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Background and Purpose— 18 F-fluorodeoxyglucose positron emission tomography and dynamic contrast-enhanced MRI have been proposed to quantitatively assess plaque inflammation by probing macrophages and neovessels, respectively. We examined their correlation to study the in vivo relationship between macrophage and neovessel activities in atherogenesis. Methods— Forty-one patients (34 men; aged 65±12 years) with a total of 68 carotid plaques (thickness ≥2 mm on ultrasound; 20 symptomatic) were assessed by both 18 F-fluorodeoxyglucose positron emission tomography/computed tomography and dynamic contrast-enhanced MRI within 2 weeks, measured as target-to-background ratio and transfer constant ( K trans ), respectively. Results— Overall, the correlation between target-to-background ratio and K trans was weak and marginal ( r =0.22; P =0.068). They were correlated in the symptomatic plaques ( r =0.59; P =0.006) but not in the asymptomatic plaques ( r =0.07; P =0.625; P =0.033 for difference in r ). Neither target-to-background ratio nor K trans was significantly higher in the symptomatic plaques, but both showed an inverse relationship with time since last neurological event ( r =−0.94 and −0.69 for target-to-background ratio and K trans , respectively). Conclusions— The correlation between 18 F-fluorodeoxyglucose positron emission tomography and dynamic contrast-enhanced MRI measurements varied with clinical conditions, pointing to a complex interplay between macrophages and neovessels under different pathophysiological conditions. The moderate correlation shown only in symptomatic plaques indicates the presence of acute plaque inflammation with increased metabolic activity and cytokine production by inflammatory cells.

Dysfunction of cardiac cells under hypoxia has been identified as an essential event leading to myocytes functional failure. MiRNAs are importantly regulatory small-noncoding RNAs that negatively regulate gene expression through the direct binding of 3′-UTR region of their target mRNAs. Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under pathological conditions.Pyruvate dehydrogenase kinase 1 (PDK1) is a kinase which phosphorylates pyruvate dehydrogenase to inactivate it, leading to elevated anaerobic glycolysis and decreased cellular respiration. In the present study, we report that miR-138 expressions were significantly suppressed under long exposure to hypoxia. In addition, overexpression of miR-138 protects human cardiac cells against hypoxia. We observed miR-138 inhibits glycolysis but promotes mitochondrial respiration through directly targetting PDK1. Moreover, we demonstrate that hypoxia induces cardiac cell death through increased glycolysis and decreased mitochondrial respiration. Inhibition of glycolysis by either glycolysis inhibitor or knockdown glycolysis enzymes, Glucose transportor 1 (Glut1) or PDK1 contributes to cardiac cells’ survival. The cell sentivity to hypoxia was recovered when the PDK1 level was restored in miR-138 overexpressing cardiac cells. The present study leads to the intervention of novel therapeutic strategies against cardiac cells dysfunction during surgery or ischemia.

Rationale: Cardiac fibrosis is observed in nearly every form of myocardial disease. Long non-coding RNAs (lncRNAs) have been shown to play an important role in cardiac fibrosis, but the detailed molecular mechanism remains unknown.Object: We aimed at characterizing lncRNA 554 expression in murine cardiac fibroblasts (CFs) after myocardial infarction (MI) to identify CF-enriched lncRNA and investigate its function and contribution to cardiac fibrosis and function.Methods and Results: In this study, we identified lncRNA NONMMUT022554 (lncRNA 554) as a regulator of MI-induced cardiac fibrosis. We found that lncRNA 554 was significantly up-regulated in the mouse hearts following MI. Further study showed that lncRNA 554 was predominantly expressed in cardiac fibroblasts, indicating a potential role of lncRNA 554 in cardiac fibrosis. In vitro knockdown of lncRNA 554 by siRNA suppressed fibroblasts migration and expression of extracellular matrix (ECM); while overexpression of lncRNA 554 promoted expression of ECM genes. Consistently, lentivirus mediated in vivo knockdown of lncRNA 554 could inhibit cardiac fibrosis and improve cardiac function in mouse model of MI. More importantly, TGF-β1 inhibitor (TEW-7197) could reverse the pro-fibrotic function of lncRNA 554 in CFs. This suggests that the effects of lncRNA 554 on cardiac fibrosis is TGF-β1 dependent.Conclusion: Collectively, our study illustrated the role of lncRNA 554 in cardiac fibrosis, suggested that lncRNA 554 might be a novel target for cardiac fibrosis.

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RNA N6-methyladenosine (m6A) has emerged as an important epigenetic modification for its role in regulating the stability, structure, processing, and translation of RNA. Instability of m6A homeostasis may result in flaws in stem cell regulation, decrease in fertility, and risk of cancer. To this day, experimental detection and quantification of RNA m6A modification are still time-consuming and labor-intensive. There is only a limited number of epitranscriptome samples in existing databases, and a matched RNA methylation profile is not often available for a biological problem of interests. As gene expression data are usually readily available for most biological problems, it could be appealing if we can estimate the RNA methylation status from gene expression data using in silico methods. In this study, we explored the possibility of computational prediction of RNA methylation status from gene expression data using classification and regression methods based on mouse RNA methylation data collected from 73 experimental conditions. Elastic Net-regularized Logistic Regression (ENLR), Support Vector Machine (SVM), and Random Forests (RF) were constructed for classification. Both SVM and RF achieved the best performance with the mean area under the curve (AUC) = 0.84 across samples; SVM had a narrower AUC spread. Gene Site Enrichment Analysis was conducted on those sites selected by ENLR as predictors to access the biological significance of the model. Three functional annotation terms were found statistically significant: phosphoprotein, SRC Homology 3 (SH3) domain, and endoplasmic reticulum. All 3 terms were found to be closely related to m6A pathway. For regression analysis, Elastic Net was implemented, which yielded a mean Pearson correlation coefficient = 0.68 and a mean Spearman correlation coefficient = 0.64. Our exploratory study suggested that gene expression data could be used to construct predictors for m6A methylation status with adequate accuracy. Our work showed for the first time that RNA methylation status may be predicted from the matched gene expression data. This finding may facilitate RNA modification research in various biological contexts when a matched RNA methylation profile is not available, especially in the very early stage of the study.

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BackgroundOsteoarthritis (OA) is one of the most prevalent joint disease, and there are still no effective therapeutic agents or clinical methods for the cure of this disease to date. The degradation of cartilage extracellular matrix (ECM) is a major cause of OA.MethodIL-1β was used to induce chondrogenic degradation. Q-PCR and Western blotting were used to detect mRNA and protein level, respectively. ELISA was used to detect the secreted TNF-α and IL-6 level. Immunofluorescence was used to detect the protein level of Aggrecan, Collagen II and ki67. TUNEL and flow cytometry were used to examine cell apoptosis of chondrocytes. ChIP and luciferase assay were used to study molecular gene regulation. Osteoarthritic animal model and Safranin-O staining were used to determine the in vivo OA phenotype.ResultsThe expression of ADAM8 was up-regulated in osteoarthritic chondrocytes. Knockdown of ADAM8 suppressed the OA phenotype in the in vitro OA cell model. ADAM8 regulated OA progression through the activation of EGFR/ERK/NF-κB signaling pathway. Inhibition of Notch signaling suppressed OA phenotype in the in vitro OA cell model. Notch signaling regulated the gene expression of ADAM8 directly via Hes1. Notch1-ADAM8 positive feedback loop promoted the progression of OA in vivo.ConclusionNotch1-ADAM8 feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression.