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https://www.readbyqxmd.com/read/29156357/generation-of-complement-molecular-complex-c5b-9-c5b-9-in-response-to-poly-traumatic-hemorrhagic-shock-and-evaluation-of-c5-cleavage-inhibitors-in-non-human-primates
#1
R Madelaine Paredes, Sarah Reyna, Philip Vernon, Douglas K Tadaki, Jurandir J Dallelucca, Forest Sheppard
Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b-9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock. Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock...
November 17, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29110694/effects-of-freezer-storage-time-on-levels-of-complement-biomarkers
#2
Angharad R Morgan, Caroline O'Hagan, Samuel Touchard, Simon Lovestone, B Paul Morgan
BACKGROUND: There is uncertainty regarding how stable complement analytes are during long-term storage at - 80 °C. As part of our work program we have measured 17 complement biomarkers (C1q, C1 inhibitor, C3, C3a, iC3b, C4, C5, C9, FB, FD, FH, FI, TCC, Bb, sCR1, sCR2, Clusterin) and the benchmark inflammatory marker C-reactive protein (CRP) in a large set of plasma samples (n = 720) that had been collected, processed and subsequently stored at - 80 °C over a period of 6.6-10.6 years, prior to laboratory analysis...
November 6, 2017: BMC Research Notes
https://www.readbyqxmd.com/read/29097196/recurrent-allograft-c3-glomerulonephritis-and-unsuccessful-eculizumab-treatment
#3
Kati Kaartinen, Leena Martola, Anne Räisänen-Sokolowski, Seppo Meri
There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement-mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab...
October 31, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29056341/the-human-knockout-gene-clybl-connects-itaconate-to-vitamin-b12
#4
Hongying Shen, Gregory C Campanello, Daniel Flicker, Zenon Grabarek, Junchi Hu, Cheng Luo, Ruma Banerjee, Vamsi K Mootha
CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator...
November 2, 2017: Cell
https://www.readbyqxmd.com/read/29032033/effect-of-mofezolac-galactose-distance-in-conjugates-targeting-cyclooxygenase-cox-1-and-cns-glut-1-carrier
#5
Maria Grazia Perrone, Paola Vitale, Savina Ferorelli, Angelina Boccarelli, Mauro Coluccia, Alessandra Pannunzio, Federica Campanella, Giuseppe Di Mauro, Carmela Bonaccorso, Cosimo G Fortuna, Antonio Scilimati
Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15-20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5 and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28980670/complement-c5-inhibiting-therapy-for-the-thrombotic-microangiopathies-accumulating-evidence-but-not-a-panacea
#6
Vicky Brocklebank, David Kavanagh
Thrombotic microangiopathy (TMA), characterized by organ injury occurring consequent to severe endothelial damage, can manifest in a diverse range of diseases. In complement-mediated atypical haemolytic uraemic syndrome (aHUS) a primary defect in complement, such as a mutation or autoantibody leading to over activation of the alternative pathway, predisposes to the development of disease, usually following exposure to an environmental trigger. The elucidation of the pathogenesis of aHUS resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice...
October 2017: Clinical Kidney Journal
https://www.readbyqxmd.com/read/28975712/structure-activity-studies-of-n-butyl-1-deoxynojirimycin-nb-dnj-analogs-discovery-of-potent-and-selective-aminocyclopentitol-inhibitors-of-gba1-and-gba2
#7
Gunda Ingrid Georg, Xingxiang Gu, Vijayalaxmi Gupta, Yan Yang, Jinyi Zhu, Erick Carlson, Carolyn Kingsley, Joseph Tash, Ernst Schonbrunn, Jon Hawkinson
Analogs of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal -glucosidase 2 (GBA2) and the lysosomal -glucosidase 1 (GBA1). Compounds 6a-6f that carry sterically demanding nitrogen substituents, and compound 14, devoid of the C3 and C5 hydroxyl groups present in DNJ/NB-DGJ (N-butyl-deoxygalactojirimycin showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N-(n-butyl)- and N-(n-nonyl)-DGJ (compounds 25) also led to a loss of activity in these assays...
October 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28971874/modified-penicillin-molecule-with-carbapenem-like-stereochemistry-specifically-inhibits-class-c-%C3%AE-lactamases
#8
Xuehua Pan, Yunjiao He, Tianfeng Chen, Kin-Fai Chan, Yanxiang Zhao
Bacterial β-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature β-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based Class A, C and D β-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule MPC-1 by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C5 and C6 instead of cis, and a 6-α hydroxyethyl moiety to replace the original 6-β aminoacyl group...
October 2, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28970843/substrate-specificity-and-inhibitor-sensitivity-of-plant-udp-sugar-producing-pyrophosphorylases
#9
Daniel Decker, Leszek A Kleczkowski
UDP-sugars are essential precursors for glycosylation reactions producing cell wall polysaccharides, sucrose, glycoproteins, glycolipids, etc. Primary mechanisms of UDP sugar formation involve the action of at least three distinct pyrophosphorylases using UTP and sugar-1-P as substrates. Here, substrate specificities of barley and Arabidopsis (two isozymes) UDP-glucose pyrophosphorylases (UGPase), Arabidopsis UDP-sugar pyrophosphorylase (USPase) and Arabidopsis UDP-N-acetyl glucosamine pyrophosphorylase2 (UAGPase2) were investigated using a range of sugar-1-phosphates and nucleoside-triphosphates as substrates...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28945765/in-vitro-and-in-vivo-effects-of-2-4-diaminoquinazoline-inhibitors-of-the-decapping-scavenger-enzyme-dcps-context-specific-modulation-of-smn-transcript-levels
#10
Jonathan J Cherry, Christine J DiDonato, Elliot J Androphy, Alessandro Calo, Kyle Potter, Sara K Custer, Sarah Du, Timothy L Foley, Ariamala Gopalsamy, Emily J Reedich, Susana M Gordo, William Gordon, Natalie Hosea, Lyn H Jones, Daniel K Krizay, Gregory LaRosa, Hongxia Li, Sachin Mathur, Carol A Menard, Paraj Patel, Rebeca Ramos-Zayas, Anne Rietz, Haojing Rong, Baohong Zhang, Michael A Tones
C5-substituted 2,4-diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS (DAQ-DcpSi) have been developed for the treatment of spinal muscular atrophy (SMA), which is caused by genetic deficiency in the Survival Motor Neuron (SMN) protein. These compounds are claimed to act as SMN2 transcriptional activators but data underlying that claim are equivocal. In addition it is unclear whether the claimed effects on SMN2 are a direct consequence of DcpS inhibitor or might be a consequence of lysosomotropism, which is known to be neuroprotective...
2017: PloS One
https://www.readbyqxmd.com/read/28932227/targeted-delivery-of-neutralizing-anti-c5-antibody-to-renal-endothelium-prevents-complement-dependent-tissue-damage
#11
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
#12
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
#13
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
#14
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...
October 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
#15
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 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28806402/multi-functional-mechanisms-of-immune-evasion-by-the-streptococcal-complement-inhibitor-c5a-peptidase
#16
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
#17
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
#18
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
#19
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
#20
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
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