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Palmitoylation is a type of lipid modification that plays an important role in various aspects of neuronal function. Over the past few decades, several studies have shown that the palmitoylation of synaptic proteins is involved in neurotransmission and synaptic functions. Palmitoyl acyltransferases (PATs), which belong to the DHHC family, are major players in the regulation of palmitoylation. Dysregulated palmitoylation of synaptic proteins and mutated/dysregulated DHHC proteins are associated with several neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). In this review, we summarize the recent discoveries on the subcellular distribution of DHHC proteins and analyze their expression patterns in different brain cells. In particular, this review discusses how palmitoylation of synaptic proteins regulates synaptic vesicle exocytotic fusion and the localization, clustering, and transport of several postsynaptic receptors, as well as the role of palmitoylation of other proteins in regulating synaptic proteins. Additionally, some of the specific known associations of these factors with neurodegenerative disorders are explored, with a few suggestions for the development of therapeutic strategies. Finally, this review provides possible directions for future research to reveal detailed and specific mechanisms underlying the roles of synaptic protein palmitoylation.
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Lipoilação , Doenças Neurodegenerativas , Sinapses , Humanos , Doenças Neurodegenerativas/metabolismo , Animais , Sinapses/metabolismo , Aciltransferases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Transmissão SinápticaRESUMO
OBJECTIVES: This meta-analysis aimed to examine the relationship between automatic processes and behavior as well as their moderators. METHODS: There were 126 effect sizes (Fisher's Z) extracted from 55 independent research studies involving 10,432 participants. Meta-analyses were conducted using Comprehensive Meta-Analysis Version 3.3. Univariate meta-regression models were used to analyze underlying moderators. RESULTS: Meta-analysis after correction found that automatic processes could significantly and positively predict behavior, but the effect size was small (Fisher's Z = 0.057, p < 0.001, 95% CI [0.043, 0.070]). CONCLUSIONS: Different components of automatic processes, task reliability, and study design moderated the relationship between automatic processes and behavior. Future research could explore automatic measures at a neurophysiological level or use population-matched stimuli for specific populations to improve measure validity. In addition, future research should accumulate evidence on how to reduce sedentary behavior.
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Exercício Físico , Comportamento Sedentário , Humanos , Exercício Físico/psicologiaRESUMO
This study was conducted to assess the effects of dietary copper source and level on hematological parameters, copper accumulation and transport, resistance to low temperature, antioxidant capacity and immune response of white shrimp (Litopenaeus vannamei Boone, 1931). Seven experimental diets with different copper sources and levels were formulated: C, no copper supplementation; S, 30 mg/kg copper in the form of CuSO4·5H2O; SO, 15 mg/kg copper in CuSO4·5H2O + 7.5 mg/kg copper in Cu-proteinate; O1, O2, O3 and O4, 10, 20, 30 and 40 mg/kg copper in the form of Cu-proteinate, respectively. A total of 840 shrimp (5.30 ± 0.04 g) were randomly distributed to 21 tanks (3 tanks/diet, 40 shrimp/tank). An 8-week feeding trial was conducted. The results showed that there was no significant difference in growth performance and whole shrimp chemical compositions among all groups. Compared with inorganic copper, dietary organic copper (O2 and O3) increased total protein, albumin, and glucose content of plasma, while decreased triglyceride and total cholesterol of plasma. Copper concentration in plasma and muscle and gene expression of metallothionein and copper-transporting ATPase 2 like in hepatopancreas were higher in shrimp fed organic copper (SO, O2, O3 and O4). The lowest mortality after low temperature (10 °C) challenge test was observed in the O2 and O3 groups. Organic copper (SO, O2, O3 and O4) significantly enhanced the antioxidant capacity (in terms of higher activities of total superoxide dismutase, copper zinc superoxide dismutase, catalase, glutathione peroxidase and total antioxidant capacity, lower malondialdehyde concentration of plasma, and up-regulated gene expression of superoxide dismutase, copper zinc superoxide dismutase, catalase and glutathione peroxidase of hepatopancreas). Organic copper (SO, O2, O3 and O4) enhanced the immune response (in terms of higher number of total hemocytes, higher activities of acid phosphatase, alkaline phosphatase, phenoloxidase, hemocyanin and lysozyme in plasma, and higher gene expressions of alkaline phosphatase, lysozyme and hemocyanin in hepatopancreas). Inorganic copper (Diet S) also had positive effects on white shrimp compared with the C diet, but the SO, O2, O3 and O4 diets resulted in better results, among which the O2 diet appeared to be the best one. In conclusion, organic copper was more beneficial to shrimp health than copper sulfate.
