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BACKGROUND AND AIMS: Despite advances in technology and techniques, the recurrence rate of persistent atrial fibrillation (AF) following catheter ablation remains high. The Shensong Yangxin (SSYX) capsule, a renowned traditional Chinese medicine formula, is used in the treatment of cardiac arrhythmias. This trial aimed to investigate whether the SSYX can improve clinical outcomes in patients who have undergone catheter ablation for persistent AF. METHODS: A multi-centre, randomized, double-blind, placebo-controlled clinical trial was conducted at 66 centres in China among 920 patients with persistent AF undergoing first ablation. Participants were randomized to oral SSYX, 1.6â g (.4â g/granule) thrice daily (n = 460), or matched placebo (n = 460) for 12 months. The primary endpoint was recurrent atrial tachyarrhythmias lasting for ≥30â s following a blanking period of 3 months. Secondary endpoints included time to first documented atrial tachyarrhythmias, AF burden, cardioversion, stroke/systemic embolism, changes in echocardiographic parameters, and quality-of-life (QoL) score. Analyses were performed according to the intention-to-treat principle. RESULTS: A total of 920 patients underwent randomization (460 assigned to SSYX group and 460 assigned to placebo group). During the follow-up of 12 months, patients assigned to SSYX had a higher event-free rate from recurrent atrial tachyarrhythmias when compared with the placebo group (12-month Kaplan-Meier event-free rate estimates, 85.5% and 77.7%, respectively; hazard ratio, .6; 95% confidence interval .4-.8; P = .001). Patients assigned to receive SSYX had a better QoL score at 12 months compared to those randomized to placebo. There was no significant difference in the incidence of serious adverse events between the two groups. CONCLUSIONS: Treatment with SSYX following radiofrequency catheter ablation for persistent AF reduced the incidence of recurrent atrial tachyarrhythmias and led to clinically significant improvements in QoL during a 12-month follow-up in a Chinese population.
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BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin as a background therapy has become the standard care after percutaneous coronary intervention. However, some adverse noncardiac effects limited the use of aspirin in clinical practice. Thus, evaluation of pharmacological alternatives to aspirin is attractive. Previous data indicated that indobufen could lessen the unwanted side effects of aspirin while retaining the antithrombotic efficacy, but its combination with a P2Y12 inhibitor still lacks randomized clinical trial evidence. METHODS: In this randomized, open-label, noninferiority trial, patients with negative cardiac troponin undergoing coronary drug-eluting stent implantation were randomly assigned in a 1:1 ratio to receive either indobufen-based DAPT (indobufen 100 mg twice a day plus clopidogrel 75 mg/d for 12 months) or conventional DAPT (aspirin 100 mg/d plus clopidogrel 75 mg/d for 12 months). The primary end point was a 1-year composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, definite or probable stent thrombosis, or Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding. The end points were adjudicated by an independent Clinical Event Committee. RESULTS: Between January 11, 2018, and October 12, 2020, 4551 patients were randomized in 103 cardiovascular centers: 2258 patients to the indobufen-based DAPT group and 2293 to the conventional DAPT group. The primary end point occurred in 101 patients (4.47%) in the indobufen-based DAPT group and 140 patients (6.11%) in the conventional DAPT group (absolute difference, -1.63%; Pnoninferiority<0.001; hazard ratio, 0.73 [95% CI, 0.56-0.94]; P=0.015). Cardiovascular death, nonfatal myocardial infarction, ischemic stroke, and stent thrombosis were observed in 0.13%, 0.40%, 0.80%, and 0.22% of patients in the indobufen-based DAPT group and 0.17%, 0.44%, 0.83%, and 0.17% of patients in the conventional DAPT group (all P>0.05). The occurrence of Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding events was lower in the indobufen-based DAPT group compared with the conventional DAPT group (2.97% versus 4.71%; hazard ratio, 0.63 [95% CI, 0.46-0.85]; P=0.002), with the main decrease in type 2 bleeding (1.68% versus 3.49%; hazard ratio, 0.48 [95% CI, 0.33-0.70]; P<0.001). CONCLUSIONS: In Chinese patients with negative cardiac troponin undergoing drug-eluting stent implantation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of 1-year net clinical outcomes, which was driven mainly by a reduction in bleeding events without an increase in ischemic events. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-IIR-17013505.
