Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
J Affect Disord ; 240: 88-98, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30059939

RESUMO

BACKGROUND: Neuroinflammation is suggested to be a crucial factor in the pathophysiology of major depressive disorder (MDD). Analysis of neuron-derived exosomes (NDE) in peripheral blood has recently been highlighted to reveal the pathophysiology of brain diseases without using brain biopsy. Currently, human NDE studies require a considerable amount of peripheral blood to measure multiple substances inside exosomes. Previously, NDE-based clinical studies focusing on MDD have not been reported. METHODS: As an exploratory pilot case-control study between healthy controls (HC) and drug-free MDD patients (each; N = 34), we searched for NDE-related blood biomarkers with a small amount of peripheral blood using a novel sandwich immunoassay between anti-neuron antibody and antibodies against CD81 (an exosome marker) and against other proteins related to neuroinflammation and synaptic functions. RESULTS: Most neuron-related blood biomarkers had moderately to strongly positive correlation with CD81 (NDE), thus we normalized the above biomarkers by CD81 (quantity of each biomarker/CD81) to predict NDE-related blood substances. Interleukin 34 (IL34)/CD81 levels were significantly higher in MDD group compared to HC group. Synaptophysin (SYP), SYP/CD81, and tumor necrosis factor receptor 1 (TNFR1)/CD81 were positively correlated with severities of depression and/or various sub-symptoms. LIMITATIONS: We did not actually extract NDE from peripheral blood. CONCLUSIONS: Using a small amount of peripheral blood, we have successfully detected possible NDE-related blood biomarkers. This is the first study to suggest that not only SYP and TNFR1 but also IL34 are important blood biomarkers for patients with MDD. Further studies are warranted to evaluate the present study.


Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico , Interleucinas/sangue , Neurônios/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Sinaptofisina/sangue , Adulto , Anticorpos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Exossomos/metabolismo , Feminino , Humanos , Imunoensaio , Mediadores da Inflamação/sangue , Masculino , Neurônios/patologia , Projetos Piloto , Tetraspanina 28/imunologia , Adulto Jovem
2.
Sci Rep ; 7(1): 13905, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066822

RESUMO

Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated). We validated that mRNA of MEX3D (mex-3 RNA binding family member D) was lower in NF1-iN cells by real-time PCR with 12 sex-mixed samples. In NF1-iN cells on day 14, higher expression of FOS mRNA was observed with lower expression of MEX3D mRNA. Interestingly, BCL2 mRNA was higher in NF1-iN cells on day 5 (early-period) but not on day 14. Our data suggest that aberrant molecular signals due to NF1 mutations may disturb gene expressions, a subset of which defines continuum of the neuronal phenotypes of NF1 with ASD. Further translational studies using induced pluripotent stem (iPS) cell-derived neuronal cells are needed to validate our preliminary findings especially confirming meanings of analysis using early-period iN cells.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Neurofibromatose 1/genética , Neurônios/citologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas de Ligação a RNA/genética , Animais , Estudos de Casos e Controles , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Neurofibromatose 1/patologia , Neurônios/metabolismo , Projetos Piloto , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo
3.
PLoS One ; 11(12): e0165267, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27984586

RESUMO

Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.


Assuntos
Biomarcadores/sangue , Cromatografia Líquida/métodos , Depressão/psicologia , Espectrometria de Massas/métodos , Metabolômica/métodos , Ácido 3-Hidroxibutírico/sangue , Betaína/sangue , Ácido Cítrico/sangue , Creatinina/sangue , Depressão/metabolismo , Feminino , Humanos , Aprendizado de Máquina , Masculino , Projetos Piloto , Escalas de Graduação Psiquiátrica , Autorrelato , Índice de Gravidade de Doença , Ideação Suicida , Ácido gama-Aminobutírico/sangue
4.
Schizophr Res ; 178(1-3): 35-43, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27614570

RESUMO

Viral infections during fetal and adolescent periods, as well as during the course of schizophrenia itself have been linked to the onset and/or relapse of a psychosis. We previously reported that the unique antipsychotic aripiprazole, a partial D2 agonist, inhibits the release of tumor necrosis factor (TNF)-α from interferon-γ-activated rodent microglial cells. Polyinosinic-polycytidylic acid (polyI:C) has recently been used as a standard model of viral infections, and recent in vitro studies have shown that microglia are activated by polyI:C. Aripiprazole has been reported to ameliorate behavioral abnormalities in polyI:C-induced mice. To clarify the anti-inflammatory properties of aripiprazole, we investigated the effects of aripiprazole on polyI:C-induced microglial activation in a cellular model of murine microglial cells and possible surrogate cells for human microglia. PolyI:C treatment of murine microglial cells activated the production of TNF-α and enhanced the p38 mitogen-activated protein kinase (MAPK) pathway, whereas aripiprazole inhibited these responses. In addition, polyI:C treatment of possible surrogate cells for human microglia markedly increased TNF-α mRNA expression in cells from three healthy volunteers. Aripiprazole inhibited this increase in cells from two individuals. PolyI:C consistently increased intracellular Ca2+ concentration ([Ca2+]i) in murine microglial cells by influx of extracellular Ca2+. We demonstrated that transient receptor potential in melastatin 7 (TRPM7) channels contributed to this polyI:C-induced increase in [Ca2+]i. Taken together, these data suggest that aripiprazole may be therapeutic for schizophrenia by reducing microglial inflammatory reactions, and TRPM7 may be a novel therapeutic target for schizophrenia. Further studies are needed to validate these findings.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Células Cultivadas , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/citologia , Poli I-C/toxicidade , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/metabolismo , Canais de Cátion TRPM/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Brain Behav Immun ; 55: 17-24, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26551431

