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Vasilev V, Georgieva K, Arabadzhiyska D, Delchev S, Gerginska F, Komrakova M, Boeker KO, Schilling AF, Boaydjiev N. Ligandrol lowers endurance and negatively affects lipid and hormonal profile of male rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04028-8. [PMID: 40087185 DOI: 10.1007/s00210-025-04028-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
Selective androgen receptor modulators are currently not approved but are widely used in gyms. In the present study, the effects of ligandrol and its combination with endurance training on functional and clinically important parameters were studied in male healthy rats. Fourteen-week-old male rats were divided into four groups: two training (40 min, 5 times/week) and two non-training (5 min, 3 times/week). The velocity was 25 m/min at a track elevation of 5° for all groups. Ligandrol (0.4 mg/kg body weight, 5 times/week) was administered to one training and one non-training group and vehicle to the other groups (n = 10 per group) for 8 weeks. We conducted functional tests and examined morphometric, functional, hematological, hormonal, and clinical chemistry indicators in rats and histological and gene expression analyses in gastrocnemius muscle. Endurance training had a positive effect on all functional tests and increased vascular endothelial growth factor a (Vegf-a) gene expression. Ligandrol treatment reduced submaximal endurance, maximal oxygen consumption, concentrations of glucose, follicle-stimulating hormone, and testosterone. It increased grip strength, triglycerides, and total cholesterol concentrations and had no effect on maximal sprinting speed, maximal time to exhaustion, hematological and morphometric parameters, and gene expression of myostatin and insulin-like growth factor 1. The negative effects of ligandrol treatment outweighed its benefits in this study. Endurance training alone had favorable effects, and its combination with ligandrol did not seem to have an advantage. In the training group, ligandrol decreased Vegf-a gene expression and the size of muscle fibers type I and IIa.
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Affiliation(s)
- Veselin Vasilev
- Department of Physiology, Medical University Plovdiv, 15A V. Aprilov Blvd., Plovdiv, 4002, Bulgaria.
| | - Katerina Georgieva
- Department of Physiology, Medical University Plovdiv, 15A V. Aprilov Blvd., Plovdiv, 4002, Bulgaria
| | | | - Slavi Delchev
- Department of Anatomy, Histology, Embryology, Medical University Plovdiv, Plovdiv, Bulgaria
| | - Fanka Gerginska
- Department of Anatomy, Histology, Embryology, Medical University Plovdiv, Plovdiv, Bulgaria
| | - Marina Komrakova
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Kai O Boeker
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Arndt F Schilling
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Nikolay Boaydjiev
- Department of Physiology, Medical University Plovdiv, 15A V. Aprilov Blvd., Plovdiv, 4002, Bulgaria
- Research Institute, Medical University Plovdiv, Plovdiv, Bulgaria
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Hosseini S, Hosseini S, Aligholi H, Salehi M. Embryo vitrification impacts learning and spatial memory by altering the imprinting genes expression level in the mouse offspring' hippocampus. Sci Rep 2025; 15:5419. [PMID: 39948414 PMCID: PMC11825692 DOI: 10.1038/s41598-025-89857-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 02/10/2025] [Indexed: 02/16/2025] Open
Abstract
The safety and impact of embryo vitrification as a more reliable approach for cryopreservation in assisted reproductive techniques (ARTs) on the nervous system is uncertain. This study was aimed to investigate the expression level of imprinting genes in the hippocampus of offspring derived from vitrified embryo transfer. The hippocampus of the 2-day-old offspring from three experimental groups included vitrification (blastocysts derived from vitrified embryos), sham (the embryos at the blastocyst stage obtained through in vitro fertilization (IVF)) and control was removed for molecular, histological and behavioral analysis. There was no statistically noteworthy difference in survival, cleavage and blastocysts rate between vitrification and sham groups. Dnmt1, Dnmt3a, 3b and Igf2 upregulated in the vitrified group compared to the sham and control groups. The gene expression level of Meg3 declined dramatically and the intensity of DNA methylation in CpG island of Meg3 significantly elevated in the vitrification group. A notable disparity was observed in the quantity of dark neurons in the hippocampus of the offspring, spatial learning and memory abilities between the control and vitrification groups. According to these results, embryo vitrification may alters gene expression in brain hippocampus tissue and disturbs genomic imprinting, dark neuron formation and spatial memory.
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Affiliation(s)
- Samira Hosseini
- Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Hosseini
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hadi Aligholi
- Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohammad Salehi
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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3
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Oguntoyinbo IO, Goyal R. The Role of Long Intergenic Noncoding RNA in Fetal Development. Int J Mol Sci 2024; 25:11453. [PMID: 39519006 PMCID: PMC11546696 DOI: 10.3390/ijms252111453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
The role of long intergenic noncoding RNAs (lincRNAs) in fetal development has emerged as a significant area of study, challenging the traditional protein-centric view of gene expression. While messenger RNAs (mRNAs) have long been recognized for their role in encoding proteins, recent advances have illuminated the critical functions of lincRNAs in various biological processes. Initially identified through high-throughput sequencing technologies, lincRNAs are transcribed from intergenic regions between protein-coding genes and exhibit unique regulatory functions. Unlike mRNAs, lincRNAs are involved in complex interactions with chromatin and chromatin-modifying complexes, influencing gene expression and chromatin structure. LincRNAs are pivotal in regulating tissue-specific development and embryogenesis. For example, they are crucial for proper cardiac, neural, and reproductive system development, with specific lincRNAs being associated with organogenesis and differentiation processes. Their roles in embryonic development include regulating transcription factors and modulating chromatin states, which are essential for maintaining developmental programs and cellular identity. Studies using RNA sequencing and genetic knockout models have highlighted the importance of lincRNAs in processes such as cell differentiation, tissue patterning, and organ development. Despite their functional significance, the comprehensive annotation and understanding of lincRNAs remain limited. Ongoing research aims to elucidate their mechanisms of action and potential applications in disease diagnostics and therapeutics. This review summarizes current knowledge on the functional roles of lincRNAs in fetal development, emphasizing their contributions to tissue-specific gene regulation and developmental processes.
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Affiliation(s)
- Ifetoluwani Oluwadunsin Oguntoyinbo
- School of Animal and Comparative Biomedical Sciences, College of Agriculture, Life & Environmental Sciences, University of Arizona, Tucson, AZ 85721, USA;
| | - Ravi Goyal
- Department of Obstetrics and Gynecology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA
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Wang W, Yang H, Fan Z, Shi R. STL Inhibited Angiogenesis of DPSCs Through Depressing Mitochondrial Respiration by Enhancing RNF217. Adv Biol (Weinh) 2024; 8:e2400042. [PMID: 38880848 DOI: 10.1002/adbi.202400042] [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: 01/22/2024] [Revised: 05/10/2024] [Indexed: 06/18/2024]
Abstract
Angiogenesis is the determining factor during dental pulp regeneration. Six-twelve leukemia (STL) is identified as a key regulatory factor on the biological function of dental pulp stem cells (DPSCs) under hypoxic conditions, but its effect on angiogenesis is unclear. Co-culture of DPSCs and human umbilical vein endothelial cells (HUVECs) is used to detect tubule formation ability in vitro and the angiogenesis ability in vivo. RNA-seq and bioinformatic analyses are performed to screen differentially expressed genes. Seahorse Cell Mito Stress Test is proceeded to exam mitochondrial respiration. STL decreased tubule formation and mitochondrial respiration of DPSCs in vitro and restrained the number of blood vessels and the expression of VEGF in new formed tissue in vivo. Furthermore, pretreating STL-depleted DPSCs with rotenone, a mitochondrial respiration inhibitor, counteracted the promoting effect of STL knockdown on tubule formation. Then, RNA-seq and bioinformatic analyses identified some angiogenesis relevant genes and pathways in STL-depleted DPSCs. And STL enhanced expression of mRNA-ring finger protein 217 (RNF217), which inhibited the tubule formation and mitochondrial respiration of DPSCs. STL inhibited the angiogenesis of DPSCs through depressing mitochondrial respiration by enhancing RNF217, indicating that STL is a potential target for angiogenesis of DPSCs.
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Affiliation(s)
- Wanqing Wang
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, 100050, China
| | - Haoqing Yang
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, 100050, China
| | - Zhipeng Fan
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, 100050, China
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, 100069, China
- Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ruitang Shi
- Department of Endodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, 100050, China
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Dunn-Davies H, Dudnakova T, Nogara A, Rodor J, Thomas AC, Parish E, Gautier P, Meynert A, Ulitsky I, Madeddu P, Caporali A, Baker A, Tollervey D, Mitić T. Control of endothelial cell function and arteriogenesis by MEG3:EZH2 epigenetic regulation of integrin expression. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102173. [PMID: 38617973 PMCID: PMC11015509 DOI: 10.1016/j.omtn.2024.102173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/14/2024] [Indexed: 04/16/2024]
Abstract
Epigenetic processes involving long non-coding RNAs regulate endothelial gene expression. However, the underlying regulatory mechanisms causing endothelial dysfunction remain to be elucidated. Enhancer of zeste homolog 2 (EZH2) is an important rheostat of histone H3K27 trimethylation (H3K27me3) that represses endothelial targets, but EZH2 RNA binding capacity and EZH2:RNA functional interactions have not been explored in post-ischemic angiogenesis. We used formaldehyde/UV-assisted crosslinking ligation and sequencing of hybrids and identified a new role for maternally expressed gene 3 (MEG3). MEG3 formed the predominant RNA:RNA hybrid structures in endothelial cells. Moreover, MEG3:EZH2 assists recruitment onto chromatin. By EZH2-chromatin immunoprecipitation, following MEG3 depletion, we demonstrated that MEG3 controls recruitment of EZH2/H3K27me3 onto integrin subunit alpha4 (ITGA4) promoter. Both MEG3 knockdown or EZH2 inhibition (A-395) promoted ITGA4 expression and improved endothelial cell migration and adhesion to fibronectin in vitro. The A-395 inhibitor re-directed MEG3-assisted chromatin remodeling, offering a direct therapeutic benefit by increasing endothelial function and resilience. This approach subsequently increased the expression of ITGA4 in arterioles following ischemic injury in mice, thus promoting arteriogenesis. Our findings show a context-specific role for MEG3 in guiding EZH2 to repress ITGA4. Novel therapeutic strategies could antagonize MEG3:EZH2 interaction for pre-clinical studies.
