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1.
Antioxidants (Basel) ; 8(12)2019 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-31817977

RESUMO

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer's disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ - 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW's impact on amyloid-ß plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

2.
J Cheminform ; 9(1): 55, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29086154

RESUMO

An end-to-end platform for chemical science research has been developed that integrates data from computational and experimental approaches through a modern web-based interface. The platform offers an interactive visualization and analytics environment that functions well on mobile, laptop and desktop devices. It offers pragmatic solutions to ensure that large and complex data sets are more accessible. Existing desktop applications/frameworks were extended to integrate with high-performance computing resources, and offer command-line tools to automate interaction-connecting distributed teams to this software platform on their own terms. The platform was developed openly, and all source code hosted on the GitHub platform with automated deployment possible using Ansible coupled with standard Ubuntu-based machine images deployed to cloud machines. The platform is designed to enable teams to reap the benefits of the connected web-going beyond what conventional search and analytics platforms offer in this area. It also has the goal of offering federated instances, that can be customized to the sites/research performed. Data gets stored using JSON, extending upon previous approaches using XML, building structures that support computational chemistry calculations. These structures were developed to make it easy to process data across different languages, and send data to a JavaScript-based web client.

3.
Neurosci Lett ; 646: 24-29, 2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28279707

RESUMO

The medicinal plant Centella asiatica has long been used to improve memory and cognitive function. We have previously shown that a water extract from the plant (CAW) is neuroprotective against the deleterious cognitive effects of amyloid-ß (Aß) exposure in a mouse model of Alzheimer's disease, and improves learning and memory in healthy aged mice as well. This study explores the physiological underpinnings of those effects by examining how CAW, as well as chemical compounds found within the extract, modulate synaptic health in Aß-exposed neurons. Hippocampal neurons from amyloid precursor protein over-expressing Tg2576 mice and their wild-type (WT) littermates were used to investigate the effect of CAW and various compounds found within the extract on Aß-induced dendritic simplification and synaptic loss. CAW enhanced arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites and loss of spines caused by Aß exposure in Tg2576 neurons. Triterpene compounds present in CAW were found to similarly improve arborization although they did not affect spine density. In contrast caffeoylquinic acid (CQA) compounds from CAW were able to modulate both of these endpoints, although there was specificity as to which CQAs mediated which effect. These data suggest that CAW, and several of the compounds found therein, can improve dendritic arborization and synaptic differentiation in the context of Aß exposure which may underlie the cognitive improvement observed in response to the extract in vivo. Additionally, since CAW, and its constituent compounds, also improved these endpoints in WT neurons, these results may point to a broader therapeutic utility of the extract beyond Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Centella , Espinhas Dendríticas/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Centella/metabolismo , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos Transgênicos
4.
J Ethnopharmacol ; 180: 78-86, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26785167

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: This study investigates the cognitive enhancing effects of the plant Centella asiatica which is widely used Ayurvedic and traditional Chinese medicine. AIM OF THE STUDY: The goal of this study was to determine the effects of a water extract of the medicinal plant Centella asiatica (CAW) on cognitive ability as well as mitochondrial and antioxidant response pathways in vivo. MATERIALS AND METHODS: Old and young C57BL/6 mice were treated with CAW (2mg/mL) in their drinking water. Learning and memory was assessed using Morris Water Maze (MWM) and then tissue was collected and gene expression analyzed. RESULTS: CAW improved performance in the MWM in aged animals and had a modest effect on the performance of young animals. CAW also increased the expression of mitochondrial and antioxidant response genes in the brain and liver of both young and old animals. Expression of synaptic markers was also increased in the hippocampus and frontal cortex, but not in the cerebellum of CAW-treated animals. CONCLUSIONS: These data indicate a cognitive enhancing effect of CAW in healthy mice. The gene expression changes caused by CAW suggest a possible effect on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes could contribute to cognitive improvement.


Assuntos
Nootrópicos/farmacologia , Triterpenos/farmacologia , Envelhecimento/fisiologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cognição/efeitos dos fármacos , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo
5.
J Alzheimers Dis ; 41(1): 179-92, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24595193

RESUMO

The aggregation of amyloid-ß in Alzheimer's disease can be affected by free transition metals such as copper and zinc in the brain. Addition of copper and zinc with amyloid acts to increase aggregation and copper additionally promotes the formation of reactive oxygen species. We propose that reduction of brain copper by blocking uptake of copper from the diet is a viable strategy to regulate the formation of insoluble amyloid-ß in the brain of Tg2576 mice. Mice were treated with regimens of zinc acetate, which acts with metallothionein to block copper uptake in the gut, at various times along their lifespan to model prevention and treatment paradigms. We found that the mice tolerated zinc acetate well over the six month course of study. While we did not observe significant changes in cognition and behavior, there was a reduction in insoluble amyloid-ß in the brain. This observation coincided with a reduction in brain copper and interestingly no change in brain zinc. Our findings show that blocking copper uptake from the diet can redistribute copper from the brain and reduce amyloid-ß aggregation.


