RESUMO
BACKGROUND: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. OBJECTIVE: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF. STUDY DESIGN: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). CONCLUSIONS: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Fibrilação Atrial/cirurgia , Veias Pulmonares/cirurgia , Estudos Prospectivos , Átrios do Coração/cirurgia , Etanol , Ablação por Cateter/métodos , Resultado do Tratamento , RecidivaRESUMO
BACKGROUND: Perimitral atrial tachycardia (PMAT) is the most frequent type of iatrogenic atrial tachycardia (AT) after atrial fibrillation (AF) ablation. Vein of Marshall ethanol infusion (EIVOM) is a promising technique in mitral isthmus (MI) ablation. METHODS: A total of 165 patients with PMAT were divided into three groups according to ablation strategies, including RF only group (n = 89), RF-EIVOM group (initial RF ablation with adjunctive EIVOM, n = 28), and EIVOM-RF group (first-step EIVOM with touch-up RF ablation, n = 48). Acute and follow-up procedure outcomes were evaluated. RESULTS: PMAT terminated in 89.9%, 89.3%, and 93.7% of patients in RF only, RF-EIVOM and EIVOM-RF groups, respectively (p = .715), with complete MI block achieved in 80.9%, 89.3%, and 95.8% of patients (EIVOM-RF vs. RF only, p = .012). First-step utilization of EIVOM was associated with a significant shortening of RF ablation time at MI (EIVOM-RF 2.1 ± 1.3 min, RF only 7.9 ± 5.9 min, RF-EIVOM 6.8 ± 5.8 min; p < .001) and a decrease in the proportion of patients need ablation within coronary sinus (CS, EIVOM-RF 14.6%, RF only 61.8%, RF-EIVOM 64.3%; p < .001). After a mean follow-up of 12.1 ± 6.2 months, AF/AT recurred in 39 (43.8%), 6 (21.4%), and 12 (25.0%) patients in RF only, RF-EIVOM, and EIVOM-RF group (RF-EIVOM vs. RF only, p = .026; EIVOM-RF vs. RF only, p = .022). CONCLUSIONS: EIVOM was associated with an enhanced acute MI block rate as well as reduced AF/AT recurrence. First-step utilization of EIVOM promises to significantly simplify the RF ablation process. CONDENSED ABSTRACT: PMAT is the most common type of iatrogenic AT after AF ablation procedures. EIVOM contributed to a higher acute MI block rate and lower arrhythmia recurrence risk during follow-up. First-step utilization of EIVOM significantly reduced the need for radiofrequency ablation at MI and inside CS with the advantage of creating a homogenous, transmural lesion and eliminating epicardial connections.
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Fibrilação Atrial , Ablação por Cateter , Taquicardia Supraventricular , Humanos , Etanol , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Doença Iatrogênica , Resultado do Tratamento , RecidivaRESUMO
Endoplasmic reticulum (ER) homeostasis is regulated by ER-resident E3 ubiquitin ligase Hrd1, which has been implicated in inflammatory bowel disease (IBD). Ginsenoside Rb1 (GRb1) is the major ginsenoside in ginseng with multiple pharmacological activities. In this study we investigated the role of Hrd1 in IBD and its regulation by GRb1. Two mouse colitis models were established to mimic human IBD: drinking water containing dextran sodium sulfate (DSS) as well as intra-colonic infusion of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Colitis mice were treated with GRb1 (20, 40 mg·kg-1·d-1, ig) or a positive control drug sulfasalazine (500 mg·kg-1·d-1, ig) for 7 days. The model mice showed typical colitis symptoms and pathological changes in colon tissue. In addition to significant inflammatory responses and cell apoptosis in colon tissue, colon epithelial expression of Hrd1 was significantly decreased, the expression of ER stress markers GRP78, PERK, CHOP, and caspase 12 was increased, and the expression of Fas was increased (Fas was removed by Hrd1-induced ubiquitination). These changes were partially, or completely, reversed by GRb1 administration, whereas injection of Hrd1 inhibitor LS102 (50 mg·kg-1· d-1, ip, for 6 days) exacerbated colitis symptoms in colitis mice. GRb1 administration not only normalized Hrd1 expression at both the mRNA and protein levels, but also alleviated the ER stress response, Fas-related apoptosis, and other colitis symptoms. In intestinal cell line IEC-6, the expression of Hrd1 was significantly decreased by LPS treatment, but was normalized by GRb1 (200 µM). GRb1 alleviated LPS-induced ER stress and cell apoptosis in IEC-6 cells, and GRb1 action was inhibited by knockdown of Hrd1 using small interfering RNA. In summary, these results reveal a pathological role of Hrd1 in colitis, and provide a novel insight into alternative treatment of colitis using GRb1 activating Hrd1 signaling pathway.
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Colite/tratamento farmacológico , Retículo Endoplasmático/metabolismo , Ginsenosídeos/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Colite/induzido quimicamente , Colite/patologia , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Sulfassalazina/farmacologiaRESUMO
BACKGROUND: Since December 2019, over 80,000 patients with coronavirus disease 2019 (COVID-19) have been confirmed in China. With the increasing number of recovered patients, more attention should be paid to the follow-up of these patients. METHODS: In the study, 576 patients with COVID-19 discharged from hospital in Chongqing, China from January 24, 2020, to March 10, 2020 were evaluated by viral nucleic acid tests for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) to determine if they could be released from quarantine. Among the 576 patients, 61 patients (10.6%) had positive RT-PCR test results of SARS-CoV-2. We aimed to analyze the demographics, clinical characteristics and treatment of 61 patients. RESULTS: These positive patients were characterized by older age, chronic medical illness and mild conditions. 38 (62.3%) patients who were asymptomatic without abnormalities on chest radiographs were found in the positive with COVID-19. Also, they showed positive results of stool or sputum specimens with negative results of nasal and pharyngeal swab specimens. The median duration of positive result of SARS-CoV-2 was varied from 3 days to 35 days in the patients discharged from hospital with no family member infection. CONCLUSIONS: Multi-site screening of SARS-CoV-2 including nasal and pharyngeal swabs, stool and sputum specimens could be considered to improve the diagnosis, treatment and infection control in patients with COVID-19. Our findings provide the important information and clinical evidence for the improved management of patients recovered from COVID-19.
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Infecções por Coronavirus/diagnóstico , Alta do Paciente , Pneumonia Viral/diagnóstico , Adulto , Idoso , Betacoronavirus , COVID-19 , Teste para COVID-19 , China , Técnicas de Laboratório Clínico , Fezes/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nariz/virologia , Pandemias , Faringe/virologia , RNA Viral/isolamento & purificação , SARS-CoV-2 , Escarro/virologiaRESUMO
Ubiquitination is one of the basic mechanisms of cell protein homeostasis and degradation and is accomplished by 3 enzymes, E1, E2, and E3. Tripartite motif-containing proteins (TRIMs) constitute the largest subfamily of RING E3 ligases, with >70 current members in humans and mice. These members are involved in multiple biological processes, including growth, differentiation, and apoptosis as well as disease and tumorigenesis. Accumulating evidence has shown that many TRIM proteins are associated with various cardiac processes and pathologies, such as heart development, signal transduction, protein degradation, autophagy mediation, ion channel regulation, congenital heart disease, and cardiomyopathies. In this review, we provide an overview of the TRIM family and discuss its involvement in the regulation of cardiac proteostasis and pathophysiology and its potential therapeutic implications.
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Doenças Cardiovasculares , Animais , Camundongos , Transdução de Sinais , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND AND OBJECTIVE: Atrioesophageal fistula (AEF) is a rare but devastating complication with high mortality post atrial fibrillation (AF) ablation. The purpose of current study was to determine the epidemiology, clinical features, pathogenesis, and management of AEF after AF ablation. METHODS AND RESULTS: Patients with diagnosed AEF were included and retrospectively analyzed according to the registry of 11 centers in China from January 2010 to December 2019. A total of 16 AEF cases were identified from 44 794 patients who received a left atrial ablation procedure (0.035% per procedure). The interval from procedure to clinical onset of AEF averaged 18.3 days (3-39 days). The fever ranked the most common symptom, occurred in 14 of the 16 cases, followed by neurological deficits (n = 11), chest pain (n = 5), and hematemesis (n = 4). Patients undergoing surgical repair had a better prognosis compared to those receiving nonsurgical management ([4 of 8] 50.0% vs [8 of 8] 100%, P < .05) with an overall mortality rate of 75.0%. CONCLUSION: AEF is highly characterized by varied manifestations. Early diagnosis and urgent surgical repair are vital to those patients and associated with improved survival rates.
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Fibrilação Atrial , Ablação por Cateter , Fístula Esofágica , Fibrilação Atrial/cirurgia , Átrios do Coração/cirurgia , Humanos , Estudos RetrospectivosRESUMO
Cardiac fibrosis (CF), a repairing process following myocardial infarction (MI), is characterized by abnormal proliferation of cardiac fibroblasts and excessive deposition of extracellular matrix (ECM) resulting in inevitable resultant heart failure. TGF-ß (transforming growth factor-ß)/ALK5 (Activin receptor-like kinase 5)/Smad2/3/4 pathways have been reported to be involved in the process. Recent studies have implicated both activin and its specific downstream component ALK4 in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 is upregulated in the pressure-overloaded heart and its partial inhibition attenuated the pressure overload-induced CF and cardiac dysfunction. However, the role of ALK4 in the pathogenesis of MI-induced CF, which is usually more severe than that induced by pressure-overload, remains unknown. Here we report: 1) In a wild-type mouse model of MI, ALK4 upregulation was restricted in the fibroblasts of the infarct border zone; 2) In contrast, ALK4+/- mice with a haplodeficiency of ALK4 gene, showed a significantly attenuated CF in the border zone, with a smaller scar size, a preserved cardiac function and an improved survival rate post-MI; 3) Similarly to pressure-overloaded heart, these beneficial effects might be through a partial inactivation of the Smad3/4 pathway but not MAPK cascades; 4) The apoptotic rate of the cardiomyocytes were indistinguishable in the border zone of the wild-type control and ALK4+/- mice; 5) Cardiac fibroblasts isolated from ALK4+/- mice showed reduced migration, proliferation and ECM synthesis in response to hypoxia. These results indicate that partial inhibition of ALK4 may reduce MI-induced CF, suggesting ALK4 as a novel target for inhibition of unfavorable CF and for preservation of LV systolic function induced by not only pressure-overload but also MI.
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Receptores de Ativinas Tipo I/genética , Haploinsuficiência , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Receptores de Ativinas Tipo I/deficiência , Receptores de Ativinas Tipo I/metabolismo , Animais , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Ecocardiografia , Matriz Extracelular , Fibrose , Regulação da Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Mortalidade , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miofibroblastos/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Função VentricularRESUMO
Dual-specificity phosphatase 14 (Dusp14), an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways, has been implicated in inflammatory immune response, cancers, cell differentiation and proliferation. The role of Dusp14 in chronic pressure overload-induced cardiac hypertrophy has not been explored. Here we have shown that Dusp14-/- knockout mice and cardiac-specific Dusp14 transgenic mice were generated and subjected to aortic banding (AB) for 4 weeks. Our results demonstrated that genetic loss of Dusp14 significantly aggravated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction, whereas transgenic cardiac-specific Dusp14 overexpression significantly attenuated AB-induced cardiac dysfunction and remodeling. In vitro, adenoviral overexpression of constitutive Dusp14 blocked angiotensin II-induced hypertrophic growth of cardiomyocytes, while Dusp14 knockdown led to opposite effects. Mechanistically, excessive phosphorylation of TAK1, P38MAPK and JNK1/2 was evidenced in Dusp14-/- knockout mice post-AB and inactivation of TAK1-P38MAPK and -JNK1/2 signaling using TAK1 inhibitor 5Z-7-ox shares similar antihypertrophic effect as Dusp14 overexpression. Moreover, we show that Dusp14 directly interacted with TAK1. Results from present experiments indicate that Dusp14 protects the heart from AB-induced cardiac hypertrophy and dysfunction possibly through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway. Future studies are warranted to test the feasibility of overexpressing Dusp14 as a therapeutic strategy to attenuate cardiac hypertrophy and failure.
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Cardiomegalia/enzimologia , Fosfatases de Especificidade Dupla/metabolismo , Insuficiência Cardíaca/enzimologia , Sistema de Sinalização das MAP Quinases , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Angiotensina II , Animais , Sequência de Bases , Estudos de Casos e Controles , Células Cultivadas , Fosfatases de Especificidade Dupla/genética , Células HEK293 , Humanos , MAP Quinase Quinase Quinases/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Miócitos Cardíacos/fisiologia , RatosRESUMO
AIMS: Myocardial infarction (MI) induces neural remodelling of the left stellate ganglion (LSG), which may contribute to ischaemia-induced arrhythmias. The neural chemorepellent Semaphorin 3a (Sema3a) has been identified as a negative regulator of sympathetic innervation in the LSG and heart. We previously reported that overexpression of Sema3a in the border zone could reduce the arrhythmogenic effects of cardiac sympathetic hyperinnervation post-MI. This study investigated whether Sema3a overexpression within the LSG confers an antiarrhythmic effect after MI through decreasing extra- and intra-cardiac neural remodelling. METHODS AND RESULTS: Sprague-Dawley rats were subjected to MI, and randomly allocated to intra-LSG microinjection of either phosphate-buffered saline (PBS), adenovirus encoding green fluorescent protein (AdGFP), or adenovirus encoding Sema3a (AdSema3a). Sham-operated rats served as controls. Two weeks after infarction, MI-induced nerve sprouting and sympathetic hyperinnervation in the LSG and myocardium were significantly attenuated by intra-LSG injection with AdSema3a, as assessed by immunohistochemistry and western blot analysis of growth-associated protein 43 and tyrosine hydroxylase. This was also confirmed by sympathetic nerve function changes assessed by cardiac norepinephrine content. Additionally, intra-LSG injection with AdSema3a alleviated MI-induced accumulation of dephosphorylated connexin 43 in the infarct border zone. Furthermore, Sema3a overexpression in the LSG reduced the incidence of inducible ventricular tachyarrhythmia by programmed electrical stimulation post-MI, and arrhythmia scores were significantly lower in the AdSema3a group than in the PBS and AdGFP groups. CONCLUSION: Semaphorin 3a overexpression in the LSG ameliorates the inducibility of ventricular arrhythmias after MI, mainly through attenuation of neural remodelling within the cardiac-neuraxis.
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Infarto do Miocárdio/complicações , Semaforina-3A/uso terapêutico , Gânglio Estrelado/metabolismo , Taquicardia Ventricular/terapia , Animais , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Terapia Genética , Coração/inervação , Masculino , Miocárdio/metabolismo , Norepinefrina , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Semaforina-3A/genética , Gânglio Estrelado/efeitos dos fármacos , TransfecçãoRESUMO
Organic light emitting diodes (OLEDs) with a quasi-crystal (QC) structure are analyzed and applied in a head-mounted display (HMD) system in this study. We adopt a hybrid simulated method to evaluate the light extraction efficiency (LEE) and far-field pattern in the air, and study the relationship between them. The simulation results show that OLEDs implanted with the QC structure can provide a collimated far-field pattern to increase the brightness. Using this 10-fold QC arrangement the maxima LEE of the OLEDs can be increased by 1.20 times. Compared with conventional OLEDs, the viewing angle of the OLED panel decreases from 120 degrees to 26 degrees with an improvement in the optical efficiency of the HMD system by 2.66 times. Moreover, the normalized on-axis intensity in the pupil of the eyepiece can be enlarged up to 3.95 times which suggests that the OLED panel can save 74.68% energy while achieving the same on-axis intensity as conventional OLEDs.
RESUMO
We propose a design for a high-efficiency backlight module that does not require a brightness enhancement film (BEF). With the high-efficiency backlight module it is possible to achieve almost the same half-luminance angle as a conventional edge-lit backlight module can achieve. The backlight system is comprised of a crisscross light guide plate (LGP) and one diffuser sheet. The crisscross LGP is composed of a LGP and optically patterned film (OPF). The backlight module allows light to be extracted through the direct guiding mode and top guiding mode, respectively. We controlled arrangement of the microstructures to increase the optical efficiency and the uniformity by two modes. Compared to the conventional edge-lit backlight module, there is a two-fold improvement in both the total optical efficiency and on-axis luminance with the high-efficiency backlight module.
Assuntos
Apresentação de Dados , Iluminação/instrumentação , Refratometria/instrumentação , Ressonância de Plasmônio de Superfície/instrumentação , Desenho Assistido por Computador , Desenho de Equipamento , Análise de Falha de Equipamento , Luz , Espalhamento de RadiaçãoRESUMO
Condylar-base-associated multiple mandibular fractures are more prevalent than single ones. Direct trauma to mandibular symphysis, body or angle are prone to induce indirect condylar fracture. However, little is known about the effects of various rigid internal fixation modalities in condylar base for relevant multiple mandibular fractures, especially when we are confused in the selection of operative approach. Within the finite element analysis, straight-titanium-plate implanting positions in condylar base contained posterolateral zone (I), anterolateral zone (II), and intermediate zone (III). Von Mises stress (SS) in devices and bone and mandibular displacement (DT) were solved, while maximum values (SSmax and DTmax) were documented. For rigid internal fixation in condylar-base-and-symphysis fractures, I + II modality exhibited least SSmax in screws and cortical bone and least DTmax, I + III modality exhibited least SSmax in plates. For rigid internal fixation in condylar-base-and-contralateral-body fractures, I + III modality exhibited least SSmax in screws and cortical bone, I + II modality exhibited least SSmax in plates and least DTmax. For rigid internal fixation in condylar-base-and-contralateral-angle fractures, I + III modality exhibited least DTmax. The findings suggest that either I + II or I + III modality is a valid guaranty for rigid internal fixation of condylar base fractures concomitant with symphysis, contralateral body or angle fractures.
Assuntos
Análise de Elementos Finitos , Fixação Interna de Fraturas , Côndilo Mandibular , Fraturas Mandibulares , Humanos , Fraturas Mandibulares/cirurgia , Fraturas Mandibulares/fisiopatologia , Fixação Interna de Fraturas/métodos , Fixação Interna de Fraturas/instrumentação , Côndilo Mandibular/lesões , Côndilo Mandibular/cirurgia , Côndilo Mandibular/fisiopatologia , Fenômenos Biomecânicos , Placas Ósseas , Estresse MecânicoRESUMO
BACKGROUND: Valvular calcification (VC) is an independent risk factor for cardiovascular diseases. The relationship between VC and atrial fibrillation is not clear. HYPOTHESIS: We treated the aortic valve, mitral valve, and tricuspid valve as a whole and considered the possible association between VC and recurrence of persistent atrial fibrillation (PsAF) after radiofrequency catheter ablation (RFCA). METHODS: This study involved 2687 PsAF patients who underwent RFCA. Data were collected to explore the relationship between VC and outcome. VC was defined by echocardiography in aortic valve, mitral valve, or tricuspid valve. After 1 year follow-up, subgroup analysis, mixed model regression analysis, and score system analysis were performed. The external validation of 133 patients demonstrated the accuracy of this clinical prediction model. RESULTS: Overall, 2687 inpatients were assigned to the recurrence group (n = 682) or the no recurrence group (n = 2005) with or without VC. Compared to patients with no recurrence, the incidence of VC was higher in recurrence patients. Recurrence was present in 18.5%, 34.9%, 39.3%, and 52.0% of the four groups, which met VC numbers of 0, 1, 2, and 3, respectively. After adjustment for potential confounding factors, VC was an independent risk factor for AF recurrence in several models. For multivariable logistic regression, a scoring system was established based on the regression coefficient. The receiver operating characteristic area of the scoring system was 0.787 in the external validation cohort. CONCLUSIONS: VC was an independent risk factor for AF recurrence in PsAF after RFCA. The scoring system may be a useful clinical tool to assess AF recurrence.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Resultado do Tratamento , Modelos Estatísticos , Prognóstico , Ablação por Cateter/efeitos adversos , RecidivaRESUMO
BACKGROUND: Stimulation of epithelial sodium channel (ENaC) increases Na(+) transport, a driving force of alveolar fluid clearance (AFC) to keep alveolar spaces free of edema fluid that is beneficial for acute lung injury (ALI). It is well recognized that regulation of ENaC by insulin via PI3K pathway, but the mechanism of this signaling pathway to regulate AFC and ENaC in ALI remains unclear. The aim of this study was to investigate the effect of insulin on AFC in ALI and clarify the pathway in which insulin regulates the expression of ENaC in vitro and in vivo. METHODS: A model of ALI (LPS at a dose of 5.0 mg/kg) with non-hyperglycemia was established in Sprague-Dawley rats receiving continuous exogenous insulin by micro-osmotic pumps and wortmannin. The lungs were isolated for measurement of bronchoalveolar lavage fluid(BALF), total lung water content(TLW), and AFC after ALI for 8 hours. Alveolar epithelial type II cells were pre-incubated with LY294002, Akt inhibitor and SGK1 inhibitor 30 minutes before insulin treatment for 2 hours. The expressions of α-,ß-, and γ-ENaC were detected by immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting. RESULTS: In vivo, insulin decreased TLW, enchanced AFC, increased the expressions of α-,ß-, and γ-ENaC and the level of phosphorylated Akt, attenuated lung injury and improved the survival rate in LPS-induced ALI, the effects of which were blocked by wortmannin. Amiloride, a sodium channel inhibitor, significantly reduced insulin-induced increase in AFC. In vitro, insulin increased the expressions of α-,ß-, and γ-ENaC as well as the level of phosphorylated Akt but LY294002 and Akt inhibitor significantly prevented insulin-induced increase in the expression of ENaC and the level of phosphorylated Akt respectively. Immunoprecipitation studies showed that levels of Nedd4-2 binding to ENaC were decreased by insulin via PI3K/Akt pathway. CONCLUSIONS: Our study demonstrated that insulin alleviated pulmonary edema and enhanced AFC by increasing the expression of ENaC that dependent upon PI3K/Akt pathway by inhibition of Nedd4-2.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Canais Epiteliais de Sódio/metabolismo , Insulina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alvéolos Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Glicemia/metabolismo , Células Cultivadas , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Técnicas In Vitro , Insulina/sangue , Interleucina-6/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , Modelos Animais , Ubiquitina-Proteína Ligases Nedd4 , Peroxidase/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Sacubitril/valsartan (SAC/VAL) prevents angiotensin II (AngII) from binding AT1-R and blocks degradation of natriuretic peptides. Despite its efficacy in reducing ventricular fibrosis and preserving cardiac functions, which has been extensively demonstrated in myocardial infarction or pressure overload models, few studies have been conducted to determine whether SAC/VAL could attenuate atrial fibrosis and decrease atrial fibrillation (AF) susceptibility. Our study provided evidence for the inhibition of atrial fibrosis and reduced susceptibility to AF by SAC/VAL. After 28 days of AngII continuous subcutaneous stimulation, rats in SAC/VAL group exhibited reduced extent of atrial fibrosis, inhibited proliferation, migration, and differentiation of atrial fibroblasts, and decreased susceptibility to AF. We further found that inhibition of p-Smad2/3, p-JNK, and p-p38MAPK pathways is involved in the role of SAC/VAL on AngII-induced atrial fibrosis in vivo. These results emphasize the importance of SAC/VAL in the prevention of AngII-induced atrial fibrosis and may help to enrich the options for AF pharmacotherapy.
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Angiotensina II , Fibrilação Atrial , Aminobutiratos , Animais , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/prevenção & controle , Compostos de Bifenilo , Fibrose , Ratos , Transdução de Sinais , Valsartana/farmacologiaRESUMO
Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is constitutively produced by endothelial cells and plays a vital role in maintaining vascular homeostasis. Chronic periodontitis is an inflammatory disease characterized by bleeding of periodontal tissues that support the tooth. In this study, we aimed to determine the role of PAI-1 produced by endothelial cells in response to infections caused by the primary periodontal pathogen Porphyromonas gingivalis. We demonstrated that P. gingivalis infection resulted in significantly reduced PAI-1 levels in human endothelial cells. This reduction in PAI-1 levels could be attributed to the proteolysis of PAI-1 by P. gingivalis proteinases, especially lysine-specific gingipain-K (Kgp). We demonstrated the roles of these degradative enzymes in the endothelial cells using a Kgp-specific inhibitor and P. gingivalis gingipain-null mutants, in which the lack of the proteinases resulted in the absence of PAI-1 degradation. The degradation of PAI-1 by P. gingivalis induced a delayed wound healing response in endothelial cell layers via the low-density lipoprotein receptor-related protein. Our results collectively suggested that the proteolysis of PAI-1 in endothelial cells by gingipains of P. gingivalis might lead to the deregulation of endothelial homeostasis, thereby contributing to the permeabilization and dysfunction of the vascular endothelial barrier.
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Células Endoteliais , Porphyromonas gingivalis , Adesinas Bacterianas/metabolismo , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/farmacologia , Cisteína Endopeptidases Gingipaínas , Humanos , Inibidor 1 de Ativador de Plasminogênio , Porphyromonas gingivalis/fisiologia , CicatrizaçãoRESUMO
In the title compound, C(32)H(35)BrN(4)O(3), the piperazine ring exists in a chair conformation. The quinoline ring system is oriented at dihedral angles of 82.70â (17) and 19.54â (17)° to the phenyl and meth-oxy-phenyl rings, respectively. Weak inter-molecular C-Hâ¯π inter-actions are present in the crystal structure.
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Breast cancer is one of the most common malignancies. Pathological image processing of breast has become an important means for early diagnosis of breast cancer. Using medical image processing to assist doctors to detect potential breast cancer as early as possible has always been a hot topic in the field of medical image diagnosis. In this paper, a breast cancer recognition method based on image processing is systematically expounded from four aspects: breast cancer detection, image segmentation, image registration, and image fusion. The achievements and application scope of supervised learning, unsupervised learning, deep learning, CNN, and so on in breast cancer examination are expounded. The prospect of unsupervised learning and transfer learning for breast cancer diagnosis is prospected. Finally, the privacy protection of breast cancer patients is put forward.
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Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Processamento de Imagem Assistida por Computador , Neoplasias da Mama/diagnóstico , Feminino , HumanosRESUMO
Atrial fibrillation (AF) is one of the most common tachyarrhythmias observed in the clinic and is characterized by structural and electrical remodelling. Atrial fibrosis, an emblem of atrial structural remodelling, is a complex multifactorial and patientspecific process involved in the occurrence and maintenance of AF. Whilst there is already considerable knowledge regarding the association between AF and fibrosis, this process is extremely complex, involving intricate neurohumoral and cellular and molecular interactions, and it is not limited to the atrium. Current technological advances have made the noninvasive evaluation of fibrosis in the atria and ventricles possible, facilitating the selection of patientspecific ablation strategies and upstream treatment regimens. An improved understanding of the mechanisms and roles of fibrosis in the context of AF is of great clinical significance for the development of treatment strategies targeting the fibrous region. In the present review, a focus was placed on the atrial fibrosis underlying AF, outlining its role in the occurrence and perpetuation of AF, by reviewing recent evaluations and potential treatment strategies targeting areas of fibrosis, with the aim of providing a novel perspective on the management and prevention of AF.
Assuntos
Fibrilação Atrial , Remodelamento Atrial , Ventrículos do Coração , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Fibrose , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , HumanosRESUMO
Chronic alcohol abuse increases the risk of mortality and poor outcomes in patients with acute respiratory distress syndrome. However, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the effects of chronic alcohol consumption on lung injury and clarify the signaling pathways involved in the inhibition of alveolar fluid clearance (AFC). In order to produce rodent models with chronic alcohol consumption, wildtype C57BL/6 mice were treated with alcohol. A2a adenosine receptor (AR) small interfering (si)RNA or A2bAR siRNA were transfected into the lung tissue of mice and primary rat alveolar type II (ATII) cells. The rate of AFC in lung tissue was measured during exposure to lipopolysaccharide (LPS). Epithelial sodium channel (ENaC) expression was determined to investigate the mechanisms underlying alcoholinduced regulation of AFC. In the present study, exposure to alcohol reduced AFC, exacerbated pulmonary edema and worsened LPSinduced lung injury. Alcohol caused a decrease in cyclic adenosine monophosphate (cAMP) levels and inhibited αENaC, ßENaC and γENaC expression levels in the lung tissue of mice and ATII cells. Furthermore, alcohol decreased αENaC, ßENaC and γENaC expression levels via the A2aAR or A2bARcAMP signaling pathways in vitro. In conclusion, the results of the present study demonstrated that chronic alcohol consumption worsened lung injury by aggravating pulmonary edema and impairing AFC. An alcoholinduced decrease of αENaC, ßENaC and γENaC expression levels by the A2ARmediated cAMP pathway may be responsible for the exacerbated effects of chronic alcohol consumption in lung injury.