DOCSLIB.ORG

Hydrophobic Amino-Terminal Pocket CD14 Reveals a Bent Solenoid with a the Crystal Structure of Human Soluble

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hydrophobic Amino-Terminal Pocket CD14 Reveals a Bent Solenoid with a the Crystal Structure of Human Soluble The Crystal Structure of Human Soluble CD14 Reveals a Bent Solenoid with a Hydrophobic Amino-Terminal Pocket This information is current as Stacy L. Kelley, Tiit Lukk, Satish K. Nair and Richard I. of September 25, 2021. Tapping J Immunol 2013; 190:1304-1311; Prepublished online 21 December 2012; doi: 10.4049/jimmunol.1202446 http://www.jimmunol.org/content/190/3/1304 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/12/31/jimmunol.120244 Material 6.DC1 http://www.jimmunol.org/ References This article cites 87 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/190/3/1304.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Crystal Structure of Human Soluble CD14 Reveals a Bent Solenoid with a Hydrophobic Amino-Terminal Pocket Stacy L. Kelley,* Tiit Lukk,* Satish K. Nair,* and Richard I. Tapping†,‡ Human monocyte differentiation Ag CD14 is a pattern recognition receptor that enhances innate immune responses to infection by sensitizing host cells to bacterial LPS (endotoxin), lipoproteins, lipoteichoic acid, and other acylated microbial products. CD14 physically delivers these lipidated microbial products to various TLR signaling complexes that subsequently induce intracellular proinflammatory signaling cascades upon ligand binding. The ensuing cellular responses are usually protective to the host but can also result in host fatality through sepsis. In this work, we have determined the x-ray crystal structure of human CD14. The structure reveals a bent solenoid typical of leucine-rich repeat proteins with an amino-terminal pocket that presumably binds acylated ligands including LPS. Comparison of human and mouse CD14 structures shows great similarity in overall protein fold. However, compared with mouse CD14, human CD14 contains an expanded pocket and alternative rim residues that are likely to be important for LPS Downloaded from binding and cell activation. The x-ray crystal structure of human CD14 presented in this article may foster additional ligand-bound structural studies, virtual docking studies, and drug design efforts to mitigate LPS-induced sepsis and other inflammatory diseases. The Journal of Immunology, 2013, 190: 1304–1311. D14 was first characterized as a membrane cell-surface site of infection, proinflammatory signaling resulting from CD14 differentiation marker of myeloid lineage cells (1). Mem- activity is protective, leading to local clearance of invading bac- http://www.jimmunol.org/ C brane CD14 is a GPI-anchored 55-kDa glycoprotein (2, 3) teria. However, widespread infection and activation of this proin- that is highly expressed on monocytes, macrophages, and neutrophils flammatory signaling system can cause fatality through sepsis with lower surface expression observed on a variety of other hema- (reviewed in Refs. 6, 7). In response to LPS, CD14-deficient mice topoietic and stromal cells. Soluble forms of CD14 exist in serum, have blunted proinflammatory cytokine production and lack the cerebrospinal, and other body fluids. Soluble CD14 is generated by lethargy, respiratory, and ruffled fur symptoms associated with at least three different mechanisms that include bypassing of GPI murine septic shock. CD14-deficient mice also survive challenge addition, cleavage of the GPI anchor by phospholipase D, or direct with otherwise lethal doses of LPS (8). proteolytic cleavage from the cell surface (reviewed in Ref. 4). LPS is the major lipid present in the outer membrane of Gram- CD14 is best known as a pattern recognition receptor of the negative bacteria (9). LPS is an amphipathic molecule and in en- by guest on September 25, 2021 innate immune system that plays a prominent role in sensitizing teric bacteria is composed of a hexaacylated lipid A region with cells to the presence of Gram-negative bacterial LPS (endotoxin) a diglucosamine backbone flanked by 1 and 49 phosphates. The (4). CD14 is thought to sensitize cells to LPS by delivering this length, number, and saturation of the fatty acid tails in LPS can vary agonist to the TLR4 receptor signaling complex. Membrane CD14 between different species of bacteria (10), as can the length and shuttles LPS to TLR4 complexes in a two-dimensional search (4), sugar content of the core and O-Ag regions (11). The binding of whereas soluble CD14 enables cells that lack endogenous CD14, LPS by CD14 is slow unless this binding reaction is catalyzed by including most epithelial and endothelial cells, to respond to LPS LPS-binding protein (LBP) (12, 13). LBP