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1
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Mahdizadeh F, Sobhi P, Banaei S. A class of MicroRNAs as diagnostic biomarkers and therapeutic strategies in non-alcoholic fatty liver disease: A review. Clin Res Hepatol Gastroenterol 2025; 49:102547. [PMID: 39924053 DOI: 10.1016/j.clinre.2025.102547] [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: 11/29/2024] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
MicroRNAs (miRNAs), small and noncoding RNAs that regulate gene expression through hybridization to messenger RNA, play a crucial role in the prevention or progression of non-alcoholic fatty liver disease (NAFLD). There is an urgent demand for the improvement of diagnostic tools and effective pharmacotherapies for the treatment of NAFLD, which can advance to cirrhosis and liver cancer. MiRNAs act as regulatory factors and noninvasive diagnostic agents for NAFLD, enabling the staging of the disorder, prognosis, and identification of pharmaco-therapeutic targets. NAFLD causes alterations in the expression patterns of hepatocyte miRNAs, with some specific miRNAs related to the upgrade from NAFLD to non-alcoholic steatohepatitis (NASH). These miRNAs can activate certain signaling cascade and exacerbate or improve NAFLD, additionally, act as hepatocellular signals or second messengers that transmit information between the liver and other systems. This study provides a comprehensive review of the most important miRNAs and their involvement in the pathophysiology and cellular signaling pathways related to NAFLD.
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Affiliation(s)
- Faraz Mahdizadeh
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Pouria Sobhi
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Shokofeh Banaei
- Department of Physiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
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2
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Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
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Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
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Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
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3
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Ng D, Pawling J, Dennis JW. Gene purging and the evolution of Neoave metabolism and longevity. J Biol Chem 2023; 299:105409. [PMID: 37918802 PMCID: PMC10722388 DOI: 10.1016/j.jbc.2023.105409] [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: 09/11/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 11/04/2023] Open
Abstract
Maintenance of the proteasome requires oxidative phosphorylation (ATP) and mitigation of oxidative damage, in an increasingly dysfunctional relationship with aging. SLC3A2 plays a role on both sides of this dichotomy as an adaptor to SLC7A5, a transporter of branched-chain amino acids (BCAA: Leu, Ile, Val), and to SLC7A11, a cystine importer supplying cysteine to the synthesis of the antioxidant glutathione. Endurance in mammalian muscle depends in part on oxidation of BCAA; however, elevated serum levels are associated with insulin resistance and shortened lifespans. Intriguingly, the evolution of modern birds (Neoaves) has entailed the purging of genes including SLC3A2, SLC7A5, -7, -8, -10, and SLC1A4, -5, largely removing BCAA exchangers and their interacting Na+/Gln symporters in pursuit of improved energetics. Additional gene purging included mitochondrial BCAA aminotransferase (BCAT2), pointing to reduced oxidation of BCAA and increased hepatic conversion to triglycerides and glucose. Fat deposits are anhydrous and highly reduced, maximizing the fuel/weight ratio for prolonged flight, but fat accumulation in muscle cells of aging humans contributes to inflammation and senescence. Duplications of the bidirectional α-ketoacid transporters SLC16A3, SLC16A7, the cystine transporters SLC7A9, SLC7A11, and N-glycan branching enzymes MGAT4B, MGAT4C in Neoaves suggests a shift to the transport of deaminated essential amino acid, and stronger mitigation of oxidative stress supported by the galectin lattice. We suggest that Alfred Lotka's theory of natural selection as a maximum power organizer (PNAS 8:151,1922) made an unusually large contribution to Neoave evolution. Further molecular analysis of Neoaves may reveal novel rewiring with applications for human health and longevity.
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Affiliation(s)
- Deanna Ng
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Judy Pawling
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - James W Dennis
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto Ontario, Canada.
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4
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Miyagawa S, Horie T, Nishino T, Koyama S, Watanabe T, Baba O, Yamasaki T, Sowa N, Otani C, Matsushita K, Kojima H, Kimura M, Nakashima Y, Obika S, Kasahara Y, Kotera J, Oka K, Fujita R, Sasaki T, Takemiya A, Hasegawa K, Kimura T, Ono K. Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis. Life Sci Alliance 2023; 6:e202301902. [PMID: 37263777 PMCID: PMC10235800 DOI: 10.26508/lsa.202301902] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/03/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element-binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element-binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism-related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH.
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Affiliation(s)
- Sawa Miyagawa
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Horie
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomohiro Nishino
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Koyama
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimitsu Watanabe
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Osamu Baba
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomohiro Yamasaki
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoya Sowa
- Division of Translational Research, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan
| | - Chiharu Otani
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuki Matsushita
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidenori Kojima
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro Kimura
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuhiro Nakashima
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Obika
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Yuuya Kasahara
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Jun Kotera
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, Fujisawa-shi, Japan
| | - Kozo Oka
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, Fujisawa-shi, Japan
| | - Ryo Fujita
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, Fujisawa-shi, Japan
| | - Takashi Sasaki
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, Fujisawa-shi, Japan
| | - Akihiro Takemiya
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, Fujisawa-shi, Japan
| | - Koji Hasegawa
- Division of Translational Research, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan
| | - Takeshi Kimura
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koh Ono
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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5
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Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
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6
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Ortega R, Liu B, Persaud SJ. Effects of miR-33 Deficiency on Metabolic and Cardiovascular Diseases: Implications for Therapeutic Intervention. Int J Mol Sci 2023; 24:10777. [PMID: 37445956 DOI: 10.3390/ijms241310777] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally inhibit gene expression. These small molecules are involved in several biological conditions such as inflammation, cell growth and proliferation, and regulation of energy metabolism. In the context of metabolic and cardiovascular diseases, miR-33 is of particular interest as it has been implicated in the regulation of lipid and glucose metabolism. This miRNA is located in introns harboured in the genes encoding sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, which are key transcription factors involved in lipid biosynthesis and cholesterol efflux. This review outlines the role of miR-33 in a range of metabolic and cardiovascular pathologies, such as dyslipidaemia, nonalcoholic fatty liver disease (NAFLD), obesity, diabetes, atherosclerosis, and abdominal aortic aneurysm (AAA), and it provides discussion about the effectiveness of miR-33 deficiency as a possible therapeutic strategy to prevent the development of these diseases.
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Affiliation(s)
- Rebeca Ortega
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London SE1 1UL, UK
| | - Bo Liu
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London SE1 1UL, UK
| | - Shanta J Persaud
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London SE1 1UL, UK
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7
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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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8
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Zhang W, Raza SHA, Li B, Sun B, Wang S, Pant SD, Al-Abbas NS, Shaer NA, Zan L. miR-33a Inhibits the Differentiation of Bovine Preadipocytes through the IRS2-Akt Pathway. Genes (Basel) 2023; 14:529. [PMID: 36833456 PMCID: PMC9957011 DOI: 10.3390/genes14020529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/09/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023] Open
Abstract
Several microRNAs (miRNAs) are known to participate in adipogenesis. However, their role in this process, especially in the differentiation of bovine preadipocytes, remains to be elucidated. This study was intended to clarify the effect of microRNA-33a (miR-33a) on the differentiation of bovine preadipocytes by cell culture, real-time fluorescent quantitative PCR (qPCR), Oil Red staining, BODIPY staining, and Western blotting. The results indicate that overexpression of miR-33a significantly inhibited lipid droplet accumulation and decreased the mRNA and protein expression of adipocyte differentiation marker genes such as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), and fatty acid-binding protein 4 (FABP4). In contrast, the interference expression of miR-33a promoted lipid droplet accumulation and increased the expression of marker genes. Additionally, miR-33a directly targeted insulin receptor substrate 2 (IRS2) and regulated the phosphorylation level of serine/threonine kinase (Akt). Furthermore, miR-33a inhibition could rescue defects in the differentiation of bovine preadipocytes and the Akt phosphorylation level caused by small interfering IRS2 (si-IRS2). Collectively, these results indicate that miR-33a could inhibit the differentiation of bovine preadipocytes, possibly through the IRS2-Akt pathway. These findings might help develop practical means to improve the quality of beef.
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Affiliation(s)
- Wenzhen Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
- Safety of Livestock and Poultry Products, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Bingzhi Li
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Bing Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Sihu Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Sameer D. Pant
- Gulbali Institute, Charles Sturt University, Boorooma Street, Wagga Wagga, NSW 2678, Australia
| | - Nouf S. Al-Abbas
- Department of Biology, Jamoum University College, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Nehad A. Shaer
- Department of Chemistry, Al Lieth University College, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
- National Beef Cattle Improvement Center, Northwest A&F University, Yangling 712100, China
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9
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Bibiloni P, Pomar CA, Palou A, Sánchez J, Serra F. miR-222 exerts negative regulation on insulin signaling pathway in 3T3-L1 adipocytes. Biofactors 2022; 49:365-378. [PMID: 36310379 DOI: 10.1002/biof.1914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/12/2022] [Indexed: 11/10/2022]
Abstract
Increased miR-222 levels are associated with metabolic syndrome, insulin resistance, and diabetes. Moreover, rats fed an obesogenic diet during lactation have higher miR-222 content in breast milk and the offspring display greater body fat mass and impaired insulin sensitivity in adulthood. In order to investigate the molecular mechanisms involved and to dissect the specific effects of miR-222 on adipocytes, transfection with a mimic or an inhibitor of miR-222 has been conducted on 3T3-L1 preadipocytes. 3T3-L1 cells were transfected with either a mimic or an inhibitor of miR-222 and collected after 2 days (preadipocytes) or 8 days (mature adipocytes) for transcriptomic analysis. Results showed a relevant impact on pathways associated with insulin signaling, lipid metabolism and adipogenesis. Outcomes in key genes and proteins were further analyzed with quantitative reverse transcription polymerase chain reaction and Western Blotting, respectively, which displayed a general inhibition in important effectors of the identified routes under miR-222 mimic treatment in preadipocytes. Although to a lesser extent, this overall signature was maintained in differentiated adipocytes. Altogether, miR-222 exerts a direct effect in metabolic pathways of 3T3-L1 adipocytes that are relevant to adipocyte function, limiting adipogenesis and insulin signaling pathways, offering a mechanistic explanation for its reported association with metabolic diseases.
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Affiliation(s)
- Pere Bibiloni
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Catalina A Pomar
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Andreu Palou
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Juana Sánchez
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Francisca Serra
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, Palma, Spain
- Instituto de Investigación Sanitaria Illes Balears, IdISBa, Palma, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Palihaderu PADS, Mendis BILM, Premarathne JMKJK, Dias WKRR, Yeap SK, Ho WY, Dissanayake AS, Rajapakse IH, Karunanayake P, Senarath U, Satharasinghe DA. Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm. Front Endocrinol (Lausanne) 2022; 13:1028846. [PMID: 36479211 PMCID: PMC9720316 DOI: 10.3389/fendo.2022.1028846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A "downstream branch point" in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.
