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https://www.readbyqxmd.com/read/28346099/development-of-novel-cell-lines-for-high-throughput-screening-to-detect-estrogen-related-receptor-alpha-modulators
#1
Christina T Teng, Jui-Hua Hsieh, Jinghua Zhao, Ruili Huang, Menghang Xia, Negin Martin, Xiaohua Gao, Darlene Dixon, Scott S Auerbach, Kristine L Witt, B Alex Merrick
Estrogen-related receptor alpha (ERRα), the first orphan nuclear receptor discovered, is crucial for the control of cellular energy metabolism. ERRα and its coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), are required for rapid energy production in response to environmental challenges. They have been implicated in the etiology of metabolic disorders such as type 2 diabetes and metabolic syndrome. ERRα also plays a role in the pathogenesis of breast cancer. Identification of compounds that modulate ERRα signaling may elucidate environmental factors associated with these diseases...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28338111/g-protein-coupled-receptor-30-gpr30-expression-pattern-in-inflammatory-bowel-disease-patients-suggests-its-key-role-in-the-inflammatory-process-a-preliminary-study
#2
Marcin Włodarczyk, Aleksandra Sobolewska-Włodarczyk, Adam I Cygankiewicz, Damian Jacenik, Aleksandra Piechota-Polańczyk, Krystyna Stec-Michalska, Wanda M Krajewska, Jakub Fichna, Maria Wiśniewska-Jarosińska
BACKGROUND AND AIMS: G protein-coupled receptor 30 (GPR30) is a recently de-orphanized estrogen receptor that mediates the effects of estrogens on different cells. It has been postulated that in inflammatory bowel diseases (IBD) activation of GPR30 blocks the pathways dependent on pro-inflammatory cytokines. The aim of our study was to investigate GPR30 expression in patients with IBD and its potential implication in future therapies. METHODS: Fifty-seven patients were enrolled in our study: 20 subjects with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 15 controls...
March 2017: Journal of Gastrointestinal and Liver Diseases: JGLD
https://www.readbyqxmd.com/read/28337303/the-involvement-and-possible-mechanism-of-nr4a1-in-chondrocyte-apoptosis-during-osteoarthritis
#3
Xinge Shi, Hui Ye, Xuedong Yao, Yanzheng Gao
Osteoarthritis (OA) is a joint disease caused by the breakdown of joint cartilage and underlying bone, and places great burdens to daily life of patients. Nuclear orphan receptor nuclear receptor subfamily 4, group A, member 1 (NR4A1) is vital for cell apoptosis, but little is known about its role in OA. This study aims to reveal the expression and function of NR4A1 during OA chondrocyte apoptosis. NR4A1 expression by qRT-PCR and western blot, and chondrocyte apoptosis by TUNEL assay were detected in normal and OA joint cartilage...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28325781/hete-signals-through-g-protein-coupled-receptor-gpr75-gq-to-affect-vascular-function-and-trigger-hypertension
#4
Victor Garcia, Ankit Gilani, Brian Shkolnik, Varunkumar Pandey, Frank F Zhang, Rambabu Dakarapu, Shyam K Gandham, N R Reddy, Joan P Graves, Artiom Gruzdev, Darryl C Zeldin, Jorge H Capdevila, John R Falck, Michal L Schwartzman
Rationale: 20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 (CYP) eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, migration and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction and vascular diseases. Objective: To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists...
March 21, 2017: Circulation Research
https://www.readbyqxmd.com/read/28322790/short-chain-fatty-acids-gpr41-and-gpr43-ligands-inhibit-tnf-%C3%AE-induced-mcp-1-expression-by-modulating-p38-and-jnk-signaling-pathways-in-human-renal-cortical-epithelial-cells
#5
Mamiko Kobayashi, Daisuke Mikami, Hideki Kimura, Kazuko Kamiyama, Yukie Morikawa, Seiji Yokoi, Kenji Kasuno, Naoki Takahashi, Takanobu Taniguchi, Masayuki Iwano
Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are produced predominantly by gut microbiota fermentation of dietary fiber. SCFAs are newly identified as endogenous ligands of two orphan G protein-coupled receptors, GPR41 and GPR43, which have the potential to modulate inflammation. Therefore, GPR41 and GPR43 may mediate the link between the gut microbiome status and various disease conditions including renal inflammation. This study aimed at investigating whether SCFAs activate GPR41 and GPR43, and thereby exert anti-inflammatory effects in human renal cortical epithelial cells (HRCEs) as a main component of kidney tissue...