is a 60-kDa human serum (reviewed in Ref. 5). LPS-induced TLR4 activation initiates host glycoprotein produced by liver hepatocytes (14, 15) that disag- inflammation by driving cellular production of proinflammatory gregates and catalytically transfers LPS to CD14 (16). In concert cytokines, chemokines, and cell adhesion molecules. At the local with LBP, CD14 binds monomeric LPS (12) and shuttles it to the TLR4 complex. This effectively concentrates low levels of LPS and increases the sensitivity of the system (4, 12, 13, 17, 18). The major *Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, LPS acceptor of the TLR4 receptor complex is a 25-kDa corecep- IL 61801; †Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and ‡College of Medicine, University of Illinois at Urbana- tor called MD-2, which is physically associated with TLR4. The Champaign, Urbana, IL 61801 binding of LPS to the TLR4–MD-2 complex facilitates dimeriza- Received for publication August 30, 2012. Accepted for publication November 15, tion, resulting in a homodimeric receptor signaling complex com- 2012. posed of two TLR4 monomers, two MD-2 proteins, and two LPS This work was supported by National Institutes of Health Grants R01 AI052344 (to molecules (19). Cell signaling is facilitated by the intracellular R.I.T.) and T32 GM007283 (to S.L.K.). signaling domain of TLR4, which upon dimerization creates a The protein structure coordinates presented in this article were submitted to the Protein Data Bank (http://www.rcsb.org/pdb/search/structidSearch.do?structureId=4GLP) under platform for intracellular signaling adaptors (20). Small gel filtra- accession number 4GLP. tion mixing studies have demonstrated a catalytic role for CD14 in Address correspondence and reprint requests to Prof. Richard I. Tapping, Department the delivery of LPS to the TLR4–MD-2 complex (17, 21–24). of Microbiology, University of Illinois, B103 CLSL MC-110, 601 South Goodwin As a pattern recognition receptor, CD14 is capable of binding Avenue, Urbana, IL 61801. E-mail address: [email protected] a wide variety of natural and synthetic acylated ligands in addition The online version of this article contains supplemental material. to LPS. For example, CD14 and LBP can work together to opsonize Abbreviations used in this article: LBP, LPS-binding protein; PEG, polyethylene whole bacteria and apoptotic cells, clearing infection and reducing glycol; PNGaseF, peptide N-glycosidase F. inflammation (25–29). CD14 is also able to bind and shuttle Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 certain host phospholipids (30–32). Further, CD14 has been shown www.jimmunol.org/cgi/doi/10.4049/jimmunol.1202446 The Journal of Immunology 1305 to enhance cellular inflammatory responses to a variety of acylated CD14 were collected and injected on the two tandem Protein A columns three bacterial agonists of TLR2, including lipoteichoic acid, myco- consecutive times to remove Fc. Flow-through fractions containing soluble bacterial lipoarabinomannan, atypical LPSs, and lipoproteins (33– CD14 were pooled and concentrated to 1 ml using an Amicon Ultra-15 U (Millipore). 40). Given this central role in TLR agonist delivery, CD14 is an Because glycosylation contributes to protein heterogeneity, we removed obvious drug target for the treatment of sepsis (reviewed in Refs. N-linked glycans from CD14 by a 1-h incubation at 37˚C in 1xG7 buffer 6, 7). (0.05 M sodium phosphate, pH 7.5) containing 1000 U peptide N-glycosidase The molecular interactions involved in the binding and delivery F (PNGaseF) (New England Biolabs). This deglycosylated CD14 was further purified by anion exchange chromatography using two tandem 5-ml Hi-Trap of structurally diverse ligands presumably requires multiple pro- Q anion exchange columns (GE Healthcare) and a linear NaCl gradient tein–ligand and protein–protein interaction sites on CD14 that are (0.02–1M)in0.02MTris-HCl,pH8.5at4˚Cusinga1ml/minflowrate. currently undefined. In addition, the mechanisms involved in de- CD14-containing fractions were concentrated using an Amicon Ultra-15 U livery of these ligands to multiple TLR complexes are also un- (Millipore) to 0.5 ml. Finally, size-exclusion chromatography was performed resolved. To address this gap in knowledge, many groups have using a Superdex 200 column (GE Healthcare) equilibrated with 0.02 M Tris- HCl, pH 8.5, and 0.1 M NaCl at a flow rate of 0.4 ml/min. The fractions purified various recombinant forms of soluble CD14 using bac- containing CD14 were pooled and concentrated to 10 mg/ml using an teria, yeast, insect, and human cellular expression systems (12, Amicon Ultra-4 U (Millipore) as measured by Pierce BCA assay (Pierce, 41–51), often with the goal of structure determination (49, 50).
Load more

Recommended publications
  • 1 Combined Effect of Anti-High-Mobility Group Box-1 Monoclonal Antibody and Peramivir Against Influenza a Virus-Induced Pneumoni
    Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice Kazuki Hatayama1; Nobuyuki Nosaka1*; Mutsuko Yamada1; Masato Yashiro1; Yosuke Fujii1; Hirokazu Tsukahara1; Keyue Liu3; Masahiro Nishibori3; Akihiro Matsukawa4; Tsuneo Morishima1,2 1 Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 2 Department of Pediatrics, Aichi Medical University, Japan 3 Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 4 Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 1 *Correspondence author: Nobuyuki Nosaka 2-5-1 Shikata-cho, Kita-ku, Okayama city, Okayama pref. 700-8558, Japan Tel: +81-86-235-7249 Email: [email protected] Shortened title: Anti-HMGB1 plus peramivir for influenza 2 ABSTRACT Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury (ALI) due to excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi.
    [Show full text]
  • Improving Pipeline for the Development of Influenza Antivirals
    United States Department of Health & Human Services Office of the Assistant Secretary for Preparedness and Response Improving Pipeline for the Development of Influenza Antivirals Michael W Wathen, Ph.D. Chief, Antiviral Advanced Development Influenza Division BARDA BARDA Influenza Antiviral Program Strategy Overview National Strategy Issues BARDA Strategy ASPR: Resilient People. Healthy Communities. A Nation Prepared. 2 Issues for Influenza Antivirals • Current therapies have narrow treatment window ─ Treatment within 48h of symptom onset for neuraminidase inhibitors ─ Can treatment window be expanded with novel antivirals having different mechanisms of action? • Constant threat of resistance ─ Value of M-2 blockers minimized by resistance ─ Heavy reliance on neuraminidase inhibitors ─ Few combination therapies unavailable • Limited options in U.S. for special populations ─ No IV formulations approved for patients on ventilators ─ No drugs approved for severely ill, hospitalized patients ─ Limited treatment options for pediatric patients ASPR: Resilient People. Healthy Communities. A Nation Prepared. 3 BARDA Influenza Antiviral Program Advanced Development Strategy 2005 National Strategy for Pandemic Influenza • Accelerate development, evaluation, approval and U.S.-based production of new influenza antiviral drugs Treatment Gap Issues • Special populations (pediatrics, severely ill hospitalized) Existing BARDA Advanced Development Projects • Fill critical unmet medical needs by expanding the utility of neuraminidase inhibitors •Peramivir •$235M contract with BioCryst awarded in 2007 •Development of IV peramivir in hospitalized patients •EUA designated by FDA during 2009 pandemic •First unapproved drug authorized for use under an EUA •Worldwide clinical program for licensure in U.S. •Laninamivir •$231M contract with Biota awarded in 2011 •Development of inhaled laninamivir in outpatient setting •Single-dose treatment course ASPR: Resilient People.
