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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165627, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785407

RESUMO

Macrophages play an important role in aldosterone-induced myocardial fibrosis, in which the first key steps are macrophage recruitment and infiltration. We hypothesized that IL-6 may be a key mediator of aldosterone-induced macrophage recruitment and infiltration. To test this hypothesis, we designed cell studies with a human monocytic cell line THP-1 that with monocyte/macrophage functions to explore the signaling pathway of aldosterone-induced macrophage infiltration, and further investigated the phenomenon and consequent pathway in aldosterone-infused mice studies. The results showed that aldosterone induced the expression of IL-6 via mineralocorticoid receptors, and enhanced THP-1 cell migration and infiltration. Further experiments using a protease array and siRNA revealed that expressions of MMP-1 and MMP-9 were associated with aldosterone-induced macrophage infiltration. In addition, aldosterone-induced MMP-1 and MMP-9 expressions were mediated via cyclooxygenase-II and prostaglandin E2/EP-2 and EP-4 receptors. In aldosterone-infused mice, mRNA expressions of MMP-1, MMP-9 and COX-2 in peripheral blood monocytic cells were significantly increased. Moreover, the number of mouse macrophage-restricted F4/80 protein-positive cells in the myocardium was significantly higher in the aldosterone-infused mice compared with control mice. The increase in F4/80-positive cells in the myocardium was suppressed in the aldosterone-infused mice with the aldosterone antagonist eplerenone or anti-IL-6 antibody treatment. In conclusion, interleukin-6 played an important role in aldosterone-induced macrophage recruitment and infiltration in the myocardium.

2.
J Clin Endocrinol Metab ; 105(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31512726

RESUMO

CONTEXT: A supraphysiological estradiol (E2) concentration after ovarian stimulation is known to result in lower embryo implantation rates in in vitro fertilization. Endometrial epithelial cell (EEC) apoptosis occurs after the stimulation with high E2 concentrations, and mitochondria play important roles in cell apoptosis. OBJECTIVE: To investigate the mitochondrial function in EECs after the stimulation with high E2 concentrations. MATERIALS AND METHODS: Human EECs were purified and cultured with different E2 concentrations (10-10, 10-9, 10-8, 10-7 M) in vitro, in which 10-7 M is supraphysiologically high. Eight-week-old female mouse endometrium was obtained 5.5 days after the injection of 1.25 IU or 20 IU equine chorionic gonadotropin, roughly during the embryo implantation window, to examine the in vivo effects of high E2 concentrations on mouse EECs. RESULTS: In vivo and in vitro experiments demonstrated decreased mitochondrial DNA contents and ATP formation after EECs were stimulated with supraphysiologically high E2 concentrations than those stimulated with a physiologic E2 concentration. Less prominent immunofluorescence mitochondrial staining, fewer mitochondria numbers under electron microscopy, lower 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide aggregate/monomer ratio, and greater reactive oxygen species (ROS) production were found after EECs were stimulated with supraphysiologically high E2 concentrations. The high E2-induced ROS production was reduced when EECs were pretreated with N-acetyl-cysteine in vitro, but remained unchanged after the pretreatment with coenzyme Q10. CONCLUSION: High E2 concentrations increase extramitochondrial ROS production in EECs and subsequently result in mitochondrial dysfunction.

3.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640178

RESUMO

Primary aldosteronism (PA) is characterized by excess production of aldosterone from the adrenal glands and is the most common and treatable cause of secondary hypertension. Aldosterone is a mineralocorticoid hormone that participates in the regulation of electrolyte balance, blood pressure, and tissue remodeling. The excess of aldosterone caused by PA results in an increase in cardiovascular and cerebrovascular complications, including coronary artery disease, myocardial infarction, stroke, transient ischemic attack, and even arrhythmia and heart failure. Endothelial dysfunction is a well-established fundamental cause of cardiovascular diseases and also a predictor of worse clinical outcomes. Accumulating evidence indicates that aldosterone plays an important role in the initiation and progression of endothelial dysfunction. Several mechanisms have been shown to contribute to aldosterone-induced endothelial dysfunction, including aldosterone-mediated vascular tone dysfunction, aldosterone- and endothelium-mediated vascular inflammation, aldosterone-related atherosclerosis, and vascular remodeling. These mechanisms are activated by aldosterone through genomic and nongenomic pathways in mineralocorticoid receptor-dependent and independent manners. In addition, other cells have also been shown to participate in these mechanisms. The complex interactions among endothelium, inflammatory cells, vascular smooth muscle cells and fibroblasts are crucial for aldosterone-mediated endothelial dysregulation. In this review, we discuss the association between aldosterone and endothelial function and the complex mechanisms from a molecular aspect. Furthermore, we also review current clinical research of endothelial dysfunction in patients with PA.

4.
Int J Mol Sci ; 20(20)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658764

RESUMO

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.

5.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510052

RESUMO

Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the apoptosis of KECs treated with high concentrations of C5a has also been observed. As mitochondrial damage is known to be important in cell apoptosis, the aim of this study was to examine the association between C5a-induced mouse KEC apoptosis and mitochondrial damage. Mouse KECs were isolated and treated with different concentrations of C5a. Cell viability assays showed that a high-concentration mouse recombinant protein C5a (rmC5a) treatment reduced mouse KEC growth. Cell cycle phase analysis, including apoptosis (sub-G1 phase) showed an increased percentage of the subG1 phase with a high-concentration rmC5a treatment. Cytochrome c and caspase 3/9 activities were significantly induced in the mouse KECs after a high-dose rmC5a (50 ng/mL) treatment, and this was rescued by pretreatment with the C5a receptor (C5aR) inhibitor (W-54011) and N-acetylcysteine (NAC). Reactive oxygen species (ROS) formation was detected in C5a-treated mouse KECs; however, W-54011 or NAC pretreatment inhibited high-dose rmC5a-induced ROS formation and also reduced cytochrome c release, apoptotic cell formation, and apoptotic DNA fragmentation. These factors determined the apoptosis of mouse KECs treated with high-dose C5a through C5aR and subsequently led to apoptosis via ROS regeneration and cytochrome c release. The results showed that high concentrations of C5a induced mouse KEC apoptosis via a C5aR/ROS/mitochondria-dependent pathway. These findings may shed light on the potential mechanism of glomerular sclerosis, a process in idiopathic nephrotic syndrome causing renal function impairment.

7.
J Formos Med Assoc ; 118(8): 1225-1231, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31056381

RESUMO

BACKGROUND/PURPOSE: Genetic variant of HSD3B1 1245 is known to augment androgen production at peripheral tissue as skin. This study aimed to investigate whether women with polycystic ovary syndrome inheriting this variant exhibit specific androgenic phenotypes. METHODS: A cross-sectional study of Taiwanese women with polycystic ovary syndrome, defined by Rotterdam criteria, at the reproductive endocrinology outpatient clinic in a university affiliated hospital. RESULTS: The presence of female pattern hair loss in women with polycystic ovary syndrome was significantly associated with an increased body mass index, decreased sex hormone binding globulin and high density lipoprotein cholesterol levels, elevated triglyceride levels, and increased prevalence of hypertension. Using stepwise multivariate logistic regression analysis, body mass index, triglyceride and HSD3B1 1245 AC or CC genotype were significantly related to female pattern hair loss in women with polycystic ovary syndrome after considering other variables. Overweight women with polycystic ovary syndrome had significantly higher risk of female pattern hair loss than normal-weight women with polycystic ovary syndrome. The presence of female pattern hair loss was higher in overweight women with polycystic ovary syndrome who comprised HSD3B1 AC or CC genotype compared with wild type. CONCLUSION: Carrying the HSD3B1 1245C allele and overweight are associated with the presence of female pattern hair loss in women with polycystic ovary syndrome.


Assuntos
Alopecia/genética , Complexos Multienzimáticos/genética , Sobrepeso/complicações , Síndrome do Ovário Policístico/genética , Progesterona Redutase/genética , Esteroide Isomerases/genética , Adulto , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Resistência à Insulina , Polimorfismo Genético , Taiwan , Adulto Jovem
8.
J Formos Med Assoc ; 118(1 Pt 2): 249-259, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29779926

RESUMO

BACKGROUND/PURPOSE: Abnormal folliculogenesis is one of the cardinal presentations of polycystic ovarian syndrome (PCOS) and permeability of follicular wall has been proposed to be involved in the normal follicular growth. However, whether or not there is a change in intrafollicular permeability underlies PCOS is unknown. METHODS: This was a tertiary center-based case-control study. From 2014 to 2015, thirteen patients with PCOS who underwent in vitro fertilization-embryo transfer (IVF-ET) were enrolled. Eleven normo-ovulatory patients who underwent IVF-ET due to male factor and/or tubal factor infertility were enrolled as the control group. The influence of ovarian follicular fluid (FF) on endothelial cell permeability was evaluated using a human umbilical vein endothelial cell monolayer permeability assay. The intrafollicular expression profiles of angiogenesis-related proteins were analyzed using a Human Angiogenesis Protein Array Kit. RESULTS: The FF from PCOS patients caused significantly poorer endothelial cell permeability comparing with the effect of FF from the control group (46% ± 12% vs. 58% ± 9%, P = 0.023). Among the 55 angiogenesis-related proteins tested, there was a significantly higher level of intrafollicular platelet factor 4 (PF4) and PF4/IL-8 complex in the PCOS group (p = 0.004). The anti-permeability effect of PF4 was related to the decrease in the intercellular gaps and antagonistic binding with IL-8. CONCLUSION: Our study provides the first evidence of the pathophysiologic contribution of the well-known angiostatic protein, PF4, on human reproductive biology. The increase of the intrafollicular PF4 and its anti-permeability effect might affect the formation of FF and folliculogenesis in PCOS.


Assuntos
Líquido Folicular/química , Infertilidade Feminina/patologia , Fator Plaquetário 4/química , Síndrome do Ovário Policístico/patologia , Adulto , Estudos de Casos e Controles , Feminino , Fertilização In Vitro , Humanos , Permeabilidade , Taiwan , Centros de Atenção Terciária
9.
Biol Reprod ; 100(2): 381-389, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247509

RESUMO

Embryo implantation rates have been found to be enhanced by precedent endometrial injuries, but the underlying mechanism is not fully investigated. Endometrial inflammation occurs both at peri-implantation period and after endometrial injury, in which vascular reaction is a distinctive feature of inflammation. In this study, intentional endometrial injury was done with a 0.7-mm-diameter brush inserted into the left uterine horn of female ICR mice, then turned around 720° (group 2), and the right uterine horn served as the controls without endometrial injuries (group 1). Intraperitoneal equine chorionic gonadotropin 2.5 IU was injected, followed by human chorionic gonadotropin 10 IU injection, and the uterus was dissected 5 days later, roughly at the peri-implantation period. The peri-implantation endometrium was obtained, and angiogenesis protein array revealed that matrix metalloproteinase-3 (MMP-3), plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor binding protein 1 (IGFBP-1), and IL-1α were more strongly expressed in injured endometrium (group 2) than in the controls (group 1). Immunohistochemical CD34 staining was more prominently expressed in group 2 uterus, and the treatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly decreased CD34 immunopositive cells. The capabilities of permeability, proliferation, tube formation, and migration of mouse endometrial endothelial cells were significantly enhanced in group 2 than in group 1. Our results demonstrate that enhanced endometrial angiogenesis is a possible mechanism accounting for the increased endometrial receptivity after endometrial injury.

10.
Cardiovasc Res ; 114(5): 690-702, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29360942

RESUMO

Aims: An excess of aldosterone results in cardiac remodelling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process; however, the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process. Methods and results: In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH). The PA patients had higher plasma IL-6 levels, left ventricular mass index, degree of myocardial fibrosis, and more impaired diastolic function than the EH patients. In addition, plasma IL-6 levels were positively correlated with 24-h urinary aldosterone and echocardiographic parameters. In cell studies, we investigated the possible molecular mechanism how aldosterone-induced IL-6 secretion and the further effects of collagen production. Aldosterone significantly induced IL-6 protein and mRNA production in human umbilical vein endothelial cells. Intracellular signalling occurred through the mineralocorticoid receptor/PI3K/Akt/NF-kB pathway. In cardiac fibroblasts, IL-6 trans-signalling played a critical role in aldosterone-induced IL-6-enhanced fibrosis-related factor expression. To further investigate the role of IL-6 trans-signalling in aldosterone-induced cardiac fibrosis, we measured the severity of myocardial fibrosis in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving recombinant soluble gp130 and Sgp130 Knockin Transgenic Mice prevented myocardial fibrosis and cardiac hypertrophy by aldosterone infusion. Conclusions: IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.


Assuntos
Aldosterona/metabolismo , Cardiomegalia/metabolismo , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiperaldosteronismo/metabolismo , Interleucina-6/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular , Adulto , Aldosterona/farmacologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Estudos de Casos e Controles , Células Cultivadas , Colágeno/metabolismo , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Hipertensão Essencial/etiologia , Hipertensão Essencial/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibrose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hiperaldosteronismo/complicações , Interleucina-6/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Miocárdio/patologia , Estudos Prospectivos , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais
11.
Oncotarget ; 8(37): 62081-62098, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28977928

RESUMO

Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16. Depressing G9a by either pharmacological inhibitor or gene knock down significantly reduces angiogenic factor expression. Moreover, promoting G9a gene expression augments transcription and angiogenic function. A luciferase reporter assay suggests that knockdown of G9a inhibits transcriptional activation of interleukin-8. G9a depletion suppresses xenograft tumor growth in mouse model, which is linked to a decrease in microvessel density and proliferating cell nuclear antigen expression. Clinically, higher G9a expression correlates with poorer survival for cancer patients. For patients' primary tumors a positive correlation between G9a expression and microvessel density also exists. In addition to increasing tumor cell proliferation, G9a promotes tumor angiogenesis and reduces the patient survival rate. G9a may possess great value for targeted therapies.

12.
Int J Cardiol ; 233: 43-51, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28190615

RESUMO

BACKGROUND: The clinical benefits of a combination of statins and ezetimibe in patients with acute coronary syndrome (ACS) were observed in a clinical trial. However, little is known regarding the effectiveness of using statins with or without ezetimibe in patients with ACS and multiple comorbidities in real-world clinical practice. METHODS: This is a nationwide population-based cohort study using Taiwan National Health Insurance Research Database. A total of 212,110 patients with ACS who had been discharged after their first ACS events between 2006 and 2010 were enrolled. A propensity score matching approach was used to create matched cohorts for adjusting potential confounders. Cox proportional hazards regressions were performed to estimate the risk of re-hospitalization for ACS and revascularization. RESULTS: Patients in the statins-plus-ezetimibe group had a significantly lower risk of re-hospitalization for ACS (adjusted hazard ratio [HR]=0.64, 95% confidence interval [CI]: 0.60-0.69) and revascularization (HR=0.69, 95% CI: 0.63-0.76) than those in the statins-alone group. In the statins-plus-ezetimibe group, female patients had a lower risk of re-hospitalization for ACS than male patients did, and patients without diabetes mellitus had a lower risk of re-hospitalization for ACS than did patients with diabetes mellitus. CONCLUSIONS: Patients with ACS and multiple comorbidities receiving a combination therapy of statins and ezetimibe had a lower risk of re-hospitalization for ACS and revascularization than those receiving statins alone. Significant interaction effects were observed between combination with ezetimibe, sex, and diabetes mellitus.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Dislipidemias/epidemiologia , Ezetimiba/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Vigilância da População , Síndrome Coronariana Aguda/epidemiologia , Idoso , Anticolesterolemiantes/administração & dosagem , Comorbidade , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Dislipidemias/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Taxa de Sobrevida/tendências , Taiwan/epidemiologia , Fatores de Tempo , Resultado do Tratamento
13.
J Racial Ethn Health Disparities ; 4(3): 462-471, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27352117

