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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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Mondal S, Rathor R, Singh SN, Suryakumar G. miRNA and leptin signaling in metabolic diseases and at extreme environments. Pharmacol Res Perspect 2024; 12:e1248. [PMID: 39017237 PMCID: PMC11253706 DOI: 10.1002/prp2.1248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 05/27/2024] [Accepted: 07/04/2024] [Indexed: 07/18/2024] Open
Abstract
The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.
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Affiliation(s)
- Samrita Mondal
- Defence Institute of Physiology and Allied SciencesDelhiIndia
| | - Richa Rathor
- Defence Institute of Physiology and Allied SciencesDelhiIndia
| | - Som Nath Singh
- Defence Institute of Physiology and Allied SciencesDelhiIndia
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Wu W, Ren J, Wang J, Wang J, Yu D, Zhang Y, Zeng F, Huang B. Metalloestrogens exposure and risk of gestational diabetes mellitus: Evidence emerging from the systematic review and meta-analysis. ENVIRONMENTAL RESEARCH 2024; 248:118321. [PMID: 38307186 DOI: 10.1016/j.envres.2024.118321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/04/2024] [Accepted: 01/25/2024] [Indexed: 02/04/2024]
Abstract
BACKGROUND Metalloestrogens are metals and metalloid elements with estrogenic activity found everywhere. Their impact on human health is becoming more apparent as human activities increase. OBJECTIVE Our aim is to conduct a comprehensive systematic review and meta-analysis of observational studies exploring the correlation between metalloestrogens (specifically As, Sb, Cr, Cd, Cu, Se, Hg) and Gestational Diabetes Mellitus (GDM). METHODS PubMed, Web of Science, and Embase were searched to examine the link between metalloestrogens (As, Sb, Cr, Cd, Cu, Se, and Hg) and GDM until December 2023. Risk estimates were derived using random effects models. Subgroup analyses were conducted based on study countries, exposure sample, exposure assessment method, and detection methods. Sensitivity analyses and adjustments for publication bias were carried out to assess the strength of the findings. RESULTS Out of the 389 articles identified initially, 350 met our criteria and 33 were included in the meta-analysis, involving 141,175 subjects (9450 cases, 131,725 controls). Arsenic, antimony, and copper exposure exhibited a potential increase in GDM risk to some extent (As: OR = 1.28, 95 % CI [1.08, 1.52]; Sb: OR = 1.73, 95 % CI [1.13, 2.65]; Cu: OR = 1.29, 95 % CI [1.02, 1.63]), although there is a high degree of heterogeneity (As: Q = 52.93, p < 0.05, I2 = 64.1 %; Sb: Q = 31.40, p < 0.05, I2 = 80.9 %; Cu: Q = 21.14, p < 0.05, I2 = 71.6 %). Conversely, selenium, cadmium, chromium, and mercury exposure did not exhibit any association with the risk of GDM in our study. DISCUSSION Our research indicates that the existence of harmful metalloestrogens in the surroundings has a notable effect on the likelihood of GDM. Hence, we stress the significance of environmental elements in the development of GDM and the pressing need for relevant policies and measures.
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Affiliation(s)
- Wanxin Wu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Junjie Ren
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Juan Wang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jiamei Wang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Deshui Yu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yan Zhang
- School of Biology and Food Engineering, Hefei Normal University, Hefei, 230092, Anhui, China.
| | - Fa Zeng
- Shenzhen Longhua Maternity and Child Healthcare Hospital, Shenzhen, 518109, Guangdong, China.
| | - Binbin Huang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230032, Anhui, China.
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Kunysz M, Cieśla M, Darmochwał-Kolarz D. Evaluation of miRNA Expression in Patients with Gestational Diabetes Mellitus: Investigating Diagnostic Potential and Clinical Implications. Diabetes Metab Syndr Obes 2024; 17:881-891. [PMID: 38414865 PMCID: PMC10898488 DOI: 10.2147/dmso.s443755] [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: 11/01/2023] [Accepted: 01/24/2024] [Indexed: 02/29/2024] Open
Abstract
Purpose Gestational diabetes mellitus (GDM) is common pregnancy complication (8%), characterized by hyperglycemia resulting from pathological homeostatic mechanisms. There's a concerning trend of increasing GDM prevalence. New markers, particularly epigenetic ones, are sought for early detection and enhanced care. miRNA are small non-coding RNA molecules. The main goal was to investigate the potential role of miRNA (miR-16-5p, miR-222-3p, miR-21-5p) in GDM and their association with clinical features. Patients and Methods The study included 72 pregnant patients, with 42 having GDM and 30 in the control group. miRNA expression was measured using ELISA. Results There were no significant differences in miR-222-3p expression between GDM patients and the control group. The GDM group exhibited a positive correlation between miR-16-5p expression and miR-21-5p expression as well as between miR-16-5p expression and insulin resistance. In the GDM group, a positive correlation was observed between miR-21-5p expression and fasting glucose levels. Conclusion Results do not confirm the role of miR-222-3p in GDM pathogenesis or as a diagnostic marker. Additionally, a role for miR-16-5p in GDM pathogenesis was observed. Furthermore, a potential role for miR-21-5p in monitoring GDM treatment is indicated.
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Affiliation(s)
- Mateusz Kunysz
- Department of Obstetrics & Gynecology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, Rzeszow, 35-959, Poland
| | - Marek Cieśla
- College of Medical Sciences, University of Rzeszow, Rzeszow, 35-959, Poland
| | - Dorota Darmochwał-Kolarz
- Department of Obstetrics & Gynecology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, Rzeszow, 35-959, Poland
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Mierzejewski K, Kurzyńska A, Golubska M, Całka J, Gałęcka I, Szabelski M, Paukszto Ł, Andronowska A, Bogacka I. New insights into the potential effects of PET microplastics on organisms via extracellular vesicle-mediated communication. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 904:166967. [PMID: 37699490 DOI: 10.1016/j.scitotenv.2023.166967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/23/2023] [Accepted: 09/08/2023] [Indexed: 09/14/2023]
Abstract
Plastics have become an integral part of our daily lives. In the environment, plastics break down into small pieces (<5 mm) that are referred to as microplastics. Microplastics are ubiquitous and widespread in the environment, and all living organisms are exposed to their effects. The present study provides new insights into the potential effects of polyethylene terephthalate (PET) microplastics on organisms via extracellular vesicle (EV)-mediated communication. The study demonstrated that serum-derived EVs are able to transport plastic particles. In addition, PET microplastics alter the content of miRNA in EVs. The identified differentially regulated miRNAs may target genes associated with lifestyle diseases, such as cardiovascular or metabolic diseases, and carcinogenesis. This work expands our understanding of PET microplastics' effects on organisms via EV-mediated communication and identifies directions for further research and strategies.
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Affiliation(s)
- Karol Mierzejewski
- Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, Poland.
| | - Aleksandra Kurzyńska
- Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, Poland.
| | - Monika Golubska
- Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, Poland.
| | - Jarosław Całka
- Department of Clinical Physiology, University of Warmia and Mazury in Olsztyn, Poland.
| | - Ismena Gałęcka
- Department of Clinical Physiology, University of Warmia and Mazury in Olsztyn, Poland.
| | - Mariusz Szabelski
- Department of Physics and Biophysics, University of Warmia and Mazury in Olsztyn, Poland.
| | - Łukasz Paukszto
- Department of Botany and Nature Protection, University of Warmia and Mazury in Olsztyn, Poland.
| | - Aneta Andronowska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, Poland.
| | - Iwona Bogacka
- Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, Poland.
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Ustianowski Ł, Udzik J, Szostak J, Gorący A, Ustianowska K, Pawlik A. Genetic and Epigenetic Factors in Gestational Diabetes Mellitus Pathology. Int J Mol Sci 2023; 24:16619. [PMID: 38068941 PMCID: PMC10706782 DOI: 10.3390/ijms242316619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/14/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
Gestational diabetes (GDM) is the carbohydrate intolerance occurring during pregnancy. The risk factors of GDM include obesity, advanced maternal age, polycystic ovary syndrome, multigravidity, a sedentary lifestyle, and pre-existing hypertension. Additionally, complex genetic and epigenetic processes are also believed to play a crucial role in the development of GDM. In this narrative review, we discuss the role of genetic and epigenetic factors in gestational diabetes mellitus pathogenesis.
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Affiliation(s)
- Łukasz Ustianowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
| | - Jakub Udzik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
- Department of Cardiac Surgery, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Joanna Szostak
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Anna Gorący
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Klaudia Ustianowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
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Otsuka K, Nishiyama H, Kuriki D, Kawada N, Ochiya T. Connecting the dots in the associations between diet, obesity, cancer, and microRNAs. Semin Cancer Biol 2023; 93:52-69. [PMID: 37156343 DOI: 10.1016/j.semcancer.2023.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
The prevalence of obesity has reached pandemic levels worldwide, leading to a lower quality of life and higher health costs. Obesity is a major risk factor for noncommunicable diseases, including cancer, although obesity is one of the major preventable causes of cancer. Lifestyle factors, such as dietary quality and patterns, are also closely related to the onset and development of obesity and cancer. However, the mechanisms underlying the complex association between diet, obesity, and cancer remain unclear. In the past few decades, microRNAs (miRNAs), a class of small non-coding RNAs, have been demonstrated to play critical roles in biological processes such as cell differentiation, proliferation, and metabolism, highlighting their importance in disease development and suppression and as therapeutic targets. miRNA expression levels can be modulated by diet and are involved in cancer and obesity-related diseases. Circulating miRNAs can also mediate cell-to-cell communications. These multiple aspects of miRNAs present challenges in understanding and integrating their mechanism of action. Here, we introduce a general consideration of the associations between diet, obesity, and cancer and review the current knowledge of the molecular functions of miRNA in each context. A comprehensive understanding of the interplay between diet, obesity, and cancer could be valuable for the development of effective preventive and therapeutic strategies in future.
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Affiliation(s)
- Kurataka Otsuka
- Tokyo NODAI Research Institure, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan; R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan; Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan; Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiroshi Nishiyama
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Daisuke Kuriki
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Naoki Kawada
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan
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da Silva PHCM, Santos KDF, da Silva L, da Costa CCP, Santos RDS, Reis AADS. MicroRNAs Associated with the Pathophysiological Mechanisms of Gestational Diabetes Mellitus: A Systematic Review for Building a Panel of miRNAs. J Pers Med 2023; 13:1126. [PMID: 37511739 PMCID: PMC10381583 DOI: 10.3390/jpm13071126] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
miRNAs, a class of small non-coding RNAs, play a role in post-transcriptional gene expression. Therefore, this study aimed to conduct a systematic review of miRNAs associated with GDM to build a panel of miRNAs. A bibliographic search was carried out in the PubMed/Medline, Virtual Health Library (VHL), Web of Science, and EMBASE databases, selecting observational studies in English without time restriction. The protocol was registered on the PROSPERO platform (number CRD42021291791). Fifty-five studies were included in this systematic review, and 82 altered miRNAs in GDM were identified. In addition, four miRNAs were most frequently dysregulated in GDM (mir-16-5p, mir-20a-5p, mir-222-3p, and mir-330-3p). The dysregulation of these miRNAs is associated with the mechanisms of cell cycle homeostasis, growth, and proliferation of pancreatic β cells, glucose uptake and metabolism, insulin secretion, and resistance. On the other hand, identifying miRNAs associated with GDM and elucidating its main mechanisms can assist in the characterization and definition of potential biomarkers for the diagnosis and treatment of GDM.
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Affiliation(s)
- Pedro Henrique Costa Matos da Silva
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Kamilla de Faria Santos
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Laura da Silva
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Caroline Christine Pincela da Costa
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
| | - Rodrigo da Silva Santos
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
- Department of Biochemistry and Molecular Biology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil
| | - Angela Adamski da Silva Reis
- Laboratory of Molecular Pathology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil (K.d.F.S.)
- Department of Biochemistry and Molecular Biology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia 74690-090, GO, Brazil
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11
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Elhag DA, Al Khodor S. Exploring the potential of microRNA as a diagnostic tool for gestational diabetes. J Transl Med 2023; 21:392. [PMID: 37330548 PMCID: PMC10276491 DOI: 10.1186/s12967-023-04269-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating host gene expression. Recent studies have indicated a role of miRNAs in the pathogenesis of gestational diabetes mellitus (GDM), a common pregnancy-related disorder characterized by impaired glucose metabolism. Aberrant expression of miRNAs has been observed in the placenta and/or maternal blood of GDM patients, suggesting their potential use as biomarkers for early diagnosis and prognosis. Additionally, several miRNAs have been shown to modulate key signaling pathways involved in glucose homeostasis, insulin sensitivity, and inflammation, providing insights into the pathophysiology of GDM. This review summarizes the current knowledge on the dynamics of miRNA in pregnancy, their role in GDM as well as their potential as diagnostic and therapeutic targets.
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Affiliation(s)
- Duaa Ahmed Elhag
- Maternal and Child Health Division, Research Branch, Sidra Medicine, Doha, Qatar
| | - Souhaila Al Khodor
- Maternal and Child Health Division, Research Branch, Sidra Medicine, Doha, Qatar.
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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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Vp V, Kannan A, Perumal MK. Role of adipocyte-derived extracellular vesicles during the progression of liver inflammation to hepatocellular carcinoma. J Cell Physiol 2023; 238:1125-1140. [PMID: 36960683 DOI: 10.1002/jcp.31008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/03/2023] [Accepted: 03/11/2023] [Indexed: 03/25/2023]
Abstract
Extracellular vesicles are membrane-bound cargos that vary in size and are stably transported through various bodily fluids. Extracellular vesicles communicate information between the cells and organs. Extracellular vesicles from the diseased cells alter cellular responses of the recipient cells contributing to disease progression. In obesity, adipocytes become hypertrophic and the extracellular vesicles from these dysfunctional adipocytes showed altered cargo contents instigating pathophysiological response leading to chronic liver diseases. In this review, the role of adipocyte-derived extracellular vesicles on the progression of liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are extensively discussed. Newer approaches are crucial to take advantage of extracellular vesicles and their content as biomarkers to diagnose initial liver inflammation before reaching to an irreversible liver failure stage.
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Affiliation(s)
- Venkateish Vp
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Anbarasu Kannan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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14
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Chang YC, Chan MH, Yang YF, Li CH, Hsiao M. Glucose transporter 4: Insulin response mastermind, glycolysis catalyst and treatment direction for cancer progression. Cancer Lett 2023; 563:216179. [PMID: 37061122 DOI: 10.1016/j.canlet.2023.216179] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 04/17/2023]
Abstract
The glucose transporter family (GLUT) consists of fourteen members. It is responsible for glucose homeostasis and glucose transport from the extracellular space to the cell cytoplasm to further cascade catalysis. GLUT proteins are encoded by the solute carrier family 2 (SLC2) genes and are members of the major facilitator superfamily of membrane transporters. Moreover, different GLUTs also have their transporter kinetics and distribution, so each GLUT member has its uniqueness and importance to play essential roles in human physiology. Evidence from many studies in the field of diabetes showed that GLUT4 travels between the plasma membrane and intracellular vesicles (GLUT4-storage vesicles, GSVs) and that the PI3K/Akt pathway regulates this activity in an insulin-dependent manner or by the AMPK pathway in response to muscle contraction. Moreover, some published results also pointed out that GLUT4 mediates insulin-dependent glucose uptake. Thus, dysfunction of GLUT4 can induce insulin resistance, metabolic reprogramming in diverse chronic diseases, inflammation, and cancer. In addition to the relationship between GLUT4 and insulin response, recent studies also referred to the potential upstream transcription factors that can bind to the promoter region of GLUT4 to regulating downstream signals. Combined all of the evidence, we conclude that GLUT4 has shown valuable unknown functions and is of clinical significance in cancers, which deserves our in-depth discussion and design compounds by structure basis to achieve therapeutic effects. Thus, we intend to write up a most updated review manuscript to include the most recent and critical research findings elucidating how and why GLUT4 plays an essential role in carcinogenesis, which may have broad interests and impacts on this field.
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Affiliation(s)
- Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Hsien Chan
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Hsiu Li
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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15
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Karami M, Mousavi SH, Rafiee M, Heidari R, Shahrokhi SZ. Biochemical and molecular biomarkers: unraveling their role in gestational diabetes mellitus. Diabetol Metab Syndr 2023; 15:5. [PMID: 36631877 PMCID: PMC9832639 DOI: 10.1186/s13098-023-00980-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is the most prevalent metabolic disorder during pregnancy, causing short- and long-term complications for both mother and baby. GDM is a multifactorial disease, and it may be affected by interactions between genetic, epigenetic, and environmental factors. However, the exact etiology is poorly understood. Despite the high prevalence of GDM, there is still debate regarding the optimal time for screening, the diagnostic threshold to apply, and the best strategies for treatment. Identifying effective strategies for therapeutic purposes as well as accurate biomarkers for prognostic and diagnostic purposes will reduce the GDM incidence and improve its management. In recent years, new biochemical and molecular biomarkers such as microRNAs, single-nucleotide polymorphisms, and DNA methylation have received great interest in the diagnosis of GDM. In this review, we discuss current and future diagnostic approaches for the detection of GDM and evaluate lifestyle and pharmacological strategies for GDM prevention.
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Affiliation(s)
- Masoumeh Karami
- Department of Biochemistry, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Seyyed Hossein Mousavi
- Department of Cardiology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Mohammad Rafiee
- Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Reza Heidari
- Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran
- Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
| | - Seyedeh Zahra Shahrokhi
- Department of Biochemistry, School of Medicine, AJA University of Medical Sciences, Tehran, Iran.
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16
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Chan GCK, Than WH, Kwan BCH, Lai KB, Chan RCK, Teoh JYC, Ng JKC, Chow KM, Cheng PMS, Law MC, Leung CB, Li PKT, Szeto CC. Adipose and Plasma microRNAs miR-221 and 222 Associate with Obesity, Insulin Resistance, and New Onset Diabetes after Peritoneal Dialysis. Nutrients 2022; 14:nu14224889. [PMID: 36432575 PMCID: PMC9699429 DOI: 10.3390/nu14224889] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The correlation between microRNA, obesity, and glycemic intolerance in patients on peritoneal dialysis (PD) is unknown. We aimed to measure the adipose and plasma miR-221 and -222 levels, and to evaluate their association with adiposity, glucose intolerance, and new onset diabetes mellitus (NODM) after the commencement of PD. METHODS We prospectively recruited incident adult PD patients. miR-221 and -222 were measured from adipose tissue and plasma obtained during PD catheter insertion. These patients were followed for 24 months, and the outcomes were changes in adiposity, insulin resistance, and NODM after PD. RESULTS One hundred and sixty-five patients were recruited. Patients with pre-existing DM had higher adipose miR-221 (1.1 ± 1.2 vs. 0.7 ± 0.9-fold, p = 0.02) and -222 (1.9 ± 2.0 vs. 1.2 ± 1.3-fold, p = 0.01). High adipose miR-221 and -222 levels were associated with a greater increase in waist circumference (miR-221: beta 1.82, 95% CI 0.57-3.07, p = 0.005; miR-222: beta 1.35, 95% CI 0.08-2.63, p = 0.038), Homeostatic Model Assessment for Insulin Resistance (HOMA) index (miR-221: beta 8.16, 95% CI 2.80-13.53, p = 0.003; miR-222: beta 6.59, 95% CI 1.13-12.05, p = 0.018), and insulin requirements (miR-221: beta 0.05, 95% CI 0.006-0.09, p = 0.02; miR-222: beta 0.06, 95% CI 0.02-0.11, p = 0.002) after PD. The plasma miR-222 level predicted the onset of NODM (OR 8.25, 95% CI 1.35-50.5, p = 0.02). CONCLUSION miR-221 and -222 are associated with the progression of obesity, insulin resistance, and NODM after PD.
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Affiliation(s)
- Gordon Chun Kau Chan
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-3505-1729; Fax: +852-2637-3852
| | - Win Hlaing Than
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
- Li Ka Shing Institute of Health Sciences (LiHS), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Bonnie Ching Ha Kwan
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ka Bik Lai
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ronald Cheong Kin Chan
- Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jeremy Yuen Chun Teoh
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jack Kit Chung Ng
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Kai Ming Chow
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Phyllis Mei Shan Cheng
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Man Ching Law
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Chi Bon Leung
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Philip Kam Tao Li
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Cheuk Chun Szeto
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
- Li Ka Shing Institute of Health Sciences (LiHS), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
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17
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Ma L, Gilani A, Yi Q, Tang L. MicroRNAs as Mediators of Adipose Thermogenesis and Potential Therapeutic Targets for Obesity. BIOLOGY 2022; 11:1657. [PMID: 36421371 PMCID: PMC9687157 DOI: 10.3390/biology11111657] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 07/30/2023]
Abstract
Obesity is a growing health problem worldwide, associated with an increased risk of multiple chronic diseases. The thermogenic activity of brown adipose tissue (BAT) correlates with leanness in adults. Understanding the mechanisms behind BAT activation and the process of white fat "browning" has important implications for developing new treatments to combat obesity. MicroRNAs (miRNAs) are small transcriptional regulators that control gene expression in various tissues, including adipose tissue. Recent studies show that miRNAs are involved in adipogenesis and adipose tissue thermogenesis. In this review, we discuss recent advances in the role of miRNAs in adipocyte thermogenesis and obesity. The potential for miRNA-based therapies for obesity and recommendations for future research are highlighted, which may help provide new targets for treating obesity and obesity-related diseases.
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Affiliation(s)
- Lunkun Ma
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Ankit Gilani
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Qian Yi
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou 646099, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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18
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The Relationship between Serum Adipokines, miR-222-3p, miR-103a-3p and Glucose Regulation in Pregnancy and Two to Three Years Post-Delivery in Women with Gestational Diabetes Mellitus Adhering to Mediterranean Diet Recommendations. Nutrients 2022; 14:nu14224712. [PMID: 36432399 PMCID: PMC9698999 DOI: 10.3390/nu14224712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/29/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
The San Carlos Gestational Diabetes Mellitus (GDM) prevention study, a nutritional intervention RCT based on a Mediterranean Diet (MedDiet), has been shown to reduce the incidence of GDM. The objective of this study is to investigate the relationship of leptin, adiponectin, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), insulin and HOMA-IRand circulating miRNAs (miR-29a-3p, miR-103a-3p, miR-132-3p, miR-222-3p) with the appearance of GDM and with MedDiet-based nutritional intervention, at 24−28 gestational weeks (GW), and in glucose regulation 2−3 years post-delivery (PD). A total of 313 pregnant women, 77 with GDM vs. 236 with normal glucose tolerance (NGT), 141 from the control group (CG, MedDiet restricting the consumption of dietary fat including EVOO and nuts during pregnancy) vs. 172 from the intervention group (IG, MedDiet supplemented with extra virgin olive oil (EVOO) and pistachios during pregnancy) were compared at Visit 1 (8−12 GW), Visit 2 (24−28 GW) and Visit 3 (2−3 years PD). Expression of miRNAs was determined by the Exiqon miRCURY LNA RT-PCR system. Leptin, adiponectin, IL-6 and TNF-α, were measured by Milliplex® immunoassays on Luminex 200 and insulin by RIA. Women with GDM vs. NTG had significantly higher leptin median (Q1−Q3) levels (14.6 (9.2−19.4) vs. 9.6 (6.0−15.1) ng/mL; p < 0.05) and insulin levels (11.4 (8.6−16.5) vs. 9.4 (7.0−12.8) µUI/mL; p < 0.001) and lower adiponectin (12.9 (9.8−17.2) vs. 17.0 (13.3−22.4) µg/mL; p < 0.001) at Visit 2. These findings persisted in Visit 3, with overexpression of miR-222-3p (1.45 (0.76−2.21) vs. 0.99 (0.21−1.70); p < 0.05)) and higher levels of Il-6 and TNF-α. When the IG is compared with the CG lower levels of insulin, HOMA-IR-IR, IL-6 levels at Visit 2 and 3 and leptin levels only at Visit 2 were observed. An overexpression of miR-222-3p and miR-103a-3p were also observed in IG at Visit 2 and 3. The miR-222-3p and miR103a-3p expression correlated with insulin levels, HOMA-IR, IL-6 and TNF-α at Visit 2 (all p < 0.05). These data support the association of leptin, adiponectin and insulin/HOMA-IR with GDM, as well as the association of insulin/HOMA-IR and IL-6 and miR-222-3p and miR-103a-3p expression with a MedDiet-based nutritional intervention.
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19
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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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20
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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: 39] [Impact Index Per Article: 13.0] [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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21
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Downregulation of peripheral lipopolysaccharide binding protein impacts on perigonadal adipose tissue only in female mice. Biomed Pharmacother 2022; 151:113156. [PMID: 35643066 DOI: 10.1016/j.biopha.2022.113156] [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: 03/06/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND AND AIMS The sexual dimorphism in fat-mass distribution and circulating leptin and insulin levels is well known, influencing the progression of obesity-associated metabolic disease. Here, we aimed to investigate the possible role of lipopolysaccharide-binding protein (LBP) in this sexual dimorphism. METHODS The relationship between plasma LBP and fat mass was evaluated in 145 subjects. The effects of Lbp downregulation, using lipid encapsulated unlocked nucleomonomer agent containing chemically modified-siRNA delivery system, were evaluated in mice. RESULTS Plasma LBP levels were associated with fat mass and leptin levels in women with obesity, but not in men with obesity. In mice, plasma LBP downregulation led to reduced weight, fat mass and leptin gain after a high-fat and high-sucrose diet (HFHS) in females, in parallel to increased expression of adipogenic and thermogenic genes in visceral adipose tissue. This was not observed in males. Plasma LBP downregulation avoided the increase in serum LPS levels in HFHS-fed male and female mice. Serum LPS levels were positively correlated with body weight and fat mass gain, and negatively with markers of adipose tissue function only in female mice. The sexually dimorphic effects were replicated in mice with established obesity. Of note, LBP downregulation led to recovery of estrogen receptor alpha (Esr1) mRNA levels in females but not in males. CONCLUSION LBP seems to exert a negative feedback on ERα-mediated estrogen action, impacting on genes involved in thermogenesis. The known decreased estrogen action and negative effects of metabolic endotoxemia may be targeted through LBP downregulation.