RESUMO

The role of microglia in stress responses has recently been highlighted, yet the underlying mechanisms of action remain unresolved. The present study examined disruption in working memory due to acute stress using the water-immersion resistant stress (WIRS) test in mice. Mice were subjected to acute WIRS, and biochemical, immunohistochemical, and behavioral assessments were conducted. Spontaneous alternations (working memory) significantly decreased after exposure to acute WIRS for 2h. We employed a 3D morphological analysis and site- and microglia-specific gene analysis techniques to detect microglial activity. Morphological changes in hippocampal microglia were not observed after acute stress, even when assessing ramification ratios and cell somata volumes. Interestingly, hippocampal tumor necrosis factor (TNF)-α levels were significantly elevated after acute stress, and acute stress-induced TNF-α was produced by hippocampal-ramified microglia. Conversely, plasma concentrations of TNF-α were not elevated after acute stress. Etanercept (TNF-α inhibitor) recovered working memory deficits in accordance with hippocampal TNF-α reductions. Overall, results suggest that TNF-α from hippocampal microglia is a key contributor to early-stage stress-to-mental responses.


Assuntos
Hipocampo/metabolismo , Transtornos da Memória , Memória de Curto Prazo/efeitos dos fármacos , Microglia/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Etanercepte/farmacologia , Hipocampo/efeitos dos fármacos , Imunossupressores/farmacologia , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Estresse Psicológico/complicações , Fator de Necrose Tumoral alfa/antagonistas & inibidores
6.
Sci Rep ; 4: 4957, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24825127

RESUMO

Microglia have been implicated in various neurological and psychiatric disorders in rodent and human postmortem studies. However, the dynamic actions of microglia in the living human brain have not been clarified due to a lack of studies dealing with in situ microglia. Herein, we present a novel technique for developing induced microglia-like (iMG) cells from human peripheral blood cells. An optimized cocktail of cytokines, GM-CSF and IL-34, converted human monocytes into iMG cells within 14 days. The iMG cells have microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. To confirm clinical utilities, we developed iMG cells from a patient of Nasu-Hakola disease (NHD), which is suggested to be directly caused by microglial dysfunction, and observed that these cells from NHD express delayed but stronger inflammatory responses compared with those from the healthy control. Altogether, the iMG-technique promises to elucidate unresolved aspects of human microglia in various brain disorders.


Assuntos
Diferenciação Celular , Microglia/citologia , Microglia/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Citocinas/farmacologia , Feminino , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Lipodistrofia/genética , Lipodistrofia/imunologia , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microglia/efeitos dos fármacos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Osteocondrodisplasias/genética , Osteocondrodisplasias/imunologia , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Interferência de RNA , Panencefalite Esclerosante Subaguda/genética , Panencefalite Esclerosante Subaguda/imunologia , Panencefalite Esclerosante Subaguda/metabolismo , Panencefalite Esclerosante Subaguda/patologia
7.
J Neurochem ; 115(3): 606-13, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20796177

RESUMO

We examined the effect of concanamycin A and bafilomycin A1, inhibitors of the vacuolar proton-ATPase, on maturation and expression of Ret, a tyrosine kinase receptor for glial cell line-derived neurotrophic factor. Ret appeared as 150- and 170-kDa bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels and both forms were sensitive to peptide-N-glycosidase F. Western and immunocytochemical analyses revealed that the 150-kDa immature form of Ret accumulated in the Golgi apparatus upon treatment with vacuolar proton-ATPase inhibitors, whereas, the 170-kDa mature form of Ret was dramatically decreased. The result suggests that glycosylation of Ret during the conversion from immature forms to mature forms is pH sensitive, and is likely initiated in the acidic trans-Golgi apparatus. In contrast, glycosylation of nascent receptors to become immature receptors appeared to be pH insensitive, and are likely to take place in the endoplasmic reticulum. The immature form of Ret was present in the plasma membrane when the cells were treated with the vacuolar proton-ATPase inhibitors. In conclusion, the acidification of the Golgi apparatus is crucial for maturation of Ret but not indispensable for trafficking of receptors to the membrane.


Assuntos
Complexo de Golgi/fisiologia , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Biotinilação , Western Blotting , Membrana Celular/metabolismo , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Receptores ErbB/metabolismo , Imuno-Histoquímica , Macrolídeos/farmacologia , Células PC12 , Ratos , Receptor trkA/biossíntese , Receptor trkA/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA