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Milan KL, Anuradha M, Ramkumar KM. Role of miR-125b-5p in modulating placental SIRT7 expression and its implications for lipid metabolism in gestational diabetes. J Reprod Immunol 2025; 167:104422. [PMID: 39755065 DOI: 10.1016/j.jri.2024.104422] [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: 11/21/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/06/2025]
Abstract
Gestational diabetes is marked impaired glucose tolerance, poses various adverse outcomes including increased BMI and obesity. These outcomes results from excess lipid accumulation which is marked by elevated triglycerides. In GDM, placenta exhibits altered lipid metabolism, including reduced fatty acid oxidation and increased triglyceride accumulation. These elevated triglycerides can also contribute to oxidative stress in GDM. SIRT7 plays an important role in regulating lipid metabolism and triglycerides levels. This study aimed to investigate the potential of miRNA to regulate the placental SIRT7 in GDM. PCR analysis reveals that SIRT7 expression along with oxidative stress markers elevated in GDM placenta. These elevated SIRT7 levels were positively correlated with BMI and triglycerides levels in GDM subjects. miR-125b-5p was identified to regulate SIRT7 mRNA using in-silico approaches. Expression levels of miR-125b-5p were found to be downregulated in GDM placenta and found to be negatively correlated with SIRT7 mRNA expression. To confirm the hypothesis BeWo cells were transfected with anti-miR-125b and miR-125b-mimic. Anti-miR overexpressed the SIRT7 expression where mimic dysregulated it. Additionally, overexpressing miR-125b-5p controlled the elevated SIRT7 caused by the exposure of high glucose in BeWo cells. Collectively this study indicated that miR-125b-5p may regulate lipid metabolism via SIRT7 contributing to GDM. These findings highlights the warrant of further research to develop the therapeutic approaches that target miR-125b-5p to reduce lipid accumulation and obesity in GDM.
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Affiliation(s)
- K L Milan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603 203, India
| | - M Anuradha
- Department of Obstetrics & Gynaecology, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu 603203, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603 203, India.
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Milan KL, Gayatri V, Kriya K, Sanjushree N, Vishwanathan Palanivel S, Anuradha M, Ramkumar KM. MiR-142-5p mediated Nrf2 dysregulation in gestational diabetes mellitus and its impact on placental angiogenesis. Placenta 2024; 158:192-199. [PMID: 39488088 DOI: 10.1016/j.placenta.2024.10.021] [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: 03/23/2024] [Revised: 08/23/2024] [Accepted: 10/23/2024] [Indexed: 11/04/2024]
Abstract
INTRODUCTION Gestational diabetes mellitus (GDM) presents significant risks during pregnancy, including adverse perinatal outcomes and placental dysfunction. Impaired angiogenesis, involving crucial factors like Vascular Endothelial Growth Factor (VEGF), contributes to these complications. The Nrf2/Keap1 pathway, crucial for vascular redox homeostasis, has been linked to GDM-associated angiogenesis dysregulation. METHODS This study aimed to investigate the molecular mechanisms underlying placental Nrf2 regulation, focusing on angiomiRs, key regulators of angiogenesis in GDM. Computational analysis identified miR-142-5p targeting Nrf2 mRNA. Expression levels of miR-142-5p were assessed in GDM placenta and correlated with Nrf2 expression. Experimental validation utilized human trophoblastic cell lines (BeWo) exposed to hyperglycemic conditions, assessing the effects of anti-miR-142 transfection on Nrf2 expression and angiogenic marker levels. RESULTS miR-142-5p expression was significantly downregulated in GDM placenta, correlating positively with Nrf2 expression. In BeWo cells exposed to hyperglycemia, anti-miR-142 transfection notably increased Nrf2 expression alongside angiogenic marker levels, confirming the computational predictions. DISCUSSION Our findings highlight the pivotal role of miRNAs in GDM-associated impaired angiogenesis by modulating Nrf2 expression. Understanding these molecular mechanisms provides insights into potential therapeutic targets for improving pregnancy outcomes in GDM cases.
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Affiliation(s)
- K L Milan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - V Gayatri
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Kumaran Kriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - N Sanjushree
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Sri Vishwanathan Palanivel
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - M Anuradha
- Department of Obstetrics & Gynaecology, SRM Medical College Hospital and Research Centre, Kattankulathur, 603203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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Ha SE, Singh R, Jin B, Baek G, Jorgensen BG, Zogg H, Debnath S, Park HS, Cho H, Watkins CM, Cho S, Kim MS, Lee MY, Yu TY, Jeong JW, Ro S. miR-10a/b-5p-NCOR2 Regulates Insulin-Resistant Diabetes in Female Mice. Int J Mol Sci 2024; 25:10147. [PMID: 39337631 PMCID: PMC11432729 DOI: 10.3390/ijms251810147] [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: 08/24/2024] [Revised: 09/14/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.
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Affiliation(s)
- Se Eun Ha
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Rajan Singh
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Byungchang Jin
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Gain Baek
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Brian G. Jorgensen
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Hannah Zogg
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Sushmita Debnath
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Hahn Sung Park
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Hayeong Cho
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Claudia Marie Watkins
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Sumin Cho
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Min-Seob Kim
- Department of Physiology, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Republic of Korea; (M.-S.K.); (M.Y.L.)
| | - Moon Young Lee
- Department of Physiology, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Republic of Korea; (M.-S.K.); (M.Y.L.)
| | - Tae Yang Yu
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea; (T.Y.Y.); (J.W.J.)
| | - Jin Woo Jeong
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea; (T.Y.Y.); (J.W.J.)
| | - Seungil Ro
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
- RosVivo Therapeutics, Applied Research Facility, 1664 N. Virginia St., Reno, NV 89557, USA
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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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Jin T, Wu L, Wang J, Wang X, He Z, Di W, Yang Q, Wei X. Exosomes derived from diabetic serum accelerate the progression of osteoarthritis. Arch Biochem Biophys 2024; 755:109960. [PMID: 38513770 DOI: 10.1016/j.abb.2024.109960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 03/23/2024]
Abstract
Diabetes mellitus (DM) has been demonstrated to accelerate the progression of osteoarthritis (OA) by largely unknown mechanisms. Studies have shown that DM dysfunctional adipocyte-derived exosomes play a crucial role in the pathogenesis of remote organ functions. The present study aimed to clarify whether and how diabetic adipocyte-derived exosomes mediate the pathological regulation of OA. We found that intraarticular injection of DM serum exosomes in the non-diabetic mice significantly exacerbated OA injury as evidenced by a rough and fractured cartilage surface as well as increased chondrocyte apoptosis, decreased mitochondrial membrane potential (△Ψ) and increased expression of cleaved caspase-3. Mechanistic investigation identified that miR-130b-3p was significantly increased in circulating exosomes derived from DM mice and exosomes derived from HG-treated normal adipocytes, and we demonstrated that transfection of miR-130b-3p mimics significantly exacerbated the mitochondrial function of chondrocytes. Our data also indicated that miR-130b-3p impaired the △Ψ, increased cleaved caspase-3 levels, and decreased the expression of 5'-adenosine monophosphate-activated protein kinase α1 (AMPKα1), Silent mating-type information regulation 2 homolog 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in chondrocytes. Pharmacologic activation of AMPKα1 using AICAR reversed the △Ψ and catabolic responses in chondrocytes transfected with miR-130b-3p mimics. Moreover, AICAR decreased the effects of miR-130b-3p mimics on chondrocytes transfected with SIRT1-siRNA or PGC-1α-siRNA. The current study demonstrated that adipocyte-derived exosomal miR-130b-3p under DM conditions suppresses mitochondrial function in chondrocytes through targeting the AMPKα1/SIRT1/PGC1-α pathway, thus exacerbating OA injury.
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Affiliation(s)
- Tao Jin
- First Clinical Medical College of Gansu University of Traditional Chinese Medicine, Gansu, 730000, PR China; Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China
| | - Lei Wu
- Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, 100000, PR China
| | - Jizu Wang
- Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China
| | - Xingbo Wang
- Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China
| | - Zongru He
- Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China
| | - Wenfei Di
- Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China
| | - Qingshan Yang
- Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China.
| | - Xiaodong Wei
- Department of Emergency, Gansu Provincial Hospital, Gansu, 730000, PR China.
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Mitra T, Gulati R, Ramachandran K, Rajiv R, Enninga EAL, Pierret CK, Kumari R S, Janardhanan R. Endocrine disrupting chemicals: gestational diabetes and beyond. Diabetol Metab Syndr 2024; 16:95. [PMID: 38664841 PMCID: PMC11046910 DOI: 10.1186/s13098-024-01317-9] [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: 10/15/2023] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Gestational Diabetes Mellitus (GDM) has been on the rise for the last two decades along with the growing incidence of obesity. The ubiquitous use of Endocrine-Disrupting Chemicals (EDCs) worldwide has been associated with this increase in GDM incidence. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation have been associated with prenatal exposure to EDCs. EDC exposure can also drive a sustained disruption of the hypothalamus-pituitary-thyroid axis and various other signaling pathways such as thyroid signaling, PPARγ signaling, PI3K-AKT signaling. This disruption leads to impaired glucose metabolism, insulin resistance as well as β-cell dysfunction, which culminate into GDM. Persistent EDC exposure in pregnant women also increases adipogenesis, which results in gestational weight gain. Importantly, pregnant mothers transfer these EDCs to the fetus via the placenta, thus leading to other pregnancy-associated complications such as intrauterine growth restriction (IUGR), and large for gestational age neonates. Furthermore, this early EDC exposure of the fetus increases the susceptibility of the infant to metabolic diseases in early life. The transgenerational impact of EDCs is also associated with higher vascular tone, cognitive aberrations, and enhanced susceptibility to lifestyle disorders including reproductive health anomalies. The review focuses on the impact of environmental toxins in inducing epigenetic alterations and increasing the susceptibility to metabolic diseases during pregnancy needs to be extensively studied such that interventions can be developed to break this vicious cycle. Furthermore, the use of EDC-associated ExomiRs from the serum of patients can help in the early diagnosis of GDM, thereby leading to triaging of patients based on increasing risk factor of the clinicopathological condition.
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Affiliation(s)
- Tridip Mitra
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Richa Gulati
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Krithika Ramachandran
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Rohan Rajiv
- Dietrich School of Arts and Sciences, University of Pittsburgh, 15260, Pittsburgh, PA, USA
| | | | - Chris K Pierret
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Sajeetha Kumari R
- Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India
| | - Rajiv Janardhanan
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, 603 203, Kattankulathur, Tamil Nadu, India.
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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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Li X, Han Y, Meng Y, Yin L. Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases. RNA Biol 2024; 21:1-20. [PMID: 38174992 PMCID: PMC10773649 DOI: 10.1080/15476286.2023.2293343] [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] [Revised: 09/21/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30-100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.
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Affiliation(s)
- Xiaqing Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan, China
| | - Yi Han
- Traditional Chinese Medicine Department, People’s Hospital of Yanjiang District, Ziyang, Sichuan, China
| | - Yu Meng
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan, China
| | - Lianghong Yin
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
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Diniz MS, Hiden U, Falcão-Pires I, Oliveira PJ, Sobrevia L, Pereira SP. Fetoplacental endothelial dysfunction in gestational diabetes mellitus and maternal obesity: A potential threat for programming cardiovascular disease. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166834. [PMID: 37541330 DOI: 10.1016/j.bbadis.2023.166834] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/08/2023] [Accepted: 07/27/2023] [Indexed: 08/06/2023]
Abstract
Gestational diabetes mellitus (GDM) and maternal obesity (MO) increase the risk of adverse fetal outcomes, and the incidence of cardiovascular disease later in life. Extensive research has been conducted to elucidate the underlying mechanisms by which GDM and MO program the offspring to disease. This review focuses on the role of fetoplacental endothelial dysfunction in programming the offspring for cardiovascular disease in GDM and MO pregnancies. We discuss how pre-existing maternal health conditions can lead to vascular dysfunction in the fetoplacental unit and the fetus. We also examine the role of fetoplacental endothelial dysfunction in impairing fetal cardiovascular system development and the involvement of nitric oxide and hydrogen sulfide in mediating fetoplacental vascular dysfunction. Furthermore, we suggest that the L-Arginine-Nitric Oxide and the Adenosine-L-Arginine-Nitric Oxide (ALANO) signaling pathways are pertinent targets for research. Despite significant progress in this area, there are still knowledge gaps that need to be addressed in future research.
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Affiliation(s)
- Mariana S Diniz
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Ph.D. Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
| | - Ursula Hiden
- Department of Obstetrics and Gynecology, Medical University of Graz, 8063 Graz, Austria; Research Unit Early Life Determinants (ELiD), Medical University of Graz, 8036 Graz, Austria
| | - Inês Falcão-Pires
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Luis Sobrevia
- Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; Medical School (Faculty of Medicine), São Paulo State University (UNESP), São Paulo, Brazil; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Australia; Tecnologico de Monterrey, Eutra, The Institute for Obesity Research (IOR), School of Medicine and Health Sciences, Monterrey, Nuevo León, Mexico.
| | - Susana P Pereira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal.
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11
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Sharma S, Bhonde R. Dilemma of Epigenetic Changes Causing or Reducing Metabolic Disorders in Offsprings of Obese Mothers. Horm Metab Res 2023; 55:665-676. [PMID: 37813098 DOI: 10.1055/a-2159-9128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
Maternal obesity is associated with fetal complications predisposing later to the development of metabolic syndrome during childhood and adult stages. High-fat diet seems to influence individuals and their subsequent generations in mediating weight gain, insulin resistance, obesity, high cholesterol, diabetes, and cardiovascular disorder. Research evidence strongly suggests that epigenetic alteration is the major contributor to the development of metabolic syndrome through DNA methylation, histone modifications, and microRNA expression. In this review, we have discussed the outcome of recent studies on the adverse and beneficial effects of nutrients and vitamins through epigenetics during pregnancy. We have further discussed about the miRNAs altered during maternal obesity. Identification of new epigenetic modifiers such as mesenchymal stem cells condition media (MSCs-CM)/exosomes for accelerating the reversal of epigenetic abnormalities for the development of new treatments is yet another aspect of the present review.
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Affiliation(s)
- Shikha Sharma
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Ramesh Bhonde
- Stem Cells and Regenerative Medicine, Dr. D. Y. Patil Vidyapeeth Pune (Deemed University), Pune, India
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12
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Goyal S, Rani J, Bhat MA, Vanita V. Genetics of diabetes. World J Diabetes 2023; 14:656-679. [PMID: 37383588 PMCID: PMC10294065 DOI: 10.4239/wjd.v14.i6.656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/13/2023] [Accepted: 04/17/2023] [Indexed: 06/14/2023] Open
Abstract
Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic, epigenetic, and environmental variables. It is one of the world's fastest-growing diseases, with 783 million adults expected to be affected by 2045. Devastating macrovascular consequences (cerebrovascular disease, cardiovascular disease, and peripheral vascular disease) and microvascular complications (like retinopathy, nephropathy, and neuropathy) increase mortality, blindness, kidney failure, and overall quality of life in individuals with diabetes. Clinical risk factors and glycemic management alone cannot predict the development of vascular problems; multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications. In the twenty-first century, technological advancements (genome-wide association studies, next-generation sequencing, and exome-sequencing) have led to the identification of genetic variants associated with diabetes, however, these variants can only explain a small proportion of the total heritability of the condition. In this review, we address some of the likely explanations for this "missing heritability", for diabetes such as the significance of uncommon variants, gene-environment interactions, and epigenetics. Current discoveries clinical value, management of diabetes, and future research directions are also discussed.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Jyoti Rani
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Mohd Akbar Bhat
- Department of Ophthalmology, Georgetown University Medical Center, Washington DC, DC 20057, United States
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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13
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Yan YS, Feng C, Yu DQ, Tian S, Zhou Y, Huang YT, Cai YT, Chen J, Zhu MM, Jin M. Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia. Front Nutr 2023; 10:1067282. [PMID: 37255932 PMCID: PMC10226394 DOI: 10.3389/fnut.2023.1067282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 04/06/2023] [Indexed: 06/01/2023] Open
Abstract
Diabetes mellitus during pregnancy, which can be classified into pregestational diabetes and gestational diabetes, has become much more prevalent worldwide. Maternal diabetes fosters an intrauterine abnormal environment for fetus, which not only influences pregnancy outcomes, but also leads to fetal anomaly and development of diseases in later life, such as metabolic and cardiovascular diseases, neuropsychiatric outcomes, reproduction malformation, and immune dysfunction. The underlying mechanisms are comprehensive and ambiguous, which mainly focus on microbiota, inflammation, reactive oxygen species, cell viability, and epigenetics. This review concluded with the influence of intrauterine hyperglycemia on fetal structure development and organ function on later life and outlined potential mechanisms that underpin the development of diseases in adulthood. Maternal diabetes leaves an effect that continues generations after generations through gametes, thus more attention should be paid to the prevention and treatment of diabetes to rescue the pathological attacks of maternal diabetes from the offspring.
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Affiliation(s)
- Yi-Shang Yan
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chun Feng
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dan-Qing Yu
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shen Tian
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yin Zhou
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi-Ting Huang
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi-Ting Cai
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Chen
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Miao-Miao Zhu
- Department of Operating Theatre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Min Jin
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
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14
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Juárez-Barber E, Segura-Benítez M, Carbajo-García MC, Bas-Rivas A, Faus A, Vidal C, Giles J, Labarta E, Pellicer A, Cervelló I, Ferrero H. Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy. Reprod Biomed Online 2023; 46:470-481. [PMID: 36697316 DOI: 10.1016/j.rbmo.2022.12.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
RESEARCH QUESTION Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility? DESIGN A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis. RESULTS miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli. CONCLUSIONS Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.
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Affiliation(s)
- Elena Juárez-Barber
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Marina Segura-Benítez
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, 46010 Valencia, Spain
| | - María Cristina Carbajo-García
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, 46010 Valencia, Spain
| | - Alba Bas-Rivas
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Amparo Faus
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Carmen Vidal
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Valencia, 46015 Valencia, Spain
| | - Juan Giles
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Valencia, 46015 Valencia, Spain
| | - Elena Labarta
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Valencia, 46015 Valencia, Spain
| | - Antonio Pellicer
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Rome, 00197 Rome, Italy
| | - Irene Cervelló
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Hortensia Ferrero
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain.
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15
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Analysis of serum circulating MicroRNAs level in Malaysian patients with gestational diabetes mellitus. Sci Rep 2022; 12:20295. [PMID: 36434110 PMCID: PMC9700700 DOI: 10.1038/s41598-022-23816-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/07/2022] [Indexed: 11/26/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a severe global issue that requires immediate attention. MicroRNA expression abnormalities are possibly disease-specific and may contribute to GDM pathological processes. To date, there is limited data on miRNA profiling in GDM, especially that involves a longitudinal study. Here, we performed miRNA expression profiling in the entire duration of pregnancy (during pregnancy until parturition and postpartum) using a miRNA- polymerase chain reaction array (miRNA-PCRArray) and in-silico analysis to identify unique miRNAs expression and their anticipated target genes in Malay maternal serum. MiRNA expression levels and their unique potential as biomarkers were explored in this work. In GDM patients, the expression levels of hsa-miR-193a, hsa-miR-21, hsa-miR-23a, and hsa-miR-361 were significantly increased, but miR-130a was significantly downregulated. The area under the curve (AUC) and receiver operating characteristic (ROC) curve study demonstrated that hsa-miR-193a (AUC = 0.89060 ± 04,470, P = 0.0001), hsa-miR-21 (AUC = 0.89500 ± 04,411, P = 0.0001), and miR-130a (AUC = 0.6939 ± 0.05845, P = 0.0025) had potential biomarker features in GDM. In-silico analysis also revealed that KLF (Kruppel-Like family of transcription factor), ZNF25 (Zinc finger protein 25), AFF4 (ALF transcription elongation factor 4), C1orf143 (long intergenic non-protein coding RNA 2869), SRSF2 (serine and arginine rich splicing factor 2), and ZNF655 (Zinc finger protein 655) were prominent genes targeted by the common nodes of miR23a, miR130, miR193a, miR21, and miR361.Our findings suggest that circulating microRNAs in the first trimester has the potential for GDM screening in the Malay population.
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16
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Luo W, Kim Y, Jensen ME, Herlea-Pana O, Wang W, Rudolph MC, Friedman JE, Chernausek SD, Jiang S. miR-130b/301b Is a Negative Regulator of Beige Adipogenesis and Energy Metabolism In Vitro and In Vivo. Diabetes 2022; 71:2360-2371. [PMID: 36001751 PMCID: PMC9630090 DOI: 10.2337/db22-0205] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022]
Abstract
Thermogenic brown or beige adipocytes dissipate energy in the form of heat and thereby counteract obesity and related metabolic complications. The miRNA cluster miR-130b/301b is highly expressed in adipose tissues and has been implicated in metabolic diseases as a posttranscriptional regulator of mitochondrial biogenesis and lipid metabolism. We investigated the roles of miR-130b/301b in regulating beige adipogenesis in vivo and in vitro. miR-130b/301b declined in adipose progenitor cells during beige adipogenesis, while forced overexpression of miR-130b-3p or miR-301b-3p suppressed uncoupling protein 1 (UCP1) and mitochondrial respiration, suggesting that a decline in miR-130b-3p or miR-301b-3p is required for adipocyte precursors to develop the beige phenotype. Mechanistically, miR-130b/301b directly targeted AMP-activated protein kinase (AMPKα1) and suppressed peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α), key regulators of brown adipogenesis and mitochondrial biogenesis. Mice lacking the miR-130b/301b miRNA cluster showed reduced visceral adiposity and less weight gain. miR-130b/301b null mice exhibited improved glucose tolerance, increased UCP1 and AMPK activation in subcutaneous fat (inguinal white adipose tissue [iWAT]), and increased response to cold-induced energy expenditure. Together, these data identify the miR-130b/301b cluster as a new regulator that suppresses beige adipogenesis involving PGC-1α and AMPK signaling in iWAT and is therefore a potential therapeutic target against obesity and related metabolic disorders.
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Affiliation(s)
- Wenyi Luo
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Youngsil Kim
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Mary Ellen Jensen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Oana Herlea-Pana
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Weidong Wang
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Michael C. Rudolph
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Steven D. Chernausek
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Section of Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Shaoning Jiang
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Section of Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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17
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Pandey A, Ajgaonkar S, Jadhav N, Saha P, Gurav P, Panda S, Mehta D, Nair S. Current Insights into miRNA and lncRNA Dysregulation in Diabetes: Signal Transduction, Clinical Trials and Biomarker Discovery. Pharmaceuticals (Basel) 2022; 15:1269. [PMID: 36297381 PMCID: PMC9610703 DOI: 10.3390/ph15101269] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/27/2022] [Accepted: 10/09/2022] [Indexed: 01/24/2023] Open
Abstract
Diabetes is one of the most frequently occurring metabolic disorders, affecting almost one tenth of the global population. Despite advances in antihyperglycemic therapeutics, the management of diabetes is limited due to its complexity and associated comorbidities, including diabetic neuropathy, diabetic nephropathy and diabetic retinopathy. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are involved in the regulation of gene expression as well as various disease pathways in humans. Several ncRNAs are dysregulated in diabetes and are responsible for modulating the expression of various genes that contribute to the 'symptom complex' in diabetes. We review various miRNAs and lncRNAs implicated in diabetes and delineate ncRNA biological networks as well as key ncRNA targets in diabetes. Further, we discuss the spatial regulation of ncRNAs and their role(s) as prognostic markers in diabetes. We also shed light on the molecular mechanisms of signal transduction with diabetes-associated ncRNAs and ncRNA-mediated epigenetic events. Lastly, we summarize clinical trials on diabetes-associated ncRNAs and discuss the functional relevance of the dysregulated ncRNA interactome in diabetes. This knowledge will facilitate the identification of putative biomarkers for the therapeutic management of diabetes and its comorbidities. Taken together, the elucidation of the architecture of signature ncRNA regulatory networks in diabetes may enable the identification of novel biomarkers in the discovery pipeline for diabetes, which may lead to better management of this metabolic disorder.
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Affiliation(s)
| | | | | | - Praful Saha
- Viridis Biopharma Pvt. Ltd., Mumbai 400 022, India
| | - Pranay Gurav
- Viridis Biopharma Pvt. Ltd., Mumbai 400 022, India
| | | | - Dilip Mehta
- Synergia Life Sciences Pvt. Ltd., Mumbai 400 022, India
| | - Sujit Nair
- Viridis Biopharma Pvt. Ltd., Mumbai 400 022, India
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18
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Cardiovascular Disease-Associated MicroRNAs as Novel Biomarkers of First-Trimester Screening for Gestational Diabetes Mellitus in the Absence of Other Pregnancy-Related Complications. Int J Mol Sci 2022; 23:ijms231810635. [PMID: 36142536 PMCID: PMC9501303 DOI: 10.3390/ijms231810635] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM.
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19
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Sharma AK, Singh S, Singh H, Mahajan D, Kolli P, Mandadapu G, Kumar B, Kumar D, Kumar S, Jena MK. Deep Insight of the Pathophysiology of Gestational Diabetes Mellitus. Cells 2022; 11:2672. [PMID: 36078079 PMCID: PMC9455072 DOI: 10.3390/cells11172672] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 12/19/2022] Open
Abstract
Diabetes mellitus is a severe metabolic disorder, which consistently requires medical care and self-management to restrict complications, such as obesity, kidney damage and cardiovascular diseases. The subtype gestational diabetes mellitus (GDM) occurs during pregnancy, which severely affects both the mother and the growing foetus. Obesity, uncontrolled weight gain and advanced gestational age are the prominent risk factors for GDM, which lead to high rate of perinatal mortality and morbidity. In-depth understanding of the molecular mechanism involved in GDM will help researchers to design drugs for the optimal management of the condition without affecting the mother and foetus. This review article is focused on the molecular mechanism involved in the pathophysiology of GDM and the probable biomarkers, which can be helpful for the early diagnosis of the condition. The early diagnosis of the metabolic disorder, most preferably in first trimester of pregnancy, will lead to its effective long-term management, reducing foetal developmental complications and mortality along with safety measures for the mother.
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Affiliation(s)
- Amarish Kumar Sharma
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Sanjeev Singh
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Himanshu Singh
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Deviyani Mahajan
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Prachetha Kolli
- Microgen Health Inc., 14225 Sullyfield Cir Suite E, Chantilly, VA 20151, USA
| | | | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Dharmendra Kumar
- Animal Physiology and Reproduction Division, ICAR-Central Institute for Research on Buffaloes, Hisar 125001, Haryana, India
| | - Sudarshan Kumar
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal 132001, Haryana, India
| | - Manoj Kumar Jena
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
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Gao Z, Wang N, Liu X. Human placenta mesenchymal stem cell-derived exosome shuttling microRNA-130b-3p from gestational diabetes mellitus patients targets ICAM-1 and perturbs human umbilical vein endothelial cell angiogenesis. Acta Diabetol 2022; 59:1091-1107. [PMID: 35676597 DOI: 10.1007/s00592-022-01910-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/18/2022] [Indexed: 11/01/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the roles of miR-130b-3p and ICAM-1 in gestational diabetes mellitus (GDM) and their potential association. METHODS Human placenta mesenchymal stem cells (PlaMSCs) were isolated from GDM patients, and the effects of the PlaMSCs from GDM patients (GDM-MSCs) and the exosomes secreted by GDM-MSCs on human umbilical vein endothelial cell (HUVEC) proliferation, migration, and angiogenesis were detected. Next, GDM-MSCs were transfected with miR-130b-3p antagomir to modify miR-130b-3p expression in GDM-MSCs-derived exosomes, and the exosomes with modified miR-130b-3p expression were cultured with HUVECs to evaluate exosomal miR-130b-3p on HUVEC function. Furthermore, a target gene of miR-130b-3p was predicted and assessed. The miR-130b-3p-modified exosomes were cultured with HUVECs transfected with ICAM-1 shRNA to determine the effect of miR-130b-3p-ICAM-1 crosstalk on HUVEC function. Additionally, a GDM mouse model was conducted to further study the effect of miR-130b-3p in GDM in vivo. RESULTS GDM-MSCs inhibited HUVEC proliferation and angiogenesis. The elevated expression of miR-130b-3p was found in GDM-MSCs-derived exosomes. GDM-MSCs-derived exosomes repressed the proliferation and angiogenesis of HUVECs and miR-130b-3p inhibition could restrain the inhibition of the exosomes on HUVEC function. Mechanistically, miR-130b-3p downregulated ICAM-1 expression in a targeted manner, and thereby enhanced HUVEC proliferation, migration, and angiogenesis and increased the expression of angiogenesis-related factors. Moreover, miR-130b-3p inhibition promoted placental angiogenesis in GDM mice and upregulated ICAM-1 expression. CONCLUSION Conclusively, GDM-MSCs-derived exosomes shuttling miR-130b-3p repressed proliferation, migration, and angiogenesis of HUVECs by regulating ICAM-1 expression.
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Affiliation(s)
- Zhou Gao
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Nan Wang
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Xinli Liu
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China.
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21
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Bhushan R, Rani A, Gupta D, Ali A, Dubey PK. MicroRNA-7 regulates insulin signaling pathway by targeting IRS1, IRS2, and RAF1 genes in gestational diabetes mellitus. Microrna 2022; 11:57-72. [PMID: 35422233 DOI: 10.2174/2211536611666220413100636] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/19/2021] [Accepted: 02/08/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Small non-coding micro RNAs (miRNAs) are indicated in various metabolic processes and play a critical role in disease pathology, including gestational diabetes mellitus (GDM). OBJECTIVE The purpose of this study was to examine the altered expression of miRNAs and their target genes in placental tissue (PL), cord blood (CB), and maternal blood (MB) of matched non-glucose tolerant (NGT) and GDM mother. METHODS In a case-control study, micro-RNA was quantified from forty-five serum (MB n = 15, CB n = 15, and PL n = 15) and matched placental tissue using stem-loop RT-qPCR followed by target prediction, network construction and functional and pathways enrichment analysis. Further, target genes were verified in-vitro through transfection and RT-qPCR. RESULTS Five miRNAs, namely hsa-let 7a-5P, hsa-miR7-5P, hsa-miR9-5P, hsa-miR18a-5P, and hsa-miR23a-3P were significantly over-expressed (p < 0.05) in all three samples namely PL, CB, and MB of GDM patients. However, the sample-wise comparison reveals higher expression of miRNA 7 in MB while lowest in CB than control. Furthermore, a comparison of fold change expression of target genes discloses a lower expression of IRS1, IRS2, and RAF1 in MB while comparatively higher expression of NRAS in MB and CB. In-vitro validation reveals lower expression of IRS1/2 and RAF1 in response to overexpression of miR-7 and vice-versa. Thus it is evident that increased miRNA7 expression causes down-regulation of its target genes IRS1, IRS2, and RAF1 in GDM mother compared to control. Further, target prediction, pathway enrichment, and hormone analysis (significantly higher FSH & LH in MB of GDM compared to NGT) revealed the insulin signaling, inflammatory and GnRH signaling as major pathways regulated by miRNA7. CONCLUSIONS Thus, an elevated level of miRNA7 may be associated with the progression of GDM by altering the multiple pathways like insulin, GnRH, and inflammatory signaling pathways via targeting IRS1, IRS2, and RAF1, implicating a new therapeutic target for GDM.
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Affiliation(s)
- Ravi Bhushan
- Centre for Genetic Disorders, Institute of Science, Banaras Hindu University Varanasi 221005, Uttar Pradesh, India
| | - Anjali Rani
- Department of Obstetrics and Gynecology, Institute of Medical Science, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Deepali Gupta
- Department of Obstetrics and Gynecology, Ashirwad Hospital, Varanasi 221005, Uttar Pradesh, India
| | - Akhtar Ali
- Centre for Genetic Disorders, Institute of Science, Banaras Hindu University Varanasi 221005, Uttar Pradesh, India
| | - Pawan K Dubey
- Centre for Genetic Disorders, Institute of Science, Banaras Hindu University Varanasi 221005, Uttar Pradesh, India
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Filardi T, Catanzaro G, Grieco GE, Splendiani E, Trocchianesi S, Santangelo C, Brunelli R, Guarino E, Sebastiani G, Dotta F, Morano S, Ferretti E. Identification and Validation of miR-222-3p and miR-409-3p as Plasma Biomarkers in Gestational Diabetes Mellitus Sharing Validated Target Genes Involved in Metabolic Homeostasis. Int J Mol Sci 2022; 23:ijms23084276. [PMID: 35457094 PMCID: PMC9028517 DOI: 10.3390/ijms23084276] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/16/2022] Open
Abstract
Gestational diabetes mellitus (GDM) causes both maternal and fetal adverse outcomes. The deregulation of microRNAs (miRNAs) in GDM suggests their involvement in GDM pathogenesis and complications. Exosomes are extracellular vesicles (EVs) of endosomal origin, released via exocytosis into the extracellular compartment. Through EVs, miRNAs are delivered in distant target cells and are able to affect gene expression. In this study, miRNA expression was analyzed to find new miRNAs that could improve GDM classification and molecular characterization. MiRNA were profiled in total plasma and EVs in GDM patients and normal glucose tolerance (NGT) women. Samples were collected at third trimester of gestation from two diabetes centers. MiRNA expression was profiled in a discovery cohort using the multiplexed NanoString nCounter Human v3 miRNA. Validation analysis was performed in a second independent cohort using RT-qPCR. A set of miRNAs resulted to be differentially expressed (DE) in total plasma and EVs in GDM. Among them, total plasma miR-222-3p and miR-409-3p were validated in the independent cohort. MiR-222-3p levels correlated with fasting plasma glucose (FPG) (p < 0.001) and birth weight (p = 0.012), whereas miR-409-3p expression correlated with FPG (p < 0.001) and inversely with gestational age (p = 0.001). The major validated target genes of the deregulated miRNAs were consistently linked to type 2 diabetes and GDM pathophysiology. MiR-222-3p and miR-409-3p are two circulating biomarkers that could improve GDM classification power and act in the context of the molecular events leading to the metabolic alterations observed in GDM.
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Affiliation(s)
- Tiziana Filardi
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
| | - Giuseppina Catanzaro
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
- Correspondence:
| | - Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (G.S.); (F.D.)
- Fondazione Umberto di Mario, Toscana Life Sciences, 53100 Siena, Italy
| | - Elena Splendiani
- Department of Molecular Medicine, “Sapienza” University, 00161 Rome, Italy; (E.S.); (S.T.)
| | - Sofia Trocchianesi
- Department of Molecular Medicine, “Sapienza” University, 00161 Rome, Italy; (E.S.); (S.T.)
| | - Carmela Santangelo
- Center for Gender-Specific Medicine, Gender Specific Prevention and Health Unit, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Roberto Brunelli
- Maternal and Child Health and Urological Sciences, “Sapienza” University, 00161 Rome, Italy;
| | - Elisa Guarino
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (G.S.); (F.D.)
- Fondazione Umberto di Mario, Toscana Life Sciences, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (G.S.); (F.D.)
- Fondazione Umberto di Mario, Toscana Life Sciences, 53100 Siena, Italy
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
- Tuscany Centre for Precision Medicine (CReMeP), 53100 Siena, Italy
| | - Susanna Morano
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
| | - Elisabetta Ferretti
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
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Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis. Int J Mol Sci 2022; 23:ijms23073514. [PMID: 35408874 PMCID: PMC8998752 DOI: 10.3390/ijms23073514] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 11/16/2022] Open
Abstract
One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.
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24
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li X, Dong Z, chang H, zhou H, Wang J, Yang Z, Min Q, Bai W, Shi S. Screening and identification of key microRNAs and regulatory pathways associated with renal fibrosis process. Mol Omics 2022; 18:520-533. [DOI: 10.1039/d1mo00498k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To reveal the pathogenesis of renal fibrosis. Renal fibrosis was induced with unilateral ureteral obstruction (UUO). Related biochemical indices in rat serum were determined, and histopathological morphology observed. Tissue transcriptome...
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25
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Kochhar P, Dwarkanath P, Ravikumar G, Thomas A, Crasta J, Thomas T, Kurpad AV, Mukhopadhyay A. Placental expression of RNU44, RNU48 and miR-16-5p: stability and relations with fetoplacental growth. Eur J Clin Nutr 2021; 76:722-729. [PMID: 34508256 DOI: 10.1038/s41430-021-01003-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 08/04/2021] [Accepted: 08/24/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND/OBJECTIVES The current study aimed to identify suitable reference miRNA for placental miRNA expression analysis in a set of well-characterized and fetal-sex balanced small- (SGA) and appropriate- (AGA) for gestational age full-term singleton pregnancies. SUBJECTS/METHODS In this retrospective study, placental samples (n = 106) from 35 SGA (19 male and 16 female) and 71 AGA (30 male and 41 female) full-term singleton pregnancies were utilized. Placental transcript abundance of three widely used reference miRNAs [miR-16-5p and Small nucleolar RNAs (snoRNAs) RNU44 and RNU48] were assessed by real-time quantitative PCR. Raw cycle threshold (Ct) analysis and RefFinder tool analysis were conducted for evaluating stability of expression of these miRNAs. RESULTS Raw Ct values of miR-16-5p were similar between SGA and AGA births (P = 0.140) and between male and female births within SGA (P = 0.159) and AGA (P = 0.060) births while that of RNU44 and RNU48 were higher in SGA births (P = 0.008 and 0.006 respectively) and in male births within the SGA group (P = 0.005) for RNU44 and in female births within the AGA group (P = 0.048) for RNU48. Across all 106 samples tested using the RefFinder tool, miR-16-5p and RNU44 were equally stable reference miRNAs. CONCLUSION We recommend miR-16-5p and RNU44 as suitable reference miRNAs for placental samples from settings similar to our study.
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Affiliation(s)
- P Kochhar
- Division of Nutrition, St. John's Research Institute, A recognized research centre of University of Mysore, Bangalore, Karnataka, India
| | - P Dwarkanath
- Division of Nutrition, St. John's Research Institute, A recognized research centre of University of Mysore, Bangalore, Karnataka, India
| | - G Ravikumar
- Department of Pathology, St John's Medical College Hospital, Bangalore, Karnataka, India
| | - A Thomas
- Department of Obstetrics and Gynaecology, St John's Medical College Hospital, Bangalore, Karnataka, India
| | - J Crasta
- Department of Pathology, St John's Medical College Hospital, Bangalore, Karnataka, India
| | - T Thomas
- Department of Biostatistics, St. John's Medical College Hospital, Bangalore, Karnataka, India
| | - A V Kurpad
- Division of Nutrition, St. John's Research Institute, A recognized research centre of University of Mysore, Bangalore, Karnataka, India
| | - A Mukhopadhyay
- Division of Nutrition, St. John's Research Institute, A recognized research centre of University of Mysore, Bangalore, Karnataka, India.
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Léniz A, Martínez-Maqueda D, Fernández-Quintela A, Pérez-Jiménez J, Portillo MP. Potential Relationship between the Changes in Circulating microRNAs and the Improvement in Glycaemic Control Induced by Grape Pomace Supplementation. Foods 2021; 10:foods10092059. [PMID: 34574169 PMCID: PMC8470177 DOI: 10.3390/foods10092059] [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: 06/30/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 12/01/2022] Open
Abstract
MicroRNAs (miRNAs) represent important tools in medicine and nutrition as new biomarkers, and can act as mediators of nutritional and pharmacological interventions. The aim of the present study was to analyse the effect of grape pomace supplementation on the expression of seven selected miRNAs and their potential relationship with the observed positive effect on glycaemic control, in order to shed light on the mechanism underlying the beneficial effect of this dietary intervention. For this purpose, plasma samples were obtained from 49 subjects with metabolic syndrome. After supplementation with grape pomace (6 weeks), these subjects were categorised as responders (n = 23) or non-responders (n = 26) according to the changes in their fasting insulin rate. MiRNA expression at baseline and at the end of the supplementation was analysed by RT-PCR, and the MiRecords Database was used to identify potential target genes for the studied miRNAs. The increase observed in miR-23a in the whole cohort was present in both subgroups of participants. The increase in miR-181a was significant among non-responders but not responders. The decrease in miR-30c and miR-222 was found in the responders, but not in the non-responders. No changes were observed in miR-10a, miR-151a, miR-181a, and miR-let-7a expressions. After analysing these results, a potential involvement of the reduced expression of miR-30c and miR-222, two microRNAs associated with insulin resistance and diabetes, in the improvement of glycaemic control produced by grape pomace administration, can be proposed. Further research is needed to confirm the involvement of glycolytic enzymes, PI3K, AMPK, and IRS-1 in the effect of grape pomace, as suggested by the changes induced in microRNAs.
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Affiliation(s)
- Asier Léniz
- Araba Integrated Health Care Organization, Basque Health Service (Osakidetza), 01006 Vitoria-Gasteiz, Spain;
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
- Nutrition and Obesity Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain
| | - Daniel Martínez-Maqueda
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), José Antonio Novais 10, 28040 Madrid, Spain; (D.M.-M.); (J.P.-J.)
- Department of Agrifood Research, Madrid Institute for Rural, Agricultural and Food Research and Development (IMIDRA), A-2 Km. 38.2, 28805 Alcalá de Henares, Spain
| | - Alfredo Fernández-Quintela
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
- Nutrition and Obesity Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain
- Correspondence: ; Tel.: +34-945-013-066; Fax: +34-945-013-014
| | - Jara Pérez-Jiménez
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), José Antonio Novais 10, 28040 Madrid, Spain; (D.M.-M.); (J.P.-J.)
| | - María P. Portillo
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
- Nutrition and Obesity Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain
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Song F, Cai A, Ye Q, Chen X, Lin L, Hao X. MiR-34b-3p Impaired HUVECs Viability and Migration via Targeting PDK1 in an In Vitro Model of Gestational Diabetes Mellitus. Biochem Genet 2021; 59:1381-1395. [PMID: 33856598 DOI: 10.1007/s10528-021-10064-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 03/25/2021] [Indexed: 12/28/2022]
Abstract
Gestational diabetes mellitus (GDM) leads to poor pregnancy outcomes. The methods for GDM early diagnosis and treatment are still unknown. This study aimed to investigate the expression and diagnostic potential of miR-34b-3p in GDM patients and further analyzed the effects of miR-34b-3p on HUVECs viability and migration. The expression of miR-34b-3p was detected in HUVECs of GDM and normal pregnant women by qRT-PCR. Then the HUVECs were isolated from normal pregnant women. High glucose (HG) was used to treat the HUVECs to mimic the GDM in vitro. The cell viability and migration were determined by MTT, wound healing assay, and transwell assay. The interaction between miR-34b-3p and PDK1 was evaluated by luciferase activity assay. Our results showed that miR-34b-3p was up-regulated in HUVECs of GDM patients. Then the HUVECs were isolated from normal pregnant women and they were treated with HG to mimic the GDM in vitro. Interestingly, knockdown of miR-34b-3p restored the impairment of HG treatment-induced effects in HUVECs. More importantly, PDK1 was proved to be a potential target of miR-34b-3p. Finally, the rescue experiments confirmed that miR-34b-3p impaired cell viability and migration ability in HUVECs by targeting PDK1. These findings concluded that miR-34b-3p impaired HUVECs viability and migration in GDM by targeting PDK1, which might provide a novel perspective for the pathogenesis and underlying therapeutic target for GDM.
