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BACKGROUND: Colchicine has been approved to reduce cardiovascular risk in patients with coronary heart disease on the basis of its potential benefits demonstrated in the COLCOT (Colchicine-Optical Coherence Tomography Trial) and LoDoCo2 studies. Nevertheless, there are limited data available about the specific impact of colchicine on coronary plaques. METHODS: This was a prospective, single-center, randomized, double-blind clinical trial. From May 3, 2021, until August 31, 2022, a total of 128 patients with acute coronary syndrome aged 18 to 80 years with lipid-rich plaque (lipid pool arc >90°) detected by optical coherence tomography were included. The subjects were randomly assigned in a 1:1 ratio to receive either colchicine (0.5 mg once daily) or placebo for 12 months. The primary end point was the change in the minimal fibrous cap thickness from baseline to the 12-month follow-up. RESULTS: Among 128 patients, 52 in the colchicine group and 52 in the placebo group completed the study. The mean age of the 128 patients was 58.0±9.8 years, and 25.0% were female. Compared with placebo, colchicine therapy significantly increased the minimal fibrous cap thickness (51.9 [95% CI, 32.8 to 71.0] µm versus 87.2 [95% CI, 69.9 to 104.5] µm; difference, 34.2 [95% CI, 9.7 to 58.6] µm; P=0.006), and reduced average lipid arc (-25.2° [95% CI, -30.6° to -19.9°] versus -35.7° [95% CI, -40.5° to -30.8°]; difference, -10.5° [95% CI, -17.7° to -3.4°]; P=0.004), mean angular extension of macrophages (-8.9° [95% CI, -13.3° to -4.6°] versus -14.0° [95% CI, -18.0° to -10.0°]; difference, -6.0° [95% CI, -11.8° to -0.2°]; P=0.044), high-sensitivity C-reactive protein level (geometric mean ratio, 0.6 [95% CI, 0.4 to 1.0] versus 0.3 [95% CI, 0.2 to 0.5]; difference, 0.5 [95% CI, 0.3 to 1.0]; P=0.046), interleukin-6 level (geometric mean ratio, 0.8 [95% CI, 0.6 to 1.1] versus 0.5 [95% CI, 0.4 to 0.7]; difference, 0.6 [95% CI, 0.4 to 0.9]; P=0.025), and myeloperoxidase level (geometric mean ratio, 1.0 [95% CI, 0.8 to 1.2] versus 0.8 [95% CI, 0.7 to 0.9]; difference, 0.8 [95% CI, 0.6 to 1.0]; P=0.047). CONCLUSIONS: Our findings suggested that colchicine resulted in favorable effects on coronary plaque stabilization at optical coherence tomography in patients with acute coronary syndrome. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04848857.
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Sacubitril/valsartan (Sac/Val) is a recently approved drug that is commonly used for treatment of heart failure. Several studies indicated that Sac/Val also regulated the secretion of inflammatory factors. However, the effect and mechanism of this drug modulation of inflammatory immune responses are uncertain. In this study, an experimental autoimmune myocarditis (EAM) mouse model was established by injection of α-myosin-heavy chain peptides. The effect of oral Sac/Val on EAM was evaluated by histological staining of heart tissues, measurements of cardiac troponin T and inflammatory markers (IL-6 and hsCRP). The effects of Sac/Val on NLRP3 inflammasome activation and Th1/Th17 cell differentiation were also determined. To further explore the signaling pathways, the expressions of cardiac soluble guanylyl cyclase (sGC) and NF-κB p65 were investigated. The results showed that Sac/Val downregulated the inflammatory response and attenuated the severity of EAM, but did not influence NLRP3 inflammasomes activation. Moreover, Sac/Val treatment inhibited cardiac Th17 cell differentiation, and this might be associated with sGC/NF-κB p65 signaling pathway. These findings indicate the potential use of Sac/Val for treatment of myocarditis.
