RESUMO
A series of N-(benzoylphenyl)-carboxamide derivatives (2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a and 6b) was prepared with good yields by reacting the corresponding carbonyl chlorides with aminobenzophenones at room temperature. This was followed by evaluating the hypotriglyceridemic and hypocholesterolemic effects of 3b, 5a and 5b. Triton WR-1339 (300 mg/kg) was intraperitoneally administered to overnight-fasted rats to induce hyperlipidemia. Rats were divided into six groups: control, hyperlipidemic, hyperlipidemic plus compounds 3b, 5a and 5b and hyperlipidemic plus bezafibrate. Results showed that after 18 h of treatment at a dose of 15 mg/kg body weight of each of the test compounds, the elevated plasma levels of triglycerides (TG) and total cholesterol (TC) were significantly lowered by compounds 5b and 3b (p < 0.001) and by 5a (p < 0.0001), compared to the hyperlipidemic control group. Compounds 3b and 5a significantly increased levels of high-density lipoprotein cholesterol (HDL-C) by 58 and 71%, respectively. In addition, compounds 3b and 5a caused significant reduction (p < 0.0001) of low-density lipoprotein cholesterol (LDL-C) levels compared to the control group. These results suggest a promising potential for compounds 3b, 5a and 5b as lipid-lowering agents, which may contribute to reducing the risk of atherosclerosis and cardiovascular disease
Assuntos
Animais , Masculino , Ratos , Piridinas/farmacologia , Hiperlipidemias/induzido quimicamente , Lipídeos/sangue , Hipolipemiantes/farmacologia , Polietilenoglicóis , Piridinas/síntese química , Triglicerídeos/sangue , Colesterol/sangue , Ratos Wistar , Modelos Animais de Doenças , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas LDL/efeitos dos fármacos , Hipolipemiantes/síntese químicaRESUMO
The efficiency of cholesterol efflux from cells promoted by high-density lipoproteins (HDLs) depends on HDL concentration and functional properties. The term "dysfunctional HDL" describes HDLs with impaired protective properties. Cholesterol efflux capacity (CEC) of HDL is reduced in patients with atherosclerosis, but the exact mechanisms underlying this impairment are not well characterized. Enriching HDLs with phospholipids (PLs) improves CEC. Herein, we assessed the potential of PL nanoparticles in improving HDL functionality. We lipidated HDL subfractions by incubating with PL nanoparticles containing soybean polyunsaturated phosphatidylcholine. Incubating blood plasma with PL nanoparticles resulted in the dose-dependent lipidation of all HDL subfractions. Changes in apolipoprotein A1 (apoA-1) and PL concentrations were the most prominent in the HDL2 fraction. Concentrations of PL in the HDL3 fraction and the fraction with a density > 1.21 g/mL increased by 30-50%, whereas apoA-1 levels decreased. We hypothesized that PL nanoparticles may cause HDL remodeling that can improve their functions. The CECs of lipidated HDLs were analyzed by incubating apolipoprotein B (apoB)-depleted plasma with 3H-cholesterol-labeled THP-1 macrophages. The findings revealed a two-fold increase in cholesterol efflux compared with native apoB-depleted plasma. Moreover, intravenous administration of PL nanoparticles restored lipid profiles and effectively protected blood vessels from atherosclerosis progression in cholesterol-fed rabbits compared with that of fenofibrate and atorvastatin. PL nanoparticles also protected against atherosclerosis and decreased the atherogenic index. Altogether, these results indicate that PL nanoparticles can be used to correct the lipid composition and CEC of HDLs. DATA AVAILABILITY: Additional data can be provided upon reasonable request from the date of publication of this article within 5 years. The request should be sent to the author-correspondent at the address cd95@mail.ru.
