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BACKGROUND: Non-resolving inflammation associates with obesity and insulin resistance, and may be dependent on the balance of inflammatory substances and specialised pro-resolving mediators of inflammation (SPM) that act to halt the inflammatory response. This controlled trial examined the effect of weight loss on neutrophil synthesis of SPM in volunteers with the metabolic syndrome (MetS). METHODS: Volunteers with MetS (nâ¯=â¯42) were matched for age and gender and randomly assigned to a 12-wk weight loss program followed by 4-wk weight stabilization or a 16-wk weight maintenance program. At baseline and 16 weeks, isolated neutrophils were stimulated with calcium ionophore and the released SPM were measured by LC-MS/MS. RESULTS: At baseline the SPM resolvin (Rv) E1, 18R-RvE3, RvD2 and Maresin-1 (MaR-1) were detected from stimulated neutrophils. The concentration of released RvE1 was at least 6-fold that of other detected SPM. Weight loss of 4.7⯱â¯0.8â¯kg, led to a 2-fold increase in RvE1, Pâ¯=â¯0.013, relative to the weight maintenance group. The increase in RvE1 after weight loss was related to, but independent of leukotriene B4. CONCLUSION: Following weight loss, human neutrophils from individuals with the metabolic syndrome are capable of releasing larger amounts of RvE1 upon stimulation.
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Ionóforos de Calcio/farmacología , Ácidos Docosahexaenoicos/análisis , Síndrome Metabólico/terapia , Neutrófilos/metabolismo , Programas de Reducción de Peso/métodos , Adulto , Anciano , Cromatografía Liquida , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/análisis , Ácidos Grasos Insaturados/análisis , Femenino , Humanos , Masculino , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND: Nitric oxide (NO) is an important vascular signaling molecule that plays a role in vascular homeostasis. A reduction in NO bioavailability is thought to contribute to endothelial dysfunction, an early risk factor for both cardiovascular disease and type 2 diabetes. Dietary nitrate, through the nitrate-nitrite-NO pathway, may provide an alternate source of NO when the endogenous eNOS system is compromised. In addition to a role in the vascular system, NO may also play a role in the metabolic syndrome including obesity and glucose tolerance. AIM: To investigate the effect of long-term dietary nitrate supplementation on development of the metabolic syndrome in mice fed a high-fat diet. METHODS: Following 1 week of acclimatisation, male (6-8 weeks) C57BL6 mice were randomly assigned to the following groups (10/group) for 12 weeks: (i) normal chow + NaCl (1 mmol/kg/day), (ii) normal chow + NaNO3 (1 mmol/kg/day), (iii) high-fat diet + NaCl (1 mmol/kg/day), and (iv) high-fat diet + NaNO3 (1 mmol/kg/day). Body weight and food consumption were monitored weekly. A subset of mice (5/group) underwent running wheel assessment. At the end of the treatment period, all mice underwent fasting glucose tolerance testing. Caecum contents, serum, and tissues (liver, skeletal muscle, white and brown adipose, and kidney) were collected, frozen, and stored at -80°C until analysis. RESULTS: Consumption of the high-fat diet resulted in significantly greater weight gain that was not affected by dietary nitrate. Mice on the high-fat diet also had impaired glucose tolerance that was not affected by dietary nitrate. There was no difference in adipose tissue expression of thermogenic proteins or energy expenditure as assessed by the running wheel activity. Mice on the high-fat diet and those receiving dietary nitrate had reduced caecum concentrations of both butyrate and propionate. CONCLUSIONS: Dietary nitrate does not prevent development of the metabolic syndrome in mice fed a high-fat diet. This may be due, in part due, to reductions in the concentration of important short-chain fatty acids.
