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1.
EuroIntervention ; 17(13): 1112-1119, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-34219664

RESUMO

BACKGROUND: An atrial septal occluder (ASO) represents a major obstacle to the widespread adoption of atrial fibrillation (AF) catheter ablation in patients with prior atrial septal defect (ASD) closure. AIMS: The aim of this study was to describe the 'sequential technique' of transseptal puncture (TSP) in AF patients with ASO. METHODS: Sixty-four drug-refractory AF patients with ASO who underwent catheter ablation in our centre from September 2007 to March 2020 were enrolled. RESULTS: Puncture through the native septum was achieved in 29 patients (Group A) and through the device in 35 patients (Group B). The mean diameter of the occluder was significantly larger in Group B than in Group A (31.6±4.6 mm vs 22.8±3.5 mm, p<0.001). The mean time of TSP (24.9±8.8 vs 5.8±2.1 min, p<0.001), total fluoroscopy time (23.7±10.9 vs 7.5±4.4 min, p<0.001), and total procedure time (172.7±58.3 vs 123.4±43.8 min, p=0.001) of Group B were significantly longer than those of Group A. In Group B, the external sheath crossed the device by reshaping the needle and adjusting the puncture angle and position in 23 patients (Group B1), while the external sheath crossed the device with the assistance of balloon dilation in 12 patients (Group B2). No patient had thrombus, periprocedural interatrial shunt or procedural complications. CONCLUSIONS: TSP and AF ablation in patients with ASO are feasible and safe. The 'sequential technique' could be safely used in patients with ASO.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Comunicação Interatrial , Dispositivo para Oclusão Septal , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Comunicação Interatrial/cirurgia , Humanos , Punções , Resultado do Tratamento
2.
Clin Cardiol ; 44(10): 1422-1431, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34318505

RESUMO

BACKGROUND: Atrial fibrillation (AF) and stable coronary artery disease (SCAD) frequently coexist. HYPOTHESIS: To investigate the prognosis of catheter ablation versus drug therapy in patients with AF and SCAD. METHODS: In total, 25 512 patients with AF in the Chinese AF Registry between 2011 and 2019 were screened for SCAD. 815 patients with AF and SCAD underwent catheter ablation therapy were matched with patients by drug therapy in a 1:1 ratio. Primary end point was composite of thromboembolism, coronary events, major bleeding, and all-cause death. The secondary endpoints were each component of the primary endpoint and AF recurrence. RESULTS: Over a median follow-up of 45 ± 23 months, the patients in the catheter ablation group had a higher AF recurrence-free rate (53.50% vs. 18.41%, p < .01). In multivariate analysis, there was no significant difference between the strategy of catheter ablation and drug therapy in primary composite end point (adjusted HR 074, 95%CI 0.54-1.002, p = .0519). However, catheter ablation was associated with fewer all-cause death independently (adjusted HR 0.36, 95%CI 0.22-0.59, p < .01). In subgroup analysis, catheter ablation was an independent risk factor for all-cause death in the high-stroke risk group (adjusted HR 0.39, 95%CI 0.23-0.64, p < .01), not in the low-medium risk group (adjusted HR 0.17, 95%CI 0.01-2.04, p = .17). CONCLUSIONS: In the patients with AF and SCAD, catheter ablation was not independently associated with the primary composite endpoint compared with drug therapy. However, catheter ablation was an independent protective factor of all-cause death.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Doença da Artéria Coronariana , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Estudos de Coortes , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Humanos , Prognóstico , Estudos Prospectivos , Recidiva , Fatores de Risco , Resultado do Tratamento
3.
J Cardiovasc Electrophysiol ; 32(7): 1849-1856, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34028114

RESUMO

INTRODUCTION: Linear ablation in addition to pulmonary vein antrum isolation (PVAI) has failed to improve the success rate for persistent atrial fibrillation (PeAF), due to incomplete block of ablation lines, especially in the mitral isthmus (MI). METHODS AND RESULTS: The study enrolled 191 patients (66 in group 1 and 125 in group 2). In group 1, ethanol infusion into the vein of Marshall was first performed, followed by radiofrequency (RF) applications targeting bilateral PVAI and bidirectional block in the roofline, cavotricuspid isthmus, and MI. In group 2, PVAI and the three linear ablations were completed using only RF energy. MI block was achieved in 63 (95.5%) and 101 (80.8%) patients in groups 1 and 2, respectively (p = .006). Patients in group 1 had shorter ablation time for left pulmonary vein antrum (8.15 vs. 12.59 min, p < .001) and MI (7.0 vs. 11.8 min, p < .001) and required less cardioversion (50 [78.5%] vs. 113 [90.4%], p = .007). During the 12-month follow-up, 58 (87.9%) patients were free from atrial fibrillation/atrial tachycardia in group 1 compared with 81 (64.8%) in group 2 (p < .001). In multivariate cox regression, the "upgraded 2C3L" procedure is associated with a lower recurrence rate (hazard ratio = 0.27, 95% confidence interval = 0.12-0.59). CONCLUSION: Compared with the conventional "2C3L" approach, the "upgraded 2C3L" approach has higher effectiveness for ablation of PeAF.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Etanol/efeitos adversos , Humanos , Veias Pulmonares/cirurgia , Recidiva , Taquicardia , Resultado do Tratamento
4.
Pacing Clin Electrophysiol ; 44(5): 773-781, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32856303

RESUMO

BACKGROUND: Catheter ablation of perimitral atrial tachycardia (PMAT) is challenging. Epicardial conduction of the Marshall bundle (MB) across the mitral isthmus (MI) remains an important cause of recurrent tachycardia. The role of ethanol infusion into the vein of Marshall (EI-VOM) for PMAT has not been fully elucidated. METHODS: The study enrolled 28 consecutive patients with recurrent PMAT after atrial fibrillation (AF) ablation. Conventional PMAT (group 1, n = 15) and MB-related PMAT (group 2, n = 13) were diagnosed by detailed activation mapping and entrainment mapping. VOM venography and EI-VOM were first performed, and additional ablation was performed if necessary. RESULTS: The VOM was accessible in 24 (85.7%) patients (12 [80%] in group 1 and 12 [92.3%] in group 2). Patients with MB-related PMAT were more responsive to EI-VOM (as shown by PMAT termination or tachycardia cycle length prolongation) (92.4% vs 53.3%, P = .038). In the 16 patients requiring additional ablation after EI-VOM, all residual MI conduction gaps were located on the annular side of the MI. At the end of the procedure, MI bidirectional block was achieved in 14 (93.3%) patients in group 1 and in 12 (92.3%) patients in group 2 (P = 1.000). After a mean follow-up of 7.5 ± 3.1 months, three (10.7%) patients had recurrent AT. CONCLUSIONS: EI-VOM is feasible and effective in the treatment of PMAT after AF ablation, especially in patients with MB-related PMAT.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Etanol/administração & dosagem , Taquicardia Supraventricular/tratamento farmacológico , Idoso , Angiografia Coronária , Mapeamento Epicárdico , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Recidiva , Taquicardia Supraventricular/fisiopatologia
5.
Europace ; 22(11): 1712-1717, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830238

RESUMO

AIMS: Accessory pathways (APs) successfully ablated at the aortomitral continuity (AMC) were sporadically reported but relevant data are very limited. We aimed to describe the electrophysiological characteristics of AMC-AP and the related anatomy. METHODS AND RESULTS: This study involved eight (male/female = 3/5, mean age 42.6 ± 10.5 years) patients with left-sided AP successfully ablated in the AMC region. The retrograde atrial activation sequence was analysed and compared via recordings at the His-bundle (HB), coronary sinus (CS), and roving catheter during tachycardia, and the peak of QRS from the same cardiac circle used as time reference. Of the eight patients, two received prior ablations. During tachycardia, the activation time at the proximal CS (CSp), lateral CS (CSl), and HB region averaged 120 ± 26 ms, 124 ± 29 ms, and 117 ± 21 ms following the reference, respectively (P = 0.86). The latest atrial activation was recorded in the posterior CS which averaged 135 ± 25 ms following the reference. Placing the ablation catheter to AMC via retrograde approach was attempted in all cases but stable positioning achieved in none. Via transseptal approach, the ablation catheter could be easily placed at the AMC and recorded the earliest retrograde atrial activations with 60 ± 27 ms earlier than the relatively 'earliest' CS/HB recordings, and ablation at this site successfully eliminated AP conduction. No patients had recovered AP conduction after at least 12-month follow-up. CONCLUSION: AMC-AP is featured by recording comparable retrograde atrial activation times at CSp, CSl, and HB with the latest recordings at the posterior CS. Stable placement and successful ablation in the AMC via retrograde aortic approach was difficult but can be achieved via transseptal approach.


Assuntos
Feixe Acessório Atrioventricular , Ablação por Cateter , Feixe Acessório Atrioventricular/cirurgia , Adulto , Eletrocardiografia , Feminino , Átrios do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia
6.
Pacing Clin Electrophysiol ; 43(9): 922-929, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32638394

RESUMO

BACKGROUND: The association between physical activity (PA) and atrial tachyarrhythmia (AT) recurrence after ablation for atrial fibrillation (AF) remains unclear. METHODS: We consecutively enrolled 496 patients treated with AF ablation therapy in Beijing Anzhen Hospital. After excluding six patients with valvular heart disease, seven patients with congenital heart disease, 33 patients lost to follow-up, and 14 patients who did not provide PA level during follow-ups, 436 patients had their PA level assessed by the International Physical Activity Questionnaire-Short Form before ablation and each time of follow-up. The association between PA level (measured at the time closest to AT recurrence, or the end of 12-month follow-up if no AT recurrence), as well as active PA during follow-up, and postablation AT recurrence was tested by multivariate logistic regression. RESULTS: Of the enrolled patients, 134 (30.7%) patients experienced AT recurrence in the first 12 months postablation. Compared to patients with low PA, patients with moderate or high PA had a lower risk of AT recurrence (odds ratio [OR] = .44; 95% confidence interval [CI], .25-.80; P = .01 for patients with moderate PA; and OR = .43 [95% CI, .21-.85], P = .02 for patients with high PA). Compared to patients without active PA, patients with active PA had a lower risk of AT recurrence (OR = .44 [95% CI, .27-.70], P < .01). CONCLUSIONS: Moderate and high PA are associated with a lower risk of AT recurrence after AF ablation. Active PA during follow-up is also associated with a significantly lower risk of AT recurrence in the postablation AF population.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Exercício Físico , Taquicardia/fisiopatologia , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva
7.
J Pharmacol Sci ; 143(3): 141-147, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253103

RESUMO

Acute inflammation often contributes to the increased arrhythmogenesis in the cardiomyocytes. We investigated the protective effects of pravastatin on calcium disorders induced by acute administration of pro-inflammatory cytokines in isolated ventricular myocytes and its underlying mechanisms. Wild-type mice were intraperitoneally injected for five days with either pravastatin 20 mg/kg per day or an equal volume of normal saline. Cytosol Ca2+ handling was studied in freshly isolated ventricular myocytes after acute exposure of interleukin-6 (IL-6) (1 ng/ml) for 120 min by Ionoptix and confocal microscopy. Acute administration of clinically relevant concentrations of IL-6 disturbed calcium handling in ventricular myocytes, which presented as decreased amplitudes, prolonged decay times of Ca2+ transients, and reduced sarcoplasmic reticulum (SR) calcium stores. The frequency of spontaneous Ca2+ release, including calcium sparks and spontaneous calcium waves, was dramatically enhanced in the setting of IL-6. Notably, the pretreatment of pravastatin alleviated disturbed Ca2+ cycling, reduced spontaneous Ca2+ leakage induced by IL-6. Mitochondrial ROS pathway may constitute the underlying mechanism of the protective effects of pravastatin. Pravastatin protected the cardiomyocytes against calcium disorders induced by IL-6 via the mitochondrial ROS pathway, which suggests that pravastatin may represent a promising auxiliary therapeutic strategy for cardiac injury under acute inflammation.


Assuntos
Cálcio/metabolismo , Cardiotônicos , Ventrículos do Coração/citologia , Interleucina-6/efeitos adversos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Pravastatina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Animais , Cardiomiopatias/tratamento farmacológico , Células Cultivadas , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pravastatina/administração & dosagem , Retículo Sarcoplasmático/metabolismo
8.
Pacing Clin Electrophysiol ; 43(6): 583-592, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32333413

RESUMO

BACKGROUND: Existing data on the effectiveness and safety of atrial fibrillation (AF) ablation in females are limited to studies of small sample size, lacking longer term follow-up or adjustment for potential confounders. METHODS: A total of 6421 patients (2072 females) undergoing a first AF ablation procedure after enrollment in the Chinese Atrial Fibrillation Registry (China-AF) study between August 2011 and December 2017 were analyzed. We evaluated the effectiveness (recurrence of documented [symptomatic or not] atrial tachyarrhythmia (AT)) and the safety (incidence of procedure-related complications) of AF ablation in female patients compared to male patients. Sensitivity analyses based on routine data were also utilized to avoid potential sex differences in reporting of AF symptoms. RESULTS: Females were about 5 years older than males at the time of ablation (mean age 63.4 ± 9.5 vs 58.3 ± 10.8, P < .0001). A higher proportion of female patients had paroxysmal AF (74.3% vs 56.7%, P < .0001), hypertension (69.7% vs 61.3%, P < .0001), and hyperlipidemia (57.2% vs 52.9%, P = .001). Female sex was found to be an independent risk factor of AT recurrence in multivariate analyses (HR = 1.26, 95% CI 1.15-1.38, P < .0001). These findings were confirmed in sensitivity analyses using only Holter data. Female sex was also associated with a higher risk of periprocedural complications after adjustment for baseline variables (OR = 1.41, 95% CI 1.03-1.94, P = .03). CONCLUSIONS: Female sex is an independent risk factor of AT recurrence and periprocedural complications after AF ablation.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais , Resultado do Tratamento
9.
Front Physiol ; 10: 353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984031

RESUMO

Background: "Pill-in-the-pocket" (PIP) treatment with type IC drugs for cardioversion of recent-onset atrial fibrillation (AF) has been recommended in guidelines. Major adverse effects have been often reported, and the underlying mechanisms are proposed to be associated with the genetic backgrounds. Methods and Results: A male patient was treated with PIP approach (propafenone 600 mg.po) for the conversion of new onset AF. His symptoms got worse and referred to emergency room; ECG showed a typical Brugada syndrome (BrS) type I ECG pattern with sinus rhythm. Genetic screening identified a common SCN5A polymorphism R1193Q. Propafenone blockade of INa was studied in HEK293 cells expressed SCN5A R1193Q channel and WT channel using patch clamp techniques. There was no significant difference in peak current and steady-state gating parameters between R1193Q and WT at baseline. At clinically relevant concentration of 2 µmol/L propafenone, use-dependent block (UDB) of INa was more pronounced in R1193Q versus WT (44.2 ± 7.2 versus 24.8 ± 5.7% at the frequency of 2 Hz, P < 0.05); IC50 of UDB was 2.9 ± 0.7 µmol/L for R1193Q and 8.1 ± 1.8 µmol/L for WT, respectively. Propafenone produced more left shift of steady-state inactivation and slower recovery from inactivation in R1193Q compared with WT. Conclusion: A common SCN5A polymorphism R1193Q enhances UDB by propafenone and predisposes the patients to drug-induced BrS with PIP treatment. Our data suggest that R1193Q polymorphism is likely to be a genetic marker for the major adverse effects associated with propafenone PIP approach for AF patients' management. Ajmaline challenge to rule out the presence of BrS should be considered prior to propafenone PIP therapy in AF patients who are identified to have R1193Q polymorphism.

10.
Biomed Pharmacother ; 114: 108823, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30965238

RESUMO

We previously developed propranolol-encapsulated liposomes-in-microspheres (PLIM) to realize the sustained propranolol release for the treatment of hemangiomas. However, the liposomes released from the microspheres still lacked specificity for CD133-positive hemangioma-derived stem cells (HemSCs) which are considered to be the seeds of hemangiomas. Therefore, we hereby encapsulated propranolol-loaded CD133 aptamers conjugated liposomes in poly(lactic-co-glycolic acid (PLGA) microspheres to develop propranolol-loaded CD133 aptamers conjugated liposomes-in-microspheres (PCLIM), to realize the aim of the sustained and targeted therapy of hemangiomas. The evaluation of the release of propranolol from PCLIM was carried out, and the cytotoxic effect and angiogenic growth factor expression inhibitory ability of PCLIM were performed in HemSCs. The in vivo hemangioma inhibitory ability of PCLIM was also investigated in nude mice with subcutaneous human hemangiomas. PCLIM possessed a desired size of 29.2 µm, drug encapsulation efficiency (25.3%), and a prolonged drug release for 40 days. Importantly, PCLIM could inhibit HemSCs proliferation and the protein expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF) in HemSCs to a greater extent compared with PLIM. In nude mice bearing hemangioma xenograft, PCLIM showed the best therapeutic efficacy towards hemangiomas, as reflected by remarkably decreased hemangioma volume, weight and microvessel density (MVD). Thus, our results demonstrated that PCLIM realized the sustained and targeted treatment of hemangiomas, resulting in remarkable inhibition of hemangiomas.


Assuntos
Antígeno AC133/química , Aptâmeros de Nucleotídeos/química , Preparações de Ação Retardada/farmacologia , Hemangioma/tratamento farmacológico , Lipossomos/química , Propranolol/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Preparações de Ação Retardada/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Hemangioma/metabolismo , Humanos , Camundongos Nus , Microesferas , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Propranolol/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Heart Rhythm ; 16(9): 1374-1382, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30959203

RESUMO

BACKGROUND: Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear. OBJECTIVE: The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms. METHODS: In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-ß-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca2+ handling and action potentials in atrial myocytes were evaluated. RESULTS: Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca2+ handling disorders in atrial myocytes, such as reduced Ca2+ transient amplitude, enhanced spontaneous Ca2+ release, and reduced sarcoplasmic Ca2+ capacity; (5) enhanced delayed afterdepolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17. CONCLUSION: The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca2+ handling disorders in the atrium.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Fibrilação Atrial , Remodelamento Atrial/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Átrios do Coração , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia/métodos , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Piperidinas
12.
Life Sci ; 223: 22-28, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30851338

RESUMO

AIMS: Infantile hemangioma (IH) is one of the most common benign vascular tumors occurred in infants. Linc00152 is a kind of long non-coding RNAs (lncRNAs) and acts as a tumor oncogene. Recent study reported that Linc00152 is highly expressed in clinical IH tissues. However, the exact biological roles have not yet been investigated. The aim of the present study was to investigate the oncogenic roles of Linc00152 in IH and the underlying mechanism in vitro. MAIN METHODS: The expressions of Linc00152 in IH tissues and hemangioma-derived endothelial cells (HemECs) were determined using quantitative real time-PCR (qRT-PCR) analysis. The expressions of Akt/mTOR and Notch1 pathways related proteins were detected using western blot analysis. Cell proliferation was assessed by detecting Ki67 expression and CCK-8 assay. Cell apoptosis was evaluated by detecting apoptotic rate, caspase-3/7 activity, and Bcl-2 and Bax expression. KEY FINDINGS: The results demonstrated Linc00152 was up-regulated in clinical IH tissues and HemECs. Knockdown of Linc00152 in HemECs suppressed the activation of Akt/mTOR and Notch1 signaling pathways and caused reduction in cell proliferation and Ki67 expression in HemECs. Besides, Linc00152 knockdown resulted in a significant increase in apoptotic rate, caspase-3/7 activity, and Bax expression level, as well as a decrease in Bcl-2 expression level. However, the effects of Linc00152 knockdown on cell proliferation and apoptosis were mitigated by overexpression of Akt or Notch1. SIGNIFICANCE: Knockdown of Linc00152 suppressed HemECs proliferation and induced apoptosis via inhibiting Akt/mTOR and Notch1 signaling pathways.


Assuntos
Células Endoteliais/metabolismo , Técnicas de Silenciamento de Genes , Hemangioma/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Receptor Notch1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Pré-Escolar , Feminino , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Lactente , Masculino , RNA Longo não Codificante/antagonistas & inibidores , Transdução de Sinais/genética , Regulação para Cima
13.
Front Microbiol ; 10: 3035, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31993039

RESUMO

The mushroom, Sanghuang is widely used in Asian countries. This medicinal fungus produces diverse bioactive compounds and possesses a potent ability to degrade the wood of the mulberry tree. However, the genes, pathways, and mechanisms that are involved in the biosynthesis of the active compounds and wood degradation by Sanghuang mushroom are still unknown. Here, we report a 34.5 Mb genome-encoding 11,310 predicted genes-of this mushroom. About 16.88% (1909) of the predicted genes have been successfully classified as EuKaryotic Orthologous Groups, and approximately 27.23% (665) of these genes are involved in metabolism. Additionally, a total of 334 genes encoding CAZymes-and their characteristics-were compared with those of the other fungi. Homologous genes involved in triterpenoid, polysaccharide, and flavonoid biosynthesis were identified, and their expression was examined during four developmental stages, 10 and 20 days old mycelia, 1 year old and 3 years old fruiting bodies. Importantly, the lack of chalcone isomerase 1 in the flavonoid biosynthesis pathway suggested that different mechanisms were used in this mushroom to synthesize flavonoids than those used in plants. In addition, 343 transporters and 4 velvet family proteins, involved in regulation, uptake, and redistribution of secondary metabolites, were identified. Genomic analysis of this fungus provides insights into its diverse secondary metabolites, which would be beneficial for the investigation of the medical applications of these pharmacological compounds in the future.

14.
J Cell Biochem ; 120(4): 5128-5136, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30367514

RESUMO

The aim of this study was to investigate the manner of urea-modulated UT-B urea transporter (UT) internalization in infantile hemangioma-derived vascular endothelial cells (HemECs). The immunohistochemistry assay was performed to identify infancy hemangioma-derived endothelial cell line (XPTS-1) cells. Cell toxicity was detected with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Quantitative real-time polymerase chain reaction and Western blot analysis were measured to analyze the expression of UT-B. UT-B internalization was observed by confocal microscopy. The clathrin inhibitor chlorpromazine (CPZ) and caveolin endocytic disrupter methyl-ß-cyclodextrin (MßCD) were used in XPTS-1 cells transfected with UT-B-GFP to repress endocytosis. Urea-promoted UT-B expression in a concentration-dependent manner in an infantile XPTS-1 cell line. CPZ and MßCD significantly inhibited UT-B protein internalization. The pretreatment of UT-B-GFP cells with adaptor protein2 (AP2)-µ2-siRNA and caveolin-siRNA significantly inhibited UT-B protein internalization. Our findings suggested that urea-mediated UT-B UT internalization is clathrin and caveolae dependent in infantile HemECs.


Assuntos
Cavéolas/metabolismo , Clatrina/metabolismo , Endocitose , Células Endoteliais/metabolismo , Hemangioma/metabolismo , Hemangioma/patologia , Proteínas de Membrana Transportadoras/metabolismo , Ureia/farmacologia , Cavéolas/efeitos dos fármacos , Linhagem Celular , Endocitose/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Frações Subcelulares/metabolismo
15.
J Am Heart Assoc ; 7(19): e009391, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30371338

RESUMO

Background Previous studies have provided conflicting results as to whether women are at higher risk than men for thromboembolism in the setting of atrial fibrillation ( AF ). We investigated whether women with AF were at higher risk of ischemic stroke in the China-AF (China Atrial Fibrillation Registry) Study. Methods and Results A total of 19 515 patients were prospectively enrolled between August 2011 and December 2016 in the China- AF Study. After exclusion of patients receiving anticoagulation or ablation therapy, 6239 patients (2574 women) with results from at least 6 months of follow-up were used for the analysis. Cox proportional hazards models were performed to evaluate whether female sex was an independent risk factor for thromboembolism after multivariate adjustment. The primary outcome was the time to the first occurrence of ischemic stroke or systemic embolism. After a mean follow-up of 2.81±1.46 years, 152 female patients reached the primary outcome, as compared with 172 male patients. Crude incidence rates of thromboembolism between women and men were of borderline statistical significance (2.08 versus 1.68 per 100 patient-years, P=0.058). After multivariable analysis, female sex was not independently associated with an increased thromboembolism risk (hazard ratio 1.09, 95% confidence interval 0.86-1.39). There was no significant difference in thromboembolism risk by sex stratified by age and presence or absence of risk factors ( P for interaction all >0.1). Conclusions Although crude incidence rates of thromboembolism were higher in Chinese female patients with AF compared with male patients, female sex did not emerge as an independent risk factor for thromboembolism on multivariate analysis. Clinical Trial Registration URL : http://www.chictr.org.cn/ . Unique identifier: Chi CTR - OCH -13003729.


Assuntos
Fibrilação Atrial/complicações , Isquemia Encefálica/epidemiologia , Sistema de Registros , Medição de Risco/métodos , Tromboembolia/epidemiologia , Idoso , Isquemia Encefálica/etiologia , China/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Tromboembolia/etiologia
16.
Europace ; 20(8): 1367-1374, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29045723

RESUMO

Aims: The arrhythmogenic mechanisms of atrial fibrillation (AF) that are induced by acute inflammation, such as postoperative AF, are not well understood. We investigated the acute effects of tumour necrosis factor-α (TNF-α) that mimic acute inflammation on Ca2+ handling in isolated atrial myocytes and its underlying mechanisms. Methods and results: Cytosol Ca2+ handling and mitochondrial reactive oxygen species (ROS) production were studied in freshly isolated atrial myocytes of wild-type mice that were exposed to TNF-α (0.05 ng/mL) for 2 h by Ionoptix and confocal microscopy. The acute effects of TNF-α on Ca2+ handling were decreased amplitudes and prolonged decay times of Ca2+ transients in isolated atrial myocytes. A significant reduction in the sarcoplasmic reticulum (SR) Ca2+ content was detected in TNF-α treated cells, which was associated with increased spontaneous Ca2+ release events. In particular, physiological concentrations of TNF-α dramatically promoted the frequency of spontaneous Ca2+ waves and Ca2+ sparks, while the spark mass presented with reduced amplitudes and prolonged durations. The underlying mechanisms of pro-arrhythmic effects of TNF-α were further investigated. Acute exposure to TNF-α rapidly promoted mitochondrial ROS production that was correlated with the acute effect of TNF-α on Ca2+ handling, and enhanced the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) and the phosphorylation of RyR2. However, the performance of ROS inhibitor, DL-Dithiothreitol (DTT), reversed Ca2+ handling disorders induced by TNF-α. Conclusion: Tumour necrosis factor-α rapidly increases spontaneous Ca2+ release and promotes atrial arrhythmogenesis via the ROS pathway, which suggests that antioxidant therapy is a promising strategy for acute inflammation related AF.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Sinalização do Cálcio/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Inflamação/induzido quimicamente , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Potenciais de Ação , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Fatores de Tempo
17.
Peptides ; 88: 196-207, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27993557

RESUMO

Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro, NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro. Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.


Assuntos
Estresse do Retículo Endoplasmático/genética , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Neuregulina-1/genética , Animais , Apoptose/efeitos dos fármacos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Cardiotônicos/administração & dosagem , Caspase 12/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neuregulina-1/administração & dosagem , Neuregulina-1/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Tunicamicina/toxicidade
18.
Oncotarget ; 7(48): 79187-79202, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27816971

RESUMO

Although natural killer cells (NK cells) were traditionally classified as members of the innate immune system, NK cells have recently been found also to be an important player in the adaptive immune systems. In this context, in vitro activation of NK cells by cytokines leads to generation of NK cells with memory-like properties characterized by increased interferon-γ (IFNγ) production. However, it remains to be defined whether these memory-like NK cells exist in vivo after cytokine activation. Furthermore, it is also unclear whether such memory-like NK cells induced in vivo by cytokines could have effective anti-leukemia response. To address these issues, we used an in vivo pre-activation and re-stimulation system that was able to produce NK cells with increased IFNγ secretion. It was found that after in vivo pre-activation and re-stimulation with interleukins (ILs), NK cells retained a state to produce increased amount of IFNγ. Of note, whereas this intrinsic capacity of enhanced IFNγ production after in vivo IL pre-activation and re-stimulation could be transferred to the next generation of NK cells and was associated with prolonged survival of the mice with acute lymphoid leukemia. Moreover, the anti-leukemia activity of these memory-like NK cells was associated with IFNγ production and up-regulation of NK cells activation receptor-NK Group 2 member D (NKG2D). Together, these findings argue strongly that in vivo IL pre-activation and re-stimulation is capable to induce memory-like NK cells as observed previously in vitro, which are effective against acute lymphoblastic leukemia, likely via NKG2D-dependent IFNγ production, in intact animals.


Assuntos
Interleucinas/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cardiovasc Res ; 111(1): 56-65, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27084844

RESUMO

AIMS: The H19 lncRNA, a highly abundant and conserved imprinted gene, has been implicated in many essential biological processes and diseases. However, the function of H19 in the heart remains unknown. In this study, we investigated the function and underlying mechanism of H19 in regulating cardiomyocyte hypertrophy. METHODS AND RESULTS: We first detected the expression of H19 and its encoded miR-675 in both normal and diseased hearts and verified their up-regulations in pathological cardiac hypertrophy and heart failure. Adenovirus-mediated expression and a siRNA-mediated silence of H19 showed that H19 overexpression reduced cell size both at baseline and in response to phenylephrine, whereas knock-down of H19 induced cardiomyocyte hypertrophy. Overexpression or knock-down of miR-675 in cardiomyocytes demonstrated that miR-675 also inhibited cardiomyocyte hypertrophy. Moreover, inhibition of miR-675 reversed the reduction of cardiomyocyte size in H19-overexpressing cardiomyocytes, while infection with an adenovirus carrying H19 fragment without pre-miR-675 (H19-Tru) or with mutant sequences of pre-miR-675 (H19-Mut) failed to reduce cardiomyocyte size, indicating that miR-675 mediated the inhibitory effect of H19 on cardiomyocyte hypertrophy. We also identified that CaMKIIδ was a direct target of miR-675 and partially mediated the effect of H19 on cardiomyocyte hypertrophy. Furthermore, in vivo silencing of miR-675 using a specific antagomir in a pressure overload-induced mouse model of heart failure increased cardiac CaMKIIδ expression and exacerbated cardiac hypertrophy. CONCLUSION: These findings reveal a novel function of H19-miR-675 axis targeting CaMKIIδ as a negative regulator of cardiac hypertrophy, suggesting its potential therapeutic role in cardiac diseases.


Assuntos
Cardiomegalia/metabolismo , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células HEK293 , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Mutação , Miócitos Cardíacos/patologia , Interferência de RNA , RNA Longo não Codificante/genética , Transdução de Sinais , Transfecção
20.
Eur J Med Chem ; 46(9): 4709-14, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21821321

RESUMO

A representative synthetic process of derivatizing the natural product podophyllotoxin utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is described including molecular design, reaction optimization and X-ray structure confirmation. Evaluation of cytotoxicity against human cancer cell lines (Hela, K562 and K562/A02) using MTT assay proves that these triazole derivatives have good antitumor activities. High activities toward the drug resistant K562/A02 cell line reveal promising future for these derivatives. The rarely prepared 1,5-disubstituted triazole isomers, which would be omitted by the "click chemistry", were found to have superior cytotoxicities to that of the 1,4-disubstituted isomers.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Podofilotoxina/síntese química , Podofilotoxina/farmacologia , Triazóis/química , Antineoplásicos/química , Azidas/química , Linhagem Celular Tumoral , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Podofilotoxina/química , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho
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