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Rationale: Forkhead/winged helix transcriptional factor P3 (FoxP3) is a well-studied transcription factor that maintains the activity of T cells, but whether cardiomyocytic FoxP3 participates in cardiac remodeling (CR) remains unclear. The present study was to investigate the role of cardiomyocytic FoxP3 in CR from the perspective of mitophagy. Methods: CR was induced by angiotensin II (AngII) in vitro, or by isoproterenol (Iso) in vivo using male C57 mice or FoxP3DTR mice. Histological changes were observed by hematoxylin-eosin and Masson staining. Molecular changes were detected by immunohistochemistry, immunofluorescence, immunoblotting, and real-time PCR. Mitophagy was shaped by transmission electron microscopy and co-localization. The mRNA expression was operated by siRNA or adeno associated virus (AAV). Molecular interactions were detected by co-localization, immunoprecipitation (IP), and chromatin IP. Results: The expression and nuclear translocation of cardiomyocytic FoxP3 were downregulated in CR, while they were upregulated after triptolide (TP) treatment. In left ventricle (LV) remodeling in mice, autophagy was activated continuously in the myocardium, and TP significantly attenuated it. AngII induced massive mitophagy characterized by the activation of autophagy regulatory protein 5 (Atg5)-dependent autophagic flux. Critically, Parkin was identified as the main adaptor mediated myocardial mitophagy and was responsible for the effect of TP. Moreover, FoxP3 was responsible for the downregulation of Parkin and inhibited AngII-induced cardiac mitophagy. We found that mitophagy increased significantly and the inhibition of TP treatment reversed completely in FoxP3-deficient LVs. Mechanistically, FoxP3 interacted with a motif located downstream of the activating transcription 4 (ATF4)-binding motif involved in the promoter of Parkin and hijacked free nuclear ATF4 to decrease Parkin mRNA expression in CR. Conclusion: Cardiomyocytic FoxP3 could negatively regulate Parkin-mediated mitophagy in CR, and restoring cardiomyocytic FoxP3 activity provided a cardioprotective strategy by inhibiting excessive cardiac mitophagy.
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Mitofagia , Remodelación Ventricular , Angiotensina II/farmacología , Animales , Diterpenos , Compuestos Epoxi , Factores de Transcripción Forkhead/metabolismo , Masculino , Ratones , Mitocondrias/metabolismo , Mitofagia/genética , Fenantrenos , ARN Mensajero/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
INTRODUCTION: It has well established that metabolic syndrome (MetS) can predict the risk of type 2 diabetes mellitus (T2DM) in some population groups. However, limited evidence is available regarding the predictive effect of MetS for incident T2DM in mainland Chinese population. METHODS: A 3-year cohort study was performed for 9735 Chinese without diabetes at baseline. MetS and its components were assessed by multivariable analysis using Cox regression. Prediction models were developed. Discrimination was assessed with area under the receiver operating characteristic curves (AUCs), and performance was assessed by a calibration curve. RESULTS: The 3-year cumulative incidence of T2DM was 11.29%. Baseline MetS was associated with an increased risk of T2DM after adjusting for age (HR = 2.68, 95% CI, 2.27-3.17 in males; HR = 2.59, 95% CI, 1.83-3.65 in females). Baseline MetS exhibited relatively high specificity (88% in males, 94% in females) and high negative predictive value (90% in males, 94% in females) but low sensitivity (36% in males, 23% in females) and low positive predictive value (31% in males and females) for predicting the 3-year risk of T2DM. AUCs, including age and components of MetS, for the prediction model were 0.779 (95% CI: 0.759-0.799) in males and 0.860 (95% CI: 0.836-0.883) in females. Calibration curves revealed good agreement between prediction and observation results in males; however, the model could overestimate the risk when the predicted probability is >40% in females. CONCLUSIONS: MetS predicts the risk of T2DM. The quantitative MetS-based prediction model for T2DM risk may improve preventive strategies for T2DM and present considerable public health benefits for the people in mainland China.
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Previous investigations have shown that changes in total prostate volume (TPV) are highly variable among aging men, and a considerable proportion of aging men have a stable or decreasing prostate size. Although there is an abundance of literature describing prostatic enlargement in association with benign prostatic hyperplasia, less is known about the appropriate age cut-off points for TPV growth rate. In this community-based cohort study, TPV was examined once a year in men who had consecutive health checkup, during a follow-up of 4 years. A total of 5058 men (age 18-92 years old) were included. We applied multiple regression analyses to estimate the correlation between TPV growth rate and age. Overall, 3232 (63.9%) men had prostate growth, and 1826 (36.1%) had a stable or decreased TPV during the study period. The TPV growth rate was correlated negatively with baseline TPV (r=-0.32, P<0.001). Among 2620 men with baseline TPV <15 cm3, the TPV growth rate increased with age (ß=0.98, 95% CI: 0.77%-1.18%) only up to 53 years old. Among 2188 men with baseline TPV of 15-33.6 cm3, the TPV growth rate increased with age (ß=0.84, 95% CI, 0.66%-1.01%) only up to 61 years old after adjusting for factors of hypertension, obesity, baseline TPV, diabetes mellitus and dyslipidemia. In this longitudinal study, the TPV growth rate increased negatively with baseline TPV, only extending to a certain age and not beyond. Further research is needed to identify the mechanism underlying such differences in prostate growth.
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Próstata/crecimiento & desarrollo , Hiperplasia Prostática/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , China , Humanos , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Tamaño de los Órganos , Próstata/patología , Características de la Residencia/estadística & datos numéricosRESUMEN
In order to investigate the adaption of Locusta migratoria tibetensis to the. environment, this paper adopted the experiments with full light exposure (24L/OD), total. darkness (OL/24D), and low temperature (5 °C) to study the effects of low temperature and illumination stress on the cold-resistant substances of L. migratoria tibetensis. The results showed that the fat content of L. migratoria tibetensis reached 11.8%, which was the highest under the condition of full light exposure (24L/OD) without low temperature stress. The fat content of body in low temperature and darkness treatment (OL/24D) was 4.7%, which was the lowest. The trehalose, mannitol and sorbitol contents of locust after low temperature stress were significantly higher than that of locust without the same stress. Glycogen content of locust treated by full light exposure without low temperature 'stress was the highest (6.40 mg . g-1). Besides, low temperature and darkness treatment stimulated the accumulation of alanine, glutamic acid, lysine, and phenylalanine, benefiting the accumulation of multi-amino acids, glycerinum, micro-molecule carbohydrate, and the reduction of glycogen and fat content.
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Frío , Locusta migratoria/química , Fotoperiodo , Estrés Fisiológico , Aclimatación , Aminoácidos/análisis , Animales , Carbohidratos/análisis , Glucógeno/análisis , LuzRESUMEN
BACKGROUND: Morbidities related to atherosclerosis, such as acute coronary syndrome (ACS), remain the leading cause of mortality. Axl is a receptor tyrosine kinase that is expressed in mammalian vascular and immune cells. Axl signaling is involved in the regulation of the inflammatory response. A considerable amount of evidence indicates that inflammation is responsible for the development of atherosclerosis in patients with ACS. METHODS: To assess the relation of Axl and ACS, we recruited 64 patients with coronary heart disease: 34 with ACS, 30 with stable coronary heart disease, and 24 apparently healthy controls. Serum concentrations of soluble Axl (sAxl) were quantified by enzyme-linked immunosorbent assay. High-sensitivity C-reactive protein, tumor necrosis factor alpha, troponin I, and other routine biochemical markers were also measured. RESULTS: The levels of sAxl were significantly higher in patients with ACS than in the controls (P=0.005). Furthermore, correlation analysis indicated that sAxl was significantly associated with serum levels of high-sensitivity C-reactive protein (r=0.283, P=0.008), tumor necrosis factor alpha (r=0.565, P<0.001), and troponin I (r=0.264, P=0.013). Logistic regression analysis (odds ratio=1.038, 95% confidence interval, 1.008-1.069, P=0.012) indicated a significant association between sAxl and ACS. CONCLUSIONS: Serum levels of sAxl correlate to inflammatory biochemical markers. These findings demonstrate for the first time that sAxl does have a role in ACS, presumably connected to the inflammation.
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Síndrome Coronario Agudo/sangre , Proteínas Proto-Oncogénicas/sangre , Proteínas Tirosina Quinasas Receptoras/sangre , Adulto , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Troponina I/sangre , Tirosina Quinasa del Receptor AxlRESUMEN
In the present study, we investigated the systematically induced production of defense-related compounds, including DIMBOA, total phenol, trypsin inhibitors (TI) and chymotrypsin inhibitor (CI), by Tetranychus cinnabarinus infestation in Zea mays. The first leaves of two corn in-bred line seedlings, the mite-tolerant line ' H1014168' and the mite-sensitive line 'H1014591', were sucked by T. cinnabarinus adult female for seven days, and then the contents of DIMBOA, total phenol, TI and CI were measured in the second leaf and in the roots, respectively. Results showed that as compared to the unsucked control, all contents of DIMBOA, total phenol, TI and CI induced by T. cinnabarinus sucking were significantly higher in the second leaf of both inbred lines as well as in the roots of the mite-tolerant 'H1014168'. However, in the roots of 'H1014591', these defense compounds had different trends, where there was a higher induction of TI and a lower level of total phenol than that of the healthy control, while had almost no difference in DIMBOA and CI. These findings suggested that the infestation of T. cinnabarinus could systematically induce accumulation of defense-related compounds, and this effect was stronger in the mite-tolerant inbred line than in the mite-sensitive inbred line.
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Benzoxazinas/análisis , Proteínas de Plantas/análisis , Tetranychidae/patogenicidad , Zea mays/química , Zea mays/parasitología , Animales , Quimotripsina/antagonistas & inhibidores , Femenino , Hojas de la Planta , Raíces de Plantas , PlantonesRESUMEN
Concerns have arisen regarding the risk of ischemic heart disease with the novel antiangiogenic agent bevacizumab, a recombinant humanised monoclonal antibody to the vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in ischemic heart disease is controversial. This meta-analysis was therefore performed to assess the overall risk of ischemic heart disease associated with the use of bevacizumab. The databases of PubMed, EMBASE and Web of Science were searched for English language studies of randomised controlled trials comparing bevacizumab with control therapy published through October 25, 2012. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 4,617 patients from 7 randomised controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%-1.4%). Patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with an RR of 2.49 (95% CI, 1.37-4.52) compared with controls. In addition, both high doses and low doses of bevacizumab increased the risk of cardiac ischemia (low dose at 2.5 mg/kg per week: RR, 2.14 [95% CI, 1.09-4.19]; high dose at 5 mg/kg per week: RR, 4.81 [95% CI, 1.03-22.42]). Bevacizumab was also found to significantly increase the risk of cardiac ischemia in patients with colorectal cancer (RR, 2.13; 95% CI, 1.11-4.06) compared with controls. This meta-analysis shows the use of bevacizumab was associated with an increased risk of developing ischemic heart disease in colorectal cancer patients receiving this drug. Our conclusions are limited by the available data. Further evaluations of high-quality RCTs are needed.
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Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Isquemia Miocárdica/inducido químicamente , Neoplasias/tratamiento farmacológico , Bevacizumab , Humanos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
BACKGROUND: Many studies have focused on the association between the apolipoprotein A5 (ApoA5) polymorphism and the risk of metabolic syndrome (MetS). However, these studies drew inconsistent conclusions. The aim of this study was to evaluate the exact association between the ApoA5 polymorphism and MetS in a large-scale meta-analysis. METHODS: The PubMed, Embase, and Science Citation Index (ISI Web of Science) databases were searched to collect all publications on the association between the ApoA5 polymorphism and MetS. Two common variants of ApoA5 (namely -1131T>C in the promoter region and c.56C>G in the coding region) with the risk of MetS were analyzed. The overall odd ratios (ORs) and 95% confidence intervals (CIs) for -1131T>C (CC+TC) versus TT genotype and c.C56G (GG+GC) versus CC were assessed between the MetS and control group. Subgroup analysis was further performed by ethnicity. The meta-analysis was performed by Stata11.0. RESULTS: Twelve studies from 10 publications were chosen in our meta-analysis. The combined results showed that C allele carriers (CC+TC) of -1131T>C had a significantly higher risk of MetS for the overall (OR=1.32; 95% CI: 1.14-1.53; p=0.000) with moderate heterogeneity (I2=54.9%, p=0.014). Subgroup analysis was further performed according to ethnicity, and the association was still significant in Asians (OR=1.42; 95% CI: 1.25-1.62; p=0.000), but not in white populations (OR=1.25; 95% CI: 0.97-1.61; p=0.087). When analyzing the association between c.C56G and MetS, the G allele carrier (GG+GC) genotype significantly increased the risk of MetS (OR=1.32; 95% CI: 1.15-1.50; p=0.000) in white populations. No significant publication bias was observed in either -1131T>C or c.C56G. CONCLUSIONS: Our study suggested that the ApoA5 -1131T>C polymorphism was significantly associated with the risk of MetS in Asians, but not in white populations. However, the c.C56G polymorphism was significantly associated with MetS in white populations.
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Apolipoproteínas A/genética , Predisposición Genética a la Enfermedad , Síndrome Metabólico/genética , Polimorfismo Genético , Adulto , Anciano , Apolipoproteína A-V , Pueblo Asiatico/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Población Blanca/genéticaRESUMEN
Growth arrest-specific gene 6 (GAS6) encodes a vitamin K-dependent protein that regulates inflammation, angiogenesis, and atherosclerotic plaque formation. The level of GAS6 expression is associated with plaque stability and stroke. We explored the role of GAS6 in cardiovascular disease, particularly in acute coronary syndrome (ACS). We determined the plasma levels of GAS6 protein by using an enzyme-linked immunosorbent assay method and investigated the role of the single nucleotide polymorphism (c.834+7G>A) in ACS. The median (interquartile range) plasma GAS6 levels were 16.9 microg/L (13-28 microg/L) in healthy control subjects and 10.65 microg/L (5.7-27.5 microg/L) in patients with ACS. The genotype frequencies for GG, AG, and AA, respectively, in patients with ACS were 66% (37/56), 29% (16/56), and 5% (3/56) and were 35% (14/40), 45% (18/40), 20% (8/40) in the control group. The AA genotype and A allele were less frequent in patients with ACS than in control subjects (P < .001). Our study indicates that GAS6 plasma concentrations at admission reflect the presence of common cardiovascular risk factors and can predict cardiovascular events. In addition, the AA genotype and A allele of the GAS6 gene relate to ACS, which may have a protective role against ACS.