Background Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-like receptor (TLR) signaling triggers cell apoptosis through multiple mechanisms. Up-regulation of TLR4 expression has been shown in diabetic mice. This study aimed to delineate the role of TLR4 in myocardial apoptosis, and to block this process through gene silencing of TLR4 in the myocardia of diabetic mice. Methods Diabetes was induced in C57/BL6 mice by the injection of streptozotocin. Diabetic mice were treated with 50 μg of TLR4 siRNA or scrambled siRNA as control. Myocardial apoptosis was determined by TUNEL assay. Results After 7 days of hyperglycemia, the level of TLR4 mRNA in myocardial tissue was significantly elevated. Treatment of TLR4 siRNA knocked down gene expression as well as diminished its elevation in diabetic mice. Apoptosis was evident in cardiac tissues of diabetic mice as detected by a TUNEL assay. In contrast, treatment with TLR4 siRNA minimized apoptosis in myocardial tissues. Mechanistically, caspase-3 activation was significantly inhibited in mice that were treated with TLR4 siRNA, but not in mice treated with control siRNA. Additionally, gene silencing of TLR4 resulted in suppression of apoptotic cascades, such as Fas and caspase-3 gene expression. TLR4 deficiency resulted in inhibition of reactive oxygen species (ROS) production and NADPH oxidase activity, suggesting suppression of hyperglycemia-induced apoptosis by TLR4 is associated with attenuation of oxidative stress to the cardiomyocytes. Conclusions In summary, we present novel evidence that TLR4 plays a critical role in cardiac apoptosis. This is the first demonstration of the prevention of cardiac apoptosis in diabetic mice through silencing of the TLR4 gene.

Primary multiple intracranial aneurysm (MIA) is a vascular disease that frequently leads to fatal vascular rupture and subarachnoid hemorrhage. However, the epigenetic regulation associated with MIA has remained largely elusive. Circular RNAs (circRNAs) serve important roles in cardiovascular diseases; however, their association with MIA has remained to be investigated. The present study initially aimed to explore novel mechanisms of MIA through examining circRNA expression profiles. Comprehensive circRNA expression profiles were detected by RNA sequencing (RNA-Seq) in human peripheral blood mononuclear cells. The RNA-Seq results were validated by reverse transcription-quantitative PCR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested the functions of these circRNAs. A competing endogenous RNA network was constructed to reveal the circRNA-microRNA-mRNA relationship. Among the 3,328 differentially expressed circRNAs between the MIA and matched control groups, 60 exhibited significant expression changes (|log2 fold change|≥2; P<0.05). Among these 60 circRNAs, 20 were upregulated, while the other 40 were downregulated. A number of downregulated circRNAs were involved in inflammation. The most significant KEGG pathway was ‘leukocyte transendothelial migration’. The circRNAs Homo sapiens (hsa)_circ_0135895, hsa_circ_0000682 and hsa_circ_0000690, which were also associated with the above-mentioned pathway, were indicated to be able to regulate protein tyrosine kinase 2, protein kinase Cβ and integrin subunit αL, respectively. To the best of our knowledge, the present study was the first to perform a circRNA sequencing analysis of MIA. The results specifically predicted the regulatory role of circRNAs in the pathogenesis of MIA. ‘Leukocyte transendothelial migration’ may be critical for the pathogenesis of MIA.

Introduction Sepsis is life‐threatening organ dysfunction caused by infection‐related inflammatory response. Therapeutic plasma exchange (TPE) can remove inflammatory mediators and benefit patients in different disease settings. However, no solid evidence showed the efficacy and safety of TPE in sepsis. Methods This study was a secondary analysis of a randomized controlled trial. Critically ill patients with sepsis were divided into two groups according to whether treated with TPE. The primary outcome was the delta Sequential Organ Failure Assessment (SOFA) score from days 1 to 7. Secondary outcomes included new‐onset organ failure, intensive care unit (ICU)‐free and alive days to day 28, and 28‐day mortality. Propensity score‐matched (PSM) analysis was applied to control confounders. Analysis of covariance (ANCOVA) and logistic regression were used to assess the association between TPE and selected outcomes. Results Among the 2772 critically ill patients enrolled in the trial, 742 patients with sepsis were selected and 22 patients received TPE were matched with 22 control patients. No significant difference was found in the delta SOFA score and 28‐day mortality between TPE group and control group. The ICU‐free and alive days in the TPE group were significantly shorter than the control group. Conclusions TPE may be not associated with improvement of organ failure and mortality in critically ill patients with sepsis and may be associated with a prolonged ICU stay.