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https://www.readbyqxmd.com/read/29335241/the-mfhr1-fusion-protein-is-a-novel-synthetic-multitarget-complement-inhibitor-with-therapeutic-potential
#1
Stefan Michelfelder, Friedericke Fischer, Astrid Wäldin, Kim V Hörle, Martin Pohl, Juliana Parsons, Ralf Reski, Eva L Decker, Peter F Zipfel, Christine Skerka, Karsten Häffner
The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1...
January 15, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29327939/blockade-of-the-complement-c5a-c5ar1-axis-impairs-lung-cancer-bone-metastasis-by-cxcl16-mediated-effects
#2
Daniel Ajona, Carolina Zandueta, Leticia Corrales, Haritz Moreno, María J Pajares, Sergio Ortiz-Espinosa, Elena Martínez-Terroba, Naiara Perurena, Fernando J de Miguel, Eloisa Jantus-Lewintre, Carlos Camps, Silvestre Vicent, Jackeline Agorreta, Luis M Montuenga, Ruben Pio, Fernando Lecanda
RATIONALE: C5aR1(CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of NSCLC cells is poorly understood. OBJECTIVES: To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of NSCLC cells, particularly in skeletal colonization, a preferential lung metastasis site. METHODS: Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry...
January 12, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29322327/combined-and-sequential-liver-kidney-transplantation-in-children
#3
Ryszard Grenda, Piotr Kaliciński
Combined and sequential liver-kidney transplantation (CLKT and SLKT) is a definitive treatment in children with end-stage organ failure. There are two major indications: - terminal insufficiency of both organs, or - need for transplanting new liver as a source of lacking enzyme or specific regulator of the immune system in a patient with renal failure. A third (uncommon) option is secondary end-stage renal failure in liver transplant recipients. These three clinical settings use distinct qualification algorithms...
January 10, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/29315316/the-c3ar-promotes-macrophage-infiltration-and-regulates-anca-production-but-does-not-affect-glomerular-injury-in-experimental-anti-myeloperoxidase-glomerulonephritis
#4
Jonathan Dick, Poh-Yi Gan, A Richard Kitching, Stephen R Holdsworth
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides are autoimmune diseases associated with significant morbidity and mortality. They often affect the kidney causing rapidly progressive glomerulonephritis. While signalling by complement anaphylatoxin C5a though the C5a receptor is important in this disease, the role of the anaphylatoxin C3a signalling via the C3a receptor (C3aR) is not known. Using two different murine models of anti-myeloperoxidase (MPO) glomerulonephritis, one mediated by passive transfer of anti-MPO antibodies, the other by cell-mediated immunity, we found that the C3aR did not alter histological disease severity...
2018: PloS One
https://www.readbyqxmd.com/read/29300009/structure-of-the-complement-c5a-receptor-bound-to-the-extra-helical-antagonist-ndt9513727
#5
Nathan Robertson, Mathieu Rappas, Andrew S Doré, Jason Brown, Giovanni Bottegoni, Markus Koglin, Julie Cansfield, Ali Jazayeri, Robert M Cooke, Fiona H Marshall
The complement system is a crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins including C5a and C3a. C5a exerts a pro-inflammatory effect via the G-protein-coupled receptor C5a anaphylatoxin chemotactic receptor 1 (C5aR1, also known as CD88) that is expressed on cells of myeloid origin. Inhibitors of the complement system have long been of interest as potential drugs for the treatment of diseases such as sepsis, rheumatoid arthritis, Crohn's disease and ischaemia-reperfusion injuries...
January 3, 2018: Nature
https://www.readbyqxmd.com/read/29297237/species-specific-differences-in-regulation-of-macrophage-inflammation-by-the-c3a-c3a-receptor-axis
#6
Tathagat Dutta Ray, Samrawit Mekasha, Yanmei Liang, Bao Lu, Sanjay Ram, Robin R Ingalls
Complement is an important arm of the innate immune system. Recent studies have shown that products of complement pathway activation can interact directly with other innate immune signaling molecules, including TLRs and inflammasome family members, during some infectious and chronic inflammatory disorders. Activation of the complement system generates anaphylatoxins, such as C3a and C5a, which modulate inflammation. However, the biological effects of interactions between the anaphylatoxins with their receptors may vary across species...
