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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
2.
DNA Cell Biol ; 38(10): 1025-1029, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31532239

RESUMO

Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines. A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury. Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.


Assuntos
Aterosclerose/genética , Colite/genética , Esclerose Múltipla/genética , Neutrófilos/metabolismo , Receptor CB2 de Canabinoide/genética , Traumatismo por Reperfusão/genética , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Citocinas/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Ligantes , Camundongos , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Infiltração de Neutrófilos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/deficiência , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
3.
Vasc Health Risk Manag ; 15: 209-220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371977

RESUMO

Cholesterol-embolization syndrome (CES) is a multisystemic disease with various clinical manifestations. CES is caused by embolization of cholesterol crystals (CCs) from atherosclerotic plaques located in the major arteries, and is induced mostly iatrogenically by interventional and surgical procedures; however, it may also occur spontaneously. Embolized CCs lead to both ischemic and inflammatory damage to the target organ. Therefore, anti-inflammatory agents, such as corticosteroids and cyclophosphamide, have been investigated as treatment for CES in several studies, with conflicting results. Recent research has revealed that CES is actually a kind of autoinflammatory disease in which inflammasome pathways, such as NLRP3 and IL1, are induced by CCs. These recent findings may have clinical implications such that colchicine and IL1 inhibitors, namely canakinumab, may be beneficial in the early stages of CES.


Assuntos
Aterosclerose , Colesterol/sangue , Embolia de Colesterol , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Biomarcadores/sangue , Cristalização , Embolia de Colesterol/sangue , Embolia de Colesterol/diagnóstico , Embolia de Colesterol/epidemiologia , Embolia de Colesterol/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Inflamassomos/sangue , Mediadores da Inflamação/sangue , Interleucina-1/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Placa Aterosclerótica , Prognóstico , Fatores de Risco , Síndrome
4.
Int J Cardiovasc Imaging ; 35(9): 1745-1753, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312997

RESUMO

No data exist whether statins have robust anti-inflammatory effects of atherosclerotic plaques primarily during the early treatment period or continuously throughout use. This prospective three time point 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study of the carotid artery assessed anti-inflammatory effects of statin during the early treatment period (initiation to 3 months) and late treatment period (3 months to 1 year) and their correlation with lipid and inflammatory profile changes during a year of therapy. Nine statin-naïve stable angina patients with inflammatory carotid plaques received 20 mg/day atorvastatin after undergoing initial 18F-FDG PET/CT scanning of carotid arteries and ascending thoracic aorta, and then completed serial 18F-FDG PET/CT imaging at 3 and 12 months whose data were analyzed. The primary outcome was the inter-scan percent change in target-to-background ratio (ΔTBR) within the index vessel. At 3 months of atorvastatin treatment, mean serum low-density lipoprotein cholesterol (LDL-C) level decreased by 36.4% to < 70 mg/dL (p = 0.001) and mean serum high-density lipoprotein cholesterol level increased to > 40 mg/dL (p = 0.041), with both maintained with no further reduction up to 1 year (p = 0.516 and 0.715, respectively) while mean serum high sensitivity C-reactive protein level only numerically decreased (p = 0.093). The index vessel ΔTBR showed continuous plaque inflammation reduction over 1 year, by 4.4% (p = 0.015) from the initiation to 3rd months and 6.2% (p = 0.009) from 3rd months to 1 year, respectively, without correlation with lipid profile changes. The ΔTBR of the bilateral carotid arteries and ascending aorta also continuously decreased from 3 months to 1 year. Three time point 18F-FDG PET/CT imaging demonstrates that statin's anti-inflammatory effect continues throughout its use up to 1 year, even though yielding stable below-target plasma LDL-C levels at 3 months.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/tratamento farmacológico , Fluordesoxiglucose F18/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Idoso , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/patologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
5.
Biomed Khim ; 65(3): 227-230, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31258146

RESUMO

The experimental study in vivo was aimed at evaluation of hypolipidemic action of the original natural microbial enzyme preparation of cholesterol oxidase (CHO). In preliminary chronic experiments in rats, rabbits, dogs, low toxicity, good tolerability, and anti-atherosclerotic activity of the CHO preparation were established. To assess the effect of CHO under conditions of moderate, nutritional, atherogenic dyslipoproteinemia, experiments were carried out in rats, guinea pigs, and rabbits. It was shown that administration of CHO had the pronounced lipid-lowering effect in models of atherogenic dyslipoproteinemia induced in these animals.


