RESUMEN
Physical exercise is the cornerstone of cardiovascular disease treatment. The present study investigated whether exercise training affects atherosclerotic plaque composition through the modification of inflammatory-related pathways in apolipoprotein E knockout (apoE(-/-)) mice with diabetic atherosclerosis. Forty-five male apoE(-/-) mice were randomized into three equivalent (n=15) groups: control (CO), sedentary (SED), and exercise (EX). Diabetes was induced by streptozotocin administration. High-fat diet was administered to all groups for 12 weeks. Afterwards, CO mice were euthanatized, while the sedentary and exercise groups continued high-fat diet for 6 additional weeks. Exercising mice followed an exercise program on motorized-treadmill (5 times/week, 60 min/session). Then, blood samples and atherosclerotic plaques in the aortic root were examined. A considerable (P<0.001) regression of the atherosclerotic lesions was observed in the exercise group (180.339 ± 75.613 x10(3)µm(2)) compared to the control (325.485 ± 72.302 x10(3)µm(2)) and sedentary (340.188 ± 159.108 x 10(3)µm(2)) groups. We found decreased macrophages, matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-8 and interleukin-6 (IL-6) concentrations (P<0.05) in the atherosclerotic plaques of the exercise group. Compared to both control and sedentary groups, exercise training significantly increased collagen (P<0.05), elastin (P<0.001), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) (P<0.001) content in the atherosclerotic plaques. Those effects paralleled with increased fibrous cap thickness and less internal elastic lamina ruptures after exercise training (P<0.05), while body-weight and lipid parameters did not significantly change. Plasma MMP-2 and MMP-3 concentrations in atherosclerotic tissues followed a similar trend. From our study we can conclude that exercise training reduces and stabilizes atherosclerotic lesions in apoE-/- mice with diabetic atherosclerosis. A favorable modification of the inflammatory regulators seems to explain those beneficial effects.
Asunto(s)
Apolipoproteínas E , Diabetes Mellitus Experimental , Interleucina-6/sangre , Metaloproteinasas de la Matriz/sangre , Condicionamiento Físico Animal , Placa Aterosclerótica , Inhibidor Tisular de Metaloproteinasa-2/sangre , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/terapia , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/farmacología , Inflamación/sangre , Inflamación/genética , Inflamación/patología , Inflamación/terapia , Masculino , Ratones , Ratones Noqueados , Placa Aterosclerótica/sangre , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Placa Aterosclerótica/terapia , Factores de TiempoRESUMEN
OBJECTIVES: To test the hypothesis that vein graft intimal hyperplasia can be significantly suppressed by a single intra-operative transfection of the graft with a decoy oligonucleotide (ODN) binding the transcription factor Egr-1. DESIGN: Experimental study. MATERIALS AND METHODS: Jugular vein to carotid artery interposition grafts in rabbits were treated with Egr-1 decoy, mutant decoy ODN, vehicle alone, using a non-distending pressure of 300 mm Hg for 20 min, or were left untreated. All animals were fed a 2% cholesterol diet. The animals were sacrificed after 48h, 6 weeks and 12 weeks. Paraffin-embedded vein sections were subjected to angiometric analysis. RESULTS: Successful delivery of the ODN was confirmed by DAPI staining. Quantitative real-time PCR revealed a 60% decrease of the Egr-1 gene expression in the animals in which the Egr-1 decoy ODN was delivered. Cellular proliferation was also significantly decreased as indicated by the Ki-67 labelling index. An increase in intimal and medial thickness was found in all vein grafts. However, intimal thickness was significantly reduced in the grafts treated with Egr-1 decoy ODN, whereas luminal area was significantly increased. CONCLUSION: A single intra-operative pressure-mediated transfection of vein grafts with Egr-1 decoy ODN significantly suppresses intimal hyperplasia in a rabbit hypercholesterolaemic model.
