DOCSLIB.ORG

Development of Novel Synthetic Routes to the Epoxyketooctadecanoic Acids

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development of Novel Synthetic Routes to the Epoxyketooctadecanoic Acids DEVELOPMENT OF NOVEL SYNTHETIC ROUTES TO THE EPOXYKETOOCTADECANOIC ACIDS (EKODES) AND THEIR BIOLOGICAL EVALUATION AS ACTIVATORS OF THE PPAR FAMILY OF NUCLEAR RECEPTORS By ROOZBEH ESKANDARI Submitted in partial fulfillment of the requirements for The Degree of Doctor of Philosophy Thesis Advisor: Gregory P. Tochtrop, Ph.D. Department of Chemistry CASE WESTERN RESERVE UNIVERSITY January, 2016 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ROOZBEH ESKANDARI Candidate for the Ph.D degree *. (signed) Anthony J. Pearson, PhD (Chair of the committee) Gregory P. Tochtrop, PhD (Advisor) Michael G. Zagorski, PhD Blanton S. Tolbert, PhD Witold K. Surewicz, PhD (Department of Physiology and Biophysics) (date) 14th July, 2015 *We also certify that written approval has been obtained for any proprietary material contained therein. I dedicate this work to my sister Table of Contents Table of Contents ........................................................................................................................ i List of Tables .............................................................................................................................. vi List of Figures ........................................................................................................................... vii List of Schemes .......................................................................................................................... ix Acknowledgements ................................................................................................................... xi List or Abbreviations ............................................................................................................ xiii Abstract ................................................................................................................................... xxiii CHAPTER 1 General Introduction ........................................................................................ 1 1.1 Discovery of prostaglandins .............................................................................................. 1 1.2 The role of synthesis in the advancement of prostaglandins research ...................3 1.3 Discovery of leukotrienes ...........................................................................................6 1.4 The role of synthesis in the advancement of leukotrienes research .......................6 1.5 Non-enzymatic oxidation of PUFAs ..........................................................................8 1.6 The role of synthesis in the advancement of LPO products ..................................10 1.7 Formation of LPO products .....................................................................................12 1.8 Oxidative stress (OS) ................................................................................................16 1.8.1 Formation of reactive oxygen species/reactive nitrogen species (ROS/RNS) ............................................................................................................................................17 1.8.2 Reactive oxygen species (ROS) ............................................................................. 17 i 1.8.2.1 Singlet oxygen .................................................................................... 17 1.8.2.2 Superoxide radical ............................................................................. 18 1.8.2.3 Hydrogen peroxide ............................................................................ 19 1.8.2.4 Hydroxyl radical................................................................................. 19 1.8.3 Reactive nitrogen species (RNS) .................................................................... 19 1.8.3.1 Nitric oxide (NO.) .............................................................................. 19 1.8.3.2 Peroxynitrite (ONOO-) .................................................................... 19 1.8.4 Reactivity of ROS/RNS. ................................................................................... 20 1.9. Biological roles of oxidized lipids .................................................................................. 22 1.9.1 Oxidized lipid and G protein-coupled receptors (GPCRs) ...................... 23 1.9.2 Oxidized lipid and peroxisome-proliferator-activated receptors (PPARs) ...................................................................................................................................... 24 1.10 References ......................................................................................................................... 26 CHAPTER 2 Development of novel synthetic routes to the epoxyketooctadecenoic acids (EKODEs) ........................................................................................................................ 31 2.1 Introduction ........................................................................................................................ 31 2.2 EKODE structure and nomenclature ............................................................................ 34 2.3 EKODE-(E)-I family ......................................................................................................... 35 2.3.1 Retrosynthetic analysis of trans-EKODE-(E)- I ......................................... 