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Mohamed Abdelgawwad El-Sehrawy AA, Mohammed MH, Salahldin OD, Uthirapathy S, Ballal S, Kalia R, Arya R, Joshi KK, Kadim AS, Kadhim AJ. Crosstalk between microRNA and inflammation; critical regulator of diabetes. Exp Cell Res 2025; 447:114507. [PMID: 40058448 DOI: 10.1016/j.yexcr.2025.114507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
A growing body of evidence indicates that microRNAs (miRNAs may be used as biomarkers for the diagnosis, prognosis, and treatment of diabetes, given their changed expression profile as the disease progresses. There is growing interest in using individual miRNAs or whole miRNA clusters linked to diabetes as therapeutic targets because of their abnormal expression and functioning. In diabetes, miRNAs are also involved in inflammatory and immunological responses. Additionally, the inflammatory response controls the generation, processing, and stability of pre- or mature miRNAs and miRNA biogenesis. With a comprehensive grasp of molecular biological activities and the signaling axis, this review emphasizes the critical functions of miRNAs in inflammatory and immunological processes in diabetes. We further emphasized the potential role of these miRNAs in controlling inflammation associated with diabetes. This assessment will direct the shift from many studies to practical applications for tailored diabetes treatment and assist in identifying new therapeutic targets and approaches.
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Affiliation(s)
| | - Mohammed Hashim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, Al-maarif University, Anbar, Iraq.
| | | | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Rishiv Kalia
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Renu Arya
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India.
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, 248002, Uttarakhand, India; Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India.
| | - Arshed Shakir Kadim
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, Babylon, 51001, Iraq.
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq.
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2
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Auddino S, Aiello E, Grieco GE, Fignani D, Licata G, Bruttini M, Mori A, Berteramo AF, Pedace E, Nigi L, Formichi C, Guay C, Quero G, Tondolo V, Di Giuseppe G, Soldovieri L, Ciccarelli G, Mari A, Giaccari A, Mezza T, Po A, Regazzi R, Dotta F, Sebastiani G. Comprehensive sequencing profile and functional analysis of IsomiRs in human pancreatic islets and beta cells. Diabetologia 2025:10.1007/s00125-025-06397-4. [PMID: 40102237 DOI: 10.1007/s00125-025-06397-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 01/28/2025] [Indexed: 03/20/2025]
Abstract
AIMS/HYPOTHESIS MiRNAs regulate gene expression, influencing beta cell function and pathways. Isoforms of miRNA (isomiRs), sequence variants of miRNAs with post-transcriptional modifications, exhibit cell-type-specific expression and functions. Despite their biological significance, a comprehensive isomiR profile in human pancreatic islets and beta cells remains unexplored. This study aims to profile isomiR expression in four beta cell sources: (1) laser capture microdissected human islets (LCM-HI); (2) collagenase-isolated human islets (CI-HI); (3) sorted beta cells; and (4) the EndoC-βH1 beta cell line, and to investigate their potential role in beta cell function. METHODS Small RNA-seq and/or small RNA dataset analysis was conducted on human pancreatic islets and beta cells. Data were processed using the sRNAbench bioinformatics pipeline to classify isomiRs based on sequence variations. A beta cell-specific isomiR signature was identified via cross-validation across datasets. Correlations between LCM-HI isomiR expression and in vivo clinical parameters were analysed using regression models. Functional validation of isomiR-411-5p-Ext5p(+1) was performed via overexpression in EndoC-βH1 cells and CI-HI, followed by glucose-stimulated insulin secretion (GSIS) assays and/or transcriptomic analysis. RESULTS IsomiRs constituted 59.2 ± 1.9% (LCM-HI), 59.6 ± 2.4% (CI-HI), 42.3 ± 7.2% (sorted beta cells) and 43.8 ± 1.2% (EndoC-βH1) of total miRNA reads (data represented as mean ± SD), with 3' end trimming (Trim3p) being the predominant modification. A beta cell-specific isomiR signature of 30 sequences was identified, with isomiR-411-5p-Ext5p(+1) showing a significant inverse correlation with basal insulin secretion (p=0.0009, partial R2=0.68) and total insulin secretion (p=0.005, partial R2=0.54). Overexpression of isomiR-411-5p-Ext5p(+1), but not of its canonical counterpart, importantly reduced GSIS by 51% ( ± 15.2%; mean ± SD) (p=0.01) in EndoC-βH1 cells. Transcriptomic analysis performed in EndoC-βH1 cells and CI-HI identified 47 genes significantly downregulated by isomiR-411-5p-Ext5p(+1) (false discovery rate [FDR]<0.05) but not by the canonical miRNA, with enriched pathways related to Golgi vesicle biogenesis (FDR=0.017) and trans-Golgi vesicle budding (FDR=0.018). TargetScan analysis confirmed seed sequence-dependent target specificity for 81 genes uniquely regulated by the isomiR (p=1.1 × 10⁻⁹). CONCLUSIONS/INTERPRETATION This study provides the first comprehensive isomiR profiling in human islets and beta cells, revealing their substantial contribution to miRNA regulation. IsomiR-411-5p-Ext5p(+1) emerges as a distinct key modulator of insulin secretion and granule dynamics in beta cells. These findings highlight isomiRs as potential biomarkers and therapeutic targets for diabetes, warranting further exploration of their roles in beta cell biology.
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Affiliation(s)
- Stefano Auddino
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Elena Aiello
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giuseppina E Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Marco Bruttini
- Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
| | - Alessia Mori
- Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
| | - Andrea F Berteramo
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Erika Pedace
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Giuseppe Quero
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Vincenzo Tondolo
- General Surgery Unit, Fatebenefratelli Isola Tiberina-Gemelli Isola, Rome, Italy
| | - Gianfranco Di Giuseppe
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Laura Soldovieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gea Ciccarelli
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Andrea Giaccari
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Agnese Po
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy.
- Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy.
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
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Zhang Y, Qian B, Yang Y, Niu F, Lin C, Yuan H, Wang J, Wu T, Shao Y, Shao S, Liu A, Wu J, Sun P, Chang X, Bi Y, Tang W, Zhu Y, Chen F, Su D, Han X. Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion. Diabetes 2024; 73:1832-1847. [PMID: 39186314 PMCID: PMC11493764 DOI: 10.2337/db24-0177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 08/09/2024] [Indexed: 08/27/2024]
Abstract
Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db/db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Yaqin Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bin Qian
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yang Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Fandi Niu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Cardiology, Xijing Hospital, Air Force Military Medical University, Xi’an, Shanxi, China
| | - Changsong Lin
- Department of Bioinformatics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Honglei Yuan
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianan Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tijun Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yixue Shao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shulin Shao
- Department of Laboratory, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Aiming Liu
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingwen Wu
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital affiliated to Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China
| | - Wei Tang
- Department of Endocrinology, Islet Cell Senescence and Function Research Laboratory, Jiangsu Province Geriatric Institute, Nanjing, Jiangsu, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
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Deng F, Zhou B, Zhang S, Cai L. Dexmedetomidine-mediated improvement of perioperative neurocognitive disorders by miR-184-3p-mediated NLRP3. Brain Res 2024; 1842:149051. [PMID: 38830564 DOI: 10.1016/j.brainres.2024.149051] [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: 02/02/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND Perioperative neurocognitive disorders (PND) is a neurological complication in the perioperative period, which may lead to severe poor prognosis. Dexmedetomidine (Dex) is a commonly used sedative in the perioperative period. However, the effect of intraoperative anesthetic Dex on PND remains complicated and confusing. METHODS PND model was established using aged male mice, treated with Dex, and subjected to behavioral tests. The effect of Dex on pyroptosis was assessed by western blot, enzyme-linked immunosorbent assay and immunofluorescence. In addition, the miRNA expression profile of PND mice was identified by small RNA sequencing and performed PCR to detect miRNAs. Finally, the effect of miRNA on mice neuron pyroptosis was verified in vitro. RESULTS We found postoperative cognitive was declined in PND mice compared with control group, while preoperative injection of Dex improved short-term working memory and anxious exploration behavior, alleviated the cognitive impairment. Intriguingly, Dex ameliorated hippocampal inflammation and neuron pyroptosis in PND mice as evidenced by the reduced GSDMD, NLRP3, IL-1β and IL-18. The miRNA expression profile of PND mice hippocampus was disordered, including 5 miRNAs up-regulated and 17 miRNAs down-regulated, compared to the sham group. Dysregulated miRNAs were mainly enriched in biological functions related to neuronal development and signaling pathways related to pyroptosis. MiR-184-3p was the key miRNA, overexpression of miR-184-3p blocked the inhibitory effect of Dex on neuron pyroptosis, which was manifested as increased expression of GSDMD and NLRP3, increased inflammatory factors IL-1β and IL-18. CONCLUSIONS This study revealed that miR-184-3p may mediate NLRP3 to prevent the alleviating effect of Dex on PND, which provides a new potential way to improve the therapeutic intervention of PND.
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Affiliation(s)
- Fumou Deng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Bin Zhou
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Shenglan Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Lily Cai
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China..
