Orphan GPR26 Counteracts Early Phases of Hyperglycemia-Mediated Monocyte Activation and Is Suppressed in Diabetic Patients

Diabetes is the ninth leading cause of death, with an estimated 1.5 million deaths worldwide. Type 2 diabetes (T2D) results from the body's ineffective use of insulin and is largely the result of excess body weight and physical inactivity. T2D increases the risk of cardiovascular diseases, retinopathy, and kidney failure by two-to three-fold. Hyperglycemia, as a hallmark of diabetes, acts as a potent stimulator of inflammatory condition by activating endothelial cells and by dysregulating monocyte activation. G-protein couple receptors (GPCRs) can both exacerbate and promote inflammatory resolution. Genome-wide association studies (GWAS) indicate that GPCRs are differentially regulated in inflammatory and vessel cells from diabetic patients. However, most of these GPCRs are orphan receptors, for which the mechanism of action in diabetes is unknown. Our data indicated that orphan GPCR26 is downregulated in the PBMC isolated from T2D patients. In contrast, GPR26 was initially upregulated in human monocytes and PBMC treated with high glucose (HG) levels and then decreased upon chronic and prolonged HG exposure. GPR26 levels were decreased in T2D patients treated with insulin compared to non-insulin treated patients. Moreover, GPR26 inversely correlated with the BMI and the HbA1c of diabetic compared to non-diabetic patients. Knockdown of GPR26 enhanced monocyte ROS production, MAPK signaling, pro-inflammatory activation, monocyte adhesion to ECs, and enhanced the activity of Caspase 3, a pro-apoptotic molecule. The same mechanisms were activated by HG and exacerbated when GPR26 was knocked down. Hence, our data indicated that GPR26 is initially activated to protect monocytes from HG and is inhibited under chronic hyperglycemic conditions

Supplementary data from: Role of endothelial micronuclei-contained DNA in atherosclerosis

HASH(0x55d3863a5770

Insights into the Function of Regulatory RNAs in Bacteria and Archaea

Non-coding RNAs (ncRNAs) are functional RNA molecules that comprise about 80% of both mammals and prokaryotes genomes. Recent studies have identified a large number of small regulatory RNAs in Escherichia coli and other bacteria. In prokaryotes, RNA regulators are a diverse group of molecules that modulate a wide range of physiological responses through a variety of mechanisms. Similar to eukaryotes, bacterial microRNAs are an important class of ncRNAs that play an important role in the development and secretion of proteins and in the regulation of gene expression. Similarly, riboswitches are cis-regulatory structured RNA elements capable of directly controlling the expression of downstream genes in response to small molecule ligands. As a result, riboswitches detect and respond to the availability of various metabolic changes within cells. The most extensive and most widely studied set of small RNA regulators act through base pairing with RNAs. These types of RNAs are vital for prokaryotic life, activating or suppressing important physiological processes by modifying transcription or translation. The majority of these small RNAs control responses to changes in environmental conditions. Finally, clustered regularly interspaced short palindromic repeat (CRISPR) RNAs, a newly discovered RNA regulator group, contains short regions of homology to bacteriophage and plasmid sequences that bacteria use to splice phage DNA as a defense mechanism. The detailed mechanism is still unknown but devoted to target homologous foreign DNAs. Here, we review the known mechanisms and roles of non-coding regulatory RNAs, with particular attention to riboswitches and their functions, briefly introducing translational applications of CRISPR RNAs in mammals

Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice.

The CXC chemokine receptor 4 (CXCR4) in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is crucial for vascular integrity. The atheroprotective functions of CXCR4 in vascular cells may be counteracted by atherogenic functions in other nonvascular cell types. Thus, strategies for cell-specifically augmenting CXCR4 function in vascular cells are crucial if this receptor is to be useful as a therapeutic target in treating atherosclerosis and other vascular disorders. Here, we identified miR-206-3p as a vascular-specific CXCR4 repressor and exploited a target-site blocker (CXCR4-TSB) that disrupted the interaction of miR-206-3p with CXCR4 in vitro and in vivo. In vitro, CXCR4-TSB enhanced CXCR4 expression in human and murine ECs and VSMCs to modulate cell viability, proliferation, and migration. Systemic administration of CXCR4-TSB in Apoe-deficient mice enhanced Cxcr4 expression in ECs and VSMCs in the walls of blood vessels, reduced vascular permeability and monocyte adhesion to endothelium, and attenuated the development of diet-induced atherosclerosis. CXCR4-TSB also increased CXCR4 expression in B cells, corroborating its atheroprotective role in this cell type. Analyses of human atherosclerotic plaque specimens revealed a decrease in CXCR4 and an increase in miR-206-3p expression in advanced compared with early lesions, supporting a role for the miR-206-3p-CXCR4 interaction in human disease. Disrupting the miR-206-3p-CXCR4 interaction in a cell-specific manner with target-site blockers is a potential therapeutic approach that could be used to treat atherosclerosis and other vascular diseases