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Affiliation(s)
| | | | | | | | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Selangor, Malaysia
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
| | | | | | - Panduka Karunanayake
- Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Upul Senarath
- Department of Community Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Dilan Amila Satharasinghe
- Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Peradeniya, Sri Lanka
- *Correspondence: Dilan Amila Satharasinghe,
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11
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Wu HX, Li L, Zhang H, Tang J, Zhang MB, Tang HN, Guo Y, Zhou ZG, Zhou HD. Accurate diagnosis and heterogeneity analysis of a 17q12 deletion syndrome family with adulthood diabetes onset and complex clinical phenotypes. Endocrine 2021; 73:37-46. [PMID: 33745123 DOI: 10.1007/s12020-021-02682-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 03/05/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE 17q12 Deletion Syndrome is heterogeneous and the reasons remain unclear. We clarified the clinical characteristics of adulthood diabetes onset 17q12 deletion syndrome and investigated the unclear phenotype-genotype correlation. METHODS We collected the clinical history and laboratory results of a family with autosomal dominant inheritance diabetes and renopathy. Sanger sequencing of HNF1B and a panel of monogenic diabetic genes were performed to identify the monogenetic diabetes. Semiquantitative PCR and Chromosome 100 K sequence analysis were performed to analyze the copy numbers variation of diabetes related genes. Allelic specific quantitative PCR were used for TBC1D3 and paralogues diagnosis. The reported cases were reviewed and assessed to compare with patients in this study. RESULTS Differential variants in genomic DNA and clinical presentations among family members were explored to determine the probable phenotype-genotypes correlation. The four patients were diagnosed with 17q12 deletion syndrome with 1.47-1.76 Mb heterogeneous deletion, which led to the haploinsufficiency of HNF1B, ACACA, LHX1, PIGW, miRNA2909 and other genes. The patients had different amount of genes deletion in TBC1D3 and paralogues, which might associate with the heterogeneous clinical phenotypes. CONCLUSIONS We first reported an adulthood diabetes onset 17q12 deletion syndrome family with the largest number of patients. The heterogeneous clinical phenotypes might be related to the haploinsufficiency of TBC1D3 and its paralogues.
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Affiliation(s)
- Hui-Xuan Wu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Long Li
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Hong Zhang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Mei-Biao Zhang
- Department of Endocrinology and Metabolism, The First People's Hospital of Huaihua, Huaihua, 418000, Hunan, China
| | - Hao-Neng Tang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yue Guo
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Zhi-Guang Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Hou-De Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory For Metabolic Bone Diseases, and Department of Endocrinology and Metabolism, the Second XiangYa Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China.
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12
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Baghbani E, Noorolyai S, Duijf PHG, Silvestris N, Kolahian S, Hashemzadeh S, Baghbanzadeh Kojabad A, FallahVazirabad A, Baradaran B. The impact of microRNAs on myeloid-derived suppressor cells in cancer. Hum Immunol 2021; 82:668-678. [PMID: 34020831 DOI: 10.1016/j.humimm.2021.04.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/28/2021] [Accepted: 04/28/2021] [Indexed: 02/08/2023]
Abstract
Inflammation promotes cancer development. To a large extent, this can be attributed to the recruitment of myeloid-derived suppressor cells (MDSCs) to tumors. These cells are known for establishing an immunosuppressive tumor microenvironment by suppressing T cell activities. However, MDSCs also promote metastasis and angiogenesis. Critically, as small non-coding RNAs that regulate gene expression, microRNAs (miRNAs) control MDSC activities. In this review, we discuss how miRNA networks regulate key MDSC signaling pathways, how they shape MDSC development, differentiation and activation, and how this impacts tumor development. By targeting the expression of miRNAs in MDSCs, we can alter their main signaling pathways. In turn, this can compromise their ability to promote multiple hallmarks of cancer. Therefore, this may represent a new powerful strategy for cancer immunotherapy.
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Affiliation(s)
- Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Noorolyai
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pascal H G Duijf
- Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Australia; University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Nicola Silvestris
- IRCCS Bari, Italy. Medical Oncology Unit-IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy, Department of Biomedical Sciences and Human Oncology DIMO-University of Bari, Bari, Italy
| | - Saeed Kolahian
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Division of Pharmacogenomics, University of Tübingen, Tübingen, Germany; Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany; Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Shahryar Hashemzadeh
- General and Vascular Surgery Department, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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13
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Price NL, Goedeke L, Suárez Y, Fernández-Hernando C. miR-33 in cardiometabolic diseases: lessons learned from novel animal models and approaches. EMBO Mol Med 2021; 13:e12606. [PMID: 33938628 PMCID: PMC8103095 DOI: 10.15252/emmm.202012606] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 12/28/2022] Open
Abstract
miRNAs have emerged as critical regulators of nearly all biologic processes and important therapeutic targets for numerous diseases. However, despite the tremendous progress that has been made in this field, many misconceptions remain among much of the broader scientific community about the manner in which miRNAs function. In this review, we focus on miR‐33, one of the most extensively studied miRNAs, as an example, to highlight many of the advances that have been made in the miRNA field and the hurdles that must be cleared to promote the development of miRNA‐based therapies. We discuss how the generation of novel animal models and newly developed experimental techniques helped to elucidate the specialized roles of miR‐33 within different tissues and begin to define the specific mechanisms by which miR‐33 contributes to cardiometabolic diseases including obesity and atherosclerosis. This review will summarize what is known about miR‐33 and highlight common obstacles in the miRNA field and then describe recent advances and approaches that have allowed researchers to provide a more complete picture of the specific functions of this miRNA.
