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1.
J Agric Food Chem ; 69(35): 10114-10120, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34428895

RESUMO

Our previous study showed that lycopene reduced the absorption of cholesterol in Caco-2 cells through inhibiting Niemann-Pick C1-Like 1 (NPC1L1) expression. Herein, we aimed to explore whether lycopene supplementation can decrease cholesterol absorption in the intestine and prevent atherosclerosis progression in high-fat diet (HFD)-fed apolipoprotein E knockout (ApoE-/-) mice. Male ApoE-/- mice were fed a high-fat diet with or without lycopene for 19 weeks. Supplementation of lycopene markedly lowered serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Additionally, serum high-density lipoprotein cholesterol (HDL-C) levels were increased after lycopene administration. Lycopene also downregulated the expression of NPC1L1 and hepatocyte nuclear factor-1α (HNF-1α) in the small intestine. Furthermore, the Oil Red O staining of the aorta and aortic sinus showed that lycopene supplementation remarkably reduced atherosclerotic lesions. These results indicated that lycopene inhibited intestinal cholesterol absorption and protected against HFD-induced atherosclerosis through inhibiting HNF-1α and NPC1L1 expression. Lycopene exhibits a potential antiatherosclerotic effect through suppressing intestinal cholesterol absorption.


Assuntos
Apolipoproteínas E , Aterosclerose , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/prevenção & controle , Células CACO-2 , Colesterol , Fator 1-alfa Nuclear de Hepatócito , Humanos , Absorção Intestinal , Licopeno , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
Artigo em Inglês | MEDLINE | ID: mdl-34444289

RESUMO

It is well known that rapeseed oil improves lipid profile and has antiatherosclerotic properties. Recently, amaranth oil has also become popular due to its potential health benefits. However, the effect of this oil on atherosclerosis markers in humans is not clear. Therefore, this study aimed to compare the effect of amaranth and rapeseed oils on selected atherosclerosis-related parameters in overweight and obese subjects. In this randomized cross-over study, 44 subjects were instructed to consume 20 mL of amaranth oil and rapeseed oil during two consecutive three-week intervention periods separated by a washout period of the same duration as the intervention. The outcome variables included changes in tumor necrosis factor-alpha, adiponectin, oxidized low-density lipoprotein, apolipoproteins (Apo) A1, B and E as well as glucose and insulin homeostasis markers. Compared to rapeseed oil, amaranth oil had a slight positive effect on adiponectin levels (mean (95% confidence interval): 0.55 (0.22-0.89) vs. -0.29 (-0.75-0.16), p = 0.0002) but negatively affected ApoB concentrations (0.05 (-0.01-0.11) vs. 0.03 (-0.07-0.00), p = 0.0004) and ApoB/A1 ratio (0.01 (-0.03-0.05) vs. -0.02 (-0.04-0.00), p = 0.0113). No differences between the other analyzed parameters were observed. In conclusion, amaranth oil does not have a greater beneficial effect on atherosclerosis markers than rapeseed oil. However, further studies with a longer intervention period are needed. The study was retrospectively registered with the German Clinical Trials Register within the number: DRKS00014046, date of registration: 3 May 2018.


Assuntos
Aterosclerose , Óleos Vegetais , Aterosclerose/prevenção & controle , Estudos Cross-Over , Método Duplo-Cego , Humanos , Obesidade , Sobrepeso , Óleo de Brassica napus
3.
Am J Cardiol ; 154: 41-47, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256942

RESUMO

Saphenous vein grafts are imperfect yet indispensable conduits commonly used for coronary artery bypass grafting. Their degeneration ultimately leading to occlusion results from the pathological response of the vein to altered blood rheology and several types of vascular injury. Surgical techniques minimizing vessel damage, and prolonged antiplatelet and lipid-lowering treatment are established methods of mitigating the degeneration process hence preventing graft occlusions. Percutaneous interventions in degenerated vein grafts carry high risk of embolization, periprocedural myocardial infarction and restenosis. Thus, native vessel should be the preferred treatment target in case of graft failure whenever technically feasible.


Assuntos
Aterosclerose/prevenção & controle , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Oclusão de Enxerto Vascular/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Veia Safena/transplante , Trombose/prevenção & controle , Aterosclerose/fisiopatologia , Aterosclerose/terapia , Oclusão de Enxerto Vascular/fisiopatologia , Oclusão de Enxerto Vascular/terapia , Humanos , Hipolipemiantes/uso terapêutico , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/terapia , Recidiva , Trombose/fisiopatologia , Trombose/terapia
4.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205487

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with excess mortality worldwide. The cardiovascular system is the second most common target of SARS-CoV-2, which leads to severe complications, including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism, as well as other major thrombotic events because of direct endothelial injury and an excessive systemic inflammatory response. This review focuses on the similarities and the differences of inflammatory pathways involved in COVID-19 and atherosclerosis. Anti-inflammatory agents and immunomodulators have recently been assessed, which may constitute rational treatments for the reduction of cardiovascular events in both COVID-19 and atherosclerotic heart disease.


Assuntos
Aterosclerose/patologia , COVID-19/patologia , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/etiologia , Citocinas/metabolismo , Humanos , Prognóstico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo
5.
Nutrients ; 13(6)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204127

RESUMO

Risk factors for ischemic stroke is suggested to differ by etiologic subtypes. The purpose of this study was to examine the associations between modifiable and non-modifiable risk factors and atherothrombotic stroke (i.e., excluding cardioembolic stroke), and to examine if the potential benefit of modifiable lifestyle factors differs among subjects with and without predisposing comorbidities. After a median follow-up of 21.2 years, 2339 individuals were diagnosed with atherothrombotic stroke out of 26,547 study participants from the Malmö Diet and Cancer study. Using multivariable Cox regression, we examined non-modifiable (demographics and family history of stroke), semi-modifiable comorbidities (hypertension, dyslipidemia, diabetes mellitus and atherosclerotic disease), and modifiable (smoking, body mass index, diet quality, physical activity, and alcohol intake) risk factors in relation to atherothrombotic stroke. Higher age, male gender, family history of stroke, and low educational level increased the risk of atherothrombotic stroke as did predisposing comorbidities. Non-smoking (hazard ratio (HR) = 0.62, 95% confidence interval (CI) 0.56-0.68), high diet quality (HR = 0.83, 95% CI 0.72-0.97) and high leisure-time physical activity (HR = 0.89, 95% CI 0.80-0.98) decreased the risk of atherothrombotic ischemic stroke independent of established risk factors, with non-significant associations with body mass index and alcohol intake. The effect of the lifestyle factors was independent of predisposing comorbidities at baseline. The adverse effects of several cardiovascular risk factors were confirmed in this study of atherothrombotic stroke. Smoking cessation, improving diet quality and increasing physical activity level is likely to lower risk of atherothrombotic stroke in the general population as well as in patient groups at high risk.


Assuntos
Aterosclerose/prevenção & controle , Dieta/métodos , AVC Isquêmico/prevenção & controle , Neoplasias/dietoterapia , Trombose/prevenção & controle , Idoso , Aterosclerose/etiologia , Dieta Saudável , Exercício Físico , Feminino , Seguimentos , Fatores de Risco de Doenças Cardíacas , Humanos , AVC Isquêmico/etiologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Modelos de Riscos Proporcionais , Sistema de Registros , Suécia , Trombose/etiologia
6.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209567

RESUMO

Collagen tripeptide (CTP) is defined as a functional food material derived from collagenase digests of type I collagen and contains a high concentration of tripeptides with a Gly-X-Y sequence. CTP has several biological effects, including the acceleration of fracture healing, ameliorating osteoarthritis, and improving dryness and photoaging of the skin. Recently, an antiatherosclerotic effect of CTP has been reported, although its molecular mechanism is yet to be determined. In this study, we examined the effects of CTP on primary cultured human aortic endothelial cells (HAECs) under oxidative stress, because oxidative endothelial dysfunction is a trigger of atherosclerosis. DNA microarray and RT-qPCR analyses showed that CTP treatment recovered the downregulated expression of several genes, including the interleukin-3 receptor subunit alpha (IL3RA), which were suppressed by reactive oxygen species (ROS) treatment in HAECs. Furthermore, IL3RA knockdown significantly decreased the viability of HAECs compared with control cells. RT-qPCR analysis also showed that solute carrier 15 family peptide transporters, which are involved in CTP absorption into cells, were expressed in HAECs at levels more than comparable to those of a CTP-responsive human osteoblastic cell line. These results indicated that CTP exerts a protective effect for HAECs, at least in part, by regulating the recovery of ROS-induced transcriptional repression.


Assuntos
Aorta/citologia , Colágeno Tipo I/farmacologia , Células Endoteliais/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ativação Transcricional/efeitos dos fármacos , Aterosclerose/prevenção & controle , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Alimento Funcional/análise , Humanos , Subunidade alfa de Receptor de Interleucina-3/efeitos dos fármacos , Osteoblastos , Estresse Oxidativo , Transportador 1 de Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
7.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209930

RESUMO

High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in regulating reverse cholesterol transport (RCT), a process by which excess cholesterol is transported back to the liver for elimination. However, RCT can be altered in the presence of cardiovascular risk factors, such as aging, which contributes to the increase in the incidence of cardiovascular diseases (CVD). The present study was aimed at investigating the effect of extra virgin olive oil (EVOO) intake on the cholesterol efflux capacity (CEC) of HDL, and to elucidate on the mechanisms by which EVOO intake improves the anti-atherogenic activity of HDL. A total of 84 healthy women and men were enrolled and were distributed, according to age, into two groups: 27 young (31.81 ± 6.79 years) and 57 elderly (70.72 ± 5.6 years) subjects. The subjects in both groups were given 25 mL/d of extra virgin olive oil (EVOO) for 12 weeks. CEC was measured using J774 macrophages radiolabeled with tritiated cholesterol ((3H) cholesterol). HDL subclass distributions were analyzed using the Quantimetrix Lipoprint® system. The HDL from the elderly subjects exhibited a lower level of CEC, at 11.12% (p < 0.0001), than the HDL from the young subjects. The CEC of the elderly subjects returned to normal levels following 12 weeks of EVOO intake. An analysis of the distribution of HDL subclasses showed that HDL from the elderly subjects were composed of lower levels of large HDL (L-HDL) (p < 0.03) and higher levels of small HDL (S-HDL) (p < 0.002) compared to HDL from the young subjects. A multiple linear regression analysis revealed a positive correlation between CEC and L-HDL levels (r = 0.35 and p < 0.001) as well as an inverse correlation between CEC and S-HDL levels (r = -0.27 and p < 0.01). This correlation remained significant even when several variables, including age, sex, and BMI as well as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and glucose levels (ß = 0.28, p < 0.002, and ß = 0.24, p = 0.01) were accounted for. Consuming EVOO for 12 weeks modulated the age-related difference in the distribution of HDL subclasses by reducing the level of S-HDL and increasing the level of intermediate-HDL/large-HDL (I-HDL/L-HDL) in the elderly subjects. The age-related alteration of the CEC of HDL was due, in part, to an alteration in the distribution of HDL subclasses. A diet enriched in EVOO improved the functionality of HDL through an increase in I-HDL/L-HDL and a decrease in S-HDL.


Assuntos
Envelhecimento/sangue , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Lipoproteínas HDL/sangue , Azeite de Oliva/administração & dosagem , Adulto , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino
8.
Free Radic Biol Med ; 172: 152-166, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34087429

RESUMO

Atherosclerosis develops due to lipid accumulation in the arterial wall and sclerosis as result of increased hyperlipidemia, oxidative stress, lipid oxidation, and protein oxidation. However, improving antioxidant status through diet may prevent the progression of atherosclerotic cardiovascular disease. It is believed that polyphenol-rich plants contribute to the inverse relationship between fruit and vegetable intake and chronic disease. Anthocyanins are flavonoid polyphenols with antioxidant properties that have been associated with reduced risk of cardiovascular disease. The consumption of anthocyanins increases total antioxidant capacity, antioxidant defense enzymes, and HDL antioxidant properties by several measures in preclinical and clinical populations. Anthocyanins appear to impart antioxidant actions via direct antioxidant properties, as well as indirectly via inducing intracellular Nrf2 activation and antioxidant gene expression. These actions counter oxidative stress and inflammatory signaling in cells present in atherosclerotic plaques, including macrophages and endothelial cells. Overall, anthocyanins may protect against atherosclerosis and cardiovascular disease through their effects on cellular antioxidant status, oxidative stress, and inflammation; however, their underlying mechanisms of action appear to be complex and require further elucidation.


Assuntos
Antocianinas , Aterosclerose , Antioxidantes/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Células Endoteliais , Flavonoides , Humanos , Estresse Oxidativo
9.
Atherosclerosis ; 328: 23-32, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34077868

RESUMO

BACKGROUND AND AIMS: The thiol transferase glutaredoxin 1 controls redox signaling and cellular functions by regulating the S-glutathionylation status of critical protein thiols. Here we tested the hypothesis that by derepressing the expression of glutaredoxin 1, inhibition of histone deacetylase 2 prevents nutrient stress-induced protein S-glutathionylation and monocyte dysfunction and protects against atherosclerosis. METHODS: Using both a pharmacological inhibitor and shRNA-mediated knockdown of histone deacetylase 2, we determine the role of this deacetylase on glutaredoxin 1 expression and nutrient stress-induced inactivation of mitogen-activated protein kinase phosphatase 1 activity and monocyte and macrophage dysfunction. To assess whether histone deacetylase 2 inhibition in myeloid cells protects against atherosclerosis, we fed eight-week-old female and male HDAC2-/-MyeloidLDLR-/- mice and age and sex-matched LysMcretg/wtLDLR-/- control mice a high-calorie diet for 12 weeks and assessed monocyte function and atherosclerotic lesion size. RESULTS: Myeloid histone deacetylase 2 deficiency in high-calorie diet-fed LDLR-/- mice reduced atherosclerosis in males by 39% without affecting plasma lipid and lipoprotein profiles or blood glucose levels but had no effect on atherogenesis in female mice. Macrophage content in plaques of male mice was reduced by 31%. Histone deacetylase 2-deficient blood monocytes from male mice showed increased acetylation on histone 3, and increased Grx1 expression, and was associated with increased MKP-1 activity and reduced recruitment of monocyte-derived macrophages, whereas in females, myeloid HDAC2 deficiency had no effect on Grx1 expression, did not prevent nutrient stress-induced loss of MKP-1 activity in monocytes and was not atheroprotective. CONCLUSIONS: Specific histone deacetylase 2 inhibitors may represent a potential novel therapeutic strategy for the prevention and treatment of atherosclerosis, but any benefits may be sexually dimorphic.


Assuntos
Aterosclerose , Monócitos , Animais , Aterosclerose/prevenção & controle , Dieta , Feminino , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Histona Desacetilase 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Oxirredução , Receptores de LDL/genética , Receptores de LDL/metabolismo , Compostos de Sulfidrila
10.
Atherosclerosis ; 328: 83-91, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118596

RESUMO

BACKGROUND AND AIMS: The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. METHODS: Low-density lipoprotein (LDL) receptor null (LDLr-/-) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. RESULTS: Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. CONCLUSIONS: Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.


Assuntos
Aterosclerose , Óxido Nítrico Sintase Tipo III , Animais , Apolipoproteína A-I , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Biopterina/análogos & derivados , Células Endoteliais , Endotélio Vascular , GTP Cicloidrolase , Guanosina Trifosfato , Camundongos , Óxido Nítrico , Peptídeos , Superóxidos
11.
FASEB J ; 35(7): e21698, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34085350

RESUMO

Regular exercise maintains arterial endothelial cell homeostasis and protects the arteries from vascular disease, such as peripheral artery disease and atherosclerosis. Autophagy, which is a cellular process that degrades misfolded or aggregate proteins and damaged organelles, plays an important role in maintaining organ and cellular homeostasis. However, it is unknown whether regular exercise stimulates autophagy in aorta endothelial cells of mice prone to atherosclerosis independently of their circulating lipid profile. Here, we observed that 16 weeks of voluntary exercise reduced high-fat diet-induced atherosclerotic plaque formation in the aortic root of ApoE deficient mice, and that this protection occurred without changes in circulating triglycerides, total cholesterol, and lipoproteins. Immunofluorescence analysis indicated that voluntary exercise increased levels of the autophagy protein LC3 in aortic endothelial cells. Interestingly, human umbilical vein endothelial cells (HUVECs) exposed to serum from voluntarily exercised mice displayed significantly increased LC3-I and LC3-II protein levels. Analysis of circulating cytokines demonstrated that voluntary exercise caused changes directly relevant to IL-1 signaling (ie, decreased interleukin-1 receptor antagonist [IL-1ra] while also increasing IL-1α). HUVECs exposed to IL-1α and IL-1ß recombinant protein significantly increased LC3 mRNA expression, LC3-I and LC3-II protein levels, and autophagy flux. Collectively, these results suggest that regular exercise protects arteries from ApoE deficient mice against atherosclerosis at least in part by stimulating endothelial cell autophagy via enhanced IL-1 signaling.


Assuntos
Aterosclerose/prevenção & controle , Autofagia , Dieta Hiperlipídica , Endotélio Vascular/fisiologia , Interleucina-1/metabolismo , Condicionamento Físico Animal , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Endotélio Vascular/citologia , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE
14.
J Agric Food Chem ; 69(25): 6989-6999, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34142543

