311 research outputs found
Different strategies in the correction of arterial hypertension: use of microparticles and polyphenols
Procédés pour l’identification de nouveaux composés activateurs des ERα dans la production du monoxyde d’azote endothélial
La présente invention décrit l\u27utilisation de composés chimiques dérivés de la delphinidine dans des procédés de criblage pour identifier des composés capables d\u27activer sélectivement le récepteur aux œ strogènes ERa, et de stimuler la production de monoxyde d\u27azote (NO) par l\u27endothélium, de tels composés pouvant être par la suite incorporés dans des compositions pharmaceutiques destinées à traiter notamment les maladies cardiovasculaires
Reactive Nitrogen Species: Molecular Mechanisms and Potential Significance in Health and Disease
Reactive nitrogen species (RNS) are various nitric oxide–derived compounds, including nitroxyl anion, nitrosonium cation, higher oxides of nitrogen, S-nitrosothiols, and dinitrosyl iron complexes. RNS have been recognized as playing a crucial role in the physiologic regulation of many, if not all, living cells, such as smooth muscle cells, cardiomyocytes, platelets, and nervous and juxtaglomerular cells. They possess pleiotropic properties on cellular targets after both posttranslational modifications and interactions with reactive oxygen species. Elevated levels of RNS have been implicated in cell injury and death by inducing nitrosative stress. The aim of this comprehensive review is to address the mechanisms of formation and removal of RNS, highlighting their potential cellular targets: lipids, DNA, and proteins. The specific importance of RNS and their paradoxic effects, depending on their local concentration under physiologic conditions, is underscored. An increasing number of compounds that modulate RNS processing or targets are being identified. Such compounds are now undergoing preclinical and clinical evaluations in the treatment of pathologies associated with RNS-induced cellular damage. Future research should help to elucidate the involvement of RNS in the therapeutic effect of drugs used to treat neurodegenerative, cardiovascular, metabolic, and inflammatory diseases and cancer
Engineered microparticles bearing the morphogen Sonic Hedgehog protect endothelial cells against actinomycin D-induced apoptosis
It has been reported that microparticles generated from T lymphocytes undergoing activation and apoptosis, bear the morphogen Sonic Hedgehog (MPsShh+), and possessed the dual ability to increase NO and reduce ROS productions. Here, we investigated whether MPsShh+ protected human umbical vein endothelial cells (HUVECs) against actinomycin D (ActD)-induced apoptosis. MPsShh+ were obtained by activation of human lymphocyte with phytohemagglutinin and then, by stimulation with phorbol-12 myristate-13 acetate and ActD. HUVECs were grown for 24 h in absence or presence of pro-apoptotic agent, ActD (1 μg/mL), and/or 10 μg protein/mL of MPsShh+. Apoptosis evaluation was based on flow cytometry, TUNEL labelling and cytochrome c release. We showed that MPsShh+ treatment significantly prevented HUVECs apoptosis evoked by ActD. Also, caspases inhibitor z-vad.fmk (50 μM ) reduced cell death either in presence or in absence of MPsShh+, indicating the implication of caspases in ActD-induced apoptosis. To investigate the implication of Shh pathway in this effect, its agonist SAG and its antagonist CUR61414 were tested. SAG reduced apoptosis in a dose-dependent manner; by itself, CUR61414 had no effect on its own but abolished the antiapoptotic effect of MPsShh, revealing a contribution of Shh pathway. In contrast, MPsShh+ were still able to reduce apoptosis in the presence of NO synthase inhibitor, L-NA (100 μM ), or when the PI3-kinase and ERK were inhibited with LY294002 (10 μM ) and U0126 (10 μM ) respectively, showing that these pathways were not associated with protection against apoptosis. Besides, we explored changes in ROS production at different times, by electronic paramagnetic resonance. ROS levels were increased in ActD-treated cells at 2 h and 10 h. This elevation was prevented by MPsShh+ only at 2 h. When sources of ROS, xanthine oxidase, NAD(P)H oxidase and respiratory chain complex I, were inhibited using allopurinol (50 μM ), apocynin (100 μM ) and rotenone (5 μM), respectively, we found that only rotenone reduced ActD-induced apoptosis. Also, the superoxide dismutase (SOD) mimetic, MnTMPyP (100 μM ), reduced ActD-evoked cell death and the protective effect of MPsShh+. These results indicate that, under these experimental conditions, MPsShh+ may act in the early phase of apoptosis at mitochondrial level and behave as a SOD mimetic. These findings provide additional mechanisms by which MPsShh+ exert their vasculoprotective effects, preserving integrity of endothelial monolayer. Supported by ANR-07-PHYSIO-010-01
The role of Smoothened and Hh signaling in neovascularization
New vessel formation plays a key role not only in physiological processes such as embryonic development and wound repair but also during several pathological situations. In this respect, favoring
neovascularization represents a promising therapeutic approach that would allow inducing tissue repair. Among the candidate proteins able to modulate neovascularization, evidence show that the administration of recombinant hedgehog (Hh) protein, gene, or cell therapy based on Hh transfer or using extracellular vesicles as vectors enhance new vessel formation. Here, we summarized the role of Hh pathway on angiogenesis and its therapeutic potential during myocardial infarction and diabetes
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