DOCSLIB.ORG

Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders Via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders Via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid nutrients Review Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid Tsutomu Fukuwatari Department of Nutrition, School of Human Cultures, the University of Shiga Prefecture, 2500 Hassaka, Hikone, Shiga 522-8533, Japan; [email protected]; Tel.: +81-749-28-8443 Received: 14 March 2020; Accepted: 12 May 2020; Published: 13 May 2020 Abstract: Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan catabolism, acts as an antagonist for both the α7 nicotinic acetylcholine receptor and glycine coagonist sites of the N-methyl-d-aspartic acid receptor at endogenous brain concentrations. Elevation of brain kynurenic acid levels reduces the release of neurotransmitters such as dopamine and glutamate, and kynurenic acid is considered to be involved in psychiatric disorders such as schizophrenia and depression. Thus, the control of kynurenine pathway, especially kynurenic acid production, in the brain is an important target for the improvement of brain function or the effective treatment of brain disorders. Astrocytes uptake kynurenine, the immediate precursor of kynurenic acid, via large neutral amino acid transporters, and metabolize kynurenine to kynurenic acid by kynurenine aminotransferases. The former transport both branched-chain and aromatic amino acids, and the latter have substrate specificity for amino acids and their metabolites. Recent studies have suggested the possibility that amino acids may suppress kynurenic acid production via the blockade of kynurenine transport or via kynurenic acid synthesis reactions. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with elevated kynurenic acid levels. Keywords: dopamine; kynurenic acid; kynurenine; large neutral amino acid transporter; neuropsychiatric disorders; neurotransmitter; α7 nicotinic acetylcholine receptor; N-methyl-d-aspartic acid (NMDA) receptor; tryptophan 1. Introduction The essential amino acid tryptophan is well known as a precursor of several bioactive compounds such as serotonin and melatonin. More than 90% of tryptophan is metabolized by the kynurenine pathway [1], and this pathway plays a critical role in tryptophan catabolism and coenzyme nicotinamide adenine dinucleotide (NAD+) supply (Figure1). Recently, many researchers have studied the kynurenine pathway, because the pathway has interesting intermediates and metabolites. For example, kynurenine regulates immunoreaction as an aryl hydrocarbon receptor agonist [2], and kynurenic acid (KYNA) affects brain function as an antagonist for both the α7 nicotinic acetylcholine receptors (α7nAchRs) and the N-methyl-d-aspartic acid (NMDA) receptor [3,4] and an agonist for the G protein-coupled receptor (GPR) 35 (GPR35) [5]. 3-hydroxykynurenine is a potential endogenous neurotoxin and oxidative stress generator [6], and quinolinic acid produces excitotoxicity as an NMDA receptor agonist [7]. Especially, KYNA function research has dramatically developed since 2001, and one of the targets for KYNA research is to manipulate KYNA production in the brain to prevent and improve psychiatric disorders such as schizophrenia and depression. In the present article, we briefly review recent advances in KYNA research and further describe the ability of amino acids to modulate KYNA production. The structure of tryptophan, kynurenine, and KYNA are shown in Figure2. Nutrients 2020, 12, 1403; doi:10.3390/nu12051403 www.mdpi.com/journal/nutrients Nutrients 2020, 12, x FOR PEER REVIEW 2 of 11 Nutrients 2020, 12, x FOR PEER REVIEW 2 of 11 ability of amino acids to modulate KYNA production. The structure of tryptophan, kynurenine, and Nutrients 2020, 12, 1403 2 of 11 abilityKYNA of areamino shown acids in toFigure modulate 2. KYNA production. The structure of tryptophan, kynurenine, and KYNA are shown in Figure 2. FigureFigure 1.1. TryptophanTryptophan degradation degradation pathway. pathway. (1) (1)Tryptophan Tryptophan 2,3- 2,3-dioxygenasedioxygenase/Indoleamine/Indoleamine 2,3- Figure2,3-dioxygenasedioxygenase 1. Tryptophan (2) form (2) amidadegradation formamidase,se, (3) kynureninepathway. (3) kynurenine (1) 3- monoxygenTryptophan 3-monoxygenase,ase, 2,3 (4)-dioxygenase/Indoleamine kynureninase, (4) kynureninase,(5) kynurenine 2,3- dioxygenase(5)aminotransferase, kynurenine (2) form (6)amida aminotransferase,3-hydroxyanthranilicse, (3) kynurenine (6)3acid-monoxygen oxygenase, 3-hydroxyanthranilicase, (4)(7) kynureninase,2-amino-3- acidcarboxymuconate (5) kynurenine oxygenase,-6 - aminotransferase,(7)semialdehyde 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, (6) 3-hydroxyanthranilic (8) nonenzymatic acid reaction, oxygenase, decarboxylase, (9) quinolinate (7) 2- (8)amino phosphoribosyltransferase, nonenzymatic-3-carboxymuconate reaction,-6- semialdehyde(9)(10) quinolinate nicotinic decarboxylase, acid phosphoribosyltransferase, (nicotinamide) (8) nonenzymatic mononucleotide (10) reaction, nicotinic adenylyltransfer (9) quinolinate acid (nicotinamide)ase, phosphoribosyltransferase, (11) NAD mononucleotide+ synthetase, (12) + + (10)adenylyltransferase,NAD nicotinic+ degrading acid (nicotinamide) (11)enzyme, NAD (13) mononucleotidesynthetase, nicotinamide (12) adenylyltransfer NADphosphoribosyltransferase,degradingase, enzyme,(11) NAD (13)+(14) synthetase, nicotinamidenicotinamide (12) NADphosphoribosyltransferase,methyltransferase,+ degrading enzyme,(15) 2-Py -(13)forming (14) nicotinamide nicotinamideN1-methylnicotinamide phosphoribosyltransferase, methyltransferase, oxidase, and (16) (15)(14) 4 -Pynicotinamide 2-Py-forming-forming N 1- 1 1 methyltransferase,Nmethylnicotinamide-methylnicotinamide (15) oxidase. oxidase,2-Py-forming Abbreviations: and (16) N1 4-Py-forming-methylnicotinamide NAD+:N nicotinamide-methylnicotinamide oxidase, adenine and (16) oxidase.dinucleotide 4-Py Abbreviations:-forming; 2 Py: N 1N- 1- + 1 methylnicotinamideNADmethyl: nicotinamide-2-pyridone -oxidase.5- adeninecarboxamide; Abbreviations: dinucleotide; and 4 Py: 2NA N Py:1-Dmethyl+N: nicotinamide-methyl-2-pyridone-5-carboxamide;-4-pyridone adenine-3-carboxamide dinucleotide. ; 2 and Py: 4N Py:1- 1 methylN -methyl-4-pyridone-3-carboxamide.-2-pyridone-5-carboxamide; and 4 Py: N1-methyl-4-pyridone-3-carboxamide. Figure 2. Structures of tryptophan, kynurenine, and kynurenic acid. Figure 2. Structures of tryptophan, kynurenine, and kynurenic acid. Figure 2. Structures of tryptophan, kynurenine, and kynurenic acid. Nutrients 2020, 12, 1403 3 of 11 Nutrients 2020, 12, x FOR PEER REVIEW 3 of 11 2. Function of Kynurenic Acid in the Brain 2. Function of Kynurenic Acid in the Brain In 1989, Kessler et al. found that KYNA competitively inhibited glycine coagonist site of the NMDAIn 1989, receptor Kessler at low et concentrational. found that with KYNA an ICcompetitively50 of 8 µmol/ L[inhibit3]. Aed decade glycine later, coagonist Hilmas etsite al. of found the NMDAthat KYNA receptor noncompetitively at low concentration inhibited withα an7nAchRs IC50 of 8 with μmol/L an IC [3]50. Aof decade 7 µmol /later,L using Hilmas the patch-clampet al. found thattechnique KYNA withnoncompetitively cultured hippocampal inhibited neuronsα7nAchRs [4 ].with Furthermore, an IC50 of 7 Wang μmol/L et al.using found the thatpatch KYNA-clamp is techniqueligand for with GPR35, cultured whose hippocampal EC50s are 10.7, neurons 7.4, and 39.2[4]. µFurthermore,mol/L in mouse, Wang rat, et and al. human, found respectivelythat KYNA [is5]. ligandSince physiologicalfor GPR35, wh concentrationsose EC50s are 10.7, of 7.4 brain, and KYNA 39.2 μmol/L are 5 pmol in mouse,/g wet rat wt,, and 15 human, pmol/g respectively wet wt, and [5].150 Since pmol physiological/g wet wt in mouse,concentrations rat and of human, brain KYNA respectively are 5 pmol/g [8], elevation wet wt, of 15 brain pmol/g KYNA wet haswt, beenand 150considered pmol/g wet to a ffwtect in these mouse, receptors. rat and E ffhuman,ects of KYNArespectively increase [8], on elevation the neurotransmitter of brain KYNA release has been were consideredinvestigated to usingaffect microdialysisthese receptors. technique, Effects of andKYNA KYNA increase concentration-dependently on the neurotransmitter and release reversibly were invesreducedtigated extracellular using microdialysis glutamate, technique, dopamine, and and KYNAγ-aminobutyric concentration acid-dependently (GABA) to less and than reversibly 50% of reducedbaseline extracellular concentrations glutamate, [9–11]. Conversely,dopamine, and inhibition γ-aminobutyric of endogenous acid (GABA) KYNA formationto less than by 50% reverse of baselinedialysis ofconcentrations KYNA synthesis [9–11]. inhibitor Conversely,(S)-4-(ethylsulfonyl) inhibition of benzoylalanine endogenous KYNA (S-ESBA) formation reversibly by increasesreverse dialysisdopamine, of glutamate,KYNA synthesis and GABA inhibitor levels in(S) the-4-( rodentethylsulfonyl) brain [11 benzoylalanine–13]. Although these(S-ESBA findings) reversibly suggest increasesthat changes dopamine, of brain glutamate KYNA levels, and aff ectGABA neurotransmitter levels in the release rodent via brain modulation [11–13]. of Although above receptors, these findingsunderstanding suggest thethat mechanism changes of brain of action KYNA of KYNAlevels affect is di ffineurotransmittercult. There is disagreementrelease via modulation about the ofinteraction above receptors between, KYNAunderstanding and α7nAchRs, the mechanism because several of action studies of
Load more

Recommended publications
  • Expression and Regulation of the Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Brain by Alexandra Kelly Brooks Di
    EXPRESSION AND REGULATION OF THE RATE-LIMITING ENZYMES OF THE KYNURENINE PATHWAY IN THE MOUSE BRAIN BY ALEXANDRA KELLY BROOKS DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Doctoral Committee: Research Assistant Professor Robert H. McCusker, Chair Assistant Professor Andrew J. Steelman Assistant Professor Monica Uddin Professor Rodney W. Johnson P a g e | ii ABSTRACT During the mid-1900’s, early anti-depressants were developed to increase levels of catecholamines within the brain, leading to the theory that depression symptomology was a result of an imbalance of neurotransmitters within the brain. To date, the catecholamine theory of depression is still held to be the prevailing theory as selective serotonin reuptake inhibitors being the most commonly prescribed anti-depressants. However, the incidence of depression is still rising with a vast amount of patients failing to respond to current treatments, and with this knowledge, additional theories of the neurobiology of depression have arisen over the past 30 years. A leading theory is Kynurenine Pathway activation in relation to inflammation- or stress- induced depression-like behaviors. There has been a tremendous amount of data connecting activated immune system (or hypothalamic-pituitary-adrenal axis), increased kynurenine production and depression symptomology. Thus, understanding the factors that activate this
    [Show full text]
  • Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents
    Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents Haojun Chen*1,2, Orit Jacobson*2, Gang Niu2, Ido D. Weiss3, Dale O. Kiesewetter2, Yi Liu2, Ying Ma2, Hua Wu1, and Xiaoyuan Chen2 1Department of Nuclear Medicine, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, China; 2Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and 3Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland One of the major design considerations for a drug is its The goal of drug development is to achieve high activity and pharmacokinetics in the blood. A drug with a short half-life in specificity for a desired biologic target. However, many potential the blood is less available at a target organ. Such a limitation pharmaceuticals that meet these criteria fail as therapeutics because dictates treatment with either high doses or more frequent doses, of unfavorable pharmacokinetics, in particular, rapid blood clearance, both of which may increase the likelihood of undesirable side effects. To address the need for additional methods to improve which prevents the achievement of therapeutic concentrations. For the blood half-life of drugs and molecular imaging agents, we some drugs, the administration of large or frequently repeated doses developed an “add-on” molecule that contains 3 groups: a trun- is required to achieve and maintain therapeutic levels (1) but can, in cated Evans blue dye molecule that binds to albumin with a low turn, increase the probability of undesired side effects.
    [Show full text]
  • Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells in Vitro and in Vivo
    materials Article Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo Hai Thanh Pham 1,2 , Mitsuaki Ono 3,*, Emilio Satoshi Hara 4,* , Ha Thi Thu Nguyen 1,2,3, Anh Tuan Dang 1,2,3, Hang Thuy Do 1,2,3, Taishi Komori 1, Ikue Tosa 1, Yuri Hazehara-Kunitomo 1,3, Yuya Yoshioka 1, Yasutaka Oida 1, Kentaro Akiyama 1 and Takuo Kuboki 1 1 Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; [email protected] (H.T.P.); [email protected] (H.T.T.N.); [email protected] (A.T.D.); [email protected] (H.T.D.); [email protected] (T.K.); [email protected] (I.T.); [email protected] (Y.H.-K.); [email protected] (Y.Y.); [email protected] (Y.O.); [email protected] (K.A.); [email protected] (T.K.) 2 Faculty of Dentistry, Hai Phong University of Medicine and Pharmacy, Haiphong 04211, Vietnam 3 Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan 4 Department of Biomaterials, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan * Correspondence: [email protected] (M.O.); [email protected] (E.S.H.); Tel.: +81-86-235-7127 (M.O.); +81-86-235-6667 (E.S.H.); Fax: +81-86-222-7768 (M.O.); +81-86-235-6669 (E.S.H.) Abstract: Aging tissues present a progressive decline in homeostasis and regenerative capacities, Citation: Pham, H.T.; Ono, M.; Hara, which has been associated with degenerative changes in tissue-specific stem cells and stem cell E.S.; Nguyen, H.T.T.; Dang, A.T.; Do, niches.
    [Show full text]
  • Solutions to 7.012 Problem Set 1
    MIT Biology Department 7.012: Introductory Biology - Fall 2004 Instructors: Professor Eric Lander, Professor Robert A. Weinberg, Dr. Claudette Gardel Solutions to 7.012 Problem Set 1 Question 1 Bob, a student taking 7.012, looks at a long-standing puddle outside his dorm window. Curious as to what was growing in the cloudy water, he takes a sample to his TA, Brad Student. He wanted to know whether the organisms in the sample were prokaryotic or eukaryotic. a) Give an example of a prokaryotic and a eukaryotic organism. Prokaryotic: Eukaryotic: All bacteria Yeast, fungi, any animial or plant b) Using a light microscope, how could he tell the difference between a prokaryotic organism and a eukaryotic one? The resolution of the light microscope would allow you to see if the cell had a true nucleus or organelles. A cell with a true nucleus and organelles would be eukaryotic. You could also determine size, but that may not be sufficient to establish whether a cell is prokaryotic or eukaryotic. c) What additional differences exist between prokaryotic and eukaryotic organisms? Any answer from above also fine here. In addition, prokaryotic and eukaryotic organisms differ at the DNA level. Eukaryotes have more complex genomes than prokaryotes do. Question 2 A new startup company hires you to help with their product development. Your task is to find a protein that interacts with a polysaccharide. a) You find a large protein that has a single binding site for the polysaccharide cellulose. Which amino acids might you expect to find in the binding pocket of the protein? What is the strongest type of interaction possible between these amino acids and the cellulose? Cellulose is a polymer of glucose and as such has many free hydroxyl groups.
    [Show full text]
  • An Investigation of D-Cycloserine As a Memory Enhancer NCT00842309 Marchmay 23, 15, 2016 2019 Sabine Wilhelm, Ph.D
    MayMarch 23, 2016 15, 2019 An investigation of D-cycloserine as a memory enhancer NCT00842309 MarchMay 23, 15, 2016 2019 Sabine Wilhelm, Ph.D. May 23, 2016 1. Background and Significance BDD is defined as a preoccupation with an imagined defect in appearance; if a slight physical anomaly is present, the concern is markedly excessive (American Psychiatric Association [APA], 1994). Preoccupations may focus on any body area but commonly involve the face or head, most often the skin, hair, or nose (Phillips et al., 1993). These preoccupations have an obsessional quality, in that they occur frequently and are usually difficult to resist or control (Phillips et al., 1998). Additionally, more than 90% of BDD patients perform repetitive, compulsive behaviors (Phillips et al., 1998), such as frequent mirror checking (Alliez & Robin, 1969), excessive grooming (Vallat et al., 1971), and skin picking (Phillips & Taub, 1995). Accordingly, a core component of Cognitive-Behavioral treatment for BDD is exposure and response prevention (ERP). Exposure and response prevention involves asking patients to gradually expose themselves to situations that make them anxious (e.g. talking to a stranger, going to a party) while refraining from engaging in any rituals (e.g. excessive grooming or camouflaging) or safety behaviors (e.g. avoiding eye contact). Rituals and safety behaviors are thought to maintain the fear response because they prevent the sufferer from staying in contact with the stimulus long enough for his or her anxiety to extinguish. By exposing the patient to the feared situation while preventing the rituals and safety behaviors, the patient’s anxiety is allowed to naturally extinguish and he is able to acquire a sense of safety in the presence of the feared stimulus.
    [Show full text]
  • Genefor the De Novo
    Agric. Biol. Chem., 47 (10), 2405~2408, 1983 2405 Rapid Paper B; these two proteins are collectively termed quinolinate synthetase, (2) Protein B converts Synthesis of Quinolinic Acid by aspartic acid to an intermediate capable of the EnzymePreparation of undergoing condensation with DHAP cata- Escherichia coli Which Contains lyzed by Protein A, (3) Proteins A and B are coded by nadA and nadB, respectively, and (4) a Plasmid Carrying the nad the quinolinate synthetase system is subjected Gene for the de novo to feedback inhibition as well as end product Synthesis of NAD repression. An outline of quinolinic acid syn- thesis is shown in Fig. 1. Intermediates of Masaaki Kuwahara, Mizuyo Yonehana, quinolinic acid synthesis, however, have not Tetsuhiro Kimura and Yutaka Ishida yet been isolated in pure forms except for butynedioic acid and its amination product2) Department of Food Science, KagawaUniversity, which are proposed to be intermediates. Our Miki-cho, Kagawa 761-07, Japan experiment aimed to elucidate the inter- Received March 17, 1983 mediary metabolism of the de novo pathway for NADsynthesis using recombinant DNA A plasmid, pNADHl, carrying the nad gene for the de techniques with an E. coli host-vector system. novo synthesis of NADwas constructed with pBR322 and chromosomal DNAof Escherichia coli. Cleavage by re- MATERIALS AND METHODS striction endonucleases showed that the plasmid contained a DNAinsert of 8.9 Kbp at the Hin&lll site ofpBR322. Strains. Escherichia coli C600 (F~, thr~, leu", thi ~, m~, The cell-free extract of a transformant of E. coli C600 r~, LacY) and HB101 carrying plasmid pBR322 were which contained the plasmid formed 5 times more quinol- provided by Prof.
    [Show full text]
  • THE ROLE of KYNURENINE, a TRYPTOPHAN METABOLITE THAT INCREASES with AGE, in MUSCLE ATROPHY and LIPID PEROXIDATION) by Helen Eliz
    THE ROLE OF KYNURENINE, A TRYPTOPHAN METABOLITE THAT INCREASES WITH AGE, IN MUSCLE ATROPHY AND LIPID PEROXIDATION) By Helen Elizabeth Kaiser Submitted to the Faculty of the Graduate School of Augusta University in partial fulfillment of the Requirements of the Degree of (Doctor of Philosophy in Cellular Biology and Anatomy) April 2020 COPYRIGHT© 2020 by Helen Kaiser ACKNOWLEDGEMENTS I wish to express my deepest gratitude to my mentor Dr. Mark Hamrick. His support and advice were invaluable to my learning and development as a scientist. I would like to especially recognize Dr. Hamrick’s honesty to data, and kindness to everyone around him. It was an honor to work as his student, and to be a part of this project. I would like to thank my committee members, Drs. Carlos Isales, Meghan McGee-Lawrence, and Yutao Liu, for their continued support, guidance, and helpful suggestions. They have helped to shape and focus this project, and have augmented my experience as a student during the development of my dissertation. Additionally, I want to recognize and thank Dr. Sadanand Fulzele for sharing his wealth of knowledge in techniques, and always keeping his door open for student’s questions. Next, a most heartfelt thanks to my lab mates: Andrew Khayrullin, Bharati Mendhe, Ling Ruan and Emily Parker. This project has been a team effort, all of them have been fundamental to its success. I further want to show my appreciation for the rest of the department of Cellular Biology and Anatomy at Augusta University. The histology core members Donna Kumiski and Penny Roon for their direct help in sectioning, and contributions to this project.