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Li Y, Yang Y, Sun Y, He L, Zhao L, Sun H, Chang X, Liang R, Wang S, Han X, Zhu Y. The miR-203/ZBTB20/MAFA Axis Orchestrates Pancreatic β-Cell Maturation and Identity During Weaning and Diabetes. Diabetes 2024; 73:1673-1686. [PMID: 39058664 DOI: 10.2337/db23-0604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
Maturation of postnatal β-cells is regulated in a cell-autonomous manner, and metabolically stressed β-cells regress to an immature state, ensuring defective β-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to β-cell maturation remain largely unknown. Here, we report a mature form of miRNA (miR-203)/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that the level of the mature form of miRNA (miR-203) in β-cells changes during the nutritional transition and that miR-203 inhibits β-cell maturation at the neonatal stage and under high-fat diet conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature β-cells into CgBHi endocrine cells while suppressing gene expressions associated with β-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional β-cell numbers to alleviate diabetes. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Yating Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuqian Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yi Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu He
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Zhao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haoran Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Liang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
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Yuan H, He M, Yang Q, Niu F, Zou Y, Liu C, Yang Yang, Liu A, Chang X, Chen F, Wu T, Han X, Zhang Y. Obesity-induced upregulation of miR-483-5p impairs the function and identity of pancreatic β-cells. Diabetes Obes Metab 2024; 26:4510-4521. [PMID: 39072950 DOI: 10.1111/dom.15805] [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: 04/04/2024] [Revised: 06/15/2024] [Accepted: 06/28/2024] [Indexed: 07/30/2024]
Abstract
AIM To assess the expression and function of miR-483-5p in diabetic β cells. METHODS The expression of miR-483-5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual-luciferase activity, and western blotting assays, were utilized for miR-483-5p target gene verification. Mice with β cell-specific miR-483-5p downregulation were studied under metabolic stress (i.e. a high-fat diet) condition. Lineage tracing was used to determine β-cell fate. RESULTS miR-483-5p increased in the islets of obese mouse models. Expression levels of miR-483-5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR-483-5p in β cells results in impaired insulin secretion and β-cell identity. Cell lineage-specific analyses revealed that miR-483-5p overexpression deactivated β-cell identity genes (insulin, Pdx1 and MafA) and derepressed β-cell dedifferentiation (Ngn3) genes. miR-483-5p downregulation in β cells of high-fat diet-fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR-483-5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β-cell maturation. CONCLUSIONS These findings indicate that the miR-483-5p-mediated reduction of mRNAs specifies β-cell identity as a contributor to β-cell dysfunction via the loss of cellular differentiation.
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Affiliation(s)
- Honglei Yuan
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Mei He
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Qinnan Yang
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Fandi Niu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Yuchen Zou
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Chen Liu
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Yang Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Aiming Liu
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Tijun Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Yaqin Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
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7
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Elsayed AK, Aldous N, Alajez NM, Abdelalim EM. Identifying miRNA Signatures Associated with Pancreatic Islet Dysfunction in a FOXA2-Deficient iPSC Model. Stem Cell Rev Rep 2024; 20:1915-1931. [PMID: 38916841 PMCID: PMC11445299 DOI: 10.1007/s12015-024-10752-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2024] [Indexed: 06/26/2024]
Abstract
The pathogenesis of diabetes involves complex changes in the expression profiles of mRNA and non-coding RNAs within pancreatic islet cells. Recent progress in induced pluripotent stem cell (iPSC) technology have allowed the modeling of diabetes-associated genes. Our recent study using FOXA2-deficient human iPSC models has highlighted an essential role for FOXA2 in the development of human pancreas. Here, we aimed to provide further insights on the role of microRNAs (miRNAs) by studying the miRNA-mRNA regulatory networks in iPSC-derived islets lacking the FOXA2 gene. Consistent with our previous findings, the absence of FOXA2 significantly downregulated the expression of islet hormones, INS, and GCG, alongside other key developmental genes in pancreatic islets. Concordantly, RNA-Seq analysis showed significant downregulation of genes related to pancreatic development and upregulation of genes associated with nervous system development and lipid metabolic pathways. Furthermore, the absence of FOXA2 in iPSC-derived pancreatic islets resulted in significant alterations in miRNA expression, with 61 miRNAs upregulated and 99 downregulated. The upregulated miRNAs targeted crucial genes involved in diabetes and pancreatic islet cell development. In contrary, the absence of FOXA2 in islets showed a network of downregulated miRNAs targeting genes related to nervous system development and lipid metabolism. These findings highlight the impact of FOXA2 absence on pancreatic islet development and suggesting intricate miRNA-mRNA regulatory networks affecting pancreatic islet cell development.
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Affiliation(s)
- Ahmed K Elsayed
- Laboratory of Pluripotent Stem Cell Disease Modeling, Translational Medicine Department, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
- Stem Cell Core, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Noura Aldous
- Laboratory of Pluripotent Stem Cell Disease Modeling, Translational Medicine Department, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Essam M Abdelalim
- Laboratory of Pluripotent Stem Cell Disease Modeling, Translational Medicine Department, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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8
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. FASEB J 2024; 38:e23885. [PMID: 39139039 PMCID: PMC11378476 DOI: 10.1096/fj.202401078r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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Affiliation(s)
- Nejc Haberman
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Rebecca Cheung
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Grazia Pizza
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Nevena Cvetesic
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Dorka Nagy
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Hannah Maude
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Lorea Blazquez
- Department of Neurosciences, Biogipuzkoa Health Research Institute, San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- CIBERNED, ISCIII (CIBER, Carlos III Institute, Spanish Ministry of Sciences and Innovation), Madrid, Spain
| | - Boris Lenhard
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
- Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Faculté de Médecine, Université de Montréal, Montréal, Quebec, Canada
- Lee Kong Chian Medical School, Nanyang Technological University, Singapore, Singapore
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
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9
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Tjandrawinata RR, Nurkolis F. A Comparative Analysis on Impact of Extraction Methods on Carotenoids Composition, Antioxidants, Antidiabetes, and Antiobesity Properties in Seagrass Enhalus acoroides: In Silico and In Vitro Study. Mar Drugs 2024; 22:365. [PMID: 39195481 DOI: 10.3390/md22080365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 08/07/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024] Open
Abstract
Enhalus acoroides, a tropical seagrass, is known for its significant contribution to marine ecosystems and its potential health benefits due to bioactive compounds. This study aims to compare the carotenoid levels in E. acoroides using green extraction via ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) and to evaluate the biological properties of these extracts against oxidative stress, diabetes, and obesity through in silico and in vitro analyses. E. acoroides samples were collected from Manado City, Indonesia, and subjected to UAE and MAE. The extracts were analyzed using UHPLC-ESI-MS/MS to identify carotenoids, including β-carotene, lutein, lycopene, β-cryptoxanthin, and zeaxanthin. In silico analysis was conducted to predict the compounds' bioactivity, toxicity, and drug-likeness using WAY2DRUG PASS and molecular docking with CB-Dock2. The compounds C3, C4, and C7 demonstrated notable interactions, with key metabolic proteins and microRNAs, further validating their potential therapeutic benefits. In vitro assays evaluated antioxidant activities using DPPH and FRAP assays, antidiabetic properties through α-glucosidase and α-amylase inhibition, and antiobesity effects via lipase inhibition and MTT assay with 3T3-L1 cells. Results indicated that both UAE and MAE extracts exhibited significant antioxidant, antidiabetic, and antiobesity activities. MAE extracts showed higher carotenoid content and greater biological activity compared to UAE extracts. These findings suggest that E. acoroides, mainly when extracted using MAE, has promising potential as a source of natural bioactive compounds for developing marine-based antioxidant, antidiabetic, and antiobesity agents. This study supplements existing literature by providing insights into the efficient extraction methods and the therapeutic potential of E. acoroides carotenoids.
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Affiliation(s)
- Raymond Rubianto Tjandrawinata
- Center for Pharmaceutical and Nutraceutical Research and Policy, Atma Jaya Catholic University of Indonesia, Jakarta 12930, Indonesia
| | - Fahrul Nurkolis
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Padjadjaran, Sumedang 45363, Indonesia
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10
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Mohsin F, Javaid S, Tariq M, Mustafa M. Molecular immunological mechanisms of impaired wound healing in diabetic foot ulcers (DFU), current therapeutic strategies and future directions. Int Immunopharmacol 2024; 139:112713. [PMID: 39047451 DOI: 10.1016/j.intimp.2024.112713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/02/2024] [Accepted: 07/15/2024] [Indexed: 07/27/2024]
Abstract
Diabetic foot ulcer (DFU) is a foremost cause of amputation in diabetic patients. Consequences of DFU include infections, decline in limb function, hospitalization, amputation, and in severe cases, death. Immune cells including macrophages, regulatory T cells, fibroblasts and other damage repair cells work in sync for effective healing and in establishment of a healthy skin barrier post-injury. Immune dysregulation during the healing of wounds can result in wound chronicity. Hyperglycemic conditions in diabetic patients influence the pathophysiology of wounds by disrupting the immune system as well as promoting neuropathy and ischemic conditions, making them difficult to heal. Chronic wound microenvironment is characterized by increased expression of matrix metalloproteinases, reactive oxygen species as well as pro-inflammatory cytokines, resulting in persistent inflammation and delayed healing. Novel treatment modalities including growth factor therapies, nano formulations, microRNA based treatments and skin grafting approaches have significantly augmented treatment efficiency, demonstrating creditable efficacy in clinical practices. Advancements in local treatments as well as invasive methodologies, for instance formulated wound dressings, stem cell applications and immunomodulatory therapies have been successful in targeting the complex pathophysiology of chronic wounds. This review focuses on elucidating the intricacies of emerging physical and non-physical therapeutic interventions, delving into the realm of advanced wound care and comprehensively summarizing efficacy of evidence-based therapies for DFU currently available.
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Affiliation(s)
- Fatima Mohsin
- KAM School of Life Sciences, Forman Christian College (A Chartered University), Lahore, Pakistan.
| | - Sheza Javaid
- KAM School of Life Sciences, Forman Christian College (A Chartered University), Lahore, Pakistan.
| | - Mishal Tariq
- KAM School of Life Sciences, Forman Christian College (A Chartered University), Lahore, Pakistan.
| | - Muhammad Mustafa
- KAM School of Life Sciences, Forman Christian College (A Chartered University), Lahore, Pakistan.
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11
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Carr ER, Higgins PB, McClenaghan NH, Flatt PR, McCloskey AG. MicroRNA regulation of islet and enteroendocrine peptides: Physiology and therapeutic implications for type 2 diabetes. Peptides 2024; 176:171196. [PMID: 38492669 DOI: 10.1016/j.peptides.2024.171196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/05/2024] [Accepted: 03/14/2024] [Indexed: 03/18/2024]
Abstract
The pathogenesis of type 2 diabetes (T2D) is associated with dysregulation of glucoregulatory hormones, including both islet and enteroendocrine peptides. Microribonucleic acids (miRNAs) are short noncoding RNA sequences which post transcriptionally inhibit protein synthesis by binding to complementary messenger RNA (mRNA). Essential for normal cell activities, including proliferation and apoptosis, dysregulation of these noncoding RNA molecules have been linked to several diseases, including diabetes, where alterations in miRNA expression within pancreatic islets have been observed. This may occur as a compensatory mechanism to maintain beta-cell mass/function (e.g., downregulation of miR-7), or conversely, lead to further beta-cell demise and disease progression (e.g., upregulation of miR-187). Thus, targeting miRNAs has potential for novel diagnostic and therapeutic applications in T2D. This is reinforced by the success seen to date with miRNA-based therapeutics for other conditions currently in clinical trials. In this review, differential expression of miRNAs in human islets associated with T2D will be discussed along with further consideration of their effects on the production and secretion of islet and incretin hormones. This analysis further unravels the therapeutic potential of miRNAs and offers insights into novel strategies for T2D management.
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Affiliation(s)
- E R Carr
- Department of Life and Physical Sciences, Atlantic Technology University, Donegal, Ireland; Department of Life Sciences, Atlantic Technological University, Sligo, Ireland
| | - P B Higgins
- Department of Life and Physical Sciences, Atlantic Technology University, Donegal, Ireland
| | - N H McClenaghan
- Department of Life Sciences, Atlantic Technological University, Sligo, Ireland
| | - P R Flatt
- School of Biomedical Sciences, Ulster University, Coleraine, UK
| | - A G McCloskey
- Department of Life and Physical Sciences, Atlantic Technology University, Donegal, Ireland.
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12
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Jacovetti C, Donnelly C, Menoud V, Suleiman M, Cosentino C, Sobel J, Wu K, Bouzakri K, Marchetti P, Guay C, Kayser B, Regazzi R. The mitochondrial tRNA-derived fragment, mt-tRF-Leu TAA, couples mitochondrial metabolism to insulin secretion. Mol Metab 2024; 84:101955. [PMID: 38704026 PMCID: PMC11112368 DOI: 10.1016/j.molmet.2024.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/29/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
OBJECTIVE The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-LeuTAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-LeuTAA, on mitochondrial metabolism and pancreatic islet functions. METHODS We used antisense oligonucleotides to reduce mt-tRF-LeuTAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-LeuTAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-LeuTAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays. RESULTS Our study unveils a modulation of mt-tRF-LeuTAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-LeuTAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-LeuTAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-LeuTAA impairs insulin secretion of rat and human pancreatic β-cells. CONCLUSIONS Our findings indicate that mt-tRF-LeuTAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion.
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Affiliation(s)
- Cecile Jacovetti
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
| | - Chris Donnelly
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Véronique Menoud
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Mara Suleiman
- Department of Clinical and Experimental Medicine, Diabetes Unit, University of Pisa, Pisa, Italy
| | - Cristina Cosentino
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Jonathan Sobel
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Kejing Wu
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Karim Bouzakri
- UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Diabetes Unit, University of Pisa, Pisa, Italy
| | - Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Bengt Kayser
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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13
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593867. [PMID: 38798508 PMCID: PMC11118353 DOI: 10.1101/2024.05.13.593867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell- selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors important for β-cell identity, such as FOXA, MAFA or RFX6 and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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14
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Anuradha U, Mehra NK, Khatri DK. Understanding molecular mechanisms and miRNA-based targets in diabetes foot ulcers. Mol Biol Rep 2024; 51:82. [PMID: 38183502 DOI: 10.1007/s11033-023-09074-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 11/21/2023] [Indexed: 01/08/2024]
Abstract
In today's culture, obesity and overweight are serious issues that have an impact on how quickly diabetes develops and how it causes complications. For the development of more effective therapies, it is crucial to understand the molecular mechanisms underlying the chronic problems of diabetes. The most prominent effects of diabetes are microvascular abnormalities such as retinopathy, nephropathy, and neuropathy, especially diabetes foot ulcers, as well as macrovascular abnormalities such as heart disease and atherosclerosis. MicroRNAs (miRNAs), which are highly conserved endogenous short non-coding RNA molecules, have been implicated in several physiological functions recently, including the earliest stages of the disease. By binding to particular messenger RNAs (mRNAs), which cause mRNA degradation, translation inhibition, or even gene activation, it primarily regulates posttranscriptional gene expression. These molecules exhibit considerable potential as diagnostic biomarkers for disease and are interesting treatment targets. This review will provide an overview of the latest findings on the key functions that miRNAs role in diabetes and its complications, with an emphasis on the various stages of diabetic wound healing.
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Affiliation(s)
- Urati Anuradha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Hyderabad, Telangana, 500037, India
| | - Neelesh Kumar Mehra
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Hyderabad, Telangana , 500037, India.
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Hyderabad, Telangana, 500037, India.
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15
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Guo YC, Cao HD, Lian XF, Wu PX, Zhang F, Zhang H, Lu DH. Molecular mechanisms of noncoding RNA and epigenetic regulation in obesity with consequent diabetes mellitus development. World J Diabetes 2023; 14:1621-1631. [DOI: 10.4239/wjd.v14.i11.1621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/26/2023] [Accepted: 09/27/2023] [Indexed: 11/14/2023] Open
Abstract
Diabetes mellitus (DM) and obesity have become two of the most prevalent and challenging diseases worldwide, with increasing incidence and serious complications. Recent studies have shown that noncoding RNA (ncRNA) and epigenetic regulation play crucial roles in the pathogenesis of DM complicated by obesity. Identification of the involvement of ncRNA and epigenetic regulation in the pathogenesis of diabetes with obesity has opened new avenues of investigation. Targeting these mechanisms with small molecules or RNA-based therapies may provide a more precise and effective approach to diabetes treatment than traditional therapies. In this review, we discuss the molecular mechanisms of ncRNA and epigenetic regulation and their potential therapeutic targets, and the research prospects for DM complicated with obesity.
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Affiliation(s)
- Yi-Chen Guo
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
- Department of Endocrinology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Hao-Di Cao
- Department of Endocrinology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Xiao-Fen Lian
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Pei-Xian Wu
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Fan Zhang
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Hua Zhang
- Department of Endocrinology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
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16
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Zhang JY, Ren CQ, Cao YN, Ren Y, Zou L, Zhou C, Peng LX. Role of MicroRNAs in Dietary Interventions for Obesity and Obesity-Related Diseases. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:14396-14412. [PMID: 37782460 DOI: 10.1021/acs.jafc.3c03042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Obesity and related metabolic syndromes pose a serious threat to human health and quality of life. A proper diet is a safe and effective strategy to prevent and control obesity, thus maintaining overall health. However, no consensus exists on the connotations of proper diet, and it is attributed to various factors, including "nutritional dark matter" and the "matrix effect" of food. Accumulating evidence confirms that obesity is associated with the in vivo levels of miRNAs, which serve as potential markers and regulatory targets for obesity onset and progression; food-derived miRNAs can regulate host obesity by targeting the related genes or gut microbiota across the animal kingdom. Host miRNAs mediate food nutrient-gut microbiota-obesity interactions. Thus, miRNAs are important correlates of diet and obesity onset. This review outlines the recent findings on miRNA-mediated food interventions for obesity, thereby elucidating their potential applications. Overall, we provide new perspectives and views on the evaluation of dietary nutrition, which may bear important implications for dietary control and obesity prevention.
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Affiliation(s)
- Ji-Yue Zhang
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Sichuan Province Engineering Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, People's Republic of China
| | - Chao-Qin Ren
- Aba Teachers University, Wenchuan, Sichuan 623002, People's Republic of China
| | - Ya-Nan Cao
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Sichuan Province Engineering Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, People's Republic of China
| | - Yuanhang Ren
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Sichuan Province Engineering Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, People's Republic of China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Sichuan Province Engineering Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, People's Republic of China
| | - Chuang Zhou
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Sichuan Province Engineering Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, People's Republic of China
| | - Lian-Xin Peng
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Sichuan Province Engineering Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, People's Republic of China
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17
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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: 4] [Impact Index Per Article: 2.0] [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: 05/23/2023] [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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18
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Natalicchio A, Montagnani M, Gallo M, Marrano N, Faggiano A, Zatelli MC, Mazzilli R, Argentiero A, Danesi R, D'Oronzo S, Fogli S, Giuffrida D, Gori S, Ragni A, Renzelli V, Russo A, Franchina T, Tuveri E, Sciacca L, Monami M, Cirino G, Di Cianni G, Colao A, Avogaro A, Cinieri S, Silvestris N, Giorgino F. MiRNA dysregulation underlying common pathways in type 2 diabetes and cancer development: an Italian Association of Medical Oncology (AIOM)/Italian Association of Medical Diabetologists (AMD)/Italian Society of Diabetology (SID)/Italian Society of Endocrinology (SIE)/Italian Society of Pharmacology (SIF) multidisciplinary critical view. ESMO Open 2023; 8:101573. [PMID: 37263082 PMCID: PMC10245125 DOI: 10.1016/j.esmoop.2023.101573] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/27/2023] [Accepted: 04/26/2023] [Indexed: 06/03/2023] Open
Abstract
Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, ⁓22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches.
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Affiliation(s)
- A Natalicchio
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - M Montagnani
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - M Gallo
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy
| | - N Marrano
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - M C Zatelli
- Section of Endocrinology, Geriatrics, and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - R Mazzilli
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - A Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - R Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - S D'Oronzo
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - S Fogli
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - D Giuffrida
- Department of Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | - S Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona, Italy
| | - A Ragni
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy
| | - V Renzelli
- Diabetologist and Endocrinologist, Italian Association of Clinical Diabetologists, Rome, Italy
| | - A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - T Franchina
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - E Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ASL-Sulcis, Carbonia, Sardinia, Italy
| | - L Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania, Catania, Italy
| | - M Monami
- Diabetology, Careggi Hospital and University of Florence, Firenze, Italy
| | - G Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - G Di Cianni
- Diabetes Unit, Livorno Hospital, Livorno, Italy
| | - A Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy; UNESCO Chair, Education for Health and Sustainable Development, Federico II University, Naples, Italy
| | - A Avogaro
- Department of Medicine, University of Padova, Padua, Italy
| | - S Cinieri
- Medical Oncology Division and Breast Unit, Senatore Antonio Perrino Hospital, ASL Brindisi, Brindisi, Italy
| | - N Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - F Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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19
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Behrooz M, Hajjarzadeh S, Kahroba H, Ostadrahimi A, Bastami M. Expression pattern of miR-193a, miR122, miR155, miR-15a, and miR146a in peripheral blood mononuclear cells of children with obesity and their relation to some metabolic and inflammatory biomarkers. BMC Pediatr 2023; 23:95. [PMID: 36859176 PMCID: PMC9976520 DOI: 10.1186/s12887-023-03867-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/25/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND The widespread presence of childhood obesity has increased considerably over three decades. The present study was designed to investigate expression patterns of miR-146a, miR-155, miR-15a, miR-193a, and miR-122 in peripheral blood mononuclear cells (PBMCs) in children who are obese along with their association with metabolic and inflammatory biomarkers. METHODS Ninety test subjects were admitted. The profile of blood pressure, resting energy expenditure (REE), anthropometric measures, body composition, dietary intakes, physical activity levels, insulin, and lipid profile, fasting blood glucose (FBG), high-sensitivity C-reactive protein (hs-CRP), and pubertal stage have been measured. Total RNA (including small RNAs) was extracted from PBMCs. The expression levels of miRNAs were measured by stem-loop RT-qPCR. RESULTS The miR-155a expression level was significantly lower in obese children, children with high hs-CRP, and children with high-fat mass. Obese girls had significantly higher PBMC levels of miR-122. MiR-155a had a significant negative association with fasting insulin, HOMA-IR, and hs-CRP. There were significant positive associations between miR-193a and miR-122 expression levels and fasting insulin, HOMA-IR, and TG. MiR-15a was positively correlated with fasting insulin and HOMA-IR. Children with metabolic syndrome, insulin resistance, and high-fat mass had higher PBMC levels of miR-122 and miR-193a. Higher miR-193a and miR-122 levels were also detected in PBMCs of children with fast REE, compared to those with slow REE, and the subjects with high hs-CRP, respectively. CONCLUSION lower level of miR-155 expression in obese subjects and significant associations unfolds the need for more studies to detect the possible underlying mechanisms.
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Affiliation(s)
- Maryam Behrooz
- Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Pediatric Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Hajjarzadeh
- Student of Nutrition Sciences. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Houman Kahroba
- Department of Toxicogenomics, GROW School of Oncology and Development Biology, Maastricht University, Maastricht, Netherlands.,Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Alireza Ostadrahimi
- Department of Clinical Nutrition, Nutrition Research Center, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Milad Bastami
- Department of Medical Genetics, Tabriz University of Medical Sciences, Golgasht St, Attar Neyshabouri Av, Tabriz, Iran.
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20
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Takaya J, Tanabe Y, Kaneko K. Sonic hedgehog N-terminal level correlates with adiponectin level and insulin resistance in adolescents. J Pediatr Endocrinol Metab 2023; 36:126-131. [PMID: 36585801 DOI: 10.1515/jpem-2022-0385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 12/12/2022] [Indexed: 01/01/2023]
Abstract
OBJECTIVES Extracellular vesicles (EVs) are small vesicles released by nearly all types of cells. They deliver different types of substances, including proteins and nucleic acids, to nearby or distant cells and play a role in the mediation of cell-to-cell communication. The aim of this study was to explore the association between EVs and insulin resistance in adolescents with obesity or type 2 diabetes mellitus (DM2). METHODS The subjects were eight adolescents with DM2 (DM2 group; four males and four females; age: 18.1 ± 2.3 years), 18 adolescents with simple obesity (obesity group; 12 males and six females; age: 12.2 ± 3.4 years), and 20 controls (control group; 10 males and 10 females; age: 13.0 ± 1.4 years). As markers of EVs, serum CD9/CD63 and sonic hedgehog N-terminal (Shh-N) levels were measured using enzyme-linked immunosorbent assay. RESULTS The CD9/CD63 level in the control group was similar to that in the DM2 group, whereas the obesity group had a significantly higher CD9/CD63 level. In the entire study group, correlations were observed between serum Shh-N level and Homeostasis Model Assessment of insulin resistance (HOMA-IR) score (r=0.371, p=0.0143), Homeostasis Model Assessment-β cell function score (r=0.382, p=0.0115), serum insulin level (r=0.350, p=0.0171), and serum adiponectin level (r=0.367, p=0.0122). Multiple regression analysis revealed that serum Shh-N level was the most significant risk factor for HOMA-IR score and serum insulin level. CONCLUSIONS Shh is correlated with insulin resistance via its association with adiponectin in adolescents.
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Affiliation(s)
- Junji Takaya
- Department of Pediatrics, Kawachi General Hospital Higashi-Osaka, Osaka, Japan.,Department of Pediatrics, Kansai Medical University Hirakata, Osaka, Japan
| | - Yuko Tanabe
- Department of Pediatrics, Kansai Medical University Hirakata, Osaka, Japan
| | - Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University Hirakata, Osaka, Japan
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21
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Aldous N, Elsayed AK, Alajez NM, Abdelalim EM. iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes. Stem Cell Rev Rep 2023; 19:1082-1097. [PMID: 36749553 DOI: 10.1007/s12015-023-10515-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2023] [Indexed: 02/08/2023]
Abstract
Recently, we reported that forkhead box A2 (FOXA2) is required for the development of human pancreatic α- and β-cells. However, whether miRNAs play a role in regulating pancreatic genes during pancreatic development in the absence of FOXA2 expression is largely unknown. Here, we aimed to capture the dysregulated miRNAs and to identify their pancreatic-specific gene targets in pancreatic progenitors (PPs) derived from wild-type induced pluripotent stem cells (WT-iPSCs) and from iPSCs lacking FOXA2 (FOXA2-/-iPSCs). To identify differentially expressed miRNAs (DEmiRs), and genes (DEGs), two different FOXA2-/-iPSC lines were differentiated into PPs. FOXA2-/- PPs showed a significant reduction in the expression of the main PP transcription factors (TFs) in comparison to WT-PPs. RNA sequencing analysis demonstrated significant reduction in the mRNA expression of genes involved in the development and function of exocrine and endocrine pancreas. Furthermore, miRNA profiling identified 107 downregulated and 111 upregulated DEmiRs in FOXA2-/- PPs compared to WT-PPs. Target prediction analysis between DEmiRs and DEGs identified 92 upregulated miRNAs, predicted to target 1498 downregulated genes in FOXA2-/- PPs. Several important pancreatic TFs essential for pancreatic development were targeted by multiple DEmiRs. Selected DEmiRs and DEGs were further validated using RT-qPCR. Our findings revealed that FOXA2 expression is crucial for pancreatic development through regulating the expression of pancreatic endocrine and exocrine genes targeted by a set of miRNAs at the pancreatic progenitor stage. These data provide novel insights of the effect of FOXA2 deficiency on miRNA-mRNA regulatory networks controlling pancreatic development and differentiation.
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Affiliation(s)
- Noura Aldous
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Ahmed K Elsayed
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar. .,Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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22
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Mohseni R, Teimouri M, Safaei M, Arab Sadeghabadi Z. AMP-activated protein kinase is a key regulator of obesity-associated factors. Cell Biochem Funct 2023; 41:20-32. [PMID: 36468539 DOI: 10.1002/cbf.3767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/29/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022]
Abstract
An imbalance between caloric intake and energy expenditure leads to obesity. Obesity is an important risk factor for the development of several metabolic diseases including insulin resistance, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. So, controlling obesity could be effective in the improvement of obesity-related diseases. Various factors are involved in obesity, such as AMP-activated protein kinases (AMPK), silent information regulators, inflammatory mediators, oxidative stress parameters, gastrointestinal hormones, adipokines, angiopoietin-like proteins, and microRNAs. These factors play an important role in obesity by controlling fat metabolism, energy homeostasis, food intake, and insulin sensitivity. AMPK is a heterotrimeric serine/threonine protein kinase known as a fuel-sensing enzyme. The central role of AMPK in obesity makes it an attractive molecule to target obesity and related metabolic diseases. In this review, the critical role of AMPK in obesity and the interplay between AMPK and obesity-associated factors were elaborated.
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Affiliation(s)
- Roohollah Mohseni
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Clinical Biochemistry & Nutrition, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Maryam Teimouri
- Department of Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohsen Safaei
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Arab Sadeghabadi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Clinical Biochemistry & Nutrition, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
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23
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Dinesen S, El-Faitarouni A, Dalgaard LT. Circulating microRNAs associated with gestational diabetes mellitus: useful biomarkers? J Endocrinol 2023; 256:JOE-22-0170. [PMID: 36346274 DOI: 10.1530/joe-22-0170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/08/2022] [Indexed: 11/09/2022]
Abstract
Different types of small non-coding RNAs, especially miRNAs, may be found in the circulation, either protein-bound or enclosed in extracellular vesicles. During gestation, and particularly during gestational diabetes mellitus (GDM), the levels of several miRNAs are altered. Worldwide the incidence of GDM is increasing, in part driven by the current obesity epidemic. This is a point of public health concern because offspring of women with GDM frequently suffer from short- and long-term complications of maternal GDM. This has prompted the investigation of whether levels of specific miRNA species, detected early in gestation, may be used as diagnostic or prognostic markers for the development of GDM. Here, we summarize the mechanisms of RNA secretion and review circulating miRNAs associated with GDM. Several miRNAs are associated with GDM: miR-29a-3p and miR-29b-3p are generally upregulated in GDM pregnancies, also when measured prior to the development of GDM, while miR-16-5p is consistently upregulated in GDM pregnancies, especially in late gestation. miR-330-3p in circulation is increased in late gestation GDM women, especially in those with poor insulin secretion. miR-17-5p, miR-19a/b-3p, miR-223-3p, miR-155-5p, miR-125-a/b-5p, miR-210-3p and miR-132 are also associated with GDM, but less so and with more contradictory results reported. There could be a publication bias as miRNAs identified early are investigated the most, suggesting that it is likely that additional, more recently detected miRNAs could also be associated with GDM. Thus, circulating miRNAs show potential as biomarkers of GDM diagnosis or prognosis, especially multiple miRNAs containing prediction algorithms show promise, but further studies are needed.
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Affiliation(s)
- Sofie Dinesen
- Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde, Denmark
| | - Alisar El-Faitarouni
- Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde, Denmark
| | - Louise T Dalgaard
- Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde, Denmark
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24
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Zeng Y, Wu Y, Zhang Q, Xiao X. Non-coding RNAs: The link between maternal malnutrition and offspring metabolism. Front Nutr 2022; 9:1022784. [DOI: 10.3389/fnut.2022.1022784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
Early life nutrition is associated with the development and metabolism in later life, which is known as the Developmental Origin of Health and Diseases (DOHaD). Epigenetics have been proposed as an important explanation for this link between early life malnutrition and long-term diseases. Non-coding RNAs (ncRNAs) may play a role in this epigenetic programming. The expression of ncRNAs (such as long non-coding RNA H19, microRNA-122, and circular RNA-SETD2) was significantly altered in specific tissues of offspring exposed to maternal malnutrition. Changes in these downstream targets of ncRNAs lead to abnormal development and metabolism. This review aims to summarize the existing knowledge on ncRNAs linking the maternal nutrition condition and offspring metabolic diseases, such as obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD).
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25
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Melnik BC, Schmitz G. Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life. Int J Mol Sci 2022; 23:ijms231911503. [PMID: 36232796 PMCID: PMC9569743 DOI: 10.3390/ijms231911503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction).
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Affiliation(s)
- Bodo C. Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany
- Correspondence: ; Tel.: +49-52-4198-8060
| | - Gerd Schmitz
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, University of Regensburg, D-93053 Regensburg, Germany
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26
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Sinha T, Mishra SS, Singh S, Panda AC. PanCircBase: An online resource for the exploration of circular RNAs in pancreatic islets. Front Cell Dev Biol 2022; 10:942762. [PMID: 36060809 PMCID: PMC9437246 DOI: 10.3389/fcell.2022.942762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Circular RNAs (circRNAs) are a novel class of covalently closed RNA molecules that recently emerged as a critical regulator of gene expression in development and diseases. Recent research has highlighted the importance of novel circRNAs in the biosynthesis and secretion of insulin from β-cells of pancreatic islets. However, all circRNAs expressed in pancreatic islets or β-cells are not readily available in the database. In this study, we analyzed publicly available RNA-sequencing datasets of the pancreatic islets to catalog all circRNAs expressed in pancreatic islets to construct the PanCircBase (https://www.pancircbase.net/) database that provides the following resources: 1) pancreatic islet circRNA annotation details (genomic position, host gene, exon information, splice length, sequence, other database IDs, cross-species conservation), 2) divergent primers for PCR analysis of circRNAs, 3) siRNAs for silencing of target circRNAs, 4) miRNAs associated with circRNAs, 5) possible protein-coding circRNAs and their polypeptides. In summary, this is a comprehensive online resource for exploring circRNA expression and its possible function in pancreatic β-cells.
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Affiliation(s)
- Tanvi Sinha
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
- Regional Center for Biotechnology, Faridabad, India
| | | | - Suman Singh
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
- Regional Center for Biotechnology, Faridabad, India
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27
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Grieco GE, Brusco N, Fignani D, Nigi L, Formichi C, Licata G, Marselli L, Marchetti P, Salvini L, Tinti L, Po A, Ferretti E, Sebastiani G, Dotta F. Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation. Cell Death Dis 2022; 8:340. [PMID: 35906204 PMCID: PMC9338237 DOI: 10.1038/s41420-022-01142-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022]
Abstract
The loss of functional β-cell mass in type 2 diabetes (T2D) is associated with molecular events that include β-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several β-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects β-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in β-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human β-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the β-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects β-cells from apoptosis through a CRTC1-dependent mechanism.
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Affiliation(s)
- Giuseppina E Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | | | - Laura Tinti
- TLS-Toscana Life Sciences Foundation, Siena, Italy
| | - Agnese Po
- Department of Experimental Medicine, Sapienza University, 00161, Rome, Italy
| | - Elisabetta Ferretti
- Department of Experimental Medicine, Sapienza University, 00161, Rome, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy.
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy.,Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
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28
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MicroRNA-21 promotes pancreatic β cell function through modulating glucose uptake. Nat Commun 2022; 13:3545. [PMID: 35729232 PMCID: PMC9213410 DOI: 10.1038/s41467-022-31317-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/08/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic β cell dysfunction contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we identify the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We find that miR-21βKO mice develop glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies reveal that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets results in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrate that delivery of miR-21 into the pancreas of type 2 diabetic db/db male mice is able to promote Glut2 expression and reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the regulation of pancreatic β cell function in type 2 diabetes.
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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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30
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Molecular dissection of cellular response of pancreatic islet cells to Bisphenol-A (BPA): a comprehensive review. Biochem Pharmacol 2022; 201:115068. [DOI: 10.1016/j.bcp.2022.115068] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/11/2022] [Accepted: 04/25/2022] [Indexed: 12/15/2022]
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31
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Brown MR, Matveyenko AV. It's What and When You Eat: An Overview of Transcriptional and Epigenetic Responses to Dietary Perturbations in Pancreatic Islets. Front Endocrinol (Lausanne) 2022; 13:842603. [PMID: 35355560 PMCID: PMC8960041 DOI: 10.3389/fendo.2022.842603] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/07/2022] [Indexed: 01/07/2023] Open
Abstract
Our ever-changing modern environment is a significant contributor to the increased prevalence of many chronic diseases, and particularly, type 2 diabetes mellitus (T2DM). Although the modern era has ushered in numerous changes to our daily living conditions, changes in "what" and "when" we eat appear to disproportionately fuel the rise of T2DM. The pancreatic islet is a key biological controller of an organism's glucose homeostasis and thus plays an outsized role to coordinate the response to environmental factors to preserve euglycemia through a delicate balance of endocrine outputs. Both successful and failed adaptation to dynamic environmental stimuli has been postulated to occur due to changes in the transcriptional and epigenetic regulation of pathways associated with islet secretory function and survival. Therefore, in this review we examined and evaluated the current evidence elucidating the key epigenetic mechanisms and transcriptional programs underlying the islet's coordinated response to the interaction between the timing and the composition of dietary nutrients common to modern lifestyles. With the explosion of next generation sequencing, along with the development of novel informatic and -omic approaches, future work will continue to unravel the environmental-epigenetic relationship in islet biology with the goal of identifying transcriptional and epigenetic targets associated with islet perturbations in T2DM.
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Affiliation(s)
- Matthew R. Brown
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Aleksey V. Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
- Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
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32
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Hu Q, Mu J, Liu Y, Yang Y, Liu Y, Pan Y, Zhang Y, Li L, Liu D, Chen J, Zhang F, Jin L. Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-Cell Proliferation Through the CPEB1/CDKN1B Pathway. Diabetes 2022; 71:394-411. [PMID: 35029277 DOI: 10.2337/db21-0134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022]
Abstract
Pancreatic β-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated β-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity.
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Affiliation(s)
- Qianxing Hu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Jinming Mu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yuhong Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yue Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yue Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Yanfeng Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
- Pancreatic Research Institute, Southeast University, Nanjing, Jiangsu Province, China
| | - Dechen Liu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Jianqiu Chen
- College of Engineering, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Fangfang Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu Province, China
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33
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Zhou Z, Collado A, Sun C, Tratsiakovich Y, Mahdi A, Winter H, Chernogubova E, Seime T, Narayanan S, Jiao T, Jin H, Alvarsson M, Zheng X, Yang J, Hedin U, Catrina SB, Maegdefessel L, Pernow J. Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes. Diabetes 2022; 71:285-297. [PMID: 34753800 DOI: 10.2337/db21-0093] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022]
Abstract
Red blood cells (RBC) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBC were coincubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBC from patients with T2DM and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human RBC from patients with T2DM (T2DM RBC) than in RBC from healthy subjects. Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in healthy subjects RBC or RBC from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in patients without diabetes. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBC via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.
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MESH Headings
- Animals
- Case-Control Studies
- Cells, Cultured
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/physiopathology
- Diabetic Angiopathies/blood
- Diabetic Angiopathies/genetics
- Diabetic Angiopathies/metabolism
- Diabetic Angiopathies/physiopathology
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Erythrocytes/metabolism
- Humans
- Male
- Mice
- Mice, Knockout
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/physiology
- Rats
- Rats, Wistar
- Reactive Oxygen Species/metabolism
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Affiliation(s)
- Zhichao Zhou
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Aida Collado
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Changyan Sun
- Division of Molecular Vascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Yahor Tratsiakovich
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ali Mahdi
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Hanna Winter
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany
| | - Ekaterina Chernogubova
- Division of Molecular Vascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Till Seime
- Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Sampath Narayanan
- Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Tong Jiao
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Hong Jin
- Division of Molecular Vascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Michael Alvarsson
- Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Xiaowei Zheng
- Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Jiangning Yang
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ulf Hedin
- Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Sergiu-Bogdan Catrina
- Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Centrum for Diabetes, Academic Specialist Centrum, Stockholm, Sweden
| | - Lars Maegdefessel
- Division of Molecular Vascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany
| | - John Pernow
- Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
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34
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Dubey R, Prabhakar PK, Gupta J. Epigenetics: key to improve delayed wound healing in type 2 diabetes. Mol Cell Biochem 2022; 477:371-383. [PMID: 34739665 DOI: 10.1007/s11010-021-04285-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 10/23/2021] [Indexed: 12/13/2022]
Abstract
Diabetes-related delayed wound healing is a multifactorial, nuanced, and intertwined complication that causes substantial clinical morbidity. The etiology of diabetes and its related microvascular complications is affected by genes, diet, and lifestyle factors. Epigenetic modifications such as DNA methylation, histone modifications, and post-transcriptional RNA regulation (microRNAs) are subsequently recognized as key facilitators of the complicated interaction between genes and the environment. Current research suggests that diabetes-persuaded dysfunction of epigenetic pathways, which results in changed expression of genes in target cells and cause diabetes-related complications including cardiomyopathy, nephropathy, retinopathy, delayed wound healing, etc., which are foremost drivers to diabetes-related adverse outcomes. In this paper, we discuss the role of epigenetic mechanisms in controlling tissue repair, angiogenesis, and expression of growth factors, as well as recent findings that show the alteration of epigenetic events during diabetic wound healing.
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Affiliation(s)
- Rupal Dubey
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar-Delhi G.T. Road, 144411, Phagwara, Punjab, India
| | - Pranav Kumar Prabhakar
- Department of Medical Laboratory Sciences, School of Physiotherapy and Paramedical Sciences, Lovely Professional University, 144411, Phagwara, Punjab, India
| | - Jeena Gupta
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar-Delhi G.T. Road, 144411, Phagwara, Punjab, India.
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35
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Ji H, Fan L, Shan A, Wang W, Ning G, Cao Y, Jiang X. Let7b-5p inhibits insulin secretion and decreases pancreatic β-cell mass in mice. Mol Cell Endocrinol 2022; 540:111506. [PMID: 34801668 DOI: 10.1016/j.mce.2021.111506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/01/2021] [Accepted: 11/08/2021] [Indexed: 10/19/2022]
Abstract
MicroRNAs are crucial regulators for the development, mass and function of pancreatic β-cells. MiRNA dysregulation is associated with β-cell dysfunction and development of diabetes. The members of let7 family are important players in regulating cellular growth and metabolism. In this study we investigated the functional role of let7b-5p in the mouse pancreatic β-cells. We generated pancreatic β-cell-specific let7b-5p transgenic mouse model and analyzed the glucose metabolic phenotype, β-cells mass and insulin secretion in vivo. Luciferase reporter assay, immunofluorescence staining and western blot were carried out to study the target genes of let7b-5p in β-cells. Let7b-5p overexpression impaired the insulin production and secretion of β-cells and resulted impaired glucose tolerance in mice. The overexpressed let7b-5p inhibited pancreatic β-cell proliferation and decreased the expression of cyclin D1 and cyclin D2. Our findings demonstrated that let7b-5p was critical in regulating the proliferation and insulin secretion of pancreatic β-cells.
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Affiliation(s)
- He Ji
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liwen Fan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aijing Shan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanan Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Research Center for Translational Medicine, National Key Scientific Infrastructure for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China
| | - Xiuli Jiang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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36
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Yi Q, Xie W, Sun W, Sun W, Liao Y. A Concise Review of MicroRNA-383: Exploring the Insights of Its Function in Tumorigenesis. J Cancer 2022; 13:313-324. [PMID: 34976192 PMCID: PMC8692686 DOI: 10.7150/jca.64846] [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: 07/12/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that commonly have 18-22 nucleotides and play important roles in the regulation of gene expression via directly binding to the 3'-UTR of target mRNAs. Approximately 50% of human genes are regulated by miRNAs and they are involved in many human diseases, including various types of cancers. Recently, microRNA-383 (miR-383) has been identified as being aberrantly expressed in multiple cancers, such as malignant melanoma, colorectal cancer, hepatocellular cancer, and glioma. Increasing evidence suggests that miR-383 participates in tumorigenic events including proliferation, apoptosis, invasion, and metastasis as well as drug resistance. Although downstream targets including CCND1, LDHA, VEGF, and IGF are illustrated to be regulated by miR-383, its roles in carcinogenesis are still ambiguous and the underlying mechanisms are still unclear. Herein, we review the latest studies on miR-383 and summarize its functions in human cancers and other diseases. The goal of this review is to provide new strategies for targeted therapy and further investigations.
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Affiliation(s)
- Qian Yi
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518035, P.R. China.,Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan province 646099, P.R. China.,Laboratory of Anesthesia and Organ Protection, Southwest Medical University, Luzhou, Sichuan province 646099, P.R. China
| | - Wei Xie
- Department of Orthopedics, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| | - Wei Sun
- Department of Orthopedics, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| | - Weichao Sun
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518035, P.R. China.,Department of Orthopedics, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| | - Yi Liao
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518035, P.R. China
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37
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Du H, Yin Z, Zhao Y, Li H, Dai B, Fan J, He M, Nie X, Wang CY, Wang DW, Chen C. miR-320a induces pancreatic β cells dysfunction in diabetes by inhibiting MafF. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:444-457. [PMID: 34631276 PMCID: PMC8479292 DOI: 10.1016/j.omtn.2021.08.027] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 08/19/2021] [Indexed: 11/01/2022]
Abstract
A variety of studies indicate that microRNAs (miRNAs) are involved in diabetes. However, the direct role of miR-320a in the pathophysiology of pancreatic β cells under diabetes mellitus remains unclear. In the current study, islet transplantation and hyperglycemic clamp assays were performed in miR-320a transgenic mice to explore the effects of miR-320a on pancreatic β cells in vivo. Meanwhile, β cell-specific overexpression or inhibition of miR-320a was delivered by adeno-associated virus (AAV8). In vitro, overexpression or downregulation of miR-320a was introduced in cultured rat islet tumor cells (INS1). RNA immunoprecipitation sequencing (RIP-Seq), luciferase reporter assay, and western blotting were performed to identify the target genes. Results showed that miR-320a was increased in the pancreatic β cells from high-fat-diet (HFD)-treated mice. Overexpression of miR-320a could not only deteriorate the HFD-induced pancreatic islet dysfunction, but also initiate pancreatic islet dysfunction spontaneously in vivo. Meanwhile, miR-320a increased the ROS level, inhibited proliferation, and induced apoptosis of cultured β cells in vitro. Finally, we identified that MafF was the target of miR-320a that responsible for the dysfunction of pancreatic β cells. Our data suggested that miR-320a could damage the pancreatic β cells directly and might be a potential therapeutic target of diabetes.
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Affiliation(s)
- Hengzhi Du
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Zhongwei Yin
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Yanru Zhao
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Beibei Dai
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Jiahui Fan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Mengying He
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Xiang Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, 1095 Jiefang Ave., Wuhan 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
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Sałówka A, Martinez-Sanchez A. Molecular Mechanisms of Nutrient-Mediated Regulation of MicroRNAs in Pancreatic β-cells. Front Endocrinol (Lausanne) 2021; 12:704824. [PMID: 34803905 PMCID: PMC8600252 DOI: 10.3389/fendo.2021.704824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cells within the islets of Langerhans respond to rising blood glucose levels by secreting insulin that stimulates glucose uptake by peripheral tissues to maintain whole body energy homeostasis. To different extents, failure of β-cell function and/or β-cell loss contribute to the development of Type 1 and Type 2 diabetes. Chronically elevated glycaemia and high circulating free fatty acids, as often seen in obese diabetics, accelerate β-cell failure and the development of the disease. MiRNAs are essential for endocrine development and for mature pancreatic β-cell function and are dysregulated in diabetes. In this review, we summarize the different molecular mechanisms that control miRNA expression and function, including transcription, stability, posttranscriptional modifications, and interaction with RNA binding proteins and other non-coding RNAs. We also discuss which of these mechanisms are responsible for the nutrient-mediated regulation of the activity of β-cell miRNAs and identify some of the more important knowledge gaps in the field.
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Affiliation(s)
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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Ates KM, Estes AJ, Liu Y. Potential underlying genetic associations between keratoconus and diabetes mellitus. ADVANCES IN OPHTHALMOLOGY PRACTICE AND RESEARCH 2021; 1:100005. [PMID: 34746916 PMCID: PMC8570550 DOI: 10.1016/j.aopr.2021.100005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/18/2021] [Accepted: 08/29/2021] [Indexed: 12/14/2022]
Abstract
Background Keratoconus (KC) is the most common ectatic corneal disease, characterized by significantly localized thinning of the corneal stroma. Genetic, environmental, hormonal, and metabolic factors contribute to the pathogenesis of KC. Additionally, multiple comorbidities, such as diabetes mellitus, may affect the risk of KC. Main Body Patients with diabetes mellitus (DM) have been reported to have lower risk of developing KC by way of increased endogenous collagen crosslinking in response to chronic hyperglycemia. However, this remains a debated topic as other studies have suggested either a positive association or no association between DM and KC. To gain further insight into the underlying genetic components of these two diseases, we reviewed candidate genes associated with KC and central corneal thickness in the literature. We then explored how these genes may be regulated similarly or differentially under hyperglycemic conditions and the role they play in the systemic complications associated with DM. Conclusion Our comprehensive review of potential genetic factors underlying KC and DM provides a direction for future studies to further determine the genetic etiology of KC and how it is influenced by systemic diseases such as diabetes.
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Affiliation(s)
- Kristin M. Ates
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Amy J. Estes
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Yutao Liu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
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Title AC, Silva PN, Godbersen S, Hasenöhrl L, Stoffel M. The miR-200-Zeb1 axis regulates key aspects of β-cell function and survival in vivo. Mol Metab 2021; 53:101267. [PMID: 34116231 PMCID: PMC8258987 DOI: 10.1016/j.molmet.2021.101267] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/24/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The miR-200-Zeb1 axis regulates the epithelial-to-mesenchymal transition (EMT), differentiation, and resistance to apoptosis. A better understanding of these processes in diabetes is highly relevant, as β-cell dedifferentiation and apoptosis contribute to the loss of functional β-cell mass and diabetes progression. Furthermore, EMT promotes the loss of β-cell identity in the in vitro expansion of human islets. Though the miR-200 family has previously been identified as a regulator of β-cell apoptosis in vivo, studies focusing on Zeb1 are lacking. The aim of this study was thus to investigate the role of Zeb1 in β-cell function and survival in vivo. METHODS miR-200 and Zeb1 are involved in a double-negative feedback loop. We characterized a mouse model in which miR-200 binding sites in the Zeb1 3'UTR are mutated (Zeb1200), leading to a physiologically relevant upregulation of Zeb1 mRNA expression. The role of Zeb1 was investigated in this model via metabolic tests and analysis of isolated islets. Further insights into the distinct contributions of the miR-200 and Zeb1 branches of the feedback loop were obtained by crossing the Zeb1200 allele into a background of miR-141-200c overexpression. RESULTS Mild Zeb1 derepression in vivo led to broad transcriptional changes in islets affecting β-cell identity, EMT, insulin secretion, cell-cell junctions, the unfolded protein response (UPR), and the response to ER stress. The aggregation and insulin secretion of dissociated islets of mice homozygous for the Zeb1200 mutation (Zeb1200M) were impaired, and Zeb1200M islets were resistant to thapsigargin-induced ER stress ex vivo. Zeb1200M mice had increased circulating proinsulin levels but no overt metabolic phenotype, reflecting the strong compensatory ability of islets to maintain glucose homeostasis. CONCLUSIONS This study signifies the importance of the miR-200-Zeb1 axis in regulating key aspects of β-cell function and survival. A better understanding of this axis is highly relevant in developing therapeutic strategies for inducing β-cell redifferentiation and maintaining β-cell identity in in vitro islet expansion.
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Affiliation(s)
- Alexandra C Title
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland; Competence Center Personalized Medicine, ETH Zürich, Voltastrasse 24, 8044, Zürich, Switzerland
| | - Pamuditha N Silva
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland
| | - Svenja Godbersen
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland
| | - Lynn Hasenöhrl
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland
| | - Markus Stoffel
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland; Competence Center Personalized Medicine, ETH Zürich, Voltastrasse 24, 8044, Zürich, Switzerland; Medical Faculty, University of Zürich, 8091, Zürich, Switzerland.
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Liu L, Chen R, Jia Z, Li X, Tang Y, Zhao X, Zhang S, Luo L, Fang Z, Zhang Y, Chen M. Downregulation of hsa-miR-203 in peripheral blood and wound margin tissue by negative pressure wound therapy contributes to wound healing of diabetic foot ulcers. Microvasc Res 2021; 139:104275. [PMID: 34717969 DOI: 10.1016/j.mvr.2021.104275] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/17/2021] [Accepted: 10/26/2021] [Indexed: 12/09/2022]
Abstract
Negative pressure wound therapy (NPWT) has been widely used in the treatment of chronic wounds, including diabetic foot ulcers (DFU) as the severe manifestation of diabetic foot. Hsa-miR-203 is proven to be correlated with the severity of DFU. To investigate whether NPWT influences hsa-miR-203 levels in persons with DFU, we detected hsa-miR-203 levels in peripheral plasma and wound margin tissue from the following patients: type 2 diabetic (T2D) patients with DFU (DFU group), T2D patients without DFU (NDFU group), patients with chronic skin ulcer and normal glucose tolerance (SUC group), and healthy volunteers with normal glucose tolerance (NC group). All patients in SUC group received NPWT. As contrast, some of patients in DFU group received NPWT (NPWT group) while others chose routine dressing therapy (non-NPWT group). In vitro experiments were also performed to determine influences of negative pressure on cell proliferation and migration of HaCaT cells (human keratinocytes). Results showed that before NPWT, levels of hsa-miR-203 in peripheral plasma (P-miR-203) and wound margin tissue (T-miR-203) of DFU group were obviously increased compared to SUC group while expression of P-miR-203 decreased in NDFU group compared with NC group. After NPWT, levels of P-miR-203 and T-miR-203 in DFU and SUC group were significantly lower than before. Changes of P-miR-203 and T-miR-203 after NPWT were positively correlated with 4-week ulcer healing rate in NPWT and SUC group. In vitro, negative pressure lowered the expression of hsa-miR-203, enhancing cell proliferation and migration in HaCaT cells via up-regulation of p63 protein. Meanwhile, the effects of negative pressure on cells were remarkable reduced by high-glucose intervention. Our study suggests that NPWT promotes DFU healing by reducing the expression of hsa-miR-203 in peripheral blood and wound tissue. The changes of hsa-miR-203 in peripheral blood and wound tissue may be related to the therapeutic effect of NPWT.
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Affiliation(s)
- Lei Liu
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Zeguo Jia
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Xueting Li
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Ying Tang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Xiaotong Zhao
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Shiqi Zhang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Li Luo
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Zhaohui Fang
- Department of Endocrinology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, People's Republic of China
| | - Yuanzhi Zhang
- Hefei Institute of Physical Science, Chinese Academy of Sciences, People's Republic of China
| | - Mingwei Chen
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China; Department of Endocrinology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, People's Republic of China.
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Abuelezz NZ, E Shabana M, Rashed L, Nb Morcos G. Nanocurcumin Modulates miR-223-3p and NF-κB Levels in the Pancreas of Rat Model of Polycystic Ovary Syndrome to Attenuate Autophagy Flare, Insulin Resistance and Improve ß Cell Mass. J Exp Pharmacol 2021; 13:873-888. [PMID: 34475786 PMCID: PMC8405883 DOI: 10.2147/jep.s323962] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Polycystic ovary syndrome (PCOS) is a prevalent female endocrine disorder. 50–70% of PCOS patients suffer from glucose intolerance, insulin and β cell impairments. Updated studies reveal the crucial regulatory role of inflammation modulators in various diseases, by manipulating autophagy and oxidative stress. However, the data available about autophagy in PCOS pancreas, especially in relation to inflammation key players are little. This study investigated pancreatic autophagy status in PCOS rat model, with miR-223-3p and NF-κB levels as pivotal regulators of oxidative stress-autophagy axis, insulin, and β cell integrity. We then analyzed nanocurcumin effects as a putative anti-inflammatory nutraceutical on the disrupted parameters. Methods Nanocurcumin was characterized using transmission electron microscopy (TEM) and Fourier-transform IR (FT-IR) spectroscopy. Adult virgin Wistar rats were selected, and PCOS was induced using letrozole (1mg/kg). Nanocurcumin was ingested following letrozole. Sex hormones and insulin resistance were determined. miR-223-3p expression was determined using real-time PCR. Immunohistochemistry and Western blotting determined β cells, NF-κB, and autophagy markers p62 and LC3II. Results PCOS group showed significant disruptions in sex hormones and a double fold increase in glucose and insulin levels, exhibiting insulin resistance. Immunostaining confirmed around 46% deterioration of ß cell mass. Real-time PCR showed significant downregulation of miR-223-3p. Immunohistochemistry and Western blotting revealed a drastic upsurge of NF-κB, and autophagy markers p62 and LC3II, confirming bioinformatics target analysis. Interestingly, compared to PCOS group, nanocurcumin (200mg/kg) significantly upregulated miR-223-3p expression by 30%. It subsided NF-κB and autophagy eruption to restore ß cell mass and attenuate insulin resistance. Conclusion To the best of our knowledge, this study is the first to highlight the vital contribution of miR-223-3p and NF-κB levels in aggravating PCOS pancreatic autophagy and consequent impairments. It spots nanocurcumin potential as an inflammation and autophagy modulator, for possible better management of PCOS complications.
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Affiliation(s)
- Nermeen Z Abuelezz
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt
| | - Marwa E Shabana
- Pathology Department, Medical Division, National Research Center, Cairo, Egypt
| | - Laila Rashed
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - George Nb Morcos
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.,Basic Medical Science Department, Faculty of Medicine, King Salman International University, El Tur, Egypt
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Understanding the Long-Lasting Effects of Fetal Nutrient Restriction versus Exposure to an Obesogenic Diet on Islet-Cell Mass and Function. Metabolites 2021; 11:metabo11080514. [PMID: 34436455 PMCID: PMC8401811 DOI: 10.3390/metabo11080514] [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: 07/13/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
Early life represents a window of phenotypic plasticity. Thus, exposure of the developing fetus to a compromised nutritional environment can have long term consequences for their health. Indeed, undernutrition or maternal intake of an obesogenic diet during pregnancy leads to a heightened risk of type 2 diabetes (T2D) and obesity in her offspring in adult life. Given that abnormalities in beta-cell function are crucial in delineating the risk of T2D, studies have investigated the impact of these exposures on islet morphology and beta-cell function in the offspring in a bid to understand why they are more at risk of T2D. Interestingly, despite the contrasting maternal metabolic phenotype and, therefore, intrauterine environment associated with undernutrition versus high-fat feeding, there are a number of similarities in the genes/biological pathways that are disrupted in offspring islets leading to changes in function. Looking to the future, it will be important to define the exact mechanisms involved in mediating changes in the gene expression landscape in islet cells to determine whether the road to T2D development is the same or different in those exposed to different ends of the nutritional spectrum.
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Karere GM, Cox LA, Bishop AC, South AM, Shaltout HA, Mercado-Deane MG, Cuda S. Sex Differences in MicroRNA Expression and Cardiometabolic Risk Factors in Hispanic Adolescents with Obesity. J Pediatr 2021; 235:138-143.e5. [PMID: 33831442 PMCID: PMC8926296 DOI: 10.1016/j.jpeds.2021.03.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To evaluate sex differences in microRNA (miRNA) expression, anthropometric measures, and cardiometabolic risk factors in Hispanic adolescents with obesity. STUDY DESIGN Cross-sectional study of 68 (60% male) Hispanic adolescents with obesity, aged 13-17 years, recruited from a pediatric weight management clinic. We used small RNA sequencing to identify differentially expressed circulating miRNAs. We used ingenuity pathway analysis and David bioinformatic resource tools to identify target genes for these miRNAs and enriched pathways. We used standard procedures to measure anthropometric and cardiometabolic factors. RESULTS We identified 5 miRNAs (miR-24-3p, miR-361-3p, miR-3605-5p, miR-486-5p, and miR-199b-3p) that differed between females and males. miRNA targets-enriched pathways included phosphatidylinositol 3-kinase-protein, 5' AMP-activated protein kinase, insulin resistance, sphingolipid, transforming growth factor-β, adipocyte lipolysis regulation, and oxytocin signaling pathways. In addition, there were sex differences in blood pressure, skeletal muscle mass, lean body mass, and percent body fat. CONCLUSIONS We have identified sex differences in miRNA expression in Hispanic adolescents relevant to cardiometabolic health. Future studies should focus on sex-specific mechanistic roles of miRNAs on gene pathways associated with obesity pathophysiology to support development of precision cardiometabolic interventions.
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Affiliation(s)
- Genesio M. Karere
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina,Corresponding author Department of Internal Medicine, Center for Precision Medicine, Wake Forest Baptist, Medical Center, Winston-Salem, NC 27157., Telephone: (336) 713-7561, Fax: (336) 713-7566,
| | - Laura A. Cox
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Andrew C. Bishop
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Andrew M. South
- Department of Pediatrics, Brenner Children’s Hospital, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina,Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Hossam A. Shaltout
- Department of Obstetrics and Gynecology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Maria-Gisela Mercado-Deane
- Department of Radiology, Baylor College of Medicine, Children’s Hospital of San Antonio, San Antonio, Texas
| | - Suzanne Cuda
- Department of Pediatrics, Baylor College of Medicine, Children’s Hospital of San Antonio, San Antonio, Texas
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Formichi C, Nigi L, Grieco GE, Maccora C, Fignani D, Brusco N, Licata G, Sebastiani G, Dotta F. Non-Coding RNAs: Novel Players in Insulin Resistance and Related Diseases. Int J Mol Sci 2021; 22:7716. [PMID: 34299336 PMCID: PMC8306942 DOI: 10.3390/ijms22147716] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
The rising prevalence of metabolic diseases related to insulin resistance (IR) have stressed the urgent need of accurate and applicable tools for early diagnosis and treatment. In the last decade, non-coding RNAs (ncRNAs) have gained growing interest because of their potential role in IR modulation. NcRNAs are variable-length transcripts which are not translated into proteins but are involved in gene expression regulation. Thanks to their stability and easy detection in biological fluids, ncRNAs have been investigated as promising diagnostic and therapeutic markers in metabolic diseases, such as type 2 diabetes mellitus (T2D), obesity and non-alcoholic fatty liver disease (NAFLD). Here we review the emerging role of ncRNAs in the development of IR and related diseases such as obesity, T2D and NAFLD, and summarize current evidence concerning their potential clinical application.
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Affiliation(s)
- Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Carla Maccora
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University, 00185 Rome, Italy;
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
- Tuscany Centre for Precision Medicine (CReMeP), 53100 Siena, Italy
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The MicroRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts. Cells 2021; 10:cells10071693. [PMID: 34359863 PMCID: PMC8304265 DOI: 10.3390/cells10071693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/16/2021] [Accepted: 06/24/2021] [Indexed: 01/12/2023] Open
Abstract
Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 h before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to the identification of eight microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome, and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.
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MacDonald-Ramos K, Martínez-Ibarra A, Monroy A, Miranda-Ríos J, Cerbón M. Effect of Dietary Fatty Acids on MicroRNA Expression Related to Metabolic Disorders and Inflammation in Human and Animal Trials. Nutrients 2021; 13:1830. [PMID: 34072137 PMCID: PMC8226960 DOI: 10.3390/nu13061830] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022] Open
Abstract
Dietary fatty acids (DFAs) play key roles in different metabolic processes in humans and other mammals. DFAs have been considered beneficial for health, particularly polyunsaturated (PUFAs) and monounsaturated fatty acids (MUFAs). Additionally, microRNAs (miRNAs) exert their function on DFA metabolism by modulating gene expression, and have drawn great attention for their potential as biomarkers and therapeutic targets. This review explicitly examined the effects of DFAs on miRNA expression associated with metabolic diseases, such as obesity, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD), as well as inflammation, published in the last ten years. DFAs have been shown to induce and repress miRNA expression associated with metabolic disease and inflammation in different cell types and organisms, both in vivo and in vitro, depending on varying combinations of DFAs, doses, and the duration of treatment. However, studies are limited and heterogeneous in methodology. Additionally, recent studies demonstrated that high fat ketogenic diets, many enriched with saturated fats, do not increase serum saturated fat content in humans, and are not associated with increased inflammation. Thus, these findings shed light on the complexity of novel treatment and DFA interventions for metabolic disease and to maintain health. Further studies are needed to advance molecular therapeutic approaches, including miRNA-based strategies in human health and disease.
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Affiliation(s)
- Karla MacDonald-Ramos
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
| | - Alejandra Martínez-Ibarra
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico
| | - Adriana Monroy
- Servicio de Oncología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México 06720, Mexico;
| | - Juan Miranda-Ríos
- Unidad de Genética de la Nutrición, Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Ciudad de México 04530, Mexico;
- Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
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Wang Z, Mohan R, Chen X, Matson K, Waugh J, Mao Y, Zhang S, Li W, Tang X, Satin LS, Tang X. microRNA-483 Protects Pancreatic β-Cells by Targeting ALDH1A3. Endocrinology 2021; 162:6132087. [PMID: 33564883 PMCID: PMC7951052 DOI: 10.1210/endocr/bqab031] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Indexed: 12/14/2022]
Abstract
Pancreatic β-cell dysfunction is central to the development and progression of type 2 diabetes. Dysregulation of microRNAs (miRNAs) has been associated with pancreatic islet dysfunction in type 2 diabetes. Previous study has shown that miR-483 is expressed relatively higher in β-cells than in α-cells. To explore the physiological function of miR-483, we generated a β-cell-specific knockout mouse model of miR-483. Loss of miR-483 enhances high-fat diet-induced hyperglycemia and glucose intolerance by the attenuation of diet-induced insulin release. Intriguingly, mice with miR-483 deletion exhibited loss of β-cell features, as indicated by elevated expression of aldehyde dehydrogenase family 1, subfamily A3 (Aldh1a3), a marker of β-cell dedifferentiation. Moreover, Aldh1a3 was validated as a direct target of miR-483 and overexpression of miR-483 repressed Aldh1a3 expression. Genetic ablation of miR-483 also induced alterations in blood lipid profile. Collectively, these data suggest that miR-483 is critical in protecting β-cell function by repressing the β-cell disallowed gene Aldh1a3. The dysregulated miR-483 may impair insulin secretion and initiate β-cell dedifferentiation during the development of type 2 diabetes.
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Affiliation(s)
- Zhihong Wang
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Ramkumar Mohan
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Xinqian Chen
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Katy Matson
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Jackson Waugh
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Yiping Mao
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Shungang Zhang
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Wanzhen Li
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Xiaohu Tang
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
| | - Leslie S Satin
- Department of Pharmacology, Brehm Center for Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Xiaoqing Tang
- Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA
- Correspondence: Xiaoqing Tang, PhD, Michigan Technological University, 1400 Townsend Dr., Houghton, MI 49931, USA.
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Zhu Y, Zhu Y, Liu Y, Liu Y, Chen X. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 correlates with microRNA-125b/microRNA-146a/microRNA-203 and predicts 2-year restenosis risk in coronary heart disease patients. Biomark Med 2021; 15:257-271. [PMID: 33565328 DOI: 10.2217/bmm-2020-0715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: To investigate correlations of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1) and its target microRNAs with clinical features and restenosis risk in coronary heart disease (CHD) patients post drug-eluting stent-percutaneous coronary intervention (DES-PCI). Materials & methods: A total of 274 CHD patients undergoing DES-PCI were enrolled, pre-operative plasma samples were obtained to detect lnc-MALAT1, miR-125b, miR-146a, miR-203 by RT-qPCR; 2-year restenosis was determined by quantitative coronary angiography. Results: Lnc-MALAT1 negatively correlated with miR-125b, miR-146a and miR-203. Furthermore, lnc-MALAT1, miR-125b, miR-146a and miR-203 correlated with diabetes mellitus, hyperuricemia, lesion properties, cholesterol, inflammation and cardiac function indexes. Additionally, lnc-MALAT1 was increased, while miR-125b and miR-146a were decreased in patients with 2-year restenosis than patients without 2-year restenosis; however, miR-203 did not differ. Conclusion: Lnc-MALAT1 and its target miRNAs might help manage restenosis risk in CHD patients post DES-PCI.
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Affiliation(s)
- Yankuo Zhu
- Department of Cardiology, People's Hospital of Mudan, Heze, PR China
| | - Yinchuan Zhu
- Department of Vasculocardiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Yingchao Liu
- Department of Clinical Laboratory, The Second People's Hospital of Liaocheng, The Second Hospital of Liaocheng Affiliated to Shandong First Medical University, Linqing, PR China
| | - Yanru Liu
- Department of Cardiology, People's Hospital of Mudan, Heze, PR China
| | - Xiaoyu Chen
- Department of Clinical Laboratory, People's Hospital of Mudan, Heze, PR China
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Soltani A, Jafarian A, Allameh A. The Predominant microRNAs in β-cell Clusters for Insulin Regulation and Diabetic Control. Curr Drug Targets 2021; 21:722-734. [PMID: 31886749 DOI: 10.2174/1389450121666191230145848] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 12/20/2022]
Abstract
micro (mi)-RNAs are vital regulators of multiple processes including insulin signaling pathways and glucose metabolism. Pancreatic β-cells function is dependent on some miRNAs and their target mRNA, which together form a complex regulative network. Several miRNAs are known to be directly involved in β-cells functions such as insulin expression and secretion. These small RNAs may also play significant roles in the fate of β-cells such as proliferation, differentiation, survival and apoptosis. Among the miRNAs, miR-7, miR-9, miR-375, miR-130 and miR-124 are of particular interest due to being highly expressed in these cells. Under diabetic conditions, although no specific miRNA profile has been noticed, the expression of some miRNAs and their target mRNAs are altered by posttranscriptional mechanisms, exerting diverse signs in the pathobiology of various diabetic complications. The aim of this review article is to discuss miRNAs involved in the process of stem cells differentiation into β-cells, resulting in enhanced β-cell functions with respect to diabetic disorders. This paper will also look into the impact of miRNA expression patterns on in vitro proliferation and differentiation of β-cells. The efficacy of the computational genomics and biochemical analysis to link the changes in miRNA expression profiles of stem cell-derived β-cells to therapeutically relevant outputs will be discussed as well.
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Affiliation(s)
- Adele Soltani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arefeh Jafarian
- Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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