January 1, 2018: Innate Immunity
https://www.readbyqxmd.com/read/29296968/a-fully-recombinant-human-igg1-fc-multimer-gl-2045-inhibits-complement-mediated-cytotoxicity-and-induces-ic3b
#7
Hua Zhou, Henrik Olsen, Edward So, Emmanuel Mérigeon, Denis Rybin, Jane Owens, Gregory LaRosa, David S Block, Scott E Strome, Xiaoyu Zhang
GL-2045 is a recombinant human immunoglobulin G1 (IgG1)-based Fc multimer designed to recapitulate the anti-inflammatory activities of intravenous immunoglobulin (IVIG) on the innate and adaptive immune responses. We used functional in vitro studies to determine if GL-2045 could mimic the modulatory activity of IVIG on complement activation. GL-2045, at log-order lower concentrations than heat-aggregated IgG (HAGG) and IVIG, protected antibody-opsonized cells from complement-dependent cytotoxicity. These protective effects were completely mediated by the higher order multimer fractions of GL-2045 and were partially dependent upon sequestration of C1q...
March 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/29288518/participation-of-delta-annexin-a3-in-the-ribosomal-protein-s19-c-terminus-dependent-inhibitory-mechanism-of-the-neutrophil-c5a-receptor-through-delta-lactoferrin
#8
Koji Yamanegi, Naoko Yamada, Keiji Nakasho, Hiroshi Nishiura
Although C5a receptor (C5aR) interacting with its agonist C5a promotes acute inflammation during the initiation phase, the roles of the recycling C5aR during the resolution phase are still unclear. We found that C5aR interacted with its antagonist/agonist ribosomal protein S19 (RP S19) polymer or a RP S19 polymer functional analogue S-tagged C5a/RP S19, which connects an RP S19 C-terminus (IAGQVAAANKKH) to the S-tagged C5a C-terminus, promoted acute inflammation at the resolution phase via an activation of the apoptosis-inducing transcription factor delta lactoferrin (δLf) in neutrophils and the membrane mobilizing factor full-length annexin A3 (ANXA3) in macrophages...
December 29, 2017: Pathology International
https://www.readbyqxmd.com/read/29286075/genome-expression-profiling-predicts-the-molecular-mechanism-of-peripheral-myelination
#9
Xiaoming Wu
The present study aimed to explore the molecular mechanism of myelination in the peripheral nervous system (PNS) based on genome expression profiles. Microarray data (GSE60345) was acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were integrated and subsequently subjected to pathway and term enrichment analysis. A protein‑protein interaction network was constructed and the top 200 DEGs according to their degree value were further subjected to pathway enrichment analysis...
December 22, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29285167/effectiveness-of-c5a-aptamers-in-a-tnbs-induced-colitis-mouse-model
#10
Zhiping Li, Xiwen Wang, Man Chen, Yuanyuan Wang, Rui Sun, Han Qu, Yu Sun, Weicun Gao, Bo Li, Xiaolin Dong, Yandong Zhang, Zhiping Xia
The complement-activated product, complement component 5a (C5a), is a potent inflammatory peptide with a broad spectrum of functions. In vivo and in vitro studies have demonstrated that C5a serves an important role in inflammation; however, the role of C5a in the pathogenesis of inflammatory bowel disease (IBD) is not known. The purpose of the current study was to investigate the role of C5a in IBD using an experimental mouse model of colitis. Colitis was induced in mice using 2,4,6-trinitrobenzene sulfonic acid (TNBS), and C5a aptamers were subsequently administered via intraperitoneal injection...
December 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29277896/c5ar-activation-in-the-absence-of-c5a-a-new-disease-mechanism-of-autoimmune-hemolytic-anemia-in-mice
#11
Shahzad N Syed, Eduard Rau, Mareen Ziegelmann, Georgios Sogkas, Bernhard Brüne, Reinhold E Schmidt
IgG Fc receptors (FcγRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease...
December 25, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29274925/role-of-complement-anaphylatoxin-receptors-in-a-mouse-model-of-acute-burn-induced-pain
#12
Michael Morgan, Jennifer R Deuis, Trent M Woodruff, Richard J Lewis, Irina Vetter
The complement system is an essential component of the innate immune response. The anaphylatoxins C3a and C5a are key drivers of the complement system, acting through the receptors C3aR, C5aR1 and C5aR2 to regulate inflammation. While a role for C5a activation of C5aR1 in inflammatory and neuropathic pain has been established, the role of the complement system in burn-induced pain has not been investigated. To address this gap, we assessed the role of complement receptors C3aR, C5aR1 and C5aR2 in a mouse model of acute burn-induced pain...
December 21, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/29241626/c5a-receptor-1-promotes-autoimmunity-neutrophil-dysfunction-and-injury-in-experimental-anti-myeloperoxidase-glomerulonephritis
#13
Jonathan Dick, Poh-Yi Gan, Sharon L Ford, Dragana Odobasic, Maliha A Alikhan, Sven H Loosen, Pam Hall, Clare L Westhorpe, Anqi Li, Joshua D Ooi, Trent M Woodruff, Charles R Mackay, A Richard Kitching, Michael J Hickey, Stephen R Holdsworth
The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described...
