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1.
Infectio ; 25(4): 293-295, oct.-dic. 2021. tab, graf
Artigo em Espanhol | LILACS, COLNAL | ID: biblio-1286725

RESUMO

Resumen La trombosis venosa cerebral (TVC) es una presentación clínica poco común del tromboembolismo venoso caracterizada por cefalea, crisis convulsivas, déficits neurológicos focales y papiledema. El diagnóstico es confirmado con Tomografía axial computarizada (TAC) de cráneo y Resonancia magnética nuclear (RMN) cerebral. La TVC tiene una relación importante con el virus de inmunodeficiencia humana (VIH), ya que los pacientes VIH positivos cursan con hiperviscosidad san guínea, alteraciones de factores anticoagulantes endógenos y riesgo de sobreinfección, entre otros; que predisponen a estados protrombóticos y lesión vascular como lo es la TVC. El tratamiento de la TVC es terapia anticoagulante, por lo general se utiliza heparina no fraccionada o heparina de bajo peso molecular para la fase aguda y anticoagulantes orales como la warfarina para el mantenimiento posterior. Reportamos el primer caso documentado de TVC en un paciente VIH positivo en Colombia.


Abstract Cerebral venous thrombosis (CVT) is a rare clinical presentation of venous thromboembolism characterized by headache, seizures, neurological deficits and papi lledema. The diagnosis is confirmed using computed tomography scan (CT scan) and magnetic resonance imaging (MRI) of the brain. CVT has an important relationship with the human immunodeficiency virus (HIV) given that HIV-positive patients may present with blood hyperviscosity, irregular levels of endogenous anticoagulation factors and risk of sepsis among others, that predispose to prothrombotic states and vascular injury such as CVT. The treatment of CVT is anticoagulant therapy, generally unfractionated heparin or low molecular weight heparin for the early phase and oral anticoagulants such as warfarin for the late phase. This case reports the first documented case of CVT in an HIV positive patient in Colombia.


Assuntos
Humanos , Masculino , Adulto , Tromboembolia Venosa , Crânio , Encéfalo , Imageamento por Ressonância Magnética , HIV , Cefaleia , Hepatite B
2.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500626

RESUMO

We investigated the protective effect and mechanisms of apigenin against cognitive impairments in a scopolamine-injected mouse model. Our results showed that intraperitoneal (i.p.) injection of scopolamine leads to learning and memory dysfunction, whereas the administration of apigenin (synthetic compound, 100 and 200 mg/kg/day) improved cognitive ability, which was confirmed by behavioral tests such as the T-maze test, novel objective recognition test, and Morris water maze test in mice. In addition, scopolamine-induced lipid peroxidation in the brain was attenuated by administration of apigenin. To further evaluate the protective mechanisms of apigenin on cognitive and memory function, Western blot analysis was carried out. Administration of apigenin decreased the B-cell lymphoma 2-associated X/B-cell lymphoma 2 (Bax/Bcl-2) ratio and suppressed caspase-3 and poly ADP ribose polymerase cleavage. Furthermore, apigenin down-regulated the ß-site amyloid precursor protein-cleaving enzyme, along with presenilin 1 (PS1) and PS2 protein levels. Apigenin-administered mice showed lower protein levels of a receptor for advanced glycation end-products, whereas insulin-degrading enzyme, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) expression were promoted by treatment with apigenin. Therefore, this study demonstrated that apigenin is an active substance that can improve cognitive and memory functions by regulating apoptosis, amyloidogenesis, and BDNF/TrkB signaling pathways.


Assuntos
Apigenina/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Neurônios/efeitos dos fármacos , Escopolamina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Virulence ; 12(1): 2430-2442, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34517779

RESUMO

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 representing most aspects of the clinical manifestations of COVID-19 with systemic symptoms. Here we report that a Roborovski hamster strain SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection upon SARS-CoV-2 infection as in the case of the human counterpart, unlike current COVID-19 animal models. Roborovski hamster strain SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, labored breathing, dyspnea, cough, hunched posture, progressive weight loss, ruffled fur, and high fever following shaking chills. Histological examinations also revealed initial right-predominated pneumonia as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection in human, this hamster model seems to provide an ideal tool to investigate COVID-19.


