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https://www.readbyqxmd.com/read/29331477/atypical-presentation-of-pregnancy-related-hemolytic-uremic-syndrome
#1
Salim Baghli, Catherine Abendroth, Umar Farooq, Jennifer A Schaub
The cause of acute kidney injury during pregnancy and in the postpartum period can be particularly challenging to diagnose, especially when it is necessary to differentiate among preeclampsia; eclampsia; hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome; and thrombotic microangiopathies (TMAs). All these disease entities can present with kidney failure, microangiopathic hemolytic anemia, and thrombocytopenia. We present a teaching case of atypical hemolytic uremic syndrome in the postpartum period in a young woman who was found to have mutations of uncertain clinical significance in the complement cascade, including in C3, CFH, and CFI...
January 10, 2018: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/29329521/treating-c3-glomerulopathy-with-eculizumab
#2
Thomas Welte, Frederic Arnold, Julia Kappes, Maximilian Seidl, Karsten Häffner, Carsten Bergmann, Gerd Walz, Elke Neumann-Haefelin
BACKGROUND: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown. METHODS: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab...
January 12, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29329518/the-use-of-eculizumab-in-gemcitabine-induced-thrombotic-microangiopathy
#3
Vinod Krishnappa, Mohit Gupta, Haikoo Shah, Abhijit Das, Natthavat Tanphaichitr, Robert Novak, Rupesh Raina
BACKGROUND: Thrombotic microangiopathy (TMA) secondary to gemcitabine therapy (GiTMA) is a very rare pathology that carries a poor prognosis, with nearly half of the cases progressing to end stage renal disease. GiTMA is most commonly associated with adenocarcinomas, most notably pancreatic cancers. The mainstay of management is withdrawal of the offending drug and supportive care. Plasmapheresis has a limited role and hemodialysis may help in the management of fluid overload secondary to renal failure...
January 12, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29314145/toward-complement-inhibition-2-0-next-generation-anti-complement-agents-for-paroxysmal-nocturnal-hemoglobinuria
#4
Antonio M Risitano, Serena Marotta
Therapeutic complement inhibition by eculizumab has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH) with a major impact on its natural history. Nevertheless, emerging unmet clinical needs may benefit from the development of novel complement inhibitors. Novel strategies of complement inhibition exploit different agents targeting C5, as well as compound intercepting the complement cascade at the level of its key component C3, or even upstream at the level of components involved in complement alternative pathway initiation...
January 4, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29279246/complement-system-biomarkers-in-first-episode-psychosis
#5
Maja Kopczynska, Wioleta Zelek, Samuel Touchard, Fiona Gaughran, Marta Di Forti, Valeria Mondelli, Robin Murray, Michael C O'Donovan, B Paul Morgan
Several lines of evidence implicate immunological/inflammatory factors in development of schizophrenia. Complement is a key driver of inflammation, and complement dysregulation causes pathology in many diseases. Here we explored whether complement dysregulation occurred in first episode psychosis (FEP) and whether this provides a source of biomarkers. Eleven complement analytes (C1q, C3, C4, C5, factor B [FB], terminal complement complex [TCC], factor H [FH], FH-related proteins [FHR125], Properdin, C1 inhibitor [C1inh], soluble complement receptor 1 [CR1]) plus C-reactive protein (CRP) were measured in serum from 136 first episode psychosis (FEP) cases and 42 mentally healthy controls using established in-house or commercial ELISA...
December 23, 2017: Schizophrenia Research
https://www.readbyqxmd.com/read/29225802/effective-immunosuppressive-management-with-belatacept-and-eculizumab-in-post-transplant-ahus-due-to-a-homozygous-deletion-of-cfhr1-cfhr3-and-the-presence-of-cfh-antibodies
#6
Johannes Münch, Anette Bachmann, Maik Grohmann, Christof Mayer, Michael Kirschfink, Tom H Lindner, Carsten Bergmann, Jan Halbritter
Atypical haemolytic uraemic syndrome (aHUS) may clinically present as acute renal graft failure resulting from excessive activation of the complement cascade. While mutations of complement-encoding genes predispose for aHUS, it is generally thought to require an additional insult (e.g. drugs) to trigger and manifest the full-blown clinical syndrome. Calcineurin inhibitors (CNIs) used for immunosuppression act as potential triggers, especially in the post-transplantation setting. Therefore, CNI-free immunosuppressive regimens may be beneficial...
December 2017: Clinical Kidney Journal
https://www.readbyqxmd.com/read/29183817/structural-characterization-of-a-lepidopteran-type-ii-farnesyl-diphosphate-synthase-from-the-spruce-budworm-choristoneura-fumiferana-implications-for-inhibitor-design
#7
Marie-Ève Picard, Audrey Nisole, Catherine Béliveau, Stephanie Sen, Aline Barbar, Rong Shi, Michel Cusson
Farnesyl diphosphate synthase (FPPS) is an enzyme from the class of short chain (E)-prenyltransferases that catalyzes the condensation of two molecules of isopentenyl diphosphate (IPP, C5) with dimethylallyl diphosphate (DMAPP, C5) to generate the C15 product FPP. In insects, FPPS plays a key role in the biosynthesis of the morphogenetic and gonadotropic "juvenile hormone" (JH). Lepidopteran genomes encode two very distinct FPPS paralogs, one of which ("type-II") is expressed almost exclusively in the JH-producing glands, the corpora allata...
November 25, 2017: Insect Biochemistry and Molecular Biology
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
#8
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...
January 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29110694/effects-of-freezer-storage-time-on-levels-of-complement-biomarkers
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
EDITORIAL
Benjamin Blass
No abstract text is available yet for this article.
August 10, 2017: ACS Medicinal Chemistry Letters
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