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1.
Artigo em Inglês | MEDLINE | ID: mdl-32197575

RESUMO

IntroductionThe Eph-ephrin is a cell-cell communication system generating a forward signal in cell expressing Eph receptors and a reverse signal in ephrin-ligand expressing cells. While clearly involved in the insurgence and progression of cancer, the understanding of the molecular mechanisms regulated by this system needs development; this is a hurdle to the development of therapeutic strategies that can target the Eph receptors and/or their ephrin ligandsAreas covered: We have taken the opportunity to share some key questions on the most effective strategies to target the Eph-ephrin system. This article is based on our experience of the field and therefore is a Perspective and not comprehensive examination of the literature.Expert opinionTargeting of the Eph-ephrin system has emerged as a potential valuable approach for cancer therapy. Pharmacological tools have been reported in the last 15 years and these include forward signaling blockers such as kinases inhibitors and antagonists of forward and reverse signaling. Also, biologics including antibodies and recombinant proteins have been developed and some have reached early clinical stages. Data deem the Eph-ephrin system as a signaling axis that is an elusive target. A better understanding of the basic pharmacology behind the activity of available agents and a comprehensive knowledge of the ephrin biology is necessary. We are looking forward to knowing the opinion of the readers.

2.
Nutr. metab. cardiovasc. dis ; 30(2): 254-264, Feb., 2020. tab., graf.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1052921

RESUMO

BACKGROUND AND AIM: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. We investigated if potentially other HDL protective actions may be affected with weight gain and these changes may occur even before the obesity range in a cross-sectional analysis. METHODS AND RESULTS: Lipid profile, body mass index (BMI), biochemical measurements, and carotid intima-media thickness (cIMT) were obtained in this cross-sectional study with 899 asymptomatic individuals. Lipoproteins were separated by ultracentrifugation and HDL physical-chemical characterization, CEC, antioxidant activity, anti-inflammatory activity, HDL-mediated platelet aggregation inhibition were measured in a randomly-selected subgroup (n = 101). Individuals with increased HDL-C had an attenuated increase in cIMT with elevation of BMI (interaction effect ß = -0.054; CI 95% -0.0815, -0.0301). CEC, HDL-C, HDL size and HDL-antioxidant activity were negatively associated with cIMT. BMI was inversely correlated with HDL-mediated inhibition of platelet aggregation (Spearman's rho -0.157, p < 0.03) and CEC (Spearman's rho -0.32, p < 0.001), but surprisingly it was directly correlated with the antioxidant activity (Spearman's rho 0.194, p = 0.052). Thus, even in non-obese, non-diabetic individuals, increased BMI is associated with a wide change in protective functions of HDL, reducing CEC and increasing antioxidant activity. In these subjects, decreased HDL concentration, size or function are related to increased atherosclerotic burden. CONCLUSION: Our findings demonstrate that in non-obese, non-diabetic individuals, the increasing values of BMI are associated with impaired protective functions of HDL and concomitant increase in atherosclerotic burden. (AU)


Assuntos
Aterosclerose , HDL-Colesterol , Obesidade
3.
Nutr Metab Cardiovasc Dis ; 30(2): 254-264, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31753789

