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Sphingosine kinase 1 (SphK1) is an important signaling molecule for cell proliferation and survival. However, the role of SphK1 in acrylamide (ACR)-induced nerve injury remains unclear. The purpose of this study was to investigate the role and potential mechanism of SphK1 in ACR-induced nerve injury. Liquid chromatography triple quadrupole tandem mass spectrometry (LC-MS/MS) and reverse transcription-quantitative PCR (RT-qPCR) were used to detect sphingosine 1-phosphate (S1P) content in serum and SphK1 content in whole blood from an occupational work group exposed to ACR compared to a non-exposed group. For in vitro experiments, SphK1 in human SH-SY5Y neuroblastoma cells was activated using SphK1-specific activator phorbol 12-myristate 13-acetate (PMA). Our research also utilized cell viability assays, flow cytometry, western blots, RT-qPCR and related protein detection to assess activity of the mitogen activated protein kinase (MAPK) signaling pathway. The results of the population study showed that the contents of SphK1 and S1P in the ACR-exposed occupational contact group were lower than in the non-exposed group. The results of in vitro experiments showed that expression of SphK1 decreased with the increase in ACR concentration. Activating SphK1 improved the survival rate of SH-SY5Y cells and decreased the apoptosis rate. Activating SphK1 in SH-SY5Y cells also regulated MAPK signaling, including enhancing the phosphorylation of extracellular signal-regulated protein kinases (ERK) and inhibiting the phosphorylation of c-Jun N-terminal kinase (JNK) and p38. These results suggest that activating SphK1 can protect against nerve cell damage caused by ACR.
Assuntos
Acrilamida , Espectrometria de Massas em Tandem , Acrilamida/toxicidade , Cromatografia Líquida , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neurônios/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)RESUMO
BACKGROUND: Mood and psychotic disorders are both associated with verbal memory impairments. Verbal memory represents an important treatment target for both disorders. However, whether the neurocognitive and neurophysiological profiles of verbal memory impairments differ between specific disorders within these two diagnostic categories and healthy controls remains unclear. The current systematic review synthesized findings from comparative studies which used behavioural and neuroimaging tasks to investigate verbal memory impairments between: (1) mood disorder, psychotic disorder, and healthy control groups; and (2) mood disorder without psychotic features, mood disorder with psychotic features, and healthy control groups. METHODS: The search strategy combined terms related to three main concepts: 'mood disorders', 'psychotic disorders', and 'verbal memory'. Searches were executed in Embase, MEDLINE, PsycInfo, and PubMed databases. A total of 38 articles met the full eligibility criteria and were included in the final narrative synthesis. Findings were stratified by memory domain (overall composite score, verbal working memory, immediate recall, delayed recall, and recognition memory) and by illness phase (acute and non-acute). RESULTS: Mood and psychotic disorders displayed consistent verbal memory impairments compared to healthy controls during the acute and non-acute phases. Few significant differences were identified in the literature between mood and psychotic disorders, and between mood disorders with and without psychotic features. Individuals with schizophrenia were found to have decreased immediate and delayed verbal recall performance compared to bipolar disorder groups during the acute phase. Major depressive disorder groups with psychotic features were also found to have decreased delayed verbal recall performance compared to those without psychosis during the acute phase. No consistent differences were identified between mood and psychotic disorders during the non-acute phase. Finally, preliminary evidence suggests there may be functional abnormalities in important frontal and temporal brain regions related to verbal memory difficulties in both mood and psychotic disorders. DISCUSSION: The current findings have potential implications for the diagnosis and treatment of cognitive impairments in mood and psychotic disorders. Verbal recall memory may serve as a sensitive tool in the risk stratification of cognitive impairments for certain mood and psychotic disorders. Moreover, since no widespread differences between clinical groups were identified, the evidence supports providing targeted interventions for verbal memory, such as pharmacological and non-pharmacological interventions, through a trans-diagnostic approach in mood and psychotic disorders.