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Affiliation(s)
- Feiluan Song
- Department of Obstetrics and Gynecology, Ruian People's Hospital, No. 108 Wansong Road, Yuhai Street, Ruian City, Wenzhou City, 325200, Zhejiang Province, China
| | - Anli Cai
- Department of Obstetrics and Gynecology, Ruian People's Hospital, No. 108 Wansong Road, Yuhai Street, Ruian City, Wenzhou City, 325200, Zhejiang Province, China.
| | - Qianwen Ye
- Department of Obstetrics and Gynecology, Ruian People's Hospital, No. 108 Wansong Road, Yuhai Street, Ruian City, Wenzhou City, 325200, Zhejiang Province, China
| | - Xiang Chen
- Department of Obstetrics and Gynecology, Ruian People's Hospital, No. 108 Wansong Road, Yuhai Street, Ruian City, Wenzhou City, 325200, Zhejiang Province, China
| | - Lin Lin
- Department of Obstetrics and Gynecology, Ruian People's Hospital, No. 108 Wansong Road, Yuhai Street, Ruian City, Wenzhou City, 325200, Zhejiang Province, China
| | - Xi Hao
- Department of Obstetrics and Gynecology, Ruian People's Hospital, No. 108 Wansong Road, Yuhai Street, Ruian City, Wenzhou City, 325200, Zhejiang Province, China
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Shah KB, Chernausek SD, Teague AM, Bard DE, Tryggestad JB. Maternal diabetes alters microRNA expression in fetal exosomes, human umbilical vein endothelial cells and placenta. Pediatr Res 2021; 89:1157-1163. [PMID: 32663836 PMCID: PMC7854929 DOI: 10.1038/s41390-020-1060-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/28/2020] [Accepted: 06/22/2020] [Indexed: 11/14/2022]
Abstract
BACKGROUND Exposure to diabetes in utero influences future metabolic health of the offspring. MicroRNAs (miRNA) are small noncoding RNAs that may contribute mechanistically to the effects on offspring imparted by diabetes mellitus (DM) during pregnancy. We hypothesized that exposure to DM during pregnancy influences select miRNAs in fetal circulation, in human umbilical vein endothelial cells (HUVEC), and placenta. METHODS miRNA abundance was quantified using real-time PCR from RNA isolated from umbilical cord serum exosomes, HUVEC, and placenta exposed to diabetes or normoglycemia during pregnancy. The abundance of each of these miRNAs was determined by comparison to a known standard and the relative expression assessed using the 2-ΔΔCt method. Multivariable regression models examined the associations between exposure to diabetes during pregnancy and miRNA expression. RESULTS miR-126-3p was highly abundant in fetal circulation, HUVEC, and placenta. Diabetes exposure during pregnancy resulted in lower expression of miR-148a-3p and miR-29a-3p in the HUVEC. In the placenta, for miR-126-3p, there was a differential effect of DM by birth weight between DM versus control group, expression being lower at the lower birth weight, however not different at the higher birth weight. CONCLUSION Exposure to DM during pregnancy alters miRNA expression in the offspring in a tissue-specific manner. IMPACT miRNAs are differentially expressed in fetal tissues from offspring exposed to in utero diabetes mellitus compared to those who were not exposed. miRNA expression differs among tissue types (human umbilical vein endothelial cells, placenta and circulation exosomes) and response to diabetes exposure varies according to tissue of origin. miRNA expression is also affected by maternal and infant characteristics such as infant birth weight, infant sex, maternal age, and maternal BMI. miRNAs might be one of the potential mechanisms by which offspring's future metabolic status may be influenced by maternal diabetes mellitus.
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Affiliation(s)
- Kruti B Shah
- Department of Pediatrics, Section of Diabetes/Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Steven D Chernausek
- Department of Pediatrics, Section of Diabetes/Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - April M Teague
- Department of Pediatrics, Section of Diabetes/Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - David E Bard
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jeanie B Tryggestad
- Department of Pediatrics, Section of Diabetes/Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Harold Hamm Diabetes Center, Oklahoma City, OK, USA.
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Human Milk Exosomal MicroRNA: Associations with Maternal Overweight/Obesity and Infant Body Composition at 1 Month of Life. Nutrients 2021; 13:nu13041091. [PMID: 33801634 PMCID: PMC8066780 DOI: 10.3390/nu13041091] [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: 02/26/2021] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 12/11/2022] Open
Abstract
Among all the body fluids, breast milk is one of the richest sources of microRNAs (miRNAs). MiRNAs packaged within the milk exosomes are bioavailable to breastfeeding infants. The role of miRNAs in determining infant growth and the impact of maternal overweight/obesity on human milk (HM) miRNAs is poorly understood. The objectives of this study were to examine the impact of maternal overweight/obesity on select miRNAs (miR-148a, miR-30b, miR-29a, miR-29b, miR-let-7a and miR-32) involved in adipogenesis and glucose metabolism and to examine the relationship of these miRNAs with measures of infant body composition in the first 6 months of life. Milk samples were collected from a cohort of 60 mothers (30 normal-weight [NW] and 30 overweight [OW]/obese [OB]) at 1-month and a subset of 48 of these at 3 months of lactation. Relative abundance of miRNA was determined using real-time PCR. The associations between the miRNAs of interest and infant weight and body composition at one, three, and six months were examined after adjusting for infant gestational age, birth weight, and sex. The abundance of miR-148a and miR-30b was lower by 30% and 42%, respectively, in the OW/OB group than in the NW group at 1 month. miR-148a was negatively associated with infant weight, fat mass, and fat free mass, while miR-30b was positively associated with infant weight, percent body fat, and fat mass at 1 month. Maternal obesity is negatively associated with the content of select miRNAs in human milk. An association of specific miRNAs with infant body composition was observed during the first month of life, suggesting a potential role in the infant's adaptation to enteral nutrition.
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Lin X, Han L, Gu C, Lai Y, Lai Q, Li Q, He C, Meng Y, Pan L, Liu S, Li A. MiR-452-5p promotes colorectal cancer progression by regulating an ERK/MAPK positive feedback loop. Aging (Albany NY) 2021; 13:7608-7626. [PMID: 33658394 PMCID: PMC7993669 DOI: 10.18632/aging.202657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND MiR-452-5p plays an essential role in the development of a variety of tumors, but little is known about its biological function and mechanism in colorectal cancer (CRC). METHODS The expression levels of miR-452-5p in CRC tissues and cells were detected by real-time quantitative PCR (qRT-PCR). Besides, the biological effects of miR-452-5p on CRC were investigated by functional experiments in vitro and in vivo. Furthermore, bioinformatics analysis, dual-luciferase reporter assay, chromatin immunecipitation assay, western blotting and recovery experiments were implemented to investigate the underlying molecular mechanism. RESULTS The expression level of miR-452-5p was up-regulated in CRC tissues. MiR-452-5p promoted CRC cell proliferation, cell cycle transition and chemoresistance, and inhibited cell apoptosis. Moreover, miR-452-5p directly targeted PKN2 and DUSP6 and subsequently activated the ERK/MAPK signaling pathway, and it was transcriptionally regulated by c-Jun. CONCLUSION To conclude, miR-452-5p expression is up-regulated in CRC, which promotes the progression of CRC by activating the miR-452-5p-PKN2/DUSP6-c-Jun positive feedback loop. These findings indicate that miR-452-5p may act as a potential therapeutic target and clinical response biomarker for CRC.
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Affiliation(s)
- Xin Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Lu Han
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Chuncai Gu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Yihong Lai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Qiuhua Lai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Qingyuan Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Chengcheng He
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Yan Meng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Lei Pan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
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Liu L, Zhang J, Liu Y. MicroRNA-1323 serves as a biomarker in gestational diabetes mellitus and aggravates high glucose-induced inhibition of trophoblast cell viability by suppressing TP53INP1. Exp Ther Med 2021; 21:230. [PMID: 33603839 PMCID: PMC7851622 DOI: 10.3892/etm.2021.9661] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 12/14/2020] [Indexed: 12/21/2022] Open
Abstract
Gestational diabetes mellitus (GDM) leads to poor pregnancy outcomes, and microRNAs (miRNAs/miRs) have been suggested to be associated with GDM, but the pathological mechanisms remain unclear. The present study aimed to investigate the diagnostic value of miR-1323 in GDM patients and its effects on trophoblast cell viability. Additionally, the present study investigated the correlation between miR-1323 and TP53INP1 to understand the pathological mechanism of GDM progression. Reverse transcription-quantitative polymerase chain reaction was used to detect the miR-1323 expression and TP53INP1 mRNA expression. The diagnostic value of serum miR-1323 was evaluated by receiver operating characteristic analysis. HTR-8/SVneo and BeWo cells were treated with high glucose (HG) to construct cell models of GDM, and trophoblast cell viability was assessed using an MTT assay. The protein expression of TP53INP1 was detected by western blot analysis. The correlation between miR-1323 and TP53INP1 was investigated by luciferase reporter assay. The miR-1323 expression was increased in patients with GDM, which had relatively high diagnostic accuracy for GDM screening and was positively correlated with fasting blood glucose in patients GDM. HG upregulated the miR-1323 expression and inhibited trophoblast cell viability. Overexpression of miR-1323 significantly inhibited the viability of HG-induced trophoblast cells. TP53INP1, a target gene of miR-1323, was negatively correlated with miR-1323. TP53INP1 overexpression reversed the inhibitory effect of miR-1323 overexpression on the viability of HG-treated trophoblast cells. Increased levels of serum miR-1323 may be a diagnostic biomarker for GDM. Additionally, miR-1323 may inhibit trophoblast cell viability by inhibiting TP53INP1, suggesting that it may be a potential therapeutic target for GDM.
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Affiliation(s)
- Lijun Liu
- Department of Gynecology, Weifang Maternal and Child Health Hospital, Weifang, Shandong 261011, P.R. China
| | - Jun Zhang
- Department of Pharmacy, Weifang Maternal and Child Health Hospital, Weifang, Shandong 261011, P.R. China
| | - Yujuan Liu
- Department of Central Supply Room, Weifang Maternal and Child Health Hospital, Weifang, Shandong 261011, P.R. China
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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: 13] [Impact Index Per Article: 3.3] [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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Liu J, Song G, Meng T, Zhao G, Si S. The effect of gestational diabetes on identification of key genes and pathways in human umbilical vein endothelial cell by integrated bioinformatics analysis. J OBSTET GYNAECOL 2020; 41:881-887. [PMID: 33228420 DOI: 10.1080/01443615.2020.1819211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Maternal diabetes may lead to long-term risks for the offspring. The study aims at identifying the potential crucial genes and pathways associated with foetal metabolism and malformation of gestational diabetes mellitus (GDM). Gene Expression Series 49524 and 87295 were downloaded from Gene Expression Omnibus database, including eight from GDM and eight from non-GDM. A total of 35 differentially expressed genes were identified. Gene ontology functional annotation and signalling pathway analyses were performed. Four hub genes were identified by protein-protein interaction network: SHH, E2F1, STAT1, and HOXA9. The four hub genes were assessed by western blot and real-time quantitative PCR in clinical samples. The results of this data mining and integration help to reveal the pathophysiologic and molecular mechanism imprinted in primary umbilical cord-derived cells from GDM offspring. These genes and pathways identified are potential stratification biomarkers and provide further insight for developing therapeutic intervention for the offspring of diabetic mothers.Impact statementWhat is already known on this subject? Maternal diabetes may lead to long-term risks for the offspring. A high glucose environment might change the umbilical cord expression of genes implicated in foetal metabolism and development. However, underlying molecular mechanisms have not been investigated thoroughly.What do the results of this study add? GO functional annotation showed that the biological functions of differentially expressed genes mainly involved in metanephros development, salivary gland morphogenesis, fat cell differentiation, vasculogenesis, muscle cell proliferation, heart morphogenesis and Wnt signalling pathway. Signalling pathway analyses found that these differentially expressed genes mainly implicated in the apoptosis, cell cycle, Hedgehog, P53, and NOTCH signalling pathway. Four hub genes were identified by protein-protein interaction network: SHH, E2F1, STAT1 and HOXA9.What are the implications of these findings for clinical practice and/or further research? The genes and pathways identified in the present study are potential stratification biomarkers and provide further insight for developing therapeutic intervention for the offspring of diabetic mothers.