RESUMO

BACKGROUND AND AIM: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. We investigated if potentially other HDL protective actions may be affected with weight gain and these changes may occur even before the obesity range in a cross-sectional analysis. METHODS AND RESULTS: Lipid profile, body mass index (BMI), biochemical measurements, and carotid intima-media thickness (cIMT) were obtained in this cross-sectional study with 899 asymptomatic individuals. Lipoproteins were separated by ultracentrifugation and HDL physical-chemical characterization, CEC, antioxidant activity, anti-inflammatory activity, HDL-mediated platelet aggregation inhibition were measured in a randomly-selected subgroup (n = 101). Individuals with increased HDL-C had an attenuated increase in cIMT with elevation of BMI (interaction effect ß = -0.054; CI 95% -0.0815, -0.0301). CEC, HDL-C, HDL size and HDL-antioxidant activity were negatively associated with cIMT. BMI was inversely correlated with HDL-mediated inhibition of platelet aggregation (Spearman's rho -0.157, p < 0.03) and CEC (Spearman's rho -0.32, p < 0.001), but surprisingly it was directly correlated with the antioxidant activity (Spearman's rho 0.194, p = 0.052). Thus, even in non-obese, non-diabetic individuals, increased BMI is associated with a wide change in protective functions of HDL, reducing CEC and increasing antioxidant activity. In these subjects, decreased HDL concentration, size or function are related to increased atherosclerotic burden. CONCLUSION: Our findings demonstrate that in non-obese, non-diabetic individuals, the increasing values of BMI are associated with impaired protective functions of HDL and concomitant increase in atherosclerotic burden.

4.
Adv Clin Chem ; 92: 105-140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31472752

RESUMO

The reduction of plasma apolipoprotein B (apoB) containing lipoproteins has long been pursued as the main modifiable risk factor for the development of cardiovascular disease (CVD). This has led to an intense search for strategies aiming at reducing plasma apoB-lipoproteins, culminating in reduction of overall CV risk. Despite 3 decades of progress, CVD remains the leading cause of morbidity and mortality worldwide and, as such, new therapeutic targets are still warranted. Clinical and preclinical research has moved forward from the original concept, under which some lipids must be accumulated and other removed to achieve the ideal condition in disease prevention, into the concept that mechanisms that orchestrate lipid movement between lipoproteins, cells and organelles is equally involved in CVD. As such, this review scrutinizes potentially atherogenic changes in lipid trafficking and assesses the molecular mechanisms behind it. New developments in risk assessment and new targets for the mitigation of residual CVD risk are also addressed.


Assuntos
Doenças Cardiovasculares/sangue , Lipídeos/sangue , Doenças Cardiovasculares/patologia , Humanos
5.
Arterioscler Thromb Vasc Biol ; 39(8): 1550-1564, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31189429

RESUMO

Despite decades of therapeutic advances, myocardial infarction remains a leading cause of death worldwide. Recent studies have identified HDLs (high-density lipoproteins) as a potential candidate for mitigating coronary ischemia/reperfusion injury via a broad spectrum of signaling pathways. HDL ligands, such as S1P (sphingosine-1-phosphate), Apo (apolipoprotein) A-I, clusterin, and miRNA, may influence the opening of the mitochondrial channel, insulin sensitivity, and production of vascular autacoids, such as NO, prostacyclin, and endothelin-1. In parallel, antioxidant activity and sequestration of oxidized molecules provided by HDL can attenuate the oxidative stress that triggers ischemia/reperfusion. Nevertheless, during myocardial infarction, oxidation and the capture of oxidized and proinflammatory molecules generate large phenotypic and functional changes in HDL, potentially limiting its beneficial properties. In this review, new findings from cellular and animal models, as well as from clinical studies, will be discussed to describe the cardioprotective benefits of HDL on myocardial infarction. Furthermore, mechanisms by which HDL modulates cardiac function and potential strategies to mitigate postmyocardial infarction risk damage by HDL will be detailed throughout the review.


Assuntos
Lipoproteínas HDL/fisiologia , Infarto do Miocárdio/prevenção & controle , Animais , Colesterol/metabolismo , Células Endoteliais/fisiologia , Glucose/metabolismo , Homeostase , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/fisiologia , Estresse Oxidativo , Transdução de Sinais/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia
6.
Cardiovasc Drugs Ther ; 33(3): 371-381, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30778806

RESUMO

It is now apparent that a variety of deleterious mechanisms intrinsic to myocardial infarction (MI) exists and underlies its high residual lethality. Indeed, despite effective coronary patency therapies, ischemia and reperfusion (I/R) injury accounts for about 50% of the infarcted mass. In this context, recent studies in animal models have demonstrated that coronary reperfusion with high-density lipoproteins (HDL) may reduce MI size in up to 30%. A spectrum of mechanisms mediated by either HDL-related apolipoproteins or phospholipids attenuates myocardial cell death. Hence, promising therapeutic approaches such as infusion of reconstituted HDL particles, new HDL by genomic therapy, or the infusion of apoA-I mimetic peptides have been sought as a way of ensuring protection against I/R injury. In this review, we will explore the limitations and potential therapeutic effects of HDL therapies during the acute phase of MI.

7.
Int J Mol Sci ; 20(2)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654461

RESUMO

Several studies have demonstrated that polyphenol-enriched diets may have beneficial effects against the development of degenerative diseases, including atherosclerosis and disorders affecting the central nervous system. This activity has been associated not only with antioxidant and anti-inflammatory properties, but also with additional mechanisms, such as the modulation of lipid metabolism and gut microbiota function. However, long-term studies on humans provided controversial results, making the prediction of polyphenol impact on health uncertain. The aim of this review is to provide an overview and critical analysis of the literature related to the effects of the principal dietary polyphenols on cardiovascular and neurodegenerative disorders. We critically considered and meta-analyzed randomized controlled clinical trials involving subjects taking polyphenol-based supplements. Although some polyphenols might improve specific markers of cardiovascular risk and cognitive status, many inconsistent data are present in literature. Therefore, definitive recommendations for the use of these compounds in the prevention of cardiovascular disease and cognitive decline are currently not applicable. Once pivotal aspects for the definition of polyphenol bioactivity, such as the characterization of pharmacokinetics and safety, are addressed, it will be possible to have a clear picture of the realistic potential of polyphenols for disease prevention.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Polifenóis/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/fisiopatologia , Cognição/efeitos dos fármacos , Humanos , Doenças Neurodegenerativas/fisiopatologia , Substâncias Protetoras
8.
Nutrients ; 10(12)2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30513887

RESUMO

It has been well established that moderate alcohol consumption inversely correlates with cardiovascular morbidity and mortality, whereas binge alcohol drinking increases cardiovascular disease risk. The aim of this study was to assess in vivo the impact of different drinking patterns on reverse cholesterol transport (RCT); the atheroprotective process leading to the removal of excess cholesterol from the body. RCT was measured with a standardized, radioisotope-based technique in three groups of atherosclerosis-prone apolipoprotein E knock out mice: Placebo group, receiving water, which would mimic the abstainers; moderate group, receiving 0.8 g/kg alcohol/day for 28 days, which would mimic a moderate intake; binge group, receiving 0.8 g/kg alcohol/day for 5 days/week, followed by the administration of 2.8 g/kg alcohol/day for 2 days/week, which would mimic a heavy intake in a short period. Mice in the binge drinking group displayed an increase in total cholesterol, high density lipoprotein cholesterol (HDL-c) and non-HDL-c (all p < 0.0001 vs. placebo), and a significantly reduced elimination of fecal cholesterol. The moderate consumption did not lead to any changes in circulating lipids, but slightly improved cholesterol mobilization along the RCT pathway. Overall, our data confirm the importance of considering not only the total amount, but also the different consumption patterns to define the impact of alcohol on cardiovascular risk.


Assuntos
Consumo de Bebidas Alcoólicas , Colesterol/metabolismo , Etanol/administração & dosagem , Etanol/efeitos adversos , Animais , Apolipoproteínas E/metabolismo , Transporte Biológico/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Nutrients ; 10(10)2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30326655

RESUMO

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv®, an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv® is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of fruit and vegetables commonly consumed within the Mediterranean diet. A total of 21 Golden Syrian hamsters were divided into three groups. The standard group (STD) was fed a normolipidemic diet for 12 weeks, while the control group (CTRL) and Oleactiv® goup (OLE) were fed a high-fat diet. After sacrifice, the aortic fatty streak area (AFSA), plasmatic total cholesterol (TC), high-density lipoproteins (HDL-C), non-HDL-C and triglycerides (TG), were assessed. The cholesterol efflux capacity (CEC) of hamster plasma was quantified using a radiolabeled technique in murine macrophages J774. OLE administration induced a significant reduction of AFSA (-69%, p < 0.0001). Hamsters of the OLE group showed a significant decrease of both non-HDL-C (-173 mmol/L, p < 0.05) and TG (-154 mmol/L, p < 0.05). Interestingly, OLE induced a significant increase of total CEC (+17,33%, p < 0,05). Oleactiv® supplementation prevented atheroma development and had positive effects on the lipid profile of hypercholesterolemic hamsters. The increased CEC underlines the anti-atherosclerotic mechanism at the root of the atheroma reduction observed.


Assuntos
Anticolesterolemiantes/farmacologia , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Colesterol/sangue , Suplementos Nutricionais , Hipercolesterolemia/tratamento farmacológico , Polifenóis/farmacologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Linhagem Celular , HDL-Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Mesocricetus , Camundongos , Placa Aterosclerótica , Triglicerídeos/sangue
12.
Sci Rep ; 8(1): 2267, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396513

RESUMO

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1ß, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1ß (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR-/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR-/- and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.


Assuntos
Citocinas/metabolismo , Macrófagos/imunologia , Pró-Proteína Convertase 9/metabolismo , Animais , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Masculino , Camundongos
13.
J Lipid Res ; 59(4): 714-721, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436385

RESUMO

Several studies have revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here, we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated either with calcium score or with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification, or napking-ring sign. In addition, no association was detected between CEC and telomere length, a marker of biological aging that has been linked to atherosclerosis extent. Interestingly, elderly subjects presented a remarkably higher CEC (+30.2%; P < 0.0001) compared with values obtained from a cohort of sex-matched, cardiovascular event-free, middle-aged individuals. In conclusion, serum CEC is not related to traditional risk factors in very old, cardiovascular event-free subjects, but has significantly higher values compared with a healthy, younger population. Whether this improved HDL functionality may represent a protective factor in CVD onset must be established in future studies.


Assuntos
Cálcio/sangue , HDL-Colesterol/sangue , Placa Aterosclerótica/genética , Telômero/genética , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Placa Aterosclerótica/sangue , Fatores de Risco
14.
Nutrients ; 9(10)2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28937600

RESUMO

Trimethylamine-N-oxide (TMAO) is a small organic molecule, derived from the intestinal and hepatic metabolism of dietary choline and carnitine. Although the involvement of TMAO in the framework of many chronic diseases has been recently described, no evidence on its putative role in the central nervous system has been provided. The aim of this study was to evaluate whether TMAO is present at detectable levels in human cerebrospinal fluid (CSF). CSF was collected for diagnostic purposes from 58 subjects by lumbar puncture and TMAO was quantified by using liquid chromatography coupled with multiple-reaction monitoring mass spectrometry. The molecule was detected in all samples, at concentrations ranging between 0.11 and 6.43 µmol/L. Further analysis on CSF revealed that a total of 22 subjects were affected by Alzheimer's disease (AD), 16 were affected by non-AD related dementia, and 20 were affected by other neurological disorders. However, the stratification of TMAO levels according to the neurological diagnoses revealed no differences among the three groups. In conclusion, we provide the first evidence that TMAO can be assessed in human CSF, but the actual impact of this dietary metabolite in the patho-physiolgy of the central nervous system requires further study.


Assuntos
Bactérias/metabolismo , Demência/líquido cefalorraquidiano , Microbioma Gastrointestinal , Intestinos/microbiologia , Metilaminas/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/microbiologia , Cromatografia Líquida , Demência/diagnóstico , Demência/microbiologia , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Punção Espinal
15.
Eur J Med Chem ; 142: 152-162, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28780190

RESUMO

It is well established that the Eph/ephrin system plays a central role in the embryonic development, with minor implications in the physiology of the adult. However, it is overexpressed and deregulated in a variety of tumors, with a primary involvement in tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. Targeting the Eph/ephrin system with biologicals, including antibodies and recombinant proteins, reduces tumor growth in animal models of hematological malignancies, breast, prostate, colon, head and neck cancers and glioblastoma. Currently, some of these biopharmaceutical agents are under investigations in phase I or phase II clinical trials. Peptides and small molecules targeting protein-protein-interaction (PPI) are in the late preclinical phase where they are showing promising activity in models of glioblastoma, ovarian and lung cancer. The present review summarizes the most critical findings proposing the Eph/ephrin signaling system as a new target in molecularly targeted oncology.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Efrinas/metabolismo , Neoplasias/tratamento farmacológico , Receptores da Família Eph/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Humanos , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Neoplasias/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
16.
Mol Nutr Food Res ; 61(9)2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276197

RESUMO

SCOPE: Consumption of products rich in flavan-3-ols, such as tea and cocoa, has been associated with decreased obesity, partially dependent on their capacity to enhance energy expenditure. Despite these phenolics having been reported to increase the thermogenic program in brown and white adipose tissue, flavan-3-ols are vastly metabolised in vivo to phenyl-γ-valerolactones. Therefore, we hypothesize that phenyl-γ-valerolactones may directly stimulate the differentiation and the activation of brown adipocytes. METHODS AND RESULTS: Immortalized brown pre-adipocytes were differentiated in presence of (R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL1), (R)-5-(3´-hydroxyphenyl)-γ-valerolactone-4'-O-sulphate (VL2), (R)-5-phenyl-γ-valerolactone-3´,4´-di-O-sulphate (VL3), at concentrations of 2 or 10µM, whereas fully differentiated brown adipocyte were treated acutely (6-24h). None of the treatments regulated the expression levels of the uncouple protein 1, nor of the main transcription factors involved in brown adipogenesis. Similarly, mitochondrial content was unchanged after treatments. Moreover these compounds did not display peroxisome proliferator-activated receptor γ-agonist activity, as evaluated by luciferase assay, and did not enhance norepinephrine-stimulated lipolysis in mature adipocytes. However, both VL1 and VL2 prevented oxidative stress caused by H2 O2 . CONCLUSION: Phenyl-γ-valerolactones and their sulphated forms do not influence brown adipocyte development or function at physiological or supraphysiological doses in vitro, but they are active protecting brown adipocytes from increased reactive oxygen species production.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Flavonoides/metabolismo , Lactonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Colo/metabolismo , Citoproteção , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/agonistas
17.
J Alzheimers Dis ; 55(1): 315-320, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27662294

RESUMO

BACKGROUND: Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. OBJECTIVE: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4. METHODS: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased Aß42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. RESULTS: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE ɛ4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454). CONCLUSION: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Pró-Proteína Convertase 9/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
18.
J Med Chem ; 60(2): 787-796, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28005388

RESUMO

Metadynamics (META-D) is emerging as a powerful method for the computation of the multidimensional free-energy surface (FES) describing the protein-ligand binding process. Herein, the FES of unbinding of the antagonist N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan (UniPR129) from its EphA2 receptor was reconstructed by META-D simulations. The characterization of the free-energy minima identified on this FES proposes a binding mode fully consistent with previously reported and new structure-activity relationship data. To validate this binding mode, new N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan derivatives were designed, synthesized, and tested for their ability to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists, namely compounds 21 and 22, displayed high affinity versus the EphA2 receptor and resulted endowed with better physicochemical and pharmacokinetic properties than the parent compound. These findings highlight the importance of free-energy calculations in drug design, confirming that META-D simulations can be used to successfully design novel bioactive compounds.


Assuntos
Simulação por Computador , Desenho de Drogas , Ácido Litocólico/análogos & derivados , Receptor EphA2/antagonistas & inibidores , Triptofano/análogos & derivados , Animais , Estabilidade de Medicamentos , Ligantes , Ácido Litocólico/administração & dosagem , Ácido Litocólico/síntese química , Ácido Litocólico/química , Ácido Litocólico/farmacocinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor EphA2/química , Relação Estrutura-Atividade , Triptofano/administração & dosagem , Triptofano/síntese química , Triptofano/química , Triptofano/farmacocinética
19.
Atherosclerosis ; 256: 1-6, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27940374

RESUMO

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) may have extra-hepatic effects on cholesterol homeostasis of vascular macrophages. In this study, we aimed to investigate PCSK9 role on the anti-atherogenic process of ATP binding cassette transporter A1 (Abca1)-mediated cholesterol efflux. METHODS: Abca1-mediated cholesterol efflux was evaluated by a radioisotopic technique in mouse peritoneal macrophages (MPM) from wild-type (WT) or LDL receptor knock-out (Ldlr-/-) mice exposed to human recombinant PCSK9, in the presence of liver X receptor/retinoid X receptor (LXR/RXR) ligands or acetylated LDL (AcLDL) to stimulate Abca1 expression. Protein and gene expression was evaluated by Western blot and quantitative real time PCR, respectively. RESULTS: PCSK9 inhibited Abca1-mediated cholesterol efflux induced by LXR/RXR agonists in WT MPM (-55%, p < 0.05) but not in Ldlr-/- MPM. This effect was fully abrogated by the co-incubation with an anti-PCSK9 antibody. The inhibition of Abca1-dependent efflux induced by PCSK9 was associated with a reduction of Abca1 protein expression only in WT cells. Abca1 gene expression was significantly downregulated by PCSK9 in WT macrophages (-64%, p < 0.001) and, to a lesser extent, in MPM lacking Ldlr (-35%, p < 0.001). The inhibitory effect on Abca1-mediated efflux was also confirmed in AcLDL-treated macrophages. PCSK9 had a marginal or no effect on the expression of the lipid transporters Sr-b1 and Abcg1. CONCLUSIONS: PCSK9 plays a direct role on Abca1-mediated cholesterol efflux through a downregulation of Abca1 gene and Abca1 protein expression. This extrahepatic effect may influence relevant steps in the pathogenesis of atherosclerosis, such as foam cell formation.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Pró-Proteína Convertase 9/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Transporte Biológico , Células Cultivadas , Regulação para Baixo , Genótipo , Ligantes , Lipoproteínas LDL/farmacologia , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Macrófagos Peritoneais/enzimologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores X Retinoide/agonistas , Receptores X Retinoide/metabolismo
20.
Arch Biochem Biophys ; 599: 42-50, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26891591

RESUMO

Atherosclerosis, one of the leading causes of death worldwide, is characterized by impaired endothelial function and lipid metabolism, among other factors. Ellagitannins are a class of phenolic compounds that may play a role in cardiovascular health. This work aimed to study the potential atheroprotective effects of urolithins, ellagitannin-derived gut microbiota metabolites, on different key factors in atherosclerosis development: the ability of monocytes to adhere to endothelial cells and the uptake and efflux of cholesterol by macrophages. The biotransformations urolithins undergo in peripheral cells were also evaluated. Results indicated that some urolithins and ellagic acid were able to reduce the adhesion of THP-1 monocytes to human umbilical vein endothelial cells (HUVECs) and the secretion of a cellular adhesion molecule (sVCAM-1) and pro-inflammatory cytokine (IL-6). Urolithin C, a combination of urolithins A and B, and ellagic acid also decreased the accumulation of cholesterol in THP-1-derived macrophages, but they were not able to promote cholesterol efflux. The analysis of cell media by UHPLC-ESI-MS(n) indicated urolithins and ellagic underwent extensive metabolism, with sulfate and methyl conjugation. This evidence indicates that atherosclerotic processes may be attenuated by urolithins, but future human intervention trials are required to establish if is translated in vivo.


Assuntos
Colesterol/metabolismo , Cumarínicos/farmacologia , Ácido Elágico/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Taninos Hidrolisáveis/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Linhagem Celular Tumoral , Humanos , Interleucina-6/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
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