Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Antioxidants (Basel) ; 11(5)2022 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-35624693

RESUMO

Aberrant lipid metabolism is reported to be closely related to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Selenium (Se) and folate are two ideal and safe nutritional supplements, whose biological effects include regulating redox and homocysteine (Hcy) homeostasis in vivo. Here, to achieve effective multitarget therapy for AD, we combined Se and folic acid in a co-supplementation regimen (Se-FA) to study the therapeutic potential and exact mechanism in two transgenic mouse models of AD (APP/Tau/PSEN and APP/PS1). In addition to a reduction in Aß generation and tau hyperphosphorylation, a restoration of synaptic plasticity and cognitive ability was observed in AD mice upon Se-FA administration. Importantly, by using untargeted metabolomics, we found that these improvements were dependent on the modulation of brain lipid metabolism, which may be associated with an antioxidant effect and the promotion of Hcy metabolism. Thus, from mechanism to effects, this study systematically investigated Se-FA as an intervention for AD, providing important mechanistic insights to inform its potential use in clinical trials.

2.
Antioxid Redox Signal ; 35(11): 863-884, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-32475153

RESUMO

Aims: Strong evidence has implicated synaptic failure as a direct contributor to cognitive decline in Alzheimer's disease (AD), and selenium (Se) supplementation has demonstrated potential for AD treatment. However, the exact roles of Se and related selenoproteins in mitigating synaptic deficits remain unclear. Results: Our data show that selenomethionine (Se-Met), as the major organic form of Se in vivo, structurally restored synapses, dendrites, and spines, leading to improved synaptic plasticity and cognitive function in triple transgenic AD (3 × Tg-AD) mice. Furthermore, we found that Se-Met ameliorated synaptic deficits by inhibiting extrasynaptic N-methyl-d-aspartate acid receptors (NMDARs) and stimulating synaptic NMDARs, thereby modulating calcium ion (Ca2+) influx. We observed that a decrease in selenoprotein K (SELENOK) levels was closely related to AD, and a similar disequilibrium was found between synaptic and extrasynaptic NMDARs in SELENOK knockout mice and AD mice. Se-Met treatment upregulated SELENOK levels and restored the balance between synaptic and extrasynaptic NMDAR expression in AD mice. Innovation: These findings establish a key signaling pathway linking SELENOK and NMDARs with synaptic plasticity regulated by Se-Met, and thereby provide insight into mechanisms by which Se compounds mediate synaptic deficits in AD. Conclusion: Our study demonstrates that Se-Met restores synaptic deficits through modulating Ca2+ influx mediated by synaptic and extrasynaptic NMDARs in 3 × Tg-AD mice, and suggests a potentially functional interaction between SELENOK and NMDARs. Antioxid. Redox Signal. 35, 863-884.


Assuntos
Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Receptores de N-Metil-D-Aspartato/metabolismo , Selênio/metabolismo , Selenoproteínas/metabolismo , Sinapses/metabolismo , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Transgênicos
3.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248178

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the presence of extracellular senile plaques primarily composed of Aß peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins. Olfactory dysfunction is an early clinical phenotype in AD and was reported to be attributable to the presence of NFTs, senile Aß plaques in the olfactory bulb (OB). Our previous research found that selenomethionine (Se-Met), a major form of selenium (Se) in organisms, effectively increased oxidation resistance as well as reduced the generation and deposition of Aß and tau hyperphosphorylation in the olfactory bulb of a triple transgenic mouse model of AD (3×Tg-AD), thereby suggesting a potential therapeutic option for AD. In this study, we further investigated changes in the transcriptome data of olfactory bulb tissues of 7-month-old triple transgenic AD (3×Tg-AD) mice treated with Se-Met (6 µg/mL) for three months. Comparison of the gene expression profile between Se-Met-treated and control mice revealed 143 differentially expressed genes (DEGs). Among these genes, 21 DEGs were upregulated and 122 downregulated. The DEGs were then annotated against the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The results show that upregulated genes can be roughly classified into three types. Some of them mainly regulate the regeneration of nerves, such as Fabp7, Evt5 and Gal; some are involved in improving cognition and memory, such as Areg; and some are involved in anti-oxidative stress and anti-apoptosis, such as Adcyap1 and Scg2. The downregulated genes are mainly associated with inflammation and apoptosis, such as Lrg1, Scgb3a1 and Pglyrp1. The reliability of the transcriptomic data was validated by quantitative real time polymerase chain reaction (qRT-PCR) for the selected genes. These results were in line with our previous study, which indicated therapeutic effects of Se-Met on AD mice, providing a theoretical basis for further study of the treatment of AD by Se-Met.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Selênio/farmacologia , Transcriptoma , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Animais Geneticamente Modificados , Biologia Computacional/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Camundongos , Reprodutibilidade dos Testes , Selênio/uso terapêutico
4.
Biol Trace Elem Res ; 192(2): 263-276, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30790121