36 2.3.2 Synthesis of trans-EKODE-(E)- Ia ................................................................ 37 ii 2.3.3 Synthesis of trans-EKODE-(E)- Ib ................................................... 38 2.3.4 Retrosynthetic analysis of cis-EKODE-(E)- Ib .............................. 40 2.3.5 Synthesis of cis-EKODE-(E)- Ib ....................................................... 40 2.4 EKODE-(E)-II family .......................................................................................... 42 2.4.1 Retrosynthetic analysis of trans-EKODE-(E)-II ........................... 44 2.4.2 Synthesis of bifunctional conjunctive ylide .................................... 45 2.4.3 Synthesis of trans-EKODE-(E)-II ..................................................... 47 2.4.4 Divergent synthesis for diverse library of trans-EKODE-(E)-II .......................................................................................................................................... 49 2.4.4.1 Synthesis of alkyne-end aldehyde ..................................... 49 2.4.4.2 Synthesis of deuterated labeled aldehyde ....................... 49 2.5 Experimental part ................................................................................................ 52 2.5.1 General experimental details ............................................................. 52 2.5.2 Syntheses ................................................................................................ 54 2.6 References ............................................................................................................... 88 Chapter 3. Biological evaluation of EKODEs as potential activators of the PPAR family of nuclear receptors .................................................................................................... 91 3.1 Peroxisome proliferator-activated receptors (PPARs) structure and activity ..... 91 3.2. The physiological functions of the PPARs .................................................................. 95 3.2.1 Functional role of PPARα ............................................................................... 95 iii 3.2.1.1 Exogenous ligands (synthetic Xenobiotics) of PPARα .............. 95 3.2.1.2 Endogenous ligands (biological molecules) of PPARα ............. 96 3.2.2 Functional role of PPARɣ ................................................................................ 97 3.2.2.1 Exogenous ligands of PPARɣ ......................................................... 98 3.2.2.2 Endogenous ligands of PPARɣ ....................................................... 99 3.2.3. Functional role of PPARβ/δ ......................................................................... 101 3.2.3.1 Exogenous ligands of PPARβ/δ .................................................... 102 3.2.3.2 Endogenous ligands of PPARβ/δ ................................................. 102 3.3 EKODEs as potential endogenous metabolites ......................................................... 103 3.4 Target reporter assay ..................................................................................................... 105 3.4.1 Bioluminescence ............................................................................................... 105 3.4.2 Cell-based reporter assay .............................................................................. 105 3.4.3 Single luciferase reporter assay ................................................................... 106 3.4.4 Luciferase enzyme mechanism ..................................................................... 107 3.4.5 Colorimetric β-galactosidase assay ............................................................. 108 3.5 Experimental .................................................................................................................... 110 3.5.1 Materials ............................................................................................................ 110 3.5.2 Cell transient transfection assay .................................................................. 110 3.5.3 Methods ............................................................................................................
Load more

Recommended publications
  • Chemicals in the Fourth Report and Updated Tables Pdf Icon[PDF
    Chemicals in the Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 CDC’s Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 provides exposure data on the following chemicals or classes of chemicals. The Updated Tables contain cumulative data from national samples collected beginning in 1999–2000 and as recently as 2015-2016. Not all chemicals were measured in each national sample. The data tables are available at https://www.cdc.gov/exposurereport. An asterisk (*) indicates the chemical has been added since publication of the Fourth National Report on Human Exposure to Environmental Chemicals in 2009. Adducts of Hemoglobin Acrylamide Formaldehyde* Glycidamide Tobacco Alkaloids and Metabolites Anabasine* Anatabine* Cotinine Cotinine-n-oxide* Hydroxycotinine* Trans-3’-hydroxycotinine* 1-(3-Pyridyl)-1-butanol-4-carboxylic acid* Nicotine* Nicotine-N’-oxide* Nornicotine* Tobacco-Specific Nitrosamines (TSNAs) N’-Nitrosoanabasine (NAB)* N’-Nitrosoanatabine (NAT)* N’-Nitrosonornicotine (NNN)* Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL)* Volatile N-nitrosamines (VNAs) N-Nitrosodiethylamine (NDEA)* N-Nitrosoethylmethylamine (NMEA)* N-Nitrosomorpholine (NMOR)* N-Nitrosopiperidine (NPIP)* N-Nitrosopyrrolidine (NPYR)* Disinfection By-Products Bromodichloromethane Dibromochloromethane Tribromomethane (Bromoform) Trichloromethane (Chloroform) Personal Care and Consumer Product Chemicals and Metabolites Benzophenone-3 Bisphenol A Bisphenol F* Bisphenol
    [Show full text]
  • Telmisartan Use in Rats with Preexisting Osteoporotics Bone
    Life Sciences 237 (2019) 116890 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Telmisartan use in rats with preexisting osteoporotics bone disorders T increases bone microarchitecture alterations via PPARγ Antonio Marcos Birocalea, Antonio Ferreira de Melo Jr.b, Pollyana Peixotob, Phablo Wendell Costalonga Oliveirab, Leandro Dias Gonçalves Ruffonic, Liliam Masako Takayamad, Breno Valentim Nogueirae, Keico Okino Nonakac, ∗ Rosa Maria Rodrigues Pereirad, José Martins de Oliveira Jr.f, Nazaré Souza Bissolib, a Department of Health Integrated Education, Federal University of Espirito Santo, Vitória, ES, Brazil b Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES, Brazil c Department of Physiological Sciences, Federal University of São Carlos, São Carlos, SP, Brazil d Department of Medical Clinic, Medicine College, University of São Paulo, São Paulo, SP, Brazil e Department of Morphology, Federal University of Espirito Santo, Vitoria, ES, Brazil f Laboratory of Applied Nuclear Physics, University of Sorocaba, Sorocaba, SP, Brazil ARTICLE INFO ABSTRACT Keywords: Aims: Telmisartan (TEL), an angiotensin II type I receptor blocker and PPARγ partial agonist, has been used for Telmisartan to treat hypertension. It is known that PPARγ activation induces bone loss. Therefore, we evaluate the effects of PPARγ telmisartan on PPARγ protein expression, biomechanics, density and bone microarchitecture of femurs and Hypertension lumbar vertebrae in SHR ovariectomized animals, a model of hypertension in which preexisting bone impair- Ovariectomy ment has been demonstrated. Bone Main methods: SHR females (3 months old) were distributed into four groups: sham (S), sham + TEL (ST), OVX (C) and OVX + TEL (CT). TEL (5 mg/kg/day) or vehicle were administered according to the groups.
    [Show full text]
  • Independent Discovery in Biology: Investigating Styles of Scientific Research
    Medical History, 1993, 37: 432-441. INDEPENDENT DISCOVERY IN BIOLOGY: INVESTIGATING STYLES OF SCIENTIFIC RESEARCH by NICHOLAS RUSSELL * INTRODUCTION The fact that discoveries are often made independently is a commonplace of the history and sociology of science. Analysis of independent discovery has potential for evaluating the relative importance of social and individual components in the conduct of scientific research.' For instance, in a classic paper, Barber and Fox2 discussed the independent discovery of a bizarre phenomenon by two scientists. Aaron Kellner and Lewis Thomas both found that injections of the enzyme papain caused the upright ears of rabbits to droop over their heads like spaniels'. At first neither could find an explanation for it. Both abandoned the search and Kellner never returned to it, even though he went on to use the floppy ear response as a technical assay for measuring the potency of papain samples. Lewis Thomas did look into it again and discovered that papain completely altered the structure of the matrix of cartilage, not only in the ears but everywhere else in the animal as well. Both Thomas and Kellner had originally missed these changes because they had assumed that cartilage was a stable and uninteresting tissue. Barber and Fox concluded that Thomas persisted with the problem because it played a role in his developing research while the floppy-eared phenomenon was irrelevant to Kellner's interests. Barber and Fox hinted that more personal factors were involved as well, a theme expanded by Thomas in a later autobiographical essay.3 Thomas had found the collapsed ears amusing.
    [Show full text]
  • Pfoa) Or Perfluorooctane Sulfonate (Pfos
    National Toxicology Program NTP U.S. Department of Health and Human Services NTP Monograph Immunotoxicity Associated with Exposure to Perfluorooctanoic Acid or Perfluorooctane Sulfonate September 2016 NTP MONOGRAPH ON IMMUNOTOXICITY ASSOCIATED WITH EXPOSURE TO PERFLUOROOCTANOIC ACID (PFOA) OR PERFLUOROOCTANE SULFONATE (PFOS) September, 2016 Office of Health Assessment and Translation Division of the National Toxicology Program National Institute of Environmental Health Sciences National Institutes of Health U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Systematic Review of Immunotoxicity Associated with Exposure to PFOA or PFOS TABLE OF CONTENTS Table of Contents ...............................................................................................................................II List of Table and Figures ................................................................................................................... IV Abstract ............................................................................................................................................. 1 Peer Review Of The Draft NTP Monograph ......................................................................................... 2 Peer-Review Panel .............................................................................................................................. 2 Introduction ...................................................................................................................................... 3 Objective and Specific Aims ...............................................................................................................
