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1. EG-VEGF maternal levels predict spontaneous preterm birth in the second and third trimesters in pregnant women with risk factors for placenta-mediated complications

Author: Tiphaine Raia-Barjat, Céline Chauleur, Constance Collet, Florence Rancon, Pascale Hoffmann, Morgane Desseux, Nicolas Lemaitre, Mohamed Benharouga, Antoine Giraud, and Nadia Alfaidy
Subjects: Medicine, Science
Abstract: Abstract Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels for prediction of spontaneous preterm birth in the second and third trimesters in pregnant women at high risk for placenta-mediated complications. A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p = 0.03, 0.02 and
Published: 2023
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2. Effects of Prokineticins on Cerebral Cell Function and Blood–Brain Barrier Permeability

Author: Hadi Younes, Ioanna Kyritsi, Zineb Mahrougui, Mohamed Benharouga, Nadia Alfaidy, and Christel Marquette
Subjects: prokineticin, prokineticin receptor, receptors antagonists, blood–brain barrier integrity, brain endothelial cells, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Prokineticins are a family of small proteins with diverse roles in various tissues, including the brain. However, their specific effects on different cerebral cell types and blood–brain barrier (BBB) function remain unclear. The aim of this study was to investigate the effects of PROK1 and PROK2 on murine cerebral cell lines, bEnd.3, C8.D30, and N2a, corresponding to microvascular endothelial cells, astrocytes and neurons, respectively, and on an established BBB co-culture model. Western blot analysis showed that prokineticin receptors (PROKR1 and PROKR2) were differentially expressed in the considered cell lines. The effect of PROK1 and PROK2 on cell proliferation and migration were assessed using time-lapse microscopy. PROK1 decreased neural cells’ proliferation, while it had no effect on the proliferation of endothelial cells and astrocytes. In contrast, PROK2 reduced the proliferation of all cell lines tested. Both PROK1 and PROK2 increased the migration of all cell lines. Blocking PROKRs with the PROKR1 antagonist (PC7) and the PROKR2 antagonist (PKR-A) inhibited astrocyte PROK2-mediated migration. Using the insert co-culture model of BBB, we demonstrated that PROKs increased BBB permeability, which could be prevented by PROKRs’ antagonists.
Published: 2023
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3. Vitamin D deficiency during late pregnancy mediates placenta-associated complications

Author: Tiphaine Raia-Barjat, Camille Sarkis, Florence Rancon, Lise Thibaudin, Jean-Christophe Gris, Nadia Alfaidy, and Céline Chauleur
Subjects: Medicine, Science
Abstract: Abstract During pregnancy, maternal vitamin D insufficiency could increase the risk of preeclampsia. Aim of the study was to evaluate the relationship between vitamin D status and the occurrence of placenta-mediated complications (PMCs) in a population at high risk. A prospective multicenter cohort study of 200 pregnant patients was conducted. The vitamin D level of patients with placenta-mediated complications was lower at 32 weeks compared to uncomplicated pregnancies (P = 0.001). At 32 weeks, the risk of occurrence of PMCs was five times higher in patients with vitamin D deficiency (RR: 5.14 95% CI (1.50–17.55)) compared to patients with normal vitamin D levels. There was a strong, inverse relationship between serum 25(OH)D levels at 32 weeks and the subsequent risk of PMCs (P = 0.001). At 32 weeks, the vitamin D level of patients with late-onset PMCs was lower than the one of patients with early-onset PMCs and of patients without PMCs (P
Published: 2021
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4. NLRP7 Enhances Choriocarcinoma Cell Survival and Camouflage in an Inflammasome Independent Pathway

Author: Déborah Reynaud, Nadia Alfaidy, Constance Collet, Nicolas Lemaitre, Frederic Sergent, Céline Miege, Emmanuelle Soleilhac, Alaa Al Assi, Padma Murthi, Gilles Courtois, Marie-Odile Fauvarque, Rima Slim, Mohamed Benharouga, and Roland Abi Nahed
Subjects: NLRP7, inflammasome, gestational choriocarcinoma, camouflage, NF-κB, cancer, Cytology, QH573-671
Abstract: Background: Gestational choriocarcinoma (GC) is a highly malignant trophoblastic tumor that often develops from a complete hydatidiform mole (HM). NLRP7 is the major gene responsible for recurrent HM and is involved in the innate immune response, inflammation and apoptosis. NLRP7 can function in an inflammasome-dependent or -independent pathway. Recently, we have demonstrated that NLRP7 is highly expressed in GC tumor cells and contributes to their tumorigenesis. However, the underlying mechanisms are still unknown. Here, we investigated the mechanism by which NLRP7 controls these processes in malignant (JEG-3) and non-tumor (HTR8/SVneo) trophoblastic cells. Cell survival, dedifferentiation, camouflage, and aggressiveness were compared between normal JEG-3 cells or knockdown for NLRP7, JEG-3 Sh NLRP7. In addition, HTR8/SVneo cells overexpressing NLRP7 were used to determine the impact of NLRP7 overexpression on non-tumor cells. NLRP7 involvement in tumor cell growth and tolerance was further characterized in vivo using the metastatic mouse model of GC. Results: We demonstrate that NLRP7 (i) functions in an inflammasome-dependent and -independent manners in HTR8/SVneo and JEG-3 cells, respectively; (ii) differentially regulates the activity of NF-κB in tumor and non-tumor cells; (iii) increases malignant cell survival, dedifferentiation, and camouflage; and (iv) facilitates tumor cells colonization of the lungs in the preclinical model of GC. Conclusions: This study demonstrates for the first time the mechanism by which NLRP7, independently of its inflammasome machinery, contributes to GC growth and tumorigenesis. The clinical relevance of NLRP7 in this rare cancer highlights its potential therapeutic promise as a molecular target to treat resistant GC patients.
Published: 2023
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5. The Deletion of TRPC6 Channels Perturbs Iron and Zinc Homeostasis and Pregnancy Outcome in Mice

Author: Jessy Hasna, Roland Abi Nahed, Frédéric Sergent, Nadia Alfaidy, and Alexandre Bouron
Subjects: Physiology, QP1-981, Biochemistry, QD415-436
Published: 2019
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6. The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects

Author: Nadia Alfaidy, Sophie Brouillet, Gayathri Rajaraman, Bill Kalionis, Pascale Hoffmann, Tiphaine Barjat, Mohamed Benharouga, and Padma Murthi
Subjects: vessel development, endothelial cells, angiogenesis, prokineticins, homeobox genes, vascularization, Physiology, QP1-981
Abstract: Vasculogenesis and angiogenesis are key processes of placental development, which occur throughout pregnancy. Placental vasculogenesis occurs during the first trimester of pregnancy culminating in the formation of hemangioblasts from intra-villous stem cells. Placental angiogenesis occurs subsequently, forming new blood vessels from existing ones. Angiogenesis also takes place at the fetomaternal interface, allowing essential spiral arteriole remodeling to establish the fetomaternal circulation. Vasculogenesis and angiogenesis in animal models and in humans have been studied in a wide variety of in vitro, physiological and pathological conditions, with a focus on the pro- and anti-angiogenic factors that control these processes. Recent studies revealed roles for new families of proteins, including direct participants such as the prokineticin family, and regulators of these processes such as the homeobox genes. This review summarizes recent advances in understanding the molecular mechanisms of actions of these families of proteins. Over the past decade, evidence suggests increased production of placental anti-angiogenic factors, as well as angiogenic factors are associated with fetal growth restriction (FGR) and preeclampsia (PE): the most threatening pathologies of human pregnancy with systemic vascular dysfunction. This review also reports novel clinical strategies targeting members of these family of proteins to treat PE and its consequent effects on the maternal vascular system.
Published: 2020
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7. The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Author: Irvan Alfian, Amlan Chakraborty, Hannah E. J. Yong, Sheetal Saini, Ricky W. K. Lau, Bill Kalionis, Evdokia Dimitriadis, Nadia Alfaidy, Sharon D. Ricardo, Chrishan S. Samuel, and Padma Murthi
Subjects: fetal growth restriction, placental function, inflammasomes, NLRP3, caspase-1, cytokines, Cytology, QH573-671
Abstract: Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.
Published: 2022
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8. Animal Models of Chorioamnionitis: Considerations for Translational Medicine

Author: Tiphaine Raia-Barjat, Margaux Digonnet, Antoine Giraud, Taghreed Ayash, Seline Vancolen, Mohamed Benharouga, Céline Chauleur, Nadia Alfaidy, and Guillaume Sébire
Subjects: animal models, chorioamnionitis, preterm birth, Biology (General), QH301-705.5
Abstract: Preterm birth is defined as any birth occurring before 37 completed weeks of gestation by the World Health Organization. Preterm birth is responsible for perinatal mortality and long-term neurological morbidity. Acute chorioamnionitis is observed in 70% of premature labor and is associated with a heavy burden of multiorgan morbidities in the offspring. Unfortunately, chorioamnionitis is still missing effective biomarkers and early placento- as well as feto-protective and curative treatments. This review summarizes recent advances in the understanding of the underlying mechanisms of chorioamnionitis and subsequent impacts on the pregnancy outcome, both during and beyond gestation. This review also describes relevant and current animal models of chorioamnionitis used to decipher associated mechanisms and develop much needed therapies. Improved knowledge of the pathophysiological mechanisms underpinning chorioamnionitis based on preclinical models is a mandatory step to identify early in utero diagnostic biomarkers and design novel anti-inflammatory interventions to improve both maternal and fetal outcomes.
Published: 2022
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9. Role of NLRP7 in Normal and Malignant Trophoblast Cells

Author: Roland Abi Nahed, Maya Elkhoury Mikhael, Deborah Reynaud, Constance Collet, Nicolas Lemaitre, Thierry Michy, Pascale Hoffmann, Frederic Sergent, Christel Marquette, Padma Murthi, Tiphaine Raia-Barjat, Nadia Alfaidy, and Mohamed Benharouga
Subjects: NLRP7, inflammasome, choriocarcinoma, pregnancy, maternal immune tolerance, tumor microenvironment, Biology (General), QH301-705.5
Abstract: Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
Published: 2022
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10. Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

Author: Constance Collet, Jonathan Lopez, Christophe Battail, Fabienne Allias, Mojgan Devouassoux-Shisheboran, Sophie Patrier, Nicolas Lemaitre, Touria Hajri, Jérôme Massardier, Benoit You, François Mallet, François Golfier, Nadia Alfaidy, and Pierre-Adrien Bolze
Subjects: gestational trophoblastic disease, gestational trophoblastic neoplasia, choriocarcinoma, hydatidiform mole, trophoblast, placenta, Biology (General), QH301-705.5
Abstract: The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets.
Published: 2021
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11. Risk factors and poor prognostic factors of preeclampsia in Ibn Rochd University Hospital of Casablanca: about 401 preeclamptic cases

Author: Meriem Benfateh, Souadou Cissoko, Houssine Boufettal, Jean-Jacques Feige, Naima Samouh, Touria Aboussaouira, Mohamed Benharouga, and Nadia Alfaidy
Subjects: preeclampsia, risk factors, maternal prognostic, fetal prognostic, Medicine
Abstract: Preeclampsia is a gestational pathology that complicates 2 to 8% of pregnancies and is one of the major causes of maternal and fetal morbidity and mortality worldwide. The aim of this work was to study the epidemiological profile of preeclampsia in Casablanca and to identify risk factors as well as factors of poor maternal and fetal prognosis. 401 preeclamptic cases were collected in the gynecology-obstetrics "C" Service of Lalla Meryem Maternity of Ibn Rochd University Hospital of Casablanca (2010-2011) were included in this study and a statistical analysis with the SPSS software version (16.0) was performed. We used the Chi-2 test to analyze qualitatives variables and Student's test and ANOVA (analysis of variance) for quantitative variables. The incidence of preeclampsia was (7.1%). The epidemiological profile was that of a primipara (57.6%), average age 30 years and (66.8%) of pregnancies were not followed. Multiparity was a factor of poor maternal prognosis (p = 0.007). The low gestational age and no prenatal care were factors of poor prognosis maternal as well as fetal. Risk factors frequently found in our patients were obesity (15.21%) and chronic hypertension (5.73%) as vascular-renal history; abortion (16.46%) and perinatal death (5.24%) as obstetric history. Pre-eclampsia is a common obstetric pathology in our context. Better prenatal care and early diagnosis could reduce its incidence.
Published: 2018
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12. Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy

Author: Deborah Reynaud, Frederic Sergent, Roland Abi Nahed, Wael Traboulsi, Constance Collet, Christel Marquette, Pascale Hoffmann, Gianfranco Balboni, Qun-Yong Zhou, Padma Murthi, Mohamed Benharouga, and Nadia Alfaidy
Subjects: prokineticin antagonists, EG-VEGF, pregnancy pathologies, therapy, angiogenesis, trophoblast invasion, Biology (General), QH301-705.5
Abstract: Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta; contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion; thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.
Published: 2021
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13. Copper-Associated Oxidative Stress Contributes to Cellular Inflammatory Responses in Cystic Fibrosis

Author: Amal Kouadri, Johanna Cormenier, Kevin Gemy, Laurence Macari, Peggy Charbonnier, Pierre Richaud, Isabelle Michaud-Soret, Nadia Alfaidy, and Mohamed Benharouga
Subjects: inflammation, cystic fibrosis, oxidative stress, CFTR, copper, lung, Biology (General), QH301-705.5
Abstract: Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF Transmembrane Conductance Regulator (CFTR), an apical chloride channel. An early inflammation (EI) in the lung of CF patients occurring in the absence of any bacterial infection has been reported. This EI has been proposed to be associated with oxidative stress (OX-S), generated by deregulations of the oxidant/antioxidant status. Recently, we demonstrated that copper (Cu), an essential trace element, mediates OX-S in bronchial cells. However, the role of this element in the development of CF-EI, in association with OX-S, has never been investigated. Using healthy (16HBE14o-; HBE), CF (CFBE14o-; CFBE), and corrected-wild type CFTR CF (CFBE-wt) bronchial cells, we characterized the inflammation and OX-S profiles in relation to the copper status and CFTR expression and function. We demonstrated that CFBE cells exhibited a CFTR-independent intrinsic inflammation. These cells also exhibited an alteration in mitochondria, UPR (Unfolded Protein Response), catalase, Cu/Zn- and Mn-SOD activities, and an increase in the intracellular content of iron, zinc, and Cu. The increase in Cu concentration was associated with OX-S and inflammatory responses. These data identify cellular Cu as a key factor in the generation of CF-associated OX-S and opens new areas of investigation to better understand CF-associated EI.
Published: 2021
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14. Cyclooxygenase (I&II) Inhibitors and Prostaglandin Dehydrogenase Regulation on PGE2 Output in Human Placental Trophoblast Cells

Author: Naser Mirazi, Nadia Alfaidy, and Jan Challis
Subjects: cyclooxygenases, human placental trophoblast cells, prostaglandin dehydrogenase, prostaglandin e2, Medicine
Abstract: Recent studies in amnion and chorion trophoblasts have shown that glucocorticoids (GC) increase and decrease expression and activity of PGHS and PGDH enzymes respectively. However, the effects of GC on the expression of these enzymes in placental cells (PC) is unknown. Human placenta were obtained from uncomplicated term pregnancies after elective cesarian section delivery. The dispresed cells were filtered and loaded on to a continous percoll gradient (5-70%) and after 72 hrs incubation of primary culture cell medium were washed and changed and then treated for 24 hrs in the presence or absence of arachidonic acid (5mM), plus various combinations of meloxicam (MEL , 1mM), indomethacin (Ind , 1mM) dexamethasone (DEX , 1mM) and sulphasalazine (SFZ , 1mM). fter incubation period cell mediums were collected for determination of PGE2 by radioimmunoassay. One-way ANOVA test and student’s t-test were used to assess statistical differences and ststistical significances were set at P
Published: 2003

15. EG-VEGF Maternal levels predict spontaneous preterm birth in the second and third trimesters of pregnancy

Author: Tiphaine Raia-Barjat, Céline CHAULEUR, Constance Collet, Florence Rancon, Pascale Hoffmann, Morgane Desseux, Nicolas Lemaitre, Mohamed Benharouga, Antoine Giraud, and Nadia Alfaidy
Abstract: Background: Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels in pregnant women at high risk for prediction of spontaneous preterm birth in the second and third trimesters. Methods: A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Results: Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p= 0.03, 0.02 and Conclusions: Serum EG-VEGF concentrations could be considered as a reliable biomarker of spontaneous preterm birth in high-risk pregnant women.
Published: 2023

16. All suupplemental figures clean from Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Author: Nadia Alfaidy, Mohamed Benharouga, Jean J. Feige, Touria Aboussaouira, François Mallet, Philippe Sauthier, Aude Salomon, Pierre A. Bolze, Valentina Onnis, Gianfranco Balboni, Qun Y. Zhou, Mohammed Benlahfid, Pascale Hoffmann, Rima Slim, Sophie Brouillet, Houssine Boufettal, Frédéric Sergent, and Wael Traboulsi
Abstract: Supplemental Methods Figure S1: Reports clinical information's about normal pregnant women, patients with complete hydatiform moles or choriocarcinoma. Figure S2: Experimental procedure. Figure S3: Quantification of EG-VEGF PROKR1 and PROKR2 protein expression in CTL, Complete hydatiform mole (CHM) and choriocarcinoma (CC) placental section. Figure S4: EG-VEGF effect on JEG3 migration, in the absence or presence of PROKR1 or PROKR2 antagonists. Figure S5: JEG3-luc injected mice exhibited arrested gestation and disorganized vascularization. Figure S6: Antibody microarray analysis. Figure S7: Characterization of the angiogenic status of sera and placentas collected from CTL, CHM and CC patients. Figure S8: Antibody angiogenic microarray analysis of sera collected from CTL, CHM and CC patients.
Published: 2023

17. Data from Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Author: Nadia Alfaidy, Mohamed Benharouga, Jean J. Feige, Touria Aboussaouira, François Mallet, Philippe Sauthier, Aude Salomon, Pierre A. Bolze, Valentina Onnis, Gianfranco Balboni, Qun Y. Zhou, Mohammed Benlahfid, Pascale Hoffmann, Rima Slim, Sophie Brouillet, Houssine Boufettal, Frédéric Sergent, and Wael Traboulsi
Abstract: Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy.Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice.Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions.Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.
Published: 2023

18. Soluble CD146 is increased in preeclampsia and interacts with galectin-1 to regulate trophoblast migration through VEGFR2 receptor

Author: Ahmad Joshkon, Alexandrine Foucault-Bertaud, Wael Traboulsi, Christophe Demattei, Françoise Dignat-George, Nadia Alfaidy, Richard Bachelier, Odile Paulmyer-Lacroix, Jean-Christophe Gris, Aurélie S. Leroyer, Marcel Blot-Chabaud, Sylvie Bouvier Pharm, V. Letouzey, Nathalie Bardin, Mathieu Fortier, Sandra M. Blois, Marie Nollet, Eve Mousty, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie [CHU Nîmes] (BESPIM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Sechenov First Moscow State Medical University, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Institut de Recherches en Technologies et Sciences pour le Vivant (IRTSV), and GRIS, Jean-Christophe
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Galectin 1, MESH: Pre-Eclampsia, MESH: Trophoblasts, CD146 Antigen, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Preeclampsia, Andrology, MESH: Pregnancy, Pre-Eclampsia, Trophoblast migration, Pregnancy, Galectin-1, Blocking antibody, Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target, medicine, Humans, Prospective Studies, Receptor, reproductive and urinary physiology, MESH: Galectin 1, MESH: Humans, Eclampsia, business.industry, Trophoblast, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, Trophoblasts, MESH: Prospective Stufies, carbohydrates (lipids), [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.anatomical_structure, CD146/sCD146, Female, Signal transduction, MESH: CD146 Antigen, business, MESH: Female
Abstract: International audience; Objective: To explore the regulatory role of soluble CD146 (sCD146) and its interaction with galectin-1 (Gal1) in placenta-mediated complications of pregnancy.Design: Prospective pilot and experimental studies.Setting: University-affiliated hospital and academic research laboratory.Patient(s): One hundred fifteen women divided into three groups: 30 healthy, nonpregnant women, 50 women with normal pregnancies, and 35 with placenta-mediated pregnancy complications.Intervention(s): Wound-healing experiments were conducted to study trophoblast migration.Main outcome measure(s): Quantification of sCD146 and Gal1 by enzyme-linked immunosorbent assay. Analysis of trophoblast migration by wound closure.Result(s): Concomitant detection of sCD146 and Gal1 showed lower sCD146 and higher Gal1 concentrations in women with normal pregnancies compared with nonpregnant women. In addition, follow-up of these women revealed a decrease in sCD146 associated with an increase in Gal1 throughout pregnancy. In contrast, in women with preeclampsia, we found significantly higher sCD146 concentrations compared with women with normal pregnancies and no modification of Gal1. We emphasize the opposing effects of sCD146 and Gal, since, unlike Gal1, sCD146 inhibits trophoblast migration. Moreover, the migratory effect of Gal1 was abrogated with the use of an anti-CD146 blocking antibody or the use of small interfering RNA to silence VEGFR2 expression. This suggests that trophoblast migration is mediated though the interaction of Gal1 with CD146, further activating the VEGFR2 signaling pathway. Significantly, sCD146 blocked the migratory effects of Gal1 on trophoblasts and inhibited its secretion, suggesting that sCD146 acts as a ligand trap.Conclusion(s): Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target. Clinical trial registration number: NCT 01736826.Trial registration: ClinicalTrials.gov NCT01736826.
Published: 2022

19. Epidemiological Profile and Risk Factors of Ovarian Cancer in Ibn Rochd University Hospital of Casablanca Morocco: About 131 Cases

Author: Benfateh Meriem, Abdellatif Benider, Mohammed Benlahfid, Nadia Alfaidy, Souha Sahraoui, and Touria Aboussaouira
Subjects: medicine.medical_specialty, Pediatrics, business.industry, Peritoneal carcinosis, Incidence (epidemiology), medicine.disease, University hospital, Menopause, Epidemiology, medicine, General Earth and Planetary Sciences, Medical history, Ovarian cancer, business, Cystadenocarcinoma, General Environmental Science
Abstract: Introduction: Ovarian cancer is one of the leading causes of morbidity and mortality in women worldwide, generally characterized by a poor prognosis. Most cases are diagnosed at an advanced stage. The standardized incidence rate for the world population is 8.1/100,000 women per year, with an estimated 239,000 new cases and 152,000 deaths per year worldwide. Methods: This study aims to evaluate the epidemiological characteristics and risk factors of ovarian cancer by studying the risk factors of this pathology on a sample of 131 cases followed at the Ibn Rochd University Hospital in Casablanca from 2010 to 2012 using SPSS version 16.0 software. Results: The average age of the patients is 51.47±13 years, the significant risk factors observed are multiparity (64.3%), menopause (58%) as personal history and hypertension (77.78%) as medical history. The majority of the patients (60%) came from urban areas, (50.4%) had cystic looking tumors (34.4%) on the right side, cystadenocarcinoma (20.6%) was the most frequent histological type, (74.8%) metastases were noted, including (44.3%) peritoneal carcinosis. Conclusion: We concluded that the epidemiological profile of ovarian cancer is close to national and Maghreb data. A better biological investigation as well as an adequate management would allow its early diagnosis and the reduction of its incidence.
Published: 2020

20. [Prevalence and characteristics of serum autoantibodies in patients followed for infertility at Grenoble University Hospital]

Author: Pascale Hoffman, Chloé Wackenheim, Laurence Bouillet, Alban Deroux, Nadia Alfaidy, Chantal Dumestre-Pérard, CHU Grenoble, Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CCSD, Accord Elsevier, Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Invasion mechanisms in angiogenesis and cancer (IMAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Hôpital Michallon
Subjects: 0301 basic medicine, Infertility, medicine.medical_specialty, Anti-nuclear antibody, medicine.disease_cause, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, medicine, skin and connective tissue diseases, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, Autoimmune disease, Gynecology, Pregnancy, 030219 obstetrics & reproductive medicine, biology, business.industry, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Retrospective cohort study, General Medicine, medicine.disease, 3. Good health, stomatognathic diseases, 030104 developmental biology, Fertility Disorders, biology.protein, Antibody, business
Abstract: International audience; Introduction: Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease.Methods: We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected.Results: The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies.
Published: 2019

21. Role of NLRP7 in Normal and Malignant Trophoblast Cells

Author: Roland Abi Nahed, Maya Elkhoury Mikhael, Deborah Reynaud, Constance Collet, Nicolas Lemaitre, Thierry Michy, Pascale Hoffmann, Frederic Sergent, Christel Marquette, Padma Murthi, Tiphaine Raia-Barjat, Nadia Alfaidy, Mohamed Benharouga, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction
Abstract: International audience; Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
Published: 2021

22. Vitamin D deficiency during late pregnancy mediates placenta-associated complications

Author: Céline Chauleur, Jean-Christophe Gris, Tiphaine Raia-Barjat, Nadia Alfaidy, Florence Rancon, Camille Sarkis, Lise Thibaudin, Hôpital Nord (Saint Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sechenov First Moscow State Medical University, Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), Alfaidy, Nadia, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), I.M. Sechenov First Moscow State Medical University [Moscow, Russia] (MSMU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Saint-Etienne, CHU Grenoble, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Ingénierie et Santé (CIS-ENSMSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), CEA- Saclay (CEA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: medicine.medical_specialty, Placenta, Science, Population, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030204 cardiovascular system & hematology, Predictive markers, Gastroenterology, Article, vitamin D deficiency, Preeclampsia, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, 03 medical and health sciences, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Internal medicine, medicine, Vitamin D and neurology, Humans, Prospective Studies, Vitamin D, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, Multidisciplinary, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Vitamin D Deficiency, medicine.disease, Late pregnancy, 3. Good health, Pregnancy Complications, medicine.anatomical_structure, Medicine, Female, business, Biomarkers, Cohort study
Abstract: During pregnancy, maternal vitamin D insufficiency could increase the risk of preeclampsia. Aim of the study was to evaluate the relationship between vitamin D status and the occurrence of placenta-mediated complications (PMCs) in a population at high risk. A prospective multicenter cohort study of 200 pregnant patients was conducted. The vitamin D level of patients with placenta-mediated complications was lower at 32 weeks compared to uncomplicated pregnancies (P = 0.001). At 32 weeks, the risk of occurrence of PMCs was five times higher in patients with vitamin D deficiency (RR: 5.14 95% CI (1.50–17.55)) compared to patients with normal vitamin D levels. There was a strong, inverse relationship between serum 25(OH)D levels at 32 weeks and the subsequent risk of PMCs (P = 0.001). At 32 weeks, the vitamin D level of patients with late-onset PMCs was lower than the one of patients with early-onset PMCs and of patients without PMCs (P
Published: 2021

23. Significance of the placental barrier in antenatal viral infections

Author: Hannah E.J. Yong, Gayathri Rajaraman, Padma Murthi, Shiao-Yng Chan, Frantisek Staud, Amlan Chakraborty, Nadia Alfaidy, Sharon D. Ricardo, Mohamed Benharouga, Université Grenoble Alpes, Inserm, CEA, BIG-Biologie du Cancer et de l’Infection, Grenoble, France, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Offspring, viruses, Placenta, HIV Infections, Zika virus, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Barrier function, 03 medical and health sciences, 0302 clinical medicine, Syncytiotrophoblast, Immune system, Fetus, Pregnancy, Medicine, Humans, Severe acute respiratory syndrome coronavirus 2, Pregnancy Complications, Infectious, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Viral infections, biology, business.industry, Transmission (medicine), SARS-CoV-2, Zika Virus Infection, Human immunodeficiency virus, Immune cells, COVID-19, Zika Virus, medicine.disease, biology.organism_classification, Infectious Disease Transmission, Vertical, 3. Good health, medicine.anatomical_structure, Virus Diseases, 030220 oncology & carcinogenesis, embryonic structures, Immunology, HIV-1, Molecular Medicine, Female, business
Abstract: The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.
Published: 2021

24. NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Author: Padma Murthi, Roland Abi Nahed, Deborah Reynaud, Vincent Sapin, Nadia Alfaidy, Christophe Battail, Mohamed Benharouga, Nicolas Lemaitre, Touria Aboussaouira, Pierre-Adrien Bolze, Wael Traboulsi, Rima Slim, Odile Filhol, Pascale Hoffmann, Houssine Boufettal, Frederic Sergent, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Georgetown University Medical Center, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand, Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Centre Hospitalier Universitaire [Grenoble] (CHU), Monash Biomedicine Discovery Institute, Monash University [Clayton], University of Melbourne, McGill University = Université McGill [Montréal, Canada], Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Alfaidy, Nadia, and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: 0301 basic medicine, Cancer Research, orthotopic model of choriocarcinoma, [SDV.BDLR.RA]Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, Article, Gestational choriocarcinoma, Immune tolerance, Proinflammatory cytokine, NLRP7, 03 medical and health sciences, 0302 clinical medicine, Immune system, Downregulation and upregulation, medicine, choriocarcinoma, tumor microenvironment, [SDV.BDLR.RA] Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, reproductive and urinary physiology, RC254-282, Tumor microenvironment, Gene knockdown, business.industry, Choriocarcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, hydatidiform mole, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, business, maternal immune tolerance
Abstract: The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC, (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization, and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.
Published: 2021

25. Disrupted placental serotonin synthetic pathway and increased placental serotonin

Author: Suveena Ranzil, Euan M. Wallace, Peter R. Ebeling, Anthony J. Borg, Stacey J. Ellery, Cathy Vaillancourt, Jan Jaap H. M. Erwich, Alexander Bonnin, Padma Murthi, Nadia Alfaidy, David W. Walker, Monash University [Clayton], Hudson Institute of Medical Research [Clayton], Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Keck School of Medicine [Los Angeles], University of Southern California (USC), The Royal Women's Hospital, University of Groningen [Groningen], University of Melbourne, This work was supported by an award to PM and PRE from the Australian Institute of Musculoskeletal Science, Western Health, Victoria, Australia., Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and Reproductive Origins of Adult Health and Disease (ROAHD)
Subjects: Adult, 0301 basic medicine, Serotonin, Placenta, Pregnancy Trimester, Third, ENDOMETRIUM, Intrauterine growth restriction, INFANTS, Placental insufficiency, Tryptophan Hydroxylase, Biology, Article, Preeclampsia, Andrology, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, PREGNANCIES, Humans, Serotonin Plasma Membrane Transport Proteins, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Fetus, Fetal Growth Retardation, 030219 obstetrics & reproductive medicine, TPH1, CONSEQUENCES, TPH2, Obstetrics and Gynecology, Placental Insufficiency, medicine.disease, VESICULAR MONOAMINE TRANSPORTER, RELATIVE GENE-EXPRESSION, Up-Regulation, PREECLAMPSIA, 030104 developmental biology, medicine.anatomical_structure, Reproductive Medicine, Case-Control Studies, Chorionic villi, Gestation, UPDATE, Female, IMPLANTATION, VILLOUS TREE, Metabolic Networks and Pathways, Developmental Biology
Abstract: Objectives: Placental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR).Methods: The components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10-12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA.Results: Gene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p Conclusion: This study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies.
Published: 2019

26. NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation

Author: Wael Traboulsi, Déborah Reynaud, Padma Murthi, Nadia Alfaidy, M. N. Dieudonné, A. Wetzel, M. Dakouane-Giudicelli, R. Abi Nahed, Mohamed Benharouga, Anthony J. Borg, Vincent Sapin, Sophie Brouillet, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Hudson Institute of Medical Research [Clayton], The Royal Women's Hospital, Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Gamètes, implantation, gestation (GIG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Obstetrics and Gynaecology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Adult, Placenta, Cellular differentiation, Interleukin-1beta, Inflammation, Biology, Cell Line, NLRP7, Inflammasome, Andrology, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Pregnancy, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Discovery, medicine, Humans, Hypoxia, Receptor, reproductive and urinary physiology, Genetics (clinical), Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Fetal Growth Retardation, Interleukin-18, Trophoblast, Cell Differentiation, FGR, Trophoblasts, 3. Good health, Pregnancy Trimester, First, Trophoblast invasion, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Molecular Medicine, Female, medicine.symptom, medicine.drug
Abstract: International audience; Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n = 38) and from FGR (n = 40) and age-matched controls (n = 32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.
Published: 2019

27. Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy

Author: Constance Collet, C. Marquette, Déborah Reynaud, Wael Traboulsi, Qun-Yong Zhou, Nadia Alfaidy, Pascale Hoffmann, Padma Murthi, Roland Abi Nahed, Mohamed Benharouga, Gianfranco Balboni, Frederic Sergent, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Angiogenesis, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, Preeclampsia, 03 medical and health sciences, chemistry.chemical_compound, angiogenesis, 0302 clinical medicine, vascularization, trophoblast invasion, medicine, EG-VEGF, Receptor, lcsh:QH301-705.5, 030304 developmental biology, prokineticins, 0303 health sciences, Pregnancy, prokineticin antagonists, therapy, business.industry, Trophoblast, pregnancy pathologies, homeobox genes, medicine.disease, Prokineticin, endothelial cells, 3. Good health, Vascular endothelial growth factor, vessel development, medicine.anatomical_structure, chemistry, lcsh:Biology (General), pregnancy, business, 030217 neurology & neurosurgery, Endocrine gland
Abstract: Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta, contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion, thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.
Published: 2021

28. Vascular endothelial growth factor (VEGF) and Endocrine gland-VEGF (EG-VEGF) are down regulated in head and neck cancer

Author: Mohammed Benlahfid, Wael Traboulsi, Nadia Alfaidy, Mustapha Sidqui, Mohamed Benharouga, Touria Aboussaouira, Si Mohamed Bouzoubaa, Chouaib Rifki, Sophie Brouillet, Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Biologie des Métaux (BioMet ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Oncology, CD31, Male, Vascular Endothelial Growth Factor A, Angiogenesis, Epulis, PROKR2, PROKR1, CD34, chemistry.chemical_compound, 0302 clinical medicine, 030223 otorhinolaryngology, Receptor, Immunohistochemistry, VEGF, Vascular endothelial growth factor, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Disease Progression, Female, OSCC, Ki67, Adult, medicine.medical_specialty, Down-Regulation, Enzyme-Linked Immunosorbent Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Young Adult, Internal medicine, Endocrine Glands, medicine, Biomarkers, Tumor, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, EG-VEGF, business.industry, Head and neck cancer, medicine.disease, HNC, stomatognathic diseases, Otorhinolaryngology, chemistry, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, business
Abstract: International audience; Objective To characterise the role of VEGF, EG-VEGF and its receptors in the development and progression of HNC. Design Human serum and tissues samples were collected from healthy, epulis and HNC patients and used for ELISA assays and immunohistochemistry studies, respectively. Setting Ibn Rochd Hospital of Casablanca (Morocco), INSERM and University of Grenoble Alpes (France). Participants We used serum from 64 patients with head and neck cancers and from 71 controls without general pathology. Tissues samples were collected from seven patients with OSCC and from seven patients with Epulis. Main outcome measures We compared circulating VEGF and EG-VEGF in normal and HNC patients and determined the expression, localisation and quantification of VEGF, EG-VEGF and its receptors; PROKR1 and PROKR2 as well as Ki67, CD31 and CD34 in OSCC and Epulis patients. Results Both EG-VEGF and VEGF circulating levels were significantly decreased in the HNC (P < .01). OSCC patients expressed less EG-VEGF and VEGF proteins, higher PROKR1 and PROKR2 with no change in CD31 and CD34 levels. A significant increase in Ki67 was observed in OSCC. Conclusions We demonstrated that circulating VEGF and EG-VEGF are downregulated in HNC patients and in OSCC tissue. EG-VEGF receptors were increased in OSCC, along with a stabilisation of two key markers of angiogenesis. These findings strongly suggest that downregulation of angiogenesis in HNC might explain its moderate metastatic feature.
Published: 2020

29. Protein kinase CK2 contributes to placental development: physiological and pathological implications

Author: Nicolas Lemaitre, Claude Cochet, Daniel Vaiman, Déborah Reynaud, Odile Filhol, Mohamed Benharouga, Nadia Alfaidy, Roland Abi Nahed, Solene Lartigue, Caroline Roelants, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Inovarion, Inovarion [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Biologie des Métaux (BioMet ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Invasion de trophoblastes, Modèle animal, Prééclampsie, Adolescent, Protein subunit, Placenta, Biology, Preeclampsia, Andrology, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, In vivo, Cell Line, Tumor, Drug Discovery, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Casein Kinase II, Genetics (clinical), reproductive and urinary physiology, Trophoblast, medicine.disease, Molecular medicine, Placentation, In vitro, Trophoblasts, Mice, Inbred C57BL, Disease Models, Animal, Pregnancy Trimester, First, Protéine kinase CK2, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, embryonic structures, Molecular Medicine, Female, Ex vivo, 030215 immunology
Abstract: International audience; Preeclampsia (PE) is the most threatening pathology of human pregnancy. Its development is thought to be due to a failure in the invasion of trophoblast cells that establish the feto-maternal circulation. Protein kinase CK2 is a ubiquitous enzyme reported to be involved in the control of cell invasion. CK2 consists of two subunits, a catalytic subunit, CK2α, and a regulatory subunit, CK2β. To date, no data exist regarding the expression and role of this enzyme in normal and PE pregnancies. We performed studies, at the clinical level using distinctive cohorts from early pregnancy (n = 24) and from PE (n = 23) and age-matched controls (n = 28); in vitro, using trophoblast cell lines; ex vivo, using placental explants; and in vivo, using PE mouse models. We demonstrated that (i) CK2 is more expressed during the late first trimester of pregnancy and is mainly localized in differentiated trophoblast cells, (ii) the inhibition of its enzymatic activity decreased the proliferation, migration, invasion, and syncytialization of trophoblast cells, both in 2D and 3D culture systems, and (iii) CK2 activity and the CK2α/CK2β protein ratio were increased in PE human placentas. The pattern and profile of CK2 expression were confirmed in gravid mice along with an increase in the PE mouse models. Altogether, our results demonstrate that CK2 plays an essential role in the establishment of the feto-maternal circulation and that its deregulation is associated with PE development. The increase in CK2 activity in PE might constitute a compensatory mechanism to ensure proper pregnancy progress.
Published: 2020

30. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor PROKR2 are associated to human colorectal cancer progression and peritoneal carcinomatosis

Author: Abdelaziz Fadil, Mohammed Benlahfid, Mohamed Benharouga, Driss Erguibi, Mehdi Karkouri, Khalid Elhattabi, Hicham Elattar, Wael Traboulsi, Yassine Fahmi, Frederic Sergent, Nadia Alfaidy, Touria Aboussaouira, Faculty of Medicine and Pharmacy, University Hassan II Casablanca, Laboratory of Scientific and Clinical Researches in Cancerous Pathologies, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Laboratory of anatomopathology Moulay Driss 1e⁢r, Casablanca, Morocco., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Adolescent, Receptors, Peptide, Colorectal cancer, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Prokineticin, Receptors, G-Protein-Coupled, Metastasis, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Genetics, Humans, Medicine, Endocrine system, EG-VEGF, Risk factor, Receptor, Peritoneal Neoplasms, Aged, business.industry, peritoneal carcinomatosis, General Medicine, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, Vascular endothelial growth factor, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Disease Progression, Cancer research, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Colorectal Neoplasms, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Endocrine gland
Abstract: International audience; BACKGROUND:The highest risk factor for mortality among malignant tumors is metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor which biological activity is mediated via two G protein-coupled receptors, prokineticin receptor1 (PROKR1) and PROKR2. Recent studies suggested that EG-VEGF expression is deregulated in multiple cancers including colorectal cancer (CRC).METHODS:Using distinctive CRC and peritoneal carcinomatosis (PC) cohorts and corresponding control cohort, we determined the circulating levels of EG-VEGF and its in situ expression, and that of its related receptors.RESULTS:Circulating EG-VEGF levels were significantly increased in patients with metastatic PC compared to CRC and control patients (p< 0.05). Furthermore, according to clinicopathologic examinations, local EG-VEGF expression correlated with higher tumor and nodal stages (p< 0.001) of CRC. EG-VEGF and PROKR2 were highly expressed in colorectal primary lesions compared to positive controls. PROKR1 expression was lower and did not change in tumor specimens. Also, EG-VEGF and its receptor PROKR2 were differentially expressed in the colorectal primary lesions and in the control groups.CONCLUSION:Altogether these findings suggest that EG-VEGF/receptors system might be an important actor in the CRC progression into PC and might be involved in the ability of tumor cells to invade other organs. Circulating EG-VEGF could be proposed as a prognostic marker in human CRC and its progression into PC.
Published: 2018

31. Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

Author: Jonathan Lopez, Christophe Battail, François Golfier, Fabienne Allias, Pierre-Adrien Bolze, Constance Collet, Benoit You, Mojgan Devouassoux-Shisheboran, Nadia Alfaidy, Touria Hajri, François Mallet, Jérôme Massardier, Nicolas Lemaître, Sophie Patrier, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire [Grenoble] (CHU), Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Rouen, Normandie Université (NU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), BIOMERIEUX, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université de Lyon-Université de Lyon, Hôpital Edouard Herriot [CHU - HCL], Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alfaidy, Nadia, and Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3)
Subjects: placenta, QH301-705.5, Angiogenesis, Medicine (miscellaneous), Biology, Article, General Biochemistry, Genetics and Molecular Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Gestational choriocarcinoma, 03 medical and health sciences, 0302 clinical medicine, SALL4, Placenta, gestational trophoblastic neoplasia, choriocarcinoma, medicine, gestational trophoblastic disease, Biology (General), reproductive and urinary physiology, 030304 developmental biology, transforming growth factor beta, 0303 health sciences, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Gestational trophoblastic disease, Choriocarcinoma, Trophoblast, Transforming growth factor beta, medicine.disease, trophoblast, female genital diseases and pregnancy complications, 3. Good health, hydatidiform mole, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, biology.protein
Abstract: International audience; The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets.
Published: 2021

32. Prokineticin 1 is a new biomarker of human oocyte competence: expression and hormonal regulation throughout late folliculogenesis

Author: Guillaume Martinez, Aurore Gueniffey, Yannick Antoine, Nadia Alfaidy, Julien Bessonnat, Pascale Hoffmann, Déborah Reynaud, Laure Villaret, Eve Melloul, Wael Traboulsi, Thomas Boueihl, Sylviane Hennebicq, Camille Dunand, Samir Hamamah, Anna Lamotte, Chloé Baron, Sophie Brouillet, Charles Coutton, Charlotte Mauroy, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: 0301 basic medicine, Pregnancy Rate, medicine.medical_treatment, Gene Expression, Oocyte Retrieval, Cohort Studies, Follicle-stimulating hormone, PROK1, Oogenesis, 0302 clinical medicine, Pregnancy, Follicular phase, Prospective Studies, Cells, Cultured, reproductive and urinary physiology, 030219 obstetrics & reproductive medicine, General Medicine, Prognosis, Treatment Outcome, medicine.anatomical_structure, Female, France, Folliculogenesis, Gonadotropin, Quality Control, medicine.drug_class, Embryonic Development, Fertilization in Vitro, Biology, Gastrointestinal Hormones, Andrology, 03 medical and health sciences, medicine, Humans, Sperm Injections, Intracytoplasmic, Blastocyst, EG-VEGF, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, In vitro fertilisation, Cell Biology, Oocyte, Follicular fluid, Hormones, In vitro fertilization (IVF), Follicular Fluid, 030104 developmental biology, Reproductive Medicine, Oocytes, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Follicular development, Biomarkers, Gonadotropins
Abstract: Context Prokineticin 1 (PROK1) quantification in global follicular fluid (FF) has been recently reported as a predictive biomarker of in vitro fertilization (IVF) outcome. It is now necessary to evaluate its clinical usefulness in individual follicles. Objectives To evaluate the clinical value of PROK1 secretion in individual FF to predict oocyte competence. To determine the impact of follicular size, oocyte maturity, and gonadotropin treatments on PROK1 secretion. Design and setting Prospective cohort study from May 2015 to May 2017 at the University Hospital of Grenoble. Patients A total of 69 infertile couples underwent IVF. Intervention(s) Collection of 298 individual FF from 44 women undergoing IVF; 52 individual cumulus cell (CC) samples and 15 CC primary cultures from 25 women undergoing IVF-intracytoplasmic sperm injection (ICSI). Main Outcome Measure(s) Oocyte competence was defined as the ability to sustain embryo development to the blastocyst stage. Follicular size was measured by 2D-sonography. PROK1 concentration was quantified by ELISA assay. Results PROK1 concentration was correlated to follicular size (r = 0.85, P = 2.2 × 10−16). Normalized PROK1 concentration in FF was predictive of subsequent oocyte competence (AUROC curve = 0.76 [95% CI, 0.69–0.83]; P = 1.7 × 10−9), irrespectively of day-2 embryo morphokinetic parameters. The expression and secretion of PROK1 were increased in FF and CC of mature oocytes (P < 0.01). Follicle Stimulating Hormone and hCG up-regulated PROK1 secretion in CC primary cultures (P < 0.01; P < 0.05), probably through the cAMP pathway (P < 0.01). Conclusions PROK1 quantification in individual FF could constitute a new predictive biomarker of oocyte competence in addition with embryo morphokinetic parameters. Trial registration number none.
Published: 2019

33. The Deletion of TRPC6 Channels Perturbs Iron and Zinc Homeostasis and Pregnancy Outcome in Mice

Author: Alexandre Bouron, Nadia Alfaidy, Jessy Hasna, Roland Abi Nahed, Frederic Sergent, Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Invasion mechanisms in angiogenesis and cancer (IMAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Bouron, Alexandre, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and ANR-16-CE29-0024,ImaZinc,Homéostasie du zinc lors de la corticogénese(2016)
Subjects: 0301 basic medicine, Male, Litter Size, Physiology, Placenta, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Kidney, lcsh:Physiology, TRPC6, Mice, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Homeostasis, lcsh:QD415-436, Lung, TRPC, Mice, Knockout, lcsh:QP1-981, Chemistry, Brain, DNA-Binding Proteins, Platelet Endothelial Cell Adhesion Molecule-1, Zinc, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Female, TRPC, Ion channels, Metals, Brain, Placenta, Adult, Cations, Divalent, Iron, Preeclampsia, lcsh:Biochemistry, Andrology, 03 medical and health sciences, medicine, TRPC6 Cation Channel, Animals, Humans, TRPC Cation Channels, Ion Transport, Embryogenesis, Neuropeptides, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Transcription Factors
Abstract: International audience; BACKGROUND/AIMS:Transient receptor potential canonical 6 (TRPC6) protein is a nonselective cation channel permitting the uptake of essential elements such as iron (Fe) and zinc (Zn). TRPC6 is found throughout the body with high expression levels in the placenta. However, its role in this organ is still to be determined. To further advance our understanding of the physiological relevance of TRPC6, we have studied the placental histology, pregnancy outcome and the Fe and Zn status of organs (placenta, brain, kidney, liver and lung) collected from TRPC6 deficient (TRPC6-/-) mice and sex and age-matched C57Bl6/J and B6129SF2/J mice.METHODS:Metal content was quantified by inductively coupled plasma-atomic emission spectrometry (ICP-AES). Quantitative reverse transcriptase PCR (qRT-PCR) and Western Blottings (WB) were performed to analyze the expression of placental markers and TRPC6.RESULTS:Our data show that TRPC6-/- mice displayed reduced litter sizes, structural changes of the placenta, along with altered mRNA levels of CD31 and Gcm1, two markers of placental development. Furthermore, immunoblots revealed elevated amounts of TRPC6 proteins in placentas from women diagnosed with preeclampsia, a common gestational disease. When compared to C57Bl6/J and B6129SF2/J, TRPC6-/- mice had elevated Zn levels in placenta, liver and kidney during embryonic development and postnatally, but not at adulthood. High amounts of Fe were found in the adult brain and liver of TRPC6-/- mice. The lung was however not affected by the deletion of TRPC6, indicating that this mouse strain developed organ and age-dependent perturbations in their Zn and Fe status.CONCLUSION:This work indicates that TRPC6 exerts critical pathophysiological functions in placenta, and provides further evidence for a role of this channel in the homeostasis of cations like Zn and Fe.
Published: 2019

34. [Prevalence and characteristics of serum autoantibodies in patients followed for infertility at Grenoble University Hospital]

Author: Chloé, Wackenheim, Pascale, Hoffman, Chantal, Dumestre-Pérard, Laurence, Bouillet, Nadia, Alfaidy, and Alban, Deroux
Subjects: Endometriosis, Autoimmunity, Autoantigens, Iodide Peroxidase, Immunomodulation, Pregnancy, Antibodies, Antinuclear, Iron-Binding Proteins, Antibodies, Antiphospholipid, Humans, Female, Embryo Implantation, France, Infertility, Female, Autoantibodies, Retrospective Studies
Abstract: Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease.We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected.The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies.
Published: 2019

35. Involvement of the Prion Protein in the Protection of the Human Bronchial Epithelial Barrier Against Oxidative Stress

