DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2003/0185793 A1 Kratz (43) Pub

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2003/0185793 A1 Kratz (43) Pub US 2003.0185793A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0185793 A1 Kratz (43) Pub. Date: Oct. 2, 2003 (54) THERAPEUTIC AND DIAGNOSTIC LIGAND (30) Foreign Application Priority Data SYSTEMS COMPRISING TRANSPORT MOLECULE BINDING PROPERTIES AND Mar. 13, 2000 (DE)........................................ 1OO12120.9 MEDICAMENTS CONTAINING THE SAME Publication Classification (76) Inventor: Felix Kratz, Ihringen (DE) (51) Int. Cl." ......................... A61K 38/19; A61K 38/14; A61K 38/16 Correspondence Address: (52) U.S. Cl. .................... 424/85.1; 514/2; 514/6; 514/8; WEINGARTEN, SCHURGIN, GAGNEBIN & 514/27; 514/44; 530/350; 530/351; LEBOVICI LLP 530/322; 530/391.1 TEN POST OFFICE SQUARE BOSTON, MA 02109 (US) (57) ABSTRACT The invention relates to transport molecule binding ligand (21) Appl. No.: 10/221,544 compounds which comprise a therapeutically and/or diag nostically active Substance and a carrier molecule-affine (22) PCT Filed: Mar. 13, 2001 Substance with a high association constant to the carrier molecule. The invention also relates to medicaments con (86) PCT No.: PCT/EP01/02833 taining these ligand compounds and to diagnostic kits. US 2003/0185793 A1 Oct. 2, 2003 THERAPEUTIC AND DIAGNOSTIC LIGAND action (for example, as a cytostatic agent and as an anti SYSTEMS COMPRISING TRANSPORT rheumatic agent etc.). The term "diagnostically active Sub MOLECULE BINDING PROPERTIES AND stance' means that the respective Substance is detectable, MEDCAMENTS CONTAINING THE SAME preferably also quantifiable, in the organism or parts thereof, Such as for example cells and/or fluids, Such as for example DESCRIPTION Serum, by means of Suitable chemical and/or physical mea Surement methods. 0001. The present invention relates to carrier molecule binding ligand compounds comprising a therapeutically 0009. The carrier-molecule-affinitive substance in the and/or diagnostically active Substance and a carrier-mol carrier-molecule-binding ligand compound according to the ecule-affinitive Substance with a high asSociation constant invention has no covalent interaction with the carrier mol relative to the carrier molecule, as well as pharmaceutical ecule, i.e., the carrier-molecule-affinitive Substance binds to products and diagnostic kits containing these ligand com the carrier molecule on the basis of interactions of physical pounds. nature Such as electroStatic interactions, hydrogen bonds, van der Waals bonds, and/or hydrophobic interactions. 0002. A number of transport proteins for lipids, hor Moreover, with regard to the Specificity of the carrier mones, metabolites, pharmaceutical drugs, and Vitamins molecule-affinitive Substance (in respect) to the carrier mol circulate in the bloodstream. Examples of Such transport ecule, it is crucial that the equilibrium constant of the proteins are albumin, haptoglobin, prealbumin, low-density asSociation reaction between the carrier molecule and the lipoprotein (LDL), retinol-binding protein, transcortin, Vita carrier-molecule-affinitive Substance be Sufficiently high, min D-binding protein, or transcobalamin. The affinity which according to the invention corresponds to a value of between the transport protein and its ligand is described in >10M (log K-3), preferably at least 10'M' (log K at particular by means of the association constant KA. least 4), more preferably >10 M' (log Ka-5), even more 0003. It is known that a number of compounds, such as preferably >107M (log K-7) at most preferably >108 for example dyes, porphyrins, organic acids or pharmaceu M (log KA>8). In the ligand compound according to the tical drugs, enter into a distinct noncovalent, i.e., physical invention, the therapeutically and/or diagnostically active interaction with certain transport proteins in the blood Substance may be bound directly to