RESUMO

Selenium (Se), as a nutritionally essential trace element, has been shown to decrease with age and is closely related to Alzheimer's disease (AD). To probe the effects of Se on AD pathology, two-dimensional fluorescence difference gel electrophoresis was applied to the serum samples collected from the wild-type (WT) mice and the triple transgenic (PS1M146V/AßPPSwe/TauP301L) AD mice (3xTg-AD), treated with or without sodium selenate in drinking water for 4 months beginning at 2 months of age. Proteomics results revealed 17 differentially expressed proteins between WT and 3xTg-AD mice. It was found that the administration of selenate reversed the alterations of the differentially expressed serum proteins by up-regulating 13 proteins and down-regulating 2 proteins which were reported to be involved in the key pathogenesis of AD, including regulation of Aß production, lipid metabolism regulation, and anti-inflammation. These results suggested that a dietary supplement with selenate is effective for prevention and treatment of AD, and the mechanism was maybe related to its role in Aß regulation, lipid metabolism, and anti-inflammation. Moreover, we also presented that α-2 macroglobulin, transthyretin, haptoglobin, alpha-2-HS-glycoprotein, and alpha-1-antitrypsin in the serum can be used to evaluate the effect of selenate on AD pathology.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Proteômica , Ácido Selênico/farmacologia , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Animais , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/sangue , Haptoglobinas/análise , Haptoglobinas/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Pré-Albumina/análise , Pré-Albumina/antagonistas & inibidores , alfa 2-Macroglobulinas Associadas à Gravidez/análise , alfa 2-Macroglobulinas Associadas à Gravidez/antagonistas & inibidores , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/metabolismo
5.
Food Funct ; 9(7): 3965-3973, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-29974078

RESUMO

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disease that exhibits multiple pathogeneses and heterogeneity. Selenium (Se) is an essential trace element for human and animal nutrition. It has been shown that supplementation with two organic forms of Se, Se-enriched yeast (Se-yeast) and selenomethionine (Se-Met), could improve cognitive impairment, reverse synaptic deficits and mitigate tau pathology in triple-transgenic (3× Tg) AD mice. Se-yeast is well known for its high Se-Met content, which may mediate its anti-AD effects. In addition, a large amount of the physiological and biochemical mechanisms of these two Se drugs in the amelioration AD pathology remains unknown. In this study, the content of Se-yeast aside from Se was analyzed, and the effects of Se-Met and Se-yeast on 3× Tg-AD mice were investigated and compared. The results showed that both Se-Met and Se-yeast not only significantly increased the Se levels, enhanced the antioxidant capacity and improved the cognitive decline in the model, but also decreased the Aß and tau pathologies in the brain tissue of the AD mice. Moreover, the ability of Se-Met to increase the Se levels in different tissues of the AD mice was more significant than that of Se-yeast. However, the positive effect of Se-yeast on improving the cognitive ability of the AD mice was better than that of Se-Met, likely due to the various elements, vitamins and other nutrients in Se-yeast. Collectively, these results suggest that Se-yeast has potential as a clinical health product or drug for AD but that Se-Met, as a pure organic Se compound, is more suitable for studying the therapeutic mechanism of Se because of its comprehensive effects on AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Saccharomyces cerevisiae/química , Selênio/administração & dosagem , Selenometionina/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Suplementos Nutricionais/análise , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Selênio/metabolismo
6.
Metallomics ; 10(8): 1107-1115, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30043821