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Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Terapia Genética/métodos , Oclusión de Injerto Vascular/prevención & control , Túnica Íntima/patología , Animales , Arterias Carótidas/cirugía , Proliferación Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Oclusión de Injerto Vascular/genética , Hiperplasia , Periodo Intraoperatorio , Venas Yugulares/cirugía , Masculino , Oligonucleótidos/química , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
AIM: This study assessed the impact of regular exercise on inflammatory markers (high-sensitivity C-reactive protein [hsCRP], fibrinogen), and matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), in patients with type 2 diabetes mellitus (T2DM). PATIENTS: Fifty overweight patients with T2DM were randomly assigned to two groups: (A) an exercise group (EXG, n=25), with self-controlled exercise for at least 150 min/week and one additional supervised exercise session/week; and (B) a control group (COG, n=25), with no exercise instructions. All participants were taking oral antidiabetic drugs, and none had diabetic complications. Clinical parameters, exercise capacity (VO(2 peak)), ventilatory threshold (VT), insulin resistance indices (fasting insulin, HOMA-IR, HOMA%S), hsCRP, fibrinogen, MMP-2, MMP-9, TIMP-1 and TIMP-2 were assessed at baseline and after 16 weeks. RESULTS: No significant changes were found in body mass index, waist/hip ratio, insulin-resistance indices, MMP-2 and TIMP-1 throughout the study in either group (P>0.05). Compared with controls, the EXG showed a significant decrease in systolic and mean blood pressure, total and LDL cholesterol, and HbA(1c) (P<0.05). Also, exercise significantly suppressed levels of fibrinogen (P=0.047), hsCRP (P=0.041) and MMP-9 (P=0.028), and the MMP-9-to-TIMP-1 ratio (P=0.038), whereas VO(2 peak) (P=0.011), VT (P=0.008) and plasma TIMP-2 levels (P=0.022) were considerably upregulated in the EXG vs. COG. Standard multiple-regression analyses revealed that MMP-9 changes were independently associated with fibrinogen and HbA(1c) changes, while fibrinogen changes independently predicted TIMP-2 alterations with exercise. CONCLUSION: Mostly self-controlled exercise of moderate intensity ameliorated serum levels of pro- and anti-atherogenic markers in patients with T2DM, with no effects on body weight. These data offer further insight into the cardioprotective mechanisms of exercise in patients with T2DM.
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Diabetes Mellitus Tipo 2/sangre , Ejercicio Físico/fisiología , Metaloproteinasa 9 de la Matriz/sangre , Inhibidor Tisular de Metaloproteinasa-2/sangre , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Distribución de Chi-Cuadrado , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/terapia , Femenino , Fibrinógeno/análisis , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores de RiesgoRESUMEN
OBJECTIVES/DESIGN: In symptomatic patients treated with ipsilateral carotid artery stenting (CAS) plus intensive lipid lowering, we assessed the changes of osteopontin (OPN), osteoprotegerin (OPG) and the Gray-Scale Median (GSM) score contralateral to symptomatic carotid stenosis. MATERIALS/METHODS: Forty-six symptomatic patients (group A) with significant carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial (NASCET): >70%) underwent ipsilateral CAS. Those patients had simultaneously contralateral low-grade carotid stenosis (NASCET: 30-69%). Group B included 67 symptomatic patients with low-grade bilateral carotid stenosis (NASCET: 30-69%), but without indications for revascularisation. All patients were treated with atorvastatin (10-80mg) to target low-density lipoprotein (LDL)<100mgdl(-1). Blood samples and plaques' GSM score contralateral to brain infarct were assayed at baseline and after 6 months. RESULTS: At baseline, there were no significant differences between groups (p>0.05). Six-month atorvastatin treatment equivalently improved lipid profile in both groups (p<0.05). The parameters hsCRP, OPN and OPG were significantly down-regulated within both groups, but to a greater extent in group A (p<0.05). Besides this, contralateral GSM score was significantly improved from baseline in both groups (p<0.01), but that increment was more pronounced in group A (vs. group B; p=0.041). These changes were inversely correlated with changes in OPN (p=0.014), OPG (p=0.011) and LDL (p=0.041). CONCLUSION: Ipsilateral CAS plus intensive lipid-lowering therapy was associated with enhanced contralateral carotid plaque stability and attenuated inflammatory burden and calcification inhibitors to a greater extent than atorvastatin therapy alone in patients with bilateral carotid stenosis.