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Transtorno Depressivo Maior , Transtornos Psicóticos , Humanos , Transtornos do Humor/complicações , Transtorno Depressivo Maior/complicações , Testes Neuropsicológicos , Transtornos Psicóticos/psicologia , Memória de Curto Prazo , Transtornos da Memória/complicaçõesRESUMO
BACKGROUND: The impact of acrylamide (ACR) on learning and memory has garnered considerable attention. However, the targets and mechanisms are still unclear. RESULTS: Elongation factor 2 (eEF2) was significantly upregulated in the results of serum proteomics. Results from in vitro and in vivo experiments indicated a notable upregulation of Eukaryotic elongation factor 2 kinase (eEF2K), the sole kinase responsible for eEF2 phosphorylation, following exposure to ACR (P < 0.05). Subsequent in vitro experiments using eEF2K siRNA and in vivo experiments with eEF2K-knockout mice demonstrated significant improvements in abnormal indicators related to ACR-induced learning and memory deficits (P < 0.05). Proteomic analysis of the hippocampus revealed Lpcat1 as a crucial downstream protein regulated by eEF2K. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that eEF2K may play a role in the process of ACR-induced learning and memory impairment by affecting ether lipid metabolism. CONCLUSIONS: In summary, eEF2K as a pivotal treatment target in the mechanisms underlying ACR-induced learning and memory impairment, and studies have shown that it provides robust evidence for potential clinical interventions targeting ACR-induced impairments.
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Aqueous zinc ion batteries (ZIBs) are considered as promising energy storage devices in the post-lithium-ion era, due to their high energy density, low cost, high safety, and environmental benignity, however their commercialization is hindered by the sluggish diffusion kinetics of cathode materials due to the large hydrate Zn2+ radius. In this work, we propose a unique structure inheritance strategy for preparing Bi2S3 micro-straws in which a metal-organic framework (MOF) denoted as Bi-PYDC (PYDC2- = 3,5-pyridinedicarboxylate) with a string of [Bi2O2]2+ chains is judiciously selected as the structure-directing template to induce the formation of micro-straws based on a topochemical reaction. The distinctive hollow structure significantly enhances the ionic storage kinetics. Impressively, the obtained battery exhibits an ultra-long cycle life of more than 10 000 cycles at a current density of 1 A g-1 while maintaining a capacity of more than 153.4 mA h g-1. In addition, the Zn2+ insertion/extraction mechanism of Bi2S3 micro-straws is also investigated by multiple analytical methods, revealing the involvement of Zn2+ rather than H+ in the electrochemical storage process. This work may lead a new direction for constructing high performance cathodes of Zn-ion batteries through a MOF-based structure-directing template.
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Acrylamide is widely found in a variety of fried foods and cigarettes and is not only neurotoxic and carcinogenic, but also has many potential toxic effects. The current assessment of acrylamide intake through dietary questionnaires is confounded by a variety of factors, which poses limitations to safety assessment. In this review, we focus on the levels of AAMA, the urinary metabolite of acrylamide in humans, and its association with other diseases, and discuss the current research gaps in AAMA and the future needs. We reviewed a total of 25 studies from eight countries. In the general population, urinary AAMA levels were higher in smokers than in non-smokers, and higher in children than in adults; the highest levels of AAMA were found in the population from Spain, compared with the general population from other countries. In addition, AAMA is associated with several diseases, especially cardiovascular system diseases. Therefore, AAMA, as a biomarker of internal human exposure, can reflect acrylamide intake in the short term, which is of great significance for tracing acrylamide-containing foods and setting the allowable intake of acrylamide in foods.
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Acetilcisteína , Acrilamida , Adulto , Criança , Humanos , Acrilamida/toxicidade , Biomarcadores/urina , Inquéritos e QuestionáriosRESUMO
Introduction: The aim of this study is to establish a prognostic risk model based on ferroptosis to prognosticate the severity of Alzheimer's disease (AD) through gene expression changes. Methods: The GSE138260 dataset was initially downloaded from the Gene expression Omnibus database. The ssGSEA algorithm was used to evaluate the immune infiltration of 28 kinds of immune cells in 36 samples. The up-regulated immune cells were divided into Cluster 1 group and Cluster 2 group, and the differences were analyzed. The LASSO regression analysis was used to establish the optimal scoring model. Cell Counting Kit-8 and Real Time Quantitative PCR were used to verify the effect of different concentrations of Aß1-42 on the expression profile of representative genes in vitro. Results: Based on the differential expression analysis, there were 14 up-regulated genes and 18 down-regulated genes between the control group and Cluster 1 group. Cluster 1 and Cluster 2 groups were differentially analyzed, and 50 up-regulated genes and 101 down-regulated genes were obtained. Finally, nine common differential genes were selected to establish the optimal scoring model. In vitro, CCK-8 experiments showed that the survival rate of cells decreased significantly with the increase of Aß1-42 concentration compared with the control group. Moreover, RT-qPCR showed that with the increase of Aß1-42 concentration, the expression of POR decreased first and then increased; RUFY3 was firstly increased and then decreased. Discussion: The establishment of this research model can help clinicians make decisions on the severity of AD, thus providing better guidance for the clinical treatment of Alzheimer's disease.
