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BACKGROUND: Improving dietary fat quality strongly affects serum cholesterol levels and hence the risk of cardiovascular diseases (CVDs). Recent studies have identified dietary fat as a potential modulator of the gut microbiota, a central regulator of host metabolism including lipid metabolism. We have previously shown a significant reduction in total cholesterol levels after replacing saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFAs). The aim of the present study was to investigate the effect of dietary fat quality on gut microbiota, short-chain fatty acids (SCFAs), and bile acids in healthy individuals. In addition, to investigate how changes in gut microbiota correlate with blood lipids, bile acids, and fatty acids. METHODS: Seventeen participants completed a randomized, controlled dietary crossover study. The participants received products with SFAs (control) or PUFAs in random order for three days. Fecal samples for gut microbiota analyses and fasting blood samples (lipids, fatty acids, and bile acids) were measured before and after the three-day intervention. RESULTS: Of a panel of 40 bacteria, Lachnospiraceae and Bifidobacterium spp. were significantly increased after intervention with PUFAs compared with SFAs. Interestingly, changes in Lachnospiraceae, as well as Phascolarlactobacterium sp. and Eubacterium hallii, was also found to be negatively correlated with changes in total cholesterol levels after replacing the intake of SFAs with PUFAs for three days. No significant differences in SCFAs or bile acids were found after the intervention. CONCLUSION: Replacing SFAs with PUFAs increased the abundance of the gut microbiota family of Lachnospiraceae and Bifidobacterium spp. Furthermore, the reduction in total cholesterol after improving dietary fat quality correlated with changes in the gut microbiota family Lachnospiraceae. Future studies are needed to reveal whether Lachnospiraceae may be targeted to reduce total cholesterol levels. TRIAL REGISTRATION: The study was registered at Clinical Trials ( https://clinicaltrials.gov/ , registration identification number: NCT03658681).
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Ácidos Grasos Insaturados , Ácidos Grasos , Ácidos y Sales Biliares , Colesterol , Estudios Cruzados , Grasas de la Dieta , Humanos , LípidosRESUMEN
BACKGROUND: Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited. In the study outlined in this protocol, we will evaluate if dietary SAA restriction can reduce body weight and improve resting energy expenditure (REE) and parameters related to metabolic health. METHOD/DESIGN: Men and women (calculated sample size = 60), aged 18-45 years, with body mass index of 27-35 kg/m2 will be included in a double-blind 8-week dietary intervention study. The participants will be randomized in a 1:1 manner to a diet with either low or high SAA. Both groups will receive an equal base diet consisting of low-SAA plant-based whole foods and an amino acid supplement free of SAA. Contrasting SAA contents will be achieved using capsules with or without methionine and cysteine (SAAhigh, total diet SAA ~ 50-60 mg/kg body weight/day; SAAlow, total diet SAA ~ 15-25 mg/kg body weight/day). The primary outcome is body weight change. Data and material collection will also include body composition (dual X-ray absorptiometry), resting energy expenditure (whole-room indirect calorimetry) and samples of blood, urine, feces and adipose tissue at baseline, at 4 weeks and at study completion. Measures will be taken to promote and monitor diet adherence. Data will be analyzed using linear mixed model regression to account for the repeated measures design and within-subject correlation. DISCUSSION: The strength of this study is the randomized double-blind design. A limitation is the restrictive nature of the diet which may lead to poor compliance. If this study reveals a beneficial effect of the SAAlow diet on body composition and metabolic health, it opens up for new strategies for prevention and treatment of overweight, obesity and its associated disorders. Trial registration ClinicalTrials.gov: NCT04701346, Registration date: January 8th, 2021.
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Aminoácidos Sulfúricos , Obesidad , Adolescente , Adulto , Aminoácidos , Composición Corporal , Metabolismo Energético , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
Replacing intake of SFA with PUFA reduces serum cholesterol levels and CVD risk. The effect on glycaemic regulation is, however, less clear. The main objective of the present study was to investigate the short-term effect of replacing dietary SFA with PUFA on glycaemic regulation. Seventeen healthy, normal-weight participants completed a 25-d double-blind, randomised and controlled two-period crossover study. Participants were allocated to either interventions with PUFA products or SFA products (control) in a random order for three consecutive days, separated by a 1·5-week washout period between the intervention periods. Glucose, insulin and TAG were measured before and after an oral glucose tolerance test. In addition, fasting total cholesterol, NEFA and plasma total fatty acid profile were measured before and after the 3-d interventions. Fasting and postprandial glucose, insulin, and TAG levels and fasting levels of NEFA and plasma fatty acid profile did not differ between the groups. However, replacing dietary SFA with PUFA significantly reduced total cholesterol levels by 8 % after 3 d (P = 0·002). Replacing dietary SFA with PUFA for only 3 d has beneficial cardio-metabolic effects by reducing cholesterol levels in healthy individuals.