Asunto(s)
Angioplastia/instrumentación , Calcinosis/terapia , Estenosis Carotídea/terapia , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Osteopontina/sangre , Osteoprotegerina/sangre , Pirroles/uso terapéutico , Stents , Ultrasonografía Doppler , Anciano , Atorvastatina , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Calcinosis/sangre , Calcinosis/diagnóstico por imagen , Calcinosis/tratamiento farmacológico , Estenosis Carotídea/sangre , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/tratamiento farmacológico , Terapia Combinada , Regulación hacia Abajo , Femenino , Grecia , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: Visfatin (nampt) and ghrelin are the most recently identified adipocytokines, but their role in atherosclerosis is poorly clarified. In our study we investigated their association with advanced carotid atherosclerosis and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (T2DM). METHODS: 122 patients (50 males) with T2DM, aged 55-70 were enrolled. Sixty-four age- and sex-matched healthy individuals served as controls (group A). CIMT was assayed in all participants by ultrasound. Among diabetic patients, 47 appeared with carotid plaques (group B), while 75 without plaques (group C). Anthropometric parameters, blood pressure, glycemic and lipid profile, high-sensitivity CRP (hsCRP), insulin resistance (HOMA-IR), fibrinogen, nampt and ghrelin were measured. RESULTS: Diabetic patients had a higher mean-CIMT, increased body-mass index, worse lipid profile, elevated blood pressure and higher levels of white blood cells count, nampt and hsCRP with respect to controls (p<0.01). Among diabetic patients, groups B and C were comparable in anthropometric, glycemic and lipid parameters. Serum nampt was significantly higher in group B rather than in groups A and C (p<0.05). On the other hand, ghrelin levels were considerably lower only in diabetic patients with carotid atherosclerosis compared with healthy individuals. In univariate analysis, mean-CIMT correlated with age (r=0.312; p=0.003), nampt (r=0.341; p<0.001) and ghrelin (r=-0.421; p=0.002) and the latter associations remained significant in multiple regression analysis. CONCLUSIONS: High nampt and low ghrelin serum levels are significantly associated with advanced carotid atherosclerosis in patients with T2DM. Moreover these adipocytokines are independently associated with CIMT, implicating their role as novel atherosclerotic biomarkers and providing another important link between adiposity and atherosclerosis.
Asunto(s)
Aterosclerosis/sangre , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/sangre , Diabetes Mellitus Tipo 2/sangre , Ghrelina/sangre , Nicotinamida Fosforribosiltransferasa/sangre , Anciano , Análisis de Varianza , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico por imagen , Biomarcadores/sangre , Glucemia/metabolismo , Presión Sanguínea/fisiología , Índice de Masa Corporal , Proteína C-Reactiva , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Túnica Íntima/diagnóstico por imagen , UltrasonografíaRESUMEN
OBJECTIVES/DESIGN: Carotid plaque echogenicity quantified by the Gray-Scale Median (GSM) score has been associated with plaque vulnerability. The aim of this study was to assess whether intensive lipid-lowering treatment with atorvastatin in patients with carotid artery stenosis ameliorates novel vascular calcification inhibitors, such as osteopontin (OPN) and osteoprotegerin (OPG), and improves GSM score. METHODS: Ninety-seven patients with carotid stenosis (>40%), but without indication for intervention, were treated for 6 months with atorvastatin (10mg-80mg) to target LDL<100mg/dl. Fifty-two age-and sex-matched healthy individuals served as the control group. Blood samples and GSM were obtained at the beginning and after 6 months. RESULTS: Systolic blood pressure, hsCRP, fibrinogen, OPN and OPG levels differed significantly between patients with carotid stenosis and healthy controls at baseline (p<0.05). Atorvastatin treatment improved lipid profile and significantly reduced hsCRP (p=0.002), WBC count (p=0.041), OPN (p<0.001) and OPG levels (p<0.001). GSM score increased considerably after atorvastatin therapy (from 58.33+/-24.38 to 79.33+/-22.3; p<0.001) and that effect appeared related to OPN (p=0.001), OPG (p=0.013) and LDL (p=0.01) reduction. CONCLUSIONS: In patients with carotid stenosis, intensive lipid-lowering therapy with statins attenuates serum OPN and OPG levels and enhances carotid plaque echogenicity, outlining their beneficial effects on plaque stability.
Asunto(s)
Calcinosis/tratamiento farmacológico , Estenosis Carotídea/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Osteopontina/sangre , Osteoprotegerina/sangre , Pirroles/uso terapéutico , Anciano , Atorvastatina , Biomarcadores/sangre , Presión Sanguínea , Proteína C-Reactiva/metabolismo , Calcinosis/sangre , Calcinosis/diagnóstico por imagen , Estenosis Carotídea/sangre , Estenosis Carotídea/diagnóstico por imagen , Femenino , Fibrinógeno/metabolismo , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , UltrasonografíaRESUMEN
The aim of this study was to investigate the patterns of renal function recovery during partial nephrectomy (PN) on an experimental solitary kidney rabbit model and establish the upper tolerable time limits of applied ischemia. Forty-eight New Zealand rabbits underwent an open right nephrectomy and after 30 days, the animals were clustered into five groups (A, B, C, D, E). The first four groups received an open left PN, under different types of ischemia. Groups A (n = 8) and B (n = 10) were subjected to 90 and 60 min of warm ischemia (WI), respectively, while groups C (n = 10) and D (n = 10) received 90 and 120 min of cold ischemia (CI) with ice-slush cooling. Group E (n = 10) served as sham group. Serum determinations of creatinine (SCr) and BUN were recorded preoperatively and on postoperative days (POD) 1, 3, 6 and 15. The animals were euthanized and the remaining kidneys were harvested and evaluated microscopically. The type and duration of ischemia were statistically significant parameters (P < 0.001). Groups B, C and D exhibited a similar pattern of recovery from trial initiation to the 15th POD (P = 0.788 and P = 0.068, respectively). Group A was extremely differentiated, with 100% mortality caused by uremia. The microscopic findings were consistent to the serum biochemistry. In our solitary kidney rabbit model, the upper limits of tolerable WI seem to be set on 60 min. CI can safely preserve the model's renal function--even up to 120 min.
Asunto(s)
Isquemia Fría/efectos adversos , Hipoxia/etiología , Riñón/fisiopatología , Nefrectomía/métodos , Isquemia Tibia/efectos adversos , Animales , Nitrógeno de la Urea Sanguínea , Isquemia Fría/métodos , Creatinina/sangre , Modelos Animales de Enfermedad , Riñón/patología , Riñón/cirugía , Nefrectomía/efectos adversos , Conejos , Estadísticas no ParamétricasRESUMEN
BACKGROUND AND AIM: Low-density lipoprotein (LDL) oxidation is a potential atherogenic agent, and protecting LDL from oxidation prevents atherogenesis. It has been shown that L-aspartate and L-glutamate decrease lipid peroxidation after reoxygenation by means of the initiation of the cardiopulmonary bypass circuit (CPB), when supplemented to the CPB prime, and so they may protect against atherogenesis. The aim of this study was to evaluate the effect of the dietary administration of L-aspartate and L-glutamate on fatty streak onset in cholesterol-fed rabbit. METHODS AND RESULTS: Male New Zealand white rabbits were fed for four weeks with either a high-cholesterol plus corn oil diet (control group) or the same diet supplemented with 12.5 mM L-aspartate and 12.5 mM L-glutamate in drinking water (Asp + Glu group). The mononuclear cells adhering to the endothelium and the intimal foam cells of the thoracic aorta were used to quantify the extent of atherosclerosis. Total serum cholesterol and lipid peroxidation activity, measured as thiobarbituric acid reactive substances (TBARS), were determined 0, 1 and 4 weeks after a 2-week adaptation period. There were no between-group differences in body weight or food intake during the intervention. Serum TBARS were significantly increased in both groups during the experimental period but without any statistical difference between groups. At the end of the dietary intervention, there was a ten-fold increase in total serum cholesterol concentration in both groups vs baseline. The numbers of adherent mononuclear cells and intimal foam cells were both significantly lower in the Asp + Glu group. CONCLUSIONS: Our results suggest that dietary supplementation with L-aspartate and L-glutamate seems to protect the arterial wall from atherogenesis in an experimental animal.
Asunto(s)
Arteriosclerosis/prevención & control , Ácido Aspártico/administración & dosificación , Colesterol en la Dieta/administración & dosificación , Ácido Glutámico/administración & dosificación , Lipoproteínas LDL/metabolismo , Animales , Arteriosclerosis/sangre , Ácido Aspártico/farmacología , Colesterol/sangre , Dieta Aterogénica , Modelos Animales de Enfermedad , Células Espumosas/metabolismo , Ácido Glutámico/farmacología , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/efectos de los fármacos , Masculino , Oxidación-Reducción , Conejos , Distribución Aleatoria , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
To evaluate the penetration of cefepime in the inflamed pancreas, three doses of 50 mg/kg were administered intramuscularly at 8-h intervals after induction of acute necrotizing pancreatitis using intraperitoneal injection of DL-ethionine in 35 rabbits and in 33 controls. Animals were sacrificed and concentrations of cefepime were determined by a microbiological assay. Cefepime reached its peak concentrations 60 min after the last drug dose when mean values of 46.05 microg/ml, 22.34 microg/g and 34.74 microg/ml were found in serum, pancreas and bile, respectively, in rabbits with acute necrotizing pancreatitis and 45.19 microg/ml, 12.68 microg/g and 20.77 microg/ml respectively in controls. Tissue/serum ratios of cefepime were 0.48, 0.23, 0.15 and 0.09 at 60, 90, 120 and 180 min, respectively, after the last dose of cefepime in rabbits with acute necrotizing pancreatitis and 0.28, 0.18, 0.16 and 0.16, respectively at 60, 90, 120 and 180 min in controls. It is concluded that the administration of cefepime in rabbits with acute necrotizing pancreatitis resulted in pancreatic tissue levels well above the MIC90s of the common pathogens involved in pancreatic superinfection, so that its administration might be proposed for the therapy of superinfection following acute necrotizing pancreatitis in humans.
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Cefalosporinas/farmacocinética , Pancreatitis Aguda Necrotizante/tratamiento farmacológico , Animales , Antimetabolitos/administración & dosificación , Antimetabolitos/efectos adversos , Cefepima , Cefalosporinas/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Etionina/administración & dosificación , Etionina/efectos adversos , Inyecciones Intramusculares , Masculino , Pancreatitis Aguda Necrotizante/veterinaria , Conejos , Distribución TisularRESUMEN
The objective of this study was to evaluate multiple structural characteristics, in addition to vasa vasorum density, in different aortic regions. The aorta of healthy Landrace pigs was divided into four thoracic and three abdominal segments. Transverse sections were reserved for morphometric analysis. Image analysis showed the aortic diameter, the thickness of the media, the number of elastic lamellae and the thickness of elastic membranes being reduced with increased distance from the heart (P < 0.05). The average thickness of lamellar units remained constant in the thoracic, but increased in the abdominal aorta (P < 0.05). The number of lamellar units, contained in the avascular zone of the media, and the density of vasa vasorum decreased peripherally (P < 0.05), still the average thickness of the avascular zone was invariant. In conclusion, the anatomical properties of the vessel wall alter through the aorta, being optimal for the varying stresses to which the aorta is subjected along its length. The distinct aortic parts may exhibit inherent morphological features, responsible for the various pathological processes that affect the aorta.
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Aorta/anatomía & histología , Porcinos/anatomía & histología , Animales , Aorta/patología , Aorta Abdominal/anatomía & histología , Aorta Abdominal/patología , Aorta Torácica/anatomía & histología , Aorta Torácica/patología , Femenino , Procesamiento de Imagen Asistido por Computador , Masculino , Vasa VasorumRESUMEN
OBJECTIVE: To investigate the alterations of structure and mechanical properties of the aortic wall, resulting from impairment of vasa vasorum flow. METHODS: Eight healthy Landrace pigs were subjected to interruption of vasa vasorum flow to the upper segment of their descending thoracic aorta. Under sterile conditions, the periaortic tissue was excised and the contiguous intercostal arteries were ligated. Ten sham-operated pigs were used as controls. Fifteen days postoperatively, the animals were sacrificed and their upper descending thoracic aortas were removed. Histology, and collagen and elastin content determination by image analysis technique were performed. Mechanical analysis of aortic strips was carried out with a uniaxial tension device and stress-strain curves were obtained. RESULTS: In contrast to normal aortic walls of the control group, histology of the avascular aortas revealed severe ischemic necrosis of the outer media along with abnormal straightening of the elastin and collagen fibers, without significant collagen and elastin content changes. The borderline between the outer ischemic and inner non-ischemic media was sharp, and an outset of dissection was observed at this point. Mechanical analysis showed that at the same level of strain, the ischemic aorta was significantly stiffer at both low (P=0.03) and high strains (P=0. 003). CONCLUSIONS: Impairment of blood supply to the thoracic aorta leads to abnormal morphology of elastin and collagen fibers of the outer media, resulting in increased aortic stiffness under a wide range of stresses. In the clinical setting, decreased vasa vasorum flow, reportedly occurring in arterial hypertension, may increase the stiffness of the outer media of the thoracic aorta and produce interlaminar shear stresses, contributing to the development of aortic dissection.
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Aorta Torácica/patología , Aneurisma de la Aorta Torácica/patología , Aneurisma de la Aorta Torácica/fisiopatología , Disección Aórtica/patología , Disección Aórtica/fisiopatología , Vasa Vasorum/fisiopatología , Animales , Aorta Torácica/fisiopatología , Aorta Torácica/ultraestructura , Fenómenos Biomecánicos , Técnicas de Cultivo , Modelos Animales de Enfermedad , Elasticidad , Femenino , Masculino , Necrosis , Distribución Aleatoria , Valores de Referencia , Sensibilidad y Especificidad , Estrés Mecánico , Porcinos , Vasa Vasorum/patología , Vasa Vasorum/ultraestructuraRESUMEN
Possible protective effects of two therapeutical agents (nimesulid and metoprolol) in adriamycin-induced cardiotoxicity were examined in rat cardiomyocytes at the mitochondrial DNA (mt DNA) level. Analysis by PCR revealed the presence of multiple deletions in a large region of the long arc of mt DNA which codes for several important genes involved in oxidative phosphorylation, in all animals under drug administration. No differences were found in the frequency of defective mt DNA between the animals that received only adriamycin (83%, 10/12), nimesulid and adriamycin (92%, 13/14), or metoprolol and adriamycin (80, 12/15) (p = 0.004).
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ADN Mitocondrial/efectos de los fármacos , Doxorrubicina/toxicidad , Corazón/efectos de los fármacos , Metoprolol/farmacología , Sulfonamidas/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Antioxidantes/farmacología , Secuencia de Bases , Daño del ADN , ADN Mitocondrial/genética , Masculino , Datos de Secuencia Molecular , Mutación Puntual , Reacción en Cadena de la Polimerasa , Ratas , Ratas Wistar , Mapeo Restrictivo , Eliminación de SecuenciaRESUMEN
This study is related to the serious side effects of Doxorubicin-cardiotoxicity and serum lipid caused by the drug's cumulative effect. Studies were performed on experimental animals treated with intensive administration of Doxorubicin. Seventy five wistar rats were divided in two equal groups A and B. Group A was used for doxorubicin administration and B for doxorubicin and dextrazoxane. The drugs were administered weekly for twelve weeks at doses 0.2 mg/100 g BW for doxorubicin and 1.5 mg/100 g BW for dextrazoxane. Histological examination of the cardiac muscle, large vessels, liver and other organs and biochemical examination for serum lipids and liver enzymes were performed on certain weeks. Comparison of the findings of the two groups showed a) a reduction in doxorubicin cardiotoxicity by dextrazoxane and b) the addition of dextrazoxane to doxorubicin resulted in lowering the increase of serum lipids produced by doxorubicin. c) In vitro tests by chemiluminescence showed that dextrazoxane acts as a scavenger of oxygen free radicals.
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Antibióticos Antineoplásicos/antagonistas & inhibidores , Fármacos Cardiovasculares/farmacología , Doxorrubicina/antagonistas & inhibidores , Corazón/efectos de los fármacos , Lípidos/sangre , Razoxano/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Doxorrubicina/toxicidad , Femenino , Hígado/efectos de los fármacos , Mediciones Luminiscentes , Ratas , Ratas WistarRESUMEN
Circulating testosterone concentrations and seminal vesicles weights, as well as thymus and spleen weights and histology were assessed in male Wistar rats from the infantile to post-pubertal period. The widely used anti-estrogenic agent tamoxifen was then administered in adult intact and castrated male rats and its long-term effects on thymic involution and splenic growth were examined. The results showed that: (1) age-related involution of the male thymus from the juvenile period through puberty to post-puberty depends on the rising testosterone levels and represents mainly a decrease of thymic lymphoid-cell elements; (2) tamoxifen administration reverses thymic involution in intact adult male rats and this effect is related to a dose-dependent, tamoxifen-induced castration and decrease of testosterone levels; (3) the changes of circulating testosterone levels, either resulting from maturity, or induced by tamoxifen or by castration, have a minimal effect on splenic growth and weight; and (4) in contrast to intact animals, administration of tamoxifen at pharmacological doses to adult castrated rats results in thymic regression. Underscoring the critical role of testosterone on thymic involution, these findings show that tamoxifen is able to reverse ageing changes in the thymus by suppressing testosterone production, while conversely, exerts thymolytic effects in the absence of androgens.
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Antagonistas de Estrógenos/farmacología , Bazo/efectos de los fármacos , Tamoxifeno/farmacología , Testosterona/sangre , Timo/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Vesículas Seminales/anatomía & histología , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/crecimiento & desarrollo , Bazo/anatomía & histología , Bazo/crecimiento & desarrollo , Timo/anatomía & histología , Timo/crecimiento & desarrolloRESUMEN
BACKGROUND AND OBJECTIVES: Decreased expression of the E-cadherin/alpha-catenin cell-cell adhesion complex is considered to elicit detachment of tumor cells from primary lesions and development of metastases. The immunohistochemical profile of alpha-catenin in colorectal cancer, as well as its correlation with differentiation, lymph node/liver metastasis and patient survival is presented in this study. METHODS: Alpha-Catenin expression was investigated with immunohistochemistry technique, in 85 paraffin-embedded and 21 fresh frozen specimens, including 82 colon adenocarcinomas, 10 adenomas, 10 lymph nodes, and 3 liver metastases. Preserved alpha-catenin expression was considered for those tumors that demonstrated more than 90% alpha-catenin(+) cancer cells and reduced alpha-catenin expression for those tumors with less than 90% alpha-catenin(+) cancer cells. The chi2-test was used to calculate the statistical correlation of alpha-catenin expression with grade of differentiation and metastatic potential and the log-rank test for the correlation with survival rate. RESULTS: Normal mucosa, as well as 8/10 of the colon adenomas, showed strong membranous alpha-catenin expression. Reduced alpha-catenin expression was found in 32/82 (39%) colorectal cancers examined, which was associated with de-differentiation (P < 0.01), lymph node metastasis (P < 0.025), and poor clinical outcome (P < 0.012). Alpha-Catenin expression was preserved in 3 liver metastases and their corresponding primary tumors. By contrast, 6/10 of lymphogenous metastases showed decreased alpha-catenin expression. CONCLUSIONS: Our findings demonstrate a significant down-regulation of alpha-catenin expression in colorectal cancer which is associated with poor differentiation, higher metastatic potential and unfavorable prognosis. These preliminary results suggest that alpha-catenin may be a useful marker of invasiveness, metastatic potential, and survival in colorectal cancer patients.
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Adenocarcinoma/secundario , Neoplasias Colorrectales/patología , Proteínas del Citoesqueleto/análisis , Ganglios Linfáticos/patología , Adenocarcinoma/química , Adenoma/química , Adenoma/patología , Adhesión Celular , Neoplasias Colorrectales/química , Humanos , Inmunohistoquímica , Mucosa Intestinal/patología , Neoplasias Hepáticas/secundario , Metástasis Linfática , Invasividad Neoplásica , Adhesión en Parafina , Análisis de Supervivencia , alfa CateninaRESUMEN
Adriamycin (ADR), a broad spectrum anticancer agent, has a limit to total dose used, due to cumulative cardiotoxicity. This side effect has been tested in the present study in combined administration with 5-fluorouracil a cytotoxic drug that often is applied together with ADR in cancer treatment. The study was performed on Wistar rats, and the experiment consisted of weekly administration for 12 weeks of adriamycin alone, of 5-fluorouracil alone, a combination of both, and a control group (normal saline) in separate groups comprising 42 animals each. The histology of the cardiac muscle, large vessels and liver, biochemistry of serum cholesterol, triglycerides and HDL-C and oxygen free radical production were examined. It was found that addition of 5-FU to the ADR administration reduced significantly the cardiac lesions, delayed and reduced the increase of serum lipids, produced by ADR alone and oxygen free radical production was also reduced, indicating that 5-fluorouracil is acting as a scavenger of free radicals.
