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1.
Pharmacol Res ; 153: 104653, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31931117

RESUMO

Among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) in regulating the activity of lipoprotein lipase (LPL), antagonizing the hydrolysis of triglycerides (TG). Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants. In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia. In humans, loss-of-function mutations of ANGPTL3 are associated with a marked reduction of plasma levels of VLDL, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Carriers of loss-of-function mutations of ANGPTL4 show instead lower TG-rich lipoproteins and a modest but significant increase of HDL. The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets is proven by the development of monoclonal antibodies or antisense oligonucleotides. Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects. Inhibition of both targets also partially reduces LDL-C, independent of the LDL receptor. Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-LRX. The genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias. Conclusive data of phase 2 and 3 clinical trials are still needed in order to define their safety and efficacy profile.

4.
Arch Med Sci ; 15(6): 1365-1374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31749863

RESUMO

Introduction: The aim of this meta-analysis was to establish whether vascular pulse wave velocity (PWV) as a measure of arterial stiffness is changed in patients with familial hypercholesterolemia (FH). Material and methods: Studies comparing PWV between patients with FH and controls were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (up to November 26, 2017). A meta-analysis was conducted using Comprehensive Meta-Analysis V2 software. A random-effects model (using the DerSimonian-Laird method) and the generic inverse variance method were used to compensate for the heterogeneity of studies concerning demographic characteristics and differences in the studies' design. Results: This meta-analysis of 8 studies involving 317 patients with FH and 244 non-FH individuals did not suggest a significantly altered PWV in FH patients versus controls (weighted mean difference (WMD): 0.17 m/s, 95% confidence interval (CI): -0.31, 0.65, p = 0.489; I 2 = 80.15%). The result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. Subanalysis of 6 of these studies which had data on intima-media thickness (IMT) indicated an increased IMT in FH patients when compared with controls (WMD = 0.03 mm, 95% CI: 0.003, 0.06, p = 0.034; I 2 = 48.95%). However, the effect size was sensitive to some of the included studies. Conclusions: This meta-analysis suggests that FH patients do not have significantly altered PWV when compared with normocholesterolemic individuals. However, a subanalysis of studies in which IMT was measured indicated that IMT is increased in FH patients compared with controls.

5.
Cell Metab ; 30(6): 1055-1074.e8, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31708446

RESUMO

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.

7.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489930

RESUMO

Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.


Assuntos
Aterosclerose/genética , Predisposição Genética para Doença , Doenças Metabólicas/genética , PPAR alfa/genética , Polimorfismo de Nucleotídeo Único , Alelos , Substituição de Aminoácidos , Animais , Aterosclerose/metabolismo , Dieta , Regulação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Lipoproteínas/sangue , Lipoproteínas/metabolismo , Doenças Metabólicas/metabolismo
8.
Nutr J ; 18(1): 54, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500629

RESUMO

Following publication of the original article [1], the authors reported an error in the affiliation of the third author, Sara Gandini. The correct affiliation should read: Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy.

9.
Atherosclerosis ; 288: 146-155, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404822

RESUMO

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite excellent pharmacological and revascularization approaches. Low-density lipoproteins (LDL) are undoubtedly the most significant biochemical variables associated with atheroma, however, compelling data identify inflammation as critical for the maintenance of the atherosclerotic process, underlying some of the most feared vascular complications. Although its causal role is questionable, high-sensitivity C-reactive protein (hs-CRP) represents a major biomarker of inflammation and associated risk in CVD. While statin-associated reduced risk may be related to the lowering of both LDL-C and hs-CRP, PCSK9 inhibitors leading to dramatic LDL-C reductions do no alter hs-CRP levels. On the other hand, hs-CRP levels identify groups of patients with a high risk of CV disease achieving better ASCVD prevention in response to PCSK9 inhibition. In the FOURIER study, even in patients with extremely low levels of LDL-C, there was a stepwise risk increment according to the values of hs-CRP: +9% (<1 mg/L), +10.8% (1-3 mg/L) and +13.1% (>3 mg/L). Likewise, in the SPIRE-1 and -2 studies, bococizumab patients with hs-CRP> 3 mg/L had a 60% greater risk of future CV events. Most of the patients enrolled in the PCSK9 trials were on maximally tolerated statin therapy at baseline, and an elevated hs-CRP may reflect residual inflammatory risk after standard LDL-C lowering therapy. Moreover, data on changes in inflammation markers in carriers of PCSK9 loss-of-function mutations are scanty and not conclusive, thus, evidence from the effects of anti-inflammatory molecules on PCSK9 levels might help unravel this hitherto complex tangle.

10.
Nutr Metab Cardiovasc Dis ; 29(11): 1245-1253, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31439394

RESUMO

BACKGROUND AND AIMS: The novel nutraceutical combination containing red yeast rice (monacolin K 3.3 mg), Berberis aristata cortex extract (Berberine 531.25 mg) and Morus alba leaves extract (1-deoxynojirimycin 4 mg) is effective in the management of elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The aim of the present study was to investigate the effects of the three components on proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of LDL receptor (LDLR) expression, in hepatocyte cell lines and to compare their effects on LDL cellular uptake. METHODS AND RESULTS: HepG2 and Huh7 cells were incubated with B. aristata cortex extract (BCE), red yeast rice (RYR) and M. alba leaves extract (MLE) alone or in combination for 24 h. RYR (50 µg/mL) increased PCSK9 protein expression (Western blot analysis and ELISA), PCSK9 mRNA (qPCR) and its promoter activity (luciferase reporter assay). BCE (40 µg/mL) reduced instead PCSK9 expression, mRNA levels and promoter activity. MLE determined a concentration-dependent reduction of PCSK9 at the mRNA and protein levels, with a maximal reduction at 1 mg/mL, without significant changes of PCSK9 promoter activity. MLE also downregulated the expression of 3-hydroxy-3-methyl-3-glutaryl coenzyme A reductase and fatty acid synthase mRNA levels. The combination of RYR, BCE and MLE reduced the PCSK9 mRNA and protein levels, as well as the promoter activity. Finally, the single components and their combination induced LDL receptor and LDL uptake by the hepatocytes. CONCLUSION: The positive effect of MLE on PCSK9 supports the rationale of using the nutraceutical combination of RYR, BCE and MLE to control hyperlipidemic conditions.


Assuntos
Anticolesterolemiantes/farmacologia , Berberis/química , Produtos Biológicos/farmacologia , LDL-Colesterol/metabolismo , Hepatócitos/efeitos dos fármacos , Lovastatina/farmacologia , Morus/química , Extratos Vegetais/farmacologia , Pró-Proteína Convertase 9/metabolismo , Anticolesterolemiantes/isolamento & purificação , Relação Dose-Resposta a Droga , Regulação para Baixo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Regulação Enzimológica da Expressão Gênica , Células Hep G2 , Hepatócitos/enzimologia , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Pró-Proteína Convertase 9/genética
11.
Arch Med Sci ; 15(4): 936-943, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31360188

RESUMO

Resveratrol (3,5,4'-trihydroxystilbene) belongs to a family of polyphenolic compounds known as stilbenes, particularly concentrated in grape and red wine. The aim of our review was to critically review the available evidence of resveratrol effects on brain function and its potential impact on therapy. In preclinical models of cognitive decline, resveratrol displays potent antioxidant activity by scavenging free radicals, reducing quinone reductase 2 activity and upregulating endogenous enzymes. Resveratrol also inhibits pro-inflammatory enzyme expression, reduces nuclear factor-κB activation and cytokine release. Treatment with resveratrol can affect multiple signaling pathway effectors involved in cell survival, programmed cell death and synaptic plasticity. Direct and/or indirect activation of the deacetylase sirtuins by resveratrol has also been suggested. In humans, clinical evidence derived from randomized clinical trials suggests that resveratrol is able to improve cerebral blood flow, cerebral vasodilator responsiveness to hypercapnia, some cognitive tests, perceived performances, and the Aß40 plasma and cerebrospinal fluid level.

12.
Cardiovasc Diabetol ; 18(1): 71, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164165

RESUMO

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.


Assuntos
Benzoxazóis/uso terapêutico , Butiratos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , PPAR alfa/agonistas , Animais , Benzoxazóis/efeitos adversos , Biomarcadores/sangue , Butiratos/efeitos adversos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Consenso , Dislipidemias/sangue , Dislipidemias/diagnóstico , Humanos , Hipolipemiantes/efeitos adversos , Terapia de Alvo Molecular , PPAR alfa/metabolismo , Segurança do Paciente , Medição de Risco , Fatores de Risco , Transdução de Sinais , Resultado do Tratamento
13.
Front Aging Neurosci ; 11: 120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178716

RESUMO

Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.

14.
Eur J Prev Cardiol ; : 2047487319845314, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060364

RESUMO

Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). LDL-C is unquestionably causal in the development of atherogenesis and atherosclerotic cardiovascular disease, but new options are required to address triglyceride-rich lipoproteins and lipoprotein(a). For hypercholesterolaemia, pitavastatin provides a very low dose and potent statin that does not adversely affect glucose metabolism; bempedoic acid acts at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and is not associated with muscular side effects. For hypertriglyceridaemia, pemafibrate displays a unique and selective agonist activity on peroxisomal proliferator activated receptor-α that does not elevate homocysteine or creatinine. Although omega-3 fatty acids supplementation is not effective in secondary prevention, high dose eicosapentaenoic ethyl ester can lead to a remarkable fall in first and recurrent events in high risk patients with hypertriglyceridaemia/low HDL-C. Gemcabene, a dicarboxylic acid regulating apolipoprotein B-100, is effective in reducing both cholesterol and triglycerides. Among cholesteryl ester transfer protein antagonists that elevate HDL-C, only anacetrapib reduces cardiovascular events. Probucol stimulates reverse cholesteryl ester transport, lowers LDL-C stabilizing plaques and may lower incidence of cardiovascular events. These agents, which act through novel mechanisms, afford good and potentially safe treatment choices that may increase adherence and the attainment of therapeutic targets.

16.
Drugs ; 79(7): 751-766, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989634

RESUMO

AIM: Our aim was to assess the efficacy and safety of mipomersen through a systematic review of the literature and a meta-analysis of the available clinical studies. METHODS: A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to January 20, 2019, in order to identify clinical trials assessing the effect of mipomersen on lipoproteins, and the safety profile of mipomersen. Effect sizes for lipid changes were expressed as weighted mean differences (WMD) and 95% confidence intervals (CI). For safety analysis, odd ratios (OR) and 95% CI were calculated using the Mantel-Haenszel method. Data were pooled from 13 clinical studies comprising 49 arms, which included 1053 subjects overall, with 729 in the active-treated arm and 324 in the control arm. RESULTS: Meta-analysis of data suggested that mipomersen significantly reduced low-density lipoprotein cholesterol (WMD - 1.52, 95% CI - 1.85 to - 1.19; p < 0.001), total cholesterol (WMD - 1.55, 95% CI - 1.97 to - 1.13; p < 0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (WMD - 1.66, 95% CI - 2.06 to - 1.27; p < 0.001), lipoprotein(a) (WMD - 0.99, 95% CI - 1.37 to - 0.62; p < 0.001), apolipoprotein B (WMD - 1.66, 95% CI - 2.04 to - 1.27; p < 0.001), triglycerides (WMD -0.61, 95% CI - 0.76 to - 0.46, p < 0.001), very-low-density lipoprotein cholesterol (WMD - 0.58, 95% CI - 0.73 to - 0.43; p < 0.001) and apolipoprotein A-I (WMD - 0.25, 95% CI - 0.51 to - 0.001; p = 0.049) without affecting HDL-C levels (WMD 0.11, 95% CI - 0.03 to 0.26; p = 0.124). However, treatment with mipomersen was positively associated with an increased risk of discontinuation of treatment (OR 3.02, 95% CI 1.96-4.65; p < 0.001), injection-site reaction (OR 11.41, 95% CI 7.88-16.52; p < 0.001), hepatic steatosis (OR 4.96, 95% CI 1.99-12.39; p = 0.001), hepatic enzymes elevation (OR 3.61, 95% CI 2.09-6.24; p < 0.001) and flu-like symptoms (OR 2.02, 95% CI 1.45-2.81; p < 0.001). CONCLUSION: Despite favourable effects on the lipid profile, some concerns are reinforced from the safety profile. As a matter of fact, mipomersen therapy is more likely discontinued and associated with increased risk of injection-site reactions, hepatic steatosis, hepatic enzyme elevation, and flu-like symptoms.


Assuntos
Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/metabolismo , LDL-Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Feminino , Humanos , Lipídeos , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triglicerídeos/metabolismo
17.
J Lipid Res ; 60(6): 1144-1153, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30918065

RESUMO

Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P < 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (P < 0.05). The rs236918 C allele was associated with upregulation of a new "intra-PCSK7" long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P < 0.01), which correlated with triglycerides (P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor ß pathway activation, and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.

20.
J Clin Endocrinol Metab ; 104(8): 3097-3107, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30835274

RESUMO

CONTEXT: Low testosterone levels are associated with an increased incidence of cardiovascular (CV) events, but the underlying biochemical mechanisms are not fully understood. The clinical condition of hypogonadism offers a unique model to unravel the possible role of lipoprotein-associated abnormalities in CV risk. In particular, the assessment of the functional capacities of high-density lipoproteins (HDLs) may provide insights besides traditional risk factors. DESIGN: To determine whether reduced testosterone levels correlate with lipoprotein function, HDL cholesterol (HDL-C) efflux capacity (CEC) and serum cholesterol loading capacity (CLC). PARTICIPANTS: Genetic and idiopathic hypogonadal patients (n = 20) and control subjects (n = 17). RESULTS: Primary and secondary hypogonadal patients presented with lower HDL ATP-binding cassette transporter A1 (ABCA1)-, ATP-binding cassette transporter G1 (ABCG1)-, and aqueous diffusion-mediated CEC (-19.6%, -40.9%, and -12.9%, respectively), with a 16.2% decrement of total CEC. In the whole series, positive correlations between testosterone levels and both total HDL CEC (r2 = 0.359, P = 0.0001) and ABCG1 HDL CEC (r2 = 0.367, P = 0.0001) were observed. Conversely, serum CLC was markedly raised (+43%) in hypogonadals, increased, to a higher extent, in primary vs secondary hypogonadism (18.45 ± 2.78 vs 15.15 ± 2.10 µg cholesterol/mg protein) and inversely correlated with testosterone levels (r2 = 0.270, P = 0.001). HDL-C concentrations did not correlate with either testosterone levels, HDL CEC (total, ABCG1, and ABCA1) or serum CLC. CONCLUSIONS: In hypogonadal patients, proatherogenic lipoprotein-associated changes are associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk.

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