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Juglans/química , Lipoproteínas/efectos de los fármacos , Anciano , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: Despite aggressive reduction of low-density lipoprotein cholesterol (LDL-C), there is a residual risk of cardiovascular disease (CVD). Hypertriglyceridemia is known to be associated with increased CVD risk, independently of LDL-C. Triglycerides are one component of the heterogenous class of triglyceride-rich lipoproteins (TGRLs). METHODS/RESULTS: Growing evidence from biology, epidemiology, and genetics supports the contribution of TGRLs to the development of CVD via a number of mechanisms, including through proinflammatory, proapoptotic, and procoagulant pathways. CONCLUSION: New genetics-guided pharmacotherapies to reduce levels of triglycerides and TGRLs and thus reduce risk of CVD have been developed and will be discussed here.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/fisiopatología , Lipoproteínas/efectos de los fármacos , Lipoproteínas/metabolismo , Triglicéridos/metabolismo , Aterosclerosis/genética , Aterosclerosis/fisiopatología , Enfermedades Cardiovasculares/genética , Quilomicrones/metabolismo , Predisposición Genética a la Enfermedad , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Mediadores de Inflamación/metabolismo , Lipoproteína Lipasa/metabolismo , Conducta de Reducción del RiesgoRESUMEN
Mycoprotein consumption has been shown to improve acute postprandial glycaemic control and decrease circulating cholesterol concentrations. We investigated the impact of incorporating mycoprotein into the diet on insulin sensitivity (IS), glycaemic control and plasma lipoprotein composition. Twenty healthy adults participated in a randomised, parallel-group trial in which they consumed a 7 d fully controlled diet where lunch and dinner contained either meat/fish (control group, CON) or mycoprotein (MYC) as the primary source of dietary protein. Oral glucose tolerance tests were performed pre- and post-intervention, and 24 h continuous blood glucose monitoring was applied throughout. Fasting plasma samples were obtained pre- and post-intervention and were analysed using quantitative, targeted NMR-based metabonomics. There were no changes within or between groups in blood glucose or serum insulin responses, nor in IS or 24 h glycaemic profiles. No differences between groups were found for 171 of the 224 metabonomic targets. Forty-five lipid concentrations of different lipoprotein fractions (VLDL, LDL, intermediate-density lipoprotein and HDL) remained unchanged in CON but showed a coordinated decrease (7-27 %; all P < 0·05) in MYC. Total plasma cholesterol, free cholesterol, LDL-cholesterol, HDL2-cholesterol, DHA and n-3 fatty acids decreased to a larger degree in MYC (14-19 %) compared with CON (3-11 %; P < 0·05). Substituting meat/fish for mycoprotein twice daily for 1 week did not modulate whole-body IS or glycaemic control but resulted in changes to plasma lipid composition, the latter primarily consisting of a coordinated reduction in circulating cholesterol-containing lipoproteins.
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Glucemia/efectos de los fármacos , Proteínas en la Dieta/farmacología , Proteínas Fúngicas/farmacología , Resistencia a la Insulina , Lipoproteínas/efectos de los fármacos , Automonitorización de la Glucosa Sanguínea , Colesterol/sangre , Ayuno/sangre , Femenino , Proteínas de Peces en la Dieta/farmacología , Prueba de Tolerancia a la Glucosa , Control Glucémico , Voluntarios Sanos , Humanos , Insulina/sangre , Lipidómica , Masculino , Proteínas de la Carne/farmacología , Periodo Posprandial/efectos de los fármacos , Adulto JovenRESUMEN
Although numerous trials have convincingly shown benefits of statin therapy in both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), most showed relative risk reductions of 25-40%, and thus many individuals continue to have ASCVD events despite statin therapy. Substantial progress has been made in developing therapies that address the residual risk for ASCVD despite statin therapy. In this review, we summarize progress of currently available therapies along with therapies under development that further reduce low-density lipoprotein cholesterol and apolipoprotein B-containing lipoproteins, reduce lipoprotein(a), reduce ASCVD events in patients with high triglycerides, and directly target inflammation to reduce ASCVD risk.
