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1.
Life Sci ; 232: 116664, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325426

RESUMO

AIMS: MicroRNAs have been demonstrated to be involved in the development of atherosclerosis. The present study aimed to evaluate the effect of miR-99a-5p and its target gene Homeobox A1 (HOXA1) in atherosclerosis. MAIN METHODS: The biological functions of miR-99a-5p on human aortic smooth muscle cells (ASMCs) were assessed by MTT, wound healing and transwell assays. The target genes of microRNAs were predicted by TargetScan and miRDB. The binding of miR-99a-5p and HOXA1 was confirmed by luciferase reporter assay. In the in vivo study, high-fat diet-induced atherosclerosis model was established in Apolipoprotein E knockout mice. Hematoxylin-eosin (H&E), oil Red O and Masson trichrome staining were performed for determination of atherosclerotic lesion. The levels of miR-99a-5p and HOXA1 mRNA were detected by real-time PCR. HOXA1 and migration-associated protein levels were detected by western blot or immunohistochemistry analysis. KEY FINDINGS: MiR-99a-5p inhibited HOXA1 expression by targeting 3'UTR of HOXA1 mRNA. Enforced HOXA1 significantly promoted the proliferation, migration, and invasion of ASMCs. Furthermore, miR-99a-5p overexpression inhibited the proliferation, migration, and invasion of ASMCs stimulated by HOXA1, whereas miR-99a-5p inhibition reversed the effects of HOXA1 knockdown on these behaviours of ASMCs. In vivo, the specific overexpression of miR-99a-5p significantly abated atherosclerotic lesions formatted, accompanied with a significant down-regulation of HOXA1 mRNA and protein expression levels. SIGNIFICANCE: We demonstrate for first time that miR-99a-5p may serve as a potential inhibitor of the atherosclerosis, and miR-99a-5p plays its role partially through targeting HOXA1.


Assuntos
Aterosclerose/prevenção & controle , Regulação da Expressão Gênica , Genes Homeobox , Proteínas de Homeodomínio/genética , MicroRNAs/fisiologia , Fatores de Transcrição/genética , Regiões 3' não Traduzidas , Animais , Aterosclerose/genética , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Proteínas de Homeodomínio/fisiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fatores de Transcrição/fisiologia
2.
Expert Rev Clin Pharmacol ; 12(8): 771-780, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31269825

RESUMO

Introduction: The current approach of using only antiplatelet therapy for secondary prevention leaves a substantial risk of recurrent cardiovascular complications and mortality. Areas covered: In this manuscript, the role of coagulation in atherothrombosis is reviewed, as well as the impact of vascular doses of rivaroxaban on major cardiovascular outcomes and major adverse limb events. Expert opinion: In COMPASS, among patients with coronary heart disease and/or peripheral artery disease, compared to aspirin, the addition of rivaroxaban 2.5 mg twice daily to aspirin, significantly reduced the risk of major atherosclerotic outcomes, cardiovascular death and death for any cause, with a significant increase in the risk of major bleeding, but not fatal or intracranial bleedings. Preclinical data strongly suggest that rivaroxaban exerts vascular protection through different mechanisms, including improvement of endothelial functionality and fibrinolytic activity at endothelium, anti-inflammatory properties, and platelet-dependent thrombin generation. All these data indicate that among patients with atherosclerotic vascular disease, the addition of rivaroxaban 2.5 mg may provide further vascular protection.


Assuntos
Aterosclerose/prevenção & controle , Inibidores do Fator Xa/administração & dosagem , Rivaroxabana/administração & dosagem , Animais , Aspirina/administração & dosagem , Aterosclerose/patologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Quimioterapia Combinada , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacologia , Hemorragia/induzido quimicamente , Humanos , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacologia , Prevenção Secundária/métodos
3.
Zool Res ; 40(4): 317-323, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31310065

