DOCSLIB.ORG

Engineering 3D Systems with Tunable Mechanical Properties to Mimic the Tumor Microenvironment Shalini Raj Unnikandam Veettil Iowa State University

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2018 Engineering 3D systems with tunable mechanical properties to mimic the tumor microenvironment Shalini Raj Unnikandam Veettil Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Chemical Engineering Commons Recommended Citation Unnikandam Veettil, Shalini Raj, "Engineering 3D systems with tunable mechanical properties to mimic the tumor microenvironment" (2018). Graduate Theses and Dissertations. 17339. https://lib.dr.iastate.edu/etd/17339 This Thesis is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Engineering 3D systems with tunable mechanical properties to mimic the tumor microenvironment by Shalini Raj Unnikandam Veettil A thesis submitted to the graduate faculty in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Major: Chemical Engineering Program of Study Committee: Ian C Schneider, Major Professor Kaitlin Bratlie Michael Bartlett The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this thesis. The Graduate College will ensure this thesis is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2018 Copyright © Shalini Raj Unnikandam Veettil, 2018. All rights reserved. ii DEDICATION This thesis is dedicated to my family and friends who have been a great source of support. iii TABLE OF CONTENTS Page ABBREVIATIONS ............................................................................................................. vi ACKNOWLEDGMENTS ................................................................................................. vii ABSTRACT ....................................................................................................................... viii CHAPTER 1. INTRODUCTION ........................................................................................1 1.1Motivation ....................................................................................................................1 1.2 Background and Introduction ......................................................................................2 1.2.1 Metastasis requires directed migration ................................................................2 1.2.2 Cells produce, remodel and degrade extracellular matrix ...................................3 1.2.3 Cell - ECM interactions and regulation of cellular responses .............................4 1.2.4 Techniques used to tune stiffness ........................................................................6 1.2.5 Cell morphology and migration in 2D systems with tunable mechanical properties ......................................................................................................................8 1.2.6 3D systems with tunable mechanical properties .................................................9 1.2.7 Durotaxis ...........................................................................................................11 CHAPTER 2. RESEARCH OBJECTIVES .....................................................................13 2.1 Develop and Characterize a TME Mimicking 3D System with Tunable Mechanical Properties .....................................................................................................13 2.2 Evaluate How Cell Migration and Morphology Vary in 3D as a Function of Gel Thickness and Surface Chemistry Linking the Soft and Stiff Interface ..........................14 2.3 Examine if Durotactic Responses Could Be Elicited in the Surface Tunable 3D Systems ............................................................................................................................15 CHAPTER 3. TUNING SURFACE FUNCTIONALIZATION AND COLLAGEN GEL THICKNESS TO REGULATE CANCER CELL MIGRATION ........................16 3.1 Abstract ......................................................................................................................16 3.2 Highlights ..................................................................................................................17 3.3 Introduction ...............................................................................................................18 3.4 Material and Methods ................................................................................................21 3.4.1 Surface modifications generating high and low collagen binding surfaces ......21 3.4.2 Characterization of amine density on glass surfaces .........................................21 3.4.3 Contact angle measurement ...............................................................................22 3.4.4 Adhesion characterization .................................................................................22 3.4.5 Cell culture and characterization of cell morphology on 2D functionalized glass surfaces ..............................................................................................................23 3.4.6 Preparation of collagen gel in 3D chambers .....................................................24 3.4.7 Fixing and staining of cells ...............................................................................25 3.4.8 Data Analysis ....................................................................................................25 3.4.9 Statistical analysis .............................................................................................26 iv 3.5 Results .......................................................................................................................27 3.5.1 Surface modification of glass generating high and low collagen binding surfaces .......................................................................................................................27 3.5.2 Cell spreading on 2D functionalized glass surfaces ..........................................28 3.5.3 Adhesion of collagen to functionalized glass surfaces ......................................28 3.5.4 Quantitative cell morphology in 3D collagen chambers with different glass functionalization .........................................................................................................29 3.5.5 Cell motility in 3D collagen chambers with different glass functionalization ..31 3.6 Discussion ..................................................................................................................33 3.7 Conclusions ...............................................................................................................37 3.8 Acknowledgements ...................................................................................................38 3.9 Competing Interests ...................................................................................................38 3.10 Contributions ...........................................................................................................38 3.11 References ...............................................................................................................39 3.12 Figure Legends ........................................................................................................44 4.1 Investigating the Biophysical Effects of Hyaluronan Molecular Weight and Concentration on Breast Cancer Cell Migration in Collagen Matrices ...........................54 4.2 Investigating the Influence of Surface Topographical Cues to Elicit Durotaxis in 3D Systems Among Breast Cancer Cells ........................................................................56 REFERENCES ....................................................................................................................59 APPENDIX. MATLAB CODE ..........................................................................................68 v LIST OF FIGURES Page Figure 1 Characterization of surface properties on functionalized glass surfaces ..................44 Figure 2 Characterization of cell spreading on functionalized glass surfaces. ........................45 Figure 3 Characterization of adhesion of collagen to functionalized glass surfaces. ..............46 Figure 4 Characterization of cell morphology in 3D collagen chambers of different thicknesses and glass functionalization. ....................................................................47 Figure 5 Characterization of cell shape in 3D collagen chambers of different thicknesses and glass functionalization ........................................................................................49 Figure 6 Motility characterization in 3D collagen chambers with functionalized glass surfaces. .....................................................................................................................50 Figure 7 Motility characterization in 3D collagen chambers with step change in thickness ...52 Figure 8 The structure of hyaluronan consisting of repeating disaccharides of glucuronic acid and N-acetylglucosamine ...................................................................................56 Figure 9 Schematic of pyramidal 3D structure used to provide soft-stiff interfaces (scale
Recommended publications
  • Development of Microfluidic Devices to Study Algal Chemotaxis and Long-Term Growth Dynamics" (2016)

    Development of Microfluidic Devices to Study Algal Chemotaxis and Long-Term Growth Dynamics" (2016)

    Louisiana State University LSU Digital Commons LSU Master's Theses Graduate School 2016 Development of Microfluidic evD ices to Study Algal Chemotaxis and Long-Term Growth Dynamics Benjamin Seth Roberts Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_theses Part of the Chemical Engineering Commons Recommended Citation Roberts, Benjamin Seth, "Development of Microfluidic Devices to Study Algal Chemotaxis and Long-Term Growth Dynamics" (2016). LSU Master's Theses. 4496. https://digitalcommons.lsu.edu/gradschool_theses/4496 This Thesis is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Master's Theses by an authorized graduate school editor of LSU Digital Commons. For more information, please contact [email protected]. DEVELOPMENT OF MICROFLUIDIC DEVICES TO STUDY ALGAL CHEMOTAXIS AND LONG-TERM GROWTH DYNAMICS A Thesis Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Master of Science in The Cain Department of Chemical Engineering by Benjamin S. Roberts B.S., Mississippi State University, 2014 December 2016 TABLE OF CONTENTS ABSTRACT ................................................................................................................................... iii CHAPTER 1. INTRODUCTION ....................................................................................................1
  • Morphological Study of Cell Protrusions During Redirected Migration in Human Fibroblast Cells

    Morphological Study of Cell Protrusions During Redirected Migration in Human Fibroblast Cells

    MORPHOLOGICAL STUDY OF CELL PROTRUSIONS DURING REDIRECTED MIGRATION IN HUMAN FIBROBLAST CELLS Congyingzi Zhang A Thesis Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE August 2013 Committee: Dr. Carol Heckman, Advisor Dr. Roudabeh Jamasbi Dr. Peter Gorsevski ii ABSTRACT Carol A. Heckman, Advisor From the perspective of cell motility mechanisms, migration patterns arise from two opposing sources which can be viewed as forces. One, called intrinsic, maintains the cell persistence. The extrinsic arises from signals (repulsive or attractive) exerted by an external stimulus. The extrinsic force is stronger than the intrinsic, since it can overcome the intrinsic force and cause the cell to change direction. The current studies were designed to determine whether these forces were associated with different protrusions. I studied human fibroblast cells that collide with a haptotactic boundary between an adhesive substrate (germanium) and a non- adhesive substrate (plastic) in a chemokinesis system. The morphologies of cells migrating on the two substrates reflected the cells’ preference for the adhesive substrate. I measured the prevalence of various protrusions during the process of cells turning away from the boundary and reorienting their direction of travel. Classes that corresponded to protrusive features were identified by extracting latent factors from a number of primary, geometric variables, and included factor 4 (filopodia), factor 5 (cell mass displacement), and factor 7 (nascent neurites). The data showed that as cells moved further and further from the boundary, they had progressively lower values of factor 5. The correlation coefficient between the values is -0.4924.
  • 1Β IL-12 Receptor Viral Inflammation Are Mediated Through Macrophage

    1Β IL-12 Receptor Viral Inflammation Are Mediated Through Macrophage

    IL-12 p40 Homodimer-Dependent Macrophage Chemotaxis and Respiratory Viral Inflammation Are Mediated through IL-12 Receptor β1 This information is current as of September 24, 2021. Tonya D. Russell, Qingyun Yan, Guangshun Fan, Anthony P. Khalifah, D. Keith Bishop, Steven L. Brody and Michael J. Walter J Immunol 2003; 171:6866-6874; ; doi: 10.4049/jimmunol.171.12.6866 Downloaded from http://www.jimmunol.org/content/171/12/6866 References This article cites 63 articles, 41 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/171/12/6866.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-12 p40 Homodimer-Dependent Macrophage Chemotaxis and Respiratory Viral Inflammation Are Mediated through IL-12 Receptor ␤11 Tonya D. Russell,* Qingyun Yan,* Guangshun Fan,* Anthony P.
  • Negative Durotaxis: Cell Movement Toward Softer Environments

    Negative Durotaxis: Cell Movement Toward Softer Environments

    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.27.357178; this version posted October 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Negative durotaxis: cell movement toward softer environments Aleksi Isomursu1,*, Keun-Young Park2,*, Jay Hou3,*, Bo Cheng4,5,*, Ghaidan Shamsan3, Benjamin Fuller3, Jesse Kasim3, M. Mohsen Mahmoodi2, Tian Jian Lu6,7, Guy M. Genin4,5,8, Feng Xu4,5, Min Lin4,5,#, Mark Distefano2,#, Johanna Ivaska1,9,#, and David J. Odde3,# 1Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland 2Department of Chemistry, University of Minnesota, Minneapolis 55455, MN, USA 3Department of Biomedical Engineering, University of Minnesota, Minneapolis 55455, MN, USA 4The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, P.R. China 5Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an 710049, P.R. China 6State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, NanjinG 210016, P.R. China 7MOE Key Laboratory of Multifunctional Materials and Structures, Xi’an JiaotonG University, Xi’an 710049, P.R. China 8NSF Science and TechnoloGy Center for EnGineerinG MechanobioloGy, WashinGton University in St. Louis, St. Louis 63130, MO, USA 9Department of Biochemistry, University of Turku, 20520 Turku, Finland *Equal contribution #Corresponding authors Email: [email protected] (D.J.O.); [email protected] (J.I.); [email protected] (M.D.); [email protected] (M.L.) Abstract: Durotaxis – the ability of cells to sense and migrate along stiffness gradients – is important for embryonic development and has been implicated in pathologies including fibrosis and cancer.
  • Bimodal Rheotactic Behavior Reflects Flagellar Beat Asymmetry in Human Sperm Cells

    Bimodal Rheotactic Behavior Reflects Flagellar Beat Asymmetry in Human Sperm Cells

    Bimodal rheotactic behavior reflects flagellar beat asymmetry in human sperm cells Anton Bukatina,b,1, Igor Kukhtevichb,c,1, Norbert Stoopd,1, Jörn Dunkeld,2, and Vasily Kantslere aSt. Petersburg Academic University, St. Petersburg 194021, Russia; bInstitute for Analytical Instrumentation of the Russian Academy of Sciences, St. Petersburg 198095, Russia; cITMO University, St. Petersburg 197101, Russia; dDepartment of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139-4307; and eDepartment of Physics, University of Warwick, Coventry CV4 7AL, United Kingdom Edited by Charles S. Peskin, New York University, New York, NY, and approved November 9, 2015 (received for review July 30, 2015) Rheotaxis, the directed response to fluid velocity gradients, has whether this effect is of mechanical (20) or hydrodynamic (21, been shown to facilitate stable upstream swimming of mamma- 22) origin. Experiments (23) show that the alga’s reorientation lian sperm cells along solid surfaces, suggesting a robust physical dynamics can lead to localization in shear flow (24, 25), with mechanism for long-distance navigation during fertilization. How- potentially profound implications in marine ecology. In contrast ever, the dynamics by which a human sperm orients itself relative to taxis in multiflagellate organisms (2, 5, 18, 26, 27), the navi- to an ambient flow is poorly understood. Here, we combine micro- gation strategies of uniflagellate cells are less well understood. fluidic experiments with mathematical modeling and 3D flagellar beat For instance, it was discovered only recently that uniflagellate reconstruction to quantify the response of individual sperm cells in marine bacteria, such as Vibrio alginolyticus and Pseudoalteromonas time-varying flow fields. Single-cell tracking reveals two kinematically haloplanktis, use a buckling instability in their lone flagellum to distinct swimming states that entail opposite turning behaviors under change their swimming direction (28).
  • A Hybrid Computational Model for Collective Cell Durotaxis

    A Hybrid Computational Model for Collective Cell Durotaxis

    Biomechanics and Modeling in Mechanobiology https://doi.org/10.1007/s10237-018-1010-2 ORIGINAL PAPER A hybrid computational model for collective cell durotaxis Jorge Escribano1 · Raimon Sunyer2,5 · María Teresa Sánchez3 · Xavier Trepat2,4,5,6 · Pere Roca-Cusachs2,4 · José Manuel García-Aznar1 Received: 13 September 2017 / Accepted: 17 February 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Collective cell migration is regulated by a complex set of mechanical interactions and cellular mechanisms. Collective migration emerges from mechanisms occurring at single cell level, involving processes like contraction, polymerization and depolymerization, of cell–cell interactions and of cell–substrate adhesion. Here, we present a computational framework which simulates the dynamics of this emergent behavior conditioned by substrates with stiffness gradients. The computational model reproduces the cell’s ability to move toward the stiffer part of the substrate, process known as durotaxis. It combines the continuous formulation of truss elements and a particle-based approach to simulate the dynamics of cell–matrix adhesions and cell–cell interactions. Using this hybrid approach, researchers can quickly create a quantitative model to understand the regulatory role of different mechanical conditions on the dynamics of collective cell migration. Our model shows that durotaxis occurs due to the ability of cells to deform the substrate more in the part of lower stiffness than in the stiffer part. This effect explains why cell collective movement is more effective than single cell movement in stiffness gradient conditions. In addition, we numerically evaluate how gradient stiffness properties, cell monolayer size and force transmission between cells and extracellular matrix are crucial in regulating durotaxis.
  • The Role of 5-Lipoxygenase in Pathophysiology and Management of Neuropathic Pain

    The Role of 5-Lipoxygenase in Pathophysiology and Management of Neuropathic Pain

    REVIEW ARTICLE THE ROLE OF 5-LIPOXYGENASE IN PATHOPHYSIOLOGY AND MANAGEMENT OF NEUROPATHIC PAIN Pascanus Lamsihar PT∗, Faldi Yaputra∗∗, Jimmy FA Barus4 and I Putu Eka Widyadharma∗∗,1 ∗Department of Neurology, Provincial Mental Hospital, West Borneo, Indonesia., ∗∗Department of Neurology, Faculty of Medicine, Udayana University-Sanglah General Hospital, Bali, Indonesia., 4Department of Neurology, Faculty of Medicine, Atma Jaya Catholic University, Jakarta-Indonesia. ABSTRACT Neuropathic pain (NP) is a pain caused by lesions in the nervous system. Several causes of NP are traumatic, metabolic disorders, ischemia, toxins, infections, immune-related, and hereditary. The pathophysiology of NP is very complicated and unknown entirely. Therefore the treatment of NP is still unsatisfactory. Recent studies believed the critical role of primary inflammatory mediators in the pathophysiology of NP especially leukotrienes (LTs). The 5- lipoxygenase enzyme (5-LOX) is an enzyme that plays a role in the metabolism of arachidonic acid into LTs. Leukotrienes (LTs) are the essential inflammatory mediators in the pathophysiology of NP. Leukotriene B4 (LTB4) can cause chemotaxis on neutrophils, lowering nociceptors threshold and may contribute to NP. Several studies believed the administration of 5-LOX inhibitors or LTs receptor antagonists could be useful in the management of NP. The purpose of this review is to summarize the involvement of 5-LOX enzyme as an essential role in the pathophysiology and management of NP. KEYWORDS 5-lipoxygenase, leukotrienes,
  • Planarian Behavior: a Student-Designed Laboratory Exercise

    Planarian Behavior: a Student-Designed Laboratory Exercise

    Planarian Behavior: A Student-Designed Laboratory Exercise Linda T. Collins and Brent W. Harker Department of Biological and Environmental Sciences University of Tennessee at Chattanooga Chattanooga, TN 37403 [email protected] Reprinted From: Collins, L. T. and B. W. Harker. 1999. Planarian behavior: A student-designed laboratory exercise. Pages 375-379, in Tested studies for laboratory teaching, Volume 20 (S. J. Karcher, Editor). Proceedings of the 20th Workshop/Conference of the Association for Biology Laboratory Education (ABLE), 399 pages. - Copyright policy: http://www.zoo.utoronto.ca/able/volumes/copyright.htm Although the laboratory exercises in ABLE proceedings volumes have been tested and due consideration has been given to safety, individuals performing these exercises must assume all responsibility for risk. The Association for Biology Laboratory Education (ABLE) disclaims any liability with regards to safety in connection with the use of the exercises in its proceedings volumes. © Linda T. Collins and Brent W. Harker Objectives 1. Know that different types of stimuli can affect planarian movement. 2. Distinguish between kinesis and taxis. 3. After preliminary observations, state a hypothesis to predict or explain planarian movement in response to an external stimulus. Test the hypothesis and reach a conclusion. Introduction Planarians are in the flatworm phylum, Platyhelminthes. Most planarians are free-living and are common in freshwater habitats. They are also found in marine and terrestrial environments. Planarians display bilateral symmetry, meaning the right and left halves are approximately mirror images of each other. The nervous system of planarians consists of an anterior “brain” consisting of large ganglia. Two ventral nerve cords run the length of the body from the ganglia.
  • PGE2 Signaling Via the Neuronal EP2 Receptor Increases Injury in a Model of Cerebral Ischemia

    PGE2 Signaling Via the Neuronal EP2 Receptor Increases Injury in a Model of Cerebral Ischemia

    PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia Qingkun Liua, Xibin Liangb, Qian Wanga, Edward N. Wilsona, Rachel Lamb, Jing Wanga, William Kongc, Connie Tsaia, Tingting Pana, Paul B. Larkina, Mehrdad Shamloob, and Katrin I. Andreassona,d,e,1 aDepartment of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA 94305; bDepartment of Neurosurgery, Comparative Medicine, and Neurology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305; cInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; dStanford Neuroscience Institute, Stanford University, Stanford, CA 94305; and eStanford Immunology Program, Stanford University, Stanford, CA 94305 Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 9, 2019 (received for review November 4, 2018) The inflammatory prostaglandin E2 (PGE2) EP2 receptor is a master innate immunity (11), AD (4, 5, 12, 13), Parkinson’s disease (PD) suppressor of beneficial microglial function, and myeloid EP2 signal- (14, 15), and amyotrophic lateral sclerosis (16). More recently, ing ablation reduces pathology in models of inflammatory neurode- studies using myeloid cell conditional knockout strategies identified generation. Here, we investigated the role of PGE2 EP2 signaling in a EP2 receptor-driven pathologic microglial responses in models of model of stroke in which the initial cerebral ischemic event is fol- innate immunity, PD, and AD (4, 12, 15) where ablation of a lowed by an extended poststroke inflammatory response. Myeloid microglial EP2 receptor increased microglial chemotaxis and lineage cell-specific EP2 knockdown in Cd11bCre;EP2lox/lox mice at- phagocytosis and suppressed proinflammatory gene expression, tenuated brain infiltration of Cd11b+CD45hi macrophages and synaptic injury, and memory deficits.
  • Thiazolidine-2,4-Dione Attenuates Atherosclerosis Possibly by Reducing Monocyte Recruitment to the Lesion

    Thiazolidine-2,4-Dione Attenuates Atherosclerosis Possibly by Reducing Monocyte Recruitment to the Lesion

    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 8, 471-478, August 2011 5-(4-Hydroxy-2,3,5-trimethylbenzylidene) thiazolidine-2,4-dione attenuates atherosclerosis possibly by reducing monocyte recruitment to the lesion Jae-Hoon Choi1,2*, Jong-Gil Park2,3*, Accepted 20 June 2011 Hyung Jun Jeon2, Mi-Sun Kim4, Mi-Ran Lee2, Available Online 21 June 2011 2 2 5 Mi-Ni Lee , SeongKeun Sonn , Jae-Hong Kim , Abbreviations: 5-LOX, 5-lipoxygenase; BHB-TZD, 5-(3,5-di- Mun Han Lee3, Myung-Sook Choi6, tert-butyl-4-hydroxybenzylidene) thiazolidin-2,4-dione; COX, Yong Bok Park7, Oh-Seung Kwon8, cyclooxygenase; HMB-TZD, 5-(4-hydroxy-2,3,5-trimethyl- Tae-Sook Jeong9, Woo Song Lee10, Hyun Bo Shim2, benzylidene) thiazolidin-2,4-dione; ICAM-1, intercellular 4 2,11 adhesion molecule-1; Ldlr, low density lipoprotein receptor; Dong Hae Shin and Goo Taeg Oh TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1 1Department of Life Science College of Natural Sciences Hanyang University Abstract Seoul 133-791, Korea 2Division of Life and Pharmaceutical Sciences A variety of benzylidenethiazole analogs have been Ewha Womans University demonstrated to inhibit 5-lipoxygenase (5-LOX). Here Seoul 120-750, Korea we report the anti-atherogenic potential of 5-(4-hy- 3 Department of Veterinary Biochemistry droxy-2,3,5-trimethylbenzylidene) thiazolidin-2,4-di- College of Veterinary Medicine one (HMB-TZD), a benzylidenethiazole analog, and its Seoul National University potential mechanism of action in LDL receptor-defi- Seoul 151-742, Korea cient (Ldlr-/-) mice. HMB-TZD Treatment reduced leuko- 4Division of Life and Pharmaceutical Sciences triene B4 (LTB4) production significantly in RAW264.7 College of Pharmacy macrophages and SVEC4-10 endothelial cells.
  • Intrinsic 5-Lipoxygenase Activity Is Required for Neutrophil Responsivity

    Intrinsic 5-Lipoxygenase Activity Is Required for Neutrophil Responsivity

    Proc. Natl. Acad. Sci. USA Vol. 91, pp. 8156-8159, August 1994 Cell Biology Intrinsic 5-lipoxygenase activity is required for neutrophil responsivity DAVID M. GUIDOT, MICHAEL J. REPINE, JAY Y. WESTCOTT, AND JOHN E. REPINE Webb-Waring Institute for Biomedical Research and Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C-321, Denver, CO 80262 Communicated by David W. Talmage, May 6, 1994 (receivedfor review March 9, 1994) ABSTRACT We found that intrinsic neutrophil 5-lipoxy- neutrophil-mediated injury in isolated lungs given IL-8 intra- genase activity was necessary for human neutrophil adherence tracheally. and chemotaxis in viro and human neutrophil-mediated acute edematous injury in isolated perfused rat lungs given interleu- kin 8 intratracheally. Treatment with either Zileuton (a specific MATERIALS AND METHODS reversible competitive inhibitor of 5-lipoxygenase) or MK886 Purification of Human Neutrophils. Heparinized blood was (a specific irreversible inhibitor ofthe 5-lipoxygenase activator obtained from healthy volunteers. Neutrophils were isolated protein) prevented stimulated neutrophil adherence and by using a Percoll gradient and differential centrifugation. chemotaxis (but not superoxide anion production) in vitro. Each preparation contained highly purified (>99%o) neutro- Zileuton- or MK886-inhibited neutrophil chemotaxis was not phils that were suspended in Hanks' balanced salt solution restored by adding leukotriene B4 in vitro. Perfusion with (Sigma) at a concentration of
  • Inflammation, Cancer and Oxidative Lipoxygenase Activity Are Intimately Linked

    Inflammation, Cancer and Oxidative Lipoxygenase Activity Are Intimately Linked

    Cancers 2014, 6, 1500-1521; doi:10.3390/cancers6031500 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked Rosalina Wisastra and Frank J. Dekker * Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +31-5-3638030; Fax: +31-5-3637953. Received: 16 April 2014; in revised form: 27 June 2014 / Accepted: 2 July 2014 / Published: 17 July 2014 Abstract: Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically recognized pro-inflammatory effects, anti-inflammatory effects are also being described in recent years. Interestingly, these lipid mediators are involved in activation of pro-inflammatory signal transduction pathways such as the nuclear factor κB (NF-κB) pathway, which illustrates the intimate link between lipid signaling and transcription factor activation. The identification of the role of arachidonic acid metabolites in several inflammatory diseases led to a significant drug discovery effort around arachidonic acid metabolizing enzymes. However, to date success in this area has been limited. This might be attributed to the lack of selectivity of the developed inhibitors and to a lack of detailed understanding of the functional roles of arachidonic acid metabolites in inflammatory responses and cancer.