    [Show full text]
  • Advancing the Development Pipeline for the Treatment of Influenza
    United States Department of Health & Human Services Office of the Assistant Secretary for Preparedness and Response Advancing the Development Pipeline for the Treatment of Influenza Melissa Willis, Ph.D. Chief, Influenza Therapeutics Influenza Division BARDA Roadmap • What is our goal? • Where have we been? • Where are we going? • Why now? • What strategies we are pursuing to achieve the goal? ASPR: Resilient People. Healthy Communities. A Nation Prepared. 2 BARDA Influenza Antiviral Program Program Goal “Reduce morbidity and mortality in all patient populations during an influenza pandemic by supporting advanced development, evaluation, and approval of new influenza antiviral drugs” • Mission established in the 2005 National Strategy for Pandemic Influenza, HHS Pandemic Influenza Plan and the 2006 Implementation Plan for the National Strategy for Pandemic Influenza • Initial stockpiling goal and advanced development projects • Stockpile total of 81M treatment courses of influenza antiviral drugs • Advanced development of new antiviral drugs • New BARDA advanced development projects are focused on developing drugs to address critical unmet needs in treating severely ill, hospitalized patients and in pediatric populations • Novel mechanisms of action • Combination therapy Our total reliance on monotherapy with NAI’s has placed us at risk of no treatment options to ASPR:address Resilient a potentialPeople. Healthy NAI- resistantCommunities. pandemic A Nation Prepared. 3 BARDA Influenza Therapeutics Program Line-Up • Two large, full development
    [Show full text]
  • TLR4 Signaling Pathway Modulators As Potential Therapeutics in Inflammation and Sepsis
    vaccines Review TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis Nikolay N. Kuzmich 1,2,*, Konstantin V. Sivak 1, Vladimir N. Chubarev 3, Yury B. Porozov 2,4, Tatiana N. Savateeva-Lyubimova 1 and Francesco Peri 5,* ID 1 Department of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, Russia; [email protected] (K.V.S.); [email protected] (T.N.S.-L.) 2 Laboratory of Bioinformatics, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia; [email protected] 3 Department of Pharmacology, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia; [email protected] 4 Laboratory of Bioinformatics, ITMO University, 49 Kronverkskiy Pr., Saint Petersburg 197101, Russia 5 Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy * Correspondence: [email protected] (N.N.K.); Tel.: +7-921-3491-750 (N.N.K.); [email protected] (F.P.); Tel.: +39-026-448-3453 (F.P.); Fax: +7-812-499-15-15 (N.N.K.) Academic Editor: Paola Massari Received: 5 September 2017; Accepted: 1 October 2017; Published: 4 October 2017 Abstract: Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries.
    [Show full text]
  • TLR4-Targeting Therapeutics: Structural Basis and Computer-Aided Drug Discovery Approaches
    molecules Review TLR4-Targeting Therapeutics: Structural Basis and Computer-Aided Drug Discovery Approaches Qurat ul Ain, Maria Batool and Sangdun Choi * Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea; [email protected] (Q.u.A.); [email protected] (M.B.) * Correspondence: [email protected]; Tel.: +82-31-219-2600; Fax: +82-31-219-1615 Academic Editor: Julio Caballero Received: 5 January 2020; Accepted: 29 January 2020; Published: 31 January 2020 Abstract: The integration of computational techniques into drug development has led to a substantial increase in the knowledge of structural, chemical, and biological data. These techniques are useful for handling the big data generated by empirical and clinical studies. Over the last few years, computer-aided drug discovery methods such as virtual screening, pharmacophore modeling, quantitative structure-activity relationship analysis, and molecular docking have been employed by pharmaceutical companies and academic researchers for the development of pharmacologically active drugs. Toll-like receptors (TLRs) play a vital role in various inflammatory, autoimmune, and neurodegenerative disorders such as sepsis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s disease, multiple sclerosis, cancer, and systemic lupus erythematosus. TLRs, particularly TLR4, have been identified as potential drug targets for the treatment of these diseases, and several relevant compounds are under preclinical and clinical evaluation. This review covers the reported computational studies and techniques that have provided insights into TLR4-targeting therapeutics. Furthermore, this article provides an overview of the computational methods that can benefit a broad audience in this field and help with the development of novel drugs for TLR-related disorders.
    [Show full text]
  • A Meeting Report from the 6Th Isirv Antiviral Group Conference T
    Antiviral Research 167 (2019) 45–67 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference T ∗ John H. Beigela, , Hannah H. Namb, Peter L. Adamsc, Amy Kraffta, William L. Inced, Samer S. El-Kamaryd, Amy C. Simse a National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA bNorthwestern University, Feinberg School of Medicine, Chicago, IL, USA c Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA d Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S Food and Drug Administration, Silver Spring, MD, USA e Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA ARTICLE INFO ABSTRACT Keywords: The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv- Influenza AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on Respiratory syncytial virus therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including Coronavirus MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several Antiviral therapy influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, Host-directed therapeutics pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies in- cluding nitazoxanide, eritoran, and diltiazem.
    [Show full text]
  • Low-Dose Naltrexone/Acetaminophen
    medRxiv preprint doi: https://doi.org/10.1101/2021.03.22.21254145; this version posted March 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 Low-Dose Naltrexone/Acetaminophen Combinations and Each Component in the Acute Treatment of Migraine: Findings of a Small, Randomized, Double- Blind, and Placebo-Controlled Clinical Trial Annette C. Toledano, M.D.1 1 Sponsor/investigator. Founder/medical director, Allodynic Therapeutics, LLC, North Miami, Florida. Corresponding author: Annette Toledano, M.D. E-mail: [email protected] Phone: 305 895 6808 ABSTRACT We tested two low-dose naltrexone/acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively- identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
    [Show full text]
  • Antivirals - Influenza
    Antivirals - Influenza There are two principal classes of antivirals licensed for prophylaxis and treatment of influenza, those targeted against the M2 proton channel and those against the neuraminidase. An inhibitors of the membrane fusion activity of the HA is licensed in a number of countries, and an inhibitor of the RNA polymerase has recently received a restricted license. Amantadine (Symmetrel®), developed in the 1960s, and rimantadine (Flumadine®) inhibit the function of the M2 protein of influenza A in virus uncoating, but are not effective against influenza B. They have not been widely used and resistance of currently circulating A(H1N1)pdm09 and A(H3N2) viruses has removed their usefulness against seasonal influenza. Zanamivir (Relenza®) and oseltamivir (Tamiflu®) were developed in the 1990s against the neuraminidase, which is involved in the release and spread of progeny virus. They are effective against both influenza A and B viruses, and are widely available. Whereas zanamivir is administered by inhalation, oseltamivir is administered orally and has proved to be more widely accepted, and has been the principal choice for antiviral stockpiles as a component of pandemic preparedness. However resistance to oseltamivir has occurred more frequently than resistance to zanamivir. Two other neuraminidase inhibitors have been licensed more recently: laninamivir (Inavir®) a long-lasting analogue of zanamivir, administered by inhalation as a single therapeutic dose, has been licensed in Japan; peramivir, which possesses the active moieties of both zanamivir and oseltamivir, has been licensed in Japan (Rapiacta®) and Korea (PeramiFlu®) for intravenous administration. Arbidol falls within a third class of antivirals, which targets the membrane fusion activity of the HA in vitro.
