RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Baizhu Tianma decoction (BBTD) is a classical representative prescription for expelling phlegm, extinguishing wind, strengthening the spleen and dissipating excessive fluid in traditional Chinese medicine (TCM). According to both TCM theory and about 300 years of clinical practice, BBTD is especially suitable for hypertensive patients of abdominal obesity and lacking physical activity. AIM OF THE STUDY: The present study tried to interpret the pharmacology of the ancient formula of BBTD. Herein, we focused on the plasma metabonomics of BBTD and evaluated the effect and targets of BBTD on endothelial protective effect. METHODS: Obesity-related hypertensive mice were induced by high-fat diet for 20 weeks. BBTD (17.8 g/kg) was administered intragastrically for 8 weeks, and telmisartan group (12.5 mg/kg) was used as positive drug. Body weight, blood pressure, triglyceride and cholesterol were recorded to evaluate the efficacy of BBTD in vivo. Lipid deposition in aortic roots was assessed by oil red O staining, while morphology of aortas was observed by HE staining. Ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed to study the plasma non-targeted metabonomics. According to the data of metabonomics, human aortic endothelial cells (HAECs) were treated by oxidized low-density lipoprotein (ox-LDL, 50 µg/mL) with/without BBTD (2, 1 or 0.5 mg/mL). Apoptosis rate (Annexin V-FITC/PI), migration (Transwell), cytoskeleton (Phalloidin) and density of VE-cadherin (Immunofluorescence staining) were used to investigate the effect of BBTD in vitro. Transcriptome sequencing was performed (2 mg/mL BBTD vs ox-LDL) to screen the possible targets of BBTD in endothelial protection against ox-LDL. RESULTS: BBTD effectively reduced the body weight and total cholesterol, and decreased 12.1 mmHg in SBP and 10.5 mmHg in DBP of obesity-related hypertensive mice (P < 0.05). BBTD attenuated lipid deposition in arterial roots and improved the morphology of aortas in vivo. Plasma metabolite profiles identified 94 differential metabolites and suggested BBTD mainly affected glycerophospholipids and fatty acyls. Bioinformatics analysis indicated sphingolipid metabolism and fluid shear stress and atherosclerosis were main pathways. Therefore, we focused on endothelial protective effect of BBTD against ox-LDL. In vitro, BBTD demonstrated endothelial protective effects, decreasing apoptosis rate, improving cell migration in dose-dependent manner and maintaining cell morphology. Transcriptome sequencing identified 251 downregulated and 603 upregulated mRNAs after 24h-BBTD treatment, which reversed 51.8% change in mRNAs (393 DE mRNAs) induced by ox-LDL. Bioinformatics analysis supported the potential of BBTD in hypertension and suggested that BBTD improved endothelial cells by targeting mainly on p53 and PPAR signaling pathways. CONCLUSIONS: BBTD attenuates obesity-related hypertension by regulating metabolism of glycerophospholipids and endothelial protection.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Hipertensión/tratamiento farmacológico , Metabolómica , Obesidad/prevención & control , Animales , Aorta/citología , Aorta/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Hipertensión/complicaciones , Hipertensión/metabolismo , Lipoproteínas LDL/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismoRESUMEN
It is important, in our opinion, to provide physicians with a brief update of scientifically-sound evidence in preventive nutrition, to be employed in their everyday practice, since the latest scientific and clinical advances in this area are generally not well known. Here, we review the most recent evidence in support of an optimal cardio-protective diet, and we identify the need to focus mainly on protective food which should be part of such diet, rather than on nutrients with negative effects to be limited (salt, saturated fats, simple sugars). We conclude that, to favor patient compliance, it is also necessary to underscore indications on the topics for which there is convincing and coherent literature, leaving other less-explored aspects to individual preferences.
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Enfermedades Cardiovasculares/dietoterapia , Dieta/métodos , Cooperación del Paciente/psicología , Consumo de Bebidas Alcohólicas/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Dieta/normas , Dieta Hiposódica/efectos adversos , Dieta Hiposódica/estadística & datos numéricos , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/efectos adversos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Fibras de la Dieta/administración & dosificación , Fibras de la Dieta/efectos adversos , Fibras de la Dieta/estadística & datos numéricos , Suplementos Dietéticos/efectos adversos , Suplementos Dietéticos/estadística & datos numéricos , Medicina Basada en la Evidencia/educación , Medicina Basada en la Evidencia/métodos , Femenino , Humanos , Lipoproteínas LDL/administración & dosificación , Lipoproteínas LDL/efectos adversos , Masculino , Médicos , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Conducta de Reducción del RiesgoRESUMEN
Eucommia ulmoides leaves (EULs), referred to as Du-zhong, are utilized to lower blood pressure and improve liver and kidney tone, and also have been applied to cardiovascular disease in Korea, China, and Japan. Endothelial dysfunction, which is caused by endothelial nitric oxide synthase (eNOS) uncoupling, is an initial step in atherosclerosis. In this study, we investigated the protective effects of EUL aqueous extract against ox-LDL-induced eNOS uncoupling and its possible mechanisms in human umbilical vein endothelial cells (HUVECs). A EUL component, aucubin, was also applied to ox-LDL-exposed HUVECs. Whereas ox-LDL significantly decreased nitric oxide (NO) levels in HUVECs, EUL extract and aucubin led to significant recovery of NO levels. When treated with ox-LDL in the presence of EUL extracts or aucubin, O2- production was markedly reduced in HUVECs compared to treatment with ox-LDL alone. EUL extract and aucubin also led to recovery of phospho-eNOS Thr495 expression, a critical signaling component in eNOS uncoupling, suggesting that EUL has regulatory effects against eNOS uncoupling and might play preventive/regulatory roles against vascular endothelial dysfunction.
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Endotelio Vascular/efectos de los fármacos , Eucommiaceae/química , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Endotelio Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Glucósidos Iridoides/aislamiento & purificación , Glucósidos Iridoides/farmacología , Lipoproteínas LDL/administración & dosificación , Óxido Nítrico Sintasa de Tipo III/metabolismo , Hojas de la Planta , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: Dietary intake of the natural omega-3 fatty acid docosahexaenoic acid (DHA) has been implicated in protecting patients with viral hepatitis B or C from developing hepatocellular carcinoma (HCC). Little is known about the effects of DHA on established solid tumors. Here we describe a low-density lipoprotein-based nanoparticle that acts as a transporter for unesterified DHA (LDL-DHA) and demonstrates selective cytotoxicity toward HCC cells. We investigated the ability of LDL-DHA to reduce growth of orthotopic hepatomas in rats. METHODS: AxC-Irish (ACI) rats were given intrahepatic injections of rat hepatoma cells (H4IIE); 24 tumor-bearing rats (mean tumor diameter, â¼1 cm) were subject to a single hepatic artery injection of LDL nanoparticles (2 mg/kg) loaded with DHA (LDL-DHA), triolein (LDL-TO), or sham surgery controls. Tumor growth was measured by magnetic resonance imaging and other methods; tumor, liver, and serum samples were collected and assessed by histochemical, immunofluorescence, biochemical, and immunoblot analyses. RESULTS: Three days after administration of LDL-TO or sham surgery, the control rats had large, highly vascularized tumors that contained proliferating cells. However, rats given LDL-DHA had smaller, pale tumors that were devoid of vascular supply and >80% of the tumor tissue was necrotic. Four to 6 days after injection of LDL-DHA, the tumors were 3-fold smaller than those of control rats. The liver tissue that surrounded the tumors showed no histologic or biochemical evidence of injury. Injection of LDL-DHA into the hepatic artery of rats selectively deregulated redox reactions in tumor tissues by increasing levels of reactive oxygen species and lipid peroxidation, depleting and oxidizing glutathione and nicotinamide adenine dinucleotide phosphate, and significantly down-regulating the antioxidant enzyme glutathione peroxidase-4. Remarkably, the redox balance in the surrounding liver was not disrupted. CONCLUSION: LDL-DHA nanoparticle selectively kills hepatoma cells and reduces growth of orthotopic liver tumors in rats. It induces tumor-specific necrosis by selectively disrupting redox balance within the cancer cell.
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Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Ácidos Docosahexaenoicos/administración & dosificación , Portadores de Fármacos , Lipoproteínas LDL/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas , Animales , Antineoplásicos/metabolismo , Antioxidantes/metabolismo , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ácidos Docosahexaenoicos/metabolismo , Relación Dosis-Respuesta a Droga , Arteria Hepática , Infusiones Intraarteriales , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Necrosis , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , Carga Tumoral/efectos de los fármacosRESUMEN
The early stages of the atherosclerotic process are initiated by accumulation of oxidized low-density lipoprotein (oxLDL) and damage to the structure or function of the endothelium. Antioxidant supplementation may be a plausible strategy to prevent atherosclerotic disease by quenching excessive reactive oxidative species. In the present study, we demonstrated that idebenone at suitable concentrations significantly prevented oxLDL-induced endothelial dysfunction. The underlying mechanisms of idebenone included inhibition of oxidative damage, suppression of the down-regulation of Bcl-2 and up-regulation of Bax and cleaved caspase-3 in human umbilical vein endothelial cells (HUVECs) exposed to oxLDL. Moreover, idebenone pretreatment inhibited oxLDL-mediated HUVECs damage by attenuating lipid peroxidation and promoting SOD activity. Finally, pro-incubation with idebenone inhibited mitochondrial dysfunction induced by oxLDL through the mitochondrial-dependent apoptotic pathway and GSK3ß/ß-catenin signalling pathways. In summary, idebenone is a promising agent in the treatment or prevention of atherosclerosis via inhibiting oxidative stress and improving mitochondrial function.
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Células Endoteliales/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Lipoproteínas LDL/administración & dosificación , Mitocondrias/metabolismo , Ubiquinona/análogos & derivados , beta Catenina/metabolismo , Antioxidantes , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Femenino , Glucógeno Sintasa Quinasa 3 beta , Humanos , Mitocondrias/ultraestructura , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Resultado del Tratamiento , Ubiquinona/administración & dosificaciónRESUMEN
AIM: The natural omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), has recently been credited for possessing anticancer properties. Herein, we investigate the cytotoxic actions of DHA-loaded low-density lipoprotein (LDL) nanoparticles in normal and liver cancer cells. MATERIALS & METHODS: LDL-DHA nanoparticles were prepared and subjected to extensive biophysical characterization. The therapeutic utility of LDL-DHA nanoparticles was evaluated in normal and malignant murine hepatocyte cell lines, TIB-73 and TIB-75, respectively. RESULTS & DISCUSSION: The engineered LDL-DHA nanoparticles possessed enhanced physical and oxidative stabilities over native LDL and free DHA. Dose-response studies showed that therapeutic doses of LDL-DHA nanoparticles that completely killed TIB-75 were innocuous to TIB-73. The selective induction of lipid peroxidation and reactive oxygen species in the cancer cells was shown to play a central role in LDL-DHA nanoparticle-mediated cytotoxicity. CONCLUSION: In summary, these findings indicate that LDL-DHA nanoparticles show great promise as a selective anticancer agent against hepatocellular carcinoma.
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Muerte Celular/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Lipoproteínas LDL/administración & dosificación , Neoplasias Hepáticas Experimentales/patología , Animales , Línea Celular Tumoral , Técnicas de Cocultivo , RatonesRESUMEN
OBJECTIVE: Recent advances have established a fundamental role for inflammation in mediating all stages of atherosclerosis, from initiation through progression. Quercetin may be a powerful bioactive constituent of the human diet, as a free radical scavenging agent and through interactions with various endogenous proteins. The present study focused on the effect of quercetin on inflammation induced by a hypercholesterolemic diet (HCD) in rabbits. METHODS: The animals were subjected to two different experiments, atherosclerotic progression and regression. In the atherosclerotic progression study, quercetin (25 mg/kg of body weight) was administered with the HCD for 90 d. In the atherosclerotic regression study, the animals were fed with the HCD for 90 d and then supplemented with quercetin (25 mg/kg of body weight) for another 90 d. The inflammatory enzyme activities were examined and a histopathologic examination of the aorta was performed. RESULTS: In the atherosclerotic progression study, quercetin coadministered with the HCD significantly decreased the activities of inflammatory enzymes such as cyclooxygenase, lipoxygenases (LOX) such as 5-LOX and 12-LOX in monocytes, nitric oxide synthase activity in the plasma, myeloperoxidase activity in the aorta, and the level of C-reactive protein in serum. In the regression study, quercetin administration significantly decreased the increased activities of inflammatory mediators such as cyclooxygenase, 5-LOX, 12-LOX, myeloperoxidase, and nitric oxide synthase and the serum level of C-reactive protein in HCD-fed rabbits compared with regression control rabbits. This effect was confirmed by histopathologic examination of the aorta. CONCLUSION: This study demonstrates that quercetin modulates the deleterious inflammatory effects induced by an HCD in vivo in rabbits, suggesting its beneficial effect in decreasing inflammation in atherosclerotic progression and regression.
