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1.
ACS Chem Neurosci ; 11(15): 2159-2162, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32786343

RESUMO

Immune system and renin-angiotensin-aldosterone system dysregulation with associated cytokine release syndrome may be a key feature of early stage of SARS-CoV-2 organotropism and infection. Following viral mediated brain injury, dysregulated neurochemical activity may cause neurogenic stress cardiomyopathy, which is characterized by transient myocardial dysfunction and arrhythmias. Cardiomyopathy along with acute acute inflammatory thromboembolism and endotheliitis (fragile endothelium) might at least partially explain the underlying mechanisms of rapidly evolving life-threatening COVID-19. Further studies are clearly required to explore these complex pathologies.


Assuntos
Betacoronavirus/metabolismo , Química Encefálica/fisiologia , Encéfalo/metabolismo , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Pneumonia Viral/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia
2.
Aquat Toxicol ; 226: 105564, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32683169

RESUMO

Millions of pharmaceuticals are prescribed each year. Wastewater treatment plants fail to remove all pharmaceuticals from discharge leading to detectable concentrations entering aquatic ecosystems where the compounds can encounter nontarget organisms. Selective serotonin reuptake inhibitor (SSRI) class of antidepressants interact with transporters in the brain and peripheral nervous system to change serotonin levels in the synapse. Sublethal exposure to SSRIs can impact fish feeding behaviors, which can have impacts on ecological fitness. We exposed hybrid striped bass (Morone saxatilis x Morone chrysops) to low, medium, and high concentrations of sertraline (4.5 ± 0.84 µg/L, 35.4 ± 2.18 µg/L, and 96.8 ± 6.4 µg/L) over six days with six additional recovery days. Concentrations were chosen to compare results with a mixture study previously completed in our lab. Every three days we tracked how long each bass took to consume four fathead minnows (Pimephales promelas) and conducted destructive sampling to obtain brain and plasma samples. Brain and plasma samples were analyzed for sertraline levels and we calculated whole brain serotonin levels. During the exposure period, bass showed an increased time to capture prey, but time to capture prey returned to control levels during the six-day recovery period. Sertraline was detected in brain and plasma during the duration of the experiment, though not always in a dose-dependent fashion. While we demonstrated a relationship between time to capture prey and decrease whole brain serotonin levels, the decrease in time to capture prey during the recovery period suggests the serotonin levels in the brain are not solely responsible for the outward behavioral expression observed.


Assuntos
Bass/fisiologia , Química Encefálica/efeitos dos fármacos , Comportamento Predatório/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bass/sangue , Bass/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ecossistema , Comportamento Alimentar/efeitos dos fármacos , Serotonina/metabolismo
4.
Proc Natl Acad Sci U S A ; 117(26): 14694-14702, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554491

RESUMO

Innate immune cells destroy pathogens within a transient organelle called the phagosome. When pathogen-associated molecular patterns (PAMPs) displayed on the pathogen are recognized by Toll-like receptors (TLRs) on the host cell, it activates inducible nitric oxide synthase (NOS2) which instantly fills the phagosome with nitric oxide (NO) to clear the pathogen. Selected pathogens avoid activating NOS2 by concealing key PAMPs from their cognate TLRs. Thus, the ability to map NOS2 activity triggered by PAMPs can reveal critical mechanisms underlying pathogen susceptibility. Here, we describe DNA-based probes that ratiometrically report phagosomal and endosomal NO, and can be molecularly programmed to display precise stoichiometries of any desired PAMP. By mapping phagosomal NO produced in microglia of live zebrafish brains, we found that single-stranded RNA of bacterial origin acts as a PAMP and activates NOS2 by engaging TLR-7. This technology can be applied to study PAMP-TLR interactions in diverse organisms.


Assuntos
Encéfalo/enzimologia , DNA/química , Corantes Fluorescentes/química , Óxido Nítrico Sintase Tipo II , Animais , Encéfalo/metabolismo , Química Encefálica , DNA/metabolismo , Corantes Fluorescentes/metabolismo , Técnicas de Inativação de Genes , Camundongos , Microglia/química , Microglia/enzimologia , Microglia/metabolismo , Microscopia de Fluorescência , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Óxido Nítrico Sintase Tipo II/análise , Óxido Nítrico Sintase Tipo II/química , Óxido Nítrico Sintase Tipo II/metabolismo , Fagossomos/química , Fagossomos/metabolismo , Peixe-Zebra
5.
Biomed Khim ; 66(2): 151-155, 2020 Feb.
Artigo em Russo | MEDLINE | ID: mdl-32420896

RESUMO

The aim of the study was to determine the level of sex steroid hormones in white matter of the brain of rats with tumors combined with chronic neurogenic pain (CNP), which was modeled by bilateral sciatic nerve ligation. The study included albino male rats (n=74). In the main group, M1 sarcoma was transplanted subcutaneously (n=11) or into the subclavian vein (n=11) 45 days after CNP modeling. Two comparison groups (n=13 each) included sham operated animals (without CNP) with M1 sarcoma transplanted subcutaneously and intravenously. Control groups included animals with CNP and sham operated animals. Rats were euthanized on day 21 of the carcinogenesis. Levels of total and free testosterone (T), estrone (E1), estradiol (E2), estriol (E3) and progesterone (P4) in the brain white matter were measured using ELISA kits ("Cusabio", China). CNP caused a decrease in the total and free T by 1.5 times (p<0.05), E2 and P4 by 1.9 and 3 times, respectively, E3 by 1.6 times (p<0.05), as well as an increase in E1 by 1.4 times (p<0.05) as compared to the corresponding levels in the brain white matter of rats without CNP. CNP stimulated M1 sarcoma growth in both subcutaneous and intravenous transplantation. Regardless of the tumor site, the dynamics of total T, E2 and E3 in the brain had similar features, but the dynamics of free T, P4 and E1 differed. Thus, changes in the level of neurosteroids in the white matter of rat brain with CNP and tumor growth alone or associated with CNP are a reaction to stress.


Assuntos
Química Encefálica , Neoplasias Experimentais/patologia , Neuroesteroides/análise , Dor/patologia , Sarcoma/patologia , Animais , Estradiol , Estrona , Masculino , Transplante de Neoplasias , Progesterona , Ratos
6.
Proc Natl Acad Sci U S A ; 117(21): 11753-11759, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32398374

RESUMO

Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.


Assuntos
Transtorno Autístico/induzido quimicamente , Glicina/análogos & derivados , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Glicina/efeitos adversos , Masculino , Camundongos , Gravidez
7.
PLoS Comput Biol ; 16(4): e1007794, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32339163

RESUMO

In single-cell RNA-seq (scRNA-seq) experiments, the number of individual cells has increased exponentially, and the sequencing depth of each cell has decreased significantly. As a result, analyzing scRNA-seq data requires extensive considerations of program efficiency and method selection. In order to reduce the complexity of scRNA-seq data analysis, we present scedar, a scalable Python package for scRNA-seq exploratory data analysis. The package provides a convenient and reliable interface for performing visualization, imputation of gene dropouts, detection of rare transcriptomic profiles, and clustering on large-scale scRNA-seq datasets. The analytical methods are efficient, and they also do not assume that the data follow certain statistical distributions. The package is extensible and modular, which would facilitate the further development of functionalities for future requirements with the open-source development community. The scedar package is distributed under the terms of the MIT license at https://pypi.org/project/scedar.