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Affiliation(s)
- Hywel Dunn-Davies
- Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building Max Born Crescent, King’s Buildings, Edinburgh EH9 3BF, UK
| | - Tatiana Dudnakova
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Antonella Nogara
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Julie Rodor
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Anita C. Thomas
- Bristol Medical School, Translational Health Sciences, University of Bristol, Research and Teaching Floor Level 7, Queens Building, Bristol Royal Infirmary, Bristol BS2 8HW, UK
| | - Elisa Parish
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Philippe Gautier
- MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
| | - Alison Meynert
- MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
| | - Igor Ulitsky
- Department of Immunology and Regenerative Biology and Department of Molecular Neuroscience, Weizmann-UK Building rm. 007, Weizmann Institute of Science Rehovot 76100, Israel
| | - Paolo Madeddu
- Bristol Medical School, Translational Health Sciences, University of Bristol, Research and Teaching Floor Level 7, Queens Building, Bristol Royal Infirmary, Bristol BS2 8HW, UK
| | - Andrea Caporali
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Andrew Baker
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - David Tollervey
- Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building Max Born Crescent, King’s Buildings, Edinburgh EH9 3BF, UK
| | - Tijana Mitić
- University/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
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Wang G, Li Z, Wang G, Sun Q, Lin P, Wang Q, Zhang H, Wang Y, Zhang T, Cui F, Zhong Z. Advances in Engineered Nanoparticles for the Treatment of Ischemic Stroke by Enhancing Angiogenesis. Int J Nanomedicine 2024; 19:4377-4409. [PMID: 38774029 PMCID: PMC11108071 DOI: 10.2147/ijn.s463333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/02/2024] [Indexed: 05/24/2024] Open
Abstract
Angiogenesis, or the formation of new blood vessels, is a natural defensive mechanism that aids in the restoration of oxygen and nutrition delivery to injured brain tissue after an ischemic stroke. Angiogenesis, by increasing vessel development, may maintain brain perfusion, enabling neuronal survival, brain plasticity, and neurologic recovery. Induction of angiogenesis and the formation of new vessels aid in neurorepair processes such as neurogenesis and synaptogenesis. Advanced nano drug delivery systems hold promise for treatment stroke by facilitating efficient transportation across the the blood-brain barrier and maintaining optimal drug concentrations. Nanoparticle has recently been shown to greatly boost angiogenesis and decrease vascular permeability, as well as improve neuroplasticity and neurological recovery after ischemic stroke. We describe current breakthroughs in the development of nanoparticle-based treatments for better angiogenesis therapy for ischemic stroke employing polymeric nanoparticles, liposomes, inorganic nanoparticles, and biomimetic nanoparticles in this study. We outline new nanoparticles in detail, review the hurdles and strategies for conveying nanoparticle to lesions, and demonstrate the most recent advances in nanoparticle in angiogenesis for stroke treatment.
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Affiliation(s)
- Guangtian Wang
- Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
- Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Zhihui Li
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China
| | - Gongchen Wang
- Department of Vascular Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China
| | - Qixu Sun
- Department of Gastroenterology, Penglai People’s Hospital, Yantai, Shandong, 265600, People’s Republic of China
| | - Peng Lin
- Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Qian Wang
- Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Huishu Zhang
- Teaching Center of Biotechnology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Yanyan Wang
- Teaching Center of Morphology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Tongshuai Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Feiyun Cui
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Zhaohua Zhong
- Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
- Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
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Malhi NK, Southerland KW, Lai L, Chen ZB. Epigenetic Regulation of Angiogenesis in Peripheral Artery Disease. Methodist Debakey Cardiovasc J 2023; 19:47-57. [PMID: 38028966 PMCID: PMC10655766 DOI: 10.14797/mdcvj.1294] [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] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 12/01/2023] Open
Abstract
Peripheral arterial disease (PAD) represents a global health concern with a rising prevalence attributed to factors such as obesity, diabetes, aging, and smoking. Among patients with PAD, chronic limb-threatening ischemia (CLTI) is the most severe manifestation, associated with substantial morbidity and mortality. While revascularization remains the primary therapy for CLTI, not all patients are candidates for such interventions, highlighting the need for alternative approaches. Impaired angiogenesis, the growth of new blood vessels, is a central feature of PAD, and despite decades of research, effective clinical treatments remain elusive. Epigenetics, the study of heritable changes in gene expression, has gained prominence in understanding PAD pathogenesis. Here, we explore the role of epigenetic regulation in angiogenesis within the context of PAD, with a focus on long non-coding RNAs and fibroblast-endothelial cell transdifferentiation. Additionally, we discuss the interplay between metabolic control and epigenetic regulation, providing insights into potential novel therapeutic avenues for improving PAD treatments. This review aims to offer a concise update on the application of epigenetics in angiogenesis and PAD research, inspiring further investigations in this promising field.
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Affiliation(s)
| | | | - Li Lai
- Houston Methodist Research Institute, Houston, Texas, US
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Bink DI, Pauli J, Maegdefessel L, Boon RA. Endothelial microRNAs and long noncoding RNAs in cardiovascular ageing. Atherosclerosis 2023; 374:99-106. [PMID: 37059656 DOI: 10.1016/j.atherosclerosis.2023.03.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/16/2023]
Abstract
Atherosclerosis and numerous other cardiovascular diseases develop in an age-dependent manner. The endothelial cells that line the vessel walls play an important role in the development of atherosclerosis. Non-coding RNA like microRNAs and long non-coding RNAs are known to play an important role in endothelial function and are implicated in the disease progression. Here, we summarize several microRNAs and long non-coding RNAs that are known to have an altered expression with endothelial aging and discuss their role in endothelial cell function and senescence. These processes contribute to aging-induced atherosclerosis development and by targeting the non-coding RNAs controlling endothelial cell function and senescence, atherosclerosis can potentially be attenuated.
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Affiliation(s)
- Diewertje I Bink
- Department of Physiology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, the Netherlands
| | - Jessica Pauli
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany
| | - Lars Maegdefessel
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany; Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Reinier A Boon
- Department of Physiology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, the Netherlands; Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt am Main, Frankfurt am Main, Germany; German Centre for Cardiovascular Research DZHK, Partner site Frankfurt Rhein/Main, Frankfurt Am Main, Germany.
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Zhang Z, Shi S, Li J, Costa M. Long Non-Coding RNA MEG3 in Metal Carcinogenesis. TOXICS 2023; 11:toxics11020157. [PMID: 36851033 PMCID: PMC9962265 DOI: 10.3390/toxics11020157] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 06/06/2023]
Abstract
Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.
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Shekher A, Puneet, Awasthee N, Kumar U, Raj R, Kumar D, Gupta SC. Association of altered metabolic profiles and long non-coding RNAs expression with disease severity in breast cancer patients: analysis by 1H NMR spectroscopy and RT-q-PCR. Metabolomics 2023; 19:8. [PMID: 36710275 DOI: 10.1007/s11306-023-01972-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Globally, one of the major causes of cancer related deaths in women is breast cancer. Although metabolic pattern is altered in cancer patients, robust metabolic biomarkers with a potential to improve the screening and disease monitoring are lacking. A complete metabolome profiling of breast cancer patients may lead to the identification of diagnostic/prognostic markers and potential targets. OBJECTIVES The aim of this study was to analyze the metabolic profile in the serum from 43 breast cancer patients and 13 healthy individuals. MATERIALS & METHODS We used 1H NMR spectroscopy for the identification and quantification of metabolites. q-RT-PCR was used to examine the relative expression of lncRNAs. RESULTS Metabolites such as amino acids, lipids, membrane metabolites, lipoproteins, and energy metabolites were observed in the serum from both patients and healthy individuals. Using unsupervised PCA, supervised PLS-DA, supervised OPLS-DA, and random forest classification, we observed that more than 25 metabolites were altered in the breast cancer patients. Metabolites with AUC value > 0.9 were selected for further analysis that revealed significant elevation of lactate, LPR and glycerol, while the level of glucose, succinate, and isobutyrate was reduced in breast cancer patients in comparison to healthy control. The level of these metabolites (except LPR) was altered in advanced-stage breast cancer patients in comparison to early-stage breast cancer patients. The altered metabolites were also associated with over 25 signaling pathways related to metabolism. Further, lncRNAs such as H19, MEG3 and GAS5 were dysregulated in the breast tumor tissue in comparison to normal adjacent tissue. CONCLUSION The study provides insights into metabolic alteration in breast cancer patients. It also provides an avenue to examine the association of lncRNAs with metabolic patterns in patients.
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Affiliation(s)
- Anusmita Shekher
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
| | - Puneet
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
| | - Nikee Awasthee
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
- Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Umesh Kumar
- Centre of Biomedical Research (CBMR), SGPGIMS, Lucknow, Uttar Pradesh, 226 014, India
| | - Ritu Raj
- Centre of Biomedical Research (CBMR), SGPGIMS, Lucknow, Uttar Pradesh, 226 014, India
| | - Dinesh Kumar
- Centre of Biomedical Research (CBMR), SGPGIMS, Lucknow, Uttar Pradesh, 226 014, India.
| | - Subash Chandra Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India.
- Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, 781101, India.
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Xia X, Huang L, Zhou S, Han R, Li P, Wang E, Xia W, Fei G, Zeng D, Wang R. Hypoxia-induced long non-coding RNA plasmacytoma variant translocation 1 upregulation aggravates pulmonary arterial smooth muscle cell proliferation by regulating autophagy via miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways. Int J Cardiol 2023; 370:368-377. [PMID: 36174828 DOI: 10.1016/j.ijcard.2022.09.060] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 09/11/2022] [Accepted: 09/22/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND The lncRNA PVT1 reportedly functions as a competing endogenous RNA (ceRNA) of miR-186 and miR-26b in different tissue types. In this study, we investigated the possible involvement of the miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways in the pathogenesis of hypoxia-induced PAH. METHODS Expression of PVT1, miR-186, miR-26b, and Srf and Ctgf mRNAs were evaluated by real-time polymerase chain reaction. Protein expression of SRF, CTGF, LC3B-I, LC3B-II, and Beclin-I was evaluated using western blotting. The regulatory relationship between the lncRNA, miRNAs, and target mRNAs was explored using luciferase assays. Immunohistochemistry was used to evaluate the expression of SRF and CTGF in situ. MTT assay was performed to assess the proliferation of PASMCs. RESULTS Exposure to hypoxia markedly altered the expression of PVT1, Srf, Ctgf, miR-186, and miR-26b in a rat model. MiR-186 binding sites in the sequences of Srf mRNA and PVT1 were confirmed by luciferase assays, indicating that miR-186 may interact with both PVT1 and Srf mRNA. Additionally, miR-26b binding sites were identified in the sequences of Ctgf mRNA and PVT1, suggesting that miR-26b may interact with both PVT1 and Ctgf mRNA. In line with this, we found that overexpression of PVT1 reduced expression of miR-26b and miR-186 but activated expression of Srf, Ctgf, LC3B-II, and Beclin-I. CONCLUSIONS Upregulation of PVT1 by exposure to hypoxia promoted the expression of CTGF, leading to deregulation of autophagy and abnormal proliferation of PASMCs. Dysregulation of the miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways may be involved in the pathogenesis of hypoxia-induced PASMCs.
