Dose-dependent biphasic leptin-induced proliferation is caused by non-specific IL-6/NF-κB pathway activation in human myometrial cells
Background and Purpose Leptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labour (PTL), as it is able to prevent in vitro uterine contractility and remodelling associated with labour onset. Another common feature of labour onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence. Experimental Approach We stimulated human primary myometrial smooth muscle cells with leptin in the presence or …
Lipoproteins LDL versus HDL as nanocarriers to target either cancer cells or macrophages
free open access article 31 p.; International audience; In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupl…
Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial
SummaryBackground A phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC). Aim To estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life. Methods Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20% of patients. Results Twenty-one patients were enrolled, inclu…
Macrophage-induced reactive oxygen species promote myometrial contraction and labor-associated mechanisms
AbstractAt labor, the myometrium is infiltrated by a massive influx of macrophages that secrete high levels of pro-inflammatory cytokines inducing the expression of specific labor-associated markers. However, the interactions between myocytes and macrophages and the role of macrophages in the myometrium at labor remain to be elucidated. In this work, we studied the role of myometrium-infiltrated macrophages and their interaction with myocytes in lipopolysaccharide-induced preterm labor. A co-culture model of human primary myometrial cells and macrophages was developed and validated. Collagen lattices were used to evaluate myocyte contraction. Differentiation steps were assessed by (i) phall…
Effects of Leptin on Lipopolysaccharide-Induced Remodeling in an In Vitro Model of Human Myometrial Inflammation1
Reorganization of myometrial extracellular matrix (ECM) is essential for the uterus to achieve powerful synchronous contractions during labor. Remodeling of the ECM has been implicated in membrane rupture and cervical ripening. Because maternal obesity is associated with both delivery disorders and elevated circulating leptin levels, this study aimed to assess the ability of leptin to interfere with lipopolysaccharide (LPS)-induced myometrial ECM remodeling. Myometrial biopsy samples were obtained from women undergoing cesarean delivery before labor onset. Myometrial explants were incubated for 48 h with LPS and leptin. LPS challenge was associated with a marked decrease in collagen content…
SAR150640, a selective β3-adrenoceptor agonist, prevents human myometrial remodelling and activation of matrix metalloproteinase in an in vitro model of chorioamnionitis
Background and purpose: The uterine pathophysiology underlying inflammatory conditions such as chorioamnionitis remains largely unclear. As we have shown that β3-adrenoceptors act as regulators of myometrial inflammation, we wanted to investigate the potential role of β3-adrenoceptors in preventing uterine remodelling induced by inflammation. Experimental approach: The consequences of human chorioamnionitis on myometrial remodelling were characterized by Sirius Red staining and metalloproteinase (MMP) expression, and compared with the effects of incubating human myometrial samples with Escherichia coli lipopolysaccharide (LPS) in vitro. We also assessed the effect of SAR150640, a selectiv…
Obésité et grossesse : étude de l'influence d'un marqueur de l'obésité sur les mécanismes cellulaires et tissulaires de l'accouchement dans un modèle d'explants myométriaux humains
Maternal obesity is associated with a wide spectrum of delivery disorders, such as delayed or post-term delivery, that might be explained partly by the increase in plasma leptin levels in obese women, as leptin inhibits in vitro myometrial contractility. Delivery involves uterine apoptosis and remodelling of the extracellular matrix, via the activation of matrix metalloproteinases (MMP). This study was aimed to assess the role of leptin on human myometrium, by studying the interaction of leptin with lipopolysaccharide (LPS)-induced apoptosis and degradation of myometrial collagen.Myometrial biopsies were obtained from women undergoing caesarean delivery before labour onset. The effects of l…
Effects of leptin on lipopolysaccharide-induced myometrial apoptosis in an in vitro human model of chorioamnionitis.
Objective This study was aimed at assessing the role of leptin on human myometrium, by studying its receptor expression in pregnant myometrium and the interaction of leptin with inflammation-induced apoptosis. Study Design Myometrial samples were obtained from women with uncomplicated pregnancies who underwent cesarean delivery at term before labor onset. The effect of leptin on apoptosis was assessed by the incubation of myometrial strips with leptin (10 –10 to 10 –8 mol/L; 48 hours) before lipopolysaccharide treatment (10 μg/mL; 48 hours). Results Long and short leptin receptor isoforms were expressed in myometrial cells of pregnant women. Leptin prevented lipopolysaccharide-induced apopt…
Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell proliferation
Abstract The beta3 adrenergic receptor (B3-AR) reportedly induces cell proliferation, but the signaling pathways that were proposed, involving either Gs or Gi coupling, remain controversial. To further investigate the role of G protein coupling in B3-AR induced proliferation, we stimulated primary human myometrial smooth muscle cells with SAR150640 (B3-AR agonist) in the absence or presence of variable G-protein inhibitors. Specific B3-AR stimulation led to an Erk1/2 induced proliferation. We observed that the proliferative effects of B3-AR require two Erk1/2 activation peaks (the first after 3 min, the second at 8 h). Erk1/2 activation at 3 min was mimicked by forskolin (adenylyl-cyclase a…
Beta3 adrenergic receptor stimulation in human macrophages inhibits NADPHoxidase activity and induces catalase expression via PPARγ activation
IF 4.521; International audience; The beta3 adrenergic receptor (β3-AR) stimulation plays a protective role against preterm labor by blocking myometrial contraction, cytokine production, remodeling and apoptosis. We previously demonstrated that macrophage-induced ROS production in the myometrium was a key element leading to the induction of all these labor-associated features. We thus aimed to investigate if the β3-AR could be expressed in human macrophages and could trigger its protective role in the myometrium by directly inhibiting ROS production. Using lipopolysaccharide (LPS)-stimulated myometrial samples and cell co-culture experiments, we demonstrated that β3-AR stimulation inhibits …