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

Exploring Land Use Scenarios in Metropolitan Areas: Food Balance in a Local Agricultural System by Using a Multi-objective Optimization Model☆

Abstract The assessment of sustainability of agro-food systems is based on different and several tools. However, economic and policy implications of structural changes, such as land use change, and other modifications, for instance a different orientation or farming technique, could be mainly determined through scenario analysis. Especially in metropolitan regions, where the agricultural sector is threatened by various different pressures, a food supply adequately respondent to the demand is needed. In this sense the paper proposes the utilization of mathematical programming to assess some possible scenarios related to a higher compliance between food supply and demand. The approach is based on a linear programming model that takes into account the production and consumption dimensions in the Milan Metropolitan Area. Five scenarios are simulated, with different levels of sustainability and compliance with demand, demonstrating the potentialities of the regional agro-food system in adapting and adjusting itself to such modifications

Identification of murine phosphodiesterase 5A isoforms and their functional characterization in HL-1 cardiac cell line

Phosphodiesterase 5A (PDE5A) specifically degrades the ubiquitous second messenger cGMP and experimental and clinical data highlight its important role in cardiac diseases. To address PDE5A role in cardiac physiology, three splice variants of the PDE5A were cloned for the first time from mouse cDNA library (mPde5a1, mPde5a2 and mPde5a3). The predicted amino acidic sequences of the three murine isoforms are different in the N-terminal regulatory domain. mPDE5A isoforms were transfected in HEK293T cells and they showed high affinity for cGMP and similar sensitivity to sildenafil inhibition. RT-PCR analysis showed that mPde5a1, mPde5a2 and mPde5a3 had differential tissue distribution. In the adult heart, mPde5a1 and mPde5a2 were expressed at different levels whereas mPde5a3 was undetectable. Overexpression of mPDE5As induced an increase of HL-1 number cells which progress into cell cycle. mPDE5A1 and mPDE5A3 overexpression increased the number of polyploid and binucleated cells, mPDE5A3 widened HL-1 areas and modulated hypertrophic markers more efficiently respect to the other mPDE5A isoforms. Moreover, mPDE5A isoforms had differential subcellular localization: mPDE5A1 was mainly localized in the cytoplasm, mPDE5A2 and mPDE5A3 were also nuclear localized. These results demonstrate for the first time the existence of three PDE5A isoforms in mouse and highlight their potential role in the induction of hypertrophy. This article is protected by copyright. All rights reserved

The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia

Mesenchymal stromal cells (MSCs) have, for a long time, been recognized as pivotal contributors in the set up and maintenance of the hematopoietic stem cell (HSC) niche, as well as in the development and differentiation of the lympho-hematopoietic system. MSCs also have a unique immunomodulatory capacity, which makes them able to affect, both in vitro and in vivo, the function of immune cells. These features, namely the facilitation of stem cell engraftment and the inhibition of lymphocyte responses, have both proven essential for successful allogeneic stem cell transplantation (allo-SCT), which remains the only curative option for several hematologic malignancies. For example, in steroid-refractory acute graft-vs. host disease developing after allo-SCT, MSCs have produced significant results and are now considered a treatment option. However, more recently, the other side of the MSC coin has been unveiled, because of their emerging role in creating a protective and immune-tolerant microenvironment able to support the survival of leukemic cells and affect the response to therapies. In this light, it has been proposed that the failure of current treatments to efficiently override the stroma-mediated protection of leukemic cells accounts for the high rate of relapse in acute myeloid leukemia, at least in part. In this review, we will focus on emerging microenvironment-driven mechanisms conferring a survival advantage to leukemic cells overt physiological HSCs. This body of evidence increasingly highlights the opportunity to consider tumor-microenvironment interactions when designing new therapeutic strategies

The economic performance of urban gardening in three European cities – examples from Ljubljana, Milan and London

Urban gardening is not a new phenomenon but it has received considerably more practical and academic interest in recent years. Studies on economic aspects such as crop yields, inputs and outputs of production, productivity, gross margins and the contribution to home economics are rare, especially in Europe. While urban gardening plays an important role in the Global South, its role in Western Europe for food productivity and home eco- nomics is currently under-researched. The aim of this study is to analyse European urban gardeners\u2019 economic performance and self-sufficiency on a household level, as well as to reach a better understanding of their con- tribution to food self-provision and food security in the metropolitan areas. In a study carried out in 2014 with on-site personal and with online questionnaires participated 180 urban gardeners from three case study cities (Ljubljana, Milan, and London). Results from the economic analysis showed that although for most urban gar- deners, profit is not their main motivation, the economic calculation shows that productivity in small urban plots can be comparable to market garden production. Urban gardeners are saving money, especially when, compared to retail prices for regular produce or organic produce, their input is included in the gross margin calculation. We conclude that, in the case-study cities, the self-provisional potential of urban gardeners\u2019 households to ade- quately cover the annual vegetable need of five-a-day servings can be met under three conditions: (1) sufficient garden size; (2) increased area productivity, and (3) sufficient labour-hour inputs

Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication

none11MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR-126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM.noneMonaco, Federica; Gaetani, Simona; Alessandrini, Federica; Tagliabracci, Adriano; Bracci, Massimo; Valentino, Matteo; Neuzil, Jiri; Amati, Monica; Bovenzi, Massimo; Tomasetti, Marco; Santarelli, LoryMonaco, Federica; Gaetani, Simona; Alessandrini, Federica; Tagliabracci, Adriano; Bracci, Massimo; Valentino, Matteo; Neuzil, Jiri; Amati, Monica; Bovenzi, Massimo; Tomasetti, Marco; Santarelli, Lor

Hereditary hyperhomocysteinemia associated with nephrotic syndrome complicated by artery thrombosis and chronic thromboembolic pulmonary hypertension: A case report.

We present here the case of a 30-year-old man with a long term history of nephrotic syndrome (NS) who developed an episode of acute left main pulmonary artery thrombosis complicated by a lung abscess. During the hospital admission was also identified a concomitant hyperhomocysteinemia. After an atypical resection of the left upper pulmonary lobe and the starting of long term anticoagulation the patient was discharged but did not attend the planned follow up visits until one year later when he was seen again for severe dyspnea and exercise intolerance. At this time chronic thromboembolic pulmonary hypertension (CTEPH) was diagnosed by lung perfusion scintigraphy and right heart catheterization. He initially refused the surgical treatment but, after six months, for the presence of worsening dyspnea was referred for bilateral pulmonary endarterectomy followed by a cardio-thoracic rehabilitation program. After a follow-up of seven years the patient is alive and in stable conditions. NS and hyperhomocysteinemia are both known risk factors for pulmonary embolism (PE), but their association with CTEPH is extremely rare. We discuss here the possible mechanisms linking these conditions. CTEPH must be suspected in any patient with NS, with or without hyperhomocysteinemia, and unexplained dyspnea

Epidemiology of West Nile in Europe and in the Mediterranean Basin

In the last 30 years several cases of West Nile (WN) virus infection were reported in horses and humans in Europe and in the Mediterranean Basin. Most of them were determined by strains of the Lineage 1 included in the European Mediterranean/Kenyan cluster. Strains of this cluster are characterised by a moderate pathogenicity for horses and humans and limited or no pathogenicity for birds. In recent years, however, WN cases determined by strains grouped in the Israeli/American cluster of Lineage 1 or in the lineage 2 have been reported in Hungary and Austria. The role of migrating birds in introducing new viruses to Europe has been often demonstrated. The migratory birds, which may be infected in their African wintering places, carry the virus northward to European sites during spring migrations. In the past, the virus introduction determined occasional cases of WN. In the recent years, new epidemiological scenarios are developing. In few occasions it has been evidenced the capability of WNV strains of overwintering by using local birds and mosquitoes. Species of Culex amongst mosquitoes and magpies (Pica pica), carrion crows (Corvus corone) and rock pigeons (Columba livia) amongst resident birds are the most probable species involved in this hypothetical WND endemic cycle

Characterization of three PDE5 isoforms in murine cardiomyocytes

Phosphodiesterase 5 (PDE5A) is responsible for hydrolysis of cGMP, a second messenger regulating many physiological functions in cardiac myocytes. PDE5A involvement in cardiac hypertrophy has been reported and the use of its inhibitor, sildenafil, has reverted the pathological increase of cardiac size in humans and in animal models (Nagendran et al., 2007). In humans, a single PDE5 gene encodes for three isoforms (PDE5A1, A2 and A3), which differ in their N-terminus being translated from alternative initiation sites (Lin et al., 2000). The isoforms exhibit specific tissue expression patterns and different sensitivities to pharmacological inhibitors. However, little is known about their specific biological roles. The existence of three murine PDE5A isoforms was predicted through human gene homology and confirmed by RT-PCR. Tissue expression pattern of each variant was uncovered by RT-PCR and western blot analysis. In adult heart, transcripts encoding for the three isoforms were detected. In cardiomyocytes primary cultures and cell lines PDE5A isoforms localization was revealed by fluorescence microscopy analysis and subcellular fractioning. Their phosphodiesterasic activities and sildenafil sensibilities were measured by radioactive assays. Finally, post-translational modifications were explored. Hypertrophic stimuli resulted in Ser 92 phosphorylation of PDE5A isoforms, possibly through by Protein Kinase A. In summary, the understanding of PDE5A isoforms localization and differential activation and activity might be an important step toward the improvement of the diagnostic, prognostic, and predictive values of PDE5A in hypertrophy treatment

Antibodies against Schmallenberg virus detected in cattle in the Otjozondjupa region, Namibia

Several ruminant species have been shown to be susceptible to Schmallenberg virus (SBV), but adult animals usually recover after showing mild or no clinical signs. However, transplacental infection can occur and lead to abortion, malformations and stillborn lambs, calves and goat kids. During November and December 2014, malformations were observed in 11 stillborn calves from two farms in the north-eastern region of Namibia. Blood samples were collected from 9 of the 11 cows that delivered stillborn and malformed calves. All these animals tested negative for Rift Valley fever, bovine viral diarrhoea and infectious bovine rhinotracheitis and were serologically positive for bluetongue virus, SBV and epizootic haemorrhagic disease virus. Clinical findings and serological results suggested that SBV may be circulating in Namibia