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complement inhibitor

Guankui Wang, Fangfang Chen, Nirmal K Banda, V Michael Holers, LinPing Wu, S Moein Moghimi, Dmitri Simberg
While having tremendous potential as therapeutic and imaging tools, the clinical use of engineered nanoparticles has been associated with serious safety concerns. Activation of the complement cascade and the release of proinflammatory factors C3a and C5a may contribute to infusion-related reactions, whereas opsonization with C3 fragments promotes rapid recognition and clearance of nanomaterials by mononuclear phagocytes. We used dextran-coated superparamagnetic iron oxide nanoparticles (SPIO), which are potent activators of the complement system, to study the role of nanoparticle surface chemistry in inciting complement in human serum...
2016: Frontiers in Immunology
Jürgen Maibaum, Sha-Mei Liao, Anna Vulpetti, Nils Ostermann, Stefan Randl, Simon Rüdisser, Edwige Lorthiois, Paul Erbel, Bernd Kinzel, Fabrice A Kolb, Samuel Barbieri, Julia Wagner, Corinne Durand, Kamal Fettis, Solene Dussauge, Nicola Hughes, Omar Delgado, Ulrich Hommel, Ty Gould, Aengus Mac Sweeney, Bernd Gerhartz, Frederic Cumin, Stefanie Flohr, Anna Schubart, Bruce Jaffee, Richard Harrison, Antonio Maria Risitano, Jörg Eder, Karen Anderson
Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH)...
October 24, 2016: Nature Chemical Biology
P Dhakal, V R Bhatt
Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development...
October 24, 2016: Bone Marrow Transplantation
Pirow Bekker, Daniel Dairaghi, Lisa Seitz, Manmohan Leleti, Yu Wang, Linda Ertl, Trageen Baumgart, Sarah Shugarts, Lisa Lohr, Ton Dang, Shichang Miao, Yibin Zeng, Pingchen Fan, Penglie Zhang, Daniel Johnson, Jay Powers, Juan Jaen, Israel Charo, Thomas J Schall
The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood...
2016: PloS One
Christian M Felix, Marc H Levin, Alan S Verkman
BACKGROUND: Neuromyelitis optica (NMO), an autoimmune inflammatory disease of the central nervous system, is often associated with retinal abnormalities including thinning of the retinal nerve fiber layer and microcystic changes. Here, we demonstrate that passive transfer of an anti-aquaporin-4 autoantibody (AQP4-IgG) produces primary retinal pathology. METHODS: AQP4-IgG was delivered to adult rat retinas by intravitreal injection. Rat retinas and retinal explant cultures were assessed by immunofluorescence...
October 20, 2016: Journal of Neuroinflammation
Astrid Escudero-Esparza, Michael Bartoschek, Chrysostomi Gialeli, Marcin Okroj, Sioned Owen, Karin Jirström, Akira Orimo, Wen G Jiang, Kristian Pietras, Anna M Blom
Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients...
October 18, 2016: Oncotarget
Julia Smedbråten, Geir Mjøen, Anders Hartmann, Anders Åsberg, Halvor Rollag, Tom Eirik Mollnes, Leiv Sandvik, Morten W Fagerland, Steffen Thiel, Solbjørg Sagedal
BACKGROUND: Higher incidence of malignancy and infectious diseases in kidney transplant recipients is related to immunosuppressive treatment after transplantation and the recipient's native immune system. The complement system is an essential component of the innate immunity. The aim of the present study was to investigate the association of effector molecules of the lectin complement pathway with graft and patient survival after kidney transplantation. METHODS: Two mannan-binding lectin (MBL) associated proteases, MASP-2 and MASP-3 (activators of the lectin pathway) and two MBL-associated proteins, MAp44 and MAp19 (inhibitors of the lectin pathway) were measured at the time of transplantation in 382 patients (≥17 years old) transplanted in 2000-2001...
October 18, 2016: BMC Nephrology
Jinshan Jin, Ying-Hsin Hsieh, Jianmei Cui, Krishna Damera, Chaofeng Dai, Arpana S Chaudhary, Hao Zhang, Hsiuchin Yang, Nannan Cao, Chun Jiang, Martti Vaara, Binghe Wang, Phang C Tai
With the widespread emergence of drug resistance, there is an urgent need to search for new antimicrobials, especially those against Gram-negative bacteria. Along this line, the identification of viable targets is a critical first step. The protein translocase SecA is commonly believed to be an excellent target for the development of broad-spectrum antimicrobials. In recent years, we developed three structural classes of SecA inhibitors that have proven to be very effective against Gram-positive bacteria. However, we have not achieved the same level of success against Gram-negative bacteria, despite the potent inhibition of SecA in enzyme assays by the same inhibitors...
October 18, 2016: ChemMedChem
S Lieb, T Littmann, N Plank, J Felixberger, M Tanaka, T Schäfer, S Krief, S Elz, K Friedland, G Bernhardt, J Wegener, T Ozawa, A Buschauer
A set of histamine H1 receptor (H1R) agonists and antagonists was characterized in functional assays, using dynamic mass redistribution (DMR), electric cell-substrate impedance sensing (ECIS) and various signaling pathway specific readouts (Fura-2 and aequorin calcium assays, arrestin recruitment (luciferase fragment complementation) assay, luciferase gene reporter assay). Data were gained from genetically engineered HEK293T cells and compared with reference data from GTPase assays and radioligand binding. Histamine and the other H1R agonists gave different assay-related pEC50 values, however, the order of potency was maintained...
October 14, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Joachim R Kalden
Diverse strategies to develop novel treatments for rheumatoid arthritis which specifically target those patients who do not respond to available medications, including biologics, are currently being explored. New potential therapeutic approaches which may become available as part of standard therapeutic regimens include the propagation of regulatory T cells and-in the future-of regulatory B cells. New biologic disease-modifying antirheumatic drugs (b-DMARDs) against interleukin-17 and -6, granulocyte-macrophage colony-stimulating factor, and complement component 5 are now standard components of clinical treatment programs...
June 2016: Rheumatol Ther
Ryan Hakimi, Ankur Garg
PURPOSE OF REVIEW: Hemorrhagic stroke comprises approximately 15% to 20% of all strokes. This article provides readers with an understanding of the indications and significance of various neuroimaging techniques available for patients presenting with hemorrhagic strokes of distinct causes. RECENT FINDINGS: The most common initial neuroimaging study is a noncontrast head CT, which allows for the identification of hemorrhage. Once an intracranial hemorrhage has been identified, the pattern of blood and the patient's medical history, neurologic examination, and laboratory studies lead the practitioner to pursue further neuroimaging studies to guide the medical, surgical, and interventional management...
October 2016: Continuum: Lifelong Learning in Neurology
Dennis Åsberg, Marek Leśko, Jörgen Samuelsson, Anders Karlsson, Krzysztof Kaczmarski, Torgny Fornstedt
The adsorption of the proton-pump inhibitor omeprazole was investigated using RP-LC with chemometric models combined with adsorption isotherm modelling to study the effect of pH and type of organic modifier (i.e., acetonitrile or methanol). The chemometric approach revealed that omeprazole was tailing with methanol and fronting with acetonitrile along with increased fronting at higher pH. The increased fronting with higher pH for acetonitrile was explored using a pH-dependent adsorption isotherm model that was determined using the inverse method and it agreed well with the experimental data...
2016: Chromatographia
Brandi M Baughman, Huanchen Wang, Yi An, Dmitri Kireev, Michael A Stashko, Henning J Jessen, Kenneth H Pearce, Stephen V Frye, Stephen B Shears
Pharmacological tools-'chemical probes'-that intervene in cell signaling cascades are important for complementing genetically-based experimental approaches. Probe development frequently begins with a high-throughput screen (HTS) of a chemical library. Herein, we describe the design, validation, and implementation of the first HTS-compatible strategy against any inositol phosphate kinase. Our target enzyme, PPIP5K, synthesizes 'high-energy' inositol pyrophosphates (PP-InsPs), which regulate cell function at the interface between cellular energy metabolism and signal transduction...
2016: PloS One
Jiangwei Yao, Megan E Ericson, Matthew W Frank, Charles O Rock
Enoyl-acyl carrier protein reductase catalyzes the last step in each elongation cycle of type II bacterial fatty acid synthesis and is a key regulatory protein in bacterial fatty acid synthesis. The facultative intracellular pathogen Listeria monocytogenes encodes two functional enoyl-ACP isoforms based on their ability to complement the temperature-sensitive growth phenotype of E. coli strain JP1111 (fabI(Ts)). The FabI isoform was inactivated by the FabI selective inhibitor AFN-1252, but the FabK isoform was not affected by the drug as expected...
October 10, 2016: Infection and Immunity
L Mascarell, S Airouche, N Berjont, C Gary, C Gueguen, G Fourcade, B Bellier, D Togbe, B Ryffel, D Klatzmann, V Baron-Bodo, P Moingeon
The complement subunit C1q was recently identified as a marker for monocyte-derived regulatory dendritic cells supporting the differentiation of interleukin (IL)-10-secreting CD4(+) T cells with a suppressive activity. Furthermore, C1q expression is upregulated in peripheral blood mononuclear cells of allergic patients in the course of successful allergen immunotherapy. Herein, we investigated a potential direct role of C1q in downregulating allergic inflammation. In mice with ovalbumin (OVA) or birch pollen (BP)-induced allergic asthma, C1q is as efficacious as dexamethasone to reduce both airway hyperresponsiveness (AHR), eosinophil, and ILC2 infiltrates in bronchoalveolar lavages, as well as allergen-specific T helper 2 cells in the lungs...
October 12, 2016: Mucosal Immunology
Erika van der Maten, Cynthia M de Bont, Ronald de Groot, Marien I de Jonge, Jeroen D Langereis, Michiel van der Flier
Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population...
October 6, 2016: Cytokine
A Frazer-Abel, L Sepiashvili, M M Mbughuni, M A V Willrich
Historically, complement disorders have been attributed to immunodeficiency associated with severe or frequent infection. More recently, however, complement has been recognized for its role in inflammation, autoimmune disorders, and vision loss. This paradigm shift requires a fundamental change in how complement testing is performed and interpreted. Here, we provide an overview of the complement pathways and summarize recent literature related to hereditary and acquired angioedema, infectious diseases, autoimmunity, and age-related macular degeneration...
2016: Advances in Clinical Chemistry
Kenta Fujimoto, Takehiro Motowaki, Naoya Tamura, Yasuaki Aratani
Myeloperoxidase (MPO), a major component of neutrophils, catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride anion. Phagocytosis is a critical event induced by neutrophils for host defense and inflammation. Interestingly, we found that MPO-deficient (MPO(-/-)) neutrophils engulfed larger amounts of zymosan than wild-type neutrophils. Blocking of the CD11b subunit of complement receptor 3 (CR3) as well as inhibition of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) dramatically reduced zymosan phagocytosis...
October 4, 2016: Free Radical Research
Jinrong Fu, Furong Guo, Cheng Chen, Xiaoman Yu, Ke Hu, Mingjiang Li
The optimal treatment for chronic intermittent hypoxia (CIH)-induced cardiovascular injuries has yet to be determined. The aim of the current study was to explore the potential protective effect and mechanism of a C1 inhibitor in CIH in the myocardium. The present study used a rat model of CIH in which complement regulatory protein, known as C1 inhibitor (C1INH), was administered to the rats in the intervention groups. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling...
October 2016: Experimental and Therapeutic Medicine
Chaoqun Yang, Peipei Ding, Qingkai Wang, Long Zhang, Xin Zhang, Jianquan Zhao, Enjie Xu, Na Wang, Jianfeng Chen, Guang Yang, Weiguo Hu, Xuhui Zhou
Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-β1 in serum...
October 4, 2016: Scientific Reports
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