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Aanstoot HJ, Varkevisser RDM, Mul D, Dekker P, Birnie E, Boesten LSM, Brugts MP, van Dijk PR, Duijvestijn PHLM, Dutta S, Fransman C, Gonera RK, Hoogenberg K, Kooy A, Latres E, Loves S, Nefs G, Sas T, Vollenbrock CE, Vosjan-Noeverman MJ, de Vries-Velraeds MMC, Veeze HJ, Wolffenbuttel BHR, van der Klauw MM. Cohort profile: the 'Biomarkers of heterogeneity in type 1 diabetes' study-a national prospective cohort study of clinical and metabolic phenotyping of individuals with long-standing type 1 diabetes in the Netherlands. BMJ Open 2024; 14:e082453. [PMID: 38904129 PMCID: PMC11191834 DOI: 10.1136/bmjopen-2023-082453] [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: 11/23/2023] [Accepted: 04/30/2024] [Indexed: 06/22/2024] Open
Abstract
PURPOSE The 'Biomarkers of heterogeneity in type 1 diabetes' study cohort was set up to identify genetic, physiological and psychosocial factors explaining the observed heterogeneity in disease progression and the development of complications in people with long-standing type 1 diabetes (T1D). PARTICIPANTS Data and samples were collected in two subsets. A prospective cohort of 611 participants aged ≥16 years with ≥5 years T1D duration from four Dutch Diabetes clinics between 2016 and 2021 (median age 32 years; median diabetes duration 12 years; 59% female; mean glycated haemoglobin (HbA1c) 61 mmol/mol (7.7%); 61% on insulin pump; 23% on continuous glucose monitoring (CGM)). Physical assessments were performed, blood and urine samples were collected, and participants completed questionnaires. A subgroup of participants underwent mixed-meal tolerance tests (MMTTs) at baseline (n=169) and at 1-year follow-up (n=104). Genetic data and linkage to medical and administrative records were also available. A second cross-sectional cohort included participants with ≥35 years of T1D duration (currently n=160; median age 64 years; median diabetes duration 45 years; 45% female; mean HbA1c 58 mmol/mol (7.4%); 51% on insulin pump; 83% on CGM), recruited from five centres and measurements, samples and 5-year retrospective data were collected. FINDINGS TO DATE Stimulated residual C-peptide was detectable in an additional 10% of individuals compared with fasting residual C-peptide secretion. MMTT measurements at 90 min and 120 min showed good concordance with the MMTT total area under the curve. An overall decrease of C-peptide at 1-year follow-up was observed. Fasting residual C-peptide secretion is associated with a decreased risk of impaired awareness of hypoglycaemia. FUTURE PLANS Research groups are invited to consider the use of these data and the sample collection. Future work will include additional hormones, beta-cell-directed autoimmunity, specific immune markers, microRNAs, metabolomics and gene expression data, combined with glucometrics, anthropometric and clinical data, and additional markers of residual beta-cell function. TRIAL REGISTRATION NUMBER NCT04977635.
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Affiliation(s)
- Henk-Jan Aanstoot
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
| | | | - Dick Mul
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
| | - Pim Dekker
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
| | - Erwin Birnie
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
- Department of Genetics, UMCG, Groningen, Groningen, The Netherlands
| | - Lianne S M Boesten
- Department of Clinical Chemistry, IJsselland Ziekenhuis, Capelle aan den IJssel, The Netherlands
| | - Michael P Brugts
- Department of Internal Medicine, Ikazia Hospital, Rotterdam, The Netherlands
| | | | | | | | - Christine Fransman
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
| | - Rob K Gonera
- Department of Internal Medicine, Wilhelmina Hospital, Assen, The Netherlands
| | - Klaas Hoogenberg
- Department of Internal Medicine, Martini Ziekenhuis, Groningen, The Netherlands
| | - Adriaan Kooy
- Bethesda Diabetes Research Center & Treant, Treant Care Group, Hoogeveen, Drenthe, The Netherlands
- Department of Internal Medicine, UMCG, Groningen, Groningen, Netherlands
| | | | - Sandra Loves
- Department of Internal Medicine, Treant Care Group, Hoogeveen, Drenthe, Netherlands
| | - Giesje Nefs
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
- Department of Medical Psychology, Radboudumc, Nijmegen, The Netherlands
- Department of Medical and Clinical Psychology, Center of Research on Psychological disordersand Somatic diseases (CoRPS), Tilburg, Netherlands
| | - Theo Sas
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
- Department of Paediatrics, Division of Paediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands
| | | | | | | | - Henk J Veeze
- Diabeter Netherlands, Center for Type 1 Diabetes Care and Research, Rotterdam, The Netherlands
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Sebastiani G, Grieco GE, Bruttini M, Auddino S, Mori A, Toniolli M, Fignani D, Licata G, Aiello E, Nigi L, Formichi C, Fernandez-Tajes J, Pugliese A, Evans-Molina C, Overbergh L, Tree T, Peakman M, Mathieu C, Dotta F. A set of circulating microRNAs belonging to the 14q32 chromosome locus identifies two subgroups of individuals with recent-onset type 1 diabetes. Cell Rep Med 2024; 5:101591. [PMID: 38838677 PMCID: PMC11228666 DOI: 10.1016/j.xcrm.2024.101591] [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: 10/19/2023] [Revised: 02/02/2024] [Accepted: 05/13/2024] [Indexed: 06/07/2024]
Abstract
Circulating microRNAs (miRNAs) are linked to the onset and progression of type 1 diabetes mellitus (T1DM), thus representing potential disease biomarkers. In this study, we employed a multiplatform sequencing approach to analyze circulating miRNAs in an extended cohort of prospectively evaluated recent-onset T1DM individuals from the INNODIA consortium. Our findings reveal that a set of miRNAs located within T1DM susceptibility chromosomal locus 14q32 distinguishes two subgroups of individuals. To validate our results, we conducted additional analyses on a second cohort of T1DM individuals, confirming the identification of these subgroups, which we have named cluster A and cluster B. Remarkably, cluster B T1DM individuals, who exhibit increased expression of a set of 14q32 miRNAs, show better glycemic control and display a different blood immunomics profile. Our findings suggest that this set of circulating miRNAs can identify two different T1DM subgroups with distinct blood immunomics at baseline and clinical outcomes during follow-up.
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Affiliation(s)
- Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Marco Bruttini
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy; Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
| | - Stefano Auddino
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Alessia Mori
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy; Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
| | - Mattia Toniolli
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Elena Aiello
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | | | - Alberto Pugliese
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Carmella Evans-Molina
- Center for Diabetes and Metabolic Diseases and the Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lut Overbergh
- Katholieke Universiteit Leuven/Universitaire Ziekenhuizen, Leuven, Belgium
| | - Timothy Tree
- Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Mark Peakman
- Immunology & Inflammation Research Therapeutic Area, Sanofi, Boston, MA, USA
| | - Chantal Mathieu
- Katholieke Universiteit Leuven/Universitaire Ziekenhuizen, Leuven, Belgium
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy; Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy.
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Zhang G, Wu S, Xia G. MiR-326 sponges TET2 triggering imbalance of Th17/Treg differentiation to exacerbate pyroptosis of hepatocytes in concanavalin A-induced autoimmune hepatitis. Ann Hepatol 2024; 29:101183. [PMID: 38043702 DOI: 10.1016/j.aohep.2023.101183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/30/2023] [Accepted: 11/04/2023] [Indexed: 12/05/2023]
Abstract
INTRODUCTION AND OBJECTIVES MicroRNA-326 is abnormally expressed in autoimmune diseases, but its roles in autoimmune hepatitis (AIH) are unknown. In this study, we aimed to investigate the effect of miR-326 on AIH and the underlying mechanism. MATERIALS AND METHODS Concanavalin A was administrated to induce AIH in mice and the expression levels of miR-326 and TET2 was evaluated by qRT-PCR and western blot, respectively. The percentages of Th17 and Treg cells were evaluated by flow cytometry and their marker proteins were determined by western blot and ELISA. The mitochondrial membrane potential (MMP) and ROS level were tested with the JC-1 kit and DCFH-DA assay. The binding relationships between miR-326 and TET2 were verified by dual-luciferase reporter assay. The liver tissues were stained by the HE staining. In vitro, AML12 cells were cocultured with mouse CD4+T cells. The expression levels of pyroptosis-related proteins were assessed by western blot. RESULTS Concanavalin A triggered AIH and enhanced the expression level of miR-326 in mice. It increased both Th17/Treg ratio and the levels of their marker proteins. The expression of TET2 was decreased in AIH mice. Knockdown of miR-326 could decrease the levels of pyroptosis-related proteins, the ROS level and increase MMP. In mouse CD4+T cells, miR-326 sponged TET2 to release IL-17A. Coculture of AML12 cells with isolated CD4+T cells from miR-326 knockdown AIH mice could relieve pyroptosis. CONCLUSIONS Knockdown of miR-326 exerted anti-pyroptosis effects via suppressing TET2 and downstream NF-κB signaling to dampen AIH. We highlighted a therapeutic target in AIH.
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Affiliation(s)
- Genglin Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; Key Lab for Biotech-Drugs of National Health Commission; Key Lab for Rare & Uncommon Diseases of Shandong Province, Jinan city, Shandong province 250062, PR China
| | - Sensen Wu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan city, Shandong province 250012, PR China
| | - Guangtao Xia
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), No. 324, Jingwuweiqi Road, Jinan city, Shandong province 250021, PR China.
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Al-Nakhle H, Mohsen I, Elnaem B, Alharbi A, Alnakhli I, Almoarfi S, Fallatah J. Altered Expression of Vitamin D Metabolism Genes and Circulating MicroRNAs in PBMCs of Patients with Type 1 Diabetes: Their Association with Vitamin D Status and Ongoing Islet Autoimmunity. Noncoding RNA 2023; 9:60. [PMID: 37888206 PMCID: PMC10609170 DOI: 10.3390/ncrna9050060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/24/2023] [Accepted: 10/06/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND The immunomodulatory role of 1,25-Dihydroxy vitamin D3 (1,25(OH)2D3) is exerted through its interaction with the vitamin D receptor (VDR) present on pancreatic and immune cells. While a deficiency in vitamin D has been linked to Type 1 Diabetes Mellitus (T1DM), the exact molecular mechanism driving this down-regulation in T1DM is yet to be fully understood. This study aimed to decipher differences in the expression of genes associated with vitamin D metabolism in T1DM patients and to ascertain if there is a correlation between serum 1,25(OH)2D3 levels and the expression of these genes. We also sought to understand the influence of specific microRNAs (miRNAs) on the expression of vitamin D metabolism genes in peripheral blood mononuclear cells (PBMCs) of T1DM patients. Furthermore, the study delved into the potential implications of altered vitamin D metabolism genes and miRNAs on autoimmune processes. METHODS Utilizing real-time PCR, we assessed the expression profiles of genes encoding for 1-hydroxylases (CYP27B1) and 24-hydroxylases (CYP24A1), as well as related miRNAs, in PBMCs from 30 T1DM patients and 23 healthy controls. ELISA tests facilitated the measurement of 1,25(OH)2D3, GAD65, and IA-2 levels. RESULTS Our findings showcased downregulated CYP27B1 mRNA levels, while CYP24A1 expression remained stable compared to healthy subjects (CYP27B1, p = 0.0005; CYP24A1, p = 0.205, respectively). In T1DM patients, the levels of has-miR-216b-5p were found to be increased, while the levels of has-miR-21-5p were decreased in comparison to the control group. Notably, no correlation was identified between the expression of CYP27B1 in T1DM patients and the levels of has-miR-216b-5p, has-miR-21-5p, and 1,25(OH)2D3. A significant negative correlation was identified between CYP27B1 mRNA levels in PBMCs of T1DM and IA2, but not with GAD65. CONCLUSIONS The study highlights there were reduced levels of both CYP27B1 mRNA and has-miR-21-5p, along with elevated levels of has-miR-216b-5p in the PBMCs of T1DM. However, the absence of a correlation between the expression of CYP27B1, levels of has-miR-216b-5p, and the status of 1,25(OH)2D3 suggests the possible existence of other regulatory mechanisms. Additionally, the inverse relationship between IA2 autoantibodies and CYP27B1 expression in T1DM patients indicates a potential connection between this gene and the autoimmune processes inherent in T1DM.
