Microglia and Neuroinflammation: What Place for P2RY12?
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Population-Specific Associations of Deleterious Rare Variants In
International Journal of Molecular Sciences Article Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients Piotr K. Janicki 1, Ceren Eyileten 2 ID , Victor Ruiz-Velasco 3, Khaled Anwar Sedeek 3, Justyna Pordzik 2, Anna Czlonkowska 2,4, Iwona Kurkowska-Jastrzebska 4 ID , Shigekazu Sugino 1, Yuka Imamura-Kawasawa 5, Dagmara Mirowska-Guzel 2 and Marek Postula 1,2,* ID 1 Perioperative Genomics Laboratory, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] (P.K.J.); [email protected] (S.S.) 2 Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, 02-097 Warsaw, Poland; [email protected] (C.E.); [email protected] (J.P.); [email protected] (A.C.); [email protected] (D.M.-G.) 3 Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] (V.R.-V.); [email protected] (K.A.S.) 4 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland; [email protected] 5 Genome Sciences Facility, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] * Correspondence: [email protected]; Tel.: +48-221-166-160 Received: 20 September 2017; Accepted: 7 December 2017; Published: 11 December 2017 Abstract: The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population. -
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. -
P2Y6 Receptors Regulate CXCL10 Expression and Secretion in Mouse Intestinal Epithelial Cells
fphar-09-00149 February 26, 2018 Time: 17:57 # 1 ORIGINAL RESEARCH published: 28 February 2018 doi: 10.3389/fphar.2018.00149 P2Y6 Receptors Regulate CXCL10 Expression and Secretion in Mouse Intestinal Epithelial Cells Mabrouka Salem1,2, Alain Tremblay2, Julie Pelletier2, Bernard Robaye3 and Jean Sévigny1,2* 1 Département de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada, 2 Centre de Recherche du CHU de Québec – Université Laval, Québec City, QC, Canada, 3 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Gosselies, Belgium In this study, we investigated the role of extracellular nucleotides in chemokine (KC, MIP- 2, MCP-1, and CXCL10) expression and secretion by murine primary intestinal epithelial cells (IECs) with a focus on P2Y6 receptors. qRT-PCR experiments showed that P2Y6 was the dominant nucleotide receptor expressed in mouse IEC. In addition, the P2Y6 Edited by: ligand UDP induced expression and secretion of CXCL10. For the other studies, we Kenneth A. Jacobson, −=− National Institutes of Health (NIH), took advantage of mice deficient in P2Y6 (P2ry6 ). Similar expression levels of P2Y1, −=− United States P2Y2, P2X2, P2X4, and A2A were detected in P2ry6 and WT IEC. Agonists of Reviewed by: TLR3 (poly(I:C)), TLR4 (LPS), P2Y1, and P2Y2 increased the expression and secretion Fernando Ochoa-Cortes, of CXCL10 more prominently in P2ry6−=− IEC than in WT IEC. CXCL10 expression Universidad Autónoma de San Luis −=− Potosí, Mexico and secretion induced by poly(I:C) in both P2ry6 and WT IEC were inhibited by Markus Neurath, general P2 antagonists (suramin and Reactive-Blue-2), by apyrase, and by specific Universitätsklinikum Erlangen, Germany antagonists of P2Y1, P2Y2, P2Y6 (only in WT), and P2X4. -
Cangrelor Ameliorates CLP-Induced Pulmonary Injury in Sepsis By
Luo et al. Eur J Med Res (2021) 26:70 https://doi.org/10.1186/s40001-021-00536-4 European Journal of Medical Research RESEARCH Open Access Cangrelor ameliorates CLP-induced pulmonary injury in sepsis by inhibiting GPR17 Qiancheng Luo1†, Rui Liu2†, Kaili Qu3, Guorong Liu1, Min Hang1, Guo Chen1, Lei Xu1, Qinqin Jin1 , Dongfeng Guo1* and Qi Kang1* Abstract Background: Sepsis is a common complication of severe wound injury and infection, with a very high mortality rate. The P2Y12 receptor inhibitor, cangrelor, is an antagonist anti-platelet drug. Methods: In our study, we investigated the protective mechanisms of cangrelor in CLP-induced pulmonary injury in sepsis, using C57BL/6 mouse models. Results: TdT-mediated dUTP Nick-End Labeling (TUNEL) and Masson staining showed that apoptosis and fbrosis in lungs were alleviated by cangrelor treatment. Cangrelor signifcantly