Base de dados : MEDLINE
Pesquisa : D12.644.024 [Categoria DeCS]
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[PMID]:29107146
[Au] Autor:Jang JY; Rhim H; Kang S
[Ad] Endereço:Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
[Ti] Título:NABi, a novel ß-sheet breaker, inhibits Aß aggregation and neuronal toxicity: Therapeutic implications for Alzheimer's disease.
[So] Source:Biochim Biophys Acta;1862(1):71-80, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Amyloid beta (Aß) aggregates are an important therapeutic target for Alzheimer's disease (AD), a fatal neurodegenerative disease. To date, AD still remains a big challenge due to no effective treatments. Based on the property that Aß aggregates have the cross-ß-structure, a common structural feature in amyloids, we systemically designed the Aß-aggregation inhibitor that maintains Aß-interacting ability but removes toxic part from SOD1 (superoxide dismutase 1)-G93A. We identified NABi (Natural Aß Binder and Aß-aggregation inhibitor) composed of ß2-3 strands, a novel breaker of Aß aggregation, which does not self-aggregate and has no cytotoxicity at all. The NABi blocks Aß-fibril formation in vitro and in vivo and prevents neuronal cell death, a hallmark of AD pathogenesis. Such anti-amyloidogenic properties can provide novel strategies for treating AD. Furthermore, our study provides molecular insights into the design of amyloidogenic inhibitors to cure various neurodegenerative and amyloid-associated diseases, as NABi would regulate aggregation of other toxic ß-sheet proteins other than Aß.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Peptídeos beta-Amiloides/antagonistas & inibidores
Neurônios/metabolismo
Agregação Patológica de Proteínas/tratamento farmacológico
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Peptídeos beta-Amiloides/metabolismo
Animais
Linhagem Celular Tumoral
Seres Humanos
Camundongos
Neurônios/patologia
Agregação Patológica de Proteínas/metabolismo
Agregação Patológica de Proteínas/patologia
Estrutura Secundária de Proteína
Superóxido Dismutase/antagonistas & inibidores
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); EC 1.15.1.1 (SOD1 G93A protein); EC 1.15.1.1 (Superoxide Dismutase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171107
[St] Status:MEDLINE


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[PMID]:29381739
[Au] Autor:Smith EE; Muzikansky A; McCreary CR; Batool S; Viswanathan A; Dickerson BC; Johnson K; Greenberg SM; Blacker D
[Ad] Endereço:Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
[Ti] Título:Impaired memory is more closely associated with brain beta-amyloid than leukoaraiosis in hypertensive patients with cognitive symptoms.
[So] Source:PLoS One;13(1):e0191345, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hypertension is the strongest modifiable risk factor for subcortical ischemic changes and is also a risk factor for Alzheimer's dementia. We used neuroimaging to investigate the pathological basis of early cognitive symptoms in patients with hypertension. METHODS: In this cross-sectional cohort study 67 patients age >60 years with hypertension and Clinical Dementia Rating scale score of 0.5 without dementia, and without history of symptomatic stroke, underwent MRI for measurement of subcortical vascular changes and positron emission tomography (PET) scan with Pittsburgh Compound B (PiB-PET) to detect beta-amyloid deposition. These imaging measures were related to neuropsychological tests of memory, executive function and processing speed. RESULTS: Mean age was 75.0 (standard deviation, SD, 7.3). Mean neuropsychological Z scores were: episodic memory -0.63 (SD 1.23), executive function -0.40 (SD 1.10), processing speed -0.24 (SD 0.88); 22 of the 67 subjects met criteria for mild cognitive impairment (MCI) and the remaining 45 subjects had subjective cognitive concerns only. In multivariable models adjusting for age and years of education, each 0.1 unit increase in mean cortical PiB-PET binding was associated with 0.14 lower mean Z score for episodic memory (95% CI -0.28 to -0.01). This means that for every 0.1 unit increase in mean cortical PiB-PET, episodic memory was 0.14 standard deviations lower. White matter hyperintensity volume, silent brain infarcts and microbleeds were not associated with neuropsychological test scores. CONCLUSIONS: Episodic memory was prominently affected in hypertensive participants with MCI or subjective cognitive concerns, and was associated with PiB-PET binding. This suggests a prominent role for Alzheimer pathology in cognitive impairment even in hypertensive participants at elevated risk for vascular cognitive impairment.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/metabolismo
Encéfalo/metabolismo
Cognição
Hipertensão/complicações
Hipertensão/fisiopatologia
Leucoaraiose/complicações
[Mh] Termos MeSH secundário: Idoso
Feminino
Seres Humanos
Hipertensão/diagnóstico
Hipertensão/metabolismo
Masculino
Tomografia por Emissão de Pósitrons
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Amyloid beta-Peptides)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180131
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191345


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[PMID]:29353726
[Au] Autor:Czarnecka K; Chufarova N; Halczuk K; Maciejewska K; Girek M; Skibinski R; Jonczyk J; Bajda M; Kabzinski J; Majsterek I; Szymanski P
[Ad] Endereço:Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland. Electronic address: kamila.czarnecka@umed.lodz.pl.
[Ti] Título:Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment.
[So] Source:Eur J Med Chem;145:760-769, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 9-amino-1,2,3,4-tetrahydroacridine and 5,6-dichloronicotinic acid moiety were conjugated with different linkers. Afterwards new derivatives were evaluated as potential multifunctional acetylcholinesterase inhibitors (AChEIs), anti-Alzheimer's disease (AD) drug candidates. All the compounds were synthesized and tested for capacity for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Specifically, the most promising derivative 3b (IC = 1.02 nM) had higher inhibitory potency compared to the reference drug, tacrine. Consequently, kinetic studies of 3b compound showed a mixed-type inhibition of both AChE and BuChE. Afterwards the best potent AChE inhibitor has been examined on amyloid ß (Aß) self-induced aggregation. Furthermore, 3b compound was tested in various concentrations and had moderate activity against Aß aggregation. Inhibition of Aß aggregation was 46.63% and 19.41% at 50 µM and 5  µM concentrations, respectively. Moreover, no cytotoxicity was observed for the mentioned concentrations. Therefore, 3b compound is a promising multipotent agent for the treatment of AD.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Acridinas/farmacologia
Doença de Alzheimer/tratamento farmacológico
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Ácidos Nicotínicos/farmacologia
[Mh] Termos MeSH secundário: Acridinas/química
Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Ácidos Nicotínicos/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,6-dichloronicotinic acid); 0 (Acridines); 0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Nicotinic Acids); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29339255
[Au] Autor:Sun G; Wang J; Guo X; Lei M; Zhang Y; Wang X; Shen X; Hu L
[Ad] Endereço:Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 2100
[Ti] Título:Design, synthesis and biological evaluation of LX2343 derivatives as neuroprotective agents for the treatment of Alzheimer's disease.
[So] Source:Eur J Med Chem;145:622-633, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC value of 0.22 µM. Further investigation demonstrated that compound A6 can significantly reduce Aß production and increase Aß clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice. The present study evidently showed that compound A6 is a potent neuroprotective agent and might serve as a promising lead candidate for the treatment of Alzheimer's disease.
[Mh] Termos MeSH primário: Acetamidas/farmacologia
Doença de Alzheimer/tratamento farmacológico
Desenho de Drogas
Fármacos Neuroprotetores/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Acetamidas/síntese química
Acetamidas/química
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Relação Dose-Resposta a Droga
Células HEK293
Seres Humanos
Aprendizagem em Labirinto/efeitos dos fármacos
Transtornos da Memória/tratamento farmacológico
Camundongos
Camundongos Transgênicos
Estrutura Molecular
Fármacos Neuroprotetores/síntese química
Fármacos Neuroprotetores/química
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Amyloid beta-Peptides); 0 (LX2343); 0 (Neuroprotective Agents); 0 (Sulfonamides)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE


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[PMID]:29248770
[Au] Autor:Hupert M; Elfgen A; Schartmann E; Schemmert S; Buscher B; Kutzsche J; Willbold D; Santiago-Schübel B
[Ad] Endereço:Forschungszentrum Jülich GmbH, Central Institute for Engineering, Analytics (ZEA-3), Jülich, Germany.
[Ti] Título:Development and validation of an UHPLC-ESI-QTOF-MS method for quantification of the highly hydrophilic amyloid-ß oligomer eliminating all-D-enantiomeric peptide RD2 in mouse plasma.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1073:123-129, 2018 Jan 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:During preclinical drug development, a method for quantification of unlabeled compounds in blood plasma samples from treatment or pharmacokinetic studies in mice is required. In the current work, a rapid, specific, sensitive and validated liquid chromatography mass-spectrometric UHPLC-ESI-QTOF-MS method was developed for the quantification of the therapeutic compound RD2 in mouse plasma. RD2 is an all-D-enantiomeric peptide developed for the treatment of Alzheimer's disease, a progressive neurodegenerative disease finally leading to dementia. Due to RD2's highly hydrophilic properties, the sample preparation and the chromatographic separation and quantification were very challenging. The chromatographic separation of RD2 and its internal standard were accomplished on an Acquity UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm particle size) within 6.5 min at 50 °C with a flow rate of 0.5 mL/min. Mobile phases consisted of water and acetonitrile with 1% formic acid and 0.025% heptafluorobutyric acid, respectively. Ions were generated by electrospray ionization (ESI) in the positive mode and the peptide was quantified by QTOF-MS. The developed extraction method for RD2 from mouse plasma revealed complete recovery. The linearity of the calibration curve was in the range of 5.3 ng/mL to 265 ng/mL (r > 0.999) with a lower limit of detection (LLOD) of 2.65 ng/mL and a lower limit of quantification (LLOQ) of 5.3 ng/mL. The intra-day and inter-day accuracy and precision of RD2 in plasma ranged from -0.54% to 2.21% and from 1.97% to 8.18%, respectively. Moreover, no matrix effects were observed and RD2 remained stable in extracted mouse plasma at different conditions. Using this validated bioanalytical method, plasma samples of unlabeled RD2 or placebo treated mice were analyzed. The herein developed UHPLC-ESI-QTOF-MS method is a suitable tool for the quantitative analysis of unlabeled RD2 in plasma samples of treated mice.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/sangue
Cromatografia Líquida de Alta Pressão/métodos
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Peptídeos beta-Amiloides/química
Peptídeos beta-Amiloides/isolamento & purificação
Animais
Interações Hidrofóbicas e Hidrofílicas
Limite de Detecção
Modelos Lineares
Masculino
Camundongos
Camundongos Transgênicos
Oligonucleotídeos/isolamento & purificação
Oligonucleotídeos/metabolismo
Reprodutibilidade dos Testes
Espectrometria de Massas por Ionização por Electrospray/métodos
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Oligonucleotides)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:28449688
[Au] Autor:Li ZY; Chung YH; Shin EJ; Dang DK; Jeong JH; Ko SK; Nah SY; Baik TG; Jhoo JH; Ong WY; Nabeshima T; Kim HC
[Ad] Endereço:Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
[Ti] Título:YY-1224, a terpene trilactone-strengthened Ginkgo biloba, attenuates neurodegenerative changes induced by ß-amyloid (1-42) or double transgenic overexpression of APP and PS1 via inhibition of cyclooxygenase-2.
[So] Source:J Neuroinflammation;14(1):94, 2017 Apr 27.
[Is] ISSN:1742-2094
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Ginkgo biloba has been reported to possess free radical-scavenging antioxidant activity and anti-inflammatory properties. In our pilot study, YY-1224, a terpene trilactone-strengthened extract of G. biloba, showed anti-inflammatory, neurotrophic, and antioxidant effects. RESULTS: We investigated the pharmacological potential of YY-1224 in ß-amyloid (Aß) (1-42)-induced memory impairment using cyclooxygenase-2 (COX-2) knockout (-/-) and APPswe/PS1dE9 transgenic (APP/PS1 Tg) mice. Repeated treatment with YY-1224 significantly attenuated Aß (1-42)-induced memory impairment in COX-2 (+/+) mice, but not in COX-2 (-/-) mice. YY-1224 significantly attenuated Aß (1-42)-induced upregulation of platelet-activating factor (PAF) receptor gene expression, reactive oxygen species, and pro-inflammatory factors. In addition, YY-1224 significantly inhibited Aß (1-42)-induced downregulation of PAF-acetylhydrolase-1 (PAF-AH-1) and peroxisome proliferator-activated receptor γ (PPARγ) gene expression. These changes were more pronounced in COX-2 (+/+) mice than in COX-2 (-/-) mice. YY-1224 significantly attenuated learning impairment, Aß deposition, and pro-inflammatory microglial activation in APP/PS1 Tg mice, whereas it significantly enhanced PAF-AH and PPARγ expression. A preferential COX-2 inhibitor, meloxicam, did not affect the pharmacological activity by YY-1224, suggesting that the COX-2 gene is a critical mediator of the neuroprotective effects of YY-1224. The protective activity of YY-1224 appeared to be more efficacious than a standard G. biloba extract (Gb) against Aß insult. CONCLUSIONS: Our results suggest that the protective effects of YY-1224 against Aß toxicity may be associated with its PAF antagonistic- and PPARγ agonistic-potential as well as inhibition of the Aß-mediated pro-inflammatory switch of microglia phenotypes through suppression of COX-2 expression.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/toxicidade
Ciclo-Oxigenase 2/metabolismo
Ginkgo biloba
Doenças Neurodegenerativas/metabolismo
Fragmentos de Peptídeos/toxicidade
Extratos Vegetais/uso terapêutico
[Mh] Termos MeSH secundário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/genética
Doença de Alzheimer/metabolismo
Precursor de Proteína beta-Amiloide/biossíntese
Precursor de Proteína beta-Amiloide/genética
Animais
Expressão Gênica
Lactonas/isolamento & purificação
Lactonas/uso terapêutico
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/prevenção & controle
Extratos Vegetais/isolamento & purificação
Extratos Vegetais/farmacologia
Presenilina-1/biossíntese
Presenilina-1/genética
Espécies Reativas de Oxigênio/antagonistas & inibidores
Espécies Reativas de Oxigênio/metabolismo
Terpenos/isolamento & purificação
Terpenos/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Lactones); 0 (Peptide Fragments); 0 (Plant Extracts); 0 (Presenilin-1); 0 (Reactive Oxygen Species); 0 (Terpenes); 0 (amyloid beta-protein (1-42)); 0 (trilactone); EC 1.14.99.1 (Cyclooxygenase 2)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1186/s12974-017-0866-x


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[PMID]:29253878
[Au] Autor:Asam K; Staniszewski A; Zhang H; Melideo SL; Mazzeo A; Voronkov M; Huber KL; Pérez E; Stock M; Stock JB; Arancio O; Nicholls RE
[Ad] Endereço:Department of Pathology and Cell Biology, Columbia University, New York, NY, United States of America.
[Ti] Título:Eicosanoyl-5-hydroxytryptamide (EHT) prevents Alzheimer's disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid.
[So] Source:PLoS One;12(12):e0189413, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Soluble forms of oligomeric beta-amyloid (Aß) are thought to play a central role in Alzheimer's disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aß. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aß. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aß-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aß-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aß-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Peptídeos beta-Amiloides/química
Transtornos Cognitivos/prevenção & controle
Serotonina/análogos & derivados
[Mh] Termos MeSH secundário: Doença de Alzheimer/patologia
Animais
Café
Cognição/efeitos dos fármacos
Condicionamento (Psicologia)
Modelos Animais de Doenças
Eletrofisiologia
Medo
Feminino
Potenciação de Longa Duração
Masculino
Aprendizagem em Labirinto
Metilação
Camundongos
Camundongos Endogâmicos C57BL
Doenças do Sistema Nervoso/tratamento farmacológico
Doenças do Sistema Nervoso/patologia
Plasticidade Neuronal
Fosforilação
Serotonina/farmacologia
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Coffee); 0 (eicosanoyl-5-hydroxytryptamide); 333DO1RDJY (Serotonin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189413


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[PMID]:29441925
[Au] Autor:Cai QY; Liu XL; Zhang XQ; Liu YX; Li M; Zhao CZ; Zhang XM; Meng QH
[Ti] Título:Anti-neuroinflammation activity of acetylpuerarin mediated by a PKC-δ-dependent caspase signaling pathway: and studies.
[So] Source:Pharmazie;71(10):575-582, 2016 Oct 01.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: This study was performed to evaluate the regulating effects of acetylpuerarin on inflammation in an Alzheimer's disease (AD) rat model and an inflammatory cell model. METHODS: Healthy female Wistar rats and mouse BV2 microglia cells were selected. AD rat models were established with the method of bilateral intrahippocampal amyloid-ß(Aß)1-42 injections and the inflammatory cell models were established using Aß25-35-induced mouse BV2 microglia cells. The cytotoxicity of acetylpuerarin on BV2 microglial cells was detected by MTT assay and the morphological changes of BV2 microglia cells were observed under inverted phase contrast microscope. As inflammatory parameters, the expressions of IL-1ß, iNOS, IL-6 and TNF-α were examined by Elisa, Immunohistochemistry, Quantitative real-time PCR (qRT-PCR), Western blot and Immunofluorescence analyses. We also examined the acetylpuerarin's effect on the activity of PKC-δ, IKKß and caspase-8/caspase-3 pathway. RESULTS: Acetylpuerarin exerted no significant cytotoxicity on BV2 microglia cells and was applied in all subsequent experiments. Acetylpuerarin treatment mitigated Aß25-35-induced morphological changes associated with microglia activation. Moreover, the expressions of caspase-8, cleaved caspase-3, PKC-δ, IKKß, iNOS, IL-1ß and TNF-α in Aß25-35-stimulated BV2 microglia cells were significantly suppressed by acetylpuerarin and in a dose-dependent manner. Additionally, the expression of IL-1ß in hippocampus and the level of IL-6 in serum of Aß1-42 treated rat were reduced by acetylpuerarin and in a concentration-dependent manner. CONCLUSION: Our results suggest that acetylpuerarin's anti-inflammation mechanism on AD may be mediated through the PKC-δ-dependent caspase signalling pathway.
[Mh] Termos MeSH primário: Caspases/efeitos dos fármacos
Encefalite/tratamento farmacológico
Isoflavonas/farmacologia
Proteína Quinase C-delta/efeitos dos fármacos
[Mh] Termos MeSH secundário: Doença de Alzheimer/induzido quimicamente
Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/patologia
Peptídeos beta-Amiloides
Animais
Sobrevivência Celular/efeitos dos fármacos
Citocinas/metabolismo
Encefalite/induzido quimicamente
Feminino
Ativação de Macrófagos/efeitos dos fármacos
Camundongos
Microglia/efeitos dos fármacos
Fragmentos de Peptídeos
Ratos
Ratos Wistar
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[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cytokines); 0 (Isoflavones); 0 (Peptide Fragments); 0 (acetylpuerarin); 0 (amyloid beta-protein (1-42)); 0 (amyloid beta-protein (25-35)); EC 2.7.1.- (Prkcd protein, rat); EC 2.7.11.13 (Protein Kinase C-delta); EC 3.4.22.- (Caspases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6660


  9 / 24375 MEDLINE  
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[PMID]:29362733
[Au] Autor:Mancini O; Wellbrock T; Rolinski OJ; Kubiak-Ossowska K; Mulheran PA
[Ad] Endereço:Department of Chemical Engineering and Process Engineering, University of Strathclyde, Glasgow, G1 1XJ, UK. paul.mulheran@strath.ac.uk.
[Ti] Título:Probing beta amyloid aggregation using fluorescence anisotropy: experiments and simulation.
[So] Source:Phys Chem Chem Phys;20(6):4216-4225, 2018 Feb 07.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aggregation of beta amyloid (Ab) protein is associated with the development of Alzheimer's disease. In this work we monitor Ab aggregation using fluorescence anisotropy, a technique that provides information on the rotational diffusion of the fluorescing tyrosine (Tyr) side chains. We also perform Monte Carlo (MC) and fully atomistic Molecular Dynamics (MD) simulations to interpret the experiments. The experimental results show that there are two different rotational timescales contributing to the anisotropy. Our MC simulation captures this behaviour in a coarse-scale manner, and, more importantly, shows that the Tyr side chains must have their movements restricted in order to reproduce the anisotropy. The MD simulations provide a molecular scale view, and indeed show that aggregation restricts the Try side chains to yield anisotropy in line with the experimental results. This combination of experiment and simulation therefore provides a unique insight into the aggregation process, and we suggest how this approach might be used to gain further information on aggregating protein systems.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/química
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Polarização de Fluorescência
Método de Monte Carlo
Estrutura Secundária de Proteína
Tirosina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 42HK56048U (Tyrosine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp08217g


  10 / 24375 MEDLINE  
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[PMID]:29311465
[Au] Autor:Taniguchi A
[Ad] Endereço:Graduate School of Pharmaceutical Sciences, The University of Tokyo.
[Ti] Título:[Amyloid-selective Photooxygenation toward Treatment for Amyloid Diseases].
[So] Source:Yakugaku Zasshi;138(1):47-53, 2018.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:Amyloid proteins and peptides form aggregates which lead to amyloid diseases. For example, Alzheimer's disease-related amyloid ß (Aß) forms oligomers, protofibrils, and amyloid fibrils, which exhibit neurotoxicity. Controlling the aggregation and toxicity of Aß would be a therapeutic strategy for the treatment of Alzheimer's disease. Recently, we have investigated an artificial oxygenative modification (chemical introduction of oxygen atoms) of amyloid proteins using a photocatalyst, which attenuated the aggregation potency and toxicity of these proteins. The oxygenation of Aß1-42 was efficiently induced using a riboflavin catalyst (1). The oxygenated Aß was less aggregative and cytotoxic than native Aß. The oxygenated Aß also showed inhibitory activity against aggregation and the onset of toxicity of native Aß. Flavin catalyst 2, bearing an Aß-binding peptide, allowed the selective oxygenation of Aß even in the presence of living cells, due to its Aß-affinity. Furthermore, "On/Off" switchable photooxygenation catalysts 3 and 4, which can sense a higher-order amyloid structure (i.e., cross-ß-sheet structure), were developed based on the amyloid fluorescence probe thioflavin-T. The photo-excited catalysts generated singlet oxygens to induce oxygenation when binding to the amyloid structure ("On"). In contrast, the free catalysts, without binding to the amyloid structure, produced no singlet oxygen, even if photo-excited ("Off"). This "On/Off" switchable function enabled highly Aß-selective oxygenation. Catalyst 3 was successfully used for the selective oxygenation of other amyloid proteins and peptides. These findings suggest that amyloid-selective oxygenation could provide a versatile system in developing effective new treatments for amyloid diseases.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Peptídeos beta-Amiloides/metabolismo
Dinitrocresóis
Agregação Patológica de Proteínas/prevenção & controle
Riboflavina
Tiazóis
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/química
Peptídeos beta-Amiloides/toxicidade
Catálise
Descoberta de Drogas
Seres Humanos
Oxirredução
Processos Fotoquímicos
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Dinitrocresols); 0 (Thiazoles); 1604ZJR09T (4,6-dinitro-o-cresol); 2390-54-7 (thioflavin T); TLM2976OFR (Riboflavin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.17-00186-2



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