RESUMO

Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditions. However, its role in atherosclerosis remains undefined. In this study, we administered vehicle or LECT2 to male Apoe-/- mice fed a Western diet for 15 weeks. Atherosclerotic lesions were visualized and quantified with Oil-red O and hematoxylin staining. The mRNA expression levels of MCP-1, MMP-1, IL-8, IL-1ß, and TNF-α were analyzed by quantitative real-time polymerase chain reaction. Serum TNF-α, IL-1ß, IL-8, MCP-1, and MMP-1 concentrations were measured by enzyme-linked immunosorbent assay. CD68, CD31, and α-SMA, markers of macrophages, endothelial cells, and smooth muscle cells, respectively, were detected by immunostaining. Results showed that LECT2 reduced total cholesterol and low-density lipoprotein concentrations in serum and inhibited the development of atherosclerotic lesions, accompanied by reductions in inflammatory cytokines and lower MCP-1, MMP-1, TNF-α, IL-8, and IL-1ß mRNA abundance. Furthermore, LECT2 decreased CD68, but increased α-SMA in atherosclerotic lesions, suggesting an increase in smooth muscle cells and reduction in macrophages. In summary, LECT2 inhibited the development of atherosclerosis in mice, accompanied by reduced serum total cholesterol concentration and lower inflammatory responses.


Assuntos
Aterosclerose/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória
4.
BMC Complement Altern Med ; 19(1): 111, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146723

RESUMO

BACKGROUND: Atherosclerosis is a condition with the vascular accumulation of lipid plaques, and its main major contributing factor is endothelial injury induced by oxidized low-density lipoprotein (ox-LDL). Salidroside (SAL) is the primary active ingredient of Rhodiola rosea, and exhibits antioxidant properties on endothelial cells and alleviates atherosclerosis. However, the effect of SAL on autophagy in ox-LDL-induced vascular endothelial injury remains unclear. Here, we investigated the effect and underlying mechanisms of SAL on autophagy in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were incubated with ox-LDL to induce in vitro atherosclerosis model. The cell viability and injury were evaluated by cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) release assay. The oxidative stress was evaluated by NADPH oxidase, malondialdehyde (MDA) and superoxide dismutase (SOD) activities. Immunofluorescence was performed to detect autophagy using LC3ß antibody. Quantitative real-time PCR (qRT-PCR) and western blot were performed to measure the mRNA expressions of SIRT1 and Forkhead box O1 (FOXO1). Nicotinamide (NAM) and AS1842856 were used to inhibit activities of SIRT1 and FOXO1, respectively. RESULTS: Exposure of HUVECs to ox-LDL (100 µg/mL) reduced cell viability, increased cellular MDA, and reduced SOD in a concentration-dependent manner. The pretreatment with SAL (20, 50 and 100 µM) significantly enhanced the cell viability and decreased LDH release in HUVECs exposed to ox-LDL (100 µg/mL). ox-LDL induced autophagy in HUVECs, which was further enhanced by pretreatment with SAL. However, SAL attenuated increase in oxidative stress in HUVECs induced by ox-LDL. ox-LDL reduced mRNA and protein expressions of SIRT1 and FOXO1, which could be reversed by SAL. The protective, anti-oxidative and pro-autophagic effects of SAL could be obviously abolished by cotreatment with SIRT1 inhibitor or FOXO1 inhibitor. CONCLUSION: Salidroside shows protective effect on endothelial cell induced by ox-LDL, and the mechanisms might be related to autophagy induction via increasing SIRT1 and FoxO1 expressions.


Assuntos
Autofagia/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Glucosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Rhodiola , Aterosclerose/prevenção & controle , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/metabolismo , Proteína Forkhead Box O1/metabolismo , Glucosídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipoproteínas LDL , Estresse Oxidativo/efeitos dos fármacos , Fenóis/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Sirtuína 1/metabolismo
5.
Biochimie ; 163: 152-162, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199942

RESUMO

Extra-cellular signal regulated kinase-5 (Erk-5), a transcriptional activator and regulator of endothelial cells (ECs) homeostasis, has been implicated in shear stress-induced endothelial dysfunction (ED), however its role in oxidized low-density lipoprotein (oxLDL)- induced ED during metabolic stress is not known. Herein, regulation and function of Erk-5 in oxLDL-induced EC death, inflammation and dysfunction has been investigated. Primary Human Umbilical Vein Endothelial Cells (pHUVECs) were stimulated with oxLDL. MTT and Trypan blue exclusion assays to assess cell viability, RT-qPCR and Western blotting assays to determine expression of endothelial and inflammatory markers and ED mediators at mRNA and protein levels, respectively were performed. Monocyte adhesion assay was performed to examine monocytes adherence to oxLDL-stimulated pHUVECs. The exposure of oxLDL induced a dose- and time-dependent decrease in pHUVECs viability, which concurred with decreased Erk-5 expression. Further, oxLDL (100 µg/ml) decreased the expression of endothelial markers eNOS and vWF, and increased the expression of ICAM-1, at both mRNA and protein levels. SiRNA-mediated silencing of Erk-5 or its inhibition showed that changes in eNOS, vWF and ICAM-1 expression could be mediated through Erk-5. Furthermore, oxLDL decreased the levels of Erk-5's upstream regulator MEK5 and downstream regulators Mef2c and KLF2, which were similar to their expressions in Erk-5 silenced cells. Fisetin, a phytochemical and bioflavonoid, could reduce the effect of oxLDL in ECs by upregulating the expression of endothelial markers including Erk-5, and downregulating the expression of inflammation markers. These results suggest that Erk-5 could be a critical regulator of oxLDL-induced EC death, inflammation and dysfunction via downregulation of Erk-5/Mef2c-KLF2 signaling pathway, which can be ameliorated by a bioflavonoid, fisetin.


Assuntos
Flavonoides/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/toxicidade , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Monócitos/fisiologia , Transdução de Sinais , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Células Cultivadas , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lipoproteínas LDL/farmacologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Substâncias Protetoras/farmacologia
6.
High Blood Press Cardiovasc Prev ; 26(3): 199-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236902

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-related discoveries of the turn of the century have translated into substantial novelty in dyslipidemia treatment in the last 5 years. With chronic preventable atherosclerotic cardiovascular diseases (ASCVD) representing an epidemic of morbidity and mortality worldwide, low-density lipoprotein cholesterol (LDL-c) reduction represents a public health priority. By overcoming two major statin-related issues, namely intolerance and ineffectiveness, PCSK9 inhibitors have offered a safe and effective option in selected clinical settings where LDL-c reduction is required. Herein, we recapitulate recent findings, clinical applications, and ASCVD prevention potential of PCSK9 inhibition, with focus on anti-PCSK9 monoclonal antibodies, evolocumab and alirocumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/epidemiologia , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
7.
Kardiologiia ; 59(6): 70-80, 2019 Jun 26.
Artigo em Russo | MEDLINE | ID: mdl-31242843

RESUMO

Modern strategies of primary prevention of cardiovascular complications of atherosclerotic etiology are presented in this article: traditional approach based on assessment of risk of development of complication and coming to replace it concept of prevention based on direct application of results of prospective clinical studies. The article contains detailed presentation of new opportunities of computer tomography of the heart allowing to substantially elevate precision of assessment of risk of cardiovascular complications of atherosclerotic etiology. Main attention is paid to the coronary artery calcification index, which determination substantially simpli- fies decision making relative to strategy of primary prevention in clinical practice.


Assuntos
Aterosclerose , Doença da Artéria Coronariana , Aterosclerose/prevenção & controle , Humanos , Prevenção Primária , Estudos Prospectivos , Medição de Risco , Fatores de Risco
8.
J Photochem Photobiol B ; 196: 111508, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31152936

RESUMO

Cardiovascular malady (CVM) isn't just the essential driver of death in created western nations, yet additionally, its sickness load is expanding in China. Oxidative pressure initiated free radicals assume a basic job in cell forms involved in atherosclerosis and numerous other heart illnesses. Quercetin (QC) is cancer prevention agents medicate which is demonstrated that successfully secures against CVMs. Encapsulations of medications in polymeric materials are generally utilized in creating continued and controllable medication discharge, or to keep away from the debasement of non-discharged medications. In this present work, a novel arrangement of polymeric superparamagnetic nano-silica (SiN)@poly(lactic-co-glycolic acid) (PLGA) (SiN@PLGA) stacked with QC was created by means of lyophilization method so as to improve poor watery solvency and steadiness of the medication with the point of preventing atherosclerosis. The aftereffects of SEM investigation and the checking, TEM affirmed the manufacture of the circular nanocomposite, smooth surface, and thin size dispersion. The discharge profile of QC from the particles was explored by deciding the medication sum discharged at explicit interims for by iridescence. The data got from this investigation encourages the structure and manufacture of nanocomposite as conceivable conveyance frameworks for epitome, assurance and controlled arrival of the flavonoid QC which is expecting to secure against CVMs.


Assuntos
Nanocompostos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quercetina/química , Dióxido de Silício/química , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Nanocompostos/toxicidade , Quercetina/metabolismo , Quercetina/uso terapêutico
9.
J Manag Care Spec Pharm ; 25(5): 588-592, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31039060

RESUMO

BACKGROUND: Nearly half of statin users discontinue therapy within the first year of treatment. Nonadherence to statin therapy may lead to an increased risk of atherosclerotic cardiovascular disease and, thus, higher costs due to hospitalizations. Value-based care models, such as accountable care organizations (ACO), are measured on adherence rates to statins through proportion of days covered (PDC). However, there is little research describing pharmacy student-based interventions within value-based care models. OBJECTIVES: To (a) identify mean change in PDC for statins following implementation of a pharmacy student adherence outreach program and (b) identify the proportion of patients converted to PDC ≥ 0.80 following the implementation of the outreach program. METHODS: This single-center retrospective quasi-experimental study included patients actively enrolled in a Humana Medicare Advantage Prescription Drug (MA-PD) plan who completed at least 1 adherence outreach telephone call performed by a pharmacy student between January 1, 2017, and December 31, 2017. RESULTS: 99 patients met inclusion criteria. Atorvastatin was the most commonly prescribed statin (43%), followed by simvastatin (38%). Sixty-four percent of patients had a baseline PDC of < 0.80. Mean (SD) PDC was 0.66 (±0.24) before the pharmacy student adherence outreach intervention, and 0.79 (± 0.23)-a 0.13 increase-after the pharmacy student adherence outreach intervention (P < 0.001). Among patients who had PDC < 0.80 at baseline, 35% of patients (n = 35) were converted to PDC ≥ 0.80 (P < 0.001), and 5% of patients with a baseline PDC ≥ 0.80 had a decrease in PDC to < 0.80 following the intervention. CONCLUSIONS: Among patients enrolled in a Humana MA-PD plan within an ACO, mean PDC for statins increased following exposure to a pharmacy student adherence outreach program. One third of patients converted their PDCs to ≥ 0.80 following the intervention. Value-based care programs may consider incorporating pharmacy student services to improve adherence to statins. DISCLOSURES: No outside funding supported this research. The authors have no financial conflicts of interest to disclose. At the time of conducting this research, all authors were employed at Nova Southeastern University. Preliminary results were presented as a poster at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.


Assuntos
Aterosclerose/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Conduta do Tratamento Medicamentoso/organização & administração , Estudantes de Farmácia , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/economia , Feminino , Custos de Cuidados de Saúde , Implementação de Plano de Saúde , Hospitalização/economia , Humanos , Masculino , Programas de Assistência Gerenciada/organização & administração , Medicare Part C/economia , Medicare Part C/estatística & dados numéricos , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Telefone , Estados Unidos
10.
Drugs Today (Barc) ; 55(5): 329-344, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131843

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of death all over the world. Its etiopathogenesis involves many correlated processes, with hypercholesterolemia being one of the main risk factors. Several large clinical trials have established the association between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. With the aim to take control over high LDL-C levels, several drugs with different targets in the cholesterol pathway have been developed. Statins are the cornerstone of pharmacological lipid-lowering treatment, although they are not always successful in attaining the recommended LDL-C levels. Therefore, newer and more potent therapies have been developed, being prominent among them ezetimibe and especially the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recent trials with these new therapies have reaffirmed the theory of 'the lower, the better' when it comes to LDL-C levels, and 'the earlier, the better' when it comes to atherosclerotic physiopathology.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/antagonistas & inibidores , Pró-Proteína Convertase 9/antagonistas & inibidores , Subtilisinas/antagonistas & inibidores , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Humanos
11.
Methodist Debakey Cardiovasc J ; 15(1): 9-15, 2019 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31049144

RESUMO

Given its role in many biochemical processes essential to life, cholesterol remains a topic of intense research. Of all the plasma lipids, cholesterol is distinctive because it is a precursor to steroidogenic molecules, some of which regulate metabolism, and its blood concentration in the form of low- and high-density lipoprotein cholesterol (HDL-C) are positive and negative risk factors for atherosclerotic cardiovascular disease (ASCVD). New research, however, has challenged the widely held belief that high HDL-C levels are atheroprotective and is showing that both low and high plasma HDL-C levels confer an increased risk of ASCVD. Furthermore, it is disputing the widely cited mechanism involved in reverse cholesterol transport. This review explores the evolution of cholesterol research starting with the Gofman and Framingham studies, the development of traditional and emerging lipid-lowering therapies, and the role of reverse cholesterol transport in HDL cardioprotection.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/etiologia , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/sangue , HDL-Colesterol/efeitos adversos , HDL-Colesterol/sangue , LDL-Colesterol/efeitos adversos , LDL-Colesterol/sangue , Animais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/genética , Aterosclerose/prevenção & controle , Transporte Biológico , Humanos , Placa Aterosclerótica , Prognóstico , Fatores de Proteção , Fatores de Risco
12.
Postgrad Med ; 131(4): 268-277, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31063407

RESUMO

Eicosapentaenoic acid (EPA) is a key anti-inflammatory/anti-aggregatory long-chain polyunsaturated omega-3 fatty acid. Conversely, the omega-6 fatty acid, arachidonic acid (AA) is a precursor to a number of pro-inflammatory/pro-aggregatory mediators. EPA acts competitively with AA for the key cyclooxygenase and lipoxygenase enzymes to form less inflammatory products. As a result, the EPA:AA ratio may be a marker of chronic inflammation, with a lower ratio corresponding to higher levels of inflammation. It is now well established that inflammation plays an important role in cardiovascular disease. This review examines the role of the EPA:AA ratio as a marker of cardiovascular disease and the relationship between changes in the ratio (mediated by EPA intake) and changes in cardiovascular risk. Epidemiological studies have shown that a lower EPA:AA ratio is associated with an increased risk of coronary artery disease, acute coronary syndrome, myocardial infarction, stroke, chronic heart failure, peripheral artery disease, and vascular disease. Increasing the EPA:AA ratio through treatment with purified EPA has been shown in clinical studies to be effective in primary and secondary prevention of coronary artery disease and reduces the risk of cardiovascular events following percutaneous coronary intervention. The EPA:AA ratio is a valuable predictor of cardiovascular risk. Results from ongoing clinical trials will help to define thresholds for EPA treatment associated with better clinical outcomes.


Assuntos
Ácido Araquidônico/metabolismo , Doenças Cardiovasculares/prevenção & controle , Ácido Eicosapentaenoico/metabolismo , Inflamação/prevenção & controle , Aterosclerose/prevenção & controle , Biomarcadores , Doenças Cardiovasculares/sangue , Doença Crônica , Suplementos Nutricionais , Ácido Eicosapentaenoico/administração & dosagem , Humanos , Inflamação/sangue , Mediadores da Inflamação/metabolismo , Prostaglandinas/metabolismo , Fatores de Risco
13.
BMC Res Notes ; 12(1): 200, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940182

RESUMO

OBJECTIVE: Therapeutic effects of focal adhesion kinase (FAK) inhibition using a small molecule inhibitor was evaluated in apolipoprotein E (apoE) knockout (KO) and low-density lipoprotein receptor (LDLr) KO mouse atherosclerosis models. RESULTS: The prevention trial consisted of an 8-week treatment with an FAK inhibitor concurrent treatment with a high fat (HF)/high cholesterol (HC) diet. The intervention trial consisted of 6- and 8-week treatment after 6- and 8-week pre-loading, respectively, of a HF/HC diet in apoE KO and LDLr KO mice, respectively. The inhibitor was admixed with a HF/HC diet and mice were given free access to the admixture. The FAK inhibitor exhibited marked inhibition against the development of the atherosclerosis in both of prevention and intervention trials at a dose of 0.03% without showing any remarkable toxic properties in biochemical examinations. These results indicated that FAK inhibition might be a possible candidate for novel therapeutic targets against atherosclerosis.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores de LDL/deficiência , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout
14.
Eur J Pharmacol ; 852: 167-178, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30826323

RESUMO

2',3',5'-Tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine, a cordycepin derivative that is also known as IMM-H007, is a new adenosine analogue and anti-hyperlipidaemic drug that was developed in our laboratory. It has been previously reported to alleviate atherosclerosis by regulating blood lipid levels. The purpose of the current study was to determine the protective effects of IMM-H007 on endothelial function and vascular inflammation independent of its lipid-lowering effect. Vascular reactivity was determined using a pressure myography system-120CP. Vascular inflammation was assessed to quantify leukocyte-endothelial adhesion in the mesenteric microcirculation. Relative levels of endothelial nitric oxide synthase(eNOS)activity were detected using a fluorescent nitric oxide(NO)probe, and NO production was detected using Griess reagent. Atherosclerotic plaques were evaluated with en face and cross section analyses. Here, IMM-H007 improved endothelial dysfunction through a mechanism independent of its lipid-lowering effect. IMM-H007 suppressed vascular inflammation both in the initial stage and during the progression of atherosclerosis. The in vitro study using human umbilical vein endothelial cells (HUVECs) revealed that IMM-H007 increased eNOS activity and nitric oxide production, which were closely related to the increased phosphorylation of AMP-activated protein kinase (AMPK), protein kinase B (Akt) and eNOS induced by IMM-H007. Furthermore, inhibition of AMPK by Compound C completely blocked IMM-H007-induced Akt and eNOS activation. IMM-H007 suppressed the formation of atherosclerotic lesions in ApoE-/- mice. We have presented evidence that IMM-H007 represents a potential therapeutic strategy to improve endothelial function and attenuate inflammation, and it is a promising, novel therapeutic approach to treating atherosclerosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adenosina/análogos & derivados , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Adenosina/farmacologia , Animais , Aterosclerose/prevenção & controle , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Ativação Enzimática/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Camundongos , Camundongos Knockout para ApoE , Óxido Nítrico/biossíntese , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
15.
Chin Med J (Engl) ; 132(9): 1079-1086, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870265

RESUMO

BACKGROUND: Endothelial dysfunction, the initial pathogenic factor in atherosclerosis, can be alleviated via transient limb ischemia. We observed the effects of regular transient limb ischemia (RTLI) on atherosclerosis in hypercholesterolemic rabbits. METHODS: Twenty-eight rabbits were randomized to control, cholesterol, sham, ischemia groups (n = 7 each) between October 2010 and March 2011. They were fed a normal diet in the control group and hypercholesterolemic diet in other groups for 12 weeks. Six cycles of RTLI were performed once per day on the ischemia group. Serum samples were prepared to measure the total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) before the experiment (W0), at the end of weeks 4, 8, 12 (W4, W8, W12). The whole aorta was harvested at W12 and stained using Sudan IV to identify the plaque. The plaque area was measured using Image J. Results were analyzed by analysis of variance or rank sum test. RESULTS: Concentrations of TC in the cholesterol group were higher than those in the control group at W4 (29.60 [23.75, 39.30] vs. 1.00 [0.80, 1.55], Z = -2.745, P = 0.006), W8 (41.78 [28.08, 47.37] vs. 0.35 [0.10, 0.68], Z = -2.739, P = 0.006), W12 (48.32 [40.04, 48.95] vs. 0.61 [0.50, 0.86], Z = -2.739, P = 0.006). Similar results were obtained for HDL-C and LDL-C. Serum concentrations of TC, HDL-C, and LDL-C in the hypercholesterolemic groups had no differences (all P > 0.05). The percentage of plaque area in the cholesterol group was higher than that in the control group (47.22 ±â€Š23.89% vs. 0, Z = -2.986, P = 0.003). Square root of the percentage of plaque area was smaller in the ischemia group than that in the cholesterol (0.44 ±â€Š0.13 vs. 0.67 ±â€Š0.18, P = 0.014) or sham groups (0.44 ±â€Š0.13 vs. 0.61 ±â€Š0.12, P = 0.049). CONCLUSION: In hypercholesterolemic rabbits, RTLI might prevent atherosclerosis progression by reducing the percentage of plaque area.


Assuntos
Aterosclerose/sangue , Aterosclerose/prevenção & controle , Extremidades/patologia , Hipercolesterolemia/sangue , Ataque Isquêmico Transitório/sangue , Pós-Condicionamento Isquêmico/métodos , Animais , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Masculino , Coelhos , Triglicerídeos/sangue
16.
Klin Lab Diagn ; 64(2): 68-77, 2019.
Artigo em Russo | MEDLINE | ID: mdl-30917246

RESUMO

Although the biochemistry of the positive effects of medium-chain fatty acids (FA) and triglycerides (TG) of the same name in vivo is not fully understood, food enriched with medium-chain LC and the same TG is effective in patients with type I diabetes, insulin resistance syndrome and in neurodegenerative pathology. Lauric C12 LC is half the FA in coconut oil. Residents of southeast Asia with constant use of coconut oil, have a low level of diseases of the cardiovascular system in the population. With a regulatory intake with food C12:0 laurin FA formed moderate ketosis and neuroprotective effect. Unlike long-chain LC, medium-chain TG cells are not deposited either in visceral fat cells, or in insulin-dependent adipocytes. Medium-chain fatty acids rapidly oxidize mitochondria; the formation of acetyl-CoA cells is used to form ketone bodies, activating thermogenesis in orange and brown adipocytes. Experiments with animals and observations in the clinic showed that taking medium-chain TG with food is more physiological than long-chain oils. This significantly increases the level of cholesterol in high-density lipoproteins. Food enriched with medium chain TG is optimal for increasing the ketone content in blood plasma, cerebrospinal fluid without limiting the carbohydrate content in food. The formation of excess ketone bodies by cells can be achieved by activating the metabolic transformations of medium-chain FAs, without fasting and preserving carbohydrates in food. Coconut oil has a positive effect on the cardiovascular system, preventing the formation of atherosclerosis and atheromatosis. Effective in the prevention of the pathology of the cardiovascular system is a decrease in food amounts of palmitic acid, an increase in oleic acid, polyene FA with a simultaneous increase in the proportion of medium-chain FA.


Assuntos
Aterosclerose/prevenção & controle , Ácidos Graxos/metabolismo , Hiperlipidemias/patologia , Resistência à Insulina , Triglicerídeos/metabolismo , Animais , Dieta , Humanos
17.
Biosci Biotechnol Biochem ; 83(6): 1094-1101, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30871430

RESUMO

Oxidized low-density lipoprotein (ox-LDL) leads to atherosclerosis via lectin-like oxidized lipoprotein receptor-1 (LOX-1), one of the major receptor for ox-LDL. Inhibition of the binding of ox-LDL to LOX-1 decreases the proinflammatory and atherosclerotic events. The aim of the present study was to investigate whether protamine, a polybasic nuclear protein, interferes the binding of ox-LDL to LOX-1. Using sandwich ELISA with newly generated antibody, we measured the blocking effect of protamine on the binding of ox-LDL to LOX-1. Protamine dose-dependently inhibited the binding of ox-LDL to LOX-1. DiI-labeled ox-LDL uptake assay in two types of cultured human endothelial cells was performed with fluorescence microplate reader. Activation of extracellular-signal-regulated kinase (ERK)1/2 by ox-LDL was analyzed by immunoblotting. We found that protamine suppressed uptake of ox-LDL in endothelial cells and inhibited ERK1/2 activation by ox-LDL. These results suggest that protamine may possess anti-atherogenic potential by inhibiting ox-LDL binding to LOX-1 through electrostatic interactions.


Assuntos
Aterosclerose/prevenção & controle , Lipoproteínas LDL/metabolismo , Protaminas/farmacologia , Receptores Depuradores Classe E/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Fluorescência , Humanos , Lipoproteínas LDL/antagonistas & inibidores , Protaminas/administração & dosagem , Ligação Proteica , Receptores Depuradores Classe E/antagonistas & inibidores
18.
Medicine (Baltimore) ; 98(9): e14737, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817628

RESUMO

INTRODUCTION: High-intensity interval training (HIIT) programs have demonstrated positive effects on cardiorespiratory fitness and cardiometabolic parameters, but their impact on other health parameters (such as body mass and fat) and cognition remains unclear. This paper presents the rationale and methods of a HIIT after-school physical activity (PA) intervention (MOVI-daFIT!) on reducing fat mass and cardiovascular risk, and improving physical fitness, executive function, and academic achievement among children aged 9 to 11 years old. METHODS: A cluster randomized controlled trial (RCT), including 10 schools from Cuenca province, Spain, was designed. Schools were randomly assigned to the MOVI-daFIT! intervention and to the control group. Children were evaluated at the beginning (September 2017) and at the end (June 2018) of the school year. Children in the intervention group were involved in 60-minute after-school sessions 4 days per week developed in the school setting. Each session consisted of 15 minutes of set-up and warm-up games, 28 minutes of games using the HIIT protocol, and 10 minutes of cool down. In addition, children in the intervention and control groups received 2 regular 50-minute physical education sessions per week, as it is compulsory by law in Spanish schools. CONCLUSION: This study will determine the effect of an after-school physical activity intervention (MOVI-daFIT!), designed as a HIIT program, on reducing fat mass and cardiovascular risk, and improving fitness and cognition, including executive function and academic achievement.


Assuntos
Adiposidade/fisiologia , Aterosclerose/prevenção & controle , Aptidão Cardiorrespiratória/fisiologia , Cognição/fisiologia , Exercício/fisiologia , Sucesso Acadêmico , Glicemia , Pressão Sanguínea , Pesos e Medidas Corporais , Criança , Fatores de Confusão (Epidemiologia) , Função Executiva/fisiologia , Feminino , Humanos , Lipídeos/sangue , Masculino , Projetos de Pesquisa , Espanha
19.
Chin J Nat Med ; 17(1): 50-58, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30704624

RESUMO

Atherosclerotic cardiovascular disease (ASCVD) is the deadliest disease in the world, with endothelial injury occurring throughout the course of the disease. Therefore, improvement in endothelial function is of essential importance in the prevention of ASCVD. Red yeast rice (RYR), a healthy traditional Chinese food, has a lipid modulation function and also plays a vital role in the improvement of endothelial reactivity and cardiovascular protection; thus, it is significant in the prevention and treatment of ASCVD. This article reviews the molecular mechanisms of RYR and its related products in the improvement of endothelial function in terms of endothelial reactivity, anti-apoptosis of endothelial progenitor cells, oxidative stress alleviation and anti-inflammation.


Assuntos
Aterosclerose/prevenção & controle , Produtos Biológicos/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Medicamentos de Ervas Chinesas/química , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Humanos , Inflamação/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
20.
Vascul Pharmacol ; 115: 46-54, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30797043

RESUMO

Chemotherapeutic agents used in cancer treatment associated to nanoparticles (LDE) that mimic the composition of low-density lipoprotein and buffer their toxicity can have strong anti-atherosclerosis action, as we showed in cholesterol-fed rabbits. Here, a novel preparation of docetaxel (DTX) carried in LDE was evaluated. Eighteen rabbits were fed 1% cholesterol during 8 weeks. After the first 4 weeks, 9 animals were treated for 4 weeks with intravenous LDE-DTX (1 mg/kg/week) and 9 with LDE only (controls) once a week for 4 weeks. Animals were then euthanized and the aortas were analyzed for morphometry, immunohistochemistry and Western blot. LDE-DTX treated group showed 80% reduction of atheroma area compared to controls. LDE-DTX treatment reduced in 60% the protein expression of macrophage marker CD68 and of MCP-1 in 80%. LDE-DTX pronouncedly lowered expression of pro-inflammatory markers NF-κB, TNF-α, IL-1ß, IL-6 and von Willebrand factor and elicited 40% reduction in cell proliferation marker PCNA. The presence of smooth muscle cells in the intima was 85% smaller than in controls. Pro-apoptotic caspase 3, caspase 9, Bax, and anti-apoptotic Bcl-2 all were reduced by LDE-DTX. Protein expression of MMP-2 and MMP-9, TGF-ß, and collagen 1 and 3 were also markedly lowered by the LDE-DTX treatment. Animals showed no hematological, hepatic or renal toxicity consequent to LDE-DTX treatment. In conclusion, LDE-DTX showed a wide array of strong effects on pro-inflammatory and proliferation-promoting factors that drive the lesion development. These findings and the lack of observable toxicity indicate that LDE-DTX can be a candidate for future clinical trials.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Docetaxel/farmacologia , Lipídeos/química , Nanopartículas , Placa Aterosclerótica , Animais , Anti-Inflamatórios/química , Aorta/metabolismo , Aorta/patologia , Aortite/metabolismo , Aortite/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Morte Celular/efeitos dos fármacos , Colesterol na Dieta , Dieta Hiperlipídica , Modelos Animais de Doenças , Docetaxel/química , Composição de Medicamentos , Colágenos Fibrilares/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fator de von Willebrand/metabolismo
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