Assuntos
Aterosclerose/prevenção & controle , Colesterol/metabolismo , Lipoproteínas HDL/efeitos dos fármacos , Fosfolipídeos/farmacologia , Animais , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/sangue , Aterosclerose/sangue , Chinchila , Colesterol/sangue , Colesterol na Dieta , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Macrófagos/metabolismo , Masculino , Nanopartículas , Fosfatidilcolinas/farmacologia , CoelhosRESUMO
Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.
Assuntos
Aterosclerose/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipoproteínas LDL/efeitos dos fármacos , Doenças Cardiovasculares , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas HDL/efeitos dos fármacos , Niacina/farmacologia , Comportamento de Redução do RiscoRESUMO
To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.
Assuntos
Adalimumab/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/efeitos dos fármacos , MasculinoRESUMO
AIMS: Oxidized phospholipids (OxPLs) are formed as a result of oxidative stress, which potentially mediate multiple pathological effects. We aimed to evaluate the effects of hydrogen (H2) on OxPLs in vivo and the underlying mechanism. MAIN METHODS: Rats were randomly assigned to three groups: control group fed with a chow diet, model group fed with a high-fat diet, and H2-treated group fed with a high-fat diet and treated by 4% H2 inhalation for ten weeks. OxPLs in liver and plasma were analyzed by liquid chromatography-mass spectrometry. High-density lipoprotein (HDL) was separated by ultracentrifugation. A proteomic analysis was performed to reveal the alternation of HDL protein composition and he antioxidant capacity of HDL was tested by low-density lipoprotein oxidation experiment. Furthermore, the activity or expression of HDL-associated enzymes were evaluated. KEY FINDINGS: Inhalation of 4% H2 decreased the accumulation of OxPLs in rats. In vitro tests revealed that the different concentrations of H2 did not inhibit the formation of OxPLs mediated by non-enzymatic oxidation. H2 inhalation altered the components and enhanced the anti-oxidative capacity of HDL in rats fed with a high-fat diet. Further experiments showed that H2 significantly regulated the activity of lipoprotein-associated phospholipase A2, paraoxonase-1, and the expression of lecithin:cholesterol acyltransferase. SIGNIFICANCE: Our findings revealed that H2 may reduce the OxPLs levels through its influence on HDL-associated enzymes that can act on OxPLs, suggesting that H2 can be used in alleviating diseases related to lipid peroxidation due to oxidative stress.
Assuntos
Hidrogênio/metabolismo , Hidrogênio/farmacologia , Fosfolipídeos/metabolismo , Administração por Inalação , Animais , Antioxidantes/farmacologia , Apolipoproteína A-I/metabolismo , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/metabolismo , Cromatografia Líquida/métodos , Dieta Hiperlipídica/efeitos adversos , Peroxidação de Lipídeos , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Proteômica/métodos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. METHODS: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. RESULTS: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. CONCLUSIONS: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.
Assuntos
Aorta Torácica/efeitos dos fármacos , Benzoxazóis/farmacologia , Butiratos/farmacologia , Dieta Hiperlipídica , Endotélio/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Quinolinas/farmacologia , Cloreto de Sódio na Dieta , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , VLDL-Colesterol/sangue , VLDL-Colesterol/efeitos dos fármacos , Quilomícrons/sangue , Quilomícrons/efeitos dos fármacos , Quimioterapia Combinada , Endotélio/fisiopatologia , Hipertensão/fisiopatologia , Hipolipemiantes/farmacologia , Resistência à Insulina , Lipoproteínas HDL/sangue , Lipoproteínas HDL/efeitos dos fármacos , PPAR alfa , Ratos , Ratos Endogâmicos Dahl , Triglicerídeos/sangue , Vasodilatação/fisiologiaRESUMO