Assuntos
Amiloidose/tratamento farmacológico , Amiloidose/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Acetato de Zinco/administração & dosagem , Administração Oral , Doença de Alzheimer , Precursor de Proteína beta-Amiloide/genética , Amiloidose/patologia , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Encéfalo/patologia , Ceruloplasmina/metabolismo , Cobre/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Distribuição Aleatória , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Zinco/metabolismo
6.
Proc Natl Acad Sci U S A ; 110(41): 16634-9, 2013 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-24062436

RESUMO

Social interactions provide agents with the opportunity to earn higher benefits than when acting alone and contribute to evolutionary stable strategies. A basic requirement for engaging in beneficial social interactions is to recognize the actor whose movement results in reward. Despite the recent interest in the neural basis of social interactions, the neurophysiological mechanisms identifying the actor in social reward situations are unknown. A brain structure well suited for exploring this issue is the striatum, which plays a role in movement, reward, and goal-directed behavior. In humans, the striatum is involved in social processes related to reward inequity, donations to charity, and observational learning. We studied the neurophysiology of social action for reward in rhesus monkeys performing a reward-giving task. The behavioral data showed that the animals distinguished between their own and the conspecific's reward and knew which individual acted. Striatal neurons coded primarily own reward but rarely other's reward. Importantly, the activations occurred preferentially, and in approximately similar fractions, when either the own or the conspecific's action was followed by own reward. Other striatal neurons showed social action coding without reward. Some of the social action coding disappeared when the conspecific's role was simulated by a computer, confirming a social rather than observational relationship. These findings demonstrate a role of striatal neurons in identifying the social actor and own reward in a social setting. These processes may provide basic building blocks underlying the brain's function in social interactions.


Assuntos
Corpo Estriado/citologia , Discriminação Psicológica/fisiologia , Macaca mulatta/fisiologia , Neurônios/metabolismo , Recompensa , Comportamento Social , Análise de Variância , Animais , Movimentos Oculares/fisiologia , Modelos Lineares , Masculino , Curva ROC
7.
J Alzheimers Dis ; 22(2): 619-29, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20847401

RESUMO

The inflammatory status of the brain in patients as well as animal models of Alzheimer's disease (AD) has been extensively studied. Accumulation of activated microglia producing tumor necrosis factor-α and monocyte chemotactic protein-1 contribute to the pathology of the disease. However, little is known about the changes in the spleen and associated peripheral immunity that might contribute to AD pathology. The goal of this study was to characterize phenotypic and functional changes in spleen, blood and brain cell populations that contribute to development of an AD-like disease in a triple transgenic (3xTg-AD) mouse model. The 3xTg-AD mice had increased percentages of brain Gr-1+ granulocytes, dendritic cells and macrophages, spleen and blood derived CD8+Ly6C+ memory T cells and CCR6+ B cells, as well as increased levels of secreted interleukin-6. Brain tissue from older 12 month old symptomatic 3xTg-AD female mice exhibited highly elevated mRNA expression of CCR6 compared to wild-type mice. Importantly, this pronounced increase in expression of CCR6 was also detected in brain and spleen tissue from pre-symptomatic 5--6 month old 3xTg-AD females and males. Our data demonstrate increased expression of CCR6 in the brain and peripheral immune organs of both pre-symptomatic and symptomatic 3xTg-AD mice, strongly suggesting an ongoing inflammatory process that precedes onset of clinical AD-like disease.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Células Sanguíneas/patologia , Encéfalo/patologia , Receptores CCR6/metabolismo , Baço/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Antígenos CD/metabolismo , Encéfalo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo/métodos , Humanos , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Receptores CCR6/genética , Baço/metabolismo , Proteínas tau/genética
8.
J Alzheimers Dis ; 21(3): 903-14, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20693639

RESUMO

There is increasing evidence for the crucial role of metals in the pathology of Alzheimer's disease. Both the aggregation and neurotoxicity of amyloid-ß are dependent on the presence of copper. This study investigated the ability of the copper-complexing drug tetrathiomolybdate to reduce amyloid-ß pathology and spatial memory impairment in both a prevention and a treatment paradigm in the Tg2576 mouse model of Alzheimer's disease. Tetrathiomolybdate treatment lowered brain copper and reduced amyloid-ß levels in the prevention paradigm, but not in the treatment paradigm. Our data suggests that controlled lowering of systemic copper may achieve anti-amyloid effects if initiated early in the disease process.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/efeitos dos fármacos , Cobre/metabolismo , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Molibdênio/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Análise de Variância , Animais , Western Blotting , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Ceruloplasmina/metabolismo , Quelantes/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Distribuição Aleatória
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