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Tang D, Wang CF, Wang J, Jing XT, Ma J. Mechanism of the epidermal growth factor receptor in promoting endothelial cell dysfunction in gestational diabetes mellitus. World J Diabetes 2025; 16:105173. [DOI: 10.4239/wjd.v16.i6.105173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/29/2025] [Accepted: 05/08/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is a transmembrane protein that is differentially expressed in gestational diabetes mellitus (GDM). Endothelial dysfunction is a hallmark of GDM and plays a key role in its pathogenesis. EGFR is associated with endothelial dysfunction in the context of various diseases. However, the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown, particularly its regulation at the transcriptional and protein levels.
AIM To explore the molecular mechanism by which EGFR influences endothelial cell dysfunction in GDM at the transcriptional and protein levels.
METHODS Quantitative real-time polymerase chain reaction was used to detect the expression of EGFR and H19. Western blotting was used to detect the expression of endothelial cell dysfunction markers. A cell counting kit 8 assay was used to assess cell viability, flow cytometry was used to assess apoptosis, scratch and Transwell assays were used to assess cell migration, and a tube formation assay was used to assess cell vascular formation. Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.
RESULTS In this study, EGFR was upregulated in clinical samples, GDM animal models and GDM cell models, and the knockdown of EGFR could mitigate the effect of streptozotocin (STZ) and high glucose (HG); promoted the proliferation, migration and vascularization of human umbilical vein endothelial cells (HUVECs); inhibited cell apoptosis and the expression of endothelial cell dysfunction markers (vascular cell adhesion molecule-1, tumor necrosis factor-α, vascular endothelial growth factor-A, and intercellular cell adhesion molecule-1); and alleviated the process of GDM in vivo. Mechanistically, EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA, thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice. In addition, ERRFI1 also regulated the expression of EGFR, and ERRFI1 inhibited EGFR activity by binding to EGFR, thereby inhibiting HG-induced HUVECs dysfunction.
CONCLUSION Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.
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Affiliation(s)
- Dan Tang
- Department of Obstetrics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Cheng-Fen Wang
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jue Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Xiao-Tao Jing
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing Ma
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Waye AA, Moeller J, Veiga-Lopez A. Epidermal growth factor receptor in placental health and disease: pathways, dysfunction, and chemical disruption. Toxicol Sci 2025; 205:11-27. [PMID: 39985453 PMCID: PMC12038240 DOI: 10.1093/toxsci/kfaf024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2025] Open
Abstract
Formation of the placenta during gestation is required to support fetal growth and development. Derived from the placenta, trophoblast cells express nuclear and membrane-bound receptors. Among these receptors is the epidermal growth factor receptor (EGFR) which plays a key role in placental development. Activation of EGFR-mediated signaling in trophoblast cells regulates critical processes, such as proliferation, differentiation, invasion, and fusion during pregnancy, making it essential for normal placental formation. Dysfunction of EGFR in placental trophoblast cells has been associated with adverse pregnancy outcomes, including intrauterine growth restriction, preeclampsia, and preterm birth. Ubiquitous environmental chemicals, like polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorine pesticides, and bisphenols, have been reported to modulate EGFR signaling pathways, potentially contributing to placental dysfunction. This review explores the pivotal role of EGFR signaling in placental development and function, with a focus on how environmental chemicals interfere with EGFR-mediated pathways and placental cell functions as well as their implications for pregnancy outcomes. Findings presented herein underscore the need for further research into the effects of exposure to environmental chemicals on modulating EGFR signaling pathways in the context of placental health.
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Affiliation(s)
- Anita A Waye
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, United States
| | - Jacob Moeller
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, United States
| | - Almudena Veiga-Lopez
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, United States
- The Chicago Center for Health and Environment, University of Illinois at Chicago, Chicago, IL 60612, United States
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Barrozo ER, Racusin DA, Jochum MD, Garcia BT, Suter MA, Delbeccaro M, Shope C, Antony K, Aagaard KM. Discrete placental gene expression signatures accompany diabetic disease classifications during pregnancy. Am J Obstet Gynecol 2025; 232:326.e1-326.e15. [PMID: 38763341 DOI: 10.1016/j.ajog.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/06/2024] [Accepted: 05/11/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUND Gestational diabetes mellitus affects up to 10% of pregnancies and is classified into subtypes gestational diabetes subtype A1 (GDMA1) (managed by lifestyle modifications) and gestational diabetes subtype A2 (GDMA2) (requiring medication). However, whether these subtypes are distinct clinical entities or more reflective of an extended spectrum of normal pregnancy endocrine physiology remains unclear. OBJECTIVE Integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomics harbors the potential to reveal disease gene signatures in subsets of cells and tissue microenvironments. We aimed to combine these high-resolution technologies with rigorous classification of diabetes subtypes in pregnancy. We hypothesized that differences between preexisting type 2 and gestational diabetes subtypes would be associated with altered gene expression profiles in specific placental cell populations. STUDY DESIGN In a large case-cohort design, we compared validated cases of GDMA1, GDMA2, and type 2 diabetes mellitus (T2DM) to healthy controls by bulk RNA-seq (n=54). Quantitative analyses with reverse transcription and quantitative PCR of presumptive genes of significant interest were undertaken in an independent and nonoverlapping validation cohort of similarly well-characterized cases and controls (n=122). Additional integrated analyses of term placental single-cell, single-nuclei, and spatial transcriptomics data enabled us to determine the cellular subpopulations and niches that aligned with the GDMA1, GDMA2, and T2DM gene expression signatures at higher resolution and with greater confidence. RESULTS Dimensional reduction of the bulk RNA-seq data revealed that the most common source of placental gene expression variation was the diabetic disease subtype. Relative to controls, we found 2052 unique and significantly differentially expressed genes (-22 thresholds; q<0.05 Wald Test) among GDMA1 placental specimens, 267 among GDMA2, and 1520 among T2DM. Several candidate marker genes (chorionic somatomammotropin hormone 1 [CSH1], period circadian regulator 1 [PER1], phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [PIK3CB], forkhead box O1 [FOXO1], epidermal growth factor receptor [EGFR], interleukin 2 receptor subunit beta [IL2RB], superoxide dismutase 3 [SOD3], dedicator of cytokinesis 5 [DOCK5], suppressor of glucose, and autophagy associated 1 [SOGA1]) were validated in an independent and nonoverlapping validation cohort (q<0.05 Tukey). Functional enrichment revealed the pathways and genes most impacted for each diabetes subtype, and the degree of proximal similarity to other subclassifications. Surprisingly, GDMA1 and T2DM placental signatures were more alike by virtue of increased expression of chromatin remodeling and epigenetic regulation genes, while albumin was the top marker for GDMA2 with increased expression of placental genes in the wound healing pathway. Assessment of these gene signatures in single-cell, single-nuclei, and spatial transcriptomics data revealed high specificity and variability by placental cell and microarchitecture types. For example, at the cellular and spatial (eg, microarchitectural) levels, distinguishing features were observed in extravillous trophoblasts (GDMA1) and macrophages (GDMA2). Lastly, we utilized these data to train and evaluate 4 machine learning models to estimate our confidence in predicting the control or diabetes status of placental transcriptome specimens with no available clinical metadata. CONCLUSION Consistent with the distinct association of perinatal outcome risk, placentae from GDMA1, GDMA2, and T2DM-affected pregnancies harbor unique gene signatures that can be further distinguished by altered placental cellular subtypes and microarchitectural niches.
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Affiliation(s)
- Enrico R Barrozo
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Diana A Racusin
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Michael D Jochum
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Brandon T Garcia
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, TX
| | - Melissa A Suter
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Melanie Delbeccaro
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Cynthia Shope
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Kathleen Antony
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Kjersti M Aagaard
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
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Jia T, Guo Y, Zhao X. Silencing miR-126-5p protects trabecular meshwork cells against chronic oxidative injury by upregulating HSPB8 to activate PI3K/AKT pathway. J Mol Histol 2024; 56:58. [PMID: 39729156 DOI: 10.1007/s10735-024-10337-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024]
Abstract
Chronic oxidative stress (COS) is related to the pathophysiology of the trabecular meshwork (TM) in glaucoma. MicroRNAs (miRNAs) have a key role in the oxidative stress-mediated glaucoma. This work investigated the function of miR-126-5p in human trabecular meshwork cells (TMCs) under chronic oxidative stress (COS). The miR-126-5p inhibitor was transfected into TMCs to assess the function of miR-126-5p. The targets of miR-126-5p were predicted by bioinformatic analysis. A luciferase assay was applied to test the relationship between miR-126-5p and its target. Cell proliferation was assessed using MTT. Flow cytometry and TUNEL were used for the assessment of apoptosis. We found that the miR-126-5p level was elevated in TMCs exposed to COS. MiR-126-5p inhibitor markedly promoted TMC proliferation and inhibited the increases in apoptosis and extracellular matrix (ECM) proteins induced by COS. Heat shock protein B8 (HSPB8) was identified to be targeted by miR-126-5p. MiR-126-5p inhibitor restored the expression level of HSPB8 in TMCs under COS. Additionally, miR-126-5p depletion activated PI3K/AKT signaling in TMCs by upregulating HSPB8. HSPB8 downregulation or LY294002 treatment prevented the effects mediated by miR-126-5p inhibition on apoptosis and ECM in COS-treated TMCs. Overall, silencing miR-126-5p protects TMCs against COS-induced injury by upregulating HSPB8 to activate PI3K/AKT signaling.
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Affiliation(s)
- Tianqi Jia
- Department of Ophthalmology, Harbin Bright Eye Hospital, No.563 Xianfeng Road, Nangang District, Harbin, 150000, China
| | - Yujia Guo
- Department of Ophthalmology, Fengtai District Hospital of Traditional Chinese Medicine, No.3 Nanyuan CCBA Hutong, Fengtai District, Beijing, 100076, China
| | - Xiaolong Zhao
- Department of Ophthalmology, First Affilliated Hospital, Heilongjiang University of Chinese Medicine, No.26 Heping Road, Xiangfang District, Harbin, 150000, China.
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Owen MD, Kennedy MG, Quilang RC, Scott EM, Forbes K. The role of microRNAs in pregnancies complicated by maternal diabetes. Clin Sci (Lond) 2024; 138:1179-1207. [PMID: 39289953 PMCID: PMC11409017 DOI: 10.1042/cs20230681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/14/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
With the global prevalence of diabetes increasing, more people of reproductive age are experiencing hyperglycaemic pregnancies. Maternal Type 1 (T1DM) or Type 2 (T2DM) diabetes mellitus, and gestational diabetes mellitus (GDM) are associated with maternal cardiovascular and metabolic complications. Pregnancies complicated by maternal diabetes also increase the risk of short- and long-term health complications for the offspring, including altered fetal growth and the onset of T2DM and cardiometabolic diseases throughout life. Despite advanced methods for improving maternal glucose control, the prevalence of adverse maternal and offspring outcomes associated with maternal diabetes remains high. The placenta is a key organ at the maternal-fetal interface that regulates fetal growth and development. In pregnancies complicated by maternal diabetes, altered placental development and function has been linked to adverse outcomes in both mother and fetus. Emerging evidence suggests that microRNAs (miRNAs) are key molecules involved in mediating these changes. In this review, we describe the role of miRNAs in normal pregnancy and discuss how miRNA dysregulation in the placenta and maternal circulation is associated with suboptimal placental development and pregnancy outcomes in individuals with maternal diabetes. We also discuss evidence demonstrating that miRNA dysregulation may affect the long-term health of mothers and their offspring. As such, miRNAs are potential candidates as biomarkers and therapeutic targets in diabetic pregnancies at risk of adverse outcomes.
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Affiliation(s)
- Manon D Owen
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, U.K
| | - Margeurite G Kennedy
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, U.K
- Anthony Nolan Research Institute, Royal Free Hospital, Hampstead, London, U.K
- UCL Cancer Institute, Royal Free Campus, London, U.K
| | - Rachel C Quilang
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, U.K
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Eleanor M Scott
- Division of Clinical and Population Sciences, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, U.K
| | - Karen Forbes
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, U.K
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He L, Wang X, Chen X. Unveiling the role of microRNAs in metabolic dysregulation of Gestational Diabetes Mellitus. Reprod Biol 2024; 24:100924. [PMID: 39013209 DOI: 10.1016/j.repbio.2024.100924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/26/2024] [Accepted: 06/05/2024] [Indexed: 07/18/2024]
Abstract
Gestational Diabetes Mellitus (GDM) presents a significant health concern globally, necessitating a comprehensive understanding of its metabolic intricacies for effective management. MicroRNAs (miRNAs) have emerged as pivotal regulators in GDM pathogenesis, influencing glucose metabolism, insulin signaling, and lipid homeostasis during pregnancy. Dysregulated miRNA expression, both upregulated and downregulated, contributes to GDM-associated metabolic abnormalities. Ethnic and temporal variations in miRNA expression underscore the multifaceted nature of GDM susceptibility. This review examines the dysregulation of miRNAs in GDM and their regulatory functions in metabolic disorders. We discuss the involvement of specific miRNAs in modulating key pathways implicated in GDM pathogenesis, such as glucose metabolism, insulin signaling, and lipid homeostasis. Furthermore, we explore the potential diagnostic and therapeutic implications of miRNAs in GDM management, highlighting the promise of miRNA-based interventions for mitigating the adverse consequences of GDM on maternal and offspring health.
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Affiliation(s)
- Ling He
- Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Wang
- Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyi Chen
- Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Bodai L, Borosta R, Ferencz Á, Kovács M, Zsindely N. The Role of miR-137 in Neurodegenerative Disorders. Int J Mol Sci 2024; 25:7229. [PMID: 39000336 PMCID: PMC11241563 DOI: 10.3390/ijms25137229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.
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Affiliation(s)
- László Bodai
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
| | - Roberta Borosta
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
| | - Ágnes Ferencz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
| | - Mercédesz Kovács
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
- Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
| | - Nóra Zsindely
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
- Department of Genetics, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
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8
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Zhang Y, Liu Y, Shi Y, Bai C, Wang T, Ruan F, Hu C. Upregulation of MMPs in placentas of patients with gestational diabetes mellitus: Involvement of the PI3K/Akt pathway. Heliyon 2024; 10:e32518. [PMID: 39021921 PMCID: PMC11252657 DOI: 10.1016/j.heliyon.2024.e32518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/20/2024] Open
Abstract
In recent years, there has been a notable rise in the incidence of pregnancies complicated by gestational diabetes mellitus (GDM), characterized by glucose intolerance first identified during pregnancy. Analysis of placental tissue has revealed that placentas from women with GDM tend to be larger and heavier compared to control placentas, indicating potential changes in trophoblast proliferation, differentiation, and apoptosis. In this study, transcriptome sequencing was conducted on placentas obtained from both normal pregnancies and pregnancies with GDM to investigate the molecular mechanisms underlying this condition. The original sequencing data were subjected to sequencing analysis, resulting in the identification of 935 upregulated genes and 256 downregulated genes. The KEGG and GO analysis techniques on differential genes uncovered evidence suggesting that the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway may contribute to the pathogenesis of GDM. Subsequent analysis indicated that the expression levels of matrix metalloproteinases (MMP) 11, MMP12, MMP14, and MMP15, which are regulated by the PI3K/Akt pathway, were upregulated in the placentas of patients with GDM when compared to those of individuals with normal placental function. Additionally, our investigation into alternative splicing patterns revealed an increase in exon skipping alternative splicing of CSF3R in the placenta of patients with GDM compared to that in the control group. The CSF3R-PI3K-MMP pathway is speculated to regulate the pathogenesis of GDM.
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Affiliation(s)
- Yanan Zhang
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, 272029, PR China
| | - Yufen Liu
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, 272029, PR China
| | - Yanyan Shi
- Department of Pediatric Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, 272029, PR China
| | - Chunyu Bai
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining, Shandong, 272067, PR China
| | - Ting Wang
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, 272029, PR China
| | - Fang Ruan
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, 272029, PR China
| | - Chuanbing Hu
- Department of Pediatric Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, 272029, PR China
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Ghaneialvar H, Mohseni MM, Kenarkoohi A, Kakaee S. Are miR-26a and miR-26b microRNAs potent prognostic markers of gestational diabetes? Health Sci Rep 2024; 7:e2152. [PMID: 38831779 PMCID: PMC11144624 DOI: 10.1002/hsr2.2152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 03/02/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024] Open
Abstract
Background Gestational diabetes mellitus is a common public health problem, accompanied by complications for the mother and fetus. So, introducing new biomarkers to identify early diabetes is essential. As serum miRNAs are potentially appropriate markers, we investigated miR-26a and miR-26b expression levels in pregnant women with and without gestational diabetes. Method Demographic and clinical characteristics of 40 gestational diabetic patients and 40 healthy controls were assessed. The expression level of miR-26a and miR-26b microRNAs was measured by real-time PCR. Statistical analysis was done with GraphPad Prism software (version 8.4.3). Result The findings of this study showed that the expression level of miR-26a and miR-26b increased in women with gestational diabetes compared with healthy pregnant women, but the increase in expression was only significant for miR-26a (p < 0.05). Conclusion According to the statistical and ROC curves, we suggest miR-26a as a potential biomarker for the early diagnosis of gestational diabetes mellitus.
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Affiliation(s)
- Hori Ghaneialvar
- Biotechnology and Medicinal Plants Research CenterIlam University of Medical SciencesIlamIran
| | | | - Azra Kenarkoohi
- Department of Laboratory Sciences, School of Allied Medical SciencesIlam University of Medical SciencesIlamIran
| | - Saeed Kakaee
- Biotechnology and Medicinal Plants Research CenterIlam University of Medical SciencesIlamIran
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10
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Yi Y, Wang T, Xu W, Zhang SH. Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring. World J Diabetes 2024; 15:378-391. [PMID: 38591094 PMCID: PMC10999040 DOI: 10.4239/wjd.v15.i3.378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/30/2023] [Accepted: 02/06/2024] [Indexed: 03/15/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development. As a bridge between the mother and the fetus, the placenta has nutrient transport functions, endocrine functions, etc., and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status. Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus. There are many reports on the placental pathophysiological changes associated with GDM, the impacts of GDM on the growth and development of offspring, and the prevalence of GDM in offspring after birth. Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases. This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.
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Affiliation(s)
- Yan Yi
- Department of Ultrasonography, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - Tao Wang
- Clinical Molecular Immunology Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wei Xu
- Department of Ultrasonography, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - San-Hong Zhang
- Department of Pediatric, Xiantao First People’s Hospital, Xiantao 433000, Hubei Province, China
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11
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Lizárraga D, Gómez-Gil B, García-Gasca T, Ávalos-Soriano A, Casarini L, Salazar-Oroz A, García-Gasca A. Gestational diabetes mellitus: genetic factors, epigenetic alterations, and microbial composition. Acta Diabetol 2024; 61:1-17. [PMID: 37660305 DOI: 10.1007/s00592-023-02176-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023]
Abstract
Gestational diabetes mellitus (GDM) is a common metabolic disorder, usually diagnosed during the third trimester of pregnancy that usually disappears after delivery. In GDM, the excess of glucose, fatty acids, and amino acids results in foetuses large for gestational age. Hyperglycaemia and insulin resistance accelerate the metabolism, raising the oxygen demand, and creating chronic hypoxia and inflammation. Women who experienced GDM and their offspring are at risk of developing type-2 diabetes, obesity, and other metabolic or cardiovascular conditions later in life. Genetic factors may predispose the development of GDM; however, they do not account for all GDM cases; lifestyle and diet also play important roles in GDM development by modulating epigenetic signatures and the body's microbial composition; therefore, this is a condition with a complex, multifactorial aetiology. In this context, we revised published reports describing GDM-associated single-nucleotide polymorphisms (SNPs), DNA methylation and microRNA expression in different tissues (such as placenta, umbilical cord, adipose tissue, and peripheral blood), and microbial composition in the gut, oral cavity, and vagina from pregnant women with GDM, as well as the bacterial composition of the offspring. Altogether, these reports indicate that a number of SNPs are associated to GDM phenotypes and may predispose the development of the disease. However, extrinsic factors (lifestyle, nutrition) modulate, through epigenetic mechanisms, the risk of developing the disease, and some association exists between the microbial composition with GDM in an organ-specific manner. Genes, epigenetic signatures, and microbiota could be transferred to the offspring, increasing the possibility of developing chronic degenerative conditions through postnatal life.
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Affiliation(s)
- Dennise Lizárraga
- Laboratory of Molecular and Cell Biology, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico
| | - Bruno Gómez-Gil
- Laboratory of Microbial Genomics, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico
| | - Teresa García-Gasca
- Laboratory of Molecular and Cellular Biology, Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Avenida de las Ciencias s/n, 76230, Juriquilla, Querétaro, Mexico
| | - Anaguiven Ávalos-Soriano
- Laboratory of Molecular and Cell Biology, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico
| | - Livio Casarini
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi 287, 41125, Modena, Italy
| | - Azucena Salazar-Oroz
- Maternal-Fetal Department, Instituto Vidalia, Hospital Sharp Mazatlán, Avenida Rafael Buelna y Dr. Jesús Kumate s/n, 82126, Mazatlán, Sinaloa, Mexico
| | - Alejandra García-Gasca
- Laboratory of Molecular and Cell Biology, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico.
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12
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Vedika R, Sharma P, Reddy A. Signature precursor and mature microRNAs in cervical ripening during gestational diabetes mellitus lead to pre-term labor and other impediments in future. J Diabetes Metab Disord 2023; 22:945-965. [PMID: 37975145 PMCID: PMC10638342 DOI: 10.1007/s40200-023-01232-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/29/2023] [Indexed: 11/19/2023]
Abstract
Gestational diabetes mellitus (GDM) is a pathological condition in which the placenta releases a hormone called human placental lactogen that prevents maternal insulin uptake. GDM is characterised by varying degrees of carbohydrate intolerance and is first identified during pregnancy. Around 5-17% of pregnancies are GDM pregnancies. Older or obese women have a higher risk of developing GDM during gestation. Hyperglycemia is a classic manifestation of GDM and leads to alterations in eNOS and iNOS expression and subsequently causes ROS and RNS overproduction. ROS and RNS play an important role in maintaining normal physiology, when present in low concentrations. Increased concentrations of ROS is harmful and can cause cellular and tissue damage. Oxidative stress is defined as an imbalance between pro-oxidant and antioxidant molecules that manifests due to hyperglycemia. miRNAs are short, non-coding RNAs that play a critical role in regulating gene expression. Studies have shown that the placenta expresses more than 500 miRNAs, which play a crucial role in trophoblast division, movement, and apoptosis. Latest research has revealed that hyperglycemic conditions and increased oxidative stress, characteristic of GDM, can lead to the dysregulation of miRNAs. The placenta also releases miRNAs into the maternal circulation. The secreted miRNAs are encapsulated in exosomes or vesicles. These exosomes interact with tissues and organs at distant sites, releasing their cargo intracellularly. This crosstalk between hyperglycemia, ROS and miRNA expression in GDM has detrimental effects on both foetal and maternal health. One of the complications of GDM is preterm labour. GDM induced iNOS expression has been implicated in cervical ripening, which in turn causes preterm birth. This article focuses on the speculations of oxidative and nitrative stress markers that lead to detrimental effects in GDM. We have also envisaged the role of non-coding miRNA interactions in regulating gene expression for oxidative damage. Graphical Abstract Holistic view of miRNA in GDM. I)(A) Placenta as a metabolic organ that provides the foetus with nutrients, oxygen and hormones to maintain pregnancy. Human placental lactogen (hPL) is one such hormone that is released into maternal circulation. hPL is known to induce insulin resistance. (B) ß-cell dysfunction leads to reduced glucose sensing and insulin production. Insulin resistance, a characteristic of GDM, exacerbates insulin ß cell dysfunction leading to maternal hyperglycemia. Hyperglycemia leads to increased ROS and RNS production through several mechanisms. Consequently, GDM is characterised by increased oxidative and nitrative stress.II)Exposure to maternal hyperglycemia causes increased ROS and RNS production in trophoblast cells. Oxidative stress caused by hyperglycemia may lead to eNOS uncoupling, causing eNOS to behave as a superoxide producing enzyme. iNOS expression in trophoblast cells leads to increased NO production. iNOS-derived NO reacts with ROS to produce RNS, thereby increasing nitrosative stress. Expression of antioxidant defences are reduced. Hyperglycemia and oxidative stress may alter the expression of some miRNAs. Some miRNAs are upregulated while others are downregulated. Some miRNAs are secreted into maternal circulation in the form of exosomes. Oxidative stress markers, nitrative stress markers and circulating miRNAs are found to be increased in maternal circulation.
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Affiliation(s)
- R. Vedika
- Animal cell culture laboratory, Department of Biotechnology, SRMIST, Kattankulathur, Tamil Nadu India
| | - Priyanshy Sharma
- Animal cell culture laboratory, Department of Biotechnology, SRMIST, Kattankulathur, Tamil Nadu India
| | - Amala Reddy
- Animal cell culture laboratory, Department of Biotechnology, SRMIST, Kattankulathur, Tamil Nadu India
- Department of Biotechnology, SRMIST, Kattankulathur, Kancheepuram 603203 India
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13
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Pinto-Hernandez P, Castilla-Silgado J, Coto-Vilcapoma A, Fernández-Sanjurjo M, Fernández-García B, Tomás-Zapico C, Iglesias-Gutiérrez E. Modulation of microRNAs through Lifestyle Changes in Alzheimer's Disease. Nutrients 2023; 15:3688. [PMID: 37686720 PMCID: PMC10490103 DOI: 10.3390/nu15173688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
Lifestyle factors, including diet and physical activity (PA), are known beneficial strategies to prevent and delay Alzheimer's disease (AD) development. Recently, microRNAs have emerged as potential biomarkers in multiple diseases, including AD. The aim of this review was to analyze the available information on the modulatory effect of lifestyle on microRNA expression in AD. Few studies have addressed this question, leaving important gaps and limitations: (1) in human studies, only circulating microRNAs were analyzed; (2) in mice studies, microRNA expression was only analyzed in brain tissue; (3) a limited number of microRNAs was analyzed; (4) no human nutritional intervention studies were conducted; and (5) PA interventions in humans and mice were poorly detailed and only included aerobic training. Despite this, some conclusions could be drawn. Circulating levels of let-7g-5p, miR-107, and miR-144-3p were associated with overall diet quality in mild cognitive impairment patients. In silico analysis showed that these microRNAs are implicated in synapse formation, microglia activation, amyloid beta accumulation, and pro-inflammatory pathways, the latter also being targeted by miR-129-5p and miR-192-5p, whose circulating levels are modified by PA in AD patients. PA also modifies miR-132, miR-15b-5p, miR-148b-3p, and miR-130a-5p expression in mice brains, which targets are related to the regulation of neuronal activity, ageing, and pro-inflammatory pathways. This supports the need to further explore lifestyle-related miRNA changes in AD, both as biomarkers and therapeutic targets.
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Affiliation(s)
- Paola Pinto-Hernandez
- Department of Functional Biology, Physiology, University of Oviedo, 33006 Asturias, Spain; (P.P.-H.); (J.C.-S.); (A.C.-V.); (M.F.-S.); (C.T.-Z.)
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
| | - Juan Castilla-Silgado
- Department of Functional Biology, Physiology, University of Oviedo, 33006 Asturias, Spain; (P.P.-H.); (J.C.-S.); (A.C.-V.); (M.F.-S.); (C.T.-Z.)
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
| | - Almudena Coto-Vilcapoma
- Department of Functional Biology, Physiology, University of Oviedo, 33006 Asturias, Spain; (P.P.-H.); (J.C.-S.); (A.C.-V.); (M.F.-S.); (C.T.-Z.)
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
| | - Manuel Fernández-Sanjurjo
- Department of Functional Biology, Physiology, University of Oviedo, 33006 Asturias, Spain; (P.P.-H.); (J.C.-S.); (A.C.-V.); (M.F.-S.); (C.T.-Z.)
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
| | - Benjamín Fernández-García
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
- Department of Morphology and Cell Biology, Anatomy, University of Oviedo, 33006 Asturias, Spain
| | - Cristina Tomás-Zapico
- Department of Functional Biology, Physiology, University of Oviedo, 33006 Asturias, Spain; (P.P.-H.); (J.C.-S.); (A.C.-V.); (M.F.-S.); (C.T.-Z.)
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
| | - Eduardo Iglesias-Gutiérrez
- Department of Functional Biology, Physiology, University of Oviedo, 33006 Asturias, Spain; (P.P.-H.); (J.C.-S.); (A.C.-V.); (M.F.-S.); (C.T.-Z.)
- Health Research Institute of the Principality of Asturias (ISPA), 33011 Asturias, Spain;
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14
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Zheng Z, Mo J, Lin F, Wang J, Chen J, Luo H, Liu Y, Su C, Gu X, Xiong F, Zha L. Milk Exosomes from Gestational Diabetes Mellitus (GDM) and Healthy Parturient Exhibit Differential miRNAs Profiles and Distinct Regulatory Bioactivity on Hepatocyte Proliferation. Mol Nutr Food Res 2023; 67:e2300005. [PMID: 37357556 DOI: 10.1002/mnfr.202300005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/27/2023] [Indexed: 06/27/2023]
Abstract
SCOPE Exosomes, a novel type of bioactive component in human milk (HM), affect infant development, growth, and health. Recent studies indicate that HM exosomes and miRNAs relate to gestational diabetes mellitus (GDM). However, the miRNAs profiles and functionalities of HM exosomes from GDM parturient remain unclear. This study aims to compare the differential miRNAs in HM exosomes from GDM and healthy parturient, and investigate the HM exosomes bioactivities in regulating hepatocyte proliferation and insulin sensitivity. METHODS AND RESULTS This study extracted HM exosomes from GDM (GDM-EXO) and healthy (NOR-EXO) parturient by ultracentrifugation, high-throughput sequenced and compared the exosomal miRNAs profiles, and explored the regulatory bioactivities on hepatocyte proliferation in HepG2 cells and Balb/c mice. As compared to NOR-EXO, GDM-EXO has similar morphology, size, concentration, and exosome-specific markers (CD9 and TSG101) expression. GDM-EXO and NOR-EXO specifically harbor 1299 and 8 miRNAs, respectively. Moreover, GDM-EXO had 176 upregulated and 47 downregulated miRNAs compared with NOR-EXO. Both GDM-EXO and NOR-EXO were absorbed in cultured HepG2 hepatocytes and mice liver. GDM-EXO inhibited hepatocytes proliferation by downregulating mammalian target of rapamycin (mTOR) possibly via exosomal miR-101-3p delivery. CONCLUSION HM exosomes from GDM and healthy parturient exhibit differential miRNAs profiles and distinct regulatory bioactivity on hepatocyte proliferation.
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Affiliation(s)
- Zhongdaixi Zheng
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
- Department of Environmental Health, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Jiaqi Mo
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Fengjuan Lin
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Jiexian Wang
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Junbin Chen
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Huiyu Luo
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Yuguo Liu
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Chuhong Su
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Xiangfu Gu
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Fei Xiong
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, School of Public Health, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
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da Silva PHCM, Santos KDF, da Silva L, da Costa CCP, Santos RDS, Reis AADS. MicroRNAs Associated with the Pathophysiological Mechanisms of Gestational Diabetes Mellitus: A Systematic Review for Building a Panel of miRNAs. J Pers Med 2023; 13:1126. [PMID: 37511739 PMCID: PMC10381583 DOI: 10.3390/jpm13071126] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
miRNAs, a class of small non-coding RNAs, play a role in post-transcriptional gene expression. Therefore, this study aimed to conduct a systematic review of miRNAs associated with GDM to build a panel of miRNAs. A bibliographic search was carried out in the PubMed/Medline, Virtual Health Library (VHL), Web of Science, and EMBASE databases, selecting observational studies in English without time restriction. The protocol was registered on the PROSPERO platform (number CRD42021291791). Fifty-five studies were included in this systematic review, and 82 altered miRNAs in GDM were identified. In addition, four miRNAs were most frequently dysregulated in GDM (mir-16-5p, mir-20a-5p, mir-222-3p, and mir-330-3p). The dysregulation of these miRNAs is associated with the mechanisms of cell cycle homeostasis, growth, and proliferation of pancreatic β cells, glucose uptake and metabolism, insulin secretion, and resistance. On the other hand, identifying miRNAs associated with GDM and elucidating its main mechanisms can assist in the characterization and definition of potential biomarkers for the diagnosis and treatment of GDM.
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Affiliation(s)
- Pedro Henrique Costa Matos da Silva
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Kamilla de Faria Santos
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Laura da Silva
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Caroline Christine Pincela da Costa
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Rodrigo da Silva Santos
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
- Department of Biochemistry and Molecular Biology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil
| | - Angela Adamski da Silva Reis
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
- Department of Biochemistry and Molecular Biology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil
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16
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Elhag DA, Al Khodor S. Exploring the potential of microRNA as a diagnostic tool for gestational diabetes. J Transl Med 2023; 21:392. [PMID: 37330548 PMCID: PMC10276491 DOI: 10.1186/s12967-023-04269-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating host gene expression. Recent studies have indicated a role of miRNAs in the pathogenesis of gestational diabetes mellitus (GDM), a common pregnancy-related disorder characterized by impaired glucose metabolism. Aberrant expression of miRNAs has been observed in the placenta and/or maternal blood of GDM patients, suggesting their potential use as biomarkers for early diagnosis and prognosis. Additionally, several miRNAs have been shown to modulate key signaling pathways involved in glucose homeostasis, insulin sensitivity, and inflammation, providing insights into the pathophysiology of GDM. This review summarizes the current knowledge on the dynamics of miRNA in pregnancy, their role in GDM as well as their potential as diagnostic and therapeutic targets.
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Affiliation(s)
- Duaa Ahmed Elhag
- Maternal and Child Health Division, Research Branch, Sidra Medicine, Doha, Qatar
| | - Souhaila Al Khodor
- Maternal and Child Health Division, Research Branch, Sidra Medicine, Doha, Qatar.
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17
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Ren J, Jin H, Zhu Y. The Role of Placental Non-Coding RNAs in Adverse Pregnancy Outcomes. Int J Mol Sci 2023; 24:ijms24055030. [PMID: 36902459 PMCID: PMC10003511 DOI: 10.3390/ijms24055030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are transcribed from the genome and do not encode proteins. In recent years, ncRNAs have attracted increasing attention as critical participants in gene regulation and disease pathogenesis. Different categories of ncRNAs, which mainly include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are involved in the progression of pregnancy, while abnormal expression of placental ncRNAs impacts the onset and development of adverse pregnancy outcomes (APOs). Therefore, we reviewed the current status of research on placental ncRNAs and APOs to further understand the regulatory mechanisms of placental ncRNAs, which provides a new perspective for treating and preventing related diseases.
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Affiliation(s)
- Jiawen Ren
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
| | - Heyue Jin
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
| | - Yumin Zhu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China
- Correspondence:
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18
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Ticiani E, Villegas JA, Murga-Zamalloa C, Veiga-Lopez A. Binding sites in the epidermal growth factor receptor are responsible for bisphenol S effects on trophoblast cell invasion. CHEMOSPHERE 2023; 318:137960. [PMID: 36716934 PMCID: PMC9993481 DOI: 10.1016/j.chemosphere.2023.137960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 01/14/2023] [Accepted: 01/23/2023] [Indexed: 06/18/2023]
Abstract
Bisphenol S (BPS) is an endocrine disrupting chemical and the second most abundant bisphenol detected in humans. We have recently demonstrated that in utero exposure to BPS reduces human placenta cell fusion by interfering with epidermal growth factor (EGF)-dependent EGF receptor (EGFR) activation. Our previous work suggests that this occurs via binding of BPS to the extracellular domain of EGFR. However, whether BPS directly binds to EGFR has not been confirmed. We evaluated the binding ability of BPA, BPF and BPS to EGFR to determine whether EGFR binding is a unique attribute of BPS. To test these hypotheses, we first exposed HTR-8/SVneo cells to BPS, BPA, or BPF, with or without EGF. When co-exposed to EGF, BPS, but not BPA nor BPF, reduced EGFR phosphorylation by ∼60%, demonstrating that only BPS can interfere with EGF-dependent EGFR activation. As this indicates that BPS binding to the extracellular domain is responsible for its effect, we performed a computational search for putative binding sites on the EGFR extracellular domain, and performed ligand docking of BPS, BPA, and BPF at these sites. We identified three sites where polar interactions between positively charged residues and the sulfonyl group of BPS could lead binding selectivity over BPA and BPF. To test whether EGFR mutations at the predicted BPS binding sites (Arg255, Lys454, and Arg297) could prevent BPS's interference on EGFR activation, mutations for each EGFR target amino acids (R255A, R297A, and K454A) were introduced. For variants with R297A or K454A mutations, BPS did not affect EGF-mediated EGFR phosphorylation or EGFR-mediated cell invasion, suggesting that these residues are needed for the BPS antagonism effect on EGFR. In conclusion, BPS, but not BPA or BPF, interferes with EGFR-mediated trophoblast cell functions through binding at Arg297 and Lys454 amino acid residues in the extracellular domain of EGFR.
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Affiliation(s)
- Elvis Ticiani
- Department of Pathology, University of Illinois Chicago, Chicago, IL, 60612, USA
| | - José A Villegas
- Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, 60612, USA
| | | | - Almudena Veiga-Lopez
- Department of Pathology, University of Illinois Chicago, Chicago, IL, 60612, USA.
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Liang L, Chen Y, Wu C, Cao Z, Xia L, Meng J, He L, Yang C, Wang Z. MicroRNAs: key regulators of the trophoblast function in pregnancy disorders. J Assist Reprod Genet 2023; 40:3-17. [PMID: 36508034 PMCID: PMC9742672 DOI: 10.1007/s10815-022-02677-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
The placenta is essential for a successful pregnancy and healthy intrauterine development in mammals. During human pregnancy, the growth and development of the placenta are inseparable from the rapid proliferation, invasion, and migration of trophoblast cells. Previous reports have shown that the occurrence of many pregnancy disorders may be closely related to the dysfunction of trophoblasts. However, the function regulation of human trophoblast cells in the placenta is poorly understood. Therefore, studying the factors that regulate the function of trophoblast cells is necessary. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNA molecules. Increasing evidence suggests that miRNAs play a crucial role in regulating trophoblast functions. This review outlines the role of miRNAs in regulating the function of trophoblast cells and several common signaling pathways related to miRNA regulation in pregnancy disorders.
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Affiliation(s)
- Lingli Liang
- grid.412017.10000 0001 0266 8918Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, 421001 China
| | - Yanjun Chen
- grid.412017.10000 0001 0266 8918Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, 421001 China
| | - Chunyan Wu
- grid.412017.10000 0001 0266 8918Department of Cardiovascular, The Third Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Zitong Cao
- grid.412017.10000 0001 0266 8918Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, 421001 China
| | - Linzhen Xia
- grid.412017.10000 0001 0266 8918Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, 421001 China
| | - Jun Meng
- grid.461579.8Department of Function, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Lu He
- grid.461579.8Department of Gynecology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Chunfen Yang
- grid.461579.8Department of Gynecology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Zuo Wang
- grid.412017.10000 0001 0266 8918Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, 421001 China
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Salameh MA, Oniya O, Chamseddine RS, Konje JC. Maternal Obesity, Gestational Diabetes, and Fetal Macrosomia: An Incidental or a Mechanistic Relationship? MATERNAL-FETAL MEDICINE 2023; 5:27-30. [PMID: 40406531 PMCID: PMC12094358 DOI: 10.1097/fm9.0000000000000125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/05/2021] [Indexed: 11/26/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a well-established risk factor for fetal macrosomia. A significant number of patients with GDM also suffer from obesity, a factor associated with fetal macrosomia. An important question is whether GDM is independently associated with fetal macrosomia, or whether this relationship is merely the result of maternal obesity acting as a confounder. In this review of the literature, we attempt to further elucidate the relationship between GDM, maternal obesity, and fetal macrosomia.
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Affiliation(s)
- Mohammad A. Salameh
- Department of Medical Education, Weill Cornell Medicine – Qatar, Doha, Qatar
| | - Olubunmi Oniya
- Department of Medical Education, Weill Cornell Medicine – Qatar, Doha, Qatar
- Department of Obstetrics & Gynecology, Sidra Medicine, Doha, Qatar
| | - Reem S. Chamseddine
- Department of Medical Education, Weill Cornell Medicine – Qatar, Doha, Qatar
| | - Justin C. Konje
- Department of Medical Education, Weill Cornell Medicine – Qatar, Doha, Qatar
- Department of Obstetrics & Gynecology, Sidra Medicine, Doha, Qatar
- Department of Health Sciences, University of Leicester, Leicester LE1 7HA, UK
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21
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Östling H, Lodefalk M, Backman H, Kruse R. Global microRNA and protein expression in human term placenta. Front Med (Lausanne) 2022; 9:952827. [PMID: 36330066 PMCID: PMC9622934 DOI: 10.3389/fmed.2022.952827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction Description of the global expression of microRNAs (miRNAs) and proteins in healthy human term placentas may increase our knowledge of molecular biological pathways that are important for normal fetal growth and development in term pregnancy. The aim of this study was to explore the global expression of miRNAs and proteins, and to point out functions of importance in healthy term placentas. Materials and methods Placental samples (n = 19) were identified in a local biobank. All samples were from uncomplicated term pregnancies with vaginal births and healthy, normal weight newborns. Next-generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used to analyse miRNA and protein expression, respectively. Results A total of 895 mature miRNAs and 6,523 proteins were detected in the placentas, of which 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14, and X. Analysis of the highly abundant miRNAs and proteins showed several significantly predicted functions in common, including immune and inflammatory response, lipid metabolism and development of the nervous system. Discussion The predicted function inflammatory response may reflect normal vaginal delivery, while lipid metabolism and neurodevelopment may be important processes for the term fetus. The data presented in this study, with complete miRNA and protein findings, will enhance the knowledge base for future research in the field of placental function and pathology.
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Affiliation(s)
- Hanna Östling
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- *Correspondence: Hanna Östling,
| | - Maria Lodefalk
- Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Helena Backman
- Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Robert Kruse
- iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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Li M, Huang Y, Xi H, Zhang W, Xiang Z, Wang L, Li X, Guo H. Circ_FOXP1 promotes the growth and survival of high glucose-treated human trophoblast cells through the regulation of miR-508-3p/SMAD family member 2 pathway. Endocr J 2022; 69:1067-1078. [PMID: 35545535 DOI: 10.1507/endocrj.ej21-0528] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is a health risk for pregnant women and infants. Emerging evidence suggests that the deregulation of circular RNAs (circRNAs) is associated with the progression of this disorder. The objective of this study was to investigate the role of circ_FOXP1 in GDM. Cell models of GDM were established by treating human trophoblast cells with high glucose (HG). The expression of circ_FOXP1, miR-508-3p and SMAD family member 2 (SMAD2) mRNA was detected by quantitative real-time PCR (qPCR). Cell proliferation was assessed by EdU assay and MTT assay, and cell cycle and cell apoptosis were determined by flow cytometry assay. The protein levels of proliferation- and apoptosis-related markers and SMAD2 were measured by western blot. The relationship between miR-508-3p and circ_FOXP1 or SMAD2 was validated by dual-luciferase reporter assay or pull-down assay. The expression of circ_FOXP1 was downregulated in HG-treated HTR-8/SVneo cells. Circ_FOXP1 overexpression promoted HG-inhibited HTR-8/SVneo cell proliferation and suppressed HG-induced HTR-8/SVneo cell cycle arrest and apoptosis. Circ_FOXP1 positively regulated the expression of SMAD2 by targeting miR-508-3p. MiR-508-3p was overexpressed in HG-treated HTR-8/SVneo cells, and its overexpression reversed the effects of circ_FOXP1 overexpression. MiR-508-3p inhibition also alleviated HG-induced HTR-8/SVneo cell injuries, while the knockdown of SMAD2 abolished these effects. Collectively, circ_FOXP1 promotes the growth and survival of HG-treated human trophoblast cells through the miR-508-3p/SMAD2 pathway, hinting that circ_FOXP1 was involved in GDM progression.
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Affiliation(s)
- Mingqun Li
- Department of Gynecology and Obstetrics, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Yuqin Huang
- Department of Gynecology and Obstetrics, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Hongli Xi
- Department of Gynecology and Obstetrics, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Wei Zhang
- Department of Gynecology and Obstetrics, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Ziwu Xiang
- Department of Pathology, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Lingyun Wang
- Department of Central Laboratory, Xiangyang No.1 Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Xuanyu Li
- Department of Gynecology and Obstetrics, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Hongyan Guo
- Department of Gynecology and Obstetrics, Xiangyang NO.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
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The Mystery of Exosomes in Gestational Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2169259. [PMID: 35720179 PMCID: PMC9200544 DOI: 10.1155/2022/2169259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 05/31/2022] [Indexed: 11/27/2022]
Abstract
Gestational diabetes mellitus (GDM) is one of the common pregnancy complications, which increases the risk of short-term and long-term adverse consequences in both the mother and offspring. However, the pathophysiological mechanism of GDM is still poorly understood. Inflammation, insulin resistance and oxidative stress are considered critical factors in the occurrence and development of GDM. Although the lifestyle intervention and insulin are the primary treatment, adverse pregnancy outcomes still cannot be ignored. Exosomes have a specific function of carrying biological information, which can transmit information to target cells and play an essential role in intercellular communication. Their possible roles in normal pregnancy and GDM have been widely concerned. The possibility of exosomal cargos as biomarkers of GDM is proposed. This paper reviews the literature in recent years and discusses the role of exosomes in GDM and their possible mechanisms to provide some reference for the prediction, prevention, and treatment of GDM and improve the outcome of pregnancy.
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Li W, Yuan X, He X, Yang L, Wu Y, Deng X, Zeng Y, Hu K, Tang B. The downregulation of miR-22 and miR-372 may contribute to gestational diabetes mellitus through regulating glucose metabolism via the PI3K/AKT/GLUT4 pathway. J Clin Lab Anal 2022; 36:e24557. [PMID: 35712865 PMCID: PMC9279990 DOI: 10.1002/jcla.24557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/07/2022] [Accepted: 05/25/2022] [Indexed: 11/27/2022] Open
Abstract
Background Identifying effective regulatory mechanisms will be significant for Gestational diabetes mellitus (GDM) diagnosis and treatment. Methods The expressions of miR‐22 and miR‐372 in placenta tissues from 75 pregnant women with GDM and 75 matched healthy controls and HRT8/SVneo cells (a model of insulin resistance) were analyzed by qPCR. The expressions of PI3K, AKT, IRS, and GLUT4 in high glucose‐treated HRT8/SVneo cells transfected with miR‐22 or miR‐372 mimics or inhibitors was assessed by Western blot. A luciferase gene reporter assay was employed to verify miRNAs' target genes. Results The expressions of miR‐22 and miR‐372 in placental tissues from GDM patients and HRT8/SVneo cells were significantly decreased compared with the respective controls. The GLUT4 expression was significantly decreased in the placenta tissues of GDM and HRT8/SVneo cells with high glucose transfected with miR‐22 and miR‐372 inhibitors. We confirmed that SLC2A4, the gene encoding GLUT4, was a direct target of miR‐22 and miR‐372. In this study, we report that the lower expressions of miR‐22 and miR‐372 in placental tissue from GDM patients. Conclusion Our results further suggested that the downregulations of miR‐22 and miR‐372 may contribute to GDM through regulating the PI3K/GLUT4 pathway.
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Affiliation(s)
- Wei Li
- Department of Endocrinology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Xianlin Yuan
- Department of Food and Biological Engineering, Guangdong Industry Technical College, Guangzhou, China
| | - Xin He
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Li Yang
- Department of Endocrinology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Yingyuan Wu
- Department of Obstetrics and Gynecology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Xiaofeng Deng
- Department of Central Sterile Supply, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Yiwen Zeng
- Department of Endocrinology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Kesheng Hu
- Department of Clinical Laboratory, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Bo Tang
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Andrews SV, Yang IJ, Froehlich K, Oskotsky T, Sirota M. Large-scale placenta DNA methylation integrated analysis reveals fetal sex-specific differentially methylated CpG sites and regions. Sci Rep 2022; 12:9396. [PMID: 35672357 PMCID: PMC9174475 DOI: 10.1038/s41598-022-13544-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 05/17/2022] [Indexed: 11/14/2022] Open
Abstract
Although male–female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas from full term pregnancies (N = 532 samples), 5212 CpGs met genome-wide significance (p < 1E−8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E−14), chemokine activity (FDR p-value = 1.56E−2), and eosinophil migration (FDR p-value = 1.83E−2). Nine differentially methylated regions were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life.
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Affiliation(s)
- Shan V Andrews
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA
| | - Irene J Yang
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA.,Dougherty Valley High School, San Ramon, CA, USA
| | - Karolin Froehlich
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA
| | - Tomiko Oskotsky
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA. .,Department of Pediatrics, UCSF, San Francisco, CA, USA.
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA. .,Department of Pediatrics, UCSF, San Francisco, CA, USA.
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Radojičić O, Dobrijević Z, Robajac D, Gligorijević N, Mandić Marković V, Miković Ž, Nedić O. Gestational Diabetes is Associated with an Increased Expression of miR-27a in Peripheral Blood Mononuclear Cells. Mol Diagn Ther 2022; 26:421-435. [PMID: 35578107 DOI: 10.1007/s40291-022-00591-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Dysregulation of microRNA-based mechanisms is associated with various human pathologies, including gestational diabetes mellitus (GDM), suggesting they may be potential diagnostic and/or prognostic biomarkers of GDM. METHODS The expression of miR-340-5p, miR-27a-3p and miR-222-3p in peripheral blood mononuclear cells (PBMCs) obtained from patients with GDM (n = 42) and healthy controls (n = 34) were evaluated, together with their correlation to the clinical parameters of participants and their newborns. Expression of the selected microRNAs was quantified by quantitative real-time polymerase chain reaction (qPCR), after reverse transcription with microRNA-specific stem-loop primers. RESULTS The expression of miR-27a-3p was significantly higher in patients with GDM than in controls (p = 0.036), whereas no significant difference between groups was found for the other two tested microRNAs. The expression level of miR-27a-3p in GDM patients was found to negatively correlate with the number of erythrocytes, concentration of haemoglobin, haematocrit, and low- and high-density lipoprotein (LDL/HDL) ratio, and positively with the concentration of glycated haemoglobin (HbA1c). In the case of miR-222-3p, a negative correlation between its expression and the concentration of cholesterol, LDL and LDL/HDL ratio was found only in healthy pregnant women. The expression level of miR-340-5p negatively correlated with erythrocyte count, haemoglobin concentration and haematocrit in GDM patients, as well as with the concentration of cholesterol, LDL and LDL/HDL ratio in healthy women. CONCLUSIONS The results obtained illustrate the potential of PBMC-derived microRNA miR-27a-3p to serve as a diagnostic biomarker of GDM. On the other hand, MiR-27a and miR-340 may help in assessing the metabolic status relevant for pregnancy.
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Affiliation(s)
- Ognjen Radojičić
- University Clinic for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia
| | - Zorana Dobrijević
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia.
| | - Dragana Robajac
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia
| | - Nikola Gligorijević
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia
| | - Vesna Mandić Marković
- University Clinic for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia
- Medical School, University of Belgrade, Belgrade, Serbia
| | - Željko Miković
- University Clinic for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia
- Medical School, University of Belgrade, Belgrade, Serbia
| | - Olgica Nedić
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia
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Du R, Bai Y, Li L. Biological networks in gestational diabetes mellitus: insights into the mechanism of crosstalk between long non-coding RNA and N 6-methyladenine modification. BMC Pregnancy Childbirth 2022; 22:384. [PMID: 35505296 PMCID: PMC9066898 DOI: 10.1186/s12884-022-04716-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/28/2022] [Indexed: 12/24/2022] Open
Abstract
Background Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. The mechanism underlying the crosstalk between long non-coding RNAs (lncRNAs) and N6-methyladenine (m6A) modification in GDM remain unclear. Methods We generated a lncRNA-mediated competitive endogenous RNA (ceRNA) network using comprehensive data from the Gene Expression Omnibus database, published data, and our preliminary findings. m6A-related lncRNAs were identified based on Pearson correlation coefficient (PCC) analysis using our previous profiles. An integrated pipeline was established to constructed a m6A-related subnetwork thereby predicting the potential effects of the m6A-related lncRNAs. Results The ceRNA network was composed of 16 lncRNAs, 17 microRNAs, 184 mRNAs, and 338 edges. Analysis with the Kyoto Encyclopedia of Genes and Genomes database demonstrated that genes in the ceRNA network were primarily involved in the development and adverse outcomes of GDM, such as those in the fatty acid-metabolism pathway, the peroxisome proliferator-activated receptor signaling pathway, and thyroid hormone signaling pathway. Four m6A-related lncRNAs were involved in the ceRNA network, including LINC00667, LINC01087, AP000350.6, and CARMN. The m6A-related subnetwork was generated based on these four lncRNAs, their ceRNAs, and their related m6A regulators. Genes in the subnetwork were enriched in certain GDM-associated hormone (thyroid hormone and oxytocin) signaling pathways. LINC00667 was positively correlated with an m6A “reader” (YTHDF3; PCC = 0.95) and exhibited the highest node degree in the ceRNA network. RIP assays showed that YTHDF3 directly bind LINC00667. We further found that MYC possessed the highest node degree in a protein–protein interaction network and competed with LINC00667 for miR-33a-5p. qPCR analysis indicated that LINC00667, YTHDF3 and MYC levels were upregulated in the GDM placentas, while miR-33a-5p was downregulated. In a support-vector machine classifier, an m6A-related module composed of LINC00667, YTHDF3, MYC, and miR-33a-5p showed excellent classifying power for GDM in both the training and the testing dataset, with an accuracy of 76.19 and 71.43%, respectively. Conclusions Our results shed insights into the potential role of m6A-related lncRNAs in GDM and have implications in terms of novel therapeutic targets for GDM. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-022-04716-w.
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Affiliation(s)
- Runyu Du
- Department of Endocrinology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Yu Bai
- Department of Endocrinology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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Extracellular Vesicles—New Players in Cell-To-Cell Communication in Gestational Diabetes Mellitus. Biomedicines 2022; 10:biomedicines10020462. [PMID: 35203669 PMCID: PMC8962272 DOI: 10.3390/biomedicines10020462] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 12/17/2022] Open
Abstract
Research in extracellular vesicles (EVs) has contributed to a better understanding of physiological and pathophysiological conditions. Biologically active cargo, such as miRNAs and proteins, is critical in many different biological processes. In this context, pregnancy is one of the most complex physiological states, which needs a highly regulated system to ensure the correct nourishment and development of the baby. However, pre-existent maternal conditions and habits can modify the EV-cargo and dysregulate the system leading to pregnancy complications, with gestational diabetes mellitus (GDM) being one of the most reported and influential. Calcification and aging of muscle cells, protein modification in vascular control or variations in the levels of specific miRNAs are some of the changes observed or led by EV populations as adaptation to GDM. Interestingly, insulin sensitivity and glucose tolerance changes are not fully understood to date. Nevertheless, the increasing evidence generated has opened new possibilities in the biomarker discovery field but also in the understanding of cellular mechanisms modified and involved in GDM. This brief review aims to discuss some of the findings in GDM and models used for that purpose and their potential roles in the metabolic alterations during pregnancy, with a focus on insulin sensitivity and glucose tolerance.
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Yuan Y, Li Y, Hu L, Wen J. Exosomal RNA Expression Profiles and Their Prediction Performance in Patients With Gestational Diabetes Mellitus and Macrosomia. Front Endocrinol (Lausanne) 2022; 13:864971. [PMID: 35547007 PMCID: PMC9082313 DOI: 10.3389/fendo.2022.864971] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Exosomes are cell-derived vesicles that are present in many biological fluids. Exosomal RNAs in cord blood may allow intercellular communication between mother and fetus. We aimed to establish exosomal RNA expression profiles in cord blood from patients with gestational diabetes mellitus and macrosomia (GDM-M) and evaluate their prediction performance. METHODS We used microarray technology to establish the differential messenger RNA (mRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) expression profiles in cord blood exosomes from 3 patients with GDM-M compared with 3 patients with GDM and normal neonatal weight, followed by qPCR validation in an additional 40 patients with GDM. Logistic regression, receiver operating characteristic (ROC) curves, and graphical nomogram were applied to evaluate the performance of exosomal RNA (in peripheral blood) in macrosomia prediction. RESULTS A total of 98 mRNAs, 372 lncRNAs, and 452 circRNAs were differentially expressed in cord blood exosomes from patients with GDM-M. Pathway analysis based on screening data showed that the differential genes were associated with Phosphatidylinositol 3'-kinase (PI3acK)-Akt signaling pathway, Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, Transforming growth factor (TGF)-beta signaling pathway, insulin resistance, glycerolipid metabolism, fatty acid degradation, and mammalian target of rapamycin (mTOR) signaling pathway. After validation by qPCR, the expressions of GDF3, PROM1, AC006064.4, lnc-HPS6-1:1, and circ_0014635 were significantly increased and the expression of lnc-ZFHX3-7:1 was significantly decreased in cord blood exosomes of an additional 20 patients with GDM-M. The risk prediction performance of the expression of these validated genes (in peripheral blood exosomes) for GDM-related macrosomia was also evaluated. Only GDF3 expression and AC006064.4 expression showed well prediction performance [area under the curve (AUC) = 0.78 and 0.74, respectively]. Excitingly, the model including maternal age, fasting plasma glucose, 2-h plasma glucose, GDF3 expression, and AC006064.4 expression in peripheral blood exosomes had better prediction performance with an AUC of 0.86 (95% CI = 0.75-0.97). CONCLUSION These results showed that exosomal RNAs are aberrantly expressed in the cord blood of patients with GDM-M and highlighted the importance of exosomal RNAs in peripheral blood for GDM-M prediction.
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Affiliation(s)
- Yingdi Yuan
- Department of Pediatrics, The First People’s Hospital of Lianyungang, Xuzhou Medical University Affiliated Hospital of Lianyungang (Lianyungang Clinical College of Nanjing Medical University), Lianyungang, China
| | - Ying Li
- Department of Obstetrics and Gynecology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Lingmin Hu
- Department of Reproduction, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
- *Correspondence: Lingmin Hu, ; Juan Wen,
| | - Juan Wen
- Nanjing Maternity and Child Health Care Institute, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
- *Correspondence: Lingmin Hu, ; Juan Wen,
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Masete M, Dias S, Malaza N, Adam S, Pheiffer C. A Big Role for microRNAs in Gestational Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:892587. [PMID: 35957839 PMCID: PMC9357936 DOI: 10.3389/fendo.2022.892587] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/24/2022] [Indexed: 12/16/2022] Open
Abstract
Maternal diabetes is associated with pregnancy complications and poses a serious health risk to both mother and child. Growing evidence suggests that pregnancy complications are more frequent and severe in pregnant women with pregestational type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) compared to women with gestational diabetes mellitus (GDM). Elucidating the pathophysiological mechanisms that underlie the different types of maternal diabetes may lead to targeted strategies to prevent or reduce pregnancy complications. In recent years, microRNAs (miRNAs), one of the most common epigenetic mechanisms, have emerged as key players in the pathophysiology of pregnancy-related disorders including diabetes. This review aims to provide an update on the status of miRNA profiling in pregnancies complicated by maternal diabetes. Four databases, Pubmed, Web of Science, EBSCOhost, and Scopus were searched to identify studies that profiled miRNAs during maternal diabetes. A total of 1800 articles were identified, of which 53 are included in this review. All studies profiled miRNAs during GDM, with no studies on miRNA profiling during pregestational T1DM and T2DM identified. Studies on GDM were mainly focused on the potential of miRNAs to serve as predictive or diagnostic biomarkers. This review highlights the lack of miRNA profiling in pregnancies complicated by T1DM and T2DM and identifies the need for miRNA profiling in all types of maternal diabetes. Such studies could contribute to our understanding of the mechanisms that link maternal diabetes type with pregnancy complications.
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Affiliation(s)
- Matladi Masete
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Stephanie Dias
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
| | - Nompumelelo Malaza
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Sumaiya Adam
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- Center for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa
- *Correspondence: Carmen Pheiffer,
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Hung TH, Wu CP, Chen SF. Differential Changes in Akt and AMPK Phosphorylation Regulating mTOR Activity in the Placentas of Pregnancies Complicated by Fetal Growth Restriction and Gestational Diabetes Mellitus With Large-For-Gestational Age Infants. Front Med (Lausanne) 2021; 8:788969. [PMID: 34938752 PMCID: PMC8685227 DOI: 10.3389/fmed.2021.788969] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/18/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Dysregulation of placental mechanistic target of rapamycin (mTOR) activity has been implicated in the pathophysiology of pregnancies complicated by idiopathic fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) with large-for-gestational-age (LGA) infants. However, the underlying mechanisms remain unclear. Methods: We obtained placentas from women with normal pregnancies (n = 11) and pregnancies complicated by FGR (n = 12) or GDM with LGA infants (n = 12) to compare the levels of total and phosphorylated forms of Akt, AMPK, TSC2, and mTOR among the three groups and used primary cytotrophoblast cells isolated from 30 normal term placentas to study the effects of oxygen–glucose deprivation (OGD) and increasing glucose concentrations on the changes of these factors in vitro. Results: Placentas from FGR pregnancies had lower phosphorylated Akt (p-Akt) levels (P < 0.05), higher p-AMPKα levels (P < 0.01), and lower mTOR phosphorylation (P < 0.05) compared to that of normal pregnant women. Conversely, women with GDM and LGA infants had higher p-Akt (P < 0.001), lower p-AMPKα (P < 0.05), and higher p-mTOR levels (P < 0.05) in the placentas than normal pregnant women. Furthermore, primary cytotrophoblast cells subjected to OGD had lower p-Akt and p-mTOR (both P < 0.05) and higher p-AMPKα levels (P < 0.05) than those cultured under standard conditions, but increasing glucose concentrations had opposite effects on the respective levels. Administering compound C, an AMPK inhibitor, did not significantly affect Akt phosphorylation but partially reversed mTOR phosphorylation. Administering LY294002, an Akt inhibitor, decreased p-mTOR levels, but did not change the levels of total and phosphorylated AMPKα. Conclusion: These results suggest that Akt and AMPK are involved in the regulation of trophoblast mTOR activity in the placentas of pregnancies complicated by FGR and GDM with LGA infants.
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Affiliation(s)
- Tai-Ho Hung
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei, Taiwan.,Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Pu Wu
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei, Taiwan.,Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology and Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Szu-Fu Chen
- Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan
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32
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Flowers AE, Gonzalez TL, Joshi NV, Eisman LE, Clark EL, Buttle RA, Sauro E, DiPentino R, Lin Y, Wu D, Wang Y, Santiskulvong C, Tang J, Lee B, Sun T, Chan JL, Wang ET, Jefferies C, Lawrenson K, Zhu Y, Afshar Y, Tseng HR, Williams J, Pisarska MD. Sex differences in microRNA expression in first and third trimester human placenta†. Biol Reprod 2021; 106:551-567. [PMID: 35040930 DOI: 10.1093/biolre/ioab221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 11/09/2021] [Accepted: 12/04/2021] [Indexed: 12/13/2022] Open
Abstract
Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.
