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https://www.readbyqxmd.com/read/28103033/design-synthesis-and-biological-evaluation-of-small-high-affinity-siglec-7-ligands-toward-novel-inhibitors-of-cancer-immune-evasion
#1
Horst Prescher, Martin Frank, Stephan Gütgemann, Elena Kuhfeldt, Astrid Schweizer, Lars Nitschke, Carsten Watzl, Reinhard Brossmer
Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion...
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28100677/paired-siglec-receptors-generate-opposite-inflammatory-responses-to-a-human-specific-pathogen
#2
Flavio Schwarz, Corinna S Landig, Shoib Siddiqui, Ismael Secundino, Joshua Olson, Nissi Varki, Victor Nizet, Ajit Varki
Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen Escherichia coli K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing...
January 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28062010/splenic-cd163-macrophages-as-targets-of-porcine-reproductive-and-respiratory-virus-role-of-siglecs
#3
María Yuste, Teresa Fernández-Caballero, Cinta Prieto, Belén Álvarez, Javier Martínez-Lobo, Isabel Simarro, José María Castro, Fernando Alonso, Ángel Ezquerra, Javier Domínguez, Concepción Revilla
CD169 and CD163 have been involved in the process of PRRS virus attachment and infection in macrophages, although recent studies have challenged the requirement for CD169. In addition to CD169, macrophages express other siglecs, whose role in PRRS virus infection is so far unknown. Splenic CD163(+) macrophages express Siglec-3 and Siglec-5 but almost undetectable levels of CD169. Hence, we considered this cell population appropriate for analysing the role of these siglecs in the attachment and internalization of PRRS virus into macrophages...
January 2017: Veterinary Microbiology
https://www.readbyqxmd.com/read/28012129/expression-of-cd24-and-siglec-10-in-first-trimester-placenta-implications-for-immune-tolerance-at-the-fetal-maternal-interface
#4
Marei Sammar, Monika Siwetz, Hamutal Meiri, Viktor Fleming, Peter Altevogt, Berthold Huppertz
During pregnancy, the fetal-maternal interface establishes immune tolerance between the fetus and the mother. CD24, a mucin-like glycoprotein expressed at the surface of hematopoietic cells and diverse tumor cells, is known to interact with the sialic acid-binding immunoglobulin-type lectins (Siglecs). This interaction was assessed as a candidate complex for the immune suppression response in the placenta. CD24 was affinity purified from term placenta and characterized by SDS-PAGE, Western blot and ELISA. Binding of recombinant Siglecs to placental CD24 was evaluated by ELISA...
December 23, 2016: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28006787/role-of-mir-215-in-hirschsprung-s-disease-pathogenesis-by-targeting-siglec-8
#5
Hao Lei, Hongxing Li, Hua Xie, Chunxia Du, Yankai Xia, Weibing Tang
BACKGROUND/AIMS: Hirschsprung's disease (HSCR), known as aganglionosis, is an infrequent congenital gut motility disorder characterized by absence of enteric neurons. In this study, we focus on the role of the intronic miR-215 and its host gene isoleucyl-tRNA synthetase 2 (IARS2) in the pathogenesis of HSCR. METHODS: Quantitative real time PCR and Western blot were used to detect the miRNA, mRNAs, and proteins levels. The dual-luciferase reporter gene assay confirmed the direct regulation of the specific mRNA and miRNAs in cell lines...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27999993/the-sugar-code-in-neuronal-physiology
#6
REVIEW
Alonso M Higuero, Natalia Díez-Revuelta, José Abad-Rodríguez
Carbohydrate-related interactions are necessary for the correct development and function of the nervous system. As we illustrate with several examples, those interactions are controlled by carbohydrate-modifying enzymes and by carbohydrate-binding proteins that regulate a plethora of complex axonal processes. Among others, glycan-related proteins as sialidase Neu3 or galectins-1, -3, and -4 play central roles in the determination of axonal fate, axon growth, guidance and regeneration, as well as in polarized axonal glycoprotein transport...
December 20, 2016: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/27975143/sialylation-of-n-glycans-mechanism-cellular-compartmentalization-and-function
#7
REVIEW
Gaurang P Bhide, Karen J Colley
Sialylated N-glycans play essential roles in the immune system, pathogen recognition and cancer. This review approaches the sialylation of N-glycans from three perspectives. The first section focuses on the sialyltransferases that add sialic acid to N-glycans. Included in the discussion is a description of these enzymes' glycan acceptors, conserved domain organization and sequences, molecular structure and catalytic mechanism. In addition, we discuss the protein interactions underlying the polysialylation of a select group of adhesion and signaling molecules...
December 14, 2016: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/27973630/synthesis-of-end-functionalized-glycopolymers-containing-%C3%AE-2-8-disialic-acids-via-%C3%AF-allyl-nickel-catalyzed-coordinating-polymerization-and-their-interaction-with-siglec-7
#8
Shuichi Ohira, Yu Yasuda, Ikuyoshi Tomita, Ken Kitajima, Takashi Takahashi, Chihiro Sato, Hiroshi Tanaka
An allene monomer containing an α(2,8) disialic acid was polymerized by a π-allyl nickel complex with an azido group to produce end-functional glycopolymers with an excellent polydispersity index. The polymers allowed terminal modification with a fluorescent dye by click chemistry. The glycopolymers can dissociate Siglec-7-GD3 interactions at low concentrations.
January 3, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27920204/studies-on-the-detection-expression-glycosylation-dimerization-and-ligand-binding-properties-of-mouse-siglec-e
#9
Shoib Siddiqui, Flavio Schwarz, Stevan Springer, Zahra Khedri, Hai Yu, Lingquan Deng, Andrea Verhagen, Yuko Naito-Matsui, Weiping Jiang, Daniel Kim, Jie Zhou, Beibei Ding, Xi Chen, Nissi Varki, Ajit Varki
CD33-related Siglecs are a family of proteins widely expressed on innate immune cells. Binding of sialylated glycans or other ligands triggers signals that inhibit or activate inflammation. Immunomodulation by Siglecs has been extensively studied, but relationships between structure and functions are poorly explored. Here we present new data relating the structure and function of Siglec-E, the major CD33-related Siglec expressed on mouse neutrophils, monocytes, macrophages, and dendritic cells. We generated nine new rat monoclonal antibodies specific to mouse Siglec-E, with no cross-reactivity to Siglec-F...
December 5, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27893774/multivalent-interactions-of-human-primary-amine-oxidase-with-the-v-and-c22-domains-of-sialic-acid-binding-immunoglobulin-like-lectin-9-regulate-its-binding-and-amine-oxidase-activity
#10
Heli Elovaara, Vimal Parkash, Ruth Fair-Mäkelä, Outi M H Salo-Ahen, Gabriela Guédez, Eva Bligt-Lindén, Janne Grönholm, Sirpa Jalkanen, Tiina A Salminen
Sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on leukocyte surface is a counter-receptor for endothelial cell surface adhesin, human primary amine oxidase (hAOC3), a target protein for anti-inflammatory agents. This interaction can be used to detect inflammation and cancer in vivo, since the labeled peptides derived from the second C2 domain (C22) of Siglec-9 specifically bind to the inflammation-inducible hAOC3. As limited knowledge on the interaction between Siglec-9 and hAOC3 has hampered both hAOC3-targeted drug design and in vivo imaging applications, we have now produced and purified the extracellular region of Siglec-9 (Siglec-9-EC) consisting of the V, C21 and C22 domains, modeled its 3D structure and characterized the hAOC3-Siglec-9 interactions using biophysical methods and activity/inhibition assays...
2016: PloS One
https://www.readbyqxmd.com/read/27892504/soluble-siglec-5-associates-to-psgl-1-and-displays-anti-inflammatory-activity
#11
Marion Pepin, Soraya Mezouar, Julie Pegon, Vincent Muczynski, Frédéric Adam, Elsa P Bianchini, Amine Bazaa, Valerie Proulle, Alain Rupin, Jerome Paysant, Laurence Panicot-Dubois, Olivier D Christophe, Christophe Dubois, Peter J Lenting, Cécile V Denis
Interactions between endothelial selectins and the leukocyte counter-receptor PSGL1 mediates leukocyte recruitment to inflammation sites. PSGL1 is highly sialylated, making it a potential ligand for Siglec-5, a leukocyte-receptor that recognizes sialic acid structures. Binding assays using soluble Siglec-5 variants (sSiglec-5/C4BP and sSiglec-5/Fc) revealed a dose- and calcium-dependent binding to PSGL1. Pre-treatment of PSGL1 with sialidase reduced Siglec-5 binding by 79 ± 4%. In confocal immune-fluorescence assays, we observed that 50% of Peripheral Blood Mononuclear Cells (PBMCs) simultaneously express PSGL1 and Siglec-5...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27892478/continuous-single-cell-imaging-reveals-sequential-steps-of-plasmacytoid-dendritic-cell-development-from-common-dendritic-cell-progenitors
#12
Ezgi Dursun, Max Endele, Andrea Musumeci, Henrik Failmezger, Shu-Hung Wang, Achim Tresch, Timm Schroeder, Anne B Krug
Functionally distinct plasmacytoid and conventional dendritic cells (pDC and cDC) shape innate and adaptive immunity. They are derived from common dendritic cell progenitors (CDPs) in the murine bone marrow, which give rise to CD11c(+) MHCII(-) precursors with early commitment to DC subpopulations. In this study, we dissect pDC development from CDP into an ordered sequence of differentiation events by monitoring the expression of CD11c, MHC class II, Siglec H and CCR9 in CDP cultures by continuous single cell imaging and tracking...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27878892/influence-of-siglec9-polymorphisms-on-copd-phenotypes-including-exacerbation-frequency
#13
Takeo Ishii, Takashi Angata, Emily S Wan, Michael H Cho, Takashi Motegi, Congxiao Gao, Kazuaki Ohtsubo, Shinobu Kitazume, Akihiko Gemma, Peter D ParÉ, David A Lomas, Edwin K Silverman, Naoyuki Taniguchi, Kozui Kida
BACKGROUND AND OBJECTIVE: The exacerbation-prone phenotype of COPD is particularly important, as exacerbations lead to poor quality of life and disease progression. We previously found that COPD patients who lack Siglec-14, a myeloid cell protein that recognizes bacteria and triggers inflammatory responses, are less prone to exacerbation. We hypothesized that the variations in other SIGLEC genes could also influence COPD exacerbation frequency, and investigated the association between SIGLEC9 polymorphisms and the exacerbation-prone phenotype of COPD...
November 22, 2016: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/27874015/metabolic-sialic-acid-blockade-lowers-the-activation-threshold-of-modcs-for-tlr-stimulation
#14
Christian Büll, Estel Collado-Camps, Esther D Kers-Rebel, Torben Heise, Jonas N Søndergaard, Martijn H den Brok, Barbara M Schulte, Thomas J Boltje, Gosse J Adema
Sialic acid sugars cover the surface of dendritic cells (DCs) and have been suggested to impact several aspects of DC biology. Research into the role of sialic acids in DCs, however, is complicated by the limited number of tools available to modulate sialic acid expression. Here we report on a synthetic, fluorinated sialic acid mimetic, Ac53FaxNeu5Ac, which potently blocks sialic acid expression in human monocyte-derived DCs (moDCs). Sialic acid blockade enhanced the responsiveness of moDCs to Toll-like receptor (TLR) stimulation as measured by increased maturation marker expression and cytokine production...
November 22, 2016: Immunology and Cell Biology
https://www.readbyqxmd.com/read/27871915/inhibition-of-siglec-1-by-lentivirus-mediated-small-interfering-rna-attenuates-atherogenesis-in-apoe-deficient-mice
#15
Yi-Song Xiong, Ai-Lin Wu, Dong Mu, Juan Yu, Ping Zeng, Yi Sun, Jie Xiong
BACKGROUND: Siglec-1 is highly expressed on circulating monocytes and plaque macrophages in atherosclerotic patients, but the exact role of Siglec-1 in atherosclerosis has not been elucidated. METHODS: Lentiviral vector containing small interfering RNA targeting Siglec-1 (Lv-shSiglec-1) or control vector (Lv-shNC) were injected intravenously into 6-week old Apoe(-/-) mice. Then onset of atherosclerosis was observed. RESULTS: Siglec-1 was highly expressed in aortic plaques and it can be down-regulated by Lv-shSiglec-1 injection...
November 15, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27808110/structural-characterisation-of-high-affinity-siglec-2-cd22-ligands-in-complex-with-whole-burkitt-s-lymphoma-bl-daudi-cells-by-nmr-spectroscopy
#16
Paul D Madge, Andrea Maggioni, Mauro Pascolutti, Moein Amin, Mario Waespy, Bernadette Bellette, Robin J Thomson, Sørge Kelm, Mark von Itzstein, Thomas Haselhorst
Siglec-2 undergoes constitutive endocytosis and is a drug target for autoimmune diseases and B cell-derived malignancies, including hairy cell leukaemia, marginal zone lymphoma, chronic lymphocytic leukaemia and non-Hodgkin's lymphoma (NHL). An alternative to current antibody-based therapies is the use of liposomal nanoparticles loaded with cytotoxic drugs and decorated with Siglec-2 ligands. We have recently designed the first Siglec-2 ligands (9-biphenylcarboxamido-4-meta-nitrophenyl-carboxamido-Neu5Acα2Me, 9-BPC-4-mNPC-Neu5Acα2Me) with simultaneous modifications at C-4 and C-9 position...
November 3, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27780012/lectin-receptors-expressed-on-myeloid-cells
#17
Gordon D Brown, Paul R Crocker
Lectins recognize a diverse array of carbohydrate structures and perform numerous essential biological functions. Here we focus on only two families of lectins, the Siglecs and C-type lectins. Triggering of intracellular signaling cascades following ligand recognition by these receptors can have profound effects on the induction and modulation of immunity. In this chapter, we provide a brief overview of each family and then focus on selected examples that highlight how these lectins can influence myeloid cell functioning in health and disease...
October 2016: Microbiology Spectrum
https://www.readbyqxmd.com/read/27731409/leukocyte-trafficking-associated-vascular-adhesion-protein-1-is-expressed-and-functionally-active-in-atherosclerotic-plaques
#18
Johanna M U Silvola, Helena Virtanen, Riikka Siitonen, Sanna Hellberg, Heidi Liljenbäck, Olli Metsälä, Mia Ståhle, Tiina Saanijoki, Meeri Käkelä, Harri Hakovirta, Seppo Ylä-Herttuala, Pekka Saukko, Matti Jauhiainen, Tibor Z Veres, Sirpa Jalkanen, Juhani Knuuti, Antti Saraste, Anne Roivainen
Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms...
October 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27714250/screening-of-neu5ac%C3%AE-2-6-gal-isomer-preferences-of-siglecs-with-a-sialic-acid-microarray
#19
Rohan Yadav, Shani Leviatan Ben-Arye, Balamurugan Subramani, Vered Padler-Karavani, Raghavendra Kikkeri
Sialic acids (Sias) are important terminal sugars on cell surfaces involved in a wide range of protein-carbohydrate interactions. Hence, agents modulating sias-mediated protein interactions are promising inhibitors or vaccine candidates. Here, we report the synthesis of Neu5Acα(2-6)Gal structural analogs and their binding to a series of siglecs. The results showed distinct binding patterns with conserved siglecs (hCD22 and mCD22) compared to rapid evolving siglecs (Siglecs -3 & -10).
September 27, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27711121/identification-of-ompa-like-protein-of-tannerella-forsythia-as-an-o-linked-glycoprotein-and-its-binding-capability-to-lectins
#20
Toshi Horie, Megumi Inomata, Takeshi Into, Yoshiaki Hasegawa, Noriyuki Kitai, Fuminobu Yoshimura, Yukitaka Murakami
Bacterial glycoproteins are associated with physiological and pathogenic functions of bacteria. It remains unclear whether bacterial glycoproteins can bind to specific classes of lectins expressed on host cells. Tannerella forsythia is a gram-negative oral anaerobe that contributes to the development of periodontitis. In this study, we aimed to find lectin-binding glycoproteins in T. forsythia. We performed affinity chromatography of wheat germ agglutinin, which binds to N-acetylglucosamine (GlcNAc) and sialic acid (Sia), and identified OmpA-like protein as the glycoprotein that has the highest affinity...
2016: PloS One
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