Assuntos
COVID-19 , Cricetinae/classificação , Modelos Animais de Doenças , SARS-CoV-2 , Animais , Temperatura Corporal , Encéfalo/patologia , COVID-19/patologia , COVID-19/fisiopatologia , Feminino , Fígado/patologia , Pulmão/patologia , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos
4.
Nanoscale ; 13(33): 14166-14178, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34477698

RESUMO

Ischemic stroke is caused by a reduction in blood flow to the brain due to narrowed cerebral arteries. Thrombolytic agents have been used to induce reperfusion of occluded cerebral arteries. However, brain damage continues to progress after reperfusion and induces ischemia-reperfusion (I/R) injury. The receptor for advanced glycation end-products (RAGE) is overexpressed in hypoxic cells of the ischemic brain. In this study, an exosome linked to RAGE-binding-peptide (RBP-Exo) was developed as a hypoxia-specific carrier for nose-to-brain delivery of anti-microRNA oligonucleotide (AMO). The RBP-Exos were less than 50 nm in size and had negative surface charge. In vitro studies showed that RBP-Exos delivered AMO181a to Neuro2A cells more efficiently than unmodified exosomes (Unmod-Exos). In addition, RAGE was downregulated by RBP-Exos, suggesting that the RBP moiety of the RBP-Exos reduced the RAGE-mediated signal pathway. MicroRNA-181a (miR-181a) is one of the upregulated miRNAs in the ischemic brain and its downregulation can reduce the damage to the ischemic brain. Cholesterol-modified AMO181a (AMO181a-chol) was loaded onto the RBP-Exo by hydrophobic interaction. The AMO181a-chol-loaded RBP-Exo (RBP-Exo/AMO181a-chol) was administered intranasally to a rat middle cerebral artery occlusion (MCAO) model. MiR-181a was knocked down and Bcl-2 was upregulated by intranasal delivery of RBP-Exo/AMO181a-chol. In addition, tumor necrosis factor-α (TNF-α) expression and apoptosis were reduced by RBP-Exo/AMO181a-chol. As a result, RBP-Exo/AMO181a-chol significantly suppressed infarct size compared with the controls. In conclusion, RBP-Exo was a hypoxia-specific carrier for nose-to-brain delivery of AMO181a-chol in an ischemic stroke model. Furthermore, the combined effects of RBP and AMO181a-chol exerted neuroprotective effects in the ischemic brain.


Assuntos
Isquemia Encefálica , Exossomos , AVC Isquêmico , MicroRNAs , Acidente Vascular Cerebral , Animais , Antagomirs , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Hipóxia , MicroRNAs/genética , Oligonucleotídeos , Ratos , Receptor para Produtos Finais de Glicação Avançada/genética , Acidente Vascular Cerebral/tratamento farmacológico
5.
Rev Med Chil ; 149(2): 295-303, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34479278

RESUMO

Rheumatoid meningitis (RM) is a rare complication of rheumatoid arthritis (RA). RM mimics many other conditions such as subdural empyema, unsteady gait, focal brain dysfunction, stroke, relapsing-remitting motor signs, headache, neuropsychiatric disorders, seizures, parkinsonism, and meningeal tumors. RM is considered a disease with poor prognosis. However, cases reported in the last decade show a good outcome. We report two cases with a favorable outcome. A 48-year-old man with a three-year history of RA admitted for headache, sensory disturbances, and speech difficulties. Brain magnetic resonance imaging (MRI) showed a left parietal subdural laminar lesion with restricted diffusion and a small left superior frontal acute infarction. A subdural empyema was originally suspected, and antimicrobials were prescribed. A follow-up MRI did not show progression of the subdural lesion and the patient was discharged 14 days after admission without focal deficits. A 44-year-old female patient with two years of seronegative RA was admitted for severe headache, confusion, nausea and vomiting. Brain MRI showed subtle supra and infratentorial leptomeningeal involvement and a left cerebellar acute infarct. A meningoencephalitis due to etanercept was initially thought and treated with dexamethasone. The patient was discharged but had to be admitted again and a new MRI showed a progression of the leptomeningeal involvement. She worsened and required endotracheal intubation. Cyclophosphamide was started and the patient became asymptomatic three months later. We propose that treatment should not be delayed waiting a biopsy when a diagnosis of RM is made and after a cerebrospinal fluid infection has been ruled out.


