Hepatitis C Virus Utilizes VLDLR As a Novel Entry Pathway
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Binding and Uptake of H-Ferritin Are Mediated by Human Transferrin Receptor-1
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Caltech Authors Binding and uptake of H-ferritin are mediated by human transferrin receptor-1 Li Lia, Celia J. Fanga,b, James C. Ryana,b, Eréne C. Niemib, José A. Lebrónc,1, Pamela J. Björkmanc,d,2, Hisashi Arasee, Frank M. Tortif, Suzy V. Tortig, Mary C. Nakamuraa,b, and William E. Seamana,b,h,2 aDepartment of Medicine, Veterans Administration Medical Center, San Francisco, CA 94121; bDepartment of Medicine, University of California, San Francisco, CA 94143; cDivision of Biology, California Institute of Technology, Pasadena, CA 91125; dHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; eDepartment of Immunochemistry, World Premier International Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; fDepartment of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157; gDepartment of Biochemistry, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and hDepartment of Microbiology and Immunology, University of California, San Francisco, CA 94143 Contributed by Pamela J. Björkman, November 18, 2009 (sent for review October 5, 2009) − Ferritin is a spherical molecule composed of 24 subunits of two constant of ∼6.5 × 10 7 L/mol and ∼10,000 receptors sites per cell; types, ferritin H chain (FHC) and ferritin L chain (FLC). Ferritin stores subsequently, they endocytose HFt (13). Activated fresh lympho- iron within cells, but it also circulates and binds specifically and cytes also bind HFt (16), as do erythroid precursors, in which the saturably to a variety of cell types. -
High Efficiency Blood-Brain Barrier Transport Using a VNAR Targeting the Transferrin Receptor 1 (Tfr1)
bioRxiv preprint doi: https://doi.org/10.1101/816900; this version posted October 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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. Title: High efficiency blood-brain barrier transport using a VNAR targeting the Transferrin Receptor 1 (TfR1) Authors: Pawel Stocki§, Jaroslaw M Szary§, Charlotte LM Jacobsen¶, Mykhaylo Demydchuk§, Leandra Northall§, Torben Moos¶, Frank S Walsh§ and J Lynn Rutkowski§* §Ossianix, Inc, Stevenage Bioscience Catalyst, Gunnels Wood Rd, Stevenage, Herts, SG1 2FX, UK and 3675 Market St, Philadelphia, PA 19104, USA ¶Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3, 9220 Aalborg, Denmark Address correspondence to: *J. Lynn Rutkowski, PhD Ossianix, Inc, 3675 Market St., Philadelphia, PA 19104, USA Email: [email protected] Tel: +1(610)291-1724 A one-sentence summary: Development of highly efficient, TfR1 specific, cross-species reactive blood-brain barrier (BBB) shuttle based on shark single domain VNAR antibody. Definitions of all symbols, abbreviations, and acronyms: Transferrin Receptor 1 (TfR1), blood-brain barrier (BBB), Transferrin (Tf), central nervous system (CNS), Variable domain of New Antigen Receptors (VNAR), complementarity-determining region 3 (CDR3), room temperature (RT), size exclusion chromatography (SEC), human serum albumin (HSA), Neurotensin (NT), Immunohistochemistry (IHC), next generation sequencing (NGS), Pharmacokinetic (PK), blood-CSF barrier (BCSFB), Percentage injected dose (%ID), Area under the curve (AUC), attenuated effector function (AEF), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS- PAGE), Western blot (WB), intravenous (IV) 1 bioRxiv preprint doi: https://doi.org/10.1101/816900; this version posted October 30, 2019. -
Mitochondrial Iron Metabolism and Its Role in Neurodegeneration
