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PURPOSE: The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. METHODS: A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 -1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. RESULTS: A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 -1639C>T, and POR*37 831-35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831-35C>T to warfarin dose variation was only 3.9 %. CONCLUSIONS: For the first time, the SNP POR*37 831-35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.
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Anticoagulantes/administración & dosificación , Pueblo Asiatico/genética , Sistema Enzimático del Citocromo P-450/genética , Modelos Biológicos , Warfarina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Warfarina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. METHODS: We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. RESULTS: Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40-1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%-0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. CONCLUSIONS: Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.
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Fibrilación Atrial/complicaciones , Insuficiencia Renal Crónica/complicaciones , Accidente Cerebrovascular/etiología , Tromboembolia/etiología , Tasa de Filtración Glomerular , Humanos , Insuficiencia Renal Crónica/fisiopatología , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Serious particulate matter (PM) pollution problems in many polluted regions of China have been frequently reported in recent years. Long-term exposure to ambient PM pollution is significantly associated with adverse health effects. Characterizing the long-term trends and variation in PM pollution is a basic requirement for evaluating long-term exposure and for guiding future policies to reduce the effects of air pollution on health. However, long-term, ground-based PM measurements are only available at a few fixed stations. In this study, an algorithm is developed and validated to estimate PM concentrations based on the satellite atmospheric optical depth with 1 km spatial resolution. The long-term trends of PM10 concentrations in the entire Pearl River Delta (PRD) region and different cities are quantified and discussed. From 2001 to 2013, the PM10 pollution of the entire PRD region was dominated by a decreasing trend of -0.15 ± 0.23 µg/m(3)·yr. This decreasing PM10 trend was apparent over 75% of the PRD area, with the most significant decreases observed in the center of the region. However, the remaining 25%, mostly located in the outskirts of the region, showed an increasing PM10 trend. This overall decreasing trend indicates the effectiveness of the control measures applied in the past decade for the primary pollutants.
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Contaminación del Aire/análisis , Material Particulado/análisis , Tecnología de Sensores Remotos/métodos , Algoritmos , China , Ciudades , Monitoreo del Ambiente/métodos , Reproducibilidad de los Resultados , Comunicaciones por SatéliteRESUMEN
BACKGROUND: Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose-response relationship exists. METHODS AND FINDINGS: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09-1.25) for ever smokers, 1.23 (95% CI 1.14-1.33) for current smokers, and 1.10 (95% CI 1.03-1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%-11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%-8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24-1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%-12.3%) for ever smoking, 5.8% (95% CI 3.6%-8.2%) for current smoking, and 2.7% (95% CI 0.8%-4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4-26.7) cases per 100,000 person-years. CONCLUSIONS: Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE. Please see later in the article for the Editors' Summary.
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Fumar/efectos adversos , Tromboembolia Venosa/etiología , Estudios de Casos y Controles , Estudios de Cohortes , Heterogeneidad Genética , Humanos , Incidencia , Factores de Riesgo , Tromboembolia Venosa/epidemiologíaRESUMEN
Few of the current methods of improving air quality, including end-pipe treatment, industrial, energy and transportation structure adjustments, are from the viewpoint of the spatial pattern optimization of pollutant emissions. Therefore, based on factors such as natural environment, human health, pollutant transmission capability, and meteorological diffusion conditions, our research group used the threshold approach, natural breaks, spatial erasure, and other methods to define the layout area suitable for atmospheric pollution sources. Based on these results, the emissions pattern was optimized to achieve air quality improvement. Taking Guangdong Province as an example, we examined the application of the emissions pattern optimization of air quality improvement and atmospheric environment zoning. The results indicate that the first class area of environmental air quality accounts for 9% of total province area, the densely populated area accounts for 3%, the sensitive area of the national air quality monitor stations accounts for 15%, the pollutant accumulation area accounts for 22%, and the layout area suitable for atmospheric pollution sources primarily distributed in the west part of the province accounts for 60%. By shifting the non-thermal power industrial sources into those area, the concentration level of PM2.5 will decrease by 4% at the provincial scale and 10% at the city scale. Emissions pattern optimization has become an innovative aided support technology for the continuous improvement of air quality. In practical applications, it can be combined with energy and industrial structure adjustments, pollution control technology enhancements, and cross-regional prevention and control to formulate the most feasible air quality improvement plan.
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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Genetic polymorphisms of VKORC1 and CYP2C9 are known to influence warfarin dosage. * Recent studies among Caucasians showed that polymorphisms of CYP4F2 also play a role in warfarin pharmacogenetics. * The contribution of CYP4F2 variants to the variability inwarfarin dose requirement in Chinese subjects remains to be investigated. WHAT THIS STUDY ADDS * This research was to study the effect of CYP4F2 variants on warfarin requirements in the Han Chinese population. * This study developed a multiple regression model including CYP2C9, VKORC1 3673G>A, CYP4F2 genotypes and age, weight, combination use of amiodarone which could explain 56.1% of the individual variability in warfarin dose CYP4F2 could explain 4% of the variance in warfarin dose. * We found that one novel genotypic polymorphism 5417G>T for Asp36Tyr, which was identified as an important marker of warfarin resistance, was absent in the Han Chinese population in our study. AIMS The objective of this study was to assess the effect of the CYP4F2 on the daily stable warfarin dose requirement in Han Chinese patients with mechanical heart valve replacement (MHVR). METHODS From March 2007 to November 2008, 222 Han Chinese MHVR patients were recruited in our study. VKORC1 3673G>A, 5417G>T, CYP2C9*3 and CYP4F2 rs2108622 were genotyped by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Polymorphisms of VKORC1 9041G>A were detected by direct sequencing. Multiple linear regression analysis was used to investigate the contribution of CYP4F2. RESULTS The CYP4F2 rs2108622 CT/TT group took a significantly higher stable warfarin dose (3.2 mg day(-1)) than the CC group (2.9 mg day(-1), 95% CI 0.2, 1.0, P= 0.033). The multiple linear regression model included VKORC1 3673G>A, CYP2C9, CYP4F2 genotypes and clinical characteristics. The model could explain 56.1% of the variance in stable warfarin dose in Han Chinese patients with MHVR. CYP4F2 contributed about 4% to the variance in the warfarin dose. There was no variation in the SNPs of VKORC1 5417G>T. CONCLUSION CYP4F2 is a minor significant factor of individual variability in the stable warfarin dose in Han Chinese patients with MHVR. The effect of CYP2C9 and VKORC1 genotypes on variability in the stable warfarin dose had also been confirmed.
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Anticoagulantes/administración & dosificación , Sistema Enzimático del Citocromo P-450/genética , Genotipo , Implantación de Prótesis de Válvulas Cardíacas , Warfarina/administración & dosificación , Adulto , Alelos , Hidrocarburo de Aril Hidroxilasas/genética , Pueblo Asiatico/genética , China , Citocromo P-450 CYP2C9 , Familia 4 del Citocromo P450 , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia de los Genes , Válvulas Cardíacas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Análisis de Secuencia de ADN , Vitamina K Epóxido ReductasasRESUMEN
OBJECTIVE: To explore the effects of Angiotensin (ANG)-(1-7) on postangioplasty fibrotic remodeling and the involvement of TGF-beta/Smad signaling pathway in this process. METHODS: Thirty two healthy New Zealand white rabbits were randomly divided into 4 groups: sham group, control group, ANG-(1-7) group and ANG-(1-7) + A-779 group. Rabbits underwent angioplasty in the abdominal aorta or sham surgery. Subsequently, an osmotic minipump was implanted for saline, ANG-(1-7) (576 microg x kg(-1) x d(-1)) or ANG-(1-7) + A-779 (576 microg x kg(-1) x d(-1)) delivery. Before and after 4 weeks treatment, the levels of ANG II in plasma were measured by ELISA. At week 4, angiography and histomorphometric analysis were performed, mRNA levels of collagen I and III were assayed by RT-PCR and protein levels of TGF-beta1 and Smad2 in local vessel were assayed by Western blot. RESULTS: Following 4 weeks treatment, ANG-(1-7) and ANG-(1-7) + A-779 group displayed a significant elevation in lumen diameter [(4.11 +/- 0.10) mm and (3.34 +/- 0.11) mm vs. (2.88 +/- 0.08) mm, P < 0.05, respectively] and reduction in neointimal thickness [(208 +/- 17) microm and (407 +/- 25) microm vs. (448 +/- 15) microm, P < 0.05, respectively], neointimal area [(0.27 +/- 0.09) mm2 and (0.38 +/- 0.01) mm2 vs. (0.41 +/- 0.02) mm2, P < 0.05, respectively] and restenosis rate [(28.1 +/- 2.7)% and (36.8 +/- 2.2)% vs. (40.1 +/- 2.7)%, P < 0.05, respectively] compared with control group. Collagen I, III mRNA and TGF-beta1, Smad2 protein levels were significantly elevated in control group, ANG-(1-7) group and ANG-(1-7) +A-779 group compared to sham group (P < 0.01 or P < 0.05) and reduced in ANG-(1-7) group compared to control group (all P < 0.05). Co-treatment with A-779 reversed the inhibitory action of ANG-(1-7). Plasma levels of ANG II postangioplasty were similar in control and ANG-(1-7) group and both were significantly higher than preoperation levels. CONCLUSION: ANG-(1-7) attenuates postangioplasty collagen synthesis in rabbits possibly through down-regulating the expression of TGF-beta1 and inhibiting the activation of Smad2 pathway.
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Angiotensina I/farmacología , Aorta Abdominal/efectos de los fármacos , Fibrosis/metabolismo , Músculo Liso Vascular/metabolismo , Fragmentos de Péptidos/farmacología , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Conejos , Transducción de Señal , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: Angiotensin-(1-7) [ANG-(1-7)] has been reported to attenuate neointimal formation after vascular injury and stent implantation in rats, but the mechanism remains mostly unresolved. Interestingly, the levels of circulating transforming growth factor-beta1 (TGF-beta1) after myocardial infarction were suppressed by ANG-(1-7), which suggests a possible downstream target for the anti-remodeling action of ANG-(1-7). Our study focused on the effects of ANG-(1-7) on vascular remodeling, including neointimal formation and collagen synthesis, and determining whether or not these effects were dependent upon the TGF-beta signaling pathway. METHODS: Thirty-two New Zealand white rabbits underwent sham surgery or angioplasty in abdominal aorta. The animals were divided into four groups, which were sham, control, ANG-(1-7), and ANG-(1-7)+A-779. Subsequently, an osmotic minipump was implanted to deliver saline, ANG-(1-7) (576 microg kg(-1)d(-1)) or ANG-(1-7)+A-779 (576 microg kg(-1)d(-1)) for 4 weeks. RESULTS: The ANG-(1-7) group displayed a significant reduction in neointimal thickness (207.51+/-16.70 microm vs. 448.08+/-15.30 microm, P<0.001), neointimal area (0.266+/-0.009 mm(2) vs. 0.408+/-0.002 mm(2), P<0.001), and restenosis rate (28.13+/-2.74% vs. 40.13+/-2.74%, P<0.001) when compared to the control group. ANG-(1-7) also inhibited collagen synthesis by significantly decreasing the mRNA expression of Collagen I and Collagen III (vs. CONTROL GROUP: 0.2190+/-0.0036 vs. 0.3852+/-0.0212, P<0.001 and 1.1328+/-0.0554 vs. 1.7378+/-0.1164, P<0.001, respectively). Furthermore, the expression of TGF-beta1 and phosphor-Smad2 (p-Smad2) were significantly suppressed by ANG-(1-7) (vs. CONTROL GROUP: 1.21+/-0.07 vs. 1.54+/-0.08, P<0.001 and 0.31+/-0.01 vs. 0.43+/-0.02, P<0.001, respectively), but no effect on p38 phosphorylation was observed. [d-Ala(7)]-ANG-(1-7) (A-779), showed a tendency to attenuate the anti-remodeling effects of ANG-(1-7). CONCLUSION: ANG-(1-7) decreases the amount of vascular remodeling, including a reduction in neointimal formation and collagen synthesis, after angioplasty in rabbits. The responsible mechanism may function through the possible down-regulation of TGF-beta1 levels and inhibition of the Smad2 pathway.
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Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/cirugía , Regeneración/efectos de los fármacos , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Túnica Íntima/efectos de los fármacos , Angioplastia , Animales , Aorta Abdominal/fisiología , Presión Sanguínea/efectos de los fármacos , Colágeno Tipo I/biosíntesis , Colágeno Tipo III/biosíntesis , Frecuencia Cardíaca/efectos de los fármacos , Conejos , Ratas , Proteína Smad2/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Túnica Íntima/fisiología , Túnica Íntima/cirugíaRESUMEN
Based on observational data for pollutants and meteorology, this study analyzed the pollution episode that occurred during Dec 17th to 23th in 2018 in Zhaoqing, Guangdong Province, China. Using the source apportionment model CMAQ-ISAM and the hybrid receptor model, the regional contributions to air pollution were examined. The results showed that low-pressure conditions had an adverse effect on the diffusion of pollutants during this pollution episode in Zhaoqing. Prior to the pollution episode, pollutants were mainly derived from Zhaoqing and Qingyuan, accounting for 19.2% and 10.7% of pollutants, respectively. As well as pollutants from Guangdong Province, long-distance transport of pollutants from Jiangxi, Hunan, Hubei, and Shaanxi accounted for approximately 64.5% of the total during the non-pollution period. During the polluted episode, major cities in Pearl River Delta and the eastern part of Guangdong Province contributed more pollutants as a surface high-pressure field moved southward. Zhaoqing, Foshan, Dongguan, Guangzhou, and Huizhou contributed 25.5%, 14.8%, 9.8%, 9.5%, and 5.3% of the pollutants, respectively. Cities in the eastern part of Guangdong Province including Heyuan, Meizhou, Shanwei, Jieyang, Shantou, and Chaozhou contributed 13.7% of the total pollutants. In addition, pollutants from Fujian, Jiangxi, and the Yangtze River Delta accounted for approximately 32.9%. Furthermore, pollutants transported under marine influences were one of the main causes of this pollution episode in Zhaoqing.
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An emission inventory of atmospheric pollutants from crop residue burning in Guangdong for the period 2008-2016 was developed, based on crop yield data. Emissions of species of volatile organic compounds(VOCs)and corresponding ozone formation potential (OFP) in 2016 were also estimated. Results showed that emissions of atmospheric pollutants from crop residue burning in 2013-2016 were lower than in 2008-2012. This was mainly due to the policy of prohibiting open burning of straw and to improvement of rural living standards, which reduced the proportion of straw burning. In 2016, emissions of SO2, NOx, NH3, CH4, EC, OC, NMVOC, CO, and PM2.5 were 2443.7, 16187.9, 6943.8, 29174.4, 3625.5, 14830.7, 65612.6, 591613.9, and 49463.0 t, respectively. Rice straw burning was the main source of pollutants, accounting for about 68.55% of total pollutant emissions. The five municipalities with highest atmospheric pollutant emissions were Zhanjiang, Maoming, Meizhou, Zhaoqing, and Shaoguan, together accounting for about 58.63% of total emissions. The top 10 VOC species for mass-based emissions consisted of ethylene, acetaldehyde, formaldehyde, benzene, ethyne, propylene, ethane, toluene, propane, and propionaldehyde, together contributing 67.91% to total emissions. The top ten OFP-based VOC species were ethylene, formaldehyde, acetaldehyde, propylene, 1-butylene, propionaldehyde, toluene, acrolein, isoprene, and crotonaldehyde, accounting for 80.83% of total OFP.
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Atmospheric environmental capacity is an important reference in environmental planning. To meet the PM2.5 standard, a new method is proposed to balance the capacity among cities of Guangdong, with screening of the most unfavorable meteorological year and combining it with the regional transportation calculated by the CAMx-PSAT module. Pollutant overloading and capacity scenarios were also calculated. The results showed that, under the constraints of the cities' annual PM2.5 ≤ 35 µg·m-3, the capacities of SO2, NOx, NH3, and PM2.5 in Guangdong were about 6.8×105 tons, 1.35×106 tons, 4.6×105 tons, and 5.1×105 tons, respectively. Based on the benchmark scenario, SO2 emissions in Guangdong were overloaded by 10%, and the emissions of NOx, NH3, and PM2.5 exceeded by 12%, 9%, and 20%, respectively, compared to those of the capacity scenario. Ranked by the number of overloaded species in Guangdong, the cities of Guangzhou, Foshan, Zhongshan, and Qingyuan were on top. When achieving the capacity scenario, the annual PM2.5 concentration in Guangdong was about 30 µg·m-3, which meets the national secondary ambient air quality standard.
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To meet the requirements of regional air quality management (AQM), the Air Quality Subarea Management (AQSM) system was proposed. A case study was conducted for Guangdong Province. By using the method of air quality numerical simulation and satellite remote sensing inversion analysis, the key factors were selected from the meteorological simulation field, the pollutant concentration simulation field, and the satellite image interpretation to form the index system for AQSM. On this basis, a hierarchical cluster analysis method was used to divide Guangdong Province into three types of AQSM:Strict Control Subarea, Continuous Improvement Subarea, and Coordinated Development Subarea. It was shown that the Strict Control Subarea, Continuous Improvement Subarea, and Coordinated Development Subarea in Guangdong Province covered 16.3%, 28.0%, and 55.7%, respectively. The Strict Control Subarea in the Pearl River Delta, Eastern Guangdong, Western Guangdong, and Northern Guangdong accounted for 27.9%, 19.3%, 4.4%, and 12.5%, respectively, and the subarea should implement the most stringent AQM policies to promote air quality improvement. The Continuous Improvement Subarea in the Pearl River Delta, Eastern Guangdong, Western Guangdong, and Northern Guangdong accounted for 34.4%, 15.8%, 7.8%, and 34.5%, respectively, and the subarea should implement relatively strict AQM policies to ensure sustained and stable standards. The Coordinated Development Subarea in the Pearl River Delta, Eastern Guangdong, Western Guangdong, and Northern Guangdong accounted for 37.7%, 64.9%, 87.8%, and 53.0%, respectively, and the subarea could implement more liberal AQM policies to ensure relatively good air quality. In general, the strict AQM policies in Guangdong Province should be mainly concentrated in the Pearl River Delta region, followed by Northern Guangdong, Eastern Guangdong, and Western Guangdong in order.
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The transplantation of mesenchymal stem cells (MSCs) has been a reported method for alleviating atherosclerosis (AS). Because the availability of bone marrowderived MSCs (BMMSCs) is limited, the authors used this study to explore the use of a new type of MSC, human induced pluripotent stem cellderived MSCs (iPSCMSCs), to evaluate whether these cells could alleviate AS. iPSCMSCs were intravenously administered to ApoE knock out mice fed on a highfat diet (HFD) for 12 weeks. It was reported that systematically administering iPSCMSCs clearly reduced the size of plaques. In addition, the numbers of macrophages and lipids in plaques were lower in the HFD + iPSCMSCs group than in the HFD group. Furthermore, iPSCMSCs attenuated ASassociated inflammation by decreasing the levels of inflammatory cytokines, such as tumor necrosis factorα and interleukin6, in serum. In addition, the expression of Notch1 was higher in the HFD group, and injecting iPSCMSCs reversed this effect. In conclusion, the current study provides the first evidence indicating that iPSCMSCs may be a new optional MSCbased strategy for treating AS.
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Aterosclerosis/terapia , Células Madre Pluripotentes Inducidas/citología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Animales , Aterosclerosis/sangre , Aterosclerosis/complicaciones , Aterosclerosis/inmunología , Células Cultivadas , Citocinas/sangre , Citocinas/inmunología , Humanos , Células Madre Pluripotentes Inducidas/inmunología , Inflamación/sangre , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/terapia , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide mainly generated from cleavage of Angâ and Angâ ¡, possesses physiological and pharmacological properties, including antiinflammatory and antidiabetic properties. Activation of the phosphoinositide 3-kinase and protein kinase B (PI3K̸Akt) signaling pathway has been confirmed to participate in cardioprotection against hyperglycaemia-induced injury. The aim of the present study was to test the hypothesis that Ang-(1-7) protects H9c2 cardiomyoblast cells against high glucose (HG)-induced injury by activating the PI3K̸Akt pathway. To examine this hypothesis, H9c2 cells were treated with 35 mmol/l (mM) glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. The cells were co-treated with 1 µmol/l (µM) Ang-(1-7) and 35 mM glucose. The findings of the present study demonstrated that exposure of H9c2 cells to HG for 24 h markedly induced injury, as evidenced by an increase in the percentage of apoptotic cells, generation of reactive oxygen species and level of inflammatory cytokines, as well as a decline in cell viability and mitochondrial luminosity. These injuries were significantly attenuated by co-treatment of the cells with Ang-(1-7) and HG. In addition, PI3K̸Akt phosphorylation was suppressed by HG treatment, but this effect was abolished when the H9c2 cells were co-treated with Ang-(1-7) and HG. Furthermore, the cardioprotection of Ang-(1-7) against HG-induced injury in H9c2 cardiomyoblasts was highly attenuated in the presence of either D-Ala7-Ang-(1-7) (A-779, an antagonist of the Mas receptor) or LY294002 (an inhibitor of PI3K̸Akt). In conclusion, the present study provided new evidence that Ang-(1-7) protects H9c2 cardiomyoblasts against HG-induced injury by activating the PI3K̸Akt signaling pathway.
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Angiotensina I/farmacología , Cardiotónicos/farmacología , Hiperglucemia/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Fragmentos de Péptidos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citoprotección/efectos de los fármacos , Glucosa/toxicidad , Inflamación/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Subsequently to the publication of this article, the authors have realized that an address affiliation associated with certain of the authors had been omitted. The authors' affiliation information should have appeared as follows (the omitted address affiliation is featured in bold): YiYing Yang1,2*, XiuTing Sun1,2*, ZhengXun Li1,2, WeiYan Chen3, Xiang Wang4, MeiLing Liang5, Hui Shi1,2, ZhiSheng Yang1,2 and WuTao Zeng1,2 1Department of Cardiology, The First Affiliated Hospital, Sun YatSen University; 2Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, Guangdong 510080; 3Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260; 4Department of Cardiology, Laiwu City People's Hospital, Laiwu, Shandong 27110; 5Department of Cardiology, Sun YatSen Cardiovascular Hospital, Shenzhen, Guangdong 518020, P.R. China *Contributed equally. The authors regret this error in the affiliations, and apologize for any inconvenience caused. [the original article was published in the International Journal of Molecular Medicine 41: 12831292, 2018; DOI: 10.3892/ijmm.2017.3322].
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OBJECTIVE: To investigate the effect of telmisartan on the protein and gene expression of angiotensin-converting enzyme-2 (ACE2) in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were treated with various concentrations of telmisartan (10(-7), 10(-6) and 10(-5) mol/L) for 24 hours. In a time-control experiment, HUVECs were treated with telmisartan at the final concentration of 10(-6) mol/L for 6, 12 and 24 hours, respectively. In another experiment, HUVECs were treated with PD123319 (10(-6) mol/L) only or combined with same final concentration of telmisartan for 12 hours, respectively. Changes in both protein and gene expression of ACE2 were determined with Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) technique, respectively. RESULTS: Telmisartan induced a concentration and time dependent increase in both protein and gene expression of ACE2 (P<0.05 or P<0.01). Compared with control group, treatment of HUVECs with telmisartan at the concentration of 10(-7), 10(-6) and 10(-5) mol/L stimulated 1.5-, 2.7- and 4.6-fold increase in the ACE2 protein expression, as well as 1.2-, 2.3- and 4.5-fold increase in its gene expression, respectively. After treatment of HUVECs with telmisartan for 6, 12, and 24 hours at the concentration of 10(-6) mol/L, the ACE2 protein expression increased 1.6-, 2.7- and 4.2-fold, and its gene expression increased 1.3-, 2.3- and 4.0-fold, respectively. Compared with control and telmisartan groups, PD123319 had no effect on both protein and gene expression of ACE2 (P>0.05). CONCLUSION: Telmisartan up-regulates the protein and gene expression of ACE2 in HUVECs in a concentration and time dependent manner. This effect may be mediated via its specific pathway.
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Bencimidazoles/farmacología , Benzoatos/farmacología , Células Endoteliales/enzimología , Endotelio Vascular/citología , Peptidil-Dipeptidasa A/metabolismo , Enzima Convertidora de Angiotensina 2 , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Expresión Génica , Humanos , Peptidil-Dipeptidasa A/genética , ARN Mensajero/genética , Telmisartán , Venas Umbilicales/citología , Regulación hacia ArribaRESUMEN
BACKGROUND: The safety and long-term outcome of systemic thrombolysis in patients receiving antiplatelet medications remain subjects of great clinical significance. The objective of this meta-analysis was to determine how prestroke antiplatelet therapy affects the risks and benefits of intravenous thrombolysis in patients with acute ischemic stroke. METHODS AND RESULTS: A dual-reviewer search was conducted in PubMed and EMBASE databases through November 2015, from which 19 studies involving a total of 108 588 patients with acute ischemic stroke were identified based on preset inclusion criteria. Information on study designs, patient characteristics, exposures, outcomes, and adjusting confounders was extracted, and estimates were combined by using random-effects models. The pooled crude estimates suggested that taking long-term antiplatelet medications was associated with higher odds of symptomatic intracranial hemorrhage (odds ratio [OR] 1.70, 95% CI 1.47-1.97) and death (OR 1.46, 95% CI 1.22-1.75) and lower odds of favorable functional outcomes (OR 0.86, 95% CI 0.80-0.93). However, the combined confounder-adjusted results only confirmed a relatively weak positive association between prior antiplatelet therapy and symptomatic intracranial hemorrhage (OR 1.21, 95% CI 1.02-1.44) and demonstrated no significant relationship between antiplatelet therapy and the other 2 outcomes (favorable outcome OR 1.09, 95% CI 0.96-1.24; death OR 1.02, 95% CI 0.98-1.07). Subgroup analyses revealed that the associations between prestroke antiplatelet therapy and outcomes were dependent on time and antiplatelet agents. CONCLUSIONS: Patients with acute ischemic stroke receiving long-term antiplatelet medications were associated with greater risks of developing symptomatic intracranial hemorrhage after systemic thrombolysis. However, the overall independent association between prestroke antiplatelet therapy and unfavorable outcomes or mortality was insignificant.
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Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Hemorragias Intracraneales/epidemiología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica/métodos , Activador de Tejido Plasminógeno/uso terapéutico , Administración Intravenosa , Isquemia Encefálica/complicaciones , Humanos , Hemorragias Intracraneales/inducido químicamente , Oportunidad Relativa , Factores de Riesgo , Accidente Cerebrovascular/etiologíaRESUMEN
Digoxin has long been used for rate control in atrial fibrillation (AF); its safety remains controversial.We performed a literature search using MEDLINE (source PubMed, January 1, 1966, to July 31, 2015) and EMBASE (January 1, 1980, to July 31, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. Pooled effect estimates were obtained by using random-effects meta-analysis.Twenty-two studies involving 586,594 patients were identified. Patients taking digoxin, as compared with those who took no digoxin, experienced an increased risk of death from any cause (RR: 1.29[95% CI 1.16-1.43]), even after reported adjustment for propensity scores (RR: 1.28[95% CI 1.18-1.39]). The risk of death was increased with patients with or without heart failure (RR: 1.12[95% CI 1.02-1.23] and RR: 1.26[95% CI 1.15-1.29], respectively), and patients taking or not taking beta blockers (RR: 1.17 [95% CI 1.06-1.30] and RR: 1.28 [95% CI 1.08-1.51], respectively). Digoxin use was also associated with increased risk of cardiovascular death (RR: 1.32 [95% CI 1.07-1.64]), arrhythmic death (RR: 1.38 [95% CI 1.07-1.79]), and stroke (RR: 1.20 [95% CI 1.004-1.44]). Digoxin treatment is associated with an absolute risk increase of 19 (95% CI 13-26) additional deaths from any cause per 1000 person-years.Digoxin use is associated with a significant increased risk for death from any cause in patients with AF. This finding suggests a need for reconsideration of present treatment recommendations on use of digoxin in AF.
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Fibrilación Atrial/tratamiento farmacológico , Digoxina/efectos adversos , Digoxina/uso terapéutico , Fibrilación Atrial/mortalidad , Causas de Muerte , Humanos , Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Chronic heart failure (CHF) is associated with calcium transients and calcium handling proteins. Angiotensin converting enzyme (ACE) inhibitor has been demonstrated to have beneficial effect on CHF. Yet studies addressed to the relationship between ACE inhibitor and calcium transients in CHF are rare. The aim of this study was to investigate the influence of ACE inhibitor (perindopril) on the contractility and calcium transients and calcium handling proteins in ventricular myocytes from rats with experimental heart failure. METHODS: Male Wistar rats were randomized to heart failure group treated with perindopril [CHF-T, 3 mg.kg(-1).d(-1)], heart failure group without treatment (CHF-C) and sham-operated group (PS). Heart failure was induced by abdominal aortic constriction. All groups were further followed up for 12 weeks. Left ventricular myocytes were then isolated. Single cell shortening fraction and [Ca(2+)]i were simultaneously measured by laser scanning confocal microscope under the field stimulation (1.0 Hz). Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate the changes of mRNA and protein of Na(+)-Ca(2+) exchanger (NCX1), sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) and phospholamban (PLB). RESULTS: The fraction of cell shortening (FS%) and [Ca(2+)]imax (nmol/L) were significantly reduced in group CHF-C compared with group PS (FS%: 7.51 +/- 1.15 vs 13.21 +/- 1.49; [Ca(2+)]i max: 330.85 +/- 50.05 vs 498.16 +/- 14.07; both P < 0.01), and restored at least partially in CHF-T group. In CHF-C group, the left ventricular mRNA of NCX1 and PLB were significantly upregulated in comparing with PS group (RNCX1/beta-Actin: 0.51 +/- 0.12 vs 0.19 +/- 0.06, P < 0.01; RPLB/beta-Actin: 0.26 +/- 0.12 vs 0.20 +/- 0.08, P < 0.05), while SERCA2 mRNA was downregulated (0.48 +/- 0.10 vs 0.80 +/- 0.11, P < 0.01). The mRNA levels of NCX1 and SERCA2 in CHF-T group were between the CHF-C and PS group, and the differences of the latter two groups were significant (all P < 0.05). In CHF-C and CHF-T groups, the protein expression of NCX1 were 1.141 +/- 0.047 and 1.074 +/- 0.081 times of that in PS group respectively (both P < 0.05), and SERCA2 protein levels were 0.803 +/- 0.100 and 0.893 +/- 0.084 times of that in PS group respectively (both P < 0.05). The protein expression of NCX1 and SERCA2 in the CHF-C and CHF-T groups is significantly different (both P < 0.05). CONCLUSION: ACE inhibitor could improve cardiac function of failing heart through directly enhancing the contractility of single cardiomyocyte, and these effects are probably mediated by its roles in preventing the deleterious changes of calcium transients and calcium handling proteins in CHF.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Calcio/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Perindopril/farmacología , Animales , Proteínas de Unión al Calcio/genética , ATPasas Transportadoras de Calcio/genética , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Masculino , Miocitos Cardíacos/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Wistar , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Intercambiador de Sodio-Calcio/genéticaRESUMEN
OBJECTIVE: To test the hypothesis that chronic administration of angiotensin-(1-7) [Ang-(1-7)] attenuates cardiac hypertrophy in rats in vivo. METHODS: Coarctation of the suprarenal abdominal aorta was performed in 41 8-week-old male Sprague Dawley rats. Twenty-four hours after the operation, osmotic minipumps were surgically implanted subcutaneously in the rats, which were randomly divided into 3 groups, including a sham-operation group (n=15) receiving infusion with normal saline, a suprarenal aortic coarctation group (n=12), and a suprarenal aortic coarctation group (n=14) with Ang-(1-7) treatment at the dose of 25 mug x kg(-1) x h(-1). Four weeks later, the systolic and diastolic blood pressures were measured and the left ventricular mass index (LVMI, mg/g) was calculated from the ratio of left ventricular weight to body weight. The concentrations of Ang II in the plasma and myocardium were measured by radioimmunoassay, and myocardial interstitial collagen volume fraction (ICVF) was determined by quantitative morphometry of the sections with Picrosirius red staining using an automated image analyzer. RESULTS: Suprarenal abdominal aortic coarctation induced a significant increase in carotid artery systolic and diastolic blood pressure, heart weight, LVMI, ICVF, and the concentration of Ang II in the myocardium (P<0.01). Chronic administration of Ang-(1-7) attenuated the increase in the heart weight, LVMI, ICVF and left ventricular diastolic end pressure (LVEDP) caused by suprarenal abdominal aortic coarctation (P<0.05). Ang-(1-7) also increased the formerly decreased maximum left ventricular pressure reduction rate (-dP/dt(max)) (P<0.05), but had no effect on blood pressure and the concentration of Ang II in the myocardium. No difference was noted in plasma concentration of Ang II between the 3 groups. CONCLUSIONS: Ang-(1-7) attenuates cardiac hypertrophy and fibrosis and preserved the impaired left ventricular function induced by left ventricular pressure-overload in rats. These effects are not associated with the changes in the concentrations of Ang II in the left ventricular myocardium and plasma.