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Indigenous animals show unique gut microbiota (GM) in the Tibetan plateau. However, it is unknown whether the hypertensive indigenous people in plateau also have the distinct gut bacteria, different from those living in plains. We sequenced the V3-V4 region of the gut bacteria 16S ribosomal RNA (rRNA) gene of feces samples among hypertensive patients (HPs) and healthy individuals (HIs) from 3 distinct altitudes: Tibetans from high altitude (3600-4500 m, n = 38 and 34), Hans from middle altitude (2260 m, n = 49 and 35), and Hans from low altitude (13 m, n = 34 and 35) and then analyzed the GM composition among hypertensive and healthy subgroups using the bioinformatics analysis, respectively. The GM of high-altitude Tibetan and middle-altitude Han HPs presented greater α- and ß-diversities, lower ratio of Firmicutes/Bacteroidetes (F/B), and higher abundance of beneficial Verrucomicrobia and Akkermansia than the low-altitudes HPs did. The GM of high-altitude Tibetan and middle-altitude HIs showed greater α-diversity and lower ratio of F/B than the low-altitudes HIs did. But, ß-diversity and abundance of Verrucomicrobia and Akkermansia among different subgroups of HIs did not show any differences. Conclusively, the high-altitude Tibetan and middle-altitude Han HPs have a distinct feature of GM, which may be important in their adaptation to hypertension in the plateau environments.
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Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Hospitalização/tendências , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Troponina I/sangue , Idoso , Biomarcadores/sangue , COVID-19 , Infecções por Coronavirus/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Pandemias , Pneumonia Viral/diagnóstico , Valor Preditivo dos Testes , SARS-CoV-2RESUMO
AIMS: A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts. METHODS AND RESULTS: Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ, granzyme B, and perforin. CONCLUSION: We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.
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Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Clonais/metabolismo , Progressão da Doença , Granzimas/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Memória Imunológica/genética , Interferon gama/metabolismo , Isquemia , Infarto do Miocárdio/metabolismo , Perforina/metabolismo , Fenótipo , Remodelação VentricularRESUMO
Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI). Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling. Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival. Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.
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Coração/fisiologia , Interleucinas/administração & dosagem , Fígado/metabolismo , Infarto do Miocárdio/patologia , Regeneração , Animais , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/análise , Perfilação da Expressão Gênica , Testes de Função Cardíaca , Injeções Subcutâneas , Camundongos , Fator de Transcrição STAT3/análise , Remodelação Ventricular , Interleucina 22RESUMO
The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.
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Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Epistasia Genética , Regulação da Expressão Gênica , Interleucina-33/genética , Receptores de Citocinas/genética , Idoso , Alelos , Estudos de Casos e Controles , China , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Citocinas/sangue , Citocinas/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-33/metabolismo , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Receptores de Citocinas/metabolismo , Receptores de Interleucina-7/genética , Transdução de Sinais , Linfopoietina do Estroma do TimoRESUMO
Interleukin-13 (IL-13) has important functions in atherosclerosis, but its role in coronary artery disease (CAD) is unclear. Here, we studied the genetic role of IL-13 in CAD in a Chinese Han population using tag SNPs covering the whole IL13 gene (i.e., rs1881457, rs2069744 and rs20541) and a two-stage cohort containing 1863 CAD cases and 1841 controls. Traditional risk factors for CAD, such as age, BMI, and other factors, were used as covariates in logistic regression analysis. In the total population, we found that two haplotypes of IL13 (ATG and ATA, ordered rs1881457C-rs2069744T-rs20541A) significantly contributed to the risk of CAD with adjusted p values less than 0.05 (padj = 0.019 and padj = 0.042, respectively). In subgroup population analyses, the variant rs1881457C was found to significantly contribute to a nearly two fold increase in the risk of CAD in men (padj = 0.023, OR = 1.91, 95% CI: 1.09-3.33). The variant rs1881457C also significantly contributed to a nearly twofold risk of late-onset CAD (padj = 0.024, OR = 1.93, 95% CI: 1.09-3.42). In conclusion, IL13 might be involved in CAD via different mechanisms under different conditions in the Chinese Han population.
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Povo Asiático/genética , Doença da Artéria Coronariana/etiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Interleucina-13/genética , Adulto , Alelos , Estudos de Casos e Controles , China/epidemiologia , Comorbidade , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/metabolismo , Feminino , Humanos , Interleucina-13/metabolismo , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Medição de RiscoRESUMO
BACKGROUND/AIMS: Newly identified IL-10-producing regulatory B cells (Bregs) have been shown to play an important role in the suppression of immune responses. Chronic immune activation participates in the pathogenesis of dilated cardiomyopathy (DCM) but whether Bregs are involved in its development remains unclear. We aimed to investigate the circulating frequency and function of Bregs in DCM. METHODS: In total, 35 DCM patients (20 men and 15 women) and 44 healthy controls (23 men and 21 women) were included in the experiment, and the frequency of Bregs was detected using flow cytometry. RESULTS: According to our results, the frequency of circulating IL-10-producing Bregs was significantly lower in DCM patients compared with healthy controls. Furthermore, the CD24hiCD27+ B cell subset in which IL-10-producing Bregs were mainly enriched from DCM patients showed impaired IL-10 expression and a decreased ability to suppress the TNF-α production of CD4+CD25- Tconv cells and to maintain Tregs differentiation. Correlation analysis showed that the frequency of IL-10-producing Bregs and the suppressive function of CD24hiCD27+ B cells were positively correlated with left ventricular ejection fraction and negatively correlated with NT-proBNP in DCM patients. CONCLUSIONS: In conclusion, the reduced frequency and impaired functions suggest a potential role of Bregs in the development of DCM.
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Linfócitos B Reguladores/metabolismo , Cardiomiopatia Dilatada/patologia , Adulto , Idoso , Linfócitos B Reguladores/citologia , Antígeno CD24/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In this study, we prepared DPPBTDA, a diketopyrrolopyrrole-based small molecule presenting a terminal cross-linkable azido group, as a cathode modifying layer for organic photovoltaics (OPVs) having the inverted device structure glass/indium tin oxide/zinc oxide (ZnO) with or without the interfacial layer (IFL)/active layer/MoO3/Ag. The active layer comprising a blend of poly[4,8-bis(5-(2-ethylhexyl)thien-2-yl)benzo[1,2- b;4,5- b']dithiophene-2,6-diyl- alt-(4-(2-ethylhexyl)-3-fluorothieno[3,4- b]thiophene)-2-carboxylate-2,6-diyl] (PTB7-Th) as the electron donor and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as the electron acceptor. Atomic force microscopy, space-charge-limited current mobility, surface energy, electron spectroscopy for chemical analysis depth profile, ultraviolet photoelectron spectroscopy analysis, and OPV performance data revealed that the surface status of ZnO changed after inserting the DPPBTDA/PCBM hybrid IFL and induced an optimized blend morphology, having a preferred gradient distribution of the conjugated polymer and PC71BM, for efficient carrier transport. The power conversion efficiency (AM 1.5 G, 1000 W m-2) of the device incorporating the hybrid IFL increased to 9.4 ± 0.11% from 8.5 ± 0.15% for the preoptimized PTB7-Th/PCBM device (primarily because of an enhancement in the fill factor from 68.7 ± 1.1 to 72.1 ± 0.8%).
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Transient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia/reperfusion (I/R). Recently, we found that treatment with a selective TRPV4 antagonist HC-067047 significantly reduced infarct size, decreased troponin T levels and improved cardiac function in murine model myocardial I/R. This study was undertaken to investigate the mechanism underlying TRPV4-mediated myocardial I/R injury. To mimic myocardial I/R injury, we established a hypoxia/reoxygenation (H/R) model in H9C2 cells and neonatal rat ventricle myocytes (NRVMs) in vitro. TRPV4 mRNA and protein expression was confirmed in the H9C2 and NRVM, whereas functional TRPV4 activity was assessed from Ca2+ influx response to a TRPV4 agonist GSK1016790A. TRPV4 functional expression was significantly enhanced during H/R. Furthermore, H/R increased the intracellular Ca2+ concentration ([Ca2+]i) and induced cell injury, which were reversed by HC-067047 but was further aggravated by GSK1016790A. Moreover, HC-067047 treatment significantly alleviated the increase of reactive oxygen species (ROS) generation, the depolarization of mitochondrial membrane potential (Δψm) and the opening of mitochondrial permeability transition pore (mPTP) during H/R. On the contrary, GSK1016790A exacerbated those effects. Meanwhile, increase in [Ca2+]i and ROS induced by activation of TRPV4 was almost abolished when cells were cultured in Ca2+-free medium. In addition, ROS scavenger NAC obviously reversed activation of TRPV4-induced changes of Δψm and mPTP opening. Finally, we confirmed the direct roles of TRPV4 on cardiac injury and ROS generation in murine model myocardial I/R in vivo. In conclusion, activation of TRPV4 induces Ca2+ influx in cardiomyocytes, with subsequent ROS release, depolarizing of Δψm, opening mPTP, inducing injury and TRPV4 has key roles during I/R via these pathways.
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Hipóxia/metabolismo , Hipóxia/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxigênio/farmacologia , Canais de Cátion TRPV/metabolismo , Animais , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Citoplasma/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Morfolinas/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Pirróis/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R). This study tested whether blockade of TRPV4 can alleviate myocardial I/R injury in mice. TRPV4 expression began to increase at 1 h, reached statistically at 4 h, and peaked at 24-72 h. Treatment with the selective TRPV4 antagonist HC-067047 or TRPV4 knockout markedly ameliorated myocardial I/R injury as demonstrated by reduced infarct size, decreased troponin T levels and improved cardiac function at 24 h after reperfusion. Importantly, the therapeutic window for HC-067047 lasts for at least 12 h following reperfusion. Furthermore, treatment with HC-067047 reduced apoptosis, as evidenced by the decrease in TUNEL-positive myocytes, Bax/Bcl-2 ratio, and caspase-3 activation. Meanwhile, treatment with HC-067047 attenuated the decrease in the activation of reperfusion injury salvage kinase (RISK) pathway (phosphorylation of Akt, ERK1/2, and GSK-3ß), while the activation of survival activating factor enhancement (SAFE) pathway (phosphorylation of STAT3) remained unchanged. In addition, the anti-apoptotic effects of HC-067047 were abolished by the RISK pathway inhibitors. We conclude that blockade of TRPV4 reduces apoptosis via the activation of RISK pathway, and therefore might be a promising strategy to prevent myocardial I/R injury.
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Traumatismo por Reperfusão Miocárdica/genética , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Expressão Gênica , Técnicas de Inativação de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Testes de Função Cardíaca , Camundongos , Terapia de Alvo Molecular , Morfolinas/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismoRESUMO
Previous investigations have shown that changes in total prostate volume (TPV) are highly variable among aging men, and a considerable proportion of aging men have a stable or decreasing prostate size. Although there is an abundance of literature describing prostatic enlargement in association with benign prostatic hyperplasia, less is known about the appropriate age cut-off points for TPV growth rate. In this community-based cohort study, TPV was examined once a year in men who had consecutive health checkup, during a follow-up of 4 years. A total of 5058 men (age 18-92 years old) were included. We applied multiple regression analyses to estimate the correlation between TPV growth rate and age. Overall, 3232 (63.9%) men had prostate growth, and 1826 (36.1%) had a stable or decreased TPV during the study period. The TPV growth rate was correlated negatively with baseline TPV (r=-0.32, P<0.001). Among 2620 men with baseline TPV <15 cm3, the TPV growth rate increased with age (ß=0.98, 95% CI: 0.77%-1.18%) only up to 53 years old. Among 2188 men with baseline TPV of 15-33.6 cm3, the TPV growth rate increased with age (ß=0.84, 95% CI, 0.66%-1.01%) only up to 61 years old after adjusting for factors of hypertension, obesity, baseline TPV, diabetes mellitus and dyslipidemia. In this longitudinal study, the TPV growth rate increased negatively with baseline TPV, only extending to a certain age and not beyond. Further research is needed to identify the mechanism underlying such differences in prostate growth.
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Próstata/crescimento & desenvolvimento , Hiperplasia Prostática/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Tamanho do Órgão , Próstata/patologia , Características de Residência/estatística & dados numéricosRESUMO
Th17 cells play a key role in the progression of coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). However, the direct effect of virus on Th17 cell differentiation is still unknown. Recently, nucleoporin (Nup) 98 has been proved to be associated with lymphocyte differentiation. Therefore, we investigated whether Nup98 mediated Th17 cell differentiation in AVMC. In our study, patients with AVMC and healthy controls were recruited. The results showed that CVB3 could enter into the CD4+ T cells in AVMC patients and healthy controls. After transfecting purified CD4+ T cells with CVB3 in vitro, the Th17 cell frequency, IL-17 secretion, and RORγT synthesis were increased while the Nup98 levels were decreased. Furthermore, down-regulating Nup98 expression by siRNA-Nup98 in CD4+ T cells resulted in the elevated Th17 cell frequency and IL-17 secretion, along with enhanced levels of RORγT, dissociative p300/CBP, and acetylated Stat3. Up-regulation of Nup98 expression by pcDNA3.1-Nup98 showed the opposite effects. Our results suggested that CVB3 directly induced CD4+ T cell differentiation into Th17 cells by inhibiting Nup98 expression, representing a therapeutic target in AVMC.
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Diferenciação Celular , Infecções por Coxsackievirus/virologia , Enterovirus/patogenicidade , Miocardite/virologia , Complexo de Proteínas Formadoras de Poros Nucleares/efeitos dos fármacos , Células Th17/virologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus , Infecções por Coxsackievirus/sangue , Enterovirus/isolamento & purificação , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-17/metabolismo , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Fator de Transcrição STAT3 , Adulto JovemRESUMO
Myocardial injuries in viral myocarditis (VMC) are caused by viral infection and related autoimmune disorders. Recent studies suggest that IL-9 mediated both antimicrobial immune and autoimmune responses in addition to allergic diseases. However, the role of IL-9 in viral infection and VMC remains controversial and uncertain. In this study, we infected Balb/c mice with Coxsackievirus B3 (CVB3), and found that IL-9 was enriched in the blood and hearts of VMC mice on days 5 and 7 after virus infection. Most of IL-9 was secreted by CD8+ T cells on day 5 and CD4+ T cells on day 7 in the myocardium. Further, IL-9 knockout exacerbated cardiac damage following CVB3 infection, along with a sharp increase in viral replication and IL-17a expression, as well as a decrease in TGF-ß. In contrast, the repletion of IL-9 in Balb/c mice with CVB infection induced the opposite effect. Studies in vitro further revealed that IL-9 directly inhibited viral replication in cardiomyocytes by reducing coxsackie and adenovirus receptor expression, which might be associated with upregulation of TGF-ß autocrine effect in these cells. However, IL-9 had no direct effect on apoptosis in cardiomyocytes. Our data indicated that IL-9 played a protective role in disease progression by inhibiting CVB3 replication in the early stages of VMC.
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B cells contribute to the development of dilated cardiomyopathy (DCM) by inducing myocyte injuries and myocardial fibrosis. Our recent research indicated that microRNA (miR) -185 participated in human B-cell activation. Thus, this study was aimed to explore the relationship between miR-185 and DCM progression. Forty-one healthy volunteers and fifty newly diagnosed DCM patients were enrolled. The levels of plasma miR-185, TNF-α secreting B cells, and anti-heart autoantibody were detected. We found that the mean levels of plasma miR-185 in DCM patients were significantly higher than those in healthy controls. Furthermore, these DCM patients could be divided into miR-185(high) and miR-185(low) groups according to the cluster distribution. During one-year follow-up period, the miR-185(high) group showed apparent improvements in left ventricular ejection fraction, left ventricular end diastolic diameter, and NT-proBNP, accompanied by significant declines in both cardiovascular mortality and total admissions for heart failure re-hospitalizations. In addition, the levels of anti-ß1-AR antibody and TNF-α secreting B cells were also reduced in miR-185(high) group. These findings suggested that high miR-185 levels might be associated with a favorable prognosis by repressing B cell function in DCM. The findings of this study need to be confirmed with larger sample size and longer duration of observation.
Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , MicroRNA Circulante , MicroRNAs/genética , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/mortalidade , Estudos de Casos e Controles , Feminino , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Avaliação de Sintomas , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Postoperative atrial fibrillation is a frequent complication in cardiac surgery. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) contributes to the pathogenesis of atrial fibrillation. MicroRNA-21 (miR-21) promotes atrial fibrosis. Recent studies support the existence of reciprocal regulation between STAT3 and miR-21. Here, we test the hypothesis that these 2 molecules might form a feedback loop that contributes to postoperative atrial fibrillation by promoting atrial fibrosis. METHODS AND RESULTS: A sterile pericarditis model was created using atrial surfaces dusted with sterile talcum powder in rats. The inflammatory cytokines interleukin (IL)-1ß, IL-6, transforming growth factor-ß, and tumor necrosis factor-α, along with STAT3 and miR-21, were highly upregulated in sterile pericarditis rats. The inhibition of STAT3 by S3I-201 resulted in miR-21 downregulation, which ameliorated atrial fibrosis and decreased the expression of the fibrosis-related genes, α-smooth muscle actin, collagen-1, and collagen-3; reduced the inhomogeneity of atrial conduction; and attenuated atrial fibrillation vulnerability. Meanwhile, treatment with antagomir-21 decreased STAT3 phosphorylation, alleviated atrial remodeling, abrogated sterile pericarditis-induced inhomogeneous conduction, and prevented atrial fibrillation promotion. The culturing of cardiac fibroblasts with IL-6 resulted in progressively augmented STAT3 phosphorylation and miR-21 levels. S3I-201 blocked IL-6 induced the expression of miR-21 and fibrosis-related genes in addition to cardiac fibroblast proliferation. Transfected antagomir-21 decreased the IL-6-induced cardiac fibroblast activation and STAT3 phosphorylation. The overexpression of miR-21 in cardiac fibroblasts caused the upregulation of STAT3 phosphorylation, enhanced fibrosis-related genes, and increased cell numbers. CONCLUSIONS: Our results have uncovered a novel reciprocal loop between STAT3 and miR-21 that is activated after heart surgery and can contribute to atrial fibrillation.
Assuntos
Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , MicroRNAs/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Fibrilação Atrial/cirurgia , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/fisiopatologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pericardite/fisiopatologia , Fosforilação , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
BACKGROUND: High-sensitivity cardiac troponin is the most specific and sensitive biomarker of myocardial injury. However, no study has investigated whether the early concentration of high-sensitivity cardiac troponin is increased or is of value in predicting short-term prognosis in patients with type-A acute aortic dissection (AAD) in the emergency department. AIMS: To measure the high-sensitivity cardiac troponin T (hs-TnT) concentration in patients with type-A AAD upon hospital admission, and to assess its value in predicting short-term prognosis. METHODS: We enrolled consecutive patients with type-A AAD. Blood samples were collected on admission; hs-TnT concentrations were measured on the Elecsys 2010 system. High-sensitivity C-reactive protein (hs-CRP), D-dimer and other biochemical indicators were measured. Patients were divided into two groups according to hs-TnT concentration on admission (< or ≥0.014ng/mL). RESULTS: More than half (61.2%) of the 103 included patients had an hs-TnT concentration ≥0.014ng/mL. hs-TnT concentrations were significantly higher in those who died compared with survivors (0.292±0.516 vs. 0.069±0.154ng/mL; P=0.003). Multivariable Cox regression analysis suggested that hs-TnT is an independent factor for predicting in-hospital mortality risk (odds ratio: 2.202, 95% confidence interval: 1.111-4.367; P=0.024). Kaplan-Meier curves revealed a significant increase in hospital mortality in the hs-TnT(+) group compared with the hs-TnT(-) group (P=0.021). When hs-TnT was ≥0.042ng/mL, the sensitivity and specificity in predicting hospital short-term mortality were 70.8% and 76.4%, respectively. CONCLUSIONS: Our study suggests that hs-TnT concentration could be used as an early biomarker for the risk stratification of patients with type-A AAD in the emergency department; the relationship between hs-TnT concentration and long-term prognosis needs further investigation.