Assuntos
Biologia Computacional/métodos , RNA-Seq/métodos , Análise de Célula Única/métodos , Software , Algoritmos , Animais , Química Encefálica , Células Cultivadas , Análise por Conglomerados , Humanos , Camundongos , RNA Citoplasmático Pequeno/genética , Transcriptoma/genética
8.
J Chromatogr A ; 1621: 461086, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32327225

RESUMO

Mass spectrometry imaging (MSI) has been used for localization of various biomolecules in tissues, but it is still challenging to have absolute pixel-to-pixel quantitation of analytes and differentiation of isobaric ions by MSI. In this proof-of-concept study, we present a quantitative MSI method for amino acids with distinguishing their constitutional isomers by exhaustive liquid microjunction surface sampling (LMJSS)-tandem mass tags (TMT) labeling-ultra performance liquid chromatography (UPLC)-MS. TMT6 reagents were used to differentially isotopically label amino acids in extracts from 6 pixels of brain section, resulting in multiplexed analysis of 6 pixels and largely shortening the LC-MSI time. From the results, with TMT labeling, the MS signals of amino acids in brain tissue extract were enhanced by (3-141)-fold. The calibration curves of TMT-labeled amino acids had good linearity in both MS1 and MS2 detection, which is essential for quantitation. A new extraction solvent for LMJSS (10% hexafluoroisopropanol-40% methanol-0.5% acetic acid-water) was developed to improve the extraction efficiencies of polar amino acids from brain tissue. The results showed that the extraction efficiencies of amino acids from different tissue regions were in the range of 75-110% with the new solvent, which made LMJSS an exhaustive sampling. Due to the complete extraction of amino acids from tissue, TMT0-labeled amino acid standards were directly added into the extracts for absolute quantitation. Finally, UPLC-MS was coupled with LMJSS to successfully separate the isobaric labeled amino acids in each pixel, allowing separate imaging of them. The imaging results of amino acid standard pattern demonstrate 500 µm spatial resolution of the MSI method. The brain tissue imaging results showed that the new method enabled quantitative MSI of 11 amino acids including three pairs of isomers, and the quantitation results were highly comparable and correlated with that by traditional bulk extraction-LC-MS method (correlation coefficient = 0.97, the slope of the correlation curve = 0.96).


Assuntos
Aminoácidos/química , Química Encefálica , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Animais , Calibragem , Isomerismo , Masculino , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Solventes , Extratos de Tecidos
9.
Toxicol Appl Pharmacol ; 396: 114994, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251685

RESUMO

Anticholinergic treatment is key for effective medical treatment of nerve agent exposure. Atropine is included at a 2 mg intramuscular dose in so-called autoinjectors designed for self- and buddy-aid. As patient cohorts are not available, predicting and evaluating the efficacy of medical countermeasures relies on animal models. The use of atropine as a muscarinic antagonist is based on efficacy achieved in studies in a variety of species. The dose of atropine administered varies considerably across these studies. This is a complicating factor in the prediction of efficacy in the human situation, largely because atropine dosing also influences therapeutic efficacy of oximes and anticonvulsants generally part of the treatment administered. To improve translation of efficacy of dosing regimens, including pharmacokinetics and physiology provide a promising approach. In the current study, pharmacokinetics and physiological parameters obtained using EEG and ECG were assessed in naïve rats and in sarin-exposed rats for two anticholinergic drugs, atropine and scopolamine. The aim was to find a predictive parameter for therapeutic efficacy. Scopolamine and atropine showed a similar bioavailability, but brain levels reached were much higher for scopolamine. Scopolamine exhibited a dose-dependent loss of beta power in naïve animals, whereas atropine did not show any such central effect. This effect was correlated with an enhanced anticonvulsant effect of scopolamine compared to atropine. These findings show that an approach including pharmacokinetics and physiology could contribute to improved dose scaling across species and assessing the therapeutic potential of similar anticholinergic and anticonvulsant drugs against nerve agent poisoning.


