Sphingosine 1-phosphate receptors: do they have a therapeutic potential in cardiac fibrosis?

Sphingosine 1-phosphate (S1P) is a bioactive lipid that is characterized by a peculiar mechanism of action. In fact, S1P, which is produced inside the cell, can act as an intracellular mediator, whereas after its export outside the cell, it can act as ligand of specific G-protein coupled receptors, which were initially named endothelial differentiation gene (Edg) and eventually renamed sphingosine 1-phosphate receptors (S1PRs). Among the five S1PR subtypes, S1PR1, S1PR2 and S1PR3 isoforms show broad tissue gene expression, while S1PR4 is primarily expressed in immune system cells, and S1PR5 is expressed in the central nervous system. There is accumulating evidence for the important role of S1P as a mediator of many processes, such as angiogenesis, carcinogenesis and immunity, and, ultimately, fibrosis. After a tissue injury, the imbalance between the production of extracellular matrix (ECM) and its degradation, which occurs due to chronic inflammatory conditions, leads to an accumulation of ECM and, consequential, organ dysfunction. In these pathological conditions, many factors have been described to act as pro- and anti-fibrotic agents, including S1P. This bioactive lipid exhibits both pro- and anti-fibrotic effects, depending on its site of action. In this review, after a brief description of sphingolipid metabolism and signaling, we emphasize the involvement of the S1P/S1PR axis and the downstream signaling pathways in the development of fibrosis. The current knowledge of the therapeutic potential of S1PR subtype modulators in the treatment of the cardiac functions and fibrinogenesis are also examined

Molecular markers of influenza B lineages and clades

Co-circulation of two influenza B virus lineages, B/Yamagata and B/Victoria, has been recognized since the late 1980s. The assessment of the prevalent lineage and the group of viruses in circulation is of importance in order to decide on the vaccine composition and evaluate its efficacy. The molecular characterization of influenza B viruses in circulation has been the aim of this study; this was approached by identifying and locating nucleotide substitutions in the influenza B virus hemagglutinin (HA) and neuraminidase (NA), specific for the lineage and/or clade. By the alignment of 3456 sequences from the influenza GISAID EpiFlu database, a high number of lineage- and group-specific nucleotide positions have been observed in the HA gene, but not in the NA gene. Additionally, an RT-PCR method has been developed, applicable directly to clinical specimens, which amplifies a short HA region that includes a group of unique molecular signatures. Twenty eight influenza B virus-positive respiratory specimens, collected in Tuscany in the seasons 2012–2013 and 2013–2014, were analyzed. The results revealed two clearly distinguishable patterns: one, more frequent, was characterized by all of the nucleotide changes associated with the B/Yamagata lineage (in most cases of Group 2), whereas the other exhibited all of the changes associated with the B/Victoria lineage. It can be concluded that the analysis of this short HA sequence can permit a rapid, highly sensitive determination of influenza B virus lineages and clades

Vitamin D and Sphingolipids: Role in Bone and Neural System

1-Alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) is known to play an important physiological role on growth and differentiation in a variety of nonmalignant and malignant cell types through classical actions, mediated by its specific receptor (VDR), and nongenomic actions resulting in the activation of specific signalling pathways. Due to the broad distribution of Vitamin D Receptor (VDR) in many tissues and the ability of 1,25(OH)2D3 to regulate fundamental processes, such as cell proliferation and differentiation, this steroid hormone has been suggested in the treatment of different diseases, from cancer to neurodegenerative diseases. In fact, structural 1,25(OH)2D3 analogues, with weaker collateral effects, have recently entered in clinical trials. Other interesting molecules due to their pleiotropic actions are the bioactive sphingolipids (SLs), in particular ceramide (Cer) and sphingosine 1-phosphate (S1P). Cells maintain a dynamic balance of these metabolites since Cer and sphingoid bases mediate cell death, while S1P exerts mitogenic effects and promotes differentiation of several cell types including osteogenic and neural cells. The biological actions of 1,25(OH)2D3 and SLs, in particular S1P, share many common effectors, including calcium regulation, growth factor expression, inflammatory cytokines, etc., but whether they could act synergistically is still unknown and deserves further investigation

Sphingosine 1-Phosphate Receptors: Do They Have a Therapeutic Potential in Cardiac Fibrosis?