Author: Pierre Richaud, Mariam El Khatib, Sylvain Chauvet, Micheline El Khoury, Johanna Cormenier, Christelle Coraux, Wael Zeinyeh, Mohamed Benharouga, Laurence Macari, Nadia Alfaidy, Isabelle Michaud-Soret, Amal Kouadri, Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), GON, Nathalie, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Copper Sulfate, Physiology, animal diseases, Clinical Biochemistry, Bronchial epithelium, Bronchi, Oxidative phosphorylation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, medicine.disease_cause, Biochemistry, Desmoglein, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Prion Proteins, Cell Line, Adherens junction, 03 medical and health sciences, Cell polarity, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, General Environmental Science, Messenger RNA, 030102 biochemistry & molecular biology, biology, Tight junction, Chemistry, Desmoplakin, Cell Polarity, Epithelial Cells, Adherens Junctions, Cell Biology, Cell biology, nervous system diseases, 030104 developmental biology, Prion protein, A549 Cells, Oxidative stress, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, General Earth and Planetary Sciences, Junctional proteins, Copper
Abstract: International audience; AIM: Bronchial epithelium acts as a defensive barrier against inhaled pollutants and microorganisms. This barrier is often compromised in inflammatory airway diseases that are characterized by excessive oxidative stress responses, leading to bronchial epithelial shedding, barrier failure, and increased bronchial epithelium permeability. Among proteins expressed in the junctional barrier and participating to the regulation of the response to oxidative and to environmental stresses is the cellular prion protein (PrPC). However, the role of PrPC is still unknown in the bronchial epithelium. Herein, we investigated the cellular mechanisms by which PrPC protein participates into the junctional complexes formation, regulation, and oxidative protection in human bronchial epithelium.RESULTS: Both PrPC messenger RNA and mature protein were expressed in human epithelial bronchial cells. PrPC was localized in the apical domain and became lateral, at high degree of cell polarization, where it colocalized and interacted with adherens (E-cadherin/γ-catenin) and desmosomal (desmoglein/desmoplakin) junctional proteins. No interaction was detected with tight junction proteins. Disruption of such interactions induced the loss of the epithelial barrier. Moreover, we demonstrated that PrPC protection against copper-associated oxidative stress was involved in multiple processes, including the stability of adherens and desmosomal junctional proteins.INNOVATION: PrPC is a pivotal protein in the protection against oxidative stress that is associated with the degradation of adherens and desmosomal junctional proteins.CONCLUSION: Altogether, these results demonstrate that the loss of the integrity of the epithelial barrier by oxidative stress is attenuated by the activation of PrPC expression, where deregulation might be associated with respiratory diseases.
Published: 2019

36. Prenatal Exposure to Select Phthalates and Phenols and Associations with Fetal and Placental Weight among Male Births in the EDEN Cohort (France)

Author: Rémy Slama, Nadia Alfaidy, Barbara Heude, Claire Philippat, Jérémie Botton, Antonia M. Calafat, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Equipe 6 : ORCHAD - Origines précoces de la santé du développement de l'enfant (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Sorbonne Paris Cité (USPC), Epidemiologia Ambiental, Centre for Research in Environmental Epidemiology (CREAL)-Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP) of Pamplona-Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, INSERM U823, équipe 12 (Epidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Alfaidy, Nadia, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Male, medicine.medical_specialty, Health, Toxicology and Mutagenesis, Birth weight, Placenta, Phthalic Acids, Physiology, 010501 environmental sciences, 01 natural sciences, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Phenols, Pregnancy, Epidemiology, Medicine, Birth Weight, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, Fetus, business.industry, Research, Public Health, Environmental and Occupational Health, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Environmental Exposure, medicine.disease, 3. Good health, medicine.anatomical_structure, Maternal Exposure, Prenatal Exposure Delayed Effects, embryonic structures, Cohort, Female, France, business, Biomarkers, Cohort study
Abstract: Background: The placenta performs crucial physiological functions to ensure normal fetal development. Few epidemiological studies investigated placental weight sensitivity to phthalates and phenols. Objective: Our goal was to explore whether maternal exposure to select phthalates and phenols is associated with changes in placental weight at birth and in placental–to–birth weight ratio (PFR). Methods: Placental weight and birth weight were available for 473 mother–son pairs in the EDEN (Etude des Déterminants pré et postnatals du développement et de la santé de l’Enfant) cohort for whom 9 phenols (4 parabens, 2 dichlorophenols, triclosan, benzophenone-3, bisphenol A) and 11 phthalate metabolites were measured in spot urine samples collected between weeks 23 and 29 of gestation. We used adjusted Elastic Net penalized regression models (ENET) to select biomarkers associated with placental weight, birth weight and PFR. Unpenalized effect estimates were then obtained by fitting linear regression models simultaneously adjusted for the ENET-selected biomarkers and a priori chosen confounders. Results: The multipollutant ENET model for placental weight retained four biomarkers: triclosan and monocarboxy-isononyl phthalate (MCNP), which were negatively associated with placental weight, and benzophenone-3 and the sum of parabens, which were positively associated with this outcome. The ENET model for PFR retained two phthalate metabolites [MCNP and monocarboxy-isooctyl phthalate (MCOP)], which were negatively associated with this outcome. Discussion: The positive association between the sum of parabens and placental weight was consistent with results of a previous study among 49 male births. Our results provide preliminary evidence of possible associations between other compounds such as triclosan, benzophenone-3, MCNP, and MCOP and both placental weight and PFR. These associations were not reported in previous studies and should be seen as hypothesis generating. Studies relying on repeated assessments of exposure in prospective mother–child cohorts are needed to substantiate the plausibility of the hypotheses generated by our results. https://doi.org/10.1289/EHP3523
Published: 2019

37. Risk factors and poor prognostic factors of preeclampsia in Ibn Rochd University Hospital of Casablanca: about 401 preeclamptic cases

Author: Mohamed Benharouga, Touria Aboussaouira, Souadou Cissoko, Nadia Alfaidy, Meriem Benfateh, Naïma Samouh, Jean-Jacques Feige, Houssine Boufettal, Unité de Culture Cellulaire, CED, Faculté de Médecine et de Pharmacie, Service C de Gynécologie, CHU Ibn Rochd, Faculté de Médecine et de Pharmacie, Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine et Pharmacie Casablanca, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Context (language use), Prenatal care, 030204 cardiovascular system & hematology, Abortion, Preeclampsia, 03 medical and health sciences, 0302 clinical medicine, Epidemiology, medicine, risk factors, Case Series, 030212 general & internal medicine, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Obstetrics, business.industry, Incidence (epidemiology), fetal prognostic, Gestational age, General Medicine, medicine.disease, maternal prognostic, 3. Good health, Gestation, business
Abstract: International audience; Preeclampsia is a gestational pathology that complicates 2 to 8% of pregnancies and is one of the major causes of maternal and fetal morbidity and mortality worldwide. The aim of this work was to study the epidemiological profile of preeclampsia in Casablanca and to identify risk factors as well as factors of poor maternal and fetal prognosis. 401 preeclamptic cases were collected in the gynecology-obstetrics "C" Service of Lalla Meryem Maternity of Ibn Rochd University Hospital of Casablanca (2010-2011) were included in this study and a statistical analysis with the SPSS software version (16.0) was performed. We used the Chi-2 test to analyze qualitative variables and Student's test and ANOVA (analysis of variance) for quantitative variables. The incidence of preeclampsia was (7.1%). The epidemiological profile was that of a primipara (57.6%), average age 30 years and (66.8%) of pregnancies were not followed. Multiparity was a factor of poor maternal prognosis (p = 0.007). The low gestational age and no prenatal care were factors of maternal as well as fetal prognosis. Risk factors frequently found in our patients were obesity (15.21%) and chronic hypertension (5.73%) as vascular-renal history; abortion (16.46%) and perinatal death (5.24%) as obstetric history. Preeclampsia is a common obstetric pathology in our context. Better prenatal care and early diagnosis could reduce its incidence.
Published: 2018

38. Erratum to: EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Déborah, Reynaud, Frédéric, Sergent, Roland, Abi Nahed, Sophie, Brouillet, Mohamed, Benharouga, and Nadia, Alfaidy
Published: 2018

39. Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction

Author: Peter R. Ebeling, Jonathan M. Morris, Martha Lappas, Laura J. Parry, Bryan Leaw, Anthony J. Borg, Ratana Lim, Nadia Alfaidy, Kelly J. McKelvey, Padma Murthi, Joanna L. James, Sharon A. McCracken, Katie L. Powell, Euan M. Wallace, Claire T. Roberts, Harmeet Singh, Thierry Fournier, Evdokia Dimitriadis, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Hudson Institute of Medical Research [Clayton], Department of Obstetrics and Gynaecology [Melbourne], Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne-Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: 0301 basic medicine, Embryology, Angiogenesis, Placenta, medicine.medical_treatment, angiogenesis, 0302 clinical medicine, Pregnancy, hormone production, Receptors, Lipoxin, reproductive and urinary physiology, Tube formation, Fetal Growth Retardation, 030219 obstetrics & reproductive medicine, apoptosis, Obstetrics and Gynecology, Cell Differentiation, differentiation, female genital diseases and pregnancy complications, Trophoblasts, medicine.anatomical_structure, Cytokine, embryonic structures, Female, Signal Transduction, Pregnancy Trimester, Third, education, Placental insufficiency, Biology, growth restriction, Preeclampsia, Andrology, 03 medical and health sciences, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Interleukin 8, Molecular Biology, Endothelial Cells, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, medicine.disease, Receptors, Formyl Peptide, Pregnancy Trimester, First, 030104 developmental biology, Reproductive Medicine, formyl peptide receptor 2, inflammation, Developmental Biology
Abstract: STUDY QUESTION: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)? SUMMARY ANSWER: Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro. WHAT IS KNOWN ALREADY: FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth. STUDY DESIGN, SIZE, DURATION: The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group). Fpr2 expression was also determined in placental tissues obtained from a murine model of FGR (n = 4). The functional role of FPR2 in primary trophoblasts and endothelial cells in vitro was assessed in diverse assays in a time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placentae from third-trimester pregnancies complicated by idiopathic FGR (n = 25) and those from gestation-matched pregnancies with appropriately grown infants as controls (n = 25) were collected at gestation 27-40 weeks. Placental tissues were also collected from a spontaneous CBA/CaH × DBA/2 J murine model of FGR. Placental FPR2/Fpr2 mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence FPR2 expression in primary trophoblasts and in human umbilical vein endothelial cells (HUVEC), and the quantitation of cytokines, chemokines and apoptosis was performed following a cDNA array analyses. Functional effects of trophoblast differentiation were measured using HCGB/β-hCG and syncytin-2 expression as well as markers of apoptosis, tumour protein 53 (TP53), caspase 8, B cell lymphoma 2 (BCL2) and BCL associated X (BAX). Endothelial function was assessed by proliferation, network formation and permeability assays. MAIN RESULTS AND THE ROLE OF CHANCE: Placental FPR2/Fpr2 expression was significantly decreased in FGR placentae (n = 25, P < 0.05) as well as in murine FGR placentae compared to controls (n = 4, P < 0.05). FPR2 siRNA (siFPR2) in term trophoblasts significantly increased differentiation markers, HCGB and syncytin-2; cytokines, interleukin (IL)-6, CXCL8; and apoptotic markers, TP53, caspase 8 and BAX, but significantly reduced the expression of the chemokines CXCL12 and its receptors CXCR4 and CXCR7; CXCL16 and its receptor, CXCR6; and cytokine, IL-10, compared with control siRNA (siCONT). Treatment of HUVECs with siFPR2 significantly reduced proliferation and endothelial tube formation, but significantly increased permeability of HUVECs. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Reduced expression of placental FPR2/Fpr2 was observed in the third trimester at delivery after development of FGR, suggesting that FPR2 is associated with FGR pregnancies. However, there is a possibility that the decreased placental FPR2 observed in FGR may be a consequence rather than a cause of FGR, although our in vitro functional analyses using primary trophoblasts and endothelial cells suggest that FPR2 may have a direct or indirect regulatory role on trophoblast differentiation and endothelial function in FGR. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study linking placental FPR2 expression with changes in the trophoblast and endothelial functions that may explain the placental insufficiency observed in FGR. STUDY FUNDING/COMPETING INTERESTS: P.M. and P.R.E. received funding from the Australian Institute of Musculoskeletal Science, Western Health, St. Albans, Victoria 3021, Australia. M.L. is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; Grant no. 1047025). Monash Health is supported by the Victorian Government's Operational Infrastructure Support Programme. The authors declare that there is no conflict of interest in publishing this work.
Published: 2018

40. Erratum to: EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Sophie Brouillet, Déborah Reynaud, Roland Abi Nahed, Nadia Alfaidy, Frederic Sergent, and Mohamed Benharouga
Subjects: Andrology, business.industry, Early gestation, Hypertensive animal, Pregnancy induced, Medicine, business
Published: 2018

41. EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Déborah, Reynaud, Frédéric, Sergent, Roland, Abi Nahed, Sophie, Brouillet, Mohamed, Benharouga, and Nadia, Alfaidy
Subjects: Male, Disease Models, Animal, Mice, Pre-Eclampsia, Pregnancy, Animals, Humans, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Hypertension, Pregnancy-Induced, Trophoblasts
Abstract: During the last decade, multiple animal models have been developed to mimic hallmarks of pregnancy-induced hypertension (PIH) diseases, which include gestational hypertension, preeclampsia (PE), or eclampsia. Converging in vitro, ex vivo, and clinical studies from our group strongly suggested the potential involvement of the new angiogenic factor EG-VEGF (endocrine gland-derived-VEGF) in the development of PIH. Here, we described the protocol that served to demonstrate that maintenance of EG-VEGF production over 11.5 days post coitus (dpc) in the gravid mice caused the development of PIH. The developed model exhibited most hallmarks of preeclampsia.
Published: 2017

42. EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Déborah Reynaud, Mohamed Benharouga, Roland Abi Nahed, Sophie Brouillet, Frederic Sergent, and Nadia Alfaidy
Subjects: 0301 basic medicine, Gestational hypertension, Pregnancy, Eclampsia, business.industry, Glomerulosclerosis, Physiology, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Preeclampsia, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Placenta, embryonic structures, medicine, Endocrine system, business, reproductive and urinary physiology, Ex vivo
Abstract: During the last decade, multiple animal models have been developed to mimic hallmarks of pregnancy-induced hypertension (PIH) diseases, which include gestational hypertension, preeclampsia (PE), or eclampsia. Converging in vitro, ex vivo, and clinical studies from our group strongly suggested the potential involvement of the new angiogenic factor EG-VEGF (endocrine gland-derived-VEGF) in the development of PIH. Here, we described the protocol that served to demonstrate that maintenance of EG-VEGF production over 11.5 days post coitus (dpc) in the gravid mice caused the development of PIH. The developed model exhibited most hallmarks of preeclampsia.
Published: 2017

43. Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Author: Touria Aboussaouira, Rima Slim, Pierre Adrien Bolze, François Mallet, Nadia Alfaidy, Philippe Sauthier, Houssine Boufettal, Jean-Jacques Feige, Sophie Brouillet, Mohamed Benharouga, Aude Salomon, Wael Traboulsi, Valentina Onnis, Mohammed Benlahfid, Frederic Sergent, Gianfranco Balboni, Qun-Yong Zhou, Pascale Hoffmann, INSERM, Institut national de la santé et de la recherche médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Faculty of Medicine and Pharmacy, University Hassan II Casablanca, Obstetrics and Gynecology Department, Ibn Rochd Hospital of Casablanca, Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France, Departments of Human Genetics and Oncology, McGill University Health Center [Montreal] (MUHC), Department of Pharmacology [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Department of Life and Environmental Sciences, Università degli Studi di Cagliari = University of Cagliari (UniCa), Department of Gynecological Surgery and Oncology, Obstetrics, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), French Reference Center for Gestational Trophoblastic Diseases, University Hospital Lyon Sud, Joint Unit Hospices Civils de Lyon-bioMerieux, Cancer Biomarkers Research Group, University Hospital Lyon Sud, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité Grenoble, Grenoble, France.University Grenoble-Alpes, Grenoble, France., Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of California [Irvine] (UCI), University of California-University of California, University of Cagliari, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), INSERM, Institut national de la santé et de la recherche médicale ( INSERM ), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) ( BIG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation ( CECOS ), McGill University Health Centre Research Institute, Montréal, Quebec, Canada., University of California [Irvine] ( UCI ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 ( PI3 ), Institut des Sciences Pharmaceutiques et Biologiques ( ISPB ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), and Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA )
Subjects: 0301 basic medicine, Placental growth factor, Cancer Research, Pathology, medicine.medical_specialty, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Targeted therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Placenta, medicine, Receptor, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Gestational trophoblastic disease, Choriocarcinoma, Trophoblast, medicine.disease, 3. Good health, Vascular endothelial growth factor, 030104 developmental biology, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer research
Abstract: Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.
Published: 2017

44. PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development

Author: Wael Traboulsi, Aude Salomon, Valentina Onnis, Béatrice Desvergne, Cenzo Congiu, Mohamed Benharouga, Carine Winkler, Jean-Jacques Feige, Thierry Fournier, Sophie Brouillet, Qun-Yong Zhou, Pascale Hoffmann, Nadia Alfaidy, Vanessa Garnier, Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Department of Life and Environmental Sciences, University of Cagliari, Physiopathologie et Pharmacotoxicologie Placentaire Humaine ( U1139 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Center for Integrative Genomics - Institute of Bioinformatics, Génopode ( CIG ), University of Lausanne, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Department of Pharmacology [Irvine], University of California [Irvine] ( UCI ), Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), University of California [Irvine] (UCI), University of California-University of California, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Universités-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Male, Pyridines, Physiology, Placenta, Endocrinology, Diabetes and Metabolism, Peroxisome proliferator-activated receptor, ANGIOGENESIS, HUMAN FETOPLACENTAL VASCULOGENESIS, Mice, trophoblast invasion, Pregnancy, Cricetinae, human pregnancy, MOLECULAR CHARACTERIZATION, Receptor, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cells, Cultured, chemistry.chemical_classification, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Pregnancy Outcome, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.BDLR ] Life Sciences [q-bio]/Reproductive Biology, medicine.anatomical_structure, embryonic structures, Benzamides, Female, EXPRESSION, Transcriptional Activation, medicine.medical_specialty, PATHOLOGICAL IMPLICATIONS, Mice, Transgenic, Biology, Rosiglitazone, endocrine gland-derived vascular endothelial growth factor, PROTEIN-COUPLED RECEPTORS, In vivo, Physiology (medical), Internal medicine, medicine, Animals, Humans, Embryo Implantation, OXYGEN REGULATION, Placentation, Trophoblast, Prokineticin receptor 1, Embryo, Mammalian, EXTRAVILLOUS TROPHOBLASTS, peroxisome proliferator-activated receptor-gamma knockout, PPAR gamma, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Endocrinology, chemistry, ENDOTHELIAL GROWTH-FACTOR, CELLS, Thiazolidinediones, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Ex vivo
Abstract: PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants ( n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ+/− and PPARγ−/− mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ−/− mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.
Published: 2015

45. Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression

Author: Wael, Traboulsi, Frédéric, Sergent, Houssine, Boufettal, Sophie, Brouillet, Rima, Slim, Pascale, Hoffmann, Mohammed, Benlahfid, Qun Y, Zhou, Gianfranco, Balboni, Valentina, Onnis, Pierre A, Bolze, Aude, Salomon, Philippe, Sauthier, François, Mallet, Touria, Aboussaouira, Jean J, Feige, Mohamed, Benharouga, and Nadia, Alfaidy
Subjects: Receptors, Peptide, Gene Expression, Antineoplastic Agents, Prognosis, Xenograft Model Antitumor Assays, Receptors, G-Protein-Coupled, Disease Models, Animal, Mice, Cell Transformation, Neoplastic, Genes, Reporter, Cell Line, Tumor, Biomarkers, Tumor, Disease Progression, Animals, Humans, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Choriocarcinoma, Molecular Targeted Therapy, Signal Transduction
Published: 2017

46. Prokinéticines

Author: Nadia Alfaidy, Sophie Brouillet, Jean-Jacques Feige, and Pascale Hoffmann
Subjects: Pregnancy, Ectopic pregnancy, Uterus, General Medicine, Biology, medicine.disease, Bioinformatics, Oocyte, Polycystic ovary, General Biochemistry, Genetics and Molecular Biology, Human reproduction, medicine.anatomical_structure, Placenta, medicine, Receptor
Abstract: During the last decade, there has been growing evidence for the involvement of prokineticins and their receptors (PROK/PROKR) in human reproduction, with multiple roles in the female and male reproductive systems. The PROK/PROKR signalling complex has been reported as a new actor in ovary, uterus, placenta, and testis physiology, with marked dysfunction in various pathological conditions such as polycystic ovary syndrome, recurrent pregnancy loss, preeclampsia, and ectopic pregnancy. Altogether, the results strongly suggest the involvement of prokineticins in spermatogenesis, oocyte competence, embryo implantation, pregnancy, and delivery, and argue for the clinical relevance of these cytokines and their receptors as diagnostic markers for several reproductive diseases.
Published: 2014

47. PROK1, biomarqueur de l’implantation embryonnaire ?

Author: Nadia Alfaidy, P. Hoffmann, Jean-Jacques Feige, Sylviane Hennebicq, C. Thomas-Cadi, U. Bergues, and Sophie Brouillet
Subjects: Gynecology, 0303 health sciences, medicine.medical_specialty, Pregnancy, 030219 obstetrics & reproductive medicine, Assisted reproductive technology, medicine.medical_treatment, Embryogenesis, Obstetrics and Gynecology, Embryo, General Medicine, Biology, medicine.disease, Prokineticin, Embryo transfer, Andrology, 03 medical and health sciences, 0302 clinical medicine, Reproductive Medicine, Cohort, medicine, Biomarker (medicine), 030304 developmental biology
Abstract: In spite of improvements in assisted reproductive technology (ART) during the last 30 years, the rate of pregnancy remains constrained, as only about 25 % of embryo transfer lead to successful pregnancies, even with an average of two embryos replaced. Embryo selection is currently based on the establishment of morphokinetic scores, a method that obviously exhibits limitations. Therefore, the assessment of embryo development potency by criteria of higher predictive value is mandatory in order to increase the rates of pregnancy. Nowadays, there is increasing evidence that angiogenic factors might contribute to the success of the implantation and to the pregnancy outcome. Among these factors, prokineticin 1 (PROK1) and its receptors (PROKRs) constitute new targets that showed over the last ten years strong biological features directly linked to ovarian physiology, endometrial receptivity, embryo implantation and thus successful pregnancies. In ART, the rates of circulating PROK1 were reported in 2012 as significantly linked to the quality of embryonic cohort, as well as to the rates of pregnancy. Our preliminary data suggest a high potential of this cytokine in the success of implantation and pregnancy, and strongly overtones the emergency to investigate the value of its measurement in conditioned media of oocytes and embryo cultures in ART.
Published: 2013

48. Prion Protein Expression and Functional Importance in Developmental Angiogenesis: Role in Oxidative Stress and Copper Homeostasis

Author: Catherine Aude-Garcia, Jean-Marc Moulis, P. Hoffmann, Pierre Richaud, Annie Andrieux, Aude Salomon, Yasmina Saoudi, Jean-Jacques Feige, Mohamed Benharouga, Nadia Alfaidy, Sylvain Chauvet, Sandrine Donadio-Andrei, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie végétale et microbiologie environnementale - UMR7265 (BVME), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), CNRS (LCBM-UMR 5249) INSERM (U1036) UJF CEA/DSV/iRTSV, Andrieux, Annie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN)
Subjects: Physiology, Placenta, animal diseases, Clinical Biochemistry, Pregnancy Proteins, medicine.disease_cause, Biochemistry, Transcriptome, Mice, 0302 clinical medicine, Cell Movement, Pregnancy, Cricetinae, Homeostasis, reproductive and urinary physiology, General Environmental Science, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, Fetal Growth Retardation, Cell Death, Cell Hypoxia, Trophoblasts, Up-Regulation, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Knockout mouse, Female, Programmed cell death, Neovascularization, Physiologic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, 03 medical and health sciences, Downregulation and upregulation, medicine, Animals, Humans, PrPC Proteins, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Cell Proliferation, 030304 developmental biology, Reactive oxygen species, Trophoblast, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, nervous system diseases, Mice, Inbred C57BL, Oxidative Stress, chemistry, General Earth and Planetary Sciences, Reactive Oxygen Species, Copper, Oxidative stress
Abstract: International audience; AIM: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrP(C)), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrP(C) in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrP(C) knockout mice [PrP(-/-)], and PrP(C) overexpressing mice [Tga20]). RESULTS: At the cellular level, PrP(C) protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP(-/-)) or overexpression (Tga20) of PrP(C) in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. INNOVATION: PrP(C) could serve as a marker for the idiopathic IUGR disease. CONCLUSION: These findings demonstrate the stress-protective role of PrP(C) during development, and propose PrP(C) dysregulation as a novel causative element of IUGR.
Published: 2013

49. Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension

Author: Mohamed Benharouga, Nadia Alfaidy, Aude Salomon, Vanessa Garnier, Jean-Jacques Feige, Pascale Hoffmann, Frederic Sergent, Sophie Brouillet, Padma Murthi, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France, Hudson Institute of Medical Research [Clayton], Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: 0301 basic medicine, Gestational hypertension, Placenta, Intrauterine growth restriction, 030204 cardiovascular system & hematology, Receptors, G-Protein-Coupled, Mice, Random Allocation, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, reproductive and urinary physiology, pregnancy-induced hypertension, Biopsy, Needle, Immunohistochemistry, 3. Good health, Vascular endothelial growth factor, Phenotype, medicine.anatomical_structure, embryonic structures, Female, medicine.medical_specialty, hypertension, endocrine gland-derived endothelial growth factor, Blotting, Western, Mice, Inbred Strains, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Preeclampsia, preeclampsia, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Internal Medicine, medicine, Animals, prokineticin 1, Eclampsia, business.industry, Trophoblast, Hypertension, Pregnancy-Induced, medicine.disease, Disease Models, Animal, Pregnancy Trimester, First, 030104 developmental biology, Endocrinology, chemistry, Pregnancy, Animal, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, business
Abstract: International audience; Pregnancy-induced hypertension diseases are classified as gestational hypertension, preeclampsia, or eclampsia. The mechanisms of their development and prediction are still to be discovered. Endocrine gland–derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor secreted by the placenta during the first trimester of human pregnancy that was shown to control trophoblast invasion, to be upregulated by hypoxia, and to be abnormally elevated in pathological pregnancies complicated with preeclampsia and intrauterine growth restriction. These findings suggested that sustaining EG-VEGF levels beyond the first trimester of pregnancy may contribute to pregnancy-induced hypertension. To test this hypothesis, osmotic minipumps delivering EG-VEGF were implanted subcutaneously into gravid OF1 (Oncins France 1) mice on day 11.5 post coitus, which is equivalent to the end of the first trimester of human pregnancy. Mice were euthanized at 15.5 and 18.5 days post coitus to assess (1) litter size, placental, and fetal weights; (2) placental histology and function; (3) maternal blood pressure; (4) renal histology and function; and (5) circulating soluble fms-like tyrosine kinase 1 and soluble endoglin. Increased EG-VEGF levels caused significant defects in placental organization and function. Both increased hypoxia and decreased trophoblast invasion were observed. Treated mice had elevated circulating soluble fms-like tyrosine kinase 1 and soluble endoglin and developed gestational hypertension with dysregulated maternal kidney function. EG-VEGF effect on the kidney function was secondary to its effects on the placenta as similarly treated male mice had normal kidney functions. Altogether, these data provide a strong evidence to confirm that sustained EG-VEGF beyond the first trimester of pregnancy contributes to the development of pregnancy-induced hypertension.
Published: 2016

50. Prokineticin1 and pregnancy

Author: Nadia Alfaidy, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Placenta, Biology, Prokineticin, Preeclampsia, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Pre-Eclampsia, Pregnancy, IUGR, Internal medicine, medicine, Animals, Humans, EG-VEGF, Receptor, RCIU, Prokinéticine, Pré-eclampsie, Fetal Growth Retardation, 030219 obstetrics & reproductive medicine, Parturition, Trophoblast, Placentation, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, General Medicine, Hypoxia (medical), medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, medicine.symptom
Abstract: International audience; Prokineticin 1 (PROK1), also called EG-VEGF, is a peptide of 86 amino acids with multiple biological functions. PROK1 acts via two G-protein coupled receptors: PROKR1 PROKR2. PROK1 is highly expressed in the placenta. This article reports the expression and the role of PROK1 during normal and pathological pregnancies: (i) during early pregnancy, PROK1 exhibits a peak of placental expression shortly before the establishment of the feto-maternal circulation; (ii) its receptors, PROKR1 PROKR2 are highly expressed in human placenta; (iii) its expression is increased by hypoxia; (iv) PROK1 inhibits extravillous trophoblasts migration and invasion and increases their proliferation and survival; (v) PROK1 is also a pro-angiogenic placental factor that increases microvascular placental endothelial cells proliferation, migration, invasion, and permeability. Circulating PROK1 levels are five times higher in pregnant women during the first trimester compared to the second and third trimesters. Also, its serum levels are higher in patients with preeclampsia (PE) and in patients with isolated intra-uterine growth restriction (IUGR). In mice, maintaining high level of PROK1 beyond its normal period of production (>10.5dpc) reproduces symptoms of PE. To date, our results demonstrated that PROK1 is a central factor of human placentation with direct roles both in the control of trophoblast invasion and villous growth. Thus, a failure in the expression of PROK1 and/or its receptor during pregnancy may contribute to the development of PE and/or IUGR. Besides theses original findings, we also report a direct role of this factor in parturition.
Published: 2016

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