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The Mystery of Exosomes in Gestational Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2169259. [PMID: 35720179 PMCID: PMC9200544 DOI: 10.1155/2022/2169259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 05/31/2022] [Indexed: 11/27/2022]
Abstract
Gestational diabetes mellitus (GDM) is one of the common pregnancy complications, which increases the risk of short-term and long-term adverse consequences in both the mother and offspring. However, the pathophysiological mechanism of GDM is still poorly understood. Inflammation, insulin resistance and oxidative stress are considered critical factors in the occurrence and development of GDM. Although the lifestyle intervention and insulin are the primary treatment, adverse pregnancy outcomes still cannot be ignored. Exosomes have a specific function of carrying biological information, which can transmit information to target cells and play an essential role in intercellular communication. Their possible roles in normal pregnancy and GDM have been widely concerned. The possibility of exosomal cargos as biomarkers of GDM is proposed. This paper reviews the literature in recent years and discusses the role of exosomes in GDM and their possible mechanisms to provide some reference for the prediction, prevention, and treatment of GDM and improve the outcome of pregnancy.
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Li W, Yuan X, He X, Yang L, Wu Y, Deng X, Zeng Y, Hu K, Tang B. The downregulation of miR-22 and miR-372 may contribute to gestational diabetes mellitus through regulating glucose metabolism via the PI3K/AKT/GLUT4 pathway. J Clin Lab Anal 2022; 36:e24557. [PMID: 35712865 PMCID: PMC9279990 DOI: 10.1002/jcla.24557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/07/2022] [Accepted: 05/25/2022] [Indexed: 11/27/2022] Open
Abstract
Background Identifying effective regulatory mechanisms will be significant for Gestational diabetes mellitus (GDM) diagnosis and treatment. Methods The expressions of miR‐22 and miR‐372 in placenta tissues from 75 pregnant women with GDM and 75 matched healthy controls and HRT8/SVneo cells (a model of insulin resistance) were analyzed by qPCR. The expressions of PI3K, AKT, IRS, and GLUT4 in high glucose‐treated HRT8/SVneo cells transfected with miR‐22 or miR‐372 mimics or inhibitors was assessed by Western blot. A luciferase gene reporter assay was employed to verify miRNAs' target genes. Results The expressions of miR‐22 and miR‐372 in placental tissues from GDM patients and HRT8/SVneo cells were significantly decreased compared with the respective controls. The GLUT4 expression was significantly decreased in the placenta tissues of GDM and HRT8/SVneo cells with high glucose transfected with miR‐22 and miR‐372 inhibitors. We confirmed that SLC2A4, the gene encoding GLUT4, was a direct target of miR‐22 and miR‐372. In this study, we report that the lower expressions of miR‐22 and miR‐372 in placental tissue from GDM patients. Conclusion Our results further suggested that the downregulations of miR‐22 and miR‐372 may contribute to GDM through regulating the PI3K/GLUT4 pathway.
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Affiliation(s)
- Wei Li
- Department of Endocrinology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Xianlin Yuan
- Department of Food and Biological Engineering, Guangdong Industry Technical College, Guangzhou, China
| | - Xin He
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Li Yang
- Department of Endocrinology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Yingyuan Wu
- Department of Obstetrics and Gynecology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Xiaofeng Deng
- Department of Central Sterile Supply, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Yiwen Zeng
- Department of Endocrinology, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Kesheng Hu
- Department of Clinical Laboratory, Armed Police Corps Hospital of Guangdong Province, Guangzhou, China
| | - Bo Tang
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Liebmann M, Asuaje Pfeifer M, Grupe K, Scherneck S. Estradiol (E2) Improves Glucose-Stimulated Insulin Secretion and Stabilizes GDM Progression in a Prediabetic Mouse Model. Int J Mol Sci 2022; 23:ijms23126693. [PMID: 35743136 PMCID: PMC9223537 DOI: 10.3390/ijms23126693] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 01/27/2023] Open
Abstract
Female New Zealand obese (NZO) mice are an established model of preconceptional (pc.) prediabetes that progresses as gestational diabetes mellitus (GDM) during gestation. It is known that NZO mice show improvement in insulin sensitivity and glucose-stimulated insulin secretion (GSIS) during gestation in vivo. The latter is no longer detectable in ex vivo perifusion experiments in isolated islets of Langerhans, suggesting a modulation by extrapancreatic factors. Here, we demonstrated that plasma 17β-estradiol (E2) levels increased markedly in NZO mice during gestation. The aim of this work was to determine whether these increased E2 levels are responsible for the improvement in metabolism during gestation. To achieve this goal, we examined its effects in isolated islets and primary hepatocytes of both NZO and metabolically healthy NMRI mice. E2 increased GSIS in the islets of both strains significantly. Hepatic glucose production (HGP) failed to be decreased by insulin in NZO hepatocytes but was reduced by E2 in both strains. Hepatocytes of pregnant NZO mice showed significantly lower glucose uptake (HGU) compared with NMRI controls, whereby E2 stimulation diminished this difference. Hepatocytes of pregnant NZO showed reduced glycogen content, increased cyclic adenosine monophosphate (cAMP) levels, and reduced AKT activation. These differences were abolished after E2 stimulation. In conclusion, our data indicate that E2 stabilizes and prevents deterioration of the metabolic state of the prediabetic NZO mice. E2 particularly increases GSIS and improves hepatic glucose utilization to a lower extent.
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Dietary Improvement during Lactation Normalizes miR-26a, miR-222 and miR-484 Levels in the Mammary Gland, but Not in Milk, of Diet-Induced Obese Rats. Biomedicines 2022; 10:biomedicines10061292. [PMID: 35740314 PMCID: PMC9219892 DOI: 10.3390/biomedicines10061292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 02/01/2023] Open
Abstract
We aimed to evaluate in rats whether the levels of specific miRNA are altered in the mammary gland (MG) and milk of diet-induced obese dams, and whether improving maternal nutrition during lactation attenuates such alterations. Dams fed with a standard diet (SD) (control group), with a Western diet (WD) prior to and during gestation and lactation (WD group), or with WD prior to and during gestation but moved to SD during lactation (Rev group) were followed. The WD group showed higher miR-26a, miR-222 and miR-484 levels than the controls in the MG, but the miRNA profile in Rev animals was not different from those of the controls. The WD group also displayed higher miR-125a levels than the Rev group. Dams of the WD group, but not the Rev group, displayed lower mRNA expression levels of Rb1 (miR-26a’s target) and Elovl6 (miR-125a’s target) than the controls in the MG. The WD group also presented lower expression of Insig1 (miR-26a’s target) and Cxcr4 (miR-222’s target) than the Rev group. However, both WD and Rev animals displayed lower expression of Vegfa (miR-484’s target) than the controls. WD animals also showed greater miR-26a, miR-125a and miR-222 levels in the milk than the controls, but no differences were found between the WD and Rev groups. Thus, implementation of a healthy diet during lactation normalizes the expression levels of specific miRNAs and some target genes in the MG of diet-induced obese dams but not in milk.
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Radojičić O, Dobrijević Z, Robajac D, Gligorijević N, Mandić Marković V, Miković Ž, Nedić O. Gestational Diabetes is Associated with an Increased Expression of miR-27a in Peripheral Blood Mononuclear Cells. Mol Diagn Ther 2022; 26:421-435. [PMID: 35578107 DOI: 10.1007/s40291-022-00591-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Dysregulation of microRNA-based mechanisms is associated with various human pathologies, including gestational diabetes mellitus (GDM), suggesting they may be potential diagnostic and/or prognostic biomarkers of GDM. METHODS The expression of miR-340-5p, miR-27a-3p and miR-222-3p in peripheral blood mononuclear cells (PBMCs) obtained from patients with GDM (n = 42) and healthy controls (n = 34) were evaluated, together with their correlation to the clinical parameters of participants and their newborns. Expression of the selected microRNAs was quantified by quantitative real-time polymerase chain reaction (qPCR), after reverse transcription with microRNA-specific stem-loop primers. RESULTS The expression of miR-27a-3p was significantly higher in patients with GDM than in controls (p = 0.036), whereas no significant difference between groups was found for the other two tested microRNAs. The expression level of miR-27a-3p in GDM patients was found to negatively correlate with the number of erythrocytes, concentration of haemoglobin, haematocrit, and low- and high-density lipoprotein (LDL/HDL) ratio, and positively with the concentration of glycated haemoglobin (HbA1c). In the case of miR-222-3p, a negative correlation between its expression and the concentration of cholesterol, LDL and LDL/HDL ratio was found only in healthy pregnant women. The expression level of miR-340-5p negatively correlated with erythrocyte count, haemoglobin concentration and haematocrit in GDM patients, as well as with the concentration of cholesterol, LDL and LDL/HDL ratio in healthy women. CONCLUSIONS The results obtained illustrate the potential of PBMC-derived microRNA miR-27a-3p to serve as a diagnostic biomarker of GDM. On the other hand, MiR-27a and miR-340 may help in assessing the metabolic status relevant for pregnancy.
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Affiliation(s)
- Ognjen Radojičić
- University Clinic for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia
| | - Zorana Dobrijević
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia.
| | - Dragana Robajac
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia
| | - Nikola Gligorijević
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia
| | - Vesna Mandić Marković
- University Clinic for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia
- Medical School, University of Belgrade, Belgrade, Serbia
| | - Željko Miković
- University Clinic for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia
- Medical School, University of Belgrade, Belgrade, Serbia
| | - Olgica Nedić
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Belgrade, Serbia
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Salomon C, Das S, Erdbrügger U, Kalluri R, Kiang Lim S, Olefsky JM, Rice GE, Sahoo S, Andy Tao W, Vader P, Wang Q, Weaver AM. Extracellular Vesicles and Their Emerging Roles as Cellular Messengers in Endocrinology: An Endocrine Society Scientific Statement. Endocr Rev 2022; 43:441-468. [PMID: 35552682 PMCID: PMC10686249 DOI: 10.1210/endrev/bnac009] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Indexed: 12/15/2022]
Abstract
During the last decade, there has been great interest in elucidating the biological role of extracellular vesicles (EVs), particularly, their hormone-like role in cell-to-cell communication. The field of endocrinology is uniquely placed to provide insight into the functions of EVs, which are secreted from all cells into biological fluids and carry endocrine signals to engage in paracellular and distal interactions. EVs are a heterogeneous population of membrane-bound vesicles of varying size, content, and bioactivity. EVs are specifically packaged with signaling molecules, including lipids, proteins, and nucleic acids, and are released via exocytosis into biofluid compartments. EVs regulate the activity of both proximal and distal target cells, including translational activity, metabolism, growth, and development. As such, EVs signaling represents an integral pathway mediating intercellular communication. Moreover, as the content of EVs is cell-type specific, it is a "fingerprint" of the releasing cell and its metabolic status. Recently, changes in the profile of EV and bioactivity have been described in several endocrine-related conditions including diabetes, obesity, cardiovascular diseases, and cancer. The goal of this statement is to highlight relevant aspects of EV research and their potential role in the field of endocrinology.
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Affiliation(s)
- Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Saumya Das
- Cardiovascular Research Center of Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Uta Erdbrügger
- Department of Medicine, Nephrology Division, University of Virginia, Charlottesville, VA, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Jerrold M Olefsky
- Department of Medicine, University of California-San Diego, La Jolla, CA, USA
| | | | - Susmita Sahoo
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - W Andy Tao
- Department of Biochemistry, Purdue University, West Lafayette, IN, USA
| | - Pieter Vader
- CDL Research, Division LAB, UMC Utrecht, Utrecht, the Netherlands Faculty of Medicine, Utrecht University, Utrecht, the Netherlands; Laboratory of Experimental Cardiology, UMC Utrecht, Utrecht, The Netherlands
| | - Qun Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Alissa M Weaver
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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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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Tackling the effects of extracellular vesicles in fibrosis. Eur J Cell Biol 2022; 101:151221. [PMID: 35405464 DOI: 10.1016/j.ejcb.2022.151221] [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: 01/20/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022] Open
Abstract
Fibrosis is a physiological process of tissue repair that turns into pathological when becomes chronic, damaging the functional structure of the tissue. In this review we outline the current status of extracellular vesicles as modulators of the fibrotic process at different levels. In adipose tissue, extracellular vesicles mediate the intercellular communication not only between adipocytes, but also between adipocytes and other cells of the stromal vascular fraction. Thus, they could be altering essential processes for the functionality of adipose tissue, such as adipocyte hypertrophy/hyperplasia, tissue plasticity, adipogenesis and/or inflammation, and ultimately trigger fibrosis. This process is particularly important in obesity, and may eventually, influence the development of obesity-associated alterations. In this regard, obesity is now recognized as an independent risk factor for the development of chronic kidney disease, although the role of extracellular vesicles in this connection has not been explored so far. Nonetheless, the role of extracellular vesicles in the onset and progression of renal fibrosis has been highlighted due to the critical role of fibrosis as a common feature of kidney diseases. In fact, the content of extracellular vesicles disturbs cellular signaling cascades involved in fibrosis in virtually all types of renal cells. What is certain is that the study of extracellular vesicles is complex, as their isolation and manipulation is still difficult to reproduce, which complicates the overview of their physiopathological effects. Nevertheless, new strategies have been developed to exploit the potential of extracellular vesicles and their cargo, both as biomarkers and as therapeutic tools to prevent the progression of fibrosis towards an irreversible event.
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Brasil Brandao B, Lino M, Kahn CR. Extracellular miRNAs as mediators of obesity-associated disease. J Physiol 2022; 600:1155-1169. [PMID: 34392542 PMCID: PMC8845532 DOI: 10.1113/jp280910] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular miRNAs are found in a variety of body fluids and mediate intercellular and interorgan communication, thus regulating gene expression and cellular metabolism. These miRNAs are secreted either in small vesicles/exosomes (sEV) or bound to proteins such as Argonaute and high-density lipoprotein. Both exosomal and protein-bound circulating miRNAs are altered in obesity. Although all tissues can contribute to changes in circulating miRNAs, adipose tissue itself is an important source of these miRNAs, especially those in sEVs. These are derived from both adipocytes and macrophages and participate in crosstalk between these cells, as well as peripheral tissues, including liver, skeletal muscle and pancreas, whose function may be impaired in obesity. Changes in levels of circulating miRNAs have also been linked to the beneficial effects induced by weight loss interventions, including diet, exercise and bariatric surgery, further indicating a role for these miRNAs as mediators of disease pathogenesis. Here, we review the role of circulating miRNAs in the pathophysiology of obesity and explore their potential use as biomarkers and in therapy of obesity-associated metabolic syndrome.
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Affiliation(s)
- Bruna Brasil Brandao
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215
| | - Marsel Lino
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215
| | - C. Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215
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Li R, Yu Y, Jaafar SO, Baghchi B, Farsimadan M, Arabipour I, Vaziri H. Genetic Variants miR-126, miR-146a, miR-196a2, and miR-499 in Polycystic Ovary Syndrome. Br J Biomed Sci 2022; 79:10209. [PMID: 35996522 PMCID: PMC8915673 DOI: 10.3389/bjbs.2021.10209] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/02/2021] [Indexed: 12/15/2022]
Abstract
Introduction: Alterations in certain microRNAs (miRNAs) and their target genes have reported in polycystic ovary syndrome (PCOS) and other disease of the female reproductive system, and so may be potential biomarkers. We hypothesised alterations in the prevalence of four miRNAs single nucleotide polymorphism (SNP) variants miR-126 rs4636297, miR-146a rs2910164, miR-196a2 rs11614913, and miR-499 rs3746444 in women with PCOS in comparison to healthy controls. Methods: SNPs in the four miRNAs were determined in 385 patients and 385 controls by standard RT-PCR techniques. Results: SNPs in miR-126 and miR-246a were significant linked with PCOS under the allelic, dominant, co-dominant, and recessive models (all p ≤ 0.01). The SNP in miR-499 was linked to PCOS in allelic (T, p = 0.002), dominant (p = 0.035) and recessive (p = 0.003) models. The SNPs -196a was significant linked to PCOS only in the recessive model (p = 0.037). Combining these SNPs in miR-499, mi146a, miR-196a and miR-126 respectively into allele haplotypes found highly significant odds ratios (95% CI) of 0.40 (0.29–0.54) (p < 0.001) for the C-G-C-G haplotype, and 0.46 (0.30–0.70) (p = 0.002) for the C-C-C-A haplotype (p = 0.002) for PCOS. Conclusion: Single SNPs and haplotype combinations in certain SNPs in miR-126, miR-146a, miR-196a2 and miR-499 are strongly linked to PCOS, and so may be useful predictors of this condition.
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Affiliation(s)
- R. Li
- Department of Abdominal and Pelvic Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China
| | - Y. Yu
- Department of Obstetrics and Gynecology, Nanchong Central Hospital, Nanchong, China
| | - S. O. Jaafar
- Department of Obstetrics and Gynecology, College of Medicine, Hawler Medical University, Erbil, Iraq
| | - B. Baghchi
- Department of Emergency Medicine, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - M. Farsimadan
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - I. Arabipour
- Department of Biotechnology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - H. Vaziri
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
- *Correspondence: H. Vaziri, ,
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Zhang T, Gao Z, Chen K. Exosomal microRNAs: potential targets for the prevention and treatment of diabetic cardiomyopathy. J Cardiol 2022; 80:423-431. [PMID: 35000826 DOI: 10.1016/j.jjcc.2021.12.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 01/06/2023]
Abstract
Diabetic cardiomyopathy (DCM), a condition in which myocardial dysfunction is caused by diabetes mellitus, has become an epidemic disorder in the world. DCM initially presents as diastolic relaxation dysfunction and will progress to heart failure in the absence of coronary artery disease, valvular disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. However, the underlying molecular mechanisms of DCM are poorly understood. Recent studies reveal that exosomal miRNAs are associated with multiple DCM risk factors and may act as potential therapeutic targets. Therefore, this review summarizes the recent advancements to understand the role of exosomal miRNAs in DCM development and explores potential preventative and therapeutic strategies.
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Affiliation(s)
- Tao Zhang
- Department of Pharmacology, Ningbo University School of Medicine, Ningbo, China
| | - Zhe Gao
- Ningbo Institute of Medical Sciences, Ningbo, China.
| | - Kuihao Chen
- Department of Pharmacology, Ningbo University School of Medicine, Ningbo, China.
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Sun Y, Yu Z, Zhang Y, Wang H, Chi Z, Chen X, Xu D. Downregulation of microRNA?342-3p eases insulin resistance and liver gluconeogenesis via regulating Rfx3 in gestational diabetes mellitus. Crit Rev Eukaryot Gene Expr 2022; 32:83-95. [DOI: 10.1615/critreveukaryotgeneexpr.2022043275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Zhang Y, Tang S, Yang W, Du F. let-7b-5p suppresses the proliferation and migration of pulmonary artery smooth muscle cells via down-regulating IGF1. Clinics (Sao Paulo) 2022; 77:100051. [PMID: 35636162 PMCID: PMC9156868 DOI: 10.1016/j.clinsp.2022.100051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/12/2022] [Accepted: 05/06/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES Some previous studies indicated that the excessive proliferation and migration of Pulmonary Artery Smooth Muscle Cells (PASMCs) could be observed in pulmonary artery intima after Pulmonary Embolism (PE) occurred. In addition, recent studies identified some miRNAs that are differentially expressed in the blood of PE patients, which might be used as a diagnostic biomarker for PE, including let-7a-5p, let-7b-5p, and miR-150-5p. Hence, the authors sought to explore the effects of let-7b-5p in PASMC proliferation and migration and the corresponding regulatory mechanism. METHODS Platelet-Derived Growth Factor (PDGF) was utilized to induce the hyper-proliferation model in PASMCs. The mRNA and protein expression levels were detected by RT-qPCR and western blot, respectively. The proliferation of PASMCs was evaluated by the detection of PCNA expression, as well as CCK-8 and Edu assays. Wound healing and Transwell assays were exploited to assess the migration ability of PASMCs. The targets of let-7b-5p were predicted based on two bioinformatics online tools. Dual-luciferase and Ago2 pull-down assays were applied to confirm the interaction between let-7b-5p and IGF1. RESULTS 40 ng/mL PDGF was selected as the optimal concentration to induce PASMCs. let-7b-5p mimics suppressed the proliferation and migration of PDGF-induced PASMCs, while let-7b-5p inhibitor led to the opposite result. In further mechanism exploration, IGF1 was predicted and confirmed as the direct target gene of let-7b-5p. The promotion role of IGF1 overexpression on the proliferation and migration of PDGF-induced PASMCs was dramatically countered by let-7b-5p mimics. CONCLUSION let-7b-5p prohibits the proliferation and migration of PDGF-induced PASMCs by modulating IGF1.
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Affiliation(s)
- Yadi Zhang
- Department of Respiratory Medicine, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
| | - Sihui Tang
- Department of Respiratory Medicine, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
| | - Wanchun Yang
- Department of Respiratory Medicine, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
| | - Fangbing Du
- Department of Respiratory Medicine, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China.
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Li Y, Yang J, Tao W, Yang M, Wang X, Lu T, Li C, Yang Y, Yao Y. The Single Nucleotide Polymorphisms (rs1292037 and rs13137) in miR-21 Were Associated with T2DM in a Chinese Population. Diabetes Metab Syndr Obes 2022; 15:189-198. [PMID: 35087281 PMCID: PMC8789254 DOI: 10.2147/dmso.s345758] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Insulin receptor (INSR), insulin receptor substrate (IRS) and glucose transporter 4 (GLUT4) play important roles in the insulin resistance pathway. The microRNA (miRNA or miR) involved in INSR, IRS or GLUT4 could be associated with the development of type 2 diabetes (T2DM). METHODS The aim of this study was to investigate the association of T2DM with 12 single nucleotide polymorphisms (SNPs) in 7 miRNAs (miR-195, miR-126, miR-144, miR-155, miR-21, miR-93 and miR-222) involved in the insulin resistance pathway. A total of 1593 subjects with T2DM and 1656 nondiabetic subjects were genotyped. Then, the associations of these SNPs with the development of T2DM and individual metabolic traits were evaluated, such as fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1C). RESULTS Our data showed that the C allele of rs1292037 in miR-21 could increase the risk of developing T2DM (P = 0.002, OR = 1.17; 95% CI: 1.06-1.29). In addition, the T allele of rs13137 in miR-21 could be a risk factor for T2DM (P = 0.003, OR = 1.16; 95% CI: 1.05-1.28). According to inheritance mode analysis, compared with the T/T-T/C genotype, the C/C genotype of rs1292037 showed a risk effect in T2DM in the recessive mode (P = 0.001, OR = 1.35; 95% CI: 1.13-1.63). For rs13137, compared with the A/A-A/T genotype, the T/T genotype also showed a risk effect in T2DM in the recessive mode (P = 0.001, OR = 1.35; 95% CI: 1.13-1.62). Moreover, in the nondiabetic group, compared with the rs78312845 A/G (FPG = 5.177±0.488mmol/L; HbA1C = 5.147±0.293%) and A/A genotypes (FPG = 5.155±0.486mmol/L; HbA1C = 5.136±0.299%), the G/G genotype (FPG = 4.887±0.482mmol/L; HbA1C = 4.960±0.397%) was associated with lower FPG (P = 0.012 and 0.019) and HbA1C (P = 0.008 and 0.011). CONCLUSION Our results revealed that rs1292037 and rs13137 in miR-21 were associated with T2DM susceptibility in a Han Chinese population. Moreover, the rs78312845 in miR-195 contributed to the level of FPG and HbA1C in nondiabetic group in the Han Chinese population.
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Affiliation(s)
- Yiping Li
- Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China
| | - Jia Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming City, People’s Republic of China
| | - Wenyu Tao
- Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China
| | - Man Yang
- Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China
| | - Xiaoling Wang
- Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China
| | - Tinglian Lu
- Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China
- School of Clinic Medicine, Dali University, Dali City, Yunnan, People’s Republic of China
| | - Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming City, People’s Republic of China
| | - Ying Yang
- Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China
- Correspondence: Ying Yang Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming, 650021, Yunnan, People’s Republic of China Email
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming City, People’s Republic of China
- Yufeng Yao Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan, 650118, People’s Republic of China Email ;
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Sun Y, Zhu B, Meng X, Yin B, Wu K, Liu Y, Zou D, Xue J, Sun X, Zhang D, Ma Z. Effect of maternal body mass index on the steroid profile in women with gestational diabetes mellitus. Front Endocrinol (Lausanne) 2022; 13:999154. [PMID: 36440200 PMCID: PMC9681895 DOI: 10.3389/fendo.2022.999154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE To explore the effect of maternal body mass index (BMI) on steroid hormone profiles in women with gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). METHODS We enrolled 79 women with NGT and 80 women with GDM who had a gestational age of 24-28 weeks. The participants were grouped according to their BMI. We quantified 11 steroid hormones profiles by liquid chromatography-tandem mass spectrometry and calculated the product-to-precursor ratios in the steroidogenic pathway. RESULTS Women with GDM and BMI<25kg/m2 showed higher concentrations of dehydroepiandrosterone (DHEA) (p<0.001), testosterone (T) (p=0.020), estrone (E1) (p=0.010) and estradiol (E2) (p=0.040) and lower Matsuda index and HOMA-β than women with NGT and BMI<25kg/m2. In women with GDM, concentrations of E1 (p=0.006) and E2 (p=0.009) declined, accompanied by reduced E2/T (p=0.008) and E1/androstenedione (A4) (p=0.010) in the BMI>25 kg/m2 group, when compared to that in the BMI<25 kg/m2 group. The values of E2/T and E1/A4 were used to evaluate the cytochrome P450 aromatase enzyme activity in the steroidogenic pathway. Both aromatase activities negatively correlated with the maternal BMI and positively correlated with the Matsuda index in women with GDM. CONCLUSIONS NGT women and GDM women with normal weight presented with different steroid hormone profiles. Steroidogenic pathway profiling of sex hormones synthesis showed a significant increase in the production of DHEA, T, E1, and E2 in GDM women with normal weight. Additionally, the alteration of steroid hormone metabolism was related to maternal BMI in women with GDM, and GDM women with overweight showed reduced estrogen production and decreased insulin sensitivity compared with GDM women with normal weight.
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Affiliation(s)
- Yanni Sun
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Clinical Prenatal Diagnosis Center, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bo Zhu
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Clinical Prenatal Diagnosis Center, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xingjun Meng
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Clinical Prenatal Diagnosis Center, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Binbin Yin
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Clinical Prenatal Diagnosis Center, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kaiqi Wu
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Clinical Prenatal Diagnosis Center, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yifeng Liu
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Women’s Reproductive Health of Zhejiang Province, and Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dandan Zou
- Hangzhou BIOZON Medical Laboratory co. Ltd., Hangzhou, Zhejiang, China
| | - Jianyou Xue
- Hangzhou BIOZON Medical Laboratory co. Ltd., Hangzhou, Zhejiang, China
| | - Xiao Sun
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Women’s Reproductive Health of Zhejiang Province, and Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dan Zhang
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Women’s Reproductive Health of Zhejiang Province, and Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Zhixin Ma, ; Dan Zhang,
| | - Zhixin Ma
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Clinical Prenatal Diagnosis Center, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Zhixin Ma, ; Dan Zhang,
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Masete M, Dias S, Malaza N, Adam S, Pheiffer C. A Big Role for microRNAs in Gestational Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:892587. [PMID: 35957839 PMCID: PMC9357936 DOI: 10.3389/fendo.2022.892587] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/24/2022] [Indexed: 12/16/2022] Open
Abstract
Maternal diabetes is associated with pregnancy complications and poses a serious health risk to both mother and child. Growing evidence suggests that pregnancy complications are more frequent and severe in pregnant women with pregestational type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) compared to women with gestational diabetes mellitus (GDM). Elucidating the pathophysiological mechanisms that underlie the different types of maternal diabetes may lead to targeted strategies to prevent or reduce pregnancy complications. In recent years, microRNAs (miRNAs), one of the most common epigenetic mechanisms, have emerged as key players in the pathophysiology of pregnancy-related disorders including diabetes. This review aims to provide an update on the status of miRNA profiling in pregnancies complicated by maternal diabetes. Four databases, Pubmed, Web of Science, EBSCOhost, and Scopus were searched to identify studies that profiled miRNAs during maternal diabetes. A total of 1800 articles were identified, of which 53 are included in this review. All studies profiled miRNAs during GDM, with no studies on miRNA profiling during pregestational T1DM and T2DM identified. Studies on GDM were mainly focused on the potential of miRNAs to serve as predictive or diagnostic biomarkers. This review highlights the lack of miRNA profiling in pregnancies complicated by T1DM and T2DM and identifies the need for miRNA profiling in all types of maternal diabetes. Such studies could contribute to our understanding of the mechanisms that link maternal diabetes type with pregnancy complications.
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Affiliation(s)
- Matladi Masete
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Stephanie Dias
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
| | - Nompumelelo Malaza
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Sumaiya Adam
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- Center for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa
- *Correspondence: Carmen Pheiffer,
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Ruiz GP, Camara H, Fazolini NPB, Mori MA. Extracellular miRNAs in redox signaling: Health, disease and potential therapies. Free Radic Biol Med 2021; 173:170-187. [PMID: 33965563 DOI: 10.1016/j.freeradbiomed.2021.05.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
Extracellular microRNAs (miRNAs) have emerged as important mediators of cell-to-cell communication and intertissue crosstalk. MiRNAs are produced by virtually all types of eukaryotic cells and can be selectively packaged and released to the extracellular medium, where they may reach distal cells to regulate gene expression cell non-autonomously. By doing so, miRNAs participate in integrative physiology. Oxidative stress affects miRNA expression, while miRNAs control redox signaling. Disruption in miRNA expression, processing or release to the extracellular compartment are associated with aging and a number of chronic diseases, such as obesity, type 2 diabetes, neurodegenerative diseases and cancer, all of them being conditions related to oxidative stress. Here we discuss the interplay between redox balance and miRNA function and secretion as a determinant of health and disease states, reviewing the findings that support this notion and highlighting novel and yet understudied venues of research in the field.
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Affiliation(s)
- Gabriel Palermo Ruiz
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Henrique Camara
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Narayana P B Fazolini
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Marcelo A Mori
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, SP, Brazil.
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Valencia-Ortega J, Saucedo R, Sánchez-Rodríguez MA, Cruz-Durán JG, Martínez EGR. Epigenetic Alterations Related to Gestational Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22179462. [PMID: 34502370 PMCID: PMC8430976 DOI: 10.3390/ijms22179462] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 02/06/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy, which affects the future health of both the mother and the newborn. Its pathophysiology involves nutritional, hormonal, immunological, genetic and epigenetic factors. Among the latter, it has been observed that alterations in DNA (deoxyribonucleic acid) methylation patterns and in the levels of certain micro RNAs, whether in placenta or adipose tissue, are related to well-known characteristics of the disease, such as hyperglycemia, insulin resistance, inflammation and excessive placental growth. Furthermore, epigenetic alterations of gestational diabetes mellitus are observable in maternal blood, although their pathophysiological roles are completely unknown. Despite this, it has not been possible to determine the causes of the epigenetic characteristics of GDM, highlighting the need for integral and longitudinal studies. Based on this, this article summarizes the most relevant and recent studies on epigenetic alterations in placenta, adipose tissue and maternal blood associated with GDM in order to provide the reader with a general overview of the subject and indicate future research topics.
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Affiliation(s)
- Jorge Valencia-Ortega
- Unidad de Investigación Médica en Enfermedades Endocrinas, UMAE Hospital de Especialidades, Instituto Mexicano del Seguro Social, Mexico City 06600, Mexico;
| | - Renata Saucedo
- Unidad de Investigación Médica en Enfermedades Endocrinas, UMAE Hospital de Especialidades, Instituto Mexicano del Seguro Social, Mexico City 06600, Mexico;
- Correspondence: ; Tel.: +55-55887521
| | - Martha A. Sánchez-Rodríguez
- Unidad de Investigación en Gerontología, Facultad de Estudios Superiores Zaragoza, Universidad Autónoma de México, Mexico City 04510, Mexico;
| | - José G. Cruz-Durán
- UMAE Hospital de Gineco-Obstetricia No. 3, Instituto Mexicano del Seguro Social, Mexico City 06600, Mexico;
| | - Edgar G. Ramos Martínez
- Universidad Autónoma Benito Juárez de Oaxaca and Instituto de Cómputo Aplicado en Ciencias, Oaxaca 68120, Mexico;
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Florijn BW, Duijs JMGJ, Klaver M, Kuipers EN, Kooijman S, Prins J, Zhang H, Sips HCM, Stam W, Hanegraaf M, Limpens RWAL, Nieuwland R, van Rijn BB, Rabelink TJ, Rensen PCN, den Heijer M, Bijkerk R, van Zonneveld AJ. Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452. Eur J Endocrinol 2021; 185:539-552. [PMID: 34342596 PMCID: PMC8436186 DOI: 10.1530/eje-21-0267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 08/03/2021] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. METHODS Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. RESULTS Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). CONCLUSION This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.
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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
- Correspondence should be addressed to B W Florijn;
| | - 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
| | - Maartje Klaver
- Department of Internal Medicine, Division of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands
| | - Eline N Kuipers
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Sander Kooijman
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Jurrien Prins
- 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
| | - Huayu Zhang
- 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
| | - Hetty C M Sips
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Wendy Stam
- 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
| | - Maaike Hanegraaf
- 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
| | - Ronald W A L Limpens
- Department of Cell and Chemical Biology (Section Electron Microscopy), Leiden University Medical Center, Leiden, The Netherlands
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, Department of Clinical Chemistry and Vesicle Observation Center, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Bas B van Rijn
- Department of Obstetrics and Fetal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ton J Rabelink
- 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
| | - Patrick C N Rensen
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Martin den Heijer
- Department of Internal Medicine, Division of Endocrinology, VU University Medical Center, Amsterdam, 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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Fodor A, Lazar AL, Buchman C, Tiperciuc B, Orasan OH, Cozma A. MicroRNAs: The Link between the Metabolic Syndrome and Oncogenesis. Int J Mol Sci 2021; 22:ijms22126337. [PMID: 34199293 PMCID: PMC8231835 DOI: 10.3390/ijms22126337] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/03/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.
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Affiliation(s)
- Adriana Fodor
- Department of Diabetes and Nutrtion, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Andrada Luciana Lazar
- Department of Dermatology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Cristina Buchman
- Department of Oncology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Brandusa Tiperciuc
- Department of Pharmaceutical Chemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Olga Hilda Orasan
- Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.H.O.); (A.C.)
| | - Angela Cozma
- Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.H.O.); (A.C.)
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Catanzaro G, Filardi T, Sabato C, Vacca A, Migliaccio S, Morano S, Ferretti E. Tissue and circulating microRNAs as biomarkers of response to obesity treatment strategies. J Endocrinol Invest 2021; 44:1159-1174. [PMID: 33111214 PMCID: PMC8124039 DOI: 10.1007/s40618-020-01453-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Obesity, characterized by an increased amount of adipose tissue, is a metabolic chronic alteration which has reached pandemic proportion. Lifestyle changes are the first line therapy for obesity and a large variety of dietary approaches have demonstrated efficacy in promoting weight loss and improving obesity-related metabolic alterations. Besides diet and physical activity, bariatric surgery might be an effective therapeutic strategy for morbid obese patients. Response to weight-loss interventions is characterised by high inter-individual variability, which might involve epigenetic factors. microRNAs have critical roles in metabolic processes and their dysregulated expression has been reported in obesity. AIM The aim of this review is to provide a comprehensive overview of current studies evaluating changes in microRNA expression in obese patients undergoing lifestyle interventions or bariatric surgery. RESULTS A considerable number of studies have reported a differential expression of circulating microRNAs before and after various dietary and bariatric surgery approaches, identifying several candidate biomarkers of response to weight loss. Significant changes in microRNA expression have been observed at a tissue level as well, with entirely different patterns between visceral and subcutaneous adipose tissue. Interestingly, relevant differences in microRNA expression have emerged between responders and non-responders to dietary or surgical interventions. A wide variety of dysregulated microRNA target pathways have also been identified, helping to understand the pathophysiological mechanisms underlying obesity and obesity-related metabolic diseases. CONCLUSIONS Although further research is needed to draw firm conclusions, there is increasing evidence about microRNAs as potential biomarkers for weight loss and response to intervention strategies in obesity.
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Affiliation(s)
- G Catanzaro
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - T Filardi
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - C Sabato
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - A Vacca
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - S Migliaccio
- Department of Movement, Human and Health Sciences, "Foro Italico" University of Rome, Rome, Italy
| | - S Morano
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - E Ferretti
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
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Wawrzkiewicz-Jałowiecka A, Lalik A, Soveral G. Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue. Int J Mol Sci 2021; 22:5226. [PMID: 34069293 PMCID: PMC8157194 DOI: 10.3390/ijms22105226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023] Open
Abstract
The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient's hormonal status.
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Affiliation(s)
- Agata Wawrzkiewicz-Jałowiecka
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Anna Lalik
- Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland;
- Biotechnology Center, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
| | - Graça Soveral
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisboa, Portugal;
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Abstract
MicroRNAs orchestrate the tight regulation of numerous cellular processes and the deregulation in their activities has been implicated in many diseases, including diabetes and cancer. There is an increasing amount of epidemiological evidence associating diabetes, particularly type 2 diabetes mellitus, to an elevated risk of various cancer types, including breast cancer. However, little is yet known about the underlying molecular mechanisms and even less about the role miRNAs play in driving the tumorigenic potential of the cell signaling underlying diabetes pathogenesis. This article reviews the role of miRNA in bridging the diabetes–breast cancer association by discussing specific miRNAs that are implicated in diabetes and breast cancer and highlighting the overlap between the disease-specific regulatory miRNA networks to identify a 20-miRNA signature that is common to both diseases. Potential therapeutic targeting of these molecular players may help to alleviate the socioeconomic burden on public health that is imposed by the type 2 diabetes mellitus (T2DM)–breast cancer association.
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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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Pregnancy-Related Extracellular Vesicles Revisited. Int J Mol Sci 2021; 22:ijms22083904. [PMID: 33918880 PMCID: PMC8068855 DOI: 10.3390/ijms22083904] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/20/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are small vesicles ranging from 20–200 nm to 10 μm in diameter that are discharged and taken in by many different types of cells. Depending on the nature and quantity of their content—which generally includes proteins, lipids as well as microRNAs (miRNAs), messenger-RNA (mRNA), and DNA—these particles can bring about functional modifications in the receiving cells. During pregnancy, placenta and/or fetal-derived EVs have recently been isolated, eliciting interest in discovering their clinical significance. To date, various studies have associated variations in the circulating levels of maternal and fetal EVs and their contents, with complications including gestational diabetes and preeclampsia, ultimately leading to adverse pregnancy outcomes. Furthermore, EVs have also been identified as messengers and important players in viral infections during pregnancy, as well as in various congenital malformations. Their presence can be detected in the maternal blood from the first trimester and their level increases towards term, thus acting as liquid biopsies that give invaluable insight into the status of the feto-placental unit. However, their exact roles in the metabolic and vascular adaptations associated with physiological and pathological pregnancy is still under investigation. Analyzing peer-reviewed journal articles available in online databases, the purpose of this review is to synthesize current knowledge regarding the utility of quantification of pregnancy related EVs in general and placental EVs in particular as non-invasive evidence of placental dysfunction and adverse pregnancy outcomes, and to develop the current understanding of these particles and their applicability in clinical practice.
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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: 17] [Impact Index Per Article: 4.3] [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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Ramos‐Romero S, Léniz A, Martínez‐Maqueda D, Amézqueta S, Fernández‐Quintela A, Hereu M, Torres JL, Portillo MP, Pérez‐Jiménez J. Inter‐Individual Variability in Insulin Response after Grape Pomace Supplementation in Subjects at High Cardiometabolic Risk: Role of Microbiota and miRNA. Mol Nutr Food Res 2020; 65:e2000113. [DOI: 10.1002/mnfr.202000113] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 10/30/2020] [Indexed: 12/29/2022]
Affiliation(s)
- Sara Ramos‐Romero
- Institute of Advanced Chemistry of Catalonia (IQAC‐CSIC) Barcelona 08034 Spain
- Department of Cell Biology Physiology and Immunology Faculty of Biology University of Barcelona Barcelona 08028 Spain
| | - Asier Léniz
- Basque Health Service (Osakidetza) Araba Integrated Health Care Organization Vitoria 01009 Spain
- Nutrition and Obesity Group, Department of Nutrition and Food Science Faculty of Pharmacy and Lucio Lascaray Research Center University of the Basque Country (UPV/EHU) Vitoria 01006 Spain
| | - Daniel Martínez‐Maqueda
- Department of Metabolism and Nutrition Technology and Nutrition (ICTAN‐CSIC) Institute of Food Science José Antonio Novais 10 Madrid 28040 Spain
| | - Susana Amézqueta
- Departament d'Enginyeria Química i Química Analítica and Institut de Biomedicina (IBUB) Universitat de Barcelona Barcelona 08028 Spain
| | - Alfredo Fernández‐Quintela
- Nutrition and Obesity Group, Department of Nutrition and Food Science Faculty of Pharmacy and Lucio Lascaray Research Center University of the Basque Country (UPV/EHU) Vitoria 01006 Spain
- Instituto de Salud Carlos III (ISCIII) CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Madrid 28029 Spain
| | - Mercè Hereu
- Institute of Advanced Chemistry of Catalonia (IQAC‐CSIC) Barcelona 08034 Spain
| | - Josep Luís Torres
- Institute of Advanced Chemistry of Catalonia (IQAC‐CSIC) Barcelona 08034 Spain
| | - María P. Portillo
- Nutrition and Obesity Group, Department of Nutrition and Food Science Faculty of Pharmacy and Lucio Lascaray Research Center University of the Basque Country (UPV/EHU) Vitoria 01006 Spain
- Instituto de Salud Carlos III (ISCIII) CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Madrid 28029 Spain
| | - Jara Pérez‐Jiménez
- Department of Metabolism and Nutrition Technology and Nutrition (ICTAN‐CSIC) Institute of Food Science José Antonio Novais 10 Madrid 28040 Spain
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Zhang H, Luan S, Xiao X, Lin L, Zhao X, Liu X. Silenced microRNA-222 suppresses inflammatory response in gestational diabetes mellitus mice by promoting CXCR4. Life Sci 2020; 266:118850. [PMID: 33278386 DOI: 10.1016/j.lfs.2020.118850] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Gestational diabetes mellitus (GDM) is induced by multiple factors, and the microRNAs (miRNAs) are well-known to be implicated in GDM progression. We aimed to explore the functional mechanisms of miR-222 in the inflammatory response in GDM by mediating C-X-C chemokine receptor type 4 (CXCR4) and NLRP3 inflammasomes. METHODS GDM models were established by intraperitoneal injection of streptozocin, and the levels of miR-222 and CXCR4 in GDM patients' placenta tissues as well as GDM mice' placenta and pancreatic tissues were determined. The GDM mice were treated with miR-222 Antagomir/Agomir or overexpressed CXCR4 to evaluate the apoptosis and pathological changes in tissues, and the levels of blood glucose, insulin, biochemical indices, inflammatory factors and inflammasome-related proteins. Importantly, the target relation between miR-222 and CXCR4 was verified. RESULTS MiR-222 was increased while CXCR4 was decreased in GDM patients and mice. The down-regulated miR-222 and up-regulated CXCR4 could promote insulin sensitivity and insulin level, while inhibit apoptosis, inflammation and glucagon level in GDM mice. Moreover, CXCR4 was targeted by miR-222. CONCLUSION We demonstrated that the silenced miR-222 could suppress inflammatory response in GDM mice by promoting CXCR4 and inactivating NLRP3 inflammasomes, which may contribute to GDM treatment.
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Affiliation(s)
- Haiyu Zhang
- Department of Prenatal Diagnosis, Weifang People's Hospital, Weifang 261041, Shandong, China
| | - Shoujing Luan
- Department of Endocrinology and Metabolism, Weifang People's Hospital, Weifang 261041, Shandong, China
| | - Xiao Xiao
- Department of Endocrinology and Metabolism, Weifang People's Hospital, Weifang 261041, Shandong, China
| | - Lingyu Lin
- Clinical Laboratory, Weifang People's Hospital, Weifang 261041, Shandong, China
| | - Xiaowei Zhao
- Department of Prenatal Diagnosis, Weifang People's Hospital, Weifang 261041, Shandong, China
| | - Xueyao Liu
- Clinical Laboratory, Weifang People's Hospital, Weifang 261041, Shandong, China.
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