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1.
J Ethnopharmacol ; 266: 113474, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33068650

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba extract (GbE) is derived from a medicinal plant and suggested as a treatment for diabetic nephropathy (DN), but the mechanism was not clarified. AIM OF STUDY: The present study investigated whether GbE prevented DN via activation of heme oxygenase (HO)-1. MATERIALS AND METHODS: Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human and murine podocytes were used for the in vitro study. RESULTS: GbE improved renal function via decreasing glomerular hypertrophy, the kidney/body weight ratio, and albuminuria in DN mice. GbE reversed the reduction of synaptopodin and nephrin and enhanced HO-1 expression in the kidneys of DN mice. GbE decreased the enhancement of TNF-α, IL-6, fibronectin, and lipid accumulation in the glomeruli of DN mice. GbE attenuated the uptake of oxidized low-density lipoprotein and reduced the production of ROS in high glucose-stimulated podocytes, and HO-1 inhibitor treatment abrogated the protective effects of GbE. Nuclear factor erythroid 2-related factor 2 (Nrf-2) siRNA significantly abolished the beneficial effects of GbE via decreased HO-1 expression and enhanced TNF-α and IL-6 levels. CONCLUSIONS: GbE protected podocytes against hyperglycemia and prevented the development of DN via Nrf-2/HO-1 activation. Our findings provide further mechanistic insight into the potential use of GbE in clinical DN.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Dieta Hiperlipídica , Ginkgo biloba , Heme Oxigenase-1/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fator 2 Relacionado a NF-E2/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina
2.
Acta Ophthalmol ; 98(2): e238-e244, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31496121

RESUMO

PURPOSE: The decreased level of melatonin, the substance involved in the control of the sleep-wake cycle, has been reported among the patients with age-related macular degeneration (AMD). However, knowledge about the relationship between sleep disturbance and AMD is still limited. This longitudinal case-control study aims to investigate the risk of incident AMD among the patients with clinically diagnosed insomnia using the Taiwan National Health Insurance Research Database. METHODS: The insomnia cohort (n = 15 465) consisted of newly diagnosed insomnia cases aged ≥55 years between 2000 and 2009. Subjects without insomnia, matched for age, gender and enrolment time, were randomly sampled as the control cohort (n = 92 790). Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of incident AMD for the two cohorts after adjusting for potential confounders. RESULTS: Of the 108 255 sampled subjects, 2094 (1.9%) were diagnosed with AMD, including 214 (0.2%) with neovascular AMD, during a mean follow-up period of 5.1 ± 2.8 years. Insomnia patients were more likely to have subsequent AMD than those without insomnia (2.5% versus 1.8%, p < 0.001). Further, the incidence of exudative AMD was also higher in the insomnia cohort than the control cohort (0.3% versus 0.2%, p = 0.002). The adjusted HR was 1.33 (95% confidence interval [CI], 1.18-1.48, p < 0.001) for AMD and 1.67 (95% CI, 1.20-2.33, p = 0.002) for exudative AMD. CONCLUSIONS: Clinically diagnosed insomnia is an independent indicator for the increased risk of subsequent AMD development.


Assuntos
Distúrbios do Início e da Manutenção do Sono/complicações , Degeneração Macular Exsudativa/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Taiwan/epidemiologia , Acuidade Visual , Degeneração Macular Exsudativa/diagnóstico
3.
Sci Rep ; 9(1): 17316, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754254

RESUMO

Vascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.


Assuntos
Células Endoteliais/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Neointima/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Células-Tronco/efeitos dos fármacos , Lesões do Sistema Vascular/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Ginkgo biloba , Voluntários Saudáveis , Humanos , Camundongos , Camundongos Transgênicos , Músculo Liso/citologia , Neointima/etiologia , Neointima/patologia , Cultura Primária de Células , Protoporfirinas/administração & dosagem , Reepitelização/efeitos dos fármacos , Células-Tronco/fisiologia , Lesões do Sistema Vascular/complicações , Lesões do Sistema Vascular/patologia
4.
J Formos Med Assoc ; 116(4): 217-248, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28242176