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Enfermedades Cardiovasculares/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación/tratamiento farmacológico , Lipoproteínas/sangre , Prevención Primaria/métodos , Prevención Secundaria/métodos , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Humanos , Inflamación/sangre , Lipoproteínas/efectos de los fármacosRESUMEN
Phytosterols have been shown to improve blood lipid levels and treat atherosclerosis. This research investigated the effects of phytosterol Alisol B 23-acetate (AB23A) on jejunum lipid metabolism and atherosclerosis. The results show that intragastric administration of AB23A can significantly reduce atherosclerotic plaque area and lipid accumulation in the jejunum of ovariectomized ApoE-/- mice fed a high-fat diet and can also improve the lipid mass spectra of the plasma and jejunum. In vitro studies have shown that AB23A can increase cholesterol outflow in Caco-2 cells exposed to high fat concentrations and increase the expression of ATP-binding cassette transfer proteins G5/G8 (ABCG5/G8), the liver X receptor α (LXRα). Furthermore, inhibition of LXRα can significantly eliminate the active effect of AB23A on decreasing intracellular lipid accumulation. We also confirmed that AB23A has a negative effect on Acyl-CoA cholesterol acyltransferase 2 (ACAT2) in Caco-2 cells cultured in the high concentrations of fat, and we found that AB23A further reduces ACAT2 expression in cells treated with the ACAT2 inhibitor pyripyropene or transfected with ACAT2 siRNA. In conclusion, we confirmed that AB23A can reduce the absorption of dietary lipids in the jejunum by affecting the LXRα-ACAT2-ABCG5/G8 pathway and ultimately exert an anti-atherosclerotic effect.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/efectos de los fármacos , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/efectos de los fármacos , Aterosclerosis/metabolismo , Colestenonas/farmacología , Yeyuno/efectos de los fármacos , Lipoproteínas/efectos de los fármacos , Placa Aterosclerótica/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/metabolismo , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aterosclerosis/patología , Células CACO-2 , Colesterol/metabolismo , Ésteres del Colesterol/metabolismo , Dieta Alta en Grasa , Femenino , Glicerofosfolípidos/metabolismo , Humanos , Yeyuno/metabolismo , Yeyuno/patología , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas/metabolismo , Receptores X del Hígado/efectos de los fármacos , Receptores X del Hígado/metabolismo , Ratones , Ratones Noqueados para ApoE , Ovariectomía , Placa Aterosclerótica/patología , Esterol O-Aciltransferasa/efectos de los fármacos , Esterol O-Aciltransferasa/metabolismo , Triglicéridos/metabolismo , Esterol O-Aciltransferasa 2RESUMEN
Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.
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Dislipidemias/fisiopatología , Síndrome Nefrótico/fisiopatología , Adolescente , Adulto , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Niño , Dislipidemias/tratamiento farmacológico , Dislipidemias/etiología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Lipoproteínas/sangre , Lipoproteínas/efectos de los fármacos , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/tratamiento farmacológico , Factores de Riesgo , Adulto JovenRESUMEN
Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.
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Anticuerpos Monoclonales/farmacología , Anticolesterolemiantes/farmacología , LDL-Colesterol/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipoproteínas/efectos de los fármacos , Isquemia Miocárdica/prevención & control , LDL-Colesterol/sangre , Humanos , Lipoproteínas/sangre , Isquemia Miocárdica/tratamiento farmacológico , Proproteína Convertasa 9 , Factores de Riesgo , Triglicéridos/sangreRESUMEN
OBJECTIVES: This study aimed to determine whether an enhanced bioavailable curcumin formulation, CurQfen®, would improve circulating cardiovascular disease-related blood biomarkers and arterial function in young (age 18-35 y), obese (body mass index ≥ 30.0 kg/m2) men. METHODS: This double-blinded, placebo-controlled trial evaluated 22 men. The participants were matched based on body mass index and randomized to the intervention (curcumin formulated with fenugreek soluble fiber, for enhanced absorption) or control (fenugreek soluble fiber) group for 12 wk at 500mg/d without dietary modification or exercise. Blood samples and endothelial function measures were acquired at 0 and 12 wk, and blood samples were analyzed for cardiovascular disease-related blood biomarkers. Furthermore, central (aortic) blood pressure and augmentation index were monitored at 0, 4, 8, and 12 wk. RESULTS: After 12 wk of intervention, homocysteine levels were lower (curcumin before: 12.22 ± 2.29 µg/mL, after: 8.62 ± 1.02 µg/mL versus placebo before: 9.45 ± 0.84 µg/mL, after: 11.84 ± 1.63 µg/mL; Pâ¯=â¯0.04) and high-density lipoprotein levels were higher (curcumin before: 40.77 ± 5.37 mg/dL, after: 54.56 ± 11.72 mg/dL versus placebo before: 61.20 ± 5.76 mg/dL, after: 48.82 ± 5.49 mg/dL; Pâ¯=â¯0.04) in the curcumin group relative to the placebo group. However, there was no significant difference in changes between the circulating concentrations of glucose, insulin, leptin, adiponectin, or oxidative stress biomarkers in the curcumin group compared with the placebo group (P > 0.05). No changes were found with endothelial function, augmentation index, or central blood pressure in the curcumin group compared with the placebo group (P > 0.05). CONCLUSIONS: Our data provide evidence for an enhanced bioavailable curcumin to improve homocysteine and high-density lipoprotein concentrations, which may promote favorable cardiovascular health in young, obese men. Improvements in endothelial function or blood pressure were not observed with curcumin supplementation, thus further investigation is warranted.