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Antioxidantes , Penaeidae , Animais , Fosfatase Alcalina , Ração Animal/análise , Antioxidantes/metabolismo , Catalase , Cobre/metabolismo , Dieta/veterinária , Glutationa Peroxidase/metabolismo , Hemocianinas/farmacologia , Imunidade Inata , Muramidase/farmacologia , Superóxido Dismutase/metabolismo , Temperatura , Zinco/farmacologiaRESUMO
Whey protein powder (PP), which is mainly derived from bovine milk, is rich in milk fat globule membrane (MFGM). The MGFM has been shown to play a role in promoting neuronal development and cognition in the infant brain. However, its role in Alzheimer's disease (AD) has not been elucidated. Here, we showed that the cognitive ability of 3×Tg-AD mice (a triple-transgenic mouse model of AD) could be improved by feeding PP to mice for 3 mo. In addition, PP ameliorated amyloid peptide deposition and tau hyperphosphorylation in the brains of AD mice. We found that PP could alleviate AD pathology by inhibiting neuroinflammation through the peroxisome proliferator-activated receptor γ (PPARγ)-nuclear factor-κB signaling pathway in the brains of AD mice. Our study revealed an unexpected role of PP in regulating the neuroinflammatory pathology of AD in a mouse model.
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Doença de Alzheimer , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Doença de Alzheimer/veterinária , PPAR gama , Proteínas do Soro do Leite , Pós , Doenças Neuroinflamatórias/veterinária , Proteínas tau/metabolismo , Camundongos Transgênicos , Transdução de Sinais , Modelos Animais de DoençasRESUMO
Environmental hazards are an increasing concern due to the rapid pace of industrialization. Among these hazards, noise and carbon monoxide (CO) are common risk factors and have been shown to cause serious health problems. However, existing studies focused on the individual effects of noise and CO exposure and the combined effects of these two factors remain poorly understood. Our study aimed to examine the combined effects of noise and CO exposure on testicular function by constructing individual and combined exposure models. Our findings indicated that combined exposure to noise and CO was associated with a higher risk of testicular damage and male reproductive damage when compared to exposure alone. This was evidenced by poorer semen quality and more severe pathological damage to the testis. This combined exposure led to higher levels of oxidative stress and apoptosis in the testes, with bioinformatics analyses suggesting the signaling pathways involved in these responses. Specifically, activation of the P53 signaling pathway was found to contribute to the testicular damage caused by the combined exposure. Encouragingly, pterostilbene (PTE), a novel phytochemical, alleviated combined exposure-induced testicular damage by reducing oxidative stress and germ cell apoptosis. Overall, we identified joint reproductive toxicity resulting from the exposure to noise and CO, and found that PTE is a promising potential treatment for injuries caused by these factors. The cover image is based on the Research Article Effects and possible mechanisms of combined exposure to noise and carbon monoxide on male reproductive system in rats by Yingqing Li et al., https://doi.org/10.1002/tox.23927.
