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1.
iScience ; 27(7): 110212, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-38993665

RESUMEN

Suvorexant is an orexin receptor antagonist that targets the wake-promoting system. Orexin is also known to regulate energy metabolism in rodents, but its role in humans remains largely unknown. Here, we assessed the effect of suvorexant (20 mg) on energy metabolism during sleep and shortly after awakening in a randomized, double-blind, placebo-controlled, crossover study in 14 healthy men. Suvorexant increased rapid eye movement (REM) but decreased nonrapid eye movement (NREM) stage 1. Energy expenditure during wake after sleep onset (WASO) was higher than that during NREM and REM sleep in the placebo but not in the suvorexant trial, suggesting that the increase in energy expenditure during WASO was due to an activation of the orexin system. Fat oxidation during sleep increased, and its effect remained after waking the next morning. Suvorexant decreased protein catabolism but did not affect overall energy expenditure. The orexin system may affect fat oxidation independent of its roles in sleep regulation in humans.

2.
Sci Rep ; 12(1): 15399, 2022 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-36100642

RESUMEN

Although recent studies have examined the bidirectional associations between physical activity and sleep parameters, few have focused on older adults utilizing objective assessments, such as polysomnography. This micro-longitudinal observational study included 92 Japanese older adults (aged 65-86 years) who underwent objective evaluations of sleep quality using polysomnography and completed subjective sleep-related questionnaires. Activity levels were assessed using an accelerometer. Polysomnography, subjective sleep-related questionnaires, and accelerometer were administered for 7 consecutive days. Multilevel models (participant-, day-level) were used to examine the temporal associations of objective and subjective sleep parameters with sedentary behavior and physical activity. In the day-level analysis, higher levels of sedentary behavior during daytime were associated with longer rapid eye movement (REM) sleep, shorter REM latency, lower levels of non-REM sleep (stage N3), and reduced delta power during daytime. Higher levels of low-intensity physical activity during daytime were associated with lower levels of REM sleep, longer REM latency, and increased stage N3 sleep in the day-level analysis. Higher levels of moderate-to-vigorous physical activity were associated with increased REM latency. Longer subjective sleep time was associated with increased next-day moderate-to-vigorous physical activity. Thus, low-intensity physical activity may provide objective benefits related to deep sleep parameters in older adults.


Asunto(s)
Trastornos de Somnolencia Excesiva , Sueño , Anciano , Ejercicio Físico , Humanos , Análisis Multinivel , Polisomnografía , Conducta Sedentaria
3.
Sci Rep ; 12(1): 12799, 2022 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-35896616

RESUMEN

Scoring sleep stages from biological signals is an essential but labor-intensive inspection for sleep diagnosis. The existing automated scoring methods have achieved high accuracy but are not widely applied in clinical practice. In our understanding, the existing methods have failed to establish the trust of sleep experts (e.g., physicians and clinical technologists) due to a lack of ability to explain the evidences/clues for scoring. In this study, we developed a deep-learning-based scoring model with a reasoning mechanism called class activation mapping (CAM) to solve this problem. This mechanism explicitly shows which portions of the signals support our model's sleep stage decision, and we verified that these portions overlap with the "characteristic waves," which are evidences/clues used in the manual scoring process. In exchange for the acquisition of explainability, employing CAM makes it difficult to follow some scoring rules. Although we concerned the negative effect of CAM on the scoring accuracy, we have found that the impact is limited. The evaluation experiment shows that the proposed model achieved a scoring accuracy of [Formula: see text]. It is superior to those of some existing methods and the inter-rater reliability among the sleep experts. These results suggest that Sleep-CAM achieved both explainability and required scoring accuracy for practical usage.


Asunto(s)
Solución de Problemas , Fases del Sueño , Recolección de Datos , Electroencefalografía/métodos , Polisomnografía/métodos , Reproducibilidad de los Resultados , Sueño , Fases del Sueño/fisiología
4.
Nutrients ; 12(12)2020 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-33260552

RESUMEN

Ingesting oolong tea or caffeine acutely increases energy expenditure, and oolong tea, but not caffeine, stimulates fat oxidation. The acute effects of caffeine, such as increased heart rate and interference with sleep, diminish over 1-4 days, known as caffeine tolerance. During each 14-day session of the present study, 12 non-obese males consumed oolong tea (100 mg caffeine, 21.4 mg gallic acid, 97 mg catechins and 125 mg polymerized polyphenol), caffeine (100 mg), or placebo at breakfast and lunch. On day 14 of each session, 24-h indirect calorimetry and polysomnographic sleep recording were performed. Caffeine and oolong tea increased fat oxidation by ~20% without affecting energy expenditure over 24-h. The decrease in the respiratory quotient by oolong tea was greater than that by caffeine during sleep. The effect of oolong tea on fat oxidation was salient in the post-absorptive state. These findings suggest a role of unidentified ingredients in oolong tea to stimulate fat oxidation, and this effect is partially suppressed in a postprandial state. Two weeks of caffeine or oolong tea ingestion increased fat oxidation without interfering with sleep. The effects of subacute ingestion of caffeine and oolong tea differed from the acute effects, which is a particularly important consideration regarding habitual tea consumption.


Asunto(s)
Cafeína/farmacología , Metabolismo Energético/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Sueño/efectos de los fármacos , , Adulto , Cafeína/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino
5.
Proc Natl Acad Sci U S A ; 116(48): 24353-24358, 2019 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-31712421

RESUMEN

The majority of patients with insomnia are treated with hypnotic agents. In the present study, we evaluated the side-effect profile of an orexin receptor antagonist and γ-aminobutyric acid A (GABAA) receptor agonist on physical/cognitive functions upon forced awakening. This double-blind, randomized, placebo-controlled, cross-over study was conducted on 30 healthy male subjects. Fifteen minutes before bedtime, the subjects took a pill of suvorexant (20 mg), brotizolam (0.25 mg), or placebo and were forced awake 90 min thereafter. Physical- and cognitive-function tests were performed before taking the pill, after forced awakening, and the next morning. Polysomnographic recordings revealed that the efficacies of the hypnotic agents in prolonging total sleep time (∼30 min) and increasing sleep efficiency (∼6%) were comparable. When the subjects were allowed to go back to sleep after the forced awakening, the sleep latency was shorter under the influence of hypnotic agents (∼2 min) compared to the placebo trial (24 min), and the rapid eye movement latency was significantly shorter under suvorexant (98.8, 81.7, and 48.8 min for placebo, brotizolam, and suvorexant, respectively). Although brotizolam significantly impaired the overall physical/cognitive performance (sum of z score) compared with placebo upon forced awakening, there was no significant difference in the total z score of performance between suvorexant and placebo. Notably, the score for static balance with the eyes open was higher under suvorexant compared to brotizolam administration. The energy expenditure was lower under suvorexant and brotizolam compared with the placebo. The effect size of brotizolam (d = 0.24) to reduce the energy expenditure was larger than that of suvorexant (d < 0.01).


Asunto(s)
Azepinas/farmacología , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Sueño/efectos de los fármacos , Triazoles/farmacología , Adulto , Cognición/efectos de los fármacos , Método Doble Ciego , Metabolismo Energético/efectos de los fármacos , Voluntarios Sanos , Humanos , Hipnóticos y Sedantes/farmacología , Masculino , Polisomnografía , Vigilia/fisiología , Adulto Joven
6.
PLoS One ; 13(5): e0196422, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29723247

RESUMEN

Nectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+-independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore, we discovered multiple anti-Nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (ADCC) as the principal mechanism of action. In this report, we assessed the toxicity of Y-443, a fully human IgG1/kappa anti-Nectin-2 monoclonal antibody exhibiting strong in vitro ADCC and in vivo anti-tumor activity in cynomolgus monkeys (Macaca fascicularis (Cynos)). Unexpectedly, upon administration, Y-443 induced strong thrombocytopenia through Nectin-2 expressed on Cyno platelets, presumably followed by phagocytosis in the mononuclear phagocytic system. To mitigate the adverse safety profile, we mutated the Fc region of Y-443 to reduce the Fc binding activity to Fcγ receptor I, which is the primary receptor for phagocytosis on macrophages. Moreover, we further engineered the Fc through defucosylation to maintain ADCC activity. The resultant Fc engineered antibody, termed Y-634, demonstrated diminished thrombocytopenia in Cyno toxicological studies and maintained anti-tumor activity in a mouse xenograft model. These findings suggest that Y-634 may have a therapeutic potential for the treatment of Nectin-2 positive cancers, and moreover, Fc engineering is a potential mitigation strategy to ameliorate safety liabilities in antibody induced thrombocytopenia while maintaining antibody potency.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Nectinas/antagonistas & inhibidores , Nectinas/inmunología , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/genética , Citotoxicidad Celular Dependiente de Anticuerpos , Línea Celular Tumoral , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Macaca fascicularis , Masculino , Ratones , Ratones SCID , Nectinas/genética , Ingeniería de Proteínas , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Trombocitopenia/etiología , Trombocitopenia/prevención & control , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Mol Cancer ; 12: 60, 2013 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-23758976

