RESUMEN
BACKGROUND: Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors involved in genetic control of many cellular processes. PPAR and PPAR have been implicated in colonic malignancy. Here we provide three lines of evidence suggesting an inhibitory role for PPAR in colorectal cancer development. METHODS: Levels of PPAR mRNA and protein in human colorectal cancers were compared with matched non-malignant mucosa using RNAse protection and western blotting. APC(Min)/+ mice were randomised to receive the PPAR activator methylclofenapate 25 mg/kg or vehicle for up to 16 weeks, and small and large intestinal polyps were quantified by image analysis. The effect of methylclofenapate on serum stimulated mitogenesis (thymidine incorporation), linear cell growth, and annexin V and propidium iodide staining were assessed in human colonic epithelial cells. RESULTS: PPAR (mRNA and protein) expression levels were significantly depressed in colorectal cancer compared with matched non-malignant tissue. Methylclofenapate reduced polyp area in the small intestine from 18.7 mm(2) (median (interquartile range 11.1, 26.8)) to 9.90 (4.88, 13.21) mm(2) (p=0.003) and in the colon from 9.15 (6.31, 10.5) mm(2) to 3.71 (2.71, 5.99) mm(2) (p=0.009). Methylclofenapate significantly reduced thymidine incorporation and linear cell growth with no effect on annexin V or propidium iodide staining. CONCLUSIONS: PPAR may inhibit colorectal tumour progression, possibly via inhibition of proliferation, and may be an important therapeutic target.
Asunto(s)
Neoplasias Colorrectales/prevención & control , Pólipos Intestinales/prevención & control , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiología , Animales , Anticarcinógenos/farmacología , Clofenapato/farmacología , Neoplasias Colorrectales/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Pólipos Intestinales/genética , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Distribución Aleatoria , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genética , Células Tumorales CultivadasRESUMEN
AIMS/HYPOTHESIS: The aim of this study was to examine factors involved in chylomicron production in the streptozotocin diabetic rat, our hypothesis being that the synthesis of the chylomicron is abnormal in diabetes. METHODS: Diabetic rats (n = 20) were paired with control rats (n = 20). Cholesterol emulsion was given by gavage and the lymph duct was cannulated. Lymph was collected for 4 h. Chylomicrons were prepared from the lymph by ultracentrifugation. Lymph apolipoprotein B48 was isolated by gradient gel electrophoresis and quantified by densitometric scanning. Intestinal microsomal triglycerol transfer protein mRNA was measured by solution hybridisation nuclease protection, using a rat specific [32P]-labelled cRNA probe. RESULTS: Serum triglyceride and cholesterol were greatly increased in diabetic compared with control animals (258 +/- 77 and 8.9 +/- 6.4 mg/ml vs 1.04 +/- 0.37 and 0.54 +/- 0.03 mg/ml, p < 0.0001). Lymph chylomicron triglyceride and cholesterol were also higher in diabetic rats (29.4 +/- 27.3 and 0.28 +/- 0.3 mg/h vs 16.8 +/- 10.6 and 0.18 +/- 0.09 mg/h, p < 0.05). Lymph chylomicron apo B48 was similar in the two groups. Intestinal microsomal triglycerol transfer protein mRNA was higher in the diabetic rats (12.6 +/- 3.2 vs 3.8 +/- 3.0 amol/microgram RNA, p < 0.0001) and there was a positive correlation between lymph triglyceride and microsomal triglycerol transfer protein mRNA in the whole group (r = 0.65, p < 0.01). CONCLUSION/INTERPRETATION: The study shows that microsomal triglycerol transfer protein mRNA is raised in diabetes without an increase in apolipoprotein B48 in the lymph suggesting that microsomal triglycerol transfer protein regulates chylomicron triglyceride content but not particle number.
Asunto(s)
Proteínas Portadoras/metabolismo , Colesterol en la Dieta/metabolismo , Colesterol en la Dieta/farmacología , Quilomicrones/genética , Diabetes Mellitus Experimental/metabolismo , Mucosa Intestinal/metabolismo , Microsomas/metabolismo , Animales , Apolipoproteína B-48 , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Colesterol/sangre , Quilomicrones/biosíntesis , Regulación de la Expresión Génica , Lipoproteínas/sangre , Lipoproteínas/metabolismo , Linfa/metabolismo , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Triglicéridos/sangreRESUMEN
While it is well established that the fatty acid composition of dietary fat is important in determining plasma lipoprotein cholesterol concentrations, the effects of changing the absolute quantities of the individual fatty acids are less clear. In the present study Golden Syrian hamsters were fed on isoenergetic, low cholesterol (0.05 g/kg) diets containing 100, 150 or 200 g added fat/kg. This consisted of triolein (TO) alone, or equal proportions of TO and either trimyristin (TM), tripalmitin (TP) or tristearin (TS). Each trial also included a control group fed on a diet containing 50 g TO/kg. As the mass of TO in the diet increased, plasma VLDL-cholesterol concentrations rose. The TM-rich diets produced a concentration-dependent increase in total plasma cholesterol which was a result of significant increases in both VLDL and HDL levels. The TP-rich diets increased plasma LDL- and HDL-cholesterol levels in a concentration-dependent manner. TS-containing diets did not increase the cholesterol content of any of the major lipoprotein fractions. Hepatic LDL-receptor mRNA concentrations were significantly decreased in animals fed on TP, while apolipoprotein B mRNA concentrations were significantly increased. Thus, on a low-cholesterol diet, increasing the absolute amount of dietary palmitic acid increases LDL-cholesterol more than either myristic or stearic acid. These effects on lipoprotein metabolism may be exerted through specific modulation of the expression of the LDL receptor and apolipoprotein B genes.