Lipoprotein apheresis (LA) treatment results in a substantial reduction of low-density lipoprotein- (LDL-) cholesterol and lipoprotein(a) concentrations, which consequently decreases the rate of cardiovascular events. The additional benefit of LA may be associated with its impact on the composition and quality of high-density lipoprotein (HDL) particles, inflammation, and oxidative stress condition. To verify the effects of LA procedure, the current study is aimed at analyzing the effect of a single apheresis procedure with direct hemadsorption (DALI) and cascade filtration (MONET) on oxidative stress markers and HDL-related parameters. The study included eleven patients with familial hypercholesterolemia and hyperlipoproteinemia(a) treated with regular LA (DALI or MONET). We investigated the pre- and postapheresis concentration of the lipid-related oxidative stress markers 8-isoPGF2, oxLDL, TBARS, and PON-1. We also tracked potential changes in the main HDL apolipoproteins (ApoA-I, ApoA-II) and cholesterol contained in HDL subfractions. A single session of LA with DALI or MONET techniques resulted in a similar reduction of lipid-related oxidative stress markers. Concentrations of 8-isoPGF2 and TBARS were reduced by ~60% and ~30%, respectively. LA resulted in a 67% decrease in oxLDL levels along with a ~19% reduction in the oxLDL/ApoB ratio. Concentrations of HDL cholesterol, ApoA-I, ApoA-II, and PON-1 activity were also reduced by LA sessions, with more noticeable effects seen in the MONET technique. The quantitative proportions between HDL2 and HDL3 cholesterol did not change significantly by both methods. In conclusion, LA treatment with MONET or DALI system has a small nonselective effect on lowering HDL particles without any changes in the protein composition of these particles. Significant reduction in the level of oxidative stress parameters and less oxidation of LDL particles may provide an additional benefit of LA therapy.
Assuntos
Biomarcadores/metabolismo , Remoção de Componentes Sanguíneos/métodos , Lipoproteínas HDL/efeitos dos fármacos , Feminino , Humanos , Masculino , Estresse OxidativoRESUMO
Fibrates, peroxisome proliferator-activated receptor-α agonists, are potent lipid-modifying drugs. Their main effects are reduction of triglycerides and increase in high-density lipoprotein levels. Several randomized controlled trials have not demonstrated their benefits on cardiovascular risk reduction, especially as an "add on" to statin therapy. However, subsequent analyses by major clinical trials, meta-analyses, and real-world evidence have proposed their potential in specific patient populations with atherogenic dyslipidemia and metabolic syndrome. Here, we have reviewed and discussed the accumulated data on fibrates to understand their current status in cardiovascular risk management.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Ácidos Fíbricos/farmacologia , PPAR alfa/agonistas , Adulto , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos como Assunto , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Ácidos Fíbricos/uso terapêutico , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas HDL/efeitos dos fármacos , Metanálise como Assunto , Síndrome Metabólica/tratamento farmacológico , Prevalência , República da Coreia/epidemiologia , Triglicerídeos/metabolismoRESUMO
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a new specific vascular inflammation biomarker that is carried by the lipoproteins in the blood and plays a prominent role in the pathogenesis of atherosclerosis. Increased Lp-PLA2 levels and impaired Lp-PLA2 distribution across high-density lipoprotein (HDL) and non-HDL lipoproteins have been reported in diabetic patients, which is associated with the increase in cardiovascular disease (CVD) risk. This study is aimed at investigating the effect of alpha lipoic acid (ALA), as an antioxidant with potential cardioprotective properties, on the Lp-PLA2 mass and its distribution in diabetic patients. In a double-blind, randomized, placebo-controlled clinical trial, seventy diabetic patients were randomly allocated to ALA (1200 mg ALA as two 600 mg capsules/day) and placebo (two maltodextrin capsules/day) groups. The serum levels of total Lp-PLA2 mass, HDL-Lp-PLA2, oxidized low-density lipoproteins (ox-LDL), apolipoprotein A1 (apo A1), lipid profiles, fasting blood sugar (FBS), and insulin were measured, and apolipoprotein B- (apoB-) associated Lp-PLA2 and homeostasis model of assessment index (HOMA-IR) were calculated at the baseline and after 8 weeks of intervention. ALA significantly decreased the ox-LDL, total Lp-PLA2 mass, apoB-associated Lp-PLA2, and percent of apoB-associated Lp-PLA2 and triglyceride and increased the percent of HDL-Lp-PLA2 compared with the placebo group but had no significant effect on HDL-Lp-PLA2 mass, apo A1, lipid profiles, and glycemic indices. There was a positive correlation between the reduction in the ox-LDL level and total Lp-PLA2 mass in the ALA group. In conclusion, ALA may decrease the CVD risk by reducing the ox-LDL and Lp-PLA2 mass and improving the Lp-PLA2 distribution among lipoproteins in type 2 diabetic patients.
Assuntos
Apolipoproteína A-I/efeitos dos fármacos , Apolipoproteína B-100/efeitos dos fármacos , Suplementos Nutricionais/análise , Lipoproteínas HDL/efeitos dos fármacos , Ácido Tióctico/uso terapêutico , Adulto , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Ácido Tióctico/farmacologiaRESUMO
OBJECTIVE: We sought to investigate the effects and mechanism of lead and a high-fat diet on cognitive function and the central nervous system in mice. METHODS: Eighty-four healthy male mice were randomly divided into a control group (n = 21) (fed with common diet and free drinking), a lead exposure group (n = 21) (fed with common diet and 300 mg/L lead acetate solution), a high-fat group (n = 21) (fed with high-fat diet and free drinking), and a lead + high-fat group (n = 21) (fed with high-fat diet and 300 mg/L lead acetate solution). In 10 weeks after lead exposure, the mice of all groups were tested for the cognition, learning and memory abilities, body weight, serum triglyceride (TG), low-density lipoprotein, and high-density lipoprotein, as well as for the contents of lead, interleukin 6 (IL-6), interleukin 17 (IL-17), interferon γ, advanced glycation end products (AGEs), glutathione S-transferase (GSH-ST), and hydrogen peroxide in the brain tissues. RESULTS: Compared with the control group and the lead-exposed group, the body weights of mice in the high-fat group and the lead + high-fat group increased significantly from the sixth week of the experiment, of which the difference was statistically significant (P < 0.05). Compared with the control group and the high-fat group, the lead content in brain tissue of the lead exposure group and the lead + high-fat group increased significantly, of which the difference was statistically significant (P < 0.05). Compared with the control group, the escape latent period, triglyceride, low-density lipoprotein, IL-6, IL-17, interferon γ, and AGEs of the remaining 3 groups increased significantly, but the recognition index, passing platform times, high-density lipoprotein, and GSH-ST significantly decreased (P < 0.05); the second and third escape latent periods, IL-6, IL-17, and AGEs of lead + high-fat group, were obviously higher than the remaining 3 groups, but the passing platform times were obviously lower than the remaining 3 groups, of which the difference was statistically significant. The content of hydrogen peroxide in brain tissues had no difference among groups (P > 0.05). CONCLUSIONS: The lead and high-fat diet resulted in lipid metabolism disorders and impaired the cognitive function and central nervous system by promoting the secretion of inflammatory factors in glial cells, inducing the inflammatory reaction of brain tissue, inhibiting GSH-ST expression, and increasing AGEs content.
Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dieta Hiperlipídica , Intoxicação por Chumbo/psicologia , Chumbo/toxicidade , Animais , Encéfalo/metabolismo , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Produtos Finais de Glicação Avançada/metabolismo , Peróxido de Hidrogênio/metabolismo , Interferon gama/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Intoxicação por Chumbo/metabolismo , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Distribuição Aleatória , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Polycystic Ovary Syndrome (PCOS) is known as the most common endocrine disorder of women in reproductive ages. With the increasing prevalence of PCOS in different countries, the use of herbal medicine as an alternative treatment is growing in these patients. This study aimed to evaluate the effects of flaxseed powder supplementation on metabolic biomarkers of patients with PCOS. METHODS: This randomized open-labeled controlled clinical trial was conducted on 41 patients with PCOS. The participants were randomized to take either flaxseed powder (30 g/day) plus lifestyle modification or only lifestyle modification for 12 weeks. Anthropometric and biochemical evaluations were performed for all patients at the beginning and end of the study. RESULTS: The flaxseed group showed a significant reduction in body weight, insulin concentration, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Triglycerides (TG), high-sensitivity C-Reactive Protein (hs-CRP), and leptin and an increase in Quantitative Insulin-Sensitivity Check Index (QUICKI), High Density Lipoprotein (HDL), and adiponectin compared to the baseline (p < 0.05). Flaxseed supplementation also led to a significant reduction in insulin concentration, HOMA-IR, TG, hs-CRP, Interleukin 6 (IL- 6), and leptin and an increase in QUICKI, HDL, and adiponectin compared to the control group (p < 0.05). No significant changes were observed in other parameters. CONCLUSIONS: Flaxseed supplementation plus lifestyle modification was more effective compared to lifestyle modification alone in biochemical and anthropometric variables in patients with PCOS. TRIAL REGISTRATION: The trial protocol was approved by the Ethics Board at Ahvaz Jundishapur University of Medical Sciences and was registered at Iranian Registry of Clinical Trials (code: IRCT20120704010181N11).
Assuntos
Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Linho/metabolismo , Síndrome do Ovário Policístico/sangue , Adiponectina/sangue , Adolescente , Adulto , Biomarcadores/sangue , Proteína C-Reativa/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Feminino , Humanos , Insulina/sangue , Irã (Geográfico) , Leptina/sangue , Lipoproteínas HDL/sangue , Lipoproteínas HDL/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Adulto JovemRESUMO
Many population studies have shown that blood concentrations of high-density lipoprotein (HDL) cholesterol are inversely correlated with risk of cardiovascular disease (CVD). However, in recent studies, increasing blood HDL cholesterol concentrations failed to reduce CVD events. On the other hand, studies suggest that improving HDL quality can be a more efficient tool for assessing atherosclerotic risk than simply measuring blood HDL cholesterol concentration. Thus, improving HDL activity using natural substances might be a useful therapeutic approach to reducing CVD risk. We previously isolated a novel active compound from Nannochloropsis microalgae termed lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS), which increased activity of paraoxonase 1, the main antioxidant enzyme associated with HDL. Here we examined the effect of lyso-DGTS on HDL quality and function. Tryptophan-fluorescence-quenching assay showed that lyso-DGTS interacts spontaneously with the entire HDL lipoprotein and with apolipoprotein A1 (ApoA1), the major structural and functional HDL protein, with high affinity (Ka = 2.17 × 104 M-1 at 37°C). Lyso-DGTS added to HDL and to ApoA1 increased cholesterol efflux from macrophage cells, the main antiatherogenic function of HDL, dose-dependently, and significantly increased HDL's ability to induce nitric oxide production from endothelial cells. In-vivo supplementation of lyso-DGTS to the circulation of mice fed a high-fat diet via osmotic mini-pumps implanted subcutaneously enhanced HDL anti-inflammatory effect significantly as compared to controls. Our findings suggest that lyso-DGTS may have a beneficial effect in decreasing atherosclerosis risk by interacting with HDL particles and improving their quality and antiatherogenic functions.