Assuntos
Atropina/uso terapêutico , Substâncias para a Guerra Química/envenenamento , Sarina/envenenamento , Escopolamina/uso terapêutico , Animais , Atropina/sangue , Atropina/farmacocinética , Atropina/farmacologia , Química Encefálica/efeitos dos fármacos , Antagonistas Colinérgicos , Eletrocardiografia/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Masculino , Camundongos , Ratos Wistar , Sarina/antagonistas & inibidores , Escopolamina/sangue , Escopolamina/farmacocinética , Escopolamina/farmacologia , Telemetria/métodos
10.
Zhongguo Zhong Yao Za Zhi ; 45(3): 645-654, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237525

RESUMO

A sensitive and specific ultra-performance liquid chromatography-mass spectrometry(UPLC-MS/MS) method was deve-loped for analysis of rutaecarpine(Ru), evodiamine(Ev), rutaevine(Rv), limonin(Li), ginsendside Rb_1(Rb_1), ginsendside Re(Re) in rat plasma and brain tissues of nitroglycerin-induced migraine rats. Male healthy Sprague-Dawley(SD) rats were orally given multiple dose of optimized(OS) and un-optimized Wuzhuyu Decoction(UNOS), and their blood samples and brainstem were collected at different time points after injection of nitroglycerin(10 mg·kg~(-1)) into the frontal region. The drug concentrations of the 6 analytes in plasma and brainstem were determined by UPLC-MS/MS method. Subsequently, the main pharmacokinetics parameters of plasma were calculated by using Phoenix WinNolin 5.2.1 software. The methodological test showed that all of analytes in both plasma and brainstem homogenate exhibited a good linearity within the concentration range(r>0.994 7). The intra-day and inter-day accuracy, precision, matrix effect, stability of the investigated components meet the requirements for biopharmaceutical analysis. The developed method was successfully applied in pharmacokinetic studies on abovementioned ingredients in rat plasma and brain stem. The plasma pharmacokinetic parameters of active ingredients in two different Wuzhuyu Decoction group were compared, it was found that Rb_1 had higher t_(1/2), T_(max), C_(max), AUC_(0-24 h) and AUC_(0-∞ )in OS group. Meanwhile, Ev had higher t_(1/2) and T_(max) but lower C_(max), AUC_(0-24 h) and AUC_(0-∞), Ru has higher t_(1/2 )but lower C_(max), AUC_(0-24 h) and AUC_(0-∞ )in OS group. The brain tissue distribution of each component were compared between the two groups, the component with higher content in OS, such as Ru at 30 min and 2 h after administration, Ev at 30 min, Rb_1 at 30 min and Rb_1 at 2 h after administration have lower brain tissue distribution than those in UNOS group, while the component with higher content in UNOS, such as Rv at 30 min, 2 h and 12 h after administration had higher brain tissue distribution than those in OS group.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Química Encefálica , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Nitroglicerina , Plasma/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
11.
Proc Natl Acad Sci U S A ; 117(11): 5749-5760, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32132201

RESUMO

Dysregulated cholesterol metabolism is implicated in a number of neurological disorders. Many sterols, including cholesterol and its precursors and metabolites, are biologically active and important for proper brain function. However, spatial cholesterol metabolism in brain and the resulting sterol distributions are poorly defined. To better understand cholesterol metabolism in situ across the complex functional regions of brain, we have developed on-tissue enzyme-assisted derivatization in combination with microliquid extraction for surface analysis and liquid chromatography-mass spectrometry to locate sterols in tissue slices (10 µm) of mouse brain. The method provides sterolomic analysis at 400-µm spot diameter with a limit of quantification of 0.01 ng/mm2 It overcomes the limitations of previous mass spectrometry imaging techniques in analysis of low-abundance and difficult-to-ionize sterol molecules, allowing isomer differentiation and structure identification. Here we demonstrate the spatial distribution and quantification of multiple sterols involved in cholesterol metabolic pathways in wild-type and cholesterol 24S-hydroxylase knockout mouse brain. The technology described provides a powerful tool for future studies of spatial cholesterol metabolism in healthy and diseased tissues.


Assuntos
Encéfalo/metabolismo , Colesterol/análogos & derivados , Hidroxicolesteróis/metabolismo , Espectrometria de Massas/métodos , Animais , Química Encefálica , Colesterol/análise , Colesterol/metabolismo , Hidroxicolesteróis/análise , Limite de Detecção , Masculino , Espectrometria de Massas/normas , Camundongos , Camundongos Endogâmicos C57BL
12.
Nature ; 580(7802): 283-287, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32050258

RESUMO

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances1-3. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls4,5, and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau9. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats11-15. This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)16. Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE17-19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.


Assuntos
Doenças dos Gânglios da Base/patologia , Córtex Cerebral/patologia , Microscopia Crioeletrônica , Tauopatias/metabolismo , Tauopatias/patologia , Proteínas tau/química , Proteínas tau/ultraestrutura , Idoso , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Doenças dos Gânglios da Base/metabolismo , Química Encefálica , Córtex Cerebral/metabolismo , Encefalopatia Traumática Crônica/metabolismo , Encefalopatia Traumática Crônica/patologia , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Doença de Pick/metabolismo , Doença de Pick/patologia , Dobramento de Proteína , Proteínas tau/metabolismo
13.
Nat Commun ; 11(1): 712, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024837

RESUMO

Recent studies have shown that protons can function as neurotransmitters in cultured neurons. To further investigate regional and neural activity-dependent proton dynamics in the brain, the development of a device with both wide-area detectability and high spatial-ltemporal resolution is necessary. Therefore, we develop an image sensor with a high spatial-temporal resolution specifically designed for measuring protons in vivo. Here, we demonstrate that spatially deferent neural stimulation by visual stimulation induced distinct patterns of proton changes in the visual cortex. This result indicates that our biosensor can detect micrometer and millisecond scale changes of protons across a wide area. Our study demonstrates that a CMOS-based proton image sensor with high spatial and temporal precision can be used to detect pH changes associated with biological events. We believe that our sensor may have broad applicability in future biological studies.


Assuntos
Técnicas Biossensoriais/instrumentação , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Prótons , Animais , Técnicas Biossensoriais/métodos , Química Encefálica , Desenho de Equipamento , Concentração de Íons de Hidrogênio , Masculino , Camundongos Endogâmicos C57BL , Estimulação Luminosa , Análise Espaço-Temporal , Córtex Visual/diagnóstico por imagem , Córtex Visual/fisiologia
14.
Food Chem ; 316: 126305, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32066069

RESUMO

A fourth phase of water, labeled exclusion-zone or "EZ," extends from hydrophilic surfaces. Salient features include exclusion of colloidal and molecular solutes, and characteristic light absorbance at 270 nm. In cell systems, EZ water interfaces with membranes, macromolecules, and organelles, and its buildup appears to be vital for function. For years thought to build health, fats have gained a negative reputation over the last few decades. While their exact role in health remains unclear, now they have become more accepted. We tested several fats for their capacity to generate EZ water. Large EZs formed next to ghee, coconut oil, lard, organic clarified butter, and 'Brain Octane®' oil. Cold ghee surfaces produced especially large EZs. Thus, EZ growth, confirmed by microsphere exclusion and UV-VIS absorbance spectroscopy of samples flanking the fat, may be an important factor in cellular hydration and might well underlie the health-promoting function of fats.


Assuntos
Gorduras/química , Encéfalo , Química Encefálica , Interações Hidrofóbicas e Hidrofílicas , Temperatura , Água/química
15.
Nature ; 578(7794): 273-277, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025029

RESUMO

Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy1. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease2. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell3-6. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity7,8. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.