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Affiliation(s)
- Nathan L Price
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Comparative Medicine, Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, New Haven, CT, USA
| | - Leigh Goedeke
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Comparative Medicine, Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Comparative Medicine, Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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14
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Takatani T, Shirakawa J, Shibue K, Gupta MK, Kim H, Lu S, Hu J, White MF, Kennedy RT, Kulkarni RN. Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice. J Biol Chem 2021; 296:100646. [PMID: 33839150 PMCID: PMC8131928 DOI: 10.1016/j.jbc.2021.100646] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/24/2021] [Accepted: 04/07/2021] [Indexed: 11/29/2022] Open
Abstract
Dysregulated glucagon secretion deteriorates glycemic control in type 1 and type 2 diabetes. Although insulin is known to regulate glucagon secretion via its cognate receptor (insulin receptor, INSR) in pancreatic alpha cells, the role of downstream proteins and signaling pathways underlying insulin's activities are not fully defined. Using in vivo (knockout) and in vitro (knockdown) studies targeting insulin receptor substrate (IRS) proteins, we compared the relative roles of IRS1 and IRS2 in regulating alpha cell function. Alpha cell-specific IRS1-knockout mice exhibited glucose intolerance and inappropriate glucagon suppression during glucose tolerance tests. In contrast, alpha cell-specific IRS2-knockout animals manifested normal glucose tolerance and suppression of glucagon secretion after glucose administration. Alpha cell lines with stable IRS1 knockdown could not repress glucagon mRNA expression and exhibited a reduction in phosphorylation of AKT Ser/Thr kinase (AKT, at Ser-473 and Thr-308). AlphaIRS1KD cells also displayed suppressed global protein translation, including reduced glucagon expression, impaired cytoplasmic Ca2+ response, and mitochondrial dysfunction. This was supported by the identification of novel IRS1-specific downstream target genes, Trpc3 and Cartpt, that are associated with glucagon regulation in alpha cells. These results provide evidence that IRS1, rather than IRS2, is a dominant regulator of pancreatic alpha cell function.
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Affiliation(s)
- Tomozumi Takatani
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Gunma, Japan
| | - Kimitaka Shibue
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Manoj K Gupta
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cell Therapy Translational Engine (CTTE), Takeda Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Hyunki Kim
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Shusheng Lu
- Departments of Chemistry and Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jiang Hu
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Morris F White
- Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert T Kennedy
- Departments of Chemistry and Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
| | - Rohit N Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.
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15
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Quantitative proteomics and phosphoproteomic analyses of mouse livers after tick-borne Babesia microti infection. Int J Parasitol 2020; 51:167-182. [PMID: 33242464 DOI: 10.1016/j.ijpara.2020.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022]
Abstract
Babesia microti is a tick-borne protozoan parasite that infects the red blood cells of mice, humans, and other mammals. The liver tissues of BALB/c mice infected with B. microti exhibit severe injury. To further investigate the molecular mechanisms underlying liver injury and liver self-repair after B. microti infection, data-independent acquisition (DIA) quantitative proteomics was used to analyse changes in the expression and phosphorylation of proteins in liver tissues of BALB/c mice during a B. microti infection period and a recovery period. The expression of FABP1 and ACBP, which are related to fatty acid transport in the liver, was downregulated after infection with B. microti, as was the expression of Acox1, Ehhadh and Acaa1a, which are crucial rate-limiting enzymes in the process of fatty acid β oxidation. The phosphorylation levels of AMP-activated protein kinase (AMPK) and Hormone-sensitive lipase (HSL) were also downregulated. In addition, the expression of PSMB9, CTSC, and other immune-related proteins was increased, reflecting an active immune regulation mechanism in the mice. The weights of mice infected with B. microti were significantly reduced, and the phosphorylation levels of IRS-1, c-Raf, mTOR, and other proteins related to growth and development were downregulated.
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16
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Yue X, Han T, Hao W, Wang M, Fu Y. SHP2 knockdown ameliorates liver insulin resistance by activating IRS-2 phosphorylation through the AKT and ERK1/2 signaling pathways. FEBS Open Bio 2020; 10:2578-2587. [PMID: 33012117 PMCID: PMC7714075 DOI: 10.1002/2211-5463.12992] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 08/25/2020] [Accepted: 09/29/2020] [Indexed: 01/02/2023] Open
Abstract
Diabetes is a chronic metabolic disease characterized by insulin resistance (IR). SHP2 has previously been identified as a potential target to reduce IR in diabetes. Here, we examined the effects of SHP2 on glucose consumption (GC), IR level and the expression of insulin receptor substrate (IRS), AKT and extracellular signal-regulated kinase (ERK)1/2 proteins in a cellular and animal model of diabetes. IR was induced in hepatocellular carcinoma (HCC) cells, and SHP2 was up-regulated or down-regulated in cells. Diabetic rats were treated with SHP2 inhibitor. GC of cells, and the weight, total cholesterol, triglycerides, fasting blood glucose, fasting insulin, homeostasis model assessment-IR index and insulin sensitivity (ISI) of the rats were analyzed. The levels of SHP2 and the activation of IRS-2, AKT and ERK1/2 in cells and rats were measured by quantitative real-time PCR (qRT-PCR) or western blot. GC was reduced, but expression of SHP2 was enhanced in IR HCC cells. Phosphorylation of IRS-2 and AKT in IR HCC cells and diabetic rats was decreased, whereas phosphorylation of ERK1/2 was enhanced. In both the cell and animal models, SHP2 knockdown enhanced GC, ameliorated IR, activated IRS-2 and AKT, and inhibited ERK1/2 phosphorylation, in contrast with the effects of SHP2 overexpression. SHP2 knockdown may enhance GC and ameliorate IR through phosphorylation of IRS-2 via regulating AKT and ERK1/2 in liver.
