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https://www.readbyqxmd.com/read/28932227/targeted-delivery-of-neutralizing-anti-c5-antibody-to-renal-endothelium-prevents-complement-dependent-tissue-damage
#1
Paolo Durigutto, Daniele Sblattero, Stefania Biffi, Luca De Maso, Chiara Garrovo, Gabriele Baj, Federico Colombo, Fabio Fischetti, Antonio F Di Naro, Francesco Tedesco, Paolo Macor
Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28864711/meningococcal-b-vaccine-failure-with-a-penicillin-resistant-strain-in-a-young-adult-on-long-term-eculizumab
#2
Sydel R Parikh, Jay Lucidarme, Coralie Bingham, Paul Warwicker, Tim Goodship, Ray Borrow, Shamez N Ladhani
We describe a case of invasive meningococcal disease due to a vaccine-preventable and penicillin-resistant strain in a fully immunized young adult on long-term complement inhibitor therapy and daily penicillin chemoprophylaxis. Eculizumab is a humanized monoclonal antibody that binds human complement C5 protein and inhibits the terminal complement pathway. It is currently recommended for the treatment of complement-mediated thrombotic microangiopathies. An unwanted complication of inhibiting complement, however, is an increased risk of invasive meningococcal disease...
September 2017: Pediatrics
https://www.readbyqxmd.com/read/28835787/c5-c6-carbocyclic-fused-iminothiadiazine-dioxides-as-bace-inhibitors-their-compositions-and-their-use
#3
EDITORIAL
Benjamin Blass
No abstract text is available yet for this article.
August 10, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28821425/flavin-dependent-thymidylate-synthase-n5-of-flavin-as-a-methylene-carrier
#4
REVIEW
Kalani Karunaratne, Nicholas Luedtke, Daniel M Quinn, Amnon Kohen
Thymidylate is synthesized de novo in all living organisms for replication of genomes. The chemical transformation is reductive methylation of deoxyuridylate at C5 to form deoxythymidylate. All eukaryotes including humans complete this well-understood transformation with thymidylate synthase utilizing (6R)-N(5)-N(10)-methylene-5,6,7,8-tetrahydrofolate as both a source of methylene and a reducing hydride. In 2002, flavin-dependent thymidylate synthase was discovered as a new pathway for de novo thymidylate synthesis...
August 15, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28807886/mechanistic-insights-into-f420-dependent-glucose-6-phosphate-dehydrogenase-using-isotope-effects-and-substrate-inhibition-studies
#5
Mercy A Oyugi, Ghader Bashiri, Edward N Baker, Kayunta Johnson-Winters
F420-dependent glucose-6-phosphate dehydrogenase (FGD) is involved in the committed step of the pentose phosphate pathway within mycobacteria, where it catalyzes the reaction between glucose-6-phosphate (G6P) and the F420 cofactor to yield 6-phosphogluconolactone and the reduced cofactor, F420H2. Here, we aim to probe the FGD reaction mechanism using dead-end inhibition experiments, as well as solvent and substrate deuterium isotope effects studies. The dead-end inhibition studies performed using citrate as the inhibitor revealed competitive and uncompetitive inhibition patterns for G6P and F420 respectively, thus suggesting a mechanism of ordered addition of substrates in which the F420 cofactor must first bind to FGD before G6P binding...
August 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28806402/multi-functional-mechanisms-of-immune-evasion-by-the-streptococcal-complement-inhibitor-c5a-peptidase
#6
Nicola N Lynskey, Mark Reglinski, Damien Calay, Matthew K Siggins, Justin C Mason, Marina Botto, Shiranee Sriskandan
The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement-mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28801757/dft-study-of-the-interactions-between-thiophene-based-corrosion-inhibitors-and-an-fe4-cluster
#7
Duy Quang Dao, Truong Dinh Hieu, Thong Le Minh Pham, Dinh Tuan, Pham Cam Nam, Ime Bassey Obot
Understanding the physicochemical properties of corrosion inhibitors and their chemical interactions with metal surfaces is crucial to the design of improved (i.e., more efficient) corrosion inhibitors. In this work, the physicochemical properties of six thiophene-based corrosion inhibitors (2-acetylthiophene (AT), 2-formylthiophene (FT), thiophene (Th), 2-methyl-3-thiophenthiol (MTT), 2-pentylthiophene (PT), and 2-thenylthiol (TT)) were systematically studied by performing ab initio calculations at the MP2(full)/6-31G(2df,p) level of theory...
August 11, 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28798719/fulminant-acute-ascending-hemorrhagic-myelitis-treated-with-eculizumab
#8
Nang Boe Ohnmar Hsam, Klemens Angstwurm, Sebastian Peters, Kornelius Fuchs, Gerhard Schuierer, Ulrich Bogdahn, Robert Weissert
We describe an 18-year-old patient who developed back pain, rapidly ascending sensomotory deficits, bladder dysfunction, Lhermitte's sign, absent abdominal reflexes of all three levels, brisk tendon reflexes, and positive Babinski's sign. Magnetic resonance imaging of the spinal cord showed a long segment of cervical and thoracic intramedullary signal hyperintensity suggesting a longitudinally extensive transverse myelitis possibly within the course of a fast progressing ascending immune-mediated hemorrhagic myelopathy...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28720697/inhibition-of-complement-c5-protects-against-organ-failure-and-reduces-mortality-in-a-baboon-model-of-escherichia-coli-sepsis
#9
Ravi Shankar Keshari, Robert Silasi, Narcis Ioan Popescu, Maulin Mukeshchandra Patel, Hala Chaaban, Cristina Lupu, K Mark Coggeshall, Tom Eirik Mollnes, Steven J DeMarco, Florea Lupu
Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28690378/molecular-docking-analysis-of-nitisinone-with-homogentisate-1-2-dioxygenase
#10
Narges Zolfaghari
Alkaptonuria is an inherited disease that is caused by homogenticate accumulation. Deficiency or mutation in Homogentisate 1,2 dioxygenase gene (chromosome 3q21-q23) leads to production of incorrectly folded or truncated enzyme. Several studies indicated that competitive inhibitors of Homogentisate 1,2 dioxygenase like Nitisinone could be used for Alkaptonuria treatment. Therefore, it is of interest to design better inhibitors of the enzyme. We used subset 3_p.0.5 from Zinc database as the virtual screening library by PyRx software relaying on Lamarckian genetics algorithm...
2017: Bioinformation
https://www.readbyqxmd.com/read/28648461/the-structural-requirements-of-histone-deacetylase-inhibitors-saha-analogs-modified-at-the-c5-position-display-dual-hdac6-8-selectivity
#11
Ahmed T Negmeldin, Mary Kay H Pflum
Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28630122/eculizumab-treatment-and-impaired-opsonophagocytic-killing-of-meningococci-by-whole-blood-from-immunized-adults
#12
Monica Konar, Dan M Granoff
Eculizumab, a humanized anti-complement C5 monoclonal antibody (mAb) 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; 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...
August 17, 2017: Blood
https://www.readbyqxmd.com/read/28628799/a-novel-2-stage-approach-that-detects-complement-activation-in-patients-with-antiphospholipid-antibody-syndrome
#13
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/28626544/atypical-hemolytic-uremic-syndrome-a-brief-review
#14
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/28626016/the-mtor-substrate-s6-kinase-1-s6k1-is-a-negative-regulator-of-axon-regeneration-and-a-potential-drug-target-for-central-nervous-system-injury
#15
Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, Vance P Lemmon, John L Bixby
The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold...
July 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28611756/pathogenic-leptospira-secreted-proteases-target-the-membrane-attack-complex-a-potential-role-for-thermolysin-in-complement-inhibition
#16
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/28579778/iron-oxide-nanoparticles-induce-cytokine-secretion-in-a-complement-dependent-manner-in-a-human-whole-blood-model
#17
Susann Wolf-Grosse, Anne Mari Rokstad, Syed Ali, John D Lambris, Tom E Mollnes, Asbjørn M Nilsen, Jørgen Stenvik
Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28577983/monoamine-oxidase-inhibitory-activity-of-methoxy-substituted-chalcones
#18
Bijo Mathew, Githa Elizabeth Mathew, Gulberk Ucar, Monu Joy, E K Nafna, Krishnakumar K Lohidakshan, Jerad Suresh
The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity...
November 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28576714/alginate-microbeads-are-coagulation-compatible-while-alginate-microcapsules-activate-coagulation-secondary-to-complement-or-directly-through-fxii
#19
Caroline Gravastrand, Shamal Hamad, Hilde Fure, Bjørg Steinkjer, Liv Ryan, Josè Oberholzer, John D Lambris, Igor Lacík, Tom Eirik Mollnes, Terje Espevik, Ole-Lars Brekke, Anne Mari Rokstad
Alginate microspheres are presently under evaluation for future cell-based therapy. Their ability to induce harmful host reactions needs to be identified for developing the most suitable devices and efficient prevention strategies. We used a lepirudin based human whole blood model to investigate the coagulation potentials of alginate-based microspheres: alginate microbeads (Ca/Ba Beads), alginate poly-l-lysine microcapsules (APA and AP microcapsules) and sodium alginate-sodium cellulose sulfate-poly(methylene-co-cyanoguanidine) microcapsules (PMCG microcapsules)...
August 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28559893/upregulation-of-early-and-downregulation-of-terminal-pathway-complement-genes-in-subcutaneous-adipose-tissue-and-adipocytes-in-acquired-obesity
#20
Sanna Kaye, A Inkeri Lokki, Anna Hanttu, Eija Nissilä, Sini Heinonen, Antti Hakkarainen, Jesper Lundbom, Nina Lundbom, Lilli Saarinen, Olli Tynninen, Maheswary Muniandy, Aila Rissanen, Jaakko Kaprio, Seppo Meri, Kirsi H Pietiläinen
Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m(2)] with as much as 18 kg mean Δweight...
2017: Frontiers in Immunology
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