March 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28317799/a-first-insight-into-the-genetic-diversity-of-mycobacterium-tuberculosis-in-veracruz-mexico
#6
Raquel Almaraz-Velasco, Daniela Munro-Rojas, Javier Fuentes-Domínguez, Raquel Muñiz-Salazar, Maria Angélica Ibarra-Estela, Alma Delia Guevara-Méndez, Rosa Icela Chaparro-Martinez, Monserrat Perez-Navarro, Roberto Zenteno-Cuevas
OBJECTIVE/BACKGROUND: Tuberculosis (TB) remains one of the most important infectious diseases. Although Mexico is one of the Latin American countries with the largest contribution to these statistics, there are few reports that describe the genotypic characteristics of TB. The aim of this study was to use the MIRU-VNTR-24 loci to analyze the genetic diversity of M. tuberculosis circulating in the state of Veracruz, Mexico. METHODS: Here, we analyze by MIRU-VNTR-24 loci 80 clinical isolates from individuals with confirmed TB from Veracruz México, also clinical and epidemiological variables were recovered and analyzed...
January 2017: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28314976/enzyme-replacement-therapy-and-beyond-in-memoriam-roscoe-o-brady-m-d-1923-2016
#7
REVIEW
Markus Ries
Lysosomal storage disorders are strong candidates for the development of specific innovative therapies. The discovery of enzyme deficiencies is an important milestone in understanding the underlying cause of disease. Being able to replace the first missing enzyme in a lysosomal storage required three decades of dedicated research. Successful drug development for lysosomal storage disorders was fostered by the U.S. Orphan Drug Act. Various optimization strategies have the potential to overcome the current limitations of enzyme replacement therapies...
March 17, 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/28314853/activation-of-the-orphan-g-protein-coupled-receptor-gpr27-by-surrogate-ligands-promotes-%C3%AE-arrestin-2-recruitment
#8
Nadine Dupuis, Celine Laschet, Delphine Franssen, Martyna Szpakowska, Julie Gilissen, Pierre Geubelle, Arvind Soni, Anne-Simone Parent, Bernard Pirotte, Andy Chevigne, Jean-Claude Twizere, Julien Hanson
G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by a high level of conservation among vertebrates and a predominant expression in the central nervous system. In addition, it has recently been linked to insulin secretion. However, the absence of endogenous or surrogate ligands for GPR27 complicates the examination of its biological function. Our aim was to validate GPR27 signaling pathways and therefore we sought to screen a diversity oriented synthesis library to identify GPR27-specific surrogate agonists...
March 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28300844/il-27-triggers-il-10-production-in-th17-cells-via-a-c-maf-ror%C3%AE-t-blimp-1-signal-to-promote-the-progression-of-endometriosis
#9
Kai-Kai Chang, Li-Bing Liu, Li-Ping Jin, Bing Zhang, Jie Mei, Hui Li, Chun-Yan Wei, Wen-Jie Zhou, Xiao-Yong Zhu, Jun Shao, Da-Jin Li, Ming-Qing Li
Endometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10(+)Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28289782/neuro-psychopharmacological-perspective-of-orphan-receptors-of-rhodopsin-class-a-family-of-g-protein-coupled-receptors
#10
REVIEW
Muhammad Zahid Khan, Ling He
BACKGROUND: In the central nervous system (CNS), G protein-coupled receptors (GPCRs) are the most fruitful targets for neuropsychopharmacological drug development. Rhodopsin (class A) is the most studied class of GPCR and includes orphan receptors for which the endogenous ligand is not known or is unclear. Characterization of orphan GPCRs has proven to be challenging, and the production pace of GPCR-based drugs has been incredibly slow. OBJECTIVE: Determination of the functions of these receptors may provide unexpected insight into physiological and neuropathological processes...
March 13, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28289717/retinoic-acid-orphan-receptor-c-inhibition-suppresses-th17-cells-and-induces-thymic-aberrations
#11
Christine Guntermann, Alessandro Piaia, Marie-Laure Hamel, Diethilde Theil, Tina Rubic-Schneider, Alberto Del Rio-Espinola, Linda Dong, Andreas Billich, Klemens Kaupmann, Janet Dawson, Klemens Hoegenauer, David Orain, Samuel Hintermann, Rowan Stringer, Dhavalkumar D Patel, Arno Doelemeyer, Mark Deurinck, Jens Schümann
Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28283046/recommendations-from-the-european-working-group-for-value-assessment-and-funding-processes-in-rare-diseases-orph-val
#12
Lieven Annemans, Ségolène Aymé, Yann Le Cam, Karen Facey, Penilla Gunther, Elena Nicod, Michele Reni, Jean-Louis Roux, Michael Schlander, David Taylor, Carlo Tomino, Josep Torrent-Farnell, Sheela Upadhyaya, Adam Hutchings, Lugdivine Le Dez
Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process...
March 10, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28277601/the-international-hypothermia-registry-ihr-dieter-s-esao-winter-schools-and-beat-s-international-hypothermia-registry
#13
Beat H Walpoth, Marie Meyer, Christophe Gaudet-Blavignac, Philippe Baumann, Pierre Gilquin, Christian Lovis
Accidental hypothermia could be listed as an 'orphan disease,' since mild hypothermia is common but has no severe medical consequences, whereas severe hypothermia is rare and life-threatening. In order to increase our knowledge, find new outcome predictors, and propose better guidelines for the treatment of deep accidental hypothermia victims, we created the International Hypothermia Registry (IHR: https://www.hypothermia-registry.org), which will allow us to gather a large number of cases in order to achieve statistical significance and issue evidence-based recommendations...
March 7, 2017: International Journal of Artificial Organs
https://www.readbyqxmd.com/read/28276705/exploring-the-epigenetic-drug-discovery-landscape
#14
Veda Prachayasittikul, Philip Prathipati, Reny Pratiwi, Chuleeporn Phanus-Umporn, Aijaz Ahmad Malik, Nalini Schaduangrat, Kanokwan Seenprachawong, Prapimpun Wongchitrat, Aungkura Supokawej, Virapong Prachayasittikul, Jarl E S Wikberg, Chanin Nantasenamat
Epigenetic modification has been implicated in a wide range of diseases and the ability to modulate such systems is a lucrative therapeutic strategy in drug discovery. Areas covered: This article focuses on the concepts and drug discovery aspects of epigenomics. This is achieved by providing a survey of the following concepts: (i) factors influencing epigenetics, (ii) diseases arising from epigenetics, (iii) epigenetic enzymes as druggable targets along with coverage of existing FDA-approved drugs and pharmacological agents, and (iv) drug repurposing/repositioning as a means for rapid discovery of pharmacological agents targeting epigenetics...
February 28, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28274849/patient-age-sex-and-inflammatory-bowel-disease-phenotype-associate-with-course-of-primary-sclerosing-cholangitis
#15
Tobias J Weismüller, Palak J Trivedi, Annika Bergquist, Mohamad Imam, Henrike Lenzen, Cyriel Y Ponsioen, Kristian Holm, Daniel Gotthardt, Martti A Färkkilä, Hanns-Ulrich Marschall, Douglas Thorburn, Rinse K Weersma, Johan Fevery, Tobias Mueller, Olivier Chaouillères, Kornelius Schulze, Konstantinos N Lazaridis, Sven Almer, Stephen P Pereira, Cynthia Levy, Andrew Mason, Sigrid Naess, Christopher L Bowlus, Annarosa Floreani, Emina Halilbasic, Kidist K Yimam, Piotr Milkiewicz, Ulrich Beuers, Dep K Huynh, Albert Pares, Christine N Manser, George N Dalekos, Bertus Eksteen, Pietro Invernizzi, Christoph P Berg, Gabi I Kirchner, Christoph Sarrazin, Vincent Zimmer, Luca Fabris, Felix Braun, Marco Marzioni, Brian D Juran, Karouk Said, Christian Rupp, Kalle Jokelainen, Maria Benito de Valle, Francesca Saffioti, Angela Cheung, Michael Trauner, Christoph Schramm, Roger W Chapman, Tom H Karlsen, Erik Schrumpf, Christian P Strassburg, Michael P Manns, Keith D Lindor, Gideon M Hirschfield, Bettina E Hansen, Kirsten M Boberg
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large, international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries...
March 5, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28270600/diverse-regulation-of-mammary-epithelial-growth-and-branching-morphogenesis-through-noncanonical-wnt-signaling
#16
Kai Kessenbrock, Prestina Smith, Sander Christiaan Steenbeek, Nicholas Pervolarakis, Raj Kumar, Yasuhiro Minami, Andrei Goga, Lindsay Hinck, Zena Werb
The mammary gland consists of an adipose tissue that, in a process called branching morphogenesis, is invaded by a ductal epithelial network comprising basal and luminal epithelial cells. Stem and progenitor cells drive mammary growth, and their proliferation is regulated by multiple extracellular cues. One of the key regulatory pathways for these cells is the β-catenin-dependent, canonical wingless-type MMTV integration site family (WNT) signaling pathway; however, the role of noncanonical WNT signaling within the mammary stem/progenitor system remains elusive...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28270014/evidence-of-alterations-in-the-expression-of-orphan-receptors-gpr26-and-gpr39-due-to-the-etiology-of-the-metabolic-syndrome
#17
Rodrigo Romero-Nava, De-Shan Zhou, Noemí García, Armando Ruiz-Hernández, Yin-Chu Si, Fausto Sánchez-Muñoz, Fengyang Huang, Enrique Hong, Santiago Villafaña
AIMS: Metabolic syndrome (MS) is composed of several metabolic abnormalities that increase the risk of cardiovascular diseases and diabetes. Although there are treatments for the components of MS, this pathology maintains a high mortality, suggesting that there are other mechanisms in which orphan receptors such as GPR26 and GPR39 may be involved. For this reason, the aim of this work was to evaluate the expression of GPR26 and GPR39 orphan receptors in two models of MS (diet and genetics)...
March 7, 2017: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/28253932/does-the-low-prevalence-affect-the-sample-size-of-interventional-clinical-trials-of-rare-diseases-an-analysis-of-data-from-the-aggregate-analysis-of-clinicaltrials-gov
#18
Siew Wan Hee, Adrian Willis, Catrin Tudur Smith, Simon Day, Frank Miller, Jason Madan, Martin Posch, Sarah Zohar, Nigel Stallard
BACKGROUND: Clinical trials are typically designed using the classical frequentist framework to constrain type I and II error rates. Sample sizes required in such designs typically range from hundreds to thousands of patients which can be challenging for rare diseases. It has been shown that rare disease trials have smaller sample sizes than non-rare disease trials. Indeed some orphan drugs were approved by the European Medicines Agency based on studies with as few as 12 patients. However, some studies supporting marketing authorisation included several hundred patients...
March 2, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28246555/management-of-thrombosis-in-paroxysmal-nocturnal-hemoglobinuria-a-clinician-s-guide
#19
REVIEW
Morag Griffin, Talha Munir
Paroxysmal nocturnal haemoglobinuria (PNH), an ultra-orphan disease with a prevalence of 15.9 per million in Europe, is a life-threatening disorder, characterized by haemolysis, bone marrow failure and thrombosis. Patients with PNH prior to the availability of eculizumab had a median survival of between 10 and 22 years, with thrombosis accounting for 22-67% of deaths. 29-44% of patients had at least one thrombosis. This paper provides a clinician's guide to the diagnosis, management and complications of PNH, with an emphasis on thrombosis...
March 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28242276/synthesis-of-dihydroimidazole-tethered-imidazolinethiones-and-their-activity-as-novel-antagonists-of-the-nuclear-retinoic-acid-receptor-related-orphan-receptors-rors
#20
Adel Nefzi, Guya D Marconi, Maria A Ortiz, Jennifer C Davis, F Javier Piedrafita
Targeting the transcriptional activity of nuclear hormone receptors has proven an effective strategy to treat certain human diseases, and they have become a major focus point to develop novel therapies for the treatment of cancer, inflammation, autoimmune diseases, metabolic disorders, and others. One family of nuclear receptors that has attracted most interest in recent years is the retinoic acid receptor-related orphan receptors (RORs), in particular RORγ. RORγ is a critical regulator of the immune system and RORγ antagonists have shown activity in animal models of inflammatory autoimmune diseases...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
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