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Monóxido de Carbono , Análise do Sêmen , Ratos , Masculino , Animais , Monóxido de Carbono/toxicidade , Testículo , Células Germinativas , Reprodução , Estresse OxidativoRESUMO
A 12-week feeding trial was conducted to investigate the effect of the same fishmeal protein level replaced by black soldier fly larvae (Hermetia illucens) meal (BSFL) with different lipid contents on the growth performance and intestinal health of juvenile turbot (Scophthalmus maximus L.) (initial body weight 12.64 g). Three isonitrogenous and isolipidic diets were formulated: fish meal-based diet (FM), diets DF and FF, in which 14% fish meal protein of the FM diet was replaced by defatted and full-fat BSFL, respectively. There were no significant differences in growth performance, intestinal morphology, and mucosal barrier function between the DF and the FM group. However, diet FF markedly reduced the growth performance, intestinal perimeter ratio, and the gene expression of anti-inflammatory cytokine TGF-ß (P < 0.05). Compared to group FF, the communities of intestinal microbiota in group DF were more similar to group FM. Moreover, diet DF decreased the abundance of some potential pathogenic bacteria and enriched the potential probiotics, such as Bacillus. Diet FF obviously altered the composition of intestinal microbiota and increased the abundance of some potential pathogenic bacteria. These results suggested that the application of defatted BSFL showed more positive effects on fish growth and intestinal health than the full-fat BSFL, and the intestinal microbiota was closely involved in these effects.
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Bioactive polysaccharides have numerous pharmacological effects that are beneficial to human health. Akebia trifoliata (Thunb.) Koidz. has great development prospects as a food resource with medicinal value. The polysaccharides (ATFP) were extracted from A. trifoliata fruit by an aqueous two-phase system. ATFP-3, purified with DEAE-52 and Sephadex G-200 from ATFP, was mainly composed of glucose (47.55%) and galactose (20.39%). Its hydroxyl radical scavenging rate was 89.30% at 1.60 mg/mL and its IC50 was 0.29 mg/mL. ATFP-3 significantly enhanced the survival rate of Caenorhabditis elegans under thermal or oxidative stress. Furthermore, ATFP-3 could prolong the lifespan of C. elegans and improve the activities of the antioxidant enzyme, while also decrease the accumulation of lipofuscin and the level of malondialdehyde (MDA) in aging worms. Thus, ATFP-3 has application potential in health benefits for humans.
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Caenorhabditis elegans , Frutas , Animais , Humanos , Envelhecimento , Antioxidantes/farmacologia , PolissacarídeosRESUMO
In recent years, high-power, tunable terahertz (THZ) radiation sources have become the key areas of research in the world. The method of THZ waves by nonlinear optical difference frequency generation (DFG) has the advantages of wide tuning, high power, room temperature operation, and compact structure. However, the conversion efficiency of the current difference frequency method is low, which needs a trade-off between conversion efficiency and tuning range. We apply the nonlinear optical cascade difference frequency conversion theory based on stimulated Raman adiabatic passage (STIRAP) and propose a theoretical scheme to generate THZ waves. Numerical simulation investigates the cascaded difference frequency process of generating THZ waves with the help of the nonlinear medium lithium niobate (LN) crystal. The theoretical analysis shows that the maximum quantum conversion efficiency from signal laser to THZ waves is 43.2 % when the wavelength of the tuned signal laser varies between 1.044 - 1.065 µm with the fixed two pump laser wavelengths constant. The tunable THZ waves of 0.48 - 5.0 THz can be obtained and the maximum output intensity of THZ waves is 2.17 MW/cm2, and the method is robust to temperature variations. It also provides a novel idea for the cascaded difference frequency generation of THZ waves.
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Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM2.5 on Sertoli cells using the TM4 cell line and a real time whole-body PM2.5 exposure mouse model, and further explore the underlying mechanisms through the application of metabolomics and transcriptomics. The results in vivo and in vitro showed that PM2.5 reduced Sertoli cells number in seminiferous tubules and inhibited cell proliferation. PM2.5 exposure also induced Sertoli cell dysfunction by increasing androgen binding protein (ABP) concentration, reducing the blood-testis barrier (BTB)-related protein expression, and decreasing glycolysis capacity and lactate production. The results of transcriptomics, metabolomics, and integrative analysis of multi-omics in the TM4 Sertoli cells revealed the activation of xenobiotic metabolism, and the disturbance of glutathione and purine metabolism after PM2.5 exposure. Further tests verified the reduced GSH/GSSG ratio and the elevation of xanthine oxidase (XO) activity in the PM2.5-exposed TM4 cells, indicating that excessive reactive oxygen species (ROS) was generated via metabolic disorder caused by PM2.5. Moreover, the redox imbalance was proved by the increase in the mitochondrial ROS level, superoxide dismutase (SOD) and catalase (CAT) activity, as well as the activation of the Nrf2 antioxidative pathway. Further study found that the redox imbalance caused by PM2.5 induced DNA damage response and cell cycle arrest. Additionally, PM2.5 induced ferroptosis through iron overload and lipid peroxidation. Taken all together, our study provided new insights for understanding proliferation inhibition and dysfunction of TM4 Sertoli cells exposed to PM2.5 via metabolic disorder and redox imbalance-mediated DNA damage response and ferroptosis.
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Ferroptose , Células de Sertoli , Animais , Antioxidantes/metabolismo , Apoptose , Proliferação de Células , Dano ao DNA , Glutationa/metabolismo , Masculino , Metabolômica , Oxirredução , Material Particulado/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reprodução , Células de Sertoli/metabolismo , TranscriptomaRESUMO
In this paper, we propose a novel target-aware token design for transformer-based object detection. To tackle the target attribute diffusion challenge of transformer-based object detection, we propose two key components in the new target-aware token design mechanism. Firstly, we propose a target-aware sampling module, which forces the sampling patterns to converge inside the target region and obtain its representative encoded features. More specifically, a set of four sampling patterns are designed, including small and large patterns, which focus on the detailed and overall characteristics of a target, respectively, as well as the vertical and horizontal patterns, which handle the object's directional structures. Secondly, we propose a target-aware key-value matrix. This is a unified, learnable, feature-embedding matrix which is directly weighted on the feature map to reduce the interference of non-target regions. With such a new design, we propose a new variant of the transformer-based object-detection model, called Focal DETR, which achieves superior performance over the state-of-the-art transformer-based object-detection models on the COCO object-detection benchmark dataset. Experimental results demonstrate that our Focal DETR achieves a 44.7 AP in the coco2017 test set, which is 2.7 AP and 0.9 AP higher than the DETR and deformable DETR using the same training strategy and the same feature-extraction network.
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Conscientização , Fontes de Energia Elétrica , Benchmarking , DifusãoRESUMO
Selective functionalization of dielectric surfaces is required for area-selective atomic layer deposition and etching. We have identified precursors for the selective gas-phase functionalization of plasma-deposited SiO2 and SiNx surfaces with hydrocarbons. The corresponding reaction mechanism of the precursor molecules with the two surfaces was studied using in situ surface infrared spectroscopy. We show that at a substrate temperature of 70 °C, cyclic azasilanes preferentially react with an -OH-terminated SiO2 surface over a -NHx-terminated SiNx surface with an attachment selectivity of â¼5.4, which is limited by the partial oxidation of the SiNx surface. The cyclic azasilane undergoes a ring-opening reaction where the Si-N bond cleaves upon the reaction with surface -OH groups forming a Si-O-Si linkage. After ring opening, the backbone of the grafted hydrocarbon is terminated with a secondary amine, -NHCH3, which can react with water to form an -OH-terminated surface and release CH3NH2 as the product. The surface coverage of the grafted cyclic azasilane is calculated as â¼3.3 × 1014 cm-2, assuming that each reacted -OH group contributes to one hydrocarbon linkage. For selective attachment to SiNx over SiO2 surfaces, we determined the reaction selectivity of aldehydes. We demonstrate that aldehydes selectively attach to SiNx over SiO2 surfaces, and for the specific branched aliphatic aldehyde used in this work, almost no reaction was detected with the SiO2 surface. A fraction of the aldehyde molecules reacts with surface -NH2 groups to form an imine (Si-NâC) surface linker with H2O released as the byproduct. The other fraction of the aldehydes also reacts with surface -NH2 groups but do not undergo the water-elimination step and remains attached to the surface as an aminoalcohol (Si-NH-COH-). The surface coverage of the grafted aldehyde is calculated as â¼9.8 × 1014 cm-2 using a known infrared absorbance cross-section for the -C(CH3)3 groups.
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MsrB1 belongs to the methionine sulfoxide reductase family, it is also known as selenoprotein R for the sake of possessing a selenocysteine residue. It has been reported that MsrB1 could interact with actin, TRPM6, clusterin, and amyloid-beta in vitro. Thus, we presumed that MsrB1 may play an important role in central nervous system. To examine whether MsrB1 knockout has any effects on brain development or learning behavior, we carried out histological study on brains of MsrB1 deficient mice, and further tested spatial learning ability and long-term synaptic plasticity of these mice by using Morris water maze and electrophysiological methods. It was observed that loss of MsrB1 did not perturb the overall development of central nervous system except for the astrogliosis in hippocampus, however, it led mice to be incapable in spatial learning and severe impairments in LTP/LTD expression in CA1 of brain slices, along with the down-regulation of the synaptic proteins including PSD95, SYP, GluN2A and GluN2B, as well as the dramatic decrease of CaMKIIs phosphorylation at 286(287) compared with wild type mice. Taken together, these results suggest that MsrB1 is essential for mice spatial learning and LTP/LTD induction, and the MsrB1 related redox homeostasis may be involved in regulating the phosphorylation of CaMKIIs.
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Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Metionina Sulfóxido Redutases/genética , Aprendizagem Espacial/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Regulação para Baixo , Gliose/genética , Gliose/metabolismo , Gliose/patologia , Hipocampo/patologia , Metionina Sulfóxido Redutases/metabolismo , Camundongos , Camundongos Knockout , Oxirredução , Fosforilação , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
An improved current sensor aimed at measuring currents of different parts in composite insulator samples was proposed. Conventional current sensors used in water diffusion tests aim to examine the performance of composite insulators, however, it is difficult for the conventional current sensors to locate the defects. Thus, we designed a new electrode structure to measure the currents of different components in short samples of composite insulators. Based on a finite analysis method, the influence of relative permittivity and conductivity on the current was analyzed. New samples with different interfaces and samples after operation were tested using the new and conventional current sensors. The performance of a certain part in short samples can be diagnosed by analyzing the current and phase information extracted from the test results. By comparing the test results of new and traditional current sensors, it was proved that the new electrode structure is more effective in locating the defects of insulators.
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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.
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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 terapêuticoRESUMO
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.
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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/genéticaRESUMO
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.
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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 fármacosRESUMO
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.
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Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system that serves as an animal model for human Guillain-Barre syndrome. Curcumin, a naturally occurring polyphenolic phytochemical isolated from the medicinal plant Curcuma longa, has anti-inflammatory activities. Here we investigated the therapeutic effects and potential mechanisms of curcumin in EAN rats. Exogenous curcumin treatment (100 mg/kg/day) significantly delayed the onset of EAN neurological signs, ameliorated EAN neurological severity, and reduced body weight loss of EAN rats. In EAN sciatic nerves, curcumin treatment suppressed the inflammatory cell accumulation and the expression of interferon (IFN)-γ, tumor necrosis factor-α, interleukin (IL)-1ß, and IL-17. Furthermore, curcumin treatment significantly decreased the percentage of CD4(+) T helper cells in EAN spleen and suppressed concanavalin A-induced lymphocyte proliferation in vitro. In addition, curcumin altered helper T cell differentiation by decreasing IFN-γ(+) CD4(+) Th1 cells in EAN lymph node and spleen. In summary, our data demonstrate that curcumin could effectively suppress EAN by attenuating inflammation, indicating that curcumin might be a candidate for treatment of autoimmune neuropathies.