Asunto(s)
Aterosclerosis/dietoterapia , Colesterol en la Dieta/efectos adversos , Suplementos Dietéticos , Quercetina/administración & dosificación , Animales , Aorta/patología , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Proteína C-Reactiva/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Depuradores de Radicales Libres/administración & dosificación , Humanos , Inflamación/dietoterapia , Mediadores de Inflamación/metabolismo , Lípidos/sangre , Lipoproteínas LDL/administración & dosificación , Lipooxigenasas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Peroxidasa/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , ConejosRESUMEN
Two flavonoids, gnaphaliin and tiliroside, isolated from Helichrysum italicum, were studied in vitro for their capacity to inhibit Cu(2+)-induced human low density lipoprotein (LDL) and diluted plasma oxidation. LDL oxidation was monitored by conjugated diene, thiobarbituric acid-reactive substances (TBARS) formation and electrophoretic mobility on agarose gel. Gnaphaliin and tiliroside increased the lag-phase for diene conjugate production in a dose-dependent manner. The reduction of TBARS production confirmed the antioxidant activity of gnaphaliin and tiliroside with 50% inhibitory concentration (IC(50)) values of 8.0+/-3.9 microM and 7.0+/-2.6 microM respectively. Furthermore, the flavonoids negated the Cu(2+)-induced increase in electrophoretic mobility of LDL. Antioxidant activity of gnaphaliin and tiliroside was significantly different when diluted plasma was oxidised by adding 1 mM CuSO(4). Although both flavonoids again reduced the TBARS production, tiliroside showed higher activity than gnaphaliin (IC(50)=10.6+/-2.5 microM vs. IC(50)>50 microM). In conclusion, tiliroside and gnaphaliin are antioxidants against in vitro Cu(2+)-induced LDL oxidation in the same order of magnitude compared to that of the reference drug, probucol.
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Benzopiranos/farmacología , LDL-Colesterol/efectos de los fármacos , Flavonas/farmacología , Helichrysum , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/farmacología , Fitoterapia , Benzopiranos/administración & dosificación , Benzopiranos/uso terapéutico , Sulfato de Cobre/química , Flavonas/administración & dosificación , Flavonas/uso terapéutico , Flavonoides , Humanos , Concentración 50 Inhibidora , Lipoproteínas LDL/administración & dosificación , Lipoproteínas LDL/uso terapéutico , Componentes Aéreos de las Plantas , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Sustancias Reactivas al Ácido Tiobarbitúrico/químicaRESUMEN
Danshen (Salvia miltiorrhiza) and Gegen (Radix puerariae) are two herbs used in traditional Chinese medicine, most commonly for their putative cardioprotective and anti-atherosclerotic effects. In this study, we investigated the effect of a preparation of these herbs on two key processes in the early stages of atherosclerosis; macrophage lipid loading and monocyte adhesion to endothelial cells. Human monocyte derived macrophages (HMDMs) were treated with 0.1-1.0 mg/ml of the herbal mixture in aqueous buffers and loaded with acetylated LDL (AcLDL) (50 microg/ml) for 72 h, and analyzed for cholesterol (C) and cholesteryl esters (CE), via HPLC. Human endothelial cell monolayers were also treated with 0.1-1.0 mg/ml of the herbal mixture and monocyte adhesion measured. Cell adhesion molecules E-selectin, ICAM-1 and VCAM-1 were assessed via ELISA. Compared to control conditions, the herbal mixture induced a significant dose-related decrease in the total cholesterol (free and esterified) in the HMDMs (p<0.001 by ANOVA). By contrast, the herbs also induced an increase in ICAM-1 expression (p<0.001) and monocyte adhesion at higher concentrations (p<0.05). In conclusion, treatment of cells with this preparation of Danshen and Gegen, a commonly used Chinese health supplement, results in a dose-related suppression of AcLDL uptake by human macrophages, and an increase in the level of ICAM-1 expression and adhesion of monocytes to endothelial cells. These herbs therefore show the ability to modulate key early events in atherosclerosis.
