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Kuang YL, Locatelli CA, Qin Y, Zhang Y, Theusch E, Muñoz-Howell A, Sanchez G, Lu M, Nguyen MA, Yalamanchili T, Wang X, Nalula G, Mattis AN, Oni-Orisan A, Iribarren C, Krauss RM, Mulvihill EE, Medina MW. MIR192 Upregulates GLP-1 Receptor and Improves Statin-Induced Impairment of Insulin Secretion. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.18.643960. [PMID: 40166140 PMCID: PMC11956930 DOI: 10.1101/2025.03.18.643960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Statins are a commonly prescribed cholesterol lowering drug class that can increase the risk of new-onset diabetes (NOD). To investigate the molecular mechanisms underlying this effect, we generated human induced pluripotent stem cells (iPSCs) from individuals identified from electronic health records of Kaiser Permanente of Northern California who were susceptible to developing NOD after statin initiation or controls who maintained stable fasting glucose on statin treatment. RNA-seq analysis of iPSCs incubated with atorvastatin, simvastatin or mock buffer for 24 hours identified the long non-coding RNA MIR194-2HG as a top candidate gene. Statin-induced increases in its expression were observed in NOD resistant controls, while statin-induced reductions occurred in NOD susceptible cases. MIR194-2HG encompasses two microRNA genes: MIR192 and MIR194-2. The mature microRNA miR-192-5p, derived from the 5' arm of MIR192, was predicted to bind the 3'UTR of the glucagon like peptide 1 (GLP-1) receptor (GLP1R) transcript. Transfection of a rat insulinoma cell line INS-1 with a miR-192-5p mimic increased Glp1r transcript (1.41-fold) and protein (1.51-fold) levels compared to a scrambled control. Using a luciferase reporter containing the human GLP1R 3'UTR, miR-192-5p overexpression similarly increased luciferase signal (1.44-fold). The miR-192-5p mimic enhanced glucose stimulated insulin secretion (GSIS) in response to GLP1R agonists (1.64-1.81-fold) and rescued simvastatin-induced GSIS impairment in INS-1 cells. Wildtype mice treated with miR-192 AAV8 had improved glucose sensitivity. Islets isolated from these mice exhibited enhanced GLP-1 potentiated GSIS during perifusion ex vivo. These effects were absent in the DIRKO (Glp1r/Gipr double knockout) mouse islets, consistent with the idea that miR-192 promotes GLP-1 mediated GSIS through GLP1R. These findings implicate MIR192 in statin-induced impairment of GSIS by modulating GLP1R, potentially contributing to the susceptibility to NOD in statin users.
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Affiliation(s)
- Yu-Lin Kuang
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Cassandra A.A. Locatelli
- Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Ottawa, Ontario, Canada
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Yuanyuan Qin
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Yuqing Zhang
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Antonio Muñoz-Howell
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Gabriela Sanchez
- Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA, USA
| | - Meng Lu
- Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA, USA
| | - My-Anh Nguyen
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Tanvi Yalamanchili
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Xuanwen Wang
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Gilbert Nalula
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Aras N. Mattis
- Department of Pathology, University of California San Francisco, San Francisco, CA, USA
- Board Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- The Liver Center, University of California San Francisco, San Francisco, CA, USA
| | - Akinyemi Oni-Orisan
- Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Carlos Iribarren
- Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA, USA
| | - Ronald M. Krauss
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
- Department of Medicine, University of California San Francisco, Oakland, CA, USA
| | - Erin E. Mulvihill
- Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Ottawa, Ontario, Canada
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Marisa W. Medina
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
- The Liver Center, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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Li X, Hallajzadeh J. Circulating microRNAs and physical activity: Impact in diabetes. Clin Chim Acta 2025; 569:120178. [PMID: 39900127 DOI: 10.1016/j.cca.2025.120178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/05/2025]
Abstract
The term "ci-miRNAs," or "circulating microRNAs," refers to extracellular microRNAs (miRNAs) that exist outside of cells and can be detected in various bodily fluids, including blood, saliva, urine, and breast milk. These ci-miRNAs play a role in regulating gene expression and are mainly recognized for their functions beyond the cell, serving as signaling molecules in the blood. Researchers have thoroughly investigated the roles of these circulating miRNAs in various diseases. The capacity to detect and quantify ci-miRNAs in bodily fluids suggests their potential as biomarkers for monitoring several health conditions, including cancer, heart disease, brain disorders, and metabolic disorders, where fluctuations in miRNA levels may correlate with different physiological and pathological states. Current methods enable researchers to identify and measure miRNAs in these fluids, facilitating the exploration of their roles in health maintenance and disease resistance. Although research on ci-miRNAs is ongoing, recent studies focus on uncovering their significance, assessing their viability as biomarkers, and clarifying their functions. However, our understanding of how various types, intensities, and durations of exercise influence the levels of these miRNAs in the bloodstream is still limited. This section seeks to provide an overview of the changes in ci-miRNAs in response to exercise.
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Affiliation(s)
- Xiu Li
- Shanghai Minyuan College, Shanghai 201210, China.
| | - Jamal Hallajzadeh
- Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran.
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Pokharel DR, Maskey A, Kafle R, Batajoo A, Dahal P, Raut R, Adhikari S, Manandhar B, Manandhar KD. Evaluation of circulating plasma miR-9, miR-29a, miR-192, and miR-375 as potential biomarkers for predicting prediabetes and type 2 diabetes in Nepali adult population. Noncoding RNA Res 2024; 9:1324-1332. [PMID: 39104712 PMCID: PMC11298881 DOI: 10.1016/j.ncrna.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/22/2024] [Accepted: 07/08/2024] [Indexed: 08/07/2024] Open
Abstract
Circulating plasma miRNAs have emerged as potential early predictors of glucometabolic disorders. However, their biomarker potential remains unvalidated in populations with diverse genetic backgrounds, races, and ethnicities. This study aims to validate the biomarker potential of plasma miR-9, miR-29a, miR-192, and miR-375 for early detection of prediabetes and type 2 diabetes mellitus (T2DM) in Nepali populations that represent distinct genetic backgrounds, races, and ethnicities. A total of 46 adults, categorized into healthy controls (n = 25), prediabetes (n = 9), and T2DM (n = 12) groups, were enrolled. Baseline sociodemographic, anthropometric, and clinical characteristics were collected. Fold change in plasma expression of all four miRNAs was quantified using RT-qPCR against the RNU6B reference gene. Their biomarker potential was determined by receiver operating characteristic (ROC) curve analysis. Multivariate discriminant function and hierarchical cluster analyses were used to evaluate the effectiveness of the miRNA panel in reclassifying study participants who were initially categorized according to their glucose tolerance status. Plasma expression of all four miRNAs was significantly upregulated in T2DM patients compared to normoglycemic controls. Furthermore, the expression of only miR-29a and miR-375 was upregulated in T2DM patients than in prediabetic individuals. Notably, only miR-192 expression was significantly upregulated in prediabetic individuals than in the normoglycemic controls. The miRNA expression profiles had the potential of reclassifying the participants into three original groups with an accuracy of 69.6 %. ROC curve analysis identified miR-192 as the predictor for both prediabetes and T2DM, while miR-9, miR-29a, miR-192, and miR-375 were predictive only for T2DM. The specific set of miRNA combinations significantly improved their predictive accuracy. This study validates the early predictive biomarker potential of plasma miR-9, miR-29a, miR-192, and miR-375 also in the Nepali population and paves the way for future translational studies to validate their utility in clinical laboratories.
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Affiliation(s)
- Daya Ram Pokharel
- Department of Biochemistry, Manipal College of Medical Sciences, Pokhara-16, Kaski, Nepal
| | - Abhishek Maskey
- Department of Medicine, Manipal Teaching Hospital, Pokhara-11, Kaski, Nepal
| | - Ramchandra Kafle
- Department of Medicine, Manipal Teaching Hospital, Pokhara-11, Kaski, Nepal
| | - Ashim Batajoo
- Department of Medicine, Manipal Teaching Hospital, Pokhara-11, Kaski, Nepal
| | - Prajwal Dahal
- Department of Medicine, Manipal Teaching Hospital, Pokhara-11, Kaski, Nepal
| | - Roji Raut
- Central Department of Biotechnology, Tribhuvan University, Kirtipur, Kathmandu, Nepal
| | - Shailesh Adhikari
- Central Department of Biotechnology, Tribhuvan University, Kirtipur, Kathmandu, Nepal
| | - Binod Manandhar
- Department of Mathematical Sciences, Clark Atlanta University, Atlanta, Georgia
| | - Krishna Das Manandhar
- Central Department of Biotechnology, Tribhuvan University, Kirtipur, Kathmandu, Nepal
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Redling D, Bialak S, El ghormli L, Chernausek SD, Jones K, Tryggestad JB. Circulating MicroRNAs as Predictors of Beta Cell Function in Youth-onset Type 2 Diabetes: The TODAY Study. J Clin Endocrinol Metab 2024; 109:3027-3035. [PMID: 38815053 PMCID: PMC11570374 DOI: 10.1210/clinem/dgae376] [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: 01/26/2024] [Revised: 05/14/2024] [Accepted: 05/29/2024] [Indexed: 06/01/2024]
Abstract
AIMS In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome [hemoglobin A1c (HbA1c) ≥ 8% for at least 6 months] within 4 years, which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating microRNA (miRNA) species associated with a decline in beta cell function. METHODS Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. RESULTS Using a backward selection approach, 4 baseline miRNA log2 fold-changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold-changes remained significant predictors of this C-peptide oDI decline ≥20% (P < .05). Increased levels of miRNA-155 [odds ratio (OR): 1.2, 95% confidence interval (CI): 1.1-1.4] and miRNA-130b (OR:1.3, 95% CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR: 0.6, 95% CI: .4-.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24 months (R = 0.22, P < .01 and R = 0.19, P < .01, respectively) and positively correlated with proinsulin at baseline, 24, and 60 months (R = 0.26, P < 0.01, R = 0.26, P < .01, R = 0.18, P < .01, respectively). CONCLUSION The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.
