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Rawal S, Randhawa V, Rizvi SHM, Sachan M, Wara AK, Pérez-Cremades D, Weisbrod RM, Hamburg NM, Feinberg MW. miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signalling. Cardiovasc Res 2024; 120:1693-1712. [PMID: 38703377 PMCID: PMC11587565 DOI: 10.1093/cvr/cvae102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 03/04/2024] [Accepted: 05/02/2024] [Indexed: 05/06/2024] Open
Abstract
AIMS Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs orchestrate multiple signalling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear. METHODS AND RESULTS miRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose-containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxidized low density lipoprotein (oxLDL)-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation [Interleukin (lL)-1β, TNF-α, and IL-6]. Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signalling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-Seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p-treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes. CONCLUSION These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.
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MESH Headings
- Animals
- MicroRNAs/metabolism
- MicroRNAs/genetics
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Macrophages/metabolism
- Macrophages/pathology
- Signal Transduction
- Humans
- Mice, Knockout
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Atherosclerosis/genetics
- Male
- Mice, Inbred C57BL
- Disease Models, Animal
- Lipoproteins, LDL/metabolism
- Succinic Acid/metabolism
- Plaque, Atherosclerotic
- Mice
- Receptors, LDL/genetics
- Receptors, LDL/deficiency
- Receptors, LDL/metabolism
- Aortic Diseases/pathology
- Aortic Diseases/metabolism
- Aortic Diseases/genetics
- Aortic Diseases/prevention & control
- Aortic Diseases/immunology
- Cells, Cultured
- Gene Expression Regulation
- Diabetic Angiopathies/metabolism
- Diabetic Angiopathies/genetics
- Diabetic Angiopathies/pathology
- Diabetic Angiopathies/prevention & control
- Female
- Middle Aged
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Affiliation(s)
- Shruti Rawal
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Vinay Randhawa
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Syed Husain Mustafa Rizvi
- Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA
- Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Madhur Sachan
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Akm Khyrul Wara
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Daniel Pérez-Cremades
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
- Department of Physiology, University of Valencia, INCLIVA Biomedical Research Institute, Valencia 46010, Spain
| | - Robert M Weisbrod
- Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA
- Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Naomi M Hamburg
- Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA
- Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Mark W Feinberg
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
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Abbas A, Almaghrbi H, Giordo R, Zayed H, Pintus G. Pathogenic mechanisms, diagnostic, and therapeutic potential of microvesicles in diabetes and its complications. Arch Biochem Biophys 2024; 761:110168. [PMID: 39349130 DOI: 10.1016/j.abb.2024.110168] [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: 08/06/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/02/2024]
Abstract
Extracellular vesicles (EVs), particularly microvesicles (MVs), have gained significant attention for their role as mediators of intercellular communication in both physiological and pathological contexts, including diabetes mellitus (DM) and its complications. This review provides a comprehensive analysis of the emerging roles of MVs in the pathogenesis of diabetes and associated complications such as nephropathy, retinopathy, cardiomyopathy, and neuropathy. MVs, through their cargo of proteins, lipids, mRNAs, and miRNAs, regulate critical processes like inflammation, oxidative stress, immune responses, and tissue remodeling, all of which contribute to the progression of diabetes and its complications. We examine the molecular mechanisms underlying MVs' involvement in these pathological processes and discuss their potential as biomarkers and therapeutic tools, particularly for drug delivery. Despite promising evidence, challenges remain in isolating and characterizing MVs, understanding their molecular mechanisms, and validating them for clinical use. Advanced techniques such as single-cell RNA sequencing and proteomics are required to gain deeper insights. Improved isolation and purification methods are essential for translating MVs into clinical applications, with potential to develop novel diagnostic and therapeutic strategies to improve patient outcomes in diabetes.
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Affiliation(s)
- Alaa Abbas
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Heba Almaghrbi
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Roberta Giordo
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, 505055, Dubai, United Arab Emirates; Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, 07100, Sassari, Italy
| | - Hatem Zayed
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, 07100, Sassari, Italy; Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research, University of Sharjah, University City Rd, Sharjah, 27272, United Arab Emirates.
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3
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Odimegwu CL, Uwaezuoke SN, Chikani UN, Mbanefo NR, Adiele KD, Nwolisa CE, Eneh CI, Ndiokwelu CO, Okpala SC, Ogbuka FN, Odo KE, Ohuche IO, Obiora-Izuka CE. Targeting the Epigenetic Marks in Type 2 Diabetes Mellitus: Will Epigenetic Therapy Be a Valuable Adjunct to Pharmacotherapy? Diabetes Metab Syndr Obes 2024; 17:3557-3576. [PMID: 39323929 PMCID: PMC11423826 DOI: 10.2147/dmso.s479077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/03/2024] [Indexed: 09/27/2024] Open
Abstract
Although genetic, environmental, and lifestyle factors largely contribute to type 2 diabetes mellitus (T2DM) risk, the role of epigenetics in its pathogenesis is now well established. The epigenetic mechanisms in T2DM mainly consist of DNA methylation, histone modifications and regulation by noncoding RNAs (ncRNAs). For instance, DNA methylation at CpG islands in the promoter regions of specific genes encoding insulin signaling and glucose metabolism suppresses these genes. Modulating the enzyme mediators of these epigenetic marks aims to restore standard gene expression patterns and improve glycemic control. In targeting these epigenetic marks, using epigenetic drugs such as DNA methyltransferase (DNAMT), histone deacetylase (HDAC) and histone acetyltransferase (HAT) inhibitors has led to variable success in humans and experimental murine models. Specifically, the United States' Food and Drug Administration (US FDA) has approved DNAMT inhibitors like 5-azacytidine and 5-aza-2'-deoxycytidine for use in diabetic retinopathy: a T2DM microvascular complication. These DNAMT inhibitors block the genes for methylation of mitochondrial superoxide dismutase 2 (SOD2) and matrix metallopeptidase 9 (MMP-9): the epigenetic marks in diabetic retinopathy. Traditional pharmacotherapy with metformin also have epigenetic effects in T2DM and positively alter disease outcomes when combined with epigenetic drugs like DNAMT and HDAC inhibitors, raising the prospect of using epigenetic therapy as a valuable adjunct to pharmacotherapy. However, introducing small interfering RNAs (siRNAs) in cells to silence specific target genes remains in the exploratory phase. Future research should focus on regulating gene expression in T2DM using long noncoding RNA (lncRNA) molecules, another type of ncRNA. This review discusses the epigenetics of T2DM and that of its macro- and microvascular complications, and the potential benefits of combining epigenetic therapy with pharmacotherapy for optimal results.
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Affiliation(s)
- Chioma Laura Odimegwu
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Samuel Nkachukwu Uwaezuoke
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Ugo N Chikani
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Ngozi Rita Mbanefo
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Ken Daberechi Adiele
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | | | - Chizoma Ihuarula Eneh
- Department of Pediatrics, Enugu State University Teaching Hospital (ESUTH), Enugu, Nigeria
| | - Chibuzo Obiora Ndiokwelu
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Somkenechi C Okpala
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
| | - Francis N Ogbuka
- Department of Pediatrics, Enugu State University Teaching Hospital (ESUTH), Enugu, Nigeria
| | - Kenneth E Odo
- Department of Pediatrics, the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla Enugu, Nigeria
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Yadav M, Verma S, Tiwari P, Mugale MN. Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives. Life Sci 2024; 353:122934. [PMID: 39089644 DOI: 10.1016/j.lfs.2024.122934] [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: 05/09/2024] [Revised: 06/26/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.
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Affiliation(s)
- Manisha Yadav
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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5
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Ma N, Liu W, Xu N, Yin D, Zheng P, Wang G, Hui Y, Zhang J, Han G, Yang C, Lu Y, Cheng X. Relationship between circulating thrombospondin-1 messenger ribonucleic acid and microribonucleic acid-194 levels in Chinese patients with type 2 diabetic kidney disease: The outcomes of a case-control study. J Diabetes Investig 2024; 15:1248-1258. [PMID: 38932465 PMCID: PMC11363100 DOI: 10.1111/jdi.14252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/16/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
AIMS/INTRODUCTION We investigated the relationship of circulating TSP-1 mRNA and miR-194 with diabetic kidney disease's degree. MATERIALS AND METHODS We enrolled 167 hospitalized type 2 diabetes patients in the endocrinology department. Patients were split into three groups according to urinary microalbumin: A, B and C. The control group comprised healthy outpatients (n = 163). The quantities of microribonucleic acid (miR)-194 and thrombospondin-1 (TSP-1) messenger ribonucleic acid (mRNA) in the participants' circulation were measured using a quantitative real-time polymerase chain reaction. RESULTS Circulating TSP-1 mRNA (P = 0.024) and miR-194 (P = 0.029) expressions significantly increased in type 2 diabetes patients. Circulating TSP-1 mRNA (P = 0.040) and miR-194 (P = 0.007) expression levels differed significantly among the three groups; circulating TSP-1 mRNA expression increased with urinary microalbumin. However, miR-194 declined in group B and increased in group C. Circulating TSP-1 mRNA was positively correlated with cystatin-c (r = 0.281; P = 0.021) and microalbumin/creatinine ratio (UmALB/Cr; r = 0.317; P = 0.009); miR-194 was positively correlated with UmALB/Cr (r = 0.405; P = 0.003). Stepwise multivariate linear regression analysis showed cystatin-c (β = 0.578; P = 0.021) and UmALB/Cr (β = 0.001; P = 0.009) as independent factors for TSP-1 mRNA; UmALB/Cr (β = 0.005; P = 0.028) as an independent factor for miR194. Areas under the curve for circulating TSP-1 mRNA and miR194 were 0.756 (95% confidence interval 0.620-0.893; sensitivity 0.69 and specificity 0.71, P < 0.01) and 0.584 (95% confidence interval 0.421-0.748; sensitivity 0.54 and specificity 0.52, P < 0.01), respectively. CONCLUSIONS Circulating TSP-1 mRNA and miR-194 expressions significantly increased in type 2 diabetes patients. The microalbumin group had lower levels of miR-194 (a risk factor that is valuable for type 2 diabetes kidney disease evaluation).
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Affiliation(s)
- Ning Ma
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
- Department of Endocrinology and MetabolismFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Weiwei Liu
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Ning Xu
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Dong Yin
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Ping Zheng
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Guofeng Wang
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Yuan Hui
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Jiping Zhang
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Guanjun Han
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Chuanhui Yang
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Yan Lu
- Department of Endocrinology and MetabolismFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Xingbo Cheng
- Department of Endocrinology and MetabolismFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
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Bonet ML, Ribot J, Sánchez J, Palou A, Picó C. Early Life Programming of Adipose Tissue Remodeling and Browning Capacity by Micronutrients and Bioactive Compounds as a Potential Anti-Obesity Strategy. Cells 2024; 13:870. [PMID: 38786092 PMCID: PMC11120104 DOI: 10.3390/cells13100870] [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: 04/09/2024] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024] Open
Abstract
The early stages of life, especially the period from conception to two years, are crucial for shaping metabolic health and the risk of obesity in adulthood. Adipose tissue (AT) plays a crucial role in regulating energy homeostasis and metabolism, and brown AT (BAT) and the browning of white AT (WAT) are promising targets for combating weight gain. Nutritional factors during prenatal and early postnatal stages can influence the development of AT, affecting the likelihood of obesity later on. This narrative review focuses on the nutritional programming of AT features. Research conducted across various animal models with diverse interventions has provided insights into the effects of specific compounds on AT development and function, influencing the development of crucial structures and neuroendocrine circuits responsible for energy balance. The hormone leptin has been identified as an essential nutrient during lactation for healthy metabolic programming against obesity development in adults. Studies have also highlighted that maternal supplementation with polyunsaturated fatty acids (PUFAs), vitamin A, nicotinamide riboside, and polyphenols during pregnancy and lactation, as well as offspring supplementation with myo-inositol, vitamin A, nicotinamide riboside, and resveratrol during the suckling period, can impact AT features and long-term health outcomes and help understand predisposition to obesity later in life.
