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1.
Chemosphere ; 258: 127362, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947664

RESUMO

Neonicotinoids have been described as toxic to bees. In this context, the A. mellifera foragers were exposed to a sublethal concentration of thiamethoxam (LC50/100: 0,0227 ng de thiamethoxam/µL-1 diet), a neurotoxic insecticide, for 8 days; and it was decided to investigate the insecticide effect on the brain by a shotgun proteomic approach followed by label-free quantitative-based proteomics. A total of 401 proteins were identified in the control group (CG); and a total of 350 proteins in the thiamethoxam exposed group (TMX). Quantitative proteomics data showed up 251 proteins with significant quantitative values in the TMX group. These findings demonstrated the occurrence of shared and unique proteins with altered expression in the TMX group, such as ATP synthase subunit beta, heat shock protein cognate 4, spectrin beta chain-like, mushroom body large-type Kenyon cell-specific protein 1-like, tubulin alpha-1 chain-like, arginine kinase, epidermal growth factor receptor, odorant receptor, glutamine synthetase, glutamate receptor, and cytochrome P450 4c3. Meanwhile, the proteins that were expressed uniquely in the TMX group are involved mainly in the phosphorylation, cellular protein modification, and cell surface receptor signalling processes. Interaction network results showed that identified proteins are present in five different metabolic pathways - oxidative stress, cytoskeleton control, visual process, olfactory memory, and glutamate metabolism. Our scientific outcomes demonstrated that a sublethal concentration of thiamethoxam can impair biological processes and important metabolic pathways, causing damage to the nervous system of bees, and in the long term, can compromise the nutrition and physiology of individuals from the colony.


Assuntos
Abelhas/fisiologia , Encéfalo/efeitos dos fármacos , Inseticidas/toxicidade , Tiametoxam/toxicidade , Animais , Memória , Neonicotinoides , Nitrocompostos , Oxazinas , Proteômica , Tiazóis
2.
Ecotoxicol Environ Saf ; 203: 110934, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888599

RESUMO

Pharmaceuticals and personal care products are emerging contaminants that are increasingly detected in the environment worldwide. Certain classes of pharmaceuticals, such as selective serotonin reuptake inhibitors (SSRIs), are a major environmental concern due to their widespread use and the fact that these compounds are designed to have biological effects at low doses. A complication in predicting toxic effects of SSRIs in nontarget organisms is that their mechanism of action is not fully understood. To better understand the potential toxic effects of SSRIs, we employed an ultra-low input RNA-sequencing method to identify potential pathways that are affected by early exposure to two SSRIs (fluoxetine and paroxetine). We exposed wildtype zebrafish (Danio rerio) embryos to 100 µg/L of either fluoxetine or paroxetine for 6 days before extracting and sequencing mRNA from individual larval brains. Differential gene expression analysis identified 1550 genes that were significantly affected by SSRI exposure with a core set of 138 genes altered by both SSRIs. Weighted gene co-expression network analysis identified 7 modules of genes whose expression patterns were significantly correlated with SSRI exposure. Functional enrichment analysis of differentially expressed genes as well as network module genes repeatedly identified various terms associated with mitochondrial and neuronal structures, mitochondrial respiration, and neurodevelopmental processes. The enrichment of these terms indicates that toxic effects of SSRI exposure are likely caused by mitochondrial dysfunction and subsequent neurodevelopmental effects. To our knowledge, this is the first effort to study the tissue-specific transcriptomic effects of SSRIs in developing zebrafish, providing specific, high resolution molecular data regarding the sublethal effects of SSRI exposure.


Assuntos
Encéfalo/efeitos dos fármacos , Larva/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Encéfalo/embriologia , Biologia Computacional , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Humanos , Larva/genética , Análise de Sequência de RNA , Peixe-Zebra/genética
3.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
4.
J Transl Med ; 18(1): 322, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847594

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has led to a declaration of a Public Health Emergency of International Concern by the World Health Organization. As of May 18, 2020, there have been more than 4.7 million cases and over 316,000 deaths worldwide. COVID-19 is caused by a highly infectious novel coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to an acute infectious disease with mild-to-severe clinical symptoms such as flu-like symptoms, fever, headache, dry cough, muscle pain, loss of smell and taste, increased shortness of breath, bilateral viral pneumonia, conjunctivitis, acute respiratory distress syndromes, respiratory failure, cytokine release syndrome (CRS), sepsis, etc. While physicians and scientists have yet to discover a treatment, it is imperative that we urgently address 2 questions: how to prevent infection in immunologically naive individuals and how to treat severe symptoms such as CRS, acute respiratory failure, and the loss of somatosensation. Previous studies from the 1918 influenza pandemic have suggested vitamin D's non-classical role in reducing lethal pneumonia and case fatality rates. Recent clinical trials also reported that vitamin D supplementation can reduce incidence of acute respiratory infection and the severity of respiratory tract diseases in adults and children. According to our literature search, there are no similar findings of clinical trials that have been published as of July 1st, 2020, in relation to the supplementation of vitamin D in the potential prevention and treatment for COVID-19. In this review, we summarize the potential role of vitamin D extra-renal metabolism in the prevention and treatment of the SARS-CoV-2 infection, helping to bring us slightly closer to fulfilling that goal. We will focus on 3 major topics here: 1. Vitamin D might aid in preventing SARS-CoV-2 infection: Vitamin D: Overview of Renal and Extra-renal metabolism and regulation. Vitamin D: Overview of molecular mechanism and multifaceted functions beyond skeletal homeostasis. Vitamin D: Overview of local immunomodulation in human infectious diseases. Anti-viral infection. Anti-malaria and anti-systemic lupus erythematosus (SLE). 2. Vitamin D might act as a strong immunosuppressant inhibiting cytokine release syndrome in COVID-19: Vitamin D: Suppression of key pro-inflammatory pathways including nuclear factor kappa B (NF-kB), interleukin-6 (IL-6), and tumor necrosis factor (TNF). 3. Vitamin D might prevent loss of neural sensation in COVID-19 by stimulating expression of neurotrophins like Nerve Growth Factor (NGF): Vitamin D: Induction of key neurotrophic factors. .


Assuntos
Quimioprevenção/métodos , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Imunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Vitamina D/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Suplementos Nutricionais , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/fisiologia , Neuroproteção/efeitos dos fármacos , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/virologia
5.
Int J Nanomedicine ; 15: 4919-4932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764925

RESUMO

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Diagnosing AD before symptoms arise will facilitate earlier intervention. The early diagnostic approaches are thus urgently needed. Methods: The multifunctional nanoparticles W20/XD4-SPIONs were constructed by the conjugation of oligomer-specific scFv antibody W20 and class A scavenger receptor (SR-A) activator XD4 onto superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs' stability and uniformity in size were measured by dynamic light scattering and transmission electron microscopy. The ability of W20/XD4-SPIONs for recognizing Aß oligomers (AßOs) and promoting AßOs phagocytosis was assessed by immunocytochemistry and flow cytometry analysis. The blood-brain barrier permeability of W20/XD4-SPIONs was determined by a co-culture transwell model. The in vivo probe distribution of W20/XD4-SPIONs in AD mouse brains was detected by magnetic resonance imaging (MRI). Results: W20/XD4-SPIONs, as an AßOs-targeted molecular MRI contrast probe, readily reached pathological AßOs regions in brains and distinguished AD transgenic mice from WT controls. W20/XD4-SPIONs retained the property of XD4 for SR-A activation and significantly promoted microglial phagocytosis of AßOs. Moreover, W20/XD4-SPIONs exhibited the properties of good biocompatibility, high stability and low cytotoxicity. Conclusion: Compared with W20-SPIONs or XD4-SPIONs, W20/XD4-SPIONs show the highest efficiency for AßOs-targeting and significantly enhance AßOs uptake by microglia. As a molecular probe, W20/XD4-SPIONs also specifically and sensitively bind to AßOs in AD brains to provide an MRI signal, demonstrating that W20/XD4-SPIONs are promising diagnostic agents for early-stage AD. Due to the beneficial effect of W20 and XD4 on neuropathology, W20/XD4-SPIONs may also have therapeutic potential for AD .


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/imunologia , Imunoconjugados/química , Nanopartículas de Magnetita/química , Receptores Depuradores/metabolismo , Anticorpos de Cadeia Única/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Especificidade de Anticorpos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Diagnóstico Precoce , Imunoconjugados/farmacologia , Imagem por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Nanopartículas Multifuncionais/química , Fagocitose/efeitos dos fármacos , Anticorpos de Cadeia Única/imunologia
6.
Ecotoxicol Environ Saf ; 202: 110962, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800233

RESUMO

Chronic exposure to fluoride (F) beyond the permissible limit (1.5 ppm) is known to cause detrimental health effects by induction of oxidative stress-mediated DNA damage overpowering the DNA repair machinery. In the present study, we assessed F induced oxidative stress through monitoring biochemical parameters and looked into the effect of chronic F exposure on two crucial DNA repair genes Ogg1 and Rad51 having important role against ROS induced DNA damages. To address this issue, we exposed Swiss albino mice to an environmentally relevant concentration of fluoride (15 ppm NaF) for 8 months. Results revealed histoarchitectural damages in liver, brain, kidney and spleen. Depletion of GSH, increase in lipid peroxidation and catalase activity in liver and brain confirmed the generation of oxidative stress. qRT-PCR result showed that expressions of Ogg1 and Rad51 were altered after F exposure in the affected organs. Promoter hypermethylation was associated with the downregulation of Rad51. F-induced DNA damage and the compromised DNA repair machinery triggered intrinsic pathway of apoptosis in liver and brain. The present study indicates the possible association of epigenetic regulation with F induced neurotoxicity.


Assuntos
Dano ao DNA , DNA Glicosilases/genética , Reparo do DNA , Epigênese Genética/efeitos dos fármacos , Fluoretos/toxicidade , Rad51 Recombinase/genética , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
7.
Chem Biol Interact ; 329: 109217, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32750324

RESUMO

Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period. The aim of the study is to assess cobalt and iron accumulation in the brain as well as changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin, and ferroportin in suckling mice. Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18-day-old (d18) and 25-day-old (d25) mice inducing alterations in brain iron homeostasis. Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride-exposed mice with no substantial changes between d18 and d25 mice. A weak ferroportin expression was found in 18-day-old control and cobalt-treated mouse brain. Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age-matched control group. Hepcidin level in cobalt-exposed groups was decreased in d18 mice and slightly increased in d25 mice. The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration.


Assuntos
Encéfalo/metabolismo , Cobalto/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Reguladoras do Ferro/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobalto/metabolismo , Feminino , Hepcidinas/genética , Hepcidinas/metabolismo , Ferro/metabolismo , Proteínas Reguladoras do Ferro/genética , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
8.
Int J Nanomedicine ; 15: 5253-5264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801690

RESUMO

Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.


Assuntos
Benzimidazóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/administração & dosagem , Administração Intranasal , Animais , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Lipídeos/administração & dosagem , Lipídeos/química , Masculino , Nanoestruturas/química , Tamanho da Partícula , Polissacarídeos Bacterianos/química , Ratos Wistar , Solubilidade
9.
Int J Nanomedicine ; 15: 5361-5376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801694

