Pulmonary vascular remodeling is an angiogenic-related process involving changes in smooth muscle cell (SMC) homeostasis, which is frequently observed in chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are small, noncoding RNAs that regulate mRNA expression levels of many genes, leading to the manifestation of cell identity and specific cellular phenotypes. Here, we evaluate the miRNA expression profiles of pulmonary arteries (PAs) of patients with COPD and its relationship with the regulation of SMC phenotypic change. miRNA expression profiles from PAs of 12 patients with COPD, 9 smokers with normal lung function (SK), and 7 nonsmokers (NS) were analyzed using TaqMan Low-Density Arrays. In patients with COPD, expression levels of miR-98, miR-139-5p, miR-146b-5p, and miR-451 were upregulated, as compared with NS. In contrast, miR-197, miR-204, miR-485-3p, and miR-627 were downregulated. miRNA-197 expression correlated with both airflow obstruction and PA intimal enlargement. In an in vitro model of SMC differentiation, miR-197 expression was associated with an SMC contractile phenotype. miR-197 inhibition blocked the acquisition of contractile markers in SMCs and promoted a proliferative/migratory phenotype measured by both cell cycle analysis and wound-healing assay. Using luciferase assays, Western blot, and quantitative PCR, we confirmed that miR-197 targets the transcription factor E2F1. In PAs from patients with COPD, levels of E2F1 were increased as compared with NS. In PAs of patients with COPD, remodeling of the vessel wall is associated with downregulation of miR-197, which regulates SMC phenotype. The effect of miR-197 on PAs might be mediated, at least in part, by the key proproliferative factor, E2F1.

Vascular smooth muscle cells (SMC) are a highly specialized cell type that exhibit extraordinary plasticity in adult animals in response to a number of environmental cues. Upon vascular injury, SMC undergo phenotypic switch from a contractile-differentiated to a proliferative/migratory-dedifferentiated phenotype. This process plays a major role in vascular lesion formation and during the development of vascular remodeling. Vascular remodeling comprises the accumulation of dedifferentiated SMC in the intima of arteries and is central to a number of vascular diseases such as arteriosclerosis, chronic obstructive pulmonary disease or pulmonary hypertension. Therefore, it is critical to understand the molecular mechanisms that govern SMC phenotype. In the last decade, a number of new classes of noncoding RNAs have been described. These molecules have emerged as key factors controlling tissue homeostasis during physiological and pathological conditions. In this review, we will discuss the role of noncoding RNAs, including microRNAs and long noncoding RNAs, in the regulation of SMC plasticity.

The genetically related assemblages of the intestinal protozoa parasite Giardia lamblia are morphologically indistinguishable and are often derived from specific hosts. The Giardia assemblages are separated by large genetic distances, which might account for their relevant biological and pathogenic differences. In this work, we analyzed the RNAs cargo released into exosomal-like vesicles (ElVs) by the assemblages A and B, which differentially infect humans, and the assemblage E, which infects hoofed animals. The RNA sequencing analysis revealed that the ElVs of each assemblage contained distinct small RNA (sRNA) biotypes, suggesting a preference for specific packaging in each assemblage. These sRNAs were classified into three categories, ribosomal-small RNAs (rsRNAs), messenger-small RNAs (msRNAs), and transfer-small RNAs (tsRNAs), which may play a regulatory role in parasite communication and contribute to host-specificity and pathogenesis. Uptake experiments showed, for the first time, that ElVs were successfully internalized by the parasite trophozoites. Furthermore, we observed that the sRNAs contained inside these ElVs were first located below the plasma membrane but then distributed along the cytoplasm. Overall, the study provides new insights into the molecular mechanisms underlying the host-specificity and pathogenesis of G. lamblia and highlights the potential role of sRNAs in parasite communication and regulation.

Nanotechnology is a very promising technological tool to combat health problems associated with the loss of effectiveness of currently used antibiotics. Previously, we developed a formulation consisting of a chitosan and tween 80-decorated alginate nanocarrier that encapsulates rifampicin and the antioxidant ascorbic acid (RIF/ ASC), intended for the treatment of respiratory intracellular infections. Here, we investigated the effects of RIF/ASC-loaded NPs on the respiratory mucus and the pulmonary surfactant. In addition, we evaluated their cytotoxicity for lung cells in vitro, and their biodistribution on rat lungs in vivo after their intratracheal administration. Findings herein demonstrated that RIF/ASC-loaded NPs display a favorable lung biocompatibility profile and a uniform distribution throughout lung lobules. RIF/ASC-loaded NPs were mainly uptaken by lung macrophages, their primary target. In summary, findings show that our novel designed RIF/ASC NPs could be a suitable system for antibiotic lung administration with promising perspectives for the treatment of pulmonary intracellular infections.

Chagas disease is an emerging global health problem; however, it remains neglected. Increased aortic stiffness (IAS), a predictor of cardiovascular events, has recently been reported in asymptomatic chronic Chagas patients. After vascular injury, smooth muscle cells (SMCs) can undergo alterations associated with phenotypic switch and transdifferentiation, promoting vascular remodeling and IAS. By studying different mouse aortic segments, we tested the hypothesis that Trypanosoma cruzi infection promotes vascular remodeling. Interestingly, the thoracic aorta was the most affected by the infection. Decreased expression of SMC markers and increased expression of proliferative markers were observed in the arteries of acutely infected mice. In acutely and chronically infected mice, we observed cells coexpressing SMC and macrophage (Mo) markers in the media and adventitia layers of the aorta, indicating that T. cruzi might induce cellular processes associated with SMC transdifferentiation into Mo-like cells or vice versa. In the adventitia, the Mo cell functional polarization was associated with an M2-like CD206+arginase-1+ phenotype despite the T. cruzi presence in the tissue. Only Mo-like cells in inflammatory foci were CD206+iNOS+. In addition to the disorganization of elastic fibers, we found thickening of the aortic layers during the acute and chronic phases of the disease. Our findings indicate that T. cruzi infection induces a vascular remodeling with SMC dedifferentiation and increased cell populations coexpressing α-SMA and Mo markers that could be associated with IAS promotion. These data highlight the importance of studying large vessel homeostasis in Chagas disease.

Interest in epigenetics has gained substantial momentum as a result of their identified role in the regulation of tumor progression, as well as their ability to pharmacologically target genes. Pituitary Neuroendocrine tumors (PitNETs) tend to be inactivated via epigenetic modification, and although emerging evidence has suggested a role for epigenetic factors in PitNET tumorigenesis, the degree to which these factors may be targeted by new therapeutic strategies still remains poorly understood. The objective of the present study was to examine the participation of the EZH2/H3K27me3 axis in the proliferation of lactotroph tumor cells. We demonstrated that the levels of EZH2 and H3K27me3 were increased in murine experimental prolactin (PRL) tumors with respect to a control pituitary, in contrast with the low p21 mRNA levels encountered, with an H3K27me3 enrichment being observed in its promoter region in a GH3 tumor cell. Furthermore, specific EZH2/H3K27me3 axis inhibition blocked the proliferation of primary tumor cell culture and GH3 cells, thereby making it an attractive therapeutic target for prolactin PitNETs.