[Abstract unavailable

Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. This review focuses on the different stages of atherosclerosis development, ranging from endothelial dysfunction to plaque rupture. In addition, the post-transcriptional regulation and modulation of atheroma plaque by microRNAs and lncRNAs, the role of microbiota, and the importance of sex as a crucial risk factor in atherosclerosis are covered here in order to provide a global view of the disease.

Celecoxib (CE) is a nonsteroidal anti-inflammatory drug (NSAID)that is a specific inhibitor of cyclooxygenase 2 (COX2). It is indicated for a variety of chronic inflammatory conditions, including rheumatoid arthritis. Over the last few years, adverse cardiovascular effects and increased risk for heart attacks have been associated with this drug. In addition, evidence is emerging for COX2-independent molecular targets. CE has been shown to induce apoptosis in various cancer cells lines through a COX2-independent mechanism that seems to involve inactivation of protein kinase Akt and inhibition of endoplasmic reticulum (ER) Ca 2ϩ ATPase. In this study, we show that both CE and an analog devoid of COX2 inhibitory activity [1-(4-sulfamoyl phenyl)-3-trifluoromethyl-5-(4-trifluoromethylphenyl)pyrazole, CEA] inhibit the secretion of the dimeric interleukin-12 (IL-12) ␣␤ and ␤ 2 forms with identical IC 50 values of 20 and 30 M, respectively, whereas no such effect was seen with rofecoxib. Reverse transcription-polymerase chain reaction analysis showed that this inhibition was not due to a blockage of transcription of the ␣-and ␤-chain expression cassettes. Secretion of the ␤ monomer form was less strongly inhibited, suggestive for a mechanism primarily targeting dimer assembly in the ER. Analysis of intracellular fractions revealed that both CE and CEA increased the association of IL-12 with calreticulin, an endoplasmic reticulum-resident chaperone involved in the retention of misfolded cargo proteins while blocking interaction with ERp44. Our findings reveal a previously undescribed effect of celecoxib on oligomer protein folding and assembly in the endoplasmic reticulum and ensuing secretion and suggest that celecoxib-driven alteration of the secretome may be involved in some of its clinical side effects.Interleukin-12 (IL-12) is a proinflammatory cytokine involved in the initiation and control of cell-mediated immunity. The cytokine displays a heterodimeric structure composed of two disulfide-linked subunits [i.e., a p35 (␣-chain) and a p40 (␤-chain) subunit] (Brombacher et al., 2003). p40 can also form disulfide-linked homodimers, named ␤ 2 or p80. ␤ 2 Homodimers were originally described as antagonists of IL-12. However, more recent studies have ascribed chemotactic properties to the ␤ 2 homodimer (Ha et al., 1999). ␤ 2

Background and aimSeveral studies have highlighted the association of the 12q13.3–12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS.MethodsTag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses.Resultsrs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously.ConclusionsThis study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3–12q14.1 region with MS.