Publications by authors named "Marc Lombes"

Objective: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome.

Methods: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation.

View Article and Find Full Text PDF

Glucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis.

View Article and Find Full Text PDF

Background: We studied the ability of the nonsteroidal MR (mineralocorticoid receptor) antagonist finerenone to attenuate vascular remodeling and pulmonary hypertension using two complementary preclinical models (the monocrotaline and sugen/hypoxia rat models) of severe pulmonary hypertension.

Methods: We first examined the distribution pattern of MR in the lungs of patients with pulmonary arterial hypertension (PAH) and in monocrotaline and sugen/hypoxia rat lungs. Subsequent studies were performed to explore the effect of MR inhibition on proliferation of pulmonary artery smooth muscle cells derived from patients with idiopathic PAH.

View Article and Find Full Text PDF

The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in response to variations of extracellular tonicity. Herein, we highlight a novel regulatory mechanism involving the recruitment of microRNAs (miRNAs) under hypertonicity.

View Article and Find Full Text PDF

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth.

View Article and Find Full Text PDF

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood-retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media.

View Article and Find Full Text PDF

Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11β-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11β enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known.

View Article and Find Full Text PDF
Article Synopsis
  • * The mineralocorticoid receptor, present in fish, evolved to work with aldosterone, which first appeared in lungfish and amphibians, marking a key adaptation for life on land.
  • * This review explores the mineralocorticoid signaling pathway, detailing aldosterone's role in adrenal gland secretion and its effects in the kidneys during fetal and neonatal development, within an evolutionary context.
View Article and Find Full Text PDF

Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney.

View Article and Find Full Text PDF

Aldosterone, the main mineralocorticoid hormone in humans, plays a pivotal role in the control of water and salt reabsorption via activation of the mineralocorticoid receptor (MR). Alterations in MR signaling pathway lead to renal dysfunction, including chronic kidney disease and renal fibrosis, that can be prevented or treated with mineralocorticoid receptor antagonists (MRAs). Here, we used RNA-Sequencing to analyze effects of two MRAs, spironolactone and finerenone, on the aldosterone-induced transcriptome of a human renal cell line stably expressing the MR.

View Article and Find Full Text PDF
Article Synopsis
  • - The study investigates how environmental factors during the perinatal period affect adults born with intrauterine growth retardation (IUGR) and their risk for cardio-metabolic diseases using a mouse model.
  • - Researchers found that overfeeding IUGR mice during lactation led to obesity and insulin resistance by three months, while underfed mice stayed thin and insulin-sensitive, highlighting the impact of nutrition on metabolic health.
  • - Molecular changes in insulin signaling were identified in the adult mice, with specific epigenetic markers and a decrease in a particular microRNA potentially serving as early indicators of future metabolic issues, indicating their relevance in precision medicine strategies.
View Article and Find Full Text PDF

Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti-fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non-steroidal MRA finerenone (FIN) in a mouse model of high-fat diet (HFD)-induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT).

View Article and Find Full Text PDF

Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps.

View Article and Find Full Text PDF
Article Synopsis
  • Prematurity is linked to renal and cardiovascular issues, especially hypertension later in life, but the detailed molecular reasons are still not fully understood.
  • In a study using pregnant mice, findings showed that preterm males developed significant hypertension by six months, and their offspring (F2 and F3 generations) also exhibited higher blood pressure linked to renal gene expression changes.
  • The study highlighted that epigenetic modifications, such as reduced methylation of the Gilz gene, play a key role in the altered corticosteroid signaling pathways, suggesting that these effects can be passed down through generations.
View Article and Find Full Text PDF
Article Synopsis
  • 21-Hydroxylase deficiency (21OHD) leads to salt-wasting syndrome by preventing the production of cortisol and aldosterone, affecting 75% of those affected by the condition.
  • Recent advancements in mass spectrometry have allowed researchers to identify 21-deoxysteroids like 17OHP, 21DF, and 21DB, which may disrupt mineralocorticoid signaling and fludrocortisone therapy in congenital adrenal hyperplasia (CAH) patients.
  • The study measured levels of these steroids in a pediatric CAH cohort and found that elevated concentrations can impair mineralocorticoid receptor activation, indicating the need for careful monitoring and adjustment of steroid levels to improve patient management.
View Article and Find Full Text PDF

21-hydroxylase deficiency, the most common enzyme defect associated with congenital adrenal hyperplasia (CAH) is characterized by an impairment of both aldosterone and cortisol biosynthesis. Close clinical and biological monitoring of Hydrocortisone (HC) and 9α-Fludrocortisone (FDR) replacement therapies is required to achieve an optimal treatment. As frequent and repeated reassessments of plasma steroids, 17-hydroxyprogesterone (17-OHP), androstenedione (Δ4-A) and testosterone (TESTO) is needed in childhood, urine steroid profiling could represent an interesting non-invasive alternative.

View Article and Find Full Text PDF
[Not Available].

Ann Endocrinol (Paris)

September 2019

Immunotherapy and opioids treatment are new causes of secondary adrenal insufficiency (SAI). Prevalence of SAI with immunotherapy is more frequent with combined therapy (8% vs 4 to 10% with CTLA4 blocking antibody and 1% with PD1 blocking antibody). Although hypophysitis are more frequently observed with CTLA4 blocking antibody, some cases of Isolated SAI have been reported in patients treated by PD1 blocking antibody.

View Article and Find Full Text PDF

Context: Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients.

Objective: We aim at studying the GR-mediated regulation of HSD11B2.

View Article and Find Full Text PDF

Recent advances in genetic analysis technologies such as next-generation sequencing (NGS) have considerably increased the incidental discovery of genetic abnormalities. Six heterozygous missense mutations of the human glucocorticoid receptor (GR; encoded by the gene) have been identified in the context of genetic screening of endocrine pathologies. GR, a nuclear receptor, hormone-induced transcription factor, is involved in many physiological processes.

View Article and Find Full Text PDF

Mitotane (also termed o,p'‑DDD) is the most effective therapy for advanced adrenocortical carcinoma (ACC). Mitotane‑induced dyslipidemia is treated with statins. Mitotane and statins are known to exert anti‑proliferative effects in vitro; however, the effects of statins have never been directly evaluated in patients with ACC and ACC cells, at least to the best of our knowledge.

View Article and Find Full Text PDF

Fas-associated factor 1 (FAF1) was originally isolated as a Fas-associated factor and was subsequently found to interact with numerous other proteins that are involved in various cellular events including Fas-mediated apoptosis, nuclear factor (NF)-κB, Wnt/β-catenin, and transforming growth factor (TGF)-β signaling pathways, mineralocorticoid receptor (MR)-mediated transactivation, and ubiquitin-dependent processes. Herein, we defined two small ubiquitin-like modifier (SUMO)-interacting motifs (SIMs) within FAF1 and demonstrated to be crucial for transcriptional modulation of the MR. Our study demonstrated that the SIMs of FAF1 do not play a significant role in regulating its subcellular localization, Fas-mediated apoptosis, or NF-κB or Wnt/β-catenin pathways.

View Article and Find Full Text PDF

The brain-derived neurotrophic factor (BDNF) is a key player in brain functions such as synaptic plasticity, stress, and behavior. Its gene structure in rodents contains 8 untranslated exons (I to VIII) whose expression is finely regulated and which spliced onto a common and unique translated exon IX. Altered Bdnf expression is associated with many pathologies such as depression, Alzheimer's disease and addiction.

View Article and Find Full Text PDF

Context: Besides GNAS gene mutations, the molecular pathogenesis of somatotroph adenomas responsible for gigantism and acromegaly remains elusive.

Objective: To investigate alternative driver events in somatotroph tumorigenesis, focusing on a subgroup of acromegalic patients with a paradoxical increase in growth hormone (GH) secretion after oral glucose, resulting from ectopic glucose-dependent insulinotropic polypeptide receptor (GIPR) expression in their somatotropinomas.

Design, Setting, And Patients: We performed combined molecular analyses, including array-comparative genomic hybridization, RNA/DNA fluorescence in situ hybridization, and RRBS DNA methylation analysis on 41 somatotropinoma samples from 38 patients with acromegaly and three sporadic giants.

View Article and Find Full Text PDF

Objectives: The mineralocorticoid receptor (MR), a hormone-activated transcription factor, besides its role in controlling hydroelectrolytic homeostasis, exerts pro-adipogenic and anti-thermogenic effects, inhibiting mitochondrial-uncoupling protein UCP1 expression in brown adipocytes. The aim of this study was to gain insight into the molecular mechanisms by which MR participates in such metabolic regulation.

Methods: We evaluated in vivo MR effects on cold-induced UCP1 expression in MR-overexpressing mice.

View Article and Find Full Text PDF

DSD for "Differences of Sex Development" or "Sexual Differences Development" refers to situations where chromosomal, gonadal or anatomical sex is atypical. DSD 46,XX are mainly represented by congenital adrenal hyperplasia (HCS) and are not a diagnostic issue. DSD 46,XY involve genes for the determination and differenciation of the bipotential gonad, making sometimes difficult the choice of sex at birth.

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Warning

Message: fopen(/var/lib/php/sessions/ci_session4pqcn59rrcjhacl34nh0995p655btnua): Failed to open stream: No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 177

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once

A PHP Error was encountered

Severity: Warning

Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)

Filename: Session/Session.php

Line Number: 137

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once