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1
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Mehta SL, Arruri V, Vemuganti R. Role of transcription factors, noncoding RNAs, epitranscriptomics, and epigenetics in post-ischemic neuroinflammation. J Neurochem 2024; 168:3430-3448. [PMID: 38279529 PMCID: PMC11272908 DOI: 10.1111/jnc.16055] [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: 08/26/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/28/2024]
Abstract
Post-stroke neuroinflammation is pivotal in brain repair, yet persistent inflammation can aggravate ischemic brain damage and hamper recovery. Following stroke, specific molecules released from brain cells attract and activate central and peripheral immune cells. These immune cells subsequently release diverse inflammatory molecules within the ischemic brain, initiating a sequence of events, including activation of transcription factors in different brain cell types that modulate gene expression and influence outcomes; the interactive action of various noncoding RNAs (ncRNAs) to regulate multiple biological processes including inflammation, epitranscriptomic RNA modification that controls RNA processing, stability, and translation; and epigenetic changes including DNA methylation, hydroxymethylation, and histone modifications crucial in managing the genic response to stroke. Interactions among these events further affect post-stroke inflammation and shape the depth of ischemic brain damage and functional outcomes. We highlighted these aspects of neuroinflammation in this review and postulate that deciphering these mechanisms is pivotal for identifying therapeutic targets to alleviate post-stroke dysfunction and enhance recovery.
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Affiliation(s)
- Suresh L. Mehta
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Vijay Arruri
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
- William S. Middleton Veterans Hospital, Madison, WI, USA
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2
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Lyu T, Qiu X, Wang Y, Zhang L, Dai Y, Wang X, Zhao S, Xiang M, Cui L, Cheng S, Liu Y, Gu H, Jiang Y, Meng X, Wang Y, Zhao X, Wang X, Li Q, Wang M, Jiang Y, Xu Z, Huang X, Li H, Wang Y, Li Z. DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke. MedComm (Beijing) 2024; 5:e652. [PMID: 39006763 PMCID: PMC11246610 DOI: 10.1002/mco2.652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 05/18/2024] [Accepted: 05/30/2024] [Indexed: 07/16/2024] Open
Abstract
Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well-characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A-driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.
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3
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Zhu L, Xin YJ, He M, Bian J, Cheng XL, Li R, Li JJ, Wang J, Liu JY, Yang L. Downregulation of miR-337-3p in hypoxia/reoxygenation neuroblastoma cells increases KCTD11 expression. J Biochem Mol Toxicol 2024; 38:e23685. [PMID: 38495002 DOI: 10.1002/jbt.23685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/18/2023] [Accepted: 03/07/2024] [Indexed: 03/19/2024]
Abstract
Neurodegeneration is linked to the progressive loss of neural function and is associated with several diseases. Hypoxia is a hallmark in many of these diseases, and several therapies have been developed to treat this disease, including gene expression therapies that should be tightly controlled to avoid side effects. Cells experiencing hypoxia undergo a series of physiological responses that are induced by the activation of various transcription factors. Modulation of microRNA (miRNA) expression to alter transcriptional regulation has been demonstrated to be beneficial in treating multiple diseases, and in this study, we therefore explored potential miRNA candidates that could influence hypoxia-induced nerve cell death. Our data suggest that in mouse neuroblasts Neuro-2a cells with hypoxia/reoxygenation (H/R), miR-337-3p is downregulated to increase the expression of Potassium channel tetramerization domain containing 11 (KCTD11) and subsequently promote apoptosis. Here, we demonstrate for the first time that KCTD11 plays a role in the cellular response to hypoxia, and we also provide a possible regulatory mechanism by identifying the axis of miR-337-3p/KCTD11 as a promising candidate modulator of nerve cell survival after H/R exposure.
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Affiliation(s)
- Lin Zhu
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Yi-Juan Xin
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Mu He
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Jun Bian
- Department of General Surgery, Xi'an Jiaotong University Affiliated Children's Hospital, Xi'an, Shaanxi, China
| | - Xiao-Li Cheng
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Rui Li
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Jin-Jie Li
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Juan Wang
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Jia-Yun Liu
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Liu Yang
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
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Alikiaii B, Bagherniya M, Askari G, Rajendram R, Sahebkar A. MicroRNA Profiles in Critically Ill Patients. Curr Med Chem 2024; 31:6801-6825. [PMID: 37496239 DOI: 10.2174/0929867331666230726095222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 07/28/2023]
Abstract
The use of biomarkers to expedite diagnosis, prognostication, and treatment could significantly improve patient outcomes. The early diagnosis and treatment of critical illnesses can greatly reduce mortality and morbidity. Therefore, there is great interest in the discovery of biomarkers for critical illnesses. Micro-ribonucleic acids (miRNAs) are a highly conserved group of non-coding RNA molecules. They regulate the expression of genes involved in several developmental, physiological, and pathological processes. The characteristics of miRNAs suggest that they could be versatile biomarkers. Assay panels to measure the expression of several miRNAs could facilitate clinical decision-- making for a range of diseases. We have, in this paper, reviewed the current understanding of the role of miRNAs as biomarkers in critically ill patients.
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Affiliation(s)
- Babak Alikiaii
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Bagherniya
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gholamreza Askari
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rajkumar Rajendram
- Department of Medicine, King Abdulaziz Medical City, King Abdulaziz International Medical Research Center, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University of Health Sciences, Riyadh, Saudi Arabia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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5
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Mehta SL, Chokkalla AK, Bathula S, Arruri V, Chelluboina B, Vemuganti R. CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 31:57-67. [PMID: 36618263 PMCID: PMC9800254 DOI: 10.1016/j.omtn.2022.11.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia. Transient middle cerebral artery occlusion (MCAO) in adult mice significantly downregulated both CDR1as and miR-7 levels in the peri-infarct cortex between 3 and 72 h of reperfusion. Interestingly, neither pri-miR-7a nor 7b was altered in the ischemic brain. Intracerebral injection of an AAV9 vector containing a CDR1as gene significantly increased CDR1as levels by 21 days that persisted up to 4 months without inducing any observable toxicity in both sham and MCAO groups. Following transient MCAO, there was a significant increase in miR-7 levels and CDR1as binding to Ago2/miR-7 in the peri-infarct cortex of AAV9-CDR1as cohort compared with AAV9-Control cohort at 1 day of reperfusion. CDR1as overexpression significantly suppressed post-stroke α-Syn protein induction, promoted motor function recovery, decreased infarct size, and curtailed the markers of apoptosis, autophagy mitochondrial fragmentation, and inflammation in the post-stroke brain compared with AAV9-Control-treated cohort. Overall, our findings imply that CDR1as reconstitution is neuroprotective after stroke, probably by protecting miR-7 and preventing α-Syn-mediated neuronal death.
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Affiliation(s)
- Suresh L. Mehta
- Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Anil K. Chokkalla
- Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA
| | | | - Vijay Arruri
- Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Bharath Chelluboina
- Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA
- William S. Middleton Veterans Administration Hospital, Madison, WI 53792, USA
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6
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Wang YR, Cui WQ, Wu HY, Xu XD, Xu XQ. The role of T cells in acute ischemic stroke. Brain Res Bull 2023; 196:20-33. [PMID: 36906042 DOI: 10.1016/j.brainresbull.2023.03.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/02/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023]
Abstract
Acute ischemic stroke (AIS) is associated with high rates of disability and mortality, exerting a substantial impact on overall survival and health-related quality of life. Treatment of AIS remains challenging given that the underlying pathologic mechanisms remain unclear. However, recent research has demonstrated that the immune system plays a key role in the development of AIS. Numerous studies have reported infiltration of T cells into ischemic brain tissue. While some types of T cells can promote the development of inflammatory responses and aggravate ischemic damage in patients with AIS, other T cells appear to exert neuroprotective effects via immunosuppression and other mechanisms. In this review, we discuss the recent findings regarding the infiltration of T cells into ischemic brain tissue, and the mechanisms governing how T cells can facilitate tissue injury or neuroprotection in AIS. Factors influencing the function of T cells, such as intestinal microflora and sex differences, are also discussed. We also explore the recent research on the effect of non-coding RNA on T cells after stroke, as well as the potential for specifically targeting T cells in the treatment of stroke patients.
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Affiliation(s)
- Yi-Ran Wang
- College of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wen-Qiang Cui
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hong-Yun Wu
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiang-Dong Xu
- Experimental Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiang-Qing Xu
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
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7
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Liu N, Zhang Y, Zhang P, Gong K, Zhang C, Sun K, Shao G. Vascular Endothelial Growth Factor and Erythropoietin Show Different Expression Patterns in the Early and Late Hypoxia Preconditioning Phases and May Correlate with DNA Methylation Status in the Mouse Hippocampus. High Alt Med Biol 2022; 23:361-368. [PMID: 36449395 DOI: 10.1089/ham.2021.0108] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Liu, Na, Yanbo Zhang, Pu Zhang, Kerui Gong, Chunyang Zhang, Kai Sun, and Guo Shao. Vascular endothelial growth factor and erythropoietin show different expression patterns in the early and late hypoxia preconditioning phases and may correlate with DNA methylation status in the mouse hippocampus. High Alt Med Biol. 23:361-368, 2022. Background: Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have been proven to participate in neuroprotection induced by hypoxia preconditioning (HPC), and they can be regulated by hypoxia-inducible factor 1 (HIF-1). It has been reported that DNA methylation can affect VEGF and EPO expression. This study aimed to explore the expression of VEGF and EPO in the early phase and late phase of HPC and whether their expression was affected by DNA methylation. Method: Acute repeated HPC mice were used as the animal model, and detection of molecular changes was performed immediately (early phase) and 1 day (late phase) after HPC treatment. The mRNA and protein expression levels of VEGF, EPO, and DNA methyltransferases (DNMTs) in the hippocampi were measured by real-time polymerase chain reaction and western blotting, respectively. The activity of DNMTs and global methylation levels were analyzed by enzyme-linked immunosorbent assay. DNA methylation levels of VEGF and EPO promoters, which were catalyzed by DNMTs, were determined by bisulfite-modified DNA sequencing. Results: The expression of VEGF was increased in the early phase and late phase of HPC (p < 0.05), whereas the expression of EPO was unchanged in the early phase (p > 0.05) of HPC and was increased in the late phase (p < 0.05). VEGF and EPO expression were negatively correlated with the DNA methylation levels of their promoters. DNMT3A and DNMT3B were decreased in the early phase and late phase (p < 0.05), whereas DNMT1 was unchanged in the early phase and late phase (p > 0.05). Conclusions: Our data demonstrated that DNMTs affect VEGF and EPO expression by regulating the DNA methylation levels of the promoters of VEGF and EPO.
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Affiliation(s)
- Na Liu
- Department of Laboratory Medicine, Center for Translational Medicine, the Third People's Hospital of Longgang District, Shenzhen, China.,Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College of Neuroscience Institute, Baotou Medical College, Inner Mongolia, China.,Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yanbo Zhang
- Department of Laboratory Medicine, Center for Translational Medicine, the Third People's Hospital of Longgang District, Shenzhen, China.,Department of Neurology, The Second Affiliated Hospital of Shandong First Medical University, Shandong, China
| | - Pu Zhang
- Department of Laboratory Medicine, Center for Translational Medicine, the Third People's Hospital of Longgang District, Shenzhen, China.,Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College of Neuroscience Institute, Baotou Medical College, Inner Mongolia, China.,Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Kerui Gong
- Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California, USA
| | - Chunyang Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia, China
| | - Kai Sun
- Department of Laboratory Medicine, Center for Translational Medicine, the Third People's Hospital of Longgang District, Shenzhen, China.,Joint Laboratory of South China Hospital Affiliated to Shenzhen University and Third People's Hospital of Longgang District, Shenzhen University, Shenzhen, China
| | - Guo Shao
- Department of Laboratory Medicine, Center for Translational Medicine, the Third People's Hospital of Longgang District, Shenzhen, China.,Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College of Neuroscience Institute, Baotou Medical College, Inner Mongolia, China.,Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.,Department of Neurosurgery, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia, China.,Joint Laboratory of South China Hospital Affiliated to Shenzhen University and Third People's Hospital of Longgang District, Shenzhen University, Shenzhen, China
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8
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Wu QJ, Sun X, Teves L, Mayor D, Tymianski M. Mice and Rats Exhibit Striking Inter-species Differences in Gene Response to Acute Stroke. Cell Mol Neurobiol 2022; 42:2773-2789. [PMID: 34350530 PMCID: PMC11421588 DOI: 10.1007/s10571-021-01138-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 07/30/2021] [Indexed: 10/20/2022]
Abstract
Neuroprotection in acute stroke has not been successfully translated from animals to humans. Animal research on promising agents continues largely in rats and mice which are commonly available to researchers. However, controversies continue on the most suitable species to model the human situation. Generally, putative agents seem less effective in mice as compared with rats. We hypothesized that this may be due to inter-species differences in stroke response and that this might be manifest at a genetic level. Here we used whole-genome microarrays to examine the differential gene regulation in the ischemic penumbra of mice and rats at 2 and 6 h after permanent middle cerebral artery occlusion (pMCAO; Raw microarray CEL data files are available in the GEO database with an accession number GSE163654). Differentially expressed genes (adj. p ≤ 0.05) were organized by hierarchical clustering, correlation plots, Venn diagrams and pathway analyses in each species and at each time-point. Emphasis was placed on genes already known to be associated with stroke, including validation by RT-PCR. Gene expression patterns in the ischemic penumbra differed strikingly between the species at both 2 h and 6 h. Nearly 90% of significantly regulated genes and most pathways modulated by ischemia differed between mice and rats. These differences were evident globally, among stroke-associated genes, immediate early genes, genes implicated in stress response, inflammation, neuroprotection, ion channels, and signal transduction. The findings of this study may have significant implications for the choice of species for screening putative stroke therapies.
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Affiliation(s)
- Qiu Jing Wu
- Krembil Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, M5T0S8, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Xiujun Sun
- Krembil Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, M5T0S8, Canada
| | - Lucy Teves
- Krembil Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, M5T0S8, Canada
| | - Diana Mayor
- Krembil Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, M5T0S8, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Michael Tymianski
- Krembil Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, M5T0S8, Canada.
- Department of Physiology, University of Toronto, Toronto, ON, Canada.
- Division of Neurosurgery, University of Toronto, Toronto, ON, Canada.
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9
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Peng J, Ghosh D, Zhang F, Yang L, Wu J, Pang J, Zhang L, Yin S, Jiang Y. Advancement of epigenetics in stroke. Front Neurosci 2022; 16:981726. [PMID: 36312038 PMCID: PMC9610114 DOI: 10.3389/fnins.2022.981726] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/27/2022] [Indexed: 10/14/2023] Open
Abstract
A wide plethora of intervention procedures, tissue plasminogen activators, mechanical thrombectomy, and several neuroprotective drugs were reported in stroke research over the last decennium. However, against this vivid background of newly emerging pieces of evidence, there is little to no advancement in the overall functional outcomes. With the advancement of epigenetic tools and technologies associated with intervention medicine, stroke research has entered a new fertile. The stroke involves an overabundance of inflammatory responses arising in part due to the body's immune response to brain injury. Neuroinflammation contributes to significant neuronal cell death and the development of functional impairment and even death in stroke patients. Recent studies have demonstrated that epigenetics plays a key role in post-stroke conditions, leading to inflammatory responses and alteration of the microenvironment within the injured tissue. In this review, we summarize the progress of epigenetics which provides an overview of recent advancements on the emerging key role of secondary brain injury in stroke. We also discuss potential epigenetic therapies related to clinical practice.
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Affiliation(s)
- Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Dipritu Ghosh
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Fan Zhang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lei Yang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jinpeng Wu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jinwei Pang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lifang Zhang
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shigang Yin
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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10
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Can U, Marzioglu E, Akdu S. Some miRNA expressions and their targets in ischemic stroke. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2022; 41:1224-1262. [PMID: 35876186 DOI: 10.1080/15257770.2022.2098974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/15/2022] [Accepted: 07/02/2022] [Indexed: 06/15/2023]
Abstract
Ischemic stroke (IS) is a global health challenge leading to life-long disabilities or the deaths of patients. IS is a complex disease where genetic and environmental factors are both concerned with the pathophysiology of the condition. Here, we aimed to investigate various microRNA (miRNA) expressions and their targets in IS. A rapid and accurate diagnosis of acute IS is important to perform appropriate treatment. Therefore, there is a need for a more rapid and simple tool to carry out an acute diagnosis of IS. miRNAs are small RNA molecules serving as precious biomarkers due to their easy detection and stability in blood samples. The present systematic review aimed to summarize previous studies investigating several miRNA expressions and their targets in IS.
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Affiliation(s)
- Ummugulsum Can
- Department of Biochemistry, Konya City Hospital, Konya, Türkiye
| | - Ebru Marzioglu
- Department of Genetics, Konya Training and Research Hospital, Konya, Türkiye
| | - Sadinaz Akdu
- Department of Biochemistry, Fethiye State Hospital, Muğla, Turkey
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11
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Noncoding RNA as Diagnostic and Prognostic Biomarkers in Cerebrovascular Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8149701. [PMID: 35498129 PMCID: PMC9042605 DOI: 10.1155/2022/8149701] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/22/2022] [Indexed: 02/06/2023]
Abstract
Noncoding RNAs (ncRNAs), such as microRNAs, long noncoding RNAs, and circular RNAs, play an important role in the pathophysiology of cerebrovascular diseases (CVDs). They are effectively detectable in body fluids, potentially suggesting new biomarkers for the early detection and prognosis of CVDs. In this review, the physiological functions of circulating ncRNAs and their potential role as diagnostic and prognostic markers in patients with cerebrovascular diseases are discussed, especially in acute ischemic stroke, subarachnoid hemorrhage, and moyamoya disease.
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12
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Li Z, Guo W, Ding S, Feng K, Lu L, Huang T, Cai Y. Detecting Blood Methylation Signatures in Response to Childhood Cancer Radiotherapy via Machine Learning Methods. BIOLOGY 2022; 11:biology11040607. [PMID: 35453806 PMCID: PMC9030135 DOI: 10.3390/biology11040607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/09/2022] [Accepted: 04/14/2022] [Indexed: 11/16/2022]
Abstract
Radiotherapy is a helpful treatment for cancer, but it can also potentially cause changes in many molecules, resulting in adverse effects. Among these changes, the occurrence of abnormal DNA methylation patterns has alarmed scientists. To explore the influence of region-specific radiotherapy on blood DNA methylation, we designed a computational workflow by using machine learning methods that can identify crucial methylation alterations related to treatment exposure. Irrelevant methylation features from the DNA methylation profiles of 2052 childhood cancer survivors were excluded via the Boruta method, and the remaining features were ranked using the minimum redundancy maximum relevance method to generate feature lists. These feature lists were then fed into the incremental feature selection method, which uses a combination of deep forest, k-nearest neighbor, random forest, and decision tree to find the most important methylation signatures and build the best classifiers and classification rules. Several methylation signatures and rules have been discovered and confirmed, allowing for a better understanding of methylation patterns in response to different treatment exposures.
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Affiliation(s)
- Zhandong Li
- College of Food Engineering, Jilin Engineering Normal University, Changchun 130052, China;
| | - Wei Guo
- Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China;
| | - Shijian Ding
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Kaiyan Feng
- Department of Computer Science, Guangdong AIB Polytechnic College, Guangzhou 510507, China;
| | - Lin Lu
- Department of Radiology, Columbia University Medical Center, New York, NY 10032, USA
- Correspondence: (L.L.); (T.H.); or (Y.C.); Tel.: +86-21-54923269 (T.H.); +86-21-66136132 (Y.C.)
| | - Tao Huang
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (L.L.); (T.H.); or (Y.C.); Tel.: +86-21-54923269 (T.H.); +86-21-66136132 (Y.C.)
| | - Yudong Cai
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
- Correspondence: (L.L.); (T.H.); or (Y.C.); Tel.: +86-21-54923269 (T.H.); +86-21-66136132 (Y.C.)
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13
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Dagra A, Barpujari A, Bauer SZ, Olowofela BO, Mohamed S, McGrath K, Robinson C, Robicsek S, Snyder A, Lucke-Wold B. Epigenetics of Neurotrauma. NEUROLOGY (CHICAGO, ILL.) 2022; 2:42-47. [PMID: 36507115 PMCID: PMC9732507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Epigenetic changes have been linked to a host of disease states. Besides the physiological function of epigenetic changes in regulating cellular function, recent data indicates that key changes in epigenetic activity also play an important pathophysiologic role following neurotrauma specifically. Such manifestations occur through the activation or silencing of different genes. Histone methylation has emerged as a critical component of this process and can be selectively modulated after injury. Pre-clinical studies have resulted in key discoveries regarding specific methylation sites of interest. This focused review highlights some of these early findings and their relationship to clinical outcomes. These findings suggest areas of future investigation and discovery in the quest to develop ideal biomarkers and methods to utilize them in developing therapeutic interventions.