Assuntos
Aterosclerose/tratamento farmacológico , Colesterol Oxidase/farmacologia , Hipolipemiantes/farmacologia , Lipídeos/sangue , Animais , Cães , Cobaias , Coelhos , Ratos
6.
J Agric Food Chem ; 67(28): 7869-7879, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31287296

RESUMO

Carnitine, a dietary quaternary amine mainly from red meat, is metabolized to trimethylamine (TMA) by gut microbiota and subsequently oxidized to trimethylamine-N-oxide (TMAO) by host hepatic enzymes, flavin monooxygenases (FMOs). The objective of this study aims to investigate the effects of flavonoids from oolong tea and citrus peels on reducing TMAO formation and protecting vascular inflammation in carnitine-feeding mice. The results showed that mice treated with 1.3% carnitine in drinking water significantly (p < 0.05) increased the plasma levels of TMAO compared to control group, whereas the plasma TMAO was remarkedly reduced by flavonoids used. Meanwhile, these dietary phenolic compounds significantly (p < 0.05) decreased hepatic FMO3 mRNA levels compared to carnitine only group. Additionally, oolong tea extract decreased mRNA levels of vascular inflammatory markers such as tissue necrosis factor-alpha (TNF-α), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Polymethoxyflavones significantly lowered the expression of VCAM-1 and showed a decreasing trend in TNF-α and E-selectin mRNA expression compared to the carnitine group. Genus-level analysis of the gut microbiota in the cecum showed that these dietary phenolic compounds induced an increase in the relative abundances of Bacteroides. Oolong tea extract-treated group up-regulated Lactobacillus genus, compared to the carnitine only group. Administration of polymethoxyflavones increased Akkermansia in mice.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Camellia sinensis/química , Carnitina/metabolismo , Citrus/química , Flavonas/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Aterosclerose/genética , Aterosclerose/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biotransformação/efeitos dos fármacos , Feminino , Flavonas/análise , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Metilaminas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
7.
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
8.
Zhonghua Xin Xue Guan Bing Za Zhi ; 47(5): 351-359, 2019 May 24.
Artigo em Chinês | MEDLINE | ID: mdl-31142078

RESUMO

Objective: To assess the use of statins and low-density lipoprotein cholesterol (LDL-C) levels at admission in hospitalized patients aged 75 years and older with acute coronary syndrome (ACS) in China. Methods: Data used in this study derived from the Improving Care for Cardiovascular Disease in China (CCC)-ACS project, a nationwide registry with 150 tertiary hospitals reporting details of clinical information of ACS patients. This study enrolled patients 75 years and older with ACS in CCC-ACS project from November 2014 to June 2017. Patients were divided into two groups according to the history of atherosclerotic cardiovascular disease (ASCVD). Pre-hospital statin use, LDL-C levels at admission and prescription of statins at discharge were reported. Results: A total of 10 899 patients 75 years and older with ACS were enrolled. The median age was 79 years and 58.7% (6 397 cases) were male. Among patients with history of ASCVD, 33.9% (1 028 cases) of them received statins before hospitalization. Among patients without history of ASCVD, 12.7% (996/7 871) received statins before hospitalization. The mean level of LDL-C was (2.4±0.9) mmol/L and LDL-C was <1.8 mmol/L in 24.7% (747 cases) of patients with history of ASCVD. The mean level of LDL-C was (2.6±0.9) mmol/L and LDL-C was <2.6 mmol/L in 51.7% (4 072 cases) of patients without history of ASCVD. At discharge, 91.2% (9 524/10 488) of patients were prescribed with statins in patients without contraindications for statin. Conclusion: In elderly patients with recurrent ASCVD, there was an inadequate statin use before hospitalization and most patients did not reach the LDL-C target level when they had the recurrent events. In the elderly ACS patients without history of ASCVD, more than half of the patients had an ideal LDL-C level. It seems that ideal LDL-C level for primary prevention of ACS in elderly people needs to be reevaluated with further studies.


Assuntos
Síndrome Coronariana Aguda , Aterosclerose , Inibidores de Hidroximetilglutaril-CoA Redutases , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , Aterosclerose/tratamento farmacológico , China , LDL-Colesterol , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino
9.
Expert Opin Pharmacother ; 20(10): 1277-1288, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059312

RESUMO

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) and its clinical manifestations, remain a leading cause of death and disability worldwide. One of the major risk factors of ASCVD is dyslipidemia and all the available guidelines suggest the importance of strategies for lipid control in a remarkable proportion of the general population. AREAS COVERED: This review focuses on the therapeutic options available for the management of lipid disorders in adults. EXPERT OPINION: A large body of evidence supports that statins are still the first-line option for the management of hypercholesterolemia in a large percentage of patients. Statins should be given at the appropriate dose and considering the differences in lipid-lowering potency across the different medications. The main current challenge in the treatment of lipid disorders is the need of improving patient adherence and persistence to lipid-lowering treatments beyond the drug choice and the target lipid component. To achieve this goal, the best strategy would be to treat the patients by using the appropriate drugs given at adequate doses to reach the treatment target. We should also avoid drug interactions, monitor possible untoward side effects and promote adherence to treatment by tailoring treatment strategies to each patient.


Assuntos
Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Adulto , Aterosclerose/tratamento farmacológico , Humanos , Fatores de Risco
10.
Int J Nanomedicine ; 14: 2609-2618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043777

RESUMO

Background: EGFP-EGF1-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticle (ENP) has a specific affinity to tissue factor (TF). The aim of this study was to investigate the target delivery of ENP to plaques and its uptake in a mouse model of atherosclerosis in vivo and in vitro. Materials and methods: Coumarin-6- and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo cyanine iodide (DiR)-loaded ENPs were synthesized using a double-emulsion method. Mouse vascular smooth muscle cells (VSMCs) were induced with MCP-1 to obtain an increased TF expression. Fluorescence microscopy and flow cytometry assay were performed to examine the uptake of coumarin-6-loaded ENPs in cellular models. An animal model of atherosclerosis was established with an ApoE (-/-) mouse fed with continuous high-fat diets for 14 weeks. DiR-loaded ENPs (DiR-ENPs) were injected via the caudal vein. The distribution of DiR-ENPs was examined through organ imaging and confocal laser scanning microscopy. Results: Results indicated TFs were highly expressed in the cellular model. The uptake of coumarin-6-loaded ENPs was significantly higher than that of common PLGA nanoparticles. Thickening of intima and lipid deposition in the aorta could be observed in atherosclerosis mouse models. Confocal laser scanning microscopy organ imaging showed ENPs accumulated in vessels with atherosclerotic plaques, which coincided with high expressions of TF. Conclusion: This study showed that EGFP-EGF1-conjugated PLGA nanoparticles could be effectively delivered to atherosclerotic plaques in vivo and taken up by VSMCs with high TF expressions in vitro. Thus, it could be a promising carrier for targeted therapy of atherosclerosis.


Assuntos
Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Portadores de Fármacos/química , Proteínas de Fluorescência Verde/metabolismo , Nanopartículas/química , Fator G para Elongação de Peptídeos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Aorta/patologia , Cumarínicos/química , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Fluorescência , Humanos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Nanopartículas/administração & dosagem , Tamanho da Partícula , Eletricidade Estática , Tiazóis/química
11.
Curr Pharm Biotechnol ; 20(5): 422-432, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947667

RESUMO

BACKGROUND: Tanshinone IIA (Tan IIA) and Omentin-1 have a protective role in the cardiovascular system. However, if and how Tan IIA and Omentin-1 regulate cholesterol metabolism in macrophages has not been fully elucidated. OBJECTIVE: To investigate the possible mechanisms of Tan IIA and Omentin-1 on preventing macrophage cholesterol accumulation and atherosclerosis development. METHODS: The effect of Tan IIA on the protein and mRNA levels of Omentin-1 and ATP-binding cassette transporter A1 (ABCA1) in macrophages was examined by Western blot and qRT-PCR assay, respectively. Cholesterol efflux was assessed by liquid scintillation counting (LSC). Cellular lipid droplet was measured by Oil Red O staining, and intracellular lipid content was detected by high performance liquid chromatography (HPLC). In addition, the serum lipid profile of apoE-/- mice was measured by enzymatic method. The size of atherosclerotic lesion areas and content of lipids and collagen in the aortic of apoE-/- mice were examined by Sudan IV, Oil-red O, and Masson staining, respectively. RESULTS: Tan IIA up-regulated expression of Omentin-1 and ABCA1 in THP-1 macrophages, promoting ABCA1-mediated cholesterol efflux and consequently decreasing cellular lipid content. Consistently, Tan IIA increased reverse cholesterol transport in apoE-/- mice. Plasma levels of high-density lipoprotein cholesterol (HDL-C), ABCA1 expression and atherosclerotic plaque collagen content were increased while plasma levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic plaque sizes were reduced in Tan IIA-treated apoE-/- mice. These beneficial effects were, however, essentially blocked by knockdown of Omentin-1. CONCLUSION: Our results revealed that Tan IIA promotes cholesterol efflux and ameliorates lipid accumulation in macrophages most likely via the Omentin-1/ABCA1 pathway, reducing the development of aortic atherosclerosis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Diterpenos de Abietano/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Diterpenos de Abietano/uso terapêutico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Regulação para Cima
12.
Zhongguo Zhong Yao Za Zhi ; 44(2): 235-241, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30989939

