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Xiaowei Wang, Dana K Shaw, Holly L Hammond, Fayyaz S Sutterwala, Manira Rayamajhi, Kari Ann Shirey, Darren J Perkins, Joseph V Bonventre, Thangam S Velayutham, Sean M Evans, Kyle G Rodino, Lauren VieBrock, Karen M Scanlon, Nicholas H Carbonetti, Jason A Carlyon, Edward A Miao, Jere W McBride, Michail Kotsyfakis, Joao H F Pedra
Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1)...
August 2016: PLoS Pathogens
Navin Kumar, Padma Nandula, Heather Menden, Jason Jarzembowski, Venkatesh Sampath
OBJECTIVE: To quantify changes in placental expression of Toll- Like Receptors (TLRs) and Nuclear Oligomerization Domain (NOD) Like Receptors (NLRs) gene with; 1) advancing gestational age (GA), and 2) exposure to chorioamnionitis (CA) and preterm premature rupture of membrane (PPROM). METHODS: Placental tissue was collected at the time of birth from 83 subjects with live birth pregnancies from 24-40 weeks gestation between 2009 -2013. Real time RT-PCR analysis of 13 TLR/NLR genes involved in bacterial sensing was performed using specific probes...
July 20, 2016: Journal of Maternal-fetal & Neonatal Medicine
Tomoyuki Iwasaki, Naoe Kaneko, Yuki Ito, Hiroyuki Takeda, Tatsuya Sawasaki, Toshio Heike, Kiyoshi Migita, Kazunaga Agematsu, Atsushi Kawakami, Shinnosuke Morikawa, Sho Mokuda, Mie Kurata, Junya Masumoto
Nucleotide-binding oligomerization domain-containing protein (Nod) 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP), a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2). Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS)/early-onset sarcoidosis (EOS). For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system...
2016: TheScientificWorldJournal
Philipp Mertins, D R Mani, Kelly V Ruggles, Michael A Gillette, Karl R Clauser, Pei Wang, Xianlong Wang, Jana W Qiao, Song Cao, Francesca Petralia, Emily Kawaler, Filip Mundt, Karsten Krug, Zhidong Tu, Jonathan T Lei, Michael L Gatza, Matthew Wilkerson, Charles M Perou, Venkata Yellapantula, Kuan-lin Huang, Chenwei Lin, Michael D McLellan, Ping Yan, Sherri R Davies, R Reid Townsend, Steven J Skates, Jing Wang, Bing Zhang, Christopher R Kinsinger, Mehdi Mesri, Henry Rodriguez, Li Ding, Amanda G Paulovich, David Fenyö, Matthew J Ellis, Steven A Carr
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer...
June 2, 2016: Nature
Peng Fei Zou, Ming Xian Chang, Ying Li, Na Na Xue, Jun Hua Li, Shan Nan Chen, Pin Nie
NOD2/RIPK2 signalling plays essential role in the modulation of innate and adaptive immunity in mammals. In this study, NOD2 was functionally characterized in zebrafish (Danio rerio), and its interaction with a receptor-interaction protein, RIPK2, and RLRs such as MDA5 and RIG-I, as well as the adaptor, MAVS was revealed in fish innate immunity. The expression of NOD2 and RIPK2 in ZF4 cells has been constitutive and can be induced by the infection of Edwardsiella tarda and SVCV. The NOD2 can sense MDP in PGN from Gram-negative and -positive bacteria...
August 2016: Fish & Shellfish Immunology
Phoebe F Lamie
A new series of 3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ones having variable substitutions at N5 and C6 positions has been synthesized and characterized. The synthesized compounds were tested for cytotoxicity against K562 and MCF-7 cancer cell lines and for inhibition of protein kinases CDK1/cyclin B, CDK2/cyclin E and Abl. Compounds 5f and 5h killed both K562 and MCF-7 cell lines with IC50 values 8.2, 9.6μM and 15.3, 10.8μM, respectively. In addition, 5f and 5h showed antiproliferative effect through arrest in G2/M phase on cell cycle of K562 cancer cell line in a dose-dependant manner...
July 1, 2016: Bioorganic & Medicinal Chemistry Letters
Hwan Keun Kim, Fabiana Falugi, Dominique M Missiakas, Olaf Schneewind
A hallmark of Staphylococcus aureus disease in humans is persistent infections without development of protective immune responses. Infected patients generate VH3 plasmablast expansions and increased VH3 idiotype Ig; however, the mechanisms for staphylococcal modification of immune responses are not known. We report here that S. aureus-infected mice generate VH3 antibody expansions via a mechanism requiring MHC-restricted antigen presentation to CD4(+) T cells and staphylococcal protein A (SpA), a cell wall-anchored surface molecule that binds Fcγ and VH3 variant heavy chains of Ig...
May 17, 2016: Proceedings of the National Academy of Sciences of the United States of America
Steven M Chirieleison, Sylvia B Kertesy, Derek W Abbott
The RIP kinases (RIPKs) play an essential role in inflammatory signaling and inflammatory cell death. However, the function of their kinase activity has been enigmatic, and only recently has kinase domain activity been shown to be crucial for their signal transduction capacity. Despite this uncertainty, the RIPKs have been the subject of intense pharmaceutical development with a number of compounds currently in preclinical testing. In this work, we seek to determine the functional redundancy between the kinase domains of the four major RIPK family members...
May 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Aparna Prasad, Raquel Rabionet, Blanca Espinet, Luis Zapata, Anna Puiggros, Carme Melero, Anna Puig, Yaris Sarria-Trujillo, Stephan Ossowski, Maria P Garcia-Muret, Teresa Estrach, Octavio Servitje, Ingrid Lopez-Lerma, Fernando Gallardo, Ramon M Pujol, Xavier Estivill
Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome...
July 2016: Journal of Investigative Dermatology
Matous Hrdinka, Berthe Katrine Fiil, Mattia Zucca, Derek Leske, Katrin Bagola, Monica Yabal, Paul R Elliott, Rune Busk Damgaard, David Komander, Philipp J Jost, Mads Gyrd-Hansen
Innate immune signaling relies on the deposition of non-degradative polyubiquitin at receptor-signaling complexes, but how these ubiquitin modifications are regulated by deubiquitinases remains incompletely understood. Met1-linked ubiquitin (Met1-Ub) is assembled by the linear ubiquitin assembly complex (LUBAC), and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP. In this study, we report that HOIP also interacts with the deubiquitinase CYLD but that CYLD does not regulate ubiquitination of LUBAC components...
March 29, 2016: Cell Reports
Tobias Schwerd, Sumeet Pandey, Huei-Ting Yang, Katrin Bagola, Elisabeth Jameson, Jonathan Jung, Robin H Lachmann, Neil Shah, Smita Y Patel, Claire Booth, Heiko Runz, Gesche Düker, Ruth Bettels, Marianne Rohrbach, Subra Kugathasan, Helen Chapel, Satish Keshav, Abdul Elkadri, Nick Platt, Alexio M Muise, Sibylle Koletzko, Ramnik J Xavier, Thorsten Marquardt, Fiona Powrie, James E Wraith, Mads Gyrd-Hansen, Frances M Platt, Holm H Uhlig
OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP)...
March 7, 2016: Gut
Rocío Navarro, Pablo Delgado-Wicke, Natalia Nuñez-Prado, Marta Compte, Ana Blanco-Toribio, Gabriel Nuñez, Luis Álvarez-Vallina, Laura Sanz
We have recently described the response of human brain pericytes to lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4). However, Gram-negative pathogen-associated molecular patterns include not only LPS but also peptidoglycan (PGN). Given that the presence of co-purified PGN in the LPS preparation previously used could not be ruled out, we decided to analyse the expression of the intracellular PGN receptors NOD1 and NOD2 in HBP and compare the responses to their cognate agonists and ultrapure LPS...
May 2016: Journal of Cellular and Molecular Medicine
V Rainone, L Schneider, I Saulle, C Ricci, M Biasin, N M Al-Daghri, E Giani, G V Zuccotti, M Clerici, D Trabattoni
BACKGROUND: Immune activation contributes to the persistent state of inflammation associated with metabolic dysfunction in obesity. The specific immune receptors that sense metabolic stress signals and trigger inflammation are nevertheless largely unknown, and little is known on inflammatory and immune gene regulation in obesity. METHODS: The study includes a cross-sectional and a longitudinal arm. Forty children and adolescents were enrolled: 22 obese subjects and 18 age-matched normal weight controls...
June 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Arun Kapoor, Yi-Hsin Fan, Ravit Arav-Boger
We recently reported that induction of NOD2 by human Cytomegalovirus (HCMV) resulted in virus inhibition and upregulation of antiviral and inflammatory cytokines. Here we investigated the effects of muramyl dipeptide (MDP), a bacterial cell wall component that activates NOD2, on HCMV replication and antiviral responses. HCMV infection of human foreskin fibroblasts induced NOD2, the downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2), resulting in phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3)...
2016: Scientific Reports
Maria Grigoroiu-Serbanescu, Carmen C Diaconu, Stefanie Heilmann-Heimbach, Ana Iulia Neagu, Tim Becker
We investigated the influence of the age-of-onset (AO) on the association of 45 loci conferring risk for bipolar disorder (BP) and schizophrenia with BP-type-I in a Romanian sample (461 patients, 436 controls). The AO-analysis implicated the EGFR gene, as well as loci in other genes, in the AO variation of BP-type-I and revealed for the first time the link between BP-type-I and risk variants considered specific to schizophrenia (polymorphisms in MMP16/RIPK2 and CNNM2 genes).
December 30, 2015: Psychiatry Research
Karianne Fredenfeldt Lind, Bjarne Østerud, Espen Hansen, Trond Ø Jørgensen, Jeanette Hammer Andersen
BACKGROUND: Barettin is a marine natural compound with reported anti-inflammatory and antioxidant properties. The combination of these effects led us to explore barettin further as an inhibitor of atherosclerosis development. METHODS: The effect of barettin on MCP-1 and IL-10 secretion from activated immune cells was detected by ELISA. Determination of cell viability of oxidized low-density lipoprotein (oxLDL) and barettin exposed HUVEC cells were investigated by using CellTiter 96® AQ(ueous) One Solution...
2015: Immunopharmacology and Immunotoxicology
Claudius U Meyer, Gerhard Kurlemann, Matthias Sauter, Adelheid Wiemer-Kruel, Andreas Hahn, Aysefa Doganci, Julia Birkholz, Jörg Faber, Stephan Gehring, Christoph Hertzberg, Fred Zepp, Markus Knuf
OBJECTIVE: Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1/tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC. METHODS: Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC (n = 16) were compared with healthy subjects (n = 20)...
October 2015: Neuropediatrics
Peter Canning, Qui Ruan, Tobias Schwerd, Matous Hrdinka, Jenny L Maki, Danish Saleh, Chalada Suebsuwong, Soumya Ray, Paul E Brennan, Gregory D Cuny, Holm H Uhlig, Mads Gyrd-Hansen, Alexei Degterev, Alex N Bullock
RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation...
September 17, 2015: Chemistry & Biology
Roland N Wagner, John C Reed, Sumit K Chanda
BACKGROUND: HIV-1 protease (PR) is essential for viral infectivity as it cleaves Gag and Gag-Pol polyprotein precursors during viral maturation. Recent evidence suggests that cellular proteins can also be cleaved by PR, perhaps representing an important viral strategy to counter host defense mechanisms. Receptor-interacting protein kinase 1 (RIPK1) and RIPK2 belong to a family of serine/threonine kinases with conserved domain architecture and important functions in apoptosis, necrosis and innate immunity...
August 22, 2015: Retrovirology
Rfo Franca, S M Vieira, J Talbot, R S Peres, L G Pinto, D S Zamboni, P Louzada-Junior, F Q Cunha, T M Cunha
OBJECTIVES: The aim of this study was to analyse the expression and function of nucleotide-binding oligomerization domain (NOD)1 and NOD2 in isolated cells of patients with rheumatoid arthritis (RA). METHOD: mRNA expression levels of NOD1, NOD2, and receptor-interacting serine/threonine kinase 2 (RIPK2) genes were determined by quantitative polymerase chain reaction (qPCR) in peripheral blood mononuclear cells (PBMCs) and synovial fluid T cells (SFTCs) isolated from RA and osteoarthritis (OA) patients...
July 23, 2015: Scandinavian Journal of Rheumatology
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