the carrier-molecule Stream, whereby a Selectivity exists for certain transport affinitive substance. In a preferred embodiment of the ligand proteins, for example for albumin. compound according to the invention, the linkage between the therapeutically and/or diagnostically active Substance 0004 For a number of blood proteins it is further known and the carrier-molecule-affinitive Substance either is not that they accumulate in pathogenic tissue, for example in cleavable or this linkage is pH-dependent and/or enzymati malignant or inflamed tissue. For example, Such accumula cally cleavable, within the body. tion has been demonstrated for the Serum protein albumin (Kratz, F., Beyer U. (1998) Serum proteins as drug carriers 0010. In a further preferred embodiment of the ligand of anticancer agents, a review. Drug Delivery, 5, 1-19). compound according to the invention, the therapeutically and/or diagnostically active Substance and the carrier-mol 0005 The technical problem underlying the present ecule-affinitive Substance are bound to each other through a invention is to therapeutically and diagnostically utilize the Spacer molecule. Moreover, as already explained above for above-indicated carrier-molecule-binding properties, Such direct linkage between the therapeutically and/or diagnosti as for example binding to transport proteins in the blood cally active Substance and the carrier-molecule-affinitive Stream due to distinct physical interactions, and to provide Substance, the Spacer molecule and/or the linkage between a new ligand System with carrier-molecule-binding proper the therapeutically and/or diagnostically active Substance ties and pharmaceutical products containing these carrier and the Spacer molecule and/or the linkage of the carrier molecule-binding compounds. molecule-affinitive Substance and the Spacer molecule either 0006 The solution to this technical problem is achieved is uncleavable or the Spacer molecule and/or the indicated by means of the embodiments of the present invention as linkages can be pH-dependent and/or enzymatically cleav characterized in the claims. able, within the body. 0007. In particular, a carrier-molecule-binding ligand 0011. According to a further preferred embodiment, the compound is provided that comprises at least one therapeu direct linkage between the therapeutically and/or diagnosti tically or pharmaceutically and/or diagnostically active Sub cally active Substance and the carrier-molecule-affinitive stance and at least one carrier-molecule-affinitive Substance, Substance or the Spacer molecule and/or the linkage between having an association or binding constant KA relative to the the therapeutically and/or diagnostically active Substance carrier molecule of >10 M', preferably >10 M', even and the Spacer molecule and/or the linkage between the more preferably >107 M', most preferably >108 MT', carrier-molecule-affinitive Substance and the Spacer mol through a noncovalent bond. ecule contains at least one acid-labile bond. Examples of Such acid-labile bonds are ester, acetal, ketal, imine, hydra 0008. The term “therapeutically or pharmaceutically Zone, carboxylhydraZone, or SulfonylhydraZone compounds. active Substance' means that the respective Substance, either itself or after it is metabolized in the respective organism, 0012. According to a further embodiment of the ligand has a pharmacological effect, and thus the term also com compound according to the invention, either the direct prises the derivatives resulting from these conversions. Of linkage between the therapeutically and/or diagnostically course, the therapeutically active Substance can have a single active Substance and the carrier-molecule-affinitive Sub pharmacological spectrum of action (for example, only as a stance or the Spacer molecule and/or the linkage between the cytostatic agent) or a broad pharmacological spectrum of therapeutically and/or diagnostically active Substance and US 2003/0185793 A1 Oct. 