Assuntos
Curcumina/farmacologia , Inibidores Enzimáticos/farmacologia , Neurite Autoimune Experimental/imunologia , Neurite Autoimune Experimental/patologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Citometria de Fluxo , Inflamação/imunologia , Inflamação/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase em Tempo Real , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologiaRESUMO
OBJECTIVE: To observe the effect of three Chinese medical formulae (Zhifei Mixture I , Zhfei Mixture II, and Zhifei Mixture II) on main and secondary symptoms and signs of children with Totally 70 mycoplasma pneumonia in treating three types of children mycoplasma pneumonia. METHODS: children with mycoplasma pneumonia were assigned to the control group (38 cases) and the treatment group (32 case). All patients were intravenously injected with Azithromycin and took Ambroxol Hydrochloride and Clenbuterol Hydrochloride Oral Solution. Those in the treatment group additionally took Zhifei Mixture I , Zhfei Mixture II, and Zhifei Mixture Ill by syndrome typing. Their main and secondary symptoms and signs were observed before and after treatment (main symptoms and signs covered fever, cough, abundant sputum, short breath, and anoxia; secondary symptoms and signs covered aversion to cold, heart rate, facial complexion, spirit, appetite, and sweating). RESULTS: Seven patients were lost in this study. Compared with before treatment in the same group, scores for main and secondary symptoms and signs decreased in the treatment group (P <0.01). The therapeutic effect on fever and cough was obviously better in the control group (P <0.01). The main and secondary symptoms and signs were more obviously improved in the treatment group than in the control group (P <0.01). Commpared with the control group, scores for main and secondary symptoms and signs decreased more in the treatment group (P <0.01). Patients' main and secondary symptoms and signs were more obviously improved (P <0.05). CONCLUSIONS: Zhifei Mixture combined Western drugs could significantly improve main and secondary symptoms and signs of mycoplasma pneumonia children patients. Its efficacy was superior to that of using Western medicine alone.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Pneumonia por Mycoplasma/tratamento farmacológico , Ambroxol/administração & dosagem , Ambroxol/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Azitromicina/administração & dosagem , Azitromicina/uso terapêutico , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , Criança , Clembuterol/administração & dosagem , Clembuterol/uso terapêutico , Expectorantes/administração & dosagem , Expectorantes/uso terapêutico , Febre , Humanos , SíndromeRESUMO
BACKGROUND: Frequent presenters (FPs) are a group of individuals who visit the hospital emergency department (ED) frequently for urgent care. Many among the group present with the main diagnosis of mental health conditions. This group of individual tend to use ED resources disproportionally and significantly affects overall healthcare outcomes. No previous reviews have examined the profiles of FPs with mental health conditions. AIMS: This study aims to identify the key socio-demographic and clinical characteristics of patients who frequently present to ED with a mental health primary diagnosis by performing a comprehensive systematic review of the existing literature. METHOD: PRISMA guideline was used. PubMed, PsycINFO, Scopus and Web of Science (WOS) were searched in May 2023. A manual search on the reference list of included articles was conducted at the same time. Covidence was used to perform extraction and screening, which were completed independently by two authors. Inclusion and exclusion criteria were defined. RESULTS: The abstracts of 3341 non-duplicate articles were screened, with 40 full texts assessed for eligibility. 20 studies were included from 2004 to 2022 conducted in 6 countries with a total patient number of 25,688 (52% male, 48% female, mean age 40.7 years old). 27% were unemployed, 20% married, 41% homeless, and 17% had tertiary or above education. 44% had a history of substance abuse or alcohol dependence. The top 3 diagnoses are found to be anxiety disorders (44%), depressive disorders (39%) schizophrenia spectrum and other psychotic disorders (33%). CONCLUSION: On average, FPs are middle-aged and equally prevalent in both genders. Current data lacks representation for gender-diverse groups. They are significantly associated with high rates of unemployment, homelessness, lower than average education level, and being single. Anxiety disorder, depressive disorder, and schizophrenia spectrum disorders are the most common clinical diagnoses associated with the group.