RESUMO

Adherence to statins is lower in black and Hispanic patients and is linked to racial/ethnic disparities in cardiovascular mortality. Poverty, education, and prescription coverage differentials are typically invoked to explain adherence disparities, but analyses at the level of neighborhoods and their pharmacies may provide additional insights. Among individuals filling new statin prescriptions in a national pharmacy chain (N = 326,171), we compared adherence for patients residing in mostly minority neighborhoods to those living in mainly white areas. In analyses adjusting for patient-level factors associated with poor adherence, including age, insurance, payer, prescription cost, and convenience, patients residing in black and Hispanic neighborhoods had 2-3 weeks less statin therapy over 1 year, a pattern not seen in Asian areas. In black and Hispanic neighborhoods, good adherence was associated with co-pays under $10, the use of 90-day refills, and payers other than Medicaid. Efforts to improve medication adherence for vulnerable populations may benefit from interventions at the level of local pharmacies, as well as medication benefit redesign.


Assuntos
Grupos de Populações Continentais/estatística & dados numéricos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos
14.
Biol Reprod ; 95(4): 87, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27605343

RESUMO

The high serum estradiol (E2) concentrations induced during in vitro fertilization are detrimental to endometrial receptivity and may result in lower embryo implantation rates. We have previously found that high E2 concentrations inhibit the activation of nuclear factor kappa B (NF-kappa B), which led to endometrial epithelial cells (EECs) apoptosis. The objective of this study is to investigate the signaling pathways through which high E2 results in NF-kappa B downregulation in EECs. Isolated human EECs were cultured in different concentrations of E2 (10-10, 10-9, 10-8, 10-7 M). The expression of heat shock protein 70 (Hsp70) and heat shock factor 1 (HSF-1) were upregulated under supraphysiological E2 (10-7 M) concentration, whereas phosphorylated inhibitory kappa B-alpha (pI kappa B-alpha) and NF-kappa B p65 subunits were downregulated. Immunohistochemistry of C57BL/6 mouse EECs, that were exposed in vivo to high serum E2 from the administration of 20 IUs of equine chorionic gonadotropin, also demonstrated the same increase in HSF-1 and Hsp70 expression, and decrease in NF-kappa B. Immunoprecipitation of the induced Hsp70 proteins was achieved with the addition of inhibitory kappa B kinase gamma (IKK-gamma) antibodies, and elimination of this reaction occurred after addition of hsp70 siRNA. In conclusion, high E2 concentrations enhance HSF-1 and Hsp70 expression in EECs. The induced Hsp70 forms a complex with IKK-gamma and inhibits pI kappa B-alpha, which consequently suppresses NF-kappa B activation.

15.
Int J Cardiol ; 222: 895-900, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27526355

RESUMO

BACKGROUND: Ventricular remodeling following myocardial infarction (MI) is closely associated with cyclooxygenase-2 (COX-2) expression. 5-methoxytryptophan (5-MTP) was reported to control COX-2 expression. OBJECTIVES: To investigeate the association between 5-MTP and post-MI left ventricular remodeling. METHODS: This prospective study enrolled 26 non-diabetic patients with first-time ST segment elevation myocardial infarction (STEMI), and 58 controls. Levels of 5-MTP, N-terminal of pro-brain natriuretic peptide (NT-proBNP), aminoterminal propeptide of type III procollagen, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 were measured at day 1, day 3, 3months, 6months, and 1year post-MI. Echocardiography was performed during the acute stage (within 72h) and 3months, 6months, and 1year post-MI. RESULTS: The STEMI patients had a significantly lower plasma 5-MTP level at day 1 which reached a nadir at 3months post-MI. The level of 5-MTP at day 3 post-MI was significantly correlated with the level of NT-proBNP 1year post-MI, suggesting that the level of plasma 5-MTP in the early phase after MI may predict subsequent cardiac stress and failure. Receiver operating characteristic curve analysis revealed that plasma 5-MTP had the best area under the curve value to predict plasma NT-proBNP 1year post-MI. Further analysis using net reclassification improvement and integrated discrimination improvement models confirmed that plasma 5-MTP at day 3 post-MI significantly improved the predictive power of each of the parameters. CONCLUSION: In non-diabetic STEMI patients, plasma 5-MTP levels were associated with biomarkers of post-MI left ventricular remodeling and damage.


Assuntos
Insuficiência Cardíaca/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Triptofano/análogos & derivados , Remodelação Ventricular , Idoso , Biomarcadores/sangue , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Curva ROC , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Fatores de Tempo , Triptofano/sangue
16.
Hypertension ; 67(6): 1309-20, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27113051

RESUMO

Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity.


Assuntos
Colágeno/metabolismo , Hiperaldosteronismo/fisiopatologia , Metaloproteinase 1 da Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Aldosterona/metabolismo , Análise de Variância , Animais , Biópsia por Agulha , Western Blotting , Modelos Animais de Doenças , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica , Humanos , Hiperaldosteronismo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , RNA Mensageiro/genética , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transdução de Sinais
17.
Curr Diab Rep ; 16(6): 47, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27076180

RESUMO

The number of available therapies for treating type 2 diabetes has grown considerably in recent years. This growth has been fueled by availability of newer medications, whose benefits and risks have not been fully established. In this study, we review and synthesize the existing literature on the uptake, efficacy, safety, and cost-effectiveness of novel antidiabetic agents. Specifically, we focus on three drug classes that were introduced in the market recently: thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Not surprisingly, we find that the usage trends reflect the efficacy and safety profile of these novel drugs. The use of TZDs increased initially but decreased after a black-box warning was issued for rosiglitazone in 2007 that highlighted the cardiovascular risks associated with using the drug. Conversely, DPP-4 inhibitors and GLP-1 receptor agonists gained market shares due to their efficacy in glycemic control as an add-on treatment to metformin. DPP-4 inhibitors were the most commonly prescribed agents among the three novel drug classes, likely because they are relatively less expensive, have better safety profile, are administered orally, and are weight neutral. Sitagliptin was the most preferred DPP-4 inhibitor. The level of evidence on the comparative effectiveness, safety, and cost implications of using novel antidiabetic agents remains low and further studies with long-term follow-ups are needed.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Animais , Glicemia , Humanos
18.
Pediatr Neonatol ; 57(3): 207-12, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26563762

RESUMO

BACKGROUND: Acute kidney injury (AKI) is common in preterm infants and is associated with high mortality and morbidity. New biomarkers for the early detection of AKI have been identified. Specifically, urinary neutrophil gelatinase-associated lipocalin (uNGAL) is a new and powerful biomarker for AKI and sepsis. Our study evaluated the reference range of uNGAL in healthy neonates in Taiwan. METHODS: This study examined 24 preterm and 38 term infants without clinical complications. Urine samples were collected and the uNGAL values were measured at postnatal age (PNA) 3 days, 7 days, 14 days, and 21 days in the preterm infants and at PNA 3 days in the term infants. The uNGAL values were tested using enzyme-linked immunosorbent assay. RESULTS: The median uNGAL values in the preterm infants at PNA 3 days, 7 days, 14 days, and 21 days were 41.52 ng/mL, 35.82 ng/mL, 43.79 ng/mL, and 30.85 ng/mL, respectively. The median value at PNA 3 days in the term infants was 88.1 ng/mL. No significant differences associated with gestational age, birth body weight, or PNA were observed among the preterm infants. However, the uNGAL values in the female term infants were higher than those in the male term infants (p = 0.003). CONCLUSION: This study presents preliminary data on uNGAL levels in neonates in Taiwan. A large-scale study investigating the correlations between uNGAL and with gestational age, birth body weight, sex, and PNA is recommended.


Assuntos
Lesão Renal Aguda/diagnóstico , Lipocalina-2/urina , Sepse Neonatal/diagnóstico , Lesão Renal Aguda/urina , Biomarcadores/urina , Diagnóstico Precoce , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Sepse Neonatal/urina , Estudos Prospectivos , Valores de Referência , Taiwan
19.
Sci Rep ; 5: 18319, 2015 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-26674985

RESUMO

Intraovarian hyperandrogenism is one of the determining factors of follicular arrest in women with polycystic ovary syndrome (PCOS). Using androgenized rat models, we investigated the effects of androgens on metabolism, as well as on factors involved in follicular arrest and the reduced number of estrus cycles. The dihydrotestosterone (DHT)-treated rats had fewer estrus cycles, higher numbers of large arrested follicles and an increased in body weight gain compared with the dehydroepiandrostenedione (DHEA)- and placebo-treated rats. In cultured rat granulosa cells, DHT suppressed follicle stimulating hormone (FSH)-induced granulosa cell proliferation and increased the accumulation of cells in the G2/M phase. DHT decreased phosphorylated Akt (p-Akt) and cyclin D1 levels through increasing PTEN. DHT-promoted PTEN expression was regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in granulosa cells. Meanwhile, in the large follicles of the DHT-treated rats, the expressions of PPARγ and PTEN were higher, but the expression of p-Akt and proliferating cell nuclear antigen (PCNA) were lower. Conclusively, DHT and DHEA produced differential effects on metabolism in prepubertal female rats like clinical manifestations of women with PCOS. DHT treatment may affect ovarian follicular maturation by altering granulosa cell proliferation through the regulation of enhancing PPARγ dependent PTEN/p-Akt expression in the granulosa cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Hormônio Foliculoestimulante/farmacologia , Células da Granulosa/efeitos dos fármacos , PPAR gama/metabolismo , Androgênios/farmacologia , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células da Granulosa/metabolismo , PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima/efeitos dos fármacos
20.
Taiwan J Obstet Gynecol ; 54(6): 686-92, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26700986

RESUMO

OBJECTIVE: Obesity and insulin resistance are associated with increased iron stores, but have conflicting effects on ovarian reserve in women with polycystic ovary syndrome (PCOS). Iron-catalyzed oxidative stress might be detrimental to ovarian tissue and granulosa cell function. In this study we determined the association between body iron stores, obesity, and ovarian reserve in women with PCOS. MATERIALS AND METHODS: One hundred and fifty-six women diagnosed with PCOS according to Rotterdam criteria and 30 normoweight healthy control women were enrolled in this cross-sectional study. Ovarian volume, total antral follicle count, and the anti-Müllerian hormone (AMH) level were measured as an indicator of ovarian reserve. RESULTS: Ferritin and transferrin-bound iron levels were significantly higher in women with PCOS than normoweight controls. Obese women with PCOS had higher ferritin levels (p = 0.006), but lower AMH levels (p < 0.0001) than nonobese women with PCOS. Using univariate analysis, the AMH level and mean ovarian volume were inversely related to the ferritin level, homeostasis model assessment of insulin resistance, and body mass index in women with PCOS. Body mass index and ferritin level remained significantly correlated with a lower AMH level and reduced ovarian volume, respectively, after considering other confounding variables. CONCLUSION: An elevated ferritin level and obesity were negatively associated with ovarian volume and the AMH level, respectively, in women with PCOS.


Assuntos
Hormônio Antimülleriano/sangue , Ferritinas/sangue , Obesidade/complicações , Folículo Ovariano , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Adulto Jovem
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