Characterization of NO-Induced Nitrosative Status in Human Placenta from Pregnant Women with Gestational Diabetes Mellitus

Dysregulation of NO production is implicated in pregnancy-related diseases, including gestational diabetes mellitus (GDM). The role of NO and its placental targets in GDM pregnancies has yet to be determined. S-Nitrosylation is the NO-derived posttranslational protein modification that can modulate biological functions by forming NO-derived complexes with longer half-life, termed S-nitrosothiol (SNO). Our aim was to examine the presence of endogenous S-nitrosylated proteins in cysteine residues in relation to antioxidant defense, apoptosis, and cellular signal transduction in placental tissue from control (n=8) and GDM (n=8) pregnancies. S-Nitrosylation was measured using the biotin-switch assay, while the expression and protein activity were assessed by immunoblotting and colorimetric methods, respectively. Results indicated that catalase and peroxiredoxin nitrosylation levels were greater in GDM placentas, and that was accompanied by reduced catalase activity. S-Nitrosylation of ERK1/2 and AKT was increased in GDM placentas, and their activities were inhibited. Activities of caspase-3 and caspase-9 were increased, with the latter also showing diminished nitrosylation levels. These findings suggest that S-nitrosylation is a little-known, but critical, mechanism by which NO directly modulates key placental proteins in women with GDM and, as a consequence, maternal and fetal anomalies during pregnancy can occur.

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Elevated pro-angiogenic phenotype in feto-placental tissue from gestational diabetes mellitus

Placenta ◽

10.1016/j.placenta.2015.01.436 ◽

2015 ◽

Vol 36 (4) ◽

pp. 485

Author(s):

F. Troncoso ◽

J. Acurio ◽

K. Herlitz ◽

F. Ruiz ◽

P. Bertoglia ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Placental Tissue

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Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus

Acta Endocrinologica ◽

10.1530/eje-09-0031 ◽

2009 ◽

Vol 160 (4) ◽

pp. 567-578 ◽

Cited By ~ 107

Author(s):

Michelle Colomiere ◽

Michael Permezel ◽

Clyde Riley ◽

Gernot Desoye ◽

Martha Lappas

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Signaling Pathway ◽

Insulin Signaling ◽

Placental Tissue ◽

Insulin Signaling Pathway ◽

Obese Patients ◽

Obese Women ◽

Normal Controls

ObjectiveStudies in adipose tissue and skeletal muscle suggest that impaired insulin action is due to defects in the insulin signaling pathway and may play a role in the pathophysiology of insulin resistance associated with gestational diabetes mellitus (GDM) and obesity. The present study tested the hypothesis that endogenous expression levels in the human term placenta of insulin signaling components are altered in placental tissue from GDM women in comparison with normal controls and maternal obesity.Design and methodsPlacental tissue was collected from normal, diet-controlled GDM, and insulin-controlled GDM in both non-obese and obese women (n=6–7 per group). Western blotting and quantitative RT-PCR was performed to determine the level of expression in the insulin signaling pathway.ResultsThere was a significant increase in insulin receptor (IR) substrate (IRS)-1 protein expression with a concurrent decrease in IRS-2 protein expression in non-obese women with insulin-controlled GDM compared with diet-controlled GDM and normal controls. Furthermore, a decrease in both protein and mRNA expression of phosphatidyl-inositol-3-kinase (PI3-K) p85α and glucose transporter (GLUT)-4 was observed in non-obese and obese women with insulin controlled GDM compared with normal controls. When comparing non-obese to obese patients, significant decreases in mRNA expression of IR-β, PI3K p85α and GLUT-4 was found in obese patients.ConclusionOur results suggest that post receptor defects are present in the insulin signaling pathway in placenta of women with pregnancies complicated by diabetes and obesity. In addition, expression studies demonstrate post receptor alterations in insulin signaling possibly under selective maternal regulation and not fetal regulation.

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Cell Type- and Sex-Specific Dysregulation of Thyroid Hormone Receptors in Placentas in Gestational Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms21114056 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4056 ◽

Cited By ~ 1

Author(s):

Julia Knabl ◽

Lena de Maiziere ◽

Rebecca Hüttenbrenner ◽

Stefan Hutter ◽

Julia Jückstock ◽

...

Keyword(s):

Diabetes Mellitus ◽

Thyroid Hormone ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Hormone Receptors ◽

Thyroid Hormone Receptor ◽

Placental Tissue ◽

Cell Type ◽

Decidual Cells ◽

Wide Range

Thyroid hormones are essential for development of trophoblasts and the fetus. They also regulate a wide range of metabolic processes. We investigated the influence of maternal gestational diabetes mellitus (GDM) on thyroid hormone receptor (THR) isoforms THRα1, THRα2, THRβ1 and THRβ2 of the human placenta in a sex- and cell-type specific manner. Term placental tissue was obtained from women with (n = 40) or without GDM (control; n = 40). THRs levels were measured by semi-quantitative immunohistochemistry and real-time qRT-PCR. We localized THR immunostaining in syncytiotrophoblast (SCT), which was the tissue with the strongest signal. Double immunofluorescence identified THR in decidual cells in the stroma and in extravillous cytotrophoblasts. GDM did not change THRα1 immunolabelling intensity in decidua, but was associated with a stronger immunolabelling in SCT compared to GDM (p < 0.05). The SCT difference of GDM vs. control was strongest (p < 0.01) in female placentas. THRα2 was only weakly present and immunolabelling was weaker (p < 0.05) in SCT of only male GDM placentas in comparison to male controls. THRβ1/β2 immunostaining was weak in all cell types without changes in GDM. However, more THRβ1/2 protein was present (p < 0.001) in male than female placentas. All these protein changes were paralleled by changes of THR transcript levels. The data show that THR are expressed in term trophoblast in relation to fetal sex. Maternal GDM influences predominantly THRα1 in SCT, with the strongest GDM effect in SCT of female placentas.

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Epigenetic modification of the pentose phosphate pathway and the IGF-axis in women with gestational diabetes mellitus

Epigenomics ◽

10.2217/epi-2018-0206 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1371-1385 ◽

Cited By ~ 3

Author(s):

Angela Steyn ◽

Nigel J Crowther ◽

Shane A Norris ◽

Raquel Rabionet ◽

Xavier Estivill ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Epigenetic Modification ◽

Placental Tissue ◽

Maternal Blood ◽

Pentose Phosphate ◽

Igf Binding Proteins ◽

Genes Encoding ◽

Igf Binding

Aim: Gestational diabetes mellitus (GDM) has been linked with adverse long-term health outcomes for the fetus and mother. These effects may be mediated by epigenetic modifications. Materials & methods: Genome-wide RNA sequencing was performed in placental tissue and maternal blood in six GDM and six non-GDM pregnancies. Promoter region DNA methylation was examined for selected genes and correlated with gene expression to examine an epigenetic modulator mechanism. Results: Reductions of mRNA expression and increases in promoter methylation were observed for G6PD in GDM women, and for genes encoding IGF-binding proteins in GDM-exposed placenta. Conclusion: GDM involves epigenetic attenuation of G6PD, which may lead to hyperglycemia and oxidative stress, and the IGF-axis, which may modulate fetal macrosomia.

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Analysis of key genes and their functions in placental tissue of patients with gestational diabetes mellitus

Reproductive Biology and Endocrinology ◽

10.1186/s12958-019-0546-z ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 1

Author(s):

Yuxia Wang ◽

Haifeng Yu ◽

Fangmei Liu ◽

Xiue Song

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Tyrosine Phosphatase ◽

Human Leukocyte ◽

Placental Tissue ◽

Functional Enrichment ◽

Ppi Network ◽

Tissue Samples ◽

Key Genes

Abstract Background This study was aimed at screening out the potential key genes and pathways associated with gestational diabetes mellitus (GDM). Methods The GSE70493 dataset used for this study was obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in the placental tissue of women with GDM in relation to the control tissue samples were identified and submitted to protein-protein interaction (PPI) network analysis and subnetwork module mining. Functional enrichment analyses of the PPI network and subnetworks were subsequently carried out. Finally, the integrated miRNA–transcription factor (TF)–DEG regulatory network was analyzed. Results In total, 238 DEGs were identified, of which 162 were upregulated and 76 were downregulated. Through PPI network construction, 108 nodes and 278 gene pairs were obtained, from which chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, protein tyrosine phosphatase, receptor type C (PTPRC), and human leukocyte antigen (HLA) were screened out as hub genes. Moreover, genes associated with the immune-related pathway and immune responses were found to be significantly enriched in the process of GDM. Finally, miRNAs and TFs that target the DEGs were predicted. Conclusions Four candidate genes (viz., CXCL9, CXCL10, PTPRC, and HLA) are closely related to GDM. miR-223-3p, miR-520, and thioredoxin-binding protein may play important roles in the pathogenesis of this disease.

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Expression and correlation of sex hormone-binding globulin and insulin signal transduction and glucose transporter proteins in gestational diabetes mellitus placental tissue

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2016.07.003 ◽

2016 ◽

Vol 119 ◽

pp. 106-117 ◽

Cited By ~ 10

Author(s):

Bao Zhang ◽

Zhen Jin ◽

Lei Sun ◽

Yang Zheng ◽

Jiexuan Jiang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Signal Transduction ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Glucose Transporter ◽

Placental Tissue ◽

Sex Hormone Binding Globulin ◽

Hormone Binding ◽

Insulin Signal Transduction ◽

Glucose Transporter Proteins

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Circulating microRNA-7 regulates insulin, inflammatory and GnRH signaling pathways by targeting IRS1, IRS2, and RAF1 genes in gestational diabetes mellitus

10.21203/rs.3.rs-702559/v1 ◽

2021 ◽

Author(s):

Ravi BHUSHAN ◽

Anjali Rani ◽

Deepali Gupta ◽

Akhtar Ali ◽

Anima Tripathi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Signaling Pathways ◽

Target Genes ◽

Target Prediction ◽

Placental Tissue ◽

Altered Expression ◽

Lower Expression

Abstract Aims/hypothesisSmall non-coding micro RNAs (miRNAs) are indicated in various metabolic processes and play a critical role in disease pathology, including gestational diabetes mellitus (GDM). The purpose of this study was to examine the altered expression of miRNAs and their target genes in placental tissue (PL), cord blood (CB), and maternal blood (MB) of matched non-glucose tolerant (NGT) and GDM mother. MethodsIn a case-control study, micro-RNA was quantified from forty-five serum (MB n = 15, CB n = 15, and PL n = 15) and matched placental tissue using stem-loop RT-qPCR followed by target prediction, network construction and functional and pathways enrichment analysis. Further, target genes were verified in-vitro through transfection and RT-qPCR. ResultsFive miRNAs, namely hsa-let 7a-5P, hsa-miR7-5P, hsa-miR9-5P, hsa-miR18a-5P, and hsa-miR23a-3P, were significantly over-expressed (p < 0.05) in all three samples namely PL, CB, and MB of GDM patients. However, the sample-wise comparison reveals higher expression of miRNA 7 in MB while lowest in CB than control. Furthermore, a comparison of fold change expression of target genes discloses a lower expression of IRS1, IRS2, and RAF1 in MB while comparatively higher expression of NRAS in MB and CB. In-vitro validation reveals lower expression of IRS1/2 and RAF1 in response to overexpression of miR-7 and vice-versa. Thus it is evident that increased miRNA7 expression causes down-regulation of its target genes IRS1, IRS2, and RAF1 in GDM mother compared to control. Further, target prediction, pathway enrichment, and hormone analysis (significantly higher FSH & LH in MB of GDM compared to NGT) revealed the insulin signaling, inflammatory and GnRH signaling as major pathways regulated by miRNA7. Conclusions/InterpretationsThus, an elevated level of miRNA7 may be associated with the progression of GDM by altering the multiple pathways like insulin, GnRH, and inflammatory signaling pathways via targeting IRS1, IRS2, and RAF1, implicating a new therapeutic target for GDM.

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