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Colesterol/sangre , Grasas Insaturadas en la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos/administración & dosificación , Control Glucémico , Adolescente , Adulto , Anciano , Glucemia/análisis , Estudios Cruzados , Método Doble Ciego , Ácidos Grasos/sangre , Ácidos Grasos no Esterificados/sangre , Humanos , Insulina/sangre , Persona de Mediana Edad , Triglicéridos/sangre , Adulto JovenRESUMEN
BACKGROUND: Adults with intellectual disabilities living in residential houses have a high prevalence of obesity which is related to poor dietary habits. AIM: The aim of this study was to assess supporting staff`s thoughts and experiences on factors influencing their opportunities to promote a healthy diet in adults with intellectual disabilities. METHODS: 13 supporting staff members were recruited from 11 different residential houses in a community. Concept Mapping methodology was used, including group interviews, sorting, rating statement and analysing the results. RESULTS: Seven clusters most accurately captured the ideas of the supporting staff`. 'Attitudes', 'Facilitating a healthy diet', 'Practical cooking skills' and 'Applied dietary knowledge' were the four most important. CONCLUSIONS: Multiple factors influence the opportunities of supporting staff to promote a healthy diet. A holistic approach addressing all relevant factors is necessary when developing interventions to address this complex issue in persons with intellectual disabilities.
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Discapacidad Intelectual , Adulto , Dieta , Dieta Saludable , HumanosRESUMEN
BACKGROUND: Joint British Societies have developed a tool that utilizes information on cardiovascular disease (CVD) risk factors to estimate an individual's 'heart age'. We studied if using heart age as an add-on to conventional risk communication could enhance the motivation for adapting to a healthier lifestyle resulting in improved whole-blood cholesterol and omega-3 status after 4 weeks. METHODS: A total of 48 community pharmacies were cluster-randomized to use heart age+conventional risk communication (intervention) or only conventional risk communication (control) in 378 subjects after CVD risk-factor assessment. Dried blood spots were obtained with a 4-week interval to assay whole-blood cholesterol and omega-3 fatty acids. We also explored pharmacy-staff's (n=27) perceived utility of the heart age tool. RESULTS: Subjects in the intervention pharmacies (n=137) had mean heart age 64 years and chorological age 60 years. In these, cholesterol decreased by median (interquartile range) -0.10 (-0.40, 0.35) mmol/l. Cholesterol decreased by -0.20 (-0.70, 0.30) mmol/l (P difference =0.24) in subjects in the control pharmacies (n=120) with mean chronological age 60 years. We observed increased concentrations of omega-3 fatty acids after 4 weeks, non-differentially between groups. Pharmacy-staff (n=27) agreed that heart age was a good way to communicate CVD risk, and most (n=25) agreed that it appeared to motivate individuals to reduce elevated CVD risk factors. CONCLUSIONS: The heart age tool was considered a convenient and motivating communication tool by pharmacy-staff. Nevertheless, communicating CVD risk as heart age was not more effective than conventional risk communication alone in reducing whole-blood cholesterol levels and improving omega-3 status.