promoted surface expression of CD40L on platelets and inhibited CLP-induced neutrophils in Bronchoalveolar lavage fuid (BALF) (p < 0.001). We also found that cangrelor decreased the infammatory response in the CLP mouse model and inhibited the expression of infamma- tory cytokines, IL-1β (p < 0.01), IL-6 (p < 0.05), and TNF-α (p < 0.001). Western blotting and RT-PCR showed that cangre- lor inhibited the increased levels of G-protein-coupled receptor 17 (GPR17) induced by CLP (p < 0.001). Conclusion: Our study indicated that cangrelor repressed the levels of GPR17, followed by a decrease in the infam- matory response and a rise of neutrophils in BALF, potentially reversing CLP-mediated pulmonary injury during sepsis. Keywords: Sepsis, Infammation, Cangrelor, Platelet, GPR17 Background Te lung is one of the initial target organ of the systemic Sepsis is a serious disease and will lead a high mortal- infammatory response caused by sepsis, leading to alve- ity rate of approximately 22% in all over the world [1]. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
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). -
Kengrexal, INN-Cangrelor Tetrasodium
ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Kengrexal 50 mg powder for concentrate for solution for injection/infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains cangrelor tetrasodium corresponding to 50 mg cangrelor. After reconstitution 1 mL of concentrate contains 10 mg cangrelor. After dilution 1 mL of solution contains 200 micrograms cangrelor. Excipient with known effect Each vial contains 52.2 mg sorbitol. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate for solution for injection/infusion. White to off-white lyophilised powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Kengrexal, co-administered with acetylsalicylic acid (ASA), is indicated for the reduction of thrombotic cardiovascular events in adult patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. 4.2 Posology and method of administration Kengrexal should be administered by a physician experienced in either acute coronary care or in coronary intervention procedures and is intended for specialised use in an acute and hospital setting. Posology The recommended dose of Kengrexal for patients undergoing PCI is a 30 micrograms/kg intravenous bolus followed immediately by 4 micrograms/kg/min intravenous infusion. The bolus and infusion should be initiated prior to the procedure and continued for at least two hours or for the duration of the procedure, whichever is longer. At the discretion of the physician, the infusion may be continued for a total duration of four hours, see section 5.1. -
Molecular Dissection of G-Protein Coupled Receptor Signaling and Oligomerization
MOLECULAR DISSECTION OF G-PROTEIN COUPLED RECEPTOR SIGNALING AND OLIGOMERIZATION BY MICHAEL RIZZO A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Biology December, 2019 Winston-Salem, North Carolina Approved By: Erik C. Johnson, Ph.D. Advisor Wayne E. Pratt, Ph.D. Chair Pat C. Lord, Ph.D. Gloria K. Muday, Ph.D. Ke Zhang, Ph.D. ACKNOWLEDGEMENTS I would first like to thank my advisor, Dr. Erik Johnson, for his support, expertise, and leadership during my time in his lab. Without him, the work herein would not be possible. I would also like to thank the members of my committee, Dr. Gloria Muday, Dr. Ke Zhang, Dr. Wayne Pratt, and Dr. Pat Lord, for their guidance and advice that helped improve the quality of the research presented here. I would also like to thank members of the Johnson lab, both past and present, for being valuable colleagues and friends. I would especially like to thank Dr. Jason Braco, Dr. Jon Fisher, Dr. Jake Saunders, and Becky Perry, all of whom spent a great deal of time offering me advice, proofreading grants and manuscripts, and overall supporting me through the ups and downs of the research process. Finally, I would like to thank my family, both for instilling in me a passion for knowledge and education, and for their continued support. In particular, I would like to thank my wife Emerald – I am forever indebted to you for your support throughout this process, and I will never forget the sacrifices you made to help me get to where I am today. -
