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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 ................................................................................................. -
Orbital Scintigraphy with the Somatostatin Receptor Tracer 99Mtc-P829 in Patients with Graves’ Disease
CLINICAL INVESTIGATIONS Orbital Scintigraphy with the Somatostatin Receptor Tracer 99mTc-P829 in Patients with Graves’ Disease Georg Burggasser, MD1; Ingrid Hurtl, MD2; Wolfgang Hauff, MD1; Julius Lukas, MD1; Michaela Greifeneder, MD2; Bamdad Heydari, MD2; Arnulf Thaler, MD1; Andreas Wedrich, MD1; and Irene Virgolini, MD2,3 1Department of Ophthalmology and Optometry, University of Vienna, Vienna, Austria; 2Institute of Nuclear Medicine, Vienna City Hospital Lainz, Vienna, Austria; and 3Ludwig Boltzmann Institute of Experimental Oncology and Photodynamic Therapy, Vienna City Hospital Lainz, Vienna, Austria documented regarding the NOSPECS classification as well as 99m Receptors for somatostatin (SST) (SSTR) are expressed on var- the SNI. Conclusion: In TAO, Tc-P829 yields high orbital ious tumor cells as well as on activated lymphocytes. Previous binding with good clinical correlation. The better image quality data have shown that 99mTc-P829 binds with high affinity to due to the high energy of technetium, the lower radiation dose many different types of tumor cells as well as to leukocytes via for patients and personnel, and the short acquisition protocol 99m 111 the human hSSTR2, hSSTR3, and hSSTR5 target receptors. favor SSTR scintigraphy with Tc-P829 over In-labeled Consequently, 99mTc-P829 was successfully introduced as a compounds. The in-house availability of the radiotracer and peptide tracer for tumor imaging. In this study, we evaluated the cost-effectiveness are further advantages. orbital uptake of 99mTc-P829 in patients with active and inactive Key Words: somatostatin receptor; somatostatin receptor im- thyroid-associated orbitopathy (TAO), accompanied by lympho- aging; 99mTc-P829; 99mTc-NeoSpect; 99mTc-NeoTect; Graves’ cyte infiltration in the acute stage and by muscle fibrosis in the disease; thyroid associated orbitopathy chronic stage of the disease. -
Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin
0163-769X/04/$20.00/0 Endocrine Reviews 25(3):426–457 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/er.2002-0029 Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin AART J. VAN DER LELY, MATTHIAS TSCHO¨ P, MARK L. HEIMAN, AND EZIO GHIGO Division of Endocrinology and Metabolism (A.J.v.d.L.), Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; Department of Psychiatry (M.T.), University of Cincinnati, Cincinnati, Ohio 45237; Endocrine Research Department (M.L.H.), Eli Lilly and Co., Indianapolis, Indiana 46285; and Division of Endocrinology (E.G.), Department of Internal Medicine, University of Turin, Turin, Italy 10095 Ghrelin is a peptide predominantly produced by the stomach. secretion, and influence on pancreatic exocrine and endo- Ghrelin displays strong GH-releasing activity. This activity is crine function as well as on glucose metabolism. Cardiovas- mediated by the activation of the so-called GH secretagogue cular actions and modulation of proliferation of neoplastic receptor type 1a. This receptor had been shown to be specific cells, as well as of the immune system, are other actions of for a family of synthetic, peptidyl and nonpeptidyl GH secre- ghrelin. Therefore, we consider ghrelin a gastrointestinal tagogues. Apart from a potent GH-releasing action, ghrelin peptide contributing to the regulation of diverse functions of has other activities including stimulation of lactotroph and the gut-brain axis. So, there is indeed a possibility that ghrelin corticotroph function, influence on the pituitary gonadal axis, analogs, acting as either agonists or antagonists, might have stimulation of appetite, control of energy balance, influence clinical impact. -
Transcriptomic Profiling of Pancreatic Alpha, Beta and Delta Cell Populations Identifies Delta Cells As a Principal Target for Ghrelin in Mouse Islets
Diabetologia (2016) 59:2156–2165 DOI 10.1007/s00125-016-4033-1 ARTICLE Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets Alice E. Adriaenssens1 & Berit Svendsen2,3 & Brian Y. H. Lam1 & Giles S. H. Yeo1 & Jens J. Holst2,3 & Frank Reimann1 & Fiona M. Gribble 1 Received: 15 March 2016 /Accepted: 1 June 2016 /Published online: 7 July 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract using islets with delta cell restricted expression of the calcium Aims/hypothesis Intra-islet and gut–islet crosstalk are critical reporter GCaMP3, and in perfused mouse pancreases. in orchestrating basal and postprandial metabolism. The aim Results A database was constructed of all genes expressed in of this study was to identify regulatory proteins and receptors alpha, beta and delta cells. The gene encoding the ghrelin underlying somatostatin secretion though the use of receptor, Ghsr, was highlighted as being highly expressed transcriptomic comparison of purified murine alpha, beta and enriched in delta cells. Activation of the ghrelin receptor and delta cells. raised cytosolic calcium levels in primary pancreatic delta Methods Sst-Cre mice crossed with fluorescent reporters were cells and enhanced somatostatin secretion in perfused used to identify delta cells, while Glu-Venus (with Venus re- pancreases, correlating with a decrease in insulin and gluca- ported under the control of the Glu [also known as Gcg]pro- gon release. The inhibition of insulin secretion by ghrelin was moter) mice were used to identify alpha and beta cells. -
Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET
Journal of Nuclear Medicine, published on August 18, 2011 as doi:10.2967/jnumed.111.088906 Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET Julius Leyton1, Lisa Iddon2, Meg Perumal1, Bard Indrevoll3, Matthias Glaser2, Edward Robins2, Andrew J.T. George4, Alan Cuthbertson3, Sajinder K. Luthra2, and Eric O. Aboagye1 1Comprehensive Cancer Imaging Center at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom; 2MDx Discovery (part of GE Healthcare) at Hammersmith Imanet Ltd., Hammersmith Hospital, London, United Kingdom; 3GE Healthcare AS, Oslo, Norway; and 4Section of Immunobiology, Faculty of Medicine, Imperial College London, London, United Kingdom Key Words: somatostatin receptor; octreotide; 18F-fluoroethyl- The incidence and prevalence of gastroenteropancreatic triazole-Tyr3-octreotate; positron emission tomography; and neuroendocrine tumors has been increasing over the past 3 neuroendocrine decades. Because of high densities of somatostatin receptors J Nucl Med 2011; 52:1–8 (sstr)—mainly sstr-2—on the cell surface of these tumors, 111In- DOI: 10.2967/jnumed.111.088906 diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. 18F-radio- labeled analogs with suitable pharmacokinetics would permit PET with more rapid clinical protocols. Methods: We compared the affinity in vitro and tissue pharmacokinetics by PET of 5 structurally related 19F/18F-fluoroethyltriazole-Tyr3-octreotate The incidence and prevalence of gastroenteropancreatic (FET-TOCA) analogs: FET-G-polyethylene glycol (PEG)-TOCA, neuroendocrine tumors (GEP-NETs) has increased signifi- FETE-PEG-TOCA, FET-G-TOCA, FETE-TOCA, and FET-bAG- cantly over the past 3 decades (1). The most common site TOCA to the recently described 18F-aluminum fluoride NOTA- of primary GEP-NETs is the gastrointestinal tract (60%). -
Alshaer Danah Mahdi 2020.Pdf (14.70Mb)
Synthesis and physiochemical characterization of new siderophore- inspired peptide-chelators with 1- hydroxypridine-2-one (1,2-HOPO) Thesis Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy by Danah Mahdi AlShaer 2020 Supervisor: Prof. Beatriz Garcia de la Torre Co-supervisor: Prof. Fernando Albericio Synthesis and physiochemical characterization of new siderophore-inspired peptide• chelators with 1-hydrnxypridine-2-one (1,2-JB[OPO) 217078895 Danah Mahdi AllSlh.aer A thesis submitted to the School of Health Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville, for the degree of Doctor of Philosophy by research in Pharmaceutical Chemistry. This is the thesis in which the chapters are written as a set of discrete research publications that have followed each journal's format with an overall introduction and final summary. These chapters have been published in internationally recognized, peer-reviewed journals. This is to certify that the contents of this thesis are the original research work of Mrs Danah Mahdi AllSllnaer, carried out under our supervision at the Peptide Sciences Laboratory, Westville campus, University of KwaZulu-Natal, Durban, South Africa. Supervisor: --"-:I-----::... Date: gth December 2020 Date: 8th December 2020 As the candidate's supervisors we agree to the submission of this thesis Table of Contents Abstract……………..…………………………………………………………………..……1 Declaration 1: Plagiarism.……………………………………………………….…………..2 Declaration 2: Publications ….………………………………………………….…...….…..3 Acknowledgment………………………………………..………………...…………….…..5 Aim and objectives……….….……………………………………………………………...6 Chapter 1: (Introduction) Hydroxamate Siderophores: Natural Occurrence, Chemical Synthesis, Iron Binding Affinity and Use as Trojan Horses Against ………..……….. 7 Reprint………………………………………………………………………………………8 Chapter 2: Solid-phase synthesis of peptides containing 1-Hydroxypyridine-2-one (1,2-HOPO) …………………………………………………….………………………. -
Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future
International Journal of Molecular Sciences Review Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future Anna Kathrin Stueven 1, Antonin Kayser 1, Christoph Wetz 2, Holger Amthauer 2, Alexander Wree 1, Frank Tacke 1, Bertram Wiedenmann 1, Christoph Roderburg 1,* and Henning Jann 1 1 Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] (A.K.S.); [email protected] (A.K.); [email protected] (A.W.); [email protected] (F.T.); [email protected] (B.W.); [email protected] (H.J.) 2 Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] (C.W.); [email protected] (H.A.) * Correspondence: [email protected]; Tel.: +49-30-450-553022 Received: 3 May 2019; Accepted: 19 June 2019; Published: 22 June 2019 Abstract: In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). -
Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 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. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 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. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes. -
Coexpression of Human Somatostatin Receptor-2 (SSTR2) and SSTR3 Modulates Antiproliferative Signaling and Apoptosis Sajad a War and Ujendra Kumar*
War and Kumar Journal of Molecular Signaling 2012, 7:5 http://www.thrombosisjournal.com/7/1/5 RESEARCH ARTICLE Open Access Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis Sajad A War and Ujendra Kumar* Abstract Background: Somatostatin (SST) via five Gi coupled receptors namely SSTR1-5 is known to inhibit cell proliferation by cytostatic and cytotoxic mechanisms. Heterodimerization plays a crucial role in modulating the signal transduction pathways of SSTR subtypes. In the present study, we investigated human SSTR2/SSTR3 heterodimerization, internalization, MAPK signaling, cell proliferation and apoptosis in HEK-293 cells in response to SST and specific agonists for SSTR2 and SSTR3. Results: Although in basal conditions, SSTR2 and SSTR3 colocalize at the plasma membrane and exhibit heterodimerization, the cell surface distribution of both receptors decreased upon agonist activation and was accompanied by a parallel increase in intracellular colocalization. Receptors activation by SST and specific agonists significantly decreased cAMP levels in cotransfected cells in comparison to control. Agonist-mediated modulation of pERK1/2 was time and concentration-dependent, and pronounced in serum-deprived conditions. pERK1/2 was inhibited in response to SST; conversely receptor-specific agonist treatment caused inhibition at lower concentration and activation at higher concentration. Strikingly, ERK1/2 phosphorylation was sustained upon prolonged treatment with SST but not with receptor-specific agonists. On the other hand, SST and receptor-specific agonists modulated p38 phosphorylation time-dependently. The receptor activation in cotransfected cells exhibits Gi-dependent inhibition of cell proliferation attributed to increased PARP-1 expression and TUNEL staining, whereas induction of p21 and p27Kip1 suggests a cytostatic effect. -
Neurotransmission: Receptor Signaling
Neurotransmission - receptor and channel signaling GPCRs TYROSINE KINASES ION CHANNELS Neurotrophins BDNF NGF NT-3 Glutamate GABA ACh GDNF Neurturin Artemin Persepin NT-4/5 Glutamate Anandamide ATP Glycine γ 2 1 4 3 / α α α 2-AG α β / α A GFR GFR GFR GFR NTR mGLuR A/B/C X1, 2, 3 CB1/2 2 EphA/B* Ephrin RET Trk p75 AMPA/KainateNMDAR P GABA GlyR nAChR IP3 Lyn released Ephexin Fyn Rapsin Homer DAG Adenylate PI3K Grb4 Src PSD95 HAP1 Syntrophin i PD Shc Gephyrin Gi/q cyclase Gi K PLC GABARAP NcK 2RGS3 PI3 Shc + 2+ 2+ GRIF1 PI3K PLC γ Na Ca Ca P PI3K Grb2 PLCβ/γ PKC nNOS γ FAK PiP3/4 SOS MEK CaM Cl- Gephyrin Cl- ER NFkB PDEI PKA Rac RhoA RasGAP Src PTEN PKC Ras GTPase ERK CaMK Cl- 2+ PKK2 Calcineurin Ca ROCK ERK FRS2 AKT/PKB released Raf JNK nNOS SynGAP Grb2 actin MEK 1/2 P Ser133 Inhibition Excitation Src SOS Cell survival CREB of signaling of signaling RAS P CREB ERK 1/2 P P MAPK GSK3 ELK RSK NFκB CREB CREB gene Long term Cytoskeleton transcription synaptic dynamics, neurite ASK1 Bad CRE plasticity (LTP) P P extension CREB CREB Short term MKK3/6 Apoptosis plasticity Others Other GPCRs - ARA9 ACh (Muscarinic): M1, M2, M3, M4 CRE p38MAPK c-fos Potassium - ASICβ, ASIC3 Adrenalin: Alpha1b, 1c, 1d - KChIP2 - DDR 1, 2 ATP: P2Y MSK1 c-jun c-fos gene - KCNQ 3, 5 - ENSA Dopamine: D1, D4 transcription - Kv beta 2 - GJB1 GABA: GABAB receptor - Kv 1.2 - SLC31A1 μ δ κ P P Opioid: , , CREB CREB AP1 - Kv 1.3 - TRAR4 Neurotensin: 1, 2 Growth, - Kv 1.4 - TRPM7 Neurokinin: NKA, NKB, NK1, Calcitonin development & Sodium - Kv 2.2 - VR1 * forward/reverse signalling -
ANSI® Programmer’S Reference Manual
® ANSI® Programmer’s Reference Manual ANSI® Printers Programmer’s Reference Manual ® Trademark Acknowledgements Printronix, Inc. Unisys MTX, Inc. Memorex Telex Decision Systems InternationalDecision Data, Inc. makes no representations or warranties of any kind regarding this material, including, but not limited to, implied warranties of merchantability and fitness for a particular purpose. Printronix, Inc. Unisys MTX, Inc. Memorex Telex Decision Systems InternationalDecision Data, Inc. shall not be held responsible for errors contained herein or any omissions from this material or for any damages, whether direct, indirect, incidental or consequential, in connection with the furnishing, distribution, performance or use of this material. The information in this manual is subject to change without notice. This document contains proprietary information protected by copyright. No part of this document may be reproduced, copied, translated or incorporated in any other material in any form or by any means, whether manual, graphic, electronic, mechanical or otherwise, without the prior written consent of Printronix, Inc.Unisys.MTX, Inc. Memorex Telex. Decision Systems International.Decision Data, Inc. Copyright © 1998, 2010 Printronix, Inc. All rights reserved. Trademark Acknowledgements ANSI is a registered trademark of American National Standards Institute, Inc. Centronics is a registered trademark of Genicom Corporation. Dataproducts is a registered trademark of Dataproducts Corporation. Epson is a registered trademark of Seiko Epson Corporation. IBM and Proprinter are registered trademarks and PC-DOS is a trademark of International Business Machines Corporation. MS-DOS is a registered trademark of Microsoft Corporation. Printronix, IGP, PGL, LinePrinter Plus, and PSA are registered trademarks of Printronix, Inc. QMS is a registered trademark and Code V is a trademark of Quality Micro Systems, Inc. -
Inflammatory Modulation of Hematopoietic Stem Cells by Magnetic Resonance Imaging
Electronic Supplementary Material (ESI) for RSC Advances. This journal is © The Royal Society of Chemistry 2014 Inflammatory modulation of hematopoietic stem cells by Magnetic Resonance Imaging (MRI)-detectable nanoparticles Sezin Aday1,2*, Jose Paiva1,2*, Susana Sousa2, Renata S.M. Gomes3, Susana Pedreiro4, Po-Wah So5, Carolyn Ann Carr6, Lowri Cochlin7, Ana Catarina Gomes2, Artur Paiva4, Lino Ferreira1,2 1CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal, 2Biocant, Biotechnology Innovation Center, Cantanhede, Portugal, 3King’s BHF Centre of Excellence, Cardiovascular Proteomics, King’s College London, London, UK, 4Centro de Histocompatibilidade do Centro, Coimbra, Portugal, 5Department of Neuroimaging, Institute of Psychiatry, King's College London, London, UK, 6Cardiac Metabolism Research Group, Department of Physiology, Anatomy & Genetics, University of Oxford, UK, 7PulseTeq Limited, Chobham, Surrey, UK. *These authors contributed equally to this work. #Correspondence to Lino Ferreira ([email protected]). Experimental Section Preparation and characterization of NP210-PFCE. PLGA (Resomers 502 H; 50:50 lactic acid: glycolic acid) (Boehringer Ingelheim) was covalently conjugated to fluoresceinamine (Sigma- Aldrich) according to a protocol reported elsewhere1. NPs were prepared by dissolving PLGA (100 mg) in a solution of propylene carbonate (5 mL, Sigma). PLGA solution was mixed with perfluoro- 15-crown-5-ether (PFCE) (178 mg) (Fluorochem, UK) dissolved in trifluoroethanol (1 mL, Sigma). This solution was then added to a PVA solution (10 mL, 1% w/v in water) dropwise and stirred for 3 h. The NPs were then transferred to a dialysis membrane and dialysed (MWCO of 50 kDa, Spectrum Labs) against distilled water before freeze-drying. Then, NPs were coated with protamine sulfate (PS).