    [Show full text]
  • PFAS MCL Technical Support Document
    ATTACHMENT 1 New Hampshire Department of Environmental Services Technical Background Report for the June 2019 Proposed Maximum Contaminant Levels (MCLs) and Ambient Groundwater Quality Standards (AGQSs) for Perfluorooctane sulfonic Acid (PFOS), Perfluorooctanoic Acid (PFOA), Perfluorononanoic Acid (PFNA), and Perfluorohexane sulfonic Acid (PFHxS) And Letter from Dr. Stephen M. Roberts, Ph.D. dated 6/25/2019 – Findings of Peer Review Conducted on Technical Background Report June 28, 2019 New Hampshire Department of Environmental Services Technical Background Report for the June 2019 Proposed Maximum Contaminant Levels (MCLs) and Ambient Groundwater Quality Standards (AGQSs) for Perfluorooctane sulfonic Acid (PFOS), Perfluorooctanoic Acid (PFOA), Perfluorononanoic Acid (PFNA), and Perfluorohexane sulfonic Acid (PFHxS) June 28, 2019 Table of Contents Abbreviations ................................................................................................................................................. i Acknowledgements ...................................................................................................................................... iii Section I. Executive Summary ....................................................................................................................... 1 Section II. Introduction ................................................................................................................................. 2 Section III. Reference Dose Derivation ........................................................................................................
    [Show full text]
  • Us 2018 / 0296525 A1
    UN US 20180296525A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0296525 A1 ROIZMAN et al. ( 43 ) Pub . Date: Oct. 18 , 2018 ( 54 ) TREATMENT OF AGE - RELATED MACULAR A61K 38 /1709 ( 2013 .01 ) ; A61K 38 / 1866 DEGENERATION AND OTHER EYE (2013 . 01 ) ; A61K 31/ 40 ( 2013 .01 ) DISEASES WITH ONE OR MORE THERAPEUTIC AGENTS (71 ) Applicant: MacRegen , Inc ., San Jose , CA (US ) (57 ) ABSTRACT ( 72 ) Inventors : Keith ROIZMAN , San Jose , CA (US ) ; The present disclosure provides therapeutic agents for the Martin RUDOLF , Luebeck (DE ) treatment of age - related macular degeneration ( AMD ) and other eye disorders. One or more therapeutic agents can be (21 ) Appl. No .: 15 /910 , 992 used to treat any stages ( including the early , intermediate ( 22 ) Filed : Mar. 2 , 2018 and advance stages ) of AMD , and any phenotypes of AMD , including geographic atrophy ( including non -central GA and Related U . S . Application Data central GA ) and neovascularization ( including types 1 , 2 and 3 NV ) . In certain embodiments , an anti - dyslipidemic agent ( 60 ) Provisional application No . 62/ 467 ,073 , filed on Mar . ( e . g . , an apolipoprotein mimetic and / or a statin ) is used 3 , 2017 . alone to treat or slow the progression of atrophic AMD Publication Classification ( including early AMD and intermediate AMD ) , and / or to (51 ) Int. CI. prevent or delay the onset of AMD , advanced AMD and /or A61K 31/ 366 ( 2006 . 01 ) neovascular AMD . In further embodiments , two or more A61P 27 /02 ( 2006 .01 ) therapeutic agents ( e . g ., any combinations of an anti - dys A61K 9 / 00 ( 2006 . 01 ) lipidemic agent, an antioxidant, an anti- inflammatory agent, A61K 31 / 40 ( 2006 .01 ) a complement inhibitor, a neuroprotector and an anti - angio A61K 45 / 06 ( 2006 .01 ) genic agent ) that target multiple underlying factors of AMD A61K 38 / 17 ( 2006 .01 ) ( e .
    [Show full text]
  • Health Effects Support Document for Perfluorooctanoic Acid (PFOA)
    United States Office of Water EPA 822-R-16-003 Environmental Protection Mail Code 4304T May 2016 Agency Health Effects Support Document for Perfluorooctanoic Acid (PFOA) Perfluorooctanoic Acid – May 2016 i Health Effects Support Document for Perfluorooctanoic Acid (PFOA) U.S. Environmental Protection Agency Office of Water (4304T) Health and Ecological Criteria Division Washington, DC 20460 EPA Document Number: 822-R-16-003 May 2016 Perfluorooctanoic Acid – May 2016 ii BACKGROUND The Safe Drinking Water Act (SDWA), as amended in 1996, requires the Administrator of the U.S. Environmental Protection Agency (EPA) to periodically publish a list of unregulated chemical contaminants known or anticipated to occur in public water systems and that may require regulation under SDWA. The SDWA also requires the Agency to make regulatory determinations on at least five contaminants on the Contaminant Candidate List (CCL) every 5 years. For each contaminant on the CCL, before EPA makes a regulatory determination, the Agency needs to obtain sufficient data to conduct analyses on the extent to which the contaminant occurs and the risk it poses to populations via drinking water. Ultimately, this information will assist the Agency in determining the most appropriate course of action in relation to the contaminant (e.g., developing a regulation to control it in drinking water, developing guidance, or deciding not to regulate it). The PFOA health assessment was initiated by the Office of Water, Office of Science and Technology in 2009. The draft Health Effects Support Document for Perfluoroctanoic Acid (PFOA) was completed in 2013 and released for public comment in February 2014.
    [Show full text]
  • Conditional Expression of Human Pparδ and a Dominant Negative Variant of Hpparδ in Vivo
    Hindawi Publishing Corporation PPAR Research Volume 2012, Article ID 216817, 12 pages doi:10.1155/2012/216817 Research Article Conditional Expression of Human PPARδ and a Dominant Negative Variant of hPPARδ In Vivo Larry G. Higgins,1 Wojciech G. Garbacz,1 Mattias C. U. Gustafsson,2 Sitheswaran Nainamalai,3 Peter R. Ashby,1 C. Roland Wolf,1 and Colin N. A. Palmer1 1 CRUK Molecular Pharmacology Unit, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK 2 Department of Laboratory Medicine, Division of Medical Microbiology, Lund University, Solvegatan¨ 23, SE-223 62 Lund, Sweden 3 Division of Molecular Medicine, Medical Science Institute, College of Life Sciences, University of Dundee, Dundee DD1 4HN, UK Correspondence should be addressed to Colin N. A. Palmer, [email protected] Received 21 September 2011; Revised 7 December 2011; Accepted 20 December 2011 Academic Editor: James P. Hardwick Copyright © 2012 Larry G. Higgins et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The nuclear receptor, NR1C2 or peroxisome proliferator-activated receptor (PPAR)-δ, is ubiquitously expressed and important for placental development, fatty acid metabolism, wound healing, inflammation, and tumour development. PPARδ has been hypothesized to function as both a ligand activated transcription factor and a repressor of transcription in the absence of agonist. In this paper, treatment of mice conditionally expressing human PPARδ with GW501516 resulted in a marked loss in body weight that was not evident in nontransgenic animals or animals expressing a dominant negative derivative of PPARδ.
    [Show full text]
  • Integrative and Systemic Approaches for Evaluating Pparβ/Δ (PPARD)
    Integrative and systemic approaches for evaluating PPAR β/δ (PPARD) function Greta MP Giordano Attianese and Béatrice Desvergne Center for Integrative Genomics, University of Lausanne, Switzerland Footnotes: Corresponding author, BD: [email protected] Competing interests: The authors declare no competing financial interests Author contributions: Both authors have been involved in drafting the manuscript and revising it critically. Received December 5, 2014; Accepted March 9, 2015; Published April 27, 2015 Copyright © 2015 Giordano Attianese and Desvergne. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited. Abbreviations: αMyHC, α-Myosin Heavy Chain; BCL6, B-cell lymphoma 6 protein; BAT, Brown adipose tissue; ChIP, Chromatin Immunoprecipitation; CHD, Coronary heart disease; DBD, DNA-binding domain; FAO, Fatty Acid Oxidation; FA, Fatty Acid; GSIS, Glucose-stimulated insulin secretion; HSC, Hematopoietic Stem cells; H&E, Hematoxylin and Eosin; HDAC1, Histone deacetylase 1; LBD, Ligand binding domain; MCP1, Monocyte chemotactic protein 1; NFkB, Nuclear factor kappa-light-chain- enhancer of activated B cells; NR, Nuclear Receptor; NCoR1, Nuclear receptor co-repressor 1; PPARs, Peroxisome proliferator- activated receptors; PPRE, PPAR-responsive element; RER, Respiratory Exchange Ratio; RA, Retinoic Acid; RXR, Retinoid X receptor; SMRT, Silencing mediator of retinoic acid and thyroid hormone receptors; SNPs, Single Nucleotide Polymorphisms; SUMO, Small Ubiquitin-like Modifier; TZDs, Thiazolidinediones; TR, Thyroid hormone receptor; TG, Triglycerides; VLDL, Very large density lipoprotein; WOSCOPS, West of Scotland Coronary Prevention Study; WAT, White adipose tissue. Citation: Giordano Attianese G and Desvergne B (2015) Integrative and systemic approaches for evaluating PPAR β/δ (PPARD) function.
    [Show full text]
  • Department of Physiology (Pages 158-181)
    Thomas Jefferson University Jefferson Digital Commons Thomas Jefferson University - tradition and heritage, edited by Frederick B. Wagner, Jr., MD, Jefferson History and Publications 1989 January 1989 Part II: Basic Sciences --- Chapter 5: Department of Physiology (pages 158-181) Follow this and additional works at: https://jdc.jefferson.edu/wagner2 Let us know how access to this document benefits ouy Recommended Citation "Part II: Basic Sciences --- Chapter 5: Department of Physiology (pages 158-181)" (1989). Thomas Jefferson University - tradition and heritage, edited by Frederick B. Wagner, Jr., MD, 1989. Paper 5. https://jdc.jefferson.edu/wagner2/5 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Thomas Jefferson University - tradition and heritage, edited by Frederick B. Wagner, Jr., MD, 1989 by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. CHAPTER fiVE Department of Physiology LEONARD M. ROSENFELD, PH.D. A physician:Js
    [Show full text]
  • Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility
    2540 Diabetes Volume 65, September 2016 Andras Franko,1,2,3 Peter Huypens,1,3 Susanne Neschen,1,3,4 Martin Irmler,1 Jan Rozman,1,3,4 Birgit Rathkolb,1,4,5 Frauke Neff,1,6 Cornelia Prehn,7 Guillaume Dubois,1 Martina Baumann,1 Rebecca Massinger,1 Daniel Gradinger,1,3 Gerhard K.H. Przemeck,1,3 Birgit Repp,8 Michaela Aichler,9 Annette Feuchtinger,9 Philipp Schommers,10,11 Oliver Stöhr,12 Carmen Sanchez-Lasheras,13 Jerzy Adamski,3,7,14 Andreas Peter,2,3,15 Holger Prokisch,8 Johannes Beckers,1,3,16 Axel K. Walch,9 Helmut Fuchs,1,3,4 Eckhard Wolf,5 Markus Schubert,12,17 Rudolf J. Wiesner,10,18,19 and Martin Hrabe de Angelis1,3,4,16 Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice Diabetes 2016;65:2540–2552 | DOI: 10.2337/db15-1670 Bezafibrate (BEZ), a pan activator of peroxisome pro- the expression of PPAR and insulin target gene liferator–activated receptors (PPARs), has been gener- transcripts was increased. Furthermore, BEZ-treated ally used to treat hyperlipidemia for decades. Clinical mice also exhibited improved metabolic flexibility as trials with type 2 diabetes patients indicated that BEZ well as an enhanced mitochondrial mass and func- also has beneficial effects on glucose metabolism, tion in the liver. Finally, we show that the number of although the underlying mechanisms of these effects pancreatic islets and the area of insulin-positive remain elusive. Even less is known about a potential cells tended to be higher in BEZ-treated mice.
    [Show full text]
  • Targeting Energy Expenditure—Drugs for Obesity Treatment
    pharmaceuticals Review Targeting Energy Expenditure—Drugs for Obesity Treatment Carlos M. Jimenez-Munoz 1 , Marta López 1 , Fernando Albericio 2,3,4,* and Kamil Makowski 2,3,* 1 School of Chemical Sciences and Engineering Yachay Tech University, San Miguel de Urcuquí 100119, Ecuador; [email protected] (C.M.J.-M.); [email protected] (M.L.) 2 Department of Surfactants and Biotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain 3 CIBER-BBN, Networking Centre of Bioengineering, Biomaterials, and Nanomedicine, and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain 4 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa * Correspondence: [email protected] (F.A.); [email protected] or [email protected] (K.M.) Abstract: Obesity and overweight are associated with lethal diseases. In this context, obese and overweight individuals infected by COVID-19 are at greater risk of dying. Obesity is treated by three main pharmaceutical approaches, namely suppressing appetite, reducing energy intake by impairing absorption, and increasing energy expenditure. Most compounds used for the latter were first envisaged for other medical uses. However, several candidates are now being developed explicitly for targeting obesity by increasing energy expenditure. This review analyzes the compounds that show anti-obesity activity exerted through the energy expenditure pathway. They are classified on the basis of their development status: FDA-approved, Withdrawn, Clinical Trials, and Under Citation: Jimenez-Munoz, C.M.; Development. The chemical nature, target, mechanisms of action, and description of the current López, M.; Albericio, F.; Makowski, K.
    [Show full text]