2, 2003 the Spacer molecule and/or the linkage between the carrier 0016. The term “carrier molecule” comprises both natu molecule-affinitive Substance and the Spacer molecule con ral and Synthetic molecules that are Suitable for transporting tains at least one peptide bond. The peptide bond preferably ligand compounds according to the invention, for example is located within a peptide Sequence which contains at least in body fluids such as blood serum. Suitable transport one protease cleavage Sequence. Hence at least one peptide molecules are naturally occurring or Synthetic macromol bond can be realized by addition of a peptide Sequence into ecules, for example polyethylene glycol (PEG) or dextran, the direct linkage between the therapeutically and/or diag and biological macromolecules Such as proteins. Preferred nostically active Substance and the carrier-molecule-affini proteins that are Suitable as carrier molecules are Selected tive Substance or into the Spacer molecule and/or into the from the group consisting of Serum proteins. Albumin is an linkage between the therapeutically and/or diagnostically example of a preferred Suitable Serum protein. Further active Substance and the Spacer molecule and/or into the linkage between the carrier-molecule-affinitive Substance transport proteins Suitable as carrier molecules are transfer and the Spacer molecule, i.e., the respective linkage is a rin, haptoglobin, prealbumin, low-density lipoprotein peptide bond, and preferably consists of about 1 to 30 amino (LDL), retinol-binding protein, transcortin, as well as Vita acids. The peptide Sequence is preferably tailored to the min D-binding protein or transcobalamin. Substrate Specificity of certain endogenous enzymes or enzymes
Load more

Recommended publications
  • CDH12 Cadherin 12, Type 2 N-Cadherin 2 RPL5 Ribosomal
    5 6 6 5 . 4 2 1 1 1 2 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 A A A A A A A A A A A A A A A A A A A A C C C C C C C C C C C C C C C C C C C C R R R R R R R R R R R R R R R R R R R R B , B B B B B B B B B B B B B B B B B B B , 9 , , , , 4 , , 3 0 , , , , , , , , 6 2 , , 5 , 0 8 6 4 , 7 5 7 0 2 8 9 1 3 3 3 1 1 7 5 0 4 1 4 0 7 1 0 2 0 6 7 8 0 2 5 7 8 0 3 8 5 4 9 0 1 0 8 8 3 5 6 7 4 7 9 5 2 1 1 8 2 2 1 7 9 6 2 1 7 1 1 0 4 5 3 5 8 9 1 0 0 4 2 5 0 8 1 4 1 6 9 0 0 6 3 6 9 1 0 9 0 3 8 1 3 5 6 3 6 0 4 2 6 1 0 1 2 1 9 9 7 9 5 7 1 5 8 9 8 8 2 1 9 9 1 1 1 9 6 9 8 9 7 8 4 5 8 8 6 4 8 1 1 2 8 6 2 7 9 8 3 5 4 3 2 1 7 9 5 3 1 3 2 1 2 9 5 1 1 1 1 1 1 5 9 5 3 2 6 3 4 1 3 1 1 4 1 4 1 7 1 3 4 3 2 7 6 4 2 7 2 1 2 1 5 1 6 3 5 6 1 3 6 4 7 1 6 5 1 1 4 1 6 1 7 6 4 7 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m
    [Show full text]
  • Supplementary Table 1: Differentially Methylated Genes and Functions of the Genes Before/After Treatment with A) Doxorubicin and B) FUMI and in C) Responders Vs
    Supplementary Table 1: Differentially methylated genes and functions of the genes before/after treatment with a) doxorubicin and b) FUMI and in c) responders vs. non- responders for doxorubicin and d) FUMI Differentially methylated genes before/after treatment a. Doxo GENE FUNCTION CCL5, CCL8, CCL15, CCL21, CCR1, CD33, IL5, immunoregulatory and inflammatory processes IL8, IL24, IL26, TNFSF11 CCNA1, CCND2, CDKN2A cell cycle regulators ESR1, FGF2, FGF14, FGF18 growth factors WT1, RASSF5, RASSF6 tumor suppressor b. FUMI GENE FUNCTION CCL7, CCL15, CD28, CD33, CD40, CD69, TNFSF18 immunoregulatory and inflammatory processes CCND2, CDKN2A cell cycle regulators IGF2BP1, IGFBP3 growth factors HOXB4, HOXB6, HOXC8 regulation of cell transcription WT1, RASSF6 tumor suppressor Differentially methylated genes in responders vs. non-responders c. Doxo GENE FUNCTION CBR1, CCL4, CCL8, CCR1, CCR7, CD1A, CD1B, immunoregulatory and inflammatory processes CD1D, CD1E, CD33, CD40, IL5, IL8, IL20, IL22, TLR4 CCNA1, CCND2, CDKN2A cell cycle regulators ESR2, ERBB3, FGF11, FGF12, FGF14, FGF17 growth factors WNT4, WNT16, WNT10A implicated in oncogenesis TNFSF12, TNFSF15 apoptosis FOXL1, FOXL2, FOSL1,HOXA2, HOXA7, HOXA11, HOXA13, HOXB4, HOXB6, HOXB8, HOXB9, HOXC8, regulation of cell transcription HOXD8, HOXD9, HOXD11 GSTP1, MGMT DNA repair APC, WT1 tumor suppressor d. FUMI GENE FUNCTION CCL1, CCL3, CCL5,CCL14, CD1B, CD33, CD40, CD69, immunoregulatory and inflammatory IL20, IL32 processes CCNA1, CCND2, CDKN2A cell cycle regulators IGF2BP1, IGFBP3, IGFBP7, EGFR, ESR2,RARB2
    [Show full text]
  • Evidence for an Essential Role of Megalin in Transepithelial Transport of Retinol
    ARTICLES J Am Soc Nephrol 10: 685–695, 1999 Evidence for an Essential Role of Megalin in Transepithelial Transport of Retinol ERIK ILSØ CHRISTENSEN,* JAN ØIVIND MOSKAUG,‡ HENRIK VORUM,† CHRISTIAN JACOBSEN,† THOMAS E. GUNDERSEN,‡ ANDERS NYKJÆR,§ RUNE BLOMHOFF,‡ THOMAS E. WILLNOW§ and SØREN K. MOESTRUP† *Department of Cell Biology, Institute of Anatomy and †Department of Medical Biochemistry, University of Aarhus, Denmark; ‡Institute for Nutrition Research, University of Oslo, Norway; and §Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany. Abstract. Transepithelial transport of retinol is linked to reti- urinary excretion of RBP and retinol, demonstrating that glo- nol-binding protein (RBP), which is taken up and also synthe- merular filtered RBP-retinol of megalin-deficient mice escapes sized in a number of epithelia. By immunocytochemistry of uptake by proximal tubules. A direct megalin-mediated uptake human, rat, and mouse renal proximal tubules, a strong staining of purified RBP-retinol was indicated by surface plasmon in apical endocytic vacuoles, lysosomes, endoplasmic reticu- resonance analysis and uptake in immortalized rat yolk sac lum, Golgi, and basal vesicles was observed, in accordance cells. Uptake was partially inhibited by a polyclonal megalin with luminal endocytic uptake as well as a constitutive syn- antibody and the receptor-associated protein. The present data thesis and basal secretion of RBP. Analysis of mice with target show that the absence of RBP-binding megalin causes a sig- disruption of the gene for the major endocytic receptor of nificantly increased loss of RBP and retinol in the urine, proximal tubules, megalin, revealed no RBP in proximal tu- demonstrating a crucial role of megalin in vitamin A homeosta- bules of these mice.
    [Show full text]
  • Intracellular and Tissue Levels of Vitamin B12 in Hepatocytes Are Modulated by CD320 Receptor and TCN2 Transporter
    International Journal of Molecular Sciences Article Intracellular and Tissue Levels of Vitamin B12 in Hepatocytes Are Modulated by CD320 Receptor and TCN2 Transporter Joseph Boachie 1 , Antonysunil Adaikalakoteswari 1,2,* , Ilona Goljan 3 , Jinous Samavat 1, Felino R. Cagampang 4 and Ponnusamy Saravanan 1,3,5,* 1 Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; [email protected] (J.B.); [email protected] (J.S.) 2 Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK 3 Diabetes Centre, George Eliot Hospital NHS Trust College Street, Nuneaton CV10 7DJ, UK; [email protected] 4 Institute of Developmental Sciences, University of Southampton, Faculty of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK; [email protected] 5 Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK * Correspondence: [email protected] (A.A.); [email protected] (P.S.); Tel.: +44-1158-483946 (A.A.); +44-2476-968668 (P.S.) Abstract: The liver mass constitutes hepatocytes expressing receptors for vitamin B12 (B12)-bound transporters in circulation. However, intrahepatic and circulating B12 interrelationship levels remain unclear. We assessed the intracellular B12 levels at various circulating B12 concentrations in human Citation: Boachie, J.; HepG2 cell-line and liver tissue levels of B12 in the C57BL/6 mouse model. In HepG2 cells treated Adaikalakoteswari, A.; Goljan, I.; Samavat, J.; Cagampang, F.R.; with a range of B12 concentrations, the intracellular and circulatory B12 levels, transcript and protein Saravanan, P.
    [Show full text]
  • Vitamin and Minerals and Neurologic Disease
    Vitamin and Minerals and Neurologic Disease Steven L. Lewis, MD World Congress of Neurology October 2019 Dubai, UAE [email protected] Disclosures . Dr. Lewis has received personal compensation from the American Academy of Neurology for serving as Editor-in-Chief of Continuum: Lifelong Learning in Neurology and for activities related to his role as a director of the American Board of Psychiatry and Neurology, and has received royalty payments from the publishers Wolters Kluwer and Wiley-Blackwell for book authorship. He has no disclosures related to the content or topic of this talk. Objective . Discuss the association of trace mineral deficiencies and vitamin deficiencies (and excess) with neuropathy and myeloneuropathy and other peripheral neurologic syndromes Outline of Presentation . List minerals relevant to neuropathy or myeloneuropathy . Proceed through each mineral and its associated clinical syndrome . List vitamins relevant to neuropathy or myeloneuropathy . Proceed through each vitamin and its associated clinical syndrome Minerals . Naturally occurring nonorganic homogeneous substances . Elements . Required for optimal metabolic and structural processes . Both cations and anions . Essential trace minerals: must be supplied in the diet . Some have recommended daily allowances (RDA) Macrominerals . Sodium . Potassium . Calcium . Magnesium . Phosphorus . Sulfur Macrominerals . Sodium . Potassium . Calcium . Magnesium . Phosphorus . Sulfur Trace Minerals . Chromium . Cobalt . Copper . Iodine . Iron . Manganese . Molybdenum . Selenium . Zinc Trace Minerals . Chromium . Cobalt . Copper . Iodine . Iron . Manganese . Molybdenum . Selenium . Zinc Generalized dose-reponse curve for an essential nutrient Howd and Fan, 2007 Copper . Essential trace element . Human body contains approximately 100 mg Cu . Cofactor of many redox enzymes . Ceruloplasmin most abundant of the cuproenzymes . Involved in antioxidant defense, neuropeptide and blood cell synthesis, and immune function1 1 Bost, J Trace Elements 2016 Copper Deficiency .
    [Show full text]
  • Evidence for Megalin-Mediated Proximal Tubular Uptake of L-FABP, a Carrier of Potentially Nephrotoxic Molecules
    Laboratory Investigation (2005) 85, 522–531 & 2005 USCAP, Inc All rights reserved 0023-6837/05 $30.00 www.laboratoryinvestigation.org Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules Yuko Oyama1, Tetsuro Takeda1,2, Hitomi Hama1, Atsuhito Tanuma1, Noriaki Iino1, Kiyoko Sato1, Ryohei Kaseda1, Meilei Ma3, Tadashi Yamamoto3, Hiroshi Fujii4, Junichiro J Kazama5, Shoji Odani6, Yoshio Terada7, Kunihiro Mizuta8, Fumitake Gejyo1 and Akihiko Saito1,2 1Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 3Department of Structural Pathology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 4Division of Molecular and Cellular Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 5Division of Intensive Care Medicine, Niigata University Hospital, Niigata, Japan; 6Department of Biology, Faculty of Science, Niigata University, Niigata, Japan; 7Department of Homeostasis Medicine and Nephrology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan and 8Department of Otolaryngology, Hamamatsu University School of Medicine, Hamamatsu, Japan Liver-type fatty acid binding protein (L-FABP) binds with high affinity to hydrophobic molecules including free fatty acid, bile acid and bilirubin, which are potentially nephrotoxic, and is involved in their metabolism mainly in hepatocytes. L-FABP is released into the circulation, and patients with liver damage have an elevated plasma L-FABP level. L-FABP is also present in renal tubules; however, the precise localization of L-FABP and its potential role in the renal tubules are not known.
    [Show full text]
  • Regulation of GH and GH Signaling by Nutrients
    cells Review Regulation of GH and GH Signaling by Nutrients Marina Caputo 1,2, Stella Pigni 1, Emanuela Agosti 2 , Tommaso Daffara 1 , Alice Ferrero 1, Nicoletta Filigheddu 3 and Flavia Prodam 1,2,* 1 SCDU of Endocrinology, University Hospital Maggiore della Carità, 28100 Novara, Italy; [email protected] (M.C.); [email protected] (S.P.); [email protected] (T.D.); [email protected] (A.F.) 2 Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; [email protected] 3 Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; nicoletta.fi[email protected] * Correspondence: fl[email protected]; Tel.: +39-0321-660693 Abstract: Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF- I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, Citation: Caputo, M.; Pigni, S.; and treatment of GH/IGF-I deficiency or excess during life.
    [Show full text]
  • The Effect of Overfeeding and Obesity on Canine Adipose Tissue and Skeletal Muscle Transcriptomes by Ryan Walter Grant Disserta
    THE EFFECT OF OVERFEEDING AND OBESITY ON CANINE ADIPOSE TISSUE AND SKELETAL MUSCLE TRANSCRIPTOMES BY RYAN WALTER GRANT DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Nutritional Sciences in the Graduate College of the University of Illinois at Urbana-Champaign, 2011 Urbana, Illinois Doctoral Committee: Professor Sharon M. Donovan, Chair Associate Professor Kelly S. Swanson, Director of Research Associate Professor Thomas K. Graves Associate Professor Manabu T. Nakamura Abstract Overweight dogs have a reduced life expectancy and increased risk of chronic disease. During obesity development, adipose tissue undergoes major expansion and remodeling, but the biological processes involved are not well understood. The objective of study 1 was to analyze global gene expression profiles of adipose tissue in dogs, fed a high-fat (47% kcal/g) diet, during the transition from a lean to obese phenotype. Nine female beagles were randomized to ad libitum (n=5) feeding or body weight maintenance (n=4). Subcutaneous adipose tissue biopsy, skeletal muscle biopsy and blood samples were collected, and dual x-ray absorptiometry measurements were taken at 0, 4, 8, 12, and 24 wk of feeding. Ad libitum feeding increased (P<0.05) body weight, body fat mass, adipocyte size and serum leptin concentrations. Microarrays displayed 1,665 differentially expressed genes in adipose tissue over time in the ad libitum fed dogs. Alterations were observed in many homeostatic processes including metabolism, oxidative stress, mitochondrial homeostasis, and extracellular matrix. Our data implies that during obesity development subcutaneous adipose tissue has a large capacity for expansion, which is accompanied by tissue remodeling and short-term adaptations to the metabolic stresses associated with ad libitum feeding.
    [Show full text]
  • Studies on the Transcobalamin Receptor in Hog Kidney
    Kidney International, Vol. 39 (1991), pp. 289-294 Studies on the transcobalamin receptor in hog kidney 1 SHOJI YAMADA , LEENA RIITTINEN, RAIMO MAJURI, MORIMICHI FUKUDA, and RALPH GRASBECK Minerva Foundation Institute for Medical Research, Helsinki, Finland, and Department of Laboratory Diagnosis, Sapporo Medical College, Sapporo, Japan Studies on the transcobalamin receptor in hog kidney. The binding of Cbl-TC complex was reabsorbed and degraded by a similar the cobalamin-trans cobalamin complex by its solubilized receptor from process as low-molecular-weight proteins in general. The cel­ hog kidney membrane was studied. The receptor bound the complex in a system containing bivalent cations, and the affinity was dependent on lular uptake of the Cbl-TC complex begins with binding of the the NaCI concentration but not on temperature. The binding of coba­ complex to a specific surface receptor [13, 14]. This report lamin-transcobalamin to the receptor had an association constant of describes some characteristics of the Cbl-TC receptor solubi­ approximately 4.6 x 109 liter/mol and it was saturable and highly lized from hog kidney. specific as competition by other proteins was not observed. The receptor had higher affinity for the cobalamin-transcobalamin complex Methods (holo-TC) than for transcobalamin (apo-TC). Basic amino compounds known to interfere with tubular reabsorption of proteins did not inhibit Reagents the binding. Studies on subcellular fractions supported the view that the receptor was located on the brush border membrane of the kidney.2 All reagents were commercially available guaranteed-grade chemicals. Hog serum albumin (Fraction V, Sigma Chemical Co., St.
    [Show full text]
  • A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression
    Supplementary Materials A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression Table S1. Statistically significant DEGs (Adj. p-value < 0.01) derived from meta-analysis for samples irradiated with high doses of HZE particles, collected 6-24 h post-IR not common with any other meta- analysis group. This meta-analysis group consists of 3 DEG lists obtained from DGEA, using a total of 11 control and 11 irradiated samples [Data Series: E-MTAB-5761 and E-MTAB-5754]. Ensembl ID Gene Symbol Gene Description Up-Regulated Genes ↑ (2425) ENSG00000000938 FGR FGR proto-oncogene, Src family tyrosine kinase ENSG00000001036 FUCA2 alpha-L-fucosidase 2 ENSG00000001084 GCLC glutamate-cysteine ligase catalytic subunit ENSG00000001631 KRIT1 KRIT1 ankyrin repeat containing ENSG00000002079 MYH16 myosin heavy chain 16 pseudogene ENSG00000002587 HS3ST1 heparan sulfate-glucosamine 3-sulfotransferase 1 ENSG00000003056 M6PR mannose-6-phosphate receptor, cation dependent ENSG00000004059 ARF5 ADP ribosylation factor 5 ENSG00000004777 ARHGAP33 Rho GTPase activating protein 33 ENSG00000004799 PDK4 pyruvate dehydrogenase kinase 4 ENSG00000004848 ARX aristaless related homeobox ENSG00000005022 SLC25A5 solute carrier family 25 member 5 ENSG00000005108 THSD7A thrombospondin type 1 domain containing 7A ENSG00000005194 CIAPIN1 cytokine induced apoptosis inhibitor 1 ENSG00000005381 MPO myeloperoxidase ENSG00000005486 RHBDD2 rhomboid domain containing 2 ENSG00000005884 ITGA3 integrin subunit alpha 3 ENSG00000006016 CRLF1 cytokine receptor like
    [Show full text]
  • Hereditary Disorders of Sugar Metabolism
    Hereditary disorders of sugar metabolism Disorders of metabolism of monosaccharides („small molecules“) Fructose Galactose Disorders of metabolism of polysaccharides („ large molecules“) Glycogen storage disorders (also lack of product) Disorders of glycosylation of proteins product deficiency Inherited disorders of fructose metabolism Fructose Fructose (β-D-fructofuranose) Honey, vegetables and fruits Saccharose Frucose is the main sugar of seminal fluid raffinose, stachyose, inulin - no role in human nutrition sorbitol – sugar alcohol, derived from glucose, abundant in fruits. Sorbitol dehydrogenase converts sorbitol to fructose - a source of fructose. GLUT5 – glucose transporter isoform is probably responsible for fructose transport in the small intestine Fructose is probably transported into the liver by the same system as glucose and galactose Inherited disorders of fructose metabolism Daily intake of fructose in Western diets: 100 g Metabolised in liver, kidney, intestine Intravenous fructose in high-doses is toxic: hyperuricemia, hyperlactacidemia, utrastructural changes in the liver. Essential fructosuria Hereditary fructose intolerance (aldolase B deficiency) Hereditary fructose 1,6-bisphosphatase deficiency Autosomal recessive disorders Toxicity of fructose Rapid accumulation of fructose -1-phosphate The utilization of F-1-P is limited by triokinase Depletion af ATP Hyperuricemia Hyperuricemic effect of fructose results from the degradation of adenine nucleotides (ATP). Adenine dinucleotides → → → uric acid Increase in lactate Hereditary fructose intolerance Deficiency of fructoaldolase B of the liver, kidney cortex (isoenzymes A,B,C) Severe hypoglycemia upon ingestion of fructose Prolonged fructose intake : poor feeding, vomiting, hepatomegaly jaundice hemorrage, proxima tubular renal syndrome, hepatic failure, death Strong distaste for fructose containig foods Fructose -1- phosphate inhibits gluconeogenesis : phosphorylase and aldolase Patients are healthy on fructose-free food Diagnostics: (i.v.
    [Show full text]
  • Cellular Uptake of Steroid Carrier Proteins – Mechanisms and Implications Thomas E
    Cellular uptake of steroid carrier proteins – mechanisms and implications Thomas E. Willnow, Anders Nykjaer To cite this version: Thomas E. Willnow, Anders Nykjaer. Cellular uptake of steroid carrier proteins – mecha- nisms and implications. Molecular and Cellular Endocrinology, Elsevier, 2009, 316 (1), pp.93. 10.1016/j.mce.2009.07.021. hal-00550176 HAL Id: hal-00550176 https://hal.archives-ouvertes.fr/hal-00550176 Submitted on 24 Dec 2010 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. Accepted Manuscript Title: Cellular uptake of steroid carrier proteins – mechanisms and implications Authors: Thomas E. Willnow, Anders Nykjaer PII: S0303-7207(09)00380-3 DOI: doi:10.1016/j.mce.2009.07.021 Reference: MCE 7271 To appear in: Molecular and Cellular Endocrinology Received date: 29-4-2009 Revised date: 21-7-2009 Accepted date: 21-7-2009 Please cite this article as: Willnow, T.E., Nykjaer, A., Cellular uptake of steroid carrier proteins – mechanisms and implications, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009.07.021 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
    [Show full text]