RESUMEN

BACKGROUND: Nectin-2 is a Ca(2+)-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. However, little has been reported about the involvement of Nectin-2 in cancer. METHODS: To determine the expression of Nectin-2 in cancer tissues and cancer cell lines, we performed gene expression profile analysis, immunohistochemistry studies, and flow cytometry analysis. We also investigated the potential of this molecule as a target for antibody therapeutics to treat cancers by generating and characterizing an anti-Nectin-2 rabbit polyclonal antibody (poAb) and 256 fully human anti-Nectin-2 monoclonal antibodies (mAbs). In addition, we tested anti-Nectin-2 mAbs in several in vivo tumor growth inhibition models to investigate the primary mechanisms of action of the mAbs. RESULTS: In the present study, we found that Nectin-2 was over-expressed in clinical breast and ovarian cancer tissues by using gene expression profile analysis and immunohistochemistry studies. Nectin-2 was over-expressed in various cancer cell lines as well. Furthermore, the polyclonal antibody specific to Nectin-2 suppressed the in vitro proliferation of OV-90 ovarian cancer cells, which express endogenous Nectin-2 on the cell surface. The anti-Nectin-2 mAbs we generated were classified into 7 epitope bins. The anti-Nectin-2 mAbs demonstrated antibody-dependent cellular cytotoxicity (ADCC) and epitope bin-dependent features such as the inhibition of Nectin-2-Nectin-2 interaction, Nectin-2-Nectin-3 interaction, and in vitro cancer cell proliferation. A representative anti-Nectin-2 mAb in epitope bin VII, Y-443, showed anti-tumor effects against OV-90 cells and MDA-MB-231 breast cancer cells in mouse therapeutic models, and its main mechanism of action appeared to be ADCC. CONCLUSIONS: We observed the over-expression of Nectin-2 in breast and ovarian cancers and anti-tumor activity of anti-Nectin-2 mAbs via strong ADCC. These findings suggest that Nectin-2 is a potential target for antibody therapy against breast and ovarian cancers.


Asunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/inmunología , Moléculas de Adhesión Celular/inmunología , Neoplasias Ováricas/inmunología , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Epítopos/inmunología , Femenino , Expresión Génica , Humanos , Ratones , Nectinas , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Unión Proteica/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Eur J Pharmacol ; 505(1-3): 223-8, 2004 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-15556156

RESUMEN

The initiation of antigen presentation by dendritic cells requires proper internalization of antigens through various mechanisms. Internalization of immune complexes via Fc receptors has been shown to be around 100 times more efficient than the internalization of non-complexed antigens. Spleen tyrosine kinase (Syk) plays an essential role in the signaling cascade initiated by immunoglobulin receptors. We used a selective Syk inhibitor, 7-(3,4-dimethoxyphenyl)-N-1H-indazol-6-ylimidazo[1,2-c]pyrimidin-5-amine dihydrochloride (compound-D), to evaluate the role of Syk in antigen presentation by mouse bone marrow-derived dendritic cells. In line with our expectation, compound-D concentration-dependently inhibited the internalization of immune complexes but not that of antigen itself. Furthermore, when dendritic cells were pretreated with compound-D, the ability of dendritic cells to present immune complex antigens to Th2 cells was attenuated, parallel by a reduced release of interleukin-4 production in Th2 cells. Therefore, Syk kinase activity is a critical component in the process of Fcgamma receptor-mediated internalization of immune complex antigens in dendritic cells, and Syk kinase inhibitors may be beneficial in selectively suppressing antibody-mediated antigen presentation in allergic diseases.


Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Imidazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Células Cultivadas , Técnicas de Cocultivo , Conalbúmina/inmunología , Conalbúmina/farmacología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Relación Dosis-Respuesta a Droga , Inmunoglobulina G/inmunología , Inmunoglobulina G/farmacología , Interleucina-4/biosíntesis , Masculino , Ratones , Ratones Endogámicos , Proteínas Tirosina Quinasas/metabolismo , Ratas , Ratas Wistar , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo
9.
Biol Pharm Bull ; 26(12): 1685-90, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14646171

RESUMEN

To investigate the effect of flavonoids on the activation of p72(syk) (Syk) protein tyrosine kinase which plays a pivotal role in the high affinity IgE receptor-mediated degranulation of mast cells, we picked out 10 flavonoids, classified them into 4 series, and examined their effects on the activation of Syk and on the degranulation of human mast cells. Flavones and flavonols showed clear inhibition, whereas flavanones and isoflavones had either weak or no effect on Syk enzymatic activity induced by amino acid peptide corresponding to the activation loop domain and on IgE-dependent degranulation of human cultured mast cells (HCMC). On the basis of calculated logP (ClogP) values as a prediction of compound lipophilicity, some flavonoids were speculated to have low lipophilicity, the reason for poor cell permeability. A significant relationship was observed between the inhibition of Syk activity and HCMC degranulation attributable to flavonoids when the ClogP values of the compounds were taken into account (r(2)=0.89). These results suggested that the impairment of mast cell degranulation by several flavonoids classified into flavones and flavonols might be mediated via inhibition of the intracellular activation of Syk.


Asunto(s)
Degranulación de la Célula/efectos de los fármacos , Precursores Enzimáticos/antagonistas & inhibidores , Precursores Enzimáticos/genética , Flavonoides/farmacología , Mastocitos/citología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Degranulación de la Célula/genética , Degranulación de la Célula/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Precursores Enzimáticos/metabolismo , Flavanonas/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Mastocitos/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-Actividad , Quinasa Syk , Cordón Umbilical/citología
10.
J Pharmacol Exp Ther ; 306(3): 1174-81, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12766258

RESUMEN

Spleen tyrosine kinase (Syk) tyrosine kinase plays essential roles in receptors for Fc portion of immunoglobulins and B cell receptor complex signaling in various inflammatory cells; therefore, inhibitors of Syk kinase may show potential as antiasthmatic/allergic therapeutics. We identified 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-nicotinamide dihydrochloride (BAY 61-3606), a potent (Ki = 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC50 values between 5 and 46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61-3606 was highly efficacious in basophils obtained from healthy human subjects (IC50 = 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC50 = 8.1 nM). B cell receptor activation and receptors for Fc portion of IgG signaling in eosinophils and monocytes were also potently suppressed by BAY 61-3606. Oral administration of BAY 61-3606 to rats significantly suppressed antigen-induced passive cutaneous anaphylactic reaction, bronchoconstriction, and bronchial edema at 3 mg/kg. Furthermore, BAY 61-3606 attenuated antigen-induced airway inflammation in rats. Based on these anti-inflammatory effects of BAY 61-3606 both in vitro and in vivo, it was demonstrated that Syk may play a very critical role in the pathogenesis of allergic reactions.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Mastocitos/efectos de los fármacos , Niacinamida/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Administración Oral , Animales , Broncoconstricción/efectos de los fármacos , Edema/inducido químicamente , Edema/prevención & control , Inhibidores Enzimáticos/uso terapéutico , Humanos , Técnicas In Vitro , Inflamación/inducido químicamente , Inflamación/prevención & control , Mastocitos/fisiología , Ratones , Ratones Transgénicos , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Pirimidinas/uso terapéutico , Ratas , Bazo/enzimología
11.
J Immunol Methods ; 268(2): 123-30, 2002 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-12215380

RESUMEN

Protein tyrosine kinase Syk is known to play critical roles in the signal transduction from receptors for Fc portion of immunoglobulins (FcRs) and B cell receptor complex (BCR). Its importance was well studied in Fc epsilon RI-induced activation of mast cells; therefore, Syk inhibitors are expected to have anti-allergic effects and to be novel therapy for allergic diseases, such as asthma, allergic rhinitis and atopic dermatitis. We previously developed an enzyme assay of recombinant human Syk kinase for the high throughput screening. In order to evaluate the Syk kinase inhibitors in a human cell system, we have developed an assay with human monocytic cell line, U937, to monitor FcgammaRI-mediated superoxide production. We treated cells with IFN-gamma to enhance the expression of FcgammaRI and to obtain enough production of superoxide. Engagement of FcgammaRI stimulated superoxide production, which was accompanied with Syk phosphorylation. PMA, an activator of protein kinase C, also evoked superoxide production, but Syk was not phosphorylated. Moreover, the treatment of cells with antisense oligonucleotide against syk attenuated Syk protein expression and suppressed superoxide production induced by FcgammaRI-engagement, but not by PMA. These results confirm that Syk is involved in the signal transduction from FcgammaRI upstream of PKC in U937 cells and we can evaluate the efficacy and the selectivity of Syk inhibitors with this assay system.


Asunto(s)
Precursores Enzimáticos/antagonistas & inhibidores , Oligonucleótidos Antisentido/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Superóxidos/metabolismo , Humanos , Interferón gamma/farmacología , Péptidos y Proteínas de Señalización Intracelular , Fosforilación , Receptores de IgG/fisiología , Transducción de Señal , Quinasa Syk , Tirosina/metabolismo , Células U937
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