Growth Factor Products (Recombinant Protein)
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Increased Expression of Epidermal Growth Factor Receptor and Betacellulin During the Early Stage of Gastric Ulcer Healing
505-510 11/6/08 12:55 Page 505 MOLECULAR MEDICINE REPORTS 1: 505-510, 2008 505 Increased expression of epidermal growth factor receptor and betacellulin during the early stage of gastric ulcer healing GEUN HAE CHOI, HO SUNG PARK, KYUNG RYOUL KIM, HA NA CHOI, KYU YUN JANG, MYOUNG JA CHUNG, MYOUNG JAE KANG, DONG GEUN LEE and WOO SUNG MOON Department of Pathology, Institute for Medical Sciences, Chonbuk National University Medical School and the Center for Healthcare Technology Development, Jeonju, Korea Received January 2, 2008; Accepted February 22, 2008 Abstract. Epidermal growth factor receptor (EGFR) is from tissue necrosis triggered by mucosal ischemia, free important for the proliferation and differentiation of gastric radical formation and the cessation of nutrient delivery, which mucosal cells. Betacellulin (BTC) is a novel ligand for EGFR are caused by vascular and microvascular injury such as Since their role is unclear in the ulcer healing process, we thrombi, constriction or other occlusions (2). Tissue necrosis investigated their expression. Gastric ulcers in 30 Sprague- and the release of leukotriene B attract leukocytes and Dawley rats were induced by acetic acid. RT-PCR and macrophages, which release pro-inflammatory cytokines Western blotting were performed to detect EGFR and BTC. (e.g. TNFα, IL-1α, and IL-1ß). These in turn activate local Immunohistochemical studies were performed to detect fibroblasts, endothelial and epithelial cells. Histologically, an EGFR, BTC and proliferating cell nuclear antigen (PCNA). ulcer has two characteristic structures: a distinct ulcer margin The expression of EGFR and the BTC gene was significantly formed by the adjacent non-necrotic mucosa, and granulation increased at 12 h, 24 h and 3 days after ulcer induction tissue composed of fibroblasts, macrophages and proliferating (P<0.05). -
Recombinant Human Betacellulin Promotes the Neogenesis of -Cells
Recombinant Human Betacellulin Promotes the Neogenesis of -Cells and Ameliorates Glucose Intolerance in Mice With Diabetes Induced by Selective Alloxan Perfusion Koji Yamamoto, Jun-ichiro Miyagawa, Masako Waguri, Reiko Sasada, Koichi Igarashi, Ming Li, Takao Nammo, Makoto Moriwaki, Akihisa Imagawa, Kazuya Yamagata, Hiromu Nakajima, Mitsuyoshi Namba, Yoshihiro Tochino, Toshiaki Hanafusa, and Yuji Matsuzawa Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic ancreatic -cells are thought to be terminally dif- acinar cell line (AR42J) into insulin-secreting cells, ferentiated cells with little ability to regenerate. suggesting that BTC has a physiologically important However, proliferation of preexisting -cells and role in the endocrine pancreas. In this study, we exam- differentiation of -cells from precursor cells, ined the in vivo effect of recombinant human BTC P (rhBTC) on glucose intolerance and pancreatic mor- mainly residing in the pancreatic duct lining, have been phology using a new mouse model with glucose intoler- demonstrated in some animal models (1–5). Recently, we ance induced by selective alloxan perfusion. RhBTC developed a new mouse model of diabetes induced by selec- (1 µg/g body wt) or saline was injected subcutaneously tive perfusion of alloxan (100 µg/g body wt) during the every day from the day after alloxan treatment. The clamping of the superior mesenteric artery (1). In this model, intraperitoneal glucose tolerance test revealed no dif- glucose intolerance spontaneously resolves after one year ference between rhBTC-treated and rhBTC-untreated because of the proliferation of surviving -cells in the non- glucose-intolerant mice at 2–4 weeks. -
Discovery of Orphan Receptor Tie1 and Angiopoietin Ligands Ang1 and Ang4 As Novel GAG-Binding Partners