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Affiliation(s)
- A Dagra
- College of Medicine, University of Florida, USA
| | - A Barpujari
- College of Liberal Arts and Sciences, University of Florida, USA
| | - SZ Bauer
- College of Medicine, University of Nevada, USA
| | | | - S Mohamed
- College of Medicine, University of Florida, USA
| | - K McGrath
- College of Medicine, University of Florida, USA
| | - C Robinson
- Departments of Neurology and Neuroscience, McKnight Brain Institute, University of Florida, USA
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and Brain Injury Rehabilitation and Neuroresilience Center, University of Florida, USA
| | - S Robicsek
- Department of Anesthesiology, University of Florida, USA
| | - A Snyder
- Department of Neuropsychology, University of Florida, USA
| | - B Lucke-Wold
- Department of Neurosurgery, University of Florida, USA
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14
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Hashizume S, Nakano M, Kubota K, Sato S, Himuro N, Kobayashi E, Takaoka A, Fujimiya M. Mindfulness intervention improves cognitive function in older adults by enhancing the level of miRNA-29c in neuron-derived extracellular vesicles. Sci Rep 2021; 11:21848. [PMID: 34750393 PMCID: PMC8575875 DOI: 10.1038/s41598-021-01318-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 10/26/2021] [Indexed: 01/13/2023] Open
Abstract
Although mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to a non-MBSR group or a MBSR group. Before and after the intervention, the Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered, and blood samples were collected. Then, neuron-derived extracellular vesicles (NDEVs) were isolated from blood samples, and microRNAs, as well as the target mRNAs, were evaluated in NDEVs. A linear mixed model analysis showed significant effects of the MBSR x time interaction on the MoCA-J scores, the expression of miRNA(miR)-29c, DNA methyltransferase 3 alpha (DNMT3A), and DNMT3B in NDEVs. These results indicate that MBSR can improve cognitive function by increasing the expression of miR-29c and decreasing the expression of DNMT3A, as well as DNMT3B, in neurons. It was also found that intracerebroventricular injection of miR-29c mimic into 5xFAD mice prevented cognitive decline, as well as neuronal loss in the subiculum area, by down-regulating Dnmt3a and Dnmt3b in the hippocampus. The present study suggests that MBSR can prevent neuronal loss and cognitive impairment by increasing the neuronal expression of miR-29c.
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Affiliation(s)
- Shin Hashizume
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
| | - Masako Nakano
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan.
| | - Kenta Kubota
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
- Department of Physical Therapy, Hokkaido Chitose Rehabilitation College, Chitose, Hokkaido, Japan
| | - Seiichi Sato
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Nobuaki Himuro
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Eiji Kobayashi
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
- Department of Physical Therapy, Faculty of Human Science, Hokkaido Bunkyo University, Eniwa, Hokkaido, Japan
| | - Akinori Takaoka
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Mineko Fujimiya
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
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15
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Mehta SL, Chokkalla AK, Vemuganti R. Noncoding RNA crosstalk in brain health and diseases. Neurochem Int 2021; 149:105139. [PMID: 34280469 PMCID: PMC8387393 DOI: 10.1016/j.neuint.2021.105139] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/27/2022]
Abstract
The mammalian brain expresses several classes of noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). These ncRNAs play vital roles in regulating cellular processes by RNA/protein scaffolding, sponging and epigenetic modifications during the pathophysiological conditions, thereby controlling transcription and translation. Some of these functions are the result of crosstalk between ncRNAs to form a competitive endogenous RNA network. These intricately organized networks comprise lncRNA/miRNA, circRNA/miRNA, or lncRNA/miRNA/circRNA, leading to crosstalk between coding and ncRNAs through miRNAs. The miRNA response elements predominantly mediate the ncRNA crosstalk to buffer the miRNAs and thereby fine-tune and counterbalance the genomic changes and regulate neuronal plasticity, synaptogenesis and neuronal differentiation. The perturbed levels and interactions of the ncRNAs could lead to pathologic events like apoptosis and inflammation. Although the regulatory landscape of the ncRNA crosstalk is still evolving, some well-known examples such as lncRNA Malat1 sponging miR-145, circRNA CDR1as sponging miR-7, and lncRNA Cyrano and the circRNA CDR1as regulating miR-7, has been shown to affect brain function. The ability to manipulate these networks is crucial in determining the functional outcome of central nervous system (CNS) pathologies. The focus of this review is to highlights the interactions and crosstalk of these networks in regulating pathophysiologic CNS function.
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Affiliation(s)
- Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Anil K Chokkalla
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial Veteran Administration Hospital, Madison, WI, USA.
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16
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New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs. Biomed Pharmacother 2021; 140:111753. [PMID: 34044272 PMCID: PMC8222190 DOI: 10.1016/j.biopha.2021.111753] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/22/2021] [Accepted: 05/19/2021] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have critical role in the pathophysiology as well as recovery after ischemic stroke. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are critical for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. Moreover, exosomes have been considered as nanocarriers capable of transferring various cargos, such as lncRNAs and miRNAs to recipient cells, with prominent inter-cellular roles in the mediation of neuro-restorative events following strokes and neural injuries. In this review, we summarize the pathogenic role of ncRNAs and exosomal ncRNAs in the stroke.
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17
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Swahari V, Nakamura A, Hollville E, Stroud H, Simon JM, Ptacek TS, Beck MV, Flowers C, Guo J, Plestant C, Liang J, Kurtz CL, Kanke M, Hammond SM, He YW, Anton ES, Sethupathy P, Moy SS, Greenberg ME, Deshmukh M. MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation. Cell Rep 2021; 35:108946. [PMID: 33826889 PMCID: PMC8103628 DOI: 10.1016/j.celrep.2021.108946] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 12/09/2020] [Accepted: 03/14/2021] [Indexed: 11/27/2022] Open
Abstract
Although embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. We examine whether an important function of miR-29 during brain maturation is to restrict the period of CH methylation via its targeting of Dnmt3a. Deletion of miR-29 in the brain, or knockin mutations preventing miR-29 to specifically target Dnmt3a, result in increased DNMT3A expression, higher CH methylation, and repression of genes associated with neuronal activity and neuropsychiatric disorders. These mouse models also develop neurological deficits and premature lethality. Our results identify an essential role for miR-29 in restricting CH methylation in the brain and illustrate the importance of CH methylation regulation for normal brain maturation.
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Affiliation(s)
- Vijay Swahari
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
| | - Ayumi Nakamura
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA
| | - Emilie Hollville
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
| | - Hume Stroud
- Department of Neurobiology, Harvard University, Boston, MA, USA
| | - Jeremy M Simon
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA
| | - Travis S Ptacek
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA
| | - Matthew V Beck
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
| | - Cornelius Flowers
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jiami Guo
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
| | | | - Jie Liang
- Department of Immunology, Duke University, Durham, NC, USA
| | - C Lisa Kurtz
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Matt Kanke
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
| | - Scott M Hammond
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - You-Wen He
- Department of Immunology, Duke University, Durham, NC, USA
| | - E S Anton
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - Praveen Sethupathy
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
| | - Sheryl S Moy
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA
| | | | - Mohanish Deshmukh
- Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA.
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18
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Huang W, Xiao F, Huang W, Wei Q, Li X. RETRACTED: MicroRNA-29a-3p strengthens the effect of dexmedetomidine on improving neurologic damage in newborn rats with hypoxic-ischemic brain damage by inhibiting HDAC4. Brain Res Bull 2021; 167:71-79. [PMID: 33232741 DOI: 10.1016/j.brainresbull.2020.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 10/16/2020] [Accepted: 11/17/2020] [Indexed: 01/05/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 2B+E, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). The journal requested the corresponding author comment on these concerns and provide the raw data. However, the authors were not responsive to the request for comment. Since original data could not be provided, the overall validity of the results could not be confirmed. Therefore, the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Wei Huang
- Department of Anesthesiology, People's Hospital of Baise, Baise, 533000, China.
| | - Faling Xiao
- Department of Anesthesiology, People's Hospital of Baise, Baise, 533000, China
| | - Weijun Huang
- Department of Anesthesiology, People's Hospital of Baise, Baise, 533000, China
| | - Qiaosong Wei
- Department of Anesthesiology, People's Hospital of Baise, Baise, 533000, China
| | - Xisong Li
- Department of Anesthesiology, People's Hospital of Baise, Baise, 533000, China
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19
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Angius A, Cossu-Rocca P, Arru C, Muroni MR, Rallo V, Carru C, Uva P, Pira G, Orrù S, De Miglio MR. Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype. Cancers (Basel) 2020; 12:E3298. [PMID: 33171872 PMCID: PMC7695196 DOI: 10.3390/cancers12113298] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/16/2022] Open
Abstract
Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype.
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Affiliation(s)
- Andrea Angius
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Paolo Cossu-Rocca
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (P.C.-R.); (M.R.M.)
- Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, 07026 Olbia, Italy
| | - Caterina Arru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (P.C.-R.); (M.R.M.)
| | - Vincenzo Rallo
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Paolo Uva
- CRS4, Science and Technology Park Polaris, Piscina Manna, 09010 Pula, CA, Italy;
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Sandra Orrù
- Department of Pathology, “A. Businco” Oncologic Hospital, ASL Cagliari, 09121 Cagliari, Italy;
| | - Maria Rosaria De Miglio
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
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20
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Sabet Sarvestani F, Azarpira N. microRNAs Alterations of Myocardium and Brain Ischemia-Reperfusion Injury: Insight to Improve Infarction. Immunol Invest 2020; 51:51-72. [DOI: 10.1080/08820139.2020.1808672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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21
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Desjarlais M, Dussault S, Rivera JC, Chemtob S, Rivard A. MicroRNA Expression Profiling of Bone Marrow-Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors. Front Genet 2020; 11:947. [PMID: 32973881 PMCID: PMC7472865 DOI: 10.3389/fgene.2020.00947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
Background Classical cardiovascular risk factors (CRFs) are associated with impaired angiogenic activities of bone marrow–derived proangiogenic cells (PACs) related to peripheral artery diseases (PADs) and ischemia-induced neovascularization. MicroRNAs (miRs) are key regulators of gene expression, and they are involved in the modulation of PAC function and PAC paracrine activity. However, the effects of CRFs on the modulation of miR expression in PACs are unknown. Aims and Methods We used a model of hindlimb ischemia and next-generation sequencing to perform a complete profiling of miRs in PACs isolated from the bone marrow of mice subjected to three models of CRFs: aging, smoking (SMK) and hypercholesterolemia (HC). Results Approximately 570 miRs were detected in PACs in the different CRF models. When excluding miRs with a very low expression level (<100 RPM), 40 to 61 miRs were found to be significantly modulated by aging, SMK, or HC. In each CRF condition, we identified downregulated proangiogenic miRs and upregulated antiangiogenic miRs that could contribute to explain PAC dysfunction. Interestingly, several miRs were similarly downregulated (e.g., miR-542-3p, miR-29) or upregulated (e.g., miR-501, miR-92a) in all CRF conditions. In silico approaches including Kyoto Encyclopedia of Genes and Genomes and cluster dendogram analyses identified predictive effects of these miRs on pathways having key roles in the modulation of angiogenesis and PAC function, including vascular endothelial growth factor signaling, extracellular matrix remodeling, PI3K/AKT/MAPK signaling, transforming growth factor beta (TGFb) pathway, p53, and cell cycle progression. Conclusion This study describes for the first time the effects of CRFs on the modulation of miR profile in PACs related to PAD and ischemia-induced neovascularization. We found that several angiogenesis-modulating miRs are similarly altered in different CRF conditions. Our findings constitute a solid framework for the identification of miRs that could be targeted in PACs in order to improve their angiogenic function and for the future development of novel therapies to improve neovascularization and reduce tissue damage in patients with severe PAD.