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. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
P2 Receptors in Cardiovascular Regulation and Disease
Purinergic Signalling (2008) 4:1–20 DOI 10.1007/s11302-007-9078-7 REVIEW P2 receptors in cardiovascular regulation and disease David Erlinge & Geoffrey Burnstock Received: 3 May 2007 /Accepted: 22 August 2007 /Published online: 21 September 2007 # Springer Science + Business Media B.V. 2007 Abstract The role of ATP as an extracellular signalling Introduction molecule is now well established and evidence is accumulating that ATP and other nucleotides (ADP, UTP and UDP) play Ever since the first proposition of cell surface receptors for important roles in cardiovascular physiology and pathophysi- nucleotides [1, 2], it has become increasingly clear that, in ology, acting via P2X (ion channel) and P2Y (G protein- addition to functioning as an intracellular energy source, the coupled) receptors. In this article we consider the dual role of purines and pyrimidines ATP, adenosine diphosphate ATP in regulation of vascular tone, released as a cotransmitter (ADP), uridine triphosphate (UTP) and uridine diphosphate from sympathetic nerves or released in the vascular lumen in (UDP) can serve as important extracellular signalling response to changes in blood flow and hypoxia. Further, molecules [3, 4] acting on 13 P2X homo- and heteromul- purinergic long-term trophic and inflammatory signalling is timer ionotropic and 8 P2Y metabotropic receptor subtypes described in cell proliferation, differentiation, migration and [5, 6] (Table 1). To terminate signalling, ectonucleotidases death in angiogenesis, vascular remodelling, restenosis and are present in the circulation and on cell surfaces, rapidly atherosclerosis. The effects on haemostasis and cardiac degrading extracellular ATP into ADP, AMP and adenosine regulation is reviewed. The involvement of ATP in vascular [7, 8]. -
Neuroinflammation White Paper
NEUROINFLAMMATION Our understanding of the molecular pathogenesis of neuroinflammation is growing steadily. Progress in different areas of basic research, new animal models, and the generation of specific antibody markers to target essential proteins help to find and improve the treatment of patients with neuroimmunological diseases. In this white paper, we discuss the role of microglia, oligodendrocytes, and astrocytes in the neuroinflammatory processes highlighting the relevant antibody markers with a particular focus on multiple sclerosis. Neuroinflammation broadly defines the collective peripheral blood cells, mainly T-and B-cells, into reactive immune response in the brain and the brain parenchyma 1,2,3. spinal cord in response to injury and disease. Inflammation in the central nervous system Neuroinflammatory processes are the key (CNS) is commonly associated with various causative factors behind brain and spinal cord degrees of tissue damage, such as loss of myelin injury. This is true not only for acute brain and neurons. trauma and hypoxic-ischemic brain damage following stroke, but also for chronic infection The neuroinflammatory process is complex and and neurodegenerative diseases, such as involves disruption of the blood-brain barrier Alzheimer’s disease, amyotrophic lateral (BBB), peripheral leukocyte infiltration, edema, sclerosis (ALS), Lewy body dementia, and and gliosis. The inflammatory response is leukoencephalopathies like multiple sclerosis characterized by a host of cellular and molecular (MS). In addition, local peritumoral inflammation aberrations within the brain. plays a role in the clinical progression and malignancy of glioblastomas, the most aggressive Neuroinflammation arises within the CNS primary brain tumors. through phenotypic changes of different non- neuronal cell types in the brain, such as microglia, Recent studies have revealed unexpected oligodendrocytes, and astrocytes, causing the insights by providing hints of a protective role of release of different cytokines and chemokines, inflammation.