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1.
Chem Commun (Camb) ; 55(67): 9955-9958, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31364619

RESUMO

A silver nanocluster-based ratiometric fluorescent nanosensor was developed for the determination of ATP in the cerebrospinal fluid of a mouse brain. Using this useful tool with good stability and high selectivity as well as a wide linear detection range, it was found that the ATP concentration in a mouse brain with Alzheimer's disease was 2300-fold higher than that in a normal one.


Assuntos
Trifosfato de Adenosina/líquido cefalorraquidiano , Química Encefálica , DNA/química , Corantes Fluorescentes/química , Nanopartículas Metálicas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/citologia , Encéfalo/patologia , Córtex Cerebral/química , Hipocampo/química , Camundongos , Conformação de Ácido Nucleico , Prata/química , Espectrometria de Fluorescência/métodos
2.
Minerva Med ; 110(5): 455-463, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368292

RESUMO

Peripheral neuropathies are frequently encountered in clinical practice and are associated with a major impairment in quality of life. However, their management remains poor, and current therapies are often burdened with major side effects and can present poor efficacy on pain and functionality. Therefore, it has been suggested that the combination of two or more different drugs may improve analgesic efficacy and reduce side effects. Tricortin® 1000 is formulated with 12 mg of Brain cortex phospholipid liposomes + 1000 µg of Cyanocobalamin injectable solution (PL+CNCbl) for intramuscular use and is indicated in the treatment of poly-algo-neuropathic syndromes. This combination exerts a marked neurotrophic action by promoting the synthesis of endogenous phospholipids; moreover, the peculiar formulation optimizes the delivery of CNCbl which has analgesic and neurotrophic action. This paper discusses the pharmacotherapy of peripheral neuropathies, including low-back pain, neck pain, postherpetic neuropathy (PHN) and focuses on the fixed dose combination PL+CNCbl clinical efficacy in association with other treatments or in monotherapy.


Assuntos
Analgésicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Fosfolipídeos/uso terapêutico , Vitamina B 12/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Córtex Cerebral/química , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Humanos , Injeções Intramusculares , Lipossomos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fosfolipídeos/administração & dosagem , Fosfolipídeos/efeitos adversos , Vitamina B 12/administração & dosagem , Vitamina B 12/efeitos adversos
3.
J Agric Food Chem ; 67(27): 7684-7693, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31203623

RESUMO

This study investigated the alleviative effect of caffeic acid (CA) on Alzheimer's disease (AD) pathogenesis and associated mechanisms in high-fat (HF) diet-induced hyperinsulinemic rats. The results of a Morris water maze indicated that, by administrating CA (30 mg/kg b.w./day) for 30 weeks, the memory and learning impairments in HF-induced hyperinsulinemic rats were significantly ameliorated. CA also enhanced superoxide dismutase and glutathione free radical scavenger activity in hyperinsulinemic rats. The Western blot data further confirmed that protein expressions of phosphorylated-glycogen synthase kinase 3ß (GSK3ß) were significantly increased, whereas the expression of phosphorylated-tau protein decreased in the hippocampus of rats administered with CA in comparison with the HF group. Moreover, the expression of amyloid precursor protein (APP) and ß-site APP cleaving enzyme were attenuated, subsequently lowering the level of ß-amyloid 1-42 (Aß 1-42) in the hippocampus of CA-treated hyperinsulinemic rats. CA also significantly increased the expression of synaptic proteins in HF rats.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Ácidos Cafeicos/administração & dosagem , Insulina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/química , Córtex Cerebral/química , Córtex Cerebral/enzimologia , Córtex Cerebral/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Glutationa/metabolismo , Glicogênio Sintase Quinase 3 beta/análise , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/química , Hipocampo/enzimologia , Hipocampo/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Proteínas tau/análise , Proteínas tau/metabolismo
4.
Nutrients ; 11(5)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121888