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Affiliation(s)
- Michel Desjarlais
- Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, QC, Canada.,Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada
| | - Sylvie Dussault
- Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, QC, Canada
| | - José Carlos Rivera
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada.,Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada
| | - Sylvain Chemtob
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada.,Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada
| | - Alain Rivard
- Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, QC, Canada
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22
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Gao Y, Qiao H, Zhong T, Lu Z, Hou Y. MicroRNA‑29a promotes the neural differentiation of rat neural stem/progenitor cells by targeting KLF4. Mol Med Rep 2020; 22:1008-1016. [PMID: 32468029 PMCID: PMC7339629 DOI: 10.3892/mmr.2020.11177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 04/23/2020] [Indexed: 01/13/2023] Open
Abstract
Neural stem/progenitor cells (NSPCs) remain in the mammalian brain throughout life, where they have the ability to self-renew and generate different types of cell in the central nervous system (CNS). Therefore, NSPCs may be a potential novel therapeutic strategy following damage to the CNS. Previous research has reported that microRNA (miR)-29a served an important role in regulating cell proliferation, differentiation and survival; however, to the best of our knowledge, little is known of the effect of miR-29a in neural differentiation. The present study aimed to investigate the effect of miR-29a on the differentiation of NSPCs, determined via RNA interference, immunostaining, reverse transcription-quantitative PCR and western blotting. The present study discovered that the expression levels of miR-29a were significantly upregulated in a time-dependent manner during neural differentiation. Immunostaining showed that overexpression of miR-29a promoted neural differentiation, which manifested in increased expression levels of neuron-specific class III β-tubulin (Tuj1); however, miR-29a had no effect on neuroglial differentiation. The expression levels of Kruppel-like factor 4 (KLF4) were downregulated following overexpression of miR-29a, whereas the inhibition of miR-29a demonstrated the opposite effect. These results suggested that the overexpression of miR-29a may promote neural differentiation in cultured rat NSPCs by decreasing the expression levels of KLF4. Thus indicating that targeting KLF4, a crucial regulatory factor for the maintenance of stemness, may be a potential underlying mechanism of action for miR-29a. In conclusion, the findings of the present study identified a potential mechanism of action for miR-29a in NSPC differentiation and provided a novel insight into the treatment strategies for CNS damage.
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Affiliation(s)
- Yunan Gao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Hu Qiao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Tianyu Zhong
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Zhen Lu
- Department of Orthodontics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yuxia Hou
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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23
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Cui J, Liu N, Chang Z, Gao Y, Bao M, Xie Y, Xu W, Liu X, Jiang S, Liu Y, Shi R, Xie W, Jia X, Shi J, Ren C, Gong K, Zhang C, Bade R, Shao G, Ji X. Exosomal MicroRNA-126 from RIPC Serum Is Involved in Hypoxia Tolerance in SH-SY5Y Cells by Downregulating DNMT3B. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 20:649-660. [PMID: 32380415 PMCID: PMC7210387 DOI: 10.1016/j.omtn.2020.04.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/18/2020] [Accepted: 04/22/2020] [Indexed: 12/13/2022]
Abstract
Ischemic tolerance in the brain can be induced by transient limb ischemia, and this phenomenon is termed remote ischemic preconditioning (RIPC). It still remains elusive how this transfer of tolerance occurs. Exosomes can cross the blood-brain barrier, and some molecules may transfer neuroprotective signals from the periphery to the brain. Serum miRNA-126 is associated with ischemic stroke, and exosomal miRNA-126 has shown protective effects against acute myocardial infarction. Therefore, this study aims to explore whether exosomal miRNA-126 from RIPC serum can play a similar neuroprotective role. Exosomes were isolated from the venous serum of four healthy young male subjects, both before and after RIPC. Exosomal miRNA-126 was measured by real-time PCR. The miRNA-126 target sequence was predicted by bioinformatics software. SH-SY5Y neuronal cells were incubated with exosomes, and the cell cycle was analyzed by flow cytometry. The expression and activity of DNA methyltransferase (DNMT) 3B, a potential target gene of miRNA-126, were examined in SH-SY5Y cells. The cell viability of SH-SY5Y cells exposed to oxygen-glucose deprivation (OGD) was also investigated. To confirm the association between miRNA-126 and DNMT3B, we overexpressed miRNA-126 in SH-SY5Y cells using lentiviral transfection. miRNA-126 expression was upregulated in RIPC exosomes, and bioinformatics prediction showed that miRNA-126 could bind with DNMT3B. DNMT levels and DNMT3B activity were downregulated in SH-SY5Y cells incubated with RIPC exosomes. After overexpression of miRNA-126 in SH-SY5Y cells, global methylation levels and DNMT3B gene expression were downregulated in these cells, consistent with the bioinformatics predictions. RIPC exosomes can affect the cell cycle and increase OGD tolerance in SH-SY5Y cells. RIPC seems to have neuroprotective effects by downregulating the expression of DNMTs in neural cells through the upregulation of serum exosomal miRNA-126.
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Affiliation(s)
- Junhe Cui
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC
| | - Na Liu
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC
| | - Zhehan Chang
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC
| | - Yongsheng Gao
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Mulan Bao
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Yabin Xie
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC
| | - Wenqiang Xu
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Xiaolei Liu
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Shuyuan Jiang
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - You Liu
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Rui Shi
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Wei Xie
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Xiaoe Jia
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC
| | - Jinghua Shi
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC
| | - Changhong Ren
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC
| | - Kerui Gong
- Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Chunyang Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia, China
| | - Rengui Bade
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC.
| | - Guo Shao
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, PRC; Biomedicine Research Center, Basic Medical College and Baotou Medical College of the Neuroscience Institute, Baotou Medical College, Inner Mongolia, PRC; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC; Department of Neurosurgery, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia, China.
| | - Xunming Ji
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, PRC.
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Mehta SL, Dempsey RJ, Vemuganti R. Role of circular RNAs in brain development and CNS diseases. Prog Neurobiol 2020; 186:101746. [PMID: 31931031 PMCID: PMC7024016 DOI: 10.1016/j.pneurobio.2020.101746] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/13/2019] [Accepted: 12/30/2019] [Indexed: 12/13/2022]
Abstract
In mammals, many classes of noncoding RNAs (ncRNAs) are expressed at a much higher level in the brain than in other organs. Recent studies have identified a new class of ncRNAs called circular RNAs (circRNAs), which are produced by back-splicing and fusion of either exons, introns, or both exon-intron into covalently closed loops. The circRNAs are also highly enriched in the brain and increase continuously from the embryonic to the adult stage. Although the functional significance and mechanism of action of circRNAs are still being actively explored, they are thought to regulate the transcription of their host genes and sequestration of miRNAs and RNA binding proteins. Some circRNAs are also shown to have translation potential to form peptides. The expression and abundance of circRNAs seem to be spatiotemporally maintained in a normal brain. Altered expression of circRNAs is also thought to mediate several disorders, including brain-tumor growth, and acute and chronic neurodegenerative disorders by affecting mechanisms such as angiogenesis, neuronal plasticity, autophagy, apoptosis, and inflammation. This review discusses the involvement of various circRNAs in brain development and CNS diseases. A better understanding of the circRNA function will help to develop novel therapeutic strategies to treat CNS complications.
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Affiliation(s)
- Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States
| | - Robert J Dempsey
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States; William S. Middleton Veterans Hospital, Madison, WI, United States.
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25
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Circ_016719 plays a critical role in neuron cell apoptosis induced by I/R via targeting miR-29c/Map2k6. Mol Cell Probes 2020; 49:101478. [DOI: 10.1016/j.mcp.2019.101478] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 10/30/2019] [Accepted: 11/03/2019] [Indexed: 02/04/2023]
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Heydari E, Alishahi M, Ghaedrahmati F, Winlow W, Khoshnam SE, Anbiyaiee A. The role of non-coding RNAs in neuroprotection and angiogenesis following ischemic stroke. Metab Brain Dis 2020; 35:31-43. [PMID: 31446548 DOI: 10.1007/s11011-019-00485-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 08/19/2019] [Indexed: 12/24/2022]
Abstract
Stroke is the leading cause of death and physical disability worldwide. Non-coding RNAs (ncRNAs) are endogenous molecules that play key roles in the pathophysiology and retrieval processes following ischemic stroke. The potential of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in neuroprotection and angiogenesis highlights their potential as targets for therapeutic intervention. In this review, we document the miRNAs and lncRNAs that have been reported to exert regulatory actions in neuroprotective and angiogenic processes through different mechanisms involving their interaction with target coding genes. We believe that exploration of the expression profiles and the possible functions of ncRNAs during the recovery processes will help comprehension of the molecular mechanisms responsible for neuroprotection and angiogenesis, and may also contribute to find biomarkers and targets for future stroke intervention.
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Affiliation(s)
- Elaheh Heydari
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Masoumeh Alishahi
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Farhoodeh Ghaedrahmati
- Immunology Department, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - William Winlow
- Dipartimento di Biologia, Università degli Studi di Napoli, Federico II, Via Cintia 26, 80126, Napoli, Italy
- Honorary Research Fellow, Institute of Ageing and Chronic Diseases, University of Liverpool, The APEX building, 6 West Derby Street, Liverpool, L7 8TX, UK
| | - Seyed Esmaeil Khoshnam
- Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 6135715794, Iran.
| | - Amir Anbiyaiee
- Department of Obstetrics & Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 61357-15794, Iran.
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27
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Liu N, Zhang XL, Jiang SY, Shi JH, Cui JH, Liu XL, Han LH, Gong KR, Yan SC, Xie W, Zhang CY, Shao G. Neuroprotective mechanisms of DNA methyltransferase in a mouse hippocampal neuronal cell line after hypoxic preconditioning. Neural Regen Res 2020; 15:2362-2368. [PMID: 32594061 PMCID: PMC7749487 DOI: 10.4103/1673-5374.285003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Hypoxic preconditioning has been shown to improve hypoxic tolerance in mice, accompanied by the downregulation of DNA methyltransferases (DNMTs) in the brain. However, the roles played by DNMTs in the multiple neuroprotective mechanisms associated with hypoxic preconditioning remain poorly understood. This study aimed to establish an in vitro model of hypoxic preconditioning, using a cultured mouse hippocampal neuronal cell line (HT22 cells), to examine the effects of DNMTs on the endogenous neuroprotective mechanisms that occur during hypoxic preconditioning. HT22 cells were divided into a control group, which received no exposure to hypoxia, a hypoxia group, which was exposed to hypoxia once, and a hypoxic preconditioning group, which was exposed to four cycles of hypoxia. To test the ability of hypoxic preadaptation to induce hypoxic tolerance, cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. Cell viability improved in the hypoxic preconditioning group compared with that in the hypoxia group. The effects of hypoxic preconditioning on the cell cycle and apoptosis in HT22 cells were examined by western blot assay and flow cytometry. Compared with the hypoxia group, the expression levels of caspase-3 and spectrin, which are markers of early apoptosis and S-phase arrest, respectively, noticeably reduced in the hypoxic preconditioning group. Finally, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and western blot assay were used to investigate the changes in DNMT expression and activity during hypoxic preconditioning. The results showed that compared with the control group, hypoxic preconditioning downregulated the expression levels of DNMT3A and DNMT3B mRNA and protein in HT22 cells and decreased the activities of total DNMTs and DNMT3B. In conclusion, hypoxic preconditioning may exert anti-hypoxic neuroprotective effects, maintaining HT22 cell viability and inhibiting cell apoptosis. These neuroprotective mechanisms may be associated with the inhibition of DNMT3A and DNMT3B.
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Affiliation(s)
- Na Liu
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xiao-Lu Zhang
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shu-Yuan Jiang
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Jing-Hua Shi
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Jun-He Cui
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Xiao-Lei Liu
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Li-Hong Han
- Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Ke-Rui Gong
- Department of Oral and Maxillofacial Surgery, University of California San Francsico, San Francisco, CA, USA
| | - Shao-Chun Yan
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Wei Xie
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Chun-Yang Zhang
- Department of Neurosurgery, the First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Guo Shao
- Inner Mongolia Key Laboratory of Hypoxic Translational Medicine; Biomedicine Research Center, Basic Medical College and Baotou Medical College of Neuroscience Institute, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region; Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing; Department of Neurosurgery, the First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia Autonomous Region,, China
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28
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Klatt CL, Theis V, Hahn S, Theiss C, Matschke V. Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis. Cells 2019; 8:cells8091077. [PMID: 31547454 PMCID: PMC6770833 DOI: 10.3390/cells8091077] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/06/2019] [Accepted: 09/11/2019] [Indexed: 12/18/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and spinal cord. The question arises why motor neurons selectively degenerate in ALS, while other cells and systems appear to be spared the disease. Members of the intrinsic apoptotic pathway are frequent targets of altered microRNA expression. Therefore, microRNAs and their effects on cell survival are subject of controversial debates. In this study, we investigated the expression of numerous members of the intrinsic apoptotic cascade by qPCR, western blot, and immunostaining in two different regions of the CNS of wobbler mice. Further we addressed the expression of miR-29b-3p targeting BMF, Bax, and, Bak, members of the apoptotic pathway. We show a tissue-specific differential expression of BMF, Bax, and cleaved-Caspase 3 in wobbler mice. An opposing regulation of miR-29b-3p expression in the cerebellum and cervical spinal cord of wobbler mice suggests different mechanisms regulating the intrinsic apoptotic pathway. Based on our findings, it could be speculated that miR-29b-3p might regulate antiapoptotic survival mechanisms in CNS areas that are not affected by neurodegeneration in the wobbler mouse ALS model.
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Affiliation(s)
- Christina L Klatt
- Ruhr University Bochum, Medical Faculty, Institute of Anatomy, Department of Cytology, 44801 Bochum, Germany.
| | - Verena Theis
- Ruhr University Bochum, Medical Faculty, Institute of Anatomy, Department of Cytology, 44801 Bochum, Germany.
| | - Stephan Hahn
- Ruhr University Bochum, Clinical Research Center, Department of Molecular Gastrointestinal Oncology, 44801 Bochum, Germany.
| | - Carsten Theiss
- Ruhr University Bochum, Medical Faculty, Institute of Anatomy, Department of Cytology, 44801 Bochum, Germany.
| | - Veronika Matschke
- Ruhr University Bochum, Medical Faculty, Institute of Anatomy, Department of Cytology, 44801 Bochum, Germany.
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Morris-Blanco KC, Kim T, Bertogliat MJ, Mehta SL, Chokkalla AK, Vemuganti R. Inhibition of the Epigenetic Regulator REST Ameliorates Ischemic Brain Injury. Mol Neurobiol 2019; 56:2542-2550. [PMID: 30039336 PMCID: PMC6344325 DOI: 10.1007/s12035-018-1254-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/17/2018] [Indexed: 01/03/2023]
Abstract
Cerebral ischemia is known to activate the repressor element-1 (RE1)-silencing transcription factor (REST) which silences neural genes via epigenetic remodeling and promotes neurodegeneration. We presently determined if REST inhibition derepresses target genes involved in synaptic plasticity and promotes functional outcome after experimental stroke. Following transient focal ischemia induced by middle cerebral artery occlusion (MCAO) in adult rats, REST expression was upregulated significantly from 12 h to 1 day of reperfusion compared to sham control. At 1 day of reperfusion, REST protein levels were increased and observed in the nuclei of neurons in the peri-infarct cortex. REST knockdown by intracerebral REST siRNA injection significantly reduced the post-ischemic expression of REST and increased the expression of several REST target genes, compared to control siRNA group. REST inhibition also decreased post-ischemic markers of apoptosis, reduced cortical infarct volume, and improved post-ischemic functional recovery on days 5 and 7 of reperfusion compared to the control siRNA group. REST knockdown resulted in a global increase in synaptic plasticity gene expression at 1 day of reperfusion compared to the control siRNA group and significantly increased several synaptic plasticity genes containing RE-1 sequences in their regulatory regions. These results demonstrate that direct inhibition of the epigenetic remodeler REST prevents secondary brain damage in the cortex and improves functional outcome potentially via de-repression of plasticity-related genes after stroke.
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Affiliation(s)
- Kahlilia C Morris-Blanco
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave., Madison, WI, 53792, USA
- William S. Middleton Veterans Administration Hospital, Madison, WI, USA
| | - TaeHee Kim
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave., Madison, WI, 53792, USA
- William S. Middleton Veterans Administration Hospital, Madison, WI, USA
| | - Mario J Bertogliat
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave., Madison, WI, 53792, USA
| | - Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave., Madison, WI, 53792, USA
- William S. Middleton Veterans Administration Hospital, Madison, WI, USA
| | - Anil K Chokkalla
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave., Madison, WI, 53792, USA
- Cellular and Molecular Pathology Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave., Madison, WI, 53792, USA.
- William S. Middleton Veterans Administration Hospital, Madison, WI, USA.
- Cellular and Molecular Pathology Program, University of Wisconsin-Madison, Madison, WI, USA.
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30
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Wang JY, Cheng H, Zhang HY, Ye YQ, Feng Q, Chen ZM, Zheng YL, Wu ZG, Wang B, Yao J. Suppressing microRNA-29c promotes biliary atresia-related fibrosis by targeting DNMT3A and DNMT3B. Cell Mol Biol Lett 2019; 24:10. [PMID: 30906331 PMCID: PMC6410490 DOI: 10.1186/s11658-018-0134-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/18/2018] [Indexed: 12/15/2022] Open
Abstract
This study was designed to investigate the potential role of microRNA-29c (miR-29c) in biliary atresia-related fibrosis. The expression of miR-29c was determined in 15 pairs of peripheral blood samples from infants with biliary atresia (BA) and infants with non-BA neonatal cholestasis using quantitative real-time PCR. EMT was established by induction with TGF-β1 in HIBEpiC cells. MiR-29c was inhibited by lipofectamine transfection. The expressions of proteins related to epithelial-mesenchymal transition (EMT), i.e., E-cadherin, N-cadherin and vimentin, were determined using quantitative real-time PCR and western blotting. Direct interaction between miR-29c and DNMT3A and DNMT3B was identified using a luciferase reporter assay. The expressions of DNMT3A and DNMT3B were suppressed by treatment with SGI-1027. Patients with BA showed significantly lower miR-29c levels in peripheral blood samples than the control subjects. In vitro, TGF-β1-induced EMT significantly decreased the expression of miR-29c. Downregulation of miR-29c had a promotional effect on BA-related fibrosis in HIBEpiC cells, as confirmed by the decrease in E-cadherin and increase in N-cadherin and vimentin levels. MiR-29c was found to target the 3'UTR of DNMT3A and DNMT3B and inhibit their expression. Suppression of DNMT3A and DNMT3B reversed the effects of miR-29c downregulation on BA-related fibrosis in HIBEpiC cells. These data suggest that BA-related fibrosis is closely associated with the occurrence of EMT in HIBEpiC cells. MiR-29c might be a candidate for alleviating BA-related fibrosis by targeting DNMT3A and DNMT3B.
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Affiliation(s)
- Jian-yao Wang
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Hao Cheng
- Graduate School of China Medical University, Shenzhen, 110122 Liaoning Province China
| | - Hong-yan Zhang
- Graduate School of China Medical University, Shenzhen, 110122 Liaoning Province China
| | - Yong-qin Ye
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Qi Feng
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Zi-min Chen
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Yue-lan Zheng
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Zhou-guang Wu
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Bin Wang
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026 Guangdong Province China
| | - Jun Yao
- Department of Gastroenterology, Jinan University of Medical Sciences, Shenzhen Municipal People’s Hospital, Shenzhen, 518020 Guangdong Province China
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31
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Chen X, Yin J, Qu J, Huang L. MDHGI: Matrix Decomposition and Heterogeneous Graph Inference for miRNA-disease association prediction. PLoS Comput Biol 2018; 14:e1006418. [PMID: 30142158 PMCID: PMC6126877 DOI: 10.1371/journal.pcbi.1006418] [Citation(s) in RCA: 264] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 09/06/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022] Open
Abstract
Recently, a growing number of biological research and scientific experiments have demonstrated that microRNA (miRNA) affects the development of human complex diseases. Discovering miRNA-disease associations plays an increasingly vital role in devising diagnostic and therapeutic tools for diseases. However, since uncovering associations via experimental methods is expensive and time-consuming, novel and effective computational methods for association prediction are in demand. In this study, we developed a computational model of Matrix Decomposition and Heterogeneous Graph Inference for miRNA-disease association prediction (MDHGI) to discover new miRNA-disease associations by integrating the predicted association probability obtained from matrix decomposition through sparse learning method, the miRNA functional similarity, the disease semantic similarity, and the Gaussian interaction profile kernel similarity for diseases and miRNAs into a heterogeneous network. Compared with previous computational models based on heterogeneous networks, our model took full advantage of matrix decomposition before the construction of heterogeneous network, thereby improving the prediction accuracy. MDHGI obtained AUCs of 0.8945 and 0.8240 in the global and the local leave-one-out cross validation, respectively. Moreover, the AUC of 0.8794+/-0.0021 in 5-fold cross validation confirmed its stability of predictive performance. In addition, to further evaluate the model's accuracy, we applied MDHGI to four important human cancers in three different kinds of case studies. In the first type, 98% (Esophageal Neoplasms) and 98% (Lymphoma) of top 50 predicted miRNAs have been confirmed by at least one of the two databases (dbDEMC and miR2Disease) or at least one experimental literature in PubMed. In the second type of case study, what made a difference was that we removed all known associations between the miRNAs and Lung Neoplasms before implementing MDHGI on Lung Neoplasms. As a result, 100% (Lung Neoplasms) of top 50 related miRNAs have been indexed by at least one of the three databases (dbDEMC, miR2Disease and HMDD V2.0) or at least one experimental literature in PubMed. Furthermore, we also tested our prediction method on the HMDD V1.0 database to prove the applicability of MDHGI to different datasets. The results showed that 50 out of top 50 miRNAs related with the breast neoplasms were validated by at least one of the three databases (HMDD V2.0, dbDEMC, and miR2Disease) or at least one experimental literature.
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Affiliation(s)
- Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Jun Yin
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Jia Qu
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Li Huang
- Business Analytics Centre, National University of Singapore, Singapore
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He J, Gao Y, Wu G, Lei X, Zhang Y, Pan W, Yu H. Bioinformatics analysis of microarray data to reveal the pathogenesis of brain ischemia. Mol Med Rep 2018; 18:333-341. [PMID: 29749511 PMCID: PMC6059688 DOI: 10.3892/mmr.2018.9000] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 04/17/2018] [Indexed: 12/29/2022] Open
Abstract
Brain ischemia leads to energy depletion, mitochondrial dysfunction and neuronal cell death. The present study was designed to identify key genes and pathways associated with brain ischemia. The gene expression profile GSE52001, including 3 normal brain samples and 3 cerebral ischemia samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the limma package. Then functional and pathway enrichment analyses were performed by the MATHT tool. Protein‑protein interaction (PPI) network, module selection and microRNA (miRNA)‑target gene network were constructed utilizing Cytoscape software. A total of 488 DEGs were identified (including 281 upregulated and 207 downregulated genes). In the PPI network, Rac family small GTPase 2 (RAC2) had higher degrees. RAC2 was significantly enriched in the FcγR‑mediated phagocytosis pathway. miR‑29A/B/C had a higher degree in the miRNA‑target gene network. Insulin like growth factor 1 (Igf1) was identified as the target gene for miR‑29A/B/C. RAC2 may function in brain ischemia through mediating the FcγR‑mediated phagocytosis pathway. Meanwhile, miR‑29A/B/C and their targets gene Igf1 may serve important roles in the development and progression of brain ischemia.
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Affiliation(s)
- Jiaxuan He
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Ya Gao
- Department of Pediatric Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Gang Wu
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Xiaoming Lei
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Yong Zhang
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Weikang Pan
- Department of Pediatric Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Hui Yu
- Department of Pediatric Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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Abstract
Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies.
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Affiliation(s)
- Ping Sun
- Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Da Zhi Liu
- Department of Neurology and the M.I.N.D. Institute, University of California at Davis, Sacramento, CA, USA
| | - Glen C Jickling
- Department of Neurology, University of Alberta, Edmonton, Alberta, Canada
| | - Frank R Sharp
- Department of Neurology and the M.I.N.D. Institute, University of California at Davis, Sacramento, CA, USA
| | - Ke-Jie Yin
- Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Ke-Jie Yin, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST S514, Pittsburgh, PA 15213, USA. Da Zhi Liu, Department of Neurology, University of California at Davis, Sacramento, CA 95817, USA.
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Kaur H, Sarmah D, Saraf J, Vats K, Kalia K, Borah A, Yavagal DR, Dave KR, Ghosh Z, Bhattacharya P. Noncoding RNAs in ischemic stroke: time to translate. Ann N Y Acad Sci 2018; 1421:19-36. [DOI: 10.1111/nyas.13612] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/11/2017] [Accepted: 01/08/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Harpreet Kaur
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Jackson Saraf
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Kanchan Vats
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Kiran Kalia
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory; Department of Life Science and Bioinformatics; Assam University; Silchar Assam India
| | - Dileep R. Yavagal
- Department of Neurology and Neurosurgery; University of Miami Miller School of Medicine; Miami Florida
| | - Kunjan R. Dave
- Department of Neurology and Neurosurgery; University of Miami Miller School of Medicine; Miami Florida
| | - Zhumur Ghosh
- Department of Bioinformatics; Bose Institute; Kolkata India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
- Department of Neurosurgery, Boston Children's Hospital; Harvard Medical School; Boston Massachusetts
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Demuth HU, Dijkhuizen RM, Farr TD, Gelderblom M, Horsburgh K, Iadecola C, Mcleod DD, Michalski D, Murphy TH, Orbe J, Otte WM, Petzold GC, Plesnila N, Reiser G, Reymann KG, Rueger MA, Saur D, Savitz SI, Schilling S, Spratt NJ, Turner RJ, Vemuganti R, Vivien D, Yepes M, Zille M, Boltze J. Recent progress in translational research on neurovascular and neurodegenerative disorders. Restor Neurol Neurosci 2018; 35:87-103. [PMID: 28059802 PMCID: PMC5302043 DOI: 10.3233/rnn-160690] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient’s outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations.
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Affiliation(s)
- Hans-Ulrich Demuth
- Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology (IZI-MWT), Halle/Saale, Germany
| | - Rick M Dijkhuizen
- Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, The Netherlands
| | - Tracy D Farr
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Mathias Gelderblom
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karen Horsburgh
- Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK
| | - Costantino Iadecola
- Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Damian D Mcleod
- University of Newcastle, Hunter Medical Research Institute and Hunter New England Local Health District, Newcastle, Australia
| | | | - Tim H Murphy
- Department of Psychiatry, University of British Columbia, Vancouver, Canada
| | - Josune Orbe
- Atherothrombosis Laboratory, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Willem M Otte
- Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, The Netherlands.,Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Nikolaus Plesnila
- Institute for Stroke and Dementia Research (ISD), University of Munich Medical Center; Munich Cluster of Systems Neurology (Synergy), LMU Munich, Germany
| | - Georg Reiser
- Institute for Neurobiochemistry, University of Magdeburg, Magdeburg, Germany
| | - Klaus G Reymann
- Neuropharmacology Lab, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Maria A Rueger
- Department of Neurology, University Hospital of Cologne, Cologne, Germany
| | - Dorothee Saur
- Department of Neurology, University of Leipzig, Leipzig, Germany
| | - Sean I Savitz
- Department of Neurology, UTHealth Medical School, Houston, TX, USA
| | - Stephan Schilling
- Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology (IZI-MWT), Halle/Saale, Germany
| | - Neil J Spratt
- University of Newcastle, Hunter Medical Research Institute and Hunter New England Local Health District, Newcastle, Australia
| | - Renée J Turner
- Adelaide Medical School and Adelaide Centre for Neuroscience Research, The University of Adelaide, Adelaide, Australia
| | - Raghu Vemuganti
- Deptartment of Neurological Surgery, University of Wisconsin and William S. Middleton VA Hospital, Madison, WI, USA
| | - Denis Vivien
- Cell Biology and Clinical Research Department, Medical Center, Université Caen-Normandie, GIP Cyceron; Inserm, Inserm UMR-S U919, Serine Proteases and Pathophysiology of the neurovascular Unit, Caen, France
| | - Manuel Yepes
- Department of Neurology, Emory University, Atlanta, GA, USA
| | - Marietta Zille
- Department of Neurology and Neuroscience, The Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY, USA
| | - Johannes Boltze
- Department of Medical Cell Technology, Fraunhofer Research Institution for Marine Biotechnology; Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, Germany
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Bhardwaj A, Singh H, Rajapakshe K, Tachibana K, Ganesan N, Pan Y, Gunaratne PH, Coarfa C, Bedrosian I. Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer. Oncotarget 2017; 8:19645-19660. [PMID: 28160548 PMCID: PMC5386711 DOI: 10.18632/oncotarget.14902] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 01/04/2017] [Indexed: 12/21/2022] Open
Abstract
Little is understood about the early molecular drivers of triple-negative breast cancer (TNBC), making the identification of women at risk and development of targeted therapy for prevention significant challenges. By sequencing a TNBC cell line-based breast cancer progression model we have found that miRNA-29c is progressively lost during TNBC tumorigenesis. In support of the tumor suppressive role of miRNA 29c, we found that low levels predict poor overall patient survival and, conversely, that ectopic expression of miRNA-29c in preneoplastic cell models inhibits growth. miRNA-29c exerts its growth inhibitory effects through direct binding and regulation of TGFB-induced factor homeobox 2 (TGIF2), CAMP-responsive element binding protein 5 (CREB5), and V-Akt murine thymoma viral oncogene homolog 3 (AKT3). miRNA-29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells. AKT3 is an oncogene of known relevance in breast cancer, and as a proof of principle we show that inhibition of phosphoinositide 3-kinase (PI3K) activity, a protein upstream of AKT3, suppressed proliferation in TNBC preneoplastic cells. We explored additional opportunities for prevention of TNBC by studying the regulation of miRNA-29c and identified DNA methylation to have a role in the inhibition of miRNA-29c during TNBC tumorigenesis. Consistent with these observations, we found 5 aza-cytadine to relieve the suppression of miRNA-29c. Together, these results demonstrate that miRNA-29c loss plays a key role in the early development of TNBC.
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Affiliation(s)
- Anjana Bhardwaj
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Harpreet Singh
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kimal Rajapakshe
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Kazunoshin Tachibana
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nivetha Ganesan
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Pan
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Preethi H Gunaratne
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Isabelle Bedrosian
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Chuang TD, Khorram O. Glucocorticoids regulate MiR-29c levels in vascular smooth muscle cells through transcriptional and epigenetic mechanisms. Life Sci 2017; 186:87-91. [DOI: 10.1016/j.lfs.2017.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 08/02/2017] [Accepted: 08/07/2017] [Indexed: 11/28/2022]
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Mateen BA, Hill CS, Biddie SC, Menon DK. DNA Methylation: Basic Biology and Application to Traumatic Brain Injury. J Neurotrauma 2017; 34:2379-2388. [DOI: 10.1089/neu.2017.5007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Bilal A. Mateen
- Division of Medicine, University College London, London, United Kingdom
| | - Ciaran S. Hill
- John van Geest Centre for Brain Repair, School of Clinical Medicine, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Simon C. Biddie
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - David K. Menon
- John van Geest Centre for Brain Repair, School of Clinical Medicine, Addenbrookes Hospital, Cambridge, United Kingdom
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
- Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
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Bai X, Tang Y, Yu M, Wu L, Liu F, Ni J, Wang Z, Wang J, Fei J, Wang W, Huang F, Wang J. Downregulation of blood serum microRNA 29 family in patients with Parkinson's disease. Sci Rep 2017; 7:5411. [PMID: 28710399 PMCID: PMC5511199 DOI: 10.1038/s41598-017-03887-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 05/05/2017] [Indexed: 11/09/2022] Open
Abstract
There is currently no reliable and easily applicable diagnostic marker for Parkinson’s disease (PD). The aims of the present study were to compare the expression profiles of the microRNA29 family (miR-29s) in blood serum from patients with PD with healthy controls and to clarify whether the expression of miR-29s is correlated with disease severity, duration or L-dopa therapy and whether expression depends on the gender and age of patients. The levels of blood serum miR-29s in 80 patients with PD and 80 unaffected controls were assessed by reverse transcription-quantitative real-time PCR. The PCR products were confirmed by cloning and sequencing. Additionally, the expression of miR-7 in the blood serum from PD patients and control subjects was assessed. Serum miR-29 levels were significantly downregulated in PD patients compared to healthy controls. The serum miR-29 levels in female PD patients were markedly higher than in male PD patients. The expression of serum miR-29a and miR-29c expression tended to decrease with disease severity. Moreover, we found that serum miR-7 levels did not differ between PD patients and control subjects. Therefore, the reduction of serum miR-29 levels, particularly miR-29a and miR-29c, warrants further investigation of its potential serving as biomarkers for PD.
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Affiliation(s)
- Xiaochen Bai
- The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Yilin Tang
- Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Mei Yu
- The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Lei Wu
- Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Fengtao Liu
- Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Jianliang Ni
- Tongde Hospital of Zhejiang Province, 234 Gucui Road, Hangzhou, 310012, Zhejiang Province, China
| | - Zishan Wang
- The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Jinghui Wang
- The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Jian Fei
- School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China.,Shanghai Research Center for Model Organisms, Pudong, Shanghai, 201203, China
| | - Wei Wang
- Tongde Hospital of Zhejiang Province, 234 Gucui Road, Hangzhou, 310012, Zhejiang Province, China.
| | - Fang Huang
- The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China.
| | - Jian Wang
- The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China. .,Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China.
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40
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Poststroke Induction of α-Synuclein Mediates Ischemic Brain Damage. J Neurosci 2017; 36:7055-65. [PMID: 27358461 DOI: 10.1523/jneurosci.1241-16.2016] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 05/23/2016] [Indexed: 01/24/2023] Open
Abstract
UNLABELLED α-Synuclein (α-Syn), one of the most abundant proteins in the CNS, is known to be a major player in the neurodegeneration observed in Parkinson's disease. We currently report that transient focal ischemia upregulates α-Syn protein expression and nuclear translocation in neurons of the adult rodent brain. We further show that knockdown or knock-out of α-Syn significantly decreases the infarction and promotes better neurological recovery in rodents subjected to focal ischemia. Furthermore, α-Syn knockdown significantly reduced postischemic induction of phospho-Drp1, 3-nitrotyrosine, cleaved caspase-3, and LC-3 II/I, indicating its role in modulating mitochondrial fragmentation, oxidative stress, apoptosis, and autophagy, which are known to mediate poststroke neuronal death. Transient focal ischemia also significantly upregulated serine-129 (S129) phosphorylation (pα-Syn) of α-Syn and nuclear translocation of pα-Syn. Furthermore, knock-out mice that lack PLK2 (the predominant kinase that mediates S129 phosphorylation) showed better functional recovery and smaller infarcts when subjected to transient focal ischemia, indicating a detrimental role of S129 phosphorylation of α-Syn. In conclusion, our studies indicate that α-Syn is a potential therapeutic target to minimize poststroke brain damage. SIGNIFICANCE STATEMENT Abnormal aggregation of α-synuclein (α-Syn) has been known to cause Parkinson's disease and other chronic synucleinopathies. However, even though α-Syn is linked to pathophysiological mechanisms similar to those that produce acute neurodenegerative disorders, such as stroke, the role of α-Syn in such disorder is not clear. We presently studied whether α-Syn mediates poststroke brain damage and more importantly whether preventing α-Syn expression is neuroprotective and leads to better physiological and functional outcome after stroke. Our study indicates that α-Syn is a potential therapeutic target for stroke therapy.
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Mehta SL, Pandi G, Vemuganti R. Circular RNA Expression Profiles Alter Significantly in Mouse Brain After Transient Focal Ischemia. Stroke 2017; 48:2541-2548. [PMID: 28701578 DOI: 10.1161/strokeaha.117.017469] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/23/2017] [Accepted: 06/15/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND PURPOSE Circular RNAs (circRNAs) are a novel class of noncoding RNAs formed from many protein-coding genes by backsplicing. Although their physiological functions are not yet completely defined, they are thought to control transcription, translation, and microRNA levels. We investigated whether stroke changes the circRNAs expression profile in the mouse brain. METHODS Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and circRNA expression profile was evaluated in the penumbral cortex at 6, 12, and 24 hours of reperfusion using circRNA microarrays and real-time PCR. Bioinformatics analysis was conducted to identify microRNA binding sites, transcription factor binding, and gene ontology of circRNAs altered after ischemia. RESULTS One thousand three-hundred twenty circRNAs were expressed at detectable levels mostly from exonic (1064) regions of the genes in the cerebral cortex of sham animals. Of those, 283 were altered (>2-fold) at least at one of the reperfusion time points, whereas 16 were altered at all 3 time points of reperfusion after transient middle cerebral artery occlusion compared with sham. Postischemic changes in circRNAs identified by microarray analysis were confirmed by real-time PCR. Bioinformatics showed that these 16 circRNAs contain binding sites for many microRNAs. Promoter analysis showed that the circRNAs altered after stroke might be controlled by a set of transcription factors. The major biological and molecular functions controlled by circRNAs altered after transient middle cerebral artery occlusion are biological regulation, metabolic process, cell communication, and binding to proteins, ions, and nucleic acids. CONCLUSIONS This is a first study that shows that stroke alters the expression of circRNAs with possible functional implication to poststroke pathophysiology.
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Affiliation(s)
- Suresh L Mehta
- From the Department of Neurological Surgery, University of Wisconsin, Madison (S.L.M., G.P., R.V.); William S. Middleton Memorial VA Hospital, Madison, WI (R.V.); and School of Biotechnology, Madurai Kamaraj University, Tamil Nadu, India (G.P.)
| | - Gopal Pandi
- From the Department of Neurological Surgery, University of Wisconsin, Madison (S.L.M., G.P., R.V.); William S. Middleton Memorial VA Hospital, Madison, WI (R.V.); and School of Biotechnology, Madurai Kamaraj University, Tamil Nadu, India (G.P.)
| | - Raghu Vemuganti
- From the Department of Neurological Surgery, University of Wisconsin, Madison (S.L.M., G.P., R.V.); William S. Middleton Memorial VA Hospital, Madison, WI (R.V.); and School of Biotechnology, Madurai Kamaraj University, Tamil Nadu, India (G.P.).
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Selvamani A, Sohrabji F. Mir363-3p improves ischemic stroke outcomes in female but not male rats. Neurochem Int 2017; 107:168-181. [PMID: 27773791 PMCID: PMC5398946 DOI: 10.1016/j.neuint.2016.10.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/10/2016] [Accepted: 10/17/2016] [Indexed: 01/22/2023]
Abstract
With age, stroke prevalence is higher, and stroke outcome, worse, in women. Thus there is an urgent need to identify stroke neuroprotectants for this population. Using a preclinical stroke model, our studies focused on microRNAs (miRNAs), a class of translational repressors, as neuroprotectants. Analysis of circulating miRNA in the acute phase of stroke indicated potential neuroprotective capacity for miR363. Specifically, mir363 is elevated in serum of adult female rats that typically have small infarct volumes, but is deficient in age-matched males or middle-aged males and females, groups that have greater stroke-associated impairment. To directly test the effect of mir363 on stroke outcomes, first, adult females were treated with antagomirs to mir363 post stroke and next, middle-aged females were treated with mimic to mir363-3p post stroke. Antagomir treatment to adult females significantly increased infarct volume and impaired sensory motor performance. Reciprocally, mir363 mimic to middle-aged females reduced infarct volume, preserved forebrain microvessels and improved sensory motor performance. In the early acute stroke phase, mir363-3p mimic reduced the expression and functional activity of caspase-3, a critical component of the apoptotic cell cascade. In contrast, mir363-3p mimic treatment had no effect on stroke outcomes or caspase regulation in young males. Collectively, these studies show that mir363 is neuroprotective for stroke in females and implicates caspase-3 as a sex-specific miRNA-sensitive node for recovery from ischemic stroke.
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Affiliation(s)
- Amutha Selvamani
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan TX 77807, United States
| | - Farida Sohrabji
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan TX 77807, United States.
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Wang X, Suofu Y, Akpinar B, Baranov SV, Kim J, Carlisle DL, Zhang Y, Friedlander RM. Systemic antimiR-337-3p delivery inhibits cerebral ischemia-mediated injury. Neurobiol Dis 2017; 105:156-163. [PMID: 28461247 DOI: 10.1016/j.nbd.2017.04.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 04/20/2017] [Accepted: 04/27/2017] [Indexed: 11/15/2022] Open
Abstract
Modulation of miRNA expression has been shown to be beneficial in the context of multiple diseases. The purpose of this study was to determine if an inhibitor of miR-337-3p is neuroprotective for hypoxic injury after tail vein injection. We evaluated miR-337-3p expression levels and in brain tissue in vivo before and after permanent middle cerebral artery occlusion (pMCAO) in mice. Subsequently, a custom locked nucleic acid (LNA) antimir-337-3p oligonucleotide was developed and tested in vitro after induction of oxygen glucose-deprivation (OGD) and in vivo by injection into the mouse tail vein for 3 consecutive days before pMCAO. Ischemic lesion volume was measured by TTC staining. We show that systemically administered LNA antimir-337-3p crosses the blood brain-brain-barrier (BBB), penetrates into neurosn, downregulates endogenous miR-337-3p expression and reduces ischemic brain injury. The findings support the use of similar antimir-LNA constructs as novel therapies in neurological disease.
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Affiliation(s)
- Xiaomin Wang
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Yalikun Suofu
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Berkcan Akpinar
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Sergei V Baranov
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Jinho Kim
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Diane L Carlisle
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Yu Zhang
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States.
| | - Robert M Friedlander
- Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States.
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Millan MJ. Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer's disease: An integrative review. Prog Neurobiol 2017; 156:1-68. [PMID: 28322921 DOI: 10.1016/j.pneurobio.2017.03.004] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 03/09/2017] [Accepted: 03/09/2017] [Indexed: 02/06/2023]
Abstract
The human genome encodes a vast repertoire of protein non-coding RNAs (ncRNA), some specific to the brain. MicroRNAs, which interfere with the translation of target mRNAs, are of particular interest since their deregulation has been implicated in neurodegenerative disorders like Alzheimer's disease (AD). However, it remains challenging to link the complex body of observations on miRNAs and AD into a coherent framework. Using extensive graphical support, this article discusses how a diverse panoply of miRNAs convergently and divergently impact (and are impacted by) core pathophysiological processes underlying AD: neuroinflammation and oxidative stress; aberrant generation of β-amyloid-42 (Aβ42); anomalies in the production, cleavage and post-translational marking of Tau; impaired clearance of Aβ42 and Tau; perturbation of axonal organisation; disruption of synaptic plasticity; endoplasmic reticulum stress and the unfolded protein response; mitochondrial dysfunction; aberrant induction of cell cycle re-entry; and apoptotic loss of neurons. Intriguingly, some classes of miRNA provoke these cellular anomalies, whereas others act in a counter-regulatory, protective mode. Moreover, changes in levels of certain species of miRNA are a consequence of the above-mentioned anomalies. In addition to miRNAs, circular RNAs, piRNAs, long non-coding RNAs and other types of ncRNA are being increasingly implicated in AD. Overall, a complex mesh of deregulated and multi-tasking ncRNAs reciprocally interacts with core pathophysiological mechanisms underlying AD. Alterations in ncRNAs can be detected in CSF and the circulation as well as the brain and are showing promise as biomarkers, with the ultimate goal clinical exploitation as targets for novel modes of symptomatic and course-altering therapy.
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Affiliation(s)
- Mark J Millan
- Centre for Therapeutic Innovation in Neuropsychiatry, institut de recherche Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
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Mick E, Shah R, Tanriverdi K, Murthy V, Gerstein M, Rozowsky J, Kitchen R, Larson MG, Levy D, Freedman JE. Stroke and Circulating Extracellular RNAs. Stroke 2017; 48:828-834. [PMID: 28289238 PMCID: PMC5373984 DOI: 10.1161/strokeaha.116.015140] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 01/09/2017] [Accepted: 01/23/2017] [Indexed: 12/19/2022]
Abstract
Supplemental Digital Content is available in the text. Background and Purpose— There is increasing interest in extracellular RNAs (ex-RNAs), with numerous reports of associations between selected microRNAs (miRNAs) and a variety of cardiovascular disease phenotypes. Previous studies of ex-RNAs in relation to risk for cardiovascular disease have investigated small numbers of patients and assayed only candidate miRNAs. No human studies have investigated links between novel ex-RNAs and stroke. Methods— We conducted unbiased next-generation sequencing using plasma from 40 participants of the FHS (Framingham Heart Study; Offspring Cohort Exam 8) followed by high-throughput polymerase chain reaction of 471 ex-RNAs. The reverse transcription quantitative polymerase chain reaction included 331 of the most abundant miRNAs, 43 small nucleolar RNAs, and 97 piwi-interacting RNAs in 2763 additional FHS participants and explored the relations of ex-RNAs and prevalent (n=63) and incident (n=51) stroke and coronary heart disease (prevalent=286, incident=69). Results— After adjustment for multiple cardiovascular disease risk factors, 7 ex-RNAs were associated with stroke prevalence or incidence; there were no ex-RNA associated with prevalent or incident coronary heart disease. Statistically significant ex-RNA associations with stroke were specific, with no overlap between prevalent and incident events. Conclusions— This is the largest study of ex-RNAs in relation to stroke using an unbiased approach in an observational cohort and the first large study to examine human small noncoding RNAs beyond miRNAs. These results demonstrate that when studied in a large observational cohort, extracellular miRNAs are associated with stroke risk.
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Affiliation(s)
- Eric Mick
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Ravi Shah
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Kahraman Tanriverdi
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Venkatesh Murthy
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Mark Gerstein
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Joel Rozowsky
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Robert Kitchen
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Martin G Larson
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Daniel Levy
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.)
| | - Jane E Freedman
- From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
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Luginbühl J, Sivaraman DM, Shin JW. The essentiality of non-coding RNAs in cell reprogramming. Noncoding RNA Res 2017; 2:74-82. [PMID: 30159423 PMCID: PMC6096403 DOI: 10.1016/j.ncrna.2017.04.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/03/2017] [Accepted: 04/11/2017] [Indexed: 02/07/2023] Open
Abstract
In mammals, short (mi-) and long non-coding (lnc) RNAs are immensely abundant and they are proving to be more functional than ever before. Particularly in cell reprogramming, non-coding RNAs are essential to establish the pluripotent network and are indispensable to reprogram somatic cells to pluripotency. Through systematic screening and mechanistic studies, diverse functional features of both miRNA and lncRNAs have emerged as either scaffolds, inhibitors, or co-activators, necessary to orchestrate the intricacy of gene regulation. Furthermore, the collective characterizations of both miRNA and lncRNA reveal their interdependency (e.g. sequestering the function of the other) to modulate cell reprogramming. This review broadly explores the regulatory processes of cell reprogramming - with key functional examples in neuronal and cardiac differentiations - in the context of both short and long non-coding RNAs.
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Affiliation(s)
| | | | - Jay W. Shin
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan
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Martin D, Grapin-Botton A. The Importance of REST for Development and Function of Beta Cells. Front Cell Dev Biol 2017; 5:12. [PMID: 28286748 PMCID: PMC5323410 DOI: 10.3389/fcell.2017.00012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/07/2017] [Indexed: 01/10/2023] Open
Abstract
Beta cells are defined by the genes they express, many of which are specific to this cell type, and ensure a specific set of functions. Beta cells are also defined by a set of genes they should not express (in order to function properly), and these genes have been called forbidden genes. Among these, the transcriptional repressor RE-1 Silencing Transcription factor (REST) is expressed in most cells of the body, excluding most populations of neurons, as well as pancreatic beta and alpha cells. In the cell types where it is expressed, REST represses the expression of hundreds of genes that are crucial for both neuronal and pancreatic endocrine function, through the recruitment of multiple transcriptional and epigenetic co-regulators. REST targets include genes encoding transcription factors, proteins involved in exocytosis, synaptic transmission or ion channeling, and non-coding RNAs. REST is expressed in the progenitors of both neurons and beta cells during development, but it is down-regulated as the cells differentiate. Although REST mutations and deregulation have yet to be connected to diabetes in humans, REST activation during both development and in adult beta cells leads to diabetes in mice.
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Affiliation(s)
- David Martin
- Service of Cardiology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland
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Ma J, Shui S, Han X, Guo D, Li T, Yan L. microRNA-200a silencing protects neural stem cells against cerebral ischemia/reperfusion injury. PLoS One 2017; 12:e0172178. [PMID: 28222148 PMCID: PMC5319691 DOI: 10.1371/journal.pone.0172178] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 01/16/2017] [Indexed: 12/15/2022] Open
Abstract
Neural stem cells (NSCs) play major roles in neurological recovery after cerebral infarction (CI). This study was trying to investigate whether miR-200a, a vital regulator in cell proliferation, migration and apoptosis, also has a role in oxygen-glucose deprivation/reperfusion (OGD/R) injured NSCs. In this study, primary NSCs were subjected to OGD/R conditions to mimic an in vitro CI model. Before OGD/R induction, NSCs were transfected with vector or shRNA against miR-200a to overexpress or suppress miR-200a expression. The changes in cell viability, apoptosis, migration, the expression of c-Myc, and the phosphorylation of STAT1, STAT3 and MAPK were respectively assessed. Inhibitors of STAT1/3 and MAPK, i.e., Nifuroxazide and BIRB 796, were used to administrate miR-200a-silenced NSCs, and the expressions of above mentioned proteins were detected. After OGD/R exposure, miR-200a was up-regulated in NSCs (P < 0.001). miR-200a silencing alleviated OGD/R-induced the decrease of cell viability and migration (P < 0.01); meanwhile, alleviated OGD/R-induced apoptosis via reducing Bax/Bcl-2 ratio and down-regulating p53 and cytochrome c (P < 0.01 or P < 0.001). c-Myc, p-STAT1, p-STAT3, p-MAPK were all negatively regulated by miR-200a (P < 0.01 or P < 0.001); more important, the increase of c-Myc induced by miR-200a silencing was abolished by Nifuroxazide or BIRB 796 (P < 0.01 or P < 0.001). These data indicate miR-200a silencing protects NSCs from OGD/R-induced injury, possibly via regulating the STATs/c-Myc and MAPK/c-Myc signalings.
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Affiliation(s)
- Ji Ma
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shaofeng Shui
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- * E-mail:
| | - Dong Guo
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tengfei Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lei Yan
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Chandran R, Mehta SL, Vemuganti R. Non-coding RNAs and neuroprotection after acute CNS injuries. Neurochem Int 2017; 111:12-22. [PMID: 28131900 DOI: 10.1016/j.neuint.2017.01.015] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 01/17/2017] [Accepted: 01/24/2017] [Indexed: 02/07/2023]
Abstract
Accumulating evidence indicates that various classes of non-coding RNAs (ncRNAs) including microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and long non-coding RNAs (lncRNAs) play important roles in normal state as well as the diseases of the CNS. Interestingly, ncRNAs have been shown to interact with messenger RNA, DNA and proteins, and these interactions could induce epigenetic modifications and control transcription and translation, thereby adding a new layer of genomic regulation. The ncRNA expression profiles are known to be altered after acute CNS injuries including stroke, traumatic brain injury and spinal cord injury that are major contributors of morbidity and mortality worldwide. Hence, a better understanding of the functional significance of ncRNAs following CNS injuries could help in developing potential therapeutic strategies to minimize the neuronal damage in those conditions. The potential of ncRNAs in blood and CSF as biomarkers for diagnosis and/or prognosis of acute CNS injuries has also gained importance in the recent years. This review highlighted the current progress in the understanding of the role of ncRNAs in initiation and progression of secondary neuronal damage and their application as biomarkers after acute CNS injuries.
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Affiliation(s)
- Raghavendar Chandran
- Department of Neurological Surgery, University of Wisconsin-Madison and William S. Middleton Veterans Hospital, Madison, WI, USA
| | - Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin-Madison and William S. Middleton Veterans Hospital, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin-Madison and William S. Middleton Veterans Hospital, Madison, WI, USA.
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