78 Chapter 3 Discovery of Orphan Receptor Tie1 and Angiopoietin Ligands Ang1 and Ang4 as Novel GAG-Binding Partners 79 3.1 Abstract The Tie/Ang signaling axis is necessary for proper vascular development and remodeling. However, the mechanisms that modulate signaling through this receptor tyrosine kinase pathway are relatively unclear. In particular, the role of the orphan receptor Tie1 is highly disputed. Although this protein is required for survival, Tie1 has been found both to inhibit and yet be necessary for Tie2 signaling. While differing expression levels have been put forth as an explanation for its context-specific activity, the lack of known endogenous ligands for Tie1 has severely hampered understanding its molecular mode of action. Here we describe the discovery of orphan receptor Tie1 and angiopoietin ligands Ang1 and Ang4 as novel GAG binding partners. We localize the binding site of GAGs to the N- terminal region of Tie1, which may provide structural insights into the importance of this interaction regarding the formation of Tie1-Tie2 heterodimerization. Furthermore, we use our mutagenesis studies to guide the generation of a mouse model that specifically ablates GAG-Tie1 binding in vivo for further characterization of the functional outcomes of GAG-Tie1 binding. We also show that GAGs can form a trimeric complex with Ang1/4 and Tie2 using our microarray technology. Finally, we use our HaloTag glycan engineering platform to modify the cell surface of endothelial cells and demonstrate that HS GAGs can potentiate Tie2 signaling in a sulfation-specific manner, providing the first evidence of the involvement of HS GAGs in Tie/Ang signaling and delineating further the integral role of HS GAGs in angiogenesis. -
Serum Protein Fingerprinting by PEA Immunoassay Coupled with a Pattern-Recognition Algorithms Distinguishes MGUS and Multiple Myeloma
www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 41), pp: 69408-69421 Research Paper Serum protein fingerprinting by PEA immunoassay coupled with a pattern-recognition algorithms distinguishes MGUS and multiple myeloma Petra Schneiderova1,*, Tomas Pika2,*, Petr Gajdos3, Regina Fillerova1, Pavel Kromer3, Milos Kudelka3, Jiri Minarik2, Tomas Papajik2, Vlastimil Scudla2 and Eva Kriegova1 1Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic 2Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic 3Department of Computer Science, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, Ostrava, Czech Republic *These authors have contributed equally to this work Correspondence to: Eva Kriegova, email: [email protected] Keywords: serum pattern, cytokines, growth factors, proximity extension immunoassay, post-transplant serum pattern Received: May 04, 2016 Accepted: July 28, 2016 Published: August 12, 2016 Copyright: Schneiderova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Serum protein fingerprints associated with MGUS and MM and their changes in MM after autologous stem cell transplantation (MM-ASCT, day 100) remain unexplored. Using highly-sensitive Proximity Extension ImmunoAssay on 92 cancer biomarkers (Proseek Multiplex, Olink), enhanced serum levels of Adrenomedullin (ADM, Pcorr= .0004), Growth differentiation factor 15 (GDF15, Pcorr= .003), and soluble Major histocompatibility complex class I-related chain A (sMICA, Pcorr= .023), all prosurvival and chemoprotective factors for myeloma cells, were detected in MM comparing to MGUS. -
Pdgfrβ Regulates Adipose Tissue Expansion and Glucose
1008 Diabetes Volume 66, April 2017 Yasuhiro Onogi,1 Tsutomu Wada,1 Chie Kamiya,1 Kento Inata,1 Takatoshi Matsuzawa,1 Yuka Inaba,2,3 Kumi Kimura,2 Hiroshi Inoue,2,3 Seiji Yamamoto,4 Yoko Ishii,4 Daisuke Koya,5 Hiroshi Tsuneki,1 Masakiyo Sasahara,4 and Toshiyasu Sasaoka1 PDGFRb Regulates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity Diabetes 2017;66:1008–1021 | DOI: 10.2337/db16-0881 Platelet-derived growth factor (PDGF) is a key factor in The physiological roles of the vasculature in adipose tissue angiogenesis; however, its role in adult obesity remains have been attracting interest from the viewpoint of adipose unclear. In order to clarify its pathophysiological role, tissue expansion and chronic inflammation (1,2). White we investigated the significance of PDGF receptor b adipose tissue (WAT) such as visceral fat possesses the (PDGFRb) in adipose tissue expansion and glucose unique characteristic of plasticity; its volume may change metabolism. Mature vessels in the epididymal white several fold even after growth depending on nutritional adipose tissue (eWAT) were tightly wrapped with peri- conditions. Enlarged adipose tissue is chronically exposed cytes in normal mice. Pericyte desorption from vessels to hypoxia (3,4), which stimulates the production of angio- and the subsequent proliferation of endothelial cells genic factors for the supplementation of nutrients and were markedly increased in the eWAT of diet-induced oxygen to the newly enlarged tissue area (5). Selective ab- obese mice. Analyses with flow cytometry and adipose lation of the vasculature in WAT by apoptosis-inducible tissue cultures indicated that PDGF-B caused the de- peptides or the systemic administration of angiogenic in- PATHOPHYSIOLOGY tachment of pericytes from vessels in a concentration- hibitors has been shown to reduce WAT volumes and result dependent manner. -
Human B-Cell Proliferation and Intracellular Signaling: Part 3
1872 Diabetes Volume 64, June 2015 Andrew F. Stewart,1 Mehboob A. Hussain,2 Adolfo García-Ocaña,1 Rupangi C. Vasavada,1 Anil Bhushan,3 Ernesto Bernal-Mizrachi,4 and Rohit N. Kulkarni5 Human b-Cell Proliferation and Intracellular Signaling: Part 3 Diabetes 2015;64:1872–1885 | DOI: 10.2337/db14-1843 This is the third in a series of Perspectives on intracel- signaling pathways in rodent and human b-cells, with lular signaling pathways coupled to proliferation in pan- a specific focus on the links between b-cell proliferation creatic b-cells. We contrast the large knowledge base in and intracellular signaling pathways (1,2). We highlight rodent b-cells with the more limited human database. what is known in rodent b-cells and compare and contrast With the increasing incidence of type 1 diabetes and that to the current knowledge base in human b-cells. In- the recognition that type 2 diabetes is also due in part variably, the human b-cell section is very brief compared fi b to a de ciency of functioning -cells, there is great ur- with the rodent counterpart, reflecting the still primitive gency to identify therapeutic approaches to expand hu- state of our understanding of mitogenic signaling in hu- b man -cell numbers. Therapeutic approaches might man b-cells. To emphasize this difference, each figure is include stem cell differentiation, transdifferentiation, or divided into two panels, one summarizing rodent b-cell expansion of cadaver islets or residual endogenous signaling and one for human b-cells. Our intended audi- b-cells. In these Perspectives, we focus on b-cell ence includes trainees in b-cell regeneration as well as proliferation. -
As a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial
cells Review Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine Asterios S. Tsiftsoglou Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [email protected] Abstract: Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is pro- duced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid mat- uration of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis Citation: Tsiftsoglou, A.S. and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consist- Erythropoietin (EPO) as a Key ing of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal Regulator of Erythropoiesis, Bone muscle) explains the EPO pleotropic action as a protection factor for several cells, including the Remodeling and Endothelial multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces Transdifferentiation of Multipotent the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of Mesenchymal Stem Cells (MSCs): EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion Implications in Regenerative of a large number of trophic factors (secretome). -
Erythropoietin and Its Angiogenic Activity
International Journal of Molecular Sciences Review Erythropoietin and Its Angiogenic Activity Patrícia Kimáková 1,†, Peter Solár 1,*,† ID , Zuzana Solárová 2, Radovan Komel 3 and Nataša Debeljak 3 ID 1 Laboratory of Cell Biology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Košice 04001, Slovak; [email protected] 2 Institute of Pharmacology, Faculty of Medicine, P.J. Šafárik University in Košice, Košice 04001, Slovak; [email protected] 3 Medical Centre for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia; [email protected] (R.K.); [email protected] (N.D.) * Correspondence: [email protected]; Tel.: +421-55-234-1199, Fax: +421-55-622-2124 † These authors contributed equally to this work. Received: 26 May 2017; Accepted: 11 July 2017; Published: 13 July 2017 Abstract: Erythropoietin (EPO) is the main hematopoietic hormone acting on progenitor red blood cells via stimulation of cell growth, differentiation, and anti-apoptosis. However, its receptor (EPOR) is also expressed in various non-hematopoietic tissues, including endothelium. EPO is a pleiotropic growth factor that exhibits growth stimulation and cell/tissue protection on numerous cells and tissues. In this article we review the angiogenesis potential of EPO on endothelial cells in heart, brain, and leg ischemia, as well as its role in retinopathy protection and tumor promotion. Furthermore, the effect of EPO on bone marrow and adipose tissue is also discussed. Keywords: erythropoietin; erythropoietin receptor; endothelial; angiogenesis; cancer 1. Introduction Erythropoietin (EPO) is the main hematopoietic cytokine that regulates the formation of red blood cells in the process of hematopoiesis [1]. -
Growth Factors Acting Via Endothelial Cell-Specific Receptor Tyrosine Kinases: Vegfs, Angiopoietins, and Ephrins in Vascular Development
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, Angiopoietins, and ephrins in vascular development Nicholas W. Gale1 and George D. Yancopoulos Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591-6707 USA The term ‘vasculogenesis’ refers to the earliest stages of since been shown to be a critical regulator of endothelial vascular development, during which vascular endotheli- cell development. Not surprisingly, the specificity of al cell precursors undergo differentiation, expansion, and VEGF-A for the vascular endothelium results from the coalescence to form a network of primitive tubules restricted distribution of VEGF-A receptors to these (Risau 1997). This initial lattice, consisting purely of en- cells. The need to regulate the multitude of cellular in- dothelial cells that have formed rather homogenously teractions involved during vascular development sug- sized interconnected vessels, has been referred to as the gested that VEGF-A might not be alone as an endothelial primary capillary plexus. The primary plexus is then re- cell-specific growth factor. Indeed, there has been a re- modeled by a process referred to as angiogenesis (Risau cent explosion in the number of growth factors that spe- 1997), which involves the sprouting, branching, and dif- cifically act on the vascular endothelium. This explosion ferential growth of blood vessels to form the more ma- involves the VEGF family, which now totals at least five ture appearing vascular patterns seen in the adult organ- members. In addition, an entirely unrelated family of ism. This latter phase of vascular development also in- growth factors, known as the Angiopoietins, recently has volves the sprouting and penetration of vessels into been identified as acting via endothelial cell-specific re- previously avascular regions of the embryo, and also the ceptors known as the Ties. -
Review Diverse Roles of Eph Receptors and Ephrins in The
Developmental Cell, Vol. 7, 465–480, October, 2004, Copyright 2004 by Cell Press Diverse Roles of Eph Receptors Review and Ephrins in the Regulation of Cell Migration and Tissue Assembly Alexei Poliakov, Marisa Cotrina, repulsion of cells, in others they promote adhesion and and David G. Wilkinson* attraction. Recent work has shown that some cells Division of Developmental Neurobiology switch between these distinct responses. This review National Institute for Medical Research will focus on developmental roles of repulsion and at- The Ridgeway, Mill Hill traction responses to Eph/ephrin activation and then London NW7 1AA discuss biochemical mechanisms that may regulate United Kingdom these diverse responses. Structure, Clustering, and Signal Transduction Eph receptor tyrosine kinases and ephrins have key Structure and Binding Specificities of Eph roles in regulation of the migration and adhesion of Receptors and Ephrins cells required to form and stabilize patterns of cell Eph receptors are transmembrane receptor tyrosine ki- organization during development. Activation of Eph nases (RTKs) with