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Enfermedades Cardiovasculares , Farmacias , Enfermedades Cardiovasculares/prevención & control , Colesterol , Humanos , Recién Nacido , Persona de Mediana Edad , MotivaciónRESUMEN
BACKGROUND: Obesity is a global pandemic leading to increased mortality and increased risk of cardiovascular disease. Bariatric surgery is an established treatment of obesity leading to weight loss and reduction of mortality. To further elucidate how bariatric surgery improves metabolic control, we explored the fatty acid (FA) profiles in morbidly obese subjects treated with lifestyle intervention and subsequent bariatric surgery. METHODS: The intervention group consisted of 34 morbidly obese patients scheduled for bariatric surgery and the control group of 17 non-obese patients scheduled for elective laparoscopic procedures. The intervention group had to undergo lifestyle changes preoperatively. Fasting blood samples were drawn at admission, after lifestyle intervention and 1 year after bariatric surgery. RESULTS: At admission, the morbidly obese patients had significantly higher levels of monounsaturated FAs (MUFAs) and lower levels of n-6 polyunsaturated FAs (PUFAs) and n-3 PUFAs than healthy controls (all p-values <.05). In the intervention group, there was a significantly lower level of total FAs after lifestyle intervention, and from admission to 1 year after surgical intervention (both, p < .05), primarily reflecting a lower proportion of saturated FAs (SFAs). Following bariatric surgery, but not after lifestyle changes, there was an increase in the proportion of n-3 PUFA (p < .05) reaching levels not significantly different from healthy controls. CONCLUSIONS: Our findings suggest that a reduced proportion of the proposed anti-atherogenic n-3 PUFAs characterizes morbidly obese individuals, and that this FA profile is reversed by bariatric surgery, but not by lifestyle intervention.
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Ácidos Grasos Omega-3/sangre , Obesidad Mórbida/sangre , Adulto , Cirugía Bariátrica , Estudios de Casos y Controles , Ayuno , Ácidos Grasos/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/cirugía , Factores de Riesgo , Resultado del Tratamiento , Pérdida de PesoRESUMEN
Regular consumption of long-chain n-3 fatty acids (LC n-3 FA) reduces postprandial triacylglycerolaemia. Functional foods and supplements are alternative sources of LC n-3 FA; however, emulsification technologies, food matrices and altered lipid oxidation levels affect their bioavailability. Moreover, which functional foods are optimal LC n-3 FA carriers is unknown. The aim of the study was to determine the bioavailability of LC n-3 FA and the postprandial TAG response after the intake of oxidised or non-oxidised cod liver oil and after the intake of emulsified or non-emulsified LC n-3 FA using novel functional food items as LC n-3 FA carriers in a randomised cross-over acute study. A total of twenty-four healthy subjects completed the study in which subjects consumed one of four different test meals containing 1·5 g LC n-3 FA, or a control meal with no LC n-3 FA. Postprandial TAG-rich lipoproteins were isolated and their fatty acid composition was measured. The LC n-3 FA from emulsified foods were more rapidly incorporated into TAG-rich lipoproteins compared with non-emulsified foods. The incorporation of LC n-3 FA was similar for oils emulsified in yogurt or juice and was unaffected by the oxidative status of the oil. Postprandial TAG levels did not differ among the various test meals. In conclusion, emulsification increases the bioavailability of LC n-3 FA through a more rapid incorporation into TAG-rich lipoproteins, and juice and yogurt are equally suited as LC n-3 FA carriers. The acute intake of oxidised cod liver oil does not influence the incorporation of LC n-3 FA into TAG-rich lipoproteins.
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OBJECTIVE: Phytosterols are recommended in combination with diet therapy to reduce elevated LDL-cholesterol level. Meta-analyses indicate a 10% reduction in LDL-cholesterol from intake of approximately 2 g phytosterols/d incorporated into fat-based foods. However, the cholesterol lowering effect from capsules containing phytosterols is less documented. The pre-specified primary endpoint of the present study was to investigate the effect of capsules with phytosterols on circulating LDL-cholesterol in patients with mild to moderate hypercholesterolemia. METHODS: In a double-blinded, randomized, placebo-controlled crossover study, 41 men and women were randomized into two four-weeks intervention periods with softgel capsules containing either phytosterols (2.0 g/d) or sunflower oil. There was a three-weeks washout period between the intervention periods. RESULTS: No significant difference in total- or LDL-cholesterol between the phytosterol and the placebo period were observed after four weeks intervention (0.0 mmol/L (95%CI: -0.3 to 0.2), P = 0.74 and -0.1 mmol/L (95%CI: -0.3 to 0.1), P = 0.32, respectively). CONCLUSION: Daily intake of capsules containing 2 g phytosterols did not reduce total- or LDL-cholesterol significantly in a highly relevant target group for the use of phytosterol products. The present results may emphasize the importance of choosing a suitable dosage-delivery system in order to achieve optimal cholesterol lowering effect. The study was registered at www.clinicaltrials.gov, IDno:NCT00485095.