Sphingosine 1-phosphate (S1P) is a bioactive lipid that is characterized by a peculiar mechanism of action. In fact, S1P, which is produced inside the cell, can act as an intracellular mediator, whereas after its export outside the cell, it can act as ligand of specific G-protein coupled receptors, which were initially named endothelial differentiation gene (Edg) and eventually renamed sphingosine 1-phosphate receptors (S1PRs). Among the five S1PR subtypes, S1PR1, S1PR2 and S1PR3 isoforms show broad tissue gene expression, while S1PR4 is primarily expressed in immune system cells, and S1PR5 is expressed in the central nervous system. There is accumulating evidence for the important role of S1P as a mediator of many processes, such as angiogenesis, carcinogenesis and immunity, and, ultimately, fibrosis. After a tissue injury, the imbalance between the production of extracellular matrix (ECM) and its degradation, which occurs due to chronic inflammatory conditions, leads to an accumulation of ECM and, consequential, organ dysfunction. In these pathological conditions, many factors have been described to act as pro- and anti-fibrotic agents, including S1P. This bioactive lipid exhibits both pro- and anti-fibrotic effects, depending on its site of action. In this review, after a brief description of sphingolipid metabolism and signaling, we emphasize the involvement of the S1P/S1PR axis and the downstream signaling pathways in the development of fibrosis. The current knowledge of the therapeutic potential of S1PR subtype modulators in the treatment of the cardiac functions and fibrinogenesis are also examined

Exhaled Breath Condensate (EBC) for SARS-CoV-2 diagnosis still an open debate

: The real-time PCR (RT-PCR) on nasopharyngeal swabs (NPS) is the gold standard for the diagnosis of SARS-CoV-2. The exhaled breath condensate (EBC) is used to perform collection of biological fluid condensed in a refrigerated device from deep airways' exhaled air. We aimed to verify the presence of SARS-CoV-2 virus in the EBC from patients with confirmed SARS-CoV-2 infection by RT-PCR, and to determine if the EBC may represent a valid alternative to the NPS. Methods: Seventeen consecutive patients admitted to the Emergency Department of the Policlinico were enrolled in the present study with RT-PCR, clinical and radiological evidence of SARS-CoV-2. Within 24 hours from the NPS collection the EBC collection was performed on SARS-CoV-2 positive patients. Informed written consent was gathered and the Ethic Committee approved the study. Results: The mean age of patients was 60 years (24-92) and 64.7% (11/17) were male. Patient n. 9 and n.17 died. All NPS resulted positive for SARS-CoV-2 at RT-PCR. RT-PCR on EBC resulted negative for all but one patients (patient n.12). Conclusion: In this study we did not find any correlation between positive NPS and the EBC in all but one patients enrolled. Based on these data which greatly differ from previous reports on the topic, this study opens several questions related to small differences in the complex process of EBC collection and how EBC could be really standardized for the diagnosis of SARS-CoV-2 infection. Further studies will be warranted to deepen this topic

Sphingosine 1-phosphate receptor 1 is required for MMP-2 function in bone marrow mesenchymal stromal cells: implications for cytoskeleton assembly and proliferation

Bone marrow-derived mesenchymal stromal cell- (BM-MSC-) based therapy is a promising option for regenerative medicine. An important role in the control of the processes influencing the BM-MSC therapeutic efficacy, namely, extracellular matrix remodelling and proliferation and secretion ability, is played by matrix metalloproteinase- (MMP-) 2. Therefore, the identification of paracrine/autocrine regulators of MMP-2 function may be of great relevance for improving BM-MSC therapeutic potential. We recently reported that BM-MSCs release the bioactive lipid sphingosine 1-phosphate (S1P) and, here, we demonstrated an impairment of MMP-2 expression/release when the S1P receptor subtype S1PR1 is blocked. Notably, active S1PR1/MMP-2 signalling is required for F-actin structure assembly (lamellipodia, microspikes, and stress fibers) and, in turn, cell proliferation. Moreover, in experimental conditions resembling the damaged/regenerating tissue microenvironment (hypoxia), S1P/S1PR1 system is also required for HIF-1α expression and vinculin reduction. Our findings demonstrate for the first time the trophic role of S1P/S1PR1 signalling in maintaining BM-MSCs' ability to modulate MMP-2 function, necessary for cytoskeleton reorganization and cell proliferation in both normoxia and hypoxia. Altogether, these data provide new perspectives for considering S1P/S1PR1 signalling a pharmacological target to preserve BM-MSC properties and to potentiate their beneficial potential in tissue repair