a number of distinctive features com- receptors or ephrins can lead either to cell repulsion pared with other RTKs, including the extracellular region or to cell adhesion and invasion, and recent work has comprised of an N-terminal ephrin binding domain, a found that cells can switch between these distinct re- cysteine-rich EGF-like domain, and two fibronectin type sponses. This review will discuss biochemical mecha- III motifs (Figure 1). In addition to a tyrosine kinase do- nisms and developmental roles of the diverse cell re- main, the intracellular region includes a number of con- sponses controlled by Eph receptors and ephrins. -
Biomarkers in Community-Acquired Pneumonia: Still Searching for the One
EDITORIAL | RESPIRATORY INFECTION Biomarkers in community-acquired pneumonia: still searching for the one Oriol Sibila 1,2 and Marcos I. Restrepo3 Affiliations: 1Servei de Pneumologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 2Institut d´Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain. 3Division of Pulmonary Diseases and Critical Care Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Correspondence: Oriol Sibila, Servei de Pneumologia, Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni M. Claret 167, 08025 Barcelona, Spain. E-mail: [email protected] @ERSpublications Fibroblast growth factor 21 (FGF21) predicts severity of illness, clinical stability and mortality in community-acquired pneumonia. Validation is needed to confirm the application of FGF21 in clinical practice. http://ow.ly/SYI730nuRc1 Cite this article as: Sibila O, Restrepo MI. Biomarkers in community-acquired pneumonia: still searching for the one. Eur Respir J 2019; 53: 1802469 [https://doi.org/10.1183/13993003.02469-2018]. Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality worldwide [1]. Despite advances in antibiotic treatment and medical care, the mortality of CAP is still high in hospitalised patients, especially in those with severe illness [2]. Appropriate initial severity assessment is a crucial step in pneumonia management, since it has been demonstrated that an early recognition of severe CAP patients improves their clinical outcomes [3]. Several tools have been developed to evaluate disease severity, in particular focusing on predicting hospital admission and mortality [4]. However, recent studies have showed that most of these scores are not used routinely in clinical practice and may be inadequate tools to guide appropriate antibiotic treatment [5, 6]. -
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HHS Public Access Author manuscript Author Manuscript Author ManuscriptAm J Med Author Manuscript Genet B Neuropsychiatr Author Manuscript Genet. Author manuscript; available in PMC 2017 January 01. Published in final edited form as: Am J Med Genet B Neuropsychiatr Genet. 2016 January ; 171(1): 44–64. doi:10.1002/ajmg.b.32384. Genetic Influences on the Neural and Physiological Bases of Acute Threat: A Research Domain Criteria (RDoC) Perspective Jennifer A. Sumner1,2, Abigail Powers3, Tanja Jovanovic3, and Karestan C. Koenen2,4,5 1Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, NY 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 3Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 4Psychiatric and Neurodevelopmental Genetics Unit and Department of Psychiatry, Massachusetts General Hospital, Boston, MA 5The Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Cambridge, MA Abstract The NIMH Research Domain Criteria (RDoC) initiative aims to describe key dimensional constructs underlying mental function across multiple units of analysis—from genes to observable behaviors—in order to better understand psychopathology. The acute threat (“fear”) construct of the RDoC Negative Valence System has been studied extensively from a translational perspective, and is highly pertinent to numerous psychiatric conditions, including anxiety and trauma-related disorders. We examined genetic contributions to the construct of acute threat at two units of analysis within the RDoC framework: 1) neural circuits and 2) physiology. Specifically, we focused on genetic influences on activation patterns of frontolimbic neural circuitry and on startle, skin conductance, and heart rate responses.