RESUMO

In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the core pathological basis for disease progression. In the evolution of atherosclerotic plaques,the rupture of unstable plaques,plaque shedding and formation of thrombosis are the most dangerous parts. In this process,the formation of plaque fibrosis is the core mechanism regulating plaque stability. Additionally,fibrosis reflects dynamic changes in the inflammatory processes and pathological changes. In view of the inflammation regulation and fibrosis regulation,this paper clarified the process of atherosclerotic plaque,explained the roles of relevant inflammatory cells and cytokines in plaque stability,and summed up drug researches related with stable plaque in recent years. In the future,improving the fibrosis will be a new idea for stabilizing plaque in atherosclerosis drug development.


Assuntos
Aterosclerose/tratamento farmacológico , Inflamação , Placa Aterosclerótica/tratamento farmacológico , Trombose/tratamento farmacológico , Aterosclerose/patologia , Citocinas , Fibrose , Humanos , Placa Aterosclerótica/patologia , Trombose/patologia
13.
Int J Mol Sci ; 20(7)2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959963

RESUMO

Lifestyle choices play a significant role in the etiology of atherosclerosis. Male Apoe-/- mice that develop spontaneous atherosclerotic lesions were fed 0%, 0.3%, and 0.4% mangosteen extracts, composed largely of α-mangostin (MG), for 17 weeks. Body weight gains were significantly decreased in both MG-treated groups compared to the control, but the general condition remained good throughout the study. The levels of total cholesterol (decreased very-low-density lipoprotein in lipoprotein profile) and triglycerides decreased significantly in the MG-treated mice in conjunction with decreased hepatic HMG-CoA synthase and Fatty acid transporter. Additionally, increased serum lipoprotein lipase activity and histopathology further showed a significant reduction in atherosclerotic lesions at both levels of MG exposure. Real-time PCR analysis for macrophage indicators showed a significant elevation in the levels of Cd163, an M2 macrophage marker, in the lesions of mice receiving 0.4% MG. However, the levels of Nos2, associated with M1 macrophages, showed no change. In addition, quantitative immunohistochemical analysis of macrophage subtypes showed a tendency for increased M2 populations (CD68⁺/CD163⁺) in the lesions of mice given 0.4% MG. In further analysis of the cytokine-polarizing macrophage subtypes, the levels of Interleukin13 (Il13), associated with M2 polarization, were significantly elevated in lesions exposed to 0.4% MG. Thus, MG could suppress the development of atherosclerosis in Apoe-/- mice, possibly through an M2 macrophage-mediated mechanism.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Macrófagos/metabolismo , Xantonas/uso terapêutico , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/sangue , Aterosclerose/genética , Colesterol/sangue , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Placa Aterosclerótica/sangue , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Xantonas/química
14.
Inflamm Res ; 68(6): 429-441, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937466

RESUMO

BACKGROUND: Atherosclerosis (AS) is the main pathogeny of coronary heart disease, cerebral infarction and peripheral vascular disease. Endothelial dysfunction is one of the important pathogenesis of AS. As an important endothelium-derived relaxation factor, nitric oxide (NO) plays a role in cardiovascular protection and anti-AS function; but in the pathological state, endothelial nitric oxide synthase (eNOS) disorder causes an abnormal production of NO, which may damage endothelial function and trigger AS. This review summarized the research progresses in the treatment strategies for AS based on correcting the disordered eNOS/ NO signaling pathway. MAIN BODY: According to the topic, select the search terms 'atherosclerosis,' 'nitric oxide,' 'eNOS,' 'treatment,' 'management,' 'medication,' 'maintenance,' 'remission'. Using these terms, a structured literature search via multiple electronic databases was performed for the most recent trial evidence in recent years. We read and analyze these literatures carefully, classified these literatures according to their content, and then summarized and outlined the common main points in these classified literatures. Finally, literature data were organized to discuss these main points logically. We found that both aberrant expression and dysfunction of eNOS are closely related to AS development, and some new treatment strategies aimed at eNOS have been proposed, including upregulation of eNOS expression and inhibition of eNOS uncoupling. The former one is mainly related to inflammatory inhibition and protection of the PKB-eNOS signaling pathway; whereas the latter one is associated with the addition of the L-arginine substrate of eNOS, arginase inhibition, and the supplement of tetrahydrobiopterin, which can elevate no level. CONCLUSIONS: eNOS can be an important target for prevention and treatment of AS, and eNOS drugs may be another potent class of effective therapeutic treatment for AS following traditional lipid-lowering, anti-platelet, vasodilator drugs. But applying these experimental results to clinic treatment still requires further studies and development of biotechnology.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Humanos , Óxido Nítrico/metabolismo
15.
Immunity ; 50(4): 941-954, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995508

RESUMO

Arterial inflammation is a hallmark of atherosclerosis, and appropriate management of this inflammation represents a major unmet therapeutic need for cardiovascular disease patients. Here, we review the diverse contributions of immune cells to atherosclerosis, the mechanisms of immune cell activation in this context, and the cytokine circuits that underlie disease progression. We discuss the recent application of these insights in the form of immunotherapy to treat cardiovascular disease and highlight how studies on the cardiovascular co-morbidity that arises in autoimmunity might reveal additional roles for cytokines in atherosclerosis. Currently, data point to interleukin-1ß (IL-1ß), tumor necrosis factor (TNF), and IL-17 as cytokines that, at least in some settings, are effective targets to reduce cardiovascular disease progression.


Assuntos
Doenças Cardiovasculares/imunologia , Citocinas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Cardiovasculares/tratamento farmacológico , Colesterol/metabolismo , Ensaios Clínicos como Assunto , Citocinas/antagonistas & inibidores , Citocinas/uso terapêutico , Progressão da Doença , Células Espumosas/imunologia , Células Espumosas/metabolismo , Microbioma Gastrointestinal , Humanos , Inflamassomos/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/antagonistas & inibidores , Camundongos Knockout , Modelos Imunológicos , Músculo Liso Vascular/imunologia , Fagócitos/imunologia , Fagócitos/metabolismo , Transdução de Sinais , Suínos , Pesquisa Médica Translacional
16.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939745

RESUMO

The compound, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG), a primary bioactive polyphenolic component of Polygonum multiflorum exerts numerous pharmacological activities. However, its protective effect against non-alcoholic steatohepatitis (NASH), in the context of metabolic syndrome, remains poorly understood. The aim of the present study is to evaluate the effects of TSG treatment on middle-aged (12-mo-old) male LDLr-/- mice, which were fed a high fat diet for 12 weeks to induce metabolic syndrome and NASH. At the end of the experiment, the blood samples of mice were collected for determination of metabolic parameters. Liver and aorta tissues were collected for analysis, such as histology, immunofluorescence, hepatic lipid content, real-time PCR, and western blot. Our data show that TSG treatment improved the different aspects of NASH (steatosis, inflammation, and fibrosis) and atherosclerosis, as well as some of the metabolic basal characteristics. These modulatory effects of TSG are mediated, at least in part, through regulating key regulators of lipid metabolism (SREBP1c, PPARα and their target genes, ABCG5 and CYP7A1), inflammation (CD68, TNF-α, IL-6 and ICAM), fibrosis (α-SMA and TNFß) and oxidative stress (NADPH-oxidase 2/4, CYP2E1 and antioxidant enzymes). These results suggest that TSG may be a promising candidate for preventing and treating the progression of NASH.


Assuntos
Envelhecimento/patologia , Aterosclerose/tratamento farmacológico , Glucosídeos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estilbenos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/etiologia , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/farmacologia , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Receptores de LDL/genética , Estilbenos/farmacologia
17.
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
18.
Biomed Pharmacother ; 114: 108785, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909142

RESUMO

OBJECTIVE: To observe the intervention effect of Si-miao-Yong-An (SMYA) on atheroosclerosis (AS) vulnerable plaque, and to explore the mechanism by Vasa Vasorum (VV) maturation as a starting point. MATERIALS AND METHODS: SPF-class healthy male ApoE-/- mice were randomly divided into model group, SMYA group and simvastatin group, and C57BL/6 mice were used as a control group. After 8 weeks of drug intervention, the plaques of AS were observed by HE staining. The pericytes of aortic root plaques were observed by immunofiuorescence double staining (CD34, Desmin) and the density of VV. The expression of Dll4, Notch1, Hey1 and VEGF mRNA in aortic tissues was detected by real-time qPCR. RESULTS: SMYA significantly reduced the area of aortic plaque in ApoE-/- mice, significantly reduced plaque area and the ratio of plaque to lumen area, and reduced the intima medium thickness, it's effect was greater than that of simvastatin; it significantly increased the density of VV in plaque. SMYA increased the expression of Dll4 and Notch1 and Hey1mRNA, and decreased the expression of VEGF mRNA, and its effect was greater than that of simvastatin. CONCLUSION: SMYA can reduce the AS plaque area in ApoE-/- mice, promote the recruitment of VV pericytes, and stabilize AS vulnerable plaques. The mechanism may be regulate of Dll4/Notch1/ Hey1/VEGF signaling pathway. At the same time, it has a dual-direction regulation on the VV.


Assuntos
Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Vasa Vasorum/efeitos dos fármacos , Animais , Aterosclerose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Placa Aterosclerótica/metabolismo , Sinvastatina/farmacologia , Vasa Vasorum/metabolismo
19.
Int Immunopharmacol ; 70: 486-497, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30870679

RESUMO

Macrophages play a pivotal role in destabilizing atherosclerotic plaque. The diverse phenotypes and complex autophagy in macrophage are observed in atherosclerotic lesions. Tanshinone IIA (TNA) is known as the major component extracted from the root of Chinese herb Salvia miltiorrhiza, used for treatment of cardiovascular diseases. However, the therapeutic mechanism of TNA is not clear yet. In this study, we identified inflammation-related gene expression by microarray in atherosclerotic plaques in ApoE knockout mice fed with high fat diet and found miR-375 was one of the significantly high expressed microRNAs compared with wild type mice and TNA treated mice. Then we compared the levels of proteins related to the signal pathway of autophagy, and the phenotype of macrophages in atherosclerotic plaques ex vivo. We predicted KLF4 might be the key target of miR-375 that mediated the crosstalk between autophagy and polarization by TNA. Furthermore, we detected the expression of signal pathway in ox-LDL induced macrophages after treatment with TNA in vitro to verify this predict. The results suggest TNA could activate KLF4 and enhance autophagy as well as M2 polarization of macrophages by inhibiting miR-375 to Attenuate Atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Diterpenos de Abietano/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Fatores de Transcrição Kruppel-Like/metabolismo , Macrófagos/fisiologia , MicroRNAs/genética , Animais , Apolipoproteínas E/genética , Autofagia , Diferenciação Celular , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Cross-Talk , Salvia miltiorrhiza/imunologia , Transdução de Sinais
20.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925684

RESUMO

Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are frequent causes of death in the Western countries. Recently, it has been shown that autophagy dysfunction plays an important role in the pathogenesis of both atherosclerosis and NAFLD; thus, activators of autophagy might be useful for novel therapeutic interventions. Trehalose-a naturally occuring disaccharide present in plants, bacteria, fungi, insects, and certain types of shrimps-is a known inducer of autophagy. However, according to the literature, its anti-atherosclerotic and anti-steatotic potential seem to depend on the experimental setting. The aim of our study was to comprehensively describe the influence of a prolonged treatment with orally administered trehalose on the development of atherosclerotic lesions and hepatic steatosis in apolipoprotein E knockout (apoE-/-) mice in an experimental set up reflecting both moderate and severe proatherogenic conditions: male apoE-/- mice on a chow diet (CD) and female apoE-/- mice fed with a high-fat diet (HFD). We found that exogenous trehalose inhibited atherosclerosis and attenuated hepatic steatosis in apoE-/- mice. Such effects of trehalose were not associated with changes of plasma cholesterol, low-density lipoproteins (LDL), or high-density lipoproteins (HDL). Moreover, the anti-steatotic action of trehalose in the liver was associated with the induction of autophagy. The exact molecular mechanisms of both the anti-atherosclerotic action of trehalose and its inhibitory effect on liver steatosis require further clarification.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Autofagia/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Trealose/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Trealose/administração & dosagem , Trealose/farmacologia
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