Co-Incubation with Pparβ/Δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery
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Advances in Hepatology
ADVANCES IN HEPATOLOGY Current Developments in the Treatment of Hepatitis and Hepatobiliary Disease Hepatology Section Editor: Eugene R. Schiff, MD Novel Therapies for Cholestatic Liver Disease Cynthia Levy, MD Professor of Medicine Arthur Hertz Chair in Liver Diseases Associate Director, Schiff Center for Liver Diseases Division of Hepatology University of Miami Miller School of Medicine Miami, Florida G&H Currently, how is cholestatic liver G&H What are the limitations of the therapies disease in adults typically treated? currently being used? CL Cholestatic liver disease in adults mainly consists of CL Up to 40% of patients with PBC may not respond to primary biliary cholangitis (PBC) and primary sclerosing UDCA therapy, meaning that they will not have signifi- cholangitis (PSC). For PBC, the traditional first-line treat- cant biochemical improvement in alkaline phosphatase, ment is ursodeoxycholic acid (UDCA), starting at a dose which will remain elevated above 1.5 or 2 times the upper of 13 to 15 mg/kg/day. In May 2016, obeticholic acid limit of normal. In addition, in the PBC clinical trials for (Ocaliva, Intercept Pharmaceuticals) was approved by the obeticholic acid, only half of the patients met the primary US Food and Drug Administration (FDA) for second- endpoint. Furthermore, as previously mentioned, there is line treatment of PBC patients who either do not respond no FDA-approved treatment for PSC. Therefore, there are to UDCA therapy or who are intolerant of it. Dosing for unmet needs for PBC and PSC treatment, which have led noncirrhotic or well-compensated cirrhotic patients is 5 to a plethora of ongoing clinical trials exploring drugs of mg daily, which can be increased to 10 mg daily after 3 various mechanisms of action. -
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 . -
A61p1/16 (2006.01) A61p3/00 (2006.01) Km, Ml, Mr, Ne, Sn, Td, Tg)
( (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, A61P1/16 (2006.01) A61P3/00 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/192 (2006.01) C07C 321/28 (2006.01) Declarations under Rule 4.17: (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/IB2020/000808 earlier application (Rule 4.17(iii)) (22) International Filing Date: Published: 25 September 2020 (25.09.2020) — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (26) Publication Language: English amendments (Rule 48.2(h)) (30) Priority Data: 62/906,288 26 September 2019 (26.09.2019) US (71) Applicant: ABIONYX PHARMA SA [FR/FR] ; 33-43 Av¬ enue Georges Pompidou, Batiment D, 31130 Bahna (FR). (72) Inventor: DASSEUX, Jean-Louis, Henri; 7 Allees Charles Malpel, Bat. B, 31300 Toulouse (FR). (74) Agent: HOFFMANN EITLE PATENT- UND RECHTSANWALTE PARTMBB, ASSOCIATION NO. 151; Arabellastrasse 30, 81925 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 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, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. -
The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
International Journal of Molecular Sciences Review The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development Fan Hong 1,2, Pengfei Xu 1,*,† and Yonggong Zhai 1,2,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China * Correspondence: [email protected] (P.X.); [email protected] (Y.Z.); Tel.: +86-156-005-60991 (P.X.); +86-10-5880-6656 (Y.Z.) † Current address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Received: 22 June 2018; Accepted: 24 July 2018; Published: 27 July 2018 Abstract: Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development. -
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. -
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 .................................................................................................................. -
Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-ß/Δ Antagonist GSK3787
0026-895X/10/7803-419–430 MOLECULAR PHARMACOLOGY Vol. 78, No. 3 U.S. Government work not protected by U.S. copyright 65508/3613101 Mol Pharmacol 78:419–430, 2010 Printed in U.S.A. Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-/␦ Antagonist GSK3787□S Prajakta S. Palkar, Michael G. Borland, Simone Naruhn, Christina H. Ferry, Christina Lee, Ugir H. Sk, Arun K. Sharma, Shantu Amin, Iain A. Murray, Cherie R. Anderson, Gary H. Perdew, Frank J. Gonzalez, Rolf Mu¨ ller, and Jeffrey M. Peters Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, the Pennsylvania State University, University Park, Pennsylvania (P.S.P., M.G.B., C.H.F., C.L., I.A.M., C.R.A., G.H.P., J.M.P.); Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany (S.N., R.M.); Department of Pharmacology, Penn State Hershey Cancer Institute, the Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania (A.K.S., U.H.S., S.A.); and Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (F.J. G.) Received April 9, 2010; accepted June 1, 2010 ABSTRACT The availability of high-affinity agonists for peroxisome prolifera- PPAR␣ activity. Time-resolved fluorescence resonance energy tor-activated receptor-/␦ (PPAR/␦) has led to significant ad- transfer assays confirmed the ability of GSK3787 to modulate the vances in our understanding of the functional role of PPAR/␦.In association of both PPAR/␦ and PPAR␥ coregulator peptides in this study, a new PPAR/␦ antagonist, 4-chloro-N-(2-{[5-tri- response to ligand activation, consistent with reporter assays. -
Highlights in Primary Biliary Cholangitis from the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, And
February 2021 Volume 17, Issue 2, Supplement 3 A SPECIAL MEETING REVIEW EDITION Highlights in Primary Biliary Cholangitis From the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, and the AASLD 2020 Liver Meeting Digital Experience Special Reporting on: • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis From the POISE Trial Grouped Biochemically by Risk of Disease Progression • Long-Term Efficacy and Safety of Obeticholic Acid in Primary Biliary Cholangitis: Responder Analysis of More Than 5 Years of Treatment in the POISE Trial • ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis— A Phase 3, International, Randomized, Placebo-Controlled Study • Real-World Effectiveness of Obeticholic Acid in Patients With Primary Biliary Cholangitis • Results of a Phase 2, Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Saroglitazar Magnesium in Patients With Primary Biliary Cholangitis (EPICS) • Primary Biliary Cholangitis: Patient Characteristics and the Health Care Economic Burden in the United States • Bezafibrate Add-On Therapy Improves Liver Transplantation–Free Survival in Patients With Primary Biliary Cholangitis: A Japanese Nationwide Cohort Study • GLIMMER Trial—A Randomized, Double-Blind, Placebo-Controlled Study of Linerixibat, an Inhibitor of the Ileal Bile Acid Transporter, in the Treatment of Cholestatic Pruritus in Primary Biliary Cholangitis PLUS Meeting Abstract Summaries With Expert Commentary by: Kris V. Kowdley, MD Director, Liver Institute Northwest Clinical Professor, Elson S. -
A2E Induces the Transactivation of Rars, Ppars and Rxrs and Its Effects Are Counteracted by Norbixin in Retinal Pigment Epithelium Cells in Vitro
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.30.016071; this version posted April 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cells in vitro Valérie Fontaine1 *, Mylène Fournié1, Elodie Monteiro1, Thinhinane Boumedine1, Christine Balducci2, Louis Guibout2, Mathilde Latil2, Pierre J. Dilda2, José-Alain Sahel1,3,4, Stanislas Veillet2, René Lafont2, Serge Camelo2 1 Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, F-75012 Paris, France 2 Biophytis, Sorbonne Université, BC9, 4 place Jussieu, 75005 Paris, France 3 CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS CIC 1423, 28 rue de Charenton, F- 75012, Paris, France 4 Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA *Corresponding author: Valérie Fontaine Email: [email protected] Running Title: Norbixin modulates NRs activation by A2E in RPE cells Keywords: N-retinylidene-N-retinylethanolamine (A2E), angiogenesis, apoptosis, inflammation, norbixin, nuclear receptor (NR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptor (RAR), retinal pigment epithelium (RPE), retinoic X receptor (RXR) ABSTRACT transactivation induced by A2E. Norbixin also N-retinylidene-N-retinylethanolamine (A2E) inhibits PPAR-g transactivation induced by its plays a central role in age-related macular high affinity ligand troglitazone. degeneration (AMD) by inducing apoptosis, Photoprotection of RPE cells by norbixin angiogenesis and inflammation. It has been correlates with maintained levels of the proposed that A2E effects are mediated at least antiapoptotic B-cell lymphoma 2 (Bcl2) partly via the retinoic acid receptor (RAR)-a. -
Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases 1 2 3 4 5 Keith D
| PRACTICE GUIDANCE HEPATOLOGY, VOL. 0, NO. 0, 2018 Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases 1 2 3 4 5 Keith D. Lindor, Christopher L. Bowlus, James Boyer, Cynthia Levy, and Marlyn Mayo Intended for use by health care providers, this guid- Preamble ance identifies preferred approaches to the diagnostic This American Association for the Study of and therapeutic aspects of care for patients with PBC. Liver Diseases (AASLD) 2018 Practice Guidance As with clinical practice guidelines, it provides gen- on Primary Biliary Cholangitis (PBC) is an update eral guidance to optimize the care of the majority of of the PBC guidelines published in 2009. The 2018 patients and should not replace clinical judgment for updated guidance on PBC includes updates on etiol- a unique patient. ogy and diagnosis, role of imaging, clinical manifesta- The major changes from the last guideline to this tions, and treatment of PBC since 2009. The AASLD guidance include information about obeticholic acid 2018 PBC Guidance provides a data-supported (OCA) and the adaptation of the guidance format. approach to screening, diagnosis, and clinical man- agement of patients with PBC. It differs from more recent AASLD practice guidelines, which are sup- Etiology of Primary Biliary ported by systematic reviews and a multidisciplinary panel of experts that rates the quality (level) of the Cholangitis evidence and the strength of each recommendation Primary Biliary Cholangitis (PBC) is considered using the Grading of Recommendations Assessment, an autoimmune disease because of its hallmark sero- Development, and Evaluation system. In contrast, this logic signature, antimitochondrial antibody (AMA), (1-4) guidance was developed by consensus of an expert and specific bile duct pathology. -
The Role of Peroxisome Proliferator-Activated Receptor
The Pennsylvania State University The Graduate School The Huck Institutes for Life Sciences THE ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR β/δ IN VIRAL PROTEIN-INDUCED LIVER PATHOGENESIS A Dissertation in Molecular Medicine by Gayathri Balandaram © 2015 Gayathri Balandaram Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2015 The dissertation of Gayathri Balandaram was reviewed and approved* by the following: Jeffrey M. Peters Distinguished Professor of Molecular Toxicology and Carcinogenesis Dissertation Advisor Chair of Committee Gary H. Perdew John T. and Paige S. Smith Professor in Agricultural Sciences Connie J. Rogers Assistant Professor and Occupant of the Broadhurst Career Development Professorship for the Study of Health Promotion and Disease Prevention Andrew Patterson Associate Professor of Molecular Toxicology Adam B. Glick Associate Professor of Veterinary and Biomedical Sciences Chair, Molecular Medicine Program Associate Chair, Molecular Cellular and Integrative Biosciences *Signatures are on file in the Graduate School ii ABSTRACT PPARβ/δ has an established role in attenuating preneoplastic conditions in the liver such as inflammation, steatosis, proliferation and oxidative stress pointing to a chemopreventive role for this nuclear receptor in the liver. However, not much is known about its part in orchestrating the progression of hepatocellular carcinoma. The present study examined the potential of this nuclear receptor in delaying the progression of chronic hepatocellular injury-induced liver cancer. In hepatitis B virus (HBV) transgenic mice, which develop progressive inflammation and cellular injury at the early stages (2-3 months of age), followed by hyperplasia, neoplasia and eventually hepatocellular carcinoma at later stages (12-18 months of age), long-term ligand activation (8 months) with PPARβ/δ ligand (GW0742), displayed a significant attenuation in tumor multiplicity and the average number of liver foci, which was not observed in HBV mice not treated with GW0742. -
Lessons from Liver-Specific PPAR-Null Mice
International Journal of Molecular Sciences Review PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice Yaping Wang 1, Takero Nakajima 1, Frank J. Gonzalez 2 and Naoki Tanaka 1,3,* 1 Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; [email protected] (Y.W.); [email protected] (T.N.) 2 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] 3 Research Center for Social Systems, Shinshu University, Matsumoto, Nagano 390-8621, Japan * Correspondence: [email protected]; Tel.: +81-263-37-2851 Received: 21 February 2020; Accepted: 9 March 2020; Published: 17 March 2020 Abstract: Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver. Keywords: PPAR; NAFLD; NASH; insulin resistance; liver fibrosis 1. Introduction Administration of Wy-14643, nafenopin, and fibrate drugs to rodents results in hepatic peroxisome proliferation. These agents are thus designated as peroxisome proliferators (PPs) [1]. To explain a mechanism of rapid and drastic changes following PP administration, the involvement of transcription factors was assumed and the first peroxisome proliferator-activated receptor (PPAR, later defined as PPARα (NR1C1)) was identified in 1990 [2].