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Affiliation(s)
- Hakeemah Al-Nakhle
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Munawaroh P.O. Box. 344, Saudi Arabia
| | - Ihsan Mohsen
- Pediatric Endocrine Division, Department of Pediatrics, Maternity & Children Hospital, King Salman Bin Abdulaziz Medical City, Madinah P.O. Box 42319, Saudi Arabia; (I.M.); (B.E.); (A.A.); (I.A.)
| | - Bashir Elnaem
- Pediatric Endocrine Division, Department of Pediatrics, Maternity & Children Hospital, King Salman Bin Abdulaziz Medical City, Madinah P.O. Box 42319, Saudi Arabia; (I.M.); (B.E.); (A.A.); (I.A.)
| | - Abdullah Alharbi
- Pediatric Endocrine Division, Department of Pediatrics, Maternity & Children Hospital, King Salman Bin Abdulaziz Medical City, Madinah P.O. Box 42319, Saudi Arabia; (I.M.); (B.E.); (A.A.); (I.A.)
| | - Ibtisam Alnakhli
- Pediatric Endocrine Division, Department of Pediatrics, Maternity & Children Hospital, King Salman Bin Abdulaziz Medical City, Madinah P.O. Box 42319, Saudi Arabia; (I.M.); (B.E.); (A.A.); (I.A.)
| | - Shareefa Almoarfi
- Internal Medicine and Pediatrics Division, Department of Pediatrics, Maternity & Children Hospital, King Salman Bin Abdulaziz Medical City, Madinah P.O. Box 42319, Saudi Arabia;
| | - Jameela Fallatah
- Blood Bank Division, Department of Pediatrics, Maternity & Children Hospital, King Salman Bin Abdulaziz Medical City, Madinah P.O. Box 42319, Saudi Arabia;
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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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Karamanakos G, Kokkinos A, Dalamaga M, Liatis S. Highlighting the Role of Obesity and Insulin Resistance in Type 1 Diabetes and Its Associated Cardiometabolic Complications. Curr Obes Rep 2022; 11:180-202. [PMID: 35931912 DOI: 10.1007/s13679-022-00477-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW This narrative review appraises research data on the potentially harmful effect of obesity and insulin resistance (IR) co-existence with type 1 diabetes mellitus (T1DM)-related cardiovascular (CVD) complications and evaluates possible therapeutic options. RECENT FINDINGS Obesity and IR have increasingly been emerging in patients with T1DM. Genetic, epigenetic factors, and subcutaneous insulin administration are implicated in the pathogenesis of this coexistence. Accumulating evidence implies that the concomitant presence of obesity and IR is an independent predictor of worse CVD outcomes. The prevalence of obesity and IR has increased in patients with T1DM. This increase can be partly attributed to general population trends but, additionally, to iatrogenic weight gain caused by insulin treatment. This association might be the missing link explaining the excess CVD burden observed in patients with T1DM despite optimal glycemic control. Data on newer agents for type 2 diabetes mellitus (T2DM) treatment are unraveling novel ways to challenge this aggravating coexistence.
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Affiliation(s)
- Georgios Karamanakos
- First Department of Propaedeutic Internal Medicine, Medical School, National Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, Athens, 11527, Greece.
| | - Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, Athens, 11527, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic Internal Medicine, Medical School, National Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, Athens, 11527, Greece
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Progression of Type 1 Diabetes: Circulating MicroRNA Expression Profiles Changes from Preclinical to Overt Disease. J Immunol Res 2022; 2022:2734490. [PMID: 35903753 PMCID: PMC9325579 DOI: 10.1155/2022/2734490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/01/2022] [Indexed: 11/17/2022] Open
Abstract
Objectives To evaluate the potential biological involvement of miRNA expression in the immune response and beta cell function in T1D. Methods We screened 377 serum miRNAs of 110 subjects divided into four groups: healthy individuals (control group) and patients at different stages of T1D progression, from the initial immunological manifestation presenting islet autoantibodies (AbP group) until partial and strong beta cell damage in the recent (recent T1D group) and long-term T1D, with 2 to 5 years of disease (T1D 2-5y group). Results The results revealed 69 differentially expressed miRNAs (DEMs) in relation to controls. Several miRNAs were correlated with islet autoantibodies (IA2A, GADA, and Znt8A), age, and C-peptide levels, mainly from AbP, and recent T1D groups pointing these miRNAs as relevant to T1D pathogenesis and progression. Several miRNAs were related to metabolic derangements, inflammatory pathways, and several other autoimmune diseases. Pathway analysis of putative DEM targets revealed an enrichment in pathways related to metabolic syndrome, inflammatory response, apoptosis and insulin signaling pathways, metabolic derangements, and decreased immunomodulation. One of the miRNAs' gene targets was DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2), which is an autoantigen targeted by an antibody in T1D. ROC curve analysis showed hsa-miR-16 and hsa-miR-200a-3p with AUCs greater than for glucose levels, with discriminating power for T1D prediction greater than glucose levels. Conclusions/Interpretation. Our data suggests a potential influence of DEMs on disease progression from the initial autoimmune lesion up to severe beta cell dysfunction and the role of miRNAs hsa-miR-16 and hsa-miR-200a-3p as biomarkers of T1D progression.
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Zhao Y, Cui S, Wang Y, Xu R. The Extensive Regulation of MicroRNA in Immune Thrombocytopenia. Clin Appl Thromb Hemost 2022; 28:10760296221093595. [PMID: 35536600 PMCID: PMC9096216 DOI: 10.1177/10760296221093595] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
MicroRNA (miRNA) is a small, single-stranded, non-coding RNA molecule that plays
a variety of key roles in different biological processes through
post-transcriptional regulation of gene expression. MiRNA has been proved to be
a variety of cellular processes involved in development, differentiation, signal
transduction, and is an important regulator of immune and autoimmune diseases.
Therefore, it may act as potent modulators of the immune system and play an
important role in the development of several autoimmune diseases. Immune
thrombocytopenia (ITP) is an autoimmune systemic disease characterized by a low
platelet count. Several studies suggest that like other autoimmune disorders,
miRNAs are deeply involved in the pathogenesis of ITP, interacting with the
function of innate and adaptive immune responses. In this review, we discuss
emerging knowledge about the function of miRNAs in ITP and describe miRNAs in
terms of their role in the immune system and autoimmune response. These findings
suggest that miRNA may be a useful therapeutic target for ITP by regulating the
immune system. In the future, we need to have a more comprehensive understanding
of miRNAs and how they regulate the immune system of patients with ITP.
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Affiliation(s)
- Yuerong Zhao
- 74738Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Siyuan Cui
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.,Institute of Hematology, 74738Shandong University of Traditional Chinese Medicine, Jinan, China.,Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ruirong Xu
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.,Institute of Hematology, 74738Shandong University of Traditional Chinese Medicine, Jinan, China.,Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Bahreini F, Rayzan E, Rezaei N. MicroRNAs and Diabetes Mellitus Type 1. Curr Diabetes Rev 2022; 18:e021421191398. [PMID: 33588736 DOI: 10.2174/1573399817666210215111201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/11/2020] [Accepted: 01/07/2021] [Indexed: 11/22/2022]
Abstract
Type 1 diabetes mellitus is a multifactorial, progressive, autoimmune disease with a strong genetic feature that can affect multiple organs, including the kidney, eyes, and nerves. Early detection of type 1 diabetes can help critically to avoid serious damages to these organs. MicroRNAs are small RNA molecules that act in post-transcriptional gene regulation by attaching to the complementary sequence in the 3'-untranslated region of their target genes. Alterations in the expression of microRNA coding genes are extensively reported in several diseases, such as type 1 diabetes. Presenting non-invasive biomarkers for early detection of type 1 diabetes by quantifying microRNAs gene expression level can be a significant step in biotechnology and medicine. This review discusses the area of microRNAs dysregulation in type 1 diabetes and affected molecular mechanisms involved in pancreatic islet cell formation and dysregulation in the expression of inflammatory elements as well as pro-inflammatory cytokines.
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Affiliation(s)
- Farbod Bahreini
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elham Rayzan
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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10
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Lin LN, Zhang QM, Ge YY, Luo B, Xie XX. A Review of miR-326 and Female Related Diseases. Acta Histochem Cytochem 2021; 54:79-86. [PMID: 34276101 PMCID: PMC8275862 DOI: 10.1267/ahc.20-00027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 03/07/2021] [Indexed: 12/16/2022] Open
Abstract
MicroRNA (miRNA), a non-coding single-stranded RNA molecule with 20–23 nucleotides encoded by endogenous genes, plays an essential role in maintaining normal cell function and regulating cell proliferation, differentiation, apoptosis, autophagy, and cell metabolism. The imbalance between miRNA and genes can cause a series of diseases, including malignancies. miRNA-326 (miR-326) is extensively known for its core regulation of various biological processes. This review presents an overview of the highlights of miR-326 in female-related diseases. To understand the impact of miR-326 on female disorders, we search all published studies about miR-326 having a high incidence in female conditions, including cervical cancer, endometrial cancer, breast cancer, intrauterine adhesion, and multiple autoimmune diseases. We aim to learn about the mutual regulation mechanism between miR-326 and related genes and signaling pathways, as well as to elaborate on the value of miR-326 as a potential biomarker and therapeutic target of female diseases. Our results provide reliable evidence and new strategies for treating female tumors and autoimmune diseases.
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Affiliation(s)
- Li-na Lin
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University
| | - Qing-mei Zhang
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University
- Key Laboratory Research of Preclinical Medicine of Guangxi Colleges and Universities, Guangxi Medical University
| | - Ying-ying Ge
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University
- Key Laboratory Research of Preclinical Medicine of Guangxi Colleges and Universities, Guangxi Medical University
| | - Bin Luo
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University
- Key Laboratory Research of Preclinical Medicine of Guangxi Colleges and Universities, Guangxi Medical University
| | - Xiao-xun Xie
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University
- Key Laboratory Research of Preclinical Medicine of Guangxi Colleges and Universities, Guangxi Medical University
- Key Laboratory of Early Prevention and Treatment of Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education
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11
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Zhao N, Wang Z, Cui X, Wang S, Fan C, Li Y, Shan Z, Teng W. In Vivo Inhibition of MicroRNA-326 in a NOD.H-2 h4 Mouse Model of Autoimmune Thyroiditis. Front Immunol 2021; 12:620916. [PMID: 34140947 PMCID: PMC8205278 DOI: 10.3389/fimmu.2021.620916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 05/14/2021] [Indexed: 01/06/2023] Open
Abstract
Background Previous studies reported that various miRNAs participate in autoimmune diseases, but the potential regulatory mechanism of miRNAs in autoimmune thyroiditis (AIT) needs further exploration. Objective This study aimed to further verify that miR-326 contributes to AIT by regulating Th17/Treg balance through Ets-1 using lentiviral gene delivery through tail vein and thyroid injection in NOD.H-2h4 mice. Materials and Methods Five-week-old NOD.H-2h4 mice were divided randomly into tail vein and thyroid injection groups, and each received either mmu-miR-326 sponge (LV-sponge) or lentiviral vector control. Mice were divided for tail vein injection: the therapeutic LV-ctrl, therapeutic LV-sponge, prophylactic LV-ctrl, and prophylactic LV-sponge groups. The control group was fed high-iodine water without vein injection. The thyroid infiltration of lymphocytes and serum TgAb value were investigated by thyroid hematoxylin and eosin (HE) staining and ELISA, respectively. Ets-1 and lymphocyte counts were measured by RT-PCR, western blotting, and flow cytometry. The thyroid CD4+IL-17a+ cells and CD4+Ets-1+ cells were detected by immunofluorescence, and the serum cytokines were tested by ELISA. Results In the tail vein injection groups, the thyroid inflammatory score and serum TgAb titer were significantly lower in the LV-sponge groups than in the control and LV-ctrl groups while Ets-1 protein expression in mouse spleens was increased in the LV-sponge groups. Moreover, Th17/Treg ratio declined in the LV-sponge group and decreased significantly in the prophylactic LV-sponge group (P = 0.036) tested by flow cytometry. Immunofluorescence showed that, in LV-sponge groups, CD4+IL-17a+ cells were decreased significantly (P = 0.001), while CD4+Ets-1+ cells were increased significantly in the LV-sponge group (P = 0.029). The serum IL-17/IL-10 was decreased significantly in the LV-sponge group (P < 0.05). In the thyroid injection groups, the thyroid inflammatory score and serum TgAb titer in the LV-sponge group decreased significantly compared with those in the LV-ctrl group (P < 0.05). In addition, in LV-sponge groups, CD4+IL-17a+ cells were decreased, while CD4+Ets-1+ cells were increased significantly in the inhibition group evaluated by immunofluorescence. Moreover, tail vein injection of LV-sponge resulted in much lower TgAb levels in thyroiditis compared with thyroid injection. Conclusion MiR-326 targeted therapy may be a promising approach for AIT. In addition, tail vein injection may achieve a better intervention effect than thyroid injection.
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Affiliation(s)
- Na Zhao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenzhen Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuejiao Cui
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shuo Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chenling Fan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yushu Li
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhongyan Shan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Weiping Teng
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
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12
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Mármol-Sánchez E, Luigi-Sierra MG, Castelló A, Guan D, Quintanilla R, Tonda R, Amills M. Variability in porcine microRNA genes and its association with mRNA expression and lipid phenotypes. Genet Sel Evol 2021; 53:43. [PMID: 33947333 PMCID: PMC8097994 DOI: 10.1186/s12711-021-00632-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/15/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Mature microRNAs (miRNAs) play an important role in repressing the expression of a wide range of mRNAs. The presence of polymorphic sites in miRNA genes and their corresponding 3'UTR binding sites can disrupt canonical conserved miRNA-mRNA pairings, and thus modify gene expression patterns. However, to date such polymorphic sites in miRNA genes and their association with gene expression phenotypes and complex traits are poorly characterized in pigs. RESULTS By analyzing whole-genome sequences from 120 pigs and wild boars from Europe and Asia, we identified 285 single nucleotide polymorphisms (SNPs) that map to miRNA loci, and 109,724 SNPs that are located in predicted 7mer-m8 miRNA binding sites within porcine 3'UTR. In porcine miRNA genes, SNP density is reduced compared with their flanking non-miRNA regions. By sequencing the genomes of five Duroc boars, we identified 12 miRNA SNPs that were subsequently genotyped in their offspring (N = 345, Lipgen population). Association analyses of miRNA SNPs with 38 lipid-related traits and hepatic and muscle microarray expression phenotypes recorded in the Lipgen population were performed. The most relevant detected association was between the genotype of the rs319154814 (G/A) SNP located in the apical loop of the ssc-miR-326 hairpin precursor and PPP1CC mRNA levels in the liver (q-value = 0.058). This result was subsequently confirmed by qPCR (P-value = 0.027). The rs319154814 (G/A) genotype was also associated with several fatty acid composition traits. CONCLUSIONS Our findings show a reduced variability of porcine miRNA genes, which is consistent with strong purifying selection, particularly in the seed region that plays a critical role in miRNA binding. Although it is generally assumed that SNPs mapping to the seed region are those with the most pronounced consequences on mRNA expression, we show that a SNP mapping to the apical region of ssc-miR-326 is significantly associated with hepatic mRNA levels of the PPP1CC gene, one of its predicted targets. Although experimental confirmation of such an interaction is reported in humans but not in pigs, this result highlights the need to further investigate the functional effects of miRNA polymorphisms that are located outside the seed region on gene expression in pigs.
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Affiliation(s)
- Emilio Mármol-Sánchez
- Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | - María Gracia Luigi-Sierra
- Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | - Anna Castelló
- Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.,Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
| | - Dailu Guan
- Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | - Raquel Quintanilla
- Animal Breeding and Genetics Program, Institute for Research and Technology in Food and Agriculture (IRTA), Torre Marimon, 08140, Caldes de Montbui, Spain
| | - Raul Tonda
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Marcel Amills
- Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain. .,Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
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13
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Dini S, Zakeri M, Ebrahimpour S, Dehghanian F, Esmaeili A. Quercetin‑conjugated superparamagnetic iron oxide nanoparticles modulate glucose metabolism-related genes and miR-29 family in the hippocampus of diabetic rats. Sci Rep 2021; 11:8618. [PMID: 33883592 PMCID: PMC8060416 DOI: 10.1038/s41598-021-87687-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 03/25/2021] [Indexed: 02/02/2023] Open
Abstract
Quercetin (QC) is a dietary bioflavonoid that can be conjugated with nanoparticles to facilitate its brain bioavailability. We previously showed that quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) reduced the level of blood glucose in diabetic rats. Glucose transporters (GLUTs), insulin-like growth factor-1 (IGF-1), and microRNA-29 (miR-29) play a critical role in brain glucose homeostasis. In the current study, we examined the effects of QCSPION on the expression of glucose metabolism-related genes, and the miR-29 family as a candidate regulator of glucose handling in the hippocampus of diabetic rats. Our in silico analyses introduce the miR-29 family as potential regulators of glucose transporters and IGF-1 genes. The expression level of the miR-29 family, IGF-1, GLUT1, GLUT2, GLUT3, and GLUT4 were measured by qPCR. Our results indicate that diabetes significantly results in upregulation of the miR-29 family and downregulation of the GLUT1, 2, 3, 4, and IGF-1 genes. Interestingly, QCSPIONs reduced miR-29 family expression and subsequently enhanced GLUT1, 2, 3, 4, and IGF-1expression. In conclusion, our findings suggest that QCSPION could regulate the expression of the miR-29 family, which in turn increases the expression of glucose transporters and IGF-1, thereby reducing diabetic complications.
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Affiliation(s)
- Solmaz Dini
- grid.411750.60000 0001 0454 365XDepartment of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mansoureh Zakeri
- grid.411750.60000 0001 0454 365XDepartment of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Shiva Ebrahimpour
- grid.411750.60000 0001 0454 365XDepartment of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Fariba Dehghanian
- grid.411750.60000 0001 0454 365XDepartment of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Abolghasem Esmaeili
- grid.411750.60000 0001 0454 365XDepartment of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
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14
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Abstract
Type 1 diabetes (T1D) is an autoimmune disease that resulted from the severe destruction of the insulin-producing β cells in the pancreases of individuals with a genetic predisposition. Genome-wide studies have identified HLA and other risk genes associated with T1D susceptibility in humans. However, evidence obtained from the incomplete concordance of diabetes incidence among monozygotic twins suggests that environmental factors also play critical roles in T1D pathogenesis. Epigenetics is a rapidly growing field that serves as a bridge to link T1D risk genes and environmental exposures, thereby modulating the expression of critical genes relevant to T1D development beyond the changes of DNA sequences. Indeed, there is compelling evidence that epigenetic changes induced by environmental insults are implicated in T1D pathogenesis. Herein, we sought to summarize the recent progress in terms of epigenetic mechanisms in T1D initiation and progression, and discuss their potential as biomarkers and therapeutic targets in the T1D setting.
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15
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Wadhawan A, Reynolds MA, Makkar H, Scott AJ, Potocki E, Hoisington AJ, Brenner LA, Dagdag A, Lowry CA, Dwivedi Y, Postolache TT. Periodontal Pathogens and Neuropsychiatric Health. Curr Top Med Chem 2021; 20:1353-1397. [PMID: 31924157 DOI: 10.2174/1568026620666200110161105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 02/08/2023]
Abstract
Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.
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Affiliation(s)
- Abhishek Wadhawan
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States.,Department of Psychiatry, Saint Elizabeths Hospital, Washington, D.C. 20032, United States
| | - Mark A Reynolds
- Department of Advanced Oral Sciences & Therapeutics, University of Maryland School of Dentistry, Baltimore 21201, United States
| | - Hina Makkar
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States
| | - Alison J Scott
- Department of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, United States
| | - Eileen Potocki
- VA Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, United States
| | - Andrew J Hoisington
- Air Force Institute of Technology, Wright-Patterson Air Force Base, United States
| | - Lisa A Brenner
- Departments of Psychiatry, Neurology, and Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, United States.,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, United States
| | - Aline Dagdag
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States
| | - Christopher A Lowry
- Departments of Psychiatry, Neurology, and Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, United States.,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, United States.,Department of Integrative Physiology, Center for Neuroscience and Center for Microbial Exploration, University of Colorado Boulder, Boulder, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, United States
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Alabama, United States
| | - Teodor T Postolache
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, United States.,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, United States.,Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, United States
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16
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Yi X, Cheng X. Understanding Competitive Endogenous RNA Network Mechanism in Type 1 Diabetes Mellitus Using Computational and Bioinformatics Approaches. Diabetes Metab Syndr Obes 2021; 14:3865-3945. [PMID: 34526791 PMCID: PMC8436179 DOI: 10.2147/dmso.s315488] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/24/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Type 1 diabetes mellitus (T1DM), an autoimmune disease with a genetic tendency, has an increasing prevalence. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are receiving increasing attention in disease pathogenesis. However, their roles in T1DM are poorly understood. The present study aimed at identifying signature lncRNAs and circRNAs and investigating their roles in T1DM using the competing endogenous RNA (ceRNA) network analysis. METHODS The T1DM expression profile was downloaded from Gene Expression Omnibus (GEO) database to identify the differentially expressed circRNAs, lncRNAs, and mRNAs. The biological functions of these differentially expressed circRNAs, lncRNAs, and mRNAs were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Targeting relationships of circRNA-miRNA, lncRNA-miRNA, and miRNA-mRNA were predicted, and the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was established. Finally, qRT-PCR was applied to identify the effect of hsa_circ_0002202 inhibition on the IFN-I induced macrophage inflammation. RESULTS A total of 178 circRNAs, 404 lncRNAs, and 73 mRNAs were identified to be abnormally expressed in T1DM samples. Functional enrichment analysis results indicated that the differentially expressed genes were mainly enriched in extracellular matrix components and macrophage activation. CeRNA regulatory network showed that circRNAs and lncRNAs regulate mRNAs through integrate multiple miRNAs. In addition, in vitro experiments showed that hsa_circ_0002202 inhibition suppressed the type I interferon (IFN-I)-induced macrophage inflammation. CONCLUSION In the present study, the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network in T1DM was established for the first time. We also found that hsa_circ_0002202 inhibition suppressed the IFN-I-induced macrophage inflammation. Our study may lay a foundation for future studies on the ceRNA regulatory network in T1DM.
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Affiliation(s)
- Xuanzi Yi
- Department of Medicine II, Division of Endocrinology and Diabetology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
- Correspondence: Xuanzi Yi Department of Medicine II, Division of Endocrinology and Diabetology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, GermanyTel/Fax +49 761 270-73270 Email
| | - Xu Cheng
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
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17
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Crigna AT, Samec M, Koklesova L, Liskova A, Giordano FA, Kubatka P, Golubnitschaja O. Cell-free nucleic acid patterns in disease prediction and monitoring-hype or hope? EPMA J 2020; 11:603-627. [PMID: 33144898 PMCID: PMC7594983 DOI: 10.1007/s13167-020-00226-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
Interest in the use of cell-free nucleic acids (CFNAs) as clinical non-invasive biomarker panels for prediction and prevention of multiple diseases has greatly increased over the last decade. Indeed, circulating CFNAs are attributable to many physiological and pathological processes such as imbalanced stress conditions, physical activities, extensive apoptosis of different origin, systemic hypoxic-ischemic events and tumour progression, amongst others. This article highlights the involvement of circulating CFNAs in local and systemic processes dealing with the question, whether specific patterns of CFNAs in blood, their detection, quantity and quality (such as their methylation status) might be instrumental to predict a disease development/progression and could be further utilised for accompanying diagnostics, targeted prevention, creation of individualised therapy algorithms, therapy monitoring and prognosis. Presented considerations conform with principles of 3P medicine and serve for improving individual outcomes and cost efficacy of medical services provided to the population.
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Affiliation(s)
- Adriana Torres Crigna
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Marek Samec
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lenka Koklesova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Alena Liskova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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18
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Duarte L, García-Díaz DF, Pérez-Bravo F. Body fat composition and miR-378 expression profiling in patients with type 1 diabetes. Ann Pediatr Endocrinol Metab 2020; 25:118-125. [PMID: 32615692 PMCID: PMC7336264 DOI: 10.6065/apem.1938088.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 11/12/2019] [Indexed: 02/01/2023] Open
Abstract
PURPOSE Type 1 diabetes (T1D) is an autoimmune disease that involves genetic, epigenetic, and environmental factors. Change in body composition is a potential mechanism for explaining the increased incidence of T1D. Micro RNA-378 (miRNA-378) is a positive regulator of adipogenesis that has yet to be studied in such patients. This study aims to evaluate the miRNA-378 expression profile in peripheral mononuclear cells of T1D patients and controls and to determine its possible association with levels of body fat, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). METHODS Twenty-four T1D subjects and 20 controls under 18 years of age without autoimmune diseases were studied. miRNA-378 expression profile was determined by TaqMan probes. Body composition was determined by multifrequency bioimpedance. IL-6 and TNF-α serum levels were determined by LUMINEX. AntiGAD65, anti-IA2, and anti-ZnT8 antibodies were quantified in serum by enzyme immunoassays. Statistical significance was considered P<0.05. RESULTS Similar body mass index and body fat (kg) were observed between the T1D and control subjects (P=0.55 and P=0.69, respectively). The miRNA-378 expression profile was significantly higher in T1D patients compared with the controls (P<0.05). Lower miRNA-378 expression in prepubertal controls was observed compared to pubertal controls, prepubertal T1D, and pubertal T1D (P<0.05). AntiGAD65, AntilA2, and AntiZnT8 were positively correlated with miRNA-378 (P=0.002, P=0.053, and P=0.007). No statistically significant correlation was observed between miRNA-378 expression and IL-6, TNF-α, or body fat. CONCLUSION Elevated miRNA-378 expression in T1D patients compared with controls is linked to pubertal stage but is not associated with proinflammatory status or body composition.
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Affiliation(s)
- Lissette Duarte
- Nutrigenomics Laboratory, Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Diego F. García-Díaz
- Nutrigenomics Laboratory, Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Francisco Pérez-Bravo
- Nutrigenomics Laboratory, Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile,Nutrition and Food Technology Institute (INTA), University of Chile, Santiago, Chile,Address for correspondence: Francisco Pérez-Bravo, PhD Nutrigenomics Laboratory, Department of Nutrition, Faculty of Medicine, University of Chile, Av. El Libano 5524, Macul, Santiago, Chile Tel: +56-229781410 Tel: +56-2214030 E-mail:
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19
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Aghaei Zarch SM, Dehghan Tezerjani M, Talebi M, Vahidi Mehrjardi MY. Molecular biomarkers in diabetes mellitus (DM). Med J Islam Repub Iran 2020; 34:28. [PMID: 32617267 PMCID: PMC7320976 DOI: 10.34171/mjiri.34.28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Diabetes mellitus (DM) is a growing epidemic metabolic syndrome, which affects near 5.6% of the world's population. Almost 12% of health expenditure is dedicated to this disorder. Discovering and developing biomarkers as a practical guideline with high specificity and sensitivity for the diagnosis, prognosis, and clinical management of DM is one of the subjects of great interest among DM researchers due to the long-lasting asymptomatic clinical manifestation of DM. In this study, we described a recently identified molecular biomarker involved in DM. Methods: This review study was done at the Diabetes Research Center affiliated to Shahid Sadoughi University of Medical Sciences. PubMed, Scopus, Google Scholar, and Web of Science were searched using the following keywords: "diabetes mellitus", "biomarker", "microRNA", "diagnostic tool" and "clinical manifestation." Results: A total of 107 studies were finally included in this review. After evaluating numerous articles, including original, metaanalysis, and review studies, we focused on molecular biomarkers involved in DM diagnosis and management. Conclusion: Increasing interest in biomarkers associated with DM goes back to its role in decreasing diabetes-related morbidity and mortality. This review focused on major molecular biomarkers such as proteomic and microRNA (miRNAs) as novel and interesting DM biomarkers that can help achieve timely diagnosis of DM.
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Affiliation(s)
| | - Masoud Dehghan Tezerjani
- Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mehrdad Talebi
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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20
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Xie Z, Chang C, Huang G, Zhou Z. The Role of Epigenetics in Type 1 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1253:223-257. [PMID: 32445098 DOI: 10.1007/978-981-15-3449-2_9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the interaction between genetic alterations and environmental factors. More than 60 susceptible genes or loci of T1D have been identified. Among them, HLA regions are reported to contribute about 50% of genetic susceptibility in Caucasians. There are many environmental factors involved in the pathogenesis of T1D. Environmental factors may change the expression of genes through epigenetic mechanisms, thus inducing individuals with susceptible genes to develop T1D; however, the underlying mechanisms remain poorly understood. The major epigenetic modifications include DNA methylation, histone modification, and non-coding RNA. There has been extensive research on the role of epigenetic mechanisms including aberrant DNA methylation, histone modification, and microRNA in the pathogenesis of T1D. DNA methylation and microRNA have been proposed as biomarkers to predict islet β cell death, which needs further confirmation before any clinical application can be developed. Small molecule inhibitors of histone deacetylases, histone methylation, and DNA methylation are potentially important for preventing T1D or in the reprogramming of insulin-producing cells. This chapter mainly focuses on T1D-related DNA methylation, histone modification, and non-coding RNA, as well as their possible translational potential in the early diagnosis and treatment of T1D.
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Affiliation(s)
- Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Christopher Chang
- Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, 33021, USA.,Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. .,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China.
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21
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Cerna M. Epigenetic Regulation in Etiology of Type 1 Diabetes Mellitus. Int J Mol Sci 2019; 21:ijms21010036. [PMID: 31861649 PMCID: PMC6981658 DOI: 10.3390/ijms21010036] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/13/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive T cells play a pivotal role, and it is characterized by islet autoantibodies. Consequent hyperglycemia is requiring lifelong insulin replacement therapy. T1DM is caused by the interaction of multiple environmental and genetic factors. The integrations of environments and genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression. T1DM has increased several-fold over the past half century. Such a short time indicates involvement of environment factors and excludes genetic changes. This review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus.
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Affiliation(s)
- Marie Cerna
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague 10, Czech Republic
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22
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Grieco FA, Schiavo AA, Brozzi F, Juan-Mateu J, Bugliani M, Marchetti P, Eizirik DL. The miRNAs miR-211-5p and miR-204-5p modulate ER stress in human beta cells. J Mol Endocrinol 2019; 63:139-149. [PMID: 31277072 PMCID: PMC6938585 DOI: 10.1530/jme-19-0066] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 07/05/2019] [Indexed: 12/16/2022]
Abstract
miRNAs are a class of small non-coding RNAs that regulate gene expression. Type 1 diabetes is an autoimmune disease characterized by insulitis (islets inflammation) and pancreatic beta cell destruction. The pro-inflammatory cytokines interleukin 1 beta (IL1B) and interferon gamma (IFNG) are released during insulitis and trigger endoplasmic reticulum (ER) stress and expression of pro-apoptotic members of the BCL2 protein family in beta cells, thus contributing to their death. The nature of miRNAs that regulate ER stress and beta cell apoptosis remains to be elucidated. We have performed a global miRNA expression profile on cytokine-treated human islets and observed a marked downregulation of miR-211-5p. By real-time PCR and Western blot analysis, we confirmed cytokine-induced changes in the expression of miR-211-5p and the closely related miR-204-5p and downstream ER stress related genes in human beta cells. Blocking of endogenous miRNA-211-5p and miR-204-5p by the same inhibitor (it is not possible to block separately these two miRs) increased human beta cell apoptosis, as measured by Hoechst/propidium Iodide staining and by determination of cleaved caspase-3 activation. Interestingly, miRs-211-5p and 204-5p regulate the expression of several ER stress markers downstream of PERK, particularly the pro-apoptotic protein DDIT3 (also known as CHOP). Blocking CHOP expression by a specific siRNA partially prevented the increased apoptosis observed following miR-211-5p/miR-204-5p inhibition. These observations identify a novel crosstalk between miRNAs, ER stress and beta cell apoptosis in early type 1 diabetes.
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Affiliation(s)
- Fabio Arturo Grieco
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Andrea Alex Schiavo
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Flora Brozzi
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Jonas Juan-Mateu
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Marco Bugliani
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Décio L. Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
- Corresponding author: Dr. Décio L. Eizirik, ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium, 808 Route de Lennik, 1070 Brussels, Belgium, Phone: +32 2 555 6242, Fax: +32 2 555 6239,
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23
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Santos AS, Cunha Neto E, Fukui RT, Ferreira LRP, Silva MER. Increased Expression of Circulating microRNA 101-3p in Type 1 Diabetes Patients: New Insights Into miRNA-Regulated Pathophysiological Pathways for Type 1 Diabetes. Front Immunol 2019; 10:1637. [PMID: 31396209 PMCID: PMC6665278 DOI: 10.3389/fimmu.2019.01637] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 07/01/2019] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRs) are master regulators of post-transcriptional gene expression, and they are often dysregulated in individuals suffering from diabetes. We investigated the roles of miR-101-3p and miR-204-5p, both of which negatively regulate insulin secretion and cell survival and are highly expressed in pancreatic β cells, in the context of type 1 diabetes (T1D) pathogenesis. Using quantitative real time PCR, we evaluated serum levels of miR-101-3p and miR-204-5p in four groups, including recent-onset T1D patients (T1D group; n = 50), individuals with normal glucose levels expressing one islet autoantibody (Ab) (single Ab group; n = 26) or multiple autoantibodies (multiple Ab group; n = 12), and healthy controls (control group; n = 43). An in silico analysis was performed to identify potential target genes of these miRNAs and to delineate enriched pathways. The relative expression of serum miR-101-3p was approximately three times higher in the multiple Ab and T1D groups than that in the single Ab and control groups (p < 0.0001). When considering all groups together, miR-101-3p expression was positively correlated with the level of islet autoantibodies GADA (r = 0.267; p = 0.0027) and IA-2A (r = 0.291; p = 0.001), and the expression of the miRNA was not correlated with levels of ZnT8A (r = 0.125; p = 0.183). miR-101-3p expression did not correlate with HbA1c (r = 0.178; p = 0.052) or glucose levels (r = 0.177; p = 0.051). No significant differences were observed in miR-204-5p expression among the analyzed groups. Computational analysis of the miR-101-3p target gene pathways indicated a potential activation of the HGF/c-Met, Ephrin receptor, and STAT3 signaling pathways. Our study demonstrated that the circulating levels of miR-101-3p are higher in T1D patients and in individuals with normal glucose levels, testing positive for multiple autoantibodies, indicating that miR-101-3p precedes loss of glucose homeostasis. The pathogenic role of miR-101-3p in T1D may involve multiple molecular pathways.
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Affiliation(s)
- Aritania S. Santos
- Laboratório de Carboidratos e Radioimunoensios - LIM/18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Edecio Cunha Neto
- Heart Institute (InCor) and Division of Clinical Immunology and Allergy - LIM60, University of São Paulo School of Medicine, São Paulo, Brazil
- Institute for Investigation in Immunology, National Institutes of Science and Technology (iii-INCT), São Paulo, Brazil
| | - Rosa T. Fukui
- Laboratório de Carboidratos e Radioimunoensios - LIM/18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Ludmila R. P. Ferreira
- RNA Systems Biology Laboratory (RSBL), Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Maria Elizabeth R. Silva
- Laboratório de Carboidratos e Radioimunoensios - LIM/18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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24
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Vega-Cárdenas M, Uresti-Rivera EE, Cortés-García JD, Briones-Espinoza M, Ruíz-Rodríguez VM, Reynaga-Hernández E, Mendez-Mancilla A, Portales-Pérez DP. Increased levels of adipose tissue-resident Th17 cells in obesity associated with miR-326. Immunol Lett 2019; 211:60-67. [PMID: 31136754 DOI: 10.1016/j.imlet.2019.05.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/30/2019] [Accepted: 05/24/2019] [Indexed: 01/25/2023]
Abstract
miRNAs are important immune regulators in the control of the CD4 + T cells phenotype. miR-326 regulates the differentiation towards Th17 cells and the inhibition of miR-155 is associated with low levels of Treg cells. However, miRNAs expression and transcription factors associated with these lymphocyte subsets in obesity-induced adipose tissue inflammation is still unknown. The aim of this work was to identify Th17 cells in subcutaneous adipose tissue (SAT), proinflammatory cytokine production and their association with the miRNAs and transcription factors involved. We collected SAT samples obtained by lipoaspiration from individuals with normal weight, overweight and obesity. We obtained the stromal vascular fractions and then a Ficoll gradient was performed to obtain adipose tissue mononuclear cells (ATMC). Th17 cells were evaluated by flow cytometry and the expression of miR-326, miR-155, RORC2 and FOXP3 by qRT-PCR. We also analyzed cytokines from the supernatants of the ATMC culture and measured the FOXP3 methylation percentage by bisulfite conversion by PCR. According to the results, the frequency of Th17 cells and RORC2 expression was higher in individuals with obesity and associated with miR-326 expression. The ATMC from this group secreted a proinflammatory cytokine profile by in vitro assay. In contrast, lower levels of mRNA FOXP3 expression was detected in ATMC from individuals with obesity that correlated with methylation percentage of FOXP3 gene but no association with miR-155 was detected. Our results suggested that miR-326 participates in the polarization towards Th17 promoting the inflammatory state in the obesity-induced adipose tissue.
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Affiliation(s)
- Mariela Vega-Cárdenas
- Center for Research in Health Sciences and Biomedicine, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Edith E Uresti-Rivera
- Center for Research in Health Sciences and Biomedicine, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Juan D Cortés-García
- Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Sciences, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Margarita Briones-Espinoza
- Center for Research in Health Sciences and Biomedicine, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Víctor M Ruíz-Rodríguez
- Center for Research in Health Sciences and Biomedicine, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Elizabeth Reynaga-Hernández
- Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Sciences, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Alejandro Mendez-Mancilla
- Center for Research in Health Sciences and Biomedicine, Autonomus University of San Luis Potosí, UASLP, Mexico
| | - Diana P Portales-Pérez
- Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Sciences, Autonomus University of San Luis Potosí, UASLP, Mexico; Center for Research in Health Sciences and Biomedicine, Autonomus University of San Luis Potosí, UASLP, Mexico.
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25
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Małachowska B, Wyka K, Nowicka Z, Bartłomiejczyk MA, Młynarski W, Fendler W. Temporal dynamics of serum let-7g expression mirror the decline of residual beta-cell function in longitudinal observation of children with type 1 diabetes. Pediatr Diabetes 2018; 19:1407-1415. [PMID: 30259606 DOI: 10.1111/pedi.12783] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/04/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/OBJECTIVE In type 1 diabetes mellitus (T1DM), the introduction of insulin is typically followed by a brief remission period, with subsequent gradual decline in beta-cell function. Several studies described altered profile of circulating miRNAs (microRNAs) in T1DM patients and proposed them as biomarkers of associated pathologic processes. HYPOTHESIS Serum miRNA expression profile reflects residual beta-cell function and autoimmunity in T1DM. SUBJECTS The profiling group included patients with: GCK-MODY (N = 13), T1DM (N = 9), and 10 healthy controls. The longitudinal group included 34 patients with samples collected at diagnosis of T1DM and first, third, and fourth to eighth year since diagnosis. METHODS We reanalyzed data from the profiling group for miRNAs differentially expressed between patients with T1DM, other types of diabetes and controls. Afterward, we shortlisted miRNAs on the basis of this reanalysis and literature review and quantified their expression with quantitative polymerase chain reaction. Additionally, we measured the levels of anti-islet antibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, IA2 antibodies, and ZnT8A) and C-peptide concentrations across the four timepoints in the longitudinal group. RESULTS miR-24 and let-7g serum expression differed significantly between GCK-MODY, controls, and HbA1c-matched T1DM patients; P < 0.05, false discovery rate < 0.05. Autoantibodies levels showed decreasing linear trend in repeated timepoints (all P < 0.0001). C-peptide concentration peaked during the first year after diagnosis, corresponding to remission phase, and declined in consecutive measurements. This dynamic was evidenced for let-7g expression levels (P = 0.0058). CONCLUSIONS The pattern of let-7g expression change during the course of diabetes mirrors that of C-peptide levels, hinting at this microRNA's association with the residual mass of the beta cells in patients with T1DM.
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Affiliation(s)
- Beata Małachowska
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.,Post-Graduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Krystyna Wyka
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland
| | - Zuzanna Nowicka
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Marcin A Bartłomiejczyk
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.,Department of Hypertensiology, Medical University of Lodz, Lodz, Poland
| | - Wojciech Młynarski
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.,Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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26
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Grieco GE, Cataldo D, Ceccarelli E, Nigi L, Catalano G, Brusco N, Mancarella F, Ventriglia G, Fondelli C, Guarino E, Crisci I, Sebastiani G, Dotta F. Serum Levels of miR-148a and miR-21-5p Are Increased in Type 1 Diabetic Patients and Correlated with Markers of Bone Strength and Metabolism. Noncoding RNA 2018; 4:ncrna4040037. [PMID: 30486455 PMCID: PMC6315714 DOI: 10.3390/ncrna4040037] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/16/2018] [Accepted: 11/22/2018] [Indexed: 12/13/2022] Open
Abstract
Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a (p = 0.012) and miR-21-5p (p = 0.034) in sera of T1D patients vs. non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values (p = 0.042) and PTH circulating levels (p = 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.
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Affiliation(s)
- Giuseppina E Grieco
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
| | - Dorica Cataldo
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy.
| | - Elena Ceccarelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
| | - Laura Nigi
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
| | - Giovanna Catalano
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
| | - Noemi Brusco
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
| | - Francesca Mancarella
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
| | - Giuliana Ventriglia
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
| | - Cecilia Fondelli
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy.
| | - Elisa Guarino
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy.
| | - Isabella Crisci
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy.
| | - Guido Sebastiani
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
| | - Francesco Dotta
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy.
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Rodriguez H, El-Osta A. Epigenetic Contribution to the Development and Progression of Vascular Diabetic Complications. Antioxid Redox Signal 2018; 29:1074-1091. [PMID: 29304555 DOI: 10.1089/ars.2017.7347] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
SIGNIFICANCE The number of people suffering from diabetes worldwide is steadily rising. Complications from diabetes, including cardiovascular and renal disease, contribute to the high morbidity and mortality associated with this disease. Recent Advances: Hyperglycemia promotes tissue damage through diverse mechanisms involving increased production of reactive oxygen species. Increased oxidative stress drives changes in chromatin structure that mediate gene expression changes leading to the upregulation of proinflammatory and profibrotic mediators. The epigenetic contribution to diabetes-induced changes in gene expression is increasingly recognized as a key factor in the development and progression of vascular diabetic complications. CRITICAL ISSUES The mechanisms through which stimuli from the diabetic milieu promote epigenetic changes remain poorly understood. In addition, glycemic control constitutes an important factor influencing epigenetic states in diabetes, and the phenomenon of hyperglycemic memory warrants further research. FUTURE DIRECTIONS Knowledge of the molecular mechanisms underlying epigenetic changes in diabetes may allow the design of novel therapeutic strategies to reduce the burden of diabetic complications. Furthermore, certain epigenetic markers are detected early during the onset of diabetes and its complications and may prove useful as biomarkers for disease risk prediction.
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Affiliation(s)
- Hanah Rodriguez
- 1 Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University , Melbourne, Australia
| | - Assam El-Osta
- 1 Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University , Melbourne, Australia .,2 Department of Pathology, University of Melbourne , Melbourne, Australia .,3 Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong , Hong Kong SAR, China
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28
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Increased expression of microRNAs, miR-20a and miR-326 in PBMCs of patients with type 1 diabetes. Mol Biol Rep 2018; 45:1973-1980. [PMID: 30194557 DOI: 10.1007/s11033-018-4352-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 08/31/2018] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder which is characterized by autoimmune attack on β cells of pancreas and lack of insulin. The involvement of microRNAs (miRNAs) in the development of immune system and their differential expression in various autoimmune diseases including T1D have been well established. In this study, the association between expression levels of miR-20a, miR-326 and T1D were evaluated. The expression levels of miR-20a and miR-326 were measured in the PBMCs of 21 T1D patients and 16 healthy controls using qPCR method. In silico analysis was also performed on targetome of miR-20a and miR-326. Both miR-20a (p value: 0.015) and miR-326 (p value: 0.005) were upregulated in the PBMCs of T1D patients compared to healthy controls. Furthermore, different dysregulated miR326-mRNA and miR20a-mRNA interactions were also suggested using integrative computational analysis. The expression level of miR-20a and miR-326 indicates significant association with T1D which suggests the possible regulatory effects of these non-coding RNAs in T1D.
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Jadideslam G, Ansarin K, Sakhinia E, Alipour S, Pouremamali F, Khabbazi A. The MicroRNA-326: Autoimmune diseases, diagnostic biomarker, and therapeutic target. J Cell Physiol 2018; 233:9209-9222. [PMID: 30078204 DOI: 10.1002/jcp.26949] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 06/13/2018] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs) are uniquely regulated in healthy, inflamed, activated, cancerous, or other cells and tissues of a pathological state. Many studies confirm that immune dysregulation and autoimmune diseases with inflammation are correlated with various miRNA expression changes in targeted tissues and cells in innate or adaptive immunity. In this review, we will explain the history and classification of epigenetic changes. Next, we will describe the role of miRNAs changes, especially mir-326 in autoimmunity, autoinflammatory, and other pathological conditions. A systematic search of MEDLINE, Embase, and Cochrane Library was presented for all related studies from 1899 to 2017 with restrictions in the English language. In recent years, researchers have concentrated on mostly those roles of miRNA that are correlated with the inflammatory and anti-inflammatory process. Latest studies have proposed a fundamental pathogenic role in cancers and autoinflammatory diseases. Studies have described the role of microRNAs in autoimmunity and autoinflammatory diseases, cancers, and so on. The miRNA-326 expression plays a significant role in autoimmune and other types of diseases.
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Affiliation(s)
- Golamreza Jadideslam
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran.,Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Iran
| | - Khalil Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Sakhinia
- Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran.,Department of Medical Genetics, Faculty of Medicine and Tabriz Genetic Analysis Centre (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahriar Alipour
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran
| | - Farhad Pouremamali
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Khabbazi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran
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Zurawek M, Dzikiewicz-Krawczyk A, Izykowska K, Ziolkowska-Suchanek I, Skowronska B, Czainska M, Podralska M, Fichna P, Przybylski G, Fichna M, Nowak J. miR-487a-3p upregulated in type 1 diabetes targets CTLA4 and FOXO3. Diabetes Res Clin Pract 2018; 142:146-153. [PMID: 29859273 DOI: 10.1016/j.diabres.2018.05.044] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 05/16/2018] [Accepted: 05/24/2018] [Indexed: 12/12/2022]
Abstract
AIMS Type 1 diabetes (T1D) is an autoimmune disorder caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. T1D is a consequence of complex processes, influenced by genetic, epigenetic and environmental factors. MicroRNAs (miRNAs) are small non-coding RNAs that target multiple mRNAs and regulate gene expression. The implication of miRNAs in T1D pathogenesis, as potential modulators of immune response genes, remains poorly defined. The aim of this study was to investigate the expression profile of miRNAs in new onset T1D and the impact of deregulated miRNAs on target genes. METHODS Total RNA from peripheral blood mononuclear cells of newly diagnosed T1D pediatric patients and age-matched controls was screened for disease-associated miRNAs by a microarray analysis, with subsequent validation by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). miRNA targets were identified by luciferase reporter assays. RESULTS The microarray analysis revealed 91 deregulated miRNAs (P < 0.05) in T1D group compared to non-diabetic controls. Within this group we observed one upregulated and seven downregulated miRNAs with fold change >2.0. qRT-PCR validation revealed overexpression of miR-487a-3p which has not been previously reported in the context of T1D. Luciferase reporter assays indicated CTLA4 and FOXO3 genes as miR-487a-3p targets. CONCLUSION Our study suggests that miR-487a-3p might repress CTLA4 and FOXO3 by binding to their 3'UTRs and contribute to the development of T1D.
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Affiliation(s)
- Magdalena Zurawek
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
| | | | | | | | - Bogda Skowronska
- Department of Paediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Marta Podralska
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Piotr Fichna
- Department of Paediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Marta Fichna
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland; Department of Endocrinology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
| | - Jerzy Nowak
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
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31
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Junjappa RP, Patil P, Bhattarai KR, Kim HR, Chae HJ. IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases. Front Immunol 2018; 9:1289. [PMID: 29928282 PMCID: PMC5997832 DOI: 10.3389/fimmu.2018.01289] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 05/22/2018] [Indexed: 12/15/2022] Open
Abstract
Inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) is the most prominent and evolutionarily conserved endoplasmic reticulum (ER) membrane protein. This transduces the signal of misfolded protein accumulation in the ER, named as ER stress, to the nucleus as “unfolded protein response (UPR).” The ER stress-mediated IRE1α signaling pathway arbitrates the yin and yang of cell life. IRE1α has been implicated in several physiological as well as pathological conditions, including immune disorders. Autoimmune diseases are caused by abnormal immune responses that develop due to genetic mutations and several environmental factors, including infections and chemicals. These factors dysregulate the cell immune reactions, such as cytokine secretion, antigen presentation, and autoantigen generation. However, the mechanisms involved, in which these factors induce the onset of autoimmune diseases, are remaining unknown. Considering that these environmental factors also induce the UPR, which is expected to have significant role in secretory cells and immune cells. The role of the major UPR molecule, IRE1α, in causing immune responses is well identified, but its role in inducing autoimmunity and the pathogenesis of autoimmune diseases has not been clearly elucidated. Hence, a better understanding of the role of IRE1α and its regulatory mechanisms in causing autoimmune diseases could help to identify and develop the appropriate therapeutic strategies. In this review, we mainly center the discussion on the molecular mechanisms of IRE1α in the pathophysiology of autoimmune diseases.
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Affiliation(s)
- Raghu Patil Junjappa
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Chonbuk National University, Jeonju, South Korea
| | - Prakash Patil
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Chonbuk National University, Jeonju, South Korea
| | - Kashi Raj Bhattarai
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Chonbuk National University, Jeonju, South Korea
| | - Hyung-Ryong Kim
- Graduate School, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
| | - Han-Jung Chae
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Chonbuk National University, Jeonju, South Korea
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Zhang P, Lu Q. Genetic and epigenetic influences on the loss of tolerance in autoimmunity. Cell Mol Immunol 2018; 15:575-585. [PMID: 29503444 PMCID: PMC6079019 DOI: 10.1038/cmi.2017.137] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 10/21/2017] [Indexed: 12/23/2022] Open
Abstract
Immunological tolerance loss is fundamental to the development of autoimmunity; however, the underlying mechanisms remain elusive. Immune tolerance consists of central and peripheral tolerance. Central tolerance, which occurs in the thymus for T cells and bone marrow for B cells, is the primary way that the immune system discriminates self from non-self. Peripheral tolerance, which occurs in tissues and lymph nodes after lymphocyte maturation, controls self-reactive immune cells and prevents over-reactive immune responses to various environment factors. Loss of tolerance results in autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D) and primary biliary cirrhosis (PBC). The etiology and pathogenesis of autoimmune diseases are highly complicated. Both genetic predisposition and epigenetic modifications are implicated in the loss of tolerance and autoimmunity. In this review, we will discuss the genetic and epigenetic influences on tolerance breakdown in autoimmunity. Genetic and epigenetic influences on autoimmune diseases, such as SLE, RA, T1D and PBC, will also be briefly discussed.
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Affiliation(s)
- Peng Zhang
- Department of Dermatology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, 410011, Changsha, Hunan, China
| | - Qianjin Lu
- Department of Dermatology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, 410011, Changsha, Hunan, China.
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García-Díaz DF, Pizarro C, Camacho-Guillén P, Codner E, Soto N, Pérez-Bravo F. Expression of miR-155, miR-146a, and miR-326 in T1D patients from Chile: relationship with autoimmunity and inflammatory markers. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2018; 62:34-40. [PMID: 29694627 PMCID: PMC10118688 DOI: 10.20945/2359-3997000000006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 05/31/2017] [Indexed: 11/23/2022]
Abstract
Objective The aim of this research was to analyze the expression profile of miR-155, miR-146a, and miR-326 in peripheral blood mononuclear cells (PBMC) of 47 patients with type 1 diabetes mellitus (T1D) and 39 control subjects, as well as the possible association with autoimmune or inflammatory markers. Subjects and methods Expression profile of miRs by means of qPCR using TaqMan probes. Autoantibodies and inflammatory markers by ELISA. Statistical analysis using bivariate correlation. Results The analysis of the results shows an increase in the expression of miR-155 in T1D patients in basal conditions compared to the controls (p < 0.001) and a decreased expression level of miR-326 (p < 0.01) and miR-146a (p < 0.05) compared T1D patients to the controls. miR-155 was the only miRs associated with autoinmmunity (ZnT8) and inflammatory status (vCAM). Conclusion Our data show a possible role of miR-155 related to autoimmunity and inflammation in Chilean patients with T1D.
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Affiliation(s)
- Diego F García-Díaz
- Laboratorio de Nutrigenómica, Departamento de Nutrición, Facultad de Medicina, Universidad de Chile, Chile
| | - Carolina Pizarro
- Laboratorio de Nutrigenómica, Departamento de Nutrición, Facultad de Medicina, Universidad de Chile, Chile
| | - Patricia Camacho-Guillén
- Laboratorio de Nutrigenómica, Departamento de Nutrición, Facultad de Medicina, Universidad de Chile, Chile
| | - Ethel Codner
- Instituto de Investigaciones Materno Infantil (IDIMI), Hospital San Borja Arriarán, Facultad de Medicina, Universidad de Chile, Chile
| | - Néstor Soto
- Instituto de Investigaciones Materno Infantil (IDIMI), Hospital San Borja Arriarán, Facultad de Medicina, Universidad de Chile, Chile
| | - Francisco Pérez-Bravo
- Laboratorio de Nutrigenómica, Departamento de Nutrición, Facultad de Medicina, Universidad de Chile, Chile
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34
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Wang G, Gu Y, Xu N, Zhang M, Yang T. Decreased expression of miR-150, miR146a and miR424 in type 1 diabetic patients: Association with ongoing islet autoimmunity. Biochem Biophys Res Commun 2018; 498:382-387. [DOI: 10.1016/j.bbrc.2017.06.196] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 06/30/2017] [Indexed: 12/21/2022]
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Li Y, Liu D, Zhang X, Li Z, Ye Y, Liu Q, Shen J, Chen Z, Huang H, Liang Y, Han X, Liu J, An X, Mohandas N, Xu X. miR-326 regulates HbF synthesis by targeting EKLF in human erythroid cells. Exp Hematol 2018; 63:33-40.e2. [PMID: 29601850 DOI: 10.1016/j.exphem.2018.03.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 03/19/2018] [Accepted: 03/21/2018] [Indexed: 12/27/2022]
Abstract
Haploinsufficiency of erythroid Krüppel-like factor (EKLF/KLF1) has been shown recently to ameliorate the clinical severity of β-thalassemia by increased expression levels of fetal hemoglobin (HbF). The underlying mechanisms for role of EKLF in regulating HbF are of great interest but remain incompletely understood. In this study, we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs (miRs) involved in EKLF regulation and to validate the role of miR-326 in HbF modification. We found that miR-326 suppresses EKLF expression directly by targeting its 3' untranslated region. miR-326 overexpression in K562 cells or CD34+ hematopoietic progenitor cells resulted in reduced EKLF protein levels and was associated with elevated expression of γ-globin, whereas inhibition of physiological miR-326 levels increased EKLF and thus reduced γ-globin expression. Moreover, miR-326 expression is positively correlated with HbF levels in β-thalassemia patients. Our results suggest that miR-326 plays a key role in regulating EKLF expression and in modifying the HbF level, which may provide a new strategy for activating HbF in individuals with β-thalassemia or sickle cell disease.
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Affiliation(s)
- Yihong Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Dun Liu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Reproductive Medical Center, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xinhua Zhang
- Department of Hematology, 303rd Hospital of the People's Liberation Army, Nanning, Guangxi, China
| | - Zhiming Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuhua Ye
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie Shen
- Department of Endocrinology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi Chen
- Department of Endocrinology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Huajie Huang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yunhao Liang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xu Han
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Jing Liu
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA; College of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Narla Mohandas
- Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA
| | - Xiangmin Xu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
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36
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Miao C, Chang J, Zhang G, Fang Y. MicroRNAs in type 1 diabetes: new research progress and potential directions. Biochem Cell Biol 2018; 96:498-506. [PMID: 29554441 DOI: 10.1139/bcb-2018-0027] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of noncoding single-stranded RNA molecules encoded by endogenous genes of about 22 nucleotides, which are involved in post-transcriptional gene expression regulation in animals and plants. Type 1 diabetes (T1D) is an autoimmune disease that is clinically silent until the majority of β cells are destroyed, and a large number of studies have shown that miRNAs are involved in the pathological mechanism of T1D. In this review, we searched the related research in recent years and summarized the important roles of miRNAs in T1D diagnosis and treatment. Furthermore, we summarized the current understanding of miRNA-mediated regulation mechanisms of gene expression in the T1D pathogenesis as well as related signaling pathways with a focus on the important roles of miRNAs and their antagonists in T1D pathogenesis, and brought insight into the potential therapeutic value of miRNAs for T1D patients. In view of the important roles of miRNAs in T1D pathology, disordered miRNAs may be important diagnostic markers and therapeutic targets for patients with T1D.
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Affiliation(s)
- Chenggui Miao
- a Department of Pharmacy, College of Life and Health Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Jun Chang
- b Department of Orthopaedics, 4th Affiliated Hospital, Anhui Medical University, Hefei 230032, China
| | - Guoxue Zhang
- c College of Tea and Food Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Yanxi Fang
- a Department of Pharmacy, College of Life and Health Science, Anhui Science and Technology University, Fengyang 233100, China
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Åkerman L, Casas R, Ludvigsson J, Tavira B, Skoglund C. Serum miRNA levels are related to glucose homeostasis and islet autoantibodies in children with high risk for type 1 diabetes. PLoS One 2018; 13:e0191067. [PMID: 29346396 PMCID: PMC5773164 DOI: 10.1371/journal.pone.0191067] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 12/26/2017] [Indexed: 01/13/2023] Open
Abstract
Micro RNAs (miRNAs) are promising disease biomarkers due to their high stability. Their expression in serum is altered in type 1 diabetes, but whether deviations exist in individuals with high risk for type 1 diabetes remains unexplored. We therefore assessed serum miRNAs in high-risk individuals (n = 21) positive for multiple islet autoantibodies, age-matched healthy children (n = 17) and recent-onset type 1 diabetes patients (n = 8), using Serum/Plasma Focus microRNA PCR Panels from Exiqon. The miRNA levels in the high-risk group were similar to healthy controls, and no specific miRNA profile was identified for the high-risk group. However, serum miRNAs appeared to reflect glycemic status and ongoing islet autoimmunity in high-risk individuals, since several miRNAs were associated to glucose homeostasis and autoantibody titers. High-risk individuals progressing to clinical disease after the sampling could not be clearly distinguished from non-progressors, while miRNA expression in the type 1 diabetes group deviated significantly from high-risk individuals and healthy controls, perhaps explained by major metabolic disturbances around the time of diagnosis.
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Affiliation(s)
- Linda Åkerman
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Rosaura Casas
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children´s Hospital, University Hospital, Linköping, Region Östergötland, Sweden
| | - Beatriz Tavira
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Camilla Skoglund
- Division of Drug Research, Department of Medical and Health Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
- * E-mail:
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Zhao N, Zou H, Qin J, Fan C, Liu Y, Wang S, Shan Z, Teng W, Li Y. MicroRNA-326 contributes to autoimmune thyroiditis by targeting the Ets-1 protein. Endocrine 2018; 59:120-129. [PMID: 29181619 DOI: 10.1007/s12020-017-1465-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 10/26/2017] [Indexed: 10/18/2022]
Abstract
PURPOSE MicroRNA-326 (miR-326), as a member of the microRNA (miRNA) family, which includes endogenous single-stranded, conserved, noncoding small RNAs, has been reported to play important roles in autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus. However, few studies of the role of miR-326 in autoimmune thyroiditis (AIT) have been published. Here, we explored the roles of miR-326 and the involved pathway in iodine-induced AIT. METHODS NOD.H-2h4 mice, which are a model of human AIT, were randomly divided into a normal water control group and a high-iodine group. Mice in the high-iodine group were administered 0.05% NaI (~1000 times the normal daily iodine intake), and mice in the control group received sterile water. Furthermore, we evaluated small interfering RNA (siRNA) interference in spleen mononuclear cell experiments in vitro. RESULTS In this study, we found that Th17 cells were significantly increased with a high expression of miR-326 in an iodine-induced thyroiditis NOD.H-2h4 mouse model. In addition, the expression of Ets-1 protein, a negative regulator of Th17 differentiation, was significantly decreased. Intriguingly, our analysis showed that Ets-1 protein expression was negatively correlated with miR-326 levels in AIT mice (r = -0.814, p < 0.01). Our study indicated that miR-326 inhibited Ets-1 protein expression and promoted the differentiation of Th17 cells during the onset and development of AIT. The addition of a miR-326 inhibitor reversed Th17 cell production and Ets-1 protein expression, supporting this hypothesis. CONCLUSIONS The results of our study suggest that miR-326 may target the Ets-1 protein to contribute to iodide-induced thyroiditis, providing a new theoretical basis for the use of miRNA targeting therapy for the treatment of autoimmune diseases.
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Affiliation(s)
- Na Zhao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Hongjin Zou
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Jing Qin
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Chenling Fan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Yongping Liu
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Shuo Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Zhongyan Shan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Weiping Teng
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Yushu Li
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China.
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Kamalden TA, Macgregor-Das AM, Kannan SM, Dunkerly-Eyring B, Khaliddin N, Xu Z, Fusco AP, Yazib SA, Chow RC, Duh EJ, Halushka MK, Steenbergen C, Das S. Exosomal MicroRNA-15a Transfer from the Pancreas Augments Diabetic Complications by Inducing Oxidative Stress. Antioxid Redox Signal 2017; 27:913-930. [PMID: 28173719 PMCID: PMC5649125 DOI: 10.1089/ars.2016.6844] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
AIMS MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways in type 2 diabetes (T2D). Currently, little is known about how miRNAs influence disease pathogenesis by targeting cells at a distance. The purpose of this study was to investigate the role of exosomal miRNAs during T2D. RESULTS We show that miR-15a is increased in the plasma of diabetic patients, correlating with disease severity. miR-15 plays an important role in insulin production in pancreatic β-cells. By culturing rat pancreatic β-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic β-cells. We postulate that miR-15a, produced in pancreatic β-cells, can enter the bloodstream and contribute to retinal injury. miR-15a overexpression in Müller cells can be induced by exposing Müller cells to exosomes derived from INS-1 cells under high-glucose conditions and results in oxidative stress by targeting Akt3, which leads to apoptotic cell death. The in vivo relevance of these findings is supported by results from high-fat diet and pancreatic β-cell-specific miR-15a-/- mice. INNOVATION This study highlights an important and underappreciated mechanism of remote cell-cell communication (exosomal transfer of miRNA) and its influence on the development of T2D complications. CONCLUSION Our findings suggest that circulating miR-15a contributes to the pathogenesis of diabetes and supports the concept that miRNAs released by one cell type can travel through the circulation and play a role in disease progression via their transfer to different cell types, inducing oxidative stress and cell injury. Antioxid. Redox Signal. 27, 913-930.
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Affiliation(s)
- Tengku Ain Kamalden
- 1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia
| | | | - Sangeetha Marimuthu Kannan
- 2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.,3 School of Life Sciences, B.S. Abdur Rahman University , Chennai, India
| | | | - Nurliza Khaliddin
- 1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia
| | - Zhenhua Xu
- 4 Department of Ophthalmology, Johns Hopkins University , Baltimore, Maryland
| | | | - Syatirah Abu Yazib
- 1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia
| | - Rhuen Chiou Chow
- 1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia
| | - Elia J Duh
- 4 Department of Ophthalmology, Johns Hopkins University , Baltimore, Maryland
| | - Marc K Halushka
- 2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland
| | | | - Samarjit Das
- 2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland
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40
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Assmann TS, Recamonde-Mendoza M, De Souza BM, Crispim D. MicroRNA expression profiles and type 1 diabetes mellitus: systematic review and bioinformatic analysis. Endocr Connect 2017; 6:773-790. [PMID: 28986402 PMCID: PMC5682418 DOI: 10.1530/ec-17-0248] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 10/06/2017] [Indexed: 12/15/2022]
Abstract
Growing evidence indicates that microRNAs (miRNAs) have a key role in processes involved in type 1 diabetes mellitus (T1DM) pathogenesis, including immune system functions and beta-cell metabolism and death. Although dysregulated miRNA profiles have been identified in T1DM patients, results are inconclusive; with only few miRNAs being consistently dysregulated among studies. Thus, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis, to point out which miRNAs are dysregulated in T1DM-related tissues and in which pathways they act. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between T1DM patients and non-diabetic controls. Search was completed in August, 2017. Those miRNAs consistently dysregulated in T1DM-related tissues were submitted to bioinformatic analysis, using six databases of miRNA-target gene interactions to retrieve their putative targets and identify potentially affected pathways under their regulation. Thirty-three studies were included in the systematic review: 19 of them reported miRNA expressions in human samples, 13 in murine models and one in both human and murine samples. Among 278 dysregulated miRNAs reported in these studies, 25.9% were reported in at least 2 studies; however, only 48 of them were analyzed in tissues directly related to T1DM pathogenesis (serum/plasma, pancreas and peripheral blood mononuclear cells (PBMCs)). Regarding circulating miRNAs, 11 were consistently dysregulated in T1DM patients compared to controls: miR-21-5p, miR-24-3p, miR-100-5p, miR-146a-5p, miR-148a-3p, miR-150-5p, miR-181a-5p, miR-210-5p, miR-342-3p, miR-375 and miR-1275. The bioinformatic analysis retrieved a total of 5867 validated and 2979 predicted miRNA-target interactions for human miRNAs. In functional enrichment analysis of miRNA target genes, 77 KEGG terms were enriched for more than one miRNA. These miRNAs are involved in pathways related to immune system function, cell survival, cell proliferation and insulin biosynthesis and secretion. In conclusion, eleven circulating miRNAs seem to be dysregulated in T1DM patients in different studies, being potential circulating biomarkers of this disease.
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Affiliation(s)
- Taís S Assmann
- Endocrine DivisionHospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Postgraduation Program in Medical Sciences: EndocrinologyFaculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Mariana Recamonde-Mendoza
- Institute of InformaticsUniversidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Bianca M De Souza
- Endocrine DivisionHospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Postgraduation Program in Medical Sciences: EndocrinologyFaculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Daisy Crispim
- Endocrine DivisionHospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Postgraduation Program in Medical Sciences: EndocrinologyFaculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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41
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MicroRNAs and adipocytokines: Promising biomarkers for pharmacological targets in diabetes mellitus and its complications. Biomed Pharmacother 2017; 93:1326-1336. [DOI: 10.1016/j.biopha.2017.07.059] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/08/2017] [Accepted: 07/11/2017] [Indexed: 02/06/2023] Open
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Snowhite IV, Allende G, Sosenko J, Pastori RL, Messinger Cayetano S, Pugliese A. Association of serum microRNAs with islet autoimmunity, disease progression and metabolic impairment in relatives at risk of type 1 diabetes. Diabetologia 2017; 60:1409-1422. [PMID: 28500393 PMCID: PMC5839115 DOI: 10.1007/s00125-017-4294-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 03/31/2017] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS MicroRNAs (miRNAs) are key regulators of gene expression and novel biomarkers for many diseases. We investigated the hypothesis that serum levels of some miRNAs would be associated with islet autoimmunity and/or progression to type 1 diabetes. METHODS We measured levels of 93 miRNAs most commonly detected in serum. This retrospective cohort study included 150 autoantibody-positive and 150 autoantibody-negative family-matched siblings enrolled in the TrialNet Pathway to Prevention Study. This was a young cohort (mean age = 11 years), and most autoantibody-positive relatives were at high risk because they had multiple autoantibodies, with 39/150 (26%, progressors) developing type 1 diabetes within an average 8.7 months of follow-up. We analysed miRNA levels in relation to autoantibody status, future development of diabetes and OGTT C-peptide and glucose indices of disease progression. RESULTS Fifteen miRNAs were differentially expressed when comparing autoantibody-positive/negative siblings (range -2.5 to 1.3-fold). But receiver operating characteristic (ROC) analysis indicated low specificity and sensitivity. Seven additional miRNAs were differentially expressed among autoantibody-positive relatives according to disease progression; ROC returned significant AUC values and identified miRNA cut-off levels associated with an increased risk of disease in both cross-sectional and survival analyses. Levels of several miRNAs showed significant correlations (r values range 0.22-0.55) with OGTT outcomes. miR-21-3p, miR-29a-3p and miR-424-5p had the most robust associations. CONCLUSIONS/INTERPRETATION Serum levels of selected miRNAs are associated with disease progression and confer additional risk of the development of type 1 diabetes in young autoantibody-positive relatives. Further studies, including longitudinal assessments, are warranted to further define miRNA biomarkers for prediction of disease risk and progression.
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Affiliation(s)
- Isaac V Snowhite
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, 1450 NW 10th Avenue, Miami, FL, 33136, USA
| | - Gloria Allende
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, 1450 NW 10th Avenue, Miami, FL, 33136, USA
| | - Jay Sosenko
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, 1450 NW 10th Avenue, Miami, FL, 33136, USA
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Ricardo L Pastori
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, 1450 NW 10th Avenue, Miami, FL, 33136, USA
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Shari Messinger Cayetano
- Department of Epidemiology and Public Health Sciences, Division of Biostatistics, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Alberto Pugliese
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, 1450 NW 10th Avenue, Miami, FL, 33136, USA.
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA.
- Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA.
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43
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Zullo A, Sommese L, Nicoletti G, Donatelli F, Mancini FP, Napoli C. Epigenetics and type 1 diabetes: mechanisms and translational applications. Transl Res 2017; 185:85-93. [PMID: 28552218 DOI: 10.1016/j.trsl.2017.05.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 04/27/2017] [Accepted: 05/08/2017] [Indexed: 02/01/2023]
Abstract
Type 1 diabetes (T1D) is an irreversible degenerative disease with severe complications such as heart disease, nephropathy, neuropathy, and retinopathy. Although exogenous insulin administration is a life-saving therapy, it does not cure the disease. This review addresses the epigenetic mechanisms responsible for the development of T1D and discusses epigenetic-based strategies for prevention and treatment of the disease. We describe novel epigenetic biomarkers for the identification of susceptible individuals and the establishment of innovative therapies with epidrugs and cell therapy to regenerate the lost β-cells. Despite the wealth of promising data regarding the potential benefits of epigenetic tools to reduce the burden of T1D, clinical trials are still very few, and this issue needs to be resolved in the near future.
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Affiliation(s)
- Alberto Zullo
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy; CEINGE-Advanced Biotechnologies, Naples, Italy
| | - Linda Sommese
- U.O.C. Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Department of Internal and Specialty Medicine, Azienda Ospedaliera Universitaria, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
| | - Gianfranco Nicoletti
- Multidisciplinary Department of Medical-Surgical and Dental Specialties, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Francesco Donatelli
- Cardiovascular Department, Chair of Cardiosurgery, University of Milan, Milan, Italy
| | - Francesco P Mancini
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Claudio Napoli
- Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy; IRCCS SDN, Naples, Italy
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44
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Sebastiani G, Nigi L, Grieco GE, Mancarella F, Ventriglia G, Dotta F. Circulating microRNAs and diabetes mellitus: a novel tool for disease prediction, diagnosis, and staging? J Endocrinol Invest 2017; 40:591-610. [PMID: 28213644 DOI: 10.1007/s40618-017-0611-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 01/03/2017] [Indexed: 12/19/2022]
Abstract
Diabetes is a complex, multifactorial group of metabolic diseases characterized by chronic hyperglycaemia due to pancreatic beta-cell dysfunction and/or loss. It is characterized by an asymptomatic and highly variable prodromic phase, which renders diabetes mellitus difficult to be predicted with sufficient accuracy. Despite several efforts in the identification and standardization of newly trustable. Biomarkers able to predict and follow-up diabetes and to specifically subtype its different forms, few of them have proven of clinical utility. Recently, a new class of endogenous non-coding small RNAs, namely microRNAs, have been indicated as putative biomarkers, being released by cells and tissues and found in a cell-free circulating form in many biological fluids, including serum and/or plasma. MicroRNAs have been initially identified as promising biomarkers in cancer, and nowadays their application has been extended to other diseases, including diabetes. Although an increasing number of studies focused on the evaluation of circulating microRNAs in diabetes, few reproducibly identified microRNAs as biomarkers for disease prediction or follow-up. Technological problems as well as the need to obtain highly standardized operating procedures and methods are still an issue in such research field. In this review, we comprehensively resume the main and most recent findings on circulating microRNAs, and their possible use as biomarkers to predict and follow-up diabetes and its complications, as well as the methodological challenges to standardize accurate operating procedures for their analysis.
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Affiliation(s)
- G Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - L Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - G E Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - F Mancarella
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - G Ventriglia
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - F Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy.
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45
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Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, Singha RS, Malakar AK, Chakraborty S. Interplay between miRNAs and human diseases. J Cell Physiol 2017; 233:2007-2018. [PMID: 28181241 DOI: 10.1002/jcp.25854] [Citation(s) in RCA: 280] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/07/2017] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are endogenous, non-coding RNAs, which have evoked a great deal of interest due to their importance in many aspects of homeostasis and diseases. MicroRNAs are stable and are essential components of gene regulatory networks. They play a crucial role in healthy individuals and their dysregulations have also been implicated in a wide range of diseases, including diabetes, cardiovascular disease, kidney disease, and cancer. This review summarized the current understanding of interactions between miRNAs and different diseases and their role in disease diagnosis and therapy.
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Affiliation(s)
- Prosenjit Paul
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Debasree Sarkar
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Musfhia Rahman
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Minakshi Bari
- Department of Biotechnology, Assam University, Silchar, Assam, India
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Chen JQ, Papp G, Póliska S, Szabó K, Tarr T, Bálint BL, Szodoray P, Zeher M. MicroRNA expression profiles identify disease-specific alterations in systemic lupus erythematosus and primary Sjögren's syndrome. PLoS One 2017; 12:e0174585. [PMID: 28339495 PMCID: PMC5365120 DOI: 10.1371/journal.pone.0174585] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 03/10/2017] [Indexed: 11/30/2022] Open
Abstract
The discovery of microRNAs (miRNAs) and their critical role in genetic control opened new avenues in understanding of various biological processes including immune cell lineage commitment, differentiation, proliferation and apoptosis. However, a given miRNA may have hundreds of different mRNA targets and a target might be regulated by multiple miRNAs, thus the characterisation of dysregulated miRNA expression profiles could give a better insight into the development of immunological disturbances in autoimmune diseases. The aim of our study was to examine the changes in miRNA expression profiles in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). Eight SLE patients, 8 pSS patients and 7 healthy subjects were enrolled in the investigation. MiRNAs were isolated from peripheral blood mononuclear cells, and expression patterns were determined with Illumina next-generation sequencing technology. Since the immunopathogenesis of pSS and SLE encompasses pronounced B cell hyperactivity along with specific autoantibody production, we paid a special attention on the association between miRNA expression levels and altered peripheral B cell distribution. In SLE patients 135, while in pSS patients 26 miRNAs showed altered expression. Interestingly, the 25 miRNAs including miR-146a, miR-16 and miR-21, which were over-expressed in pSS patients, were found to be elevated in SLE group, as well. On the contrary, we observed the down-regulation of miR-150-5p, which is a novel and unique finding in pSS. Levels of several miRNAs over-expressed in SLE, were not changed in pSS, such as miR-148a-3p, miR-152, miR-155, miR-223, miR-224, miR-326 and miR-342. Expression levels of miR-223-5p, miR-150-5p, miR-155-5p and miR-342-3p, which miRNAs are potentially linked to B cell functions, showed associations with the B cell proportions within peripheral blood mononuclear cells. The observed differences in miRNA expression profiles and the better understanding of immune regulatory mechanisms of miRNAs may help to elucidate the pathogenesis of SLE and pSS.
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Affiliation(s)
- Ji-Qing Chen
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gábor Papp
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Krisztina Szabó
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tünde Tarr
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Bálint László Bálint
- Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Szodoray
- Centre for Immune Regulation and Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Margit Zeher
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- * E-mail:
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47
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Zheng Y, Wang Z, Zhou Z. miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes. Cell Mol Immunol 2017; 14:488-496. [PMID: 28317889 DOI: 10.1038/cmi.2017.7] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/06/2017] [Accepted: 01/06/2017] [Indexed: 02/08/2023] Open
Abstract
MicroRNAs (miRNAs) are a series of conserved, short, non-coding RNAs that modulate gene expression in a posttranscriptional manner. miRNAs are involved in almost every physiological and pathological process. Type 1 diabetes (T1D) is an autoimmune disease that is the result of selective destruction of pancreatic β-cells driven by the immune system. miRNAs are also important participants in T1D pathogenesis. Herein, we review the most recent data on the potential involvement of miRNAs in T1D. Specifically, we focus on two aspects: the roles of miRNAs in maintaining immune homeostasis and regulating β-cell survival and/or functions in T1D. We also discuss circulating miRNAs as potent biomarkers for the diagnosis and prediction of T1D and investigate potential therapeutic approaches for this disease.
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Affiliation(s)
- Ying Zheng
- Center for Medical Research, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhen Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China
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48
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Erener S, Marwaha A, Tan R, Panagiotopoulos C, Kieffer TJ. Profiling of circulating microRNAs in children with recent onset of type 1 diabetes. JCI Insight 2017; 2:e89656. [PMID: 28239651 DOI: 10.1172/jci.insight.89656] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that is clinically silent until the majority of β cells are destroyed. There is an unmet need for reliable and cost-effective biomarkers to predict and diagnose diabetes at an early stage. A number of stable microRNAs (miRNAs) have been reported in serum and plasma and are now being investigated as biomarkers of different diseases. We measured the levels of 745 miRNAs in sera of children with recent-onset T1D and age-matched controls using locked nucleic acid-enhanced (LNA-enhanced) quantitative PCR profiling. Thirty-five miRNAs were significantly different between the groups, and 27 miRNAs were elevated in T1D. Good discriminating power was obtained for 6 miRNAs (miR-454-3p, miR-222-3p, miR-144-5p, miR-345-5p, miR-24-3p, and miR-140-5p), which were not elevated at later stages of diabetes. In silico pathway analysis, based on inferred miRNA target genes, associated glycosaminoglycan biosynthesis as well as PI3K/Akt, MAPK, and Wnt signaling pathways with early stages of T1D. Among the 27 upregulated miRNAs in T1D, 2 miRNAs significantly correlated with hemoglobin A1c (HbA1c), as did 5 of 8 downregulated miRNAs. A total of 134 miRNAs significantly correlated with HbA1c when stratifying hyperglycemia-induced miRNAs from T1D-specific miRNAs. In conclusion, we have identified a serum miRNA pattern of recent-onset T1D and signaling pathways that may be involved in its pathogenesis.
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Affiliation(s)
- Suheda Erener
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ashish Marwaha
- Dermatology and Skin Sciences, Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - Rusung Tan
- Department of Pathology, Sidra Medical and Research Center and Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Doha, Qatar
| | | | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
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49
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Abstract
The immune system protects us from enormously diverse microbial pathogens but needs to be tightly regulated to avoid deleterious immune-mediated inflammation and tissue damage. A wide range of molecular determinants and cellular components work in concert to control the magnitude and duration of a given immune response. In the past decade, microRNAs (miRNAs), a major class of small non-coding RNA species, have been extensively studied as key molecular players in immune regulation. In this chapter, we will discuss how miRNAs function as negative regulators to restrict innate and adaptive immune responses. Moreover, we will review the current reports regarding miRNAs in human immunological diseases. Finally, we will also address the emerging roles of other non-coding RNAs, long non-coding RNAs (lncRNAs) in particular, in the regulation of the immune system.
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50
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Grieco FA, Sebastiani G, Juan-Mateu J, Villate O, Marroqui L, Ladrière L, Tugay K, Regazzi R, Bugliani M, Marchetti P, Dotta F, Eizirik DL. MicroRNAs miR-23a-3p, miR-23b-3p, and miR-149-5p Regulate the Expression of Proapoptotic BH3-Only Proteins DP5 and PUMA in Human Pancreatic β-Cells. Diabetes 2017; 66:100-112. [PMID: 27737950 PMCID: PMC5204315 DOI: 10.2337/db16-0592] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 10/08/2016] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease leading to β-cell destruction. MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to β-cell death in T1D and their target genes remain to be clarified. We performed an miRNA expression profile on human islet preparations exposed to the cytokines IL-1β plus IFN-γ. Confirmation of miRNA and target gene modification in human β-cells was performed by real-time quantitative PCR. Single-stranded miRNAs inhibitors were used to block selected endogenous miRNAs. Cell death was measured by Hoechst/propidium iodide staining and activation of caspase-3. Fifty-seven miRNAs were detected as modulated by cytokines. Three of them, namely miR-23a-3p, miR-23b-3p, and miR-149-5p, were downregulated by cytokines and selected for further studies. These miRNAs were found to regulate the expression of the proapoptotic Bcl-2 proteins DP5 and PUMA and consequent human β-cell apoptosis. These results identify a novel cross talk between a key family of miRNAs and proapoptotic Bcl-2 proteins in human pancreatic β-cells, broadening our understanding of cytokine-induced β-cell apoptosis in early T1D.
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Affiliation(s)
- Fabio Arturo Grieco
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Umberto Di Mario ONLUS Foundation-Toscana Life Sciences Foundation, Siena, Italy
| | - Jonas Juan-Mateu
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Olatz Villate
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Laura Marroqui
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Laurence Ladrière
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Ksenya Tugay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Marco Bugliani
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Umberto Di Mario ONLUS Foundation-Toscana Life Sciences Foundation, Siena, Italy
| | - Décio L Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
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