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1.
Mol Brain ; 14(1): 152, 2021 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-34607601

RESUMEN

The glutamatergic signaling pathway is involved in molecular learning and human cognitive ability. Specific single variants (SNVs, formerly single-nucleotide polymorphisms) in the genes encoding N-methyl-D-aspartate receptor subunits have been associated with neuropsychiatric disorders by altering glutamate transmission. However, these variants associated with cognition and mental activity have rarely been explored in healthy adolescents. In this study, we screened for SNVs in the glutamatergic signaling pathway to identify genetic variants associated with cognitive ability. We found that SNVs in the subunits of ionotropic glutamate receptors, including GRIA1, GRIN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, and calcium/calmodulin-dependent protein kinase IIα (CaMK2A) are associated with cognitive function. Plasma CaMK2A level was correlated positively with the cognitive ability of Taiwanese senior high school students. We demonstrated that elevating CaMK2A increased its autophosphorylation at T286 and increased the expression of its downstream targets, including GluA1 and phosphor- GluA1 in vivo. Additionally, methyl-CpG binding protein 2 (MeCP2), a downstream target of CaMK2A, was found to activate the expression of CaMK2A, suggesting that MeCP2 and CaMK2A can form a positive feedback loop. In summary, two members of the glutamatergic signaling pathway, CaMK2A and MeCP2, are implicated in the cognitive ability of adolescents; thus, altering the expression of CaMK2A may affect cognitive ability in youth.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Cognición/fisiología , Proteína 2 de Unión a Metil-CpG/fisiología , Psicología del Adolescente , Receptores Ionotrópicos de Glutamato/genética , Transducción de Señal/fisiología , Adolescente , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/sangre , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Línea Celular Tumoral , Activación Enzimática , Retroalimentación Fisiológica/fisiología , Femenino , Ácido Glutámico/fisiología , Células HEK293 , Humanos , Masculino , Neuroblastoma , Fosforilación , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional , Receptores Ionotrópicos de Glutamato/fisiología , Valores de Referencia , Taiwán
3.
Sci Rep ; 5: 17014, 2015 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-26594036

RESUMEN

There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and mdx (dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (P < 0.001, q < 0.01) in mdx mice. Additionally, systemic treatment with a peptide-antisense oligonucleotide conjugate designed to induce Dmd exon skipping and recover dystrophin protein expression caused many of the differentially abundant serum proteins to be restored towards wild-type levels. Results for five leading candidate protein biomarkers (Pgam1, Tnni3, Camk2b, Cycs and Adamts5) were validated by ELISA in the mouse samples. Furthermore, ADAMTS5 was found to be significantly elevated in human DMD patient serum. This study has identified multiple novel, therapy-responsive protein biomarkers in the serum of the mdx mouse with potential utility in DMD patients.


Asunto(s)
Proteínas ADAM/genética , Aptámeros de Nucleótidos/farmacología , Biomarcadores Farmacológicos/sangre , Distrofina/genética , Distrofia Muscular de Duchenne/terapia , Oligonucleótidos Antisentido/farmacología , Proteínas ADAM/sangre , Proteína ADAMTS5 , Animales , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/sangre , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Modelos Animales de Enfermedad , Distrofina/agonistas , Distrofina/deficiencia , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Monoéster Fosfórico Hidrolasas/sangre , Monoéster Fosfórico Hidrolasas/genética , Proteínas Quinasas/sangre , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas , Proteómica/métodos
4.
J Psychiatr Pract ; 20(5): 329-37, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25226193

RESUMEN

OBJECTIVE: The goals of this study were to determine the serum level of 25 hydroxyvitamin D (25[OH]D), a vitamin D metabolite, in patients with recurrent depression, to assess risk factors for vitamin D deficiency, and to evaluate whether the severity of symptoms of depression and response to treatment were associated with serum vitamin 25(OH)D level. METHOD: Ninety-one patients 18 to 65 years of age meeting the ICD-10 criteria for recurrent depression were evaluated for depressive symptoms using the Hamilton Depression Rating Scale. The control group consisted of 89 healthy subjects matched according to sex and age. Serum levels of 25(OH)D, parathyroid hormone (PTH), and calmodulin-dependent protein kinase II (Ca) were determined in all group members. RESULTS: A significantly decreased serum level of 25(OH)D was observed in the group of patients with recurrent depression compared with healthy subjects. PTH and Ca levels were within the reference values in a substantial majority of patients. No correlation was found between 25(OH)D serum level and age, sex, height, body mass index, disease duration, number of depressive episodes, type of pharmacotherapy, or effectiveness of treatment. CONCLUSIONS: Low serum levels of 25(OH)D in patients with recurrent depression suggest that these patients are an important risk group for vitamin D deficiency. However, no relationship was found between these low levels of 25(OH)D and response to treatment for depression. Nevertheless, the results indicate the need to monitor the concentration and supplementation of products containing calciferol in such patients.


Asunto(s)
Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/complicaciones , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Vitamina D/análogos & derivados , Adolescente , Adulto , Anciano , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Recurrencia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Vitamina D/sangre , Adulto Joven
5.
Sleep ; 33(4): 437-44, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20394312

RESUMEN

STUDY OBJECTIVES: This study was undertaken to provide a detailed account of the effect of chronic treatment with a small dose of caffeine on the deleterious effects of sleep loss on brain function in rats. EXPERIMENTAL DESIGN: We investigated the effects of chronic (4 weeks) caffeine treatment (0.3 g/L in drinking water) on memory impairment in acutely (24 h) sleep-deprived adult male Wistar rats. Sleep deprivation was induced using the modified multiple platform model. The effects of caffeine on sleep deprivation-induced hippocampus-dependent learning and memory deficits were studied by 3 approaches: learning and memory performance in the radial arm water maze task, electrophysiological recording of early long-term potentiation (E-LTP) in area CA1 of the hippocampus, and levels of memory- and synaptic plasticity-related signaling molecules after E-LTP induction. MEASUREMENT AND RESULTS: The results showed that chronic caffeine treatment prevented impairment of hippocampus-dependent learning, shortterm memory and E-LTP of area CA1 in the sleep-deprived rats. In correlation, chronic caffeine treatment prevented sleep deprivation-associated decrease in the levels of phosphorylated calcium/calmodulin-dependent protein kinase II (P-CaMKII) during expression of E-LTP. CONCLUSIONS: The results suggest that long-term use of a low dose of caffeine prevents impairment of short-term memory and E-LTP in acutely sleep-deprived rats.


Asunto(s)
Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Trastornos del Conocimiento/prevención & control , Plasticidad Neuronal/efectos de los fármacos , Privación de Sueño/complicaciones , Sinapsis/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Cafeína/administración & dosificación , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/sangre , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Fenómenos Electrofisiológicos/efectos de los fármacos , Hipocampo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratas , Ratas Wistar , Análisis y Desempeño de Tareas
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