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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
#1
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
#2
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
#3
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-blocks-vaccine-induced-opsonophagocytic-killing-of-meningococci-by-whole-blood-from-immunized-adults
#4
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/28628799/a-novel-2-stage-approach-that-detects-complement-activation-in-patients-with-antiphospholipid-antibody-syndrome
#5
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
#6
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
#7
Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, V P Lemmon, J L Bixby
The mammalian target of Rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Though 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 2-3 fold...
June 16, 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
#8
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
#9
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
#10
Bijo Mathew, Githa Elizabeth Mathew, Gulberk Ucar, Monu Joy, E K Nafna, 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...
May 31, 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
#11
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)...
May 30, 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
#12
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
https://www.readbyqxmd.com/read/28531373/identification-of-potential-inhibitors-for-hcv-ns3-genotype-4a-by-combining-protein-ligand-interaction-fingerprint-3d-pharmacophore-docking-and-dynamic-simulation
#13
Mahmoud Abd El-Monem El-Hasab, Eman Esmat El-Bastawissy, Tarek Faathy El-Moselhy
HCV NS3 protease domain has been one of the most attractive targets for developing new drugs for HCV infection and many drugs were successfully developed, but all of them were designed for targeting HCV genotype 1 infection. HCV genotype 4a dominant in Egypt has paid less attention. Here, we describe our protocol of virtual screening in identification of novel potential potent inhibitors for HCV NS3 of genotype 4a using homology modeling, PLIF (protein-ligand interaction fingerprint), docking, pharmacophore, and dynamic simulation...
June 7, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28480707/alkoxyallene-based-stereodivergent-syntheses-of-hyacinthacine-b4-and-of-putative-hyacinthacine-c5-epimers-proposal-of-hyacinthacine-c5-structure
#14
Tommaso Pecchioli, Francesca Cardona, Hans-Ulrich Reissig, Reinhold Zimmer, Andrea Goti
Hyacinthacines are members of the class of polyhydroxylated pyrrolizidines exhibiting outstanding biological activity as glycosidases inhibitors. Their structural complexity is embodied in the densely functionalized core, possessing a series of contiguous stereogenic centers. In this synthetic study we report a route to the more complex congeners of this class of alkaloids exploiting the diastereoselective addition of an axially chiral lithiated alkoxyallene to an enantiopure cyclic nitrone. Our stereodivergent approach enabled the installation of the targeted configuration at the ring A by minimal synthetic manipulations and at ring B by using stage dependent selective functionalizations...
May 16, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28473832/how-escherichia-coli-circumvent-complement-mediated-killing
#15
REVIEW
Afonso G Abreu, Angela S Barbosa
Complement is a crucial arm of the innate immune response against invading bacterial pathogens, and one of its main functions is to recognize and destroy target cells. Similar to other pathogens, Escherichia coli has evolved mechanisms to overcome complement activation. It is well known that capsular polysaccharide may confer resistance to complement-mediated killing and phagocytosis, being one of the strategies adopted by this bacterium to survive in serum. In addition, proteases produced by E. coli have been shown to downregulate the complement system...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28444429/hypopharyngeal-and-upper-esophageal-ulceration-after-cervical-spine-radiotherapy-concurrent-with-crizotinib
#16
Marcus H Zimmermann, Gabriele Beckmann, Pius Jung, Michael Flentje
Herein, the authors describe the case of a 31-year-old female patient with primary metastatic adenocarcinoma of the lung referred for radiation therapy of newly diagnosed intramedullary spinal cord metastasis at C4/5 and an adjacent osteolytic lesion. Radiotherapy of the cervical spine level C3 to C5, including the whole vertebra, was performed with 30 Gy in 10 fractions. The patient's systemic therapy with crizotinib 250 mg twice daily was continued. After 8 fractions of radiation the patient developed increasing dysphagia...
April 25, 2017: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
https://www.readbyqxmd.com/read/28345259/the-role-of-complement-inhibitors-beyond-controlling-inflammation
#17
REVIEW
A M Blom
The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (COMP), CUB and sushi multiple domains 1 (CSMD1), sushi domain-containing protein 4 (SUSD4) and CD59...
March 26, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28331448/antibody-mediated-rejection-a-review
#18
Jorge Carlos Garces, Sixto Giusti, Catherine Staffeld-Coit, Humberto Bohorquez, Ari J Cohen, George E Loss
BACKGROUND: Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection...
2017: Ochsner Journal
https://www.readbyqxmd.com/read/28302398/synthesis-of-isomeric-analogues-of-s-ribosylhomocysteine-analogues-with-homocysteine-unit-attached-to-c2-of-ribose
#19
Christiane Chbib
LuxS (S-ribosylhomocysteinase; EC 4.4.1.21) is an enzyme that catalyzes the cleavage of the thioether linkage in the catalytic pathway of S-ribosylhomocysteine (SRH) which produces homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD). DPD is the precursor of the signaling molecules known as autoinducer 2 (AI-2) responsible for the bacterial quorum sensing (QS) identified as cell to cell communication. Inhibitors of LuxS should be able to interfere with its catalytic pathway thus preventing the formation of the autoinducer molecules...
April 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28298523/identification-of-c3b-binding-small-molecule-complement-inhibitors-using-cheminformatics
#20
Brandon L Garcia, D Andrew Skaff, Arindam Chatterjee, Anders Hanning, John K Walker, Gerald J Wyckoff, Brian V Geisbrecht
The complement system is an elegantly regulated biochemical cascade formed by the collective molecular recognition properties and proteolytic activities of more than two dozen membrane-bound or serum proteins. Complement plays diverse roles in human physiology, such as acting as a sentry against invading microorganisms, priming of the adaptive immune response, and removal of immune complexes. However, dysregulation of complement can serve as a trigger for a wide range of human diseases, which include autoimmune, inflammatory, and degenerative conditions...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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