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1.
ACS Chem Neurosci ; 11(15): 2159-2162, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: covidwho-677409

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.
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
4.
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
5.
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
6.
Obesity (Silver Spring) ; 28(7): 1292-1300, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568462

RESUMO

OBJECTIVE: Lipedema is characterized by pain, fatigue, and excessive adipose tissue and sodium accumulation of the lower extremities. This case-control study aims to determine whether sodium or vascular dysfunction is present in the central nervous system. METHODS: Brain magnetic resonance imaging was performed at 3 T in patients with lipedema (n = 15) and control (n = 18) participants matched for sex, age, race, and BMI. Standard anatomical imaging and intracranial angiography were applied to evaluate brain volume and vasculopathy, respectively; arterial spin labeling and sodium magnetic resonance imaging were applied to quantify cerebral blood flow (CBF) (milliliters per 100 grams of tissue/minute) and brain tissue sodium content (millimoles per liter), respectively. A Mann-Whitney U test (significance criteria P < 0.05) was applied to evaluate group differences. RESULTS: No differences in tissue volume, white matter hyperintensities, intracranial vasculopathy, or tissue sodium content were observed between groups. Gray matter CBF was elevated (P = 0.03) in patients with lipedema (57.2 ± 9.6 mL per 100 g/min) versus control participants (49.8 ± 9.1 mL per 100 g/min). CONCLUSIONS: Findings provide evidence that brain sodium and tissue fractions are similar between patients with lipedema and control participants and that patients with lipedema do not exhibit abnormal radiological indicators of intracranial vasculopathy or ischemic injury. Potential explanations for elevated CBF are discussed in the context of the growing literature on lipedema symptomatology and vascular dysfunction.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Lipedema/metabolismo , Lipedema/fisiopatologia , Sódio/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Química Encefálica/fisiologia , Estudos de Casos e Controles , Feminino , Humanos , Lipedema/diagnóstico , Lipedema/psicologia , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Neuroimagem/métodos , Sódio/análise
7.
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
8.
Neurology ; 94(23): e2404-e2411, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32457210

RESUMO

OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD. METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25). RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance. CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteínas E/fisiologia , Mitocôndrias/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Apolipoproteína E4/genética , Apolipoproteína E4/fisiologia , Química Encefálica , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Mitocôndrias/ultraestrutura , Dinâmica Mitocondrial , Proteínas Mitocondriais/análise , Proteínas do Tecido Nervoso/análise , Plasticidade Neuronal/genética , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/análise , Isoformas de Proteínas/fisiologia , Sirtuína 3/análise , Aprendizagem Verbal
9.
Environ Toxicol ; 35(10): 1137-1145, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32463565

RESUMO

The low dose of radiation (LDR) has received growing attention for its beneficial neuroprotective effect. This study was designed to investigate the enhancing effect of LDR on the antidepressant potential of resveratrol against diazepam-induced depression in mice. Female mice divided into five groups; control, diazepam (2 mg/kg), LDR (0.5Gy) + diazepam, resveratrol (20 mg/kg) + diazepam, LDR + resveratrol+diazepam. Mice received diazepam showed depressive symptoms as evidenced by decreased locomotor activity in the open field and increased immobility time in the forced swimming and tail suspension tests integrated with a marked decline in biogenic amines (serotonin, norepinephrine, and dopamine) in brain tissues. These effects were ameliorated by LDR or resveratrol administration demonstrating an antidepressant activity. Interestingly, LDR triggered the antidepressant effect of resveratrol as it restored the changes in behavioral tests, neurotransmitters, and neuro-histoarchitecture. In conclusion, these findings suggested that LDR could be considered as a novel adjuvant that augmented the resveratrol antidepressant effect and might serve as a potential therapeutic approach for depression.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal , Química Encefálica , Depressão/tratamento farmacológico , Raios gama , Fármacos Neuroprotetores/farmacologia , Resveratrol/farmacologia , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/efeitos da radiação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Química Encefálica/efeitos dos fármacos , Química Encefálica/efeitos da radiação , Feminino , Elevação dos Membros Posteriores , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Fármacos Neuroprotetores/uso terapêutico , Neurotransmissores/metabolismo , Doses de Radiação , Resveratrol/uso terapêutico , Irradiação Corporal Total
10.
Inflamm Res ; 69(7): 697-710, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32350570

RESUMO

OBJECTIVE: Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. METHODS: SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS: SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1ß and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1ß and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. CONCLUSION: SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway.


Assuntos
Hidrogênio/administração & dosagem , Fator 2 Relacionado a NF-E2/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Encefalopatia Associada a Sepse/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Química Encefálica , Ceco , Córtex Cerebral/ultraestrutura , Citocinas/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Microglia/fisiologia , Mitocôndrias/fisiologia , Fator 2 Relacionado a NF-E2/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Punções , Encefalopatia Associada a Sepse/patologia , Sulfonas/farmacologia
11.
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
12.
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
13.
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
14.
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
15.
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
16.
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
18.
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
19.
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
20.
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
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