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Anticolesterolemiantes/administración & dosificación , LDL-Colesterol/sangre , Suplementos Dietéticos , Hipercolesterolemia/tratamiento farmacológico , Fitosteroles/administración & dosificación , Administración Oral , Anciano , Anticolesterolemiantes/química , Biomarcadores/sangre , Cápsulas , Química Farmacéutica , Estudios Cruzados , Método Doble Ciego , Regulación hacia Abajo , Femenino , Humanos , Hipercolesterolemia/sangre , Masculino , Persona de Mediana Edad , Noruega , Fitosteroles/química , Aceites de Plantas/química , Índice de Severidad de la Enfermedad , Aceite de Girasol , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of the present study was to evaluate the possible effects of Q10 and selenium supplementation on statin-induced myopathy (SIM), both for subjective symptoms and muscle function. DESIGN: Patients (N = 43) who had experienced previous or ongoing SIM on atorvastatin therapy were recruited. Following a 6-week washout period during which no statins were administered, the patients were re-challenged with 10 mg of atorvastatin. Patients (N = 41) who experienced SIM continued the atorvastatin treatment and were in addition randomized to receive 12 weeks supplement of 400 mg Q10 and 200 µg selenium per day or a matching double placebo. SIM was assessed using 3 validated symptom questionnaires, and a muscle function test was performed at the beginning and at the end of the study. RESULTS: The patients receiving the active supplement experienced significant increases in their serum Q10 and selenium concentrations compared with the group receiving placebo. No statistically significant differences in symptom questionnaire scores or muscle function tests were revealed between the groups. CONCLUSIONS: Despite substantial increases in the serum Q10 and selenium levels following the oral supplementation, this study revealed no significant effects on SIM compared with the placebo.
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Antioxidantes/administración & dosificación , Ácidos Heptanoicos/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/tratamiento farmacológico , Pirroles/efectos adversos , Selenio/administración & dosificación , Ubiquinona/análogos & derivados , Vitaminas/administración & dosificación , Adulto , Anciano , Atorvastatina , Suplementos Dietéticos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Ácidos Heptanoicos/administración & dosificación , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirroles/administración & dosificación , Encuestas y Cuestionarios , Resultado del Tratamiento , Ubiquinona/administración & dosificaciónRESUMEN
Intake of fish oil reduces the risk of CHD and CHD deaths. Marine n-3 fatty acids (FA) are susceptible to oxidation, but to our knowledge, the health effects of intake of oxidised fish oil have not previously been investigated in human subjects. The aim of the present study was to investigate markers of oxidative stress, lipid peroxidation and inflammation, and the level of plasma n-3 FA after intake of oxidised fish oil. In a double-blinded randomised controlled study, healthy subjects (aged 18-50 years, n 54) were assigned into one of three groups receiving capsules containing either 8 g/d of fish oil (1.6 g/d EPA+DHA; n 17), 8 g/d of oxidised fish oil (1.6 g/d EPA+DHA; n 18) or 8 g/d of high-oleic sunflower oil (n 19). Fasting blood and morning spot urine samples were collected at weeks 0, 3 and 7. No significant changes between the different groups were observed with regard to urinary 8-iso-PGF2α; plasma levels of 4-hydroxy-2-hexenal, 4-hydroxy-2-nonenal and α-tocopherol; serum high sensitive C-reactive protein; or activity of antioxidant enzymes in erythrocytes. A significant increase in plasma level of EPA+DHA was observed in both fish oil groups, but no significant difference was observed between the fish oil groups. No changes in a variety of in vivo markers of oxidative stress, lipid peroxidation or inflammation were observed after daily intake of oxidised fish oil for 3 or 7 weeks, indicating that intake of oxidised fish oil may not have unfavourable short-term effects in healthy human subjects.
