Genetic Disruption of 21-Hydroxylase in Zebrafish Causes Interrenal Hyperplasia
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Nano-Scale Liquid Chromatography Electrospray Tandem Mass Spectrometric Identification of Multiple Cytochrome P450 Isoforms in Tissues
NANO-SCALE LIQUID CHROMATOGRAPHY ELECTROSPRAY TANDEM MASS SPECTROMETRIC IDENTIFICATION OF MULTIPLE CYTOCHROME P450 ISOFORMS IN TISSUES Sonia Nisar W A Thesis Submitted for the degree of Doctor of Philosophy of the University of London Department of Pharmaceutical and Biological Chemistry The School of Pharmacy University of London 29-39 Brunswick Square London WCIN lAX February 2005 ProQuest Number: 10104297 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104297 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The cytochromes P450 (CYPs) are membrane bound proteins that collectively carry out a wide range of biological oxidations important in the metabolism of steroids, ecosanoids and xenobiotics including anticancer agents. A method of CYP separation and analysis has been developed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and nano-scale liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) for the direct identification of multiple CYPs found in rat liver, human tissues and tumours. Endoplasmic reticulum from selected tissues was prepared as microsomes using ultracentrifugation and subjected to SDS-PAGE. -
Identification and Developmental Expression of the Full Complement Of
Goldstone et al. BMC Genomics 2010, 11:643 http://www.biomedcentral.com/1471-2164/11/643 RESEARCH ARTICLE Open Access Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish Jared V Goldstone1, Andrew G McArthur2, Akira Kubota1, Juliano Zanette1,3, Thiago Parente1,4, Maria E Jönsson1,5, David R Nelson6, John J Stegeman1* Abstract Background: Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Results: Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. -
ACAT) in Cholesterol Metabolism: from Its Discovery to Clinical Trials and the Genomics Era
H OH metabolites OH Review Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era Qimin Hai and Jonathan D. Smith * Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-216-444-2248 Abstract: The purification and cloning of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzymes and the sterol O-acyltransferase (SOAT) genes has opened new areas of interest in cholesterol metabolism given their profound effects on foam cell biology and intestinal lipid absorption. The generation of mouse models deficient in Soat1 or Soat2 confirmed the importance of their gene products on cholesterol esterification and lipoprotein physiology. Although these studies supported clinical trials which used non-selective ACAT inhibitors, these trials did not report benefits, and one showed an increased risk. Early genetic studies have implicated common variants in both genes with human traits, including lipoprotein levels, coronary artery disease, and Alzheimer’s disease; however, modern genome-wide association studies have not replicated these associations. In contrast, the common SOAT1 variants are most reproducibly associated with testosterone levels. Keywords: cholesterol esterification; atherosclerosis; ACAT; SOAT; inhibitors; clinical trial Citation: Hai, Q.; Smith, J.D. Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its 1. Introduction Discovery to Clinical Trials and the The acyl-coenzyme A:cholesterol acyltransferase (ACAT; EC 2.3.1.26) enzyme family Genomics Era. Metabolites 2021, 11, consists of membrane-spanning proteins, which are primarily located in the endoplasmic 543. https://doi.org/10.3390/ reticulum [1]. -
Genetic Disruption of 21-Hydroxylase in Zebrafish Causes Interrenal Hyperplasia
RESEARCH ARTICLE Genetic Disruption of 21-Hydroxylase in Zebrafish Causes Interrenal Hyperplasia Helen Eachus,1 Andreas Zaucker,2 James A. Oakes,1,3 Aliesha Griffin,2 Meltem Weger,2 T¨ulay Guran, ¨ 2 Angela Taylor,2 Abigail Harris,4 Andy Greenfield,4 Jonathan L. Quanson,5 Karl-Heinz Storbeck,5 Vincent T. Cunliffe,1 Ferenc Muller, ¨ 6 and Nils Krone1,3 1Department of Biomedical Science, The Bateson Centre, Sheffield S10 2TN, United Kingdom; 2Centre for Endocrinology, Diabetes, and Metabolism, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; 3Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2TG, United Kingdom; 4Mammalian Genetics Unit, Medical Research Council, Harwell Institute, Oxfordshire OX11 0RD, United Kingdom; 5Department of Biochemistry, Stellenbosch University, Stellenbosch, Matieland 7602, South Africa; and 6Institute of Cancer and Genomic Sciences, University of Birmingham, College of Medical and Dental Sciences, Birmingham B15 2TT, United Kingdom Congenital adrenal hyperplasia is a group of common inherited disorders leading to glucocorticoid deficiency. Most cases are caused by 21-hydroxylase deficiency (21OHD). The systemic consequences of imbalanced steroid hormone biosynthesis due to severe 21OHD remains poorly understood. Therefore, we developed a zebrafish model for 21OHD, which focuses on the impairment of glucocorticoid biosynthesis. A single 21-hydroxylase gene (cyp21a2) is annotated in the zebrafish genome based on sequence homology. Our in silico analysis of the 21-hydroxylase (Cyp21a2) protein sequence suggests a sufficient degree of similarity for the usage of zebrafish cyp21a2 to model aspects of human 21OHD in vivo. We determined the spatiotemporal expression patterns of cyp21a2 by whole-mount in situ hybridization and reverse transcription polymerase chain reaction throughout early development. -
Supplementary Table 1 List of 335 Genes Differentially Expressed Between Primary (P) and Metastatic (M) Tumours
Supplementary Table 1 List of 335 genes differentially expressed between primary (P) and metastatic (M) tumours Spot ID I.M.A.G.E. UniGene Symbol Name Clone ID Cluster 296529 296529 In multiple clusters 731356 731356 Hs.140452 M6PRBP1 mannose-6-phosphate receptor binding protein 1 840942 840942 Hs.368409 HLA-DPB1 major histocompatibility complex, class II, DP beta 1 142122 142122 Hs.115912 AFAP actin filament associated protein 1891918 1891918 Hs.90073 CSE1L CSE1 chromosome segregation 1-like (yeast) 1323432 1323432 Hs.303154 IDS iduronate 2-sulfatase (Hunter syndrome) 788566 788566 Hs.80296 PCP4 Purkinje cell protein 4 591281 591281 Hs.80680 MVP major vault protein 815530 815530 Hs.172813 ARHGEF7 Rho guanine nucleotide exchange factor (GEF) 7 825312 825312 Hs.246310 ATP5J ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F6 784830 784830 Hs.412842 C10orf7 chromosome 10 open reading frame 7 840878 840878 Hs.75616 DHCR24 24-dehydrocholesterol reductase 669443 669443 Hs.158195 HSF2 heat shock transcription factor 2 2485436 2485436 Data not found 82903 82903 Hs.370937 TAPBP TAP binding protein (tapasin) 771258 771258 Hs.85258 CD8A CD8 antigen, alpha polypeptide (p32) 85128 85128 Hs.8986 C1QB complement component 1, q subcomponent, beta polypeptide 41929 41929 Hs.39252 PICALM phosphatidylinositol binding clathrin assembly protein 148469 148469 Hs.9963 TYROBP TYRO protein tyrosine kinase binding protein 415145 415145 Hs.1376 HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 810017 810017 Hs.179657 PLAUR plasminogen activator, -
The P450 Side Chain Cleavage Enzyme Cyp11a2 Facilitates Steroidogenesis in Zebrafish
This is a repository copy of The P450 side chain cleavage enzyme Cyp11a2 facilitates steroidogenesis in zebrafish. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/154041/ Version: Accepted Version Article: Li, N., Oakes, J.A., Storbeck, K.-H. et al. (2 more authors) (2020) The P450 side chain cleavage enzyme Cyp11a2 facilitates steroidogenesis in zebrafish. Journal of Endocrinology, 244 (2). pp. 309-321. ISSN 0022-0795 https://doi.org/10.1530/joe-19-0384 Disclaimer: this is not the definitive version of record of this article. This manuscript has been accepted for publication in Journal of Endocrinology, but the version presented here has not yet been copy-edited, formatted or proofed. Consequently, Bioscientifica accepts no responsibility for any errors or omissions it may contain. The definitive version is now freely available at https://doi.org/10.1530/JOE-19-0384, 2019. Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ 1 The P450 side chain cleavage enzyme Cyp11a2 facilitates 2 steroidogenesis in zebrafish 3 4 Nan Li1, 2, James A Oakes1, 2, Karl-Heinz Storbeck3, Vincent T Cunliffe2, 4#, 5 Nils P Krone1, 2, 5#. -
Early-Life Exposure to the Antidepressant Fluoxetine Induces A
Early-life exposure to the antidepressant fluoxetine induces a male-specific transgenerational disruption of the stress axis and exploratory behavior in adult zebrafish, Danio rerio Marilyn Nohely Vera Chang Thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the Doctorate in Philosophy degree in Biology with specialization in Chemical and Environmental Toxicology Department of Biology Faculty of Science University of Ottawa © Marilyn Nohely Vera Chang, Ottawa, Canada, 2018 ACKNOWLEDGMENTS Finishing this thesis has been both a challenging and gratifying experience. There are many people whom I must express my sincere gratitude toward as the work presented in this thesis would not have been possible without their contributions and never-ending support. First and foremost, I would like to acknowledge my supervisors, Dr. Vance Trudeau and Dr. Thomas Moon. I want to say how grateful I am for providing me with the opportunity to purse my academic and professional interests. I was first accepted by Tom and I will be forever thankful that he took a shot on me. Also, thanks to you Vance for adopting me when I was lab-less and for believing in my abilities as a scientist. Thank you to both of you for your outstanding guidance, patience and friendship which have given me an amazing experience in these past 6 years, you have been excellent mentors. Your concerns for your student’s well-being and mental health were bonus that I will not soon forget. I don’t think there are enough words to describe how thankful and fortunate I am to have benefit from your supervision not only at the academic and scientific level but also at the personal level, for all my accomplishments during this doctorate, I will forever be indebted to both of you. -
Human 3B-Hydroxysteroid Dehydrogenase Deficiency Seems
M-A Burckhardt and others Histology of HSD3B2 deficiency 173:5 K1–K12 Case Report Human 3b-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature Marie-Anne Burckhardt1, Sameer S Udhane1,†, Nesa Marti1,†, Isabelle Schnyder2, Coya Tapia3, John E Nielsen4, Primus E Mullis1, Ewa Rajpert-De Meyts4 and Christa E Flu¨ ck1 1Pediatric Endocrinology and Diabetology, Departments of Pediatrics and Clinical Research, 2Pediatric Surgery and Correspondence 3Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland and 4Department of Growth and should be addressed Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark to C E Flu¨ ck †S S Udhane and N Marti are now at Graduate School Bern, University of Bern, Bern Switzerland Email christa.fl[email protected] Abstract Context:3b-hydroxysteroid dehydrogenase deficiency (3bHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3bHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk. Objective: To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation. Methods: Biochemical, genetic and immunohistochemical investigations on human biomaterials. Results: A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 European Journal of Endocrinology deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. -
(12) Patent Application Publication (10) Pub. No.: US 2011/001412.6 A1 Evans Et Al
US 2011 0014126A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/001412.6 A1 Evans et al. (43) Pub. Date: Jan. 20, 2011 (54) USE OF VITAMIND RECEPTORAGONISTS (60) Provisional application No. 60/985,972, filed on Nov. AND PRECURSORS TO TREAT FIBROSS 6, 2007. (76) Inventors: Ronald M. Evans, La Jolla, CA Publication Classification (US); Michael Downes, San Diego, CA (US); Christopher Liddle, (51) Int. Cl. New South Wales (AU): A 6LX 3/59 (2006.01) Nanthakumar Subramaniam, A6IPL/I6 (2006.01) New South Wales (AU); Caroline CI2O 1/02 (2006.01) Flora Samer, Geneva (CH) A61R 49/00 (2006.01) CI2N 5/071 (2010.01) Correspondence Address: (52) U.S. Cl. ............. 424/9.2: 514/167; 435/29: 435/375 KLARQUIST SPARKMAN, LLP 121 S.W. SALMONSTREET, SUITE 1600 (57) ABSTRACT PORTLAND, OR 97204 (US) This application relates to methods of treating, preventing, (21) Appl. No.: 12/772,981 and ameliorating fibrosis, such as fibrosis of the liver. In particular, the application relates to methods of using a vita (22) Filed: May 3, 2010 min D receptor agonist (Such as vitamin D. Vitamin Dana logs, vitamin D precursors, and vitamin D receptor agonists Related U.S. Application Data precursors) for the treatment of liver fibrosis. Also disclosed (63) Continuation-in-part of application No. 12/266,513, are methods for screening for agents that treat, prevent, and filed on Nov. 6, 2008. ameliorate fibrosis. Stellate Cells Liver RR1,3 AR, ERa ERR1,2,3, AR, ERa CNF GR, MR CNF RARa, GR, MR NF4g Rab NF4ag RARa,b, NOR1 a, RH1 TRa,b WDR NURR1 NOR1 RORa,b,g RORag CAR Receptor SF-1 FXRa,b FXRa,b epissertoup. -
A Critical Role of Follicle-Stimulating Hormone (Fsh) in Mediating the Effect Of
Toxicology 298 (2012) 30–39 Contents lists available at SciVerse ScienceDirect Toxicology j ournal homepage: www.elsevier.com/locate/toxicol A critical role of follicle-stimulating hormone (Fsh) in mediating the effect of clotrimazole on testicular steroidogenesis in adult zebrafish a a a a a Damien Baudiffier , Nathalie Hinfray , Mélanie Vosges , Nicolas Creusot , Edith Chadili , a b a,∗ Jean-Marc Porcher , Rüdiger W. Schulz , Franc¸ ois Brion a Institut National de l’environnement industriel et des risques (INERIS), Direction des Risques Chroniques, Unité d’écotoxicologie in vitro et in vivo, BP 2, 60550 Verneuil-en-Halatte, France b University of Utrecht, Science Faculty, Department Biology, Division Developmental Biology, Reproductive Biology Group, Kruyt Building room W-606, Padualaan 8, NL-3584 CH Utrecht, The Netherlands a r t i c l e i n f o a b s t r a c t Article history: Clotrimazole is a pharmaceutical fungicide known to inhibit several cytochrome P450 enzyme activi- Received 22 February 2012 ties, including several steroidogenic enzymes. This study aimed to assess short-term in vivo effects of Received in revised form 3 April 2012 clotrimazole exposure on blood 11-ketotestosterone (11-KT) levels and on the transcriptional activity of Accepted 21 April 2012 genes in pituitary and testis tissue that are functionally relevant for androgen production with the view Available online 28 April 2012 to further characterize the mode of action of clotrimazole on the hypothalamus-pituitary-gonad axis in zebrafish, a model vertebrate in toxicology. Adult male zebrafish were exposed to measured concentra- Keywords: tions in water of 71, 159 and 258 g/L of clotrimazole for 7 days. -
Genetic Disruption of 21-Hydroxylase in Zebrafish Causes Interrenal Hyperplasia
CORE Metadata, citation and similar papers at core.ac.uk Provided by University of Birmingham Research Portal Genetic disruption of 21-hydroxylase in zebrafish causes interrenal hyperplasia Eachus, Helen; Zaucker, Andreas; Oakes, James A.; Griffin, Aliesha; Weger, Meltem; Güran, Tülay; Taylor, Angela; Harris, Abigail; Greenfield, Andy; Quanson, Jonathan L.; Storbeck, Karl-Heinz; Cunliffe, Vincent T.; Müller, Ferenc; Krone, Nils DOI: 10.1210/en.2017-00549 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Eachus, H, Zaucker, A, Oakes, JA, Griffin, A, Weger, M, Güran, T, Taylor, A, Harris, A, Greenfield, A, Quanson, JL, Storbeck, K-H, Cunliffe, VT, Müller, F & Krone, N 2017, 'Genetic disruption of 21-hydroxylase in zebrafish causes interrenal hyperplasia' Endocrinology, vol. 158, no. 12, pp. 4165-4173. https://doi.org/10.1210/en.2017- 00549 Link to publication on Research at Birmingham portal Publisher Rights Statement: Published in Endocrinology on 13/09/2017 https://doi.org/10.1210/en.2017-00549 General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. -
Culture of Bovine Ovarian Follicle Wall Sections Maintained the Highly Estrogenic Profile Under Basal and Chemically Defined Conditions
Brazilian Journal of Medical and Biological Research (2013) 46: 700-707, http://dx.doi.org/10.1590/1414-431X20133024 ISSN 1414-431X Culture of bovine ovarian follicle wall sections maintained the highly estrogenic profile under basal and chemically defined conditions R.B. Vasconcelos1, L.P. Salles2, I. Oliveira e Silva1, L.V.M. Gulart1, D.K. Souza1,3, F.A.G. Torres2, A.L. Bocca4 and A.A.M. Rosa e Silva1 1Laborato´rio de Biotecnologia da Reproduc¸a˜o, Departamento de Cieˆncias Fisiolo´gicas, Instituto de Cieˆncias Biolo´gicas, Universidade de Brası´lia, Brası´lia, DF, Brasil 2Laborato´rio de Biologia Molecular, Departamento de Biologia Celular, Instituto de Cieˆncias Biolo´gicas, Universidade de Brası´lia, Brası´lia, DF, Brasil 3Faculdade de Ceilaˆndia, Universidade de Brası´lia, Ceilaˆndia, DF, Brasil 4Departamento de Biologia Celular, Instituto de Cieˆncias Biolo´gicas, Universidade de Brası´lia, Brası´lia, DF, Brasil Abstract Follicle cultures reproduce in vitro the functional features observed in vivo. In a search for an ideal model, we cultured bovine antral follicle wall sections (FWS) in a serum-free defined medium (DM) known to induce 17b-estradiol (E2) production, and in a nondefined medium (NDM) containing serum. Follicles were sectioned and cultured in NDM or DM for 24 or 48 h. Morphological features were determined by light microscopy. Gene expression of steroidogenic enzymes and follicle- stimulating hormone (FSH) receptor were determined by RT-PCR; progesterone (P4) and E2 concentrations in the media were measured by radioimmunoassay. DM, but not NDM, maintained an FWS morphology in vitro that was similar to fresh tissue.