Development of a Novel Selective Inhibitor of the Down Syndrome-Related Kinase Dyrk1a
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Aberrant Methylation Underlies Insulin Gene Expression in Human Insulinoma
ARTICLE https://doi.org/10.1038/s41467-020-18839-1 OPEN Aberrant methylation underlies insulin gene expression in human insulinoma Esra Karakose1,6, Huan Wang 2,6, William Inabnet1, Rajesh V. Thakker 3, Steven Libutti4, Gustavo Fernandez-Ranvier 1, Hyunsuk Suh1, Mark Stevenson 3, Yayoi Kinoshita1, Michael Donovan1, Yevgeniy Antipin1,2, Yan Li5, Xiaoxiao Liu 5, Fulai Jin 5, Peng Wang 1, Andrew Uzilov 1,2, ✉ Carmen Argmann 1, Eric E. Schadt 1,2, Andrew F. Stewart 1,7 , Donald K. Scott 1,7 & Luca Lambertini 1,6 1234567890():,; Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insu- linomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing cano- nical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the cano- nical PDX1 enhancer complex, are predicted to drive INS transactivation. 1 From the Diabetes Obesity and Metabolism Institute, The Department of Surgery, The Department of Pathology, The Department of Genetics and Genomics Sciences and The Institute for Genomics and Multiscale Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. -
Neurotransmitter Resource Guide
NEUROTRANSMITTER RESOURCE GUIDE Science + Insight doctorsdata.com Doctor’s Data, Inc. Neurotransmitter RESOURCE GUIDE Table of Contents Sample Report Sample Report ........................................................................................................................................................................... 1 Analyte Considerations Phenylethylamine (B-phenylethylamine or PEA) ................................................................................................. 1 Tyrosine .......................................................................................................................................................................................... 3 Tyramine ........................................................................................................................................................................................4 Dopamine .....................................................................................................................................................................................6 3, 4-Dihydroxyphenylacetic Acid (DOPAC) ............................................................................................................... 7 3-Methoxytyramine (3-MT) ............................................................................................................................................... 9 Norepinephrine ........................................................................................................................................................................ -
Review Paper Monoamine Oxidase Inhibitors: a Review Concerning Dietary Tyramine and Drug Interactions
PsychoTropical Commentaries (2016) 1:1 – 90 © Fernwell Publications Review Paper Monoamine Oxidase Inhibitors: a Review Concerning Dietary Tyramine and Drug Interactions PK Gillman PsychoTropical Research, Bucasia, Queensland, Australia Abstract This comprehensive monograph surveys original data on the subject of both dietary tyramine and drug interactions relevant to Monoamine Oxidase Inhibitors (MAOIs), about which there is much outdated, incorrect and incomplete information in the medical literature and elsewhere. Fewer foods than previously supposed have problematically high tyramine levels because international food hygiene regulations have improved both production and handling. Cheese is the only food that has, in the past, been associated with documented fatalities from hypertension, and now almost all ‘supermarket’ cheeses are perfectly safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still advised. The interactions between MAOIs and other drugs are now well understood, are quite straightforward, and are briefly summarized here (by a recognised expert). MAOIs have no apparently clinically relevant pharmaco-kinetic interactions, and the only significant pharmaco-dynamic interaction, other than the ‘cheese reaction’ (caused by indirect sympatho-mimetic activity [ISA], is serotonin toxicity ST (aka serotonin syndrome) which is now well defined and straightforward to avoid by not co-administering any drug with serotonin re-uptake inhibitor (SRI) potency. There are no therapeutically used drugs, other than SRIs, that are capable of inducing serious ST with MAOIs. Anaesthesia is not contra- indicated if a patient is taking MAOIs. Most of the previously held concerns about MAOIs turn out to be mythical: they are either incorrect, or over-rated in importance, or stem from apprehensions born out of insufficient knowledge. -
Basic Hypothesis and Therapeutics Targets of Depression: a Review
ISSN: 2641-1911 DOI: 10.33552/ANN.2021.10.000738 Archives in Neurology & Neuroscience Review Article Copyright © All rights are reserved by Anil Kumar Basic Hypothesis and Therapeutics Targets of Depression: A Review Monika Kadian, Hemprabha Tainguriya, Nitin Rawat, Varnika Chib, Jeslin Johnson and Anil Kumar* Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh 160014, India *Corresponding author: Dr. Anil Kumar, PhD, Professor of Pharmacology, Phar- Received Date: May 11, 2021 macology division, University Institute of Pharmaceutical Sciences, Panjab Univer- sity, Chandigarh 160014, India. Published Date: June 07, 2021 Abstract Depression is a psychological disorder marked by emotional symptoms such as melancholy, anhedonia, distress mood, loss of interest in daily life activities, feeling of worthlessness, sleep disturbances and destructive tendencies. According to WHO, more than 264 million people from all randomage groups processes are suffering during with brain depression development. thus, Depression it is become is mainlya leading due cause to neurotransmitter of disability and imbalances, infirmity worldwide. HPA disturbances, It is estimated increased that oxidative 40% of riskand nitrosativefor depression damage, is genetic impairment and the in other glucose 60% metabolism, is non-genetic and whichmitochondrial involved dysfunction, acute & chronic etc. The stress, monoamine childhood hypothesis trauma, viral is based infections on attenuation and even of monoamines such as serotonin (5-HT), norepinephrine (NE) and dopamine (DA) in the brain regions (hippocampus, limbic system and frontal cortex) that can cause depression like symptoms. Depression is also marked by increased level of corticotrophin-releasing hormone (CRH) and and impaired responsiveness to glucocorticoid hormone. -
Correction of Cognitive Deficits in Mouse Models Of
Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A Thu Lan Nguyen, Arnaud Duchon, Antigoni Manousopoulou, Nadège Loaëc, Benoît Villiers, Guillaume Pani, Meltem Karatas, Anna E Mechling, Laura-Adela Harsan, Emmanuelle Limanton, et al. To cite this version: Thu Lan Nguyen, Arnaud Duchon, Antigoni Manousopoulou, Nadège Loaëc, Benoît Villiers, et al.. Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological in- hibitor of DYRK1A. Disease Models & Mechanisms, Cambridge Company of Biologists, 2018, 11 (9), pp.dmm035634. 10.1242/dmm.035634. hal-01862465 HAL Id: hal-01862465 https://hal-univ-rennes1.archives-ouvertes.fr/hal-01862465 Submitted on 17 Jul 2019 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. © 2018. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2018) 11, dmm035634. doi:10.1242/dmm.035634 RESEARCH ARTICLE Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A Thu Lan Nguyen1,2,3,4,5, Arnaud Duchon1,2,3,4, Antigoni Manousopoulou6, Nadegè Loaëc5, Benoît Villiers5, Guillaume Pani1,2,3,4, Meltem Karatas7,8, Anna E. Mechling8, Laura-Adela Harsan7,8, Emmanuelle Limanton9, Jean-Pierre Bazureau9, François Carreaux9, Spiros D. -
S41598-021-90243-1.Pdf
www.nature.com/scientificreports OPEN Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS‑COV‑2 infection Miroslava Cuperlovic‑Culf1,2*, Emma L. Cunningham3, Hossen Teimoorinia4, Anuradha Surendra1, Xiaobei Pan5, Stefany A. L. Bennett2,6, Mijin Jung5, Bernadette McGuiness3, Anthony Peter Passmore3, David Beverland7 & Brian D. Green5* Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS‑CoV‑2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium‑ susceptibility in the postoperative setting using metabolomic profling of cerebrospinal fuid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found signifcant concentration diferences in several amino acids, acylcarnitines and polyamines linking delirium‑prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS‑CoV‑2 spike protein to MAOB. The possibility that SARS‑CoV‑2 infuences MAOB activity leading to the observed neurological and platelet‑based complications of SARS‑CoV‑2 infection requires further investigation. COVID-19 is an ongoing major global health emergency caused by severe acute respiratory syndrome coro- navirus SARS-CoV-2. Patients admitted to hospital with COVID-19 show a range of features including fever, anosmia, acute respiratory failure, kidney failure and gastrointestinal issues and the death rate of infected patients is estimated at 2.2%1. -
Cooperation to Amplify Gene-Dosage-Imbalance Effects
Update TRENDS in Molecular Medicine Vol.12 No.10 Research Focus Cooperation to amplify gene-dosage-imbalance effects Susana de la Luna1 and Xavier Estivill2 1 ICREA and Gene Function Group, Genes and Disease Program, Center for Genomic Regulation-CRG, 08003-Barcelona, Spain 2 Genetic Causes of Disease Group, Genes and Disease Program, Center for Genomic Regulation-CRG and Pompeu Fabra University, Barcelona Biomedical Research Park, 08003-Barcelona, Spain Trisomy 21, also known as Down syndrome (DS), is a From gene-dosage imbalance to pathology complex developmental disorder that affects many ThepresenceofanextracopyofHSA21 genes predicts an organs, including the brain, heart, skeleton and increased expression of 1.5-fold at the RNA level for immune system. A working hypothesis for understand- those genes in trisomy. Experiments in which this effect ing the consequences of trisomy 21 is that the over- has been evaluated indicate that this is indeed the case expression of certain genes on chromosome 21, alone for most HSA21 genes in DS samples and for their or in cooperation, is responsible for the clinical features orthologs in mouse trisomic models [3].Inthesimplest of DS. There is now compelling evidence that the scenario, the overexpression of one specific gene would protein products of two genes on chromosome 21, lead to the disturbance of a biological process and, as a Down syndrome candidate region 1 (DSCR1)and result, a single gene would be responsible for each patho- dual-specificity tyrosine-(Y)-phosphorylation regulated logical feature of DS. However, it is more probable that kinase 1A (DYRK1A), interact functionally, and that the overexpression of several of the 250 HSA21 genes their increased dosage cooperatively leads to dysregu- would contribute to alter a functional pathway in a lation of the signaling pathways that are controlled by specific cell at a specific time. -
RCAN2 Isoform 2 Recombinant Protein Cat
RCAN2 Isoform 2 Recombinant Protein Cat. No.: 95-114 RCAN2 Isoform 2 Recombinant Protein Specifications SPECIES: Mouse SOURCE SPECIES: E. coli SEQUENCE: aa 2 - 197 FUSION TAG: Fusion Partner: C-terminal His-tag TESTED APPLICATIONS: ELISA, WB APPLICATIONS: This recombinant protein can be used for WB and ELISA. For research use only. PREDICTED MOLECULAR 26 kDa (Calculated) WEIGHT: Properties PURITY: ~95% PHYSICAL STATE: Liquid 100mM sodium phosphate, 10mM Tris, 500mM NaCl, 25 mM imidazole, 2mM MgCl2, 10% BUFFER: gycerol Store in working aliquots at -70˚C. Avoid freeze/thaw cycles. When working with proteins STORAGE CONDITIONS: care should be taken to keep recombinant protein at a cool and stable temperature. September 29, 2021 1 https://www.prosci-inc.com/rcan2-isoform-2-recombinant-protein-95-114.html Additional Info OFFICIAL SYMBOL: Rcan2 RCAN2 Antibody: Csp2, MCIP2, ZAKI-4, Dscr1l1, Zaki4, Calcipressin-2, Calcineurin inhibitory ALTERNATE NAMES: protein ZAKI-4 ACCESSION NO.: AAH62141 PROTEIN GI NO.: 38328420 GENE ID: 53901 Background and References Regulator of calcineurin 2 (RCAN2), also known as ZAKI4 and DSCR1L1, is expressed as two isoforms differing at their N-terminus. The longer of the two (isoform 1) is expressed exclusively in the brain, while isoform 2 is ubiquitously expressed, with highest expression in brain, heart, and muscle (1,2). Both isoforms bind to the catalytic subunit of calcineurin, a Ca++-dependent protein phosphatase involved in several neuronal functions, though BACKGROUND: their C-terminal region and inhibit calcineurin’s activity (3). Unlike isoform 1 of RCAN2, the expression of the second isoform is not induced by the thyroid hormone T3 (3). -
The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
cancers Review The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Carini Picardi Morais de Castro 1, Maria Cadefau 1,2 and Sergi Cuartero 1,2,* 1 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] (C.P.M.d.C); [email protected] (M.C.) 2 Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain * Correspondence: [email protected] Simple Summary: Leukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy. Abstract: Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and Citation: de Castro, C.P.M.; Cadefau, in signalling mediators of the JAK/STAT and RAS pathways. -
The Effects of Phenelzine and Other Monoamine Oxidase Inhibitor
British Journal of Phammcology (1995) 114. 837-845 B 1995 Stockton Press All rights reserved 0007-1188/95 $9.00 The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver 12 imidazoline-preferring receptors Regina Alemany, Gabriel Olmos & 'Jesu's A. Garcia-Sevilla Laboratory of Neuropharmacology, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07071 Palma de Mallorca, Spain 1 The binding of [3H]-idazoxan in the presence of 106 M (-)-adrenaline was used to quantitate 12 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irre- versible and reversible monoamine oxidase (MAO) inhibitors. 2 Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-', i.p.), isocarboxazid (10 mg kg-', i.p.), clorgyline (3 mg kg-', i.p.) and tranylcypromine (10mg kg-', i.p.) markedly decreased (21-71%) the density of 12 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-', i.p.) or chlordimeform (10 mg kg-', i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-', i.p.) did not alter the density of 12 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3 In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform dis- placed the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. -
(DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact
pharmaceuticals Review Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact Andreia Machado Brito-da-Costa 1 , Diana Dias-da-Silva 1,2,* , Nelson G. M. Gomes 1,3 , Ricardo Jorge Dinis-Oliveira 1,2,4,* and Áurea Madureira-Carvalho 1,3 1 Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; [email protected] (A.M.B.-d.-C.); ngomes@ff.up.pt (N.G.M.G.); [email protected] (Á.M.-C.) 2 UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 3 LAQV-REQUIMTE, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 4 Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal * Correspondence: [email protected] (D.D.-d.-S.); [email protected] (R.J.D.-O.); Tel.: +351-224-157-216 (R.J.D.-O.) Received: 21 September 2020; Accepted: 20 October 2020; Published: 23 October 2020 Abstract: Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. -
Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases Andrea I
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.01.020206; this version posted April 2, 2020. The copyright holder has placed this preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt this material for any purpose without crediting the original authors. Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases Andrea I. Krahn, Carrow Wells, David H. Drewry, Lenore K. Beitel, Thomas M. Durcan, Alison D. Axtman* ABSTRACT: Kinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anti-cancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases. KEYWORDS: kinase, neurodegeneration,