RESUMO

In Taiwan, the prevalence of hyperlipidemia increased due to lifestyle and dietary habit changes. Low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) are all significant predicting factors of coronary artery disease in Taiwan. We recognized that lipid control is especially important in patients with existed atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease (CAD), ischemic stroke and peripheral arterial disease (PAD). Because the risk of ASCVD is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and familial hypercholesterolemia (FH), lipid control is also necessary in these patients. Lifestyle modification is the first step to control lipid. Weight reduction, regular physical exercise and limitation of alcohol intake all reduce triglyceride (TG) levels. Lipid-lowering drugs include HMG-CoA reductase inhibitors (statins), cholesterol absorption inhibitors (ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, nicotinic acids (niacin), fibric acids derivatives (fibrates), and long-chain omega-3 fatty acids. Statin is usually the first line therapy. Combination therapy with statin and other lipid-lowering agents may be considered in some clinical settings. For patients with acute coronary syndrome (ACS) and stable CAD, LDL-C < 70 mg/dL is the major target. A lower target of LDL-C <55 mg/dL can be considered in ACS patients with DM. After treating LDL-C to target, non-HDL-C can be considered as a secondary target for patients with TG ≥ 200 mg/dL. The suggested non-HDL-C target is < 100 mg/dL in ACS and CAD patients. For patients with ischemic stroke or transient ischemic attack presumed to be of atherosclerotic origin, statin therapy is beneficial and LDL-C < 100 mg/dL is the suggested target. For patients with symptomatic carotid stenosis or intracranial arterial stenosis, in addition to antiplatelets and blood pressure control, LDL-C should be lowered to < 100 mg/dL. Statin is necessary for DM patients with CV disease and the LDL-C target is < 70 mg/dL. For diabetic patients who are ≥ 40 years of age, or who are < 40 years of age but have additional CV risk factors, the LDL-C target should be < 100 mg/dL. After achieving LDL-C target, combination of other lipid-lowering agents with statin is reasonable to attain TG < 150 mg/dL and HDL-C >40 in men and >50 mg/dL in women in DM. LDL-C increased CV risk in patients with CKD. In adults with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 without chronic dialysis (CKD stage 3-5), statin therapy should be initiated if LDL-C ≥ 100 mg/dL. Ezetimibe can be added to statin to consolidate the CV protection in CKD patients. Mutations in LDL receptor, apolipoprotein B and PCSK9 genes are the common causes of FH. Diagnosis of FH usually depends on family history, clinical history of premature CAD, physical findings of xanthoma or corneal arcus and high levels of LDL-C. In addition to conventional lipid lowering therapies, adjunctive treatment with mipomersen, lomitapide, or PCSK9 inhibitors become necessary to further reduce LDL-C in patients with FH. Overall, these recommendations are to help the health care professionals in Taiwan to treat hyperlipidemia with current scientific evidences. We hope the prescription rate of lipid lowering drugs and control rate of hyperlipidemia in high risk patients could be increased by implementation of the clinical guidelines. The major purpose is to improve clinical outcomes of these high risk patients through the control of hyperlipidemia.


Assuntos
Aterosclerose/epidemiologia , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/epidemiologia , Hiperlipidemias/terapia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/terapia , Dieta Saudável , Humanos , Hiperlipidemias/complicações , Estilo de Vida , Guias de Prática Clínica como Assunto , Fatores de Risco , Taiwan
5.
Int J Cardiol ; 232: 255-263, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28082092

RESUMO

BACKGROUND: Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. OBJECTIVES: We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. METHODS: Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. RESULTS: The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. CONCLUSION: This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease.


Assuntos
Cardiomiopatia Hipertrófica/etiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Metabolismo Energético/fisiologia , Doença de Fabry/genética , Células-Tronco Pluripotentes Induzidas/transplante , Miócitos Cardíacos/metabolismo , Adulto , Animais , Western Blotting , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas/métodos , Terapia de Reposição de Enzimas , Doença de Fabry/metabolismo , Doença de Fabry/terapia , Humanos , Masculino , Camundongos SCID , Microscopia Eletrônica de Transmissão , Mutação , Miócitos Cardíacos/ultraestrutura , Fenótipo
6.
Psychosom Med ; 77(7): 743-51, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26355726

RESUMO

OBJECTIVES: Insomnia may increase the risk of cardiovascular disease (CVD), but the reported magnitude of the associations between sleep characteristics and CVD is inconsistent. We investigated the association between insomnia and the risk of developing acute myocardial infarction (AMI) and/or stroke by using a nationwide, population-based cohort database in Taiwan. METHODS: The analyses were conducted using information from a random sample of 1 million people enrolled in the nationally representative Taiwan National Health Insurance Research Database. A total of 44,080 individuals who were 20 years or older, including 22,040 people who had diagnosis of insomnia during the study period and an age-, sex-, comorbidity-matched group of 22,040 people without insomnia, were enrolled in our study. The study end points were the occurrence of cardiovascular events including AMI or stroke during follow-up. RESULTS: During a 10-year follow-up, 302 AMI events and 1049 stroke events were identified. The insomnia group had a higher incidence of AMI (2.25 versus 1.08 per 1000 person-years) and stroke (8.01 versus 3.69 per 1000 person-years, p < .001). Cox proportional hazard regression model analysis showed that insomnia was independently associated with a higher risk of future AMI (hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.31-2.16, p < .001), stroke (HR = 1.85, 95% CI = 1.62-2.12, p < .001), and the composite event index (HR = 1.81, 95% CI = 1.61-2.05, p < .001), after adjusting for age, sex, and comorbidities. CONCLUSIONS: Insomnia is associated with an increased risk of future cardiovascular events.


Assuntos
Infarto do Miocárdio/etiologia , Distúrbios do Início e da Manutenção do Sono/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Programas Nacionais de Saúde/estatística & dados numéricos , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Taiwan/epidemiologia
7.
Cardiovasc Diabetol ; 13: 111, 2014 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-25027585

RESUMO

BACKGROUND: Circulating endothelial progenitor cells (EPCs) reflect endothelial repair capacity and may be a significant marker for the clinical outcomes of cardiovascular disease. While some high-dose statin treatments may improve endothelial function, it is not known whether different statins may have similar effects on EPCs.This study aimed to investigate the potential class effects of different statin treatment including pitavastatin and atorvastatin on circulating EPCs in clinical setting. METHODS: A pilot prospective, double-blind, randomized study was conducted to evaluate the ordinary dose of pitavastatin (2 mg daily) or atorvastatin (10 mg daily) treatment for 12 weeks on circulating EPCs in patients with cardiovascular risk such as hypercholesterolemia and type 2 diabetes mellitus (T2DM). Additional in vitro study was conducted to clarify the direct effects of both statins on EPCs from the patients. RESULTS: A total of 26 patients (19 with T2DM) completed the study. While the lipid-lowering effects were similar in both treatments, the counts of circulating CD34+KDR+EPCs were significantly increased (from 0.021 ± 0.015 to 0.054 ± 0.044% of gated mononuclear cells, P < 0.05) only by pitavastatin treatment. Besides, plasma asymmetric dimethylarginine level was reduced (from 0.68 ± 0.10 to 0.53 ± 0.12 µmol/L, P < 0.05) by atorvastatin, and plasma vascular endothelial growth factor (VEGF) level was increased (from 74.33 ± 32.26 to 98.65 ± 46.64 pg/mL, P < 0.05) by pitavastatin. In the in vitro study, while both statins increased endothelial nitric oxide synthase (eNOS) expression, only pitavastatin increased the phosphorylation of eNOS in EPCs. Pitavastatin but not atorvastatin ameliorated the adhesion ability of early EPCs and the migration and tube formation capacities of late EPCs. CONCLUSIONS: While both statins similarly reduced plasma lipids, only pitavastatin increased plasma VEGF level and circulating EPCs in high-risk patients, which is probably related to the differential pleiotropic effects of different statins. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT01386853.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/uso terapêutico , Quinolinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/sangue , Idoso , Atorvastatina , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Células Progenitoras Endoteliais/efeitos dos fármacos , Feminino , Seguimentos , Ácidos Heptanoicos/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Pirróis/farmacologia , Quinolinas/farmacologia , Fatores de Risco , Resultado do Tratamento
8.
Retina ; 34(9): 1867-74, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24743638

RESUMO

PURPOSE: To investigate the incidence and risk factors for central serous chorioretinopathy (CSCR) in adults who use oral corticosteroids in Taiwan. METHODS: This is a population-based nested case-control study between 2000 and 2008. From the Taiwan National Health Insurance Research Database, adults who were repetitively prescribed oral corticosteroids were included as the study cohort. Of those, newly diagnosed CSCR cases were identified and the CSCR incidence was calculated. Subjects matched for age, gender, and the enrollment time were randomly selected as the controls. Corticosteroids use was compared between the cases and controls. Poisson and conditional logistic regressions were used to analyze the potential risk factors for CSCR. RESULTS: Among 142,035 oral corticosteroids users, 320 cases of CSCR were identified, and 1,554 matched controls were randomly selected. The incidence rate of CSCR was 44.4 (95% confidence interval, 39.5-49.3) cases per 100,000 person-years. Multivariate Poisson regression showed that male patients and those aged 35 years to 44 years had significantly higher incidence rates of CSCR. There were no differences in either median dosage or mean duration of systemic corticosteroid treatment between the cases and controls. After adjusting for other confounders, current use of oral corticosteroids was found to be significantly associated with the risk of CSCR (odds ratio, 2.40; 95% confidence interval, 1.49-3.89). CONCLUSION: Male gender, middle age, and current use of oral corticosteroids were found to be the risk factors for CSCR. However, oral corticosteroids dosage and treatment duration were not associated with the CSCR risk.


Assuntos
Coriorretinopatia Serosa Central/epidemiologia , Prescrições de Medicamentos/estatística & dados numéricos , Glucocorticoides/administração & dosagem , Administração Oral , Adulto , Idoso , Estudos de Casos e Controles , Coriorretinopatia Serosa Central/induzido quimicamente , Bases de Dados Factuais , Feminino , Glucocorticoides/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Taiwan , Adulto Jovem
9.
Eur J Pharm Sci ; 48(4-5): 803-11, 2013 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-23357604

RESUMO

AIM: Hyperglycemia is one of the major risk factors leading to vascular complications in clinical diabetes mellitus. Ginkgo biloba extract (GBE), an antioxidant herbal medicine, possesses anti-inflammatory effects. We examined whether GBE can reduce high glucose-induced endothelial adhesiveness to monocytes, an in vitro sign mimicking in vivo early atherogenesis, through selective regulation of heme oxygenase (HO)-1 expression. METHODS: Human aortic endothelial cells (HAECs) were cultured with normal glucose or high glucose (25 mM) for 4 days and subsequently combined with GBE (EGb761, Dr. Willmar Schwabe, Karlsruhe, Germany) treatment in the last 18 h of the 4-day period. The endothelial reactive oxygen species (ROS) generation, adhesion molecule expression and the adhesiveness to monocytes were examined. The specific signal pathways such as HO-1 were also examined. RESULTS: High glucose increased ROS generation, adhesion molecule expression and the adhesiveness to monocytes in HAECs. These high glucose-induced phenomena could be suppressed by GBE (100 µg/ml)-induced HO-1 expression in a dose-dependent and time-dependent manner. In addition, jun N-terminal kinases inhibitor or phosphoinositide 3 kinase inhibitor could reduce GBE-induced HO-1 expression. Furthermore, HO-1 inhibitor, HO-1 siRNA, endothelial nitric oxide synthase (eNOS) siRNA, or nuclear factor erythroid 2-related factor (Nrf) 2 siRNA blocked the cytoprotective effects of GBE. Meanwhile, p38/mitogen-activated protein kinase (MAPK) inhibitor could also reduce the effects of GBE on HO-1 induction. CONCLUSION: GBE could reduce high glucose-induced endothelial adhesion via enhancing HO-1 expression through the Akt/eNOS and p38/MAPK pathways. Our findings suggest a potential strategy targeting on HO-1 induction by GBE for endothelial protection in the presence of high glucose such as that in diabetes mellitus.


Assuntos
Células Endoteliais/efeitos dos fármacos , Ginkgo biloba , Molécula 1 de Adesão Intercelular/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/fisiologia , Técnicas de Silenciamento de Genes , Glucose , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo
10.
Acta Ophthalmol ; 91(7): 666-71, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22998678

RESUMO

PURPOSE: Central serous chorioretinopathy (CSCR) mostly affects middle-aged men and has been associated with stress and hypercortisolism. We hypothesized that some factors prone to inducing CSCR could also have a harmful effect on erectile function. This study aimed to investigate the risk of subsequent erectile dysfunction after CSCR using Taiwan National Health Insurance Research Database. METHODS: The study cohort (n = 1220) consisted of newly diagnosed CSCR men aged 19-64 years between 1999 and 2007, and men matched for age, monthly income and time of enrolment were randomly selected as the control group (n = 10870). Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of clinically diagnosed erectile dysfunction (including organic origin and/or psychogenic origin) for the two groups. Erectile dysfunction-free survival analysis was assessed using a Kaplan-Meier method. RESULTS: Twenty-five patients (2.0%) from the CSCR cohort and 103 (0.9%) from the control group were diagnosed erectile dysfunction clinically during a mean observation period of 4.3 years. Patients with CSCR had a significantly higher incidence of erectile dysfunction diagnosis than those without CSCR (p < 0.001). After adjusting for age, geographic location, chronic comorbidities and medication habits, patients with CSCR were found to have a 2.22-fold [95% confidence interval (CI), 1.42-3.46] higher hazard ratio of a subsequent erectile dysfunction diagnosis than the matched controls. The adjusted HR for organic and psychogenic erectile dysfunction were 2.14 (95% CI: 1.34-3.44) and 3.83 (95% CI: 1.47-10.01), respectively. CONCLUSIONS: Central serous chorioretinopathy was independently associated with an increased risk of being diagnosed with erectile dysfunction.


Assuntos
Coriorretinopatia Serosa Central/epidemiologia , Disfunção Erétil/epidemiologia , Adulto , Coriorretinopatia Serosa Central/diagnóstico , Estudos de Coortes , Bases de Dados Factuais/estatística & dados numéricos , Disfunção Erétil/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
11.
Circ J ; 77(2): 405-10, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23149416

RESUMO

BACKGROUND: Although emerging evidence shows angiotensin-receptor blockers (ARBs) may have a beneficial effect against Alzheimer's disease (AD), the association is not consistent. We investigated the association between ARB use and the risk of development of AD using a nationwide, population-based cohort database in Taiwan. METHODS AND RESULTS: In total, 16,426 newly diagnosed hypertensive patients who were administered ARB without a previous diagnosis of AD were identified from the Taiwan National Health Insurance database. The comparison group consisted of hypertensive patients who did not receive ARB, and were matched to exposed individuals using propensity score by enrolled time, age, sex, and comorbidities. During an average of 5.24 ± 2.01 years of follow-up, a total of 1,031 cases (3.13%) of new AD occurred. The log-rank test showed no significant difference in the AD occurrence rate between subjects exposed to ARBs and non-exposed controls [488 (2.97%) vs. 543 (3.29%), P=0.221]. After adjusting for age, sex, comorbidities, and medications, only advanced age [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.12-1.13, P<0.001), female sex (HR 1.18, 95% CI 1.04-1.33, P=0.011), diabetes (HR 1.53, 95% CI 1.31-1.79, P<0.001), but not ARB (HR 1.08, 95% CI 0.96-1.22, P=0.222) were independently associated with AD development. CONCLUSIONS: The use of ARB was not significantly associated with a reduction of risk of AD in Asian patients with essential hypertension.


Assuntos
Doença de Alzheimer/mortalidade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/mortalidade , Adulto , Distribuição por Idade , Idoso , Isquemia Encefálica/mortalidade , Estudos de Coortes , Comorbidade , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Fatores de Risco , Distribuição por Sexo , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida , Taiwan/epidemiologia
12.
PLoS One ; 7(9): e46067, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23049937

RESUMO

BACKGROUND: Vascular oxidative stress may be increased with age and aggravate endothelial dysfunction and vascular injury in hypertension. This study aimed to investigate the effects of dextromethorphan (DM), a NADPH oxidase inhibitor, either alone or in combination treatment, on blood pressure (BP) and vascular protection in aged spontaneous hypertensive rats (SHRs). METHODOLOGY/PRINCIPAL FINDINGS: Eighteen-week-old WKY rats and SHRs were housed for 2 weeks. SHRs were randomly assigned to one of the 12 groups: untreated; DM monotherapy with 1, 5 or 25 mg/kg/day; amlodipine (AM, a calcium channel blocker) monotherapy with 1 or 5 mg/kg/day; and combination therapy of DM 1, 5 or 25 mg/kg/day with AM 1 or 5 mg/kg/day individually for 4 weeks. The in vitro effects of DM were also examined. In SHRs, AM monotherapy dose-dependently reduced arterial systolic BP. DM in various doses significantly and similarly reduced arterial systolic BP. Combination of DM with AM gave additive effects on BP reduction. DM, either alone or in combination with AM, improved aortic endothelial function indicated by ex vivo acetylcholine-induced relaxation. The combination of low-dose DM with AM gave most significant inhibition on aortic wall thickness in SHRs. Plasma total antioxidant status was significantly increased by all the therapies except for the combination of high-dose DM with high-dose AM. Serum nitrite and nitrate level was significantly reduced by AM but not by DM or the combination of DM with AM. Furthermore, in vitro treatment with DM reduced angiotensin II-induced reactive oxygen species and NADPH oxidase activation in human aortic endothelial cells. CONCLUSIONS/SIGNIFICANCE: Treatment of DM reduced BP and enhanced vascular protection probably by inhibiting vascular NADPH oxidase in aged hypertensive animals with or without AM treatment. It provides the potential rationale to a novel combination treatment with low-dose DM and AM in clinical hypertension.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dextrometorfano/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , NADPH Oxidases/antagonistas & inibidores , Angiotensina II/farmacologia , Animais , Linhagem Celular , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo
13.
Cardiovasc Diabetol ; 11: 49, 2012 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-22553973

RESUMO

BACKGROUND: Chronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation. MATERIALS AND METHODS: Human aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated. RESULTS: Either high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes. CONCLUSIONS: Long-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Adesão Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Ginkgo biloba , Glucose/metabolismo , Interleucina-6/metabolismo , Monócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Ginkgo biloba/química , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Manitol/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Oxirredução , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
14.
BMJ Open ; 1(2): e000200, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22116089

RESUMO

Objective The six core competencies designated by Accreditation Council for Graduate Medical Education (ACGME) are essential for establishing a patient centre holistic medical system. The authors developed a faculty programme to promote the postgraduate year 1 (PGY(1)) resident, ACGME six core competencies. The study aims to assess the clinical instructors' perception, attitudes and subjective impression towards the various sessions of the 'faculty development programme for teaching ACGME competencies.' Methods During 2009 and 2010, 134 clinical instructors participated in the programme to establish their ability to teach and assess PGY(1) residents about ACGME competencies. Results The participants in the faculty development programme reported that the skills most often used while teaching were learnt during circuit and itinerant bedside, physical examination teaching, mini-clinical evaluation exercise (mini-CEX) evaluation demonstration, training workshop and videotapes of 'how to teach ACGME competencies.' Participants reported that circuit bedside teaching and mini-CEX evaluation demonstrations helped them in the interpersonal and communication skills domain, and that the itinerant teaching demonstrations helped them in the professionalism domain, while physical examination teaching and mini-CEX evaluation demonstrations helped them in the patients' care domain. Both the training workshop and videotape session increase familiarity with teaching and assessing skills. Participants who applied the skills learnt from the faculty development programme the most in their teaching and assessment came from internal medicine departments, were young attending physician and had experience as PGY(1) clinical instructors. Conclusions According to the clinical instructors' response, our faculty development programme effectively increased their familiarity with various teaching and assessment skills needed to teach PGY(1) residents and ACGME competencies, and these clinical instructors also then subsequently apply these skills.

15.
Clin Ther ; 33(10): 1365-70, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21962452

RESUMO

BACKGROUND: Statins have been widely prescribed to treat hyperlipidemia, and can be used for primary and secondary prevention of cardiovascular diseases. Several studies have shown that statins have antiinflammatory effects in addition to cholesterol-lowering properties. There is new evidence suggesting that statins have beneficial effects on patients with chronic obstructive pulmonary disease (COPD), which is characterized by a persistent inflammatory response. OBJECTIVE: The aim of this study was to determine the association between statins and COPD by using the Taiwan National Health Insurance database. METHODS: This was a nationwide population-based cohort study. A total of 6252 newly diagnosed COPD patients (median age, 64 years; 50.3% male) who received statins for hyperlipidemia treatment were identified from the 1 million sampling cohort dataset between January 2000 and December 2007. Another 12,469 newly diagnosed COPD patients (median age, 64 years; 50.3% male) who were matched for age, gender, and medication for COPD treatment, except for statin use, were enrolled as the control group. The end point of the study was hospitalization due to COPD. RESULTS: During an average of 4.58 (2.36) years' follow-up period, there were 1832 patients who experienced hospitalization for COPD exacerbation (statin vs control = 508 [8.1%] vs 1324 [10.6%]; P = 0.001). Statin use was independently associated with the decreased risk of COPD hospitalization (hazard ratio, 0.66; 95% CI, 0.60-0.74; P < 0.001). CONCLUSIONS: In the selected Taiwanese population, statins were associated with reduced hospitalization due to COPD in patients newly diagnosed with COPD, suggesting a potential beneficial effect of statins in patients with COPD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hospitalização , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Estudos de Coortes , Uso de Medicamentos/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Taiwan/epidemiologia
16.
J Clin Endocrinol Metab ; 96(10): 3175-83, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21816781

RESUMO

CONTEXT: Primary aldosteronism (PA) is associated with a higher incidence of cardiovascular events, probably through mineralocorticoid receptor (MR)-dependent endothelial cell dysfunction, in comparison with essential hypertension (EH). OBJECTIVE: Our objective was to investigate the number and function of endothelial progenitor cells (EPC) in PA and the relationship with arterial stiffness and disease progression. DESIGN AND SETTING: We conducted a prospective study of the change of EPC number and outcome of PA patients after treatment at a tertiary medical center. PRIMARY OUTCOMES: Changes in arterial stiffness and EPC number after treatment and the curability of hypertension were assessed. PATIENTS: A total of 113 PA patients (87 patients diagnosed with aldosterone-producing adenoma, 26 with idiopathic hyperaldosteronism) and 55 patients with EH participated. RESULTS: PA patients had higher arterial stiffness than EH patients (P = 0.006), with a lower numbers of circulating EPC and endothelial colony-forming units (P < 0.05). The differences were ameliorated at 6 months after unilateral adrenalectomy or treatment with spironolactone. Expression of MR was identified in the EPC. The number of circulating EPC was inversely correlated with the plasma aldosterone concentration (P = 0.021), arterial stiffness (P = 0.029) and serum high-sensitivity C-reactive protein (P = 0.03). High-dose aldosterone (10(-5) and 10(-6) m) attenuated EPC proliferation and angiogenesis in vitro. Among the 45 patients who underwent unilateral adrenalectomy, 32 (71%) were cured of hypertension. The preoperative number of EPC [log(EPC number percent) >-3.6] predicted the curability of hypertension after adrenalectomy (P = 0.003). CONCLUSIONS: The relative deficiency of EPC in PA patients may contribute to aldosterone vasculopathy, which can be reversed by adrenalectomy and spironolactone. High aldosterone levels attenuated EPC proliferation and angiogenesis. Circulating EPC number may be a valuable biomarker to identify PA patients with a high incidence of arterial stiffness and to predict postoperative residual hypertension of aldosterone-producing adenoma.


Assuntos
Células Endoteliais/fisiologia , Hiperaldosteronismo/patologia , Células-Tronco/fisiologia , Doenças Vasculares/patologia , Adenoma/metabolismo , Adulto , Idoso , Aldosterona/biossíntese , Apoptose/fisiologia , Artérias/patologia , Biomarcadores , Proteína C-Reativa/metabolismo , Contagem de Células , Proliferação de Células , Senescência Celular/fisiologia , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Hiperaldosteronismo/complicações , Hipertensão/etiologia , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Resultado do Tratamento , Doenças Vasculares/etiologia
17.
Atherosclerosis ; 214(2): 301-9, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21144518

RESUMO

AIMS: Vascular protective effects of Ginkgo biloba extract (GBE) may involve both antioxidant-related and anti-inflammatory mechanisms. GBE was recently suggested as a heme oxygenase (HO)-1 inducer. The role of HO-1 in anti-atherogenesis and related vascular protective effects of GBE awaited further clarification. METHODS AND RESULTS: Tumor necrosis factor (TNF)-α was used to stimulate adhesiveness of human aortic endothelial cells (HAECs) to monocytes, an in vitro sign simulating atherogenesis. Pretreatment with GBE reduced TNF-α-stimulated endothelial adhesiveness, which could be attenuated by HO-1 inhibitors ZnPP IX or SnPP IX. GBE increased HO-1 expression and enzyme activity in HAECs. Pretreatment with MAP kinase inhibitor SB203580 significantly reduced GBE-induced HO-1 expression. Furthermore, GBE activated the translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and increased its binding to the antioxidant response element (ARE) of the HO-1 gene. Pretreatment with PEG-SOD or other antioxidant reagents did not alter GBE-induced endothelial HO-1 expression. In vivo study also showed that GBE treatment could reduce leukocyte adherence to injury arteries, and enhance HO-1 expression in circulating monocytes and in arteries after wire injury, suggesting the in vivo induction of HO-1 by GBE. CONCLUSION: GBE could inhibit cytokine-induced endothelial adhesiveness by inducing HO-1 expression via the activation of p38 and Nrf-2 pathways, a mechanism in which oxidative stress is not directly involved. GBE might exert its anti-atherogenesis and vascular protective effects by inducing vascular HO-1 expression.


Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose/prevenção & controle , Fármacos Cardiovasculares/farmacologia , Células Endoteliais/efeitos dos fármacos , Ginkgo biloba , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Lesões do Sistema Vascular/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Aterosclerose/enzimologia , Aterosclerose/imunologia , Sítios de Ligação , Adesão Celular/efeitos dos fármacos , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Células Endoteliais/imunologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Transporte Proteico , Interferência de RNA , RNA Mensageiro/metabolismo , Fatores de Tempo , Transfecção , Fator de Necrose Tumoral alfa/metabolismo , Células U937 , Molécula 1 de Adesão de Célula Vascular/metabolismo , Lesões do Sistema Vascular/enzimologia , Lesões do Sistema Vascular/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Front Biosci (Landmark Ed) ; 14(10): 3836-45, 2009 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-19273314

RESUMO

Homocysteine may induce vascular damage for atherosclerosis. Vitamin/folate supplementation has been proposed to reduce the cardiovascular disease risk. Nevertheless, there is no randomized clinical trial clearly proving the efficacy of reducing the homocysteine as a means of lowering the incidence of cardiovascular disease. Homocysteine induces oxidative stress leading to endothelial dysfunction. In addition, homocysteine-induced oxidative stress favors lipid peroxidation and induces production of inflammatory factors, thus accelerating atherosclerosis. In this paper, we reviewed the available evidence concerning the association between homocysteine and cardiovascular disease, with the objective of discussing the pertinence of screening, treatment, and prevention of hyperhomocysteinemia-related cardiovascular disease. Our previous findings also indicated the significant role of mononuclear cells activation in homocysteine-induced endothelial dysfunction; treatment with statins attenuated homocysteine-induced endothelial adhesiveness, indicating the novel endothelial protection effects of statins in the presence of homocysteine. Since inflammation and oxidative stress are critical to homocysteine-induced vascular damage, the improvement of endothelial dysfunction and the inhibition of mononuclear cell activation by anti-inflammatory and/or antioxidative drugs/agents may serve as the potential therapeutic strategy for hyperhomocysteinemia-related cardiovascular disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Doenças Cardiovasculares/etiologia , Homocisteína/fisiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Homocisteína/sangue , Humanos
19.
J Agric Food Chem ; 55(5): 1977-84, 2007 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-17266329

RESUMO

Toll-like receptor 4 (TLR4) initiates the inflammatory response in blood vessels in reaction to immune stimuli such as lipopolysaccharide (LPS) produced by gram-negative bacteria. LPS-induced proliferation and functional perturbation in vascular smooth muscle cells play important roles during atherogenesis. Ginkgo biloba extract is an antiatherothrombotic Chinese herbal medicine with anti-inflammatory properties. The effects of G. biloba extract on LPS-induced proliferation and TLR4 expression and the underlying mechanisms for these actions, in human aortic smooth muscle cells (HASMCs), were examined in vitro. LPS-induced proliferation was mediated by the expression of TLR4 in HASMCs. LPS increased the expression of TLR4 in HASMCs, and this effect was mediated by the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, phosphorylation of intracellular mitogen-activated protein kinases (MAPKs), and increases in the cytoplasmic level of HuR and TLR4 mRNA stability. G. biloba extract inhibited LPS-induced HASMC proliferation and decreased the expression of TLR4 by inhibiting LPS-induced NADPH oxidase activation, mRNA stabilization, and MAPK signaling pathways. These results suggest that LPS-induced TLR4 expression contributes to HASMC proliferation and that G. biloba inhibits LPS-stimulated proliferation of HASMCs by decreasing TLR4 expression.


Assuntos
Divisão Celular/efeitos dos fármacos , Ginkgo biloba/química , Lipopolissacarídeos/farmacologia , Músculo Liso Vascular/citologia , NADPH Oxidases/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Aorta , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Extratos Vegetais/farmacologia , Receptor 4 Toll-Like/genética
20.
J Cell Biochem ; 100(2): 372-84, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16924668

RESUMO

Salvianolic acid B (Sal B), a water-soluble antioxidant derived from a Chinese medicinal herb, is believed to have multiple therapeutic and preventive against human vascular diseases, including atherosclerosis and restenosis. To elucidate the underlying cellular mechanisms, we produced hypercholesterolemia by feeding apo-E-deficient mice a 0.15% cholesterol diet and inflammation in human aortic smooth muscle cells (HASMCs) with the endotoxin lipopolysaccharide (LPS), focusing on the metallopreteinases MMP-2 and MMP-9, the relevant signal transduction pathways and the effects of Sal B. Immunohistochemical analyses indicated apo-E-deficient mice fed a 0.15% cholesterol diet for 12 weeks exhibited thickened intima and elevated levels of MMP-2 and MMP-9 in aortic sections, both of which were attenuated by 0.3% Sal B dietary supplement. Western blotting and zymography analyses indicated that unstimulated HASMCs exhibited basal levels of protein and activity levels for MMP-2 and barely detectable levels for MMP-9, both of which were markedly upregulated by LPS, which also induced cell migration. Sal B significantly attenuated upregulations of both MMPs as well as the LPS-induced cell migration through the inactivation of MMP-2 and MMP-9 protein synthesis as well as the downregulation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). These results demonstrate that Sal B has anti-migration properties on smooth muscle cells and may explain its anti-atherosclerotic properties. This novel mechanism of action of Sal B, in addition to its previously reported inhibition of LDL oxidation, may help explain its efficacy in the treatment of atherosclerosis.


Assuntos
Aorta/metabolismo , Apolipoproteínas E/metabolismo , Benzofuranos/farmacologia , Lipopolissacarídeos/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Movimento Celular , Células Cultivadas , Colesterol/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fosforilação , Transdução de Sinais
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