Nucleic Acid Ligands Act As a PAM and Agonist Depending on the Intrinsic Ligand Binding State of P2RY2
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Mouse Pancreatic Islet Macrophages Use Locally Released ATP to Monitor Beta Cell Activity
Diabetologia DOI 10.1007/s00125-017-4416-y ARTICLE Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity Jonathan R. Weitz1,2 & Madina Makhmutova1,3 & Joana Almaça1 & Julia Stertmann4,5,6 & Kristie Aamodt7 & Marcela Brissova8 & Stephan Speier4,5,6 & Rayner Rodriguez-Diaz1 & Alejandro Caicedo1,2,3,9 Received: 14 February 2017 /Accepted: 14 July 2017 # Springer-Verlag GmbH Germany 2017 Abstract and used them to monitor macrophage responses to stimula- Aims/hypothesis Tissue-resident macrophages sense the mi- tion of acinar, neural and endocrine cells. croenvironment and respond by producing signals that act Results Islet-resident macrophages expressed functional locally to maintain a stable tissue state. It is now known that purinergic receptors, making them exquisite sensors of inter- pancreatic islets contain their own unique resident macro- stitial ATP levels. Indeed, islet-resident macrophages phages, which have been shown to promote proliferation of responded selectively to ATP released locally from beta cells the insulin-secreting beta cell. However, it is unclear how beta that were physiologically activated with high levels of glu- cells communicate with islet-resident macrophages. Here we cose. Because ATP is co-released with insulin and is exclu- hypothesised that islet macrophages sense changes in islet sively secreted by beta cells, the activation of purinergic re- activity by detecting signals derived from beta cells. ceptors on resident macrophages facilitates their awareness of Methods To investigate how islet-resident macrophages re- beta cell secretory activity. spond to cues from the microenvironment, we generated mice Conclusions/interpretation Our results indicate that islet mac- expressing a genetically encoded Ca2+ indicator in myeloid rophages detect ATP as a proxy signal for the activation state cells. -
The Purinergic Receptor P2Y, G-Protein Coupled, 2 (P2RY2) Gene Associated with Essential Hypertension in Japanese Men
Journal of Human Hypertension (2010) 24, 327–335 & 2010 Macmillan Publishers Limited All rights reserved 0950-9240/10 $32.00 www.nature.com/jhh ORIGINAL ARTICLE The purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene associated with essential hypertension in Japanese men Z Wang1,2, T Nakayama1,3, N Sato1, Y Izumi3, Y Kasamaki4, M Ohta4, M Soma5, N Aoi1, Y Ozawa4 andYMa2 1Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan; 2Department of Cardiovascular Medicine, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, PR China; 3Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; 4Division of Cardiovascular Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan and 5Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan P2RY2 has an important function in the regulation of respectively). Logistic regression showed that for blood pressure by activating adenosine triphosphate the total and men groups, the TG þ TT genotype of (ATP). The aim of this study was to investigate the asso- rs4944831 was more prevalent in EH patients than in the ciation between the human P2RY2 gene and essential controls (P ¼ 0.026 and 0.011, respectively). For men, the hypertension (EH) through a haplotype-based case– overall distribution of the haplotype (SNP2-SNP4-SNP5) control study that included two gender groups. The 273 was significantly different between the EH patients EH patients and 255 age-matched controls were geno- and the controls (P ¼ 0.006). As compared with controls, typed for five single-nucleotide polymorphisms (SNPs) the frequency of the T-A-G haplotype was significantly of the human P2RY2 gene (rs4944831, rs1783596, higher, whereas the T-C-G haplotype was significan- rs4944832, rs4382936 and rs10898909). -
Activation of Hypermethylated P2RY1 Mitigates Gastric Cancer by Promoting Apoptosis and Inhibiting Proliferation
Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation Yinggang Hua Xiamen University Medical College Long Li Xiamen University Medical College Liangliang Cai Zhongshan Hospital Xiamen University Guoyan Liu ( [email protected] ) Zhongshan Hospital Xiamen University Research Article Keywords: Diffuse type gastric cancer, DNA methylation 450K array, P2RY1 receptor, ERK signal pathway, Tumor suppressor gene Posted Date: July 26th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-351723/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/16 Abstract P2RY1 receptor is known to cause cancer by activating the ERK signal pathway, its DNA methylation status or even the corresponding regulatory mechanism remains unknown. In this study, DNA methylation chip was used to prole the genome-wide DNA methylation level in gastric cancer tissues. Proliferation and apoptosis of the SGC7901 gastric cancer cell line were determined after treatment with a selective P2RY1 receptor agonist, MRS2365. The promoter region of P2RY1 was found to be highly methylated with 4 hypermethylated sites (|Δβ value| >0.2) in diffuse gastric cancer and then were validated by bioinformatic analysis in TCGA database. Analysis of MRS2365-treated cells by annexin-V/PI staining and Caspase-3 activity assays indicated the induction of apoptosis in SGC7901 cells. P2RY1 receptor activation in human SGC7901 gastric cancer cells via the MRS2365 agonist induced apoptosis and reduced cell growth. High DNA methylation in the promoter region of P2RY1 may have contributed to the reduced expression of P2RY1’s mRNA, which is likely responsible for the “aggressive” nature of the diffuse type gastric cancer. -
Aptamer-Mediated Cancer Gene Therapy Dongxi Xiang , Sarah
Aptamer-Mediated Cancer Gene Therapy Dongxi Xiang1*, Sarah Shigdar 1*, Greg Qiao2, Shu-Feng Zhou3, Yong Li4, Ming Q Wei5, 6 1 7 8 9** Liang Qiao , Hadi Al.Shamaileh , Yimin Zhu , Conglong Zheng , Chunwen Pu and Wei Duan1** 1School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria, 3217, Australia. 2 Department of Chemical and Biomolecular Engineering, Melbourne School of Engineering The University of Melbourne, Parkville, Victoria 3010, Australia 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA. 4Cancer Care Centre, St George Hospital, Kogarah, NSW2217, and St George and Sutherland Clinical School, University of New South Wales (UNSW), Kensington, NSW2052, Australia 5Division of Molecular and Gene Therapies, Griffith Health Institute and School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia 6Storr Liver Unit, at the Westmead Millennium Institute, the University of Sydney at the Westmead Hospital, Westmead NSW, 2145, Australia 7Suzhou Key Laboratory of Nanobiomedicine, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu, China, 215123 8Department of Biology, Medical College, Dalian University, Liaoning, People’s Republic of China 9The Affiliated Zhongshan Hospital of Dalian University, 6 Jiefang Road, Dalian, Liaoning, The People's Republic of China, 116001. 1 * These authors contributed equally. ** Corresponding authors: E-mail: [email protected] (C. Pu); or [email protected] (W. Duan). 2 Abstract Cancer as a genetic disorder is one of the leading causes of death worldwide. Conventional anticancer options such as chemo- and/or radio-therapy have their own drawbacks and could not provide a cure in most cases at present. -
Lab-On-A-Chip Systems for Aptamer-Based Biosensing
micromachines Review Lab-on-a-Chip Systems for Aptamer-Based Biosensing Niazul I. Khan 1 and Edward Song 1,2,* 1 Department of Electrical and Computer Engineering, University of New Hampshire, Durham, NH 03824, USA; [email protected] 2 Materials Science Program, University of New Hampshire, Durham, NH 03824, USA * Correspondence: [email protected]; Tel.: +1-603-862-5498 Received: 6 January 2020; Accepted: 17 February 2020; Published: 20 February 2020 Abstract: Aptamers are oligonucleotides or peptides that are selected from a pool of random sequences that exhibit high affinity toward a specific biomolecular species of interest. Therefore, they are ideal for use as recognition elements and ligands for binding to the target. In recent years, aptamers have gained a great deal of attention in the field of biosensing as the next-generation target receptors that could potentially replace the functions of antibodies. Consequently, it is increasingly becoming popular to integrate aptamers into a variety of sensing platforms to enhance specificity and selectivity in analyte detection. Simultaneously, as the fields of lab-on-a-chip (LOC) technology, point-of-care (POC) diagnostics, and personal medicine become topics of great interest, integration of such aptamer-based sensors with LOC devices are showing promising results as evidenced by the recent growth of literature in this area. The focus of this review article is to highlight the recent progress in aptamer-based biosensor development with emphasis on the integration between aptamers and the various forms of LOC devices including microfluidic chips and paper-based microfluidics. As aptamers are extremely versatile in terms of their utilization in different detection principles, a broad range of techniques are covered including electrochemical, optical, colorimetric, and gravimetric sensing as well as surface acoustics waves and transistor-based detection. -
Real-Time PCR for Direct Aptamer Quantification on Functionalized
www.nature.com/scientificreports OPEN Real-time PCR for direct aptamer quantifcation on functionalized graphene surfaces Viviane C. F. dos Santos1,2*, Nathalie B. F. Almeida1,2, Thiago A. S. L. de Sousa1, Eduardo N. D. Araujo3, Antero S. R. de Andrade2 & Flávio Plentz1 In this study, we develop a real-time PCR strategy to directly detect and quantify DNA aptamers on functionalized graphene surfaces using a Staphylococcus aureus aptamer (SA20) as demonstration case. We show that real-time PCR allowed aptamer quantifcation in the range of 0.05 fg to 2.5 ng. Using this quantitative technique, it was possible to determine that graphene functionalization with amino modifed SA20 (preceded by a graphene surface modifcation with thionine) was much more efcient than the process using SA20 with a pyrene modifcation. We also demonstrated that the functionalization methods investigated were selective to graphene as compared to bare silicon dioxide surfaces. The precise quantifcation of aptamers immobilized on graphene surface was performed for the frst time by molecular biology techniques, introducing a novel methodology of wide application. DNA (deoxyribonucleic acid) aptamers are single strand oligonucleotides that presents high afnity and speci- fcity to their binders1. In comparison with traditional ligands, such as antibodies, aptamers present some advan- tages. Tey are chemically stable, cost-efective, more resistant to pH and temperature variations, and are more fexible in the design of their structures2. Due to these characteristics, they have great potential as sensing compo- nents in diagnostic and detection assays. Biosensor platforms based on DNA aptamers are more stable for storage and transport than the antibodies counterparts2. -
Design Strategies for Aptamer-Based Biosensors
Sensors 2010, 10, 4541-4557; doi:10.3390/s100504541 OPEN ACCESS sensors ISSN 1424-8220 www.mdpi.com/journal/sensors Review Design Strategies for Aptamer-Based Biosensors Kun Han 1,2, Zhiqiang Liang 3 and Nandi Zhou 1,4,* 1 Department of Biochemistry and National Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China 2 Suzhou Institute of Biomedical Engineering Technology, Chinese Academy of Science, Suzhou 215163, China; E-Mail: [email protected] 3 Laboratory of Biosensing Technology, School of Life Sciences, Shanghai University, Shanghai 200444, China; E-Mail: [email protected] 4 School of Biotechnology and the Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +86-510-8591-8116; Fax: +86-510-8591-8116. Received: 11 February 2010; in revised form: 1 April 2010 / Accepted: 4 April 2010 / Published: 4 May 2010 Abstract: Aptamers have been widely used as recognition elements for biosensor construction, especially in the detection of proteins or small molecule targets, and regarded as promising alternatives for antibodies in bioassay areas. In this review, we present an overview of reported design strategies for the fabrication of biosensors and classify them into four basic modes: target-induced structure switching mode, sandwich or sandwich-like mode, target-induced dissociation/displacement mode and competitive replacement mode. In view of the unprecedented advantages brought about by aptamers and smart design strategies, aptamer-based biosensors are expected to be one of the most promising devices in bioassay related applications. -
Extracellular ATP and CD39 Activate Camp-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia
Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia Nesrine Aroua1,2,#, Emeline Boet1,2,#, Margherita Ghisi1,2,#, Marie-Laure Nicolau-Travers1,2,3, Estelle Saland1,2, Ryan Gwilliam1,2, Fabienne de Toni1,2, Mohsen Hosseini1,2, Pierre-Luc Mouchel1,2,3, Thomas Farge1,2, Claudie Bosc1,2, Lucille Stuani1,2, Marie Sabatier1,2, Fetta Mazed4,5, Clément Larrue1,2, Latifa Jarrou1,2, Sarah Gandarillas6, Massimiliano Bardotti6, Muriel Picard2,7, Charlotte Syrykh1,2,8, Camille Laurent1,2,8, Mathilde Gotanègre1,2, Nathalie Bonnefoy9, Floriant Bellvert10, Jean-Charles Portais10, Nathalie Nicot11, Francisco Azuaje12, Tony Kaoma12, Carine Joffre1,2, Jérome Tamburini4,5, Christian Récher1,2,3,#, François Vergez1,2,3,# and Jean-Emmanuel Sarry1,2,* 1Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France. 2University of Toulouse, F-31077 Toulouse, France. 3Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, F- 31100 Toulouse, France. 4Institut Cochin, Département Développement, Reproduction, Cancer, UMR8104-CNRS, U1016- INSERM, Paris 5Translational Research Centre in Onco-Hematology, Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. 6Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales, Service d'Expérimentation Animale, UMS006, Inserm, F-31037 Toulouse, France 7Intensive Care Unit, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, F- 31100 Toulouse, France. 1 8Service d’Anatomopathologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, F-31100 Toulouse, France 9Institut de Recherche en Cancérologie de Montpellier, U1194, Inserm, Université de Montpellier, Institut régional du Cancer de Montpellier, F-34298 Montpellier, France 10TBI, Université de Toulouse, CNRS, INRA, INSA, Toulouse, F-31077, France. -