    [Show full text]
  • Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights Into Chronic Critical Illness
    Journal of Clinical Medicine Review Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness Grant Barker 1, Christiaan Leeuwenburgh 2, Todd Brusko 3 , Lyle Moldawer 4, Srinivasa T. Reddy 5 and Faheem W. Guirgis 1,* 1 Department of Emergency Medicine, College of Medicine-Jacksonville, University of Florida, 655 West 8th Street, Jacksonville, FL 32209, USA; [email protected]fl.edu 2 Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL 32603, USA; cleeuwen@ufl.edu 3 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL 32610, USA; tbrusko@ufl.edu 4 Department of Surgery, College of Medicine, University of Florida, Gainesville, FL 32608, USA; [email protected]fl.edu 5 Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; [email protected] * Correspondence: [email protected]fl.edu; Tel.: +1-904-244-4986 Abstract: In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflam- Citation: Barker, G.; Leeuwenburgh, matory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes C.; Brusko, T.; Moldawer, L.; Reddy, quantitative as well as qualitative changes which can be measured using the HDL inflammatory index S.T.; Guirgis, F.W.
    [Show full text]
  • The Preventive Treatment of Migraine with Low-Dose Naltrexone And
    medRxiv preprint doi: https://doi.org/10.1101/2021.03.23.21254186; this version posted April 12, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 The Preventive Treatment of Migraine with Low- Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders Annette C. Toledano1 1 Sponsor/investigator. Founder/medical director, Allodynic Therapeutics, LLC, North Miami, Florida. Corresponding author: Annette Toledano, M.D. E-mail: [email protected] Phone: 305 895 6808 ABSTRACT We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non- responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.03.23.21254186; this version posted April 12, 2021.
    [Show full text]
  • Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients with Severe Sepsis the ACCESS Randomized Trial
    CARING FOR THE CRITICALLY ILL PATIENT Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis The ACCESS Randomized Trial Steven M. Opal, MD Importance Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide Pierre-Francois Laterre, MD (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component Bruno Francois, MD of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. Steven P. LaRosa, MD Objective To determine if eritoran, a TLR4 antagonist, would significantly reduce Derek C. Angus, MD, MPH sepsis-induced mortality. Jean-Paul Mira, MD, PhD Design, Setting, and Participants We performed a randomized, double-blind, Xavier Wittebole, MD placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in Thierry Dugernier, MD September 2011. Dominique Perrotin, MD Interventions Patients with severe sepsis (n=1961) were randomized and treated Mark Tidswell, MD within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n=1304 and n=657 Luis Jauregui, MD patients, respectively. Kenneth Krell, MD Main Outcome Measures The primary end point was 28-day all-cause mortality. Jan Pachl, MD The secondary end points were all-cause mortality at 3, 6, and 12 months after be- Takeshi Takahashi, MD ginning treatment. Claus Peckelsen, MD Results Baseline characteristics of the 2 study groups were similar.
    [Show full text]
  • For Print （17KB）
    4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088 , Japan Eisai Co., Ltd. Phone: 03- 3817-5120 Fax: 03- 3811-3077 Eisai is a Human Health Care Corporation striving for innovative solutions in prevention, cure and care for the health and well-being of people worldwide. We combine our talents to understand and meet the needs of patients and their families to enhance the quality of life. FOR IMMEDIATE RELEASE No.10-10 March 26, 2010 Eisai Co., Ltd. Eisai to Continue Eritoran (E5564) Phase III Severe Sepsis Trial Eisai Co., Ltd. (Headquarters: Tokyo, President and CEO: Haruo Naito) announced today that an independent Data Monitoring Committee (DMC), which met on March 25 (United Kingdom local time), has recommended the Company continue enrolment to the preset goal of 2,000 patients in the Phase III ACCESS (A Controlled Comparison of Eritoran and Placebo in Patients with Severe Sepsis) trial, an Eisai global clinical development programme of the investigational compound eritoran (E5564) for severe sepsis. This recommendation was made based on a planned interim analysis evaluating safety and efficacy data from the ACCESS trial for the first 1,500 patients. In addition, the DMC did not express safety concerns that would warrant stopping the trial at this time. In accordance with the DMC’s recommendation, Eisai will continue enrolment to the planned goal of 2,000 patients in the trial. Sepsis is a serious condition with an extreme systemic inflammatory response to infection. In severe cases, the mortality is very high due to the onset of septic shock, disseminated intravascular coagulation and organ dysfunction lead to high mortality.
    [Show full text]