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Analysis of OAT, OCT, OCTN, and Other Family Members Reveals 8
bioRxiv preprint doi: https://doi.org/10.1101/2019.12.23.887299; this version posted December 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups Darcy Engelhart1, Jeffry C. Granados2, Da Shi3, Milton Saier Jr.4, Michael Baker6, Ruben Abagyan3, Sanjay K. Nigam5,6 1Department of Biology, University of California San Diego, La Jolla 92093 2Department of Bioengineering, University of California San Diego, La Jolla 92093 3School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla 92093 4Department of Molecular Biology, Division of Biological Sciences, University of California at San Diego, San Diego, CA, USA 5Department of Pediatrics, University of California San Diego, La Jolla 92093 6Department of Medicine, University of California San Diego, La Jolla 92093 *To whom correspondence should be addressed: [email protected] Running title: Functional subgroups for SLC22 1 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.23.887299; this version posted December 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Among transporters, the SLC22 family is emerging as a central hub of endogenous physiology. -
Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level
International Journal of Molecular Sciences Review Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level Sweilem B. Al Rihani 1 , Lucy I. Darakjian 1, Malavika Deodhar 1 , Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (S.B.A.R.); [email protected] (L.I.D.); [email protected] (M.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Abstract: The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. -
WO 2016/090486 Al 16 June 2016 (16.06.2016) W P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/090486 Al 16 June 2016 (16.06.2016) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 5/071 (2010.01) CI2N 5/073 (2010.01) kind of national protection available): AE, AG, AL, AM, C12N 11/02 (2006.01) C12Q 1/02 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/CA20 15/05 1297 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 9 December 2015 (09.12.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/089,5 12 9 December 2014 (09. 12.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: NATIONAL RESEARCH COUNCIL OF TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, CANADA [CA/CA]; M-55, 1200 Montreal Road, Ottawa, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Ontario K lA 0R6 (CA). -
Transcriptomic Gene Signatures Associated with Persistent Airflow Limitation
Hekking et al Revised manuscript ERJ-02298-2016 Transcriptomic gene signatures associated with persistent airflow limitation in patients with severe asthma P.P. Hekking1, M.J. Loza2, S. Pavlidis3, B. De Meulder4, D. Lefaudeux4, F. Baribaud2, C. Auffray4, A.H. Wagener1, P. Brinkman1, R. Lutter1, A.T. Bansal5, A.R. Sousa6, S. Bates6, Y. Pandis3, L.J. Fleming3, D.E. Shaw7, S.J. Fowler8, Y. Guo3, A. Meiser3, K. Sun3, J. Corfield9, P. Howarth10, E.H. Bel1, I.M. Adcock11, K.F. Chung11, R. Djukanovic10, P.J. Sterk1, and the U-BIOPRED Study Group* 1: Respiratory Medicine, Academic Medical Centre, Amsterdam, the Netherlands; 2: Janssen research and development; Johnsen & Johnsen, Springhouse, US; 3: Data Science Institute, Imperial College, London, UK; 4: European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS- UCBL-INSERM, Université de Lyon, France; 5: Acclarogen Ltd, Cambridge, UK; 6: Discovery Medicine, GlaxoSmithKline, Brentford, UK; 7: Respiratory Research Unit, University of Nottingham, UK; 8: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, UK; 9: Areteva, Nottingham, UK; 10: NIHR Southampton Centre for Biomedical Research, University of Southampton, UK; 11: National Heart & Lung institute - Imperial College, London, UK;*A list of the U-BIOPRED study group can be found in the online supplement Corresponding author: Pieter-Paul Hekking, Academic Medical Centre (AMC), Department of Respiratory Medicine, F5-260 1105 AZ, Amsterdam, the Netherlands Telephone: +31 (0) 20 566 1660 Fax: +31 (0) 20 566 9001 E-mail: [email protected] 1 Hekking et al Take home message Persistent airflow limitation in severe asthma is associated with a mechanism in which IL-13 and remodeling are involved. -
The Food Contaminants Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis Structure-Dependently in the Human Hepatoma Cell Line Heparg
foods Article The Food Contaminants Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis Structure-Dependently in the Human Hepatoma Cell Line HepaRG Josephin Glück 1, Marcus Henricsson 2, Albert Braeuning 1 and Stefanie Hessel-Pras 1,* 1 Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; [email protected] (J.G.); [email protected] (A.B.) 2 Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 413 45 Gothenburg, Sweden; [email protected] * Correspondence: [email protected]; Tel.: +49-30-18412-25203 Abstract: Pyrrolizidine alkaloids (PAs) are a group of secondary plant metabolites being contained in various plant species. The consumption of contaminated food can lead to acute intoxications in humans and exert severe hepatotoxicity. The development of jaundice and elevated bile acid concentrations in blood have been reported in acute human PA intoxication, indicating a connection between PA exposure and the induction of cholestasis. Additionally, it is considered that differences in toxicity of individual PAs is based on their individual chemical structures. Therefore, we aimed to elucidate the structure-dependent disturbance of bile acid homeostasis by PAs in the human hepatoma cell line HepaRG. A set of 14 different PAs, including representatives of all major structural characteristics, namely, the four different necine bases retronecine, heliotridine, otonecine and platynecine and different grades of esterification, was analyzed in regard to the expression of genes Citation: Glück, J.; Henricsson, M.; Braeuning, A.; Hessel-Pras, S. The involved in bile acid synthesis, metabolism and transport. -
NIH Public Access Author Manuscript Pharmacogenet Genomics
NIH Public Access Author Manuscript Pharmacogenet Genomics. Author manuscript; available in PMC 2012 October 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Pharmacogenet Genomics. 2011 October ; 21(10): 679–686. doi:10.1097/FPC.0b013e328343dd93. PharmGKB summary: methotrexate pathway Torben S. Mikkelsena,b, Caroline F. Thornc, Jun J. Yangb, Cornelia M. Ulrichh, Deborah Frenchb, Gianluigi Zazab, Henry M. Dunnenbergerb, Sharon Marshi, Howard L. McLeodf, Kathy Giacominie, Mara L. Beckerg, Roger Gaedigkg, James Steven Leederg, Leo Kagerj, Mary V. Rellingb, William Evansb, Teri E. Kleinc, and Russ B. Altmanc,d aDepartment of Pediatric Oncology and Hematology, Aarhus University Hospital, Skejby, Denmark bSt Jude Children’s Research Hospital, Memphis, Tennessee cDepartment of Genetics, Stanford University Medical Center, Stanford dDepartment of Bioengineering, Stanford University Medical Center, Stanford eUniversity of California, San Francisco, California fInstitute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina gDivision of Clinical Pharmacology and Medical Toxicology, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri, USA hGerman Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany iFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada jSt Anna Children’s Hospital, Vienna, Austria Keywords methotrexate; 5,10-methylenetetrahydrofolate -
Photoreceptor Cko of OTX2 Enhances OTX2 Intercellular Transfer in the Retina and Causes Photophobia
Research Article: New Research | Sensory and Motor Systems Photoreceptor cKO of OTX2 enhances OTX2 intercellular transfer in the retina and causes photophobia https://doi.org/10.1523/ENEURO.0229-21.2021 Cite as: eNeuro 2021; 10.1523/ENEURO.0229-21.2021 Received: 20 May 2021 Revised: 26 July 2021 Accepted: 3 August 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Pensieri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 1. Manuscript Title 2 Photoreceptor cKO of OTX2 enhances OTX2 intercellular transfer in the retina and causes 3 photophobia 4 2. Abbreviated Title 5 OTX2 cKO in adult photoreceptors 6 3. Author Names and Affiliations 7 Pasquale Pensieri 1,*, Annabelle Mantilleri 1,*, Damien Plassard 2, Takahisa Furukawa 3, Kenneth L. 8 Moya 4, Alain Prochiantz 4 and Thomas Lamonerie 1,# 9 1 Université Côte d’Azur, CNRS, Inserm, iBV, Nice, France. 10 2 Plateforme GenomEast, IGBMC, Illkirch, France 11 3 Laboratory for Molecular and Developmental Biology, Institute for Protein Research 12 Osaka University, Osaka, Japan 13 4 Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, UMR 7241, 14 INSERM U1050, Paris, France 15 * Equal contribution 16 4. -
RNA-Seq Reveals Altered Gene Expression Levels in Proximal
www.nature.com/scientificreports OPEN RNA‑seq reveals altered gene expression levels in proximal tubular cell cultures compared to renal cortex but not during early glucotoxicity Linnéa M. Nilsson1, Miguel Castresana‑Aguirre 2, Lena Scott3 & Hjalmar Brismar 1,3* Cell cultures are often used to study physiological processes in health and disease. It is well‑known that cells change their gene expression in vitro compared to in vivo, but it is rarely experimentally addressed. High glucose is a known trigger of apoptosis in proximal tubular cells (PTC). Here we used RNA-seq to detect diferentially expressed genes in cultures of primary rat PTC, 3 days old, compared to cells retrieved directly from rat outer renal cortex and between PTC exposed to 15 mM glucose and control for 8 h. The expression of 6,174 genes was signifcantly up- or downregulated in the cultures of PTC compared to the cells in the outer renal cortex. Most altered were mitochondrial and metabolism related genes. Gene expression of proapoptotic proteins were upregulated and gene expression of antiapoptotic proteins were downregulated in PTC. Expression of transporter related genes were generally downregulated. After 8 h, high glucose had not altered the gene expression in PTC. The current study provides evidence that cells alter their gene expression in vitro compared to in vivo and suggests that short‑term high glucose exposure can trigger apoptosis in PTC without changing the gene expression levels of apoptotic proteins. Cell cultures, both primary and immortalized, are ofen used as models in biological research to investigate physi- ological processes in health and disease. -
Inhibitory G-Protein Modulation of CNS Excitability by Jason Howard
Inhibitory G-protein Modulation of CNS Excitability by Jason Howard Kehrl A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmacology) in the University of Michigan 2014 Doctoral Committee: Professor Richard R. Neubig, Michigan State University, Co-Chair Professor Lori L. Isom, Co-Chair Professor Helen A. Baghdoyan Assistant Professor Asim A. Beg Research Associate Professor Geoffrey G. Murphy © Jason Howard Kehrl 2014 DEDICATION For Bud, Gagi, and Judy ii ACKNOWLEDGEMENTS This work would not have been possible without tremendous help from so many people. Scientifically my mentor, Rick, as he prefers to be called, was always available for collaborative discussions. He also provided me a great level of scientific freedom in pursuing what I found interesting, affording me the opportunity to learn more than I would have in most any other environment. Beyond what I’ve learned about the subject of pharmacology, what he has instilled in me is a sharp eye in the analysis of data-driven arguments, a great problem-solving toolset, and the ability to lead a team. This is what I will always value, no matter where I go in life. To my undergrads I am also exceedingly grateful. There are so many of you that I dare not name you individually for risk of putting some rank-order to the amount of fun and joy you each brought to my thesis work. I hope you each grew and learned from the experience as much as I learned from my attempts at mentoring each of you. This thesis is in no small part due to all the contributions you made. -
Bioivt Transporter Catalog DG V3
Transporter Assay Catalog Single Transporter Models Single Transporter Models Subcellular Transporter Relevance Gene Transporter Assay Species2 Cell Model3 Probe Substrate Inhibition 1 Localization in Type Type Assay Model Positive Control ASBT Bile acid uptake SLC10A2 Uptake IA H Apical MDCK-II Taurocholate NaCDC asc-1 Amino acid transport SLC7A10 Uptake IA H Basolateral MDCK-II Glycine Serine ASCT2 Amino acid transport SLC1A5 Uptake IA H Apical MDCK-II Glutamine Alanine ATB0+ Amino acid transport SLC6A14 Uptake IA H Apical MDCK-II Leucine N-Ethylmaleimide BAT1, CSNU3 Amino acid transport SLC7A9 Uptake IA H Apical MDCK-II Proline BCRP FDA & EMA DDI guidances; intestinal and BBB efflux, ABCG2 Efflux BD H Apical Caco-2 clone3 Genistein Chrysin biliary secretion, renal tubular secretion and drug resistance VA H, R N/A Vesicle CCK-8 Bromosulfophthalein BD H Apical MDCK-II Prazosin KO143 BSEP EMA DDI guidance; biliary secretion of bile salts, drug ABCB11 Efflux VA H, R, D N/A Vesicle Taurocholate Rifampicin induced liver injury CAT1 Amino acid transport SLC7A1 Uptake IA H Basolateral MDCK-II Arginine Lysine CAT2B Amino acid transport SLC7A2 Uptake IA H Basolateral MDCK-II Arginine CAT3 Amino acid transport SLC7A3 Uptake IA H Basolateral MDCK-II Arginine Lysine CHT Choline transport SLC5A7 Uptake IA H Basolateral MDCK-II Choline CNT1 Nucleoside uptake SLC28A1 Uptake IA H, R Apical MDCK-II Uridine Adenosine CNT2 Nucleoside uptake SLC28A2 Uptake IA H, R Apical MDCK-II Uridine Adenosine CNT3 Nucleoside uptake SLC28A3 Uptake IA H, R Apical MDCK-II -
Phylogenetic, Syntenic, and Tissue Expression Analysis of Slc22 Genes in Zebrafish (Danio Rerio)
Mihaljevic et al. BMC Genomics (2016) 17:626 DOI 10.1186/s12864-016-2981-y RESEARCH ARTICLE Open Access Phylogenetic, syntenic, and tissue expression analysis of slc22 genes in zebrafish (Danio rerio) Ivan Mihaljevic1†, Marta Popovic1,2†, Roko Zaja1,3 and Tvrtko Smital1* Abstract Background: SLC22 protein family is a member of the SLC (Solute carriers) superfamily of polyspecific membrane transporters responsible for uptake of a wide range of organic anions and cations, including numerous endo- and xenobiotics. Due to the lack of knowledge on zebrafish Slc22 family, we performed initial characterization of these transporters using a detailed phylogenetic and conserved synteny analysis followed by the tissue specific expression profiling of slc22 transcripts. Results: We identified 20 zebrafish slc22 genes which are organized in the same functional subgroups as human SLC22 members. Orthologies and syntenic relations between zebrafish and other vertebrates revealed consequences of the teleost-specific whole genome duplication as shown through one-to-many orthologies for certain zebrafish slc22 genes. Tissue expression profiles of slc22 transcripts were analyzed using qRT-PCR determinations in nine zebrafish tissues: liver, kidney, intestine, gills, brain, skeletal muscle, eye, heart, and gonads. Our analysis revealed high expression of oct1 in kidney, especially in females, followed by oat3 and oat2c in females, oat2e in males and orctl4 in females. oct1 was also dominant in male liver. oat2d showed the highest expression in intestine with less noticeable gender differences. All slc22 genes showed low expression in gills, and moderate expression in heart and skeletal muscle. Dominant genes in brain were oat1 in females and oct1 in males, while the highest gender differences were determined in gonads, with dominant expression of almost all slc22 genes in testes and the highest expression of oat2a. -
SLC22A6 (OAT1) and SLC22A8 (OAT3)
J Hum Genet (2006) 51:575–580 DOI 10.1007/s10038-006-0398-1 SHORT COMMUNICATION Vibha Bhatnagar Æ Gang Xu Æ Bruce A. Hamilton David M. Truong Æ Satish A. Eraly Æ Wei Wu Sanjay K. Nigam Analyses of 5¢ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3) Received: 6 January 2006 / Accepted: 23 February 2006 / Published online: 29 April 2006 Ó The Japan Society of Human Genetics and Springer-Verlag 2006 Abstract Kidney excretion of numerous organic anionic Keywords SLC22A6, OAT1, NKT Æ SLC22A8, OAT3, drugs and endogenous metabolites is carried out by a ROCT Æ Organic anion transporters Æ Promoters Æ family of multispecific organic anion transporters Single nucleotide polymorphisms (OATs). Two closely related transporters, SLC22A6, initially identified by us as NKT and also known as OAT1, and SLC22A8, also known as OAT3 and ROCT, are thought to mediate the initial steps in the transport of Introduction organic anionic drugs between the blood and proximal tubule cells of the kidney. Coding region polymorphisms The organic anion transporters (OATs) constitute a in these genes are infrequent and pairing of these genes in subfamily within the SLC22 family of solute carriers the genome suggests they may be coordinately regulated. (Eraly et al. 2003). Two members of this subfamily, Hence, 5¢ regulatory regions of these genes may be SLC22A6 (also known as OAT1), originally identified as important factors in human variation in organic anionic novel kidney transporter (NKT; Lopez-Nieto et al. 1996, drug handling. We have analyzed novel single nucleotide 1997)andSLC22A8 (also known as OAT3), originally polymorphisms in the evolutionarily conserved 5¢ regu- identified as reduced in osterosclerosis (ROCT) (Brady latory regions of the SLC22A6 and SLC22A8 genes et al.