RESUMO

The pharmacological properties of Eleutherococcus senticosus leaf have not been clarified although it is taken as a food item. In this study, the effects of water extract of Eleutherococcus senticosus leaves on memory function were investigated in normal mice. Oral administration of the extract for 17 days significantly enhanced object recognition memory. Compounds absorbed in blood and the brain after oral administration of the leaf extract were detected by LC-MS/MS analyses. Primarily detected compounds in plasma and the cerebral cortex were ciwujianoside C3, eleutheroside M, ciwujianoside B, and ciwujianoside A1. Pure compounds except for ciwujianoside A1 were administered orally for 17 days to normal mice. Ciwujianoside C3, eleutheroside M, and ciwujianoside B significantly enhanced object recognition memory. These results demonstrated that oral administration of the leaf extract of E. senticosus enhances memory function, and that active ingredients in the extract, such as ciwujianoside C3, eleutheroside M, and ciwujianoside B, were able to penetrate and work in the brain. Those three compounds as well as the leaf extract had dendrite extension activity against primary cultured cortical neurons. The effect might relate to memory enhancement.


Assuntos
Encéfalo/efeitos dos fármacos , Eleutherococcus/química , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células Cultivadas , Córtex Cerebral/química , Córtex Cerebral/embriologia , Córtex Cerebral/ultraestrutura , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Glicosídeos/análise , Glicosídeos/farmacocinética , Glicosídeos/farmacologia , Masculino , Camundongos , Extratos Vegetais/análise , Extratos Vegetais/farmacocinética , Saponinas/análise , Saponinas/farmacocinética , Saponinas/farmacologia
5.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058813

RESUMO

INTRODUCTION: Alcohol overuse may be related to increased aluminum (Al) exposure, the brain accumulation of which contributes to dementia. However, some reports indicate that silicon (Si) may have a protective role over Al-induced toxicity. Still, no study has ever explored the brain content of Al and Si in alcoholic use disorder (AUD). MATERIALS AND METHODS: To fill this gap, the present study employed inductively coupled plasma optical emission spectrometry to investigate levels of Al and Si in 10 brain regions and in the liver of AUD patients (n = 31) and control (n = 32) post-mortem. RESULTS: Al content was detected only in AUD patients at mean ± SD total brain content of 1.59 ± 1.19 mg/kg, with the highest levels in the thalamus (4.05 ± 12.7 mg/kg, FTH), inferior longitudinal fasciculus (3.48 ± 9.67 mg/kg, ILF), insula (2.41 ± 4.10 mg/kg) and superior longitudinal fasciculus (1.08 ± 2.30 mg/kg). Si content displayed no difference between AUD and control, except for FTH. Positive inter-region correlations between the content of both elements were identified in the cingulate cortex, hippocampus, and ILF. CONCLUSIONS: The findings of this study suggest that AUD patients may potentially be prone to Al-induced neurodegeneration in their brain-although this hypothesis requires further exploration.


Assuntos
Alcoolismo/complicações , Alumínio/análise , Química Encefálica , Doenças Neurodegenerativas/diagnóstico , Silício/análise , Adulto , Idoso , Alumínio/toxicidade , Autopsia , Estudos de Casos e Controles , Córtex Cerebral/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/induzido quimicamente , Espectrofotometria Atômica , Tálamo/química
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 220: 117128, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31146210

RESUMO

Aging brain is characterized by a change in biomolecular composition leading to a diverse range of neurological diseases. Anti-aging research is of current interest, to lessen the burden of age-related macromolecular damage through antioxidant supplementation and caloric restriction. However, data concerning the effect of these anti-aging regimens on age-related biomolecular changes in rat brain is still lacking. In the present study, for the first time, we employed Fourier transform infrared (FTIR) spectroscopy, to investigate the effect of quercetin, caloric restriction (CR) and combination of both on alterations in the composition of lipids and proteins of aged rat brain cerebral cortex. Aged male Wistar rats (21 months old) were divided into four groups: Control (CONT), fed pellet diet; Quercetin (QUER), fed quercetin (50 mg/kg/day); CR (caloric restriction) (fed 40% reduced CONT), and CRQ (40% CR and 50 mg/kg/day QUER). Three-month-old rats served as young control (YOUNG). Our short-term study (45 days) shows decreased band area of unsaturated lipids, decreased area ratios of olefinic/lipid and CH2 antisymmetric stretching (2925 cm-1)/lipids in CONT group compared to young rats, suggesting age-associated lipid peroxidation in aged rats. A slight decrease in the frequency of CH2 antisymmetric mode of lipids (whereas no change in CH2 symmetric mode), but a decrease in bandwidths of both CH2 antisymmetric and symmetric modes of lipids was observed for CONT group compared to YOUNG. Further, a significant decrease in the peak area of infrared bands of proteins and an increase in the peak area of the CO band of lipids was observed in the CONT group. Our data also show that lower levels of α-helical structures and higher levels of random coils, representing altered protein secondary structure composition in the CONT group compared to YOUNG group. Reduction in neuronal cell density and shrinked nucleus was also observed in aged rats. Increase in the accumulation of oxidative mediated damage to macromolecules and diminished antioxidant levels, could be the possible reason for the age-related alterations in the composition of lipids and proteins. However, the combination of quercetin and CR, but not either treatment alone, significantly prevented the age associated alterations in the lipid and protein profiles in the rat cerebral cortex. Further, our results help to understand the mechanism of action of antioxidants under non-restriction and CR conditions, this might help in the development of novel anti-aging treatments to ameliorate oxidative stress in age-related disorders.


Assuntos
Envelhecimento/efeitos dos fármacos , Restrição Calórica , Córtex Cerebral/química , Lipídeos/química , Quercetina/farmacologia , Envelhecimento/fisiologia , Amidas/química , Animais , Contagem de Células , Córtex Cerebral/efeitos dos fármacos , Suplementos Nutricionais , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Proteínas/química , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Psychopharmacology (Berl) ; 236(9): 2579-2591, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31011757

RESUMO

RATIONALE: Insular cortex supports the representation of motivational feelings through the integration of interoceptive information concerning bodily physiology. Compromised insular integrity is implicated in alcohol and drug use disorders. Alcohol-associated insular dysfunction may arise through aberrant glutamatergic neurotransmission associated with selective neuronal death and atrophy. OBJECTIVE: In a sample of alcohol users, we combined magnetic resonance spectroscopy (MRS) with voxel and surface-based morphometry (VBM, SBM) to test the hypothesis that the neurochemical and structural properties of the insula relate to alcohol use. METHODS: Twenty-three healthy individuals were characterized by measures of alcohol use and subjective craving. Right mid-insula glutamate/glutamine (Glx) and total N-acetylaspartate/N-acetyl-aspartylglutamate (TNAA) concentrations were measured using MRS. Right insular structure was quantified using VBM and SBM parameters. We tested for predictive associations between these neuroimaging and behavioral/psychometric measures using Bayesian statistics. RESULTS: Reduced insular Glx concentration was associated with increased alcohol compulsions and, to a lesser extent, with greater alcohol use severity. Anecdotal evidence for a negative relationship between alcohol use severity and levels of insular gyrification was also observed. CONCLUSIONS: This study is, to date, the first characterization of the neurochemical and morphological integrity of insular cortex in alcohol users. Our data seem to reveal a negative relationship between alcohol use and the neurochemical and structural integrity of the insula, a critical substrate for motivational behavior. These neurobiological characteristics might contribute to loss of control toward compulsive drinking with prolonged and excessive alcohol use.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Córtex Cerebral/química , Córtex Cerebral/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/metabolismo , Teorema de Bayes , Córtex Cerebral/metabolismo , Feminino , Humanos , Masculino , Neuroquímica , Neuroimagem/métodos , Adulto Jovem
8.
Nat Commun ; 10(1): 1500, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940809

RESUMO

Neural computations occurring simultaneously in multiple cerebral cortical regions are critical for mediating behaviors. Progress has been made in understanding how neural activity in specific cortical regions contributes to behavior. However, there is a lack of tools that allow simultaneous monitoring and perturbing neural activity from multiple cortical regions. We engineered 'See-Shells'-digitally designed, morphologically realistic, transparent polymer skulls that allow long-term (>300 days) optical access to 45 mm2 of the dorsal cerebral cortex in the mouse. We demonstrate the ability to perform mesoscopic imaging, as well as cellular and subcellular resolution two-photon imaging of neural structures up to 600 µm deep. See-Shells allow calcium imaging from multiple, non-contiguous regions across the cortex. Perforated See-Shells enable introducing penetrating neural probes to perturb or record neural activity simultaneously with whole cortex imaging. See-Shells are constructed using common desktop fabrication tools, providing a powerful tool for investigating brain structure and function.


Assuntos
Córtex Cerebral/química , Córtex Cerebral/fisiologia , Polímeros/química , Animais , Cálcio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Crânio/química , Crânio/fisiologia
9.
Anal Chim Acta ; 1063: 47-56, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30967185

RESUMO

We reported a novel strategy for rapidly and accurately screening biomarkers based on ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) metabolomics data. First, the preliminary variables were obtained by screening the original variables using method validation. Second, the variables were selected from the preliminary variables and formed the variable sets by testing different thresholds of single factor (variable importance in projection (VIP), fold change (FC), the area under the receiver operating characteristic curve (AUROC), and -ln(p-value)). Then the partial least squares-discriminant analysis (PLS-DA) models were performed. The best threshold of each factor, and the corresponding variable set were found by comparing the models' R2X, R2Y, and Q2. Third, the second-step-obtained variable sets were further screened by multi-factors. The best combination of the multi-factors, and the corresponding variable set were found by comparing R2X, R2Y, and Q2. The expected biomarkers were thus obtained. The proposed strategy was successfully applied to screen biomarkers in urine, plasma, hippocampus, and cortex samples of Alzheimer's disease (AD) model, and significantly decreased the time of screening and identifying biomarkers, improved the R2X, R2Y, and Q2, therefore enhanced the interpreting, grouping, and predicting abilities of the PLS-DA model compared with generally-applied procedure. This work can provide a valuable clue to scientists who search for potential biomarkers. It is expected that the developed strategy can be written as a program and applied to screen biomarkers rapidly, efficiently and accurately.


Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Cromatografia Líquida de Alta Pressão , Hipocampo/metabolismo , Espectrometria de Massas , Metabolômica , Doença de Alzheimer/diagnóstico , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Córtex Cerebral/química , Hipocampo/química , Análise dos Mínimos Quadrados , Masculino , Ratos , Ratos Sprague-Dawley
10.
Genes (Basel) ; 10(4)2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987383

RESUMO

: Lead (Pb) exposure is associated with a wide range of neurological deficits. Environmental exposures may impact epigenetic changes, such as DNA methylation, and can affect neurodevelopmental outcomes over the life-course. Mating mice were obtained from a genetically invariant C57BL/6J background agouti viable yellow Avy strain. Virgin dams (a/a) were randomly assigned 0 ppm (control), 2.1 ppm (low), or 32 ppm (high) Pb-acetate water two weeks prior to mating with male mice (Avy/a), and this continued through weaning. At age 10 months, cortex neuronal nuclei were separated with NeuN⁺ antibodies in male mice to investigate neuron-specific genome-wide promoter DNA methylation using the Roche NimbleGen Mouse 3x720K CpG Island Promoter Array in nine pooled samples (three per dose). Several probes reached p-value < 10-5 , all of which were hypomethylated: 12 for high Pb (minimum false discovery rate (FDR) = 0.16, largest intensity ratio difference = -2.1) and 7 for low Pb (minimum FDR = 0.56, largest intensity ratio difference = -2.2). Consistent with previous results in bulk tissue, we observed a weak association between early-life exposure to Pb and DNA hypomethylation, with some affected genes related to neurodevelopment or cognitive function. Although these analyses were limited to males, data indicate that non-dividing cells such as neurons can be carriers of long-term epigenetic changes induced in development.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Metilação de DNA , Chumbo/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Córtex Cerebral/química , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Epigênese Genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/química , Neurônios/efeitos dos fármacos , Gravidez , Regiões Promotoras Genéticas , Distribuição Aleatória
11.
Fitoterapia ; 134: 165-171, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30825572

RESUMO

Two novel phenanthrenoids, juncuenin H (1) and dijuncuenin B (2), together with eight known phenanthrenoids, effusol (3), dehydroeffusol (4), juncusol (5), dehydrojuncusol (6), juncuenin B (7), dehydrojuncuenin B (8), juncuenin A (9), and dehydrojuncuenin A (10), were isolated from the underground parts of Juncus setchuenensis. The structures of the compounds were determined by 1D and 2D NMR and mass spectroscopy. The anxiolytic activities of compounds 1, 6, 9, and 10 were evaluated. In order to explore the mechanisms underlying their anxiolytic activities, the levels of serotonin (5-HT), dopamine (DA), and their metabolites in the cerebral cortex and hippocampus of mice treated with compound 1 were determined by quantitative mass spectrometry. The mice treated with compound 1 had significantly lower levels of 5-HT, 3-methoxytyramine (3-MT), 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA), and 3, 4-dihydroxyphenylacetic acid (DOPAC) in the cerebral cortex than those of the vehicle control-treated mice. The levels of HVA and 5-HIAA in the hippocampus were also significantly lower in the mice treated with compound 1 than in the control group mice. These results suggest that the metabolic changes, reflected in the levels of DA and/or 5-HT, may contribute to the anxiolytic activity of the phenanthrenoids studied herein.


Assuntos
Ansiolíticos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Magnoliopsida/química , Fenantrenos/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Ansiolíticos/isolamento & purificação , Córtex Cerebral/química , China , Dopamina/análogos & derivados , Dopamina/análise , Hipocampo/química , Ácido Homovanílico/análise , Masculino , Camundongos , Estrutura Molecular , Fenantrenos/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Serotonina/análise
12.
Stroke ; 50(2): 328-335, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30661497

RESUMO

Background and Purpose- Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods- Eleven CAA cases (median [IQR] age=69 years [65-79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68-92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results- Our results demonstrated increased IgG positivity in the frontotemporal ( P=0.044) and parietooccipital ( P=0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P=0.005 and P=0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-ß-positive vessels (Spearman ρ=0.71, P=0.015 and Spearman ρ=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-ß-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P=0.005 and Spearman ρ=0.70, P=0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions- Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.


Assuntos
Barreira Hematoencefálica , Angiopatia Amiloide Cerebral/patologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/análise , Autopsia , Proteínas Sanguíneas/análise , Permeabilidade Capilar , Angiopatia Amiloide Cerebral/fisiopatologia , Córtex Cerebral/química , Exsudatos e Transudatos/química , Feminino , Fibrina/análise , Humanos , Imunoglobulina G/análise , Imagem por Ressonância Magnética , Masculino , Microvasos/patologia , Neuroimagem
13.
Antiviral Res ; 162: 130-135, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605724

RESUMO

Ribavirin (RBV) is a guanosine analogue triazole most commonly used in the treatment of chronic hepatitis C (HCV) infection. Although its mechanism of action is a matter of debate, several possibilities have been proposed, including depletion of guanine nucleotides through inhibition of inosine monophosphate dehydrogenase (IMPDH). IMPDH has been shown to assemble into micron-scale rod- and ring-shaped structures (rods/rings or RR), also called "IMPDH filaments," both in vitro and in vivo. Formation of RR structures can occur naturally, potentially to influence IMPDH activity, or when de novo guanosine monophosphate biosynthesis or IMPDH itself are inhibited by nutrient deprivation or drugs like RBV. Numerous studies have also reported the occurrence of autoantibodies targeting RR structures (anti-RR) in HCV patients previously treated or under treatment with interferon-α and ribavirin (IFN/RBV) combination therapy. For this brief study, we considered the strong association between RR autoantibodies and IFN/RBV treatment, and the lack of data assessing how RBV affects RR formation in a variety of tissues in vivo. First, RR structures formed in the spleen and pancreas of normal mice without any treatment. Then, in RBV-treated mice, we detected RR structures in a number of tissues, including stomach, liver, spleen, kidney, brain, skin, and cardiac and skeletal muscle. We made several intriguing observations: predominance of RR structures in the mucosa and submucosa layers of the stomach wall; a high proportion of RR-positive cells in the cerebral cortex, suggesting that RBV actually crosses the blood-brain barrier; and a higher ratio of rings to rods in the epidermis compared to the dermis layer of the skin. Screening for RR structures appears to be a useful method to track tissue penetration of RBV and the many RR-inducing drugs previously identified.


Assuntos
Antivirais/farmacocinética , IMP Desidrogenase/química , Ribavirina/farmacocinética , Animais , Barreira Hematoencefálica , Córtex Cerebral/química , Hepacivirus/efeitos dos fármacos , Rim/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pâncreas/química , Baço/química
14.
Drug Chem Toxicol ; 42(2): 167-175, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29745257

RESUMO

This study was conducted to investigate protective effects of Urtica dioica extract on acetylcholinesterase (AChE) activity and the oxidative damage of brain tissues in scopolamine-induced memory impairment model. The rats were treated with (1) saline (control), (2) scopolamine, and (3-5) the plant extract (20, 50, or 100 mg/kg) before scopolamine. The traveled distance and the latency to find the platform in Morris water maze (MWM) by scopolamine-treated group were longer while the time spent in target quadrant was shorter than those of the control. Scopolamine decreased the latency to enter the dark in passive avoidance test. Besides, it also increased AChE activity and malondialdehyde (MDA) concentration in the hippocampal and cortical tissues while decreased thiols content and superoxide dismutase (SOD) and catalase (CAT) activities in the brain (p < 0.01-p <0.001). Treatment by the extract reversed all the effects of scopolamine (p < 0.05-p <0.001). According to the results of present study, the beneficial effects of U. dioica on memory can be attributed to its protective effects on oxidative damage of brain tissue and AChE activity.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Escopolamina/farmacologia , Urtica dioica/química , Acetilcolinesterase/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Malondialdeído/análise , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
15.
Glia ; 67(1): 171-181, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30430665

RESUMO

Although historically regarded as a homogeneous cell population, astrocytes in different brain regions exhibit differences in their physiological properties, such as gap-junction coupling, glutamate uptake dynamics, and intracellular Ca2+ response. Recent in vivo RNA profiles have further demonstrated the molecular heterogeneity of astrocytes in the adult CNS. Astrocyte heterogeneity exists not only inter-regionally but also intra-regionally. Despite the characteristic laminal organization of cortical layers and multiple sources of radial glia progenitors for (astro)gliogenesis, the molecular profile and functional properties of astroglial subpopulations in the adult cerebral cortex remain essentially undefined. Using two astrocyte reporter mouse lines: eaat2-tdTomato and Bac aldh1l1-eGFP, we identified tdT- eGFP+ , tdTlow eGFP+ , and tdThigh eGFP+ astroglial subpopulations (in an approximate 1:7:2 ratio) within the cortex. The tdT- eGFP+ astrocyte population is selectively localized at layers I-II and exhibits increased resting membrane potential and membrane resistance but reduced functional expression of the potassium channel Kir4.1. We also isolated individual astrocyte subpopulations through fluorescence activated cell sorting (FACS) and examined their transcriptome differences by RNA-seq. We found that the whole-genome transcriptional profiles of tdT- eGFP+ astrocytes are drastically different from that of tdTlow eGFP+ and tdThigh eGFP+ astrocytes. Particularly, elevated levels of several nonastrocyte genes that are typically specific to other glial cells, such as mog, mobp, Iba1, and pdgfrα, are observed in tdT- eGFP+ astrocytes, suggesting a less-specific molecular identity of these astrocytes. Overall, our study has unveiled molecular differences between adult cortical astroglial subpopulations, shedding new light on understanding their unique functions in the adult cortex.


Assuntos
Astrócitos/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Fatores Etários , Animais , Astrócitos/química , Encéfalo/citologia , Encéfalo/fisiologia , Córtex Cerebral/química , Feminino , Citometria de Fluxo/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Distribuição Aleatória
16.
Electrophoresis ; 40(2): 247-253, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30367480

RESUMO

Levels of a reference protein must be the same as a proportion of total protein in all tissues and, in the study of human diseases, cannot vary with factors such as age, gender or disease pathophysiology. It is increasingly apparent that there may be few, if any, proteins that display the characteristics of a reference protein within the human central nervous system (CNS). To begin to challenge this hypothesis, we used Western blotting to compare variance in levels of the "gold standard" reference protein, ß-actin, in Brodmann's area 9 from 194 subjects to variance of total transferred protein measured as intensity of Ponceau S staining. The coefficient of variance of sum intensity measurements for ß-actin levels across all donors was 47% compared to 24 and 27% for the sum intensity of Ponceau S staining measured using two different detection techniques. These data strongly suggest that the level of ß-actin, proportional to total protein, is not constant in human cortex which raises further doubt about the use of reference proteins to normalise data in human CNS studies. Considering our data, we suggest an alternative approach to presenting data from Western blotting of human CNS.


Assuntos
Actinas/análise , Córtex Cerebral/química , Córtex Cerebral/metabolismo , Biomarcadores , Western Blotting/normas , Feminino , Humanos , Masculino , Transtornos Mentais/metabolismo , Pessoa de Meia-Idade , Padrões de Referência , Suicídio
17.
J Hypertens ; 37(1): 135-143, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30507864

RESUMO

: Background: Central nervous system function has been emerging as an approach to understand hypertension-mediated memory dysfunction, and chronic exercise is able to modulate the purinergic system. METHOD: Herein, we investigated the effect of chronic swimming training on the purinergic system in cortex and hippocampus of L-NAME-induced hypertensive rats. Male Wistar rats were divided into four groups: Control, Exercise, L-NAME and Exercise L-NAME. Inhibitory avoidance test was used to assess memory status. NTPDase, CD73 and adenosine deaminase activities and expression, and P2 receptors expression were analyzed. Data were analyzed using two-way ANOVA and Kruskal-Wallis tests, considering P less than 0.05. RESULTS: Physical exercise reduced the blood pressure and prevented memory impairment induced by L-NAME model of hypertension. L-NAME treatment promoted an increase in NTPDase1, NTPDase3 and CD73 expression and activity in the cortex. A2A expression is increased in hippocampus and cortex in the hypertension group and exercise prevented this overexpression. CONCLUSION: These changes suggest that hypertension increases adenosine generation, which acts through A2A receptors, and exercise prevents these effects. These data may indicate a possible mechanism by which exercise may prevent memory impairment induced by L-NAME.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Hipertensão/fisiopatologia , Memória/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Córtex Cerebral/química , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , NG-Nitroarginina Metil Éster/metabolismo , Ratos , Receptor A2A de Adenosina/metabolismo , Natação/fisiologia
18.
Drug Des Devel Ther ; 12: 3937-3949, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510402

RESUMO

Background: Gene therapy can be an intriguing therapeutic option in wide-ranging neurological disorders. Though nonviral gene carriers represent a safer delivery system to their viral counterparts, a thorough design of such vehicles is crucial to enhance their transfection properties. Purpose: This study evaluated the effects of combined use of two nonionic surfactants, poloxamer 188 (P) and polysorbate 80 (P80) into nanovesicles - based on 2,3-di(tetradecyloxy)propan-1-amine cationic lipid (D) - destined for gene delivery to central nervous system cells. Methods: Niosome formulations without and with poloxamer 188 (DP80 and DPP80, respectively) were prepared by the reverse-phase evaporation technique and characterized in terms of size, surface charge, and morphology. After the addition of pCMS-EGFP plasmid, the binding efficiency to the niosomes was evaluated in agarose gel electrophoresis assays. Additionally, transfection efficiency of complexes was also evaluated in in vitro and in vivo conditions. Results: In vitro experiments on NT2 cells revealed that the complexes based on a surfactant combination (DPP80) enhanced cellular uptake and viability when compared with the DP80 counterparts. Interestingly, DPP80 complexes showed protein expression in glial cells after administration into the cerebral cortices of rats. Conclusion: These data provide new insights for glia-centered approach for gene therapy of nervous system disorders using cationic nanovesicles, where nonionic surfactants play a pivotal role.


Assuntos
Córtex Cerebral/metabolismo , Técnicas de Transferência de Genes , Poloxâmero/química , Polissorbatos/química , Tensoativos/química , Animais , Células Cultivadas , Córtex Cerebral/química , Córtex Cerebral/citologia , Lipossomos/química , Masculino , Estrutura Molecular , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície
19.
Eur J Neurosci ; 48(9): 3082-3096, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30295969

RESUMO

The class II Rab11 family-interacting proteins, FIP3 and FIP4, also termed Arfophilin-1 and Arfophilin-2, respectively, are endosomal proteins that function as dual effector proteins for Rab11 and ADP ribosylation factor (Arf) small GTPases. In the present study, we examined the expression and role of FIP4 in neuronal migration during cerebral layer formation. FIP4 mRNA was first weakly detected in post-mitotic migrating neurons in the upper intermediate zone, and expression was markedly increased in the cortical layer. Exogenously expressed FIP4 protein was localized to subpopulations of EEA1- and syntaxin 12-positive endosomes in migrating neurons, and was partially colocalized with FIP3. Knockdown of FIP4 by in utero electroporation significantly stalled transfected neurons in the lower cortical layer and decreased the speed of neuronal migration in the upper intermediate zone and in the cortical plate compared with control small hairpin RNA (shRNA)-transfected neurons. Furthermore, co-transfection of shRNA-resistant wild-type FIP4, but not wild type FIP3 or FIP4 mutants lacking the binding region for Rab11 or Arf, significantly improved the disturbed cortical layer formation caused by FIP4 knockdown. Collectively, our findings suggest that FIP4 and FIP3 play overlapping but distinct roles in neuronal migration downstream of Arf and Rab11 during cortical layer formation.


Assuntos
Proteínas de Transporte/fisiologia , Movimento Celular/fisiologia , Córtex Cerebral/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Ligação ao Cálcio , Córtex Cerebral/química , Córtex Cerebral/citologia , Feminino , Camundongos , Camundongos Endogâmicos ICR , Neurogênese/fisiologia , Neurônios/química , Gravidez
20.
J Biol Regul Homeost Agents ; 32(4): 959-967, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30043584

RESUMO

Cardiolipin is an important cellular component, and its normal level is a key prerequisite for maintaining the structure and function of mitochondria. To accurately quantify endogenous cardiolipin content in mitochondria, a standard addition method (SAM) was developed to establish a high-performance liquid chromatographic (HPLC) technique that is both reliable and accurate. Increasing amounts of cardiolipin standards were added to a constant amount of isolated mitochondria prior to the extraction procedure, and the two were extracted together. By limiting the interference effects that occur to within an acceptable range in an analytical system examined, this procedure ensures an ideal match of the sample composition in the standards, even if the composition is extremely complex or completely unknown. Then, the desired results can be obtained by extrapolation. As such, the authentic content of the endogenous cardiolipin can be obtained with greater accuracy than with classical detection methods, e.g. external standard calibration (ESC) and internal standard calibration (ISC). This method provides an excellent means of quantifying endogenous substances in living cells. The authors expect this method to be useful for researchers working on mitochondria-related mechanisms, cell survival-related mechanisms and similar topics.


Assuntos
Química Encefálica , Cardiolipinas/análise , Córtex Cerebral/química , Cromatografia Líquida de Alta Pressão/métodos , Animais , Mitocôndrias/química , Ratos , Padrões de Referência
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