    [Show full text]
  • An Integrated Meta-Analysis of Peripheral Blood Metabolites and Biological Functions in Major Depressive Disorder
    Molecular Psychiatry https://doi.org/10.1038/s41380-020-0645-4 ARTICLE An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder 1,2,3 1,2,3 1,2,3 1,3 1,3 4,5 1,3 1,3 Juncai Pu ● Yiyun Liu ● Hanping Zhang ● Lu Tian ● Siwen Gui ● Yue Yu ● Xiang Chen ● Yue Chen ● 1,2,3 1,3 1,3 1,3 1,3 1,2,3 Lining Yang ● Yanqin Ran ● Xiaogang Zhong ● Shaohua Xu ● Xuemian Song ● Lanxiang Liu ● 1,2,3 1,3 1,2,3 Peng Zheng ● Haiyang Wang ● Peng Xie Received: 3 June 2019 / Revised: 24 December 2019 / Accepted: 10 January 2020 © The Author(s) 2020. This article is published with open access Abstract Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially 1234567890();,: 1234567890();,: expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenode- soxycholic acid and lower levels of L-acetylcarnitine, creatinine, L-asparagine, L-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, L-serine, oleic acid, myo-inositol, dodecanoic acid, L-methionine, hypoxanthine, palmitic acid, L-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls.
    [Show full text]
  • Differential Control of Steroidogenesis by Nitric Oxide and Its Adaptation with Hypoxia
    259 THEMATIC REVIEW eNOS activation and NO function: Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia Charles A Ducsay and Dean A Myers1 Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California 92350, USA 1Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, USA (Correspondence should be addressed to C A Ducsay; Email: [email protected]) Abstract Nitric oxide (NO) plays a role in a wide range of physiological regulation of NO synthases in specific endocrine tissues processes. Aside from its widely studied function in the including ovaries, testes, and adrenal glands. The effects of regulation of vascular function, NO has been shown to hypoxia on generation of NO and subsequent effects on impact steroidogenesis in a number of different tissues. The steroid biosynthesis will also be examined. Finally, a potential goal of this review is to explore the effects of NO on steroid model for the interaction of hypoxia on NO synthesis and production and further, to discern its source(s) and steroid production is proposed. mechanism of action. Attention will be given to the Journal of Endocrinology (2011) 210, 259–269 Introduction NO and steroidogenesis The initial rate-limiting step in steroidogenesis involves Nitric oxide (NO) is a diatomic free-radical gas involved in a cholesterol transport to the inner mitochondrial membrane number of physiologic processes (Moncada & Palmer 1991, by steroidogenic acute regulatory protein (StAR) and its Moncada et al.1991) and is synthesized from L-arginine by a binding partner, peripheral benzodiazepine receptor.
    [Show full text]
  • NMDA Agonists Using ALZET Osmotic Pumps
    ALZET® Bibliography References on the Administration of NMDA Agonists Using ALZET Osmotic Pumps Aspartic Acid P7453: M. Domercq, et al. Excitotoxic oligodendrocyte death and axonal damage induced by glutamate transporter inhibition. Glia 2005;52(1):36-46 ALZET Comments: Oligonucleotide, antisense; oligonucleotide sense; kainate, dihydro-; aspartic acid, DL-threo-B-benzyloxy-; Saline, sterile; CSF/CNS (optic nerve); Rabbit; 1003D; 3 days; Controls received mp w/ vehicle, or contralateral nerves; antisense (glutamate transporters GLAST + GLT-1); animal info (adult, male, white New Zealand). P6888: J. Darman, et al. Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity. Journal of Neuroscience 2004;24(34):7566-7575 ALZET Comments: Aspartic acid, dl-threo-B-hydroxy; spermine, 1-naphthyl acetyl; CSF/CNS (intrathecal, subarachnoid space); Rat; 1007D; 7 days; Controls received mp w/ saline; enzyme inhibitors (GLT-1, GluR2). P3908: A. Hirata, et al. AMPA receptor-mediated slow neuronal death in the rat spinal cord induced by long-term blockade of glutamate transporters with THA. Brain Research 1997;771(37-44 ALZET Comments: Aspartic acid, dl-threo-B-hydroxy; Glutamate, l-; CSF, artificial;; CSF/CNS (subarachnoid space, intrathecal); Rat; 2ML1; no duration posted; dose-response; cannula position verified. P0289: R. M. Mangano, et al. Chronic infusion of endogenous excitatory amino acids into rat striatum and hippocampus. Brain Res. Bull 1983;10(47-51 ALZET Comments: Aminobutyric acid, Y-; Aspartic acid, dl-threo-B-hydroxy; Aspartic acid, l-; Cysteine sulfinic acid; Glutamic acid, l-; Radio-isotopes; 3H tracer; Acetate; Saline; CSF/CNS (corpus striatum); CSF/CNS (hippocampus); Rat; 2002; 2 weeks; comparison of injec.
    [Show full text]
  • Amino Acid Transport Pathways in the Small Intestine of the Neonatal Rat
    Pediat. Res. 6: 713-719 (1972) Amino acid neonate intestine transport, amino acid Amino Acid Transport Pathways in the Small Intestine of the Neonatal Rat J. F. FITZGERALD1431, S. REISER, AND P. A. CHRISTIANSEN Departments of Pediatrics, Medicine, and Biochemistry, and Gastrointestinal Research Laboratory, Indiana University School of Medicine and Veterans Administration Hospital, Indianapolis, Indiana, USA Extract The activity of amino acid transport pathways in the small intestine of the 2-day-old rat was investigated. Transport was determined by measuring the uptake of 1 mM con- centrations of various amino acids by intestinal segments after a 5- or 10-min incuba- tion and it was expressed as intracellular accumulation. The neutral amino acid transport pathway was well developed with intracellular accumulation values for leucine, isoleucine, valine, methionine, tryptophan, phenyl- alanine, tyrosine, and alanine ranging from 3.9-5.6 mM/5 min. The intracellular accumulation of the hydroxy-containing neutral amino acids threonine (essential) and serine (nonessential) were 2.7 mM/5 min, a value significantly lower than those of the other neutral amino acids. The accumulation of histidine was also well below the level for the other neutral amino acids (1.9 mM/5 min). The basic amino acid transport pathway was also operational with accumulation values for lysine, arginine and ornithine ranging from 1.7-2.0 mM/5 min. Accumulation of the essential amino acid lysine was not statistically different from that of nonessential ornithine. Ac- cumulation of aspartic and glutamic acid was only 0.24-0.28 mM/5 min indicating a very low activity of the acidic amino acid transport pathway.
    [Show full text]
  • Metabolites Involved in Glycolysis and Amino Acid Metabolism Are Altered in Short Children Born Small for Gestational Age
    nature publishing group Basic Science Investigation Articles Metabolites involved in glycolysis and amino acid metabolism are altered in short children born small for gestational age Philip G. Murray1,2, Imogen Butcher1,2, Warwick B. Dunn1,3,4, Adam Stevens1,2, Reena Perchard1,2, Daniel Hanson1,2, Andrew Whatmore1,2, Melissa Westwood1,5 and Peter E. Clayton1,2 BACKGROUND: Later life metabolic dysfunction is a well- SGA will fail to show catch-up growth over the first 2 y of life, recognized consequence of being born small for gestational leaving approximately 1,600 children in the United Kingdom age (SGA). This study has applied metabolomics to identify who remain short (height standard deviation score (SDS) <-2) whether there are changes in these pathways in prepubertal at 2 y of age (4). As well as growth impairment children born short SGA children and aimed to compare the intracellular and SGA are at increased risk of cardiovascular disease, hyperten- extracellular metabolome in fibroblasts derived from healthy sion, hyperlipidaemia, and type 2 diabetes in adulthood (5). children and SGA children with postnatal growth impairment. The causes of children being born SGA are numerous and METHODS: Skin fibroblast cell lines were established from include maternal, placental, and fetal factors (5). There are a small eight SGA children (age 1.8–10.3 y) with failure of catch-up number of monogenic causes for a child to be born SGA and growth and from three healthy control children. Confluent cells experience poor postnatal growth (e.g., 3-M syndrome, Bloom were incubated in serum-free media and the spent growth syndrome, Microcephalic Osteodysplastic dwarfism type II, medium (metabolic footprint), and intracellular metabolome IGF-IR mutations, Seckel syndrome, and Mulibrey nanism) (6).
    [Show full text]