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Affiliation(s)
- Xinxin Yue
- Department of Clinic CollegeHe UniversityShenyangChina
| | - Tao Han
- Department of OncologyThe First Affiliated Hospital of China Medical UniversityShenyangChina
| | - Wei Hao
- Department of Clinic CollegeHe UniversityShenyangChina
| | - Min Wang
- Department of Clinic CollegeHe UniversityShenyangChina
| | - Yang Fu
- Department of Burn and Plastic SurgeryGeneral Hospital of Northern Theater CommandShenyangChina
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17
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Berberine improves insulin resistance in adipocyte models by regulating the methylation of hypoxia-inducible factor-3α. Biosci Rep 2020; 39:220717. [PMID: 31652442 PMCID: PMC6822485 DOI: 10.1042/bsr20192059] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/20/2019] [Accepted: 09/30/2019] [Indexed: 12/31/2022] Open
Abstract
Methylation of hypoxia-inducible factor-3α (HIF3A) was previously demonstrated to be highly associated with insulin resistance (IR) in patients with gestational diabetes mellitus (GDM). We aimed to study the therapeutic effects of Berberine (BBR) on GDM and the possible mechanisms. The expressions and methylated states of HIF3A in pregnant women with GDM were compared with that in healthy controls. The IR cell models of 3T3-L1 adipocytes was constructed by 1 μmol/l dexamethasone (Dex) and 1 μmol/l insulin (Ins). To evaluate the effects of BBR on IR adipocyte models, cells were subjected to BBR treatment at different concentrations. Transfection of HIF3A siRNA further confirmed the role of HIF3A in the BBR-induced improving effects. Low expression and high methylation of HIF3A gene were frequent in the GDM pregnancies. BBR treatment noticeably increased the glucose usage rates, adiponectin secretion and cell differentiation of IR 3T3-L1 adipocytes. Increased HIF3A expression and decreased methylated state of HIF3A were also found in IR adipocytes. Furthermore, HIF3A silencing not only reversed the effects of BBR on improving insulin sensibility, but also partially abolished the expression alterations of insulin-related genes in IR adipocytes induced by BBR treatment. Our results suggest that BBR improves insulin sensibility in IR adipocyte models, and the improving effects of BBR are possibly realized through the inhibition of HIF3A methylation.
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18
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Li J, Guo Y, Chen YY, Liu Q, Chen Y, Tan L, Zhang SH, Gao ZR, Zhou YH, Zhang GY, Feng YZ. miR-124-3p increases in high glucose induced osteocyte-derived exosomes and regulates galectin-3 expression: A possible mechanism in bone remodeling alteration in diabetic periodontitis. FASEB J 2020; 34:14234-14249. [PMID: 32833280 DOI: 10.1096/fj.202000970rr] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/26/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022]
Abstract
The mechanisms underlying the two-way relationship between diabetes mellitus (DM) and periodontitis are unclear. We examined a possible effect of galectin-3 (Gal-3), a factor in DM and bone metabolism, on periodontitis with or without DM. Using enzyme-linked immunosorbent assay, we detected saliva Gal-3 in patients with periodontitis, with or without type 2 diabetes mellitus (T2DM). In animal models, we measured periodontal bone microarchitecture via micro computed tomography, and detected Gal-3, Runt-related transcription factor 2 (Runx2), and interleukin-6 (IL-6) expression in alveolar bone. Applying dual luciferase reporter assay, we explored the target binding of miR-124-3p and Gal-3. We examined osteocyte-derived exosomes with transmission electron microscopy and detected miR-124-3p, Gal-3, and IL-6 expression in exosomes. Saliva Gal-3 was increased in DM compared with controls but decreased in patients with moderate periodontitis and DM compared with those who had moderate periodontitis only. Alveolar bone mass was increased in DM and exacerbated in DM with periodontitis. Gal-3 and Runx2 were both increased in periodontitis and DM compared with controls, but decreased in DM with periodontitis compared with DM alone. MiR-124-3p targeted and inhibited Gal-3 expression in vitro. Osteocytes secreted exosomes carrying miR-124-3p, Gal-3, and IL-6, which were influenced by high glucose. These findings indicate that osteocyte-derived exosomes carrying miR-124-3p may regulate Gal-3 expression of osteoblasts, especially under high-glucose conditions, suggesting a possible mechanism for DM-related alveolar bone pathologies.
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Affiliation(s)
- Jun Li
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yue Guo
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ying-Yi Chen
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiong Liu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yun Chen
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li Tan
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shao-Hui Zhang
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zheng-Rong Gao
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ying-Hui Zhou
- Department of Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Gui-Ying Zhang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yun-Zhi Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
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19
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Liu J, Liu F. The Yin and Yang function of microRNAs in insulin signalling and cancer. RNA Biol 2020; 18:24-32. [PMID: 32746694 DOI: 10.1080/15476286.2020.1804236] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Data accumulated over the past several decades uncover a vital role of microRNAs (miRNAs) in various biological processes. It is well established that, by binding to target mRNAs, miRNAs act as post-transcription suppressors to inhibit mRNA translation and/or to promote mRNA degradation. Very recently, miRNAs have been found to act as positive regulators to promote gene transcription. In this review, we briefly summarize the regulation and functional roles of miRNAs in metabolic diseases and cancer development. We also review recent advances on the mechanisms by which miRNAs regulate gene expression, focusing on their unconventional roles as enhancers to promote gene expression. Given the high potential of miRNAs as biomarkers for risk assessment and as high-value targets for therapy, a better understanding of the Yin-Yang functional feature of miRNAs and their mechanisms of action could have significant clinical implications for the treatment of various diseases such as obesity, type 2 diabetes, and cancer.
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Affiliation(s)
- Juanhong Liu
- National Clinical Research Center for Metabolic Diseases, and Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University , Changsha, China
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, and Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University , Changsha, China.,Departments of Pharmacology, University of Texas Health at San Antonio , San Antonio, TX, USA
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20
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Man XF, Hu N, Tan SW, Tang HN, Guo Y, Tang CY, Liu YQ, Tang J, Zhou CL, Wang F, Zhou HD. Insulin receptor substrate-1 inhibits high-fat diet-induced obesity by browning of white adipose tissue through miR-503. FASEB J 2020; 34:12308-12323. [PMID: 32721050 DOI: 10.1096/fj.201903283rr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/13/2020] [Accepted: 07/01/2020] [Indexed: 12/18/2022]
Abstract
Genetic variation of insulin receptor substrate 1 (IRS-1) was found to modulate the insulin resistance of adipose tissues, but the underlying mechanism was not clear. To investigate how the IRS-1 was involved in the browning of white adipose tissue through miRNA, we identified a mutated Irs-1 (Irs-1-/- ) mice model and found that this mice had a reduced subcutaneous WAT (sWAT) and increased brown adipose tissue (BAT) in the interscapular region. So we isolated the bone marrow stromal cells and analyzed differentially expressed miRNAs and adipogenesis-related genes with miRNA arrays and PCR arrays. Irs-1-/- mice showed decreased miR-503 expression, but increased expression of its target, bone morphogenetic protein receptor type 1a (BMPR1a). Overexpression of miR-503 in preadipocytes downregulated BMPR1a and impaired adipogenic activity through the phosphotidylinositol 3-kinase (PI3K/Akt) pathway, while the inhibitor had the opposite effect. In both Irs-1-/- and cold-induced models, sWAT exhibited BAT features, and showed tissue-specific increased BMPR1a expression, PI3K expression, and Akt phosphorylation. Thus, our results showed that IRS-1 regulated brown preadipocyte differentiation and induced browning in sWAT through the miR-503-BMPR1a pathway, which played important roles in high-fat diet-induced obesity.
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Affiliation(s)
- Xiao-Fei Man
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China.,Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nan Hu
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shu-Wen Tan
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao-Neng Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yue Guo
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chen-Yi Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ya-Qing Liu
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jun Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ci-La Zhou
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fang Wang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hou-De Zhou
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
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21
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Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. Int J Mol Sci 2020; 21:ijms21134725. [PMID: 32630698 PMCID: PMC7369709 DOI: 10.3390/ijms21134725] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022] Open
Abstract
Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.
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22
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Teofilović A, Brkljačić J, Djordjevic A, VojnovićMilutinović D, Tappy L, Matić G, Veličković N. Impact of insulin and glucocorticoid signalling on hepatic glucose homeostasis in the rat exposed to high-fructose diet and chronic stress. Int J Food Sci Nutr 2020; 71:815-825. [PMID: 32070154 DOI: 10.1080/09637486.2020.1728236] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Overconsumption of fructose-enriched beverages and everyday stress are involved in the pathogenesis of metabolic disorders through modulation of hepatic glucose metabolism. The aim of the study was to investigate whether interaction of high-fructose diet and chronic stress alter insulin and glucocorticoid signalling thus affecting hepatic glucose homeostasis. High-fructose diet led to hyperinsulinemia, increased glucose transporter 2 level, elevated protein kinase B (Akt) phosphorylation, increased glucokinase mRNA and phospho-to-total glycogen synthase kinase 3 ratio and decreased expression of gluconeogenic genes. Fructose diet also led to stimulated glucocorticoid prereceptor metabolism, but downstream signalling remained unchanged due to increased glucocorticoid clearance. Stress did not affect hepatic insulin and glucocorticoid signalling nor glucose metabolism, while the interaction of the factors was observed only for glucokinase expression. The results suggest that, under conditions of fructose-induced hyperinsulinemia, suppression of gluconeogenesis and glycogen synthase activation contribute to the maintenance of glucose homeostasis. The increased glucocorticoid inactivation may represent an adaptive mechanism to prevent hyperglycaemia.
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Affiliation(s)
- Ana Teofilović
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Jelena Brkljačić
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Ana Djordjevic
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Danijela VojnovićMilutinović
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Luc Tappy
- Department of Physiology, University of Lausanne, UNIL-CHUV, Lausanne, Switzerland
| | - Gordana Matić
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Nataša Veličković
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
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23
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Yue HQ, Zhou YH, Guo Y, Tang CY, Wang F, Zhou HD. Serum miR-503 is a Candidate Biomarker for Differentiating Metabolic Healthy Obesity from Metabolic Unhealthy Obesity. Diabetes Metab Syndr Obes 2020; 13:2667-2676. [PMID: 32821139 PMCID: PMC7419640 DOI: 10.2147/dmso.s262888] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/08/2020] [Indexed: 01/07/2023] Open
Abstract
PURPOSE Overweight and obesity are associated with metabolic diseases. However, a subgroup of the overweight/obese population does not present metabolic abnormalities. Hence, there is an urgent need to identify biomarkers that can distinguish different obesity phenotypes and metabolic status. PATIENTS AND METHODS A total of 98 individuals were divided into three groups: metabolically healthy normal weight (MHNW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Participants were evaluated for anthropometric and biochemical parameters and serum BMPR1A concentration and miR-503 level. Receiver operating characteristic (ROC) curve analysis and logistic regression analysis were performed. RESULTS The level of miR-503 was significantly higher in the MHO group compared with that in the MUO group, but no difference was observed between the MHNW and MHO groups. Meanwhile, no significant differences in serum BMPR1A concentration were observed between the three groups. ROC curve analysis showed that miR-503 could be used as a marker to distinguish the MUO from the MHO. Logistic regression analysis suggested that miR-503 was an important related factor associated with an unhealthy metabolic state in overweight/obese subjects. CONCLUSION miR-503 can be considered as a suitable biomarker to distinguish between the MUO and MHO, which may be a related factor for the incidence of metabolic disorders in overweight/obese subjects.
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Affiliation(s)
- Hai-Qing Yue
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of China
| | - Ying-Hui Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of China
| | - Yue Guo
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of China
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
| | - Chen-Yi Tang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of China
| | - Fang Wang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of China
| | - Hou-De Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of China
- Correspondence: Hou-De Zhou National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan, People’s Republic of ChinaTel +86-731-85292223Fax +86-731-85533525 Email
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24
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Abstract
PURPOSE OF REVIEW The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.
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Affiliation(s)
- Michaela Tencerova
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, 5000, Odense C, Denmark.
- Department of Molecular Physiology of Bone, Institute of Physiology, Czech Academy of Sciences, 142 20, Prague 4, Czech Republic.
| | - Meshail Okla
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Moustapha Kassem
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, 5000, Odense C, Denmark
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Cellular and Molecular Medicine, The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Panum Institute, University of Copenhagen, Copenhagen, Denmark
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25
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Ebrahimi R, Bahiraee A, Niazpour F, Emamgholipour S, Meshkani R. The role of microRNAs in the regulation of insulin signaling pathway with respect to metabolic and mitogenic cascades: A review. J Cell Biochem 2019; 120:19290-19309. [PMID: 31364207 DOI: 10.1002/jcb.29299] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/27/2019] [Indexed: 12/18/2022]
Abstract
Insulin resistance (IR) is a shared pathological condition among type 2 diabetes, obesity, cardiovascular disease, and other metabolic disorders. It is growing significantly all over the world and consequently, a substantial effort is needed for developing the potential novel diagnostics and therapeutics. An insulin signaling pathway is tightly modulated by different mechanisms including the epigenetic modifications. Today, a deal of great attention has been shifted towards the regulatory role of noncoding RNAs on target proteins of the insulin signaling pathway. Noncoding RNAs are a major area of the epigenetics which control gene expression at the posttranscriptional levels and include a large class of microRNAs (miRNAs). With this in view, many studies have implicated the mediatory effects of miRNAs on the downstream metabolic and mitogenic proteins of the insulin signaling pathway. Since providing new biomarkers for the early diagnosis of IR and related metabolic traits are very significant, we intended to review the possible role of miRNAs in the regulation of the insulin signaling pathway, with a primary focus on the downstream target proteins of the metabolic and mitogenic cascades.
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Affiliation(s)
- Reyhane Ebrahimi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Bahiraee
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Farshad Niazpour
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Solaleh Emamgholipour
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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26
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Zhang BH, Shen CA, Zhu BW, An HY, Zheng B, Xu SB, Sun JC, Sun PC, Zhang W, Wang J, Liu JY, Fan YQ. Insight into miRNAs related with glucometabolic disorder. Biomed Pharmacother 2019; 111:657-665. [PMID: 30611990 DOI: 10.1016/j.biopha.2018.12.123] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 12/29/2018] [Accepted: 12/30/2018] [Indexed: 12/21/2022] Open
Abstract
A microRNA (miRNA) is a single-stranded, small and non-coding RNA molecule that contains 20-25 nucleotides. More than 2000 miRNAs have been identified in human genes since the first miRNA was discovered in Caenorhabditis elegans in the early 1990s. miRNAs play a crucial role in various biological processes by regulating gene expression through post-transcriptional mechanisms. The alterations of their levels are associated with various diseases, such as glucometabolic disorder and lipid metabolism disorder. In recent years, miRNAs have been proved to be involved in regulating the functions of pancreatic β-cells, insulin resistance and other biological behaviors related to glucometabolic disorder and the pathogenesis of diabetes mellitus (DM). This review summarized specific miRNAs, including miRNA-375 (miR-375), miRNA-155 (miR-155), miRNA-21 (miR-21), miRNA-33 (miR-33), the let-7 family and some other miRNAs related to glucometabolic regulation, introduced the obstacles and challenges in miRNA therapy, and discussed the prospect of new treatment methods for glucometabolic disorder.
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Affiliation(s)
- Bo-Han Zhang
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Chuan-An Shen
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China.
| | - Bi-Wei Zhu
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Hua-Ying An
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Bo Zheng
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Sheng-Bo Xu
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Jia-Chen Sun
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Peng-Chao Sun
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Wen Zhang
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Jia Wang
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Jia-Ying Liu
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Ya-Qian Fan
- Department of Burns and Plastic Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, People's Republic of China
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27
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MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes. Int J Mol Sci 2018; 19:ijms19123705. [PMID: 30469501 PMCID: PMC6321520 DOI: 10.3390/ijms19123705] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/08/2018] [Accepted: 11/17/2018] [Indexed: 12/21/2022] Open
Abstract
The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.
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28
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Jeong DE, Heo S, Han JH, Lee EY, Kulkarni RN, Kim W. Glucose Controls the Expression of Polypyrimidine Tract-Binding Protein 1 via the Insulin Receptor Signaling Pathway in Pancreatic β Cells. Mol Cells 2018; 41:909-916. [PMID: 30165730 PMCID: PMC6199568 DOI: 10.14348/molcells.2018.0147] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 08/06/2018] [Accepted: 08/09/2018] [Indexed: 01/04/2023] Open
Abstract
In pancreatic β cells, glucose stimulates the biosynthesis of insulin at transcriptional and post-transcriptional levels. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), also named hnRNP I, acts as a critical mediator of insulin biosynthesis through binding to the pyrimidine-rich region in the 3'-untranslated region (UTR) of insulin mRNA. However, the underlying mechanism that regulates its expression in β cells is unclear. Here, we report that glucose induces the expression of PTBP1 via the insulin receptor (IR) signaling pathway in β cells. PTBP1 is present in β cells of both mouse and monkey, where its levels are increased by glucose and insulin, but not by insulin-like growth factor 1. PTBP1 levels in immortalized β cells established from wild-type (βIRWT) mice are higher than levels in β cells established from IR-null (βIRKO) mice, and ectopic re-expression of IR-WT in βIRKO cells restored PTBP1 levels. However, PTBP1 levels were not altered in βIRKO cells transfected with IR-3YA, in which the Tyr1158/1162/1163 residues are substituted with Ala. Consistently, treatment with glucose or insulin elevated PTBP1 levels in βIRWT cells, but not in βIRKO cells. In addition, silencing Akt significantly lowered PTBP1 levels. Thus, our results identify insulin as a pivotal mediator of glucose-induced PTBP1 expression in pancreatic β cells.
