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Vascular inflammation is an early manifestation and common pathophysiological basis of numerous cardiovascular and cerebrovascular diseases. However, effective surveillance methods are lacking. In this study, sulfur hexafluoride (SF6 )-loaded polylactic acid-co-glycolic acid (PLGA) nanobubbles (NBs) with a surface assembly of cyclodextrin (CD) and sphingosine-1-phosphate (S1P) (S1P@CD-PLGA NBs) are designed. The characterization results show that S1P@CD-PLGA NBs with diameters of ≈200 nm have good stability, biosafety, and ultrasound imaging-enhancement effects. When interacting with inflammatory vascular endothelial cells, S1P molecules encapsulated in cyclodextrin cavities exhibit a rapid, excellent, and stable targeting effect owing to their specific interaction with the highly expressed S1P receptor 1 (S1PR1) on the inflammatory vascular endothelial cells. Particularly, the S1P-S1PR1 interaction further activates the downstream signaling pathway of S1PR1 to reduce the expression of tumor necrosis factor-α (TNF-α) to protect endothelial cells. Furthermore, mouse models of carotid endothelial injuries and mesenteric thrombosis demonstrate that S1P@CD-PLGA NBs have excellent capabilities for in vivo targeting imaging. In summary, this study proposes a new strategy of using S1P to target inflammatory vascular endothelial cells while reducing the expression of TNF-α, which has the potential to be utilized in the targeted surveillance and treatment of vascular inflammatory diseases.
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Ciclodextrinas , Células Endoteliales , Ratones , Animales , Receptores de Esfingosina-1-Fosfato , Factor de Necrosis Tumoral alfaRESUMEN
Reactive oxygen species (ROS) play an essential role in macrophage polarization. However, the adverse effects of ROS reduction by influencing epigenetics are often ignored. In this study, lipopolysaccharide (LPS) was used to stimulate macrophages to increase the ROS in cells, and N-acetylcysteine (NAC) was used to reduce ROS. Inflammatory factors such as interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were used to evaluate the M1 polarization level of macrophages. Chip was used to detect the tri-methylation at lysine 27 of histone H3 (H3K27me3) level at the promoter site. It was found that the decrease of ROS in macrophages would also cause the increase of the H3K27me3 demethylase KDM6A and lead to the reduction of H3K27me3 in the NOX2 promoter, which would increase the transcription level of NOX2 and the production of ROS and ultimately promote the production of inflammatory factors. Knockout of KDM6A can reduce the transcription of NOX2 and the production of ROS of macrophages, thus preventing the M1 polarization of macrophages. The elimination of ROS in macrophages will affect macrophages by increasing KDM6A and making them produce more ROS, thus inducing oxidative stress. In comparison, direct inhibition of KDM6A can reduce ROS production and inhibit macrophage M1 polarization more effectively.
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Histonas , Macrófagos , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Interleucina-6/metabolismo , Histona Demetilasas/farmacologíaRESUMEN
Background Myocardial infarction (MI) is a cardiovascular disease with high morbidity and mortality. PI16 (peptidase inhibitor 16), as a secreted protein, is highly expressed in heart diseases such as heart failure. However, the functional role of PI16 in MI is unknown. This study aimed to investigate the role of PI16 after MI and its underlying mechanisms. Methods and Results PI16 levels after MI were measured by enzyme-linked immunosorbent assay and immunofluorescence staining, which showed that PI16 was upregulated in the plasma of patients with acute MI and in the infarct zone of murine hearts. PI16 gain- and loss-of-function experiments were used to investigate the potential role of PI16 after MI. In vitro, PI16 overexpression inhibited oxygen-glucose deprivation-induced apoptosis in neonatal rat cardiomyocytes, whereas knockdown of PI16 exacerbated neonatal rat cardiomyocyte apoptosis. In vivo, left anterior descending coronary artery ligation was performed on PI16 transgenic mice, PI16 knockout mice, and their littermates. PI16 transgenic mice showed decreased cardiomyocyte apoptosis at 24 hours after MI and improved left ventricular remodeling at 28 days after MI. Conversely, PI16 knockout mice showed aggravated infract size and remodeling. Mechanistically, PI16 downregulated Wnt3a (wingless-type MMTV integration site family, member 3a)/ß-catenin pathways, and the antiapoptotic role of PI16 was reversed by recombinant Wnt3a in oxygen-glucose deprivation-induced neonatal rat cardiomyocytes. PI16 also inhibited HDAC1 (class I histone deacetylase) expression, and overexpression HDAC1 abolished the inhibition of apoptosis and Wnt signaling of PI16. Conclusions In summary, PI16 protects against cardiomyocyte apoptosis and left ventricular remodeling after MI through the HDAC1-Wnt3a-ß-catenin axis.
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Infarto del Miocardio , Remodelación Ventricular , Ratones , Ratas , Animales , Remodelación Ventricular/fisiología , beta Catenina/metabolismo , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Ratones Transgénicos , Ratones Noqueados , Apoptosis/fisiología , Inhibidores de Proteasas , Modelos Animales de Enfermedad , Histona Desacetilasa 1/genéticaRESUMEN
The relationship between aldehyde exposure and metabolic syndrome is unclear; hence, we aimed to investigate the association between serum aldehyde concentrations and metabolic syndrome. We analyzed the data of 1471 participants from the National Health and Nutrition Examination Survey enrolled from 2013 to 2014. The association of serum aldehyde concentrations with metabolic syndrome was assessed via generalized linear models as well as restricted cubic splines, and endpoint events were further analyzed. After adjusting for covariates, both moderate (odds ratio [OR] = 2.73, 95% confidence interval [CI]: 1.34-5.56) and high (OR = 2.08, 95% CI: 1.06-4.07) concentrations of isovaleraldehyde were associated with the risk of metabolic syndrome. Interestingly, although a moderate concentration of valeraldehyde was associated with the risk of metabolic syndrome (OR = 1.08, 95% CI: 0.70-1.65), a high concentration was not (OR = 0.55, 95% CI: 0.17-1.79). Restricted cubic splines revealed a non-linear association between valeraldehyde and metabolic syndrome, and threshold effect analysis revealed that the inflection point for valeraldehyde concentration was 0.7 ng/mL. The results of the subgroup analysis revealed differences in the relationship of aldehyde exposure with components of metabolic syndrome. High isovaleraldehyde concentrations may increase the risk of metabolic syndrome, and valeraldehyde demonstrated a J-shaped relationship with the risk of metabolic syndrome.
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Síndrome Metabólico , Adulto , Humanos , Síndrome Metabólico/epidemiología , Encuestas Nutricionales , AldehídosRESUMEN
BACKGROUND: Cerebral ischemia-reperfusion injury (CIR) following a stroke results in secondary damage and is a leading cause of adult disability. The present study aimed to identify hub genes and networks in CIR to explore potential therapeutic agents for its treatment. METHODS: Differentially expressed genes based on the GSE23163 dataset were identified, and weighted gene co-expression network analysis was performed to explore co-expression modules associated with CIR. Hub genes were identified by intersecting immune gene profiles, differentially expressed genes, and modular genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and transcription factor-microRNA-gene regulatory network analyses were then conducted in selected crucial modules. Subsequently, their expression levels in animal models were verified using real-time quantitative polymerase chain reaction and Western blotting. Finally, potential drug molecules were screened for, and molecular docking simulations were performed to identify potential therapeutic targets. RESULTS: Seven hub genes-namely, Ccl3, Ccl4, Ccl7, Cxcl1, Hspa1a, Cd14, and Socs3-were identified. Furthermore, we established a protein interaction network using the STRING database and found that the core genes selected through the cytohubba plugin remained consistent. Animal experiments showed that at the transcriptional level, all seven genes showed significant differences (p < 0.001, fold change vs sham, 5-200). At the translational level, however, only Ccl3, Ccl4, Ccl7, Hspa1a, and Socs3 showed significant differences, while Cxcl1 and Cd14 did not. Nifedipine, with the highest predicted score, was identified as a therapeutic agent and successfully docked with the protein encoded by the hub genes. CONCLUSIONS: The expression of Ccl3, Ccl4, Ccl7, Hspa1a, and Socs3 was significantly different in CIR tissues compared to normal tissues both at the transcriptional and translational levels. Systems biology approaches indicated that these could be possible CIR marker genes, providing a stepping stone for further experimental studies.
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Isquemia Encefálica , Daño por Reperfusión , Animales , Simulación del Acoplamiento Molecular , Reperfusión , Daño por Reperfusión/genética , Biología Computacional , BiomarcadoresRESUMEN
BACKGROUND: Dilated cardiomyopathy (DCM) is one of the main causes of systolic heart failure and frequently has a genetic component. The molecular mechanisms underlying the onset and progression of DCM remain unclear. This study aimed to identify novel diagnostic biomarkers to aid in the treatment and diagnosis of DCM. METHOD: The Gene Expression Omnibus (GEO) database was explored to extract two microarray datasets, GSE120895 and GSE17800, which were subsequently merged into a single cohort. Differentially expressed genes were analyzed in the DCM and control groups, followed by weighted gene coexpression network analysis to determine the core modules. Core nodes were identified by gene significance (GS) and module membership (MM) values, and four hub genes were predicted by the Lasso regression model. The expression levels and diagnostic values of the four hub genes were further validated in the datasets GSE19303. Finally, potential therapeutic drugs and upstream molecules regulating genes were identified. RESULTS: The turquoise module is the core module of DCM. Four hub genes were identified: GYPC (glycophorin C), MLF2 (myeloid leukemia factor 2), COPS7A (COP9 signalosome subunit 7A) and ARL2 (ADP ribosylation factor like GTPase 2). Subsequently, Hub genes showed significant differences in expression in both the dataset and the validation model by real-time quantitative PCR (qPCR). Four potential modulators and seven chemicals were also identified. Finally, molecular docking simulations of the gene-encoded proteins with small-molecule drugs were successfully performed. CONCLUSIONS: The results suggested that ARL2, MLF2, GYPC and COPS7A could be potential gene biomarkers for DCM.
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Cardiomiopatía Dilatada , Biomarcadores , Complejo del Señalosoma COP9/genética , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Proteínas de Unión al GTP/genética , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Simulación del Acoplamiento Molecular , Factores de Transcripción/genéticaRESUMEN
AIMS: Aortic valve calcification is more prevalent in chronic kidney disease accompanied by hypercalcemia. Secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) is a regulator of BMP2 signalling, but the role of SMOC1 in aortic valve calcification under different conditions has not been studied. This study aimed to investigate the roles of SMOC1 in aortic valve calcification under normal and high calcium conditions, focusing on the effects on aortic valve interstitial cells (AVICs). METHODS AND RESULTS: SMOC1 was expressed by aortic valve endothelial cells and secreted into the extracellular matrix in non-calcific valves and downregulated in calcific aortic valves. In vitro studies demonstrated that HUVEC secreted SMOC1 could enter the cytoplasm of AVICs. Overexpression of SMOC1 attenuated warfarin-induced AVIC calcification but promoted high calcium/phosphate or vitamin D-induced AVIC and aortic valve calcification by regulating BMP2 signalling both in vitro and in vivo. Co-immunoprecipitation revealed that SMOC1 binds to BMP receptor II (BMPR-II) and inhibits BMP2-induced phosphorylation of p38 (p-p38) via amino acids 372-383 of its EF-hand calcium-binding domain. Inhibition of p-p38 by the p38 inhibitor SB203580 blocked the effects of SMOC1 on BMP2 signalling and AVIC calcification induced by high calcium/phosphate medium. In high-calcium-treated AVICs, SMOC1 lost its ability to bind to BMPR-II, but not to caveolin-1, promoting p-p38 and cell apoptosis due to increased expression of BMPR-II and enhanced endocytosis. CONCLUSIONS: These observations support that SMOC1 works as a dual-directional modulator of AVIC calcification by regulating p38-dependent BMP2 signalling transduction according to different extracellular calcium concentrations.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Receptores de Proteínas Morfogenéticas Óseas de Tipo II , Osteonectina , Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Calcio/metabolismo , Células Cultivadas , Células Endoteliales/metabolismo , Humanos , Osteonectina/metabolismo , Fosforilación , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Currently, standard medical therapies have limited effects on heart failure with preserved ejection fraction (HFpEF), which impacts on the life quality and survival of patients. This study aimed to evaluate the safety and efficacy of the percutaneous radiofrequency ablation-based interatrial shunting for HFpEF with a novel atrial septostomy device. METHODS: A preclinical study in 11 normal domestic pigs and the first-in-man study in 10 patients with HFpEF were performed. The major safety events and interatrial shunt performance were evaluated at baseline, 1 month, 3 months, and 6 months post-procedure in both animals and human patients. The clinical functional status was also assessed in the first-in-man study. RESULTS: Percutaneous radiofrequency ablation-based interatrial shunting therapy was performed successfully both in animals and patients. In the animal study, a left-to-right interatrial shunt was created with a mean defect size of 5.5±2.2 mm without procedure-related safety events. Seven pigs showed the continuous shunting with a mean defect size of 4.1±1.5 mm at 6 months. In the first-in-man study, a median interatrial defect diameter of 5.0 (4.0-6.0) mm was measured immediately. No major safety events including death and thromboembolism were observed. The continuous shunting with the defect size of 4.0 (3.0-4.0) mm could still be observed in 7 patients at 6 months. The clinical status was significantly improved with NT-proBNP (N-terminal pro-B-type natriuretic peptide) reduced by 2149 pg/mL ([95% CI, 204-3301] P=0.028), with 6-minute walk distance increased by 88 m ([95% CI, 50-249] P=0.008) and with New York Heart Association class improved in 8 patients at 6 months. CONCLUSIONS: The present results showed that percutaneous radiofrequency ablation-based interatrial shunting was a safe and potentially effective therapy for HFpEF, providing a nonpharmacological and nonimplanted option for HFpEF management. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900027664.
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Insuficiencia Cardíaca , Animales , Humanos , Péptido Natriurético Encefálico/uso terapéutico , Fragmentos de Péptidos , Prótesis e Implantes , Calidad de Vida , Volumen Sistólico , PorcinosRESUMEN
With the growing interest in food safety and in environmental protection, it is more attractive to develop novel biodegradable packaging films. In this regard, one new blending film was prepared with curdlan (CD)/polyvinyl alcohol (PVA)/thyme essential oil. Our results demonstrated that the mechanical properties of the blending film were the best when the ratio of the CD and PVA was 4:1. Further, the barrier properties of the film were optimized by incorporating with thyme essential oil. It was proved that not only water vapor permeability was lower, but also the elongation at break was improved, when 2% (w/w) thyme essential oil used. The potential interactions of the film matrix were analyzed by FTIR, XRD and Cryo-scanning electron microscopy. Importantly, both the antioxidant activity and antibacterial activity were improved. Finally, the blending film was employed for the preservation of chilled meat, while the shelf life was extended up to 10 days.