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Affiliation(s)
- Jing Liu
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Guang Song
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tao Meng
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ge Zhao
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Si Si
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, 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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Mandala A, Janssen RC, Palle S, Short KR, Friedman JE. Pediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms. Nutrients 2020; 12:E3166. [PMID: 33081177 PMCID: PMC7602751 DOI: 10.3390/nu12103166] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the number one chronic liver disease worldwide and is estimated to affect nearly 40% of obese youth and up to 10% of the general pediatric population without any obvious signs or symptoms. Although the early stages of NAFLD are reversible with diet and lifestyle modifications, detecting such stages is hindered by a lack of non-invasive methods of risk assessment and diagnosis. This absence of non-invasive means of diagnosis is directly related to the scarcity of long-term prospective studies of pediatric NAFLD in children and adolescents. In the majority of pediatric NAFLD cases, the mechanisms driving the origin and rapid progression of NAFLD remain unknown. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) in youth is associated with unique histological features and possible immune processes and metabolic pathways that may reflect different mechanisms compared with adults. Recent data suggest that circulating microRNAs (miRNAs) are important new biomarkers underlying pathways of liver injury. Several factors may contribute to pediatric NAFLD development, including high-sugar diets, in utero exposures via epigenetic alterations, changes in the neonatal microbiome, and altered immune system development and mitochondrial function. This review focuses on the unique aspects of pediatric NAFLD and how nutritional exposures impact the immune system, mitochondria, and liver/gastrointestinal metabolic health. These factors highlight the need for answers to how NAFLD develops in children and for early stage-specific interventions.
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Affiliation(s)
- Ashok Mandala
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
| | - Rachel C. Janssen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
| | - Sirish Palle
- Department of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Kevin R. Short
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Florijn BW, Valstar GB, Duijs JMGJ, Menken R, Cramer MJ, Teske AJ, Ghossein-Doha C, Rutten FH, Spaanderman MEA, den Ruijter HM, Bijkerk R, van Zonneveld AJ. Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury. Sci Rep 2020; 10:13945. [PMID: 32811874 PMCID: PMC7435264 DOI: 10.1038/s41598-020-70848-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/04/2020] [Indexed: 12/18/2022] Open
Abstract
Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R2 0.04, R = 0.21, p = 0.001, 95% CI 0.103–0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF.
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Affiliation(s)
- Barend W Florijn
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands. .,Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
| | - Gideon B Valstar
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.,Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Jacques M G J Duijs
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Roxana Menken
- Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Maarten J Cramer
- Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Arco J Teske
- Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Chahinda Ghossein-Doha
- Department of Obstetrics and Gynecology, Research School GROW, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Frans H Rutten
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.,Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Marc E A Spaanderman
- Department of Obstetrics and Gynecology, Research School GROW, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Hester M den Ruijter
- Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Roel Bijkerk
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Abstract
PURPOSE OF REVIEW This review examines the impact of early life exposures on glucose metabolism in the offspring and explores potential metabolic mechanisms leading to type 2 diabetes in childhood. RECENT FINDINGS One in five adolescents is diagnosed with prediabetes. Recent studies have elucidated the impact of early exposures such as maternal diabetes, but also hyperglycemia below the threshold of gestational diabetes, obesity, hyperlipidemia, and paternal obesity on the future metabolic health of the offspring. Mechanisms affecting the developmental programing of offspring toward type 2 diabetes include epigenetic modifications, alterations in stem cell differentiation, metabolome and microbiome variation, immune dysregulation, and neonatal nutrition. The risk of type 2 diabetes in offspring is increased not only by diabetes exposure in utero but also by exposure to a heterogeneous milieu of factors that accompany maternal obesity that provoke a vicious cycle of metabolic disease. The key period for intervention to prevent type 2 diabetes is within the first 1000 days of life.
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Affiliation(s)
- Ankur Rughani
- Division of Pediatric Diabetes/Endocrinology, Harold Hamm Diabetes Center, Children's Hospital, The University of Oklahoma Health Sciences Center, 1200 Children's Ave Suite 4D, Oklahoma City, OK, 73104, USA
| | - Jacob E Friedman
- Division of Pediatric Diabetes/Endocrinology, Harold Hamm Diabetes Center, Children's Hospital, The University of Oklahoma Health Sciences Center, 1200 Children's Ave Suite 4D, Oklahoma City, OK, 73104, USA
| | - Jeanie B Tryggestad
- Division of Pediatric Diabetes/Endocrinology, Harold Hamm Diabetes Center, Children's Hospital, The University of Oklahoma Health Sciences Center, 1200 Children's Ave Suite 4D, Oklahoma City, OK, 73104, USA.
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Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus-One of Several Possible Reasons for an Increased Cardiovascular Risk. Cells 2020; 9:cells9061557. [PMID: 32604801 PMCID: PMC7349356 DOI: 10.3390/cells9061557] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/19/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3-11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.
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Non-Coding RNA: Role in Gestational Diabetes Pathophysiology and Complications. Int J Mol Sci 2020; 21:ijms21114020. [PMID: 32512799 PMCID: PMC7312670 DOI: 10.3390/ijms21114020] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/30/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Gestational Diabetes Mellitus (GDM) is defined as glucose intolerance that develops in the second or third trimester of pregnancy. GDM can lead to short-term and long-term complications both in the mother and in the offspring. Diagnosing and treating this condition is therefore of great importance to avoid poor pregnancy outcomes. There is increasing interest in finding new markers with potential diagnostic, prognostic and therapeutic utility in GDM. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, are critically involved in metabolic processes and their dysregulated expression has been reported in several pathological contexts. The aberrant expression of several circulating or placenta-related ncRNAs has been linked to insulin resistance and β-cell dysfunction, the key pathophysiological features of GDM. Furthermore, significant associations between altered ncRNA profiles and GDM-related complications, such as macrosomia or trophoblast dysfunction, have been observed. Remarkably, the deregulation of ncRNAs, which might be linked to a detrimental intrauterine environment, can lead to changes in the expression of target genes in the offspring, possibly contributing to the development of long-term GDM-related complications, such as metabolic and cardiovascular diseases. In this review, all the recent findings on ncRNAs and GDM are summarized, particularly focusing on the molecular aspects and the pathophysiological implications of this complex relationship.
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40
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Jiang S, Teague AM, Tryggestad JB, Jensen ME, Chernausek SD. Role of metformin in epigenetic regulation of placental mitochondrial biogenesis in maternal diabetes. Sci Rep 2020; 10:8314. [PMID: 32433500 PMCID: PMC7239922 DOI: 10.1038/s41598-020-65415-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 04/30/2020] [Indexed: 12/30/2022] Open
Abstract
Adverse maternal environments, such as diabetes and obesity, impair placental mitochondrial function, which affects fetal development and offspring long-term health. The underlying mechanisms and effective interventions to abrogate such effect remain unclear. Our previous studies demonstrated impaired mitochondrial biogenesis in male human placenta of diabetic mothers. In the present studies, epigenetic marks possibly related to mitochondrial biogenesis in placentae of women with diabetes (n = 23) and controls (n = 23) were analyzed. Effects of metformin were examined in human placental explants from a subgroup of diabetic women and in a mouse model of maternal high fat diet feeding. We found that maternal diabetes was associated with epigenetic regulation of mitochondrial biogenesis in human placenta in a fetal sex-dependent manner, including decreased histone acetylation (H3K27 acetylation) and increased promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In male placenta, the levels of H3K27 acetylation and PGC-1α promoter methylation correlated significantly with the activity of AMP-activated protein kinase (AMPK). Metformin treatment on male diabetic placental explant activated AMPK and stimulated PGC-1α expression, concomitant with increased H3K27 acetylation and decreased PGC-1α promoter methylation. In vivo, we show that maternal metformin treatment along with maternal high fat diet significantly increased mouse placental abundance of PGC-1α expression and downstream mitochondrial transcription factor A (TFAM) and inhibited maternal high fat diet-impaired placental efficiency and glucose tolerance in offspring. Together, these findings suggest the capability of metformin to stimulate placental mitochondrial biogenesis and inhibit the aberrant epigenetic alterations occurring in maternal diabetes during pregnancy, conferring protective effects on offspring.
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Affiliation(s)
- Shaoning Jiang
- Department of Pediatrics, Section of Diabetes and Endocrinology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| | - April M Teague
- Department of Pediatrics, Section of Diabetes and Endocrinology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jeanie B Tryggestad
- Department of Pediatrics, Section of Diabetes and Endocrinology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Mary E Jensen
- Department of Pediatrics, Section of Diabetes and Endocrinology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Steven D Chernausek
- Department of Pediatrics, Section of Diabetes and Endocrinology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Liao X, Zhou Z, Zhang X. Effects of miR‑195‑5p on cell proliferation and apoptosis in gestational diabetes mellitus via targeting EZH2. Mol Med Rep 2020; 22:803-809. [PMID: 32626980 PMCID: PMC7339727 DOI: 10.3892/mmr.2020.11142] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 02/06/2020] [Indexed: 12/11/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a type of diabetes mellitus (DM) that occurs during pregnancy. The present study aimed to investigate the roles of microRNA (miR)‑195‑5p and enhancer of zeste homolog 2 (EZH2) in GDM, and their potential association. Human umbilical vein endothelial cells (HUVECs) were collected from healthy and GDM umbilical cords, and the endothelial properties were detected by flow cytometry. mRNA expression levels of miR‑195‑5p and EZH2, and EZH2 protein expression levels were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis, respectively. Cell colony formation and flow cytometry were performed to determine cell proliferation and apoptosis. Furthermore, the target gene of miR‑195‑5p was predicted and assessed using a dual‑luciferase reporter assay. The levels of cell viability, proliferation and apoptosis following the overexpression of miR‑195‑5p, EZH2 or miR‑195‑5p + EZH2, were detected using Cell Counting Kit‑8, colony formation and flow cytometry assays, respectively. In addition, the mRNA expression levels of miR‑195‑59 and EZH2, and EZH2 protein expression levels following transfection with overexpression plasmids were detected using RT‑qPCR and western blot analysis, respectively. It was identified that high mRNA expression of miR‑195‑5p, and low EZH2 mRNA and protein expression levels decreased the level of cell proliferation and the high apoptotic rate of GDM‑HUVECs. In addition, miR‑195‑5p was predicted and identified to target EZH2, and miR‑195‑5p overexpression was identified to inhibit cell proliferation and promote apoptosis. However, it was demonstrated that upregulation of EZH2 could alleviate the inhibition of cell proliferation and the increased apoptotic rate induced by miR‑195‑5p overexpression. Therefore, the present results suggested that miR‑195‑5p may inhibit cell viability, proliferation and promote apoptosis by targeting EZH2 in GDM‑induced HUVECs.
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Affiliation(s)
- Xiaojie Liao
- Department of Obstetrics, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Zhuolin Zhou
- Family Planning Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - Xiaoliu Zhang
- Department of Obstetrics, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
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Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases. Int J Mol Sci 2020; 21:ijms21072437. [PMID: 32244558 PMCID: PMC7177375 DOI: 10.3390/ijms21072437] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Mothers with a history of gestational diabetes mellitus (GDM) have an increased risk of developing diabetes in the future and a lifelong cardiovascular risk. Postpartal expression profile of cardiovascular/cerebrovascular disease associated microRNAs was assessed 3–11 years after the delivery in whole peripheral blood of young and middle-aged mothers with a prior exposure to GDM with the aim to identify a high-risk group of mothers at risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases who would benefit from implementation of early primary prevention strategies and long-term follow-up. The hypothesis of the assessment of cardiovascular risk in women was based on the knowledge that a series of microRNAs play a role in the pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases. Abnormal expression profile of multiple microRNAs was found in women with a prior exposure to GDM (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, miR-342-3p, miR-499a-5p, and-miR-574-3p). Postpartal combined screening of miR-1-3p, miR-16-5p, miR-17-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p showed the highest accuracy for the identification of mothers with a prior exposure to GDM at a higher risk of later development of cardiovascular/cerebrovascular diseases (AUC 0.900, p < 0.001, sensitivity 77.48%, specificity 93.26%, cut off >0.611270413). It was able to identify 77.48% mothers with an increased cardiovascular risk at 10.0% FPR. Any of changes in epigenome (upregulation of miR-16-5p, miR-17-5p, miR-29a-3p, and miR-195-5p) that were induced by GDM-complicated pregnancy are long-acting and may predispose mothers affected with GDM to later development of diabetes mellitus and cardiovascular/cerebrovascular diseases. In addition, novel epigenetic changes (upregulation of serious of microRNAs) appeared in a proportion of women that were exposed to GDM throughout the postpartal life. Likewise, a previous occurrence of either GH, PE, and/or FGR, as well as a previous occurrence of GDM, is associated with the upregulation of miR-1-3p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-29a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p. On the other hand, upregulation of miR-16-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-103a-3p, miR-195-5p, miR-342-3p, and miR-574-3p represents a unique feature of aberrant expression profile of women with a prior exposure to GDM. Screening of particular microRNAs may stratify a high-risk group of mothers with a history of GDM who might benefit from implementation of early primary prevention strategies.
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Xiao Y, Ding J, Shi Y, Lin L, Huang W, Shen D, Wang W. MiR-330-3p contributes to INS-1 cell dysfunction by targeting glucokinase in gestational diabetes mellitus. J Obstet Gynaecol Res 2020; 46:864-875. [PMID: 32202040 DOI: 10.1111/jog.14249] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/21/2020] [Accepted: 03/07/2020] [Indexed: 12/16/2022]
Abstract
AIMS High-expressed miR-330-3p in gestational diabetes mellitus (GDM) patients was reported. However, the role and mechanism of miR-330-3p in GDM are rarely reported. In this research, we aim to investigate the effects of miR-330-3p on GDM. METHODS MiR-330-3p expression in the GDM patients' blood was determined by q-PCR. Blood glucose of blood samples was detected using blood glucose detection kits. Glucokinase (GCK) was confirmed to be a target gene of miR-330-3p by bioinformatics and luciferase analysis. Correlations between miR-330-3p with GCK and blood glucose were analyzed by Pearson correlation analysis. After INS-1 cells were treated with glucose and transfected with mimic, inhibitor or siGCK, GCK expression was detected by western blot, and q-PCR, enzyme-linked immunosorbent assays, cell counting kit-8 and Annexin-V/propidium iodide were conducted to examine the expression of insulin, cell viability and apoptosis. RESULTS MiR-330-3p was high-expressed in GDM patients' blood, while GCK was low-expressed. The miR-330-3p expression level positively correlated with blood glucoseand and it was highly expressed in glucose-treated INS-1 cells (11 and 22 mmol/L), while miR-330-3p expression negatively correlated with GCK expression. GCK expression was inhibited by miR-330-3p mimic and enhanced by the miR-330-3p inhibitor. MiR-330-3p mimic inhibited INS-1 cells' insulin expression, cell viability and induced apoptosis. Yet miR-330-3p inhibitor and siGCK exhibited opposite effects which miR-330-3p mimic and GCK played on INS-1 cells. In addition, siGCK reversed the effect of miR-330-3p inhibitor on INS-1 cells. CONCLUSION Our findings proved that miR-330-3p targeting GCK lead to the dysfunction of INS-1 cells in GDM, and could become a therapeutic target for GDM treatment.
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Affiliation(s)
- Yuping Xiao
- Department of Pediatrics, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, People's Republic of China.,Department of Pediatrics, Zhejiang University Hospital, Hangzhou, People's Republic of China
| | - Jingchao Ding
- Department of Pediatrics, Shaoxing Hospital of Zhejiang University, Shaoxing, People's Republic of China
| | - Yulan Shi
- Department of Pediatrics, Zhenyuan County People's Hospital, Guizhou, Qiandongnan Autonomous Prefecture, People's Republic of China
| | - Long Lin
- Department of Pediatrics, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, People's Republic of China
| | - Wenyuan Huang
- Department of Pediatrics, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, People's Republic of China
| | - Dongxia Shen
- Department of Pediatrics, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, People's Republic of China
| | - Weiqun Wang
- Department of Pediatrics, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, People's Republic of China
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Docrat TF, Nagiah S, Naicker N, Baijnath S, Singh S, Chuturgoon AA. The protective effect of metformin on mitochondrial dysfunction and endoplasmic reticulum stress in diabetic mice brain. Eur J Pharmacol 2020; 875:173059. [PMID: 32131023 DOI: 10.1016/j.ejphar.2020.173059] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/23/2020] [Accepted: 02/28/2020] [Indexed: 12/26/2022]
Abstract
Diabetes is a metabolic disorder associated with mitochondrial (mt) dysfunction and oxidative stress. The molecular mechanisms involved in diabetes-associated neurological complications remain elusive. This study aims to investigate the protective effect of metformin (MF) on regulatory networks and integrated stress responses in brain tissue of Streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice were treated with MF (20 mg/kg BW), and whole brain tissue was harvested for further analysis. Protein carbonylation was measured as a marker of neuronal oxidative stress. Protein expression of mt chaperones, maintenance proteins, and regulators of the unfolded protein response (UPR) were measured by Western blot. Transcript levels of antioxidant enzyme GSTA4; mt biogenesis markers, ER stress regulators, and miR-132 and miR-148a were analysed using qPCR. The results showed that MF efficiently reduced protein carbonylation and oxidation. Mt function was improved by MF-treatment through upregulation of chaperone proteins (HSP60, HSP70 and LonP1). MF elicits the UPR to attenuate ER stress through a miR-132 repression mechanism. Additionally, MF was found to elevate deacetylases- Sirt1, Sirt3; and mt biogenesis marker PGC-1α through miR-148a repression. This is the first study to demonstrate the epigenetic regulation of mt maintenance by MF in diabetic C57BL/6 mouse whole brain tissue. We thus conclude that MF, beyond its anti-hyperglycaemic role, mediates neuroprotection through epigenomic and integrated stress responses in diabetic mice.
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Affiliation(s)
- Taskeen Fathima Docrat
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Savania Nagiah
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Nikita Naicker
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Sooraj Baijnath
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Sanil Singh
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Anil A Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa.
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Zhang J, Jazii FR, Haghighi MM, Alvares D, Liu L, Khosraviani N, Adeli K. miR-130b is a potent stimulator of hepatic very-low-density lipoprotein assembly and secretion via marked induction of microsomal triglyceride transfer protein. Am J Physiol Endocrinol Metab 2020; 318:E262-E275. [PMID: 31821038 DOI: 10.1152/ajpendo.00276.2019] [Citation(s) in RCA: 10] [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: 12/23/2022]
Abstract
miR-130b is a microRNA whose expression is particularly elevated within adipose tissue and in the circulation in diabetic states. Hepatic miR-130b expression has been linked to hepatocellular carcinoma and changes in lipid metabolism. Here, we investigated the role of miR-130b in hepatic lipid homeostasis and lipoprotein export. We observed that overexpression of miR-130b-3p or -5p in HepG2 cells markedly enhanced the secretion of very-low-density lipoprotein (VLDL) particles, enhanced the secretion of [3H]glycerol metabolically labeled triglyceride (TG), and significantly increased the number or the average size of lipid droplets (LDs), respectively. Overexpression of miR-130b also altered the expression of key genes involved in lipid metabolism and in particular markedly increased both mRNA and protein expression levels of microsomal triglyceride transfer protein (MTP). Conversely, the miR-130b inhibitor decreased mRNA levels of MTP and fatty acid synthase (FAS) in HepG2 cells. However, dual-luciferase reporter assays indicated that MTP is not a direct target of miR-130b-3p. miR-130b overexpression did not alter de novo synthesized TG or the stability and secretion of apolipoprotein B 100. Interestingly, knockdown of phosphatase and tensin homolog (PTEN) blocked the upregulation of MTP mRNA induced by miR-130b. Finally, miR-130b-induced stimulation of VLDL secretion was also observed in a second hepatocyte cell culture model, immortalized human hepatocytes, confirming the effects observed in HepG2 cells. Overall, these data suggest a potential role for miR-130b in promoting hepatic VLDL assembly and secretion mediated by marked stimulation of MTP expression and TG mobilization. Thus miR-130b overexpression corrects the defect in VLDL production in HepG2 cells.
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Affiliation(s)
- Jing Zhang
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Ferdous Rastgar Jazii
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Mahdi Montazer Haghighi
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Danielle Alvares
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Lipei Liu
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Negar Khosraviani
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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Joshi A, Azuma R, Akumuo R, Goetzl L, Pinney SE. Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus. Int J Obes (Lond) 2019; 44:1497-1507. [PMID: 31852997 PMCID: PMC7299738 DOI: 10.1038/s41366-019-0485-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 10/14/2019] [Accepted: 10/31/2019] [Indexed: 12/11/2022]
Abstract
Background/Objective Pregnancies complicated by gestational diabetes (GDM) or maternal
obesity have been linked to the development of diabetes, obesity and fatty
liver disease later in life with sex-specific manifestations. Alterations in
miRNA expression in offspring exposed to GDM and maternal obesity and
effects on hepatic development are unknown. Here we describe how exposure to
maternal obesity in utero leads to sex-specific changes in
miRNA and target gene expression in human fetal liver. Methods Candidate miRNA expression was measured in 2nd trimester
amniotic fluid (AF) from women with GDM. Targets of differentially expressed
miRNAs were determined and pathway enrichment of target genes was performed.
MiRNA and target gene expression were measured in a separate cohort of
2nd trimester primary human fetal hepatocytes (PHFH) exposed
to maternal obesity via QPCR and western blot. All studies were IRB
approved. Results GDM exposed AF had significant increases in miRNAs 199a-3p, 503-5p,
and 1268a (fold change (FC) ≥1.5, p<0.05). Female offspring
specific analysis showed enrichment in miRNAs 378a-3p, 885-5p, and 7-1-3p
(p<0.05). MiRNA gene targets were enriched in hepatic pathways. Key
genes regulating de novo lipogenesis were upregulated in
obesity exposed PHFH, especially in males. Significantly altered miRNAs in
GDM AF were measured in obese exposed PHFH, with consistent increases in
miRNAs 885-5p, 199-3p, 503-5p, 1268a and 7-1-3p (FC ≥1.5,
p<0.05). Female PHFH exposed to maternal obesity had increased
expression of miR-885-5p, miR-199-3p, miR-503-5p, miR-1268s and miR-7-1-3p,
(p<0.05), corresponding to decreased target genes expression for
ABCA1, PAK4 and INSR.
In male PHFHs, no miRNA changes were measured but there was increased
expression of ABCA1, PAK4, and
INSR (p<0.05). Conclusion Our data suggest sex-specific changes in miRNA and gene expression in
PHFH may be one mechanism contributing to the sexual dimorphism of metabolic
disease in offspring exposed to GDM and maternal obesity in
utero.
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Affiliation(s)
- Apoorva Joshi
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Rikka Azuma
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Rita Akumuo
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Laura Goetzl
- Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern School of Medicine, University of Texas, Health Sciences Center at Houston, Houston, TX, USA
| | - Sara E Pinney
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA. .,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. .,Center for Research in Reproduction and Women's Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. .,Center of Excellence in Environmental Toxicology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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Xie C, Wu W, Tang A, Luo N, Tan Y. lncRNA GAS5/miR-452-5p Reduces Oxidative Stress and Pyroptosis of High-Glucose-Stimulated Renal Tubular Cells. Diabetes Metab Syndr Obes 2019; 12:2609-2617. [PMID: 31849505 PMCID: PMC6910862 DOI: 10.2147/dmso.s228654] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage renal failure worldwide. lncRNAs are demonstrated to improve the DN by changing the expression of miRNAs. This study was aimed to investigate the effect of lncRNA GAS5/miR-452-5p on the inflammation, oxidative stress and pyroptosis of high-glucose-induced renal tubular cells. METHODS HK-2 cells were induced by HG to simulate DN cells. RT-qPCR analysis confirmed the transfection effects and detected the expression of GAS5, NLRP3, caspase1, IL-1β, pro-caspase1, pro-IL-1β, GSDMD-N and miR-452-5p. Western blot analysis determined the protein expression of NLRP3, caspase1, IL-1β, pro-caspase1, pro-IL-1β and GSDMD-N. The expression of GSDMD-N was also verified by immunofluorescence. The levels of TNF-α, IL-6, MCP-1, ROS, MDA and SOD were measured by commercial assay kits, respectively. Dual-luciferase reporter assay indicated that GAS5 could combine with miR-452-5p. RESULTS GAS5 expression was decreased in HG-induced HK-2 cells. GAS5 overexpression could decrease the levels of TNF-α, IL-6, MCP-1, ROS and MDA and increase the levels of SOD. Moreover, GAS5 overexpression suppressed the expression of NLRP3, caspase1, IL-1β and GSDMD-N, and the results of immunofluorescence verified the above results. miR-452-5p interference could cause the same changes as GAS5 overexpression for HG-induced HK-2 cells, and GAS5 inhibition could reverse the effect of miR-452-5p interference. CONCLUSION GAS5 overexpression inhibited the inflammation, oxidative stress and pyroptosis of HG-induced renal tubular cells by downregulating the expression of miR-452-5p.
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Affiliation(s)
- Cuisong Xie
- Department of Endocrinology, Chenzhou No.1 People’s Hospital, Chenzhou, Hunan423000, People’s Republic of China
| | - Weiling Wu
- Department of Endocrinology, Chenzhou No.1 People’s Hospital, Chenzhou, Hunan423000, People’s Republic of China
| | - Ainan Tang
- Department of Endocrinology, Chenzhou 3rd People’s Hospital, Chenzhou, Hunan423000, People’s Republic of China
| | - Ning Luo
- Department of Endocrinology, Chenzhou No.1 People’s Hospital, Chenzhou, Hunan423000, People’s Republic of China
| | - Yanfei Tan
- Department of Endocrinology, Chenzhou No.1 People’s Hospital, Chenzhou, Hunan423000, People’s Republic of China
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Vaiserman A, Lushchak O. Developmental origins of type 2 diabetes: Focus on epigenetics. Ageing Res Rev 2019; 55:100957. [PMID: 31473332 DOI: 10.1016/j.arr.2019.100957] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 08/19/2019] [Accepted: 08/28/2019] [Indexed: 12/15/2022]
Abstract
Traditionally, genetics and lifestyle are considered as main determinants of aging-associated pathological conditions. Accumulating evidence, however, suggests that risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. Type 2 diabetes (T2D), an age-related disease generally manifested after the age of 40, is among such disorders. Since several age-related conditions, such as pro-inflammatory states, are characteristic of both T2D and aging, this disease is conceptualized by many authors as a kind of premature or accelerated aging. There is substantial evidence that intrauterine growth restriction (IUGR), induced by poor or unbalanced nutrient intake, exposure to xenobiotics, maternal substance abuse etc., may impair fetal development, thereby causing the fetal adipose tissue and pancreatic beta cell dysfunction. Consequently, persisting adaptive changes may occur in the glucose-insulin metabolism, including reduced capacity for insulin secretion and insulin resistance. These changes can lead to an improved ability to store fat, thus predisposing to T2D development in later life. The modulation of epigenetic regulation of gene expression likely plays a central role in linking the adverse environmental conditions early in life to the risk of T2D in adulthood. In animal models of IUGR, long-term persistent changes in both DNA methylation and expression of genes implicated in metabolic processes have been repeatedly reported. Findings from human studies confirming the role of epigenetic mechanisms in linking early-life adverse experiences to the risk for T2D in adult life are scarce compared to data from animal studies, mainly because of limited access to suitable biological samples. It is, however, convincing evidence that these mechanisms may also operate in human beings. In this review, theoretical models and research findings evidencing the role of developmental epigenetic variation in the pathogenesis of T2D are summarized and discussed.
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Affiliation(s)
| | - Oleh Lushchak
- Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
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Significance of circulating microRNAs in diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and review. Cardiovasc Diabetol 2019; 18:113. [PMID: 31470851 PMCID: PMC6716825 DOI: 10.1186/s12933-019-0918-x] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022] Open
Abstract
In the light of growing global epidemic of type 2 diabetes mellitus (T2DM), significant efforts are made to discover next-generation biomarkers for early detection of the disease. Multiple mechanisms including inflammatory response, abnormal insulin secretion and glucose metabolism contribute to the development of T2DM. Platelet activation, on the other hand, is known to be one of the underlying mechanisms of atherosclerosis, which is a common T2DM complication that frequently results in ischemic events at later stages of the disease. Available data suggest that platelets contain large amounts of microRNAs (miRNAs) that are found in circulating body fluids, including the blood. Since miRNAs have been illustrated to play an important role in metabolic homeostasis through regulation of multiple genes, they attracted substantial scientific interest as diagnostic and prognostic biomarkers in T2DM. Various miRNAs, as well as their target genes are implicated in the complex pathophysiology of T2DM. This article will first review the different miRNAs studied in the context of T2DM and platelet reactivity, and subsequently present original results from bioinformatic analyses of published reports, identifying a common gene (PRKAR1A) linked to glucose metabolism, blood coagulation and insulin signalling and targeted by miRNAs in T2DM. Moreover, miRNA–target gene interaction networks built upon Gene Ontology information from electronic databases were developed. According to our results, miR-30a-5p, miR-30d-5p and miR-30c-5p are the most widely regulated miRNAs across all specified ontologies, hence they are the most promising biomarkers of T2DM to be investigated in future clinical studies.
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50
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Uchiyama T, Itaya-Hironaka A, Yamauchi A, Makino M, Sakuramoto-Tsuchida S, Shobatake R, Ota H, Takeda M, Ohbayashi C, Takasawa S. Intermittent Hypoxia Up-Regulates CCL2, RETN, and TNFα mRNAs in Adipocytes via Down-regulation of miR-452. Int J Mol Sci 2019; 20:ijms20081960. [PMID: 31013606 PMCID: PMC6515141 DOI: 10.3390/ijms20081960] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 04/18/2019] [Accepted: 04/19/2019] [Indexed: 12/16/2022] Open
Abstract
Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for insulin resistance. Recently, IH is considered to independently cause adipose tissue inflammation/dysfunction, leading to worsening insulin resistance; however, the detailed mechanism remains unknown. We exposed mouse 3T3-L1 and human SW872 adipocytes to experimental IH or normoxia for 24 h, and analyzed mRNA expression of several adipokines. We found that the mRNA levels of RETN, TNFα, and CCL2 in SW872 and 3T3-L1 adipocytes were significantly increased by IH, whereas the promoter activities of these genes were not increased. A target mRNA search of microRNA (miR)s revealed that all human mRNAs have a potential target sequence for miR-452. The miR-452 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-452 mimic and non-specific control RNA (miR-452 mimic NC) were introduced into SW872 cells, and the IH-induced up-regulation of the genes was abolished by introduction of the miR-452 mimic but not by the miR-452 mimic NC. These results indicate that IH stress down-regulates the miR-452 in adipocytes, resulting in increased levels of RETN, TNFα, and CCL2 mRNAs, leading to insulin resistance in SAS patients.
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Affiliation(s)
- Tomoko Uchiyama
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
- Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
| | - Asako Itaya-Hironaka
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
| | - Akiyo Yamauchi
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
| | - Mai Makino
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
| | | | - Ryogo Shobatake
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
| | - Hiroyo Ota
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
- Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
| | - Maiko Takeda
- Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
- Department of Laboratory Medicine and Pathology, National Hospital Organization Kinki-chuo Chest Medical Center, 1180 Nagasone-cho, Kita-ku, Sakai, Osaka 591-8025, Japan.
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
| | - Shin Takasawa
- Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
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