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Colesterol/sangre , Doxorrubicina/toxicidad , Fluorouracilo/farmacología , Depuradores de Radicales Libres , Corazón/efectos de los fármacos , Miocardio/patología , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Peso Corporal/efectos de los fármacos , HDL-Colesterol/sangre , Doxorrubicina/antagonistas & inhibidores , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Radicales Libres/metabolismo , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Miocardio/citología , Miocardio/metabolismo , Ratas , Ratas Wistar , Valores de Referencia , Factores de Tiempo , Triglicéridos/sangre , gamma-Glutamiltransferasa/sangreRESUMEN
A wide range of pharmacological actions has been attributed to the anthracyclins. In this study we examined their effect on serum lipids in experimental animals in parallel with histological alterations. Three Wistar rat groups were injected with doxorubicin, epirubicin or normal saline once a week for 12 weeks. Total serum lipids, cholesterol, triglycerides, HDL-cholesterol, transaminases, proteins and alkaline phosphatase were assayed weekly. A proportion of the animals were sacrificed at the same time points and the cardiac muscle, large vessels, liver and abdominal muscle were stained and examined under light microscopy. Serum lipids were found to increase gradually, starting after 8 weeks of drug administration, until the end of the experiment. Tissue damage was noted in the cardiac muscle, abdominal muscle and large vessels, also following an increasing trend. Doxorubicin had a more pronounced effect than epirubicin on both serum lipid increase and tissue destruction. These alterations may contribute to anthracyclin-related cardiac damage.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Epirrubicina/efectos adversos , Lípidos/sangre , Animales , Antibióticos Antineoplásicos/administración & dosificación , Colesterol/sangre , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Lipoproteínas HDL/sangre , Masculino , Ratas , Ratas Wistar , Triglicéridos/sangreRESUMEN
We investigated heparin effects on the biological behavior of SW480 human colon adenocarcinoma cells in vivo. Tumor growth, pathological features, metastatic potential and karyotype, were studied after the twelve week low-dose heparin treatment of nude mice subcutaneously injected with SW480 cells. A non statistically significant increase in tumor growth was observed (0.05 < p < 0.1, compared to the control group). No differences in tumor histology and karyotype were detected. Two of the six heparin-treated animals exhibited an increase in tumor vascularization. Metastasis to the lungs and liver was not inhibited. These results do not support the role of heparin in the prevention of the in vivo growth and metastasis of SW 480 colon cancer cells.
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Adenocarcinoma/tratamiento farmacológico , Anticoagulantes/farmacología , Neoplasias del Colon/tratamiento farmacológico , Heparina/farmacología , Adenocarcinoma/secundario , Animales , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Neoplasias del Colon/secundario , Relación Dosis-Respuesta a Droga , Humanos , Cariotipificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Células Tumorales Cultivadas/citología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
We investigated the in vitro effects of heparin on the growth and interaction of SW480 colon adenocarcinoma cells with the extracellular matrix proteins laminin, fibronectin and collagen IV. Cell adhesion assays were performed in wells precoated with the proteins mentioned. Tumor cell migration and invasiveness were assayed in Transwell cell culture chambers. SW480 cell adhesion to the matrix proteins and migration to laminin/fibronectin precoated filters were inhibited by heparin in a dose- dependent manner, whereas cell growth and invasion through collagen IV gel were not affected. Our results suggest that heparin influences the SW480 cell-matrix interaction in vitro and inhibits crucial steps of the metastatic process in an experimental model.