Journal of Alzheimer’s Disease 20 (2010) S551–S568 S551 DOI 10.3233/JAD-2010-100354 IOS Press Review Mitochondrial Iron Metabolism and Its Role in Neurodegeneration Maxx P. Horowitza,b,c and J. Timothy Greenamyreb,c,d,∗ aMedical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA bCenter for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA cDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, USA dPittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA Accepted 16 April 2010 Abstract. In addition to their well-established role in providing the cell with ATP, mitochondria are the source of iron-sulfur clusters (ISCs) and heme – prosthetic groups that are utilized by proteins throughout the cell in various critical processes. The post-transcriptional system that mammalian cells use to regulate intracellular iron homeostasis depends, in part, upon the synthesis of ISCs in mitochondria. Thus, proper mitochondrial function is crucial to cellular iron homeostasis. Many neurodegenerative diseases are marked by mitochondrial impairment, brain iron accumulation, and oxidative stress – pathologies that are inter- related. This review discusses the physiological role that mitochondria play in cellular iron homeostasis and, in so doing, attempts to clarify how mitochondrial dysfunction may initiate and/or contribute to iron dysregulation in the context of neurodegenerative disease. We review what is currently known about the entry of iron into mitochondria, the ways in which iron is utilized therein, and how mitochondria are integrated into the system of iron homeostasis in mammalian cells. Lastly, we turn to recent advances in our understanding of iron dysregulation in two neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease), and discuss the use of iron chelation as a potential therapeutic approach to neurodegenerative disease. -
CVM-Enews 2017 Mar.Pdf (970.1Kb)
CVM eNews - March 2017 http://campaign.r20.constantcontact.com/render?m=1106633030128&c... March 2017 eNews March 2017 Consultant Launches an App Cornell Consultant, the diagnostic support search engine, and arguably the primary trusted knowledge-base for veterinarians around the world is now available as an app. READ MORE Diversity Town Hall Nearly 100 members of the CVM community attended a Diversity Town Hall in February. The event was hosted by VOICE and led by Lisa Greenhill, who oversees the DiVersity Matters initiative for the AAVMC READ MORE Don Smith Memorial Service Please join us for a memorial service for Professor and Dean Emeritus Donald F. Smith on Monday, March 27th at the Moakley House. READ MORE International Programs CVM welcomed international colleagues to give seminars in February, including faculty from City University at Hong Kong and Obihiro University of Agriculture and Veterinary Medicine. READ MORE 1 of 3 3/8/2017 4:53 PM CVM eNews - March 2017 http://campaign.r20.constantcontact.com/render?m=1106633030128&c... Baker Pet Talks - Tips from Cornell Experts Dr. Dan Fletcher will lecture on the basics of Pet CPR. READ MORE Class Expansion Construction Update Construction of the new cafeteria continues and the new curtain wall is being installed on the new Library wing and courtyard side of the new Atrium. Learn about the progress. READ MORE Hellos and Goodbyes Meet the new employees who joined us in February. READ MORE Upcoming Events Date Event 3/9 Thu Trans 101: Gender Identity Concepts and Terminology, Caitlin Hepps Keeney, DVM'18 (11:30-12:30 pm, LH3) 3/9 Thu Van Gogh Vets (8:00 am - 7:00 pm, The Old Breezeway) 3/9 Thu Students vs. -
JOURNAL of VIROLOGY VOLUME 62 * SEPTEMBER 1988 * NUMBER 9 Arnold J
JOURNAL OF VIROLOGY VOLUME 62 * SEPTEMBER 1988 * NUMBER 9 Arnold J. Levine, Editor in Chief Thomas E. Shenk, Editor (1989) (1989) Princeton University Princeton University Princeton, N.J. Princeton, N.J. Michael B. A. Oldstone, Editor (1993) Anna Marie Skalka, Editor (1989) Bernard N. Fields, Editor (1993) Scripps Clinic & Research Fox Chase Cancer Center Harvard Medical School Foundation Philadelphia, Pa. Boston, Mass. La Jolla, Calif. George F. Vande Woude, Editor (1992) Robert A. Lamb Editor (1992) NCI-Frederick Cancer Research Facility Northwestern University Frederick Md. Evanston, Ill. EDITORIAL BOARD James Alwine (1988) Mary-Jane Gething (1990) Malcolm Martin (1989) Norman P. Salzman (1990) David Baltimore (1990) Joseph C. Glorioso (1989) Robert Martin (1990) Joseph Sambrook (1988) Amiya K. Banerjee (1990) Stephen P. Goff (1988) Warren Masker (1990) Charles E. Samuel (1989) Tamar Ben-Porat (1990) Larry M. Gold (1988) James McDougall (1990) Priscilla A. Schaffer (1990) Kenneth I. Berns (1988) Hidesaburo Hanafusa (1989) Thomas Merigan (1989) Sondra Schlesinger (1989) Michael Botchan (1989) John Hassell (1989) Lois K. Miller (1988) Manfred Schubert (1988) Thomas J. Braciale (1988) William S. Hayward (1990) Peter Model (1989) Bart Sefton (1988) Joan Brugge (1988) Ari H. Helenius (1990) Bernard Moss (1989) Bert L. Semler (1989) Michael J. Buchmeier (1989) Roger Hendrix (1990) Opendra Narayan (1988) Charles J. Sherr (1990) Barrie J. Carter (1990) John J. Holland (1990) Joseph R. Nevins (1988) Saul J. Silverstein (1988) Sherwood Casjens (1990) Nancy Hopkins (1989) Erling Norrby (1989) Patricia G. Spear (1990) John M. Coffin (1989) Alice S. Huang (1990) Nancy G. Nossal (1990) Bruce Stillman (1988) Charles N. -
A Novel Therapeutic Target in Ovarian Cancer Debargha Basuli University of Connecticut - Storrs, [email protected]
University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 6-8-2016 Iron Addiction In Tumor Initiating Cells: A Novel Therapeutic Target In Ovarian Cancer Debargha Basuli University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Basuli, Debargha, "Iron Addiction In Tumor Initiating Cells: A Novel Therapeutic Target In Ovarian Cancer" (2016). Doctoral Dissertations. 1248. https://opencommons.uconn.edu/dissertations/1248 Iron Addiction In Tumor Initiating Cells: A Novel Therapeutic` Target In Ovarian Cancer Debargha Basuli, M.D., PhD University of Connecticut, 2016 Ovarian cancer is a highly lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), an iron efflux pump, is decreased and transferrin receptor (TFRC), an iron importer, is increased in ovarian cancer tissue. Expression of FPN and TFRC are strongly associated with patient survival. Ovarian cancer tumor-initiating cells demonstrate a similar profile of iron excess. Iron deprivation induced by desferroxamine, knockout of IRP2, or overexpression of FPN preferentially blocks growth of tumor initiating cells. Iron restriction inhibits invasion, synthesis of MMPs and IL6, and reduces intraperitoneal spread of tumor cells in vivo. Growth of ovarian tumors is inhibited by induction of ferroptosis, an iron-dependent form of cell death. Thus, enhanced levels of iron create a metabolic vulnerability that can be exploited therapeutically. We show that this dependence is already evident in the tumor initiating cell and creates a new therapeutic opportunity. Thus, alterations in iron import and export in ovarian cancer result in an iron acquisitive phenotype and an increase in metabolically available iron. -
MONOCLONAL ANTIBODY to MOUSE CD71, TRANSFERRIN RECEPTOR 1 (TFRC) Clone ER-MP21
MONOCLONAL ANTIBODY TO MOUSE CD71, TRANSFERRIN RECEPTOR 1 (TFRC) clone ER-MP21 Catalog no HM1085 (lot number and expiry date are indicated on the label) Description The monoclonal antibody ER-MP21 recognizes CD71, the transferrin receptor 1. CD71 is a 200 kDa glycoprotein composed of two identical, disulfide-linked chains. Each chain is capable of binding transferrin, an iron-transport molecule. Binding of transferrin to its receptor followed by endocytosis of the receptor-ligand complex is a major cellular iron-uptake mechanism. Iron uptake by the proliferating cell is essential for the iron-containing enzyme ribonucleotide reductase involved with DNA synthesis. CD71 is not only expressed by cycling cells, but also by cells that require iron for other iron-dependent proteins, such as the enzyme peroxidase in monocytes. Rapidly proliferating cells, as in malignancy, generally express CD71 abundantly. Furthermore, CD71 has been described as a marker of immature, proliferating T cells. The monoclonal antibody ER-MP21 inhibits proliferation and differentiation during early T cell development. ER-MP21 recognizes murine CD71, but does not compete with transferrin binding. Aliases TFRC, TFR1, T9, p90 Species Rat IgG2a Formulation 1 ml (100 µg/ml) 0.2 µm filtered antibody solution in PBS, containing 0.1% bovine serum Application F FC FS IA IF IP P W Yes ● ● ●a No ● N.D. ● ● ● ● a = Inhibition of biological activity N.D.= Not Determined; F = Frozen sections; FC = Flow Cytometry; FS = Functional Studies; IA = Immuno Assays; IF = Immuno Fluorescence; IP = Immuno Precipitation; P = Paraffin sections; W = Western blot Use For immunohistology, and flow cytometry, dilutions to be used depend on detection system applied. -
5 Michael Schreiber Dissertation V3-NLM Formatted Illustrated
Determinants of Human Rhinovirus Cellular Tropism in Monocyte-Lineage Cells Michael Schreiber Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 © 2016 Michael Schreiber All rights reserved ABSTRACT Determinants of Human Rhinovirus Cellular Tropism in Monocyte-Lineage Cells Michael Schreiber Human rhinovirus (HRV) is responsible for the majority of common cold infections and asthma exacerbations. HRV predominantly replicates in the epithelial cells of the upper airway, where common cold symptoms are produced. However, HRV also enters the lower airway, encountering the epithelial cells and alveolar macrophages thought to produce inflammatory responses during HRV-induced asthma exacerbations. Notably, alveolar macrophages release inflammatory mediators such as MCP1/CCL2 and RANTES/CCL5 in response to HRV despite the fact that limited if any HRV replication occurs in these cells. The present study seeks to address the mechanism by which alveolar macrophages are susceptible but not permissive to HRV replication and to identify the step in the HRV replication cycle that restricts HRV to abortive replication in macrophages. Evidence presented herein demonstrates that major-group (ICAM-1 tropic) HRV replicate with limited success in cell line-derived macrophages, whereas minor-group (LDLR tropic) HRV do not replicate in these monocyte-lineage cells. In contrast, neither major- nor minor-group HRV replicate in primary human PBMC-derived macrophages. Capsid swap experiments demonstrated that difference in replicative capacity between major- and minor-group HRV is mediated at the level of permissiveness rather than susceptibility. RNA- Seq gene expression studies identified candidate host genes that may act to regulate HRV replication. -
The Role of Macrophages in Erythropoiesis and Erythrophagocytosis
CORE Metadata, citation and similar papers at core.ac.uk Provided by Frontiers - Publisher Connector REVIEW published: 02 February 2017 doi: 10.3389/fimmu.2017.00073 From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis Thomas R. L. Klei†, Sanne M. Meinderts†, Timo K. van den Berg and Robin van Bruggen* Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands Erythropoiesis is a highly regulated process where sequential events ensure the proper differentiation of hematopoietic stem cells into, ultimately, red blood cells (RBCs). Macrophages in the bone marrow play an important role in hematopoiesis by providing signals that induce differentiation and proliferation of the earliest committed erythroid progenitors. Subsequent differentiation toward the erythroblast stage is accompanied by the formation of so-called erythroblastic islands where a central macrophage provides further cues to induce erythroblast differentiation, expansion, and hemoglobinization. Edited by: Robert F. Paulson, Finally, erythroblasts extrude their nuclei that are phagocytosed by macrophages Pennsylvania State University, USA whereas the reticulocytes are released into the circulation. While in circulation, RBCs Reviewed by: slowly accumulate damage that is repaired by macrophages of the spleen. Finally, after Xinjian Chen, 120 days of circulation, senescent RBCs are removed from the circulation by splenic and University of Utah, USA Reinhard Obst, liver macrophages. Macrophages are thus important for RBCs throughout their lifespan. Ludwig Maximilian University of Finally, in a range of diseases, the delicate interplay between macrophages and both Munich, Germany developing and mature RBCs is disturbed. Here, we review the current knowledge on *Correspondence: Robin van Bruggen the contribution of macrophages to erythropoiesis and erythrophagocytosis in health [email protected] and disease. -
Noncanonical Role of Transferrin Receptor 1 Is Essential for Intestinal Homeostasis
Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis Alan C. Chena, Adriana Donovanb, Renee Ned-Sykesc, and Nancy C. Andrewsa,d,1 aDepartment of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27705; bDivision of Pharmacology and Preclinical Biology, Scholar Rock, Cambridge, MA 02142; cDivision of Laboratory Systems, Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, GA 30333; and dDepartment of Pediatrics, Duke University School of Medicine, Durham, NC 27705 Contributed by Nancy C. Andrews, August 4, 2015 (sent for review June 16, 2015; reviewed by Jerry Kaplan and Ramesh A. Shivdasani) Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through Surprisingly, the mice showed marked induction of genes asso- receptor-mediated endocytosis of iron-loaded transferrin. It is ex- ciated with epithelial–mesenchymal transition in IECs, suggest- pressed in the intestinal epithelium but not involved in dietary iron ing that Tfr1 normally acts to suppress this cell fate change. absorption. To investigate its role, we inactivated the Tfr1 gene There was also abnormal accumulation of lipids, similar to mice selectively in murine intestinal epithelial cells. The mutant mice had lacking transcription factor Plagl2, and increased expression of severe disruption of the epithelial barrier and early death. There stem cell markers. was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell Results markers, and striking induction of many genes associated with Conditional Deletion of Tfr1 in IECs. We developed Tfr1fl/fl mice epithelial-to-mesenchymal transition. Administration of parenteral carrying loxP sites flanking Tfr1 exons 3–6(Fig. -
Integrin Α2β1-Targeting Ferritin Nanocarrier Traverses the Blood
Huang et al. J Nanobiotechnol (2021) 19:180 https://doi.org/10.1186/s12951-021-00925-1 Journal of Nanobiotechnology RESEARCH Open Access Integrin α2β1-targeting ferritin nanocarrier traverses the blood–brain barrier for efective glioma chemotherapy Chiun‑Wei Huang1, Chia‑Pao Chuang2†, Yan‑Jun Chen2†, Hsu‑Yuan Wang2†, Jia‑Jia Lin1, Chiung‑Yin Huang3, Kuo‑Chen Wei3,4,5 and Feng‑Ting Huang2* Abstract Background: Ferritin, the natural iron storage protein complex, self‑assembles into a uniform cage‑like structure. Human H‑ferritin (HFn) has been shown to transverse the blood–brain barrier (BBB) by binding to transferrin receptor 1 (TfR1), which is abundant in endothelial cells and overexpressed in tumors, and enters cells via endocytosis. Ferritin is easily genetically modifed with various functional molecules, justifying that it possesses great potential for develop‑ ment into a nanocarrier drug delivery system. Results: In this study, a unique integrin α2β1‑targeting H‑ferritin (2D‑HFn)‑based drug delivery system was devel‑ oped that highlights the feasibility of receptor‑mediated transcytosis (RMT) for glioma tumor treatment. The integrin targeting α2β1 specifcity was validated by biolayer interferometry in real time monitoring and followed by cell bind‑ ing, chemo‑drug encapsulation stability studies. Compared with naïve HFn, 2D‑HFn dramatically elevated not only doxorubicin (DOX) drug loading capacity (up to 458 drug molecules/protein cage) but also tumor targeting capability after crossing BBB in an in vitro transcytosis assay (twofold) and an in vivo orthotopic glioma model. Most importantly, DOX‑loaded 2D‑HFn signifcantly suppressed subcutaneous and orthotopic U‑87MG tumor progression; in particular, orthotopic glioma mice survived for more than 80 days. -
Engineered in Vitro Disease Models Kambez H
PM10CH08-Ingber ARI 2 December 2014 10:14 Engineered In Vitro Disease Models Kambez H. Benam,1 Stephanie Dauth,1,2 Bryan Hassell,1,2 Anna Herland,1 Abhishek Jain,1 Kyung-Jin Jang,1 Katia Karalis,1,3,4 Hyun Jung Kim,1 Luke MacQueen,1,2 Roza Mahmoodian,1,2 Samira Musah,1 Yu-suke Torisawa,1 Andries D. van der Meer,1 Remi Villenave,1 Moran Yadid,1,2 Kevin K. Parker,1,2 and Donald E. Ingber1,2,5 1Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts 02115; email: [email protected] 2Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts 02139 3Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts 02115 4Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), 11527 Athens, Greece 5Vascular Biology Program and Departments of Pathology and Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 Annu. Rev. Pathol. Mech. Dis. 2015. 10:195–262 Keywords The Annual Review of Pathology: Mechanisms of disease model, tissue engineering, 3D culture, organ-on-a-chip, Disease is online at pathol.annualreviews.org microfluidic, in vitro tool This article’s doi: 10.1146/annurev-pathol-012414-040418 Abstract Copyright c 2015 by Annual Reviews. The ultimate goal of most biomedical research is to gain greater insight into All rights reserved mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition.