RESUMEN
The effects of Sasa senanensis Rehder extract (SE) by alkaline hydrolysis on histamine release from rat peritoneal exudate cells (PECs) were examined. Preincubation with SE for 5 min suppressed calcium-ionophore A23187-induced histamine release in a concentration-dependent manner. A23187 evoked a quick increase in cytoplasmic free calcium ([Ca2+]i) levels in the presence of extracellular calcium. Preincubation with SE also had an inhibitory effect on calcium influx increases induced by A23187. These results indicate that SE prevents degranulation from rat PECs by inhibiting [Ca2+]i level elevation.
Asunto(s)
Calcimicina/farmacología , Calcio/metabolismo , Exudados y Transudados/efectos de los fármacos , Liberación de Histamina/efectos de los fármacos , Ionóforos/farmacología , Extractos Vegetales/farmacología , Animales , Antiasmáticos/farmacología , Cobre/química , Cobre/farmacología , Cromolin Sódico/farmacología , Relación Dosis-Respuesta a Droga , Exudados y Transudados/citología , Exudados y Transudados/metabolismo , Hierro/química , Hierro/farmacología , Masculino , Microscopía Confocal , Peritoneo , Extractos Vegetales/química , Ratas , Ratas Sprague-DawleyRESUMEN
Apolipoprotein A-I (apo A-I) stimulates human placental lactogen (hPL) release via protein kinase C (PKC)-dependent pathways. Since PKC has been shown to activate the MAP kinase cascade in other cell types, we examined the effect of two inhibitors of the MAP kinase cascade on apo A-I-induced hPL secretion and the effect of apo A-I on MAP kinase activity in human trophoblast cells. Apigenin (10 microM) and PD98059 (100 microM) inhibited apo A-I-induced hPL release by 94 and 73%, respectively. Moreover, apo A-I activated MAP kinase in a time- and dose-dependent manner. Activation of PKC by phorbol myristate acetate (PMA) stimulated MAP kinase activity, and down-regulation of PKC completely prevented apo A-I-stimulation of MAP kinase activity. Taken together, these results strongly suggest that activation of MAP kinase is involved in the intracellular mechanism of apo A-I-induced hPL release.
Asunto(s)
Apolipoproteína A-I/farmacología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Placenta/metabolismo , Lactógeno Placentario/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Células Cultivadas , Manzanilla , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Flavonoides/farmacología , Humanos , Aceites Volátiles/farmacología , Plantas Medicinales , Embarazo/metabolismoRESUMEN
The t(11;19)(q23;p13.1) translocation is exclusively associated with myeloid leukemias. Previously, we cloned several species of MLL/MEN chimeric cDNAs in a patient with myeloid leukemia carrying the t(11;19)(q23;p13.1) translocation. The MEN sequence directly followed the 5' region of MLL cDNA in some species and otherwise there presented an inserted sequence of 120 bp between the MLL and MEN sequences in others. Because the insertion sequence contained an in-frame termination codon, they coded only for the NH2-terminal part of MLL (truncated MLL). We also cloned the normal MEN cDNA in full-length with a cDNA library derived from K562 cells. We expressed the normal MEN, MLL/MEN chimeric and truncated MLL proteins in COS7 cells with the corresponding cDNAs and detected them with antibodies raised against the MEN and MLL peptides. Immunostaining and subcellular fractionation showed nuclear localization of all these proteins. These findings suggested that MLL/MEN chimeric cDNAs were actually translated into both MLL/MEN fusion and truncated MLL proteins and that they were localized in the nucleus of leukemic cells. Recently, Conaway et al. reported that MEN is an RNA polymerase II elongation factor. The leukemogenesis by the t(11;19)(q23;p13.1) translocation may have resulted from the alteration of transcription regulation induced by the MLL/MEN fusion protein and/or the truncated MLL protein.
Asunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 19/genética , Proteínas de Unión al ADN/genética , Leucemia Mieloide/genética , Factores de Elongación de Péptidos/genética , Proto-Oncogenes , Proteínas Recombinantes de Fusión/genética , Fracciones Subcelulares/química , Factores de Transcripción , Translocación Genética , Animales , Células COS , Transformación Celular Neoplásica , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 19/ultraestructura , Clonación Molecular , ADN Complementario/genética , ADN de Neoplasias/genética , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/biosíntesis , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide/patología , Proteína de la Leucemia Mieloide-Linfoide , Factores de Elongación de Péptidos/análisis , Factores de Elongación de Péptidos/biosíntesis , Proteínas Recombinantes de Fusión/análisis , Dedos de Zinc/genéticaRESUMEN
Twenty-one patients were treated with sequential doses of MTX and 5-FU so as to be classified by MTX dosage into an intermediate MTX-dose group and a high MTX-dose group. In the intermediate-dose MTX group, the drug was given at a dosage of 100 mg/m2 intravenously (i.v.) and followed 1 hour later by 5-FU at 800 mg/m2 i.v. (dripping for 1 hour); the drugs were recycled every 1 week. In the high-dose MTX group, the drug was administered at a dose of 1.5 g/m2 i.v. (dripping for 2 hours) and followed 1 hour later by 5-FU at 1.5 g/m2 i.v. (dripping for 2 hours); the drugs were recycled every 2-3 weeks. Average MTX concentrations in serum at the start of 5-FU administration were 1.69 X 10(-5) and 1.33 X 10(-4) mol/l/h in the intermediate and high-dose MTX groups, respectively. Six (50%) of 12 patients adequately treated with intermediate-dose MTX had a partial response (PR), and one (14.3%) of 7 evaluable patients treated with high-dose MTX had a PR. Major toxicity included diarrhea (33.3%) in the intermediate-dose MTX group and hair loss (71.4%) in the high-dose MTX group. Hematological toxicity was mild in MTX group: six (50%) of 12 patients had a granulocyte count nadir less than 1,000/microliters and one (8.3%) of 12 patients had a platelet count nadir less than 10(5)/microliters in the intermediate-dose MTX group. Five (71.4%) of 7 patients had a granulocyte nadir less than 1,000/microliters and two (28.6%) of 7 patients had a platelet count nadir less than 10(5)/microliters in the high-dose MTX group.