Assuntos
Atrofia de Múltiplos Sistemas/diagnóstico , Doença de Parkinson/diagnóstico , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/química , Amiloide/química , Química Encefálica , Dicroísmo Circular , Endopeptidase K/metabolismo , Humanos , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Conformação Proteica , Desnaturação Proteica , Dobramento de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier , alfa-Sinucleína/classificação , alfa-Sinucleína/toxicidade
16.
Nat Commun ; 11(1): 289, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029711

RESUMO

Voluntary action is a fundamental element of self-consciousness. The readiness potential (RP), a slow drift of neural activity preceding self-initiated movement, has been suggested to reflect neural processes underlying the preparation of voluntary action; yet more than fifty years after its introduction, interpretation of the RP remains controversial. Based on previous research showing that internal bodily signals affect sensory processing and ongoing neural activity, we here investigated the potential role of interoceptive signals in voluntary action and the RP. We report that (1) participants initiate voluntary actions more frequently during expiration, (2) this respiration-action coupling is absent during externally triggered actions, and (3) the RP amplitude is modulated depending on the respiratory phase. Our findings demonstrate that voluntary action is coupled with the respiratory system and further suggest that the RP is associated with fluctuations of ongoing neural activity that are driven by the involuntary and cyclic motor act of breathing.


Assuntos
Encéfalo/fisiologia , Variação Contingente Negativa , Respiração , Adulto , Química Encefálica , Eletroencefalografia , Feminino , Humanos , Masculino , Adulto Jovem
17.
J Neurosci ; 40(9): 1810-1818, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31988059

RESUMO

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8-26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence.SIGNIFICANCE STATEMENT Brain tissue iron is essential to healthy brain function. Atypical basal ganglia tissue iron levels have been linked to impaired cognition in iron deficient children and adults with neurodegenerative disorders. However, the normative developmental trajectory of basal ganglia iron concentration during adolescence and its association with cognition are less well understood. In the largest study of tissue iron development yet reported, we characterize the developmental trajectory of tissue iron concentration across the basal ganglia during adolescence and provide evidence that diminished iron content is associated with poorer cognitive performance even in healthy youth. These results highlight the transition from adolescence to adulthood as a period of dynamic maturation of tissue iron concentration in the basal ganglia.


Assuntos
Química Encefálica/fisiologia , Cognição/fisiologia , Ferro/metabolismo , Adolescente , Adulto , Envelhecimento/metabolismo , Envelhecimento/psicologia , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/crescimento & desenvolvimento , Encéfalo/diagnóstico por imagem , Criança , Imagem de Tensor de Difusão , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Desempenho Psicomotor , Adulto Jovem
18.
Toxicology ; 431: 152367, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31945395

RESUMO

Many substances in cigarette smoke can induce changes in DNA methylation. Our previous studies have confirmed paternal nicotine exposure causes hyperactivity in the offspring via mmu-miR-15b. The main aim of the present study is to explore the molecular mechanism underlying the cross-generation effects of paternal nicotine exposure more comprehensively. The male C57BL/6 mice were exposed to 2 mg/kg/d nicotine for 5 weeks, and then mated with wild-type females. The offspring male mice were subjected to behavioral tests at 8 weeks after birth. The results suggested that, paternal nicotine exposure led to hyperactivity in the offspring. An analysis of the changes in DNA methylation revealed that nicotine exposure induced a rise in the total DNA methylation level of Dat in murine spermatozoa, and the hyper-methylation could imprint in the brains of the offspring mice. Then these epigenetic modifications reduced the expression of DAT in the brain of the offspring, resulting in a rise in the level of extracellular dopamine. The activation of D2 receptors caused the dephosphorylation of AKT, which led to increased activation of GSK3α/ß, and ultimately caused hyperactivity in the offspring mice. Further, in wild-type mice, injection of DAT inhibitors simulated this hyperactive phenotype, while the injection of D2s inhibitors reversed the hyperactivity of the offspring caused by paternal nicotine exposure. In conclusion, all results indicated that paternal nicotine exposure could induce hyperactivity in the offspring via the hyper-methylation of Dat. Consequently, Dat may be one of the genes that mediate the cross-generation effects of nicotine besides mmu-mmiR-15b.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Exposição Paterna/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Metilação de DNA , Dopamina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo
19.
Toxicology ; 432: 152381, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31981724

RESUMO

Chronic glutamate excitotoxicity has been thought to be involved in numerous neurodegenerative disorders. A small but significant loss of membrane cholesterol has been reported following a short stimulation of ionotropic glutamate receptors (iGluRs). We investigated the alteration of brain cholesterol following chronic glutamate treatment. The alteration of cholesterol levels was evaluated in the hippocampus from the adult rats that received the subcutaneous injection with monosodium l-glutamate at 1, 3, 5, and 7 days of age. The regulation of CYP46A1, LXRα, and ApoE levels were assayed following subtoxic glutamate treatment in SH-SY5Y cells as well as HT-22 cells lacking iGluRs. The ratio of 24S-hydroxycholesterol to cholesterol was elevated in the adult rats exposed to monosodium l-glutamate before the weaning age, compared to the control. The blockers of NMDA receptor (MK801) and mGluR5 (MPEP) attenuated the glutamate-induced loss of cholesterol and elevation of 24S-hydroxycholesterol level in SH-SY5Y cells. The induction of the mRNA levels of CYP46A1, LXRα, and ApoE by glutamate was observed in both SH-SY5Y cells and HT-22 cells; additionally, MK801 and MPEP attenuated the increases in these genes in SH-SY5Y cells. The increase in the binding of LXRα proteins with ApoE promoter following glutamate treatment was attenuated by MK801. The luciferase assay indicated the binding of CREB protein with CYP46A1 promoter, and the glutamate-induced CREB expression was inhibited by MK801. The results suggest that glutamate, the major excitatory neurotransmitter, may affect the metabolism and redistribution of cholesterol in the neuronal cells via its specific receptors during chronic exposure.


Assuntos
Apolipoproteínas E/biossíntese , Química Encefálica/efeitos dos fármacos , Colesterol 24-Hidroxilase/biossíntese , Colesterol/metabolismo , Glutamato de Sódio/farmacologia , Animais , Linhagem Celular , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase , Receptores X do Fígado/antagonistas & inibidores , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Glutamato/efeitos dos fármacos , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos
20.
J Vet Med Sci ; 82(3): 307-313, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31932535

RESUMO

D-Amino acids exert various physiological functions and are widely present in animals. However, they are absorbed to a lesser extent than L-amino acids. Little is known about D-arginine (D-Arg); however, its isomer L-Arg serves as a substrate for several metabolites and exhibits various functions including promotion of growth hormone secretion. Milk is the only nutrient source for infants; it plays an important role during their initial growth and brain development. No studies have evaluated the availability of D-Arg in the brain and milk in mammals. Here, we have studied the differential availability of orally administered D- and L-Arg in the brain and milk using ICR mice. Our results revealed that without D-Arg administration, D-Arg was undetectable in both plasma and brain samples. However, the plasma D-Arg was about twice the concentration of L-Arg post administration of the same. In the cerebral cortex and hypothalamus, L-Arg concentration remained almost constant for over period of 90 min after L-Arg treatment. Nevertheless, the L-Arg concentration decreased after D-Arg administration with time compared to the case post L-Arg administration. Contrastingly, D-Arg level sharply increased at both the brain regions with time after D-Arg treatment. Furthermore, L-Arg concentration in the milk hardly increased after L-Arg administration. Interestingly, oral administration of D-Arg showed efficient enrichment of D-Arg in milk, compared with L-Arg. Thus, our results imply that D-Arg may be available for brain development and infant nourishment through milk as an oral drug and/or nutrient supplement.


Assuntos
Arginina/química , Química Encefálica , Leite/química , Administração Oral , Animais , Arginina/administração & dosagem , Arginina/sangue , Feminino , Masculino , Camundongos Endogâmicos ICR , Estereoisomerismo
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