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Aceite de Hígado de Bacalao/efectos adversos , Aceite de Hígado de Bacalao/química , Suplementos Dietéticos/efectos adversos , Suplementos Dietéticos/análisis , Estrés Oxidativo , Adulto , Aldehídos/sangre , Biomarcadores/sangre , Biomarcadores/orina , Proteína C-Reactiva/análisis , Dinoprost/análogos & derivados , Dinoprost/orina , Método Doble Ciego , Eritrocitos/enzimología , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/sangre , Femenino , Humanos , Peroxidación de Lípido , Masculino , Noruega , Oxidación-Reducción , Oxidorreductasas/sangre , Pacientes Desistentes del Tratamiento , Adulto Joven , alfa-Tocoferol/sangreRESUMEN
The aim of the present study was to examine the effect of a single high-fat meal with different fat quality on circulating inflammatory markers and gene expression in peripheral blood mononuclear cells (PBMC) to elucidate the role of fat quality on postprandial inflammation. A postprandial study with fourteen healthy females consuming three test meals with different fat quality was performed. Test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6 h after intake were analysed. The test meal consisted of three cakes enriched with coconut fat (43 % energy as saturated fat and 1 % energy as α-linolenic acid (ALA)), linseed oil (14 % energy as ALA and 30 % energy as saturated fat) and cod liver oil (5 % energy as EPA and DHA and 5 % energy as ALA in addition to 31 % energy as saturated fat). In addition, ex vivo PBMC experiments were performed in eight healthy subjects investigating the effects of EPA and ALA on release and gene expression of inflammatory markers. The IL-8 mRNA level was significantly increased after intake of the cod liver oil cake at 6 h compared with fasting level, which was significantly different from the effect observed after the intake of linseed cake. In contrast, no effect was seen on circulating level of IL-8. In addition, ALA and EPA were shown to elicit different effects on the release and mRNA expression levels of inflammatory markers in PBMC cultured ex vivo, with EPA having the most prominent pro-inflammatory potential.
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Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/análisis , Mediadores de Inflamación/sangre , Adulto , Glucemia/metabolismo , Aceite de Coco , Aceite de Hígado de Bacalao/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Ayuno/sangre , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Aceite de Linaza/administración & dosificación , Lípidos/sangre , Masculino , Receptores Activados del Proliferador del Peroxisoma/genética , Aceites de Plantas/administración & dosificación , Periodo Posprandial/genética , Periodo Posprandial/fisiología , ARN Mensajero/sangre , ARN Mensajero/genética , Ácido alfa-Linolénico/administración & dosificaciónRESUMEN
OBJECTIVE: The aim of the present paper was to review the literature in order to summarize the effects of marine n-3 fatty acids on circulating inflammatory markers among healthy subjects, subjects with high risk of developing cardiovascular disease (CVD) and in patients with CVD in human intervention studies. METHODS: A systematic literature search in PubMed was performed. Intervention studies describing the effects of marine n-3 fatty acids on circulating inflammatory markers in healthy subjects, subjects with high risk of CVD and patients with CVD were included. The following exclusion criteria were used: (1) interventions assessing inflammatory markers with ex vivo methods (2) interventions with children (3) articles describing animal or cell culture studies. Twenty-two articles were included. Additionally, 13 papers from their literature lists were included based on the same inclusion and exclusion criteria as the literature search. RESULTS AND CONCLUSION: Intervention studies with marine n-3 fatty acids administered from either fish or fish oil demonstrate different results on inflammatory markers. No firm conclusion can be drawn about the effect of marine n-3 fatty acids on circulating inflammatory markers in healthy individuals, individuals with high risk of developing CVD or individuals with CVD related diseases.
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Biomarcadores/sangre , Enfermedades Cardiovasculares , Ácidos Grasos Omega-3/inmunología , Inflamación/sangre , Inflamación/complicaciones , Animales , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Grasas de la Dieta , Humanos , Océanos y Mares , PubMed , Factores de RiesgoRESUMEN
OBJECTIVE: The primary endpoint in our study was to investigate the effect of a red yeast rice (RYR) product on plasma lipids. DESIGN: A randomized, double-blind, placebo controlled study was performed. Patients were randomized to either RYR (HypoCol, 4 capsules/day) (n=22) or placebo (n=20) for 16 weeks. Inclusion criteria were male or female, 18-75 years, LDL-cholesterol between 3.0 and 6.0 mmol/L, fasting triglyceride level less than 4.5 mmol/L. RESULTS: Patients receiving RYR experienced a significant reduction in LDL-cholesterol (23.0%) and total cholesterol (15.5%) compared to placebo after 16 weeks of treatment (p<0.001). CONCLUSION: The tested red yeast rice product demonstrated a significant cholesterol lowering effect compared to placebo, and was well tolerated in this Caucasian population.
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Productos Biológicos/uso terapéutico , Colesterol/sangre , Suplementos Dietéticos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , LDL-Colesterol/sangre , Método Doble Ciego , Regulación hacia Abajo , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipercolesterolemia/sangre , Masculino , Persona de Mediana Edad , Noruega , Factores de Tiempo , Resultado del Tratamiento , Triglicéridos/sangre , Adulto JovenRESUMEN
Homocysteine has been related to increased risk of CVD. Matrix degradation and inflammation may be involved in this link between hyperhomocysteinaemia and CVD. Recent studies suggest that cystatin C can modulate matrix degradation and inflammation. The present study measured cystatin C at protein (plasma) and mRNA levels (peripheral blood mononuclear cells (PBMC)) in hyperhomocysteinaemic individuals (n 37, female seven and male thirty, aged 20-70 years) before and after B-vitamin supplementation for 3 months in a randomised, placebo-controlled double-blind trial. In a cross-sectional study, seventeen of the hyperhomocysteinaemic subjects were age- and sex-matched to healthy controls (n 17). Our main findings were: (i) as compared with controls, hyperhomocysteinaemic subjects tended to have higher plasma concentrations of cystatin C and lower mRNA levels of cystatin C in PBMC; (ii) compared with placebo, treatment of hyperhomocysteinaemic individuals with B-vitamins significantly increased plasma levels of cystatin C and mRNA levels of cystatin C in PBMC; (iii) while plasma levels of cystatin C were positively correlated with plasma levels of TNF receptor-1, mRNA levels of cystatin C in PBMC were inversely correlated with this TNF parameter. Taken together, our findings suggest that disturbed cystatin C levels may be a characteristic of hyperhomocysteinaemic individuals, potentially related to low-grade systemic inflammation in hyperhomocysteinaemic subjects, and that B-vitamins may modulate cystatin C levels in these individuals.
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Cistatina C/sangre , Hiperhomocisteinemia/sangre , Hiperhomocisteinemia/tratamiento farmacológico , Leucocitos Mononucleares/química , Complejo Vitamínico B/administración & dosificación , Adulto , Anciano , Estudios Transversales , Cistatina C/genética , Suplementos Dietéticos , Método Doble Ciego , Femenino , Ácido Fólico/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Placebos , ARN Mensajero/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Vitamina B 12/administración & dosificación , Vitamina B 6/administración & dosificaciónRESUMEN
BACKGROUND AND PURPOSE: Homocysteine has been linked to increased risk of ischemic stroke and other cardiovascular events. Matrix degradation and inflammation play an important role in these disorders, and we have demonstrated increased levels of matrix-degrading enzymes and inflammatory cytokines in hyperhomocysteinemic individuals. Recent studies suggest that RANK ligand (RANKL) through interaction with its receptor RANK can modulate matrix degradation and inflammation. The present study aimed to examine the role of the RANKL/RANK axis in hyperhomocystinemia. METHODS: RANKL/RANK was measured on protein or mRNA level before and after B-vitamin supplementation in hyperhomocysteinemic individuals. We also examined the in vitro effects of soluble RANKL in peripheral blood mononuclear cells from hyperhomocysteinemic individuals. RESULTS: Our main findings were: (1) compared to peripheral blood mononuclear cells from controls, cells from hyperhomocysteinemic individuals had significantly higher gene expression of RANKL and RANK; (2) folic acid treatment for 6 weeks in an open, uncontrolled study significantly reduced gene expression of RANKL/RANK in peripheral blood mononuclear cells from these individuals; (3) compared to placebo, treatment with folic acid, vitamin B(12), and vitamin B(6) for 3 months in a randomized, double-blind trial significantly lowered serum levels of soluble RANKL in hyperhomocysteinemic individuals; and (4) in vitro, soluble RANKL markedly increased the release of matrix metalloproteinase-9 and inflammatory cytokines from peripheral blood mononuclear cells in hyperhomocysteinemic subjects. CONCLUSIONS: Our findings suggest a dysregulated RANKL/RANK axis in hyperhomocysteinemic subjects. Based on their role in atherogenesis, this enhanced expression of RANKL and RANK could contribute to the increased risk of cardiovascular disease in hyperhomocystinemia. Moreover, treatment with B-vitamins may have beneficial implications for plaque stability in these individuals.
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Arteritis/sangre , Matriz Extracelular/efectos de los fármacos , Hiperhomocisteinemia/tratamiento farmacológico , Ligando RANK/efectos de los fármacos , Receptor Activador del Factor Nuclear kappa-B/efectos de los fármacos , Complejo Vitamínico B/farmacología , Adulto , Arteritis/etiología , Arteritis/fisiopatología , Células Cultivadas , Citocinas/metabolismo , Método Doble Ciego , Matriz Extracelular/metabolismo , Femenino , Ácido Fólico/farmacología , Humanos , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/fisiopatología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Placebos , Ligando RANK/metabolismo , Ligando RANK/farmacología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptor Activador del Factor Nuclear kappa-B/genética , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Vitamina B 12/farmacología , Vitamina B 6/farmacologíaRESUMEN
Tesaglitazar (GALIDA; AstraZeneca, Wilmington, DE) is a dual peroxisome proliferator-activated receptor alpha/gamma agonist previously in clinical development for the treatment of glucose and lipid abnormalities associated with type 2 diabetes mellitus and insulin resistance. This study compared the efficacy of tesaglitazar with that of pioglitazone as adjunctive therapy to atorvastatin in subjects with abdominal obesity and dyslipidemia. In this open-label, 3-way crossover study, 58 subjects received atorvastatin 10 mg once daily in a 6-week run-in period, followed by tesaglitazar 3 mg, pioglitazone 45 mg, or placebo, as adjunctive therapy to atorvastatin, in a randomized sequence for 6 weeks each. Serum triglycerides and other lipids, apolipoproteins, glucose, and insulin concentrations were compared between treatments. Tesaglitazar adjunctive therapy reduced serum triglycerides significantly more from baseline (-1.07 mmol/L) than pioglitazone (-0.33 mmol/L; P = .007) or placebo (-0.09 mmol/L; P < .0001). Tesaglitazar also resulted in significantly greater improvements in free fatty acids, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, low-density lipoprotein particle size, apolipoprotein (apo) B, apo C-III, and the apo B/apo A-I ratio compared with pioglitazone or placebo. Tesaglitazar adjunctive therapy also reduced fasting plasma glucose, fasting plasma insulin, and insulin resistance (homeostasis model assessment index) significantly more than pioglitazone or placebo (P < .0001 for all comparisons). Tesaglitazar was generally well tolerated in combination with atorvastatin, but hemoglobin and absolute neutrophil count decreased and serum creatinine increased more with tesaglitazar than with pioglitazone or placebo. These effects, also shown in previous trials, led to the discontinuation of the clinical development of the drug. In conclusion, the addition of tesaglitazar to a background of atorvastatin therapy further improved the dyslipidemia associated with insulin resistance.
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Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/farmacología , Dislipidemias/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Lípidos/sangre , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/administración & dosificación , Fenilpropionatos/farmacología , Pirroles/uso terapéutico , Adulto , Anticolesterolemiantes/uso terapéutico , Atorvastatina , Quimioterapia Adyuvante , Estudios Cruzados , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Persona de Mediana Edad , Pioglitazona , Placebos , Tiazolidinedionas/administración & dosificaciónRESUMEN
BACKGROUND: Hypertriglyceridemia and low HDL cholesterol values are associated with adiposity, type 2 diabetes and metabolic syndrome. METHODS: This review article is based on literature studies, data from Rikshospitalet and Furst Medical Laboratory, sales figures for fibrates and clinical experience. RESULTS AND INTERPRETATION: Insulin resistance is a common contributory cause to hypertriglyceridaemia. In hypertriglyceridaemia, fasting glucose, HbA1c, TSH, creatinine, ALAT, ASAT, gamma GT, ALP and urine strips should be measured. The patient must be evaluated with regard to adiposity, use of alcohol, eating disorders and pregnancy. Direct measurement of LDL cholesterol gives a correct measure independent of the triglyceride level up to 13.0 mmol/L. LDL cholesterol levels may be low despite high total cholesterol levels and high triglyceride levels. Diet and lifestyle intervention is important. Blood sugar control is crucial. Statins are the first choice of drugs in combined hyperlipidaemia. Isolated hypertriglyceridaemia >10 mmol/L represents a large risk for pancreatitis. Purified omega-3 fatty acids, fibrates and eventually niacin are the drugs of choice in this condition. If LDL cholesterol levels are elevated, statins should also be considered. Combination of statin/fibrate or statin/niacin increase the risk of myopathy.