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Affiliation(s)
- Amy E Flowers
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Tania L Gonzalez
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nikhil V Joshi
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Laura E Eisman
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ekaterina L Clark
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Rae A Buttle
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Erica Sauro
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Rosemarie DiPentino
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yayu Lin
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Di Wu
- Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yizhou Wang
- Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Chintda Santiskulvong
- CS Cancer Applied Genomics Shared Resource, CS Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jie Tang
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Bora Lee
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Tianyanxin Sun
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jessica L Chan
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Erica T Wang
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Caroline Jefferies
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kate Lawrenson
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yalda Afshar
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - John Williams
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Margareta D Pisarska
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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33
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Solvin ÅØ, Chawla K, Olsen LC, Hegre SA, Danielsen K, Jenssen M, Furberg AS, Saunes M, Hveem K, Saetrom P, Løset M. MicroRNA profiling of psoriatic skin identifies 11 miRNAs associated with disease severity. Exp Dermatol 2021; 31:535-547. [PMID: 34748247 DOI: 10.1111/exd.14497] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 12/18/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as central regulators of gene expression and powerful biomarkers of disease. Much is yet unknown about their role in psoriasis pathology. To globally characterize the miRNAome of psoriatic skin, skin biopsies were collected from psoriatic cases (n = 75) and non-psoriatic controls (n = 46) and RNA sequenced. Count data were meta-analysed with a previously published dataset (cases, n = 24, controls, n = 20), increasing the number of psoriatic cases fourfold from previously published studies. Differential gene expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell-specific analyses were performed. Across all contrasts, we identified 439 significantly differentially expressed miRNAs (DEMs), of which 85 were novel for psoriasis and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in the constitution of all skin in psoriasis. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including "thyroid hormone signalling," "insulin resistance" and various infectious diseases. Cell-specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells. This study provides the most comprehensive overview of the miRNAome in psoriatic skin to date and identifies a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.
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Affiliation(s)
- Åshild Ø Solvin
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Konika Chawla
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Lene C Olsen
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Siv Anita Hegre
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Kjersti Danielsen
- Department of Dermatology, University Hospital of North Norway, Tromsø, Norway
| | - Marita Jenssen
- Department of Dermatology, University Hospital of North Norway, Tromsø, Norway
| | - Anne-Sofie Furberg
- Faculty of Health Sciences and Social Care, Molde University College, Molde, Norway.,Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway
| | - Marit Saunes
- Department of Dermatology, Clinic of Orthopaedy, Rheumatology and Dermatology, St. Olavs Hospital Trondheim University Hospital, Trondheim, Norway
| | - Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Pål Saetrom
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Computer Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Mari Løset
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Dermatology, Clinic of Orthopaedy, Rheumatology and Dermatology, St. Olavs Hospital Trondheim University Hospital, Trondheim, Norway
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34
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Bendek MJ, Canedo-Marroquín G, Realini O, Retamal IN, Hernández M, Hoare A, Busso D, Monteiro LJ, Illanes SE, Chaparro A. Periodontitis and Gestational Diabetes Mellitus: A Potential Inflammatory Vicious Cycle. Int J Mol Sci 2021; 22:ijms222111831. [PMID: 34769262 PMCID: PMC8584134 DOI: 10.3390/ijms222111831] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 12/12/2022] Open
Abstract
Periodontitis is a chronic inflammatory immune disease associated with a dysbiotic state, influenced by keystone bacterial species responsible for disrupting the periodontal tissue homeostasis. Furthermore, the severity of periodontitis is determined by the interaction between the immune cell response in front of periodontitis-associated species, which leads to the destruction of supporting periodontal tissues and tooth loss in a susceptible host. The persistent bacterial challenge induces modifications in the permeability and ulceration of the sulcular epithelium, which facilitates the systemic translocation of periodontitis-associated bacteria into distant tissues and organs. This stimulates the secretion of pro-inflammatory molecules and a chronic activation of immune cells, contributing to a systemic pro-inflammatory status that has been linked with a higher risk of several systemic diseases, such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). Although periodontitis and GDM share the common feature of systemic inflammation, the molecular mechanistic link of this association has not been completely clarified. This review aims to examine the potential biological mechanisms involved in the association between periodontitis and GDM, highlighting the contribution of both diseases to systemic inflammation and the role of new molecular participants, such as extracellular vesicles and non-coding RNAs, which could act as novel molecular intercellular linkers between periodontal and placental tissues.
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Affiliation(s)
- María José Bendek
- Department of Periodontology, Centre for Biomedical Research, Faculty of Dentistry, Universidad de los Andes, Av. Plaza 2501, Las Condes, Santiago 7620157, Chile; (M.J.B.); (G.C.-M.); (O.R.); (I.N.R.)
| | - Gisela Canedo-Marroquín
- Department of Periodontology, Centre for Biomedical Research, Faculty of Dentistry, Universidad de los Andes, Av. Plaza 2501, Las Condes, Santiago 7620157, Chile; (M.J.B.); (G.C.-M.); (O.R.); (I.N.R.)
| | - Ornella Realini
- Department of Periodontology, Centre for Biomedical Research, Faculty of Dentistry, Universidad de los Andes, Av. Plaza 2501, Las Condes, Santiago 7620157, Chile; (M.J.B.); (G.C.-M.); (O.R.); (I.N.R.)
| | - Ignacio N. Retamal
- Department of Periodontology, Centre for Biomedical Research, Faculty of Dentistry, Universidad de los Andes, Av. Plaza 2501, Las Condes, Santiago 7620157, Chile; (M.J.B.); (G.C.-M.); (O.R.); (I.N.R.)
| | - Marcela Hernández
- Laboratory of Periodontal Biology and Department of Pathology and Oral Medicine, Faculty of Dentistry, University of Chile, Olivos 943, Independencia, Santiago 8380544, Chile;
| | - Anilei Hoare
- Laboratory of Oral Microbiology, Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago 8380544, Chile;
| | - Dolores Busso
- Program in Biology of Reproduction, Centre for Biomedical Research and Innovation (CIIB), Universidad de los Andes, Santiago 8380544, Chile; (D.B.); (L.J.M.); (S.E.I.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 8380544, Chile
| | - Lara J. Monteiro
- Program in Biology of Reproduction, Centre for Biomedical Research and Innovation (CIIB), Universidad de los Andes, Santiago 8380544, Chile; (D.B.); (L.J.M.); (S.E.I.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 8380544, Chile
| | - Sebastián E. Illanes
- Program in Biology of Reproduction, Centre for Biomedical Research and Innovation (CIIB), Universidad de los Andes, Santiago 8380544, Chile; (D.B.); (L.J.M.); (S.E.I.)
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago 8380544, Chile
| | - Alejandra Chaparro
- Department of Periodontology, Centre for Biomedical Research, Faculty of Dentistry, Universidad de los Andes, Av. Plaza 2501, Las Condes, Santiago 7620157, Chile; (M.J.B.); (G.C.-M.); (O.R.); (I.N.R.)
- Correspondence: ; Tel.: +56-998376593
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35
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Nair S, Guanzon D, Jayabalan N, Lai A, Scholz-Romero K, Kalita de Croft P, Ormazabal V, Palma C, Diaz E, McCarthy EA, Shub A, Miranda J, Gratacós E, Crispi F, Duncombe G, Lappas M, McIntyre HD, Rice G, Salomon C. Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus. J Transl Med 2021; 19:360. [PMID: 34416903 PMCID: PMC8377872 DOI: 10.1186/s12967-021-02999-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 07/23/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9-15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. METHODS Discovery: A retrospective, case-control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. RESULTS A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. CONCLUSIONS During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.
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Affiliation(s)
- Soumyalekshmi Nair
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Dominic Guanzon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Nanthini Jayabalan
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Andrew Lai
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Katherin Scholz-Romero
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
- Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile
| | - Priyakshi Kalita de Croft
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Valeska Ormazabal
- Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile
| | - Carlos Palma
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Emilio Diaz
- Faculty of Medicine, Department of Obstetrics and Gynaecology, University of Concepcion, Concepción, Chile
| | - Elizabeth A McCarthy
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia
- Mercy Hospital for Women, 163 Studley Road, Heidelberg, VIC, 3084, Australia
| | - Alexis Shub
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia
- Mercy Hospital for Women, 163 Studley Road, Heidelberg, VIC, 3084, Australia
| | - Jezid Miranda
- Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain
| | - Eduard Gratacós
- Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain
| | - Fátima Crispi
- Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain
| | - Gregory Duncombe
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Martha Lappas
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia
- Mercy Hospital for Women, 163 Studley Road, Heidelberg, VIC, 3084, Australia
| | - H David McIntyre
- Mater Research, Faculty of Medicine, University of Queensland, Mater Health, South Brisbane, Australia
| | - Gregory Rice
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia.
- Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile.
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Wang F, Li Z, Zhao M, Ye W, Wu H, Liao Q, Bu S, Zhang Y. Circulating miRNAs miR-574-5p and miR-3135b are potential metabolic regulators for serum lipids and blood glucose in gestational diabetes mellitus. Gynecol Endocrinol 2021; 37:665-671. [PMID: 34126831 DOI: 10.1080/09513590.2021.1908990] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES MicroRNAs (miRNAs) are potentially involved in the regulation of glucose and lipid metabolism. The aim of this study was to investigate potential miRNA regulators for serum lipids and blood glucose in gestational diabetes mellitus. METHODS Plasma samples were obtained from 53 women with GDM and 46 normal pregnant women. Fasting blood glucose and a blood lipid profile were measured. Plasma miRNA expression profiles were analyzed using microarray. To verify the microarray data, the expression of miRNAs was evaluated by real-time PCR. Gene ontology (GO) and genes and genomics (KEGG) pathway enrichment of the predicted target genes of miRNAs were analyzed. RESULTS The miRNA expression profiles of plasma samples from healthy and GDM women are distinct. We identified 93 differently expressed miRNAs. Compared with healthy pregnant women, 48 miRNAs including miR-574-5p and miR-3135b exhibited significantly lower expression in plasma samples from GDM patients. The expression of miR-574-5p was significantly correlated with levels of blood glucose and LDL-C; miR-3135b was significantly correlated with HDL-C. Some predicted common target genes of these two miRNAs are associated with the metabolism of glucose and lipids as well as the insulin signaling pathway. CONCLUSIONS miR-574-5p and miR-3135b may serve as metabolic regulators of glucose and lipids for GDM.
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Affiliation(s)
- Fuyan Wang
- Zhejiang Provincial Key Laboratory of Pathophysiology, Diabetes Research Center, Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Zhulin Li
- Zhejiang Provincial Key Laboratory of Pathophysiology, Diabetes Research Center, Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Ming Zhao
- Department of Medical Services, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Wen Ye
- Zhejiang Provincial Key Laboratory of Pathophysiology, Diabetes Research Center, Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Hangyu Wu
- Zhejiang Provincial Key Laboratory of Pathophysiology, Diabetes Research Center, Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Qi Liao
- Zhejiang Provincial Key Laboratory of Pathophysiology, Diabetes Research Center, Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Shizhong Bu
- Zhejiang Provincial Key Laboratory of Pathophysiology, Diabetes Research Center, Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Yisheng Zhang
- Department of Gynaecology and Obstetrics, Ningbo Medical Center Lihuili Hospital, Medical School of Ningbo University, Ningbo, Zhejiang, China
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Zhang C, Zhao D. MicroRNA-362-5p promotes the proliferation and inhibits apoptosis of trophoblast cells via targeting glutathione-disulfide reductase. Bioengineered 2021; 12:2410-2419. [PMID: 34107852 PMCID: PMC8806602 DOI: 10.1080/21655979.2021.1933678] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gestational diabetes mellitus (GDM), a common complication of pregnancy, harms the health of pregnant women and fetuses. MicroRNAs (miRNAs) dysregulation in placenta is involved in GDM. Herein, we explored the roles of miR-362-5p in GDM. After high glucose (HG) treated HTR-8/SVneo cells, CCK-8 and flow cytometry were conducted to assess the capability of the proliferation and apoptosis, respectively. The data demonstrated that HG inhibited proliferation and induced apoptosis of HTR-8/SVneo cells. MiR-362-5p level was reduced in HG-treated cells and placenta tissues of GDM patients, measured by qPCR. Overexpressed miR-362-5p accelerated the proliferation and restrained apoptosis of HG-treated cells. Furthermore, glutathione-disulfide reductase (GSR) was verified as a target of miR-362-5p, through TargetScan database and dual-luciferase reporter assay. GSR was upregulated in GDM placenta tissues and was negatively regulated by miR-362-5p. Enforced GSR level abolished the effects of miR-362-5p overexpression on the proliferation and apoptosis of HTR-8/SVneo cells. Furthermore, miR-362-5p increased p-PI3K, p-AKT and bcl-2, while reduced bax and cleaved caspase3, which were abolished by GSR. In conclusion, miR-362-5p promoted cell proliferation and inhibited apoptosis via targeting GSR and activating PI3K/AKT pathway. The findings mentioned above suggested that miR-362-5p might be a therapy target of GDM.
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Affiliation(s)
- Cuihua Zhang
- First Department of Obstetrics, Chongqing Maternal and Child Health Hospital, Chongqing, China
| | - Dan Zhao
- First Department of Obstetrics, Chongqing Maternal and Child Health Hospital, Chongqing, China
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Yong HEJ, Chan SY. Current approaches and developments in transcript profiling of the human placenta. Hum Reprod Update 2021; 26:799-840. [PMID: 33043357 PMCID: PMC7600289 DOI: 10.1093/humupd/dmaa028] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The placenta is the active interface between mother and foetus, bearing the molecular marks of rapid development and exposures in utero. The placenta is routinely discarded at delivery, providing a valuable resource to explore maternal-offspring health and disease in pregnancy. Genome-wide profiling of the human placental transcriptome provides an unbiased approach to study normal maternal–placental–foetal physiology and pathologies. OBJECTIVE AND RATIONALE To date, many studies have examined the human placental transcriptome, but often within a narrow focus. This review aims to provide a comprehensive overview of human placental transcriptome studies, encompassing those from the cellular to tissue levels and contextualize current findings from a broader perspective. We have consolidated studies into overarching themes, summarized key research findings and addressed important considerations in study design, as a means to promote wider data sharing and support larger meta-analysis of already available data and greater collaboration between researchers in order to fully capitalize on the potential of transcript profiling in future studies. SEARCH METHODS The PubMed database, National Center for Biotechnology Information and European Bioinformatics Institute dataset repositories were searched, to identify all relevant human studies using ‘placenta’, ‘decidua’, ‘trophoblast’, ‘transcriptome’, ‘microarray’ and ‘RNA sequencing’ as search terms until May 2019. Additional studies were found from bibliographies of identified studies. OUTCOMES The 179 identified studies were classifiable into four broad themes: healthy placental development, pregnancy complications, exposures during pregnancy and in vitro placental cultures. The median sample size was 13 (interquartile range 8–29). Transcriptome studies prior to 2015 were predominantly performed using microarrays, while RNA sequencing became the preferred choice in more recent studies. Development of fluidics technology, combined with RNA sequencing, has enabled transcript profiles to be generated of single cells throughout pregnancy, in contrast to previous studies relying on isolated cells. There are several key study aspects, such as sample selection criteria, sample processing and data analysis methods that may represent pitfalls and limitations, which need to be carefully considered as they influence interpretation of findings and conclusions. Furthermore, several areas of growing importance, such as maternal mental health and maternal obesity are understudied and the profiling of placentas from these conditions should be prioritized. WIDER IMPLICATIONS Integrative analysis of placental transcriptomics with other ‘omics’ (methylome, proteome and metabolome) and linkage with future outcomes from longitudinal studies is crucial in enhancing knowledge of healthy placental development and function, and in enabling the underlying causal mechanisms of pregnancy complications to be identified. Such understanding could help in predicting risk of future adversity and in designing interventions that can improve the health outcomes of both mothers and their offspring. Wider collaboration and sharing of placental transcriptome data, overcoming the challenges in obtaining sufficient numbers of quality samples with well-defined clinical characteristics, and dedication of resources to understudied areas of pregnancy will undoubtedly help drive the field forward.
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Affiliation(s)
- Hannah E J Yong
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore
| | - Shiao-Yng Chan
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore.,Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Extracellular vesicle-enriched miRNA profiles across pregnancy in the MADRES cohort. PLoS One 2021; 16:e0251259. [PMID: 33979365 PMCID: PMC8115775 DOI: 10.1371/journal.pone.0251259] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 04/22/2021] [Indexed: 12/31/2022] Open
Abstract
MicroRNA (miRNA) circulating in plasma have been proposed as biomarkers for a variety of conditions and diseases, including complications during pregnancy. During pregnancy, about 15-25% of maternal plasma exosomes, a small size-class of EVs, are hypothesized to originate in the placenta, and may play a role in communication between the fetus and mother. However, few studies have addressed changes in miRNA over the course of pregnancy with repeated measures, nor focused on diverse populations. We describe changes in miRNA in early and late pregnancy from the MADRES cohort of primarily low-income Hispanic women based in Los Angeles, CA. miRNA derived from extracellular-vesicles (EVs) were isolated from maternal blood plasma samples collected in early and late pregnancy. In this study, we identified 64 of 130 detectable miRNA which significantly increased with gestational age at the time of collection (GA), and 26 which decreased with GA. Possible fetal sex-specific associations were observed for 30 of these 90 significant miRNA. Predicted gene targets for miRNA significantly associated with GA were identified using MirDIP and were found to be enriched for Gene Ontology categories that included energetic and metabolic processes but were underrepresented in immune-related categories. Circulating EV-associated miRNA during pregnancy are likely important for maternal-fetal communication, and may play roles in supporting and maintaining a healthy pregnancy, given the changing needs of the fetus.
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Lizárraga D, García-Gasca A. The Placenta as a Target of Epigenetic Alterations in Women with Gestational Diabetes Mellitus and Potential Implications for the Offspring. EPIGENOMES 2021; 5:epigenomes5020013. [PMID: 34968300 PMCID: PMC8594713 DOI: 10.3390/epigenomes5020013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a pregnancy complication first detected in the second or third trimester in women that did not show evident glucose intolerance or diabetes before gestation. In 2019, the International Diabetes Federation reported that 15.8% of live births were affected by hyperglycemia during pregnancy, of which 83.6% were due to gestational diabetes mellitus, 8.5% were due to diabetes first detected in pregnancy, and 7.9% were due to diabetes detected before pregnancy. GDM increases the susceptibility to developing chronic diseases for both the mother and the baby later in life. Under GDM conditions, the intrauterine environment becomes hyperglycemic, while also showing high concentrations of fatty acids and proinflammatory cytokines, producing morphological, structural, and molecular modifications in the placenta, affecting its function; these alterations may predispose the baby to disease in adult life. Molecular alterations include epigenetic mechanisms such as DNA and RNA methylation, chromatin remodeling, histone modifications, and expression of noncoding RNAs (ncRNAs). The placenta is a unique organ that originates only in pregnancy, and its main function is communication between the mother and the fetus, ensuring healthy development. Thus, this review provides up-to-date information regarding two of the best-documented (epigenetic) mechanisms (DNA methylation and miRNA expression) altered in the human placenta under GDM conditions, as well as potential implications for the offspring.
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Kunysz M, Mora-Janiszewska O, Darmochwał-Kolarz D. Epigenetic Modifications Associated with Exposure to Endocrine Disrupting Chemicals in Patients with Gestational Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22094693. [PMID: 33946662 PMCID: PMC8124363 DOI: 10.3390/ijms22094693] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/27/2022] Open
Abstract
Gestational diabetes mellitus (GDM) remains a significant clinical and public health issue due to its increasing prevalence and the possibility for numerous short- and long-term complications. The growing incidence of GDM seems to coincide with the widespread use of endocrine disrupting chemicals (EDCs). The extensive production and common use of these substances in everyday life has resulted in constant exposure to harmful substances from the environment. That may result in epigenetic changes, which may manifest themselves also after many years and be passed on to future generations. It is important to consider the possible link between environmental exposure to endocrine disrupting chemicals (EDCs) during pregnancy, epigenetic mechanisms and an increased risk for developing gestational diabetes mellitus (GDM). This manuscript attempts to summarize data on epigenetic changes in pregnant women suffering from gestational diabetes in association with EDCs. There is a chance that epigenetic marks may serve as a tool for diagnostic, prognostic, and therapeutic measures.
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Zhang L, Zhang T, Sun D, Cheng G, Ren H, Hong H, Chen L, Jiao X, Du Y, Zou Y, Wang L. Diagnostic value of dysregulated microribonucleic acids in the placenta and circulating exosomes in gestational diabetes mellitus. J Diabetes Investig 2021; 12:1490-1500. [PMID: 33411988 PMCID: PMC8354507 DOI: 10.1111/jdi.13493] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 12/26/2020] [Accepted: 01/01/2021] [Indexed: 12/19/2022] Open
Abstract
Aims/Introduction Differentially expressed microribonucleic acids (miRNAs) in the placenta and circulating exosomes are of diagnostic value for gestational diabetes mellitus (GDM). In a cross‐sectional study, we identified miRNAs expressed both in the placenta and circulating exosomes of pregnant women with GDM, and estimated their diagnostic value. Materials and Methods Next‐generation sequencing was used to identify miRNAs in the placenta that were differentially expressed between GDM and normal glucose tolerance pregnancies. Quantitative polymerase chain reaction was used to validate the identified targets. Western blot and transmission electron microscopy were used to validate exosomes. Univariate logistic regression analysis was used to establish diagnostic models based on miRNAs expression, and the diagnostic value was estimated using the receiver operator characteristic curve. Results We identified 157 dysregulated miRNAs in the placental tissue obtained from GDM pregnancies. Of these, miRNA‐125b was downregulated (P < 0.001), whereas miRNA‐144 was upregulated (P < 0.001). The patterns of these two miRNAs remained the same in circulating exosomes from GDM pregnancies (all P < 0.001). miRNA‐144 levels in the circulating exosomes negatively correlated with body mass index both before pregnancy (P = 0.018) and before delivery (P = 0.039), and positively correlated with blood glucose at 1 h, estimated using the oral glucose tolerance test (P = 0.044). The area under curve for the established diagnostic model was 0.898, which was higher than blood glucose levels at 0 h. Conclusions These findings suggest that miRNA‐125b and miRNA‐144 are consistently dysregulated in circulating exosomes and the placenta from GDM pregnancies, and are of excellent diagnostic value for GDM.
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Affiliation(s)
- Lei Zhang
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Ting Zhang
- Department of Pharmacy, Jinan Infectious Disease Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Daoxu Sun
- Office of Heze Health Association, Heze, China
| | - Guanghui Cheng
- Central Research Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Hanxiao Ren
- Department of Clinical Laboratory Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Haijie Hong
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Liyu Chen
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Xue Jiao
- School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Yijia Du
- School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Yuqing Zou
- School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Lina Wang
- Department of Clinical Laboratory Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
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Song TR, Su GD, Chi YL, Wu T, Xu Y, Chen CC. Dysregulated miRNAs contribute to altered placental glucose metabolism in patients with gestational diabetes via targeting GLUT1 and HK2. Placenta 2021; 105:14-22. [PMID: 33517149 DOI: 10.1016/j.placenta.2021.01.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 01/05/2021] [Accepted: 01/14/2021] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Dysregulated genes in glucose transport and metabolize pathways have been found in patients with Gestational diabetes (GDM), but the underlying mechanisms were still unclear. MATERIALS AND METHODS Placental villous samples were collected from 31 patients with GDM and 20 healthy controls. The expression of GLUT1, GLUT4, GLUT9 and HK2 was examined by immunoblotting and qRT-PCR. The miRNAs have the potential targeting GLUT1 and HK2 were predicted using online bioinformatics tool: TargetScan. The interaction between miRNAs and target genes were confirmed by dual luciferase assay and immunoblotting. The function of miR-9 and miR-22 on glucose metabolism was examined by glucose uptake assay and lactate secretion assay. RESULTS GLUT1 and HK2 proteins level was found upregulated in patients with GDM, but the mRNA level was not significantly changed. Predicted by using bioinformatics tools and confirmed by dual luciferase assay and immunoblotting, GLUT1 was identified as a target of miR-9 and miR-22, whereas HK2 was identified as a target of miR-9. MiR-9 and miR-22 level was found reduced in the placenta villous and negatively correlated with the expression of GLUT1 and HK2. Functional studies indicated that miR-9 and miR-22 inhibitors upregulated the expression of GLUT1 and HK2, and then increased the glucose uptake, lactate secretion, cell viability and repressed apoptosis in primary syncytiotrophoblasts (STBs) and HTR8/SVneo cells. DISCUSSION The upregulation of GLUT1 and HK2 in the placenta, which is induced by miR-9 and miR-22 reduction, contributes to the disordered glucose metabolism in patients with GDM.
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Affiliation(s)
- Tian-Rong Song
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China.
| | - Gui-Dong Su
- Obstetrics and Gynecology Department, Nanfang Hospital Affiliated to Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Ya-Li Chi
- Obstetrics and Gynecology Department, Nanfang Hospital Affiliated to Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Ting Wu
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China
| | - Yue Xu
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China
| | - Chun-Chun Chen
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China
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Du R, Wu N, Li L. Aberrantly Expressed Non-Coding RNAs in the Placenta and Their Role in the Pathophysiology of Gestational Diabetes Mellitus. Diabetes Metab Syndr Obes 2021; 14:3719-3732. [PMID: 34456579 PMCID: PMC8387639 DOI: 10.2147/dmso.s325993] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/12/2021] [Indexed: 11/23/2022] Open
Abstract
Gestational diabetes mellitus (GDM), one of the most common complications during pregnancy, is associated with a high risk of short- and long-term adverse effects on the mother and offspring. Placenta-derived hormones and cytokines aggravate maternal insulin resistance (IR) during pregnancy, which in turn contribute to GDM. The hyperglycemia and IR in GDM result in aberrant placental structure and function adversely affecting fetal growth and well-being. Therefore, it is reasonable to assume that structural and functional alterations in the placenta contribute to the pathogenesis of GDM and GDM-related complications. Increasing evidence suggests that multiple non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, are dysregulated in placentas of patients with GDM and linked to abnormal placental structure, metabolism, and function. Manipulation of ncRNA expression led to some key pathophysiological features of GDM, such as trophoblast dysfunction, changes in intracellular glucose metabolism, and inflammation. Moreover, placenta-specific ncRNAs may be potential diagnostic biomarkers and even therapeutic targets for GDM. This review summarizes data published on the involvement of aberrantly expressed placental ncRNAs in GDM and provides information on their role in the pathogenesis of GDM and GDM-associated complications.
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Affiliation(s)
- Runyu Du
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China
| | - Na Wu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China
- Correspondence: Ling Li Department of Endocrinology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, Liaoning Province, 110004, People’s Republic of ChinaTel +86 18940251181Fax +86 24-25944460 Email
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Abdeltawab A, Zaki ME, Abdeldayem Y, Mohamed AA, Zaied SM. Circulating micro RNA-223 and angiopoietin-like protein 8 as biomarkers of gestational diabetes mellitus. Br J Biomed Sci 2021; 78:12-17. [PMID: 32421465 DOI: 10.1080/09674845.2020.1764211] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 04/24/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a serious health problem associated with both foetal and maternal complications. New biomarkers that can predict or help in the early diagnosis of GDM are needed to minimize the hazards of hyperglycaemia in pregnant women and their offspring. We hypothesised a link between levels of microRNA-223 (miRNA-223) and Angiopoietin-Like Protein 8 (ANGPTL8) and GDM. MATERIALS AND METHODS The study included 109 patients with confirmed early diagnosed GDM and 103 healthy control pregnant women in their second or third trimester. miRNA-223 and ANGPTL8 blood levels were assessed by real-time RT-PCR and sandwich ELISA, respectively, laboratory markers by standard methods. RESULTS There was a significant increase in mean [SD] miRNA-223 and ANGPTL8 in GDM (0.31 [0.06] relative units) and (692 [199] pg/ml), respectively, in the GDM women compared to healthy pregnant women (0.17[0.05] relative units) and (261 [127] pg/ml), respectively, P < 0.001. miRNA-223 and ANGPTL8 correlated significantly with each other (r = 0.38, P < 0.001) and with fasting, 1-h and 2-h postprandial blood glucose levels (all P ≤ 0.002) HbA1 c (P < 0.025), total cholesterol (P < 0.01), LDL-C and triglycerides (both P ≤ 0.005). The ROC area under curve (AUC) (95%CI) was 0.94 (0.91-0.97) for ANGPTL8, 0.92 (0.88-0.96) for miRNA-223 and 0.97 (0.95 - 0.99) for their combination. CONCLUSIONS These findings support the hypothesis of involvement of both miRNA-223 and ANGPTL8 in the pathogenesis of GDM. The difference between levels in GDM patients and in control pregnant women indicates potential use for early diagnosis or prediction of GDM.
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Affiliation(s)
- A Abdeltawab
- Physiology Department, College of Medicine, Jouf University , Sakaka, Saudi Arabia
- Physiology Department, Faculty of Medicine, Beni-Suef University , Beni-Suef, Egypt
| | - M E Zaki
- Clinical Pathology Department, Faculty of Medicine, Mansoura University , Mansoura, Egypt
| | - Y Abdeldayem
- Obstetric and Gynecology Department, Mansoura University , Mansoura, Egypt
| | - A A Mohamed
- Medical Biochemistry Division, Pathology Department, Jouf University , Sakaka, Saudi Arabia
- Medical Biochemistry Department, Faculty of Medicine, Beni-Suef University , Beni-Suef, Egypt
| | - S M Zaied
- Clinical and Chemical Pathology Department, Faculty of Medicine, Beni-Suef University , Beni-Suef, Egypt
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Zhang TN, Wang W, Huang XM, Gao SY. Non-Coding RNAs and Extracellular Vehicles: Their Role in the Pathogenesis of Gestational Diabetes Mellitus. Front Endocrinol (Lausanne) 2021; 12:664287. [PMID: 34093439 PMCID: PMC8173208 DOI: 10.3389/fendo.2021.664287] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/06/2021] [Indexed: 12/21/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition in the second or third trimester of pregnancy. GDM has a considerable impact on health outcomes of the mother and offspring during pregnancy, delivery, and beyond. Although the exact mechanism regarding GDM remains unclear, numerous studies have suggested that non-coding RNAs, including long non-coding (lnc)RNAs, microRNAs, and circular RNAs, were involved in the pathogenesis of GDM in which they played vital regulatory roles. Additionally, several studies have revealed that extracellular vehicles also participated in the pathogenesis of GDM, highlighting their important role in this disease. Considering the lack of effective biomarkers for the early identification of and specific treatment for GDM, non-coding RNAs and extracellular vehicles may be promising biomarkers and even targets for GDM therapies. This review provides an update on our understanding of the role of non-coding RNAs and extracellular vehicles in GDM. As our understanding of the function of lncRNAs and extracellular vehicles improves, the future appears promising for their use as potential biomarkers and treatment targets for GDM in clinical practice.
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Affiliation(s)
- Tie-Ning Zhang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wei Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xin-Mei Huang
- Department of Endocrinology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
- *Correspondence: Xin-Mei Huang, ; Shan-Yan Gao,
| | - Shan-Yan Gao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Xin-Mei Huang, ; Shan-Yan Gao,
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Liu ZN, Jiang Y, Liu XQ, Yang MM, Chen C, Zhao BH, Huang HF, Luo Q. MiRNAs in Gestational Diabetes Mellitus: Potential Mechanisms and Clinical Applications. J Diabetes Res 2021; 2021:4632745. [PMID: 34869778 PMCID: PMC8635917 DOI: 10.1155/2021/4632745] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/08/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a common pregnancy complication which is normally diagnosed in the second trimester of gestation. With an increasing incidence, GDM poses a significant threat to maternal and offspring health. Therefore, we need a deeper understanding of GDM pathophysiology and novel investigation on the diagnosis and treatment for GDM. MicroRNAs (miRNAs), a class of endogenic small noncoding RNAs with a length of approximately 19-24 nucleotides, have been reported to exert their function in gene expression by binding to proteins or being enclosed in membranous vesicles, such as exosomes. Studies have investigated the roles of miRNAs in the pathophysiological mechanism of GDM and their potential as noninvasive biological candidates for the management of GDM, including diagnosis and treatment. This review is aimed at summarizing the pathophysiological significance of miRNAs in GDM development and their potential function in GDM clinical diagnosis and therapeutic approach. In this review, we summarized an integrated expressional profile and the pathophysiological significance of placental exosomes and associated miRNAs, as well as other plasma miRNAs such as exo-AT. Furthermore, we also discussed the practical application of exosomes in GDM postpartum outcomes and the potential function of several miRNAs as therapeutic target in the GDM pathological pathway, thus providing a novel clinical insight of these biological signatures into GDM therapeutic approach.
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Affiliation(s)
- Zhao-Nan Liu
- Department of Reproductive Genetics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Ying Jiang
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - Xuan-Qi Liu
- Department of Reproductive Genetics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Meng-Meng Yang
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - Cheng Chen
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - Bai-Hui Zhao
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - He-Feng Huang
- Department of Reproductive Genetics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Qiong Luo
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
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Li Y, Zhuang J. miR-345-3p serves a protective role during gestational diabetes mellitus by targeting BAK1. Exp Ther Med 2020; 21:2. [PMID: 33235611 PMCID: PMC7678625 DOI: 10.3892/etm.2020.9434] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 03/18/2020] [Indexed: 02/07/2023] Open
Abstract
Recent studies have demonstrated that microRNAs (miRs) serve a crucial role during the development of gestational diabetes mellitus (GDM). However, the mechanisms underlying miR-345-3p and its protective role during GDM have not been previously reported. The present study investigated miR-345-3p expression and function in vitro, and the possible molecular mechanisms underlying GDM. Compared with healthy pregnant women, miR-345-3p was downregulated in the placental tissue and peripheral blood of patients with GDM. Further investigation revealed that BCL2-antagonist/killer 1 (BAK1) was a predicted target gene of miR-345-3p, and the expression of BAK1 was significantly increased in patients with GDM compared with healthy pregnant women. In vitro analysis revealed that miR-345-3p mimic significantly increased cell viability, migration and invasion, inhibited apoptosis, upregulated Bcl-2 and matrix metallopeptidase 9 expression, and decreased Bax expression compared with the control group. Furthermore, miR-245-3p mimic-induced alterations were reversed by BAK1 overexpression. The results suggested that miR-345-3p overexpression exhibited a protective role in patients with GDM by inhibiting HTR8-/SVneo cell apoptosis, and promoting cell proliferation and migration via targeting BAK1. The use of miR-345-3p for the diagnosis of GDM requires further investigation.
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Affiliation(s)
- Yuxia Li
- Department of Gynecology and Obstetrics, Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430010, P.R. China
| | - Jun Zhuang
- Department of Obstetrics, Lianshui County People's Hospital, Huai'an, Jiangsu 223400, P.R. China
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Kennedy EM, Hermetz K, Burt A, Everson TM, Deyssenroth M, Hao K, Chen J, Karagas MR, Pei D, Koestler DC, Marsit CJ. Placental microRNA expression associates with birthweight through control of adipokines: results from two independent cohorts. Epigenetics 2020; 16:770-782. [PMID: 33016211 DOI: 10.1080/15592294.2020.1827704] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs are non-coding RNAs that regulate gene expression post-transcriptionally. In the placenta, the master regulator of foetal growth and development, microRNAs shape the basic processes of trophoblast biology and specific microRNA have been associated with foetal growth. To comprehensively assess the role of microRNAs in placental function and foetal development, we have performed small RNA sequencing to profile placental microRNAs from two independent mother-infant cohorts: the Rhode Island Child Health Study (n = 225) and the New Hampshire Birth Cohort Study (n = 317). We modelled microRNA counts on infant birthweight percentile (BWP) in each cohort, while accounting for race, sex, parity, and technical factors, using negative binomial generalized linear models. We identified microRNAs that were differentially expressed (DEmiRs) with BWP at false discovery rate (FDR) less than 0.05 in both cohorts. hsa-miR-532-5p (miR-532) was positively associated with BWP in both cohorts. By integrating parallel whole transcriptome and small RNA sequencing in the RICHS cohort, we identified putative targets of miR-532. These targets are enriched for pathways involved in adipogenesis, adipocytokine signalling, energy metabolism, and hypoxia response, and included Leptin, which we further demonstrated to have a decreasing expression with increasing BWP, particularly in male infants. Overall, we have shown a robust and reproducible association of miR-532 with BWP, which could influence BWP through regulation of adipocytokines Leptin and Adiponectin.
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Affiliation(s)
- Elizabeth M Kennedy
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Karen Hermetz
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Amber Burt
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Todd M Everson
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Maya Deyssenroth
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Ke Hao
- Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jia Chen
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Margaret R Karagas
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.,Dartmouth College, Children's Environmental Health and Disease Prevention Research Center at Dartmouth, Lebanon, NH, USA
| | - Dong Pei
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USA
| | - Devin C Koestler
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USA
| | - Carmen J Marsit
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
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Cao M, Zhang L, Lin Y, Li Z, Xu J, Shi Z, Chen Z, Ma J, Wen J. Differential mRNA and Long Noncoding RNA Expression Profiles in Umbilical Cord Blood Exosomes from Gestational Diabetes Mellitus Patients. DNA Cell Biol 2020; 39:2005-2016. [PMID: 32986505 DOI: 10.1089/dna.2020.5783] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background and Aims: Exosomes contain numerous RNAs and transfer them between cells or organs, thereby establishing intercellular or interorgan communication. The roles of mRNAs and long noncoding RNAs (lncRNAs) from umbilical cord blood exosomes in gestational diabetes mellitus (GDM) occurrence and fetus growth remain poorly understood. We aimed to establish the differential mRNA and lncRNA expression profiles in umbilical cord blood exosomes from GDM patients compared with normal controls. Results: Using microarray technology, we identified 84 mRNAs and 256 lncRNAs as differentially expressed in umbilical cord blood exosomes of GDM patients compared with controls. The protein-protein interaction network revealed that the differentially expressed mRNAs were associated with glucagon signaling pathway, an important GDM-related pathway. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses were performed for mRNAs associated with differentially expressed lncRNAs. The results indicated that metabolic process, growth, and development were significantly enriched, which are important in GDM development and fetus growth. Moreover, pathway network was constructed to reveal the key pathways in GDM, such as metabolic pathways and insulin signaling pathway. Further lncRNA/miRNA interaction analysis showed that most of the exosomal lncRNAs harbored miRNA binding sites, and some were associated with GDM. Conclusion: These results showed that exosomal mRNAs and lncRNAs are aberrantly expressed in the umbilical cord blood of GDM patients and play potential roles in GDM development and fetus growth.
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Affiliation(s)
- Minkai Cao
- Department of Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Le Zhang
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China.,Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Yu Lin
- Department of Obstetrics, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Zhengying Li
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Jianjuan Xu
- Department of Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Zhonghua Shi
- Department of Obstetrics, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Zhong Chen
- Department of Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Jinqi Ma
- Department of Gynaecology and Obstetrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Juan Wen
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
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