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Liège, Belgium

Barrientos G.,University of Buenos Aires | Toro A.,University of Buenos Aires | Moschansky P.,Medicine University | Cohen M.,Laboratoire dHormonologie | And 6 more authors.

Introduction The development of the human haemochorial placenta requires complex regulatory mechanisms to protect invasive trophoblast cells from cytotoxic responses elicited by maternal immune cells. Leptin, the adipocyte derived hormone encoded by the Lep gene, is synthesized by placental trophoblasts and exerts pleiotropic effects on the immune system, including the promotion of inflammation and the activation of T cell responses. Methods To address its possible involvement in the modulation of maternal immune responses during pregnancy, we investigated the effect of leptin on the expression of the class Ib histocompatibility antigen HLA-G as one of the chief immunosuppressive strategies used by trophoblast cells. Results In vitro incubation of the trophoblast derived Swan 71 and JEG-3 cell lines with 25-50 ng/ml recombinant leptin significantly boosted HLA-G mRNA and protein expression, and this effect was abrogated upon pharmacological inhibition of the PI3K-Akt and MEK-Erk signaling pathways. A similar stimulatory effect of leptin was observed in term placental tissue explants, though 10-fold higher doses were required for stimulation. Further, JEG-3 cells treated with a leptin antisense oligodeoxynucleotide displayed decreased HLA-G expression levels, which were partially recovered by addition of stimulating doses of exogenous hormone. Immunofluorescence and qPCR analysis confirmed leptin biosynthesis in placental tissue, further showing that invasive extravillous trophoblast cells were a main source of this hormone during the first trimester of normal pregnancies. Discussion Taken together, our results show that leptin acts as an autocrine/paracrine signal promoting HLA-G expression in placental trophoblasts suggesting an important role in the regulation of immune evasion mechanisms at the fetal maternal interface. © 2015 Elsevier Ltd. All rights reserved. Source

Oral glucose tolerance test (OGTT) has been widely used for the diagnosis of impaired glucose tolerance, diabetes mellitus and gestational diabetes. Simultaneous measurements of plasma glucose and insulin (or more rarely C-peptide) levels allow to derive indices of insulin secretion and insulin sensitivity that are helpful for the understanding of disturbances in glucose metabolism and, especially, for the prediction of progression from normal glucose tolerance to impaired glucose tolerance or type 2 diabetes. Certain indices, quite simple, may be used in clinical practice ("insulinogenic index" to assess early insulin secretion, Matsuda index to assess insulin sensitivity) while others, more complex (and most often based on modelling procedures), are essentially used in research. The oral disposition index, a recently introduced marker that integrates insulin secretion and insulin sensitivity, raises increasing interest, more particularly for the prediction of type 2 diabetes. © 2010 - Elsevier Masson SAS - Tous droits réservés. Source

Nguyen G.,The Interdisciplinary Center | Nguyen G.,French National Center for Scientific Research | Blanchard A.,University of Paris Descartes | Blanchard A.,French Institute of Health and Medical Research | And 17 more authors.

A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity. © 2013 American Heart Association, Inc. Source

Delie F.,University of Geneva | Delie F.,University of Lausanne | Petignat P.,University of Geneva | Cohen M.,University of Geneva | Cohen M.,Laboratoire dHormonologie
Targeted Oncology

Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti-KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surface. © 2012 Springer-Verlag France. Source

Oral glucose tolerance test (OGTT) has been widely used for the diagnosis of diabetes mellitus, gestational diabetes, impaired glucose tolerance or reactive hypoglycemia. Since almost 10 years, however, it has been proposed to limit the use of this dynamic test, favoring instead the measurement of either fasting plasma glucose or glycated hemoglobin. Nevertheless, almost all recent important studies used OGTT as reference test. In this first article, we will consider the potential interest of OGTT as diagnostic or prognostic test able to evaluate glucose regulation. In a second article, we will describe how to use OGTT to derive indices that quantitatively evaluate insulin secretion and/or insulin sensitivity. © 2010 - Elsevier Masson SAS. Source

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