scholarly journals Ethanol consumption during gestation promotes placental alterations in IGF-1 deficient mice

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1284
Author(s):  
Irene Martín-Estal ◽  
Oscar R Fajardo-Ramírez ◽  
Mario Bermúdez De León ◽  
Carolina Zertuche-Mery ◽  
Diego Rodríguez-Mendoza ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Molecular Mechanisms ◽  
Ethanol Consumption ◽  
Placental Development ◽  
Intrauterine Environment ◽  
Female Mice ◽  
Acclimation Period ◽  
Placental Efficiency ◽  
Deficient Mice

Background: During pregnancy, the placenta is an extremely important organ as it secretes its own hormones, e.g. insulin-like growth factor 1 (IGF-1), to ensure proper intrauterine fetal growth and development. Ethanol, an addictive and widely used drug, has numerous adverse effects during pregnancy, including fetal growth restriction (FGR). To date, the molecular mechanisms by which ethanol triggers its toxic effects during pregnancy, particularly in the placenta, are not entirely known. For this reason, a murine model of partial IGF-1 deficiency was used to determine ethanol alterations in placental morphology and AAH expression. Methods: Heterozygous (HZ, Igf1+/-) female mice were given 10% ethanol during 14 days as an acclimation period and throughout pregnancy. HZ female mice given water were used as controls. At gestational day 19, pregnant dams were sacrificed, placentas were collected and genotyped for subsequent studies. Results: IGF-1 deficiency and ethanol consumption during pregnancy altered placental morphology, and decreased placental efficiency and aspartyl/asparaginyl β-hydroxylase (AAH) expression in placentas from all genotypes. No differences were found in Igf1, Igf2, Igf1r and Igf2r mRNA expression in placentas from all groups. Conclusions: IGF-1 deficiency and ethanol consumption throughout gestation altered placental development, suggesting the crucial role of IGF-1 in the establishment of an adequate intrauterine environment that allows fetal growth. However, more studies are needed to study the precise mechanism to stablish the relation between both insults.

Molecular approach to intrauterine growth retardation: an overview of recent data

1995 ◽  
Vol 7 (6) ◽  
pp. 1457 ◽  
Author(s):  
E Alsat ◽  
C Marcotty ◽  
R Gabriel ◽  
A Igout ◽  
F Frankenne ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Fetal Growth ◽  
Growth Retardation ◽  
Intrauterine Growth Retardation ◽  
Molecular Mechanisms ◽  
Late Gestation ◽  
Placental Development ◽  
Intrauterine Growth ◽  
Placental Growth Hormone

Consideration of the abnormal regulation of fetal growth leading to intrauterine growth retardation must take account of the fundamental differences between the regulation of growth before and after birth. The significance of endocrine regulators of growth differs greatly in utero. During the first trimester of pregnancy, embryonic growth might be controlled at the level of the individual organs by nutrient supply and by locally active growth factors. Later, fetal growth depends essentially upon materno-placental cooperation in delivering nutrients to the fetus. Therefore the major role of hormones in fetal growth is to mediate utilization of available substrate. Fetal growth seems to be regulated by fetal insulin, IGF-1 and certainly IGF-2, while growth hormone has only a secondary role to play. In late gestation, placental size and fetal growth rate are well correlated, pointing to a key role of the placenta in the regulation of fetal growth. It is therefore of importance to understand the molecular mechanisms involved in regulating placental development and endocrine functions. TGF alpha and EGF might play a major role as suggested by the modulation of their receptors with placental development, and by the specific alterations of epidermal growth factor receptors in intrauterine growth retardation. In addition, human placenta secretes specifically placental growth hormone. The concentration of placental growth hormone is significantly decreased in sera of pregnant women bearing a fetus with intrauterine growth retardation.

scholarly journals A comprehensive protein–protein interactome for yeast PAS kinase 1 reveals direct inhibition of respiration through the phosphorylation of Cbf1

2014 ◽  
Vol 25 (14) ◽  
pp. 2199-2215 ◽  
Author(s):  
Desiree DeMille ◽  
Benjamin T. Bikman ◽  
Andrew D. Mathis ◽  
John T. Prince ◽  
Jordan T. Mackay ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Protein Modification ◽  
Molecular Mechanisms ◽  
Binding Partners ◽  
Pas Kinase ◽  
Protein Interactome ◽  
Deficient Mice

Per-Arnt-Sim (PAS) kinase is a sensory protein kinase required for glucose homeostasis in yeast, mice, and humans, yet little is known about the molecular mechanisms of its function. Using both yeast two-hybrid and copurification approaches, we identified the protein–protein interactome for yeast PAS kinase 1 (Psk1), revealing 93 novel putative protein binding partners. Several of the Psk1 binding partners expand the role of PAS kinase in glucose homeostasis, including new pathways involved in mitochondrial metabolism. In addition, the interactome suggests novel roles for PAS kinase in cell growth (gene/protein expression, replication/cell division, and protein modification and degradation), vacuole function, and stress tolerance. In vitro kinase studies using a subset of 25 of these binding partners identified Mot3, Zds1, Utr1, and Cbf1 as substrates. Further evidence is provided for the in vivo phosphorylation of Cbf1 at T211/T212 and for the subsequent inhibition of respiration. This respiratory role of PAS kinase is consistent with the reported hypermetabolism of PAS kinase–deficient mice, identifying a possible molecular mechanism and solidifying the evolutionary importance of PAS kinase in the regulation of glucose homeostasis.

Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 697-702 ◽  
Author(s):  
Sonia Feau ◽  
Valeria Facchinetti ◽  
Francesca Granucci ◽  
Stefania Citterio ◽  
David Jarrossay ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Interleukin 2 ◽  
Adaptive Immune ◽  
Deficient Mice ◽  
Mouse System

Abstract Dendritic cells (DCs) are involved in the initiation and regulation of innate and adaptive immune responses. Several molecular mechanisms regulate these diverse DC functions, and we have previously reported that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in vitro and in vivo, in response to microbial activation and T-cell-mediated stimuli. This property is shared by different DC subtypes, including Langerhans cells. Here we show that, on appropriate stimulation, human DCs, both plasmacytoid and myeloid subtypes, also express IL-2. Interestingly, the production of IL-2 by myeloid DCs is induced by T-cell-mediated stimuli and depends on the presence of IL-15. The key role of this cytokine in regulating IL-2 production was also confirmed in the mouse system. In particular, we could show that DCs from IL-15-deficient mice were strongly impaired in the ability to produce IL-2 after interactions with different microbial stimuli. Our results indicate that DC-produced IL-2 is tightly coregulated with the expression of IL-15.

scholarly journals Fetal and trophoblast PI3Kp110α have distinct roles in regulating resource supply to the growing fetus

2018 ◽  
Author(s):  
Jorge Lopez-Tello ◽  
Vicente Perez-Garcia ◽  
Jaspreet Khaira ◽  
Laura C. Kusinski ◽  
Wendy N. Cooper ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Embryonic Stem ◽  
Prenatal Development ◽  
Complete Loss ◽  
Placental Development ◽  
Expression Of Genes ◽  
Transport Loss ◽  
Healthy Growth ◽  
Phosphoinositide 3 Kinase

AbstractPrevious studies suggest that the placental supply of nutrients to the fetus adapts according to fetal demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier work in mice has revealed that loss of the phosphoinositide 3-kinase p110α impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110α in the epiblast-derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental development and transfer function. Using conditional gene manipulations to knock-down p110α either by ∼50% or ∼100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α also resulted in abnormal placental development, although fetuses were viable. However, in response to complete loss of trophoblast p110α, the placenta failed to transport sufficient amino acid to match fetal demands for growth. Using RNA-seq, we identified several genes downstream of p110α in the trophoblast that are important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 genome targeting showed that loss of p110α differentially affects the expression of genes in trophoblast and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110α signaling in the different compartments of the conceptus, which control fetal resource acquisition and ultimately affect healthy growth.One Sentence SummaryFetal and trophoblast p110α modify resource allocation

scholarly journals MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ying Zhang ◽  
Yi Zhu ◽  
Shu-Xia Cao ◽  
Peng Sun ◽  
Jian-Ming Yang ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Gabaa Receptors ◽  
Molecular Mechanisms ◽  
Transcriptional Regulator ◽  
Fear Learning ◽  
Abnormal Behavior ◽  
Mecp2 Gene ◽  
Cholinergic Interneurons ◽  
Deficient Mice

Methyl-CpG-binding protein 2 (MeCP2) encoded by the MECP2 gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). Mecp2-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that Mecp2 gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in Mecp2-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABAA receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders.

scholarly journals The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 55
Author(s):  
Zamzam Awida ◽  
Almog Bachar ◽  
Hussam Saed ◽  
Anton Gorodov ◽  
Nathalie Ben-Califa ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Mineral Density ◽  
Female Mice ◽  
Epo Receptor

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

Abstract 5290: Cypher Long but not Short Isoform Specific Knockout Mice Result in Cardiac Signaling Defects and Dilated Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hongqiang Cheng ◽  
Ming Zheng ◽  
Farah Sheikh ◽  
Kunfu Ouyang ◽  
Li Cui ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Gene Mutations ◽  
Splice Isoforms ◽  
Functional Roles ◽  
Deficient Mice

Our previous studies have demonstrated that Cypher, a PDZ-LIM protein localized at the Z line, plays a pivotal role in heart function. We recently identified long and short splice isoforms of Cypher, which are characterized by the presence and absence of LIM domains, respectively. The LIM domain of Cypher is thought to be involved in signaling, based on its ability to directly interact with signaling proteins. In human patients with dilated cardiomyopathy (DCM) we discovered Cypher gene mutations, which affect either long or short isoform or both isoforms. However, the precise molecular mechanisms underlying the role of Cypher isoforms in DCM remain unclear. To determine the role of Cypher isoforms in cardiac signaling and disease in vivo , we generated two Cypher isoform specific knockout mice. Selective ablation of Cypher long isoforms in mice resulted in partial neonatal lethality. However, hearts from viable Cypher long isoform deficient mice displayed Z line abnormalities and decreased cardiomyocyte widths, which resulted in a progressive form of DCM, characterized by fibrosis, calcification and lethality. The effects on cardiac function and disease observed in long-isoform specific Cypher knockout mice were preceded by significant decreases in cardiac protein kinase C and extracellular signal-regulated kinase signaling. These results are in contrast to Cypher short isoform deficient mice, which were viable with no overt cardiac morphology and signaling abnormalities. These results reveal distinct functional roles for Cypher isoforms in the heart as well as shed light into the molecular mechanisms underlying dilated cardiomyopathy.

scholarly journals Inducible nitric oxide synthase provides protection against injury-induced thrombosis in female mice

2011 ◽  
Vol 301 (2) ◽  
pp. H617-H624 ◽  
Author(s):  
Rita K. Upmacis ◽  
Hao Shen ◽  
Lea Esther S. Benguigui ◽  
Brian D. Lamon ◽  
Ruba S. Deeb ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ex Vivo ◽  
Physiological Role ◽  
Thrombotic Occlusion ◽  
Female Mice ◽  
Eicosanoid Production ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Inducible Nitric Oxide

Nitric oxide (NO) is an important vasoactive molecule produced by three NO synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). While eNOS contributes to blood vessel dilation that protects against the development of hypertension, iNOS has been primarily implicated as a disease-promoting isoform during atherogenesis. Despite this, iNOS may play a physiological role via the modulation of cyclooxygenase and thromboregulatory eicosanoid production. Herein, we examined the role of iNOS in a murine model of thrombosis. Blood flow was measured in carotid arteries of male and female wild-type (WT) and iNOS-deficient mice following ferric chloride-induced thrombosis. Female WT mice were more resistant to thrombotic occlusion than male counterparts but became more susceptible upon iNOS deletion. In contrast, male mice (with and without iNOS deletion) were equally susceptible to thrombosis. Deletion of iNOS was not associated with a change in the balance of thromboxane A2 (TxA2) or antithrombotic prostacyclin (PGI2). Compared with male counterparts, female WT mice exhibited increased urinary nitrite and nitrate levels and enhanced ex vivo induction of iNOS in hearts and aortas. Our findings suggest that iNOS-derived NO in female WT mice may attenuate the effects of vascular injury. Thus, although iNOS is detrimental during atherogenesis, physiological iNOS levels may contribute to providing protection against thrombotic occlusion, a phenomenon that may be enhanced in female mice.

scholarly journals The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

2020 ◽  
Vol 21 (5) ◽  
pp. 1775 ◽  
Author(s):  
Brooke Armistead ◽  
Leena Kadam ◽  
Sascha Drewlo ◽  
Hamid-Reza Kohan-Ghadr
Keyword(s):  
Oxidative Stress ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Growth And Development ◽  
Protein Family ◽  
Growth Restriction ◽  
Placental Development ◽  
Critical Organ ◽  
And Oxidative Stress

The NFκB protein family regulates numerous pathways within the cell—including inflammation, hypoxia, angiogenesis and oxidative stress—all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required for fetal growth and development. Abnormal placental development can be observed in numerous disorders during pregnancy, including fetal growth restriction, miscarriage, and preeclampsia (PE). NFκB is highly expressed in the placentas of women with PE, however its contributions to the syndrome are not fully understood. In this review we discuss the molecular actions and related pathways of NFκB in the placenta and highlight areas of research that need attention

scholarly journals The Role of Placental Homeobox Genes in Human Fetal Growth Restriction

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Padma Murthi ◽  
Gayathri Rajaraman ◽  
Shaun Patrick Brennecke ◽  
Bill Kalionis
Keyword(s):  
Pregnancy Outcome ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Adverse Pregnancy Outcome ◽  
Growth Restriction ◽  
Placental Development ◽  
Increased Risk ◽  
Adverse Pregnancy

Fetal growth restriction (FGR) is an adverse pregnancy outcome associated with significant perinatal and paediatric morbidity and mortality, and an increased risk of chronic disease later in adult life. One of the key causes of adverse pregnancy outcome is fetal growth restriction (FGR). While a number of maternal, fetal, and environmental factors are known causes of FGR, the majority of FGR cases remain idiopathic. These idiopathic FGR pregnancies are frequently associated with placental insufficiency, possibly as a result of placental maldevelopment. Understanding the molecular mechanisms of abnormal placental development in idiopathic FGR is, therefore, of increasing importance. Here, we review our understanding of transcriptional control of normal placental development and abnormal placental development associated with human idiopathic FGR. We also assess the potential for understanding transcriptional control as a means for revealing new molecular targets for the detection, diagnosis, and clinical management of idiopathic FGR.

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