Search

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 Aβ 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.

Background. The selenocysteine(Sec)-containing proteins, selenoproteins, are an important group of proteins present in all three kingdoms of life. Although the selenoproteomes of many organisms have been analyzed, systematic studies on selenoproteins in platyhelminthes are still lacking. Moreover, comparison of selenoproteomes between free-living and parasitic animals is rarely studied.Results. In this study, three representative organisms (Schmidtea mediterranea, Schistosoma japonicum and Taenia solium) were selected for comparative analysis of selenoproteomes in Platyhelminthes. Using a SelGenAmic-based selenoprotein prediction algorithm, a total of 37 selenoprotein genes were identified in these organisms. The size of selenoproteomes and selenoprotein families were found to be associated with different lifestyles: free-living organisms have larger selenoproteome whereas parasitic lifestyle corresponds to reduced selenoproteomes. Five selenoproteins, SelT, Sel15, GPx, SPS2 and TR, were found to be present in all examined platyhelminthes as well as almost all sequenced animals, suggesting their essential role in metazoans. Finally, a new splicing form of SelW that lacked the first exon was found to be present in S. japonicum.Conclusions. Our data provide a first glance into the selenoproteomes of organisms in the phylum Platyhelminthes and may help understand function and evolutionary dynamics of selenium utilization in diversified metazoans.

Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ 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-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ 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 Aβ 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. [ABSTRACT FROM AUTHOR]

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-3β 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. [ABSTRACT FROM AUTHOR]

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 Aβ 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 Aβ 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 Aβ by inhibiting β-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-3β; (GSK-3β;) 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. [ABSTRACT FROM AUTHOR]

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 (indifferent 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Selenoprotein M (SelM), one of the executants of selenium in vivo, is highly expressed in human brain and most probably involved in antioxidation, neuroprotection, and intracellular calcium regulation, which are the key factors for preventing the onset and progression of Alzheimer's disease (AD). In this paper, human SelM was successfully overexpressed in human embryonic kidney cells HEK293T. Sodium selenite (Na2SeO3 0.5 μmol/L) increased the expression of full-length SelM and inhibited the expression of truncated SelM. The full-length SelM exhibited higher antioxidant activity than its selenocysteine-to-cysteine mutation form SelM', whereas the truncated SelM had an adverse effect that increased the oxidative stress level of cells. When β-amyloid (Aβ42, an AD relevant peptide) was cotransfected with the empty expression vector, SelM, or SelM' under the induction of 0.5 μmol/L Na2SeO3, the intracellular Aβ42 aggregation rates were detected to be 57.9% ± 5.5%, or 22.3% ± 2.6%, or 26.3% ± 2.1%, respectively, showing the inhibitory effects on Aβ aggregation by the full-length SelM and SelM'. Meanwhile, the intumescentia of mitochondria caused by Aβ42 transfection was significantly mitigated by the cotransfection of SelM or SelM' with Aβ42 under the induction of 0.5 μmol/L Na2SeO3. On the contrary, cotransfection of SelM and Aβ42 without the induction of Na2SeO3 increased Aβ42 aggregation rate to 65.1% ± 3.2%, and it could not inhibit the Aβ-induced intumescent mitochondria. In conclusion, full-length SelM and SelM' might prevent Aβ aggregation by resisting oxidative stress generated during the formation of Aβ oligomers in cells. [ABSTRACT FROM AUTHOR]

Lanthanides (Lns) compounds have been reported to possess contrary effects on cell activity, i.e., promoting cell cycle progression and cell growth by lower concentration treatment, but suppressing cell proliferation and inducing cell apoptosis at higher dosing. However, the cellular processes during the intervention and the possible underlying mechanisms are still not well clarified. Using a combination of high-throughput liquid chromatography (LC) with mass spectrometry (MS), we have investigated the metabolomic profiles of Hela cells following gadolinium chloride (GdCl) treatment in time- and concentration- dependent manners. A total of 48 metabolites released by Hela cells are identified to be differentially expressed ( P < 0.05) in different states. Metabolic pathways analyses reveal that the differential metabolites are mainly characterized by increased lipid and amino acid metabolisms and by decreased lipid, amino acid, and carbohydrate metabolisms for cells treated with GdCl at lower and higher concentrations, respectively. Notably, in the higher level GdCl case, the down-expressions of metabolites are predominantly in the glycolytic and the redox pathways. The above results, obtained by using a metabolomic strategy for the first time, disclose that different cell signaling pathways are activated by GdCl treatment with different concentrations, leading to inhibitory or promotional effect on Hela cells. [ABSTRACT FROM AUTHOR]

Fe3O4@SiO2@CeO2microspheres with magnetic core and mesoporous shell were synthesized, and the multifunctional materials were utilized to capture phosphopeptides and catalyze the dephosphorylation simultaneously, thereby labeling the phosphopeptides for rapid identification. [ABSTRACT FROM AUTHOR]