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https://www.readbyqxmd.com/read/28641140/effect-of-c1-inh-on-ischemia-reperfusion-injury-in-a-porcine-limb-ex-vivo-perfusion-model
#1
Mai M Abdelhafez, Jane Shaw, Damian Sutter, Jonas Schnider, Yara Banz, Hansjörg Jenni, Esther Voegelin, Mihai A Constantinescu, Robert Rieben
Revascularization of an amputated limb within 4-6h is essential to avoid extensive ischemia/reperfusion (I/R) injury leading to vascular leakage, edema and tissue necrosis. I/R injury is a pathological inflammatory condition that occurs during reperfusion of an organ or tissue after prolonged ischemia. It is characterized by a complex crosstalk between endothelial cell activation and the activation of plasma cascades. Vasculoprotective pharmacological intervention to prevent I/R injury might be an option to prolong the time window between limb amputation and successful replantation...
June 19, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28640789/complement-mediated-enhancement-of-monocyte-adhesion-to-endothelial-cells-by-hla-antibodies-and-blockade-by-a-specific-inhibitor-of-the-classical-complement-cascade-tnt003
#2
Nicole M Valenzuela, Kimberly A Thomas, Arend Mulder, Graham C Parry, Sandip Panicker, Elaine F Reed
BACKGROUND: Antibody-mediated rejection (AMR) of most solid organs is characterized by evidence of complement activation and/or intragraft macrophages (C4d + and CD68+ biopsies). We previously demonstrated that crosslinking of HLA I by antibodies triggered endothelial activation and monocyte adhesion. We hypothesized that activation of the classical complement pathway at the endothelial cell surface by HLA antibodies would enhance monocyte adhesion through soluble split product generation, in parallel with direct endothelial activation downstream of HLA signaling...
July 2017: Transplantation
https://www.readbyqxmd.com/read/28638625/early-eculizumab-use-in-atypical-haemolytic-uraemic-syndrome-in-a-jehovah-s-witness-refusing-blood-products
#3
May Al-Shaghana, Andrew Bentall, Mark D Jesky, William Lester, Graham Lipkin
Thrombotic microangiopathy (TMA) is characterized by microscopic angiopathic haemolytic anaemia, thrombocytopenia and organ injury. Supportive therapies include the use of blood products. Recently the terminal complement inhibitor eculizumab has been approved in atypical haemolytic uraemic syndrome (aHUS) in some countries. We report the case of a 23-year-old female Jehovah's Witness presenting with vaginal haemorrhage from thrombocytopaenia, severe anaemia (nadir Hb 28 g/L) and anuric acute kidney injury with TMA secondary to aHUS...
June 2017: Oxford Medical Case Reports
https://www.readbyqxmd.com/read/28637898/activation-of-complement-by-pigment-epithelium-derived-factor-in-rheumatoid-arthritis
#4
Leonie M Vogt, Simone Talens, Ewa Kwasniewicz, Carsten Scavenius, André Struglics, Jan J Enghild, Tore Saxne, Anna M Blom
The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family...
June 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28637511/the-emergence-of-mesencephalic-trigeminal-neurons
#5
Marcela Lipovsek, Julia Ledderose, Thomas Butts, Tanguy Lafont, Clemens Kiecker, Andrea Wizenmann, Anthony Graham
BACKGROUND: The cells of the mesencephalic trigeminal nucleus (MTN) are the proprioceptive sensory neurons that innervate the jaw closing muscles. These cells differentiate close to the two key signalling centres that influence the dorsal midbrain, the isthmus, which mediates its effects via FGF and WNT signalling and the roof plate, which is a major source of BMP signalling as well as WNT signalling. METHODS: In this study, we have set out to analyse the importance of FGF, WNT and BMP signalling for the development of the MTN...
June 21, 2017: Neural Development
https://www.readbyqxmd.com/read/28634421/the-role-of-von-willebrand-factor-in-vascular-inflammation-from-pathogenesis-to-targeted-therapy
#6
REVIEW
Felice Gragnano, Simona Sperlongano, Enrica Golia, Francesco Natale, Renatomaria Bianchi, Mario Crisci, Fabio Fimiani, Ivana Pariggiano, Vincenzo Diana, Andreina Carbone, Arturo Cesaro, Claudia Concilio, Giuseppe Limongelli, Mariagiovanna Russo, Paolo Calabrò
Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28630122/eculizumab-blocks-vaccine-induced-opsonophagocytic-killing-of-meningococci-by-whole-blood-from-immunized-adults
#7
Monica Konar, Dan M Granoff
Eculizumab, a humanized anti-complement C5 monoclonal antibody for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended, but whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A,C,W,Y vaccines...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28630087/paucimannose-rich-n-glycosylation-of-spatiotemporally-regulated-human-neutrophil-elastase-modulates-its-immune-functions
#8
Ian Loke, Ole Østergaard, Niels H H Heegaard, Nicolle H Packer, Morten Thaysen-Andersen
Human neutrophil elastase (HNE) is an important N-glycosylated serine protease in the innate immune system, but the structure and immune-modulating functions of HNE N-glycosylation remain undescribed. Herein, LC-MS/MS-based glycan, glycopeptide and glycoprotein profiling were utilised to first determine the heterogeneous N-glycosylation of HNE purified from neutrophil lysates and then from isolated neutrophil granules of healthy individuals. The spatiotemporal expression of HNE during neutrophil activation and the biological importance of its N-glycosylation were also investigated using immunoblotting, cell surface capture, native MS, receptor interaction, protease inhibition, and bacteria growth assays...
June 19, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28629465/natural-igm-antibodies-that-bind-neoepitopes-exposed-as-a-result-of-spinal-cord-injury-drive-secondary-injury-by-activating-complement
#9
Aarti Narang, Fei Qiao, Carl Atkinson, Hong Zhu, Xiaofeng Yang, Liudmila Kulik, V Michael Holers, Stephen Tomlinson
BACKGROUND: Natural IgM antibodies (Abs) function as innate immune sensors of injury via recognition of neoepitopes expressed on damaged cells, although how this recognition systems function following spinal cord injury (SCI) exposes various neoepitopes and their precise nature remains largely unknown. Here, we investigated the role of two natural IgM monoclonal Abs (mAbs), B4 and C2, that recognize post-ischemic neoepitopes following ischemia and reperfusion in other tissues. METHODS: Identification of post-SCI expressed neoepitopes was examined using previously characterized monoclonal Abs (B4 and C2 mAbs)...
June 19, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28628799/a-novel-2-stage-approach-that-detects-complement-activation-in-patients-with-antiphospholipid-antibody-syndrome
#10
Jacob H Rand, Xiao-Xuan Wu, Lucia R Wolgast, Victor Lei, Edward M Conway
INTRODUCTION: The antiphospholipid syndrome (APS) is marked by autoantibodies that recognize anionic phospholipids in a cofactor-dependent manner. A role for complement has been implicated in the pathophysiology, however, elevations of complement activation markers have not been consistently demonstrated in clinical studies. We therefore designed a proof-of-principle study to determine whether complement activation might be detectable in APS by first exposing plasmas to phospholipid vesicles...
June 9, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28628770/a-comparative-analysis-between-proteasome-and-immunoproteasome-inhibition-in-cellular-and-humoral-alloimmunity
#11
Theodoros Eleftheriadis, Georgios Pissas, Georgia Antoniadi, Vassilios Liakopoulos, Ioannis Stefanidis
Triggered by the successful administration of the proteasome inhibitor bortezomib in kidney transplant recipients with acute or chronic antibody-mediated rejection, we evaluated the effect of the proteasome inhibitor CEP-18770 and of the selective immunoproteasome inhibitor ONX-0914 on cellular and humoral alloimmunity. Cellular alloimmunity was assessed by cell proliferation in a two-way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method, where humoral alloimmunity was induced in one-way MLR...
June 16, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28627616/distinct-cellular-phenotype-linked-to-defective-dna-interstrand-crosslink-repair-and-homologous-recombination
#12
Aleksandra M Gorniewska, Katarzyna Kluzek, Lidia Gackowska, Izabela Kubiszewska, Malgorzata Z Zdzienicka, Aneta Bialkowska
Repair of DNA interstrand crosslinks (ICLs) predominantly involves the Fanconi anemia (FA) pathway and homologous recombination (HR). The HR repair system eliminates DNA double strand breaks (DSBs) that emerge during ICLs removal. The current study presents a novel cell line, CL‑V8B, representing a new complementation group of Chinese hamster cell mutants hypersensitive to DNA crosslinking factors. CL‑V8B exhibits increased sensitivity to various DNA‑damaging agents, including compounds leading to DSBs formation (bleomycin and 6‑thioguanine), and is extremely sensitive to poly (ADP-ribose) polymerase inhibitor (>400‑fold), which is typical for HR‑defective cells...
June 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28626544/atypical-hemolytic-uremic-syndrome-a-brief-review
#13
REVIEW
Kuixing Zhang, Yuxin Lu, Kevin T Harley, Minh-Ha Tran
Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury...
June 1, 2017: Hematology Reports
https://www.readbyqxmd.com/read/28626076/cardiac-fibroblast-transcriptome-analyses-support-a-role-for-interferogenic-profibrotic-and-inflammatory-genes-in-anti-ssa-ro-associated-congenital-heart-block
#14
Robert M Clancy, Androo J Markham, Tanisha Jackson, Sara E Rasmussen, Miroslav Blumenberg, Jill P Buyon
The signature lesion of SSA/Ro autoantibody-associated congenital heart block (CHB) is fibrosis and a macrophage infiltrate, supporting an experimental focus on cues influencing the fibroblast component. The transcriptomes of human fetal cardiac fibroblasts were analyzed using two complementary approaches. Cardiac injury conditions were simulated in vitro by incubating human fetal cardiac fibroblasts with supernatants from macrophages transfected with the SSA/Ro-associated hY3. The top ten upregulated transcripts in the stimulated fibroblasts reflected a type I interferon (IFN) response (e...
June 16, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28626006/atairp2-e3-ligase-affects-aba-and-high-salinity-responses-by-stimulating-its-atp1-sdirip1-substrate-turnover
#15
Tae Rin Oh, Jong Hum Kim, Seok Keun Cho, Moon Young Ryu, Seong Wook Yang, Woo Taek Kim
AtAIRP2 is a cytosolic RING-type E3 ubiquitin (Ub) ligase that positively regulates an ABA response in Arabidopsis (Arabidopsis thaliana). Yeast two-hybrid screening using AtAIRP2 as bait identified ATP1 (AtAIRP2 Target Protein 1) as a substrate of AtAIRP2. ATP1 was found to be identical to SDIRIP1, which was recently reported to be a negative factor in ABA signaling and a target protein of the RING E3 ligase SDIR1. ATP1 was accordingly renamed ATP1/SDIRIP1. A specific interaction between AtAIRP2 and ATP1/SDIRIP1 and ubiquitination of ATP1/SDIRIP1 by AtAIRP2 were demonstrated in vitro and in planta...
June 16, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28623239/-ccug-n-rna-toxicity-in-a-drosophila-model-for-myotonic-dystrophy-type-2-dm2-activates-apoptosis
#16
Vildan Betul Yenigun, Mario Sirito, Alla Amcheslavky, Tomek Czernuszewicz, Jordi Colonques-Bellmunt, Irma García-Alcover, Marzena Wojciechowska, Clare Bolduc, Zhihong Chen, Arturo López Castel, Ralf Krahe, Andreas Bergmann
The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions -- (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length (n=16 and 106)...
June 16, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28622402/prevalence-of-concurrent-prescribing-of-ace-is-and-arbs-among-beneficiaries-of-puerto-rico-s-government-sponsored-health-care-plan-during-2012-and-2013
#17
Denise Figueroa-Ríos, José J Hernández-Muñoz, Aileen García-Albarrán, Emily A García-Rodríguez, Glendaliz Méndez-Hernández, Suzette M Vélez-Rivera
OBJECTIVE: Cardiovascular conditions are the second cause of death in Puerto Rico. The individual use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) is considered the first-line therapy for the treatment of several cardiovascular-related medical conditions. However, the concurrent use of these 2 therapeutic classes of drugs is not supported by treatment guidelines. Studies have shown that their concurrent use represents a potential health risk...
June 2017: Puerto Rico Health Sciences Journal
https://www.readbyqxmd.com/read/28621538/discovery-of-highly-potent-and-selective-small-molecule-reversible-factor-d-inhibitors-demonstrating-alternative-complement-pathway-inhibition-in-vivo
#18
Edwige Lorthiois, Karen Anderson, Anna Vulpetti, Olivier Rogel, Frederic Cumin, Nils Ostermann, Stefan Steinbacher, Aengus Mac Sweeney, Omar Delgado, Sha-Mei Liao, Stefan Randl, Simon Rüdisser, Solene Dussauge, Kamal Fettis, Laurence Kieffer, Andrea de Ekernez, Louis Yang, Constanze Hartwieg, Upendra A Argikar, Laura R LaBonte, Ronald Newton, Viral Kansara, Stefanie Flohr, Ulrich Hommel, Bruce Jaffee, Jürgen Maibaum
The highly specific S1 serine protease Factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of non-covalent reversible and selective human Factor D (FD) inhibitors with drug-like properties...
June 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28611756/pathogenic-leptospira-secreted-proteases-target-the-membrane-attack-complex-a-potential-role-for-thermolysin-in-complement-inhibition
#19
Thais A Amamura, Tatiana R Fraga, Sílvio A Vasconcellos, Angela S Barbosa, Lourdes Isaac
Leptospirosis is a zoonosis caused by spirochetes from the genus Leptospira. This disease is common in tropical and subtropical areas, constituting a serious public health problem. Pathogenic Leptospira have the ability to escape the human Complement System, being able to survive when in contact with normal human serum. In a previous study, our group demonstrated that supernatants of pathogenic Leptospira (SPL) inhibit the three activation pathways of the Complement System. This inhibition can be directly correlated with the activity of secreted proteases, which cleave the Complement molecules C3, Factor B (Alternative Pathway), C4 and C2 (Classical and Lectin Pathways)...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28601470/tissue-and-serum-mrna-profile-of-mmps-2-9-as-a-potential-novel-biomarker-for-the-most-individual-approach-in-infantile-hemangiomas-and-cancer-disease
#20
Katarzyna Taran, Aneta Wnęk, Józef Kobos, Ewa Andrzejewska, Przemysław Przewratil
Propranolol is a widely-known beta-blocker approved for treating infantile hemangiomas (IH). The mechanisms behind the spectacular IH involution after propranolol treatment remain unclear. Recently, there is strong evidence of overexpression of numerous angiogenic factors in IH tissues, and it is reported that propranolol influences their pathways. However, a number of MMPs studies is highly limited. Here, for the first time, we propose a comprehensive approach by analyzing the expression levels of metalloproteinases-2/9 (MMPs-2/9) and tissue metalloproteinase inhibitor-2 (TIMP-2) in vivo on both, molecular and immunohistochemical levels, and in both, IH tissues and in the serum of IH patients, and relates the obtained results to the tumor's biology and systemic propranolol treatment...
June 3, 2017: Immunobiology
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