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F2-isoprostanes (F2-IsoP) are formed in vivo via free radical peroxidation of arachidonic acid. Enhanced oxidative stress is implicated in the development of atherosclerosis in humans and F2-IsoP have been detected in atherosclerotic plaque. Colony stimulating factor-1 (CSF-1) is essential to macrophage survival, proliferation and differentiation and has been detected in human atherosclerotic plaques. Accumulation of macrophages within the vascular wall is an important component of atherosclerosis but little is known about the effect of F2-IsoP on the migration of these cells. Our aim was to examine the effect of free and lipid-bound 15-F2t-isoprostane (15-F2t-IsoP) on macrophage migration and investigate the signalling pathways involved. Mouse macrophages (cell line BAC1.2F5) were pre-incubated with 15-F2t-IsoP (free, bound to cholesterol or monoacylglycerol or within oxidized phospholipid) and cell migration was assessed using chemotaxis towards CSF-1 in Boyden chambers. Migration was also measured using the wound healing assay with primary mouse bone marrow derived macrophages. We showed that 15-F2t-IsoP dose-dependently inhibited BAC1.2F5 macrophage spreading and adhesion but stimulated their migration towards CSF-1, with maximum effect at 10⯵M. Analysis of CSF-1 stimulated signalling pathways in BAC1.2F5 macrophages showed that phosphorylation of Akt, a key mediator of cell migration, and one of its regulators, the mTORC2 component, Rictor, was significantly decreased. In contrast, phosphorylation of the adhesion kinases, FAK and Pyk2, and the adhesion scaffold protein, paxillin, was enhanced after treatment with 15-F2t-IsoP. Mouse bone marrow macrophages were transfected with FAK or Pyk2 small interfering RNA (siRNA) to examine the role of FAK and Pyk2 in 15-F2t-IsoP signalling. Pyk2 silencing inhibited 15-F2t-IsoP-induced reduction in cell area and phospho-paxillin adhesion numbers. The size distribution of adhesions in the presence of 15-F2t-IsoP was also affected by Pyk2 silencing and there was a trend for Pyk2 silencing to reduce 15-F2t-IsoP-stimulated macrophage migration. These results demonstrate that 15-F2t-IsoP affects macrophage adhesions and migration, which are integral components of macrophage involvement in atherosclerosis.
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Aterosclerosis/genética , F2-Isoprostanos/metabolismo , Factor Estimulante de Colonias de Macrófagos/genética , Placa Aterosclerótica/genética , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Adhesión Celular/genética , Diferenciación Celular/genética , Movimiento Celular/genética , Proliferación Celular/genética , F2-Isoprostanos/genética , Radicales Libres/metabolismo , Humanos , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/metabolismo , Ratones , Estrés Oxidativo/genética , Fosforilación/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Proteínas Proto-Oncogénicas c-akt/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/genéticaRESUMEN
Population studies suggest cardiovascular health benefits of consuming fruits and vegetables rich in polyphenolic compounds such as flavonoids. We reported previously that the flavonoid quercetin protects arteries from oxidant-induced endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E gene knockout mice, with induction of heme oxygenase-1 (Hmox1) playing a critical role. The present study investigated the structural requirements of flavonoids to induce Hmox1 in human aortic endothelial cells (HAEC). We identified ortho-dihydroxyl groups and an α,ß-unsaturated system attached to a catechol as the key structural requirements for Hmox1 induction. Active but not inactive flavonoids had a low oxidation potential and prevented ascorbate autoxidation, suggesting that Hmox1 inducers readily undergo oxidation and that oxidized, rather than reduced, flavonoids may be the biological inducer of Hmox1. To test this hypothesis, we synthesized stable derivatives of caffeic acid (3-(3,4-dihyroxyphenyl)-2-propenoic acid) containing either ortho-dihydroxy or ortho-dioxo groups. Compared with the dihydroxy compound, the quinone analog induced Hmox1 more potently in HAEC and also provided enhanced protection to arteries of wild type animals against oxidant-induced endothelial dysfunction. In contrast, the quinone analog failed to provide protection against oxidant-induced endothelial dysfunction in arteries of Hmox1-/- mice, establishing a key role for Hmox1 in vascular protection. These results suggest that oxidized forms of dietary polyphenols are the likely inducers of Hmox1 and may explain in part the protective cardiovascular effects of diets rich in these compounds.
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Endotelio Vascular/enzimología , Flavonoides/farmacología , Hemo-Oxigenasa 1/efectos de los fármacos , Animales , Aorta , Línea Celular , Endotelio Vascular/efectos de los fármacos , Flavonoides/química , Humanos , Ratones , Ratones Noqueados , Oxidación-Reducción , Quercetina/química , Quercetina/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Nitric oxide (NO) is an important vascular signalling molecule. NO is synthesised endogenously by endothelial nitric oxide synthase (eNOS). An alternate pathway is exogenous dietary nitrate, which can be converted to nitrite and then stored or further converted to NO and used immediately. Atherosclerosis is associated with endothelial dysfunction and subsequent lesion formation. This is thought to arise due to a reduction in the bioavailability and/or bioactivity of endogenous NO. AIM: To determine if dietary nitrate can protect against endothelial dysfunction and lesion formation in the ApoE-/- mouse fed a high fat diet (HFD). METHODS AND RESULTS: ApoE-/- fed a HFD were randomized to receive (i) high nitrate (10mmol/kg/day, n=12), (ii) moderate nitrate (1mmol/kg/day, n=8), (iii) low nitrate (0.1mmol/kg/day, n=8), or (iv) sodium chloride supplemented drinking water (control, n=10) for 10 weeks. A group of C57BL6 mice (n=6) received regular water and served as a healthy reference group. At 10 weeks, ACh-induced vessel relaxation was significantly impaired in ApoE-/- mice versus C57BL6. Mice supplemented with low or moderate nitrate showed significant improvements in ACh-induced vessel relaxation compared to ApoE-/- mice given the high nitrate or sodium chloride. Plaque collagen expression was increased and lipid deposition reduced following supplementation with low or moderate nitrate compared to sodium chloride, reflecting increased plaque stability with nitrate supplementation. Plasma nitrate and nitrite levels were significantly increased in all three groups fed the nitrate-supplemented water. CONCLUSION: Low and moderate dose nitrate significantly improved endothelial function and atherosclerotic plaque composition in ApoE-/- mice fed a HFD.
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Apolipoproteínas E/genética , Aterosclerosis/dietoterapia , Suplementos Dietéticos , Nitratos/administración & dosificación , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico/metabolismo , Placa Aterosclerótica/dietoterapia , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Apolipoproteínas E/deficiencia , Aterosclerosis/etiología , Aterosclerosis/genética , Aterosclerosis/patología , Colágeno/genética , Colágeno/metabolismo , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nitratos/sangre , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Técnicas de Cultivo de Tejidos , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Circulating neopterin and the ratio of kynurenine to tryptophan (KYN/TRP) concentrations are biomarkers of immune activation that have been linked to cardiovascular and total mortality. Several in vitro studies indicated that tea flavonoids and other antioxidants can modulate tryptophan breakdown rates and neopterin production in immune cells. We aimed to assess the effects of regular black tea consumption on tryptophan and neopterin metabolisms in vivo. METHODS: Participants were healthy individuals, with no major illnesses and having normal to mildly elevated systolic blood pressure. They were randomly assigned to consume 3 cups/day of either powdered black tea solids (tea; n = 45) or a flavonoid-free caffeine-matched beverage (control; n = 49). Serum concentrations of tryptophan, kynurenine and neopterin were assessed at baseline and again at 3 and 6 months after daily ingestion of the respective beverage. RESULTS: Regular consumption of tea over 6 months, compared to control, did not significantly alter neopterin (p = 0.13) or tryptophan (p = 0.85) concentrations, but did result in significantly higher kynurenine (p = 0.016) and KYN/TRP (p = 0.012). Relative to the control group, in the tea group kynurenine and KYN/TRP increased during the treatment period by 0.28 µmol/L (95% CI: - 0.04, 0.60) and 3.2 µmol/mmol (95% CI: - 1.6, 8.0), respectively at 3 months, and by 0.48 µmol/L (95% CI: 0.16, 0.80) and 7.5 µmol/mmol (95% CI: 2.5, 12.5), respectively at 6 months. CONCLUSIONS: Increased circulation of kynurenine and KYN/TRP following regular black tea consumption may indicate enhanced tryptophan breakdown, possibly due to immune activation-induced tryptophan degrading enzyme indoleamine 2,3-dioxygenase. GENERAL SIGNIFICANCE: The influence of black tea consumption on biomarkers of immune system activation could relate to its general health benefits. Data suggests that the net effect strongly depends on the individual immune state, being stimulatory in healthy individuals, while acting more immune dampening in situations with an inflammatory background.
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We have investigated the effects of the major polyphenol in coffee, chlorogenic acid (CGA), on obesity, glucose intolerance, insulin resistance, systemic oxidative stress and endothelial dysfunction in a mouse model of the metabolic syndrome. Thirty C57BL6 mice were randomly divided into (n=10/group) (i) normal diet (ND), (ii) high fat diet (HFD), or (iii) high fat diet supplemented with 0.5% w/w green coffee bean extract (GCE) rich in chlorogenic acid (HFD+GCE). The high fat diet consisted of 28% fat and all animals were maintained on their diets for 12 weeks. The mice fed a HFD and HFD+GCE displayed symptoms of the metabolic syndrome compared to their normal fed counterparts, although no endothelial dysfunction was detected in the abdominal aortas after 12 weeks. GCE did not attenuate HFD-induced obesity, glucose intolerance, insulin resistance or systemic oxidative stress. Furthermore, GCE did not protect against ex vivo oxidant (hypochlorous acid)-induced endothelial dysfunction.
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Café/química , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/patología , Polifenoles/farmacología , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/fisiopatología , Peso Corporal/efectos de los fármacos , Endotelio Vascular/metabolismo , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Polifenoles/aislamiento & purificación , Polifenoles/uso terapéutico , Vasodilatación/efectos de los fármacosRESUMEN
F2-isoprostanes (F2-IsoP's) are reliable measures of in vivo lipid oxidation, but care is required to prevent artifactual elevation. We examined the effects of blood collection and storage on plasma F2-IsoP's. Blood was collected into EDTA/butylated hydroxytoluene/reduced glutathione (EDTA/BHT/GSH) or EDTA, at 4 °C or room temperature. Plasma was stored at -20 or -80 °C for 1 or 6 months before F2-IsoP's were assayed by GC-MS. The temperature of blood collection did not affect F2-IsoP's. However, storage at -20 °C or collection into EDTA resulted in significant increases in F2-IsoP's. Blood collection into EDTA/BHT/GSH and storage at -80 °C minimizes artifactual elevation of plasma F2-IsoP's.
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F2-Isoprostanos/sangre , Conservación de la Sangre , Cromatografía de Gases , Frío , F2-Isoprostanos/metabolismo , Humanos , Peroxidación de Lípido , Plasma/metabolismoRESUMEN
AIM: Oxidative stress may play an important role in the pathogenesis of hypertension. The aim of our study is to examine whether increased expression of the predominant endothelial l-arginine transporter, cationic amino acid transporter-1 (CAT1), can prevent oxidative stress-induced hypertension. METHODS: Wild-type mice (WT; n = 9) and endothelial CAT1 overexpressing (CAT+) mice (n = 6) had telemetry probes implanted for the measurement of mean arterial pressure (MAP), heart rate (HR) and locomotor activity. Minipumps were implanted for infusion of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg kg(-1) day(-1) ; 14 days) or its saline vehicle. Baseline levels of MAP, HR and locomotor activity were determined before and during chronic DETCA administration. Mice were then killed, and their plasma and kidneys collected for analysis of F2 -isoprostane levels. RESULTS: Basal MAP was less in CAT+ (92 ± 2 mmHg; n = 6) than in WT (98 ± 2 mmHg; n = 9; P < 0.001). During DETCA infusion, MAP was increased in WT (by 4.2 ± 0.5%; P < 0.001) but not in CAT+, when compared to appropriate controls (PDETCA*genotype = 0.006). DETCA infusion increased total plasma F2 -isoprostane levels (by 67 ± 11%; P = 0.05) in WT but not in CAT+. Total renal F2 -isoprostane levels were greater during DETCA infusion in WT (by 72%; P < 0.001), but not in CAT+, compared to appropriate controls. CONCLUSION: Augmented endothelial l-arginine transport attenuated the prohypertensive effects of systemic and renal oxidative stress, suggesting that manipulation of endothelial CAT1 may provide a new therapeutic approach for the treatment of cardiovascular disease associated with oxidative stress.
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Presión Sanguínea/fisiología , Canales de Calcio/metabolismo , Endotelio Vascular/metabolismo , Regulación de la Expresión Génica/fisiología , Superóxido Dismutasa/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Canales de Calcio/genética , Estradiol/análogos & derivados , Estradiol/farmacología , Isoprostanos , Riñón/metabolismo , Ratones , Estrés Oxidativo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Canales Catiónicos TRPV/genéticaRESUMEN
The cytochrome P-450 arachidonic acid metabolite 20-HETE is central to the regulation of vascular tone, renal function, and blood pressure and is synthesized in the rat kidney in response to angiotensin II (ANG II) and endothelin-1 (ET-1). There are very few studies examining the cellular synthesis of 20-HETE in humans. We aimed to measure human neutrophil and platelet 20-HETE levels under basal conditions and after ANG II, ET-1, and calcium ionophore (CaI). 20-HETE was measured in human platelets and neutrophils after saline (control), CaI (2.5 µg/ml), and ANG II or ET-1 (10 nmol/l-1 µmol/l) incubations. The effect of cells, which were preincubated with the ω-hydroxylase inhibitor N-hydroxy-N'-(4-butyl-2-methylphenyl) (HET0016, 10 nM), ANG II types 1 or 2 (AT(1) or AT(2)) receptor inhibition with irbesartan (1 µmol/l) or PD-123319 (1 µmol/l), or endothelin receptor subtypes A or B (ET(A) or ET(B)) receptor inhibition with BQ-123 or BQ-778 (100 nmol/l), was studied. Neutrophil and platelet content and release of 20-HETE was significantly increased by CaI and blocked by the ω-hydroxylase inhibitor HET0016. ANG II and ET-1 significantly increased neutrophil and platelet content and release of 20-HETE. ANG II increased 20-HETE via the AT(2) receptor. ET-1 increased 20-HETE through the ET(B) receptor in platelets and both the ET(A) and ET(B) receptors in neutrophils. These studies show that human platelets and neutrophils synthesize 20-HETE in response to ANG II and ET-1. 20-HETE synthesis in both cell types was predominantly mediated via the AT(2) and ET(B) receptors. Stimulation via these receptor pathways has generally been thought to be cardioprotective and requires further studies in clinical situations associated with low-grade inflammation or where ANG II and ET-1 are elevated to clarify the role of 20-HETE.
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Angiotensina II/farmacología , Plaquetas/efectos de los fármacos , Endotelina-1/farmacología , Ácidos Hidroxieicosatetraenoicos/biosíntesis , Neutrófilos/efectos de los fármacos , Adulto , Anciano , Amidinas/farmacología , Antagonistas de Receptores de Angiotensina/farmacología , Compuestos de Bifenilo/farmacología , Plaquetas/metabolismo , Canales de Calcio/efectos de los fármacos , Células Cultivadas , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450 , Humanos , Imidazoles/farmacología , Ionóforos/farmacología , Irbesartán , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Oligopéptidos/farmacología , Péptidos Cíclicos/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Tetrazoles/farmacología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Pre-clinical studies suggest that sesame and its lignans induce beneficial changes in risk factors related to cardiovascular disease and increase the bioavailability of mammalian lignans. However, only very few intervention trials have investigated the potential bioactivities of sesame in humans. We aimed to investigate the effects of sesame supplementation in humans on blood lipids, blood pressure, systemic oxidative stress, inflammatory biomarkers and mammalian lignan metabolism. METHODS AND RESULTS: We conducted a randomized, placebo-controlled cross-over intervention trial at a university research centre. Overweight or obese men and women (n=33) consumed 25g/d of sesame ( approximately 50mg/d of sesame lignan) and an iso-caloric placebo matched for macronutrient composition for 5 wks each. Each intervention period was preceded by a 4-wk washout period. Blood lipid profiles, day time ambulatory blood pressure, oxidative stress and inflammatory biomarkers and urinary mammalian lignans were measured before and after each intervention. Results are presented as the effect of sesame supplementation relative to placebo. Urinary excretion of the mammalian lignans, enterolactone and enterodiol, increased by approximately 8-fold (P<0.001). Blood lipids and blood pressure were not altered. In addition, markers of systemic inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) and lipid peroxidation (F(2)-isoprostanes) were not affected. CONCLUSION: Supplementation with 25g/d of sesame can significantly increase the exposure to mammalian lignans. However, this did not cause any improvement in markers of cardiovascular disease risk in overweight or obese men and women.
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Enfermedades Cardiovasculares/prevención & control , Suplementos Dietéticos , Lignanos/administración & dosificación , Obesidad/tratamiento farmacológico , Fitoterapia , Sesamum , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Estudios Cruzados , Femenino , Humanos , Mediadores de Inflamación/sangre , Lignanos/orina , Peroxidación de Lípido/efectos de los fármacos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicaciones , Obesidad/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Factores de Riesgo , Semillas , Factores de TiempoRESUMEN
AIMS: To determine in Type 1 diabetes patients if levels of pigment epithelium-derived factor (PEDF), an anti-angiogenic, anti-inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress. METHODS: Serum PEDF levels were measured by ELISA in a cross-sectional study of 123 Type 1 diabetic patients (71 without and 52 with microvascular complications) and 31 non-diabetic control subjects. PEDF associations with complication status, pulse-wave analysis and biochemical results were explored. RESULTS: PEDF levels [geometric mean (95% CI)] were increased in patients with complications 8.2 (7.0-9.6) microg/ml, vs. complication-free patients [5.3 (4.7-6.0) microg/ml, P < 0.001] and control subjects [5.3 (4.6-6.1) microg/ml, P < 0.001; anova between three groups, P < 0.001], but did not differ significantly between control subjects and complication-free patients (P > 0.05). In diabetes, PEDF levels correlated (all P < 0.001) with systolic blood pressure (r = 0.317), pulse pressure (r = 0.337), small artery elasticity (r = -0.269), glycated haemoglobin (r = 0.245), body mass index (r = 0.362), renal dysfunction [including serum creatinine (r = 0.491), cystatin C (r = 0.500)], triglycerides (r = 0.367), and inflammation [including log(e)C-reactive protein (CRP; r = 0.329), and soluble vascular cell adhesion molecule-1 (r = 0.363)]. Age, blood urea nitrogen, systolic blood pressure, pulse pressure and log(e)CRP correlated with PEDF levels in control subjects (all P < 0.04). PEDF levels were not significantly correlated with measures of oxidative stress: isoprostanes, oxidized low-density lipoprotein or paraoxonase-1 activity. On stepwise linear regression analysis (all subjects), independent determinants of PEDF levels were renal function, triglycerides, inflammation, small artery elasticity and age (r(2) = 0.427). CONCLUSIONS: In Type 1 diabetes, serum PEDF levels are associated with microvascular complications, poor vascular health, hyperglycaemia, adiposity and inflammation.
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Diabetes Mellitus Tipo 1/sangre , Nefropatías Diabéticas/sangre , Retinopatía Diabética/sangre , Proteínas del Ojo/sangre , Factores de Crecimiento Nervioso/sangre , Inhibidores de Proteasas/sangre , Serpinas/sangre , Adulto , Biomarcadores/sangre , Índice de Masa Corporal , Proteína C-Reactiva/análisis , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Femenino , Hemoglobina Glucada , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo/fisiologíaRESUMEN
CONTEXT: Neutrophil (polymorphonuclear neutrophil) production of leukotriene B4 (LTB4) may be associated with alterations in immune and inflammatory function that characterize the metabolic syndrome (MetS). OBJECTIVE: We investigated whether polymorphonuclear neutrophil production of LTB(4) and its metabolites 20-hydroxy-LTB4 (20-OH-LTB4) and 20-carboxyl-LTB4 were altered in subjects with features of the MetS before and after weight reduction. DESIGN, SETTING, PATIENTS, AND INTERVENTION: In a case-controlled comparison, men and postmenopausal women with features of the MetS were matched with controls. Subjects with MetS were then matched and randomly assigned to either a 12-wk weight reduction study followed by 4-wk weight stabilization or 16-wk weight maintenance. MAIN OUTCOME MEASURES: Measurements were performed at baseline and at the end of the 16-wk period. Stimulated neutrophil LTB4 and its metabolites were measured by HPLC. RESULTS: In the case-controlled study, body mass index, waist circumference, blood pressure, fasting triglycerides, and glucose were all significantly increased in subjects with features of the MetS (P < 0.05). Production of LTB4 and 20-OH-LTB4 was significantly lower compared with controls (P < 0.005). The weight loss intervention resulted in a 4.6-kg reduction in body weight and 6.6-cm decrease in waist circumference relative to controls and a significant increase in LTB4 and 20-OH-LTB4. CONCLUSIONS: Subjects with features of the MetS have lower stimulated LTB4, which is not due to increased metabolism of LTB4. Weight reduction restored the production of neutrophil LTB4, suggesting that in addition to modifying cardiovascular risk, weight loss may also help with the management of perturbed inflammatory responses in overweight subjects.
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Leucotrieno B4/biosíntesis , Síndrome Metabólico/metabolismo , Pérdida de Peso/fisiología , Adulto , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Ingestión de Energía , Femenino , Humanos , Técnicas para Inmunoenzimas , Insulina/sangre , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Triglicéridos/sangreRESUMEN
The aim of this paper is to provide an overview of vitamin E metabolism. The topics covered include: major classes of vitamin E metabolites; their production pathways and route of excretion; possible biological activities of vitamin E metabolites; and use of vitamin E metabolites as markers of oxidant generation. Recent investigations into vitamin E metabolism have also highlighted important new areas of research, such as the potential for high dose vitamin E supplementation to interfere with drug metabolism, as well as alternative methods to alter vitamin E bioavailability in vivo. These issues will also be discussed in the review.
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Vitamina E/metabolismo , Animales , Cromanos/metabolismo , Interacciones Farmacológicas , Humanos , Vitamina E/análogos & derivados , Vitamina E/sangre , Vitamina E/químicaRESUMEN
Reduced plasma retinol concentrations occur in human malaria but the benefits of supplementation remain uncertain. We assessed the in vivo efficacy of retinol administration, and its effect on lipid peroxidation, in a Plasmodium berghei murine model. Animals received vehicle (n=17) or retinol (i) before P. berghei inoculation (four doses), (ii) at parasitaemia 10-15% (three to four doses) or (iii) before and after inoculation (six to seven doses; n=15 in each group), with euthanasia on day 8 post-inoculation or when the parasitaemia exceeded 50%. Multiple-dose pre-inoculation retinol reduced endpoint parasitaemia by 24% (P=0.001 versus controls). A reduction of 18% (P=0.042) was observed when retinol was given to parasitaemic animals. Retinol was ineffective when given both before and after infection (11% reduction; P=0.47). Although retinol supplementation did not change plasma retinol concentrations, liver retinol content increased and correlated inversely with endpoint parasitaemia (r=-0.45, P=0.001). Malaria infection augmented concentrations of the free radical lipid peroxidation end-product F(2)-isoprostanes in plasma, erythrocytes and liver by 1.8-, 2.8- and 4.9-fold, respectively, but retinol supplementation had no effect on these increases. Consistent with some human malaria studies, prophylactic retinol reduces P. berghei parasitaemia. This effect relates to augmentation of tissue retinol stores rather than to retinol-associated changes in oxidant status.
Asunto(s)
Antimaláricos/administración & dosificación , Peroxidación de Lípido/fisiología , Malaria/tratamiento farmacológico , Plasmodium berghei/aislamiento & purificación , Vitamina A/administración & dosificación , Administración Oral , Animales , Ácido Araquidónico/análisis , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , F2-Isoprostanos/análisis , Ácidos Grasos Insaturados/análisis , Inyecciones Intraperitoneales , Hígado/metabolismo , Malaria/sangre , Malaria/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Parasitemia/dietoterapia , Parasitemia/metabolismo , Proyectos Piloto , Vitamina A/análisis , Vitamina A/sangreRESUMEN
The antioxidant activities of three prenylated flavonoids from Dorstenia mannii (6,8-diprenyleriodictyol, dorsmanin C and dorsmanin F) were compared to the common, non-prenylated flavonoid, quercetin. The prenylated flavonoids were found to be potent scavengers of the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), and are more potent than butylated hydroxy toluene (BHT), a common antioxidant used as a food additive. The prenylated flavonoids also inhibited Cu(2+)-mediated oxidation of human low density lipoprotein (LDL). Dose-response studies indicated that the prenylated flavonoids were effective inhibitors of lipoprotein oxidation with IC50 values <1 microM and had similar inhibitory potency compared to quercetin, but was not directly related to Cu binding. Unlike quercetin, they did not show any pro-oxidant activity at high doses in the Cu(2+)-mediated lipoprotein oxidation system. The medicinal action of Dorstenia mannii may be related to the high concentration of potent antioxidant prenylated flavonoids in this species.
Asunto(s)
Antioxidantes/química , Flavonoides/química , Moraceae/química , África , Antioxidantes/aislamiento & purificación , Compuestos de Bifenilo , Hidroxitolueno Butilado/química , Flavonoides/aislamiento & purificación , Depuradores de Radicales Libres/química , Picratos/química , Quercetina/química , Factores de TiempoRESUMEN
OBJECTIVE: Our objective was to assess effects of dietary supplementation with coenzyme Q10 (CoQ) on blood pressure and glycaemic control in subjects with type 2 diabetes, and to consider oxidative stress as a potential mechanism for any effects. SUBJECTS AND DESIGN: Seventy-four subjects with uncomplicated type 2 diabetes and dyslipidaemia were involved in a randomised double blind placebo-controlled 2x2 factorial intervention. SETTING: The study was performed at the University of Western Australia, Department of Medicine at Royal Perth Hospital, Australia. INTERVENTIONS: Subjects were randomly assigned to receive an oral dose of 100 mg CoQ twice daily (200 mg/day), 200 mg fenofibrate each morning, both or neither for 12 weeks. MAIN OUTCOME MEASURES: We report an analysis and discussion of the effects of CoQ on blood pressure, on long-term glycaemic control measured by glycated haemoglobin (HbA(1c)), and on oxidative stress assessed by measurement of plasma F2-isoprostanes. RESULTS: Fenofibrate did not alter blood pressure, HbA(1c), or plasma F2-isoprostanes. There was a 3-fold increase in plasma CoQ concentration (3.4+/-0.3 micro mol/l, P<0.001) as a result of CoQ supplementation. The main effect of CoQ was to significantly decrease systolic (-6.1+/-2.6 mmHg, P=0.021) and diastolic (-2.9+/-1.4 mmHg, P=0.048) blood pressure and HbA(1c) (-0.37+/-0.17%, P=0.032). Plasma F2-isoprostane concentrations were not altered by CoQ (0.14+/-0.15 nmol/l, P=0.345). CONCLUSIONS: These results show that CoQ supplementation may improve blood pressure and long-term glycaemic control in subjects with type 2 diabetes, but these improvements were not associated with reduced oxidative stress, as assessed by F2-isoprostanes. SPONSORSHIP: This study was supported by a grant from the NH&MRC, Australia.
Asunto(s)
Antioxidantes/farmacología , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Antioxidantes/uso terapéutico , Glucemia/metabolismo , Coenzimas , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Suplementos Dietéticos , Método Doble Ciego , F2-Isoprostanos/sangre , Femenino , Fenofibrato/farmacología , Hemoglobina Glucada/análisis , Hemoglobina Glucada/efectos de los fármacos , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/farmacología , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Ubiquinona/sangre , Ubiquinona/uso terapéuticoRESUMEN
Oxidation of low density lipoprotein (LDL) in vivo is thought to play a critical role in the initiation of atherosclerosis. F(2)-isoprostanes are compounds resulting from non-enzymatic oxidation of arachidonic acid and elevated levels are present in human atherosclerotic plaque. However, little is known about the formation of F(2)-isoprostanes in plaque lesions or their distribution in lipid subclasses. Given that LDL and tissue lipid subfractions (such as phospholipids, cholesterol esters and triglycerides) all contain significant levels of arachidonic acid, the aim of this study was to examine the relative distribution of F(2)-isoprostanes in the different lipid fractions of LDL oxidised in vitro, and compare this to the distribution in atherosclerotic plaque. The results reveal that while the majority of F(2)-isoprostanes are present in the phospholipid or surface lipid fractions, the core lipids (cholesterol esters/triglycerides) contribute at least 10% of the total F(2)-isoprostanes in both LDL oxidised in vitro and human atherosclerotic plaque. The remarkably similar profiles between the oxidised LDL and advanced atherosclerotic plaque suggests oxidation in vivo, is predominantly via non-enzymatic processes directed towards the surface lipids.
Asunto(s)
Arteriosclerosis/patología , Estenosis Carotídea/patología , F2-Isoprostanos/sangre , Lipoproteínas LDL/química , Ácido Araquidónico/metabolismo , Estenosis Carotídea/cirugía , Endarterectomía Carotidea , Ácidos Grasos/análisis , Humanos , Cinética , Lipoproteínas LDL/sangre , alfa-Tocoferol/metabolismoRESUMEN
Oxidized cholesterols in the diet have been shown to exacerbate arterial cholesterol deposition and the development of atherosclerosis in animal models. Dietary oxidized cholesterols are absorbed through the intestine and incorporated into lymph chylomicrons. The aim of this study was to investigate the effect of oxidized cholesterols on the metabolism of nascent chylomicrons in vivo. It was shown that oxidized cholesterols markedly delay the clearance of chylomicrons from plasma compared to rats given TG alone. However, there was no difference in the clearance of chylomicrons containing oxidized cholesterols vs. purified cholesterol, although the presence of oxysterols did appear to exacerbate the removal of these particles from circulation. The impaired clearance of chylomicrons containing oxidized cholesterols was not due to impaired lipolysis and slower conversion to the remnant form. Moreover, the incorporation of oxidized cholesterols did not alter the hepatic or splenic uptake of chylomicrons compared to chylomicrons isolated from rats given purified cholesterol or TG alone. Collectively, the results of this study suggest that the exacerbated delay in clearance of chylomicron remnants enriched with oxysterols may be due to impaired uptake by tissues other than the liver and spleen. Apolipoprotein (apo) analysis showed that oxysterol incorporation reduced the apoE content and altered the apoC phenotype of chylomicrons, which may have an impact on the removal of chylomicron remnants from plasma. In conclusion, dietary oxysterols appear to have the potential to adversely affect chylomicron metabolism. Therefore, further investigations in humans are required to determine whether dietary oxidized cholesterols found in cholesterol-rich processed foods delay the clearance of postprandial remnants, which may contribute to and exacerbate the development of atherosclerosis.
Asunto(s)
Colesterol en la Dieta/metabolismo , Colesterol en la Dieta/farmacología , Quilomicrones/sangre , Quilomicrones/metabolismo , Animales , Apolipoproteínas/sangre , Arteriosclerosis/inducido químicamente , Quilomicrones/química , Dieta , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Oxidación-Reducción , Ratas , Ratas Wistar , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
AIM/HYPOTHESIS: We assessed whether dietary supplementation with coenzyme Q(10) improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. METHODS: A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q(10) or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F(2)-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. RESULTS: The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q(10) and decreased by -0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q(10) treatment resulted in a threefold increase in plasma coenzyme Q(10) (p < 0.001) but did not alter plasma F(2)-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. CONCLUSION/INTERPRETATION: Coenzyme Q(10) supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F(2)-isoprostane concentrations.