RESUMO

Procyanidin A2 (PCA2) has been shown to improve lipid metabolism. However, it remains to know whether it can play a role in preventing atherosclerosis (AS) through gut microbiota. This study examined the effect of PCA2 on high fat diet (HFD)-induced AS in ApoE-/- mice with an intact and antibiotic-depleted microbiota. PCA2 administration for 12 weeks attenuated HFD-induced AS in ApoE-/- mice, evidenced by obviously alleviating the histological abnormalities of the aorta, lipid accumulation, oxidative stress, and inflammation, which were accompanied by downregulating the expression of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 and upregulating peroxisome proliferator-activated receptor gamma, cholesterol 7 alpha-hydroxylase, and ATP-binding cassette transporter A1. Moreover, PCA2 treatment reshaped the gut microbiota imbalance caused by HFD, especially reducing the ratio of Firmicutes/Bacteroidetes and increasing the abundance of Verrucomicrobia. However, antibiotic intervention almost offset the alleviation of AS by PCA2 and prevented the biotransformation of PCA2 by gut microbiota, thus resulting in a 2327.21-6.27-fold decrease in its microbial metabolites of plasma. There was a marked correlation among the microbiota composition, the bioavailability of PCA2-derived microbial metabolites, and AS indicators. The findings indicate that the gut microbiota robustly influences the bioavailability of microbial metabolites that may partially drive the AS resilience property of PCA2.


Assuntos
Aterosclerose , Microbioma Gastrointestinal , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/prevenção & controle , Disponibilidade Biológica , Catequina , Dieta Hiperlipídica/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Proantocianidinas
15.
Nat Commun ; 12(1): 3391, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099646

RESUMO

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.


Assuntos
Aterosclerose/prevenção & controle , Inibidores de Janus Quinases/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , HDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Janus Quinases/efeitos adversos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Fator de Transcrição STAT4/genética , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto Jovem
16.
Diabetes Obes Metab ; 23(9): 2020-2034, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34047441

RESUMO

Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid-lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce the plasma low-density lipoprotein cholesterol (LDL-C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolaemia), who do not respond to standard therapies, and other patients who cannot take these agents, remain at a high risk of ASCVD. In recent years there has been tremendous progress in understanding the mechanism and efficacy of lipid-lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase inhibitors, angiopoietin-like 3 (ANGPTL3) is another potential target for the treatment of dyslipidaemia and its clinical sequalae of atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL-C and high-density lipoprotein cholesterol (HDL-C) levels, achieved by inhibiting the activities of lipoprotein lipase and endothelial lipase. Familial combined hypolipidaemia is derived from the Angptl3 loss-of-function mutations, which leads to low levels of LDL-C, HDL-C and TG, and has a 34% decreased risk of ASCVD compared with non-carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidaemia therapy. Herein, we review the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3-targeted therapies. We also summarize evidence from basic research to clinical trials, with the aim of providing novel insights into the biological functions of ANGPTL3 and related targeted therapies.


Assuntos
Aterosclerose , Pró-Proteína Convertase 9 , Proteínas Semelhantes a Angiopoietina , Angiopoietinas , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Humanos
20.
J Toxicol Sci ; 46(5): 209-222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952798

RESUMO

OBJECTIVE: To seek out the effect of curcumin on cholesterol efflux in THP-1 macrophages and clarify its specific mechanism. METHODS: THP-1 macrophages were cultured with curcumin at different concentrations, followed by detection of the toxicity of curcumin to cells utilizing CCK-8 assay. Following culturing with serum-free ox-LDL, THP-1 macrophages were transfected with mi-miR-125a-5p, or in-miR-125a-5p, or pcDNA3.1-SIRT6, or si-SIRT6 for 24 hr, prior to treatment with curcumin at different concentrations. Oil red O staining was applied to examine the formation rate of foam cells, the kits were used for measuring intracellular lipid content of THP-1 macrophages, and the fluorescence detection kit for observing the cholesterol efflux rate. The expressions of miR-125a-5p, SIRT6, and ABCA1 were assayed by qRT-PCR and Western blot. ELISA was adopted to assess the contents of TNF-α, IL-6, and MCP-1. The interaction between miR-125a-5p and SIRT6 was evaluated by dual-luciferase reporter gene assay. RESULTS: The optimal dosage of curcumin could reduce foam cell formation and intracellular lipid content, and promote cholesterol efflux in THP-1 macrophages. Meanwhile, curcumin markedly suppressed the expression of miR-125a-5p and upregulated the expression of SIRT6. MiR-125a-5p negatively targeted SIRT6. Overexpression of SIRT6 partially reversed the inhibition role of miR-125a-5p mimic in the biological function of curcumin. Silencing of SIRT6 could partially reverse the effect of the miR-125a-5p inhibitor on the biological function of curcumin. CONCLUSION: urcumin could promote cholesterol efflux of THP-1 macrophages through miR-125a-5p/SIRT6 axis and regulate the expression of ABCA1.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Curcumina/farmacologia , Macrófagos/efeitos dos fármacos , MicroRNAs/genética , Sirtuínas/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Aterosclerose/prevenção & controle , Citocinas/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , Macrófagos/metabolismo , Sirtuínas/genética , Células THP-1
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