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Affiliation(s)
- Xingyuan Xia
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Ling Huang
- Department of Infectious Diseases, Hefei second people's hospital, Hefei 230001, China
| | - Sijing Zhou
- Department of Occupational Diseases, Hefei third clinical college of Anhui Medical University, Hefei 230022, China
| | - Rui Han
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Pulin Li
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Enze Wang
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Wanli Xia
- Department of thoracic surgery, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Guanghe Fei
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China.
| | - Daxiong Zeng
- Department of pulmonary and critical care medicine, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou 215006, China.
| | - Ran Wang
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China.
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12
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Parekh VI, Sun H, Chen M, Weinstein LS, Agarwal SK. Mice With RIP-Cre-mediated Deletion of the Long Noncoding RNA Meg3 Show Normal Pancreatic Islets and Enlarged Pituitary. J Endocr Soc 2022; 6:bvac141. [PMID: 37283960 PMCID: PMC9581224 DOI: 10.1210/jendso/bvac141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Indexed: 11/19/2022] Open
Abstract
Context Maternally expressed gene 3 (MEG3) is a long noncoding RNA (lncRNA) that has been implicated as a tumor suppressor. Objective The expression of MEG3 RNA is downregulated in various human tumors, including pituitary adenoma and pancreatic islet tumors due to MEG3 gene deletion or DNA hypermethylation. Mouse models with conventional germline deletion of Meg3 have shown that Meg3 is essential for perinatal or postnatal development and survival. However, a direct role of Meg3 loss in tumorigenesis has not been shown. Methods To observe a causal relationship between Meg3 loss and tumorigenesis, we have generated a mouse model with conditional deletion of Meg3 mediated by the RIP-Cre transgene that initiated Meg3 deletion in pancreatic islet β cells and anterior pituitary. Results Meg3 loss did not lead to the development of islet tumors. Interestingly, RIP-Cre-mediated Meg3 loss led to the development of an enlarged pituitary. The genes in the Meg3 region are transcribed together as a 210 kb RNA that is processed into Meg3 and other transcripts. Whether these tandem transcripts play a functional role in the growth of pancreatic endocrine cells and pituitary cells remains to be determined. Conclusion Our mouse model shows that Meg3 loss leads to hyperplasia in the pituitary and not in pancreatic islets, thus serving as a valuable model to study pathways associated with pituitary cell proliferation and function. Future mouse models with specific inactivation of Meg3 alone or other transcripts in the Meg3 polycistron are warranted to study tissue-specific effects on initiating neoplasia and tumor development.
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Affiliation(s)
- Vaishali I Parekh
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Hui Sun
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Min Chen
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Sunita K Agarwal
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
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13
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LncRNA Meg3 promotes oxygen and glucose deprivation injury by decreasing angiogenesis in hBMECs by targeting the miR‑122‑5p/NDRG3 axis. Exp Ther Med 2022; 24:622. [PMID: 36160904 PMCID: PMC9468836 DOI: 10.3892/etm.2022.11559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 07/22/2022] [Indexed: 11/22/2022] Open
Abstract
Oxygen-glucose deprivation (OGD) is widely used as an in vitro model for stroke. The present study aimed to explore the mechanisms of action of long non-coding RNA (lncRNA) maternally expressed gene 3 (Meg3) in angiogenesis following OGD. The human brain microvascular endothelial cell line, hCMEC/D3, was used to establish the OGD model. lncRNA Meg3 was highly expressed in hCMEC/D3 cells subjected to OGD. Furthermore, it was found that the overexpression of lncRNA Meg3 decreased the proliferation, migration and angiogenesis of hCMEC/D3 cells subjected to OGD, and increased cell apoptosis. Meg3 silencing exerted the opposite effects. Subsequently, lncRNA Meg3 increased the expression of NDRG family member 3 (NDRG3) by directly binding to miR-122-5p. The overexpression of miR-122-5p and the knockdown of NDRG3 reversed the inhibitory effects of Meg3 overexpression on the proliferation, migration and angiogenesis of hCMEC/D3 cells subjected to OGD, as well as the promoting effects of Meg3 overexpression on cell apoptosis. The present study demonstrated that lncRNA Meg3 functions as a competing endogenous RNA by targeting the miR-122-5p/NDRG3 axis in regulating OGD injury.
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14
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Shen T, Wu Y, Cai W, Jin H, Yu D, Yang Q, Zhu W, Yu J. LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway. Exp Eye Res 2022; 222:109166. [PMID: 35820465 DOI: 10.1016/j.exer.2022.109166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 06/10/2022] [Accepted: 06/23/2022] [Indexed: 11/04/2022]
Abstract
The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.
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Affiliation(s)
- Tianyi Shen
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yan Wu
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Wenting Cai
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Huizi Jin
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Donghui Yu
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Qian Yang
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China; Anhui Medical University, Hefei, China
| | - Wei Zhu
- Department of Ophthalmology, Changshu NO. 2 People's Hospital, Changshu, China.
| | - Jing Yu
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China; Department of Ophthalmology, The Third People's Hospital of Bengbu, Bengbu, China.
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15
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Rasoulinejad SA, Sarreshtehdari N, Mafi AR. The crosstalk between VEGF signaling pathway and long non-coding RNAs in neovascular retinal diseases: Implications for anti-VEGF therapy. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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16
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Mathew S, Sivasubbu S. Long Non Coding RNA Based Regulation of Cerebrovascular Endothelium. Front Genet 2022; 13:834367. [PMID: 35495157 PMCID: PMC9043600 DOI: 10.3389/fgene.2022.834367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
The rapid and high throughput discovery of long non coding RNAs (lncRNAs) has far outstripped the functional annotation of these novel transcripts in their respective cellular contexts. The cells of the blood brain barrier (BBB), especially the cerebrovascular endothelial cells (CVECs), are strictly regulated to maintain a controlled state of homeostasis for undisrupted brain function. Several key pathways are understood in CVEC function that lead to the development and maintenance of their barrier properties, the dysregulation of which leads to BBB breakdown and neuronal injury. Endothelial lncRNAs have been discovered and functionally validated in the past decade, spanning a wide variety of regulatory mechanisms in health and disease. We summarize here the lncRNA-mediated regulation of established pathways that maintain or disrupt the barrier property of CVECs, including in conditions such as ischemic stroke and glioma. These lncRNAs namely regulate the tight junction assembly/disassembly, angiogenesis, autophagy, apoptosis, and so on. The identification of these lncRNAs suggests a less understood mechanistic layer, calling for further studies in appropriate models of the blood brain barrier to shed light on the lncRNA-mediated regulation of CVEC function. Finally, we gather various approaches for validating lncRNAs in BBB function in human organoids and animal models and discuss the therapeutic potential of CVEC lncRNAs along with the current limitations.
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Affiliation(s)
- Samatha Mathew
- CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Sridhar Sivasubbu
- CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India,*Correspondence: Sridhar Sivasubbu,
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17
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Jiang Y, Zhu H, Chen H, Yu YC, Xu YT, Liu F, He SN, Sagnelli M, Zhu YM, Luo Q. Elevated Expression of lncRNA MEG3 Induces Endothelial Dysfunction on HUVECs of IVF Born Offspring via Epigenetic Regulation. Front Cardiovasc Med 2022; 8:717729. [PMID: 35047570 PMCID: PMC8761900 DOI: 10.3389/fcvm.2021.717729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular dysfunction in children born after in vitro fertilization (IVF) has been of great concern, the potential molecular mechanisms for such long-term outcomes are still unknown. Here, we found that systolic blood pressure was a little higher in IVF born offspring at 2 years old compared to those born after being naturally conceived. Besides, the expression level of maternally expressed gene 3 (MEG3) was higher in human umbilical vein endothelial cells (HUVECs) from IVF offspring than that in spontaneously born offspring. Pearson correlation test showed that MEG3 relative expression is significantly related to the children's blood pressure (Coefficient = 0.429, P = 0.0262). Furthermore, we found decreased expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) along with elevated expression of endothelial-1(ET1) in HUVECs from IVF offspring, accompanied by lower secretion of nitrite, VEGF, and higher secretion of ET1 in the umbilical cord serum of IVF offspring. Correlation analysis showed MEG3 expression highly correlated with ET1 and Nitrate concentration. With pyrosequencing technology, we found that elevated expression of MEG3 was the result of hypomethylation of the MEG3 promoter. Therefore, our results provide a potential mechanism addressing the high-risk of hypertension in IVF offspring via MEG3 epigenetic regulation.
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Affiliation(s)
- Ying Jiang
- Department of Obstetrics, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.,Shanghai Ji Ai Genetics and IVF Institute, Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Hong Chen
- Regional Community Health Service Center of Minzhi Sub-district, Shenzhen, China
| | - Yi-Chen Yu
- Department of General Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Ye-Tao Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fang Liu
- Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Sai-Nan He
- Department of Obstetrics, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, China
| | - Matthew Sagnelli
- University of Connecticut School of Medicine, Farmington, CT, United States
| | - Yi-Min Zhu
- Department of Obstetrics, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, China
| | - Qiong Luo
- Department of Obstetrics, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, China
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18
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Liu J, Qi X, Wang XH, Miao HS, Xue ZC, Zhang LL, Zhao SH, Wu LH, Gao GY, Lou MQ, Yi CQ. Downregulation of the LncRNA MEG3 Promotes Osteogenic Differentiation of BMSCs and Bone Repairing by Activating Wnt/β-Catenin Signaling Pathway. J Clin Med 2022; 11:jcm11020395. [PMID: 35054086 PMCID: PMC8781453 DOI: 10.3390/jcm11020395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/25/2021] [Accepted: 01/10/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Previous studies have demonstrated that long non-coding RNA maternally expressed gene 3 (MEG3) emerged as a key regulator in development and tumorigenesis. This study aims to investigate the function and mechanism of MEG3 in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explores the use of MEG3 in skull defects bone repairing. Methods: Endogenous expression of MEG3 during BMSCs osteogenic differentiation was detected by quantitative real-time polymerase chain reaction (qPCR). MEG3 was knockdown in BMSCs by lentiviral transduction. The proliferation, osteogenic-related genes and proteins expression of MEG3 knockdown BMSCs were assessed by Cell Counting Kit-8 (CCK-8) assay, qPCR, alizarin red and alkaline phosphatase staining. Western blot was used to detect β-catenin expression in MEG3 knockdown BMSCs. Dickkopf 1 (DKK1) was used to block wnt/β-catenin pathway. The osteogenic-related genes and proteins expression of MEG3 knockdown BMSCs after wnt/β-catenin inhibition were assessed by qPCR, alizarin red and alkaline phosphatase staining. MEG3 knockdown BMSCs scaffold with PHMG were implanted in a critical-sized skull defects of rat model. Micro-computed tomography(micro-CT), hematoxylin and eosin staining and immunohistochemistry were performed to evaluate the bone repairing. Results: Endogenous expression of MEG3 was increased during osteogenic differentiation of BMSCs. Downregulation of MEG3 could promote osteogenic differentiation of BMSCs in vitro. Notably, a further mechanism study revealed that MEG3 knockdown could activate Wnt/β-catenin signaling pathway in BMSCs. Wnt/β-catenin inhibition would impair MEG3-induced osteogenic differentiation of BMSCs. By using poly (3-hydroxybutyrate-co-3-hydroxyhexanoate, PHBHHx)-mesoporous bioactive glass (PHMG) scaffold with MEG3 knockdown BMSCs, we found that downregulation of MEG3 in BMSCs could accelerate bone repairing in a critical-sized skull defects rat model. Conclusions: Our study reveals the important role of MEG3 during osteogenic differentiation and bone regeneration. Thus, MEG3 engineered BMSCs may be effective potential therapeutic targets for skull defects.
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Affiliation(s)
- Juan Liu
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; (J.L.); (H.-S.M.); (S.-H.Z.); (G.-Y.G.)
| | - Xin Qi
- Department of Orthopaedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China; (X.Q.); (L.-H.W.)
| | - Xiao-Hong Wang
- Department of Operating Room, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China;
| | - Hong-Sheng Miao
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; (J.L.); (H.-S.M.); (S.-H.Z.); (G.-Y.G.)
| | - Zi-Chao Xue
- Department of Orthopaedics, Qingdao Municipal Hospital, Qingdao 266001, China;
| | - Le-Le Zhang
- Department of Nursing, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China;
| | - San-Hu Zhao
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; (J.L.); (H.-S.M.); (S.-H.Z.); (G.-Y.G.)
| | - Liang-Hao Wu
- Department of Orthopaedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China; (X.Q.); (L.-H.W.)
| | - Guo-Yi Gao
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; (J.L.); (H.-S.M.); (S.-H.Z.); (G.-Y.G.)
| | - Mei-Qing Lou
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; (J.L.); (H.-S.M.); (S.-H.Z.); (G.-Y.G.)
- Correspondence: (M.-Q.L.); (C.-Q.Y.)
| | - Cheng-Qing Yi
- Department of Orthopaedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China; (X.Q.); (L.-H.W.)
- Correspondence: (M.-Q.L.); (C.-Q.Y.)
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Rahimi HR, Mojarrad M, Moghbeli M. MicroRNA-96: A therapeutic and diagnostic tumor marker. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:3-13. [PMID: 35656454 DOI: 10.22038/ijbms.2021.59604.13226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/19/2021] [Indexed: 12/17/2022]
Abstract
Cancer has been always considered as one of the main human health challenges worldwide. One of the main causes of cancer-related mortality is late diagnosis in the advanced stages of the disease, which reduces the therapeutic efficiency. Therefore, novel non-invasive diagnostic methods are required for the early detection of tumors and improving the quality of life and survival in cancer patients. MicroRNAs (miRNAs) have pivotal roles in various cellular processes such as cell proliferation, motility, and neoplastic transformation. Since circulating miRNAs have high stability in body fluids, they can be suggested as efficient noninvasive tumor markers. MiR-96 belongs to the miR-183-96-182 cluster that regulates cell migration and tumor progression as an oncogene or tumor suppressor by targeting various genes in solid tumors. In the present review, we have summarized all of the studies that assessed the role of miR-96 during tumor progression. This review clarifies the molecular mechanisms and target genes recruited by miR-96 to regulate tumor progression and metastasis. It was observed that miR-96 mainly affects tumorigenesis by targeting the structural proteins and FOXO transcription factors.
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Affiliation(s)
- Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarrad
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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20
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Prasasya R, Grotheer KV, Siracusa LD, Bartolomei MS. Temple syndrome and Kagami-Ogata syndrome: clinical presentations, genotypes, models and mechanisms. Hum Mol Genet 2021; 29:R107-R116. [PMID: 32592473 DOI: 10.1093/hmg/ddaa133] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 06/22/2020] [Accepted: 06/24/2020] [Indexed: 12/13/2022] Open
Abstract
Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human chromosome 14q32. TS most frequently arises from maternal UPD14 or epimutations/deletions on the paternal chromosome, whereas KOS most frequently arises from paternal UPD14 or epimutations/deletions on the maternal chromosome. In this review, we describe the clinical symptoms and genetic/epigenetic features of this imprinted region. The locus encompasses paternally expressed protein-coding genes (DLK1, RTL1 and DIO3) and maternally expressed lncRNAs (MEG3/GTL2, RTL1as and MEG8), as well as numerous miRNAs and snoRNAs. Control of expression is complex, with three differentially methylated regions regulating germline, placental and tissue-specific transcription. The strong conserved synteny between mouse chromosome 12aF1 and human chromosome 14q32 has enabled the use of mouse models to elucidate imprinting mechanisms and decipher the contribution of genes to the symptoms of TS and KOS. In this review, we describe relevant mouse models and highlight their value to better inform treatment options for long-term management of TS and KOS patients.
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Affiliation(s)
- Rexxi Prasasya
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kristen V Grotheer
- Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, 340 Kingsland Street, Building 123, Nutley, NJ 07110, USA
| | - Linda D Siracusa
- Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, 340 Kingsland Street, Building 123, Nutley, NJ 07110, USA
| | - Marisa S Bartolomei
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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21
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Subramaniam N, Nair R, Marsden PA. Epigenetic Regulation of the Vascular Endothelium by Angiogenic LncRNAs. Front Genet 2021; 12:668313. [PMID: 34512715 PMCID: PMC8427604 DOI: 10.3389/fgene.2021.668313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/17/2021] [Indexed: 12/15/2022] Open
Abstract
The functional properties of the vascular endothelium are diverse and heterogeneous between vascular beds. This is especially evident when new blood vessels develop from a pre-existing closed cardiovascular system, a process termed angiogenesis. Endothelial cells are key drivers of angiogenesis as they undergo a highly choreographed cascade of events that has both exogenous (e.g., hypoxia and VEGF) and endogenous regulatory inputs. Not surprisingly, angiogenesis is critical in health and disease. Diverse therapeutics target proteins involved in coordinating angiogenesis with varying degrees of efficacy. It is of great interest that recent work on non-coding RNAs, especially long non-coding RNAs (lncRNAs), indicates that they are also important regulators of the gene expression paradigms that underpin this cellular cascade. The protean effects of lncRNAs are dependent, in part, on their subcellular localization. For instance, lncRNAs enriched in the nucleus can act as epigenetic modifiers of gene expression in the vascular endothelium. Of great interest to genetic disease, they are undergoing rapid evolution and show extensive inter- and intra-species heterogeneity. In this review, we describe endothelial-enriched lncRNAs that have robust effects in angiogenesis.
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Affiliation(s)
- Noeline Subramaniam
- Marsden Lab, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Marsden Lab, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
| | - Ranju Nair
- Marsden Lab, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
- Marsden Lab, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Philip A. Marsden
- Marsden Lab, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Marsden Lab, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
- Marsden Lab, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
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22
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Zhang W, Conway SJ, Liu Y, Snider P, Chen H, Gao H, Liu Y, Isidan K, Lopez KJ, Campana G, Li P, Ekser B, Francis H, Shou W, Kubal C. Heterogeneity of Hepatic Stellate Cells in Fibrogenesis of the Liver: Insights from Single-Cell Transcriptomic Analysis in Liver Injury. Cells 2021; 10:cells10082129. [PMID: 34440898 PMCID: PMC8391930 DOI: 10.3390/cells10082129] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/06/2021] [Accepted: 08/16/2021] [Indexed: 12/11/2022] Open
Abstract
Background & Aims: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolution (scRNA-seq) on HSCs in mice treated with carbon tetrachloride (CCl4). By employing LRAT-Cre:Rosa26mT/mG mice, we were able to isolate an activated GFP-positive HSC lineage derived cell population by fluorescence-activated cell sorter (FACS). A total of 8 HSC subpopulations were identified based on an unsupervised analysis. Each HSC cluster displayed a unique transcriptomic profile, despite all clusters expressing common mouse HSC marker genes. We demonstrated that one of the HSC subpopulations expressed high levels of mitosis regulatory genes, velocity, and monocle analysis indicated that these HSCs are at transitioning and proliferating phases at the beginning of HSCs activation and will eventually give rise to several other HSC subtypes. We also demonstrated cell clusters representing HSC-derived mature myofibroblast populations that express myofibroblasts hallmark genes with unique contractile properties. Most importantly, we found a novel HSC cluster that is likely to be critical in liver regeneration, immune reaction, and vascular remodeling, in which the unique profiles of genes such as Rgs5, Angptl6, and Meg3 are highly expressed. Lastly, we demonstrated that the heterogeneity of HSCs in the injured mouse livers is closely similar to that of cirrhotic human livers. Conclusions: Collectively, our scRNA-seq data provided insight into the landscape of activated HSC populations and the dynamic transitional pathway from HSC to myofibroblasts in response to liver injury.
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Affiliation(s)
- Wenjun Zhang
- Division of Transplant Surgery, Indiana University, Indianapolis, IN 46202, USA
| | - Simon J Conway
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ying Liu
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Paige Snider
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hanying Chen
- Genome Editing Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hongyu Gao
- The Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yunlong Liu
- The Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Kadir Isidan
- Division of Transplant Surgery, Indiana University, Indianapolis, IN 46202, USA
| | - Kevin J Lopez
- Division of Transplant Surgery, Indiana University, Indianapolis, IN 46202, USA
| | - Gonzalo Campana
- Division of Transplant Surgery, Indiana University, Indianapolis, IN 46202, USA
| | - Ping Li
- Division of Transplant Surgery, Indiana University, Indianapolis, IN 46202, USA
| | - Burcin Ekser
- Division of Transplant Surgery, Indiana University, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Weinian Shou
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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23
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Zhu R, Xiao T, Wang Q, Zhao Y, Liu X. Genetic polymorphisms in lncRNAs predict recurrence of ischemic stroke. Metab Brain Dis 2021; 36:1353-1359. [PMID: 33818708 DOI: 10.1007/s11011-021-00725-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/28/2021] [Indexed: 11/28/2022]
Abstract
Genetic polymorphisms in long non-coding RNAs (lncRNAs) are considered as potential genetic biomarkers for the prediction of human complex diseases such as ischemic stroke (IS). However, so far, no reports have focused on the relationship of lncRNA polymorphisms with IS onset and prognosis. In our study, eight potential functional polymorphisms of four well-known lncRNAs (H19 rs2107425 and rs2251375, MALAT1 rs4102217 and rs3200401, MEG3 rs11160608 and rs4081134, SENCR rs4526784 and rs555172) were genotyped in 657 ischemic stroke patients. Then, the association between lncRNA polymorphisms and IS onset and recurrence were investigated. These lncRNA variants were not associated with age onset of IS. However, we observed that MEG3 rs4081134 AA genotype was statistically related with a reduced risk of stroke recurrence, particularly for patients with large-artery atherosclerotic stroke. Also, the decreased risk was more prominent in elders, non-smokers, non-drinkers and hypertensive patients. Furthermore, the variant genotype AA of rs4081134 was an independent predictor for IS recurrence using the multivariate Cox regression model. Our findings indicated that MEG3 rs4081134 can serve as a useful biomarker and potential therapeutic target in IS recurrence. More researches are needed to verify our results and explore the underlying molecular mechanisms.
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Affiliation(s)
- Ruixia Zhu
- Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Tongling Xiao
- Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Qianwen Wang
- Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Yating Zhao
- Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xu Liu
- Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, Liaoning, China.
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24
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Maleki M, Khelghati N, Alemi F, Younesi S, Asemi Z, Abolhasan R, Bazdar M, Samadi-Kafil H, Yousefi B. Multiple interactions between melatonin and non-coding RNAs in cancer biology. Chem Biol Drug Des 2021; 98:323-340. [PMID: 33905613 DOI: 10.1111/cbdd.13849] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/10/2021] [Indexed: 12/14/2022]
Abstract
The melatonin hormone secreted by the pineal gland is involved in physiological functions such as growth and maturation, circadian cycles, and biological activities including antioxidants, anti-tumor, and anti-ischemia. Melatonin not only interacts with proteins but also has functional effects on regulatory RNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). In this study, we overview various physiological and pathological conditions affecting melatonin through lncRNA and miRNA. The information compiled herein will serve as a solid foundation to formulate ideas for future mechanistic studies on melatonin. It will also provide a chance to more clarify the emerging functions of the non-coding transcriptome.
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Affiliation(s)
- Masomeh Maleki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Nafiseh Khelghati
- Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Simin Younesi
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic., Australia
| | - Zatollah Asemi
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic., Australia.,Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Rozita Abolhasan
- Stem Cell and Regenerative Medicine Institute (SCARM), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahtab Bazdar
- Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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25
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Chatterjee M, Viswanathan P. Long noncoding RNAs in the regulation of p53-mediated apoptosis in human cancers. Cell Biol Int 2021; 45:1364-1382. [PMID: 33760332 DOI: 10.1002/cbin.11597] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/02/2021] [Accepted: 03/21/2021] [Indexed: 02/05/2023]
Abstract
Long noncoding RNAs (lncRNAs) are widely known for their regulatory function in transcriptional and posttranscriptional processes. The involvement of such non-protein-coding RNAs in nuclear organization and chromatin remodeling is often associated with an increased risk of human malignancies. In cancer, lncRNAs either promote cell survival or may act as a growth suppressor, thus conferring a key regulatory function other than their established role in fundamental cellular processes. Interestingly, lncRNAs interfere with the stages of apoptosis and related pathways involving p53. Many of these molecules either regulate or are regulated by p53 while mounting oncogenic events. Consequently, they may confer both prosurvival or proapoptotic functions depending upon the tissue type. Since the mechanism of cell death is bypassed in many human cancers, it has emerged that the lncRNAs are either overexpressed or knocked down to sensitize cells to apoptotic stimuli. Nonetheless, the abundant expression of lncRNAs in tumor cells renders them suitable targets for anticancer therapies. Although the role of lncRNAs in the p53 network and apoptosis has been independently defined, their interplay in activating p53-target genes during cell cycle arrest remains unexplored. Thus, we have specifically reviewed the possible involvement of lncRNAs in the p53-mediated apoptosis of human cancer cells. In particular, we summarize the growing evidence from individual studies and analyze whether lncRNAs are essential to facilitate apoptosis in a p53-dependent manner. This may lead to the identification of p53-associated lncRNAs that are suitable therapeutic targets or diagnostic/prognostic markers.
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Affiliation(s)
- Manjima Chatterjee
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Pragasam Viswanathan
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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26
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Zhang M, Hamblin MH, Yin KJ. Long non-coding RNAs mediate cerebral vascular pathologies after CNS injuries. Neurochem Int 2021; 148:105102. [PMID: 34153353 DOI: 10.1016/j.neuint.2021.105102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/12/2021] [Accepted: 06/13/2021] [Indexed: 10/21/2022]
Abstract
Central nervous system (CNS) injuries are one of the leading causes of morbidity and mortality worldwide, accompanied with high medical costs and a decreased quality of life. Brain vascular disorders are involved in the pathological processes of CNS injuries and might play key roles for their recovery and prognosis. Recently, increasing evidence has shown that long non-coding RNAs (lncRNAs), which comprise a very heterogeneous group of non-protein-coding RNAs greater than 200 nucleotides, have emerged as functional mediators in the regulation of vascular homeostasis under pathophysiological conditions. Remarkably, lncRNAs can regulate gene transcription and translation, thus interfering with gene expression and signaling pathways by different mechanisms. Hence, a deeper insight into the function and regulatory mechanisms of lncRNAs following CNS injury, especially cerebrovascular-related lncRNAs, could help in establishing potential therapeutic strategies to improve or inhibit neurological disorders. In this review, we highlight recent advancements in understanding of the role of lncRNAs and their application in mediating cerebrovascular pathologies after CNS injury.
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Affiliation(s)
- Mengqi Zhang
- Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue SL-83, New Orleans, LA, 70112, USA
| | - Ke-Jie Yin
- Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, 15261, USA.
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27
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Xu X, Zhong Z, Shao Y, Yi Y. Prognostic Value of MEG3 and Its Correlation With Immune Infiltrates in Gliomas. Front Genet 2021; 12:679097. [PMID: 34220951 PMCID: PMC8242350 DOI: 10.3389/fgene.2021.679097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence has revealed that dysregulated lncRNA expression contributes to the onset and progression of cancer. However, the mechanistic role of lncRNA in glioma progression and tumor immunology remains largely unknown. This study aimed to evaluate the significance of maternally expressed gene 3 (MEG3) in the prognosis of and its immune-related roles in gliomas. The expression levels of MEG3 were analyzed using Oncomine and TIMER database. As an important imprinted gene, the copy number variation (CNV) of MEG3 in both glioblastoma multiforme (GBM) and low-grade glioma (LGG) were analyzed using GSCALite database, whereas its prognostic significance was assessed using PrognoScan and GEPIA databases. The relationship between MEG3 and tumor-infiltrated immune cells was analyzed using TIMER. Results showed that MEG3 expression was lower in most of the human cancer tissues than in the normal tissues. We also found that heterozygous deletion of MEG3 occurred more frequent than heterozygous amplification in gliomas, and mRNA expression of MEG3 was significantly positively correlated with its CNV in both the GBM and LGG group. Survival analysis showed that the CNV level of MEG3 had significant correlation with overall survival (OS) and progression-free survival (PFS) compared with wild type in LGG. Lower MEG3 expression was related with poor prognosis. Further analysis showed that in GBM, MEG3 expression level was significantly positively correlated with that of infiltrating CD8+ T cells and significantly negatively correlated with that of infiltrating dendritic cells. In LGG, MEG3 expression level was significantly negatively correlated with levels of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Univariate Cox survival analysis demonstrated that only the level of infiltrating dendritic cells significantly affected the survival time of patients with GBM, while all six types of immune cells had a significant effect on the survival time of patients with LGG. Furthermore, MEG3 expression showed strong correlations with multiple immune markers in gliomas, especially in LGG. The current findings suggest that MEG3 expression might serve as a possible prognostic marker and potential immunotherapeutic target for gliomas.
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Affiliation(s)
- Xiaoping Xu
- Department of Neurosurgery, The Second People's Hospital of Yibin, Yibin, China
| | - Zhenglan Zhong
- Department of Health Examination, The Second People's Hospital of Yibin, Yibin, China
| | - Yongxiang Shao
- Department of Neurosurgery, The Second People's Hospital of Yibin, Yibin, China
| | - Yong Yi
- Department of Neurosurgery, The Second People's Hospital of Yibin, Yibin, China
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28
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Timmerman DM, Remmers TL, Hillenius S, Looijenga LHJ. Mechanisms of TP53 Pathway Inactivation in Embryonic and Somatic Cells-Relevance for Understanding (Germ Cell) Tumorigenesis. Int J Mol Sci 2021; 22:ijms22105377. [PMID: 34065345 PMCID: PMC8161298 DOI: 10.3390/ijms22105377] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 01/10/2023] Open
Abstract
The P53 pathway is the most important cellular pathway to maintain genomic and cellular integrity, both in embryonic and non-embryonic cells. Stress signals induce its activation, initiating autophagy or cell cycle arrest to enable DNA repair. The persistence of these signals causes either senescence or apoptosis. Over 50% of all solid tumors harbor mutations in TP53 that inactivate the pathway. The remaining cancers are suggested to harbor mutations in genes that regulate the P53 pathway such as its inhibitors Mouse Double Minute 2 and 4 (MDM2 and MDM4, respectively). Many reviews have already been dedicated to P53, MDM2, and MDM4, while this review additionally focuses on the other factors that can deregulate P53 signaling. We discuss that P14ARF (ARF) functions as a negative regulator of MDM2, explaining the frequent loss of ARF detected in cancers. The long non-coding RNA Antisense Non-coding RNA in the INK4 Locus (ANRIL) is encoded on the same locus as ARF, inhibiting ARF expression, thus contributing to the process of tumorigenesis. Mutations in tripartite motif (TRIM) proteins deregulate P53 signaling through their ubiquitin ligase activity. Several microRNAs (miRNAs) inactivate the P53 pathway through inhibition of translation. CCCTC-binding factor (CTCF) maintains an open chromatin structure at the TP53 locus, explaining its inactivation of CTCF during tumorigenesis. P21, a downstream effector of P53, has been found to be deregulated in different tumor types. This review provides a comprehensive overview of these factors that are known to deregulate the P53 pathway in both somatic and embryonic cells, as well as their malignant counterparts (i.e., somatic and germ cell tumors). It provides insights into which aspects still need to be unraveled to grasp their contribution to tumorigenesis, putatively leading to novel targets for effective cancer therapies.
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29
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Chatterjee M, Viswanathan P. Long noncoding RNAs in the regulation of p53‐mediated apoptosis in human cancers. Cell Biol Int 2021. [DOI: https://doi.org/10.1002/cbin.11597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Manjima Chatterjee
- School of Bio Sciences and Technology, Vellore Institute of Technology Vellore Tamil Nadu India
| | - Pragasam Viswanathan
- School of Bio Sciences and Technology, Vellore Institute of Technology Vellore Tamil Nadu India
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30
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Ghafouri-Fard S, Glassy MC, Abak A, Hussen BM, Niazi V, Taheri M. The interaction between miRNAs/lncRNAs and Notch pathway in human disorders. Biomed Pharmacother 2021; 138:111496. [PMID: 33743335 DOI: 10.1016/j.biopha.2021.111496] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
Notch pathway is a signaling cascade with important impacts on cell proliferation, differentiation, developmental processes and tissue homeostasis. This pathway also regulates stem cell properties, thus being involved in both normal developmental processes and metastatic capacity of cancer cells. Lots of lncRNAs and miRNAs have been recognized that control Notch pathway at some levels or their expression is regulated by this pathway. FOXD2-AS1, MEG3, ANRIL, linc-OIP5, lincRNA-p21, CBR3-AS1, HOTAIR, PVT1 and GAS5 are among lncRNAs that interact with Notch signaling. miR-19, miR-21, miR-33a, miR-8/200, miR-34a, miR-146a, miR-37, miR-100, miR-107 and several other miRNAs have functional interplay with this signaling cascade. In the present review article, we have illuminated the interplay between lncRNAs/miRNAs and Notch pathway in two distinct contexts i.e. cancers and non-neoplastic conditions.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mark C Glassy
- Translational Neuro-Oncology Laboratory, San Diego (UCSD) Moores Cancer Center, University of California, CA, United States
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bashdar Mahmud Hussen
- Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Modelling West Nile Virus and Usutu Virus Pathogenicity in Human Neural Stem Cells. Viruses 2020; 12:v12080882. [PMID: 32806715 PMCID: PMC7471976 DOI: 10.3390/v12080882] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
West Nile virus (WNV) and Usutu virus (USUV) are genetically related neurotropic mosquito-borne flaviviruses, which frequently co-circulate in nature. Despite USUV seeming to be less pathogenic for humans than WNV, the clinical manifestations induced by these two viruses often overlap and may evolve to produce severe neurological complications. The aim of this study was to investigate the effects of WNV and USUV infection on human induced pluripotent stem cell-derived neural stem cells (hNSCs), as a model of the neural progenitor cells in the developing fetal brain and in adult brain. Zika virus (ZIKV), a flavivirus with known tropism for NSCs, was used as the positive control. Infection of hNSCs and viral production, effects on cell viability, apoptosis, and innate antiviral responses were compared among viruses. WNV displayed the highest replication efficiency and cytopathic effects in hNSCs, followed by USUV and then ZIKV. In these cells, both WNV and USUV induced the overexpression of innate antiviral response genes at significantly higher levels than ZIKV. Expression of interferon type I, interleukin-1β and caspase-3 was significantly more elevated in WNV- than USUV-infected hNSCs, in agreement with the higher neuropathogenicity of WNV and the ability to inhibit the interferon response pathway.
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32
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Fan B, Pan W, Wang X, Wei M, He A, Zhao A, Chopp M, Zhang ZG, Liu XS. Long noncoding RNA mediates stroke-induced neurogenesis. Stem Cells 2020; 38:973-985. [PMID: 32346940 PMCID: PMC11062764 DOI: 10.1002/stem.3189] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 03/18/2020] [Accepted: 04/01/2020] [Indexed: 01/11/2023]
Abstract
Neurogenesis contributes to poststroke recovery. Long noncoding RNAs (lncRNAs) participate in the regulation of stem cell self-renewal and differentiation. However, the role of lncRNAs in stroke-induced neurogenesis remains unknown. In this study, we found that H19 was the most highly upregulated lncRNA in neural stem cells (NSCs) of the subventricular zone (SVZ) of rats subjected to focal cerebral ischemia. Deletion of H19 suppressed cell proliferation, promoted cell death, and blocked NSC differentiation. RNA sequencing analysis revealed that genes deregulated by H19 knockdown were those that are involved in transcription, apoptosis, proliferation, cell cycle, and response to hypoxia. H19 knockdown significantly increased the transcription of cell cycle-related genes including p27, whereas overexpression of H19 substantially reduced expression of these genes through the interaction with chromatin remodeling proteins EZH2 and SUZ12. Moreover, H19 regulated neurogenesis-related miRNAs. Inactivation of H19 in NSCs of ischemic rats attenuated spontaneous functional recovery after stroke. Collectively, our data provide novel insights into the epigenetic regulation of lncRNAs in stroke-induced neurogenesis.
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Affiliation(s)
- Baoyan Fan
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Wanlong Pan
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Xinli Wang
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Min Wei
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Annie He
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Anna Zhao
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Michael Chopp
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
- Department of Physics, Oakland University, Rochester, Michigan
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
| | - Xian Shuang Liu
- Department of Neurology, Henry Ford Health System, Detroit, Michigan
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33
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Schacker M, Cheng YH, Eckersley-Maslin M, Snaith RM, Colledge WH. Hypermethylation and reduced expression of Gtl2, Rian and Mirg at the Dlk1-Dio3 imprinted locus as a marker for poor developmental potential of mouse embryonic stem cells. Stem Cell Res 2020; 48:101931. [PMID: 32822966 PMCID: PMC7567021 DOI: 10.1016/j.scr.2020.101931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 07/19/2020] [Accepted: 07/22/2020] [Indexed: 01/10/2023] Open
Abstract
Reduced expression of Gtl2, Rian and Mirg in ES cells compromised survival of chimaeric fetuses. Reduced expression of Gtl2, Rian and Mirg was associated with hypermethylation. Compromised ES cells can be identified and eliminated from experiments to reduce animal use. Mouse embryonic stem cells (ESCs) have played a crucial role in biomedical research where they can be used to elucidate gene function through the generation of genetically modified mice. A critical requirement for the success of this technology is the ability of ESCs to contribute to viable chimaeras with germ-line transmission of the genetically modified allele. We have identified several ESC clones that cause embryonic death of chimaeras at mid to late gestation stages. These clones had a normal karyotype, were pathogen free and their in vitro differentiation potential was not compromised. Chimaeric embryos developed normally up to E13.5 but showed a significant decrease in embryo survival by E17.5 with frequent haemorrhaging. We investigated the relationship between the ESCs transcriptional and epigenomic state and their ability to contribute to viable chimaeras. RNA sequencing identified four genes (Gtl2, Rian, Mirg and Rtl1as) located in the Dlk1-Dio3 imprinted locus that were expressed at lower levels in the compromised ESC clones and this was confirmed by qRT-PCR. Bisulphite sequencing analysis showed significant hypermethylation at the Dlk1-Dio3 imprinted locus with no consistent differences in methylation patterns at other imprinted loci. Treatment of the compromised ESCs with 5-azacytidine reactivated stable expression of Gtl2 and rescued the lethal phenotype but only gave low level chimaeras.
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Affiliation(s)
- Maria Schacker
- Reproductive Physiology Group, Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK
| | - Yi-Han Cheng
- Medimmune, Sir Aaron Klug Building, Granta Park, Cambridge CB21 6GH, UK
| | | | | | - William Henry Colledge
- Reproductive Physiology Group, Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
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34
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Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9879876. [PMID: 32714991 PMCID: PMC7354644 DOI: 10.1155/2020/9879876] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/07/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023]
Abstract
Bisphosphonates (BPs) are inhibitors of osteoclast-mediated bone resorption used for the treatment of multiple myeloma (MM) patients with osteolytic lesions. Bisphosphonate-induced osteonecrosis of the jaw (BONJ) is an infrequent drug-caused adverse event of these agents. Long noncoding RNAs (lncRNAs) are a set of more than 200 base pairs, noncoding RNA molecules, which are critical posttranscriptional regulators of gene expression. Our study was aimed at evaluating 17 lncRNAs, whose targets were previously validated as key elements in MM, bone metabolism, and angiogenesis in MM subjects without BONJ (MM group), in MM subjects with BONJ (BONJ group), and a group of healthy controls (CTRL group). Our results demonstrated a different lncRNA profile in BONJ patients compared to MM patients and controls. Two lncRNAs (DANCR and MALAT1) were both downregulated compared to controls and MM, twelve (HOTAIR, MEG3, TP73-AS1, HOTTIP, HIF1A-AS2, MANTIS, CTD-2201E18, CTD1-2003C8, R-471B22, RP1-43E13, RP11-553L6.5, and RP1-286D6) were overexpressed in MM with BONJ, and one (H19) was upregulated compared with only MM. Two lncRNAs (JHDMD1 and MTMR9LP) had higher expression, but these differences were not statistically significant. The examined lncRNAs target several genes and metabolic pathways. An altered lncRNA signature could contribute to the onset of BONJ or have a protective action. Targeting these lncRNAs could offer a possibility for the prevention or therapy of BONJ.
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35
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Håkansson KEJ, Goossens EAC, Trompet S, van Ingen E, de Vries MR, van der Kwast RVCT, Ripa RS, Kastrup J, Hohensinner PJ, Kaun C, Wojta J, Böhringer S, Le Cessie S, Jukema JW, Quax PHA, Nossent AY. Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease. Cardiovasc Res 2020; 115:1519-1532. [PMID: 30544252 DOI: 10.1093/cvr/cvy309] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/30/2018] [Accepted: 12/11/2018] [Indexed: 01/12/2023] Open
Abstract
AIMS We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease. METHODS AND RESULTS We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice. CONCLUSION 14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.
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Affiliation(s)
- Kjell E J Håkansson
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Eveline A C Goossens
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Stella Trompet
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Eva van Ingen
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Margreet R de Vries
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Reginald V C T van der Kwast
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Rasmus S Ripa
- Department of Cardiology, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
| | - Jens Kastrup
- Department of Cardiology, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
| | | | - Christoph Kaun
- Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Johann Wojta
- Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Stefan Böhringer
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Saskia Le Cessie
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Paul H A Quax
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - A Yaël Nossent
- Department of Surgery, K6-R, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
- Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria
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Abstract
The advent of deep sequencing technologies led to the identification of a considerable amount of noncoding RNA transcripts, which are increasingly recognized for their functions in controlling cardiovascular diseases. MicroRNAs have already been studied for a decade, leading to the identification of several vasculoprotective and detrimental species, which might be considered for therapeutic targeting. Other noncoding RNAs such as circular RNAs, YRNAs, or long noncoding RNAs are currently gaining increasing attention, and first studies provide insights into their functions as mediators or antagonists of vascular diseases in vivo. The present review article will provide an overview of the different types of noncoding RNAs controlling the vasculature and focus on the developing field of long noncoding RNAs.
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Affiliation(s)
- Nicolas Jaé
- From the Institute for Cardiovascular Regeneration (N.J., S.D.), Goethe University Frankfurt, Germany
| | - Stefanie Dimmeler
- From the Institute for Cardiovascular Regeneration (N.J., S.D.), Goethe University Frankfurt, Germany.,Cardiopulmonary Institute (S.D.), Goethe University Frankfurt, Germany.,German Center for Cardiovascular Research (DZHK) and Cardiopulmonary Institute (CPI), Partner Site Rhine-Main, Frankfurt (S.D.)
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37
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Abstract
Long non-coding RNAs (lncRNAs) represent a major fraction of the transcriptome in multicellular organisms. Although a handful of well-studied lncRNAs are broadly recognized as biologically meaningful, the fraction of such transcripts out of the entire collection of lncRNAs remains a subject of vigorous debate. Here we review the evidence for and against biological functionalities of lncRNAs and attempt to arrive at potential modes of lncRNA functionality that would reconcile the contradictory conclusions. Finally, we discuss different strategies of phenotypic analyses that could be used to investigate such modes of lncRNA functionality.
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Affiliation(s)
- Fan Gao
- Institute of Genomics, School of Biomedical Sciences, Huaqiao University, 201 Pan-Chinese S & T Building, 668 Jimei Road, Xiamen, 361021, China
| | - Ye Cai
- Institute of Genomics, School of Biomedical Sciences, Huaqiao University, 201 Pan-Chinese S & T Building, 668 Jimei Road, Xiamen, 361021, China
| | - Philipp Kapranov
- Institute of Genomics, School of Biomedical Sciences, Huaqiao University, 201 Pan-Chinese S & T Building, 668 Jimei Road, Xiamen, 361021, China.
| | - Dongyang Xu
- Institute of Genomics, School of Biomedical Sciences, Huaqiao University, 201 Pan-Chinese S & T Building, 668 Jimei Road, Xiamen, 361021, China.
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Yeh CF, Chang YCE, Lu CY, Hsuan CF, Chang WT, Yang KC. Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases. J Biomed Sci 2020; 27:48. [PMID: 32241300 PMCID: PMC7114803 DOI: 10.1186/s12929-020-00647-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/27/2020] [Indexed: 12/31/2022] Open
Abstract
With the advances in deep sequencing-based transcriptome profiling technology, it is now known that human genome is transcribed more pervasively than previously thought. Up to 90% of the human DNA is transcribed, and a large proportion of the human genome is transcribed as long noncoding RNAs (lncRNAs), a heterogenous group of non-coding transcripts longer than 200 nucleotides. Emerging evidence suggests that lncRNAs are functional and contribute to the complex regulatory networks involved in cardiovascular development and diseases. In this article, we will review recent evidence on the roles of lncRNAs in the biological processes of cardiovascular development and disorders. The potential applications of lncRNAs as biomarkers and targets for therapeutics are also discussed.
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Affiliation(s)
- Chih-Fan Yeh
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan.,Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan
| | - Yu-Chen Eugene Chang
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan
| | - Cheng-Yuan Lu
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan
| | - Chin-Feng Hsuan
- Division of Cardiology, Department of Internal Medicine, E-Da Dachang Hospital, Kaohsiung, Taiwan.,Department of Medicine, I-Shou University School of Medicine, Kaohsiung, Taiwan
| | - Wei-Tien Chang
- Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan. .,Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan.
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39
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Interaction of Long Noncoding RNAs and Notch Signaling: Implications for Tissue Homeostasis Loss. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1227:107-129. [PMID: 32072502 DOI: 10.1007/978-3-030-36422-9_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The Notch signaling is a crucial pathway involved in cellular development, progression, and differentiation. Deregulation of Notch signaling pathway commonly impacts tissue homeostasis, being highly associated with proliferative disorders. The long noncoding RNAs (lncRNAs), which are transcripts with more than 200 nucleotides that do not code for proteins, were already described as Notch signaling pathway-interacting molecules. Many of them act as important transcriptional and posttranscriptional regulators, affecting gene expression and targeting other regulatory molecules, such as miRNAs. Due to their strong impact on function and gene expression of Notch-related molecules, lncRNAs influence susceptibility to cancer and other diseases, and can be regarded as potential biomarkers and therapeutic targets. Along this chapter, we summarize the cross talk between the Notch signaling pathway and their most important modulating lncRNAs, as well as the pathological consequences of these interactions, in different tissues.
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40
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Ji L, Ma L. MEG3 is restored by schisandrin A and represses tumor growth in choriocarcinoma cells. J Biochem Mol Toxicol 2020; 34:e22455. [PMID: 32057180 DOI: 10.1002/jbt.22455] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/17/2019] [Accepted: 01/21/2020] [Indexed: 01/01/2023]
Abstract
Schisandrin A (SchA) has been reported as a multidrug resistance-reversing agent; however, its antitumor effects have been rarely reported. Consequently, we attempted to explore whether SchA per se possesses an antitumor property in choriocarcinoma JEG-3 and BeWo cells and its potential mechanisms. JEG-3, BeWo, and HTR-8/SVneo cells were stimulated with SchA at different concentrations (10-100 μM), and cellular viability was evaluated with Cell Counting Kit-8. After stimulation with SchA, proliferation, apoptosis, migration, and invasion were detected by bromodeoxyuridine assay, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) method, and a Transwell system, in JEG-3 cells transfected with short hairpin-RNA for maternally expressed 3. Western blot was performed to quantify protein. MEG3 was examined by a quantitative reverse transcription-polymerase chain reaction. MEG3 was downregulated in choriocarcinoma tissues. SchA diminished cellular viability, decreased proliferative activity, inhibited migratory and invasive behaviors, and repressed phosphorylation of regulators of phosphatidylinositol 3 kinase/protein kinase B/nuclear factor κB (PI3K/AKT/NF-κB) signaling cascade in gestational choriocarcinoma cells. MEG3 was upregulated by SchA in JEG-3 and BeWo cells. SchA exhibited little suppressive effects in JEG-3 cells lacking MEG3. Besides, the phosphorylation of transducers was evoked in MEG3-silenced JEG-3 cells despite stimulation with SchA. SchA administration repressed the growth of JEG-3 and BeWo cells by upregulating MEG3. Besides, SchA blocked PI3K/AKT/NF-κB signal cascade by elevating MEG3.
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Affiliation(s)
- Li Ji
- Department of Obstetrics, Jining No. 1 People's Hospital, Jining, Shandong, China
| | - Li Ma
- Department of Obstetrics, Jining No. 1 People's Hospital, Jining, Shandong, China
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41
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Matveishina E, Antonov I, Medvedeva YA. Practical Guidance in Genome-Wide RNA:DNA Triple Helix Prediction. Int J Mol Sci 2020; 21:E830. [PMID: 32012884 PMCID: PMC7037363 DOI: 10.3390/ijms21030830] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/21/2020] [Accepted: 01/25/2020] [Indexed: 12/15/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) play a key role in many cellular processes including chromatin regulation. To modify chromatin, lncRNAs often interact with DNA in a sequence-specific manner forming RNA:DNA triple helices. Computational tools for triple helix search do not always provide genome-wide predictions of sufficient quality. Here, we used four human lncRNAs (MEG3, DACOR1, TERC and HOTAIR) and their experimentally determined binding regions for evaluating triplex parameters that provide the highest prediction accuracy. Additionally, we combined triplex prediction with the lncRNA secondary structure and demonstrated that considering only single-stranded fragments of lncRNA can further improve DNA-RNA triplexes prediction.
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Affiliation(s)
- Elena Matveishina
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
- Institute of Bioengineering, Research Center of Biotechnology, Russian Academy of Science, 117312 Moscow, Russia
| | - Ivan Antonov
- Institute of Bioengineering, Research Center of Biotechnology, Russian Academy of Science, 117312 Moscow, Russia
- Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | - Yulia A Medvedeva
- Institute of Bioengineering, Research Center of Biotechnology, Russian Academy of Science, 117312 Moscow, Russia
- Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
- Department of Computational Biology, Vavilov Institute of General Genetics, Russian Academy of Science, 117971 Moscow, Russia
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42
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Pérez-Cremades D, Cheng HS, Feinberg MW. Noncoding RNAs in Critical Limb Ischemia. Arterioscler Thromb Vasc Biol 2020; 40:523-533. [PMID: 31893949 DOI: 10.1161/atvbaha.119.312860] [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] [Indexed: 12/28/2022]
Abstract
Peripheral artery disease, caused by chronic arterial occlusion of the lower extremities, affects over 200 million people worldwide. Peripheral artery disease can progress into critical limb ischemia (CLI), its more severe manifestation, which is associated with higher risk of limb amputation and cardiovascular death. Aiming to improve tissue perfusion, therapeutic angiogenesis held promise to improve ischemic limbs using delivery of growth factors but has not successfully translated into benefits for patients. Moreover, accumulating studies suggest that impaired downstream signaling of these growth factors (or angiogenic resistance) may significantly contribute to CLI, particularly under harsh environments, such as diabetes mellitus. Noncoding RNAs are essential regulators of gene expression that control a range of pathophysiologies relevant to CLI, including angiogenesis/arteriogenesis, hypoxia, inflammation, stem/progenitor cells, and diabetes mellitus. In this review, we summarize the role of noncoding RNAs, including microRNAs and long noncoding RNAs, as functional mediators or biomarkers in the pathophysiology of CLI. A better understanding of these ncRNAs in CLI may provide opportunities for new targets in the prevention, diagnosis, and therapeutic management of this disabling disease state.
