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International audience; Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction.

International audience; Purpose: The purpose of this study was to assess the impact of positron emission tomography/X-ray computed tomography (PET/CT) acquisition and reconstruction parameters on the assessment of mineralization process in a mouse model of atherosclerosis.Procedures: All experiments were performed on a dedicated preclinical PET/CT system. CT was evaluated using five acquisition configurations using both a tungsten wire phantom for in-plane resolution assessment and a bar pattern phantom for cross-plane resolution. Furthermore, the radiation dose of these acquisition configurations was calculated. The PET system was assessed using longitudinal line sources to determine the optimal reconstruction parameters by measuring central resolution and its coefficient of variation. An in vivo PET study was performed using uremic ApoE($^{-/-}$), non-uremic ApoE($^{-/-}$), and control mice to evaluate optimal PET reconstruction parameters for the detection of sodium [$^{18}$F]fluoride (Na[$^{18}$F]F) aortic uptake and for quantitative measurement of Na[$^{18}$F]F bone influx (Ki) with a Patlak analysis.Results: For CT, the use of 1x1 and 2x2 binning detector mode increased both in-plane and cross-plane resolution. However, resolution improvement (163 to 62m for in-plane resolution) was associated with an important radiation dose increase (1.67 to 32.78Gy). With PET, 3D-ordered subset expectation maximization (3D-OSEM) algorithm increased the central resolution compared to filtered back projection (1.420.35mm vs. 1.91 +/- 0.08, p

Oral presentation in Poster Area; International audience; Objective: Vascular calcifications (VC) contribute to arterial stiffness and atherosclerosis and are amplified during chronic kidney disease (CKD), in part due to the accumulation of uremic toxins such as phosphate (Pi) and indoxyl sulfate (IS). We hypothesized that the activation of endothelial cells (ECs) by uremic toxins promotes vascular smooth muscle cells (SMCs)-induced calcification.Design and method: HUVECs were treated with uremic concentrations of Pi, IS or both for 48 hours, then ECs conditioned media (EC-CM) was collected. Human aortic SMCs (hASMCs) were treated with the same uremic conditions, with or without EC-CM supplementation, and then viability and calcification were assayed. To identify factors secreted from ECs exposed to uremic toxins, a cytokine array (CA) was used to screen for 40 cytokines involved in osteogenic metabolism. Next, ELISA and RT qPCR were performed to evaluate IL-8 secretion and expression from ECs, since it was modulated in the CA. The IL-8 effect on hASMCs calcification was also examined by addition of human IL-8 in the media or by evaluating the procalcifying effect of EC-CM collected from ECs transfected with IL-8 siRNA. RT qPCR was also performed to examine the osteochondrogenic switch of hASMCs.Results: Pi+IS significantly decreased the viability of hASMCs by 30% that was not affected by EC-CM. Conversely, Pi+IS significantly increased the calcification of hASMCs and this effect was aggravated by EC-CM supplementation (wrt control, 3 ± 0.9 without EC-CM vs. 4.8 ± 0.7 with EC-CM, P < 0.0001). Compared to control, Pi+IS induced IL-8 gene expression in ECs (3.4 ± 1.2 fold increase, P = 0.0144) and IL-8 release from ECs (17.5 ± 7.9 pg/ml for control vs. 1.3 ± 0.2 pg/ml for Pi+IS, P = 0.0164). IL-8 addition to hASMCs under uremic exposure significantly promoted calcification in a concentration-dependent manner. Furthermore, uremic EC-CM induced-hASMCs calcification was prevented by silencing of IL-8 gene in ECs. Finally, IL-8 prevented the Pi+IS-induced increase of osteopontin gene in hASMCs (wrt control, 2.2 ± 0.2 without IL-8 vs. 1.3 ± 0.3 with IL-8).Conclusions: These results strongly suggest, for the first time, that IL-8 secreted from ECs during uremic exposure may play a critical role in vascular calcifications and thus in the cardiovascular complications of CKD.

International audience; The calcium-sensing receptor (CaR), is a G protein-dependent receptor that responds to increments in extracellular Ca(2+) ([Ca(2+)](o)). We previously reported that an increase in [Ca(2+)](o) induced a release of intracellular calcium and Ca(2+) entry via store operated channels (SOCs). We also demonstrated that MCF-7 cells express Transient Receptor Potential canonical 1 (TRPC1) channels. Herein, we investigated CaR intracellular signaling pathways and examined the role of TRPC1 in CaR-induced cell proliferation, through the extracellular signal-regulated Kinases 1 & 2 (ERK1/2) pathways. Treatment by [Ca(2+)](o) increased both MCF-7 cell proliferation and TRPC1 expression. Both the [Ca(2+)](o) proliferative effect and TRPC1 protein levels were abolished by the ERK1/2 inhibitors. Moreover, [Ca(2+)](o) failed to increase cell proliferation either in the presence of CaR or TRPC1 siRNAs. Both [Ca(2+)](o) and the selective CaR activator spermine, elicited time and dose-dependent ERK1/2 phosphorylation. ERK1/2 phosphorylation was almost completely inhibited by treatment with the phospholipase C and the protein kinase C inhibitors. Treatment with 2-aminoethoxydiphenyl borate (2-APB), and SKF-96365 or by siTRPC1 diminished both [Ca(2+)](o)- and spermine-stimulated ERK1/2 phosphorylation. Moreover, down-regulation of TRPC1 by siRNA reduced the Ca(2+) entry induced by CaR activation. We conclude that the CaR activates ERK1/2 via a PLC/PKC-dependent pathway. Moreover, TRPC1 is required for the ERK1/2 phosphorylation, Ca(2+) entry and the CaR-proliferative effect.

International audience; This study evaluates the effect of the mother-of-pearl (nacre) organic matrix on mammalian osteoclast activity and on cathepsin K protease. Rabbit osteoclasts were cultured on bovine cortical bone slices in the presence of water-soluble molecules extracted from nacre of the pearl oyster Pinctada margaritifera. Osteoclast resorption activity was determined by quantification of the resorption surface area on bovine bone slices. Papain and cathepsin K, B and L inhibition tests were performed in the presence of the nacre water-soluble extracts. The active crude extract was fractionated by dialysis and reversed-phase high-performance liquid chromatography before electrospray mass spectrometry analysis of inhibitory fractions. The water-soluble molecules extracted from nacre decreased bone resorption without jeopardizing osteoclast survival. The hydrolytic activity of cysteine proteinases was reduced when the enzymes were incubated with the nacre water-soluble molecules. Trending towards characterization of the molecules involved, it appears that cathepsin K inhibitors remain in different nacre water-soluble organic matrix subfractions, composed of low molecular weight molecules. Mollusk shell nacre contains molecules capable of reducing osteoclast bone resorption activity by inhibiting cathepsin K, giving a new facet of the bioactivity of nacre as bone biomaterial.

International audience; Osteoclast activity was studied on nacre, the mother of pearl (MOP) in order to assess the plasticity of bone resorbing cells and their capacity to adapt to a biomineralized material with a different organic and mineral composition from that of its natural substrate, bone. Pure MOP, a natural biomineralized CaCO(3) material, was obtained from Pinctada oyster shell. When implanted in the living system, nacre has proven to be a sustainable bone grafting material although a limited surface degradation process. Osteoclast stem cells and mature osteoclasts were cultured on MOP substrate and osteoclast precursor cells were shown to differentiate into osteoclasts capable of resorbing nacre substrate. However, analysis of the organization of the cytoskeleton showed that both a sealing zone and a podosome structure were observed on the nacre substrate. Moreover, MOP resorption efficiency was consistently found to be lower than that of bone and appeared to be a limited process.

The Nador lagoon is the largest one in Morocco and along the Mediterranean. It is located on the northeastern coast near the Rif chain (North Morocco), and it is surrounded by volcanic and sedimentary rocks of various lithofacies. The watershed has an area of about 2200 km2 and is drained by a dense river network. The lagoon dimension is of 115 km2 (25 x 7.5 km) with a depth not exceeding 8 m. The island barrier is 25 km in length and 350 m in average width. The carbonate fraction is the dominant component of the present-day sedimentation in the Nador lagoon. It represents 13 to 48 % of total sediments. Its distribution within the lagoon reflects the nature of marine and continental watershed. The carbonate fraction is composed, in decreasing order of importance, of calcite, magnesium calcite, dolomite and aragonite. The Sr isotopic signatures of lagoonal carbonates sediments show that they are dominated by marine biogenic sediments deposited, and by chemical precipitation. In addition, other carbonates of external origin and less radiogenic Sr isotopic are also present, coming from aerosols and ancient carbonates and transported by streams and rivers. From northwest to southeast, the Sr concentration of these lagoon carbonates increases, showing a slow renewal of waters in the southeastern zone because of its remoteness from communication with sea.

Le cancer de la prostate (PCa) est une maladie des cellules de la prostate. Elle est caractérisée par une prolifération incontrôlée des cellules épithéliales de la glande prostatique, qui se multiplient de façon anarchique pour former une tumeur maligne. Pour traiter le PCa, la suppression androgénique (ADT), radiothérapie et la chimiothérapie sont les traitements de référence et sont prescrits depuis plusieurs années. Cependant, la maladie devient résistance à la castration après un certain temps. Face à d'évidents besoins en thérapies innovantes, le secteur pharmaceutique a montré́ un réel intérêt pour le développement de nouvelles hormonothérapies. Une nouvelle classe de hormonothérapies est disponible depuis 2011 : les hormonothérapies de deuxième génération telles que l'acétate d'abiratérone. Ces molécules ont révolutionné la prise en charge du PCa. En effet, elles ont amélioré la survie des patients et elles ont retardé la détérioration de la qualité de vie des malades mais aussi retarde l'utilisation de la thérapie cytotoxique. De ce fait, Comité de Cancérologie de l'Association Française d'Urologie (CCAFU) a mis à jour ses recommandations pour considérer que l'abiratérone en association avec l'ADT comme nouveau standard thérapeutique pour le traitement des cancers de la prostate métastatiques hormono et chimio-naïfs à haut risque nouvellement diagnostiqué.

Les glomérulonéphrites sont des pathologies rénales rares dont la physiopathologie complexe et ses répercussions à long terme sur la fonction rénale nécessitent un suivi rigoureux. De plus, on retrouve dans l’arsenal thérapeutique, les corticoïdes et autres molécules immunosuppressives qui sont contraignantes tant par leurs effets indésirables que leurs précautions d’emploi. Le but de ce travail était de réaliser des livrets d’accompagnement afin d’informer les patients sur leur maladie mais aussi sur les mesures à adopter pour supporter au mieux les traitements prescrits. L’utilisation des supports d’information écrits s’inscrit dans une pratique de la pharmacie au plus proche du parcours de soin du patient, optimise son accompagnement et l’observance de son traitement.

L’insuffisance rénale chronique induit de nombreux troubles du métabolisme minéral et osseux ainsi que des calcifications vasculaires impactant par conséquent le pronostic vital et fonctionnel. Une prise en charge exhaustive est donc essentielle pour augmenter l’espérance de vie et améliorer la qualité de vie des patients insuffisant rénaux. On distingue différentes atteintes osseuses définies par des lésions histologiques, ce sont les ostéodystrophies rénales. L’hyperparathyroïdie secondaire à l’insuffisance rénale chronique est associée à l’ostéite fibreuse, elle est caractérisée par une rétention de phosphate, une diminution de la synthèse rénale de calcitriol et une hypocalcémie. Le diagnostic des différentes atteintes osseuses s’appuie sur des examens biochimiques, radiologiques et dans certains cas sur une biopsie osseuse, examen de référence. Dans cette thèse, nous étudierons la physiopathologie de l’ostéodystrophie rénale, les traitements spécifiques de chaque atteinte ainsi que la prévention nutritionnelle. Aussi, nous verrons comment la prise en charge de l’acidose métabolique, du stress oxydatif alliée à une meilleure absorption de minéraux et vitamines peut potentiellement permettre de réduire l’incidence des atteintes osseuses.

L’hyperphosphatémie est l’un des plus importants facteurs de risque non-traditionnels liés à l’urémie qui est considéré comme facteur prédictif de la morbi-mortalité cardiovasculaire. À cet égard, différentes études épidémiologiques ont montré que des concentrations sériques élevées de phosphate étaient également associées aux maladies cardiovasculaires dans la population générale. Considérant les implications cliniques de l'hyperphosphatémie incontrôlée, les concentrations de phosphate doivent être maintenues dans une fourchette optimale malgré d'importantes fluctuations des apports en phosphate alimentaire. Ces considérations sont d’autant plus importantes puisque la teneur des aliments en phosphate est en augmentation, principalement en raison de la consommation accrue d'aliments transformés avec des additifs phosphatés. Les principales hormones et facteurs qui contribuent à la régulation rénale de phosphate comprennent l'hormone parathyroïdienne, le FGF23, klotho et la 1,25-dihydroxyvitamine D3 (1,25 (OH) 2D3). Il y a quatre principales stratégies pour contrôler la phosphatémie ; la restriction des apports alimentaires riches en phosphates, l'administration d'agents chélateurs de phosphate, le contrôle de l'hyperparathyroïdie et l’adéquation de la dialyse chez les patients en IRC avancée. Malgré toutes les stratégies disponibles, et l'introduction de nouvelles thérapeutiques sur le marché, le contrôle du phosphate sérique demeure difficile, et l'hyperphosphatémie continue d'être extrêmement fréquente chez les patients en IRC. Une meilleure compréhension des mécanismes d’altération du métabolisme du phosphate dans l’IRC peut aider à clarifier le rôle possible de l'excès de phosphate alimentaire comme facteur de risque dans la population générale.