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DNA and RNA Nanotechnology 2015; 2: 42–52 Mini review Open Access Martin Panigaj*, Jakob Reiser Aptamer guided delivery of nucleic acid-based nanoparticles DOI 10.1515/rnan-2015-0005 Evolution of Ligands by Exponential enrichment) [4,5]. Received July 15, 2015; accepted October 3, 2015 Nucleic acid-based aptamers are especially well suited Abstract: Targeted delivery of bioactive compounds is a for the delivery of nucleic acid-based therapeutics. Any key part of successful therapies. In this context, nucleic nucleic acid with therapeutic potential can be linked acid and protein-based aptamers have been shown to to an aptamer sequence [6], resulting in a bivalent bind therapeutically relevant targets including receptors. molecule endowed with a targeting aptamer moiety and In the last decade, nucleic acid-based therapeutics a functional RNA/DNA moiety like a small interfering coupled to aptamers have emerged as a viable strategy for RNA (siRNA), a micro RNA (miRNA), a miRNA antagonist cell specific delivery. Additionally, recent developments (antimiR), deoxyribozymes (DNAzymes), etc. In addition in nucleic acid nanotechnology offer an abundance of to the specific binding, many aptamers upon receptor possibilities to rationally design aptamer targeted RNA recognition elicit antagonistic or agonistic responses that, or DNA nanoparticles involving combinatorial use of in combination with conjugated functional nucleic acids various intrinsic functionalities. Although a host of issues have the potential of synergism. Since the first report including stability, safety and intracellular trafficking describing an aptamer-siRNA delivery approach in 2006 remain to be addressed, aptamers as simple functional many functional RNAs and DNAs conjugated to aptamer chimeras or as parts of multifunctional self-assembled sequences have been tested in vitro and in vivo [7-9]. -
Introduction: P2 Receptors
Current Topics in Medicinal Chemistry 2004, 4, 793-803 793 Introduction: P2 Receptors Geoffrey Burnstock* Autonomic Neuroscience Institute, Royal Free and University College, London NW3 2PF, U.K. Abstract: The current status of ligand gated ion channel P2X and G protein-coupled P2Y receptor subtypes is described. This is followed by a summary of what is known of the distribution and roles of these receptor subtypes. Potential therapeutic targets of purinoceptors are considered, including those involved in cardiovascular, nervous, respiratory, urinogenital, gastrointestinal, musculo-skeletal and special sensory diseases, as well as inflammation, cancer and diabetes. Lastly, there are some speculations about future developments in the purinergic signalling field. HISTORICAL BACKGROUND It is widely recognised that purinergic signalling is a primitive system [19] involved in many non-neuronal as well The first paper describing the potent actions of adenine as neuronal mechanisms and in both short-term and long- compounds was published by Drury & Szent-Györgyi in term (trophic) events [20], including exocrine and endocrine 1929 [1]. Many years later, ATP was proposed as the secretion, immune responses, inflammation, pain, platelet transmitter responsible for non-adrenergic, non-cholinergic aggregation, endothelial-mediated vasodilatation, cell proli- transmission in the gut and bladder and the term ‘purinergic’ feration and death [8, 21-23]. introduced by Burnstock [2]. Early resistance to this concept appeared to stem from the fact that ATP was recognized first P2X Receptors for its important intracellular roles and the intuitive feeling was that such a ubiquitous and simple compound was Members of the existing family of ionotropic P2X1-7 unlikely to be utilized as an extracellular messenger. -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. -
Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS
cells Review Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS Peter Illes 1,2,*, Patrizia Rubini 2, Henning Ulrich 3, Yafei Zhao 4 and Yong Tang 2,4 1 Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany 2 International Collaborative Centre on Big Science Plan for Purine Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; [email protected] (P.R.); [email protected] (Y.T.) 3 Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 748, Brazil; [email protected] 4 Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; [email protected] * Correspondence: [email protected]; Tel.: +49-34-1972-46-14 Received: 17 March 2020; Accepted: 27 April 2020; Published: 29 April 2020 Abstract: Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood–brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction.