miR-92a-3p promotes pulmonary fibrosis progression by regulating KLF2-mediated endothelial-to-mesenchymal transition.

Pulmonary fibrosis (PF) is a chronic lung disease that has a poor prognosis and a serious impact on the quality of life of patients. Here, we investigated the potential role of miR-92a-3p in PF. The mRNA level of miR-92a-3p was significantly increased in both the lung tissues of bleomycin (BLM)--treated mice and pulmonary microvascular endothelial cells (PMVECs). Overexpressing miR-92a-3p increased the mRNA and protein levels of α­SMA, vimentin, and Col-1 but downregulated E-cadherin. Additionally, the protein and mRNA expression levels of KLF2 were significantly decreased in the lung tissues of BLM-treated mice, suggesting that KLF2 participated in the progression of BLM-induced PF. Downregulating miR-92a-3p upregulated the expression of KLF2 and inhibited the endothelial-to-mesenchymal transition (EndoMT) process, thus alleviating PF in vivo. Altogether, a miR-92a-3p deficiency could significantly reduce the development of myofibroblasts and ameliorate PF progression.

Construction of an RNA modification-related gene predictive model associated with prognosis and immunity in gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common causes of cancer-related fatalities worldwide, and its progression is associated with RNA modifications. Here, using RNA modification-related genes (RNAMRGs), we aimed to construct a prognostic model for patients with GC. METHODS: Based on RNAMRGs, RNA modification scores (RNAMSs) were obtained for GC samples from The Cancer Genome Atlas and were divided into high- and low-RNAMS groups. Differential analysis and weighted correlation network analysis were performed for the differential expressed genes (DEGs) to obtain the key genes. Next, univariate Cox regression, least absolute shrinkage and selection operator, and multivariate Cox regression analyses were performed to obtain the model. According to the model risk score, samples were divided into high- and low-risk groups. Enrichment analysis and immunoassays were performed for the DEGs in these groups. Four external datasets from Gene Expression Omnibus data base were used to test the accuracy of the predictive model. RESULTS: We identified SELP and CST2 as key DEGs, which were used to generate the predictive model. The high-risk group had a worse prognosis compared to the low-risk group (p < 0.05). Enrichment analysis and immunoassays revealed that 144 DEGs related to immune cell infiltration were associated with the Wnt signaling pathway and included hub genes such as ELN. Overall mutation levels, tumor mutation burden, and microsatellite instability were lower, but tumor immune dysfunction and exclusion scores were greater (p < 0.05) in the high-risk group than in the low-risk group. The validation results showed that the prediction model score can accurately predict the prognosis of GC patients. Finally, a nomogram was constructed using the risk score combined with the clinicopathological characteristics of patients with GC. CONCLUSION: This risk score from the prediction model related to the tumor microenvironment and immunotherapy could accurately predict the overall survival of GC patients.

Muscle Strength, but Not Muscle Mass, Is Associated with Left Ventricular Diastolic Function during Aging in Chinese.

Sarcopenia, a progressive and systemic skeletal muscle disorder, is closely related with the incidence of cardiovascular disease (CVD) and CVD-related mortality, but its association with cardiac structure and function during aging remains unclear, particularly in the absence of serious cardiovascular diseases. This study aimed to investigate the correlation of muscle mass and muscle strength, the main components of sarcopenia, with left ventricular mass and function in Chinese subjects.A total of 265 men and 70 women (aged 25-95 years) without serious diseases that could have pronounced impact on muscle and/or cardiovascular system were included. Left ventricular mass and function were assessed by echocardiography and muscle mass and grip strength were evaluated by dual-energy X-ray absorptiometry and a Jamar hand dynamometer, respectively.Grip strength and left ventricular diastolic function, rather than left ventricular mass, demonstrated age-dependent decline in both genders. Muscle mass in males and left ventricular systolic function in females declined with age. In the multivariate-adjusted model, grip strength rather than the relative appendicular skeletal muscle mass (RASM) was positively associated with E/A ratio (r = 0.154, P = 0.019) and e´-av (r = 0.175, P = 0.008), but was negatively correlated with E/e´-av ratio (r = -0.136, P = 0.038). No significant correlation was observed between RASM, grip strength and left ventricular mass, left ventricular ejection fraction or left ventricular fractional shortening. Higher grip strength is independently associated with better left ventricular diastolic function in Chinese during aging.

Correlation between the Serum Platelet-Derived Growth Factor, Angiopoietin-1, and Severity of Coronary Heart Disease.

BACKGROUND: The expression of the platelet-derived growth factor (PDGF), angiopoietin-1 (Ang-1) in patients with coronary artery disease of different studies was inconsistent. This study was to investigate the expression of the PDGF and Ang-1 in peripheral blood and coronary artery in patients with acute coronary syndrome (ACS) and the relationship between the expression of the PDGF and Ang-1 and the severity of coronary artery disease. METHODS: A total of 81 patients with acute coronary syndrome undergoing coronary angiography were enrolled from September 2012 to December 2013. Patients with ACS included 61 patients with acute myocardial infarction (AMI group) and 20 patients with unstable angina pectoris (UAP group). The 29 patients who were hospitalized for chest pain undergoing coronary angiography without stenosis and with TIMI level 3 blood flow were selected as the control group. During coronary arteriography (CAG) or percutaneous coronary intervention (PCI), blood in the peripheral artery and in the local coronary artery was collected from all the patients. Serum PDGF and Ang-1 levels were measured by ELISA. We calculated the Gensini score of each patient with CHD according to the result of CAG. Patients with ACS were followed up, and the major adverse cardiovascular and cerebrovascular adverse events were recorded. RESULTS: In peripheral blood, the concentration of the PDGF was significantly elevated in the ACS group than that of the control group. The level of the PDGF in the AMI group was significantly higher than that in the UAP group. In coronary artery blood, the level of the PDGF in the ACS group was significantly higher than that of the UAP group. There was no significant difference in the concentration of Ang-1 in peripheral blood between patients with coronary heart disease and the control group. The concentration of Ang-1 in the coronary artery was significantly lower than that in peripheral blood. The coronary Ang-1 concentrations in the ACS group were significantly higher than those in the UAP group. The concentrations of the PDGF and Ang-1 in peripheral and coronary artery blood were positively correlated with the severity of coronary lesions. Patients with MACCE had higher PDGF and Ang-1 levels in the coronary sinus. CONCLUSION: The serum PDGF concentration in patients with acute coronary syndrome was significantly increased, especially in the local coronary artery. The serum Ang-1 in the coronary artery was significantly increased in patients with acute myocardial infarction and was related to the degree of coronary artery stenosis. Coronary sinus PDGF and Ang-1 levels can reflect the severity of lesions in patients with acute coronary syndrome.

Serum Cytokine Profile in Relation to the Severity of Coronary Artery Disease.

Objectives. To investigate the potential association of a set of serum cytokines with the severity of coronary artery disease (CAD). Methods. A total of 201 patients who underwent coronary angiography for chest discomfort were enrolled. The concentrations of serum IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-9, and IL-17 were determined by xMAP multiplex technology. The CAD severity was assessed by Gensini score (GS). Results. The serum levels of TNF-α, IL-6, IL-9, IL-10, and IL-17 were significantly higher in high GS group (GS ≥ 38.5) than those in low GS group (GS < 38.5). Positive correlations were also found between these cytokines and the severity of CAD. After adjustment for other associated factors, three serum cytokines (IL-6, IL-9, and IL-17) and two clinical risk factors (creatinine and LDL-C) were identified as the independent predictors of increased severity of CAD. ROC curve analysis revealed that the logistic regression risk prediction model had a good performance on predicting CAD severity. Conclusions. Combinatorial analysis of serum cytokines (IL-6, IL-9, and IL-17) with clinical risk factors (creatinine and LDL-C) may contribute to the evaluation of the severity of CAD and may help guide the risk stratification of angina patients, especially in primary health facilities and in the catheter lab resource-limited settings.

TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta-analysis of 2248 cases.

Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta-analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed-effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08-1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094-1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082-2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048-1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084-1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743-2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility.

Adrenergic regulation of the rapid component of delayed rectifier K+ currents in guinea pig cardiomyocytes.

BACKGROUND: Guinea pig ventricular cardiomyocytes display the rapid component of the delayed rectifier potassium current (Ikr) that contributes to ventricular repolarization and promotes stress-induced arrhythmias. Adrenergic stimulation favors ventricular arrhythmogenesis but its effects on Ikr are poorly understood. METHODS: Adrenergic modulation of Ikr was studied in isolated guinea pig ventricular cardiomyocytes using whole-cell patch clamping. RESULTS: We found that the Ikr amplitude was reduced to 0.66±0.02 and 0.62±0.03 in response to 0.1 µM phenylephrine (PE), an α1AR agonist, and 10 µM isoproterenol (ISO), a ßAR agonist, respectively. The effect of PE can be blocked by the selective α1A-adrenoceptor antagonist 5-methylurapidil, but not by the α1B-adrenoceptor antagonist chloroethylclonidine or α1D-adrenoceptor antagonist BMY7378. Additionally, the effect of ISO can be blocked by the ß1-selective AR antagonist CGP-20712A, but not by the ß2-selective AR antagonist ICI-118551. Although PE and ISO was continuously added to cells, ISO did not decrease the current to a greater extent when cells were first given PE. In addition, PE's effect on Ikr was suppressed by ß1AR stimulation. CONCLUSIONS: Ikr can by regulated by both the α1 and ß ARs system, and that in addition to direct regulation by each receptor system, crosstalk may exist between the two systems.

Beneficial effects of schisandrin B on the cardiac function in mice model of myocardial infarction.

The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.

Cardiac-specific expression of heat shock protein 27 attenuated endotoxin-induced cardiac dysfunction and mortality in mice through a PI3K/Akt-dependent mechanism.

Cardiac dysfunction is a major consequence of septic shock and may be responsible for the high mortality of sepsis. We have reported that transgenic mice with cardiac-specific overexpression of heat shock protein 27 (Hsp27 Tg) exhibited the protection against doxorubicin-induced cardiac dysfunction. We hypothesized that overexpression of Hsp27 will attenuate cardiac dysfunction during endotoxemia. Hsp27 Tg and age-matched wild-type (WT) mice were injected with LPS. Cardiac function was evaluated by echocardiography, survival rate was carefully monitored, and activities of signaling pathways were determined by immunoblot. LPS administration significantly decreased cardiac function in WT mice. In Hsp27 Tg mice, LPS-induced cardiac dysfunction was significantly attenuated as evidenced by increased ejection fraction (27.3%) and fractional shortening (37.1%), respectively, compared with LPS-treated WT mice. Heat shock protein 27 Tg mice were more resistant to LPS-induced mortality than WT. The levels of phospho-Akt and phospho-glycogen synthase kinase 3beta (phospho-GSK-3beta) in the myocardium were significantly increased in Hsp27 Tg mice compared with WT after LPS administration. Nuclear factor kappaB-binding activity was significantly decreased in Hsp27 Tg mice compared with WT mice after LPS challenge. Similar results were observed in in vitro studies using Hsp27-transfected rat cardiomyoblasts. Importantly, phosphoinositide 3-kinase inhibition abolished the protective effect of Hsp27 in LPS-induced cardiac dysfunction and mortality of endotoxemia. Our results suggest that Hsp27 plays an important role in attenuation of cardiac dysfunction and mortality in endotoxemia and that the mechanisms of the protection may involve activation of the PI3K/Akt signaling pathway.