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Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/efectos de los fármacos , Macrófagos/efectos de los fármacos , Salvia miltiorrhiza , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colesterol/biosíntesis , Relación Dosis-Respuesta a Droga , Selectina E/biosíntesis , Células Endoteliales/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/biosíntesis , Interleucina-1/biosíntesis , Lipoproteínas LDL/administración & dosificación , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Preparaciones de Plantas/farmacología , Factores de Tiempo , Molécula 1 de Adhesión Celular Vascular/biosíntesisRESUMEN
PURPOSE: Omega-3 (n-3) fatty acids (FA) have been proposed to confer tumor-inhibitory properties. In vivo, dietary FA are delivered to tumor cells by two main routes: low-density lipoproteins (LDL) and albumin complexes. High FA concentration in LDL and up-regulation of LDL receptors in tumor cells suggest that the LDL receptor pathway may be the major route for FA delivery. We compared effects of n-3FA delivered to human cancer cells by LDL and albumin. EXPERIMENTAL DESIGN: LDL was isolated from plasma of African Green monkeys fed diets enriched in fish oil (n-3 FA) or linoleic acid (n-6FA) and used to deliver FA to MCF-7 and PC3 cancer cells. Cell proliferation, apoptosis, and changes in global gene expression were monitored. RESULTS: Both LDL and albumin were effective in delivering FA to tumor cells and modifying the composition of cell phospholipids. The molar ratio of 20:4 (n-6) to 20:5 (n-3) in phosphatidylcholine and phosphatidylethanolamine was profoundly decreased. Although cell phospholipids were similarly modified by LDL and albumin-delivered FA, effects on cell proliferation and on transcription were markedly different. LDL-delivered n-3 FA were more effective at inhibiting cell proliferation and inducing apoptosis. Expression microarray profiling showed that a significantly higher number of genes were regulated by LDL-delivered than albumin-delivered n-3 FA with little overlap between the two sets of genes. CONCLUSIONS: These results show the importance of the LDL receptor pathway in activating molecular mechanisms responsible for the tumor inhibitory properties of n-3FA.
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Albúminas/administración & dosificación , Neoplasias de la Mama/patología , Sistemas de Liberación de Medicamentos , Ácidos Grasos Omega-3/administración & dosificación , Lipoproteínas LDL/administración & dosificación , Neoplasias de la Próstata/patología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Colesterol/metabolismo , Femenino , Aceites de Pescado/administración & dosificación , Perfilación de la Expresión Génica , Humanos , Ácido Linoleico/administración & dosificación , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Neoplasias de la Próstata/metabolismo , Triglicéridos/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: We used a novel lipopolymeric gene delivery system, TeplexDNA, to transfect myocardium with plasmid vascular endothelial growth factor-165 (pVEGF) and evaluated the ability of pVEGF to preserve left ventricular function and structure after coronary ligation in a rabbit model. METHODS: New Zealand white rabbits underwent circumflex coronary ligation after direct intramyocardial injection of either Terplex alone or Terplex + 50 microg pVEGF-165. Serial echocardiography and histologic studies were performed (n = 12/group). Mortality did not differ between groups. The data is reported as the mean +/- standard deviation. RESULTS: Over the 21 days following coronary ligation, pVEGF-165-treated animals demonstrated significant improvement in fractional shortening (20-25%, p = 0.02), long axis two-dimensional ejection fraction (42-51%, p=0.02) and short axis m-mode ejection fraction (46-54%, p = 0.02). No significant improvements were noted in the control group. VEGF-treated animals had a 50% increase in peri-infarct vessel density and a trend towards a smaller infarct size (20% vs. 29%, p = 0.10). In animals receiving pVEGF-165, the diastolic ventricular area increased from 1.87 +/- 0.24 cm2 prior to ligation to 2.19 +/- 0.23 cm2 at 21 days following ligation, compared to an increase from 1.84 +/- 0.38 to 2.54 +/- 0.55 cm2 over the same period in control animals (p = 0.03). Similarly, the systolic ventricular area in VEGF-165 animals increased from 1.06 +/- 0.26 cm2 prior to ligation to 1.50 +/- 0.29 cm2 at 21 days following ligation, compared to an increase from 1.16 +/- 0.30 to 1.86 +/- 0.43 cm2 over the same period in the control animals (p = 0.04). CONCLUSION: TerplexDNA mediated delivery of plasmid VEGF administered at the time of coronary occlusion improves left ventricular function and reduces left ventricular dilation following myocardial infarction.
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ADN/genética , Terapia Genética/métodos , Ventrículos Cardíacos/efectos de los fármacos , Infarto del Miocardio/terapia , Factor A de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/farmacocinética , Animales , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/fisiopatología , Vasos Coronarios/lesiones , Vasos Coronarios/fisiopatología , ADN/administración & dosificación , ADN/farmacocinética , Evaluación Preclínica de Medicamentos , Ecocardiografía , Vectores Genéticos/administración & dosificación , Vectores Genéticos/farmacocinética , Ventrículos Cardíacos/anatomía & histología , Lípidos/administración & dosificación , Lípidos/química , Lípidos/farmacocinética , Lipoproteínas LDL/administración & dosificación , Lipoproteínas LDL/genética , Lipoproteínas LDL/farmacocinética , Infarto del Miocardio/mortalidad , Infarto del Miocardio/fisiopatología , Plásmidos/administración & dosificación , Plásmidos/genética , Plásmidos/farmacocinética , Polilisina/administración & dosificación , Polilisina/genética , Polilisina/farmacocinética , Polímeros/administración & dosificación , Polímeros/química , Polímeros/farmacocinética , Conejos , Estearatos/administración & dosificación , Estearatos/farmacocinética , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/farmacocinética , Factores de Crecimiento Endotelial Vascular/administración & dosificación , Función Ventricular , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
This study was designed to evaluate whether the exchange of specific saturated fatty acids [SFA; palmitic acid (16:0) for stearic acid (18:0)] would differentially affect plasma lipids and lipoproteins, when diets contained the currently recommended levels of total SFA, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA). Ten male cynomolgus monkeys were fed one of two purified diets (using a cross-over design) enriched either in 16:0 (palmitic acid diet) or 18:0 (stearic acid diet). Both diets provided 30% of energy as fat (SFA/monounsaturated fatty acid/PUFA: 1/1/1). The palmitic acid and stearic acid diets were based on palm oil or cocoa butter (59% and 50% of the total fat, respectively). By adding different amounts of sunflower, safflower and olive oils, an effective exchange of 16:0 for 18:0 of approximately 5% of energy was achieved with all other fatty acids being held constant. Monkeys were rotated through two 10-wk feeding periods, during which time plasma lipids and in vivo lipoprotein metabolism (following the simultaneous injection of (131)I-LDL and (125)I- HDL were evaluated). Plasma triacyglycerol (0.40 +/- 0.03 vs. 0.37 +/- 0.03 mmol/L), plasma total cholesterol (3.59 +/- 0.18 vs. 3.39 +/- 0.23 mmol/L), HDL cholesterol (1.60 +/- 0.16 vs 1.53 +/- 0.16 mmol/L) and non-HDL cholesterol (2.02 +/- 0.26 vs. 1.86 +/- 0.23 mmol/L) concentrations did not differ when monkeys consumed the palmitic acid and stearic acid diets, respectively. Plasma lipoprotein compositional analyses revealed a higher cholesteryl ester content in the VLDL fraction isolated after consumption of the stearic acid diet (P < 0.10), as well as a larger VLDL particle diameter (16.3 +/- 1.7 nm vs. 13.8 +/- 3.6 nm; P < 0.05). Kinetic analyses revealed no significant differences in LDL or HDL transport parameters. These data suggest that when incorporated into diets following current guidelines, containing adequate PUFA, an exchange of 16:0 for 18:0, representing approximately 11 g/(d.10.46 mJ) [ approximately 11 g/(d.2500 kcal)] does not affect the plasma lipid profile and has minor effects on lipoprotein composition. Whether a similar effect would occur in humans under comparable dietary conditions remains to be established.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Ácido Linoleico/administración & dosificación , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Ácido Palmítico/metabolismo , Ácidos Esteáricos/metabolismo , Animales , Apolipoproteínas/sangre , Estudios Cruzados , Grasas de la Dieta/metabolismo , Cinética , Lipoproteínas HDL/administración & dosificación , Lipoproteínas LDL/administración & dosificación , Macaca fascicularis , Masculino , Aceite de Palma , Ácido Palmítico/administración & dosificación , Aceites de Plantas , Ácidos Esteáricos/administración & dosificaciónRESUMEN
Some fat-soluble bioactive substances incorporated into low density lipoprotein (LDL) may be delivered into cells via LDL receptor pathway influencing cellular functions. In this study, we synthesized a number of fat-soluble isoflavone esters and investigated their incorporation into LDL as well as their delivery into U937 cells. Using an artificial transfer system (Celite dispersion), genistein and daidzein oleates and daidzein dilinoleate were efficiently incorporated into LDL with concentrations ranging between 2.7 to 16.9 isoflavone molecules/LDL particle, while much smaller amounts of unesterified isoflavones and genistein stearates were transferred into LDL. LDL containing 7-oleates or 4',7-dioleates of genistein and daidzein significantly reduced U937 cell proliferation by 36-43%. The strongest inhibitory effect was shown by daidzein 4',7-dilinoleate with 93% reduction of cell proliferation. Neither of the 4'-oleates of genistein and daidzein contained in LDLs exhibited antiproliferative effects although they were incorporated into LDL. In summary, we demonstrated that isoflavones made fat-soluble by esterification can be incorporated into LDL in vitro and delivered into cultured U937 cells via the LDL-receptor pathway, reducing the cell proliferation.
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Antineoplásicos Fitogénicos/administración & dosificación , Glycine max/química , Isoflavonas/administración & dosificación , Isoflavonas/farmacología , Lipoproteínas LDL/administración & dosificación , Liposomas/administración & dosificación , Fitoterapia , Antineoplásicos Fitogénicos/síntesis química , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Portadores de Fármacos , Ésteres/administración & dosificación , Ésteres/síntesis química , Humanos , Isoflavonas/síntesis química , Isoflavonas/farmacocinética , Lipoproteínas LDL/química , Liposomas/síntesis química , Liposomas/farmacología , Receptores de LDL/metabolismo , Células U937RESUMEN
It has been postulated that the rate of hepatic very low density lipoprotein (VLDL) apolipoprotein (apo) B secretion is dependent upon the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. To test this hypothesis in vivo, apoB kinetic studies were carried out in miniature pigs before and after 21 days treatment with high-dose (10 mg/kg/day), atorvastatin (A) or simvastatin (S) (n = 5). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/day; 0.1%). Statin treatment decreased plasma total cholesterol [31 (A) vs. 20% (S)] and low density lipoprotein (LDL) cholesterol concentrations [42 (A) vs. 24% (S)]. Significant reductions in plasma total triglyceride (46%) and VLDL triglyceride (50%) concentrations were only observed with (A). Autologous [131I]VLDL, [125I]LDL, and [3H]leucine were injected simultaneously, and apoB kinetic parameters were determined by triple-isotope multicompartmental analysis using SAAM II. Statin treatment decreased the VLDL apoB pool size [49 (A) vs. 24% (S)] and the hepatic VLDL apoB secretion rate [50 (A) vs. 33% (S)], with no change in the fractional catabolic rate (FCR). LDL apoB pool size decreased [39 (A) vs. 26% (S)], due to reductions in both the total LDL apoB production rate [30 (A) vs. 21% (S)] and LDL direct synthesis [32 (A) vs. 23% (S)]. A significant increase in the LDL apoB FCR (15%) was only seen with (A). Neither plasma VLDL nor LDL lipoprotein compositions were significantly altered. Hepatic HMG-CoA reductase was inhibited to a greater extent with (A), when compared with (S), as evidenced by 1) a greater induction in hepatic mRNA abundances for HMG-CoA reductase (105%) and the LDL receptor (40%) (both P < 0.05); and 2) a greater decrease in hepatic free (9%) and esterified cholesterol (25%) (both P < 0.05). We conclude that both (A) and (S) decrease hepatic VLDL apoB secretion, in vivo, but that the magnitude is determined by the extent of HMG-CoA reductase inhibition.
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Apolipoproteínas B/metabolismo , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Animales , Atorvastatina , Colesterol/sangre , LDL-Colesterol/sangre , Ácidos Heptanoicos/farmacología , Cinética , Lipoproteínas/sangre , Lipoproteínas IDL , Lipoproteínas LDL/administración & dosificación , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/administración & dosificación , Lipoproteínas VLDL/sangre , Hígado/enzimología , Microsomas Hepáticos/enzimología , Pirroles/farmacología , Simvastatina/farmacología , Porcinos , Porcinos Enanos , Triglicéridos/sangreRESUMEN
Diet is fundamental in the treatment of primary hyperlipoproteinaemias. The author outlines nutritional factors affecting serum lipoproteins. In the treatment of hypercholesterolaemia the most effective is the reduction of the intake of saturated fatty acids, it being twice as effective as the reduction of dietary cholesterol, which is necessary as well. The proportion of the saturated, poly- and monounsaturated fatty acids is recommended to be 10-10-10 percent of the overall calorie intake. Such a composition of diet has no disadvantageous effect on the level of HDL cholesterol. Of carbohydrates the consumption of sugar and alcohol should be limited in the presence of hypertriglyceridaemia and/or obesity. Water soluble dietary fibres may have a cholesterol-lowering effect. The reduction of overall calorie intake is indispensable in hyperlipoproteinaemias with obesity. As a result of the diet a 10-20 percent decrease in the level of cholesterol and--in some cases--the normalization of hypertriglyceridaemia can be expected.