Assuntos
Artrite Reumatoide , Meningite , Adulto , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Encéfalo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Convulsões
6.
Artigo em Russo | MEDLINE | ID: mdl-34481451

RESUMO

On June 25-26, 2021, a round table was held in Kazan with the participation of leading neurologists of Russia, where the issues of treatment of patients with cognitive impairment due to cerebrovascular diseases were discussed. Cognitive disorders of vascular genesis (VCD) are widespread in the population, are a common cause of a decrease in the quality of life and restriction of daily activity. The cause of VCD is both acute and chronic cerebrovascular diseases. An effective way to prevent VCD is to control cardiovascular risk factors, ensure a sufficient level of cognitive and physical activity throughout life. The role of drug therapy, aimed, among other things, at normalizing metabolic processes in the brain, is extremely important. The data on the mechanisms of action of the new domestic drug prospecta, the results of its clinical trials in patients with VCD are presented.


Assuntos
Transtornos Cerebrovasculares , Transtornos Cognitivos , Disfunção Cognitiva , Encéfalo , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Humanos , Qualidade de Vida
7.
Anal Chim Acta ; 1178: 338803, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34482878

RESUMO

The use of biologics in the therapeutic landscape has increased exponentially since the last 3 decades. Nevertheless, patients with central nervous system (CNS) related disorders could not yet benefit from this revolution because the blood-brain barrier (BBB) severely hampers biologics from entering the brain. Considerable effort has been put into generating methods to modulate or circumvent the BBB for delivery of therapeutics to the CNS. A promising strategy is receptor-mediated transcytosis (RMT). Recently, Wouters et al. (2020) discovered a mouse anti-transferrin receptor nanobody that is able to deliver a biologically active peptide to the brain via RMT. The present study aims to sample a derivative of this brain-penetrating nanobody (Nb105) in the CNS. Therefore, we compared the applicability of cerebral open flow microperfusion (cOFM) and microdialysis as sampling techniques to directly obtain high molecular weight substances from the cerebral interstitial fluid. A custom AlphaScreen™ assay was validated to quantify nanobody concentrations in the samples. In vitro microdialysis probe (AtmosLM™, 1 MDa cut-off) recovery by gain and by loss for Nb105 was 18.3 ± 3.2% and 27.0 ± 2.5% respectively, whereas for cOFM it was 87.2 ± 4.0% and 97.3 ± 1.6%. Although a large difference in in vitro recovery is observed between cOFM and microdialysis, in vivo similar results were obtained. Immunohistochemical stainings showed an astrocytic and microglial reaction in the immediate vicinity along the implantation track for both probe types. Coronal sections showed higher fluorescein isothiocyanate-dextran and immunoglobulin G extravasation around the microdialysis probe track than after cOFM sampling experiments, however this leakage was clearly limited compared to a positive control where the BBB was disrupted. This is the first study that samples a bispecific nanobody in the brain's interstitial fluid in function of time, providing a pharmacokinetic profile of nanobodies in the CNS. Furthermore, this is the first time a cOFM study is performed in awake freely moving mice, providing data on inflammation and blood-brain barrier integrity in the mouse brain. Overall, this work demonstrates that, while taking into account the (bio)analytical considerations, both microdialysis and cOFM are suitable in vivo sampling techniques for quantification of nanobodies in the CNS.


Assuntos
Barreira Hematoencefálica , Encéfalo , Animais , Transporte Biológico , Líquido Extracelular , Humanos , Camundongos , Microdiálise
8.
World J Gastroenterol ; 27(30): 4999-5018, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34497431

RESUMO

Metabolic associated fatty liver disease (MAFLD), formerly named "nonalcoholic fatty liver disease" occurs in about one-third of the general population of developed countries worldwide and behaves as a major morbidity and mortality risk factor for major causes of death, such as cardiovascular, digestive, metabolic, neoplastic and neuro-degenerative diseases. However, progression of MAFLD and its associated systemic complications occur almost invariably in patients who experience the additional burden of intrahepatic and/or systemic inflammation, which acts as disease accelerator. Our review is focused on the new knowledge about the brain-gut-liver axis in the context of metabolic dysregulations associated with fatty liver, where insulin resistance has been assumed to play an important role. Special emphasis has been given to digital imaging studies and in particular to positron emission tomography, as it represents a unique opportunity for the noninvasive in vivo study of tissue metabolism. An exhaustive revision of targeted animal models is also provided in order to clarify what the available preclinical evidence suggests for the causal interactions between fatty liver, dysregulated endogenous glucose production and insulin resistance.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Animais , Encéfalo/diagnóstico por imagem , Glucose , Humanos , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem
9.
Zool Res ; 42(5): 637-649, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34472225

RESUMO

The insect brain is the central part of the neurosecretory system, which controls morphology, physiology, and behavior during the insect's lifecycle. Lepidoptera are holometabolous insects, and their brains develop during the larval period and metamorphosis into the adult form. As the only fully domesticated insect, the Lepidoptera silkworm Bombyx mori experienced changes in larval brain morphology and certain behaviors during the domestication process. Hormonal regulation in insects is a key factor in multiple processes. However, how juvenile hormone (JH) signals regulate brain development in Lepidoptera species, especially in the larval stage, remains elusive. We recently identified the JH receptor Methoprene tolerant 1 ( Met1) as a putative domestication gene. How artificial selection on Met1 impacts brain and behavioral domestication is another important issue addressing Darwin's theory on domestication. Here, CRISPR/Cas9-mediated knockout of Bombyx Met1 caused developmental retardation in the brain, unlike precocious pupation of the cuticle. At the whole transcriptome level, the ecdysteroid (20-hydroxyecdysone, 20E) signaling and downstream pathways were overactivated in the mutant cuticle but not in the brain. Pathways related to cell proliferation and specialization processes, such as extracellular matrix (ECM)-receptor interaction and tyrosine metabolism pathways, were suppressed in the brain. Molecular evolutionary analysis and in vitro assay identified an amino acid replacement located in a novel motif under positive selection in B. mori, which decreased transcriptional binding activity. The B. mori MET1 protein showed a changed structure and dynamic features, as well as a weakened co-expression gene network, compared with B. mandarina. Based on comparative transcriptomic analyses, we proposed a pathway downstream of JH signaling (i.e., tyrosine metabolism pathway) that likely contributed to silkworm larval brain development and domestication and highlighted the importance of the biogenic amine system in larval evolution during silkworm domestication.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Bombyx/metabolismo , Proteínas de Insetos/metabolismo , Hormônios Juvenis/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Bombyx/crescimento & desenvolvimento , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Sistemas CRISPR-Cas , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Proteínas de Insetos/genética , Tegumento Comum/fisiologia , Larva/crescimento & desenvolvimento , Larva/metabolismo , Filogenia , Conformação Proteica
11.
BMC Psychol ; 9(1): 133, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479637

RESUMO

BACKGROUND: This study investigated the impact of semantic relevance on the ability to comprehend the appearance and function of a product, as presented in images. METHODS: The images used the constructs of Simile, Metaphor and Analogy to correspond to congruent, related and incongruent semantic structures, and measured the amplitude of Event-Related Potentials (ERPs) to compare these images with Landscape images. Sixteen participants with design-related educational backgrounds were invited to join in the ERP experiment. RESULTS: The results found that the image depicting the Metaphor showed a stronger N600 amplitude in the right anterior region of the brain than the Landscape image and the Analogy image induced a stronger N600 effect in the left anterior and right anterior part of the brain than the Landscape image. However, the Simile image did not trigger the N600. The N600 was triggered when the meaning of the Metaphor and Analogy being presented could not be understood. This indicates that a greater processing effort to comprehend them than was required for Simile. Analogy has a wider N600 distribution than Metaphor in the anterior area, suggesting that Analogy would require higher-level thinking processes and more complex semantic processing mechanisms than Metaphor. CONCLUSIONS: The N600 implicated that an assessment method to detect the semantic relationship between appearance and function of a product would assist in determining whether a symbol was suitable to be associated with a product.


Assuntos
Mapeamento Encefálico , Semântica , Encéfalo/diagnóstico por imagem , Compreensão , Eletroencefalografia , Potenciais Evocados , Humanos , Metáfora
12.
Front Immunol ; 12: 729776, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504502

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus that has spread rapidly around the world, leading to high mortality because of multiple organ dysfunction; however, its underlying molecular mechanism is unknown. To determine the molecular mechanism of multiple organ dysfunction, a bioinformatics analysis method based on a time-order gene co-expression network (TO-GCN) was performed. First, gene expression profiles were downloaded from the gene expression omnibus database (GSE161200), and a TO-GCN was constructed using the breadth-first search (BFS) algorithm to infer the pattern of changes in the different organs over time. Second, Gene Ontology enrichment analysis was used to analyze the main biological processes related to COVID-19. The initial gene modules for the immune response of different organs were defined as the research object. The STRING database was used to construct a protein-protein interaction network of immune genes in different organs. The PageRank algorithm was used to identify five hub genes in each organ. Finally, the Comparative Toxicogenomics Database played an important role in exploring the potential compounds that target the hub genes. The results showed that there were two types of biological processes: the body's stress response and cell-mediated immune response involving the lung, trachea, and olfactory bulb (olf) after being infected by COVID-19. However, a unique biological process related to the stress response is the regulation of neuronal signals in the brain. The stress response was heterogeneous among different organs. In the lung, the regulation of DNA morphology, angiogenesis, and mitochondrial-related energy metabolism are specific biological processes related to the stress response. In particular, an effect on tracheal stress response was made by the regulation of protein metabolism and rRNA metabolism-related biological processes, as biological processes. In the olf, the distinctive stress responses consist of neural signal transmission and brain behavior. In addition, myeloid leukocyte activation and myeloid leukocyte-mediated immunity in response to COVID-19 can lead to a cytokine storm. Immune genes such as SRC, RHOA, CD40LG, CSF1, TNFRSF1A, FCER1G, ICAM1, LAT, LCN2, PLAU, CXCL10, ICAM1, CD40, IRF7, and B2M were predicted to be the hub genes in the cytokine storm. Furthermore, we inferred that resveratrol, acetaminophen, dexamethasone, estradiol, statins, curcumin, and other compounds are potential target drugs in the treatment of COVID-19.


Assuntos
COVID-19/complicações , Insuficiência de Múltiplos Órgãos/genética , Antivirais/uso terapêutico , Encéfalo/metabolismo , Encéfalo/virologia , COVID-19/tratamento farmacológico , COVID-19/genética , COVID-19/virologia , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/virologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Bulbo Olfatório/metabolismo , Bulbo Olfatório/virologia , Mapas de Interação de Proteínas , SARS-CoV-2/fisiologia , Traqueia/metabolismo , Traqueia/virologia , Transcriptoma
13.
Nat Commun ; 12(1): 5219, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471138

RESUMO

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct site of interaction between microglia and axons, in both mouse and human tissues. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglia-node interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Altered axonal K+ flux following demyelination impairs the switch towards a pro-regenerative microglia phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron interaction, that may participate in microglia-neuron communication mediating pro-remyelinating effect of microglia after myelin injury.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Potássio/metabolismo , Nós Neurofibrosos/fisiologia , Remielinização/fisiologia , Animais , Axônios , Encéfalo , Receptor 1 de Quimiocina CX3C , Sistema Nervoso Central , Doenças Desmielinizantes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla , Bainha de Mielina/fisiologia , Neuroproteção
14.
ACS Chem Neurosci ; 12(18): 3445-3455, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34477360

RESUMO

Canavan disease (CD) is a progressive, fatal neurological disorder that begins in infancy resulting from a mutation in aspartoacyclase (ASPA), an enzyme that catalyzes the deacetylation of N-acetyl aspartate (NAA) into acetate and aspartate. Increased NAA levels in the brains of affected children are one of the hallmarks of CD. Interestingly, genetic deletion of N-acetyltransferase-8-like (NAT8L), which encodes aspartate N-aceyltransferase (ANAT), an enzyme responsible for the synthesis of NAA from l-aspartate and acetyl-CoA, leads to normalization of NAA levels and improvement of symptoms in several genetically engineered mouse models of CD. Therefore, pharmacological inhibition of ANAT presents a promising therapeutic strategy for treating CD. Currently, however, there are no clinically viable ANAT inhibitors. Herein we describe the development of fluorescence-based high throughput screening (HTS) and radioactive-based orthogonal assays using recombinant human ANAT expressed in E. coli. In the fluorescence-based assay, ANAT activity was linear with respect to time of incubation up to 30 min and protein concentration up to 97.5 ng/µL with Km values for l-aspartate and acetyl-CoA of 237 µM and 11 µM, respectively. Using this optimized assay, we conducted a pilot screening of a 10 000-compound library. Hits from the fluorescence-based assay were subjected to an orthogonal radioactive-based assay using L-[U-14C] aspartate as a substrate. Two compounds were confirmed to have dose-dependent inhibition in both assays. Inhibitory kinetics studies of the most potent compound revealed an uncompetitive inhibitory mechanism with respect to l-aspartate and a noncompetitive inhibitory mechanism against acetyl-CoA. The screening cascade developed herein will enable large-scale compound library screening to identify novel ANAT inhibitors as leads for further medicinal chemistry optimization.


Assuntos
Doença de Canavan , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Ácido Aspártico , Encéfalo/metabolismo , Doença de Canavan/tratamento farmacológico , Escherichia coli/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos
15.
Nat Commun ; 12(1): 5259, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489452

RESUMO

Magnetoencephalography measures neuromagnetic activity with high temporal, and theoretically, high spatial resolution. We developed an experimental platform combining MEG-compatible optogenetic techniques in nonhuman primates for use as a functional brain-mapping platform. Here we show localization of optogenetically evoked signals to known sources in the superficial arcuate sulcus of cortex and in CA3 of hippocampus at a resolution of 750 µm3. We detect activation in subcortical, thalamic, and extended temporal structures, conforming to known anatomical and functional brain networks associated with the respective sites of stimulation. This demonstrates that high-resolution localization of experimentally produced deep sources is possible within an intact brain. This approach is suitable for exploring causal relationships between discrete brain regions through precise optogenetic control and simultaneous whole brain MEG recording with high-resolution magnetic source imaging (MSI).


Assuntos
Encéfalo/diagnóstico por imagem , Neuroimagem Funcional/métodos , Magnetoencefalografia/métodos , Animais , Proteínas de Bactérias/genética , Encéfalo/fisiologia , Chlorocebus aethiops , Potenciais Evocados/fisiologia , Feminino , Proteínas Luminescentes/genética , Microscopia Confocal , Modelos Neurológicos , Rede Nervosa , Optogenética/métodos , Processamento de Sinais Assistido por Computador
16.
J Hazard Mater ; 416: 125918, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492850

RESUMO

Polystyrene nanoplastics (PS-NPs) are known to impair the function of the digestive system, intestinal flora, immune system, and nervous system of marine organisms. We tested whether PS-NPs influence viral infection of orange-spotted grouper (Epinephelus coioides). We found that grouper spleen (GS) cells took up PS-NPs at exposure concentrations of 5, 50, and 500 µg/mL and experienced cytotoxicity at 50 and 500 µg/mL concentrations. At 12 h after exposure to 50 µg/mL of PS-NPs, the replication of Singapore grouper iridovirus (SGIV) and red-spotted grouper nervous necrosis virus (RGNNV) increased in GS cells after their invasion. Juvenile fish exposed to 300 and 3000 µg/L of PS-NPs for 7 d showed PS-NPs uptake to the spleen and vacuole formation in brain tissue. Moreover, PS-NPs exposure accelerated SGIV replication in the spleen and RGNNV replication in the brain. PS-NP exposure also decreased the expression of toll-like receptor genes and interferon-related genes before and after virus invasion in vitro and in vivo, thus reducing the resistance of cells and tissues to viral replication. This is the first report that PS-NPs have toxic effects on GS cells and spleen and brain tissues, and it provides new insights into assessing the impact of PS-NPs on marine fish.


Assuntos
Bass , Infecções por Vírus de DNA , Doenças dos Peixes , Animais , Bass/metabolismo , Encéfalo/metabolismo , Proteínas de Peixes/genética , Regulação da Expressão Gênica , Microplásticos , Filogenia , Poliestirenos , Baço/metabolismo , Replicação Viral
18.
Braz J Biol ; 83: e246194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468514

RESUMO

Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.


Assuntos
Anticonvulsivantes , Transtorno Depressivo Maior , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Encéfalo , Transtorno Depressivo Maior/tratamento farmacológico , Succinato de Desvenlafaxina/farmacologia , Camundongos , Estresse Oxidativo
19.
Rev Peru Med Exp Salud Publica ; 38(2): 345-351, 2021.
Artigo em Espanhol, Inglês | MEDLINE | ID: mdl-34468586

RESUMO

Mitochondria are complex organelles that play a critical role within the cell; mitochondrial dysfunction can result in significant cell damage or death. Previous studies have demonstrated the promising therapeutic effects of autologous mitochondria transplantation into ischemic cardiac tissue; however, few studies have examined the in vivo effects of mitochondria infusion into the brain. The aim of this study is to report a procedure for carotid infusion of autologous mitochondria into porcine brains. By using this infusion technique, we propose that a selective and minimally invasive administration is feasible and may provide benefits in the treatment of various central nervous system disorders.


Assuntos
Doenças do Sistema Nervoso Central , Mitocôndrias , Animais , Encéfalo , Artérias Carótidas , Suínos
20.
Nihon Yakurigaku Zasshi ; 156(5): 292-296, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34470934

RESUMO

Histamine is a biological amine that functions as a neurotransmitter in the brain to regulate arousal, appetite, and cognitive functions. Many pharmacological studies using histamine receptor agonists and antagonists have found that histamine promotes memory consolidation and retrieval. More recently, we have revealed that the activation of the brain histaminergic system by H3R antagonists/inverse agonists restores retrieval of forgotten long-term memory in mice and humans. The recovery of memory retrieval may involve histamine-induced excitatory effects. Histamine may increase neuronal excitability throughout the neural circuit, including both neurons that are and are not recruited into the memory trace, similar to noise added to the neural circuits for memory retrieval. Stochastic resonance can explain how adding noise to the circuit enhances memory retrieval. Memory is processed not only by consolidation and retrieval, but also by various processes such as maintenance, reconsolidation, extinction, and reinstatement. Further studies that separately analyze the memory processes are needed to elucidate the whole picture of the effects of histamine on learning and memory. Regarding the human histaminergic system, alterations in histamine signaling have been reported in several neuropsychiatric disorders, and these changes have been suggested to be involved in cognitive dysfunction in patients with the neuropsychiatric disorders. Therefore, the drugs that modulate histamine signaling, including H3R antagonists/inverse agonists, may be effective in the treatment of cognitive dysfunction, including Alzheimer's disease.


Assuntos
Histamina , Transtornos da Memória , Animais , Encéfalo , Humanos , Aprendizagem , Memória , Camundongos
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