December 11, 2017: Kidney International
https://www.readbyqxmd.com/read/29233117/elizabethkingia-miricola-as-an-opportunistic-oral-pathogen-associated-with-superinfectious-complications-in-humoral-immunodeficiency-a-case-report
#14
Przemysław Zdziarski, Mariola Paściak, Klaudia Rogala, Agnieszka Korzeniowska-Kowal, Andrzej Gamian
BACKGROUND: Elizabethkingia miricola is a rare Gram-negative bacterium found in water and clinical specimens. Typical culturing methods often misidentify Elizabethkingia spp. as Flavobacterium or Chryseobacterium. Although diagnosis is based on culturing samples taken from sterile sites, such as blood, a proper identification of this bacterium requires an expertise that goes beyond the capabilities of a typical clinical laboratory. CASE PRESENTATION: A 35-year-old woman diagnosed with common variable immunodeficiency was admitted to our center...
December 12, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/29232581/homo-and-heteroleptic-pt-ii-complexes-of-onn-donor-hydrazone-and-4-picoline-a-synthetic-structural-and-detailed-mechanistic-anticancer-investigation
#15
Faiz-Ur Rahman, Muhammad Zeeshan Bhatti, Amjad Ali, Hong-Quan Duong, Yao Zhang, Bo Yang, Satish Koppireddi, Yuejian Lin, Hui Wang, Zhan-Ting Li, Dan-Wei Zhang
Two series of homoleptic Pt(II)(hydrazone)Cl (C1a-C5a) and heteroleptic Pt(II)(hydrazone)(4-picoline). BF4 (C1b-C5b) complexes were prepared and characterized by 1H, 13C, 19F NMR and HR ESI-MS. Structure of C2b was confirmed by single crystal X-ray analysis. These complexes were studied for their in vitro anticancer activities in human multiple cancer cells including breast (MCF-7), liver (HepG2), lung (H460), colon (HCT116) and cervical (Hela) cancers. C1a-C5a and C1b-C5b showed considerable anticancer effect...
November 26, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29232196/mechanisms-of-action-of-intravenous-immunoglobulin-in-septic-encephalopathy
#16
Figen Esen, Perihan Ergin Ozcan, Erdem Tuzun, M Dustin Boone
Acute brain dysfunction associated with sepsis is a serious complication that results in morbidity and mortality. Intravenous immunoglobulin (IVIg) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Our results suggest that IVIgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation...
December 12, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29227823/lncrna-malat1-regulates-sepsis-induced-cardiac-inflammation-and-dysfunction-via-interaction-with-mir-125b-and-p38-mapk-nf%C3%AE%C2%BAb
#17
Hu Chen, Xiaoyun Wang, Xuetao Yan, Xiaoli Cheng, Xianghu He, Wenzhong Zheng
This study aimed to explore the role of MALAT1 in sepsis-induced cardiac inflammation and dysfunction. We constructed the rat sepsis models through cecal ligation and puncture (CLP). The cardiac function, including left ventricular peak pressure (LVPP), left ventricular end diastolic pressure (LVEDP) and maximum rate of rise/fall of left ventricle pressure (±dp/dtmax) as well as the contents of serum cardiac troponin I (CTn-I), creatine kinase (CK), and creative kinase isoenzyme MB (CK-MB) were detected after modeling...
December 7, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29226158/corrigendum-to-the-controversial-c5a-receptor-c5ar2-its-role-in-health-and-disease
#18
Ting Zhang, Malgorzata A Garstka, Ke Li
[This corrects the article DOI: 10.1155/2017/8193932.].
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/29220376/c5a-and-c5ar-are-elevated-in-joints-of-rheumatoid-and-psoriatic-arthritis-patients-and-c5ar-blockade-attenuates-leukocyte-migration-to-synovial-fluid
#19
Lars Hornum, Anker Jon Hansen, Ditte Tornehave, Marianne Scheel Fjording, Paula Colmenero, Inger Falbe Wätjen, Niels Henrik Søe Nielsen, Henning Bliddal, Else Marie Bartels
Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects...
2017: PloS One
https://www.readbyqxmd.com/read/29218045/factor-h-c-terminal-domains-are-critical-for-regulation-of-platelet-granulocyte-aggregate-formation
#20
Adam Z Blatt, Gurpanna Saggu, Claudio Cortes, Andrew P Herbert, David Kavanagh, Daniel Ricklin, John D Lambris, Viviana P Ferreira
Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndrome (aHUS), yet it is unknown whether increased PGA formation contributes to the thrombosis seen in patients with aHUS. Here, flow cytometry assays were used to evaluate the effects of aHUS-related mutations on FH regulation of PGA formation and characterize the mechanism...
2017: Frontiers in Immunology
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