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Hipercolesterolemia/dietoterapia , Hiperlipoproteinemias/dietoterapia , Consumo de Bebidas Alcohólicas , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Fibras de la Dieta/administración & dosificación , Ácidos Grasos Insaturados/administración & dosificación , Femenino , Humanos , Hipercolesterolemia/prevención & control , Hiperlipoproteinemias/prevención & control , Lipoproteínas LDL/administración & dosificación , Masculino , Valores de ReferenciaRESUMEN
BACKGROUND: In vitro and in vivo experiments have demonstrated the role of oxidatively modified low density lipoprotein (oxLDL) in eliciting leukocyte/endothelium interaction during early atherogenesis. METHODS AND RESULTS: In the present study we investigated the effect of dietary fish oil on oxLDL-induced leukocyte/endothelium interaction using intravital fluorescence microscopy in the dorsal skinfold chamber model in awake Syrian golden hamsters. Hamsters were fed for 4 weeks prior to the experiments with either standard laboratory chow or a diet supplemented with 5% of a fish oil concentrate (18% eicosapentaenoate, 12% docosahexaenoate). The efficacy of the fish oil diet was demonstrated by the incorporation of fish oil-derived omega-3 fatty acids into plasma, leukocyte, and erythrocyte lipids. In control hamsters (n = 7) and fish oil-fed hamsters (n = 7), leukocyte/endothelium interaction was assessed in the time course after intravenous injection of human LDL (4 mg/kg), oxidized by 7.5 microM Cu2+ (6 hours, 37 degrees C). In control hamsters, injection of oxLDL elicited the rolling and sticking of leukocytes to the endothelium of arterioles and postcapillary venules with a maximum 15 minutes after injection (arterioles: from 3 +/- 1 to 91 +/- 25 cells/mm2 at 15 minutes; venules: from 13 +/- 6 to 150 +/- 46 cells/mm2 at 15 minutes; mean +/- SD). This phenomenon was significantly reduced in fish oil-fed hamsters, where 15 minutes after injection of oxLDL leukocyte sticking reached a maximum of only 15 +/- 7 and 20 +/- 5 cells/mm2 in arterioles and postcapillary venules, respectively (p less than 0.01 versus control animals). CONCLUSIONS: The results of the present study suggest that inhibition of leukocyte/endothelium interaction may be one of the mechanisms by which dietary fish oil exerts its protective effects on experimental and clinical atherogenesis.
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Endotelio Vascular/fisiología , Aceites de Pescado/farmacología , Leucocitos/fisiología , Lipoproteínas LDL/administración & dosificación , Animales , Arteriosclerosis/prevención & control , Adhesión Celular/fisiología , Cricetinae , Ácidos Grasos Omega-3/sangre , Leucocitos/química , Lipoproteínas LDL/metabolismo , Mesocricetus , Microscopía Fluorescente , Oxidación-ReducciónRESUMEN
1. Low-density lipoproteins were isolated by ultracentrifugation from the serum of guinea pigs that were fed either on a normal diet, or on a diet supplemented with corn oil and cholesterol. 2. After labelling with tracer amounts of radioactive iodine, these lipoproteins were injected into the bloodstream of guinea pigs that were fed either on the normal or on the supplemented diet. 3. In all cases, the density of the labelled lipoproteins was increased by exposure for 24-48 h to the metabolic processes of the guinea pig. 4. The final density reached by lipoproteins isolated from fat-fed guinea pigs was less than that reached by lipoproteins from normal animals. 5. Fat-fed guinea pigs were unable to increase the density of either normal lipoproteins, or those from fat-fed guinea pits, to the same extent as animals fed on the normal diet. 6. It is concluded that the lipid-rich diet brings about a modification of lipoprotein metabolism in the guinea, pig, which plays an important part in determining the nature of the nature of the low-density lipoprotein that is present in the plasma.