DOCSLIB.ORG

Androgen-Mediated Improvement of Body Composition and Muscle

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Androgen-Mediated Improvement of Body Composition and Muscle 55 Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of b-catenin Michael A Gentile, Pascale V Nantermet, Robert L Vogel, Robert Phillips1, Daniel Holder2, Paul Hodor1, Chun Cheng1, Hongyue Dai1, Leonard P Freedman and William J Ray Merck Research Laboratories, Department of Molecular Endocrinology, West Point, Pennsylvania 19486, USA 1Department of Molecular Profiling, Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc., West Point, Pennsylvania 19486, USA 2Merck Research Laboratories, Department of Biometrics, West Point, Pennsylvania 19486, USA (Correspondence should be addressed to W J Ray who is now at Merck Research Laboratories, Department of Alzheimer’s Disease Research, West Point, Pennsylvania 19486, USA; Email: [email protected]) Abstract Androgens promote anabolism in the musculoskeletal system while generally repressing adiposity, leading to lean body composition. Circulating androgens decline with age, contributing to frailty, osteoporosis, and obesity; however, the mechanisms by which androgens modulate body composition are largely unknown. Here, we demonstrate that aged castrated rats develop increased fat mass, reduced muscle mass and strength, and lower bone mass. Treatment with testosterone or 5a-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable testosterone increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of IGF1 and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, monocyte nuclear factor, or myostatin. A genome-wide microarray screen was also performed to identify potential pro-myogenic genes that respond to androgen receptor activation in vivo within 24 h. Of 24 000 genes examined, 70 candidate genes were identified whose functions suggest initiation of remodeling and regeneration, including the type II muscle genes for myosin heavy chain type II and parvalbumin and the chemokine monocyte chemoattractant protein-1. Interestingly, Axin and Axin2, negative regulators of b-catenin, were repressed, indicating modulation of the b-catenin pathway. DHT increased total levels of b-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear b-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of b-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor. Journal of Molecular Endocrinology (2010) 44, 55–73 Introduction This loss of endogenous androgens parallels several symptoms of aging, including decreased muscle mass Androgens are important endocrine regulators of male and function (Snyder et al. 1999), increased visceral fat sexual development and maintenance of muscle, bone, (Katznelson et al. 1998) and bone loss (Katznelson et al. adipose tissue, and body composition (Vermeulen 1996). Treatment with testosterone improves muscle 1998, Vermeulen et al. 1999). Testosterone, the major mass and strength, bone density, and reduces visceral circulating androgen, can act directly or be converted fat in a variety of subjects (Bardin 1996, Katznelson et al. to the more potent androgen 5a-dihydrotestosterone 1996, Bhasin et al. 1997, 2000, Swerdloff & Wang 2003). (DHT) by 5a-reductase, or to estrogens by aromatase Thus, restoring androgens to youthful levels could (Russell & Wilson 1994, Simpson et al. 1994). Both potentially be used to manage sarcopenia, osteoporosis, testosterone and DHT activate the androgen receptor visceral obesity, and frailty. (AR), a nuclear receptor that functions as a transcrip- The mechanisms by which androgens promote tion factor in hormone-sensitive cells (Chang et al. 1995, anabolism in adult animals are largely unknown. AR Heinlein & Chang 2002). After reaching peak levels is detectable in bone and muscle cells, but levels are in early adulthood, androgen levels decline with age low compared with reproductive tissues such as the in both sexes (Tenover 1994, Lamberts et al. 1997). prostate and levator ani muscle (Antonio et al. 1999, Journal of Molecular Endocrinology (2010) 44, 55–73 DOI: 10.1677/JME-09-0048 0952–5041/10/044–055 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 05:54:11PM via free access 56 M A GENTILE and others . Androgen control of body composition Monks et al. 2004). Nevertheless, castration in rats b-Catenin, through its action in cell adhesion and reduces contractile force in muscles of the hindlimb Wnt signal transduction, plays a critical role in (Brown et al. 2001) and produces ultrastructural signs of embryonic development and regulation of adult stem degeneration and reduced protein synthesis (Ustunel cell populations in various tissues (Clevers 2006). et al. 2003). Treatment with anti-androgens limits gains In vitro, b-catenin is both necessary and sufficient for in muscle strength during weight training (Ruzic et al. myogenesis and inhibits adipogenesis (Ross et al. 2000, 2003). Conversely, repletion with testosterone increases Petropoulos & Skerjanc 2002). Moreover, b-catenin is lean mass and muscle strength, improves nitrogen balance, essential for adult skeletal muscle growth and regen- and induces myofiber hypertrophy (Sinha-Hikim et al. eration in vivo (Polesskaya et al. 2003, Reya & Clevers 2002). Thus, testosterone regulates both the mass and 2005, Armstrong et al. 2006), and myonuclear b-catenin function of skeletal muscle in adults. is up-regulated during overload-induced muscle hyper- At the cellular level, the effects of testosterone on trophy in adults (Armstrong & Esser 2005). Muscle body composition might involve recruitment or acti- regrowth following atrophy is associated with down- vation of resident myogenic precursor cells to existing regulation of glycogen synthase kinase-3b (GSK3b), a myofibers (Chen et al. 2005b). Satellite cells cultured negative regulator of b-catenin (van der Velden et al. from porcine muscle express AR, and AR agonists delay 2007, Schakman et al. 2008). Finally, b-catenin promotes their differentiation (Doumit et al. 1996). Furthermore, self-renewal of satellite stem cells (Perez-Ruiz et al. in muscle biopsies from men that exhibited gains in 2008) Together, these findings suggest that Wnt/ myofiber volume and strength following 20 weeks of b-catenin signaling plays an active role in the mainten- testosterone treatment, satellite cell number was ance of body composition in adults. However, the role increased (Sinha-Hikim et al.2003). Other studies for b-catenin in androgen-mediated muscle growth has report changes in the local expression of insulin-like not been studied. growth factor 1 (IGF1) in muscle samples from patients An important step towards understanding andro- receiving anabolic androgens (Sheffield-Moore 2000, genic signaling in regulating body composition will be Ferrando et al. 2002). As IGF1 and its related splice to define the processes governed by AR and the cell variants stimulate satellite cell proliferation and pro- type(s) in which AR exerts its anabolic effect. Since mote muscle hypertrophy (Musaro et al. 2001, Hill & many studies use testosterone, the relative contri- Goldspink 2003, Goldspink & Yang 2004), these data butions of the AR and estrogen receptors are ambig- suggest that androgens regulate muscle mass by this uous, and some report that estrogen is an essential mechanism. Some in vitro data support the concept that component of androgenic anabolism (Bilezikian et al. androgens act directly on satellite or other precursor 1998, Vandenput et al. 2002). Furthermore, the genes cells. Murine C2C12 cells, which resemble myogenic targeted by AR in muscle, fat, and bone are unknown. precursors, do not express AR, but when AR expression To address these issues, we validated the castrated rat is produced by transfection, AR-selective ligands model and characterized the effects of DHT in the increase myogenin expression and accelerate myoblast soleus muscle and identified genes that respond to differentiation and fusion (Lee 2002, Vlahopoulos et al. DHT within the first week of treatment and are 2005). Mouse C3H10T1/2 fibroblast cells express potential downstream effectors of anabolic action. endogenous AR, and DHT inhibits their differentiation into adipocytes and promotes the expression of MyoD and myosin heavy chain type II (MHC2; Compston 2001, Singh et al. 2003). In addition to satellite cells, AR is Materials and methods expressed in mature myofibers (Saartok et al. 1984, Sar Animal studies and analysis of body composition et al. 1990) in several types of motoneurons (Lumbroso et al. 1996, Piccioni et al. 2001), and in intramuscular All animal studies described in this report were fibroblasts (Monks et al. 2004), and thus could influence approved by the Institutional Animal Care and Use growth and function through activation in these cells. Committee. Sprague–Dawley rats (Taconic, Hudson, Finally, androgens regulate systemic levels of IGF1, GH, NY, USA) were purchased following orchidectomy and thyroid hormone, and may oppose the actions of (ORX) or sham orchidectomy (SHAM) at 10 weeks of glucocorticoids, any of which could contribute to the age and maintained
