EG-VEGF, nouvel acteur du développement placentaire : implications physiologiques et pathologiques

Growth of the placental villi is a key event in placental development during human pregnancy. Many growth factors have been shown to control this process; however their ubiquitous expression makes them less specific to this tissue. Recently, a new growth factor named EG-VEGF (Endocrine Gland-derived Vascular Endothelial Growth Factor), specific to endocrine glands including the placenta, has been identified. It mediates its biological activity via two G protein coupled receptors, Prokineticin Receptor 1 and 2 (PROKR1 and PROKR2). In recent work from our laboratory, we have shown that I) EG-VEGF is abundantly expressed in human placenta II) EG-VEGF levels are highest during the first trimester and III) EGVEGF circulating levels are increased in preeclampsia (PE). Altogether, our results suggested that EG-VEGF might be an important regulatory factor in the placenta. My aim was to investigate (1) EG-VEGF angiogenic effects on microvascular cells within the placenta (HPEC), (2) its hormonal regulation with hCG (human Chorionic Gonadotropin), and (3) its expression in IUGR (Intrauterine Growth Restriction) pregnancies in the third trimester. Our results show that 1) EG-VEGF increases angiogenic processes in HPEC cells via PROKR1, and also their permeability via PROKR2 2) hCG increases EG-VEGF secretion and PROKR expression in the first trimester placenta and 3) EG-VEGF increases both trophoblast proliferation and survival, and its expression is dysregulated in IUGR in the third trimester of pregnancy. Altogether, our results show that EG-VEGF is a new placental growth factor. Its dysregulation in PE and IUGR suggests that it can be considered as a potential diagnostic marker and a potential therapeutic target in future.Le développement normal du placenta est la clé du succès de la grossesse. La croissance trophoblastique et vasculaire est une composante cruciale du développement placentaire. Un déficit dans ces processus conduit à des complications de la grossesse, telles que la Toxémie Gravidique (TG) ou le Retard de Croissance Intra-Utérin (RCIU). Récemment, un nouveau facteur angiogène spécifique des glandes endocrines vient d'être découvert : EG-VEGF pour « Endocrine Gland-derived Vascular Endothelial Growth Factor» ou PROK1 pour Prokineticin 1, facteur qui se lie à deux récepteurs couplés aux protéines G, PROKR1 et PROKR2. Dans des publications récentes du laboratoire, l'équipe a montré que I) EG-VEGF est fortement exprimé dans le placenta, II) son expression est majoritaire au 1er trimestre et III) les niveaux circulants d'EG-VEGF sont augmentés dans la TG, pathologie qui résulte de défauts vasculaires importants. L'ensemble de ces résultats convergeait vers un effet potentiel important d'EG-VEGF sur le placenta. Les objectifs de ma thèse ont été de caractériser (1) l'effet angiogène d'EG-VEGF sur les cellules endothéliales microvasculaires placentaires (HPEC), (2) d'étudier sa régulation par l'hCG (human Chorionic Gonadotropin), et (3) d'étudier son expression au 3ème trimestre dans les grossesses avec RCIU. J'ai montré que 1) EG-VEGF est un facteur angiogène important, et que ses effets angiogènes sont médiés par PROKR1, alors que c'est PROKR2 qui est impliqué dans ses effets sur la perméabilité, 2) l'hCG augmente la sécrétion d'EG-VEGF, ainsi que l'expression des PROKRs au 1er trimestre de la grossesse, et 3) EG-VEGF augmente la prolifération et la survie des trophoblastes, et est augmenté ainsi que ses récepteurs au 3ème trimestre dans les grossesses avec RCIU. L'ensemble de ces résultats montre qu'EG-VEGF est un nouveau facteur de croissance du placenta. Sa dérégulation dans la TG et le RCIU suggère qu'il pourrait servir de marqueur précoce prédictif pour ces pathologies et être utilisé comme cible thérapeutique potentielle dans l'avenir

EG-VEGF, nouvel acteur du développement placentaire : implications physiologiques et pathologiques

Growth of the placental villi is a key event in placental development during human pregnancy. Many growth factors have been shown to control this process; however their ubiquitous expression makes them less specific to this tissue. Recently, a new growth factor named EG-VEGF (Endocrine Gland-derived Vascular Endothelial Growth Factor), specific to endocrine glands including the placenta, has been identified. It mediates its biological activity via two G protein coupled receptors, Prokineticin Receptor 1 and 2 (PROKR1 and PROKR2). In recent work from our laboratory, we have shown that I) EG-VEGF is abundantly expressed in human placenta II) EG-VEGF levels are highest during the first trimester and III) EGVEGF circulating levels are increased in preeclampsia (PE). Altogether, our results suggested that EG-VEGF might be an important regulatory factor in the placenta. My aim was to investigate (1) EG-VEGF angiogenic effects on microvascular cells within the placenta (HPEC), (2) its hormonal regulation with hCG (human Chorionic Gonadotropin), and (3) its expression in IUGR (Intrauterine Growth Restriction) pregnancies in the third trimester. Our results show that 1) EG-VEGF increases angiogenic processes in HPEC cells via PROKR1, and also their permeability via PROKR2 2) hCG increases EG-VEGF secretion and PROKR expression in the first trimester placenta and 3) EG-VEGF increases both trophoblast proliferation and survival, and its expression is dysregulated in IUGR in the third trimester of pregnancy. Altogether, our results show that EG-VEGF is a new placental growth factor. Its dysregulation in PE and IUGR suggests that it can be considered as a potential diagnostic marker and a potential therapeutic target in future.Le développement normal du placenta est la clé du succès de la grossesse. La croissance trophoblastique et vasculaire est une composante cruciale du développement placentaire. Un déficit dans ces processus conduit à des complications de la grossesse, telles que la Toxémie Gravidique (TG) ou le Retard de Croissance Intra-Utérin (RCIU). Récemment, un nouveau facteur angiogène spécifique des glandes endocrines vient d'être découvert : EG-VEGF pour « Endocrine Gland-derived Vascular Endothelial Growth Factor» ou PROK1 pour Prokineticin 1, facteur qui se lie à deux récepteurs couplés aux protéines G, PROKR1 et PROKR2. Dans des publications récentes du laboratoire, l'équipe a montré que I) EG-VEGF est fortement exprimé dans le placenta, II) son expression est majoritaire au 1er trimestre et III) les niveaux circulants d'EG-VEGF sont augmentés dans la TG, pathologie qui résulte de défauts vasculaires importants. L'ensemble de ces résultats convergeait vers un effet potentiel important d'EG-VEGF sur le placenta. Les objectifs de ma thèse ont été de caractériser (1) l'effet angiogène d'EG-VEGF sur les cellules endothéliales microvasculaires placentaires (HPEC), (2) d'étudier sa régulation par l'hCG (human Chorionic Gonadotropin), et (3) d'étudier son expression au 3ème trimestre dans les grossesses avec RCIU. J'ai montré que 1) EG-VEGF est un facteur angiogène important, et que ses effets angiogènes sont médiés par PROKR1, alors que c'est PROKR2 qui est impliqué dans ses effets sur la perméabilité, 2) l'hCG augmente la sécrétion d'EG-VEGF, ainsi que l'expression des PROKRs au 1er trimestre de la grossesse, et 3) EG-VEGF augmente la prolifération et la survie des trophoblastes, et est augmenté ainsi que ses récepteurs au 3ème trimestre dans les grossesses avec RCIU. L'ensemble de ces résultats montre qu'EG-VEGF est un nouveau facteur de croissance du placenta. Sa dérégulation dans la TG et le RCIU suggère qu'il pourrait servir de marqueur précoce prédictif pour ces pathologies et être utilisé comme cible thérapeutique potentielle dans l'avenir

Relating Fragile States to Social and Human Fragilities

Fragile States is a way of naming this particular category of states that have weak performance, insufficient service delivery, weak administrative and government power, and lack of legal rules. Little consideration is usually made to the fact that their own societies may also be fragile and easily jeopardised by inappropriate economic measures or external events. Poverty traps and social exclusion, unjust inequalities with lack of equity, feelings of insecurity and vulnerability, usually undermine the social fabric. Moreover, the people bear their own internal fragilities, which are based on the lack of capabilities and recognition, and interfere in the relationships between the groups that constitute the society. Therefore, dealing with the issue of fragility requires to consider various decision levels, from the personal one to the State level. Such an approach could allow fragile states to conceive preventive policies that would avoid the surge of a political crisis resulting from the combination of social conflict and individual failure.La notion d’Etats fragiles permet de caractériser des pays dont le pouvoir de gouvernement est faible, le cadre juridique et légal insuffisant, l’administration peu efficace et, en conséquence, la délivrance de services publics insuffisante. Mais elle prend peu en compte le fait que leurs propres sociétés peuvent aussi être fragiles et facilement détruites par des mesures economiques inappropriées ou par des événements extérieurs. Ainsi, les trappes à pauvreté, les structures d’inégalité pérennes, l’absence d’équité, de même que l’exclusion sociale, le sentiment d’insécurité et de vulnérabilité, ont tous pour effet de miner la cohésion sociale. De plus, les gens eux-mêmes, au sein d’une société donnée, portent aussi leur propres fragilités internes, basées sur un manque de capabilité et de reconnaissance, et ceci interfère dans les relations sociales. Si bien que si l’on veut aborder le problème de la fragilité dans toute sa dimension, il faut alors prendre en compte l’articulation des différents niveaux d’analyse où cette fragilité se déploie, du niveau personnel au niveau propre à l’Etat. L’intérêt d’une telle démarche est qu’elle permet aux Etats fragiles de concevoir des mesures de politique préventives qui leur permettraient d’éviter l’apparition de crises politiques graves, comme conséquence de la combinaison de situations sociales conflictuelles et d’échecs individualisés

Les troubles du langage dans la maladie d'Alzheimer

International audienceAlzheimer disease (AD) induces researchers to consider with attentiveness the links existing between language, memory and patients' personal experiences. In this paper, these links are comprehended through the analysis of language disorders that are specific to AD, and through their interpretation into the light of some particular models of cognition that are essential to the comprehension of the linguistic dimension of AD. Finally, we present our own ongoing research project which aims at finding some reliable early cues for AD diagnosis and which originality is to investigate the correlation between some linguistic indicators such as idea density and the efficiency of patients' cognitive system." In any well-made machine one is ignorant of the working of most of the parts - the better they work the less we are conscious of them...it is only a fault which draws our attention to the existence of a mechanism at all " [1] (" Une machine bien construite permet d'oublier le fonctionnement des parties qui la composent - mieux cela fonctionne, moins l'on est conscient de celles-ci... c'est seulement lorsque survient une incident que notre attention est attirée par l'existence d'un mécanisme sous-jacent", notre traduction). Un système aussi naturel et complexe que celui du langage révèle son fonctionnement intime plus clairement dès lors qu'il dysfonctionne (notion de " reverse engineering ") [2]. L'exemple de la maladie d'Alzheimer (MA) nous invite à considérer avec attention les rapports entre langage et mémoire. Ces rapports seront d'abord envisagés au travers des symptômes dont souffrent les patients, puis interprétés à la lumière des modèles de la cognition, essentiels à la compréhension de la dimension linguistique de la maladie

Serum progesterone concentration on pregnancy test day might predict ongoing pregnancy after controlled ovarian stimulation and fresh embryo transfer

Progesterone (P4) is essential for pregnancy. A controlled ovarian stimulation (COS) leads to a iatrogenic luteal defect that indicates a luteal phase support (LPS) at least until pregnancy test day. Some clinicians continue the LPS until week 8 or later, when P4 is mainly secreted by syncytiotrophoblast cells.Measuring serum P4 on pregnancy test day after a fresh embryo transfer could help to identify women who might benefit from prolonged LPS. In women with LPS based on P4 administered by the rectal route, P4 concentration on pregnancy test day was significantly higher in patients with ongoing pregnancy than in patients with abnormal pregnancy.This monocentric retrospective study used data on 99 consecutive cycles of COS, triggered with human chorionic gonadotropin, followed by fresh embryo transfer resulting in a positive pregnancy test (>100 IU/L) (from November 2020 to November 2022). Patients undergoing preimplantation genetic screening or with ectopic pregnancy were excluded. All patients received standard luteal phase support (i.e. micronized vaginal progesterone 600 mg per day for 15 days). The primary endpoint was P4 concentration at day 15 after oocyte retrieval (pregnancy test day) in women with ongoing pregnancy for >12 weeks and in patients with miscarriage before week 12 of pregnancy.The median P4 concentration [range] at pregnancy test day was higher in women with ongoing pregnancy than in women with miscarriage (55.9 ng/mL [11.6; 290.6] versus 18.1 ng/mL [8.3; 140.9], p = 0.002). A P4 concentration ≥16.5 ng/mL at pregnancy test day was associated with higher ongoing pregnancy rate (OR = 12.5, 95% CI 3.61 - 43.33, p <0.001). A P4 concentration ≥16.5 ng/mL at pregnancy test day was significantly associated with higher live birth rate (OR = 11.88, 95% CI 3.30–42.71, p <0.001).After COS and fresh embryo transfer, the risk of miscarriage is higher in women who discontinue luteal support after 15 days, as recommended, but with P4 concentration <16.5 ng/mL. The benefit of individualized prolonged luteal phase support should be evaluated

Optimization of spray-dried hyaluronic acid microspheres to formulate drug-loaded bone substitute materials

Wepresent here our first results concerning the evaluation of hyaluronic acid (HA) as a candidate to formulate an organic–mineral cement with sustained release properties. Incorporating drug-loaded microspheres in mineral bone cements is an alternative strategy to improve their ability as drug delivery materials. To synthesize microspheres according to a reproducible process and control at the same time their morphology and their encapsulation efficiency is one of the main challenges of the conception of such drug-loaded bone substitute. In this context, we investigated the potentialities of two HA, differing by theirmolecular weight, to form microspheres by a spray-drying technique. Erythrosin B (EB) was encapsulated as a model drug and spray-drying process conditionswere optimized. To performthis, the rheological behavior and viscosity of HA solutions have been related to their spray-drying ability, and then to the resulting microparticles morphological properties and size distribution. Reproducible microspheres, answering to the requirements in terms of size and encapsulation efficiency, have been obtained from both HA. However the HA exhibiting the lowest molecular weight, HA600, led to smaller microparticles, with a higher polydispersity index. Their swelling ability, related to their stability upon rehydration, also appeared reduced. In this context, HA850, with the highest molecular weight, was selected and the possibility to modulate drug release by HA850 microspheres incorporation into a mineral cement was explored. EB release kinetics from HA microspheres, HA microspheres loaded cement and reference cement were followed at 37 °C, in Tris buffer at pH 7.4, using European Pharmacopoeia flow-through cells. Results showed that HA microspheres incorporation into a mineral cement permitted to modify the cement drug release profile and led to a sustained release

Surface properties of biomimetic nanocrystalline apatites; applications in biomaterials

Several types of nanocrystalline apatites have been described, obtained in various ways. Among these, biomimetic nanocrystalline apatites (BNA), whose characteristics are close to those of biological apatites, have been shown to exhibit specific properties mainly related to their surface structure and composition. The aim of this paper is to review current knowledge of these compounds

Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds

The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds

A Challenge to the Episodic Account of Negative Compatibility Effect in a Gender Categorization Task: Impact of Prime-Probe Contextual Similarity Versus Time Encoding

L’Effet de Compatibilité Négative (ECN) renvoie au fait que la compatibilité des réponses entre amorçe et cible donne lieu à un ralentissement des temps de décision comparativement à une condition d’incompatibilité. Dans une tâche de catégorisation sur le genre, Versace et Allain (2001) expliquent cet effet d’amorçage négatif  par la réévocation épisodique de traces mnésiques entrant en conflit. Afin de mettre à l’épreuve cette hypothèse, nous évaluons si l’intensité de l’Effet de Compatibilité Négative augmente dans des conditions expérimentales favorisant la récupération épisodique mnésique (Fox & de Fockert, 1998; Kane et al., 1997; Wong, 2000). Dans ce but, nous manipulons la similarité contextuelle entre amorce et cible par le biais des temps d’exposition. Nos résultats montrent qu’une interprétation épisodique ne peut rendre compte de façon unifiée de l’ECN. Le facteur déterminant de l’ECN se révèle être le temps alloué à l’encodage des informations plus que la similarité des traitements entre amorces et cibles.Negative Compatibility Effect (NCE) refers to the fact that a negative priming effect appears when prime/target pairs are mapped to the same response compared to pairs that are mapped to the opposite one. In a gender categorisation task, Versace and Allain (2001) explained this result by a backward-acting memorial processes leading to the detection of a conflict between prime and target responses. In this paper, we investigated whether NCE is stronger in condition enhancing episodic retrieval (Fox & de Fockert, 1998; Kane et al., 1997; Wong, 2000). We manipulated the contextual similarity between prime and target through information exposition duration. Our results do not emphasize episodic retrieval as a unified account for NCE: The critical determinant of NCE was the time allowed for primes encoding but not the contextual overlap between prime and target.

Soy Protein Microparticles for Enhanced Oral Ibuprofen Delivery: Preparation, Characterization, and In Vitro Release Evaluation

International audienceThe objective of this work was to evaluate soy protein isolate (SPI) and acylated soy protein (SPA) as spray-drying encapsulation carriers for oral pharmaceutical applications. SPI acylation was performed by the Schotten–Baumann reaction. SPA, with an acylation rate of 41%, displayed a decrease in solubility in acidic conditions, whereas its solubility was unaffected by basic conditions. The drug encapsulation capacities of both SPI and SPA were tested with ibuprofen (IBU) as a model poorly soluble drug. IBU-SPI and IBU-SPA particles were obtained by spray-drying under eco-friendly conditions. Yields of 70 to 87% and microencapsulation efficiencies exceeding 80% were attained for an IBU content of 20 to 40% w/w, confirming the excellent microencapsulation properties of SPI and the suitability of the chemical modification. The in vitro release kinetics of IBU were studied in simulated gastrointestinal conditions (pH 1.2 and pH 6.8, 37°C). pH-sensitive release patterns were observed, with an optimized low rate of release in simulated gastric fluid for SPA formulations, and a rapid and complete release in simulated intestinal fluid for both formulations, due to the optimal pattern of pH-dependent solubility for SPA and the molecular dispersion of IBU in soy protein. These results demonstrate that SPI and SPA are relevant for the development of pH-sensitive drug delivery systems for the oral route