DOCSLIB.ORG

Microrna21 Contributes to Myocardial Disease by Stimulating MAP Kinase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Microrna21 Contributes to Myocardial Disease by Stimulating MAP Kinase Vol 456 | 18/25 December 2008 | doi:10.1038/nature07511 LETTERS MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts Thomas Thum1,2*, Carina Gross3*, Jan Fiedler1,2, Thomas Fischer3, Stephan Kissler3, Markus Bussen5, Paolo Galuppo1, Steffen Just6, Wolfgang Rottbauer6, Stefan Frantz1, Mirco Castoldi7,8,Ju¨rgen Soutschek9, Victor Koteliansky10, Andreas Rosenwald4, M. Albert Basson11, Jonathan D. Licht12, John T. R. Pena13, Sara H. Rouhanifard13, Martina U. Muckenthaler7,8, Thomas Tuschl13, Gail R. Martin5, Johann Bauersachs1 & Stefan Engelhardt3,14 MicroRNAs comprise a broad class of small non-coding RNAs that fibroblasts; expression was highest in fibroblasts from the failing control expression of complementary target messenger RNAs1,2. heart, but was low in cardiomyocytes (Fig. 2c and data not shown). Dysregulation of microRNAs by several mechanisms has been 3–5 6–10 a Early stage Intermediate stage Late stage described in various disease states including cardiac disease . 2 ) Whereas previous studies of cardiac disease have focused on 2 microRNAs that are primarily expressed in cardiomyocytes, the 1 role of microRNAs expressed in other cell types of the heart is 0 unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK–MAP kinase signalling pathway in –1 control mice (log control failure model versus failure cardiac fibroblasts, which has impacts on global cardiac structure miRNA level in heart –2 and function. miR-21 levels are increased selectively in fibroblasts *** of the failing heart, augmenting ERK–MAP kinase activity through b Non-failing inhibition of sprouty homologue 1 (Spry1). This mechanism reg- 6 Failing ulates fibroblast survival and growth factor secretion, apparently Non-failing Failing *** controlling the extent of interstitial fibrosis and cardiac hyper- Early miR-21 4 trophy. In vivo silencing of miR-21 by a specific antagomir in a Intermediate miR-21 expression 2 mouse pressure-overload-induced disease model reduces cardiac Late miR-21 (fold control) miR-21 ERK–MAP kinase activity, inhibits interstitial fibrosis and attenu- 0 ates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibro- Early Late blasts. Our results validate miR-21 as a disease target in heart * Intermediate *** failure and establish the therapeutic efficacy of microRNA thera- c * d Non-failing Failing 5 peutic intervention in a cardiovascular disease setting. 3 pre- 100 4 In a transgenic mouse model of cardiac failure11, we found that the miR-21 2 3 cardiac microRNA expression signature was progressively deregu- 50 lated with increasing severity of the disease, with miR-21 expression 40 expression 2 12–14 1 30 being most strongly affected (Fig. 1a, b). Similarly, we observed control) (fold 1 miR-21/Rnu6-2 15,16 (fold non-failing) robust upregulation of miR-21 in other models of cardiac disease miR-21 miR-21 0 20 0 (Fig. 1c), as well as in human heart failure (Fig. 1d). The finding of Iso TAC Non- increased expression of the miR-21 precursor (pre-miR-21), as Failing failing assessed by northern blotting (Fig. 1d), suggested a transcriptional Control mechanism. Figure 1 | Deregulation of miR-21 expression in cardiac disease. Using in situ hybridization, we detected only weak miR-21 signals a, MicroRNA expression in left ventricular myocardium from control and in normal myocardium, whereas in failing myocardium the hybridi- b1-adrenergic receptor transgenic mice at various disease stages. miR-21 is marked in red. b, Northern blot analysis of miR-21 expression in mice from zation signal was greatly enhanced. At high magnification, the a. c, miR-21 expression in left ventricular myocardium from mice subjected hybridization signal was restricted primarily to small interstitial cells to TAC or isoproterenol (Iso) infusion. U6 small nuclear (Rnu6-2) was used (Fig. 2a), presumably cardiac fibroblasts. Consistent with our in situ as a control. d, Northern blot analysis of miR-21 in non-failing and failing hybridization data, when we isolated cell fractions from hearts human left ventricular myocardium. Data are mean and s.e.m.; *P , 0.05, (Fig. 2b), miR-21 expression was detected predominantly in cardiac ***P , 0.005. n 5 3–5 per experiment per group. 1Department of Medicine I, 2Junior Research Group, Interdisziplina¨res Zentrum fu¨r Klinische Forschung (IZKF), 3Rudolf Virchow Center, Deutsche Forschungsgemeinschaft (DFG) Research Center for Experimental Biomedicine, 4Institute of Pathology, University of Wuerzburg, 97080 Wuerzburg, Germany. 5Department of Anatomy, University of California, San Francisco, California 94158, USA. 6Department of Internal Medicine III, 7Department of Pediatric Hematology, Oncology and Immunology, 8Molecular Medicine Partnership Unit, University of Heidelberg, 69120 Heidelberg, Germany. 9Regulus Therapeutics, Carlsbad, California 92008, USA. 10Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, USA. 11Department of Craniofacial Development, King’s College, London SE1 9RT, UK. 12Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. 13Laboratory of RNA Molecular Biology, Rockefeller University, New York, New York 10065, USA. 14Institute of Pharmacology and Toxicology, Technische Universitaet Muenchen (TUM), 80802 Muenchen, Germany. *These authors contributed equally to this work. 980 ©2008 Macmillan Publishers Limited. All rights reserved NATURE | Vol 456 | 18/25 December 2008 LETTERS ad* synthetic miR-21 precursor led to a significant increase in fibroblast miR-21 RNA growth factor 2 (FGF2) secretion (Fig. 2f). Non-failing 30 Our expression data showing that miR-21 expression in cardiomyo- 20 cytes is low and does not increase in failing hearts (Fig. 2c) indicate that miR-21 does not have a significant function in cardiomyocytes. 10 Neither enhancement nor suppression of miR-21 levels affected the 0 morphology, size or number of primary rat cardiomyocytes under Non-failing Failing resting or hypertrophy-inducing conditions (Supplementary Fig. 1). Failing *** We also generated transgenic mice overexpressing miR-21 in cardio- e *** myocytes (Supplementary Fig. 2a), but detected no notable differ- 15 *** ences in myocardial structure or function, either with age or when * scr-miR subjected to cardiac pressure overload (Supplementary Fig. 2a, b). 10 pre- Moreover, very few differences were detected by transcriptional miR-21 profiling or by determination of protein expression of predicted Apoptosis (% annexin-V-positive cells) Apoptosis (% annexin-V-positive 5 miR-21 targets in left ventricular myocardium from such miR-21 anti- b Cardiac Cardio- 0 miR-21 transgenic mice and their wild-type littermates (Supplementary Fig. fibroblasts myocytes Control PD98059 2c and data not shown). Likewise, we found few transcriptome P4HB c * f changes in primary cardiomyocytes transfected with miR-21 precur- 12 scr-miR pre-miR-21 sors and controls (Supplementary Fig. 2d). Although it has recently p-ERK1/2 been suggested that overexpression of miR-21 alters cardiomyocyte 8 14 ACTN2 morphology , our data provide strong evidence that miR-21 exerts its ERK1/2 4 effects on the heart primarily in cardiac fibroblasts. CM * Using bioinformatic algorithms to predict miR-21 targets, we iden- CF 0 tified SPRY1, a potent inhibitor of the Ras/MEK/ERK pathway19,20,asa Rnu6-2 ** 4 PECAM1 / Neonatal * 3 candidate messenger RNA target (Supplementary Table 1). The 8 3 39 untranslated region (UTR) of Spry1 mRNA contains several pre- ** miR-21 6 2 dicted microRNA-binding sites, of which only one corresponds to a 2 ACTA2 4 microRNA highly upregulated during cardiac disease (that is, miR-21). 1 1 We also identified a few other potential miR-21 targets, but these were (fold control) 2 p-ERK/ERK unaffected or only moderately downregulated on miR-21 expression in 0 0 FGF2 in supernatant 0 Adult fibroblasts (Supplementary Fig. 3). Transfection of primary cardiac fibroblasts with miR-21 precursors had no detectable effect on the Non- Spry1 mRNA level (data not shown), but resulted in strong repression failing Failing scr-miR scr-miR pre-miR-21 pre-miR-21 of SPRY1 protein expression (Fig. 3a), indicating that miR-21 affects Figure 2 | miR-21 promotes ERK–MAP-kinase-mediated cell survival in Spry1 expression by repressing translation. When we fused the Spry1 cardiac fibroblasts. a, In situ hybridization of miR-21 in non-failing and 39 UTR to a luciferase reporter gene and determined luciferase activity failing myocardium. Scale bar, 100 mm. b, Cell fractions from rat hearts in cells transfected with synthetic miR-21 precursors, miR-21 signifi- stained with DAPI and antibodies against prolyl 4-hydroxylase (P4HB), a2- cantly repressed luciferase activity, whereas neither miR-133a nor actinin (ACTN2), CD31 (PECAM1) and smooth muscle a2-actin (ACTA2). miR-206 had any effect (Fig. 3a). These experiments identify Spry1 Scale bar, 100 mm. c, miR-21 expression in cardiomyocytes (CM) and cardiac as a direct target of miR-21. fibroblasts (CF) isolated from neonatal rat or adult mouse hearts. We next determined the Spry1 expression pattern in the heart. In d, Percentage apoptotic cells in the cardiac fibroblast fraction isolated from situ hybridization on sections of neonatal wild-type heart showed b individual non-failing (wild-type) and failing (intermediate stage 1- that within the myocardium Spry1 mRNA localized to interstitial adrenergic receptor transgenic) mouse hearts. Horizontal bars indicate the mean. e, Percentage apoptotic primary rat cardiac fibroblasts after treatment cells and the smooth muscle of the coronary vessels, but was not with scrambled-miR (scr-miR), synthetic miR-21 (pre-miR-21), miR-21 detected in cardiomyocytes (data not shown). We generated an allele lacZ antagonists (anti-miR-21) and the ERK–MAP kinase inhibitor PD98059. of mouse Spry1 (Spry1 ) in which the lacZ gene replaces part of the f, Western blot assay for ERK1/2 and phospho-ERK1/2 (p-ERK1/2), and Spry1 coding sequence (Supplementary Fig. 4). Assays for lacZ ELISA of secreted FGF2. Data are mean and s.e.m.; *P , 0.05, **P , 0.01, expression in 3-week-old Spry1lacZ/1 animals indicated that Spry1 ***P , 0.005.
Load more

Recommended publications
  • Microrna-33A Regulates Cholesterol Synthesis and Cholesterol Efflux
    Kostopoulou et al. Arthritis Research & Therapy (2015) 17:42 DOI 10.1186/s13075-015-0556-y RESEARCH ARTICLE Open Access MicroRNA-33a regulates cholesterol synthesis and cholesterol efflux-related genes in osteoarthritic chondrocytes Fotini Kostopoulou1,2, Konstantinos N Malizos2,3, Ioanna Papathanasiou1 and Aspasia Tsezou1,2,4* Abstract Introduction: Several studies have shown that osteoarthritis (OA) is strongly associated with metabolism-related disorders, highlighting OA as the fifth component of the metabolic syndrome (MetS). On the basis of our previous findings on dysregulation of cholesterol homeostasis in OA, we were prompted to investigate whether microRNA-33a (miR-33a), one of the master regulators of cholesterol and fatty acid metabolism, plays a key role in OA pathogenesis. Methods: Articular cartilage samples were obtained from 14 patients with primary OA undergoing total knee replacement surgery. Normal cartilage was obtained from nine individuals undergoing fracture repair surgery. Bioinformatics analysis was used to identify miR-33a target genes. miR-33a and sterol regulatory element-binding protein 2 (SREBP-2) expression levels were investigated using real-time PCR, and their expression was also assessed after treatment with transforming growth factor-β1(TGF-β1) in cultured chondrocytes.Aktphosphorylationafter treatment with both TGF-β1 and miR-33a inhibitor or TGF-β1 and miR-33a mimic was assessed by Western blot analysis. Furthermore, we evaluated the effect of miR-33a mimic and miR-33a inhibitor on Smad7,anegative regulator of TGF-β signaling, on cholesterol efflux-related genes, ATP-binding cassette transporter A1 (ABCA1), apolipoprotein A1 (ApoA1)andliverXreceptors(LXRα and LXRβ), as well as on matrix metalloproteinase-13 (MMP-13), using real-time PCR.
    [Show full text]
  • Ablation of Mir-144 Increases Vimentin Expression and Atherosclerotic Plaque Formation Quan He1, Fangfei Wang1, Takashi Honda1, Kenneth D
    www.nature.com/scientificreports OPEN Ablation of miR-144 increases vimentin expression and atherosclerotic plaque formation Quan He1, Fangfei Wang1, Takashi Honda1, Kenneth D. Greis2 & Andrew N. Redington1* It has been suggested that miR-144 is pro-atherosclerotic via efects on reverse cholesterol transportation targeting the ATP binding cassette protein. This study used proteomic analysis to identify additional cardiovascular targets of miR-144, and subsequently examined the role of a newly identifed regulator of atherosclerotic burden in miR-144 knockout mice receiving a high fat diet. To identify afected secretory proteins, miR-144 treated endothelial cell culture medium was subjected to proteomic analysis including two-dimensional gel separation, trypsin digestion, and nanospray liquid chromatography coupled to tandem mass spectrometry. We identifed 5 gel spots representing 19 proteins that changed consistently across the biological replicates. One of these spots, was identifed as vimentin. Atherosclerosis was induced in miR-144 knockout mice by high fat diet and vascular lesions were quantifed by Oil Red-O staining of the serial sectioned aortic root and from en-face views of the aortic tree. Unexpectedly, high fat diet induced extensive atherosclerosis in miR-144 knockout mice and was accompanied by severe fatty liver disease compared with wild type littermates. Vimentin levels were reduced by miR-144 and increased by antagomiR-144 in cultured cardiac endothelial cells. Compared with wild type, ablation of the miR-144/451 cluster increased plasma vimentin, while vimentin levels were decreased in control mice injected with synthetic miR-144. Furthermore, increased vimentin expression was prominent in the commissural regions of the aortic root which are highly susceptible to atherosclerotic plaque formation.
    [Show full text]
  • Cancer Stem Cells in Pancreatic Cancer
    Cancers 2010, 2, 1629-1641; doi:10.3390/cancers2031629 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Cancer Stem Cells in Pancreatic Cancer Qi Bao †, Yue Zhao †, Andrea Renner, Hanno Niess, Hendrik Seeliger, Karl-Walter Jauch and Christiane J. Bruns * Department of Surgery, Ludwig Maximilian University of Munich, Klinikum Grosshadern, Marchioninistr. 15, D-81377, Munich, Germany; E-Mails: [email protected] (Q.B.); [email protected] (Y.Z.); [email protected] (A.R.); [email protected] (H.N.); [email protected] (H.S.); [email protected] (K.W.J.) † These authors contributed equally to this work. * Author to whom correspondence should be addressed; Tel.: +49-89-7095-3570; Fax: +49-89-7095-8894; E-Mail: [email protected]. Received: 2 July 2010; in revised form: 29 July 2010 / Accepted: 18 August 2010 / Published: 19 August 2010 Abstract: Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer. Keywords: cancer stem cells; pancreatic cancer; signaling pathways; metastasis; CSC-related therapy; microRNAs 1. Introduction Stem cells are a subpopulation of cells that have the capability to differentiate into multiple cell types and maintain their self-renewal activity.
    [Show full text]
  • Sprouty Proteins, Masterminds of Receptor Tyrosine Kinase Signaling
    CORE Metadata, citation and similar papers at core.ac.uk Provided by RERO DOC Digital Library Angiogenesis (2008) 11:53–62 DOI 10.1007/s10456-008-9089-1 ORIGINAL PAPER Sprouty proteins, masterminds of receptor tyrosine kinase signaling Miguel A. Cabrita Æ Gerhard Christofori Received: 14 December 2007 / Accepted: 7 January 2008 / Published online: 25 January 2008 Ó Springer Science+Business Media B.V. 2008 Abstract Angiogenesis relies on endothelial cells prop- Abbreviations erly processing signals from growth factors provided in Ang Angiopoietin both an autocrine and a paracrine manner. These mitogens c-Cbl Cellular homologue of Casitas B-lineage bind to their cognate receptor tyrosine kinases (RTKs) on lymphoma proto-oncogene product the cell surface, thereby activating a myriad of complex EGF Epidermal growth factor intracellular signaling pathways whose outputs include cell EGFR EGF receptor growth, migration, and morphogenesis. Understanding how eNOS Endothelial nitric oxide synthase these cascades are precisely controlled will provide insight ERK Extracellular signal-regulated kinase into physiological and pathological angiogenesis. The FGF Fibroblast growth factor Sprouty (Spry) family of proteins is a highly conserved FGFR FGF receptor group of negative feedback loop modulators of growth GDNF Glial-derived neurotrophic factor factor-mediated mitogen-activated protein kinase (MAPK) Grb2 Growth factor receptor-bound protein 2 activation originally described in Drosophila. There are HMVEC Human microvascular endothelial cell four mammalian orthologs (Spry1-4) whose modulation of Hrs Hepatocyte growth factor-regulated tyrosine RTK-induced signaling pathways is growth factor – and kinase substrate cell context – dependant. Endothelial cells are a group of HUVEC Human umbilical vein endothelial cell highly differentiated cell types necessary for defining the MAPK Mitogen-activated protein kinase mammalian vasculature.
    [Show full text]
  • T Cell Depending on the Differentiation State of the Dual
    Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell This information is current as Heonsik Choi, Sung-Yup Cho, Ronald H. Schwartz and of September 29, 2021. Kyungho Choi J Immunol 2006; 176:6034-6045; ; doi: 10.4049/jimmunol.176.10.6034 http://www.jimmunol.org/content/176/10/6034 Downloaded from References This article cites 63 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/176/10/6034.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell1 Heonsik Choi,* Sung-Yup Cho,† Ronald H. Schwartz,* and Kyungho Choi2* Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/ MAPK pathway.
    [Show full text]
  • Development of Novel Therapeutic Agents by Inhibition of Oncogenic Micrornas
    International Journal of Molecular Sciences Review Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs Dinh-Duc Nguyen and Suhwan Chang * ID Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea; [email protected] * Correspondence: [email protected] Received: 21 November 2017; Accepted: 22 December 2017; Published: 27 December 2017 Abstract: MicroRNAs (miRs, miRNAs) are regulatory small noncoding RNAs, with their roles already confirmed to be important for post-transcriptional regulation of gene expression affecting cell physiology and disease development. Upregulation of a cancer-causing miRNA, known as oncogenic miRNA, has been found in many types of cancers and, therefore, represents a potential new class of targets for therapeutic inhibition. Several strategies have been developed in recent years to inhibit oncogenic miRNAs. Among them is a direct approach that targets mature oncogenic miRNA with an antisense sequence known as antimiR, which could be an oligonucleotide or miRNA sponge. In contrast, an indirect approach is to block the biogenesis of miRNA by genome editing using the CRISPR/Cas9 system or a small molecule inhibitor. The development of these inhibitors is straightforward but involves significant scientific and therapeutic challenges that need to be resolved. In this review, we summarize recent relevant studies on the development of miRNA inhibitors against cancer. Keywords: antimiR; antagomiR; miRNA-sponge; oncomiR; CRISPR/Cas9; cancer therapeutics 1. Introduction Cancer has been the leading cause of death and a major health problem worldwide for many years; basically, it results from out-of-control cell proliferation. Traditionally, several key proteins have been identified and found to affect signaling pathways regulating cell cycle progression, apoptosis, and gene transcription in various types of cancers [1,2].
    [Show full text]
  • Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
    ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight.
    [Show full text]
  • The Positive Effect of Mir1 Antagomir on Ischemic Neurological Disorders Via Changing the Expression of Bcl-W and Bad Genes
    Basic and Clinical November, December 2020, Volume 11, Number 6 Research Paper: The Positive Effect of MiR1 Antagomir on Ischemic Neurological Disorders Via Changing the Expression of Bcl-w and Bad Genes Anis Talebi1 , Mehdi Rahnema2 , Mohammad Reza Bigdeli1* 1. Department of Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran. 2. Department of Biology, Faculty of Engineering and Basic Sciences, Zanjan Branch, Islamic Azad University, Zanjan, Iran. Use your device to scan and read the article online Citation: Talebi, A., Rahnema, M., & Bigdeli, M. R. (2020). The Positive Effect of MiR1 Antagomir on Ischemic Neurological Disorders Via Changing the Expression of Bcl-w and Bad Genes. Basic and Clinical Neuroscience, 11(6), 811-820. http://dx.doi. org/10.32598/bcn.11.6.324.3 : http://dx.doi.org/10.32598/bcn.11.6.324.3 A B S T R A C T Introduction: MicroRNAs (miRNAs or miRs) are non-coding RNAs. Studies have shown that miRNAs are expressed aberrantly in stroke. The miR1 enhances ischemic damage, and Article info: a previous study has demonstrated that reduction of miR1 level has a neuroprotective effect Received: 26 Feb 2018 on the Middle Cerebral Artery Occlusion (MCAO). Since apoptosis is one of the important First Revision:10 Mar 2018 processes in neural protection, the possible effect of miR1 on this pathway has been tested in Accepted: 15 Oct 2019 this study. Post-ischemic administration of miR1 antagomir reduces infarct volume via bcl-w Available Online: 01 Nov 2020 and bad expression. Methods: Rats were divided into four experimental groups: sham, control, positive control, and antagomir treatment group.
    [Show full text]
  • Thesis Resubmission Daphne Chen
    Integrative Modelling of Glucocorticoid Induced Apoptosis with a Systems Biology Approach A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Life Sciences 2012 Daphne Wei-Chen Chen 1 Table of Contents List of Abbreviations ..................................................................................................................... 7 List of Tables ................................................................................................................................ 11 List of Figures .............................................................................................................................. 12 Abstract ........................................................................................................................................ 14 Short Abstract ............................................................................................................................. 15 Declaration ................................................................................................................................... 15 Copyright Statement ................................................................................................................... 15 Acknowledgements ...................................................................................................................... 16 1 CHAPTER 1: Introduction .......................................................................................... 17 1.1 Glucocorticoids (GCs) .................................................................................................
    [Show full text]
  • Microrna Regulation of Human Pancreatic Cancer Stem Cells
    Review Article Page 1 of 7 microRNA regulation of human pancreatic cancer stem cells Yi-Fan Xu, Bethany N. Hannafon, Wei-Qun Ding Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Dr. Wei-Qun Ding. Department of Pathology, University of Oklahoma Health Sciences Center, BRC 411A, 975 NE 10th Street, Oklahoma City, OK 73104, USA. Email: [email protected]. Abstract: microRNAs (miRNAs) are a group of small non-coding RNAs that function primarily in the post transcriptional regulation of gene expression in plants and animals. Deregulation of miRNA expression in cancer cells, including pancreatic cancer cells, is well documented, and the involvement of miRNAs in orchestrating tumor genesis and cancer progression has been recognized. This review focuses on recent reports demonstrating that miRNAs are involved in regulation of pancreatic cancer stem cells (CSCs). A number of miRNA species have been identified to be involved in regulating pancreatic CSCs, including miR-21, miR-34, miR-1246, miR-221, the miR-17-92 cluster, the miR-200 and let-7 families. Furthermore, the Notch-signaling pathway and epithelial-mesenchymal transition (EMT) process are associated with miRNA regulation of pancreatic CSCs. Given the significant contribution of CSCs to chemo-resistance and tumor progression, a better understanding of how miRNAs function in pancreatic CSCs could provide novel strategies for the development of therapeutics and diagnostics for this devastating disease.
    [Show full text]
  • Mir-122 in Hepatic Function and Liver Diseases
    Protein Cell 2012, 3(5): 364–371 DOI 10.1007/s13238-012-2036-3 Protein & Cell REVIEW MiR-122 in hepatic function and liver diseases Jun Hu, Yaxing Xu, Junli Hao, Saifeng Wang, Changfei Li, Songdong Meng CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China Correspondence: [email protected] Received February 5, 2012 Accepted February 22, 2012 ABSTRACT habditis elegans, especially the subsequent identification of another miRNA let-7 as a new posttranscriptional regulator of As the most abundant liver-specific microRNA, mi- gene expression more than a decade ago (Fire et al., 1998; croRNA-122 (miR-122) is involved in various physio- Reinhart et al., 2000), the small non-coding RNA known as logical processes in hepatic function as well as in liver miRNA has been extensively studied in plants, animals and pathology. There is now compelling evidence that miR- human beings. miRNAs are a large class of small non-coding 122, as a regulator of gene networks and pathways in and double-stranded RNA molecules of approximately 22 hepatocytes, plays a central role in diverse aspects of nucleotides in length. Full-length miRNAs are transcripted by hepatic function and in the progress of liver diseases. RNA polymerase II, which are called pri-miRNAs (hairpin This liver-enriched transcription factors-regulated precursors). These pri-miRNAs are processed by Drosha miRNA promotes differentiation of hepatocytes and within the nuclear compartment to produce pre-miRNAs
    [Show full text]
  • Therapeutic Evaluation of Micrornas by Molecular Imaging Thillai V
    Theranostics 2013, Vol. 3, Issue 12 964 Ivyspring International Publisher Theranostics 2013; 3(12):964-985. doi: 10.7150/thno.4928 Review Therapeutic Evaluation of microRNAs by Molecular Imaging Thillai V. Sekar1, Ramkumar Kunga Mohanram1, 2, Kira Foygel1, and Ramasamy Paulmurugan1 1. Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA. 2. Current address: SRM Research Institute, SRM University, Kattankulathur– 603 203, Tamilnadu, India Corresponding author: Ramasamy Paulmurugan, Ph.D. Department of Radiology, Stanford University School of Medicine, 1501, South California Avenue, #2217, Palo Alto, CA 94304. Phone: 650-725-6097; Fax: 650-721-6921. Email: [email protected] © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2013.07.26; Accepted: 2013.09.22; Published: 2013.12.06 Abstract MicroRNAs (miRNAs) function as regulatory molecules of gene expression with multifaceted activities that exhibit direct or indirect oncogenic properties, which promote cell proliferation, differentiation, and the development of different types of cancers. Because of their extensive functional involvement in many cellular processes, under both normal and pathological conditions such as various cancers, this class of molecules holds particular interest for cancer research. MiRNAs possess the ability to act as tumor suppressors or oncogenes by regulating the expression of different apoptotic proteins, kinases, oncogenes, and other molecular mechanisms that can cause the onset of tumor development.
    [Show full text]