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Affiliation(s)
- Dakota Redling
- University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Shannon Bialak
- University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Laure El ghormli
- The Biostatistics Center, George Washington University, Rockville, MD 20852, USA
| | | | - Kenneth Jones
- University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Capetini VC, Quintanilha BJ, Garcia BREV, Rogero MM. Dietary modulation of microRNAs in insulin resistance and type 2 diabetes. J Nutr Biochem 2024; 133:109714. [PMID: 39097171 DOI: 10.1016/j.jnutbio.2024.109714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 07/13/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
The prevalence of type 2 diabetes is increasing worldwide. Various molecular mechanisms have been proposed to interfere with the insulin signaling pathway. Recent advances in proteomics and genomics indicate that one such mechanism involves the post-transcriptional regulation of insulin signaling by microRNA (miRNA). These noncoding RNAs typically induce messenger RNA (mRNA) degradation or translational repression by interacting with the 3' untranslated region (3'UTR) of target mRNA. Dietary components and patterns, which can either enhance or impair the insulin signaling pathway, have been found to regulate miRNA expression in both in vitro and in vivo studies. This review provides an overview of the current knowledge of how dietary components influence the expression of miRNAs related to the control of the insulin signaling pathway and discusses the potential application of these findings in precision nutrition.
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Affiliation(s)
- Vinícius Cooper Capetini
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil; Food Research Center (FoRC), São Paulo Research Foundation (FAPESP), São Paulo, Brazil; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, Institute of Pharmaceutical Science, Department of Pharmacology, King's College London, London, United Kingdom.
| | - Bruna Jardim Quintanilha
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil; Food Research Center (FoRC), São Paulo Research Foundation (FAPESP), São Paulo, Brazil
| | - Bruna Ruschel Ewald Vega Garcia
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Marcelo Macedo Rogero
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil; Food Research Center (FoRC), São Paulo Research Foundation (FAPESP), São Paulo, Brazil
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Sivri D, Gezmen-Karadağ M. Effects of Phytochemicals on Type 2 Diabetes via MicroRNAs. Curr Nutr Rep 2024; 13:444-454. [PMID: 38805166 PMCID: PMC11327184 DOI: 10.1007/s13668-024-00549-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 05/29/2024]
Abstract
PURPOSE OF REVIEW Type 2 diabetes, characterized by inadequate insulin secretion and resistance, is increasingly prevalent. To effectively manage type 2 diabetes, identifying new therapeutic targets is crucial. MicroRNAs, short noncoding RNA molecules, play a pivotal role in regulating β-cell function, insulin production, and resistance, and show promise as biomarkers for predicting type 2 diabetes onset. Phytochemicals, known for their antioxidant activities, may influence microRNA expression, potentially improving insulin sensitivity and mitigating associated complications. This review aims to explore the significance of microRNA in type 2 diabetes, their potential as biomarkers, and how certain phytochemicals may modulate microRNA expressions to reduce or prevent diabetes and its complications. RECENT FINDINGS Current research suggests that microRNAs show promise as novel therapeutic biomarkers for diagnosing type 2 diabetes and monitoring diabetic complications. Additionally, phytochemicals may regulate microRNAs to control type 2 diabetes, presenting a potential therapeutic strategy. The multifactorial effects of phytochemicals on type 2 diabetes and its complications through microRNAs warrant further research to elucidate their mechanisms. Comprehensive clinical trials are needed to assess the safety and efficacy of phytochemicals and their combinations. Given their ability to modulate microRNAs expression, incorporating phytochemical-rich foods into the diet may be beneficial.
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Affiliation(s)
- Dilek Sivri
- Department of Nutrition and Dietetic, Faculty of Health Science, Anadolu University, Eskişehir, Turkey.
| | - Makbule Gezmen-Karadağ
- Department of Nutrition and Dietetic, Faculty of Health Science, Gazi University, Ankara, Turkey
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Ma N, Liu W, Xu N, Yin D, Zheng P, Wang G, Hui Y, Zhang J, Han G, Yang C, Lu Y, Cheng X. Relationship between circulating thrombospondin-1 messenger ribonucleic acid and microribonucleic acid-194 levels in Chinese patients with type 2 diabetic kidney disease: The outcomes of a case-control study. J Diabetes Investig 2024; 15:1248-1258. [PMID: 38932465 PMCID: PMC11363100 DOI: 10.1111/jdi.14252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/16/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
AIMS/INTRODUCTION We investigated the relationship of circulating TSP-1 mRNA and miR-194 with diabetic kidney disease's degree. MATERIALS AND METHODS We enrolled 167 hospitalized type 2 diabetes patients in the endocrinology department. Patients were split into three groups according to urinary microalbumin: A, B and C. The control group comprised healthy outpatients (n = 163). The quantities of microribonucleic acid (miR)-194 and thrombospondin-1 (TSP-1) messenger ribonucleic acid (mRNA) in the participants' circulation were measured using a quantitative real-time polymerase chain reaction. RESULTS Circulating TSP-1 mRNA (P = 0.024) and miR-194 (P = 0.029) expressions significantly increased in type 2 diabetes patients. Circulating TSP-1 mRNA (P = 0.040) and miR-194 (P = 0.007) expression levels differed significantly among the three groups; circulating TSP-1 mRNA expression increased with urinary microalbumin. However, miR-194 declined in group B and increased in group C. Circulating TSP-1 mRNA was positively correlated with cystatin-c (r = 0.281; P = 0.021) and microalbumin/creatinine ratio (UmALB/Cr; r = 0.317; P = 0.009); miR-194 was positively correlated with UmALB/Cr (r = 0.405; P = 0.003). Stepwise multivariate linear regression analysis showed cystatin-c (β = 0.578; P = 0.021) and UmALB/Cr (β = 0.001; P = 0.009) as independent factors for TSP-1 mRNA; UmALB/Cr (β = 0.005; P = 0.028) as an independent factor for miR194. Areas under the curve for circulating TSP-1 mRNA and miR194 were 0.756 (95% confidence interval 0.620-0.893; sensitivity 0.69 and specificity 0.71, P < 0.01) and 0.584 (95% confidence interval 0.421-0.748; sensitivity 0.54 and specificity 0.52, P < 0.01), respectively. CONCLUSIONS Circulating TSP-1 mRNA and miR-194 expressions significantly increased in type 2 diabetes patients. The microalbumin group had lower levels of miR-194 (a risk factor that is valuable for type 2 diabetes kidney disease evaluation).
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Affiliation(s)
- Ning Ma
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
- Department of Endocrinology and MetabolismFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Weiwei Liu
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Ning Xu
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Dong Yin
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Ping Zheng
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Guofeng Wang
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Yuan Hui
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Jiping Zhang
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Guanjun Han
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Chuanhui Yang
- Department of Endocrinology and MetabolismLianyungang No. 1 People's HospitalLianyungangJiangsuChina
| | - Yan Lu
- Department of Endocrinology and MetabolismFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Xingbo Cheng
- Department of Endocrinology and MetabolismFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
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Manea M, Mărunțelu I, Constantinescu I. An In-Depth Approach to the Associations between MicroRNAs and Viral Load in Patients with Chronic Hepatitis B-A Systematic Review and Meta-Analysis. Int J Mol Sci 2024; 25:8410. [PMID: 39125978 PMCID: PMC11313658 DOI: 10.3390/ijms25158410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/22/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Scientists study the molecular activities of the hepatitis B virus (HBV). However, in vivo experiments are scarce. Some microRNAs are HBV-related, but their exact mechanisms are unknown. Our study provides an up-to-date view of the associations between microRNAs and HBV-DNA levels in chronically infected individuals. We conducted this large-scale research on five databases according to PRISMA guidance. Joanna Briggs Institute tools and Newcastle Ottawa Quality Assessment scores helped with quality evaluations. R 4.2.2 performed statistical computations for the meta-analysis. DIANA-microT 2023 and g:Profiler enriched the predictions of liver genes associated with miR-122 and miR-192-5p. From the 1313 records, we eliminated those irrelevant to our theme, non-article methodologies, non-English entries, and duplicates. We assessed associations between microRNAs and HBV-DNA levels. Overall, the pooled correlations favoured the general idea of the connection between non-coding molecules and viremia levels. MiR-122 and miR-192-5p were the most researched microRNAs, significantly associated with HBV-DNA levels. The connections between miR-122, miR-192-5p, let-7, miR-215, miR-320, and viral loads need further in vivo assessment. To conclude, this study evaluates systematically, for the first time, the correlations between non-coding molecules and viremia levels in patients. Our meta-analysis emphasizes potentially important pathways toward new inhibitors of the viral replication cycle.
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Affiliation(s)
- Marina Manea
- Immunology and Transplant Immunology, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
| | - Ion Mărunțelu
- Immunology and Transplant Immunology, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Ileana Constantinescu
- Immunology and Transplant Immunology, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 022328 Bucharest, Romania
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Karlin H, Sooda M, Larson M, Rong J, Huan T, Mens MMJ, van Rooij FJA, Ikram MA, Courchesne P, Freedman JE, Joehanes R, Mueller GP, Kavousi M, Ghanbari M, Levy D. Plasma Extracellular MicroRNAs Associated With Cardiovascular Disease Risk Factors in Middle-Aged and Older Adults. J Am Heart Assoc 2024; 13:e033674. [PMID: 38860398 PMCID: PMC11255734 DOI: 10.1161/jaha.123.033674] [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: 12/04/2023] [Accepted: 05/01/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level. METHODS AND RESULTS Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross-sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new-onset obesity, hypertension, type 2 diabetes, CVD, and all-cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR-193b-3p, miR-122-5p, miR-365a-3p, miR-194-5p, miR-192-5p, and miR-193a-5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR-193b-3p, miR-194-5p, and miR-193a-5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all-cause mortality in the FHS. CONCLUSIONS These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.
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Affiliation(s)
- Hannah Karlin
- Framingham Heart StudyFraminghamMAUSA
- Population Sciences BranchNational Heart, Lung, and Blood InstituteBethesdaMDUSA
| | - Meera Sooda
- Framingham Heart StudyFraminghamMAUSA
- Population Sciences BranchNational Heart, Lung, and Blood InstituteBethesdaMDUSA
| | - Martin Larson
- Framingham Heart StudyFraminghamMAUSA
- Department of BiostatisticsBoston University School of Public HealthBostonMAUSA
| | - Jian Rong
- Framingham Heart StudyFraminghamMAUSA
- Department of NeurologyBoston University Chobanian & Avedisian School of MedicineBostonMAUSA
| | - Tianxiao Huan
- Framingham Heart StudyFraminghamMAUSA
- Population Sciences BranchNational Heart, Lung, and Blood InstituteBethesdaMDUSA
- Ophthalmology and Visual SciencesUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Michelle M. J. Mens
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamThe Netherlands
- Department of Social and Behavioral SciencesHarvard T.H Chan School of Public HealthBostonMAUSA
| | - Frank J. A. van Rooij
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - M. Arfan Ikram
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Paul Courchesne
- Framingham Heart StudyFraminghamMAUSA
- Population Sciences BranchNational Heart, Lung, and Blood InstituteBethesdaMDUSA
| | - Jane E. Freedman
- Department of Medicine, Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | - Roby Joehanes
- Framingham Heart StudyFraminghamMAUSA
- Population Sciences BranchNational Heart, Lung, and Blood InstituteBethesdaMDUSA
| | - Gregory P. Mueller
- Department of Anatomy, Physiology, and Genetics, F. Edward Hebert School of MedicineUniformed Services University of the Health SciencesBethesdaMDUSA
| | - Maryam Kavousi
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Mohsen Ghanbari
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Daniel Levy
- Framingham Heart StudyFraminghamMAUSA
- Population Sciences BranchNational Heart, Lung, and Blood InstituteBethesdaMDUSA
- Boston University School of MedicineBostonMAUSA
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10
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Dandare A, Khan MJ, Naeem A, Liaquat A. Clinical relevance of circulating non-coding RNAs in metabolic diseases: Emphasis on obesity, diabetes, cardiovascular diseases and metabolic syndrome. Genes Dis 2023; 10:2393-2413. [PMID: 37554181 PMCID: PMC10404886 DOI: 10.1016/j.gendis.2022.05.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/11/2022] [Indexed: 11/22/2022] Open
Abstract
Non-coding RNAs (ncRNAs) participate in the regulation of several cellular processes including transcription, RNA processing and genome rearrangement. The aberrant expression of ncRNAs is associated with several pathological conditions. In this review, we focused on recent information to elucidate the role of various regulatory ncRNAs i.e., micro RNAs (miRNAs), circular RNAs (circRNAs) and long-chain non-coding RNAs (lncRNAs), in metabolic diseases, e.g., obesity, diabetes mellitus (DM), cardiovascular diseases (CVD) and metabolic syndrome (MetS). The mechanisms by which ncRNAs participated in disease pathophysiology were also highlighted. miRNAs regulate the expression of genes at transcriptional and translational levels. circRNAs modulate the regulation of gene expression via miRNA sponging activity, interacting with RNA binding protein and polymerase II transcription regulation. lncRNAs regulate the expression of genes by acting as a protein decoy, miRNA sponging, miRNA host gene, binding to miRNA response elements (MRE) and the recruitment of transcriptional element or chromatin modifiers. We examined the role of ncRNAs in the disease pathogenesis and their potential role as molecular markers for diagnosis, prognosis and therapeutic targets. We showed the involvement of ncRNAs in the onset of obesity and its progression to MetS and CVD. miRNA-192, miRNA-122, and miRNA-221 were dysregulated in all these metabolic diseases. Other ncRNAs, implicated in at least three diseases include miRNA-15a, miRNA-26, miRNA-27a, miRNA-320, and miRNA-375. Dysregulation of ncRNAs increased the risk of development of DM and MetS and its progression to CVD in obese individuals. Hence, these molecules are potential targets to arrest or delay the progression of metabolic diseases.
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Affiliation(s)
- Abdullahi Dandare
- Department of Biosciences, COMSATS University Islamabad, Islamabad 45550, Pakistan
- Department of Biochemistry, Usmanu Danfodiyo University, Sokoto 840104, Nigeria
| | - Muhammad Jawad Khan
- Department of Biosciences, COMSATS University Islamabad, Islamabad 45550, Pakistan
| | - Aisha Naeem
- Ministry of Public Health, POB42, Doha, Qatar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Afrose Liaquat
- Shifa College of Medicine, Shifa Tameer-E-Millat University, Islamabad 45550, Pakistan
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11
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Dähmcke M, Busch M, Pfeil JM, Brauckmann T, Schulz D, Omran W, Morawiec-Kisiel E, Wähler F, Paul S, Tayar A, Bründer MC, Grundel B, Stahl A. Circulating MicroRNAs as Biomarker for Vessel-Associated Retinal Diseases. Ophthalmologica 2023; 246:227-237. [PMID: 37721532 DOI: 10.1159/000533481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/04/2023] [Indexed: 09/19/2023]
Abstract
INTRODUCTION Vessel-associated retinal diseases are a major cause of blindness and severe visual impairment. The identification of appropriate biomarkers is of great importance to better anticipate disease progression and establish more targeted treatment options. MicroRNAs (miRNAs) are short, single-stranded, noncoding ribonucleic acids that are involved in the posttranscriptional regulation of gene expression through hybridization with messenger RNA. The expression of certain miRNAs can be different in patients with pathological processes and can be used for the detection and differentiation of various diseases. In this study, we investigate to what extent previously in vitro identified miRNAs are present as cell-free circulating miRNAs in the serum and vitreous of human patients with and without vessel-associated retinal diseases. METHODS Relative quantification by quantitative real-time polymerase chain reaction was used to analyze miRNA expression in patients with vessel-associated retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion compared with control patients. RESULTS In serum samples, miR-29a-3p and miR-192-5p showed increased expression in patients with neovascular AMD relative to control patients. Similarly, miR-335-5p, miR-192-5p, and miR-194-5p showed increased expression in serum from patients with proliferative DR. In vitreous samples, miR-100-5p was decreased in patients with proliferative DR. Differentially expressed miRNAs showed good diagnostic accuracy in receiver operating characteristic (ROC) and area under the ROC curve analysis. CONCLUSION The miRNAs investigated in this study may have the potential to serve as biomarkers for vessel-associated retinal diseases. Combining multiple miRNAs may enhance the predictive power of the analysis.
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Affiliation(s)
- Merlin Dähmcke
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Martin Busch
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Johanna M Pfeil
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Tara Brauckmann
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Daniel Schulz
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Wael Omran
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Ewa Morawiec-Kisiel
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Fabienne Wähler
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Sebastian Paul
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Allam Tayar
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | | | - Bastian Grundel
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
| | - Andreas Stahl
- Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany
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12
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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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13
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Shen Z, Li ZY, Yu MT, Tan KL, Chen S. Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains. Biomed Pharmacother 2023; 158:114206. [PMID: 36916433 DOI: 10.1016/j.biopha.2022.114206] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/30/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
The term type III diabetes (T3DM) has been proposed for Alzheimer's disease (AD) due to the shared molecular and cellular features between type 2 diabetes (T2DM) and insulin resistance-associated memory deficits and cognitive decline in elderly individuals. Astrocytes elicit neuroprotective or deleterious effects in AD progression and severity. Patients with T2DM are at a high risk of cognitive impairment, and targeting astrocytes might be promising in alleviating neurodegeneration in the diabetic brain. Recent studies focusing on cell-specific activities in the brain have revealed the important role of astrocytes in brain metabolism (e.g., glucose metabolism, lipid metabolism), neurovascular coupling, synapses, and synaptic plasticity. In this review, we discuss how astrocytes and their dysfunction result in multiple pathological and clinical features of AD and T2DM from a metabolic perspective and the potential comorbid mechanism in these two diseases from the perspective of astrocytes.
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Affiliation(s)
- Zheng Shen
- Zunyi Medical University, Zhuhai Campus, Zhuhai, Guangdong 519041, China
| | - Zheng-Yang Li
- Zunyi Medical University, Zhuhai Campus, Zhuhai, Guangdong 519041, China
| | - Meng-Ting Yu
- Zunyi Medical University, Zhuhai Campus, Zhuhai, Guangdong 519041, China
| | - Kai-Leng Tan
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, China.
| | - Si Chen
- Zunyi Medical University, Zhuhai Campus, Zhuhai, Guangdong 519041, China.
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14
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Dysregulation of Mir-193B and Mir-376A as a Biomarker of Prediabetes in Offspring of Gestational Diabetic Mice. Processes (Basel) 2022. [DOI: 10.3390/pr10122551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a type of diabetes initiated during pregnancy and is characterized by maternal hyperglycemia that induces complications in mothers and children. In the current study, we used a GDM mouse model (through i.p. injection of a single dose of streptozocin, STZ, 60 mg/kg/bw) to investigate the biochemical and immunological changes in the blood and brain of diabetic mothers and their offspring relative to their appropriate controls. In addition, we estimated the expression levels of a set of microRNAs (miRNAs) to link between the dysregulation in the levels of miRNAs and the exposure to oxidative stress during embryonic development, as well as metabolic changes that occur after birth and during puberty in offspring (5-weeks-old). At the biochemical level, newborn pups appeared mostly to suffer from the same oxidative stress conditions of their mothers as shown by the significant increase in nitric oxide (NO) and malondialdehyde (MDA) in blood and brain of diabetic mothers and their pups. However, the 5-week-old offspring showed a significant increase in proinflammatory cytokines, IL-1β, IL-6, and TNF-α, and based on their blood glucose levels, could be considered as prediabetic (with glucose mean value of 165 mg/dl). In the meantime, the tested miRNAs, especially miR-15b, miR-146a, and miR-138 showed mostly similar expression levels in diabetic mothers and newborn pups. In this regard, miR-15a and -15b, miR-146a, and miR-138 are downregulated in diabetic mothers and their newborn pups relative to their appropriate controls. However, in offspring of diabetic mothers at puberty age, these miRNAs displayed different expression levels relative to mothers and control offspring. Interestingly, miR-193 and miR-763 expression levels were significantly lower in diabetic mothers but upregulated in their 5-week-old offspring, suggesting that miR-193 and miR-763 could be used as biomarkers to differentiate between prediabetes and diabetes.
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15
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Klyucherev TO, Olszewski P, Shalimova AA, Chubarev VN, Tarasov VV, Attwood MM, Syvänen S, Schiöth HB. Advances in the development of new biomarkers for Alzheimer's disease. Transl Neurodegener 2022; 11:25. [PMID: 35449079 PMCID: PMC9027827 DOI: 10.1186/s40035-022-00296-z] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 03/28/2022] [Indexed: 12/16/2022] Open
Abstract
Alzheimer's disease (AD) is a complex, heterogeneous, progressive disease and is the most common type of neurodegenerative dementia. The prevalence of AD is expected to increase as the population ages, placing an additional burden on national healthcare systems. There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost. The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity, including pathogenic proteins, markers of synaptic dysfunction, and markers of inflammation in the blood. There is a considerable potential in using microRNA (miRNA) as markers of AD, and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients. Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease. This review focuses on the recent developments of blood, plasma, and ocular biomarkers for the diagnosis of AD.
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Affiliation(s)
- Timofey O Klyucherev
- Department of Neuroscience, Functional Pharmacology, University of Uppsala, Uppsala, Sweden.,Department of Pharmacology, Institute of Pharmacy, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Pawel Olszewski
- Department of Neuroscience, Functional Pharmacology, University of Uppsala, Uppsala, Sweden
| | - Alena A Shalimova
- Department of Neuroscience, Functional Pharmacology, University of Uppsala, Uppsala, Sweden.,Department of Pharmacology, Institute of Pharmacy, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vladimir N Chubarev
- Institute of Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vadim V Tarasov
- Department of Pharmacology, Institute of Pharmacy, I. M. Sechenov First Moscow State Medical University, Moscow, Russia.,Institute of Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Misty M Attwood
- Department of Neuroscience, Functional Pharmacology, University of Uppsala, Uppsala, Sweden
| | - Stina Syvänen
- Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Helgi B Schiöth
- Department of Neuroscience, Functional Pharmacology, University of Uppsala, Uppsala, Sweden.
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16
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Karagiannopoulos A, Esguerra JL, Pedersen MG, Wendt A, Prasad RB, Eliasson L. Human pancreatic islet miRNA-mRNA networks of altered miRNAs due to glycemic status. iScience 2022; 25:103995. [PMID: 35310942 PMCID: PMC8927907 DOI: 10.1016/j.isci.2022.103995] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/25/2022] [Accepted: 02/24/2022] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression via mRNA targeting, playing important roles in the pancreatic islets. We aimed to identify molecular pathways and genomic regulatory regions associated with altered miRNA expression due to glycemic status, which could contribute to the development of type 2 diabetes (T2D). To this end, miRNAs were identified by a combination of differential miRNA expression and correlation analysis in human islet samples from donors with normal and elevated blood glucose levels. Analysis and clustering of highly correlated, experimentally validated gene targets of these miRNAs revealed two islet-specific clusters, which were associated with key aspects of islet functions and included a high number of T2D-related genes. Finally, cis-eQTLs and public GWAS data integration uncovered suggestive genomic signals of association with insulin secretion and T2D. The miRNA-driven network-based approach presented in this study contributes to a better understanding of impaired insulin secretion in T2D pathogenesis.
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Affiliation(s)
- Alexandros Karagiannopoulos
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences-Malmö, Lund University, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
- Clinical Research Centre, Skåne University Hospital, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
| | - Jonathan L.S. Esguerra
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences-Malmö, Lund University, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
- Clinical Research Centre, Skåne University Hospital, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
| | - Morten G. Pedersen
- Department of Information Engineering, University of Padova, Padua, Italy
| | - Anna Wendt
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences-Malmö, Lund University, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
- Clinical Research Centre, Skåne University Hospital, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
| | - Rashmi B. Prasad
- Clinical Research Centre, Skåne University Hospital, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
- Genomics, Diabetes and Endocrinology, Lund University Diabetes Centre Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden
| | - Lena Eliasson
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences-Malmö, Lund University, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
- Clinical Research Centre, Skåne University Hospital, CRC 91-11, Box 50332, 202 13 Malmö, Sweden
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17
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Flowers E, Kanaya AM, Zhang L, Aouizerat BE. The Role of Racial and Ethnic Factors in MicroRNA Expression and Risk for Type 2 Diabetes. Front Genet 2022; 13:853633. [PMID: 35368704 PMCID: PMC8971619 DOI: 10.3389/fgene.2022.853633] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/07/2022] [Indexed: 11/21/2022] Open
Abstract
Prior studies focused on circulating microRNAs and the risk for complex diseases have shown inconsistent findings. The majority of studies focused on European and East Asian racial or ethnic groups, however, ancestry was not typically reported. We evaluated the risk for type 2 diabetes as an exemplar to show that race and ethnic group may contribute to inconsistent validation of previous findings of associations with microRNAs.
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Affiliation(s)
- Elena Flowers
- University of California, San Francisco, Department of Physiological Nursing, San Francisco, CA, United States
- University of California, San Francisco, Institute for Human Genetics, San Francisco, CA, United States
| | - Alka M. Kanaya
- University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, CA, United States
- University of California, San Francisco, Department of Medicine, Division of General Internal Medicine, San Francisco, CA, United States
| | - Li Zhang
- University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, CA, United States
| | - Bradley E. Aouizerat
- New York University Bluestone Center for Clinical Research, New York, NY, United States
- New York University Department of Oral and Maxillofacial Surgery, New York, NY, United States
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18
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Factors influencing circulating microRNAs as biomarkers for liver diseases. Mol Biol Rep 2022; 49:4999-5016. [DOI: 10.1007/s11033-022-07170-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/19/2022] [Indexed: 11/09/2022]
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19
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Maddah R, Shariati P, Arabpour J, Bazireh H, Shadpirouz M, Kafraj AS. Identification of critical genes and pathways associated with hepatocellular carcinoma and type 2 diabetes mellitus using integrated bioinformatics analysis. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2022.100956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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20
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Nie H, Hu H, Li Z, Wang R, He J, Li P, Li W, Cheng X, An J, Zhang Z, Bi J, Yao J, Guo H, Zhang X, He M. Associations of plasma metal levels with type 2 diabetes and the mediating effects of microRNAs. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 292:118452. [PMID: 34737026 DOI: 10.1016/j.envpol.2021.118452] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 09/30/2021] [Accepted: 10/31/2021] [Indexed: 06/13/2023]
Abstract
The present study aims to determine the associations of multiple plasma metal levels and plasma microRNAs (miRNAs) with diabetes risk, and further explore the mediating effects of plasma miRNAs on the associations of plasma metal with diabetes risk. We detected plasma levels of 23 metals by inductively coupled plasma mass spectrometry (ICP-MS) among 94 newly diagnosed and untreated diabetic cases and 94 healthy controls. The plasma miRNAs were examined by microRNA Array screening and Taqman real-time PCR validation among the same study population. The multivariate logistic regression models were employed to explore the associations of plasma metal and miRNAs levels with diabetes risk. Generalized linear regression models were utilized to investigate the relationships between plasma metal and plasma miRNAs, and mediation analysis was used to assess the mediating effects of plasma miRNAs on the relationships between plasma metals and diabetes risk. Plasma aluminum (Al), titanium (Ti), copper (Cu), zinc (Zn), selenium (Se), rubidium (Rb), strontium (Sr), barium (Ba), and Thallium (Tl) levels were correlated with elevated diabetic risk while molybdenum (Mo) with decreased diabetic risk (P < 0.05 after FDR multiple correction). MiR-122-5p and miR-3141 were positively associated with diabetes risk (all P < 0.05). Ti, Cu, and Zn were positively correlated with miR-122-5p (P = 0.001, 0.028 and 0.004 respectively). Ti, Cu, and Se were positively correlated with miR-3141 (P = 0.003, 0.015, and 0.031 respectively). In addition, Zn was positively correlated with miR-193b-3p (P = 0.002). Ti was negatively correlated with miR-26b-3p (P = 0.016), while Mo and miR-26b-3p were positively correlated (P = 0.042). In the mediation analysis, miR-122-5p mediated 48.0% of the association between Ti and diabetes risk. The biological mechanisms of the association are needed to be explored in further studies.
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Affiliation(s)
- Hongli Nie
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hua Hu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhaoyang Li
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ruixin Wang
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia He
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of Public Health, Shihezi University School of Medicine, Shihezi, 832000, Xinjiang, China
| | - Peiwen Li
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiya Li
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xu Cheng
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jun An
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zefang Zhang
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jiao Bi
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jinqiu Yao
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huan Guo
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaomin Zhang
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Meian He
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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21
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Reid LV, Spalluto CM, Watson A, Staples KJ, Wilkinson TMA. The Role of Extracellular Vesicles as a Shared Disease Mechanism Contributing to Multimorbidity in Patients With COPD. Front Immunol 2021; 12:754004. [PMID: 34925327 PMCID: PMC8675939 DOI: 10.3389/fimmu.2021.754004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/04/2021] [Indexed: 01/27/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Individuals with COPD typically experience a progressive, debilitating decline in lung function as well as systemic manifestations of the disease. Multimorbidity, is common in COPD patients and increases the risk of hospitalisation and mortality. Central to the genesis of multimorbidity in COPD patients is a self-perpetuating, abnormal immune and inflammatory response driven by factors including ageing, pollutant inhalation (including smoking) and infection. As many patients with COPD have multiple concurrent chronic conditions, which require an integrative management approach, there is a need to greater understand the shared disease mechanisms contributing to multimorbidity. The intercellular transfer of extracellular vesicles (EVs) has recently been proposed as an important method of local and distal cell-to-cell communication mediating both homeostatic and pathological conditions. EVs have been identified in many biological fluids and provide a stable capsule for the transfer of cargo including proteins, lipids and nucleic acids. Of these cargo, microRNAs (miRNAs), which are short 17-24 nucleotide non-coding RNA molecules, have been amongst the most extensively studied. There is evidence to support that miRNA are selectively packaged into EVs and can regulate recipient cell gene expression including major pathways involved in inflammation, apoptosis and fibrosis. Furthermore changes in EV cargo including miRNA have been reported in many chronic diseases and in response to risk factors including respiratory infections, noxious stimuli and ageing. In this review, we discuss the potential of EVs and EV-associated miRNA to modulate shared pathological processes in chronic diseases. Further delineating these may lead to the identification of novel biomarkers and therapeutic targets for patients with COPD and multimorbidities.
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Affiliation(s)
- Laura V Reid
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - C Mirella Spalluto
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,National Institute for Health Research Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, United Kingdom
| | - Alastair Watson
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,National Institute for Health Research Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, United Kingdom.,Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Karl J Staples
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,National Institute for Health Research Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, United Kingdom
| | - Tom M A Wilkinson
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,National Institute for Health Research Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, United Kingdom
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22
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González-Sánchez LE, Ortega-Camarillo C, Contreras-Ramos A, Barajas-Nava LA. miRNAs as biomarkers for diagnosis of type 2 diabetes: A systematic review. J Diabetes 2021; 13:792-816. [PMID: 33576054 DOI: 10.1111/1753-0407.13166] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 01/02/2021] [Accepted: 02/07/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND This systematic review summarizes results of studies that evaluated the expression of microRNAs (miRs) in prediabetes or type 2 diabetes (T2D). METHODS The information was obtained from PubMed, EMBL-EBI, Wanfang, Trip Database, Lilacs, CINAHL, Human microRNA Disease Database (HMDD) v3.0, and Google. A qualitative synthesis of the results was performed and miRs frequency was graphically represented. From 1893 identified studies, only 55 fulfilled the inclusion criteria. These 55 studies analyzed miRs in T2D, and of them, 13 also described data of prediabetes. RESULTS In diabetics, 122 miRs were reported and 35 miRs for prediabetics. However, we identified that five miRs (-122-5p, 144-3p, 210, 375, and -126b) were reported more often in diabetics and four (144-3p, -192, 29a, and -30d) in prediabetics. CONCLUSIONS Circulating miRs could be used as biomarkers of T2D. However, it is necessary to validate these microRNAs in prospective and multicenter studies with different population subgroups, considering age, gender, and risk factors.
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Affiliation(s)
- Luis Edgar González-Sánchez
- Laboratory of Developmental Biology Research and Experimental Teratogenicity, Hospital Infantil de México Federico Gómez (HIMFG), Mexico City, Mexico
| | - Clara Ortega-Camarillo
- Medical Research Unit in Biochemistry, Specialties Hospital, National Medical Center SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Alejandra Contreras-Ramos
- Laboratory of Developmental Biology Research and Experimental Teratogenicity, Hospital Infantil de México Federico Gómez (HIMFG), Mexico City, Mexico
| | - Leticia Andrea Barajas-Nava
- Evidence-Based Medicine Research Unit, Hospital Infantil de México Federico Gómez (HIMFG), Mexico City, Mexico
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23
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Ruiz GP, Camara H, Fazolini NPB, Mori MA. Extracellular miRNAs in redox signaling: Health, disease and potential therapies. Free Radic Biol Med 2021; 173:170-187. [PMID: 33965563 DOI: 10.1016/j.freeradbiomed.2021.05.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
Extracellular microRNAs (miRNAs) have emerged as important mediators of cell-to-cell communication and intertissue crosstalk. MiRNAs are produced by virtually all types of eukaryotic cells and can be selectively packaged and released to the extracellular medium, where they may reach distal cells to regulate gene expression cell non-autonomously. By doing so, miRNAs participate in integrative physiology. Oxidative stress affects miRNA expression, while miRNAs control redox signaling. Disruption in miRNA expression, processing or release to the extracellular compartment are associated with aging and a number of chronic diseases, such as obesity, type 2 diabetes, neurodegenerative diseases and cancer, all of them being conditions related to oxidative stress. Here we discuss the interplay between redox balance and miRNA function and secretion as a determinant of health and disease states, reviewing the findings that support this notion and highlighting novel and yet understudied venues of research in the field.
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Affiliation(s)
- Gabriel Palermo Ruiz
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Henrique Camara
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Narayana P B Fazolini
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Marcelo A Mori
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, SP, Brazil.
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24
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Zhang L, Li K, Tian S, Wang XQ, Li JH, Dong YC, Xia HF, Ma X. Down-regulation of microRNA-30d-5p is associated with gestational diabetes mellitus by targeting RAB8A. J Diabetes Complications 2021; 35:107959. [PMID: 34052089 DOI: 10.1016/j.jdiacomp.2021.107959] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 04/12/2021] [Accepted: 05/14/2021] [Indexed: 11/29/2022]
Abstract
Gestational Diabetes Mellitus (GDM) is a complicated clinical process, and metabolic disorders during pregnancy are closely related to the structure and function of the placenta. The aberrant expression of miRNAs in the placenta may play a role in the occurrence and development of GDM. Analysis of microRNA (miRNA) expression signature in placenta showed that the level of miR-30d-5p was significantly down-regulated in GDM patients. This study aims to explore the possible mechanism of GDM under the regulation of miR-30d-5p. In situ hybridization and qRT-PCR assay showed that miR-30d expression down-regulated in the placentas from GDM patients compared with normal control group. The trophoblast cells proliferation and glucose uptake capacity were increased, the ability of migration and invasion were also improved after inhibiting the function of endogenous mature miR-30d-5p. Bioinformatics analysis and luciferase reporter assays showed that miR-30d-5p binds to the 3'UTR of RAB8A mRNA, resulting in RAB8A suppression. Moreover, the down-regulation of RAB8A could attenuate the increase in trophoblast cell proliferation, migration, invasion and glucose uptake induced by miR-30d-5p functional inhibitor. These data imply that miR-30d-5p expression is down-regulated in placental tissue from GDM patients and affects trophoblast cell functions by targeting RAB8A, which may provide new insight into the pathogenesis of GDM.
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Affiliation(s)
- Lu Zhang
- National Research Institute for Family Planning, Beijing, China; Graduate School, Peking Union Medical College, Beijing, China
| | - Kai Li
- School of Life Sciences, Fudan University, Shanghai, China
| | - Shi Tian
- Haidian Maternal & Child Health Hospital, Beijing, China
| | - Xue-Qin Wang
- National Research Institute for Family Planning, Beijing, China; Graduate School, Peking Union Medical College, Beijing, China
| | - Jian-Hui Li
- National Research Institute for Family Planning, Beijing, China; Graduate School, Peking Union Medical College, Beijing, China
| | - Yi-Chao Dong
- National Research Institute for Family Planning, Beijing, China; Graduate School, Peking Union Medical College, Beijing, China
| | - Hong-Fei Xia
- National Research Institute for Family Planning, Beijing, China; Graduate School, Peking Union Medical College, Beijing, China.
| | - Xu Ma
- National Research Institute for Family Planning, Beijing, China; Graduate School, Peking Union Medical College, Beijing, China.
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25
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MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus. BIOLOGY 2021; 10:biology10060534. [PMID: 34203703 PMCID: PMC8232095 DOI: 10.3390/biology10060534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/23/2022]
Abstract
Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.
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26
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Tayel SI, Saleh AA, El-Hefnawy SM, Elzorkany KM, Elgarawany GE, Noreldin RI. Simultaneous Assessment of MicroRNAs 126 and 192 in Diabetic Nephropathy Patients and the Relation of these MicroRNAs with Urinary Albumin. Curr Mol Med 2021; 20:361-371. [PMID: 31629394 DOI: 10.2174/1566524019666191019103918] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/04/2019] [Accepted: 10/08/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVE Diabetic nephropathy (DN) is a major determinant of end-stage renal disease (ESRD). Altered microRNA levels lead to serious chronic diseases, such as diabetes. We aimed to measure the expression levels of two microRNAs, microRNA126 and 192 in DN and investigate their connection with albuminuria levels. METHODS This study included 229 subjects (134 DN patients and 95 controls). Serum lipid profiles, glucose levels, glycated haemoglobin (HbA1c) levels, and renal functions were assayed. The microRNA126 and microRNA192 expression levels were determined by real-time PCR. RESULTS Patients with DN had higher weights, BMI values, glucose levels (P<0.001), HbA1c levels (P<0.001), urinary albumin-creatinine ratio (ACR) values (P<0.001), urea levels (P=0.002), and creatinine levels (P=0.004) and lower expression levels of both microRNA192 (P<0.001) and microRNA126 (P<0.001) than controls. MicroRNA126 expression was positively correlated with age, estimated glomerular filtration rate (eGFR) and microRNA192 expression but negatively correlated with blood sugar, HbA1c, urea, creatinine and ACR. MicroRNA192 had higher sensitivity (91%), specificity (94%), and area under the curve (AUC) (0.967) values than microRNA126 (sensitivity, 90%; specificity, 68%; AUC, 0.897) and thus can precisely diagnose DN. CONCLUSION Both MicroRNA126 and microRNA192 expression were obviously associated with DN and might determine the progression of the disease owing to prominent relation with macroalbuminuria.
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Affiliation(s)
- Safaa I Tayel
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Egypt
| | - Amany A Saleh
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Egypt
| | - Sally M El-Hefnawy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Egypt
| | - Khaled Ma Elzorkany
- Internal Medicine Department, Faculty of Medicine, Menoufia University, Egypt
| | | | - Rasha I Noreldin
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Egypt
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27
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Lischka J, Schanzer A, Hojreh A, Ba-Ssalamah A, de Gier C, Valent I, Item CB, Greber-Platzer S, Zeyda M. Circulating microRNAs 34a, 122, and 192 are linked to obesity-associated inflammation and metabolic disease in pediatric patients. Int J Obes (Lond) 2021; 45:1763-1772. [PMID: 33986456 PMCID: PMC8310785 DOI: 10.1038/s41366-021-00842-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 03/26/2021] [Accepted: 04/26/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Obesity-associated chronic low-grade inflammation leads to dysregulation of central lipid and glucose metabolism pathways leading to metabolic disorders. MicroRNAs (miRNAs) are known to control regulators of metabolic homeostasis. We aimed to assess the relationship of circulating miRNAs with inflammatory modulators and metabolic disorders in pediatric obesity. METHODS From a pediatric cohort with severe obesity (n = 109), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test, and liver MRI, a panel of 16 circulating miRNAs was quantified using qRT-PCR. Additionally, markers of inflammation TNFα, IL1 receptor antagonist, procalcitonin, CRP, and IL-6 were measured. RESULTS Markers of obesity-associated inflammation, TNFα, IL-1Ra, and procalcitonin, all significantly correlated with concentrations of miRNAs 122 and 192. Concentrations of these miRNAs negatively correlated with serum adiponectin and were among those strongly linked to parameters of dyslipidemia and liver function. Moreover, miRNA122 concentrations correlated with HOMA-IR. Several miRNA levels including miRNAs 34a, 93, 122, and 192 were statistically significantly differing between individuals with prediabetes, impaired glucose tolerance, metabolic syndrome, or nonalcoholic fatty liver disease compared to the respective controls. Additionally, miRNA 192 was significantly elevated in metabolically unhealthy obesity. CONCLUSIONS A miRNA pattern associated with obesity-associated inflammation and comorbidities may be used to distinguish metabolically healthy from unhealthy pediatric patients with obesity. Moreover, these changes in epigenetic regulation could potentially be involved in the etiology of obesity-linked metabolic disease in children and adolescents.
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Affiliation(s)
- Julia Lischka
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Andrea Schanzer
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Azadeh Hojreh
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Ahmed Ba-Ssalamah
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Charlotte de Gier
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Isabella Valent
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Chike Bellarmine Item
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Susanne Greber-Platzer
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Maximilian Zeyda
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
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28
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Ren FJ, Yao Y, Cai XY, Fang GY. Emerging Role of MiR-192-5p in Human Diseases. Front Pharmacol 2021; 12:614068. [PMID: 33708127 PMCID: PMC7940509 DOI: 10.3389/fphar.2021.614068] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/19/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are a type of small non-coding RNAs that play an essential role in numerous biological processes by regulating the post-transcriptional expression of target genes. Recent studies have demonstrated that miR-192-5p, a member of the miR-192 family, partakes in several human diseases, especially various cancers, including cancers of the lung, liver, and breast. Importantly, the levels of miR-192-5p are abundant in biofluids, including the serum and urine, and the exosomal levels of miR-192-5p in circulation can aid in the diagnosis and prognosis of various diseases, such as chronic hepatitis B (CHB) infection disease. Notably, recent studies suggest that miR-192-5p is regulated by long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). However, there are no comprehensive overviews on the role of miR-192-5p in human diseases. This review discusses the significant studies on the role of miR-192-5p in various human diseases, with special emphasis on the diseases of the respiratory and digestive systems.
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Affiliation(s)
- Fu-Jia Ren
- Department of Pharmacy, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Yao Yao
- Department of Pharmacy, Women's Hospital School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-Yu Cai
- Department of Pharmacy, Hangzhou First People's Hospital, Hangzhou, China
| | - Guo-Ying Fang
- Department of Pharmacy, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
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29
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Ma N, Xu N, Yin D, Zheng P, Liu W, Wang G, Hui Y, Zhang J, Han G, Yang C, Chen Y, Cheng X, Cheng M. Circulating microRNA-194 levels in Chinese patients with diabetic kidney disease: a case-control study. Ther Adv Endocrinol Metab 2021; 12:20420188211049615. [PMID: 34676065 PMCID: PMC8524709 DOI: 10.1177/20420188211049615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 09/12/2021] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRNAs) regulate gene expression and are involved in diabetic kidney disease (DKD) pathogenesis. We investigated circulating miRNA-194 levels as a biomarker of DKD prevalence and incidence, and the relationship between miRNA-194 and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP). METHODS We recruited 136 type-2 diabetes mellitus (T2DM) patients at the First People's Hospital of Lianyungang and 127 healthy individuals. Circulating miRNA-194 and CHOP levels were measured using quantitative reverse transcription qRT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Anthropometric and biochemistry measurements were also made. RESULTS T2DM patients showed higher circulating miRNA-194 (p = 0.029) and lower circulating CHOP (p < 0.001) levels than controls. Circulating miRNA-194 levels were significantly higher in T2DM patients with a microalbumin/creatinine ratio (UmALB/Cr) ⩾ 300 mg/g (p < 0.001). In addition, there were significant intergroup differences in the circulating CHOP concentrations (p = 0.005). Bivariate analysis revealed that circulating miR-194 levels were negatively correlated with alpha-fetoprotein and CHOP levels (r = -0.222, -0.301; p = 0.018, 0.001, respectively), but positively correlated with fasting glucose, UmALB/Cr, Cr, Cystatin C, quantitative insulin check index (QUICKI) (r = 0.193, 0.446, 0.260, 0.339, and 0.250, respectively; p = 0.036, <0.001, 0.005, <0.001, and 0.006, respectively), particularly UmALB/Cr and Cystatin C (p < 0.001). Logistic regression analysis after adjusting for covariates associated with UmALB/Cr identified duration of T2DM, systolic blood pressure, Cr, estimated glomerular filtration rate, and waist circumference as independent factors associated with T2DM patients with UmALB/Cr > 300 (p = 0.030, 0.013, <0.001, <0.001, and 0.031, respectively). CONCLUSION Circulating miRNA-194 levels could be a novel biomarker for DKD.
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Affiliation(s)
- Ning Ma
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
- Department of Endocrinology and Metabolism, The
First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ning Xu
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Dong Yin
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Ping Zheng
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Weiwei Liu
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Guofeng Wang
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Yuan Hui
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Jiping Zhang
- Department of Endocrinology and Metabolism, The
First People’s Hospital of Lianyungang, Lianyungang, China
| | - Guanjun Han
- Department of Endocrinology and Metabolism,
The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Chuanhui Yang
- Department of Endocrinology and Metabolism,
The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Yiting Chen
- Department of Endocrinology and Metabolism,
The First Affiliated Hospital of Soochow University, Suzhou, China
| | | | - Ming Cheng
- School of Rail Transportation, Soochow
University, 1 Shizi Road, Suzhou 215006, Jiangsu, China
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Zhang Y, Zhou B, Wen M, Hu M, Peng JG, Wang Y, Fan LL, Tang L. ZG02 Improved Hepatic Glucose Metabolism and Insulin Sensitivity via Activation of AMPK/Sirt1 Signaling Pathways in a High-fat Diet/Streptozotocin-induced Type 2 Diabetes Model. Diabetes Metab Syndr Obes 2020; 13:4333-4339. [PMID: 33209046 PMCID: PMC7670175 DOI: 10.2147/dmso.s275145] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/19/2020] [Indexed: 12/26/2022] Open
Abstract
PURPOSE The aim of the present study was to investigate the hypoglycemic activity and potential mechanism of tetrahydrocarbazole derivatives ZG02 in high-fat diet/streptozotocin-induced type 2 diabetes model. METHODS C57BL/6 mice (n=30) were randomly assigned to three groups: control group (n=10) was fed with normal diet, the diabetes group (n=10) was fed with high-fat diet for eight weeks followed by intraperitoneal injection of streptozotocin (25 mg/kg) and the ZG02 group (n=10) injected intraperitoneally with ZG02 (30 mg/kg/day) for two weeks after successful modeling. The changes of weight, fasting blood glucose, oral glucose tolerance and fasting blood insulin levels in each group were evaluated. In addition, we also assessed the expression level of total AMPK, phosphorylation AMPK, SIRT1, PGC-1 and the activity of G6PC in liver. RESULTS The results demonstrated that ZG02 could significantly antagonize the high-fat diet/streptozotocin-induced fasting hyperglycemia, restore fasting blood insulin levels and also improve activity of G6PC in liver. The results from Western blot indicated that ZG02 significantly restored the expression level of phosphorylation AMPK, Sirt1 and PGC-1. CONCLUSION ZG02 improve hepatic glucose metabolism and insulin sensitivity via activation AMPK/Sirt1 signaling pathways in type 2 diabetes mice model.
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Affiliation(s)
- Yi Zhang
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
- Engineering Technology Research Center for Chemical Drug R&D, Guizhou550004, People’s Republic of China
- College of Pharmacy, Guizhou Medical University, Guizhou550004, People’s Republic of China
| | - Bo Zhou
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
- Engineering Technology Research Center for Chemical Drug R&D, Guizhou550004, People’s Republic of China
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guizhou550004, People’s Republic of China
| | - Min Wen
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
| | - Mi Hu
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
| | - Jin-Gang Peng
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
- Engineering Technology Research Center for Chemical Drug R&D, Guizhou550004, People’s Republic of China
- College of Pharmacy, Guizhou Medical University, Guizhou550004, People’s Republic of China
| | - Ying Wang
- College of Pharmacy, Guizhou Medical University, Guizhou550004, People’s Republic of China
| | - Lin-Lin Fan
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
- Engineering Technology Research Center for Chemical Drug R&D, Guizhou550004, People’s Republic of China
- College of Pharmacy, Guizhou Medical University, Guizhou550004, People’s Republic of China
| | - Lei Tang
- College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China
- Engineering Technology Research Center for Chemical Drug R&D, Guizhou550004, People’s Republic of China
- College of Pharmacy, Guizhou Medical University, Guizhou550004, People’s Republic of China
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31
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Diabetes, microRNA, and Nutrition in Geriatrics. CURRENT GERIATRICS REPORTS 2020. [DOI: 10.1007/s13670-020-00336-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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32
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Udesen PB, Glintborg D, Sørensen AE, Svendsen R, Nielsen NLS, Wissing MLM, Andersen MS, Englund ALM, Dalgaard LT. Metformin decreases miR-122, miR-223 and miR-29a in women with polycystic ovary syndrome. Endocr Connect 2020; 9:1075-1084. [PMID: 33112812 PMCID: PMC7774773 DOI: 10.1530/ec-20-0195] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023]
Abstract
Metformin is associated with increased insulin sensitivity, whereas oral contraceptive pills (OCP) could increase the risk for type 2 diabetes (T2D) in women with polycystic ovary syndrome (PCOS). Certain miRNAs might serve as biomarkers for the risk of T2D. The aim of this study was to investigate changes in circulating miRNA levels during treatment with metformin and OCP in women with PCOS. Sixty-five women with PCOS according to Rotterdam criteria were randomized to metformin (2 g/day), metformin + OCP (150 mg desogestrel + 30 µg ethinylestradiol) or OCP alone for 12 months. Serum miRNA analysis was performed with individual RT-qPCR or Taqman low density array cards of 22 selected miRNAs previously related to PCOS, glucose and/or lipid metabolism. miR-122 and miR-29a levels were decreased after treatment with metformin compared with metformin + OCP and OCP group: miR-122: log2 difference -0.7 (P = 0.01) and -0.7 (P = 0.02), miR-29a: log2 difference -0.5 (P = 0.01) and -0.4 (P = 0.04), while miR-223 levels were decreased in the metformin + OCP group after treatment: log2 difference -0.5 (P = 0.02). During the treatment period, a significant weight loss was observed in the metformin group compared with the OCP group. In the OCP group, miRNA levels were unchanged during the treatment period. Levels of circulating miRNAs associated with lipid and glucose metabolism decreased during metformin treatment. Changes in miRNA levels in the metformin group could be explained by the simultaneous weight loss in the same group. These results support the notion that metformin treatment alone may be superior for metabolic health compared with OCP.
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Affiliation(s)
- Pernille Bækgaard Udesen
- The Fertility Clinic, Department of Gynecology and Obstetrics, Zealand University Hospital, Køge, Denmark
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Dorte Glintborg
- Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark
| | | | - Rikke Svendsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Nanna Louise Skov Nielsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
- Department of Clinical Immunology, Næstved Hospital, Næstved, Denmark
| | | | | | - Anne Lis Mikkelsen Englund
- The Fertility Clinic, Department of Gynecology and Obstetrics, Zealand University Hospital, Køge, Denmark
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Włodarski A, Strycharz J, Wróblewski A, Kasznicki J, Drzewoski J, Śliwińska A. The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress. Int J Mol Sci 2020; 21:ijms21186902. [PMID: 32962281 PMCID: PMC7555602 DOI: 10.3390/ijms21186902] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress (OxS) is the cause and the consequence of metabolic syndrome (MetS), the incidence and economic burden of which is increasing each year. OxS triggers the dysregulation of signaling pathways associated with metabolism and epigenetics, including microRNAs, which are biomarkers of metabolic disorders. In this review, we aimed to summarize the current knowledge regarding the interplay between microRNAs and OxS in MetS and its components. We searched PubMed and Google Scholar to summarize the most relevant studies. Collected data suggested that different sources of OxS (e.g., hyperglycemia, insulin resistance (IR), hyperlipidemia, obesity, proinflammatory cytokines) change the expression of numerous microRNAs in organs involved in the regulation of glucose and lipid metabolism and endothelium. Dysregulated microRNAs either directly or indirectly affect the expression and/or activity of molecules of antioxidative signaling pathways (SIRT1, FOXOs, Keap1/Nrf2) along with effector enzymes (e.g., GPx-1, SOD1/2, HO-1), ROS producers (e.g., NOX4/5), as well as genes of numerous signaling pathways connected with inflammation, insulin sensitivity, and lipid metabolism, thus promoting the progression of metabolic imbalance. MicroRNAs appear to be important epigenetic modifiers in managing the delicate redox balance, mediating either pro- or antioxidant biological impacts. Summarizing, microRNAs may be promising therapeutic targets in ameliorating the repercussions of OxS in MetS.
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Affiliation(s)
- Adam Włodarski
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, 92-213 Lodz, Poland;
- Correspondence: (A.W.); (J.S.); (A.Ś.)
| | - Justyna Strycharz
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland;
- Correspondence: (A.W.); (J.S.); (A.Ś.)
| | - Adam Wróblewski
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Jacek Kasznicki
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, 92-213 Lodz, Poland;
| | - Józef Drzewoski
- Central Teaching Hospital of the Medical University of Lodz, 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 92-213 Lodz, Poland
- Correspondence: (A.W.); (J.S.); (A.Ś.)
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Kapusta P, Konieczny PS, Hohendorff J, Borys S, Totoń-Żurańska J, Kieć-Wilk BM, Wołkow PP, Malecki MT. Negative pressure wound therapy affects circulating plasma microRNAs in patients with diabetic foot ulceration. Diabetes Res Clin Pract 2020; 165:108251. [PMID: 32531327 DOI: 10.1016/j.diabres.2020.108251] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 05/01/2020] [Accepted: 06/04/2020] [Indexed: 12/31/2022]
Abstract
AIMS Negative pressure wound therapy (NPWT) is commonly used in diabetic foot ulceration (DFU). The molecular mechanisms of NPWT action, particularly outside of the wound site, have not been described. We assessed NPWT's effect on circulating miRNA expression levels in type 2 diabetes (T2DM) patients with DFU. METHODS We examined 34 T2DM patients treated with either NPWT (n = 24) or standard therapy (ST, n = 10). The group assignment was based on clinical criteria and local practice. Next-generation sequencing-based microRNA expression was determined on the patient's plasma collected before therapy and after 8 days. RESULTS NPWT patients were similar to the ST group in terms of age, BMI, and HbA1c level; however, they differed by mean wound area (12.6 cm2 vs. 1.1 cm2 p = 0.0005). First, we analyzed the change of miRNA after NPWT or ST and observed an upregulation of let-7f-2 only in the NPWT group. Then, we analyzed the differential expression between NPWT and ST groups, looking at possible wound size effects. We found 12 differentially expressed miRNAs in pre-treatment comparison, including let-7f-2, while in post-treatment analysis we identified 28 miRNAs. The pathway enrichment analysis suggests that identified miRNAs may be involved in wound healing, particularly through angiogenesis. CONCLUSION We found initial evidence that NPWT in T2DM patients with DFU affects miRNA expression in plasma. Additionally, some differences in plasma miRNA expression may be related to wound size.
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Affiliation(s)
- Przemysław Kapusta
- Centre for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Paweł S Konieczny
- Centre for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Jerzy Hohendorff
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; University Hospital, Krakow, Poland
| | - Sebastian Borys
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; University Hospital, Krakow, Poland
| | - Justyna Totoń-Żurańska
- Centre for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Beata M Kieć-Wilk
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; University Hospital, Krakow, Poland
| | - Paweł P Wołkow
- Centre for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland.
| | - Maciej T Malecki
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; University Hospital, Krakow, Poland.
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Yan LN, Zhang X, Xu F, Fan YY, Ge B, Guo H, Li ZL. Four-microRNA signature for detection of type 2 diabetes. World J Clin Cases 2020; 8:1923-1931. [PMID: 32518782 PMCID: PMC7262691 DOI: 10.12998/wjcc.v8.i10.1923] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/02/2020] [Accepted: 04/14/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Sensitive, novel, and accurate biomarkers for the detection of physiological changes in type 2 diabetes (T2DM) at an early stage are urgently needed.
AIM To build a multi-parameter diagnostic model for the early detection of T2DM.
METHODS MiR-148b, miR-223, miR-130a, and miR-19a levels were detected by real-time polymerase chain reaction in serum of healthy controls, individuals with impaired glucose regulation, and T2DM patients. The diagnostic value of miR-148b, miR-223, miR-130a, and miR-19a, alone or in combination, was analyzed.
RESULTS The area under the curve (AUC) of miR-223, which had the best diagnostic value for discriminating the impaired glucose regulation and T2DM groups, was 0.84, and the sensitivity and specificity were 73.37% and 81.37%, respectively. The AUC of the four-miRNA signature was 0.90, and the sensitivity and specificity were 78.82% and 88.23%, respectively. In the validation set, the AUC was 0.88, and the sensitivity and specificity were 78.36% and 87.63%, respectively.
CONCLUSION In summary, we have built a multi-parameter diagnostic model consisting of miR-148b, miR-223, miR-130a, and miR-19a for the detection of T2DM. It may be a potential tool for the early detection of T2DM.
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Affiliation(s)
- Li-Na Yan
- Department of Endocrinology, Inner Mongolia Baogang Hospital, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - Xin Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Interventional Therapy Department, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Fang Xu
- Department of Endocrinology, Inner Mongolia Baogang Hospital, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - Yuan-Yuan Fan
- Department of Endocrinology, Inner Mongolia Baogang Hospital, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - Biao Ge
- Department of Endocrinology, Inner Mongolia Baogang Hospital, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - Hui Guo
- Department of Endocrinology, Inner Mongolia Baogang Hospital, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - Zi-Ling Li
- Department of Endocrinology, Inner Mongolia Baogang Hospital, Baotou 014010, Inner Mongolia Autonomous Region, China
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Cai H, Jiang Z, Yang X, Lin J, Cai Q, Li X. Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1. Endocr J 2020; 67:397-408. [PMID: 31875589 DOI: 10.1507/endocrj.ej19-0271] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
It has been shown that circular RNAs, a class of non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of circular RNA HIPK3 (circHIPK3) in diabetes-associated metabolic disorders, including hyperglycemia and insulin resistance. Results show that oleate stimulated circHIPK3 increase, and that circHIPK3 enhanced the stimulatory effect of oleate on adipose deposition, triglyceride (TG) content, and cellular glucose content in HepG2 cells. MiR-192-5p was the potential target of circHIPK3, since circHIPK3 significantly decreased miR-192-5p mRNA level, whereas anti-circHIPK3 significantly increased miR-192-5p mRNA level. Further study shows that transcription factor forkhead box O1 (FOXO1) was a downstream regulator of miR-192-5p, since miR-192-5p significantly decreased FOXO1 expression, whereas circHIPK3 significantly increased FOXO1 expression. Notably, the inhibitory effect of miR-192-5p was significantly reversed by circHIPK3. In vivo study shows that anti-miR-192-5p significantly increased blood glucose content, which was significantly inhibited by FOXO1 shRNA. MiR-192-5p significantly decreased adipose deposition and TG content in HepG2 cells, which was significantly reversed by the co-treatment with circHIPK3. Forskolin/dexamethasone (FSK/DEX) significantly increased cellular glucose, mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), and this stimulatory effect of FSK/DEX was significantly inhibited by miR-192-5p. In the presence of circHIPK3, however, the inhibitory effect of miR-192-5p was totally lost. In summary, the present study demonstrated that circHIPK3 contributes to hyperglycemia and insulin resistance by sponging miR-192-5p and up-regulating FOXO1.
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Affiliation(s)
- Huiyao Cai
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, 362000, China
| | - Zhengrong Jiang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, 362000, China
| | - Xinna Yang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, 362000, China
| | - Jiayu Lin
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, 362000, China
| | - Qingyan Cai
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, 362000, China
| | - Xisheng Li
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, 362000, China
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Loganathan TS, Sulaiman SA, Abdul Murad NA, Shah SA, Abdul Gafor AH, Jamal R, Abdullah N. Interactions Among Non-Coding RNAs in Diabetic Nephropathy. Front Pharmacol 2020; 11:191. [PMID: 32194418 PMCID: PMC7062796 DOI: 10.3389/fphar.2020.00191] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 02/10/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetic Nephropathy (DN) is the most common cause of End-stage renal disease (ESRD). Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden. Recent findings showed that noncoding RNAs (ncRNAs) play an important role in DN progression, potentially can be used as biomarkers and therapeutic targets. NcRNAs refers to the RNA species that do not encode for any protein, and the most known ncRNAs are the microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Dysregulation of these ncRNAs was reported before in DN patients and animal models of DN. Importantly, there are some interactions between these ncRNAs to regulate the crucial steps in DN progression. Here, we aimed to discuss the reported ncRNAs in DN and their interactions with critical genes in DN progression. Elucidating these ncRNAs regulatory network will allow for a better understanding of the molecular mechanisms in DN and how they can act as new biomarkers for DN and also as the potential targets for treatment.
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Affiliation(s)
- Tamil Selvi Loganathan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nor Azian Abdul Murad
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Shamsul Azhar Shah
- Department of Community Health, UKM Medical Centre, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Abdul Halim Abdul Gafor
- Nephrology Unit, Faculty of Medicine, UKM Medical Centre, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Noraidatulakma Abdullah
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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van den Berg M, Krauskopf J, Ramaekers J, Kleinjans J, Prickaerts J, Briedé J. Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders. Prog Neurobiol 2020; 185:101732. [DOI: 10.1016/j.pneurobio.2019.101732] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/25/2019] [Accepted: 12/03/2019] [Indexed: 12/21/2022]
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Garavelli S, Bruzzaniti S, Tagliabue E, Prattichizzo F, Di Silvestre D, Perna F, La Sala L, Ceriello A, Mozzillo E, Fattorusso V, Mauri P, Puca AA, Franzese A, Matarese G, Galgani M, de Candia P. Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity. Int J Mol Sci 2020; 21:ijms21020477. [PMID: 31940853 PMCID: PMC7013659 DOI: 10.3390/ijms21020477] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/06/2020] [Accepted: 01/09/2020] [Indexed: 12/17/2022] Open
Abstract
Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.
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Affiliation(s)
- Silvia Garavelli
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
| | - Sara Bruzzaniti
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “G. Salvatore”, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy
- Dipartimento di Biologia, Università degli Studi di Napoli “Federico II”, 80126 Naples, Italy
| | - Elena Tagliabue
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
| | - Francesco Prattichizzo
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
| | - Dario Di Silvestre
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), 20090 Segrate (MI), Italy; (D.D.S.); (P.M.)
| | - Francesco Perna
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy;
| | - Lucia La Sala
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
| | - Antonio Ceriello
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
| | - Enza Mozzillo
- Centro Regionale di Diabetologia Pediatrica, Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy or (E.M.); (V.F.); (A.F.)
| | - Valentina Fattorusso
- Centro Regionale di Diabetologia Pediatrica, Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy or (E.M.); (V.F.); (A.F.)
| | - Pierluigi Mauri
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), 20090 Segrate (MI), Italy; (D.D.S.); (P.M.)
| | - Annibale A. Puca
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
- Dipartimento di Medicina, Chirurgia e Odontoiatria ”Scuola Medica Salernitana”, Università di Salerno, Via S. Allende, 84081 Baronissi (SA), Italy
| | - Adriana Franzese
- Centro Regionale di Diabetologia Pediatrica, Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy or (E.M.); (V.F.); (A.F.)
| | - Giuseppe Matarese
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “G. Salvatore”, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy
- Correspondence: (G.M.); or (M.G.); (P.d.C.); Tel.: +39-08-1746-4580 (G.M.); +39-08-1746-4596 (M.G.); +39-02-5540-6534 (P.d.C.)
| | - Mario Galgani
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “G. Salvatore”, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy
- Correspondence: (G.M.); or (M.G.); (P.d.C.); Tel.: +39-08-1746-4580 (G.M.); +39-08-1746-4596 (M.G.); +39-02-5540-6534 (P.d.C.)
| | - Paola de Candia
- IRCCS MultiMedica, 20138 Milan, Italy; (S.G.); (E.T.); (F.P.); (L.L.S.); (A.C.); (A.A.P.)
- Correspondence: (G.M.); or (M.G.); (P.d.C.); Tel.: +39-08-1746-4580 (G.M.); +39-08-1746-4596 (M.G.); +39-02-5540-6534 (P.d.C.)
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Iacomino G, Lauria F, Venezia A, Iannaccone N, Russo P, Siani A. microRNAs in Obesity and Metabolic Diseases. OBESITY AND DIABETES 2020:71-95. [DOI: 10.1007/978-3-030-53370-0_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Extracellular Vesicle Encapsulated MicroRNAs in Patients with Type 2 Diabetes Are Affected by Metformin Treatment. J Clin Med 2019; 8:jcm8050617. [PMID: 31067715 PMCID: PMC6571700 DOI: 10.3390/jcm8050617] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/01/2019] [Accepted: 05/03/2019] [Indexed: 01/05/2023] Open
Abstract
Recently, microRNAs (miRNAs) in circulating extracellular vesicles (EVs), have emerged as a source of potential biomarkers for various pathophysiological conditions, including metabolic disorders such as diabetes. Type 2 diabetes mellitus (T2DM), is the most prevalent form of diabetes in the USA, with 30 million diagnosed patients. Identifying miRNA biomarkers that can be used to assess response to glucose lowering treatments would be useful. Using patient plasma samples from a subset of the Danish Metagenomics of the Human Intestinal Tract (MetaHIT) cohort, we characterized miRNAs from whole plasma, plasma-derived EVs, and EV-depleted plasma by small RNA-sequencing to identify T2DM associated miRNAs. We identified several miRNAs that exhibited concentration changes between controls and non-metformin treated T2DM patients and we validated a subset of these by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The results showed that the concentrations of many T2DM-affected miRNAs in EV (but not in whole or EV-depleted plasma) decreased to levels close to those of healthy controls following metformin treatment. Among other potential uses of these differentially expressed miRNAs, some might be useful in assessing the response to metformin in T2DM patients.
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Nasias D, Evangelakos I, Nidris V, Vassou D, Tarasco E, Lutz TA, Kardassis D. Significant changes in hepatic transcriptome and circulating miRNAs are associated with diet-induced metabolic syndrome in apoE3L.CETP mice. J Cell Physiol 2019; 234:20485-20500. [PMID: 31016757 DOI: 10.1002/jcp.28649] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/07/2019] [Indexed: 12/12/2022]
Abstract
Long-term exposure to excess dietary fat leads to obesity and the metabolic syndrome (MetS). The purpose of the present study was to identify global changes in liver gene expression and circulating miRNAs in a humanized mouse model of diet-induced MetS. Male apoE3L.CETP mice received a high-fat diet (HFD) or a low-fat diet (LFD) for different time periods and the progression of MetS pathology was monitored. A separate group of mice was divided into responders (R) or nonresponders (NR) and received HFD for 16 weeks. We found that mice receiving the HFD developed manifestations of MetS and displayed an increasing number of differentially expressed transcripts at 4, 8, and 12 weeks compared with mice receiving the LFD. Significantly changed genes were functionally annotated to metabolic diseases and pathway analysis revealed the downregulation of genes in cholesterol and fatty acid biosynthesis and upregulation of genes related to lipid droplet formation, which was in line with the development of hepatic steatosis. In the serum of the apoE3L.CETP mice we identified three miRNAs that were upregulated specifically in the HFD group. We found that responder mice have a distinct gene signature that differentiates them from nonresponders. Comparison of the two diet intervention studies revealed a limited number of common differentially expressed genes but the expression of these common genes was affected in a similar way in both studies. In conclusion, the characteristic hepatic gene signatures and serum miRNAs identified in the present study provide novel insights to MetS pathology and could be exploited for diagnostic or therapeutic purposes.
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Affiliation(s)
- Dimitris Nasias
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.,Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Ioannis Evangelakos
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.,Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Vasilis Nidris
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.,Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Despoina Vassou
- Genomics Facility, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Erika Tarasco
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - Dimitris Kardassis
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.,Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
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