Asunto(s)
Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/complicaciones , Curcumina/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Obesidad/complicaciones , Adolescente , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacología , Arterias/efectos de los fármacos , Arterias/fisiología , Biomarcadores/sangre , Curcumina/administración & dosificación , Curcumina/metabolismo , Suplementos Dietéticos , Método Doble Ciego , Homocisteína/sangre , Homocisteína/efectos de los fármacos , Humanos , Lipoproteínas/sangre , Lipoproteínas/efectos de los fármacos , Masculino , Obesidad/sangre , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVES: Patients with inflammatory joint diseases (IJD) have an increased risk of cardiovascular disease (CVD). Our goal was to examine indications for, and use of, lipid-lowering therapy (LLT) and antihypertensive treatment (AntiHT) in patients with IJD. Furthermore, to investigate the frequency of low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) goal attainment among IJD patients. METHODS: The cohort was derived from the NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR). Indications for AntiHT were: systolic/diastolic BPâ¯≥â¯140/90â¯mmâ¯Hg, self-reported hypertension or AntiHT. CVD risk was estimated by the systematic coronary risk evaluation (SCORE) algorithm. LDL-c goals were <2.6â¯mmol/L in case of diabetes, total cholesterolâ¯>â¯8â¯mmol/L or a SCORE estimateâ¯≥â¯5%, and <1.8â¯mmol/L for those with established CVD or SCOREâ¯≥â¯10%. Comparisons across IJD entities were performed using age and sex adjusted logistic regression. RESULTS: In total, 2277 patients (rheumatoid arthritis: 1376, axial spondyloarthritis: 474, psoriatic arthritis: 427) were included. LLT and AntiHT were indicated in 36.1% and 52.6% of the patients, of whom 37.6% and 47.0% were untreated, respectively. LDL-c and BP targets were obtained in 26.2% and 26.3%, respectively. Guideline recommended treatment and/or corresponding treatment targets were not initiated or obtained in approximately 50%. Rheumatoid arthritis patients were particularly likely to be undertreated with LLT, whereas hypertension undertreatment was most common in psoriatic arthritis. CONCLUSIONS: Inadequate CVD prevention encompasses all the three major IJD entities. The unmet need for CVD preventive measures is not only prevalent in RA, but exists across all the major IJD entities.
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Antihipertensivos/uso terapéutico , Artritis/complicaciones , Enfermedades Cardiovasculares/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Guías de Práctica Clínica como Asunto , Medición de Riesgo , Prevención Secundaria/métodos , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Femenino , Humanos , Incidencia , Lipoproteínas/sangre , Lipoproteínas/efectos de los fármacos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Factores de RiesgoRESUMEN
: Tissue factor (TF) pathway inhibitor (TFPI) is an endogenous natural anticoagulant that readily inhibits the extrinsic coagulation initiation complex (TF-FVIIa-Xa) and prothrombinase (FXa, FVa and calcium ions). Alternatively, spliced TFPI isoforms (α, ß and δ) are expressed by vascular and extravascular cells and regulate thrombosis and haemostasis, as well as cell signalling functions of TF complexes via protease-activated receptors (PARs). Proteolysis of TFPI plays an important role in regulating physiological roles of the TF pathway in host defense and possibly haemostasis. Elimination of TFPI inhibition has therefore been proposed as an approach to improve haemostasis in haemophilia patients. In this review, we focus on posttranscription and translational modification of TFPI and its function in thrombosis and how pharmacological inhibitors and endogenous proteases interfere with TFPI and alter haemostasis.