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Affiliation(s)
- M. Luisa Bonet
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
- Artificial Intelligence Research Institute of the Balearic Islands (IAIB), University of the Balearic Islands, 07122 Palma, Spain
| | - Joan Ribot
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
| | - Juana Sánchez
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
| | - Andreu Palou
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
- Artificial Intelligence Research Institute of the Balearic Islands (IAIB), University of the Balearic Islands, 07122 Palma, Spain
| | - Catalina Picó
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
- Artificial Intelligence Research Institute of the Balearic Islands (IAIB), University of the Balearic Islands, 07122 Palma, Spain
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Burton MA, Antoun E, Garratt ES, Westbury L, Dennison EM, Harvey NC, Cooper C, Patel HP, Godfrey KM, Lillycrop KA. The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults. FASEB J 2024; 38:e23423. [PMID: 38294260 PMCID: PMC10952661 DOI: 10.1096/fj.202301089rr] [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: 06/01/2023] [Revised: 12/08/2023] [Accepted: 12/29/2023] [Indexed: 02/01/2024]
Abstract
Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR. sncRNA expression including miRNAs, transfer RNAs (tRNAs), tRNA-associated fragments (tRFs), and piwi-interacting RNAs (piRNAs) was measured in serum from 21 healthy and 21 sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) and HOMA2-IR. Associations with age, sarcopenia and HOMA2-IR were examined and predicted gene targets and biological pathways characterized. Of the total sncRNA among healthy controls, piRNAs were most abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), and tRFs (0.5%). Age was associated (FDR < 0.05) with 2 miRNAs, 58 tRNAs, and 14 tRFs, with chromatin organization, WNT signaling, and response to stress enriched among gene targets. Sarcopenia was nominally associated (p < .05) with 12 tRNAs, 3 tRFs, and 6 piRNAs, with target genes linked to cell proliferation and differentiation such as Notch Receptor 1 (NOTCH1), DISC1 scaffold protein (DISC1), and GLI family zinc finger-2 (GLI2). HOMA2-IR was nominally associated (p<0.05) with 6 miRNAs, 9 tRNAs, 1 tRF, and 19 piRNAs, linked with lysine degradation, circadian rhythm, and fatty acid biosynthesis pathways. These findings identify changes in circulating sncRNA expression in human serum associated with chronological age, sarcopenia, and IR. These may have clinical utility as circulating biomarkers of ageing and age-associated pathologies and provide novel targets for therapeutic intervention.
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Affiliation(s)
- Mark A. Burton
- Human Development and Health Academic Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
| | - Elie Antoun
- Human Development and Health Academic Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
| | - Emma S. Garratt
- Human Development and Health Academic Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK
| | - Leo Westbury
- MRC Lifecourse Epidemiology CentreUniversity of SouthamptonSouthamptonUK
| | - Elaine M. Dennison
- MRC Lifecourse Epidemiology CentreUniversity of SouthamptonSouthamptonUK
- Victoria University of WellingtonWellingtonNew Zealand
| | - Nicholas C. Harvey
- NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK
- MRC Lifecourse Epidemiology CentreUniversity of SouthamptonSouthamptonUK
| | - Cyrus Cooper
- NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK
- MRC Lifecourse Epidemiology CentreUniversity of SouthamptonSouthamptonUK
| | - Harnish P. Patel
- NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK
- MRC Lifecourse Epidemiology CentreUniversity of SouthamptonSouthamptonUK
- Academic Geriatric Medicine, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
| | - Keith M. Godfrey
- Human Development and Health Academic Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK
- MRC Lifecourse Epidemiology CentreUniversity of SouthamptonSouthamptonUK
| | - Karen A. Lillycrop
- Human Development and Health Academic Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK
- Biological SciencesUniversity of SouthamptonSouthamptonUK
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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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9
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Burada E, Roșu MM, Sandu RE, Burada F, Cucu MG, Streață I, Petre-Mandache B, Popescu-Hobeanu G, Cara ML, Țucă AM, Pinoșanu E, Albu CV. miR-499a rs3746444 A>G Polymorphism Is Correlated with Type 2 Diabetes Mellitus and Diabetic Polyneuropathy in a Romanian Cohort: A Preliminary Study. Genes (Basel) 2023; 14:1543. [PMID: 37628595 PMCID: PMC10454730 DOI: 10.3390/genes14081543] [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: 07/06/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a common metabolic disorder that results from complex interactions of both environmental and genetic factors. Many single nucleotide polymorphisms (SNPs), including noncoding RNA genes, have been investigated for their association with susceptibility to T2DM and its complications, with little evidence available regarding Caucasians. The aim of the present study was to establish whether four miRNA SNPs (miR-27a rs895819 T>C, miR-146a rs2910164 G>C, miR-196a2 rs11614913 C>T, and miR-499a rs3746444 A>G) are correlated with susceptibility to T2DM and/or diabetic polyneuropathy (DPN) in a Romanian population. A total of 167 adult T2DM patients and 324 age- and sex-matched healthy controls were included in our study. miRNA SNPs were detected by real-time PCR using a TaqMan genotyping assay. A significant association with T2DM was observed only for the miR-499a rs3746444 A>G SNP in all the tested models, and the frequencies of both the miR-499a rs3746444 AG and the GG genotypes were higher in the T2DM patients compared to the controls. No correlation was observed for the miR-27a rs895819 T>C, miR-146a rs2910164 G>C, or miR-196a2 rs11614913 C>T SNPs in any genetic model. When we assessed the association of these SNPs with DPN separately, we found a positive association for the miR-499a rs3746444 SNP in both codominant and dominant models (OR 6.47, 95% CI: 1.71-24.47; OR 2.30, 95% CI: 1.23-4.29, respectively). In conclusion, this study shows that miR-499a rs3746444 A>G may influence both T2DM and DPN susceptibility, with carriers of the GG genotype and the G allele being at an increased risk in the Romanian population.
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Affiliation(s)
- Emilia Burada
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (E.B.); (A.-M.Ț.)
- Department of Neurology, Clinical Hospital of Neuropsychiatry Craiova, 200473 Craiova, Romania; (R.E.S.); (E.P.); (C.V.A.)
| | - Maria-Magdalena Roșu
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania;
| | - Raluca Elena Sandu
- Department of Neurology, Clinical Hospital of Neuropsychiatry Craiova, 200473 Craiova, Romania; (R.E.S.); (E.P.); (C.V.A.)
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Florin Burada
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (M.G.C.); (I.S.); (B.P.-M.); (G.P.-H.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Mihai Gabriel Cucu
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (M.G.C.); (I.S.); (B.P.-M.); (G.P.-H.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Ioana Streață
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (M.G.C.); (I.S.); (B.P.-M.); (G.P.-H.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Bianca Petre-Mandache
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (M.G.C.); (I.S.); (B.P.-M.); (G.P.-H.)
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Gabriela Popescu-Hobeanu
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (M.G.C.); (I.S.); (B.P.-M.); (G.P.-H.)
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Monica-Laura Cara
- Department of Public Health, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Anca-Maria Țucă
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (E.B.); (A.-M.Ț.)
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Elena Pinoșanu
- Department of Neurology, Clinical Hospital of Neuropsychiatry Craiova, 200473 Craiova, Romania; (R.E.S.); (E.P.); (C.V.A.)
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Carmen Valeria Albu
- Department of Neurology, Clinical Hospital of Neuropsychiatry Craiova, 200473 Craiova, Romania; (R.E.S.); (E.P.); (C.V.A.)
- Department of Neurology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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10
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Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
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11
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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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12
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Beilerli A, Kudriashov V, Sufianov A, Kostin A, Begliarzade S, Ilyasova T, Liang Y, Mukhamedzyanov A, Beylerli O. Regulation and mechanism of action of miRNAs on insulin resistance in skeletal muscles. Noncoding RNA Res 2023; 8:218-223. [PMID: 36860209 PMCID: PMC9969252 DOI: 10.1016/j.ncrna.2023.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/14/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
The term "insulin resistance" is commonly understood as a decrease in the response of insulin-sensitive tissues to insulin at its sufficient concentration, leading to chronic compensatory hyperinsulinemia. Type 2 diabetes mellitus is based on mechanisms consisting in the development of resistance to insulin in target cells (hepatocytes, adipocytes, skeletal muscle cells), resulting in the termination of an adequate response of these tissues to interaction with insulin. Since in healthy people 75-80% of glucose is utilized by skeletal muscle, it is more likely that the main cause of insulin resistance is impaired insulin-stimulated glucose utilization by skeletal muscle. With insulin resistance, skeletal muscles do not respond to insulin at its normal concentration, thereby determining an increase in glucose levels and a compensatory increase in insulin production in response to this. Despite many years of studying diabetes mellitus (DM) and insulin resistance, the molecular genetic basis for the development of these pathological conditions is still the subject of numerous studies. Recent studies point to the involvement of microRNAs (miRNAs) as dynamic modifiers in the pathogenesis of various diseases. MiRNAs are a separate class of RNA molecules that play a key role in the post-transcriptional regulation of gene expression. Recent studies have shown that miRNAs dysregulation in DM is closely related to miRNAs regulatory abilities in skeletal muscle insulin resistance. This gave grounds to consider an increase or decrease in the expression of individual microRNAs in muscle tissue and consider them as new biomarkers for diagnosing and monitoring insulin resistance and promising directions for targeted therapy. This review presents the results of scientific studies examining the role of miRNAs in skeletal muscle insulin resistance.
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Affiliation(s)
- Aferin Beilerli
- Department of Obstetrics and Gynecology, Tyumen State Medical University, 54 Odesskaya Street, 625023, Tyumen, Russia
| | | | - Albert Sufianov
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Andrey Kostin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia, Moscow, Russia
| | - Sema Begliarzade
- Republican Clinical Perinatal Center, Ufa, Republic of Bashkortostan, 450106, Russia
| | - Tatiana Ilyasova
- Department of Internal Diseases, Bashkir State Medical University, Ufa, Republic of Bashkortostan, 450008, Russia
| | - Yanchao Liang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | | | - Ozal Beylerli
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Corresponding author. Рeoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russian Federation.
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13
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Ataei S, Ganjali S, Banach M, Karimi E, Sahebkar A. The effect of PCSK9 immunization on the hepatic level of microRNAs associated with the PCSK9/LDLR pathway. Arch Med Sci 2023; 19:203-208. [PMID: 36817686 PMCID: PMC9897094 DOI: 10.5114/aoms/152000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/09/2022] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) are a class of gene expression epigenetic regulators that play roles in regulating genes involved in cholesterol homeostasis, including low-density lipoprotein receptor (LDLR) and PCSK9; therefore, miRNAs have been suggested as potential therapeutic targets for treating cardiometabolic disorders. Thus, the present study aimed to assess the effect of immunotherapy with the PCSK9 peptide vaccine on the hepatic expression levels of microRNAs associated with the LDLR pathway, including miRNA-27a, miRNA-30c, and miRNA-191, in normal vaccinated mice. MATERIAL AND METHODS PCSK9 immunogenic peptide and 0.4% alum adjuvant were mixed at a 1 : 1 ratio and used as a vaccine formulation. Male albino mice were randomly assigned to the vaccine or control group. Mice in the vaccine group were injected four times at two-week intervals with a PCSK9 peptide vaccine, and mice in the control group were injected with phosphate-buffered saline (PBS). Animal livers were sampled 2 weeks after the last injection to assess miRNA expression levels. The hepatic expression levels of miRNA-27a, miRNA-30c, and miRNA-191 were evaluated by SYBR Green real-time PCR, quantified by a comparative (2- Δ Δ CT) method (fold change (FC)) and normalized to U6 small nuclear RNA (U6snRNA) expression as an internal control. RESULTS The hepatic expression level of miRNA-27a was significantly lower in mice following immunotherapy with the PCSK9 peptide vaccine compared to the control group (FC: 0.731 ±0.1, p = 0.027). Also, there was a borderline significantly lower hepatic expression level of miRNA-30c in the vaccinated group compared to the control (FC: 0.569 ±0.1, p = 0.078). However, no significant differences were found in the hepatic expression level of miRNA-191 between the two studied groups (FC: 0.852 ±0.1, p = 0.343). CONCLUSIONS According to the findings, the PCSK9 peptide vaccine could effectively reduce the hepatic expression level of miRNA-27a and may be helpful in the management of LDL-C level and atherosclerosis, which may be mediated through the LDLR pathway.