RESUMO

As the most common cause of progressive intellectual failure in elderly humans, Alzheimer's disease (AD) is pathologically featured by amyloid plaques, synaptic loss, and neurofibrillary tangles. The amyloid plaques are mainly aggregates of amyloid ß-peptide (Aß), a primary factor contributing to the pathogenesis of AD. Elimination or reduction of the level of Aß is considered an important strategy in AD treatment. The pharmacotherapeutic efficacy of selenium (Se), an essential biological trace element for mammalian species, has been confirmed in a number of experimental models of neurodegenerative diseases. Selenium-enriched yeast (Se-yeast) is commonly used as a nutritional supplement for Se. In this study, we investigated the effects and underlying mechanisms of Se-yeast on Aß pathology in a 4-month-old triple transgenic mouse model of AD (3×Tg-AD mice). The administration of Se-yeast attenuated the deposition of Aß in the brains of AD mice, which was concomitant with decreased levels of LC3II. The Se-yeast treatment decreased the level of amyloid-protein precursor (APP), downregulated the activity of AMP-activated protein kinase (AMPK) and upregulated the activity of AKT/mTOR/p70S6K. Furthermore, the levels of p62 also significantly decreased, and the cathepsin D levels increased, accompanied by increased turnover of Aß and APP in Se-yeast-treated AD mice. In addition to decreasing the generation of Aß, Se-yeast also inhibited the initiation of autophagy by modulating the AMPK/AKT/mTOR/p70S6K signaling pathway and enhanced autophagic clearance, thus reducing the burden of Aß accumulation in the brains of AD mice. Our results further highlight the potential therapeutic effects of Se-yeast on AD.


Assuntos
Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Autofagia , Modelos Animais de Doenças , Saccharomyces cerevisiae/metabolismo , Selênio/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos
7.
J Alzheimers Dis ; 59(2): 591-602, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28671121

RESUMO

Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-ß (Aß) has been recognized as the major cause of AD. Inhibiting Aß production and/or enhancing the clearance of Aß to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-ß (Aß) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aß levels in Neuron-2a/AßPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aß generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aß clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Autofagia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Selenometionina/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/ultraestrutura , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/ultraestrutura , Animais , Ácido Aspártico Endopeptidases/metabolismo , Autofagia/genética , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/genética , Humanos , Imunossupressores/farmacologia , Lactosilceramidas/metabolismo , Macrolídeos/farmacologia , Microscopia Eletrônica de Transmissão , Neuroblastoma/patologia , Neuroblastoma/ultraestrutura , Proteína Oncogênica v-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Transfecção
8.
J Agric Food Chem ; 65(24): 4970-4979, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28578584

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple histopathological changes in the brain and by impairments in memory and cognitive function. Currently, there is no effective treatment that can halt or reverse the progression of this disease. Here, we explored the effects of 3 months of treatment with selenium-enriched yeast (Se-yeast), which is commonly used as a source of organic selenium (Se) for nutrition, on cognitive dysfunction and neuropathology in the triple transgenic mouse model of AD (3×Tg-AD mice). As the results revealed that Se-yeast significantly improved the spatial learning and memory retention of 3×Tg-AD mice, promoted neuronal activity, attenuated the activation of astrocytes and microglia, mitigated synaptic deficits, and reduced the levels of total tau and phosphorylated tau though inhibiting the activity of GSK-3ß, dietary supplementation with Se-yeast exerted multiple beneficial effects on the prevention or treatment of AD. These findings provide evidence of a potentially viable compound for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Saccharomyces cerevisiae/química , Selênio/administração & dosagem , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Animais , Suplementos Nutricionais/análise , Modelos Animais de Doenças , Progressão da Doença , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Fosforilação , Saccharomyces cerevisiae/metabolismo , Selênio/metabolismo , Proteínas tau/genética
9.
J Neurosci ; 37(9): 2449-2462, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28137967