Assuntos
Dieta Hiperlipídica , Lipoproteínas HDL/sangue , Lipoproteínas HDL/efeitos dos fármacos , Microalgas , Triglicerídeos/sangue , Triglicerídeos/farmacologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos AnimaisRESUMO
Importance: Niacin remains a therapeutic option for patients with cardiovascular disease, but recent studies have called into question the effectiveness of other drugs that increase high-density lipoprotein cholesterol levels. Objective: To systematically review and evaluate the evidence supporting current US Food and Drug Administration-approved uses of niacin in cardiovascular disease prevention settings. Data Sources: MEDLINE, Embase, Cochrane Controlled Clinical Trial Register (Central), ClinicalTrials.gov, and TrialResults-center, from database inception to October 2017. Study Selection: The systematic review included clinical trials involving niacin as a treatment for cardiovascular disease. The meta-analysis included randomized clinical trials reporting niacin's effect, as exposure, on at least 1 long-term cardiovascular disease outcome. Data Extraction and Synthesis: Aggregate study-level data were extracted between November 2017 and January 2018 by 3 independent reviewers, and the analysis was performed in February 2018. Inverse-variance weighted methods were used to produce pooled risk ratios using random-effects models for between-study heterogeneity. Random effects-weighted metaregression analysis was used to assess the association of change in high-density lipoprotein cholesterol levels with the log risk ratio of the pooled results. Main Outcomes and Measures: Cardiovascular disease, coronary heart disease mortality, and other cardiovascular events, including acute coronary syndrome, fatal and nonfatal stroke, revascularization, and major adverse cardiac events. Results: Of 119 clinical trials, 17 documented niacin's effect on at least 1 cardiovascular disease outcome. The meta-analysis included 35â¯760 patients with histories of cardiovascular disease or dyslipidemia. Cumulative evidence found no preventive association of niacin with cardiovascular outcomes in secondary prevention. Stratified meta-analysis showed an association of niacin monotherapy with reduction of some cardiovascular events among patients without statin treatment (acute coronary syndrome: relative risk, 0.74; 95% CI, 0.58-0.96; stroke: relative risk, 0.74; 95% CI, 0.59-0.94; revascularization: relative risk, 0.51; 95% CI, 0.37-0.72). These results were mainly derived from 2 trials conducted in the 1970s and 1980s. Conclusions and Relevance: Niacin may have some use in lipid control for secondary prevention as monotherapy, perhaps in patients intolerant to statins, but evidence is from older studies on a population potentially not representative of current-day patients.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Niacina/uso terapêutico , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Lipoproteínas HDL/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevenção Secundária , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND AND AIMS: Anabolic androgenic steroids (AAS) have been associated with coronary artery disease (CAD). AAS abuse leads to a remarkable decrease in high-density lipoprotein (HDL) plasma concentration, which could be a key factor in the atherosclerotic process. Moreover, not only the concentration of HDL, but also its functionality, plays a pivotal role in CAD. We tested the functionality of HDL by cholesterol efflux and antioxidant capacity. We also evaluated the prevalence of CAD in AAS users. METHODS: Twenty strength-trained AAS users (AASU) age 29⯱â¯5â¯yr, 20 age-matched strength-trained AAS nonusers (AASNU), and 10 sedentary controls (SC) were enrolled in this cross-sectional study. Functionality of HDL was evaluated by 14C-cholesterol efflux and the ability of HDL in inhibiting LDL oxidation. Coronary artery was evaluated with coronary computed tomography angiography. RESULTS: Cholesterol efflux was lower in AASU compared with AASNU and SC (20 vs. 23 vs. 24%, respectively, pâ¯<â¯0.001). However, the lag time for LDL oxidation was higher in AASU compared with AASNU and SC (41 vs 13 vs 11â¯min, respectively, pâ¯<â¯0.001). We found at least 2 coronary arteries with plaques in 25% of AASU. None of the AASNU and SC had plaques. The time of AAS use was negatively associated with cholesterol efflux. CONCLUSIONS: This study indicates that AAS abuse impairs the cholesterol efflux mediated by HDL. Long-term AAS use seems to be correlated with lower cholesterol efflux and early subclinical CAD in this population.
Assuntos
Colesterol/sangue , Doença da Artéria Coronariana/sangue , Lipoproteínas HDL/sangue , Congêneres da Testosterona/efeitos adversos , Adolescente , Adulto , Anabolizantes/efeitos adversos , Biomarcadores/sangue , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/induzido quimicamente , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Seguimentos , Voluntários Saudáveis , Humanos , Lipoproteínas HDL/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Considerable evidence from preclinical and population studies suggests that HDLs (high-density lipoproteins) possess atheroprotective properties. Reports from HDL infusion studies in animals and early clinical imaging trials reported evidence of plaque regression. These findings have stimulated further interest in developing new agents targeting HDL. However, the results of more recent imaging studies in the setting of high-intensity statin use have been disappointing. As the concept of plaque changes with HDL therapeutics evolves and imaging technology to evaluate these effects advances, there will become increasing opportunity to determine the effects of HDL agents on atherosclerotic plaque (Graphic Abstract).
Assuntos
Lipoproteínas HDL/sangue , Placa Aterosclerótica/sangue , Placa Aterosclerótica/tratamento farmacológico , Animais , Progressão da Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas HDL/efeitos dos fármacos , Placa Aterosclerótica/diagnóstico por imagemRESUMO
BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.
Assuntos
Antioxidantes/farmacologia , Apolipoproteína B-48/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Hiperlipidemias/prevenção & controle , Lipoproteínas HDL/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , Vitamina E/farmacologia , Animais , Apolipoproteína B-48/sangue , Cardiotônicos/farmacologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/prevenção & controle , Citocinas/sangue , Dieta Aterogênica , Suplementos Nutricionais , Ensaio de Imunoadsorção Enzimática , Feminino , Hiperlipidemias/sangue , Immunoblotting , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas HDL/sangue , Masculino , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/sangue , Proteínas de Transferência de Fosfolipídeos/sangue , Valores de Referência , Reprodutibilidade dos Testes , Receptores Depuradores Classe B/sangue , Receptores Depuradores Classe B/efeitos dos fármacos , Resultado do TratamentoRESUMO
The açai fruit (Euterpe oleracea Martius), which is native to the Brazilian Amazon region, was shown to have high polyphenols and MUFA contents. In this study, we aimed to assess the effects of açai consumption on plasma lipids, apolipoproteins, the transfer of lipids to HDL (which is a relevant HDL function), and some biomarkers of redox metabolism. Forty healthy volunteer women aged 24 ± 3 years consumed 200 g of açai pulp/day for 4 weeks; their clinical variables and blood sample were obtained before and after this period. Açai pulp consumption did not alter anthropometric parameters, systemic arterial pressure, glucose, insulin and total, LDL and HDL cholesterol, triglycerides and apolipoprotein (apo) B, but it did increase the concentration of apo A-I. Açai consumption decreased the ROS, ox-LDL and malondialdehyde while increasing the activity of antioxidative paraoxonase 1. Overall, the total antioxidant capacity (TAC) was increased. Regarding the transfer of plasma lipids to HDL, açai consumption increased the transfer of cholesteryl esters (p = 0.0043) to HDL. Unesterified cholesterol, phospholipids and triglyceride transfers were unaffected. The increase in apo A-I and the cholesteryl ester transfer to HDL after the açai intake period suggests that an improvement in the metabolism of this lipoprotein occurred, and it is well known that HDL is protective against atherosclerosis. Another important finding was the general improvement of the anti-oxidant defences elicited by açai consumption. Our data indicate that açai has favourable actions on plasma HDL metabolism and anti-oxidant defence; therefore açai could have a beneficial overall role against atherosclerosis, and it is a consistently good candidate to consider as a functional food.
Assuntos
Apolipoproteínas/sangue , Ésteres do Colesterol/sangue , Euterpe/metabolismo , Lipoproteínas HDL/sangue , Extratos Vegetais/farmacologia , Adulto , Apolipoproteínas/efeitos dos fármacos , Biomarcadores/sangue , Dieta/métodos , Feminino , Frutas/metabolismo , Humanos , Lipídeos/sangue , Lipoproteínas HDL/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Extratos Vegetais/metabolismo , Estudos Prospectivos , Valores de Referência , Adulto JovemRESUMO
BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/ oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.
Assuntos
Animais , Masculino , Feminino , Ácido Ascórbico/farmacologia , Vitamina E/farmacologia , Isquemia Miocárdica/prevenção & controle , Apolipoproteína B-48/efeitos dos fármacos , Hiperlipidemias/prevenção & controle , Lipoproteínas HDL/efeitos dos fármacos , Antioxidantes/farmacologia , Valores de Referência , Doença da Artéria Coronariana/prevenção & controle , Doença da Artéria Coronariana/sangue , Ensaio de Imunoadsorção Enzimática , Cardiotônicos/farmacologia , Immunoblotting , Reprodutibilidade dos Testes , Citocinas/sangue , Resultado do Tratamento , Isquemia Miocárdica/sangue , Suplementos Nutricionais , Proteínas de Transferência de Fosfolipídeos/sangue , Dieta Aterogênica , Receptores Depuradores Classe B/efeitos dos fármacos , Receptores Depuradores Classe B/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Apolipoproteína B-48/sangue , Hiperlipidemias/sangue , Lipoproteínas HDL/sangue , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND AIMS: Sitosterolemia displays high plasma total sterols [high plant sterols (PS) + normal to high total cholesterol (TC)] with normal to moderately elevated low-density lipoprotein (LDL) levels. High LDL, intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, low high-density lipoprotein (HDL), and increased non-HDL and the ratios of TC and triglycerides (TG) to HDL can increase the risk for atherosclerosis. Ezetimibe (EZE) can reduce plasma PS and TC levels in sitosterolemia, but its effect on lipoprotein subclasses has not been previously reported. METHODS: Sitosterolemia patients (n = 8) were taken off EZE for 14 weeks (OFF EZE) and placed on EZE (10 mg/d) for 14 weeks (ON EZE). Serum lipids were measured enzymatically and lipoprotein subclasses were assessed by polyacrylamide gel electrophoresis. RESULTS: EZE reduced (p < 0.05) total sterols (-12.5 ± 4.1%) and LDL-sterol (-22.7 ± 5.7%) and its sterol mass of large VLDL (-24.4 ± 4.5%), VLDL remnants (-21.1 ± 7.9%) and large IDL (-22.4 ± 7.2%) compared to OFF EZE. EZE did not affect large LDL subclasses or mean LDL particle size (273.8 ± 0.6 vs. 274.6 ± 0.3 Å). EZE increased HDL-sterol (25.5 ± 8.0%, p = 0.008) including intermediate (34 ± 14%, p = 0.02) and large (33 ± 16%, p = 0.06) HDL. EZE reduced non-HDL-sterol (-21.8± 5.0%), total sterols/HDL (-28.2 ± 5.5%) and TG/HDL (-27.4 ± 6.5%, all p < 0.01). CONCLUSIONS: EZE improves VLDL and HDL subfraction distribution, thereby reducing the atherogenic lipid profile, thus providing potential clinical benefit in sitosterolemia beyond TC and PS reduction.
Assuntos
Ezetimiba/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Enteropatias/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Fitosteróis/efeitos adversos , Adolescente , Adulto , Anticolesterolemiantes/uso terapêutico , HDL-Colesterol/sangue , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Hipercolesterolemia/sangue , Enteropatias/sangue , Erros Inatos do Metabolismo Lipídico/sangue , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas IDL/sangue , Lipoproteínas IDL/efeitos dos fármacos , Lipoproteínas VLDL/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fitosteróis/sangue , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known. METHODS: We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54â weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110â weeks), enabling assessment of the impact of 1â year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54â weeks and 110â weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux. RESULTS: All HDL vascular assays were impaired in patients compared with controls. After 54â weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110â weeks. No significant trend was noted for cholesterol efflux. CONCLUSIONS: HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties.