design and chemical synthesis of µ-conopeptoid analogues (peptomers) in which we replaced Lys(7) with peptoid monomers of increasing side-chain size: N-methylglycine, N-butylglycine and N-octylglycine. In the first series of analogues, the peptide core contained all three disulfide bridges; whereas in the second series, a disulfide-depleted selenoconopeptide core was used to simplify oxidative folding. The analogues were tested for functional activity in blocking the Nav1.2 subtype of mammalian VGSCs exogenously expressed in Xenopus oocytes. All six analogues were active, with the N-methylglycine analogue, [Sar(7)]KIIIA, the most potent in blocking the channels while favouring lower efficacy. Our findings demonstrate that the use of N-substituted Gly residues in conotoxins show promise as a tool to optimize their pharmacological properties as potential analgesic drug leads.

Upregulation of human selenoprotein H in murine hippocampal neuronal cells promotes mitochondrial biogenesis and functional performance.

Overexpression of selenoprotein H (SelH) gene provides neuroprotection in neurons against UVB-induced cell death by blocking the mitochondrial-initiated apoptotic cell death pathway. This study examined the effects of SelH on mitochondrial biogenesis and mitochondrial function. The results demonstrated that overexpression of SelH gene in neuronal HT22 cells significantly increased the levels of mitochondrial biogenesis regulators, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) and mitochondrial transcription factor A (Tfam). Mitochondrial cytochrome c content was elevated, mass was increased and respiration was enhanced. SelH transfection ameliorated ultra violet B (UVB)-induced suppression of mitochondrial biogenesis markers and depolarization of mitochondrial membrane potential. Overexpression of SelH promotes mitochondrial biogenesis and improves mitochondrial functional performance.

SelK is a novel ER stress-regulated protein and protects HepG2 cells from ER stress agent-induced apoptosis.

Selenoprotein K (SelK), an endoplasmic reticulum (ER) resident protein, its biological function has been less-well studied. To investigate the role of SelK in the ER stress response, effects of SelK gene silence and ER stress agents on expression of SelK and cell apoptosis in HepG2 cells were studied. The results showed that SelK was regulated by ER stress agents, Tunicamycin (Tm) and beta-Mercaptoethanol (beta-ME), in HepG2 cells. Moreover, the SelK gene silence by RNA interference could significantly aggravate HepG2 cell death and apoptosis induced by the ER stress agents. These results suggest that SelK is an ER stress-regulated protein and plays an important role in protecting HepG2 cells from ER stress agent-induced apoptosis.

Synthesis and biological activity of seleno sunflower trypsin inhibitor analog.

Sunflower trypsin inhibitor (SFTI-1) is a cyclic peptide with 14 amino acid residues and one disulfide bond. Its synthetic acyclic analog (aSFTI-1) with N-terminal Gly and C-terminal Asp was still active. Here, we report the synthesis of seleno aSFTI-1 with the disulfide bond of aSFTI-1 replaced by diselenide bond. The formation of the diselenide bond from selenol was achieved in a single step without the aid of oxidizing agent. For comparison, aSFTI-1 itself and aSFTI-1 with its disulfide bond replaced by two serines ([Ser(3,11)] aSFTI-1) were also synthesized. The trypsin inhibitory constants of seleno aSFTI-1, aSFTI-1 and [Ser(3,11)] aSFTI-1 were determined as 6.50 x 10(-9), 1.96 x 10(-9) and 8.10 x 10(-6) respectively, indicating that the disulfide bond is essential for the structure and function of aSFTI-1, and seleno aSFTI-1 is still active, although its inhibitory constant is reduced to 30% in comparison with that of aSFTI-1.

Protection of mitochondrial integrity from oxidative stress by selenium-containing glutathione transferase.

The antioxidant activity of a novel artificial glutathione peroxidase-like enzyme, selenium-containing glutathione 5-transferase from Lucilia cuprina (seleno-LuGST1-1), was studied by using a ferrous sulfate/ascorbate-induced mitochondrial damage model system. Swelling of mitochondria, lipid peroxidation, and cytochrome-c oxidase activity were selected to evaluate the preservation of mitochondrial integrity in this system. Seleno-LuGST1-1 could effectively protect the mitochondria against oxidative damage in a dose-dependent manner and exhibited both higher catalytic activity and greater antioxidant ability than the classic mimic, 2-phenyl-1,2-benziososelenazol-3(2H)-one (Ebselen). This novel artificial biocatalyst therefore may have great potential for pharmacologic application in the treatment of reactive oxygen species-related diseases.

[Effects of selenoprotein on blood glucose, Ca2+ transfer and NO system in diabetic mice].

OBJECTIVE: To study the controlling effect of selenoprotein on blood glucose, Ca2+ transfer and NO system in diabetic mice. METHODS: Male Kunming mice of (20.3 +/- 1.7) g body weight were injected 200 mg/kg bw, 2% alloxan in abdomen to make diabetic model (DM), and were randomly divided into six groups: normal control group (I), normal + selenoprotein group(Se 100 microg/kg bw) (lI), DM control group (III), DM + lower dose selenoprotein group(Se 100 microg/kg bw) (IV), DM + higher dose selenoprotein group (Se 300 microg/kg bw) (V), DM + Na2SeO3 group (Se 100 microg/kg bw) (VI). RESULTS: The level of blood glucose in V group [(20.4 +/- 6.3 mmol/L] were significantly lower than lII group(45.3 +/- 3.3) mmol/L P < 0.05. The activity of Ca(2+) -ATPase of kidney in V group (0.90 +/- 0.5 micromol/ (h x mg prot) is significantly higher than III group [(0.35 +/- 0.1) micromol/(h x mg prot)] (P < 0.05, and the activity of NOS in V group [(25.0 +/- 4.3) U/ml] is significantly lower than III group [(35.2 +/- 4.4) U/ml] (P < 0.05). CONCLUSION: Selenoprotein that supplemented selenium doseis 300 microg Se/kg weight could significantly decrease blood glucose, increase the activities of Ca(2+) -ATPase on kidney and weaken the activities of plasma NOS in diabetic mice.