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Strategies to Increase ß-Cell Mass Expansion
This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents ................................................................................................. -
Endothelin System and Therapeutic Application of Endothelin Receptor
xperim ACCESS Freely available online & E en OPEN l ta a l ic P in h l a C r m f o a c l a o n l o r g u y o J Journal of ISSN: 2161-1459 Clinical & Experimental Pharmacology Research Article Endothelin System and Therapeutic Application of Endothelin Receptor Antagonists Abebe Basazn Mekuria, Zemene Demelash Kifle*, Mohammedbrhan Abdelwuhab Department of Pharmacology, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia ABSTRACT Endothelin is a 21 amino acid molecule endogenous potent vasoconstrictor peptide. Endothelin is synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonic, and inflammatory cells. It acts through a seven transmembrane endothelin receptor A (ETA) and endothelin receptor B (ETB) receptors belongs to G protein-coupled rhodopsin-type receptor superfamily. This peptide involved in pathogenesis of cardiovascular disorder like (heart failure, arterial hypertension, myocardial infraction and atherosclerosis), renal failure, pulmonary arterial hypertension and it also involved in pathogenesis of cancer. Potentially endothelin receptor antagonist helps the treatment of the above disorder. Currently, there are a lot of trails both per-clinical and clinical on endothelin antagonist for various cardiovascular, pulmonary and cancer disorder. Some are approved by FAD for the treatment. These agents are including both selective and non-selective endothelin receptor antagonist (ETA/B). Currently, Bosentan, Ambrisentan, and Macitentan approved -
The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands
The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands Clare Louise Wishart Submitted in accordance with the requirements for the degree of Doctor of Philosophy of Science University of Leeds School of Biomedical Sciences Faculty of Biological Sciences September 2013 I Intellectual Property and Publication Statements The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Clare Louise Wishart to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2013 The University of Leeds and Clare Louise Wishart. II Acknowledgments Firstly I would like to offer my sincerest thanks and gratitude to my supervisor, Dr. Dan Donnelly, who has been nothing but encouraging and engaging from day one. I have thoroughly enjoyed every moment of working alongside him and learning from his guidance and wisdom. My thanks go to my academic assessor Professor Paul Milner whom I have known for several years, and during my time at the University of Leeds he has offered me invaluable advice and inspiration. Additionally I would like to thank my academic project advisor Dr. Michael Harrison for his friendship, help and advice. I would like to thank Dr. Rosalind Mann and Dr. Elsayed Nasr for welcoming me into the lab as a new PhD student and sharing their experimental techniques with me, these techniques have helped me no end in my time as a research student. -
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. -
Bone-Specific Master Transcription Factor Runx2 Regulates Signaling and Metabolism Related Programs in Osteoprogenitors
ISSN 0233-7657. Biopolymers and Cell. 2010. Vol. 26. N 4 Bone-specific master transcription factor Runx2 regulates signaling and metabolism related programs in osteoprogenitors N. M. Teplyuk1, 2, V. I. Teplyuk2 1University of Massachusetts Medical School 55, Lake Ave North, 01655, Worcester, MA, USA 2Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine 150, Zabolotnogo str., Kiev, Ukraine, 03680 [email protected] Aim. Runx2 (AML3) transcription factor is the key regulator of osteoblastic lineage progression and is indispensable for the formation of mineral bones. Runx2 expression increases during differentiation of osteoblasts to induce osteoblast-specific genes necessary for the production and deposition of bone mineral matrix. However, Runx2 is also expressed at a lower level in early osteoprogenitors, where its function is less understood. Here we study how Runx2 determines the early