87 research outputs found

    Microparticles Carrying Sonic Hedgehog Favor Neovascularization through the Activation of Nitric Oxide Pathway in Mice

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    BACKGROUND: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation and during apoptosis. Human T lymphocytes undergoing activation and apoptosis generate MPs bearing morphogen Shh (MPs(Shh+)) that are able to regulate in vitro angiogenesis.METHODOLOGY/PRINCIPAL FINDINGS: Here, we investigated the ability of MPs(Shh+) to modulate neovascularization in a model of mouse hind limb ischemia. Mice were treated in vivo for 21 days with vehicle, MPs(Shh+), MPs(Shh+) plus cyclopamine or cyclopamine alone, an inhibitor of Shh signalling. Laser doppler analysis revealed that the recovery of the blood flow was 1.4 fold higher in MPs(Shh+)-treated mice than in controls, and this was associated with an activation of Shh pathway in muscles and an increase in NO production in both aorta and muscles. MPs(Shh+)-mediated effects on flow recovery and NO production were completely prevented when Shh signalling was inhibited by cyclopamine. In aorta, MPs(Shh+) increased activation of eNOS/Akt pathway, and VEGF expression, being inhibited by cyclopamine. By contrast, in muscles, MPs(Shh+) enhanced eNOS expression and phosphorylation and decreased caveolin-1 expression, but cyclopamine prevented only the effects of MPs(Shh+) on eNOS pathway. Quantitative RT-PCR revealed that MPs(Shh+) treatment increased FGF5, FGF2, VEGF A and C mRNA levels and decreased those of α5-integrin, FLT-4, HGF, IGF-1, KDR, MCP-1, MT1-MMP, MMP-2, TGFβ1, TGFβ2, TSP-1 and VCAM-1, in ischemic muscles. CONCLUSIONS/SIGNIFICANCE: These findings suggest that MPs(Shh+) may contribute to reparative neovascularization after ischemic injury by regulating NO pathway and genes involved in angiogenesis

    Molecular mechanisms of the cardiovascular protective effects of polyphenols

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    Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances

    Estrogen Receptor Alpha as a Key Target of Red Wine Polyphenols Action on the Endothelium

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    BACKGROUND: A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies

    PPARα Is Essential for Microparticle-Induced Differentiation of Mouse Bone Marrow-Derived Endothelial Progenitor Cells and Angiogenesis

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    BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovascularization. We hypothesized that microparticles (MPs), small fragments generated from the plasma membrane, can activate angiogenic programming of EPCs. METHODOLOGY/PRINCIPAL FINDINGS: We studied the effects of MPs obtained from wild type (MPs(PPARalpha+/+)) and knock-out (MPs(PPARalpha-/-)) mice on EPC differentiation and angiogenesis. Bone marrow-derived cells were isolated from WT or KO mice and were cultured in the presence of MPs(PPARalpha+/+) or MPs(PPARalpha-/-) obtained from blood of mice. Only MPs(PPARalpha+/+) harboring PPAR(alpha) significantly increased EPC, but not monocytic, differentiation. Bone marrow-derived cells treated with MPs(PPARalpha+/+) displayed increased expression of pro-angiogenic genes and increased in vivo angiogenesis. MPs(PPARalpha+/+) increased capillary-like tube formation of endothelial cells that was associated with enhanced expressions of endothelial cell-specific markers. Finally, the effects of MPs(PPARalpha+/+) were mediated by NF-kappaB-dependent mechanisms. CONCLUSIONS/SIGNIFICANCE: Our results underscore the obligatory role of PPARalpha carried by MPs for EPC differentiation and angiogenesis. PPARalpha-NF-kappaB-Akt pathways may play a pivotal stimulatory role for neovascularization, which may, at least in part, be mediated by bone marrow-derived EPCs. Improvement of EPC differentiation may represent a useful strategy during reparative neovascularization

    Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

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    Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

    MEDICIÓN Y ANÁLISIS DE LOS COMPUESTOS ORGÁNICOS VOLÁTILES EN LA ATMÓSFERA: ÚLTIMAS TÉCNICAS, APLICABILIDAD Y RESULTADOS A NIVEL EUROPEO

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    Los compuestos orgánicos volátiles (COVs) están considerados como uno de los mayores contaminantes presentes en la atmósfera; por esta razón, merecen una atención especial ya que con los óxidos de nitrógeno (NOx), son compuestos claves para entender el proceso de formación del ozono troposférico. Los COVs también participan en la formación del aerosol orgánico secundario, el cual contribuye al incremento de las partículas finas en la atmósfera y por consecuencia, a alteraciones en el clima. Los efectos de los COVs en la salud son importantes; estos van desde una simple molestia olfativa a una irritación (aldehidos) o una disminución de la capacidad respiratoria; además aumentan los riesgos mutagénicos y cancerígenos (benceno, 1,3-butadieno). Por esto, durante las últimas décadas, un cierto número de estudios han sido consagrados a la medida de los COVs en la atmósfera urbana, rural e industrial. Los métodos de medición existentes están generalmente constituidos por una unidad de muestreo, una unidad de preconcentración/desorción/inyección de los COVs contenidos en la unidad de muestreo, una columna cromatografía, y un detector de ionización de llama (FID) y/o un espectrómetro de masas.  Volatile Organic compounds (VOC) are considered as one of the most pollutants presents in the atmosphere. They deserve an especial attention because of with the nitrogen oxides they are keys compounds to understand the troposphere ozone formation. VOC can also contribute to secondary organic aerosol (SOA) formation; SOA can lead to increase finer particle matter and contribute to climate change. Health effect are also important; some VOC have little or unknown direct health effect, while other VOC, such as benzene and 1,3-butadiene, are carcinogens.   For   that   reason,   during   the   last decades, research has focused on VOC measurement on urban, rural and industrial area.Existing measurement methods are generally compose    by        a          sampling           unit, preconcentration/desorption/injection/ unit of VOC contained in sampling unit, chromatographic colon and a flame ionization detector (FID) and/or spectrometer mass

    Potential effects on ozone of future supersonic aircraft/2D simulation

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    In a previous work, the stratospheric effect of a future supersonic aircraft fleet on ozone has been simulated, by using a photochemical diffusive 1D model and a 2D photochemical, radiative dynamical model. The fleet scenario was defined by Aerospatiale and Snecma for a current technology Mach-2 aircraft; the models were limited to simplified homogeneous phase reactions. The results indicated a global ozone decrease of about 1.5% in steady-state conditions. Now the 2D model has been upgraded and includes the classical heterogeneous reactions with Polar Stratospheric Clouds (PSC) and aerosol. It also takes into account the natural or anthopogenic evolution of the background atmosphere. The scenario has been optimized to meet more realistic conditions. Thus, new results are presented. The main conclusion concerning the calculated impact of a realistic fleet for the next 20-50 years is still weaker than in the previous work: the decrease for the total ozone would always be lower than 0.3%. These results are commented, with the help of a parametric study, pointing out the importance of the background atmosphere and especially the total chlorine loading and the aerosol surface area
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