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Affiliation(s)
- Sarina Ataei
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shiva Ganjali
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Ehsan Karimi
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Wang M, Mao H, Chen J, Li Q, Ma W, Zhu N, Qi L, Wang J. Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves proanthocyanidins alleviate insulin-resistance via activating PI3K/AKT pathway in HepG2 cells. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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15
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Role of Adipose Tissue microRNAs in the Onset of Metabolic Diseases and Implications in the Context of the DOHaD. Cells 2022; 11:cells11233711. [PMID: 36496971 PMCID: PMC9739499 DOI: 10.3390/cells11233711] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/11/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
The worldwide epidemic of obesity is associated with numerous comorbid conditions, including metabolic diseases such as insulin resistance and diabetes, in particular. The situation is likely to worsen, as the increase in obesity rates among children will probably lead to an earlier onset and more severe course for metabolic diseases. The origin of this earlier development of obesity may lie in both behavior (changes in nutrition, physical activity, etc.) and in children's history, as it appears to be at least partly programmed by the fetal/neonatal environment. The concept of the developmental origin of health and diseases (DOHaD), involving both organogenesis and epigenetic mechanisms, encompasses such programming. Epigenetic mechanisms include the action of microRNAs, which seem to play an important role in adipocyte functions. Interestingly, microRNAs seem to play a particular role in propagating local insulin resistance to other key organs, thereby inducing global insulin resistance and type 2 diabetes. This propagation involves the active secretion of exosomes containing microRNAs by adipocytes and adipose tissue-resident macrophages, as well as long-distance communication targeting the muscles and liver, for example. Circulating microRNAs may also be useful as biomarkers for the identification of populations at risk of subsequently developing obesity and metabolic diseases.
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16
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Bibiloni P, Pomar CA, Palou A, Sánchez J, Serra F. miR-222 exerts negative regulation on insulin signaling pathway in 3T3-L1 adipocytes. Biofactors 2022; 49:365-378. [PMID: 36310379 DOI: 10.1002/biof.1914] [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: 06/14/2022] [Accepted: 10/12/2022] [Indexed: 11/10/2022]
Abstract
Increased miR-222 levels are associated with metabolic syndrome, insulin resistance, and diabetes. Moreover, rats fed an obesogenic diet during lactation have higher miR-222 content in breast milk and the offspring display greater body fat mass and impaired insulin sensitivity in adulthood. In order to investigate the molecular mechanisms involved and to dissect the specific effects of miR-222 on adipocytes, transfection with a mimic or an inhibitor of miR-222 has been conducted on 3T3-L1 preadipocytes. 3T3-L1 cells were transfected with either a mimic or an inhibitor of miR-222 and collected after 2 days (preadipocytes) or 8 days (mature adipocytes) for transcriptomic analysis. Results showed a relevant impact on pathways associated with insulin signaling, lipid metabolism and adipogenesis. Outcomes in key genes and proteins were further analyzed with quantitative reverse transcription polymerase chain reaction and Western Blotting, respectively, which displayed a general inhibition in important effectors of the identified routes under miR-222 mimic treatment in preadipocytes. Although to a lesser extent, this overall signature was maintained in differentiated adipocytes. Altogether, miR-222 exerts a direct effect in metabolic pathways of 3T3-L1 adipocytes that are relevant to adipocyte function, limiting adipogenesis and insulin signaling pathways, offering a mechanistic explanation for its reported association with metabolic diseases.
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Affiliation(s)
- Pere Bibiloni
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Catalina A Pomar
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Andreu Palou
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Juana Sánchez
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Francisca Serra
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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17
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Checa-Ros A, D’Marco L. Role of Omega-3 Fatty Acids as Non-Photic Zeitgebers and Circadian Clock Synchronizers. Int J Mol Sci 2022; 23:12162. [PMID: 36293015 PMCID: PMC9603208 DOI: 10.3390/ijms232012162] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/09/2022] [Accepted: 10/10/2022] [Indexed: 10/23/2024] Open
Abstract
Omega-3 fatty acids (ω-3 FAs) are well-known for their actions on immune/inflammatory and neurological pathways, functions that are also under circadian clock regulation. The daily photoperiod represents the primary circadian synchronizer ('zeitgeber'), although diverse studies have pointed towards an influence of dietary FAs on the biological clock. A comprehensive literature review was conducted following predefined selection criteria with the aim of updating the evidence on the molecular mechanisms behind circadian rhythm regulation by ω-3 FAs. We collected preclinical and clinical studies, systematic reviews, and metanalyses focused on the effect of ω-3 FAs on circadian rhythms. Twenty animal (conducted on rodents and piglets) and human trials and one observational study providing evidence on the regulation of neurological, inflammatory/immune, metabolic, reproductive, cardiovascular, and biochemical processes by ω-3 FAs via clock genes were discussed. The evidence suggests that ω-3 FAs may serve as non-photic zeitgebers and prove therapeutically beneficial for circadian disruption-related pathologies. Future work should focus on the role of clock genes as a target for the therapeutic use of ω-3 FAs in inflammatory and neurological disorders, as well as on the bidirectional association between the molecular clock and ω-3 FAs.
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Affiliation(s)
- Ana Checa-Ros
- Department of Medicine and Surgery, Faculty of Health Sciences, Universidad Cardenal Herrera—CEU, CEU Universities, 46115 Valencia, Spain
- Aston Institute of Health and Neurosciences, School of Life & Health Sciences, Aston University, Birmingham B4 7ET, UK
| | - Luis D’Marco
- Department of Medicine and Surgery, Faculty of Health Sciences, Universidad Cardenal Herrera—CEU, CEU Universities, 46115 Valencia, Spain
- Department of Nephrology, Hospital General Universitario de Valencia, 46014 Valencia, Spain
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18
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Chen CP, Su TC, Yang MJ, Chen WT, Siao AC, Huang LR, Lin YY, Kuo YC, Chung JF, Cheng CF, Ku HC, Kao YH. Green tea epigallocatechin gallate suppresses 3T3-L1 cell growth via microRNA-143/MAPK7 pathways. Exp Biol Med (Maywood) 2022; 247:1670-1679. [PMID: 35894140 PMCID: PMC9597208 DOI: 10.1177/15353702221108925] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Green tea epigallocatechin gallate (EGCG) and microRNA (miRNA) molecules modulate obesity. Nevertheless, it is still unknown whether EGCG modulates fat cell growth via miRNA-related signaling. In this study, white preadipocytes were used to examine whether the antimitogenic effect of EGCG on fat cells is regulated by the miR-143/MAPK7 pathway. We showed that EGCG upregulated the levels of miR-143, but not miR-155, in 3T3-L1 preadipocytes. Moreover, EGCG downregulated MAPK7 mRNA and protein levels time- and dose-dependently. MAPK7 expression increased during 3T3-L1 cell proliferation. miR-143 overexpression in the absence of EGCG mimicked the effects of EGCG to suppress preadipocyte growth and MAPK7 expression, whereas knockdown of miR-143 antagonized the EGCG-altered levels of miR-143, MAPK7, and pERK1/2 and reversed the EGCG-inhibited cell growth. These findings suggest that EGCG inhibits 3T3-L1 cell growth via miR-143/MAPK7 pathway.
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Affiliation(s)
- Chia-Pei Chen
- Department of Life Sciences, National
Central University, Taoyuan 320
| | - Tsung-Chen Su
- Tea Research and Extension Station,
Council of Agriculture, Taoyuan 326
| | - Meei-Ju Yang
- Tea Research and Extension Station,
Council of Agriculture, Taoyuan 326
| | - Wen-Ting Chen
- Department of Life Sciences, National
Central University, Taoyuan 320
| | - An-Ci Siao
- Department of Life Sciences, National
Central University, Taoyuan 320
| | - Ling-Ru Huang
- Department of Life Sciences, National
Central University, Taoyuan 320
| | - Yen-Yue Lin
- Department of Life Sciences, National
Central University, Taoyuan 320,Department of Emergency Medicine,
Taoyuan Armed Forces General Hospital, Taoyuan 325,Department of Emergency Medicine,
Tri-Service General Hospital, National Defense Medical Center, Taipei 114
| | - Yow-Chii Kuo
- Department of Gastroenterology,
Landseed Hospital, Taoyuan 324
| | - Jia-Fang Chung
- Department of Pediatrics, Taipei Tzu
Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142
| | - Ching-Feng Cheng
- Department of Pediatrics, Taipei Tzu
Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142,Institute of Biomedical Sciences,
Academia Sinica, Taipei 11529,Department of Pediatrics, Tzu Chi
University, Hualien 97004
| | - Hui-Chen Ku
- Department of Pediatrics, Taipei Tzu
Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142
| | - Yung-Hsi Kao
- Department of Life Sciences, National
Central University, Taoyuan 320,Yung-Hsi Kao.
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19
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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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20
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Xu Y, Tang Z, Dai H, Hou J, Li F, Tang Z, Zhang D. MiR-195 promotes pancreatic β-cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes. Obesity (Silver Spring) 2022; 30:447-459. [PMID: 35088561 DOI: 10.1002/oby.23360] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 11/10/2021] [Accepted: 11/16/2021] [Indexed: 01/20/2023]
Abstract
OBJECTIVE The aim of this study was to research the role and underlying mechanism of miR-195 involved in pancreatic β-cell dedifferentiation induced by hyperlipemia in type 2 diabetes mellitus. METHODS High-fat-diet-induced obese C57BL/6J mice and palmitate-stimulated Min6 cells were used as the models of β-cell dedifferentiation in vivo and in vitro, respectively. The expression of miR-195 and insulin secretion during β-cell dedifferentiation were measured. Also, the influence of regulated miR-195 expression on β-cell dedifferentiation was examined. Meanwhile, the IRS-1/2/Pi3k/Akt pathway and mitofusin-2 (Mfn2) expression were investigated during β-cell dedifferentiation. RESULTS MiR-195 was upregulated during lipotoxicity-induced β-cell dedifferentiation in both in vivo and in vitro experiments, and miR-195 functionally contributed to lipotoxicity-induced β-cell dedifferentiation. Furthermore, miR-195 inhibited IRS-1/2/Pi3k/Akt pathway activation, which accompanied β-cell dedifferentiation. Mfn2, a target of miR-195, was found to be downregulated and was associated with increased mitochondrial production of reactive oxygen species during β-cell dedifferentiation. Instructively, inhibition of miR-195, at least partially, reversed the downregulation of Mfn2, restored IRS-1/2/Pi3k/Akt pathway activation, and prevented β-cell dedifferentiation. CONCLUSIONS MiR-195 promoted β-cell dedifferentiation through negatively regulating Mfn2 expression and inhibiting the IRS-1/2/Pi3k/Akt pathway, providing a promising treatment for type 2 diabetes mellitus.
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Affiliation(s)
- Yuhua Xu
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Zixuan Tang
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Hui Dai
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Jue Hou
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Fangqin Li
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Zhuqi Tang
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Dongmei Zhang
- Medical Research Center, Affiliated Hospital 2 of Nantong University, Jiangsu, China
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21
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Dubey R, Prabhakar PK, Gupta J. Epigenetics: key to improve delayed wound healing in type 2 diabetes. Mol Cell Biochem 2022; 477:371-383. [PMID: 34739665 DOI: 10.1007/s11010-021-04285-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 10/23/2021] [Indexed: 12/13/2022]
Abstract
Diabetes-related delayed wound healing is a multifactorial, nuanced, and intertwined complication that causes substantial clinical morbidity. The etiology of diabetes and its related microvascular complications is affected by genes, diet, and lifestyle factors. Epigenetic modifications such as DNA methylation, histone modifications, and post-transcriptional RNA regulation (microRNAs) are subsequently recognized as key facilitators of the complicated interaction between genes and the environment. Current research suggests that diabetes-persuaded dysfunction of epigenetic pathways, which results in changed expression of genes in target cells and cause diabetes-related complications including cardiomyopathy, nephropathy, retinopathy, delayed wound healing, etc., which are foremost drivers to diabetes-related adverse outcomes. In this paper, we discuss the role of epigenetic mechanisms in controlling tissue repair, angiogenesis, and expression of growth factors, as well as recent findings that show the alteration of epigenetic events during diabetic wound healing.
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Affiliation(s)
- Rupal Dubey
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar-Delhi G.T. Road, 144411, Phagwara, Punjab, India
| | - Pranav Kumar Prabhakar
- Department of Medical Laboratory Sciences, School of Physiotherapy and Paramedical Sciences, Lovely Professional University, 144411, Phagwara, Punjab, India
| | - Jeena Gupta
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar-Delhi G.T. Road, 144411, Phagwara, Punjab, India.
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22
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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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23
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Sałówka A, Martinez-Sanchez A. Molecular Mechanisms of Nutrient-Mediated Regulation of MicroRNAs in Pancreatic β-cells. Front Endocrinol (Lausanne) 2021; 12:704824. [PMID: 34803905 PMCID: PMC8600252 DOI: 10.3389/fendo.2021.704824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cells within the islets of Langerhans respond to rising blood glucose levels by secreting insulin that stimulates glucose uptake by peripheral tissues to maintain whole body energy homeostasis. To different extents, failure of β-cell function and/or β-cell loss contribute to the development of Type 1 and Type 2 diabetes. Chronically elevated glycaemia and high circulating free fatty acids, as often seen in obese diabetics, accelerate β-cell failure and the development of the disease. MiRNAs are essential for endocrine development and for mature pancreatic β-cell function and are dysregulated in diabetes. In this review, we summarize the different molecular mechanisms that control miRNA expression and function, including transcription, stability, posttranscriptional modifications, and interaction with RNA binding proteins and other non-coding RNAs. We also discuss which of these mechanisms are responsible for the nutrient-mediated regulation of the activity of β-cell miRNAs and identify some of the more important knowledge gaps in the field.
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Affiliation(s)
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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24
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Taxifolin and Sorghum Ethanol Extract Protect against Hepatic Insulin Resistance via the miR-195/IRS1/PI3K/AKT and AMPK Signalling Pathways. Antioxidants (Basel) 2021; 10:antiox10091331. [PMID: 34572963 PMCID: PMC8465682 DOI: 10.3390/antiox10091331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/18/2021] [Accepted: 08/21/2021] [Indexed: 12/17/2022] Open
Abstract
This study aimed to evaluate the effects of taxifolin and sorghum ethanol extract on free fatty acid (FFA)-induced hepatic insulin resistance. FFA treatment decreased glucose uptake by 16.2% compared with that in the control, whereas taxifolin and sorghum ethanol extract increased the glucose uptake. Additionally, taxifolin and sorghum ethanol extract increased the expression of p-PI3K, p-IRS1, p-AKT, p-AMPK, and p-ACC in FFA-induced hepatocytes. Furthermore, FFA treatment increased the expression of miR-195. However, compared with the FFA treatment, treatment with taxifolin and sorghum ethanol extract decreased miR-195 expression in a dose-dependent manner. Taxifolin and sorghum ethanol extract enhanced p-IRS1, p-PI3K, p-AMPK, p-AKT, and p-ACC expression by suppressing miR-195 levels in miR-195 mimic- or inhibitor-transfected cells. These results indicate that taxifolin and sorghum ethanol extract attenuate insulin resistance by regulating miR-195 expression, which suggests that taxifolin and sorghum ethanol extract may be useful antidiabetic agents.
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25
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Kesharwani D, Kumar A, Poojary M, Scaria V, Datta M. RNA sequencing reveals potential interacting networks between the altered transcriptome and ncRNome in the skeletal muscle of diabetic mice. Biosci Rep 2021; 41:BSR20210495. [PMID: 34190986 PMCID: PMC8276098 DOI: 10.1042/bsr20210495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
For a global epidemic like Type 2 diabetes mellitus (T2DM), while impaired gene regulation is identified as a primary cause of aberrant cellular physiology; in the past few years, non-coding RNAs (ncRNAs) have emerged as important regulators of cellular metabolism. However, there are no reports of comprehensive in-depth cross-talk between these regulatory elements and the potential consequences in the skeletal muscle during diabetes. Here, using RNA sequencing, we identified 465 mRNAs and 12 long non-coding RNAs (lncRNAs), to be differentially regulated in the skeletal muscle of diabetic mice and pathway enrichment analysis of these altered transcripts revealed pathways of insulin, FOXO and AMP-activated protein kinase (AMPK) signaling to be majorly over-represented. Construction of networks showed that these pathways significantly interact with each other that might underlie aberrant skeletal muscle metabolism during diabetes. Gene-gene interaction network depicted strong interactions among several differentially expressed genes (DEGs) namely, Prkab2, Irs1, Pfkfb3, Socs2 etc. Seven altered lncRNAs depicted multiple interactions with the altered transcripts, suggesting possible regulatory roles of these lncRNAs. Inverse patterns of expression were observed between several of the deregulated microRNAs (miRNAs) and the differentially expressed transcripts in the tissues. Towards validation, overexpression of miR-381-3p and miR-539-5p in skeletal muscle C2C12 cells significantly decreased the transcript levels of their targets, Nfkbia, Pik3r1 and Pi3kr1, Cdkn2d, respectively. Collectively, the findings provide a comprehensive understanding of the interactions and cross-talk between the ncRNome and transcriptome in the skeletal muscle during diabetes and put forth potential therapeutic options for improving insulin sensitivity.
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Affiliation(s)
- Devesh Kesharwani
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Amit Kumar
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Mukta Poojary
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
- GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110025, India
| | - Vinod Scaria
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
- GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110025, India
| | - Malabika Datta
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
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Świderska E, Strycharz J, Wróblewski A, Czarny P, Szemraj J, Drzewoski J, Śliwińska A. Chronic and Intermittent Hyperglycemia Modulates Expression of Key Molecules of PI3K/AKT Pathway in Differentiating Human Visceral Adipocytes. Int J Mol Sci 2021; 22:ijms22147712. [PMID: 34299331 PMCID: PMC8304829 DOI: 10.3390/ijms22147712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/15/2021] [Accepted: 07/16/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Due to its prominence in the regulation of metabolism and inflammation, adipose tissue is a major target to investigate alterations in insulin action. This hormone activates PI3K/AKT pathway which is essential for glucose homeostasis, cell differentiation, and proliferation in insulin-sensitive tissues, like adipose tissue. The aim of this work was to evaluate the impact of chronic and intermittent high glucose on the expression of biomolecules of insulin signaling pathway during the differentiation and maturation of human visceral preadipocytes. Methods: Human visceral preadipocytes (HPA-V) cells were treated with high glucose (30 mM)during the proliferation and/or differentiation and/or maturation stage. The level of mRNA (by Real-Time PCR) and protein (by Elisa tests) expression of IRS1, PI3K, PTEN, AKT2, and GLUT4 was examined after each culture stage. Furthermore, we investigated whether miR-29a-3p, miR-143-3p, miR-152-3p, miR-186-5p, miR-370-3p, and miR-374b-5p may affect the expression of biomolecules of the insulin signaling pathway. Results: Both chronic and intermittent hyperglycemia affects insulin signaling in visceral pre/adipocytes by upregulation of analyzed PI3K/AKT pathway molecules. Both mRNA and protein expression level is more dependent on stage-specific events than the length of the period of high glucose exposure. What is more, miRs expression changes seem to be involved in PI3K/AKT expression regulation in response to hyperglycemic stimulation.
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Affiliation(s)
- Ewa Świderska
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (J.S.); (A.W.); (P.C.); (J.S.)
- Correspondence: ; Tel.: +48-693-843-960
| | - Justyna Strycharz
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (J.S.); (A.W.); (P.C.); (J.S.)
| | - Adam Wróblewski
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (J.S.); (A.W.); (P.C.); (J.S.)
| | - Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (J.S.); (A.W.); (P.C.); (J.S.)
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; (J.S.); (A.W.); (P.C.); (J.S.)
| | - Józef Drzewoski
- Central Hospital of Medical University, 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, 92-213 Lodz, Poland;
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27
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Da Silva FC, Rode MP, Vietta GG, Iop RDR, Creczynski-Pasa TB, Martin AS, Da Silva R. Expression levels of specific microRNAs are increased after exercise and are associated with cognitive improvement in Parkinson's disease. Mol Med Rep 2021; 24:618. [PMID: 34184078 PMCID: PMC8258464 DOI: 10.3892/mmr.2021.12257] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 12/02/2020] [Indexed: 12/19/2022] Open
Abstract
There is a consensus regarding the efficacy of physical exercise in maintaining or improving human health; however, there are few studies examining the effect of physical exercise on the expression levels of microRNAs (miRNA/miRs) in Parkinson's disease (PD). The aim of the present study was to investigate the effects of an interval training program on a cycle ergometer on the expression levels of miR‑106a‑5p, miR‑103a‑3p and miR‑29a‑3p in serum samples from men with PD. This was a quasi‑experimental study with pre‑ and post‑testing and with a non‑equivalent group design. The participants were selected based on the eligibility criteria and subsequently classified into two groups: Experimental group and control group. The evaluations were performed at the beginning of the study (week 0) and after 8 weeks of the intervention program (week 9). The interval training program was performed on a cycle ergometer for 30 min, three times a week during an 8‑week period. The expression levels of miR‑106a‑5p, miR‑103a‑3p and miR‑29a‑3p in the experimental group were increased after physical exercise and were associated with cognitive improvement in men with PD. However, further studies are required to clarify the potential use of these circulating miRNAs as markers of adaptation to physical exercise. Collectively, the present results indicated that these three miRNAs may be associated with the exercise response and cognitive improvement in men with PD.
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Affiliation(s)
- Franciele Cascaes Da Silva
- Center for Health Sciences and Sports, Adapted Physical Activity Laboratory, Santa Catarina State University, Florianópolis, Santa Catarina 88080‑350, Brazil
| | - Michele Patrícia Rode
- Pharmaceutical Sciences Department, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88010‑970, Brazil
| | - Giovanna Grunewald Vietta
- Nucleus of Epidemiology, University of Southern Santa Catarina, Palhoça, Santa Catarina 88137‑270, Brazil
| | - Rodrigo Da Rosa Iop
- Center for Health Sciences and Sports, Adapted Physical Activity Laboratory, Santa Catarina State University, Florianópolis, Santa Catarina 88080‑350, Brazil
| | - Tânia Beatriz Creczynski-Pasa
- Pharmaceutical Sciences Department, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88010‑970, Brazil
| | - Alessandra Swarowsky Martin
- Center for Health and Sport Sciences, Physical Therapy Department, Santa Catarina State University, Florianópolis, Santa Catarina 88080‑350, Brazil
| | - Rudney Da Silva
- Center for Health Sciences and Sports, Adapted Physical Activity Laboratory, Santa Catarina State University, Florianópolis, Santa Catarina 88080‑350, Brazil
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Saxena A, Mathur N, Tiwari P, Mathur SK. Whole transcriptome RNA-seq reveals key regulatory factors involved in type 2 diabetes pathology in peripheral fat of Asian Indians. Sci Rep 2021; 11:10632. [PMID: 34017037 PMCID: PMC8137704 DOI: 10.1038/s41598-021-90148-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/06/2021] [Indexed: 01/04/2023] Open
Abstract
The prevalence of Type 2 Diabetes has reached an epidemic proportion particularly in south Asian countries. We have earlier shown that the anatomical fat distribution, termed 'thin fat phenotype' in this population indeed plays a major role for their T2D-predisposition it is indeed the sick fat or adiposopathy, which is the root cause of metabolic syndrome and diabetes and affects both-peripheral, as well as visceral adipose tissue compartments. In present study, we have attempted to unravel the altered regulatory mechanisms at the level of transcription factors, and miRNAs those may likely accounts to T2D pathophysiology in femoral subcutaneous adipose tissue. We prioritized transcription factors and protein kinases as likely upstream regulators of obtained differentially expressed genes in this RNA-seq study. An inferred network of these upstream regulators was then derived and the role of TFs and miRNAs in T2D pathophysiology was explored. In conclusions, this RNS-Seq study finds that peripheral subcutaneous adipose tissue among Asian Indians show pathology characterized by altered lipid, glucose and protein metabolism, adipogenesis defect and inflammation. A network of regulatory transcription factors, protein kinases and microRNAs have been imputed which converge on the process of adipogenesis. As the majority of these genes also showed altered expression in diabetics and some of them are also circulatory, therefore they deserve further investigation for potential clinical diagnostic and therapeutic applications.
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Affiliation(s)
- Aditya Saxena
- Department of Computer Engineering and Applications, Institute of Engineering and Technology, GLA University, Mathura, 281406, India
| | - Nitish Mathur
- Department of Endocrinology, Sawai Man Singh Medical College and Hospital, Jaipur, 302004, India
| | - Pradeep Tiwari
- Department of Endocrinology, Sawai Man Singh Medical College and Hospital, Jaipur, 302004, India
- Department of Chemistry, School of Basic Sciences, Manipal University Jaipur, Jaipur, 303007, India
| | - Sandeep Kumar Mathur
- Department of Endocrinology, Sawai Man Singh Medical College and Hospital, Jaipur, 302004, India.
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Picó C, Reis F, Egas C, Mathias P, Matafome P. Lactation as a programming window for metabolic syndrome. Eur J Clin Invest 2021; 51:e13482. [PMID: 33350459 DOI: 10.1111/eci.13482] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022]
Abstract
The concept of developmental origins of health and disease (DOHaD) was initially supported by the low birth weight and higher risk of developing cardiovascular disease in adult life, caused by nutrition restriction during foetal development. However, other programming windows have been recognized in the last years, namely lactation, infancy, adolescence and even preconception. Although the concept has been developed in order to study the impact of foetal calorie restriction in adult life, it is now recognized that maternal overweight during programming windows is also harmful to the offspring. This article explores and summarizes the current knowledge about the impact of maternal obesity and obesogenic diets during lactation in the metabolic programming towards the development of metabolic syndrome in the adult life. The impact of maternal obesity and obesogenic diets in milk quality is discussed, including the alterations in specific micro and macronutrients, as well as the impact of such alterations in the development of metabolic syndrome-associated features in the newborn, such as insulin resistance and adiposity. Moreover, the impact of milk quality and formula feeding in infants' gut microbiota, immune system maturation and in the nutrient-sensing mechanisms, namely those related to gut hormones and leptin, are also discussed under the current knowledge.
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Affiliation(s)
- Catalina Picó
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics and Obesity), University of the Balearic Islands, Palma (Mallorca), Spain.,Instituto de Investigación Sanitaria Illes Balears (IdISBa), Palma (Mallorca), Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Palma (Mallorca), Spain
| | - Flávio Reis
- Faculty of Medicine, Institute of Pharmacology & Experimental Therapeutics and Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Conceição Egas
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Center of Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | | | - Paulo Matafome
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.,Faculty of Medicine, Institute of Physiology and Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, Coimbra, Portugal.,Department of Complementary Sciences, Instituto Politécnico de Coimbra, Coimbra Health School (ESTeSC), Coimbra, Portugal
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Impact of maternal obesity and prebiotic supplementation on select maternal milk microRNA levels and correlation with offspring outcomes. Br J Nutr 2021; 127:335-343. [PMID: 33814020 DOI: 10.1017/s0007114521001197] [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] [Indexed: 12/19/2022]
Abstract
Breast milk composition varies with maternal factors including diet and confers health benefits to the neonate; however, the mechanisms mediating this protection remain incompletely understood. Our aim was to investigate the effects of supplementing a maternal high-fat/sucrose (HFS) diet with prebiotic oligofructose (OFS) on milk composition in rats and associations with offspring body composition and gut microbiota. Obese Sprague-Dawley dams consumed a control, HFS, HFS + OFS (10 % wt/wt) or HFS diet weight-matched to the HFS + OFS group (HFS-WM) during pregnancy and lactation. Pups were weaned onto a HFS diet on day 21. Milk was collected at weaning and analysed for protein, leptin and microRNA (miRNA) levels. Milk produced by HFS dams contained less protein than milk from lean controls which was normalised by OFS. Six miRNA (miR-222, miR-203a, miR-200a, miR-26a, miR-27a and miR-103) were differentially expressed in milk according to maternal diet. Milk leptin content was positively correlated with maternal body fat and faecal Enterobacteriaceae in male offspring at 24 weeks of age. Milk protein content was inversely associated with maternal body fat and body weight. miR-200a was positively associated with maternal body fat and Enterobacteriaceae in female offspring at 24 weeks of age. Correlations between milk protein and multiple milk miRNA and offspring body composition and gut microbiota differed by sex. Overall, our results suggest that obesogenic diets and prebiotic supplementation can alter the protein and miRNA levels in breast milk in rats and these milk components may explain, in part, the influence of these maternal diets on offspring body composition.
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Singh R, Ha SE, Wei L, Jin B, Zogg H, Poudrier SM, Jorgensen BG, Park C, Ronkon CF, Bartlett A, Cho S, Morales A, Chung YH, Lee MY, Park JK, Gottfried-Blackmore A, Nguyen L, Sanders KM, Ro S. miR-10b-5p Rescues Diabetes and Gastrointestinal Dysmotility. Gastroenterology 2021; 160:1662-1678.e18. [PMID: 33421511 PMCID: PMC8532043 DOI: 10.1053/j.gastro.2020.12.062] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/18/2020] [Accepted: 12/26/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Interstitial cells of Cajal (ICCs) and pancreatic β cells require receptor tyrosine kinase (KIT) to develop and function properly. Degeneration of ICCs is linked to diabetic gastroparesis. The mechanisms linking diabetes and gastroparesis are unclear, but may involve microRNA (miRNA)-mediated post-transcriptional gene silencing in KIT+ cells. METHODS We performed miRNA-sequencing analysis from isolated ICCs in diabetic mice and plasma from patients with idiopathic and diabetic gastroparesis. miR-10b-5p target genes were identified and validated in mouse and human cell lines. For loss-of-function studies, we used KIT+ cell-restricted mir-10b knockout mice and KIT+ cell depletion mice. For gain-of-function studies, a synthetic miR-10b-5p mimic was injected in multiple diabetic mouse models. We compared the efficacy of miR-10b-5p mimic treatment vs antidiabetic and prokinetic medicines. RESULTS miR-10b-5p is highly expressed in ICCs from healthy mice, but drastically depleted in ICCs from diabetic mice. A conditional knockout of mir-10b in KIT+ cells or depletion of KIT+ cells in mice leads to degeneration of β cells and ICCs, resulting in diabetes and gastroparesis. miR-10b-5p targets the transcription factor Krüppel-like factor 11 (KLF11), which negatively regulates KIT expression. The miR-10b-5p mimic or Klf11 small interfering RNAs injected into mir-10b knockout mice, diet-induced diabetic mice, and TALLYHO polygenic diabetic mice rescue the diabetes and gastroparesis phenotype for an extended period of time. Furthermore, the miR-10b-5p mimic is more effective in improving glucose homoeostasis and gastrointestinal motility compared with common antidiabetic and prokinetic medications. CONCLUSIONS miR-10b-5p is a key regulator in diabetes and gastrointestinal dysmotility via the KLF11-KIT pathway. Restoration of miR-10b-5p may provide therapeutic benefits for these disorders.
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Affiliation(s)
- Rajan Singh
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Se Eun Ha
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Lai Wei
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Byungchang Jin
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Hannah Zogg
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Sandra M Poudrier
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Brian G Jorgensen
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Chanjae Park
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Charles F Ronkon
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Allison Bartlett
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Sung Cho
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Addison Morales
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Yu Heon Chung
- Division of Biological Sciences, Wonkwang University, Iksan, Chonbuk, Korea
| | - Moon Young Lee
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada; Department of Physiology, Wonkwang Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan, Chonbuk, Korea
| | - Jong Kun Park
- Division of Biological Sciences, Wonkwang University, Iksan, Chonbuk, Korea
| | - Andrés Gottfried-Blackmore
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Linda Nguyen
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada
| | - Seungil Ro
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada.
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Luo Y, Cui C, Han X, Wang Q, Zhang C. The role of miRNAs in polycystic ovary syndrome with insulin resistance. J Assist Reprod Genet 2021; 38:289-304. [PMID: 33405004 PMCID: PMC7884539 DOI: 10.1007/s10815-020-02019-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/22/2020] [Indexed: 02/07/2023] Open
Abstract
PURPOSE This review aims to summarize the key findings of several miRNAs and their roles in polycystic ovary syndrome with insulin resistance, characterize the disease pathogenesis, and establish a new theoretical basis for diagnosing, treating, and preventing polycystic ovary syndrome. METHODS Relevant scientific literature was covered from 1992 to 2020 by searching the PubMed database with search terms: insulin/insulin resistance, polycystic ovary syndrome, microRNAs, and metabolic diseases. References of relevant studies were cross-checked. RESULTS The related miRNAs (including differentially expressed miRNAs) and their roles in pathogenesis, and possible therapeutic targets and pathways, are discussed, highlighting controversies and offering thoughts for future directions. CONCLUSION We found abundant evidence on the role of differentially expressed miRNAs with its related phenotypes in PCOS. Considering the essential role of insulin resistance in the pathogenesis of PCOS, the alterations of associated miRNAs need more research attention. We speculate that race/ethnicity or PCOS phenotype and differences in methodological differences might lead to inconsistencies in research findings; thus, several miRNA profiles need to be investigated further to qualify for the potential therapeutic targets for PCOS-IR.
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Affiliation(s)
- Yingliu Luo
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan Province, People's Republic of China
| | - Chenchen Cui
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan Province, People's Republic of China
- Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, 450003, Henan Province, People's Republic of China
| | - Xiao Han
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan Province, People's Republic of China
| | - Qian Wang
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan Province, People's Republic of China
- Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, 450003, Henan Province, People's Republic of China
| | - Cuilian Zhang
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan Province, People's Republic of China.
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The Predictive Value of miR-16, -29a and -134 for Early Identification of Gestational Diabetes: A Nested Analysis of the DALI Cohort. Cells 2021; 10:cells10010170. [PMID: 33467738 PMCID: PMC7830355 DOI: 10.3390/cells10010170] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/08/2021] [Accepted: 01/14/2021] [Indexed: 12/13/2022] Open
Abstract
Early identification of gestational diabetes mellitus (GDM) aims to reduce the risk of adverse maternal and perinatal outcomes. Currently, no circulating biomarker has proven clinically useful for accurate prediction of GDM. In this study, we tested if a panel of small non-coding circulating RNAs could improve early prediction of GDM. We performed a nested case-control study of participants from the European multicenter ‘Vitamin D and lifestyle intervention for GDM prevention (DALI)’ trial using serum samples from obese pregnant women (BMI ≥ 29 kg/m2) entailing 82 GDM cases (early- and late- GDM), and 41 age- and BMI-matched women with normal glucose tolerance (NGT) throughout pregnancy (controls). Anthropometric, clinical and biochemical characteristics were obtained at baseline (<20 weeks of gestation) and throughout gestation. Baseline serum microRNAs (miRNAs) were measured using quantitative real time PCR (qPCR). Elevated miR-16-5p, -29a-3p, and -134-5p levels were observed in women, who were NGT at baseline and later developed GDM, compared with controls who remained NGT. A combination of the three miRNAs could distinguish later GDM from NGT cases (AUC 0.717, p = 0.001, compared with fasting plasma glucose (AUC 0.687, p = 0.004)) as evaluated by area under the curves (AUCs) using Receiver Operator Characteristics (ROC) analysis. Elevated levels of individual miRNAs or a combination hereof were associated with higher odds ratios of GDM. Conclusively, circulating miRNAs early in pregnancy could serve as valuable predictive biomarkers of GDM.
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Su T, Hou J, Liu T, Dai P, Qin L, Ding L, Hu Y, Guo X. MiR-34a-5p and miR-452-5p: The Novel Regulators of Pancreatic Endocrine Dysfunction in Diabetic Zucker Rats? Int J Med Sci 2021; 18:3171-3181. [PMID: 34400887 PMCID: PMC8364455 DOI: 10.7150/ijms.62843] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/30/2021] [Indexed: 01/05/2023] Open
Abstract
Objective: The pancreatic endocrinal system dominates the regulation of blood glucose levels in vivo, and the dysfunction of pancreatic endocrine β-cells is a major cause of the occurrence and development of Type 2 diabetes (T2D). Although microRNA (miRNA) have been found to be key regulators of pancreatic β-cells proliferation, differentiation and apoptosis, the underlying mechanism remains enigmatic. The aim of this study was to identify several novel miRNAs which might be involved in the etiopathogenesis of diabetic β-cells dysfunction. Methods: The miRNA expression profiles in the pancreas of high-fat diet (HFD) fed Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats feed with normal-fat diet (NFD) were detected by using miRNA microarray chip, and individually verified the most significant factors by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the target genes related to each of the identified miRNAs and the functions of these target genes in different metabolic signaling pathways. Results: Compared with the ZL rats, a total of 24 differentially expressed miRNAs were detected in ZDF rats. Among which miR-34a-5p and miR-452-5p were the most significantly up-regulated and down-regulated respectively. These miRNAs have not been reported in rats' pancreas before. By GO and KEGG enrichment analyses, we found that miR-34a-5p could negatively regulate pancreatic β-cell proliferation through the involvement of Wnt signaling pathway. In addition, it was also found to regulate insulin secretion through the insulin signaling pathway to modulate blood glucose levels. At the same time, miR-452-5p was found to positively regulate the activity of the key rate-limiting enzyme branched-chain α-keto acid dehydrogenase-β (BCKDHB) in the catabolism of branched chain amino acids (BCAA), leading to mitochondrial dysfunction in pancreatic β-cells. Conclusions: miR-34a-5p and miR-452-5p were identified as the novel regulators of pancreatic endocrine dysfunction. These miRNAs might have the potential to be utilized as the new predictive biomarkers for the diagnosis of the occurrence and development of T2D, as well as the therapeutic targets for T2D treatment.
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Affiliation(s)
- Tong Su
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, Beijing 100078, China
| | - Jiejun Hou
- Affiliated hospital of Shan'xi University of Chinese Medicine, Xianyang, Shanxi 712000, China
| | - Tonghua Liu
- Beijing University of Chinese Medicine, Beijing, Beijing 100029, China
| | - Pei Dai
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, Beijing 100078, China
| | - LingLing Qin
- Beijing University of Chinese Medicine, Beijing, Beijing 100029, China
| | - Lei Ding
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, Beijing 100078, China
| | - Yan Hu
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, Beijing 100078, China
| | - Xiangyu Guo
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, Beijing 100078, China
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Setiawan I, Adriani L, Goenawan H, Murniati Tarawan V, Lesmana R. Effect of Differents Cowmilk and Soymilk (soy yogurt) Formulation on Blood Glucose Level and <i>Glut4</i> Gene Expression in Rats Soleus Muscle. Pak J Biol Sci 2020; 23:1607-1613. [PMID: 33274893 DOI: 10.3923/pjbs.2020.1607.1613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND OBJECTIVE Soy yogurt is fermented soy milk and its nutrient-rich with isoflavones. Soy yogurt decreases blood glucose levels by utilizing the conversion of isoflavones. This study aimed to analyze the effect of soy yogurt on blood glucose level and Glut4 gene expression on rats' soleus muscle. MATERIALS AND METHODS Twenty-five rats (eighteen-weeks old) were divided into 5 groups, e.g., the control (P0), positive control (P1, 100% yogurt) and three treatment groups (P2, 50% soy yogurt+50% yogurt; P3, 75% yogurt+25% soy yogurt and P4, 75% soy yogurt+25% yogurt). All treatment groups were treated with different soy yogurt formula and administered for 12 weeks by gavaging. Under anesthetized, rats were sacrificed, then blood samples and soleus muscle were collected and stored at -80°C until use. RNA was extracted from soleus muscle and run for Glut4 mRNA expression using (RT)-PCR. Data were analyzed using one way ANOVA and followed by post hoc test LSD (Least Significant Differences test). RESULTS There is no difference in rat body weight among groups after 12 weeks of soy yogurt consumption. Blood glucose levels were decreased at least 25% lower level compared to the control baseline by the various formulation of soy yogurt. Interestingly, there is a distinct pattern of Glut4 mRNA expression level in the soleus muscle, P1 increased the expression but not with other formulations decreased the expression (P2, P3 and P4). CONCLUSION Taken together, a different formulation of soymilk and cowmilk effectively reduces blood glucose level and modulates Glut4 mRNA expression. In addition, a specific combination of bacteria type for fermenting soy yogurt could be a key to effectiveness for modulating blood glucose levels.
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Kimna C, Lieleg O. Molecular micromanagement: DNA nanotechnology establishes spatio-temporal control for precision medicine. BIOPHYSICS REVIEWS 2020; 1:011305. [PMID: 38505628 PMCID: PMC10903406 DOI: 10.1063/5.0033378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/08/2020] [Indexed: 03/21/2024]
Abstract
Current advances in DNA nanotechnology pinpoint exciting perspectives for the design of customized, patient-specific treatments. This advance is made possible by the exceptionally high precision and specificity that are typical for DNA base pairing on the one hand and our growing ability to harness those features in synthetic, DNA-based constructs on the other hand. Modern medicine may soon benefit from recent developments in this field, especially regarding the targeted delivery of drugs and the rational interference of synthetic DNA strands with cellular oligonucleotides. In this Review, we summarize selected examples from the area of DNA nanotechnology, where the development of precisely controlled, advanced functional mechanisms was achieved. To demonstrate the high versatility of these rationally designed structures, we categorize the dynamic DNA-based materials suggested for precision medicine according to four fundamental tasks: "hold & release," "heal," "detect & measure," as well as "guide & direct." In all the biomedical applications we highlight, DNA strands not only constitute structural building blocks but allow for creating stimuli-responsive objects, serve as an active cargo, or act as molecular control/guidance tools. Moreover, we discuss several issues that need to be considered when DNA-based structures are designed for applications in the field of precision medicine. Even though the majority of DNA-based objects have not been used in clinical settings yet, recent progress regarding the stability, specificity, and control over the dynamic behavior of synthetic DNA structures has advanced greatly. Thus, medical applications of those nanoscopic objects should be feasible in the near future.
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Gharanei S, Shabir K, Brown JE, Weickert MO, Barber TM, Kyrou I, Randeva HS. Regulatory microRNAs in Brown, Brite and White Adipose Tissue. Cells 2020; 9:cells9112489. [PMID: 33207733 PMCID: PMC7696849 DOI: 10.3390/cells9112489] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and messenger RNA degradation. This regulation of gene expression by miRNAs in adipose tissue (AT) can impact on the regulation of metabolism and energy homeostasis, particularly considering the different types of adipocytes which exist in mammals, i.e., white adipocytes (white AT; WAT), brown adipocytes (brown AT; BAT), and inducible brown adipocytes in WAT (beige or brite or brown-in-white adipocytes). Indeed, an increasing number of miRNAs has been identified to regulate key signaling pathways of adipogenesis in BAT, brite AT, and WAT by acting on transcription factors that promote or inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, and MiR-193b-365 activate brown adipogenesis, whereas MiR-34a, MiR-133, MiR-155, and MiR-27b are brown adipogenesis inhibitors. Given that WAT mainly stores energy as lipids, whilst BAT mainly dissipates energy as heat, clarifying the effects of miRNAs in different types of AT has recently attracted significant research interest, aiming to also develop novel miRNA-based therapies against obesity, diabetes, and other obesity-related diseases. Therefore, this review presents an up-to-date comprehensive overview of the role of key regulatory miRNAs in BAT, brite AT, and WAT.
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Affiliation(s)
- Seley Gharanei
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Kiran Shabir
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
| | - James E. Brown
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
| | - Martin O. Weickert
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Thomas M. Barber
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
- Correspondence:
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Li D, Song H, Shuo L, Wang L, Xie P, Li W, Liu J, Tong Y, Zhang CY, Jiang X, Li J, Zhang Y. Gonadal white adipose tissue-derived exosomal MiR-222 promotes obesity-associated insulin resistance. Aging (Albany NY) 2020; 12:22719-22743. [PMID: 33197889 PMCID: PMC7746358 DOI: 10.18632/aging.103891] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 07/20/2020] [Indexed: 05/10/2023]
Abstract
In this study, we investigated the role of serum exosomal miR-222 in obesity-related insulin resistance. Bioinformatics analyses showed that miR-222 levels were significantly upregulated in the white adipose tissue of obese patients with insulin resistance (GSE25402 dataset) and in serum samples from type 2 diabetes mellitus (T2DM) patients (GSE90028 dataset). Moreover, analysis of miRNA expression in adipose tissue-specific Dicer knockout mice (GitHub dataset) and diabetic model mice (GSE81976 and GSE85101 datasets), gonadal white adipose tissue (gWAT) was the main source of serum exosomal miR-222. MiR-222 levels were significantly elevated in the serum, serum exosomes and gWAT of mice fed a high-fat diet (HFD), and there was a corresponding downregulation of IRS1 and phospho-AKT levels in their liver and skeletal muscle tissues, which correlated with impaired insulin sensitivity and glucose intolerance. These effects were abrogated by surgically removing the gWAT from the HFD-fed mice. Thus, gWAT-derived serum exosomal miR-222 appears to promote insulin resistance in the liver and skeletal muscle of HFD-fed obese mice by suppressing IRS1 expression.
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Affiliation(s)
- Dameng Li
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Huichen Song
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Linghu Shuo
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Lei Wang
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Ping Xie
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Weili Li
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Jiachen Liu
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Yafei Tong
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Chen-Yu Zhang
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Xiaohong Jiang
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Jing Li
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Yujing Zhang
- Nanjing DrumTower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
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Faheem A, Rehman K, Jabeen K, Akash MSH. Nicotine-mediated upregulation of microRNA-141 expression determines adipokine-intervened insulin resistance. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 80:103506. [PMID: 33002592 DOI: 10.1016/j.etap.2020.103506] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/10/2020] [Accepted: 09/25/2020] [Indexed: 06/11/2023]
Abstract
MicroRNAs (miRNAs) are non-coding RNAs that are associated with adipokine homeostasis and insulin resistance. Whereas, smoking can disturb metabolic homeostasis. Present study was aimed to investigate the level of miRNA-141 in experimental animal model that were exposed with graded doses of nicotine. We further aimed to investigate the possible interplay of miRNA-141 expression change with adipokine homeostasis and occurrence of insulin resistance in nicotine-exposed experimental animals. Nicotine (0.5, 1.0, 3.0 and 6.0 mg/Kg) was administered to early adolescent; postnatal days ranging from 25 to 30 Wistar rats for one month. Serum was analyzed for leptin, adipokines, IL-6, MDA, HbA1c, insulin, G6PDH, hexokinase, and lipid profile. While miRNA-141 expression level was determined in plasma. Higher doses of nicotine were associated with higher glucose, HbA1c, leptin, IL-6, MDA and lipids levels, while, insulin, adiponectin, G6PDH, hexokinase and HDL levels were lower. Higher doses of nicotine also impaired glucose tolerance and exhibited significant increase in miR-141 expression signifying that nicotine exposure may influence adipokines regulation altering glycemic profile. This is accompanied with aggravated inflammatory responses where genetic expression of miRNA-141 can be an accessible biomarker for metabolic disturbances with insulin resistance and glucose intolerance.
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Affiliation(s)
- Amna Faheem
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
| | - Kanwal Rehman
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan; Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan.
| | - Komal Jabeen
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan; Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
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Ebrahimpour S, Shahidi SB, Abbasi M, Tavakoli Z, Esmaeili A. Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) increases Nrf2 expression via miR-27a mediation to prevent memory dysfunction in diabetic rats. Sci Rep 2020; 10:15957. [PMID: 32994439 PMCID: PMC7524758 DOI: 10.1038/s41598-020-71971-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/24/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress is one of the earliest defects involved in the development of diabetes-induced cognitive impairment. Nrf2 is the master regulator of the cellular antioxidant system can be regulated by some microRNAs. The study aimed to evaluate the effects of quercetin (QC) and quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on Nrf2-controlled antioxidant genes through the redox-sensitive miR-27a. Expression levels of miR-27a, Nrf2, SOD1, GPX1, and CAT were measured by quantitative real-time PCR. Moreover, the oxidative stress parameters including total antioxidant capacity (TAC) and histological alterations were investigated. The expression level of miR-27a was significantly up-regulated in diabetic rats. While expression levels of Nrf2, SOD1, GPX1, and CAT were significantly down-regulated under diabetic condition. Interestingly, QCSPIONs decreased expression level of miR-27a and subsequently enhanced the expression levels of Nrf2, SOD1, and CAT to the control level. No significant difference was observed in the expression level of GPX1. Besides, QC in pure and especially conjugated form was able to normalize TAC and regenerate pathological lesions in STZ-diabetic rats. Our result demonstrates that QCSPIONs as an effective combined therapy can decrease miR-27a expression, which in turn increases the Nrf2 expression and responsive antioxidant genes, resulting in improvement of memory dysfunction in diabetic rats.
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Affiliation(s)
- Shiva Ebrahimpour
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, P.O. Box: 8174673441, 81746-73441, Isfahan, Iran
| | - Seyedeh Bahar Shahidi
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, P.O. Box: 8174673441, 81746-73441, Isfahan, Iran
| | - Mahnoosh Abbasi
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, P.O. Box: 8174673441, 81746-73441, Isfahan, Iran
| | - Zahra Tavakoli
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, P.O. Box: 8174673441, 81746-73441, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, P.O. Box: 8174673441, 81746-73441, Isfahan, Iran.
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Monteiro MM, Lima CR, Gomes CC, Cruz MC, Horliana ACRT, Santos MF. Lowered Expression of MicroRNAs 221 and 222 Mediate Apoptosis Induced by High Glucose in Human Periodontal Ligament Cells. Cell Biochem Biophys 2020; 78:391-398. [PMID: 32681442 DOI: 10.1007/s12013-020-00932-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 07/08/2020] [Indexed: 12/26/2022]
Abstract
Impaired periodontal healing is a common complication of diabetes mellitus (DM), frequently related to hyperglycemia. MicroRNAs 221 and 222 have been studied as biomarkers for inflammatory diseases, including diabetes, but their role in the periodontal ligament (PL) is unknown. The effects of high glucose on human PL cells death were studied, as well as the expression of microRNA-221 and microRNA-222, potentially modulated by DM. Cells were obtained from the premolar teeth of young humans and cultured for 7 days under different glucose concentrations (5 or 30 mM). MicroRNAs-221/222 expressions were evaluated by real-time RT-PCR and apoptosis by TUNEL assays. Caspase-3 expression was studied by western blotting and immunocytochemistry. High glucose increased apoptosis and caspase-3 protein expression by about 3×. MicroRNA-221 and microRNA-222 expressions decreased by nearly 40% under high glucose. MicroRNA-221 and microRNA-222 inhibition using antagomiRs increased apoptosis by 2-3×, while the expression of caspase-3, a validated target for these microRNAs, was increased by 50%. The overexpression of both microRNAs using miR mimics in high glucose cells did no effect on apoptosis but increased caspase-3 expression by 30%. In conclusion, high glucose induces apoptosis of human PL cells potentially through a reduction of microRNA-221 and microRNA-222 expression and elevation of caspase-3.
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Affiliation(s)
- Mariana M Monteiro
- Instituto de Ciencias Biomedicas, Departamento de Biologia Celular e do Desenvolvimento, Universidade de Sao Paulo, Sao Paulo, SP, Brasil
| | - Cilene R Lima
- Instituto de Ciencias Biomedicas, Departamento de Biologia Celular e do Desenvolvimento, Universidade de Sao Paulo, Sao Paulo, SP, Brasil.,Universidade Cruzeiro do Sul, Sao Paulo, SP, Brasil
| | - Cibele C Gomes
- Instituto de Ciencias Biomedicas, Departamento de Biologia Celular e do Desenvolvimento, Universidade de Sao Paulo, Sao Paulo, SP, Brasil
| | - Mario C Cruz
- Instituto de Ciencias Biomedicas, Centro de Facilidades de Apoio a Pesquisa (CEFAP-USP), Universidade de Sao Paulo, Sao Paulo, SP, Brasil
| | - Anna C R T Horliana
- Programa de Pos-Graduacao em Biofotonica Aplicada a Ciencias da Saude, Universidade Nove de Julho, Sao Paulo, Brasil
| | - Marinilce F Santos
- Instituto de Ciencias Biomedicas, Departamento de Biologia Celular e do Desenvolvimento, Universidade de Sao Paulo, Sao Paulo, SP, Brasil.
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Kaur P, Kotru S, Singh S, Behera BS, Munshi A. Role of miRNAs in the pathogenesis of T2DM, insulin secretion, insulin resistance, and β cell dysfunction: the story so far. J Physiol Biochem 2020; 76:485-502. [PMID: 32749641 DOI: 10.1007/s13105-020-00760-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 07/29/2020] [Indexed: 01/24/2023]
Abstract
Diabetes, the most common endocrine disorder, also known as a silent killer disease, is characterized by uncontrolled hyperglycemia. According to the International Diabetes Federation, there were 451 million people with diabetes mellitus worldwide in 2017. It is a multifactorial syndrome caused by genetic as well as environmental factors. Noncoding RNAs, especially the miRNAs, play a significant role in the development as well as the progression of the disease. This is on account of insulin resistance or defects in β cell function. Various miRNAs including miR-7, miR-9, miR-16, miR-27, miR-24, miR-29, miR-124a, miR-135, miR-130a, miR-144, miR-181a, and miR-375 and many more have been associated with insulin resistance and other pathogenic conditions leading to the development of the disease. These miRNAs play significant roles in various pathways underlying insulin resistance such as PI3K, AKT/GSK, and mTOR. The main target genes of these miRNAs are FOXO1, FOXA2, STAT3, and PTEN. The miRNAs carry out important functions in insulin target tissues like the adipose tissue, liver, and muscle. MiRNAs miR-9, miR-375, and miR-124a, are also associated with the secretion of insulin from pancreatic cells. There is an interplay between the miRNAs and pancreatic cell growth, especially the miRNAs affecting development and proliferation of these cells. Most of the miRNAs target more than one gene which not only justifies their use as biomarkers but also their therapeutic potential. The current review has been compiled with an aim to discuss the role of various miRNAs involved in various pathogenic mechanisms including insulin resistance, insulin secretion, and the β cell dysfunction.
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Affiliation(s)
- Prabhsimran Kaur
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India
| | - Sushil Kotru
- Max Endocrinology, Diabetes and Obesity Care Centre, Max Superspeciality Hospital, Bathinda, 151001, India
| | - Sandeep Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India
| | - Bidwan Sekhar Behera
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India.
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Lionett S, Kiel IA, Camera DM, Vanky E, Parr EB, Lydersen S, Hawley JA, Moholdt T. Circulating and Adipose Tissue miRNAs in Women With Polycystic Ovary Syndrome and Responses to High-Intensity Interval Training. Front Physiol 2020; 11:904. [PMID: 32848854 PMCID: PMC7406716 DOI: 10.3389/fphys.2020.00904] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. In women with polycystic ovary syndrome (PCOS), several miRNAs are differentially expressed compared to women without PCOS, suggesting a role for miRNAs in PCOS pathophysiology. Exercise training modulates miRNA abundance and is primary lifestyle intervention for women with PCOS. Accordingly, we measured the expression of eight circulating miRNAs selected a priori along with miRNA expression from gluteal and abdominal adipose tissue (AT) in 12 women with PCOS and 12 women matched for age and body mass index without PCOS. We also determined the miRNA expression “signatures” before and after high-intensity interval training (HIT) in 42 women with PCOS randomized to either: (1) low-volume HIT (LV-HIT, 10 × 1 min work bouts at maximal, sustainable intensity, n = 13); (2) high-volume HIT (HV-HIT, 4 × 4 min work bouts reaching 90–95% of maximal heart rate, n = 14); or (3) non-exercise control (Non-Ex, n = 15). Both HIT groups trained three times/week for 16 weeks. miRNAs were extracted from plasma, gluteal and abdominal AT, and quantified via a customized plate array containing eight miRNAs associated with PCOS and/or exercise training responses. Basal expression of circulating miRNA-27b (c-miR-27b), implicated in fatty acid metabolism, adipocyte differentiation and inflammation, was 1.8-fold higher in women with compared to without PCOS (P = 0.006) despite no difference in gluteal or abdominal AT miR-27b expression. Only the HV-HIT protocol increased peak oxygen uptake (VO2peak L/min; 9%, P = 0.008). There were no changes in body composition. In LV-HIT, but not HV-HIT, the expression of c-miR-27b decreased (0.5-fold, P = 0.007). None of the remaining seven circulating miRNAs changed in LV-HIT, nor was the expression of gluteal or abdominal AT miRNAs altered. Despite increased cardiorespiratory fitness, HV-HIT did not alter the expression of any circulating, gluteal or abdominal AT miRNAs. We conclude that women with PCOS have a higher basal expression of c-miR-27b compared to women without PCOS and that 16 weeks of LV-HIT reduces the expression of this miRNA in women with PCOS. Intense exercise training had little effect on the abundance of the selected miRNAs within subcutaneous AT depots in women with PCOS.
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Affiliation(s)
- Sofie Lionett
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Obstetrics and Gynecology, St. Olav's Hospital, Trondheim, Norway.,Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia
| | - Ida A Kiel
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Obstetrics and Gynecology, St. Olav's Hospital, Trondheim, Norway
| | - Donny M Camera
- Department of Health and Medical Sciences, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Eszter Vanky
- Department of Obstetrics and Gynecology, St. Olav's Hospital, Trondheim, Norway
| | - Evelyn B Parr
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia
| | - Stian Lydersen
- Regional Centre for Child and Youth Mental Health and Child Welfare, Norwegian University of Science and Technology, Trondheim, Norway
| | - John A Hawley
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia
| | - Trine Moholdt
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Obstetrics and Gynecology, St. Olav's Hospital, Trondheim, Norway
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Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. Int J Mol Sci 2020; 21:ijms21134725. [PMID: 32630698 PMCID: PMC7369709 DOI: 10.3390/ijms21134725] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022] Open
Abstract
Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.
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Gholami M, Asgarbeik S, Razi F, Esfahani EN, Zoughi M, Vahidi A, Larijani B, Amoli MM. Association of microRNA gene polymorphisms with Type 2 diabetes mellitus: A systematic review and meta-analysis. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2020; 25:56. [PMID: 33088293 PMCID: PMC7554443 DOI: 10.4103/jrms.jrms_751_19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/22/2019] [Accepted: 02/26/2020] [Indexed: 12/11/2022]
Abstract
Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with growing prevalence and increasing economic burden. Based on the role of genetics and epigenetic factors on T2DM, we aimed to carry a systematic review and meta-analysis for all miRNA gene polymorphisms and risk of T2DM. Materials and Methods: A computerized literature search was carried out on PubMed, Web of Science, Scopus, Embase, as well as references of relevant review/meta-analysis. Key search terms were “Diabetes Mellitus, Type 2,” “MicroRNAs,” and “Polymorphism, Single Nucleotide.” All types of observational studies from January 1, 1992, to November 30, 2019, were included, without language restriction. Data analysis was performed using R programming language (3.5.2). Level of heterogeneity was obtained by Cochran's Q test (P < 0.05), and subgroup analysis was performed based on ethnicity. Results: Thirty-two polymorphisms from fifteen articles were included. Meta-analysis was carried out based on minor allele frequencies. Seven studies with 2193 cases and 3963 controls were included for rs2910164 polymorphism. In subgroup analysis, there were significant results in Caucasian population in dominant model (odds ratio [OR] =1.12; 95% confidence interval [CI]: 0.83–1.51), homozygote model (OR = 1.78; 95% CI: 1.06–3.00), heterozygote model (OR = 1.77; 95% CI: 1.03–3.05), and recessive model (OR = 1.78; 95% CI: 1.07–2.96). Four studies with 2085 cases and 1933 controls were included for rs895819 polymorphism. Overall, there was no significant result for association with rs895819, but subgroup analysis revealed that minor allele significantly decreased the risk of T2DM in Caucasians by recessive model (OR = 0.34; 95% CI: 0.18–0.66), dominant model (OR = 0.70; 95% CI: 0.52–0.94), homozygote model (OR = 0.32; 95% CI: 0.16–0.62), heterozygote model (OR = 0.37; 95% CI: 0.19–0.74), allelic model (OR = 0.67; 95% CI: 0.52–0.85). Conclusion: The minor allele of rs2910164 may increase the risk of T2DM by leading to lower level of miR-146a. In contrast, minor allele of rs895819 may decrease the risk of T2DM by leading to higher level of miR-27a.
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Affiliation(s)
- Morteza Gholami
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeedeh Asgarbeik
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Razi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ensieh Nasli Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Zoughi
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Aida Vahidi
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa Mohammad Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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46
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Chemello F, Grespi F, Zulian A, Cancellara P, Hebert-Chatelain E, Martini P, Bean C, Alessio E, Buson L, Bazzega M, Armani A, Sandri M, Ferrazza R, Laveder P, Guella G, Reggiani C, Romualdi C, Bernardi P, Scorrano L, Cagnin S, Lanfranchi G. Transcriptomic Analysis of Single Isolated Myofibers Identifies miR-27a-3p and miR-142-3p as Regulators of Metabolism in Skeletal Muscle. Cell Rep 2020; 26:3784-3797.e8. [PMID: 30917329 DOI: 10.1016/j.celrep.2019.02.105] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/29/2018] [Accepted: 02/26/2019] [Indexed: 12/27/2022] Open
Abstract
Skeletal muscle is composed of different myofiber types that preferentially use glucose or lipids for ATP production. How fuel preference is regulated in these post-mitotic cells is largely unknown, making this issue a key question in the fields of muscle and whole-body metabolism. Here, we show that microRNAs (miRNAs) play a role in defining myofiber metabolic profiles. mRNA and miRNA signatures of all myofiber types obtained at the single-cell level unveiled fiber-specific regulatory networks and identified two master miRNAs that coordinately control myofiber fuel preference and mitochondrial morphology. Our work provides a complete and integrated mouse myofiber type-specific catalog of gene and miRNA expression and establishes miR-27a-3p and miR-142-3p as regulators of lipid use in skeletal muscle.
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Affiliation(s)
- Francesco Chemello
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Francesca Grespi
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Alessandra Zulian
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Pasqua Cancellara
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Etienne Hebert-Chatelain
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Paolo Martini
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Camilla Bean
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Enrico Alessio
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Lisa Buson
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Martina Bazzega
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Andrea Armani
- Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Marco Sandri
- Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy; Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CIR-Myo Myology Center, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Ruggero Ferrazza
- Department of Physics, University of Trento, Via Sommarive 14, 38123 Povo (Trento), Italy
| | - Paolo Laveder
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Graziano Guella
- Department of Physics, University of Trento, Via Sommarive 14, 38123 Povo (Trento), Italy
| | - Carlo Reggiani
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Chiara Romualdi
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Paolo Bernardi
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Luca Scorrano
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Stefano Cagnin
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CIR-Myo Myology Center, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
| | - Gerolamo Lanfranchi
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CIR-Myo Myology Center, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
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Han N, Fang HY, Jiang JX, Xu Q. Downregulation of microRNA-873 attenuates insulin resistance and myocardial injury in rats with gestational diabetes mellitus by upregulating IGFBP2. Am J Physiol Endocrinol Metab 2020; 318:E723-E735. [PMID: 31910027 DOI: 10.1152/ajpendo.00555.2018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance, and patients with GDM have a higher risk of cardiovascular disease. Multiple microRNAs (miRNAs) are reported to be involved in the regulation of myocardial injury. Moreover, miR-873 was predicted to target insulin-like growth factor binding protein 2 (IGFBP2) through bioinformatic analysis, which was further confirmed using a luciferase assay. Thus, our objective was to assess whether microRNA-873 (miR-873) affects insulin resistance and myocardial injury in an established GDM rat model. The GDM rats were treated with miR-875 mimic or inhibitor or IGFBP2 siRNA. The effects of miR-875 and IGFBP2 on the cardiac function, insulin resistance, and myocardial injury were evaluated by hemodynamic measurements, determination of biochemical indices of myocardium and serum, and insulin homeostatic model assessment. The results indicated that downregulation of miR-873 upregulated the expression of IGFBP2 and promoted the activation of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. With downregulation of miR-873 in GDM rats, the cardiac function was improved and the myocardial apoptosis was inhibited, coupled with elevated activity of superoxide dismutase, carbon monoxide synthase, and the nitric oxide content. In addition, the inhibition of miR-873 in GDM rats modulated the insulin resistance and reduced myocardial apoptosis. Overall, the data showed that inhibition of miR-873 by targeting IGFBP2 may regulate the insulin resistance and curtail myocardial injury in GDM rats through activating the PI3K/AKT/mTOR axis, thus providing a potential means of impeding the progression of GDM.
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Affiliation(s)
- Na Han
- Department of Obstetrics, Qingdao Women and Children's Hospital, Qingdao, People's Republic of China
| | - Hai-Yan Fang
- Department of Obstetrics, Qingdao Women and Children's Hospital, Qingdao, People's Republic of China
| | - Jie-Xuan Jiang
- Department of Obstetrics, Qingdao Women and Children's Hospital, Qingdao, People's Republic of China
| | - Qian Xu
- Department of Obstetrics, Qingdao Women and Children's Hospital, Qingdao, People's Republic of China
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Wang J, Pan Y, Dai F, Wang F, Qiu H, Huang X. Serum miR-195-5p is upregulated in gestational diabetes mellitus. J Clin Lab Anal 2020; 34:e23325. [PMID: 32301163 PMCID: PMC7439337 DOI: 10.1002/jcla.23325] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 03/14/2020] [Accepted: 03/16/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is defined as varying degrees of glucose intolerance with an onset or first recognition during pregnancy in women without previously diagnosed diabetes. Accumulating evidence indicates that miRNAs exert crucial roles in the pathogenesis and development of diabetes, including GDM. In the present study, we aimed to determine the clinical performance of miR-195-5p in GDM. METHODS First, the miR-195-5p expressions in serum samples from healthy pregnant women and women with GDM at 25 weeks pregnancy were detected using real-time polymerase chain reaction (RT-qPCR). Then, receive characteristic (ROC) curve was used to determine the diagnostic value of miR-195-5p in GDM. Finally, the correlation analysis of miR-195-5p expression with related clinicopathological factors was carried out to determine the clinical value of miR-195-5p in GDM. RESULTS In this study, we found that miR-195-5p expression was significantly increased in serum samples from GDM patients as compared with that in healthy pregnancies. Furthermore, miR-195-5p might be a putative biomarker for GDM diagnosis with an area under the curve (AUC) of 0.8451; the cutoff value was 1.598, sensitivity was 73.69%, specificity was 96.85%, accuracy was 81.26%, and Youden index was 70.54%. Expression of miR-195-5p was positively associated with fasting plasma glucose, one-hour plasma glucose, and two-hour plasma glucose. CONCLUSION miR-195-5p might function as a putative diagnostic biomarker for GDM and contribute to identifying at-risk mothers in pregnancy.
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Affiliation(s)
- Jianping Wang
- Department of Obstetrics and Gynecology, The second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Yuanyuan Pan
- Department of Obstetrics and Gynecology, The second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Fen Dai
- Department of Obstetrics and Gynecology, The second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Fan Wang
- Department of Obstetrics and Gynecology, The second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Haifan Qiu
- Department of Obstetrics and Gynecology, The second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Xianping Huang
- Department of Obstetrics and Gynecology, The second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
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Parrizas M, Mundet X, Castaño C, Canivell S, Cos X, Brugnara L, Giráldez-García C, Regidor E, Mata-Cases M, Franch-Nadal J, Novials A. miR-10b and miR-223-3p in serum microvesicles signal progression from prediabetes to type 2 diabetes. J Endocrinol Invest 2020; 43:451-459. [PMID: 31721085 DOI: 10.1007/s40618-019-01129-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/03/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE Type 2 diabetes frequently remains undiagnosed for years, whereas early detection of affected individuals would facilitate the implementation of timely and cost-effective therapies, hence decreasing morbidity. With the intention of identifying novel diagnostic biomarkers, we characterized the miRNA profile of microvesicles isolated from retroactive serum samples of normoglycemic individuals and two groups of subjects with prediabetes that in the following 4 years either progressed to overt diabetes or remained stable. METHODS We profiled miRNAs in serum microvesicles of a selected group of control and prediabetic individuals participating in the PREDAPS cohort study. Half of the subjects with prediabetes were diagnosed with diabetes during the 4 years of follow-up, while the glycemic status of the other half remained unchanged. RESULTS We identified two miRNAs, miR-10b and miR-223-3p, which target components of the insulin signaling pathway and whose ratio discriminates between these two subgroups of prediabetic individuals at a stage at which other features, including glycemia, are less proficient at separating them. In global, the profile of miRNAs in microvesicles of prediabetic subjects primed to progress to overt diabetes was more similar to that of diabetic patients than the profile of prediabetic subjects who did not progress. CONCLUSION We have identified a miRNA signature in serum microvesicles that can be used as a new screening biomarker to identify subjects with prediabetes at high risk of developing diabetes, hence allowing the implementation of earlier, and probably more effective, therapeutic interventions.
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Affiliation(s)
- M Parrizas
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain
- Pathogenesis and Prevention of Diabetes Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain
| | - X Mundet
- redGDPS Foundation, Madrid, Spain
- DAP-Cat Group, Research Support Unit, University Institute for Research in Primary Care Jordi Gol (IDIAPJGol), Gran Via de les Corts Catalanes, 587, 08007, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - C Castaño
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain
- Pathogenesis and Prevention of Diabetes Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain
| | - S Canivell
- DAP-Cat Group, Research Support Unit, University Institute for Research in Primary Care Jordi Gol (IDIAPJGol), Gran Via de les Corts Catalanes, 587, 08007, Barcelona, Spain
- Primary Health Care Center Sant Martí de Provençals, Catalan Health Institute, Barcelona, Spain
- Department of Internal Medicine, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - X Cos
- DAP-Cat Group, Research Support Unit, University Institute for Research in Primary Care Jordi Gol (IDIAPJGol), Gran Via de les Corts Catalanes, 587, 08007, Barcelona, Spain
- Primary Health Care Center Sant Martí de Provençals, Catalan Health Institute, Barcelona, Spain
| | - L Brugnara
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain
- Pathogenesis and Prevention of Diabetes Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain
| | - C Giráldez-García
- redGDPS Foundation, Madrid, Spain
- Preventive Medicine Service, University Hospital Infanta Elena, Madrid, Spain
- Preventive Medicine, Public Health and History of Science Department, Complutense University of Madrid, Madrid, Spain
| | - E Regidor
- redGDPS Foundation, Madrid, Spain
- Preventive Medicine, Public Health and History of Science Department, Complutense University of Madrid, Madrid, Spain
- Epidemiology and Public Health Networking Biomedical Research Centre (CIBERESP), Madrid, Spain
- Health Research Institute, Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - M Mata-Cases
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain
- redGDPS Foundation, Madrid, Spain
- DAP-Cat Group, Research Support Unit, University Institute for Research in Primary Care Jordi Gol (IDIAPJGol), Gran Via de les Corts Catalanes, 587, 08007, Barcelona, Spain
- Primary Health Care Center La Mina, Catalan Health Institute, Sant Adrià De Besòs, Barcelona, Spain
| | - J Franch-Nadal
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
- redGDPS Foundation, Madrid, Spain.
- DAP-Cat Group, Research Support Unit, University Institute for Research in Primary Care Jordi Gol (IDIAPJGol), Gran Via de les Corts Catalanes, 587, 08007, Barcelona, Spain.
- Department of Medicine, University of Barcelona, Barcelona, Spain.
| | - A Novials
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
- Pathogenesis and Prevention of Diabetes Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain.
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50
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López-Pastor AR, Infante-Menéndez J, Escribano Ó, Gómez-Hernández A. miRNA Dysregulation in the Development of Non-Alcoholic Fatty Liver Disease and the Related Disorders Type 2 Diabetes Mellitus and Cardiovascular Disease. Front Med (Lausanne) 2020; 7:527059. [PMID: 33102495 PMCID: PMC7546803 DOI: 10.3389/fmed.2020.527059] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
According to the World Health Organization, the continuing surge in obesity pandemic creates a substantial increase in incidences of metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus, and cardiovascular disease. MicroRNAs (miRNAs) belong to an evolutionarily conserved class of short (20-22 nucleotides in length) and single-stranded non-coding RNAs. In mammals, miRNAs function as critical post-transcriptional negative regulators involved not only in many biological processes but also in the development of many diseases such as NAFLD and comorbidities. More recently, it has been described that cells can secrete miRNAs in extracellular vesicles, transported by body fluids, and uptaken by other tissues regulating gene expression. Therefore, this could be a mechanism of signaling involved not only in physiological pathways but also in the development of diseases. The association of some miRNA expression profiles with certain disorders has made them very interesting molecules for diagnosis, prognosis, and disease management. The finding of specific miRNA signatures to diagnose NAFLD and related diseases could anticipate the risk of development of related complications and, actually, it is the driving force of present health strategies worldwide. In this review, we have included latest advances in knowledge about the miRNAs involved in the development of NAFLD and related diseases and examined how this knowledge could be used to identify new non-invasive biomarkers and new pharmacological interventions.
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Affiliation(s)
- Andrea R. López-Pastor
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Jorge Infante-Menéndez
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Óscar Escribano
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Almudena Gómez-Hernández
| | - Almudena Gómez-Hernández
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, Instituto de Salud Carlos III, Madrid, Spain
- Óscar Escribano
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