RESUMEN
THP-1 cell-derived foam cells were exposed to oxidative stress through combined treatment with acetylated LDL (acLDL) and copper ions (Cu2+). The foam cells showed caspase-dependent apoptotic changes on exposure to oxidative stress for 6 h, and necrotic changes with the leakage of LDH after 24 h. KY-455, an anti-oxidative ACAT inhibitor, and ascorbic acid (VC) but not YM-750, an ACAT inhibitor, prevented apoptotic and necrotic changes. These preventive effects of KY-455 and VC were accompanied by the inhibition of lipid peroxidation in culture medium containing acLDL and Cu2+, suggesting the involvement of oxidized acLDL in apoptosis and necrosis. Foam cells accumulated esterified cholesterol (EC) for 24 h in the presence of acLDL without Cu2+, which was suppressed by KY-455 and YM-750. Foam cells showed necrotic changes and died in the presence of acLDL and Cu2+. KY-455 but not YM-750 prevented cell death and reduced the amount of EC accumulated. The foam cells treated with VC further accumulated EC without necrotic changes for 24 h even in the presence of acLDL and Cu2+. YM-750 as well as KY-455 inhibited lipid accumulation when co-incubated with VC in foam cells exposed to oxidative stress. It is concluded that an anti-oxidative ACAT inhibitor or the combination of an antioxidant and an ACAT inhibitor protects foam cells from oxidative stress and effectively reduces cholesterol levels, which would be a promising approach in anti-atherosclerotic therapy.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Colesterol/metabolismo , Células Espumosas/efectos de los fármacos , Indoles/farmacología , Estrés Oxidativo/efectos de los fármacos , Propano/análogos & derivados , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Ácido Ascórbico/farmacología , Línea Celular , Sulfato de Cobre/farmacología , Células Espumosas/metabolismo , Células Espumosas/patología , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/farmacología , Necrosis , Propano/farmacología , Conejos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
UNLABELLED: Regional myocardial blood flow (MBF) can be measured with 15O-water and PET using the 1-tissue-compartment model with perfusable tissue fraction, which provides an MBF value that is free from the partial-volume effect. Studies with 15O-water have several advantages, such as the ability to repeat a scan. However, because of the short scanning time and the small distribution volume of 15O-water in the myocardium, the image quality of 15O-water is limited, impeding the computation of MBF and perfusable tissue fraction at the voxel level. We implemented the basis function method for generating parametric images of MBF, perfusable tissue fraction, and arterial blood volume (Va) with 15O-water and PET. The basis function method linearizes the solution of the 1-tissue-compartment model, which results in a computationally much faster method than the conventional nonlinear least-squares fitting method in estimating the parameters. METHODS: To validate the basis function method, we performed a series of PET studies on miniature pigs (n = 7). After acquisition of the transmission scan for attenuation correction and the 15O-CO scan for obtaining the blood-pool image, repeated PET scans with 15O-water were obtained with varying doses of adenosine or CGS-21680 (selective adenosine A(2a) receptor agonist). MBF, perfusable tissue fraction, and Va values of the myocardial region for each scan were computed using the basis function method and the nonlinear least-squares method, and the parameters estimated by the 2 methods were compared. RESULTS: MBF images generated by the basis function method demonstrated an increase in blood flow after administration of adenosine or CGS-21680. The MBF values estimated by the basis function method and by the nonlinear least-squares method correlated strongly. CONCLUSION: The basis function method produces parametric images of MBF, perfusable tissue fraction, and Va with 15O-water and PET. These images will be useful in detecting regional myocardial perfusion abnormalities.
Asunto(s)
Algoritmos , Circulación Coronaria/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Tomografía de Emisión de Positrones/métodos , Función Ventricular , Agua , Animales , Velocidad del Flujo Sanguíneo/fisiología , Radioisótopos de Oxígeno , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Porcinos , Porcinos EnanosRESUMEN
Repetitive transcranial magnetic stimulation (rTMS) recently has been assessed as a noninvasive treatment modality for movement and psychiatric disorders, whereas the mechanism underlying the therapeutic effects is not fully understood. Studies in rodents showed lasting functional changes in some selected regions, such as limbic-associated structures, but unfocused brain stimulation did not clarify the regional effects. To address the topographical and temporal profiles of the effects on glucose metabolism in primate brain, we performed rTMS and repeated (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) before, during, and up to 16 days after rTMS in anesthetized cynomologous monkeys. We delivered a total of 2,000 pulses of 5 Hz-rTMS over the right precentral gyrus using a small-sized eight-figured coil that induced a localized electrical field. Voxel-based analysis in a standard space of the macaque brain showed statistically robust changes in FDG uptake: a decrease in the motor/premotor cortices and an increase in the limbic-associated areas involving the anterior/posterior cingulate, and orbitofrontal cortices. Interestingly, these uptake changes continued for at least 8 days and the magnitude of the lasting effects in the limbic-related areas was negatively correlated across subjects with those in the motor/premotor cortices. The results demonstrate that motor rTMS has a long-term lasting effect on motor-related regions and distant limbic-related areas via functional connections.