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- The circulating non-coding RNA landscape for biomarker research : lessons and prospects from cardiovascular diseasesPublication . Stępień, Ewa; Costa, Marina C.; Kurc, Szczepan; Drożdż, Anna; Cortez-Dias, Nuno; Enguita, Francisco J.Pervasive transcription of the human genome is responsible for the production of a myriad of non-coding RNA molecules (ncRNAs) some of them with regulatory functions. The pivotal role of ncRNAs in cardiovascular biology has been unveiled in the last decade, starting from the characterization of the involvement of micro-RNAs in cardiovascular development and function, and followed by the use of circulating ncRNAs as biomarkers of cardiovascular diseases. The human non-coding secretome is composed by several RNA species that circulate in body fluids and could be used as biomarkers for diagnosis and outcome prediction. In cardiovascular diseases, secreted ncRNAs have been described as biomarkers of several conditions including myocardial infarction, cardiac failure, and atrial fibrillation. Among circulating ncRNAs, micro-RNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been proposed as biomarkers in different cardiovascular diseases. In comparison with standard biomarkers, the biochemical nature of ncRNAs offers better stability and flexible storage conditions of the samples, and increased sensitivity and specificity. In this review we describe the current trends and future prospects of the use of the ncRNA secretome components as biomarkers of cardiovascular diseases, including the opening questions related with their secretion mechanisms and regulatory actions.
- Circulating miRNAs are associated with the systemic extent of atherosclerosis : novel observations for miR-27b and miR-146Publication . Pereira da Silva, Tiago; Napoleão, Patricia; Costa, Marina C.; Gabriel, André F.; Selas, Mafalda; Silva, Filipa; Enguita, Francisco J.; Ferreira, Rui Cruz; Carmo, Miguel MotaThe mechanisms that regulate the systemic extent of atherosclerosis are not fully understood. We investigated whether the expression of circulating miRNAs is associated with the extent of stable atherosclerosis to a single territory or multiple territories (polyvascular) and with the severity of atherosclerosis in each territory. Ninety-four participants were prospectively recruited and divided into five age- and sex-matched groups: presenting no atherosclerosis, isolated coronary atherosclerosis, coronary and lower extremity atherosclerosis, coronary and carotid atherosclerosis, and atherosclerosis of the coronary, lower extremity, and carotid territories. The expression of six circulating miRNAs with distinct biological roles was assessed. The expression of miR-27b and miR-146 differed across groups (p < 0.05), showing a decrease in the presence of atherosclerosis, particularly in the three territories. miR-27b and miR-146 expression decreased in association with a higher severity of coronary, lower extremity, and carotid atherosclerosis. Polyvascular atherosclerosis involving the three territories was independently associated with a decreased miR-27b and miR-146 expression. Both miRNAs presented an area under the curve of ≥0.75 for predicting polyvascular atherosclerosis involving the three territories. To conclude, miR-27b and miR-146 were associated with the presence of severe polyvascular atherosclerosis and with the atherosclerosis severity in each territory. Both are potential biomarkers of severe systemic atherosclerosis.
- Effects of neonatal exposure to methoxychlor on corpus luteum in gilts : a transcriptomic analysisPublication . Witek, Patrycja; Enguita, Francisco J.; Grzesiak, Malgorzata; Costa, Marina C.; Gabriel, André F.; Koziorowski, Marek; Slomczynska, Maria; Knapczyk‐Stwora, KatarzynaThis study investigated the effects of neonatal exposure to methoxychlor (MXC), a synthetic organochlorine used as an insecticide with estrogenic, antiestrogenic, and antiandrogenic activities, on luteal function in pigs. Piglets were injected subcutaneously with MXC (20 μg/kg body weight) or corn oil (control) between postnatal Days 1 and 10 (N = 5/group). Corpora lutea from sexually mature gilts were examined for luteal steroid and prostaglandin concentrations and processed for total RNA isolation and subsequent RNA sequencing. Intra-luteal concentrations of androstenedione and prostaglandin E2 were greater, while that of estrone was lower when compared to control. Fifty-three differentially expressed (DE) microRNAS (miRNAs) (p-adjusted <.05 and log2(fold change) ≥.5) and 359 DE genes (p-adjusted <.05 and log2(fold change) ≥1) were identified in luteal tissue in response to neonatal MXC treatment. MXC was found to affect the expression of genes related to lipogenesis, steroidogenesis, membrane transport, immune response, cell signaling and adhesion. These results suggest an earlier onset of structural luteolysis in pigs caused by MXC actions in neonates. Since negative correlation analysis showed the potential interactions of miRNAs with specific messenger RNAs, we propose that these miRNAs are potential mediators of the long-term MXC effect on the CL function in pigs.
- Cx43‐mediated sorting of miRNAs into extracellular vesiclesPublication . Martins Marques, Tânia; Costa, Marina C.; Catarino, Steve; Simões, Isaura; Aasen, Trond; Enguita, Francisco J.; Girao, HenriqueThrough the exchange of lipids, proteins, and nucleic acids, extracellular vesicles (EV) allow for cell-cell communication across distant cells and tissues to regulate a wide range of physiological and pathological processes. Although some molecular mediators have been discovered, the mechanisms underlying the selective sorting of miRNAs into EV remain elusive. Previous studies demonstrated that connexin43 (Cx43) forms functional channels at the EV surface, mediating the communication with recipient cells. Here, we show that Cx43 participates in the selective sorting of miRNAs into EV through a process that can also involve RNA-binding proteins. We provide evidence that Cx43 can directly bind to specific miRNAs, namely those containing stable secondary structure elements, including miR-133b. Furthermore, Cx43 facilitates the delivery of EV-miRNAs into recipient cells. Phenotypically, we show that Cx43-mediated EV-miRNAs sorting modulates autophagy. Overall, our study ascribes another biological role to Cx43, that is, the selective incorporation of miRNAs into EV, which potentially modulates multiple biological processes in target cells and may have implications for human health and disease.
- miRNAtools: advanced training using the miRNA web of knowledgePublication . Stępień, Ewa; Costa, Marina C.; Enguita, Francisco J.Micro-RNAs (miRNAs) are small non-coding RNAs that act as negative regulators of the genomic output. Their intrinsic importance within cell biology and human disease is well known. Their mechanism of action based on the base pairing binding to their cognate targets have helped the development not only of many computer applications for the prediction of miRNA target recognition but also of specific applications for functional assessment and analysis. Learning about miRNA function requires practical training in the use of specific computer and web-based applications that are complementary to wet-lab studies. In order to guide the learning process about miRNAs, we have created miRNAtools (http://mirnatools.eu), a web repository of miRNA tools and tutorials. This article compiles tools with which miRNAs and their regulatory action can be analyzed and that function to collect and organize information dispersed on the web. The miRNAtools website contains a collection of tutorials that can be used by students and tutors engaged in advanced training courses. The tutorials engage in analyses of the functions of selected miRNAs, starting with their nomenclature and genomic localization and finishing with their involvement in specific cellular functions.