Asunto(s)
Colesterol/sangre , Dieta , Ácidos Grasos/administración & dosificación , Lipoproteínas/metabolismo , Hígado/metabolismo , Animales , Apolipoproteínas B/genética , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Cricetinae , Ácidos Grasos/metabolismo , Masculino , Mesocricetus , ARN Mensajero/análisis , Receptores de LDL/genética , Triglicéridos/administración & dosificación , Triglicéridos/metabolismo , Trioleína/administración & dosificaciónRESUMEN
Different dietary fatty acids exert specific effects on plasma lipids but the mechanism by which this occurs is unknown. Hamsters were fed on low-cholesterol diets containing triacylglycerols enriched in specific saturated fatty acids, and effects on plasma lipids and the expression of genes involved in hepatic lipoprotein metabolism were measured. Trimyristin and tripalmitin caused significant rises in low-density lipoprotein (LDL) cholesterol which were accompanied by significant reductions in hepatic LDL receptor mRNA levels. Tripalmitin also increased hepatic expression of the apolipoprotein B gene, implying an increased production of LDL via very-low-density lipoprotein (VLDL) and decreased removal of LDL in animals fed this fat. Hepatic levels of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA did not vary significantly between the groups. Compared with triolein, tristearin had little effect on hepatic gene expression or total plasma cholesterol. However, it caused a marked decrease in VLDL cholesterol and a rise in LDL cholesterol such that overall it appeared to be neutral. Lipid analysis suggested a rapid desaturation of much of the dietary stearate. The differential changes in plasma lipids and hepatic mRNA levels induced by specific dietary fats suggests a role for fatty acids or a metabolite thereof in the regulation of the expression of genes involved in lipoprotein metabolism.
Asunto(s)
Apolipoproteínas B/genética , Grasas de la Dieta/farmacología , Hidroximetilglutaril-CoA Reductasas/genética , Lipoproteínas/sangre , Hígado/metabolismo , Receptores de LDL/genética , Tejido Adiposo/metabolismo , Animales , Secuencia de Bases , Colesterol/sangre , Cricetinae , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/administración & dosificación , Ácidos Grasos/metabolismo , Masculino , Mesocricetus , Datos de Secuencia Molecular , ARN Mensajero/metabolismo , Triglicéridos/administración & dosificación , Triglicéridos/sangre , Triglicéridos/metabolismo , Triglicéridos/farmacologíaAsunto(s)
Enfermedades de los Genitales Femeninos/psicología , Sexo , Femenino , Humanos , Masculino , Factores SexualesAsunto(s)
Androstenodiona/sangre , Estrógenos Conjugados (USP)/farmacología , Hormona Folículo Estimulante/sangre , Hormona Luteinizante/sangre , Menopausia/efectos de los fármacos , Norgestrel/farmacología , Adulto , Castración , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Factores de TiempoAsunto(s)
Estrógenos/uso terapéutico , Menopausia , Adulto , Anciano , Calcio/metabolismo , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Cytarabine and thioguanine therapy for acute myelomonocytic leukemia initiated in the tenth week of pregnancy (with the addition of vincristine and rubidomycin at 17 weeks) led to a short complete remission of the leukemia in a 24-year-old primigravida. This is the first case to be reported in which cytarabine was administered in the first trimester and a prostaglandin termination of pregnancy performed at 20 weeks produced an apparently normal fetus. A review of the literature suggests a slightly less than 50% chance of producing a live healthy baby if acute myelogenous leukemia is diagnosed in the first half of pregnancy, with materna mortality approaching 100% by six months postpartum. Current therapy may improve these figures.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/complicaciones , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , Aborto Terapéutico , Antineoplásicos/efectos adversos , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Mortalidad Infantil , Recién Nacido , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/mortalidad , Embarazo , Complicaciones Hematológicas del Embarazo/mortalidad , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Riesgo , Teratógenos , Tioguanina/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
Severe pre-eclampsia leading to fetal death in advanced abdominal pregnancy is reported. Attention is drawn to the low reported incidence of pre-eclampsia in this condition and possible explanations are put forward.