RESUMO

Tau pathology was recently identified as a key driver of disease progression and an attractive therapeutic target in Alzheimer's disease (AD). Selenomethionine (Se-Met), a major bioactive form of selenium (Se) in organisms with significant antioxidant capacity, reduced the levels of total tau and hyperphosphorylated tau and ameliorated cognitive deficits in younger triple transgenic AD (3xTg-AD) mice. Whether Se-Met has a similar effect on tau pathology and the specific mechanism of action in older 3xTg-AD mice remains unknown. Autophagy is a major self-degradative process to maintain cellular homeostasis and function. Autophagic dysfunction has been implicated in the pathogenesis of multiple age-dependent diseases, including AD. Modulation of autophagy has been shown to retard the accumulation of misfolded and aggregated proteins and to delay the progression of AD. Here, we found that 3xTg-AD mice showed significant improvement in cognitive ability after a 3-month treatment with Se-Met beginning at 8 months of age. In addition to attenuating the hyperphosphorylation of tau by modulating the activity of Akt/glycogen synthase kinase-3ß and protein phosphatase 2A, Se-Met-induced reduction of tau was also mediated by an autophagy-based pathway. Specifically, Se-Met improved the initiation of autophagy via the AMP-activated protein kinase-mTOR (mammalian target of rapamycin) signaling pathway and enhanced autophagic flux to promote the clearance of tau in 3xTg-AD mice and primary 3xTg neurons. Thus, our results demonstrate for the first time that Se-Met mitigates cognitive decline by targeting both the hyperphosphorylation of tau and the autophagic clearance of tau in AD mice. These data strongly support Se-Met as a potent nutraceutical for AD therapy.SIGNIFICANCE STATEMENT Selenium has been widely recognized as a vital trace element abundant in the brain with effects of antioxidant, anticancer, and anti-inflammation. In this study, we report that selenomethionine rescues spatial learning and memory impairments in aged 3xTg-AD mice via decreasing the level of tau protein and tau hyperphosphorylation. We find that selenomethionine promotes the initiation of autophagy via the AMPK-mTOR pathway and enhances autophagic flux, thereby facilitating tau clearance in vivo and in vitro We have now identified an additional, novel mechanism by which selenomethionine improves the cognitive function of AD mice. Specifically, our data suggest the effect of selenium/selenomethionine on an autophagic pathway in Alzheimer's disease.


Assuntos
Doença de Alzheimer/complicações , Encéfalo/patologia , Transtornos Cognitivos/etiologia , Selenometionina/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Autofagia/genética , Autofagia/fisiologia , Aprendizagem da Esquiva/fisiologia , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Macrolídeos/farmacologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurônios/ultraestrutura , Presenilina-1/genética , Tempo de Reação/fisiologia , Proteínas tau/genética
10.
Biochem Biophys Res Commun ; 485(1): 6-15, 2017 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-28109879

RESUMO

The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce ß-amyloid peptide (Aß) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1-10 µM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 µM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3ß activity, which would further activated the ß-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 µg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3ß-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective in promoting neurogenesis, and therefore we propose a novel mechanism for Se-Met treatment in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Selenometionina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Selenometionina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
11.
Sci Rep ; 6: 39290, 2016 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-28008954

RESUMO

Many studies have shown that imbalance of mineral metabolism may play an important role in Alzheimer's disease (AD) progression. It was recently reported that selenium could reverse memory deficits in AD mouse model. We carried out multi-time-point ionome analysis to investigate the interactions among 15 elements in the brain by using a triple-transgenic mouse model of AD with/without high-dose sodium selenate supplementation. Except selenium, the majority of significantly changed elements showed a reduced level after 6-month selenate supplementation, especially iron whose levels were completely reversed to normal state at almost all examined time points. We then built the elemental correlation network for each time point. Significant and specific elemental correlations and correlation changes were identified, implying a highly complex and dynamic crosstalk between selenium and other elements during long-term supplementation with selenate. Finally, we measured the activities of two important anti-oxidative selenoenzymes, glutathione peroxidase and thioredoxin reductase, and found that they were remarkably increased in the cerebrum of selenate-treated mice, suggesting that selenoenzyme-mediated protection against oxidative stress might also be involved in the therapeutic effect of selenate in AD. Overall, this study should contribute to our understanding of the mechanism related to the potential use of selenate in AD treatment.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Íons/análise , Minerais/análise , Ácido Selênico/administração & dosagem , Animais , Antioxidantes/análise , Modelos Animais de Doenças , Glutationa Peroxidase/análise , Camundongos Transgênicos , Tiorredoxina Dissulfeto Redutase/análise
12.
Int J Mol Sci ; 17(10)2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27689994

RESUMO

Olfactory dysfunction is an early and common symptom in Alzheimer's disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aß and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aß and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD). In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB) of 3× Tg-AD mice was investigated. The administration of Se-Met effectively decreased the production and deposition of Aß by inhibiting ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)-regulated amyloid precursor protein (APP) processing and reduced the level of total tau and phosphorylated tau, which depended on depressing the activity and expression of glycogen synthase kinase-3ß (GSK-3ß) and cyclin-dependent kinase 5 (CDK5). Meanwhile, Se-Met reduced glial activation, relieved neuroinflammation and attenuated neuronal cell death in the OB of AD mice. So Se-Met could improve pathologic changes of AD in the OB, which further demonstrated the potential therapeutic effect of Se-Met in AD.

13.
Metallomics ; 8(8): 782-9, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27465436

RESUMO

Alzheimer's disease (AD) is characterized by the production of large amounts of beta-amyloid (Aß) and the accumulation of extracellular senile plaques, which have been considered to be potential targets in the treatment of AD. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential and Se status has been shown to decrease with age and has a close relationship with cognitive competence in AD. Selenomethionine (Se-Met), a major reserve form of Se in organisms, has been shown in our previous study to ameliorate the decline in cognitive function, increase oxidation resistance, and reduce tau hyperphosphorylation in a triple transgenic mouse model of AD. However, it has not been reported whether Se-Met has any effects on Aß pathology in AD mice. To study the effect of Se-Met on Aß pathology and the function of selenoproteins/selenoenzymes in 3× Tg-AD mice, 3× Tg-AD mice at 8 months of age were treated with Se-Met for 3 months. Se-Met led to significantly reduced production and deposition of Aß, down-regulation of ß-secretase levels and enhanced activity of selenoenzymes as well as increased levels of Se in the hippocampus and cortex. Se-Met reduces amyloidogenic processing of amyloid precursor protein while modulating ß-secretase and selenoenzymatic activity in AD mice. These results indicate that Se-Met might exert its therapeutic effect through multiple pathways in AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Placa Amiloide/prevenção & controle , Selenometionina/farmacologia , Selenoproteínas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia
14.
CNS Neurosci Ther ; 22(1): 63-73, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26584824

RESUMO

AIMS: This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD). METHODS: 3 × Tg-AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration. RESULTS: Icariin significantly improved spatial learning and memory retention in 3 × Tg-AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N-acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1α, and synaptic protein PSD95, reduced Aß plaque deposition in the cortex and hippocampus of AD mice, and inhibited ß-site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Aß1-42 in 3 × Tg-AD primary neurons, modulated the distribution of Aß along the neurites, and protected against mitochondrial fragmentation in 3 × Tg-AD neurons. CONCLUSIONS: Icariin shows neuroprotective effects in 3 × Tg-AD mice and may be a promising multitarget drug in the prevention/protection against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Flavonoides/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Cognição/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Proteínas tau/genética , Proteínas tau/metabolismo
15.
ACS Appl Mater Interfaces ; 7(16): 8377-92, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25845677

RESUMO

Reversible protein phosphorylation is a key event in numerous biological processes. Mass spectrometry (MS) is the most powerful analysis tool in modern phosphoproteomics. However, the direct MS analysis of phosphorylated proteins/peptides is still a big challenge because of the low abundance and insufficient ionization of phosphorylated proteins/peptides as well as the suppression effects of nontargets. Enrichment of phosphorylated proteins/peptides by affinity materials from complex biosamples is the most widely used strategy to enhance the MS detection. The demand of efficiently enriching phosphorylated proteins/peptides has spawned diverse affinity materials based on different enrichment principles (e.g., electronic attraction, chelating). In this review, we summarize the recent development of various affinity materials for phosphorylated proteins/peptides enrichment. We will highlight the design and fabrication of these affinity materials, discuss the enrichment mechanisms involved in different affinity materials, and suggest the future challenges and research directions in this field.


Assuntos
Fosfopeptídeos/análise , Fosfoproteínas/análise , Proteômica/métodos , Nanocompostos/química , Fosforilação
16.
Genome Biol Evol ; 7(3): 664-76, 2015 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-25638258

RESUMO

Selenium (Se) is an important micronutrient that mainly occurs in proteins in the form of selenocysteine and in tRNAs in the form of selenouridine. In the past 20 years, several genes involved in Se utilization have been characterized in both prokaryotes and eukaryotes. However, Se homeostasis and the associated regulatory network are not fully understood. In this study, we conducted comparative genomics and phylogenetic analyses to examine the occurrence of all known Se utilization traits in prokaryotes. Our results revealed a highly mosaic pattern of species that use Se (in different forms) in spite that most organisms do not use this element. Further investigation of genomic context of known Se-related genes in different organisms suggested novel candidate genes that may participate in Se metabolism in bacteria and/or archaea. Among them, a membrane protein, YedE, which contains ten transmembrane domains and shows distant similarity to a sulfur transporter, is exclusively found in Se-utilizing organisms, suggesting that it may be involved in Se transport. A LysR-like transcription factor subfamily might be important for the regulation of Sec biosynthesis and/or other Se-related genes. In addition, a small protein family DUF3343 is widespread in Se-utilizing organisms, which probably serves as an important chaperone for Se trafficking within the cells. Finally, we proposed a simple model of Se homeostasis based on our findings. Our study reveals new candidate genes involved in Se metabolism in prokaryotes and should be useful for a further understanding of the complex metabolism and the roles of Se in biology.


Assuntos
Archaea/metabolismo , Proteínas Arqueais/genética , Bactérias/metabolismo , Proteínas de Bactérias/genética , Selênio/metabolismo , Archaea/genética , Bactérias/genética , Genes Arqueais , Genes Bacterianos , Genoma Arqueal , Genoma Bacteriano , Genômica
17.
BMC Genomics ; 15: 908, 2014 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-25326317

RESUMO

BACKGROUND: Selenium (Se) and sulfur (S) are closely related elements that exhibit similar chemical properties. Some genes related to S metabolism are also involved in Se utilization in many organisms. However, the evolutionary relationship between the two utilization traits is unclear. RESULTS: In this study, we conducted a comparative analysis of the selenophosphate synthetase (SelD) family, a key protein for all known Se utilization traits, in all sequenced archaea. Our search showed a very limited distribution of SelD and Se utilization in this kingdom. Interestingly, a SelD-like protein was detected in two orders of Crenarchaeota: Sulfolobales and Thermoproteales. Sequence and phylogenetic analyses revealed that SelD-like protein contains the same domain and conserved functional residues as those of SelD, and might be involved in S metabolism in these S-reducing organisms. Further genome-wide analysis of patterns of gene occurrence in different thermoproteales suggested that several genes, including SirA-like, Prx-like and adenylylsulfate reductase, were strongly related to SelD-like gene. Based on these findings, we proposed a simple model wherein SelD-like may play an important role in the biosynthesis of certain thiophosphate compound. CONCLUSIONS: Our data suggest novel genes involved in S metabolism in hyperthermophilic S-reducing archaea, and may provide a new window for understanding the complex relationship between Se and S metabolism in archaea.


Assuntos
Proteínas Arqueais/genética , Biologia Computacional/métodos , Crenarchaeota/enzimologia , Fosfotransferases/genética , Enxofre/metabolismo , Sequência de Aminoácidos , Proteínas Arqueais/química , Sequência Conservada , Crenarchaeota/química , Crenarchaeota/genética , Regulação da Expressão Gênica em Archaea , Fosfotransferases/química , Filogenia , Selênio/metabolismo
18.
Anal Chim Acta ; 812: 65-73, 2014 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-24491766

RESUMO

A simple, fast, efficient, and reusable microwave-assisted tryptic digestion system which was constructed by immobilization of trypsin onto porous core-shell Fe3O4@fTiO2 microspheres has been developed. The nanostructure with magnetic core and titania shell has multiple pore sizes (2.4 and 15.0 nm), high pore volume (0.25 cm(3) g(-1)), and large surface area (50.45 m(2) g(-1)). For the proteins, the system can realize fast and efficient microwave-assisted tryptic digestion. Various standard proteins (e.g., cytochrome c (cyt-c), myoglobin (MYO), ß-lactoglobulin (ß-LG), and bovine serum albumin (BSA)) used can be digested in 45 s under microwave radiation, and they can be confidently identified by mass spectrometry (MS) analysis; even the concentration of substrate is as low as 5 ng µL(-1). Furthermore, the system for the 45 s microwave-assisted tryptic digestion is still effective after the trypsin-immobilized microspheres have been reused for 5 times. Importantly, 1715 unique proteins from 10 µg mouse brain proteins can be identified with high confidence after treatment of 45 s microwave-assisted tryptic digestion.


Assuntos
Microesferas , Tripsina/química , Compostos Férricos/química , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Micro-Ondas , Proteínas/química , Espectrometria por Raios X , Titânio/química , Difração de Raios X
19.
J Colloid Interface Sci ; 417: 217-26, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24407680

RESUMO

In this work, novel magnetic polymeric core-shell structured microspheres with immobilized Ce(IV), Fe3O4@SiO2@PVPA-Ce(IV), were designed rationally and synthesized successfully via a facile route for the first time. Magnetic Fe3O4@SiO2 microspheres were first prepared by directly coating a thin layer of silica onto Fe3O4 magnetic particles using a sol-gel method, a poly(vinylphosphonic acid) (PVPA) shell was then coated on the Fe3O4@SiO2 microspheres to form Fe3O4@SiO2@PVPA microspheres through a radical polymerization reaction, and finally Ce(IV) ions were robustly immobilized onto the Fe3O4@SiO2@PVPA microspheres through strong chelation between Ce(IV) ions and phosphate moieties in the PVPA. The applicability of the Fe3O4@SiO2@PVPA-Ce(IV) microspheres for selective enrichment and rapid separation of phosphopeptides from proteolytic digests of standard and real protein samples was investigated. The results demonstrated that the core-shell structured Fe3O4@SiO2@PVPA-Ce(IV) microspheres with abundant Ce(IV) affinity sites and excellent magnetic responsiveness can effectively purify phosphopeptides from complex biosamples for MS detection taking advantage of the rapid magnetic separation and the selective affinity between Ce(IV) ions and phosphate moieties of the phosphopeptides. Furthermore, they can be effectively recycled and show good reusability, and have better performance than commercial TiO2 beads and homemade Fe3O4@PMAA-Ce(IV) microspheres. Thus the Fe3O4@SiO2@PVPA-Ce(IV) microspheres can benefit greatly the mass spectrometric qualitative analysis of phosphopeptides in phosphoproteome research.


Assuntos
Cério/química , Complexos de Coordenação/química , Óxido Ferroso-Férrico/química , Fosfopeptídeos/isolamento & purificação , Humanos , Imãs , Microesferas , Fosfopeptídeos/sangue , Ácidos Fosforosos/química , Polivinil/química , Dióxido de Silício/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectroscopia de Infravermelho com Transformada de Fourier , Fatores de Tempo
20.
J Mater Chem B ; 2(39): 6886-6892, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32261885

RESUMO

Magnetic composite particles immobilized with metal affinity ions show high potential in the phosphoproteome mass-spectrometric (MS) analysis. However, the preparation of this kind of material still suffers from a complicated synthesis procedure and high cost. In this work, the magnetic nanostructured composite microspheres (MPCS) incorporated into N-methylene phosphonic chitosan were first fabricated via a facile one-pot synthesis strategy and titanium ions (Ti4+) were subsequently immobilized onto the MPCS to form MPCS-Ti4+ affinity particles. The uniform spherical MPCS-Ti4+ affinity particles with abundant chelated titanium ions have a particle size distribution between 126 nm and 280 nm, and they display superparamagnetism with a saturation magnetization (Ms) value of 44.75 emu g-1. The amount of the immobilized Ti4+ ions was estimated to be 11.6 wt% by EDS. The MPCS-Ti4+ exhibited excellent dispersibility in aqueous solution, high affinity selectivity for phosphopeptides and quite fast magnetic separation within 10 s as well as good reusability. Thus, the prepared magnetic MPCS-Ti4+ nanostructured affinity materials will possess great potential in phosphoproteome research.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...