stages of osteoblastic commitment using the model system of Runx2 re-introduction in mouse calvaria cells with Runx2 null background. Method. Affymetrix analysis, Western blot analysis and quantitative real-time reverse transcriptase PCR (qRT-PCR) analysis were employed. Results. Gene expression profiling by Affymetrix microarrays revealed that along with the induction of extracellular matrix and bone mineral deposition related phenotypic markers, Runx2 regulates several cell programs related to signaling and metabolism in the early osteoprogenitors. Particularly, Runx2 regulates transcription of genes involved in G-protein coupled signaling network, FGF and BMP/TGF beta signaling pathways and in biogenesis and metabolism pathways of steroid hormones. Conclusion. The data indicate that the lineage specific program, regulated by the master regulatory transcription factor, includes the regulation of cellular signaling and metabolism which may allow the committed cell to react and behave differently in the same microenvironment. -
Immunosuppression Via Adenosine Receptor Activation by Adenosine
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref RESEARCH ARTICLE elifesciences.org Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells Hiroshi Yamaguchi1, Toshihiko Maruyama2, Yoshihiro Urade2†, Shigekazu Nagata1,3* 1Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan; 3Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kyoto, Japan Abstract Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic *For correspondence: snagata@ supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an mfour.med.kyoto-u.ac.jp ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced † Present address: Molecular high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated Sleep Biology Laboratory, that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal. WPI-International Institute for DOI: 10.7554/eLife.02172.001 Integrative Sleep Medicine, University of Tsukuba, Ibaraki, Japan Competing interests: The Introduction authors declare that no competing interests exist. -
309 Molecular Role of Dopamine in Anhedonia Linked to Reward
[Frontiers In Bioscience, Scholar, 10, 309-325, March 1, 2018] Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems Mark S. Gold8, Kenneth Blum,1-7,10 Marcelo Febo1, David Baron,2 Edward J Modestino9, Igor Elman10, Rajendra D. Badgaiyan10 1Department of Psychiatry, McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, FL, USA, 2Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of South- ern California, Los Angeles, CA, USA, 3Global Integrated Services Unit University of Vermont Center for Clinical and Translational Science, College of Medicine, Burlington, VT, USA, 4Department of Addiction Research, Dominion Diagnostics, LLC, North Kingstown, RI, USA, 5Center for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purbe Medinpur, West Bengal, India, 6Division of Neuroscience Research and Therapy, The Shores Treatment and Recovery Center, Port St. Lucie, Fl., USA, 7Division of Nutrigenomics, Sanus Biotech, Austin TX, USA, 8Department of Psychiatry, Washington University School of Medicine, St. Louis, Mo, USA, 9Depart- ment of Psychology, Curry College, Milton, MA USA,, 10Department of Psychiatry, Wright State University, Boonshoft School of Medicine, Dayton, OH ,USA. TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Anhedonia and food addiction 4. Anhedonia in RDS Behaviors 5. Anhedonia hypothesis and DA as a “Pleasure” molecule 6. Reward genes and anhedonia: potential therapeutic targets 7. Anti-reward system 8. State of At of Anhedonia 9. Conclusion 10. Acknowledgement 11. References 1. ABSTRACT Anhedonia is a condition that leads to the loss like “anti-reward” phenomena. These processes of feelings pleasure in response to natural reinforcers may have additive, synergistic or antagonistic like food, sex, exercise, and social activities. -
Trace Amine-Associated Receptor 1 Activation Regulates Glucose-Dependent
