DOCSLIB.ORG

Abstract Mahapatra, Debabrata

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Abstract Mahapatra, Debabrata ABSTRACT MAHAPATRA, DEBABRATA. Vitamin D Receptor and Xenobiotic Interactions: Insights into the diversity and complexity of molecular interactions and their outcomes (Under the direction of Seth W. Kullman). The etiology of a significant number of human diseases including hypertension, cardiovascular disease, diabetes, obesity and cancer are in part associated with exposures to environmental contaminants. Recent trends in toxicological research indicate a growing interest in chemicals capable of disrupting the endocrine system. These chemicals comprise a range of natural and synthetic molecules that interact with nuclear hormone receptors altering signaling pathways regulating adverse effects in multiple organ systems, tissue and cell types. While the interaction of endocrine disrupting xenobiotics with nuclear receptors such as the Estrogen receptor (ER), Thyroid receptor (TR), Glucocorticoid receptor (GR) and Androgen receptor (AR) has been studied in detail, similar research involving xenobiotic interactions with the Vitamin D receptor (VDR) has remained underexplored. This dissertation examines the role of vitamin d receptor as a potential target of xenobiotic induced endocrine disruption and provides new insights into the possible mechanisms underlying the complex molecular interactions between VDR and select VDR agonists and antagonists. Chapter 1 tests the usefulness and importance of orthogonal assays for validation and confirmation of activity profiles of chemicals generated by the qHTS (Quantitative Highthroughput Testing) format. A subset of compounds active against the vitamin d receptor was selected from the Tox 21qHTS data set and examined for reproducibility and concordance in orthogonal assay using a luciferase reporter construct. Initial transient transactivation assays were utilized to identify and select VDR agonists, antagonists and synergist. Next we demonstrated the complexity and variability of VDR: xenobiotic interactions at the molecular level through assessments of ligand induced VDR: coregulator interaction including obligate heterodimerization of VDR and RXR (Retinoic-X-Receptor) and recruitment of the VDR coactivator SRC-1 (Steroid Receptor Coactivator-1) in the presence of select list of xenobiotics. Our results indicate that similar to other endocrine receptors such as ER and GR, VDR is susceptible to modulation by a variety of xenobiotics including those that are known endocrine disruptors. Chapter 2 examines the novel role of trialkyltins including tributyltin (TBT) and triphenyltin (TPT) in modulating the strictly non-permissive interaction between VDR and its obligate heterodimer RXRa in a manner that is conditionally permissive. This alteration in permissivity is observed when cells co-expressing RXR:VDR constructs are exposed to a narrow low dose range of tin compounds resulting in synergistic VDR transactivation only in the presence of the active ligand 1, 25 dihydroxyvitamin D3. Additionally, this synergistic activity is diminished progressively at higher non-toxic doses thus demonstrating a unique dual activity profile. As with other non-permissive heterodimeric interactions such as RXR:RAR and RXR:TR, RXR:VDR interaction has been reported to be altered by strong RXR agonists such as 9-cis-RA. We report for the first time the ability of organic environmental pesticides (trialkyltins) to disrupt the functionality of RXR:VDR heterodimeric complex that might have profound physiological implications in humans and lower vertebrates as far as endocrine disruption is concerned. Chapter 3 examines the role of yet another well-known non-essential toxic element, cadmium, in disrupting the transcriptional activity of VDR. Cadmium exposure poses serious health risks to humans and other vertebrates. Unlike other nuclear hormone receptors such as the ER where cadmium is a demonstrated receptor agonist, we demonstrate that cadmium inhibits transactivation of ligand induced VDR in multiple cell types. Furthermore, cadmium inhibits vitamin D3 induced endogenous gene expression of a potent downstream gene (CYP24A1) regulated by VDR. Given, the ability of cadmium to disrupt zinc fingers in the DNA binding domain of nuclear receptors we investigated the role of cadmium to inhibit VDR binding to DNA as a potential mechanism of receptor inhibition. Results from mutation studies and gel retardation assays indicate that cadmium likely prevents binding of VDR to DNA. Interestingly however, cadmium also facilitated recruitment of coactivator and coregulator when protein:protein interaction was investigated. Taken together these findings clearly suggest two distinct modes of action of cadmium that likely disrupts VDR transactivation. Overall, we demonstrate that cadmium has the potential to disrupt vitamin D endocrine system. © Copyright 2017 Debabrata Mahapatra All Rights Reserved Vitamin D Receptor and Xenobiotics: Insights into the diversity and complexity of molecular interactions and their outcomes by Debabrata Mahapatra A dissertation or thesis submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Comparative Biomedical Sciences Raleigh, North Carolina 2017 APPROVED BY: _______________________________ _______________________________ Dr. Seth W. Kullman Dr. John Godwin Committee Chair _______________________________ _______________________________ Dr. Heather Hunt Dr. Heather Patisaul DEDICATION This dissertation is dedicated to members of my family especially my wife Anupama for her extraordinary moral support throughout the years of my graduate studies. ii BIOGRAPHY Debabrata Mahapatra (Deb) was born in the northern state of Bihar, located in the northern region of India. After graduation from high school in 1994, Deb relocated to Calcutta and received his Bachelor of Sciences (BS) in Biology followed by a BS degree and a Masters degree in Veterinary Medicine. His long cherished ambition of coming to the US for higher education in Veterinary Medicine came to fruition when he was admitted to West Texas A&M for an additional Masters degree in Biological sciences in 2004. Deb got firsthand experience in teaching advanced anatomy, physiology & genetics to preMed and preVet students. Following his masters in 2006 he joined Texas A&M Veterinary Medical Diagnostic Lab as a molecular diagnostician. He received training and gained experience from staff pathologists that helped him gain acceptance into a residency program in Veterinary Anatomic Pathology at the University of Florida, CVM in 2007. He went on to work at Disney’s Animal Programs as a fellow in Zoo &Wildlife Pathology. His time spent at Disney has been the best so far. He received his board certified by the American College of Veterinary Pathologist (ACVP) in 2011. In 2013 he joined Kullman lab at NCSU to pursue his PhD in Comparative Biomedical Sc. with a focus in Toxicology. iii ACKNOWLEDGMENTS I would like to acknowledge everyone who have made contributions directly or indirectly towards this work, and helped to build my career as a scientist and as a professional. First, I would like to thank my graduate mentor Dr. Seth W. Kullman for his guidance and support. I would also like to acknowledge members of my committee Dr. Heather Patisaul, Dr. Heather Shive and Dr. John Godwin for being extraordinarily supportive and accommodative. I would also like to thank members of my lab Atlee Watson and Megan Knuth for their unconditional assistance and support whenever I needed them. Additionally, I would like to acknowledge our administrative assistant Jane Roe for her assistance and advice and members of Drs. Planchart and Mattingly, Dr. Bonner, Dr. Smart and Dr. Tsuji laboratories for their help and advice when needed. Overall, it has been a worthwhile experience this past four years for being a part of educational and collegiate environment. iv TABLE OF CONTENTS LIST OF TABLES……………………………………………………………………………………………………………….viii LIST OF FIGURES………………………………………………………………………………………………………………ix GENERAL INTRODUCTION…………………………………………………………………………………………………1 Tox21 in the 21st Century…………………………………………………………………………………………………..1 Vitamin D and Vitamin D Receptor…………………………………………………………………………………….4 Rationale for research initiatives and approaches……………………………………………………………..7 Novel findings and how these address human and environmental health concerns…………..8 References…………………………………………………………………………………………………………………………11 CHAPTER ONE: Insights into the diversity and complexity of molecular interactions and their outcomes Vitamin D receptor and xenobiotics: Complexity of molecular interactions and outcomes………………………………….14 Abstract……………………………………………………………………………………………………………………………..15 Introduction……………………………………………………………………………………………………………………….17 Materials and Methods………………………………………………………………………………………………………21 Results……………………………………………………………………………………………………………………………….30 Discussion………………………………………………………………………………………………………………………….40 Conclusion………………………………………………………………………………………………………………………….53 References…………………………………………………………………………………………………………………………54 Figures……………………………………………………………………………………………………………………………….60 v CHAPTER TWO: Novel role of trialkyltins to promote conditional permissive transactivation of human VDR………………………………………………………………………90 Abstract…………………………………………………………………………………………………………………………….91 Introduction……………………………………………………………………………………………………………………….92 Materials and Methods……………………………………………………………………………………………………..97 Results……………………………………………………………………………………………………………………………..102 Discussion………………………………………………………………………………………………………………………..106
Load more

Recommended publications
  • Eldecalcitol Is More Effective for Promoting Osteogenesis Than Alfacalcidol in Cyp27b1-Knockout Mice
    bioRxiv preprint doi: https://doi.org/10.1101/349837; this version posted June 18, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Eldecalcitol is more effective for promoting osteogenesis than alfacalcidol in Cyp27b1-knockout Mice Short title: Osteogenic effect of eldecalcitol Yoshihisa Hirota1,2*¶, Kimie Nakagawa2¶, Keigo Isomoto2¶, Toshiyuki Sakaki3, Noboru Kubodera4, Maya Kamao2, Naomi Osakabe5, Yoshitomo Suhara6, Toshio Okano2* 1 Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan 2 Laboratory of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan 3 Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Kurokawa, Imizu, Toyama 939-0398, Japan 4 International Institute of Active Vitamin D Analogs, 35-6, Sankeidai, Mishima, Shizuoka 411-0017, Japan 5 Food and Nutrition Laboratory, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan 6 Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan ¶ These authors contributed equally to this work. * Corresponding authors: Yoshihisa Hirota Tel.: +81-48-7201-6037; Fax: +81-48-7201-6011; E-mail: hirotay@ shibaura-it.ac.jp Toshio Okano Tel.: (81) 78-441-7524; Fax: (81) 78-441-7524; E-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/349837; this version posted June 18, 2018.
    [Show full text]
  • Is Calcifediol Better Than Cholecalciferol for Vitamin D Supplementation?
    Osteoporosis International (2018) 29:1697–1711 https://doi.org/10.1007/s00198-018-4520-y REVIEW Is calcifediol better than cholecalciferol for vitamin D supplementation? J. M. Quesada-Gomez1,2 & R. Bouillon3 Received: 22 February 2018 /Accepted: 28 March 2018 /Published online: 30 April 2018 # International Osteoporosis Foundation and National Osteoporosis Foundation 2018 Abstract Modest and even severe vitamin D deficiency is widely prevalent around the world. There is consensus that a good vitamin D status is necessary for bone and general health. Similarly, a better vitamin D status is essential for optimal efficacy of antiresorptive treatments. Supplementation of food with vitamin D or using vitamin D supplements is the most widely used strategy to improve the vitamin status. Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2)arethemostwidelyused compounds and the relative use of both products depends on historical or practical reasons. Oral intake of calcifediol (25OHD3) rather than vitamin D itself should also be considered for oral supplementation. We reviewed all publications dealing with a comparison of oral cholecalciferol with oral calcifediol as to define the relative efficacy of both compounds for improving the vitamin D status. First, oral calcifediol results in a more rapid increase in serum 25OHD compared to oral cholecalciferol. Second, oral calcifediol is more potent than cholecalciferol, so that lower dosages are needed. Based on the results of nine RCTs comparing physiologic doses of oral cholecalciferol with oral calcifediol, calcifediol was 3.2-fold more potent than oral chole- calciferol. Indeed, when using dosages ≤ 25 μg/day, serum 25OHD increased by 1.5 ± 0.9 nmol/l for each 1 μgcholecalciferol, whereas this was 4.8 ± 1.2 nmol/l for oral calcifediol.
    [Show full text]
  • Vitamin D and Cancer
    WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER Vitamin D and Cancer IARC 2008 WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Working Group Reports Volume 5 Vitamin D and Cancer - i - Vitamin D and Cancer Published by the International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France © International Agency for Research on Cancer, 2008-11-24 Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]) Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturer’s products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication. The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full.
    [Show full text]
  • Lithocholic Acid Is a Vitamin D Receptor Ligand That Acts Preferentially in the Ileum
    International Journal of Molecular Sciences Communication Lithocholic Acid Is a Vitamin D Receptor Ligand That Acts Preferentially in the Ileum Michiyasu Ishizawa, Daisuke Akagi and Makoto Makishima * ID Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; [email protected] (M.I.); [email protected] (D.A.) * Correspondence: [email protected]; Tel.: +81-3-3972-8111 Received: 26 May 2018; Accepted: 3 July 2018; Published: 6 July 2018 Abstract: The vitamin D receptor (VDR) is a nuclear receptor that mediates the biological action of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and regulates calcium and bone metabolism. Lithocholic acid (LCA), which is a secondary bile acid produced by intestinal bacteria, acts as an additional physiological VDR ligand. Despite recent progress, however, the physiological function of the LCA−VDR axis remains unclear. In this study, in order to elucidate the differences in VDR action induced by 1,25(OH)2D3 and LCA, we compared their effect on the VDR target gene induction in the intestine of mice. While the oral administration of 1,25(OH)2D3 induced the Cyp24a1 expression effectively in the duodenum and jejunum, the LCA increased target gene expression in the ileum as effectively as 1,25(OH)2D3. 1,25(OH)2D3, but not LCA, increased the expression of the calcium transporter gene Trpv6 in the upper intestine, and increased the plasma calcium levels. Although LCA could induce an ileal Cyp24a1 expression as well as 1,25(OH)2D3, the oral LCA administration was not effective in the VDR target gene induction in the kidney.
    [Show full text]
  • A Microbial Metabolite, Lithocholic Acid, Suppresses IFN-Γ and Ahr
    bioRxiv preprint doi: https://doi.org/10.1101/491241; this version posted December 9, 2018. 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. A microbial metabolite, Lithocholic acid, suppresses IFN-g and AhR expression by human cord blood CD4 T cells Anya Nikolai* and Makio Iwashima* *Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153 Corresponding author: Makio Iwashima, Ph.D. Department of Microbiology and Immunology Stritch School of Medicine Loyola University Medical Center Building 115, Rm 270A 2160 S. First Avenue Maywood, IL 60153 Email: [email protected] Phone: 708-216-5816 Fax: 708-216-9574 Declarations of interest: none Highlights • Lithocholic acid suppresses IFNγ production by CD4 T cells. • Lithocholic acid suppresses STAT1 and IRF1 expression by activated CD4 T cells. • Lithocholic acid suppresses AhR in a comparable manner to calcitriol. bioRxiv preprint doi: https://doi.org/10.1101/491241; this version posted December 9, 2018. 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. Abstract Vitamin D is a well-known micronutrient that modulates immune responses by epigenetic and transcriptional regulation of target genes, such as inflammatory cytokines. Our group recently demonstrated that the most active form of vitamin D, calcitriol, reduces expression of a transcription factor known as the aryl hydrocarbon receptor (AhR) and inhibits differentiation of a pro-inflammatory T cell subset, Th9. Lithocholic acid (LCA), a secondary bile acid produced by commensal bacteria, is known to bind to and activate the vitamin D receptor (VDR) in a manner comparable to calcitriol.
    [Show full text]
  • A High Throughput Ultrafiltration LC-MS Platform for the Discovery of Vitamin D Receptor Ligands
    A High Throughput Ultrafiltration LC-MS Platform for the Discovery of Vitamin D Receptor Ligands BY Jerry James White B.S. (University of California at Riverside) 2006 THESIS Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medicinal Chemistry in the Graduate College of the Univeristy of Illinois at Chicago, 2012 Chicago, Illinois Defense Committee: Richard B. van Breemen, Advisor and Chair Dejan Nikolic Pavel Petukhov Brian Murphy Adam Negrusz, Biopharmaceutical Sciences Copyright Jerry James White 2012 ACKNOWLEDGEMENTS This dissertation would not have been completed without the support of family, friends, fellow graduate students, the medicinal chemistry faculty, and my advisor, Dr. Richard B. van Breemen. To Dr. van Breemen I would like to state my appreciation for fostering my scientific development in his lab, through his highly technical knowledge, practical advice and his patient disposition. I thank my dissertation committee members, Dr. Brian Murphy, Dr. Dejan Nikolic, Dr. Adam Negursz, and Dr. Pavel Pethukov, for their support and guidance with my research project. I would like to thank Mr. Rich Morrissy for his advice both in the laboratory and outside of the lab. Drs. Dejan Nikolic, Carrie Crot, and Yongsoo Choi I would also like to thank for their constant guidance during the course of my graduate education. There have been many graduate students that have stimulated intellectual debates that have shaped my research. I would like to recognize, Drs. Jeff Dahl and Shunyun Mo, Ms. Yang Yuan, Xi Qiu, Linlin Dong, Kevin Krock, and Jay Kalin. Finally, I would like to thank my wife for her love and support and by simply being pa- tient when life looked bleak at times.
    [Show full text]
  • The Vitamin D System in Humans and Mice: Similar but Not the Same
    Review The Vitamin D System in Humans and Mice: Similar but Not the Same Ewa Marcinkowska Department of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland; [email protected]; Tel.: +48-71-375-2929 Received: 7 November 2019; Accepted: 7 January 2020; Published: 10 January 2020 Abstract: Vitamin D is synthesized in the skin from 7-dehydrocholesterol subsequently to exposure to UVB radiation or is absorbed from the diet. Vitamin D undergoes enzymatic conversion to its active form, 1,25-dihydroxyvitamin D (1,25D), a ligand to the nuclear vitamin D receptor (VDR), which activates target gene expression. The best-known role of 1,25D is to maintain healthy bones by increasing the intestinal absorption and renal reuptake of calcium. Besides bone maintenance, 1,25D has many other functions, such as the inhibition of cell proliferation, induction of cell differentiation, augmentation of innate immune functions, and reduction of inflammation. Significant amounts of data regarding the role of vitamin D, its metabolism and VDR have been provided by research performed using mice. Despite the fact that humans and mice share many similarities in their genomes, anatomy and physiology, there are also differences between these species. In particular, there are differences in composition and regulation of the VDR gene and its expression, which is discussed in this article. Keywords: vitamin D; vitamin D receptor; human; murine; drug testing 1. Introduction Different animal models have been used in biomedical research. Simple organisms, such as yeast, fruit flies, C. elegans and zebrafish are useful to study function of particular genes and their roles in development.
    [Show full text]
  • Mutational Analysis and Engineering of the Human Vitamin D Receptor to Bind and Activate in Response to a Novel Small Molecule Ligand
    MUTATIONAL ANALYSIS AND ENGINEERING OF THE HUMAN VITAMIN D RECEPTOR TO BIND AND ACTIVATE IN RESPONSE TO A NOVEL SMALL MOLECULE LIGAND A Dissertation Presented to The Academic Faculty by Hilda S. Castillo In Partial Fulfillment of the Requirements for the Degree Doctorate of Philosophy in the School of Chemistry & Biochemistry Georgia Institute of Technology May 2011 MUTATIONAL ANALYSIS AND ENGINEERING OF THE HUMAN VITAMIN D RECEPTOR TO BIND AND ACTIVATE IN RESPONSE TO A NOVEL SMALL MOLECULE LIGAND Approved by: Dr. Donald Doyle, Advisor Dr. Loren Williams, Co-advisor School of Chemistry & Biochemistry School of Chemistry & Biochemistry Georgia Institute of Technology Georgia Institute of Technology Dr. Bahareh Azizi, Advisor Dr. Nicholas Hud School of Chemistry & Biochemistry School of Chemistry & Biochemistry Georgia Institute of Technology Georgia Institute of Technology Dr. Andreas Bommarius, Co-advisor Dr. Sheldon May School of Chemical & Biomolecular Engineering School of Chemistry & Biochemistry Georgia Institute of Technology Georgia Institute of Technology Date Approved: January 20, 2011 Sólo dos legados duraderos podemos dejar a nuestros hijos: uno, raíces; otro, alas. ~Hodding Carter Para mis padres, Alex y Felix Castillo. Soy quien soy gracias a ustedes. TABLE OF CONTENTS Page LIST OF TABLES vii LIST OF FIGURES ix ABBREVIATIONS xii SUMMARY xv CHAPTER 1 NUCLEAR RECEPTORS 1 1.1 The Nuclear Receptor Superfamily 1 1.2 Structure of Nuclear Receptors 2 1.3 Transcriptional Regulation by Nuclear Receptors 7 1.4 Nuclear Receptors: Drug
    [Show full text]
  • C-10(19) Oxidation of Vitamin D by Anaerobic Gastrointestinal Bacteria Robert Marshall Gardner Iowa State University
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1985 C-10(19) oxidation of vitamin D by anaerobic gastrointestinal bacteria Robert Marshall Gardner Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Microbiology Commons Recommended Citation Gardner, Robert Marshall, "C-10(19) oxidation of vitamin D by anaerobic gastrointestinal bacteria " (1985). Retrospective Theses and Dissertations. 7849. https://lib.dr.iastate.edu/rtd/7849 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quahty of the reproduction is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction. 1.The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure complete continuity. 2. When an image on the film is obliterated with a round black mark, it is an indication of either blurred copy because of movement during exposure, duplicate copy, or copyrighted materials that should not have been filmed.
    [Show full text]
  • Dietary Factors Influencing Calcium and Phosphorus Utilization By
    DIETARY FACTORS INFLUENCING CALCIUM AND PHOSPHORUS UTILIZATION BY BROILER CHICKS by ANASTASSIA LIEM (Under the Direction of Gene M. Pesti) ABSTRACT Calcium and phosphorus are the most abundant minerals in the body of animals. They are macrominerals in animal nutrition, as they are required at relatively high levels. Calcium and phosphorus absorption and metabolism are influenced by many factors, such as the levels and ratio of inclusion in the diet, vitamin D3 and its derivatives, phytase, and organic acids. The effects of the above factors are investigated in four separate battery studies. Study one investigated the effects of phytase and 1α-OHD3 on Ca, P and phytate P utilization. Supplementation of 1α-OHD3 and phytase to P-deficient corn-soybean meal and corn-peanut meal based broiler diets increased P, and phytate P utilization, as indicated by an increase in bone ash, body weight gain, plasma P, phytate P and P retention, and also reduction in incidence of P-deficiency rickets. Study two investigated the effects of combinations of phytase, methionine source, and calcium or 1α-OHD3 on phosphorus utilization in broilers. Phytase, 1α-OHD3, and HMB (an organic acid) increased phytate P utilization, and the effect of each supplement often depended on the levels of other supplements and nutrients. Study three evaluated the efficacy of several 1α-OHD3 compounds as a substitute for cholecalciferol. Slope ratio analysis of data from the measurements of 16-d BWG, plasma Ca, rickets and bone ash indicated the bioavailability of the different 1α-OHD3 (except for the 5, 6 trans 1α-OHD3 which was inactive) to be 7 to 15 times more active as compared to D3.
    [Show full text]
  • Human Cholesterol 7Α-Hydroxylase (CYP7A1) Deficiency Has a Hypercholesterolemic Phenotype
    Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype Clive R. Pullinger, … , Mary J. Malloy, John P. Kane J Clin Invest. 2002;110(1):109-117. https://doi.org/10.1172/JCI15387. Article Genetics Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. TheC YP7A1 gene encodes the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3- hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder. Find the latest version: https://jci.me/15387/pdf Human cholesterol 7α-hydroxylase See related Commentary on pages 29–31. (CYP7A1) deficiency has a hypercholesterolemic phenotype Clive R. Pullinger,1 Celeste Eng,1 Gerald Salen,2,3 Sarah Shefer,2 Ashok K.
    [Show full text]
  • Bile Acids and Their Derivatives As Vitamin D Receptor Agonists:Molecular Mechanism and Biological Actions
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Tsukuba Repository Bile Acids and Their Derivatives as Vitamin D Receptor Agonists:Molecular Mechanism and Biological Actions 著者 Adachi Ryutaro year 2018 その他のタイトル ビタミンD受容体アゴニストとしての胆汁酸および その誘導体：分子メカニズムと生物学的作用 学位授与大学 筑波大学 (University of Tsukuba) 学位授与年度 2017 報告番号 12102甲第8562号 URL http://doi.org/10.15068/00152262 Bile Acids and Their Derivatives as Vitamin D Receptor Agonists: Molecular Mechanism and Biological Actions January 2018 Ryutaro ADACHI Bile Acids and Their Derivatives as Vitamin D Receptor Agonists: Molecular Mechanism and Biological Actions A Dissertation Submitted to the Graduate School of Life and Environmental Sciences, the University of Tsukuba in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biological Science (Doctoral Program in Biological Sciences) Ryutaro ADACHI Table of Contents Abstract ......................................................................................................................................... 1 Abbreviations ................................................................................................................................ 4 General Introduction ..................................................................................................................... 7 Structure and function of nuclear receptors .............................................................................. 8 NR family as drug target ........................................................................................................
    [Show full text]