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Hemostasis/efectos de los fármacos , Lipoproteínas/metabolismo , Animales , Humanos , Lipoproteínas/efectos de los fármacos , Lipoproteínas/genética , Procesamiento Proteico-Postraduccional , Procesamiento Postranscripcional del ARN , Trombosis/etiologíaRESUMEN
Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. Sustained viral response (SVR) achievement led to decreasing incidence and prevalence of T2DM during the interferon era of HCV treatment. Currently, direct-acting antiviral drugs (DAA) are the gold standard for treating HCV infection, while yielding SVR in nearly all patients. In chronic HCV patients with T2DM (prediabetes most likely too), DAA therapy is associated with both better fasting glucose and glycated hemoglobin (HbA1C) controls; thus reducing pharmacotherapy in a certain part of patients is possible. Papers mentioned in the review confirmed DAA role in both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase. This alteration was accompanied by an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides (TG) verified by most of the studies. However, the clinical significance of lipoprotein alterations caused by DAA therapy has not been explained yet. Moreover, DAA treatment of chronic hepatitis C improves hypertension control and atherosclerotic plaques. It is very likely that DAA therapeutic regimens will decrease both T2DM prevalence and cardiovascular risk in chronic hepatitis C patients; further research, however, is needed.
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Antivirales/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Lipoproteínas/metabolismo , Antivirales/farmacología , Aterosclerosis , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Hemoglobina Glucada/efectos de los fármacos , Hepatitis C Crónica/fisiopatología , Humanos , Resistencia a la Insulina , Lipoproteínas/efectos de los fármacos , Factores de Riesgo , Respuesta Virológica SostenidaRESUMEN
The past decade has witnessed considerable progress in the field of lipids. New drugs have been "rapidly" developed and some of these drugs have already been evaluated in event-based large trials. This evidence has led to the guidelines recommending new, more aggressive treatment goals for low-density lipoprotein cholesterol (LDL-C) levels. Although LDL-C remains the principal goal for cardiovascular disease (CVD) risk reduction, there has also been considerable interest in other lipid variables, such as high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a). Statin intolerance is now considered a very important topic in daily clinical practice. This has resulted in more attention focusing on non-statin drugs [e.g., ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors] and statin-related side effects. The latter mainly involve muscles, but there is also a need to consider other adverse effects associated with statin use (e.g., new onset diabetes). New specific areas of statin use have attracted interest. For example, statin-loading before procedures (e.g., coronary stenting), the prevention of stroke, and the treatment of non-alcoholic fatty liver disease (NAFLD). Statins will remain the most widely used drugs to treat dyslipidaemia and decrease CVD risk. However, we also need to briefly consider some other lipid-lowering drugs, including those that may become available in the future.
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Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , HDL-Colesterol/efectos de los fármacos , LDL-Colesterol/efectos de los fármacos , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteínas/efectos de los fármacos , Inhibidores de Proteasas/uso terapéutico , Triglicéridos , Anticolesterolemiantes/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Proteasas/efectos adversosRESUMEN
Fundamental complications of insulin resistance and type 2 diabetes include the development of nonalcoholic fatty liver disease and an atherogenic fasting dyslipidemic profile, primarily due to increases in hepatic very-low-density lipoprotein (VLDL) production. Recently, central glucagon-like peptide-2 receptor (GLP2R) signaling has been implicated in regulating hepatic insulin sensitivity; however, its role in hepatic lipid and lipoprotein metabolism is unknown. We investigated the role of glucagon-like peptide-2 (GLP-2) in regulating hepatic lipid and lipoprotein metabolism in Syrian golden hamsters, C57BL/6J mice, and Glp2r-/- mice consuming either a normal chow or high-fat diet (HFD). In the chow-fed hamsters, IP GLP-2 administration significantly increased fasting dyslipidemia, hepatic VLDL production, and the expression of key genes involved in hepatic de novo lipogenesis. In HFD-fed hamsters and chow-fed mice, GLP-2 administration exacerbated or induced hepatic lipid accumulation. HFD-fed Glp2r-/- mice displayed reduced glucose tolerance, VLDL secretion, and microsomal transfer protein lipid transfer activity, as well as exacerbated fatty liver. Thus, we conclude that GLP-2 plays a lipogenic role in the liver by increasing lipogenic gene expression and inducing hepatic steatosis, fasting dyslipidemia, and VLDL overproduction. In contrast, the lack of Glp2r appears to interfere with VLDL secretion, resulting in enhanced hepatic lipid accumulation. These studies have uncovered a role for GLP-2 in maintaining hepatic lipid and lipoprotein homeostasis.
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Dislipidemias/metabolismo , Hígado Graso/metabolismo , Péptido 2 Similar al Glucagón/farmacología , Lipogénesis/efectos de los fármacos , Lipoproteínas VLDL/efectos de los fármacos , Hígado/efectos de los fármacos , Animales , Expresión Génica/efectos de los fármacos , Receptor del Péptido 2 Similar al Glucagón/genética , Lipogénesis/genética , Lipoproteínas/efectos de los fármacos , Lipoproteínas/metabolismo , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Masculino , Mesocricetus , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
PsaA (pneumococcal surface antigen A) is a S. pneumoniae virulence factor that belongs to the metal transport system. The Manganese PsaA binding has been associated with oxidative stress resistance becoming a pivotal element in the bacteria virulence. It has been shown that Zinc inhibits the Manganese acquisition and promotes bacteria toxicity. We have performed a PsaA conformational analysis both in the presence (Zn-rPsaA) and in the absence of Zinc (free-rPsaA). We performed experiments in the presence of different Zinc concentrations to determine the metal minimum concentration which induced a conformational change. The protein in free and Zn-binding condition was also studied in pH ranging 2.6-8.0 and in temperature ranging 25oC-85oC. pH experiments showed a decrease of fluorescence intensity only in acidic medium. Analysis of the heat-induced denaturation demonstrated that Zinc-binding promoted an increase in melting temperature from 55oC (free-rPsaA) to 78.8oC (Zn-rPsaA) according to fluorescence measurements. In addition, the rPsaA stabilization by Zinc was verified through analysis of urea and guanidine hydrochloride denaturation. Data showed that Zinc promoted an increase in the rPsaA stability and its removal by EDTA can lead to a PsaA intermediate conformation. These findings can be considered in the development of vaccines containing PsaA as antigen.
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Adhesinas Bacterianas/química , Antígenos de Superficie/química , Lipoproteínas/química , Conformación Proteica/efectos de los fármacos , Streptococcus pneumoniae/química , Zinc/farmacología , Adhesinas Bacterianas/efectos de los fármacos , Lipoproteínas/efectos de los fármacos , Espectrometría de Fluorescencia , TemperaturaRESUMEN
BACKGROUND: Lipid emulsions given i.v. are normally rapidly metabolized by apoprotein recruited from high-density lipoprotein (HDL) particles in the blood. Very low-birthweight infants (VLBWI), however, have a low rate of lipid clearance from the blood, and therefore lipid emulsions must be given carefully to minimize the risk of hyperlipidemia. The purpose of this study was to evaluate the influence of i.v. lipid emulsion on lipoprotein subclass profile in VLBWI during the early postnatal period. METHODS: Forty-six VLBWI who had been given different doses of lipid emulsion in the first few days after birth were enrolled in the present study. Triglyceride and cholesterol content of each lipoprotein subclass was measured at 3 weeks after birth, and their correlation with the total dose of lipid emulsion was calculated. RESULTS: There was no correlation between the total dose of lipid emulsion and the triglyceride and cholesterol content in any subclasses of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). There was a significant negative correlation between the total dose of lipid emulsion and the triglyceride content in very large (P < 0.05, r = -0.32), large (P < 0.01, r = -0.47) and medium HDL (P < 0.05, r = -0.34) particles; and the cholesterol content in large (P < 0.01, r = -0.47) and medium HDL (P < 0.01, r = -0.4) particles. CONCLUSION: Lipid emulsion influenced the triglyceride and cholesterol content of HDL particles in VLBWI, suggesting that lipid emulsion can affect lipid metabolism in this infant population in the early postnatal period.
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Colesterol/sangre , Emulsiones Grasas Intravenosas/efectos adversos , Lipoproteínas/efectos de los fármacos , Triglicéridos/sangre , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Lipoproteínas/sangre , MasculinoRESUMEN
BACKGROUND AND OBJECTIVE: Several studies have shown an association between periodontitis and cardiovascular disease (CVD). Atherosclerosis is the major cause of CVD, and a key event in the development of atherosclerosis is accumulation of lipoproteins within the arterial wall. Bacteria are the primary etiologic agents in periodontitis and Porphyromonas gingivalis is the major pathogen in the disease. Several studies support a role of modified low-density lipoprotein (LDL) in atherogenesis; however, the pathogenic stimuli that induce the changes and the mechanisms by which this occur are unknown. This study aims to identify alterations in plasma lipoproteins induced by the periodontopathic species of bacterium, P. gingivalis, in vitro. MATERIAL AND METHODS: Plasma lipoproteins were isolated from whole blood treated with wild-type and gingipain-mutant (lacking either the Rgp- or Kgp gingipains) P. gingivalis by density/gradient-ultracentrifugation and were studied using 2-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization mass spectrometry. Porphyromonas gingivalis-induced lipid peroxidation and antioxidant levels were measured by thiobarbituric acid-reactive substances and antioxidant assay kits, respectively, and lumiaggregometry was used for measurement of reactive oxygen species (ROS) and aggregation. RESULTS: Porphyromonas gingivalis exerted substantial proteolytic effects on the lipoproteins. The Rgp gingipains were responsible for producing 2 apoE fragments, as well as 2 apoB-100 fragments, in LDL, and the Kgp gingipain produced an unidentified fragment in high-density lipoproteins. Porphyromonas gingivalis and its different gingipain variants induced ROS and consumed antioxidants. Both the Rgp and Kgp gingipains were involved in inducing lipid peroxidation. CONCLUSION: Porphyromonas gingivalis has the potential to change the expression of lipoproteins in blood, which may represent a crucial link between periodontitis and CVD.
Asunto(s)
Adhesinas Bacterianas/metabolismo , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/farmacocinética , Lipoproteínas/efectos de los fármacos , Lipoproteínas/metabolismo , Periodontitis/metabolismo , Porphyromonas gingivalis/metabolismo , Adhesinas Bacterianas/sangre , Adhesinas Bacterianas/genética , Antioxidantes/análisis , Apolipoproteína A-I/metabolismo , Apolipoproteína B-100/metabolismo , Cisteína Endopeptidasas/sangre , Cisteína Endopeptidasas/genética , Cisteína-Endopeptidasas Gingipaínas , Humanos , Peroxidación de Lípido , Lipoproteínas/sangre , Lipoproteínas HDL/sangre , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/sangre , Lipoproteínas LDL/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Metionina/metabolismo , Periodontitis/microbiología , Porphyromonas gingivalis/patogenicidad , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Regular exercise and anabolic androgenic steroids have opposing effects on the plasma lipoprotein profile and risk of cardio-metabolic diseases in humans. Studies in humans and animal models show conflicting results. Here, we used a mice model genetically modified to mimic human lipoprotein profile and metabolism. They under-express the endogenous LDL receptor gene (R1) and express a human transgene encoding the cholesteryl ester transfer protein (CETP), normally absent in mice. The present study was designed to evaluate the independent and interactive effects of testosterone supplementation, exercise training and CETP expression on the plasma lipoprotein profile and CETP activity. CETP/R1 and R1 mice were submitted to a 6-week swimming training and mesterolone (MEST) supplementation in the last 3 weeks. MEST treatment increased markedly LDL levels (40%) in sedentary CETP/R1 mice and reduced HDL levels in exercised R1 mice (18%). A multifactorial ANOVA revealed the independent effects of each factor, as follows. CETP expression reduced HDL (21%) and increased non-HDL (15%) fractions. MEST treatment increased the VLDL concentrations (42%) regardless of other interventions. Exercise training reduced triacylglycerol (25%) and free fatty acids (20%), increased both LDL and HDL (25-33%), and reduced CETP (19%) plasma levels. Significant factor interactions showed that the increase in HDL induced by exercise is explained by reducing CETP activity and that MEST blunted the exercise-induced elevation of HDL-cholesterol. These results reinforce the positive metabolic effects of exercise, resolved a controversy about CETP response to exercise and evidenced MEST potency to counteract specific exercise benefits.
Asunto(s)
Anabolizantes/administración & dosificación , Proteínas de Transferencia de Ésteres de Colesterol/genética , Regulación hacia Abajo , Lipoproteínas/sangre , Mesterolona/administración & dosificación , Natación/fisiología , Anabolizantes/farmacología , Animales , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Humanos , Lipoproteínas/efectos de los fármacos , Mesterolona/farmacología , Ratones , Ratones Transgénicos , Modelos Animales , Receptores de LDL/genética , Conducta SedentariaRESUMEN
Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.
Asunto(s)
Apolipoproteína C-III/genética , Lipoproteínas/metabolismo , Mutación Missense , Triglicéridos/metabolismo , Anciano , Animales , Anticuerpos Monoclonales/farmacología , Apolipoproteína C-III/efectos de los fármacos , Apolipoproteínas B/metabolismo , HDL-Colesterol/metabolismo , Cromatografía Liquida , Simulación por Computador , Enfermedad Coronaria/genética , Estudios Transversales , Femenino , Humanos , Immunoblotting , Metabolismo de los Lípidos/genética , Lipoproteínas/efectos de los fármacos , Lipoproteínas VLDL/metabolismo , Masculino , Espectrometría de Masas , Ratones , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Factores Protectores , Espectrometría de Masas en TándemRESUMEN
RESUMO Objetivo Avaliar o efeito da suplementação com ômega-3 nas subfrações das lipoproteínas de alta densidade em indivíduos tabagistas. Métodos Ensaio clínico, randomizado, duplo-cego. Foi selecionada uma amostra com 33 tabagistas, de ambos os sexos, com idade entre 30 e 60 anos, suplementados com ômega-3 (n=17) ou placebo (ácidos graxos ômega-6, n=16) por dois meses. As subfrações das lipoproteínas de alta densidade foram analisadas pelo sistema Lipoprint. Os testes estatísticos foram realizados com o auxílio do programa Statistical Package for the Social Sciences, versão 20.0. Resultados A média de idade foi 49 anos, com predominância da raça branca. Após a intervenção, o grupo ômega-3 modificou positivamente o perfil lipídico e as subfrações das lipoproteínas de alta densidade dos tabagistas. Nos modelos de regressão linear testados, o percentual de ácido docosahexaenoico plasmático apresentou associações negativas com o percentual das lipoproteínas de alta densidade-pequena. Conclusão A suplementação com ômega-3 está associada a uma alteração favorável na distribuição das subfrações das lipoproteínas de alta densidade, aumentando as lipoproteínas de alta densidade-grande e diminuindo as lipoproteínas de alta densidade-pequena. Isso reforça a importância do ômega-3 na saúde cardiovascular de indivíduos tabagistas.
ABSTRACT Objective To assess the effect of omega-3 supplementation on smokers' high density lipoprotein subfractions. Methods This randomized, double-blind clinical trial included 33 male and female smokers aged 30 to 60 years. The sample took omega-3 fatty acids (n=17) or placebo (omega-6 fatty acids, n=16) for two months. The Lipoprint system analyzed the high density lipoprotein subfractions. The statistical tests were performed by the software Statistical Package for the Social Sciences, version 20.0. Results The mean age of the sample was 49 years, and most individuals were white. After the intervention, the lipid profile and high density lipoprotein subfractions of the omega-3 group improved. In the tested linear regression models, the percentage of plasma docosahexaenoic acid was negatively associated with the percentage of small high density lipoprotein. Conclusion Omega-3 supplementation is associated with a favorable change in the distribution of high density lipoprotein subfractions, increasing the large and reducing the small high density lipoproteins. This finding reinforces the importance of omega-3 fatty acids for smokers' cardiovascular health.