Trace amine-associated receptor 1 activation regulates glucose-dependent insulin secretion in pancreatic beta cells in vitro by ©Arun Kumar A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science Department of Biochemistry, Faculty of Science Memorial University of Newfoundland FEBRUARY 2021 St. John’s, Newfoundland and Labrador i Abstract Trace amines are a group of endogenous monoamines which exert their action through a family of G protein-coupled receptors known as trace amine-associated receptors (TAARs). TAAR1 has been reported to regulate insulin secretion from pancreatic beta cells in vitro and in vivo. This study investigates the mechanism(s) by which TAAR1 regulates insulin secretion. The insulin secreting rat INS-1E -cell line was used for the study. Cells were pre-starved (30 minutes) and then incubated with varying concentrations of glucose (2.5 – 20 mM) or KCl (3.6 – 60 mM) for 2 hours in the absence or presence of various concentrations of the selective TAAR1 agonist RO5256390. Secreted insulin per well was quantified using ELISA and normalized to the total protein content of individual cultures. RO5256390 significantly (P < 0.0001) increased glucose- stimulated insulin secretion in a dose-dependent manner, with no effect on KCl-stimulated insulin secretion. Affymetrix-microarray data analysis identified genes (Gnas, Gng7, Gngt1, Gria2, Cacna1e, Kcnj8, and Kcnj11) whose expression was associated with changes in TAAR1 in response to changes in insulin secretion in pancreatic beta cell function. The identified potential links to TAAR1 supports the regulation of glucose-stimulated insulin secretion through KATP ion channels. -
Multiplex Gpcr Internalization Assay Using Reverse Transduction on Adenoviral Vector Immobilized Microparticles S
MULTIPLEX GPCR INTERNALIZATION ASSAY USING REVERSE TRANSDUCTION ON ADENOVIRAL VECTOR IMMOBILIZED MICROPARTICLES S. Han1,2, H.J. Bae1,2, W. Park3 and S. Kwon1,2* 1Department of Electrical and Computer Engineering, Inter-university Semiconductor Research Center (ISRC), Seoul National University, SOUTH KOREA 2Center for Nanoparticle Research, Institute for Basic Science (IBS), SOUTH KOREA and 3Department of Electronics and Radio Engineering, Institute for Laser Engineering, Kyung Hee University, SOUTH KOREA ABSTRACT We present a new multiplexing method for high-throughput cell-based assays in a microtiter well based on reverse transduction of cells by adenoviral vectors immobilized on encoded microparticles. Our particle-based approach spatially confines the gene delivery to cells seeded on the particles and provides the code for identifying the delivered gene, thus easily achieving a multiplex cell microarray in a microtiter well by means of a single pipetting without the cross- expression of genes and the positional identification. Utilizing this method with adenoviral vectors having a G-protein coupled recpeptor (GPCR) gene, we demonstrated 3-plex GPCR internalization assay. KEYWORDS: Multiplex GPCR assay, Reverse transduction, Adenovirus, Encoded microparticle INTRODUCTION G-protein coupled receptors (GPCRs) in the cell membrane are major drug targets in pharmaceutical industry since they interact with a huge variety of endogenous ligands and trigger intracellular functions related to many physiological processes or diseases [1]. Many cell-based assay strategies have been developed to identify GPCR-targeted drugs with more biologically relevant data. Since typical cell-based assays are performed in the microtiter wells and it allows only one type of receptor for each well, multiplex cellular assay technologies have emerged to run high-throughput compound screening with over several hundreds of GPCRs. -
Supplementary Table 3 Complete List of RNA-Sequencing Analysis of Gene Expression Changed by ≥ Tenfold Between Xenograft and Cells Cultured in 10%O2
Supplementary Table 3 Complete list of RNA-Sequencing analysis of gene expression changed by ≥ tenfold between xenograft and cells cultured in 10%O2 Expr Log2 Ratio Symbol Entrez Gene Name (culture/xenograft) -7.182 PGM5 phosphoglucomutase 5 -6.883 GPBAR1 G protein-coupled bile acid receptor 1 -6.683 CPVL carboxypeptidase, vitellogenic like -6.398 MTMR9LP myotubularin related protein 9-like, pseudogene -6.131 SCN7A sodium voltage-gated channel alpha subunit 7 -6.115 POPDC2 popeye domain containing 2 -6.014 LGI1 leucine rich glioma inactivated 1 -5.86 SCN1A sodium voltage-gated channel alpha subunit 1 -5.713 C6 complement C6 -5.365 ANGPTL1 angiopoietin like 1 -5.327 TNN tenascin N -5.228 DHRS2 dehydrogenase/reductase 2 leucine rich repeat and fibronectin type III domain -5.115 LRFN2 containing 2 -5.076 FOXO6 forkhead box O6 -5.035 ETNPPL ethanolamine-phosphate phospho-lyase -4.993 MYO15A myosin XVA -4.972 IGF1 insulin like growth factor 1 -4.956 DLG2 discs large MAGUK scaffold protein 2 -4.86 SCML4 sex comb on midleg like 4 (Drosophila) Src homology 2 domain containing transforming -4.816 SHD protein D -4.764 PLP1 proteolipid protein 1 -4.764 TSPAN32 tetraspanin 32 -4.713 N4BP3 NEDD4 binding protein 3 -4.705 MYOC myocilin -4.646 CLEC3B C-type lectin domain family 3 member B -4.646 C7 complement C7 -4.62 TGM2 transglutaminase 2 -4.562 COL9A1 collagen type IX alpha 1 chain -4.55 SOSTDC1 sclerostin domain containing 1 -4.55 OGN osteoglycin -4.505 DAPL1 death associated protein like 1 -4.491 C10orf105 chromosome 10 open reading frame 105 -4.491 -
The Role of Inflammatory Pathways in Neuroblastoma Tumorigenesis — Igor Snapkov a Dissertation for the Degree of Philosophiae Doctor – August 2016 Contents
Faculty of Health Sciences Department of Medical Biology Molecular Inflammation Research Group The role of inflammatory pathways in neuroblastoma tumorigenesis — Igor Snapkov A dissertation for the degree of Philosophiae Doctor – August 2016 Contents 1. List of publications .................................................................................................................. 2 2. List of abbreviations ................................................................................................................ 3 3. Introduction ............................................................................................................................. 5 3.1 Cancer and inflammation .................................................................................................. 5 3.2.1 Pattern recognition receptors and danger signals ............................................................ 7 3.2.2 Formyl peptide receptor 1 (FPR1) ................................................................................. 9 3.3.1 Chemokines................................................................................................................. 12 3.3.2 Chemerin ..................................................................................................................... 13 3.4 Neuroblastoma ................................................................................................................ 14 3.5 Hepatic clearance of danger signals ................................................................................ -
Bradykinin Receptor Deficiency Or Antagonism Do Not Impact the Host
Ding et al. Intensive Care Medicine Experimental (2019) 7:14 Intensive Care Medicine https://doi.org/10.1186/s40635-019-0228-3 Experimental RESEARCH Open Access Bradykinin receptor deficiency or antagonism do not impact the host response during gram-negative pneumonia-derived sepsis Chao Ding1,2, Jack Yang2, Cornelis van’t Veer2 and Tom van der Poll2,3* * Correspondence: t.vanderpoll@ amc.uva.nl Abstract 2Center of Experimental and Molecular Medicine, Academic Background: Kinins are short peptides with a wide range of proinflammatory Medical Center, University of properties that are generated from kininogens in the so-called kallikrein-kinin system. Amsterdam, Meibergdreef 9, Room Kinins exert their biological activities through stimulation of two distinct receptor G2-130, 1105 AZ Amsterdam, the Netherlands subtypes, the kinin or bradykinin B1 and B2 receptors (B1R, B2R). Acute challenge 3Division of Infectious Diseases, models have implicated B1R and B2R in the pathogenesis of sepsis. However, their Academic Medical Center, role in the host response during sepsis originating from the lung is not known. University of Amsterdam, Amsterdam, the Netherlands Results: To determine the role of B1R and B2R in pneumonia-derived sepsis, B1R/ Full list of author information is B2R-deficient mice and wild-type mice treated with the B1R antagonist R-715 or the available at the end of the article B2R antagonist HOE-140 were studied after infection with the common gram- negative pathogen Klebsiella pneumoniae via the airways. Neither B1R/B2R deficiency nor B1R or B2R inhibition influenced bacterial growth at the primary site of infection or dissemination to distant body sites.