RESUMO

Background and Aim: Polymeric nanoparticles (NPs) have received much attention as promising carrier systems in lung cancer and brain metastases. Methods: Here, for the first time, we investigated the feasibility of using inhaled cholesterol-PEG co-modified poly (n-butyl) cyanoacrylate NPs (CLS-PEG NPs) of docetaxel (DTX) for sustained pulmonary drug delivery in cancer metastasis. Results: Spray-dried or freeze-dried NPs yielded sustained drug release in vitro. In vitro inhalation evaluation data indicated that the inhalation formulation had better inhalability. Compared with intravenous (IV) administration, pharmacokinetic data suggested that the inhalation formulation prolonged plasma concentration of DTX for greater than 24 h and is more quickly and completely absorbed into the rat lung after intratracheal (IT) administration. Furthermore, freeze-dried powders were found to increase the t1/2 and area under curve (AUC) by 2.3 and 6.5 fold compared to the free drug after IT administration, and spray-dried powders were found to increase the t1/2 and AUC by 3.4 and 8.8 fold, respectively. After pulmonary administration of the inhalation formulation, DTX appeared to prolong the pulmonary absorption time. In addition, the inhalation formulation was distributed to the brain in a sustained release manner. Conclusion: These experimental results demonstrated that freeze- and spray-dried powders have the potential for pulmonary sustained release, and they also have the potential to be used as a novel treatment for the delivery of drugs that pass through the air-blood barrier and enter the brain and are efficient carriers for the treatment of brain metastasis.


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Células A549 , Administração por Inalação , Animais , Encéfalo/efeitos dos fármacos , Colesterol/química , Preparações de Ação Retardada , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Embucrilato/química , Feminino , Liofilização , Humanos , Pulmão/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Pós/química , Ratos Wistar , Distribuição Tecidual
10.
Pediatrics ; 146(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32661188

RESUMO

Cannabinoids, the psychoactive compounds in marijuana, are one of the most commonly used substances in the United States. In this review, we summarize the impact of marijuana on child and adolescent health and discuss the implications of marijuana use for pediatric practice. We review the changing epidemiology of cannabis use and provide an update on medical use, routes of administration, synthetic marijuana and other novel products, the effect of cannabis on the developing brain, other health and social consequences of use, and issues related to marijuana legalization.


Assuntos
Cannabis , Uso da Maconha , Adolescente , Comportamento do Adolescente/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Canabinoides/efeitos adversos , Canabinoides/síntese química , Canabinoides/farmacologia , Cannabis/efeitos adversos , Cannabis/química , Cannabis/envenenamento , Criança , Comportamento Infantil/efeitos dos fármacos , Interações Medicamentosas , Endocanabinoides/fisiologia , Feminino , Feto/efeitos dos fármacos , Humanos , Drogas Ilícitas/efeitos adversos , Masculino , Abuso de Maconha/epidemiologia , Abuso de Maconha/terapia , Uso da Maconha/efeitos adversos , Uso da Maconha/epidemiologia , Uso da Maconha/legislação & jurisprudência , Uso da Maconha/psicologia , Meios de Comunicação de Massa , Maconha Medicinal/efeitos adversos , Maconha Medicinal/uso terapêutico , Leite Humano/química , Transtornos Neurocognitivos/induzido quimicamente , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Canabinoides/fisiologia , Uso de Tabaco/epidemiologia
11.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
12.
Anesthesiology ; 133(3): 595-610, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32701572

RESUMO

BACKGROUND: Sevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria-adenosine triphosphate (ATP)-Nuak1-Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function. METHODS: 6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice. RESULTS: Under baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2. CONCLUSIONS: Higher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage-dependent cognitive dysfunction after sevoflurane anesthesia.


Assuntos
Anestésicos Inalatórios/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Disfunção Cognitiva/etiologia , Sevoflurano/farmacologia , Proteínas tau/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos
13.
Proc Natl Acad Sci U S A ; 117(32): 19578-19589, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727894

RESUMO

The CreER/LoxP system is widely accepted to track neural lineages and study gene functions upon tamoxifen (TAM) administration. We have observed that prenatal TAM treatment caused high rates of delayed delivery and fetal mortality. This substance could produce undesired results, leading to data misinterpretation. Here, we report that administration of TAM during early stages of cortical neurogenesis promoted precocious neural differentiation, while it inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, synaptic formation, and cortical patterning in neonatal and postnatal offspring. Mechanistically, by employing single-cell RNA-sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays, we show TAM could exert these drastic effects mainly through dysregulating the Wnt-Dmrta2 signaling pathway. In adult mice, administration of TAM significantly attenuated NPC proliferation in both the subventricular zone and the dentate gyrus. This study revealed the cellular and molecular mechanisms for the adverse effects of TAM on corticogenesis, suggesting that care must be taken when using the TAM-induced CreER/LoxP system for neural lineage tracing and genetic manipulation studies in both embryonic and adult brains.


Assuntos
Encéfalo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Tamoxifeno/efeitos adversos , Animais , Encéfalo/embriologia , Encéfalo/patologia , Diferenciação Celular , Proliferação de Células , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Feminino , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/patologia , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
14.
J Thorac Cardiovasc Surg ; 160(2): e55-e66, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689704

RESUMO

OBJECTIVES: This study aims to evaluate the protective effects of progesterone on white matter injury and brain immaturity in neonatal rats with chronic hypoxia. METHODS: Three-day old Sprague-Dawley rats were randomly divided into 3 groups: (1) control (n = 48), rats were exposed to normoxia (fraction of inspired oxygen: 21% ± 0%); (2) chronic hypoxia (n = 48), rats were exposed to hypoxia (fraction of inspired oxygen: 10.5% ± 1.0%); and (3) progesterone (n = 48), rats were exposed to hypoxia and administrated with progesterone (8 mg/kg/d). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative polymerase chain reaction, and Western blot analyses were compared on postnatal day 14 in different groups. Motor skill and coordination abilities of rats were assessed via rotation experiments. RESULTS: Increased brain weights (P < .05), narrowed ventricular sizes (P < .01), and rotarod experiment scores (P < .01) were better in the progesterone group than in the chronic hypoxia group. The number of mature oligodendrocytes and myelin basic protein expression increased in the progesterone group compared with the chronic hypoxia group (P < .01). The polarization of M1 microglia cells in the corpus callosum of chronic hypoxia-induced hypomyelination rats was significantly increased, whereas there were fewer M2 microglia cells. Conversely, progesterone therapy had an opposite effect and caused an increase in M2 microglia polarization versus a reduction in M1 microglia cells. CONCLUSIONS: Progesterone could prevent white matter injury and improve brain maturation in a neonatal hypoxic rat model; this may be associated with inducing a switch from M1 to M2 in microglia.


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Plasticidade Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
15.
ACS Chem Neurosci ; 11(15): 2137-2144, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32639711

RESUMO

Now, it has been evidenced that Covid19 (SARS-CoV-2) infects the brain tissues. Along with this, a challenge has been raised for research professionals to find effective drugs for its treatment since the recent spread of this virus from Wuhan, China. Targeting the treatment of brain infection, it has also been a challenge that the clinical drug should have good CNS penetration ability to cross the blood-brain barrier.


Assuntos
Betacoronavirus , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Antivirais/administração & dosagem , Antivirais/metabolismo , Betacoronavirus/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/virologia , Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Metilprednisolona/administração & dosagem , Metilprednisolona/metabolismo , Pandemias , Resultado do Tratamento
16.
Lancet Neurol ; 19(9): 758-766, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32730766

RESUMO

Insulin is a peptide secreted by the pancreas and plays an important role in the regulation of glucose metabolism in peripheral tissues. Although the role of insulin in the periphery is well understood, less is known about its multifactorial role in the brain. However, emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics, enhances synaptic viability and dendritic spine formation, and increases turnover of neurotransmitters, such as dopamine. Insulin also has a role in proteostasis, influencing clearance of the amyloid ß peptide and phosphorylation of tau, which are hallmarks of Alzheimer's disease. Insulin also modulates vascular function through effects on vasoreactivity, lipid metabolism, and inflammation. Through these multiple pathways, insulin dysregulation could contribute to neurodegeneration. Thus, new approaches to restore cerebral insulin function that could offer therapeutic benefit to adults with Alzheimer's disease, vascular cognitive impairment, or related disorders are being investigated.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Encéfalo/metabolismo , Resistência à Insulina/fisiologia , Comportamento de Redução do Risco , Animais , Encéfalo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Insulina/farmacologia , Insulina/uso terapêutico
17.
PLoS One ; 15(7): e0236251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692754

RESUMO

This study investigated the effects of kaempferol and zinc gluconate on neurobehavioural and oxidative stress changes in Wistar rats exposed to noise. Thirty (30) rats were randomly divided into five groups: Groups I and II were administered with deionized water (DW); Group III, kaempferol (K); Group IV, zinc gluconate (Zn); Group V, kaempferol + zinc gluconate. Groups II, III, IV, and V were subjected to noise stress (N) induced by exposing rats to 100 dB (4 h/day) for 15 days, from day 33 to day 48 after starting the drug treatments. Neuromuscular coordination, motor coordination, motor strength, sensorimotor reflex, and learning and memory, were evaluated using standard laboratory methods. Levels of nitric oxide (NO), malondialdehyde (MDA) and activities of glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were evaluated in the hippocampus. Exposure of rats to noise, induced significant neurobehavioural deficits and oxidative stress while the combined administration of kaempferol and zinc gluconate significantly (P < 0.05) improved open-field performance, motor coordination, motor strength, sensorimotor reflex, and learning and memory. Co-administration of kaempferol and zinc gluconate ameliorated noise-induced oxidative stress as demonstrated by the significantly increased activities of GPx, catalase, and SOD, and decreased levels of NO and MDA (P < 0.05 and P < 0.01 respectively), compared to the DW + N group. Our results suggest that oxidative stress, evidenced by increased NO and MDA concentration and decreased activities of GPx, catalase and SOD, were involved in the molecular mechanism underlying neurobehavioural impairment in Wistar rats, exposed to noise stress. Single treatment of kaempferol exerted a more potent mitigative effect than zinc gluconate, while their combination produced an improved outcome.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Gluconatos/farmacologia , Quempferóis/farmacologia , Ruído/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Reflexo/efeitos dos fármacos , Zinco/farmacologia
18.
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
19.
Ecotoxicol Environ Saf ; 203: 110993, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32678762

RESUMO

Arsenic (As) and copper (Cu) are common environmental pollutants in nature. When they are excessively present in living organisms, they can cause heavy metal poisoning. There were relatively few studies of the toxicological concentrations of As and Cu in the brain using chicken as a model. Therefore, in this study, arsenic trioxide or/and copper sulfate were added to chicken diets for a 12-week toxicity test. The test results showed that excessive intake of As or/and Cu led to a significant reduction in the total antioxidant capacity (T-AOC), catalase (CAT) and hydroxyl radicals. And significant increase in nitric oxide synthase (NOS) indicates an imbalanced oxidation reaction. In addition, the increase in heat shock protein (HSPs), the increase of NF-κB pathway-related pro-inflammatory mediators, the change of apoptosis factors on the death receptor and mitochondrial apoptosis pathway show that, As or/and Cu exposure induced chicken brain has heat shock response (HSP), tissue inflammation and apoptosis. This damage is inseparable from the oxidative imbalance. It is worth noting that these injury changes are time-dependent, and the combined effect of these two metals is more severe than that of a single group of injuries. Our findings can inform the regulation of animal feed additives and avoid agricultural economic losses or biological health damage.


Assuntos
Apoptose/efeitos dos fármacos , Trióxido de Arsênio/toxicidade , Encéfalo/efeitos dos fármacos , Sulfato de Cobre/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Galinhas , Proteínas de Choque Térmico/metabolismo , Inflamação , Masculino , Mitocôndrias/metabolismo , NF-kappa B/metabolismo
20.
PLoS One ; 15(7): e0235979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706773

RESUMO

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidß in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid ßby trapping amyloid ß onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/administração & dosagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Transtornos da Memória/prevenção & controle , Nanofibras/administração & dosagem , Placa Amiloide/prevenção & controle , Administração Intranasal , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Feminino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanofibras/química , Placa Amiloide/etiologia , Placa Amiloide/patologia
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