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Stents Farmacológicos , Infarto do Miocárdio , Humanos , Aspirina/uso terapêutico , Clopidogrel/uso terapêutico , Quimioterapia Combinada , Stents Farmacológicos/efeitos adversos , Hemorragia/etiologia , AVC Isquêmico/etiologia , Infarto do Miocárdio/tratamento farmacológico , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose/etiologia , Resultado do Tratamento , TroponinaRESUMO
INTRODUCTION: Myeloid differentiation protein 1 (MD1), a negative regulator of toll-like receptor 4 (TLR4), is widely expressed in the heart. Recent studies have shown that MD1 plays an important role in cardiac remodelling. However, the effects and potential mechanisms underlying MD1-mediated atrial remodelling in diabetic cardiomyopathy (DCM) remain unclear. Therefore, this study was designed to explore the role of MD1 in DCM-related atrial remodelling. METHODS: MD1 knockout (MD1-KO) mice and wild-type (WT) littermates were injected with streptozotocin (STZ) to establish a diabetic mouse model. These mice were then used to evaluate MD1 expression and its effects on atrial remodelling in vivo. RESULTS: MD1 expression was significantly decreased in STZ-induced diabetic mice. The loss of MD1 aggravated atrial fibrosis, inflammation, and apoptosis in DCM mice and promoted atrial remodelling. MD1-KO diabetic mice also showed higher susceptibility to atrial fibrillation (AF) and worse cardiac function. Mechanistically, the deletion of MD1 promoted the activation of the TLR4/NF-κB signalling pathway, resulting in atrial remodelling in DCM mice via increased p65 phosphorylation. CONCLUSIONS: The deletion of MD1 plays an important role in inflammatory and apoptotic atrial remodelling and increases susceptibility to AF in DCM mice, providing a new target for the preventive treatment of DCM-related atrial remodelling.
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Fibrilação Atrial , Remodelamento Atrial , Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/induzido quimicamente , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Infecções por Coronavirus/epidemiologia , Mortalidade Hospitalar , Hipertensão/epidemiologia , Pneumonia Viral/epidemiologia , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19 , Infecções por Coronavirus/complicações , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicaçõesRESUMO
Pathological hypertrophy generally progresses to heart failure. Exploring effective and promising therapeutic targets might lead to progress in preventing its detrimental outcomes. Our current knowledge about lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) is mainly limited to regulate inflammation. However, the role of LITAF in other settings that are not that relevant to inflammation, such as cardiac remodeling and heart failure, remains largely unknown. In the present study, we found that the expression of LITAF decreased in hypertrophic hearts and cardiomyocytes. Meanwhile, LITAF protected cultured neonatal rat cardiomyocytes against phenylephrine-induced hypertrophy. Moreover, using LITAF knockout mice, we demonstrated that LITAF deficiency exacerbated cardiac hypertrophy and fibrosis compared with wild-type mice. Mechanistically, LITAF directly binds to the N-terminal of ASK1, thus disrupting the dimerization of ASK1 and blocking ASK1 activation, ultimately inhibiting ASK1-JNK/p38 signaling over-activation and protecting against cardiac hypertrophy. Furthermore, AAV9-mediated LITAF overexpression attenuated cardiac hypertrophy in vivo. Conclusions: Our findings uncover the novel role of LITAF as a negative regulator of cardiac remodeling. Targeting the interaction between LITAF and ASK1 could be a promising therapeutic strategy for pathological cardiac remodeling.
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Biomarcadores , Cardiomegalia/etiologia , Cardiomegalia/patologia , Suscetibilidade a Doenças , Fosfoproteínas/genética , Animais , Cardiomegalia/diagnóstico por imagem , Modelos Animais de Doenças , Ecocardiografia/métodos , Imunofluorescência , Expressão Gênica , Vetores Genéticos/genética , Imuno-Histoquímica , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Knockout , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Fosfoproteínas/metabolismo , Ligação Proteica , Ratos , Transdução GenéticaRESUMO
miRNA-mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR-383-dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR-383 overexpression or miR-383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR-383. Pyroptosis-related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis-related mediators including NLRP3, cleaved caspase-1, cleaved IL-1ß and IL-18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI-caused elevation of miR-383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR-383 target. miR-383 knockdown ameliorated but miR-383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti-pyroptotic effect from miR-383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR-383/RP105/AKT-dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR-383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.
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Alcaloides/farmacologia , Antígenos CD/metabolismo , Benzodioxóis/farmacologia , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piroptose , Animais , Cardiotônicos/farmacologia , Masculino , MicroRNAs/genética , Piroptose/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
ABSTRACT: Doxorubicin (DOX) is a chemotherapeutic drug for treating various cancers. However, the DOX-induced cardiotoxicity greatly limits its clinical application. MicroRNAs are emerged as critical mediators of cardiomyocyte injury. This work explored the function of miR-215-5p in the regulation of DOX-induced mouse HL-1 cardiomyocyte injury. An in vitro model of DOX-treated cardiotoxicity was established in cardiac mouse cell line HL-1. Gene expression was measured by reverse transcription quantitative polymerase chain reaction. Cell viability was detected using CCK-8. Cell death and apoptosis were tested using transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL), flow cytometry, and caspase-3/7 activity assays. Luciferase reporter assay was used to examine the target of miR-215-5p. We found that DOX induced cardiomyocyte injury and upregulated miR-215-5p in HL-1 cells. Inhibition of miR-215-5p attenuated DOX-induced cardiomyocyte death and apoptosis in vitro. Mechanistical experiments indicated that zinc finger E-box-binding homeobox (ZEB2) was targeted by miR-215-5p. In addition, ZEB2 expression was reduced in DOX-treated HL-1 cells. Rescue assays indicated that ZEB2 knockdown reversed the effects of miR-215-5p inhibition. In conclusion, miR-215-5p inhibition protects HL-1 cells against DOX-induced injury by upregulating ZEB2 expression.
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Antibióticos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Doxorrubicina/toxicidade , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade , Linhagem Celular , Regulação da Expressão Gênica , Camundongos , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
Acute myocardial infarction (AMI) is one of the most common and serious cardiovascular diseases. With high morbidity and mortality, AMI has attracted the most attention. Emerging studies indicated that long noncoding RNAs (lncRNAs) play an important role in the progression of AMI. However, the role of NORAD in AMI remained unclear. The current study aimed to investigate the function and mechanism of NORAD in AMI. Bioinformatics tools and a wide range of assays including RT-qPCR, flow cytometry, TTC staining, western blot, luciferase reporter and caspase-3 activity assays were conducted to investigate the function and mechanism of NORAD in AMI. We found out that NORAD was significantly upregulated in AMI rats. Knockdown of NORAD alleviated H9c2 cell injury by reducing apoptosis and decreasing expression levels of fibrogenic factors. In addition, NORAD inhibition ameliorated AMI in a rat model by decreasing infarct size and fibrosis. We confirmed that NORAD bound to miR-577, which was downregulated in ischemia-reperfusion (I/R) rats and hypoxia-exposed H9c2 cells. Additionally, miR-577 combined with the 3'UTR of COBLL1, which was upregulated in I/R rats and hypoxia-exposed H9c2 cells. At last, rescue assay validated that the suppressive effects of NORAD knockdown on apoptosis and expression levels of fibrogenic factors were counteracted by COBLL1 overexpression. Overall, NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via the miR-577/COBLL1 axis. This novel discovery suggested that NORAD may serve as a potential therapeutic target for AMI patients.
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MicroRNAs , Infarto do Miocárdio , RNA Longo não Codificante , Animais , Apoptose , Linhagem Celular , Fibrose , MicroRNAs/genética , Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , Ratos , Fatores de TranscriçãoRESUMO
Nonalcoholic fatty liver disease (NAFLD), ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), is the leading cause of chronic liver diseases. Until now, no medications for NAFLD have been approved by relevant governmental agencies. Dual-specificity phosphatase 9 (Dusp9) is a member of the DUSP protein family. Dusp9 is expressed in insulin-sensitive tissues, and its expression may be modified with the development of insulin resistance (IR). However, the molecular targets and mechanisms of Dusp9 action on NAFLD and NASH remain poorly understood. In this study, using conditional liver-specific Dusp9-knockout (Dusp9-CKO) mice and Dusp9-transgenic mice, we showed that Dusp9 was a key suppressor of high-fat diet-induced hepatic steatosis and inflammatory responses and that Dusp9 deficiency aggravated high-fat high-cholesterol diet-induced liver fibrosis. Dusp9 was shown to exert its effects by blocking apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and the subsequent activation of p38 and c-Jun NH2-terminal kinase signaling. Conclusion: Hepatocyte Dusp9 prevents NAFLD and NASH progression in mice, including lipid accumulation, glucose metabolism disorders, and enhanced inflammation and liver fibrosis, in an ASK1-dependent manner; these findings suggest that Dusp9 may be a promising therapeutic target for the treatment of NAFLD and NASH.
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Fosfatases de Especificidade Dupla/fisiologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/enzimologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low-grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study demonstrated that the expression of dual-specificity phosphatase 26 (Dusp26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses, and insulin resistance were exacerbated in liver-specific Dusp26-knockout (KO) mice but ameliorated in liver-specific Dusp26-transgenic mice induced by a high-fat diet. In addition, the degree of liver fibrosis was aggravated in high-fat high-cholesterol diet-induced Dusp26-KO mice. We further found that the binding of Dusp26 to transforming growth factor beta-activated kinase 1 (TAK1) to block the phosphorylation of TAK1 regulated the TAK1-p38/c-Jun NH2-terminal kinase signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusion: These findings suggest that Dusp26 is a good TAK1-dependent therapeutic target for NAFLD.
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Fosfatases de Especificidade Dupla/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Obesidade/enzimologia , Animais , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Cirrose Hepática/etiologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicaçõesRESUMO
BACKGROUND: This study aimed to investigate the correlation of pro-angiogenic microRNA (miRNA) expressions with rapid angiographic stenotic progression (RASP) and restenosis risks in coronary artery disease (CAD) patients underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: A total of 286 CAD patients underwent PCI with DES were consecutively recruited in this study. Plasma samples were collected before PCI operation, and 14 pro-angiogenic miRNAs were measured by real-time quantitative reverse transcription-polymerase chain reaction. Rapid angiographic stenotic progression at nontarget lesions and restenosis at stented lesions were evaluated by quantitative coronary angiography at 12 months after PCI operation. RESULTS: The occurrence rates of RASP and restenosis were 39.5% and 22.4%, respectively. Let-7f, miR-19a, miR-19b-1, miR-92a, miR-126, miR-210, and miR-296 were decreased in RASP patients than non-RASP patients, among which let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlated with lower RASP occurrence by multivariate analysis, followed by receiver-operating characteristic (ROC) curve exhibited that these five miRNAs showed great value in predicting RASP risk with area under curve (AUC) 0.879 (95% CI: 0.841-0.917). Besides, let-7f, miR-19a, miR-92a, miR-126, miR-130a, and miR-210 were reduced in restenosis patients than non-restenosis patients, among them miR-19a, miR-126, miR-210, and miR-378 independently correlated with lower restenosis occurrence by multivariate analysis, followed by ROC curve disclosed that these four miRNAs had good value in predicting restenosis risk with AUC 0.776 (95% CI: 0.722-0.831). CONCLUSIONS: Circulating let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlate with reduced RASP risk, while miR-19a, miR-126, miR-210, and miR-378 independently correlate with decreased restenosis risk in CAD patients underwent PCI with DES.
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MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Angiografia Coronária , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/etiologia , Estenose Coronária/diagnóstico por imagem , Regulação da Expressão Gênica , Intervenção Coronária Percutânea/efeitos adversos , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Reestenose Coronária/sangue , Reestenose Coronária/genética , Estenose Coronária/sangue , Estenose Coronária/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Fisiológica/genética , Curva ROC , Fatores de RiscoRESUMO
This article discusses regression analysis of right-censored failure time data where there may exist a cured subgroup, and also covariate effects may be varying with time, a phenomena that often occurs in many medical studies. To address the problem, we discuss a class of varying coefficient transformation models along with a logistic model for the cured subgroup. For inference, a sieve maximum likelihood approach is developed with the use of spline functions, and the asymptotic properties of the proposed estimators are established. The proposed method can be easily implemented, and the conducted simulation study suggests that the proposed method works well in practical situations. An illustrative example is provided.
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Algoritmos , Funções Verossimilhança , Modelos Logísticos , Doenças Assintomáticas/terapia , Viés , Simulação por Computador , Humanos , Transplante de Rim , Modelos de Riscos Proporcionais , Análise de RegressãoRESUMO
Regulatory mechanisms for acute inflammatory responses post myocardial infarction (MI) have yet to be fully understood. In particular, the mechanisms by which cardiac macrophages modulate MI-induced myocardial inflammation remains unclear. In this study, using a mouse MI model, we showed that ß-catenin-mediated signaling was activated in cardiac macrophages post-MI, especially in Ly-6C-positive proinflammatory macrophages. Using a RAW264.7-based ß-catenin reporter cell line, we confirmed the presence of active ß-catenin and its downstream signaling in cardiac macrophages after MI. Moreover, lentivirus-mediated inducible expression of constitutively active ß-catenin revealed that ß-catenin plays a role in promoting the inflammatory response by RAW264.7 cells. Depletion of endogenous macrophages and adoptive transfer of active ß-catenin-expressing RAW264.7 cells resulted in enhancement of acute myocardial inflammation in recipient mice after MI, as demonstrated by elevated levels of lymphocyte infiltrates and increased expression of proinflammatory cytokines. However, infarct volume, myocardial tissue repair, and left ventricle function were not influenced by the expression of active ß-catenin in the adoptive transfer assay. Our research has demonstrated that ß-catenin-mediated signaling is important for cardiac macrophages to modulate post-MI inflammatory responses. These findings may be valuable for developing novel therapeutic strategies for MI.
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Inflamação/imunologia , Macrófagos/imunologia , Infarto do Miocárdio/imunologia , Miocárdio/imunologia , beta Catenina/metabolismo , Doença Aguda , Transferência Adotiva , Animais , Antígenos Ly/metabolismo , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , beta Catenina/genéticaRESUMO
BACKGROUND Acute pancreatitis (AP) is a sudden inflammation of the pancreas. It results in multiple, severe complications, and 15-20% of patients develop severe acute pancreatitis (SAP) with mortality as high as 30%. Consequently, it is imperative to develop an effective therapy for SAP. MATERIAL AND METHODS We used 30 adult male Sprague Dawley (SD) rats. Rats were randomly divided into 3 groups - sham, SAP, and fentanyl+SAP - with 10 rats in each group. An automatic biochemical analyzer was used to analyze the concentration of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to assess the cell apoptosis rate. Pathological changes in pancreas/heart were detected with hematoxylin and eosin (HE) staining. Western immunoblot assay was used to analyze protein levels of interleukin (IL)-1ß, IL-6, and IκB. RESULTS Fentanyl pre-treatment inhibits SAP-induced elevation of CK-MB/LDH concentrations in serum. Compared with the sham group, SAP generates a higher brown/yellow staining rate, which is abated by fentanyl. In the pancreas, SAP generated more serious interstitial edema/hemorrhage and fat necrosis than in the sham group, which are attenuated by fentanyl. Likewise, compared to the sham group, SAP generates swelled/disordered myocardial fibers and congested blood vessels in myocardium, which are ameliorated by fentanyl. In the sham group, there was little IL-1ß/IL-6, and fentanyl significantly inhibited SAP-induced up-regulation of IL-1ß/IL-6 levels. Compared with the sham group, SAP significantly reduced IκB level, which was rescued by fentanyl. CONCLUSIONS Fentanyl effectively alleviates SAP-induced pancreas and heart injuries through regulating the nuclear factor-κB (NF-κB) signaling pathway.
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Fentanila/uso terapêutico , Miocárdio/patologia , NF-kappa B/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Transdução de Sinais , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Creatina Quinase Forma MB/metabolismo , Fentanila/farmacologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Inibidor de NF-kappaB alfa/metabolismo , Pancreatite/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) of endotheline receptor gene with the severity of coronary heart disease (CHD). METHODS: A total of 553 CHD patients, including 324 patients with mult-vessel disease based on result of selected coronary angiography, and 553 age- and sex-frequency matched controls were selected. Clinical data were collected. Genotypes of rs501120, rs899997, rs1878406 and rs7173743 were determined with TaqMan-MGB probes. RESULTS: The distribution of genotypes of the 4 SNPs showed no significant difference between the two groups. However, the frequency of A allele of rs501120 and T allele of rs1878406 were significantly higher in the CHD group compared with the control group (P< 0.05). For rs7173743 and rs899997, no significant difference was detected between the two groups. After adjusting for conventional risk factors by logistic regression analysis, the results suggested that the distribution of rs1878406 TT+TC genotype in severe multi-vessel disease group is significantly higher than that in the control group (OR=1.43, 95% CI: 1.05-2.07, P=0.033). CONCLUSION: The above results suggested that the rs1878406 polymorphism of endotheline receptor gene may serve as a genetic marker for severe multi-vessel disease in CHD among ethnic Han Chinese.
Assuntos
Doença das Coronárias/genética , Endotelinas/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Múltiplas Afecções CrônicasRESUMO
BACKGROUND & AIMS: Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an important adapter protein that is largely implicated in molecular events regulating immunity/inflammation and cell death. Although inflammation is closely related to and forms a vicious circle with insulin dysfunction and hepatic lipid accumulation, the role of TRAF1 in hepatic steatosis and the related metabolic disorders remains unclear. METHODS: The participation of TRAF1 in the initiation and progression of hepatic steatosis was evaluated in high fat diet (HFD)-induced and genetic obesity. Mice with global TRAF1 knockout or liver-specific TRAF1 overexpression were employed to investigate the role of TRAF1 in insulin resistance, inflammation, and hepatic steatosis based on various phenotypic examinations. Molecular mechanisms underlying TRAF1-regulated hepatic steatosis were further explored in vivo and in vitro. RESULTS: TRAF1 expression was significantly upregulated in the livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. In response to HFD administration or in ob/ob mice, TRAF1 deficiency was hepatoprotective, whereas the overexpression of TRAF1 in hepatocytes contributed to the pathological development of insulin resistance, inflammatory response and hepatic steatosis. Mechanistically, hepatocyte TRAF1 promotes hepatic steatosis through enhancing the activation of ASK1-mediated P38/JNK cascades, as evidenced by the fact that ASK1 inhibition abolished the exacerbated effect of TRAF1 on insulin dysfunction, inflammation, and hepatic lipid accumulation. CONCLUSIONS: TRAF1 functions as a positive regulator of insulin resistance, inflammation, and hepatic steatosis dependent on the activation of ASK1-P38/JNK axis.
Assuntos
Inflamação/etiologia , Resistência à Insulina , MAP Quinase Quinase Quinase 5/fisiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Fator 1 Associado a Receptor de TNF/fisiologia , Animais , Dieta Hiperlipídica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/fisiologia , Fator 1 Associado a Receptor de TNF/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
BACKGROUND/AIMS: Cardiac fibrosis is the primary cause of deteriorated cardiac function in various cardiovascular diseases. Numerous studies have demonstrated that microRNAs (miRNAs) are critical regulators of myocardial fibrosis. Specifically, many studies have reported that miR-150 is downregulated in cardiovascular diseases, such as acute myocardial infarction (AMI), myocardial hypertrophy and myocardial fibrosis. However, the exact role of miR-150 in these pathological processes remains unknown. METHODS: We used the transverse aortic constriction (TAC) mouse model to study the role of miR-150 in cardiac fibrosis induced by pressure overload. After the TAC operation, qRT-PCR was used to measure the expression profiles of miR-150 in left ventricle tissues and populations of primary heart cell types. Then, we used both miR-150 knockout mice and wild type (WT) mice in the TAC model. Changes in cardiac function and pathology were measured using transthoracic echocardiography and pathological analysis, respectively. Furthermore, we predicted the target of miR-150 in cardiac fibroblasts (CFs) and completed in vitro CF transfection experiments using miR-150 analogs and siRNA corresponding to the predicted target. RESULTS: We observed decreased expression levels of miR-150 in hearts suffering pressure overload, and these levels decreased more sharply in CFs than in cardiomyocytes. In addition, the degrees of cardiac function deterioration and cardiac fibrosis in miR-150-/- mice were more severe than were those in WT mice. By transfecting CFs with an miR-150 analog in vitro, we observed that miR-150 inhibited cardiac fibroblast activation. We predicted that the transcription factor c-Myb was the target of miR-150 in CFs. Transfecting CFs with c-Myb siRNA eliminated the effects of an miR-150 inhibitor, which promoted CF activation. CONCLUSION: These findings reveal that miR-150 acts as a pivotal regulator of pressure overload-induced cardiac fibrosis by regulating c-Myb.
Assuntos
Fibroblastos/patologia , Regulação da Expressão Gênica , MicroRNAs/genética , Miocárdio/citologia , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-myb/genética , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Miofibroblastos/patologiaRESUMO
In event history studies concerning recurrent events, two types of data have been extensively discussed. One is recurrent-event data (Cook and Lawless, 2007. The Analysis of Recurrent Event Data. New York: Springer), and the other is panel-count data (Zhao and others, 2010. Nonparametric inference based on panel-count data. Test 20: , 1-42). In the former case, all study subjects are monitored continuously; thus, complete information is available for the underlying recurrent-event processes of interest. In the latter case, study subjects are monitored periodically; thus, only incomplete information is available for the processes of interest. In reality, however, a third type of data could occur in which some study subjects are monitored continuously, but others are monitored periodically. When this occurs, we have mixed recurrent-event and panel-count data. This paper discusses regression analysis of such mixed data and presents two estimation procedures for the problem. One is a maximum likelihood estimation procedure, and the other is an estimating equation procedure. The asymptotic properties of both resulting estimators of regression parameters are established. Also, the methods are applied to a set of mixed recurrent-event and panel-count data that arose from a Childhood Cancer Survivor Study and motivated this investigation.
Assuntos
Funções Verossimilhança , Análise de Regressão , HumanosRESUMO
BACKGROUND: Supercritical carbon dioxide (SC-CO2 ) has been shown to have a good pasteurising effect on food. However, very few research papers have investigated the possibility to exploit this treatment for solid foods, particularly for seafood. Considering the microbial safety of raw seafood consumption, the study aimed to explore the feasibility of microbial inactivation of shrimp (Metapenaeus ensis) and conch (Rapana venosa) by SC-CO2 treatment. RESULTS: Response surface methodology (RSM) models were established to predict and analyse the SC-CO2 process. A 3.69-log reduction in the total aerobic plate count (TPC) of shrimp was observed by SC-CO2 treatment at 53°C, 15 MPa for 40 min, and the logarithmic reduction in TPC of conch was 3.31 at 55°C, 14 MPa for 42 min. Sensory scores of the products achieved approximately 8 (desirable). The optimal parameters for microbial inactivation of shrimp and conch by SC-CO2 might be 55°C, 15 MPa and 40 min. CONCLUSION: SC-CO2 exerted a strong bactericidal effect on the TPC of shrimp and conch, and the products maintained good organoleptic properties. This study verified the feasibility of microbial inactivation of shrimp and conch by SC-CO2 treatment.
Assuntos
Dióxido de Carbono/química , Conservação de Alimentos , Gastrópodes/microbiologia , Bactérias Aeróbias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/crescimento & desenvolvimento , Penaeidae/microbiologia , Frutos do Mar/microbiologia , Animais , China , Contagem de Colônia Microbiana , Estudos de Viabilidade , Conservação de Alimentos/instrumentação , Alimentos Congelados/análise , Alimentos Congelados/microbiologia , Gastrópodes/química , Bactérias Aeróbias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Temperatura Alta , Humanos , Viabilidade Microbiana , Penaeidae/química , Transição de Fase , Pressão , Sensação , Frutos do Mar/análise , Frutos do Mar/economia , Estatística como Assunto , Fatores de TempoRESUMO
The growing utilization of Traditional Chinese Medicine (TCM) has resulted in an increase in wastewater. Herein, a new kind of organic-inorganic redox mediator membrane by immobilizing γ-FeO(OH) and aloe-emodin(AE) with the characteristic large π-conjugation anthraquinone structure on PVDF membrane was innovatively achieved. AE exhibiting both electron deficiency and redox activity possesses a co-catalyst role in degradation of tannic acid (TA), aiding in the separation of charge carriers through the sequential hydrogenation and dehydrogenation of AE. The removal rates of TA were 92.8 % in the tannic acid solution and 60.3 % in the simulated rhubarb wastewater by the AE-γ-FeO(OH) membrane under PMS+Vis conditions in 45 min. Also, they show a higher recovery of pure water flux and owning good fouling performance. Overall, this current work presents a novel approach for the design and preparation of organic-inorganic photocatalytic composite membrane using readily available natural products for the purification TCM wastewater.