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Affiliation(s)
- Daniel Pérez-Cremades
- From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.P.-C., H.S.C., M.W.F.).,Department of Physiology, University of Valencia and INCLIVA Biomedical Research Institute, Spain (D.P.-C.)
| | - Henry S Cheng
- From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.P.-C., H.S.C., M.W.F.)
| | - Mark W Feinberg
- From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.P.-C., H.S.C., M.W.F.)
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43
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Malissovas N, Ninou E, Michail A, Politis PK. Targeting Long Non-Coding RNAs in Nervous System Cancers: New Insights in Prognosis, Diagnosis and Therapy. Curr Med Chem 2019; 26:5649-5663. [PMID: 30182849 DOI: 10.2174/0929867325666180831170227] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/13/2018] [Accepted: 07/02/2018] [Indexed: 01/17/2023]
Abstract
Long non-coding RNAs (lncRNAs) constitute one of the most broad and diverse classes of cellular transcripts, playing key roles as regulatory molecules in many biological processes. Although the biology of lncRNAs is a new and emerging field of research, several studies have already shown that alterations in the expression of lncRNAs are associated with the development and progression of cancer in different organs and tissues, including central and peripheral nervous system. In this review, we summarize the oncogenic and tumor suppressive roles of lncRNAs in malignant tumors of the nervous system, such as glioma and neuroblastoma, focusing on their functional interactions with DNA, other RNA and protein molecules. We further discuss the potential use of lncRNAs as biomarkers for diagnosis, prognosis and tumor treatment. Gaining insight into the functional association between nervous system malignancies and lncRNAs could offer new perspectives to the development of promising therapeutic tools against cancer.
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Affiliation(s)
- Nikos Malissovas
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Elpinickie Ninou
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Artemis Michail
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Panagiotis K Politis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
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44
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Synovial Fluid MicroRNA-210 as a Potential Biomarker for Early Prediction of Osteoarthritis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7165406. [PMID: 31467907 PMCID: PMC6699254 DOI: 10.1155/2019/7165406] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 07/17/2019] [Indexed: 01/28/2023]
Abstract
Early detection and treatment are critical in the management of osteoarthritis (OA). OA is closely associated with angiogenesis and the inhibition of angiogenesis presents a novel therapeutic approach to reduce inflammation and pain in OA. Recent reports suggest that circulating microRNAs (miRNAs) have great potential as biomarkers for the diagnosis and prognosis in OA. In this study, we aimed to explore the clinical significance of miR-210 in synovial fluid samples from 10 healthy volunteers and 20 early-stage OA and 20 late-stage OA patients. miR-210 expression was assessed by real-time RT-PCR. VEGF protein levels were examined by ELISA. The results show that miR-210 is significantly upregulated in early-stage OA and late-stage OA patients compared with healthy individuals. Higher levels of VEGF are also found in OA compared with the control. Moreover, miR-210 levels are positively correlated with VEGF levels, suggesting that miR-210 might contribute to OA development through promoting VEGF expression and angiogenesis. In conclusion, upregulation of miR-210 in synovial fluid may occur in the early stage of OA and can be a useful biomarker for early diagnosis of OA.
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Maternally expressed gene 3 in metabolic programming. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2019; 1863:194396. [PMID: 31271897 DOI: 10.1016/j.bbagrm.2019.06.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 06/20/2019] [Indexed: 01/10/2023]
Abstract
Maternally Expressed Gene 3 (MEG3) is a long noncoding RNA (lncRNA) that coordinates a diverse array of cellular processes requiring epigenetic regulation of genes and interactions with key signaling proteins and by acting as a competitive endogenous (ce)RNA. Epigenetic modifications driven by in utero nutrition affect MEG3 expression and its role in the development of multiple metabolic disorders. This review examines how epigenetic modification of MEG3 expression can confer adaptedness to different metabolic environments. To this end, we discuss how nutritional status that leads to an increase of MEG3 expression can protect against cancer and metabolic dysfunctions, while interventions that promote MEG3 downregulation minimize the pleiotropic costs associated with its expression. Lastly, we identify research directions that would further shed light on the role of MEG3 in metabolic regulation and in functional imprinted gene networks. This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen.
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46
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Sherpa C, Rausch JW, Le Grice SF. Structural characterization of maternally expressed gene 3 RNA reveals conserved motifs and potential sites of interaction with polycomb repressive complex 2. Nucleic Acids Res 2019; 46:10432-10447. [PMID: 30102382 PMCID: PMC6212721 DOI: 10.1093/nar/gky722] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as key players in gene regulation. However, our incomplete understanding of the structure of lncRNAs has hindered molecular characterization of their function. Maternally expressed gene 3 (Meg3) lncRNA is a tumor suppressor that is downregulated in various types of cancer. Mechanistic studies have reported a role for Meg3 in epigenetic regulation by interacting with chromatin-modifying complexes such as the polycomb repressive complex 2 (PRC2), guiding them to genomic sites via DNA-RNA triplex formation. Resolving the structure of Meg3 RNA and characterizing its interactions with cellular binding partners will deepen our understanding of tumorigenesis and provide a framework for RNA-based anti-cancer therapies. Herein, we characterize the architectural landscape of Meg3 RNA and its interactions with PRC2 from a functional standpoint.
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Affiliation(s)
- Chringma Sherpa
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD 21702, USA
| | - Jason W Rausch
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD 21702, USA
| | - Stuart Fj Le Grice
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD 21702, USA
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47
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Wang L, Yu M, Zhao S. lncRNA MEG3 modified epithelial-mesenchymal transition of ovarian cancer cells by sponging miR-219a-5p and regulating EGFR. J Cell Biochem 2019; 120:17709-17722. [PMID: 31161607 DOI: 10.1002/jcb.29037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 04/30/2019] [Accepted: 05/03/2019] [Indexed: 12/17/2022]
Abstract
This study was aimed to verify whether there existed any associations between long noncoding RNA MEG3/miR-219a-5p/EGFR axis and the development of ovarian cancer (OC). As a whole, we gathered 317 pairs of OC tissues and surgical marginal normal tissues and simultaneously acquired four OC cell lines (ie, A2780, Caov-3, OVCAR-3, and SKOV-3) and human normal ovarian surface epithelial cell line. Moreover, pcDNA3.1-MEG3, si-MEG3, miR-219a-5p mimic, miR-219a-5p inhibitor, pcDNA3.1-EGFR, and si-EGFR were, respectively, transfected into the OC cells, and their impacts on viability, proliferation, apoptosis, invasion, and migration of OC cells were assessed via conduction of MTT assay, colony formation assay, flow cytometry assay, transwell assay, and scratch assay. Ultimately, dual-luciferase reporter gene assay was performed to testify the targeted relationships among maternally expressed gene 3 (MEG3), miR-219a-5p, and estimated glomerular filtration rate (EGFR). It was indicated that underexpressed MEG3 and miR-219a-5p were significantly associated with unfavorable prognosis of patients with OC when compared with overexpressed MEG3 and miR-219a-5p (P < .05). In addition, the OC cells transfected with si-MEG3 or miR-219a-5p inhibitor exhibited stronger viability, proliferation, invasion, and migration than untreated cells (P < .05). Correspondingly, the apoptotic percentage of OC cells was reduced observably under treatments of si-MEG3 and miR-219a-5p inhibitor (P < .05). Moreover, MEG3 exerted modulatory effects on the expression of miR-219a-5p (P < .05), and there was a sponging relationship between them (P < .05). Finally, EGFR expression was modified by both MEG3 and miR-219a-5p significantly (P < .05), and raising EGFR expression could changeover the impacts of MEG3 and miR-219a-5p on the above-mentioned activity of OC cells (P < .05). Conclusively, MEG3 could serve as a promising biomarker for diagnosis and treatment of OC, considering its involvement with OC etiology via regulation of miR-219a-5p/EGFR axis.
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Affiliation(s)
- Lei Wang
- The Second Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Mingxin Yu
- The Second Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Shanshan Zhao
- The Second Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
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48
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Affiliation(s)
- Shizuka Uchida
- From the Cardiovascular Innovation Institute, University of Louisville, KY.
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Long non-coding RNAs in vascular biology and disease. Vascul Pharmacol 2019; 114:13-22. [DOI: 10.1016/j.vph.2018.03.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 12/17/2022]
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Fuschi P, Maimone B, Gaetano C, Martelli F. Noncoding RNAs in the Vascular System Response to Oxidative Stress. Antioxid Redox Signal 2019; 30:992-1010. [PMID: 28683564 DOI: 10.1089/ars.2017.7229] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Redox homeostasis plays a pivotal role in vascular cell function and its imbalance has a causal role in a variety of vascular diseases. Accordingly, the response of mammalian cells to redox cues requires precise transcriptional and post-transcriptional modulation of gene expression patterns. Recent Advances: Mounting evidence shows that nonprotein-coding RNAs (ncRNAs) are important for the functional regulation of most, if not all, cellular processes and tissues. Not surprisingly, a prominent role of ncRNAs has been identified also in the vascular system response to oxidative stress. CRITICAL ISSUES The highly heterogeneous family of ncRNAs has been divided into several groups. In this article we focus on two classes of regulatory ncRNAs: microRNAs and long ncRNAs (lncRNAs). Although knowledge in many circumstances, and especially for lncRNAs, is still fragmentary, ncRNAs are clinically interesting because of their diagnostic and therapeutic potential. We outline ncRNAs that are regulated by oxidative stress as well as ncRNAs that modulate reactive oxygen species production and scavenging. More importantly, we describe the role of these ncRNAs in vascular physiopathology and specifically in disease conditions wherein oxidative stress plays a crucial role, such as hypoxia and ischemia, ischemia reperfusion, inflammation, diabetes mellitus, and atherosclerosis. FUTURE DIRECTIONS The therapeutic potential of ncRNAs in vascular diseases and in redox homeostasis is discussed.
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Affiliation(s)
- Paola Fuschi
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Biagina Maimone
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Carlo Gaetano
- 2 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany
| | - Fabio Martelli
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
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