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Syndecan-2 induced filopodia before spinogenesis; therefore, filopodia formation was used here as a model to study the early downstream signaling of syndecan-2 that leads to spinogenesis. Screening using kinase inhibitors indicated that protein kinase A (PKA) is required for syndecan-2-induced filopodia formation in both human embryonic kidney cells and hippocampal neurons. Because neurofibromin, a syndecan-2-binding partner, activates the cyclic adenosine monophosphate pathway, the role of neurofibromin in syndecan-2-induced filopodia formation was investigated by deletion mutant analysis, RNA interference, and dominant-negative mutant. The results showed that neurofibromin mediates the syndecan-2 signal to PKA. Among actin-associated proteins, Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) were predicted as PKA effectors downstream of syndecan-2, as Ena/VASP, which is activated by PKA, induces actin polymerization. Indeed, when the activities of Ena/VASP were blocked, syndecan-2 no longer induced filopodia formation. Finally, in addition to filopodia formation, neurofibromin and Ena/VASP contributed to spinogenesis. This study reveals a novel signaling pathway in which syndecan-2 activates PKA via neurofibromin and PKA consequently phosphorylates Ena/VASP, promoting filopodia and spine formation.
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Espinhas Dendríticas/ultraestrutura , Pseudópodes/ultraestrutura , Transdução de Sinais , Sindecana-2/fisiologia , Sequência de Aminoácidos , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Espinhas Dendríticas/fisiologia , Ativação Enzimática , Humanos , Dados de Sequência Molecular , Neurofibromina 1/metabolismo , Estrutura Terciária de Proteína , Pseudópodes/fisiologia , Sindecana-2/químicaRESUMO
We have analyzed the molecular basis of sugar reception in Drosophila. We define the response spectrum, concentration dependence, and temporal dynamics of sugar-sensing neurons. Using in situ hybridization and reporter gene expression, we identify members of the Gr5a-related taste receptor subfamily that are coexpressed in sugar neurons. Neurons expressing reporters of different Gr5a-related genes send overlapping but distinct projections to the brain and thoracic ganglia. Genetic analysis of receptor genes shows that Gr5a is required for response to one subset of sugars and Gr64a for response to a complementary subset. A Gr5a;Gr64a double mutant shows no physiological or behavioral responses to any tested sugar. The simplest interpretation of our results is that Gr5a and Gr64a are each capable of functioning independently of each other within individual sugar neurons and that they are the primary receptors used in the labellum to detect sugars.
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Carboidratos/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Comportamento Alimentar/fisiologia , Receptores de Superfície Celular/genética , Paladar/genética , Vias Aferentes/metabolismo , Animais , Encéfalo/metabolismo , Drosophila melanogaster/metabolismo , Gânglios dos Invertebrados/metabolismo , Expressão Gênica/genética , Mutação , Sistema Nervoso/metabolismo , Neurônios Aferentes/metabolismoRESUMO
In certain neurons from different brain regions, a brief burst of action potentials can activate a slow afterdepolarization (sADP) in the presence of muscarinic acetylcholine receptor agonists. The sADP, if suprathreshold, can contribute to persistent non-accommodating firing in some of these neurons. Previous studies have characterized a Ca(2+)-activated non-selective cation (CAN) current (ICAN ) that is thought to underlie the sADP. ICAN depends on muscarinic receptor stimulation and exhibits a dependence on neuronal activity, membrane depolarization and Ca(2+)-influx similar to that observed for the sADP. Despite the widespread occurrence of sADPs in neurons throughout the brain, the molecular identity of the ion channels underlying these events, as well as ICAN , remains uncertain. Here we used a combination of genetic, pharmacological and electrophysiological approaches to characterize the molecular mechanisms underlying the muscarinic receptor-dependent sADP in layer 5 pyramidal neurons of mouse prefrontal cortex. First, we confirmed that in the presence of the cholinergic agonist carbachol a brief burst of action potentials triggers a prominent sADP in these neurons. Second, we confirmed that this sADP requires activation of a PLC signaling cascade and intracellular calcium signaling. Third, we obtained direct evidence that the transient receptor potential (TRP) melastatin 5 channel (TRPM5), which is thought to function as a CAN channel in non-neural cells, contributes importantly to the sADP in the layer 5 neurons. In contrast, the closely related TRPM4 channel may play only a minor role in the sADP.