Load more

Recommended publications
  • Ctsr, the Master Regulator of Stress-Response in Oenococcus
    CtsR, the Master Regulator of Stress-Response in Oenococcus oeni, Is a Heat Sensor Interacting With ClpL1 Maud Darsonval, Frédérique Julliat, Tarek Msadek, Hervé Alexandre, Cosette Grandvalet To cite this version: Maud Darsonval, Frédérique Julliat, Tarek Msadek, Hervé Alexandre, Cosette Grandvalet. CtsR, the Master Regulator of Stress-Response in Oenococcus oeni, Is a Heat Sensor Interacting With ClpL1. Frontiers in Microbiology, Frontiers Media, 2018, 9, pp.1-14. 10.3389/fmicb.2018.03135. hal-01986589 HAL Id: hal-01986589 https://hal.archives-ouvertes.fr/hal-01986589 Submitted on 18 Jan 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License fmicb-09-03135 December 15, 2018 Time: 15:10 # 1 ORIGINAL RESEARCH published: 18 December 2018 doi: 10.3389/fmicb.2018.03135 CtsR, the Master Regulator of Stress-Response in Oenococcus oeni, Is a Heat Sensor Interacting With ClpL1 Maud Darsonval1†, Frédérique Julliat1†, Tarek Msadek2,3, Hervé Alexandre1,4 and Cosette Grandvalet1,5* 1 UMR
    [Show full text]
  • Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2246 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Ryan C. Fassnacht 2010 All Rights Reserved Molecular Mechanisms Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Ryan Christopher Fassnacht, B.S. Hampden Sydney University, 2005 M.S. Virginia Commonwealth University, 2010 Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery Virginia Commonwealth University Richmond, Virginia July 9, 2010 Acknowledgement The Author wishes to thank his family and close friends for their support. He would also like to thank the members of the molecular transplant team for their help and advice. This project would not have been possible with out the help of Dr. Valeria Mas and her endearing
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • A Negative Feedback Loop of the TOR Signaling Moderates Growth And
    bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 A negative feedback loop of the TOR signaling moderates 2 growth and enables rapid sensing of stress signals in plants 3 Muhammed Jamsheer K1#*<, Sunita Jindal1#>, Mohan Sharma1, Manvi Sharma1, Sreejath Sivaj2, 4 Chanchal Thomas Mannully1^, Ashverya Laxmi1* 5 1National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi 110067, India 6 2Department of Mechanical Engineering, Indian Institute of Technology Delhi, New Delhi, 110016, 7 India 8 9 <Current affiliation: Amity Food & Agriculture Foundation, Amity University Uttar Pradesh, Sector 10 125, Noida 201313, India 11 ^Current affiliation: Cell Metabolism Laboratory, School of Pharmacy, The Hebrew University of 12 Jerusalem, Jerusalem, 9112102, Israel 13 >Current affiliation: Department of Molecular Biology and Radiology, Mendel University in Brno, 14 Brno, 613 00, Czech Republic 15 16 #Equal first authors 17 18 *Corresponding authors 19 Ashverya Laxmi 20 Muhammed Jamsheer K 21 Email: AL: [email protected] (Lead Contact); MJK: [email protected] 22 ORCID: Ashverya Laxmi (0000-0002-3430-4200); Muhammed Jamsheer K (0000-0002-2135- 23 8760) 24 25 26 27 28 29 30 31 32 33 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved.
    [Show full text]
  • Proquest Dissertations
    University of Alberta Identification of differentially expressed genes in chronic wasting disease infected elk by Sandor C. Dudas //M A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Animal Science Department of Agricultural, Food and Nutritional Sciences Edmonton, Alberta Spring 2009 Library and Archives Bibliotheque et 1*1 Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-54675-8 Our file Notre reference ISBN: 978-0-494-54675-8 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library and permettant a la Bibliotheque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par I'lnternet, preter, telecommunication or on the Internet, distribuer et vendre des theses partout dans le loan, distribute and sell theses monde, a des fins commerciales ou autres, sur worldwide, for commercial or non­ support microforme, papier, electronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in this et des droits moraux qui protege cette these. Ni thesis. Neither the thesis nor la these ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent etre imprimes ou autrement printed or otherwise reproduced reproduits sans son autorisation.
    [Show full text]
  • Application of Microrna Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease
    Article Application of microRNA Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease Jennifer L. Major, Rushita A. Bagchi * and Julie Pires da Silva * Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; [email protected] * Correspondence: [email protected] (R.A.B.); [email protected] (J.P.d.S.) Supplementary Tables Methods Protoc. 2021, 4, 5. https://doi.org/10.3390/mps4010005 www.mdpi.com/journal/mps Methods Protoc. 2021, 4, 5. https://doi.org/10.3390/mps4010005 2 of 25 Table 1. List of all hsa-miRs identified by Human microRNA Disease Database (HMDD; v3.2) analysis. hsa-miRs were identified using the term “genetics” and “circulating” as input in HMDD. Targets CAD hsa-miR-1 Targets IR injury hsa-miR-423 Targets Obesity hsa-miR-499 hsa-miR-146a Circulating Obesity Genetics CAD hsa-miR-423 hsa-miR-146a Circulating CAD hsa-miR-149 hsa-miR-499 Circulating IR Injury hsa-miR-146a Circulating Obesity hsa-miR-122 Genetics Stroke Circulating CAD hsa-miR-122 Circulating Stroke hsa-miR-122 Genetics Obesity Circulating Stroke hsa-miR-26b hsa-miR-17 hsa-miR-223 Targets CAD hsa-miR-340 hsa-miR-34a hsa-miR-92a hsa-miR-126 Circulating Obesity Targets IR injury hsa-miR-21 hsa-miR-423 hsa-miR-126 hsa-miR-143 Targets Obesity hsa-miR-21 hsa-miR-223 hsa-miR-34a hsa-miR-17 Targets CAD hsa-miR-223 hsa-miR-92a hsa-miR-126 Targets IR injury hsa-miR-155 hsa-miR-21 Circulating CAD hsa-miR-126 hsa-miR-145 hsa-miR-21 Targets Obesity hsa-mir-223 hsa-mir-499 hsa-mir-574 Targets IR injury hsa-mir-21 Circulating IR injury Targets Obesity hsa-mir-21 Targets CAD hsa-mir-22 hsa-mir-133a Targets IR injury hsa-mir-155 hsa-mir-21 Circulating Stroke hsa-mir-145 hsa-mir-146b Targets Obesity hsa-mir-21 hsa-mir-29b Methods Protoc.
    [Show full text]
  • New Mesh Headings for 2018 Single Column After Cutover
    New MeSH Headings for 2018 Listed in alphabetical order with Heading, Scope Note, Annotation (AN), and Tree Locations 2-Hydroxypropyl-beta-cyclodextrin Derivative of beta-cyclodextrin that is used as an excipient for steroid drugs and as a lipid chelator. Tree locations: beta-Cyclodextrins D04.345.103.333.500 D09.301.915.400.375.333.500 D09.698.365.855.400.375.333.500 AAA Domain An approximately 250 amino acid domain common to AAA ATPases and AAA Proteins. It consists of a highly conserved N-terminal P-Loop ATPase subdomain with an alpha-beta-alpha conformation, and a less-conserved C- terminal subdomain with an all alpha conformation. The N-terminal subdomain includes Walker A and Walker B motifs which function in ATP binding and hydrolysis. Tree locations: Amino Acid Motifs G02.111.570.820.709.275.500.913 AAA Proteins A large, highly conserved and functionally diverse superfamily of NTPases and nucleotide-binding proteins that are characterized by a conserved 200 to 250 amino acid nucleotide-binding and catalytic domain, the AAA+ module. They assemble into hexameric ring complexes that function in the energy-dependent remodeling of macromolecules. Members include ATPASES ASSOCIATED WITH DIVERSE CELLULAR ACTIVITIES. Tree locations: Acid Anhydride Hydrolases D08.811.277.040.013 Carrier Proteins D12.776.157.025 Abuse-Deterrent Formulations Drug formulations or delivery systems intended to discourage the abuse of CONTROLLED SUBSTANCES. These may include physical barriers to prevent chewing or crushing the drug; chemical barriers that prevent extraction of psychoactive ingredients; agonist-antagonist combinations to reduce euphoria associated with abuse; aversion, where controlled substances are combined with others that will produce an unpleasant effect if the patient manipulates the dosage form or exceeds the recommended dose; delivery systems that are resistant to abuse such as implants; or combinations of these methods.
    [Show full text]
  • 1 Novel Expression Signatures Identified by Transcriptional Analysis
    ARD Online First, published on October 7, 2009 as 10.1136/ard.2009.108043 Ann Rheum Dis: first published as 10.1136/ard.2009.108043 on 7 October 2009. Downloaded from Novel expression signatures identified by transcriptional analysis of separated leukocyte subsets in SLE and vasculitis 1Paul A Lyons, 1Eoin F McKinney, 1Tim F Rayner, 1Alexander Hatton, 1Hayley B Woffendin, 1Maria Koukoulaki, 2Thomas C Freeman, 1David RW Jayne, 1Afzal N Chaudhry, and 1Kenneth GC Smith. 1Cambridge Institute for Medical Research and Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK 2Roslin Institute, University of Edinburgh, Roslin, Midlothian, EH25 9PS, UK Correspondence should be addressed to Dr Paul Lyons or Prof Kenneth Smith, Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK. Telephone: +44 1223 762642, Fax: +44 1223 762640, E-mail: [email protected] or [email protected] Key words: Gene expression, autoimmune disease, SLE, vasculitis Word count: 2,906 The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases and any other BMJPGL products to exploit all subsidiary rights, as set out in their licence (http://ard.bmj.com/ifora/licence.pdf). http://ard.bmj.com/ on September 29, 2021 by guest. Protected copyright. 1 Copyright Article author (or their employer) 2009.
    [Show full text]
  • Downloaded 10/9/2021 2:06:56 AM
    Chem Soc Rev View Article Online TUTORIAL REVIEW View Journal | View Issue Tools and strategies of systems metabolic engineering for the development of microbial cell Cite this: Chem. Soc. Rev., 2020, 49,4615 factories for chemical production Yoo-Sung Ko, †a Je Woong Kim, †a Jong An Lee, a Taehee Han, a Gi Bae Kim, a Jeong Eum Park a and Sang Yup Lee *abc Sustainable production of chemicals from renewable non-food biomass has become a promising alternative to overcome environmental issues caused by our heavy dependence on fossil resources. Systems metabolic engineering, which integrates traditional metabolic engineering with systems biology, synthetic biology, and evolutionary engineering, is enabling the development of microbial cell factories capable of efficiently producing a myriad of chemicals and materials including biofuels, bulk and fine chemicals, polymers, amino acids, natural products and drugs. In this paper, many tools and strategies of systems metabolic engineering, including in silico genome-scale metabolic simulation, sophisticated enzyme engineering, optimal gene expression modulation, in vivo biosensors, de novo pathway design, Received 23rd February 2020 and genomic engineering, employed for developing microbial cell factories are reviewed. Also, detailed DOI: 10.1039/d0cs00155d procedures of systems metabolic engineering used to develop microbial strains producing chemicals and materials are showcased. Finally, future challenges and perspectives in further advancing systems rsc.li/chem-soc-rev metabolic engineering and establishing biorefineries are discussed. Key learning points (1) Systems metabolic engineering, which integrates traditional metabolic engineering with systems biology, synthetic biology, and evolutionary engineering, accelerates the development of efficient microbial cell factories. Published on 22 June 2020.
    [Show full text]
  • 1 SUPPLEMENTAL DATA Figure S1. Poly I:C Induces IFN-Β Expression
    SUPPLEMENTAL DATA Figure S1. Poly I:C induces IFN-β expression and signaling. Fibroblasts were incubated in media with or without Poly I:C for 24 h. RNA was isolated and processed for microarray analysis. Genes showing >2-fold up- or down-regulation compared to control fibroblasts were analyzed using Ingenuity Pathway Analysis Software (Red color, up-regulation; Green color, down-regulation). The transcripts with known gene identifiers (HUGO gene symbols) were entered into the Ingenuity Pathways Knowledge Base IPA 4.0. Each gene identifier mapped in the Ingenuity Pathways Knowledge Base was termed as a focus gene, which was overlaid into a global molecular network established from the information in the Ingenuity Pathways Knowledge Base. Each network contained a maximum of 35 focus genes. 1 Figure S2. The overlap of genes regulated by Poly I:C and by IFN. Bioinformatics analysis was conducted to generate a list of 2003 genes showing >2 fold up or down- regulation in fibroblasts treated with Poly I:C for 24 h. The overlap of this gene set with the 117 skin gene IFN Core Signature comprised of datasets of skin cells stimulated by IFN (Wong et al, 2012) was generated using Microsoft Excel. 2 Symbol Description polyIC 24h IFN 24h CXCL10 chemokine (C-X-C motif) ligand 10 129 7.14 CCL5 chemokine (C-C motif) ligand 5 118 1.12 CCL5 chemokine (C-C motif) ligand 5 115 1.01 OASL 2'-5'-oligoadenylate synthetase-like 83.3 9.52 CCL8 chemokine (C-C motif) ligand 8 78.5 3.25 IDO1 indoleamine 2,3-dioxygenase 1 76.3 3.5 IFI27 interferon, alpha-inducible
    [Show full text]
  • PROTEOME ANALYSIS of HUMAN LUNG EPITHELIAL CELLS INTERACTING with ASPERGILLUS TERREUS CONIDIA and STRUCTURE-FUNCTION RELATION of Nssnps in INNATE IMMUNE RECEPTORS
    PROTEOME ANALYSIS OF HUMAN LUNG Ph EPITHELIAL CELLS INTERACTING WITH . D ASPERGILLUS TERREUS CONIDIA AND . STRUCTURE-FUNCTION RELATION OF nsSNPs IN INNATE IMMUNE RECEPTORS Thesis submitted in fulfillment of the requirements for the Degree of RAMAN RAMAN DOCTOR OF PHILOSOPHY By RAMAN JUIT, WAKNAGHAT Department of Biotechnology & Bioinformatics JAYPEE UNIVERSITY OF INFORMATION TECHNOLOGY WAKNAGHAT, DISTRICT SOLAN, H.P., INDIA January 2018 2018 PROTEOME ANALYSIS OF HUMAN LUNG EPITHELIAL CELLS INTERACTING WITH ASPERGILLUS TERREUS CONIDIA AND STRUCTURE-FUNCTION RELATION OF nsSNPs IN INNATE IMMUNE RECEPTORS Thesis submitted in fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY By RAMAN Department of Biotechnology & Bioinformatics JAYPEE UNIVERSITY OF INFORMATION TECHNOLOGY WAKNAGHAT, DISTRICT SOLAN, H.P., INDIA January 2018 I Copyright @ JAYPEE UNIVERSITY OF INFORMATION TECHNOLOGY WAKNAGHAT JANUARY 2018 ALL RIGHTS RESERVED II TABLE OF CONTENTS CONTENT PAGE NO. INNER FIRST PAGE I DECLARATION VIII SUPERVISOR’S CERTIFICATE IX ACKNOWLEDGEMENT X-XI ABSTRACT XII LIST OF ABBREVIATIONS XIII-XV LIST OF FIGURES XVI-XVII LIST OF TABLES XVIII-XIX CHAPTER - 1 THESIS INTRODUCTION 1-3 CHAPTER - 2 REVIEW OF LITERATURE 4-25 2.1 ASPERGILLI 4 2.2 TAXONOMY OF ASPERGILLUS TERREUS 5 2.3 DISTRIBUTION AND MORPHOLOGY OF A. TERREUS 5 2.4 DISEASES OR MANIFESTATIONS CAUSED BY A. 6-8 TERREUS 2.5 DIAGNOSIS 8-9 2.6 IMMUNE RESPONSE TO ASPERGILLI 9-12 2.7 AIRWAY EPITHELIAL CELLS 12-13 III 2.8 THERAPIES FOR INFECTIONS CAUSED BY A. 14-17 TERREUS 2.9 SINGLE
    [Show full text]
  • BMC Genomics Bio Med Central
    BMC Genomics Bio Med Central Research article Open Access New insights into molecular pathways associated with flatfish ovarian development and atresia revealed by transcriptional analys is Angèle Tingaud-Sequeira 1,2 , François Chauvigné 1, Juanjo Lozano 3, María J Agulleiro 1,4 , Esther Asensio 5 and Joan Cerdà* 1 Address: 1Laboratory of Institut de Recerca i Tecnologia Agroalimentàries (IRTA)-Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), 08003 Barcelona, Spain, 2Génomique et Physiologie des Poissons, Université Bordeaux 1, UMR NuAGe, 33405 Talence, France, 3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain, 4Instituto de Acuicultura Torre de la Sal (CSIC), 12595 Castellón, Spain and 5IFAPA Centro El Toruño, Junta de Andalucía, Cádiz, Spain Email: Angèle Tingaud-Sequeira - [email protected]; François Chauvigné - [email protected]; Juanjo Lozano - [email protected]; María J Agulleiro - [email protected]; Esther Asensio - [email protected]; Joan Cerdà* - [email protected] * Corresponding author Published: 15 September 2009 Received: 11 May 2009 Accepted: 15 September 2009 BMC Genomics 2009, 10 :434 doi:10.1186/1471-2164-10-434 This article is available from: http://www.biomedcentral.com/1471-2164/10/434 © 2009 Tingaud-Sequeira et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The Senegalese sole ( Solea senegalensis ) is a marine flatfish of increasing commercial interest.
    [Show full text]