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Affiliation(s)
- Da Eun Jeong
- Department of Molecular Science and Technology, Ajou University, Suwon 16499,
Korea
| | - Sungeun Heo
- Department of Molecular Science and Technology, Ajou University, Suwon 16499,
Korea
| | - Ji Hye Han
- Department of Molecular Science and Technology, Ajou University, Suwon 16499,
Korea
| | - Eun-young Lee
- Department of Molecular Science and Technology, Ajou University, Suwon 16499,
Korea
| | - Rohit N. Kulkarni
- Department of Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, and Harvard Stem Cell Institute, Boston, MA 02215,
USA
| | - Wook Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 16499,
Korea
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29
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Chu F, Hu Y, Zhou Y, Guo M, Lu J, Zheng W, Xu H, Zhao J, Xu L. MicroRNA-126 deficiency enhanced the activation and function of CD4 + T cells by elevating IRS-1 pathway. Clin Exp Immunol 2018; 191:166-179. [PMID: 28987000 PMCID: PMC5758368 DOI: 10.1111/cei.13067] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2017] [Indexed: 01/01/2023] Open
Abstract
Recent evidence has shown that microRNA-126 (miR-126) has been involved in the development and function of immune cells, which contributed to the pathogenesis of related clinical diseases. However, the potential role of miR-126 in the development and function of CD4+ T cells remains largely unknown. Here we first found that the activation and proliferation, as well as the expression of interferon (IFN)-γ, of CD4+ T cells from miR-126 knock-down (KD) mice using the miRNA-sponge technique were enhanced significantly in vitro, compared with those in CD4+ T cells from wild-type (WT) mice. To monitor further the possible effect of miR-126 deficiency on the function of CD4+ T cells in vivo, we used dextran sulphate sodium (DSS)-induced murine model of acute autoimmune colitis and found that miR-126 deficiency could elevate the pathology of colitis. Importantly, the proportion of CD4+ T cells in splenocytes increased significantly in miR-126KD mice. Moreover, the expression levels of CD69 and CD44 on CD4+ T cells increased significantly and the expression level of CD62L decreased significantly. Of note, adoptive cell transfer assay showed that the pathology of colitis was more serious in carboxyfluorescein succinimidyl ester (CFSE)-labelled miR-126KD CD4+ T cell-transferred group, compared with that in the CFSE-labelled WT CD4+ T cells transferred group. Consistently, the expression levels of CD69 and CD44 on CFSE+ cells increased significantly. Furthermore, both the proliferation and IFN-γ secretion of CFSE+ cells also increased significantly in the CFSE-labelled miR-126KD CD4+ T cell-transferred group. Mechanistic evidence showed that the expression of insulin receptor substrate 1 (IRS-1), as a functional target of miR-126, was elevated in CD4+ T cells from miR-126KD mice, accompanied by altered transduction of the extracellular regulated kinase, protein B (AKT) and nuclear factor kappa B (NF-κB) pathway. Our data revealed a novel role in which miR-126 was an intrinsic regulator in the function of CD4+ T cells, which provided preliminary basis for exploring further the role of miR-126 in the development, function of CD4+ T cells and related clinical diseases.
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Affiliation(s)
- F. Chu
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - Y. Hu
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - Y. Zhou
- Department of Medical PhysicsZunyi Medical CollegeGuizhouChina
| | - M. Guo
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - J. Lu
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - W. Zheng
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - H. Xu
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - J. Zhao
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
| | - L. Xu
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education DepartmentGuizhouChina
- Department of ImmunologyZunyi Medical CollegeGuizhouChina
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Rodríguez-de la Rosa L, Lassaletta L, Calvino M, Murillo-Cuesta S, Varela-Nieto I. The Role of Insulin-Like Growth Factor 1 in the Progression of Age-Related Hearing Loss. Front Aging Neurosci 2017; 9:411. [PMID: 29311900 PMCID: PMC5733003 DOI: 10.3389/fnagi.2017.00411] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 11/27/2017] [Indexed: 12/21/2022] Open
Abstract
Aging is associated with impairment of sensorial functions and with the onset of neurodegenerative diseases. As pari passu circulating insulin-like growth factor 1 (IGF-1) bioavailability progressively decreases, we see a direct correlation with sensory impairment and cognitive performance in older humans. Age-related sensory loss is typically caused by the irreversible death of highly differentiated neurons and sensory receptor cells. Among sensory deficits, age-related hearing loss (ARHL), also named presbycusis, affects one third of the population over 65 years of age and is a major factor in the progression of cognitive problems in the elderly. The genetic and molecular bases of ARHL are largely unknown and only a few genes related to susceptibility to oxidative stress, excitotoxicity, and cell death have been identified. IGF-1 is known to be a neuroprotective agent that maintains cellular metabolism, activates growth, proliferation and differentiation, and limits cell death. Inborn IGF-1 deficiency leads to profound sensorineural hearing loss both in humans and mice. IGF-1 haploinsufficiency has also been shown to correlate with ARHL. There is not much information available on the effect of IGF-1 deficiency on other human sensory systems, but experimental models show a long-term impact on the retina. A secondary action of IGF-1 is the control of oxidative stress and inflammation, thus helping to resolve damage situations, acute or made chronic by aging. Here we will review the primary actions of IGF-1 in the auditory system and the underlying molecular mechanisms.
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Affiliation(s)
- Lourdes Rodríguez-de la Rosa
- “Alberto Sols” Biomedical Research Institute CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Luis Lassaletta
- “Alberto Sols” Biomedical Research Institute CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
- Otorhinolaryngology Department, Hospital La Paz, Madrid, Spain
| | - Miryam Calvino
- Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
- Otorhinolaryngology Department, Hospital La Paz, Madrid, Spain
| | - Silvia Murillo-Cuesta
- “Alberto Sols” Biomedical Research Institute CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Isabel Varela-Nieto
- “Alberto Sols” Biomedical Research Institute CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
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