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C5 inhibitor

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https://www.readbyqxmd.com/read/28302398/synthesis-of-isomeric-analogues-of-s-ribosylhomocysteine-analogues-with-homocysteine-unit-attached-to-c2-of-ribose
#1
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...
March 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28298523/identification-of-c3b-binding-small-molecule-complement-inhibitors-using-cheminformatics
#2
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...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28296762/effect-on-mother-and-child-of-eculizumab-given-before-caesarean-section-in-a-patient-with-severe-antiphospholipid-syndrome-a-case-report
#3
Alice Gustavsen, Lillemor Skattum, Grethe Bergseth, Bjorg Lorentzen, Yngvar Floisand, Vidar Bosnes, Tom Eirik Mollnes, Andreas Barratt-Due
RATIONALE: Antiphospholipid syndrome (APS) in pregnancy may trigger the life-threatening catastrophic antiphospholipid syndrome (CAPS). Complement activation is implicated in the pathogenesis, and inhibition of complement factor C5 is suggested as an additional treatment option. PATIENT CONCERNS, DIAGNOSIS AND INTERVENTIONS: We present a pregnant patient treated with the C5-inhibitor eculizumab due to high risk of developing devastating APS-related complications...
March 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28261486/combined-inhibition-of-c5-and-cd14-efficiently-attenuated-the-inflammatory-response-in-a-porcine-model-of-meningococcal-sepsis
#4
Bernt C Hellerud, Hilde L Orrem, Knut Dybwik, Søren E Pischke, Andreas Baratt-Due, Albert Castellheim, Hilde Fure, Grethe Bergseth, Dorte Christiansen, Miles A Nunn, Terje Espevik, Corinna Lau, Petter Brandtzæg, Erik W Nielsen, Tom E Mollnes
BACKGROUND: Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis. METHODS: Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated Neisseria meningitidis administered over 3 h...
2017: Journal of Intensive Care
https://www.readbyqxmd.com/read/28260110/inhibitory-effect-of-emodin-on-fatty-acid-synthase-colon-cancer-proliferation-and-apoptosis
#5
Kyung Ha Lee, Myung Sun Lee, Eun Young Cha, Ji Young Sul, Jin Sun Lee, Jin Su Kim, Jun Beom Park, Ji Yeon Kim
Fatty acid synthase (FASN) is a key anabolic enzyme for de novo fatty acid synthesis, which is important in the development of colon carcinoma. The high expression of FASN is considered a promising molecular target for colon cancer therapy. Emodin, a naturally occurring anthraquinone, exhibits an anticancer effect in various types of human cancer, including colon cancer; however, the molecular mechanisms remain to be fully elucidated. Cell viability was evaluated using a Cell Counting Kit‑8 assay. The apoptosis rate of cells was quantified via flow cytometry following Annexin V/propidium iodide staining...
February 28, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28258298/complement-factor-5-blockade-reduces-porcine-myocardial-infarction-size-and-improves-immediate-cardiac-function
#6
Soeren E Pischke, A Gustavsen, H L Orrem, K H Egge, F Courivaud, H Fontenelle, A Despont, A K Bongoni, R Rieben, T I Tønnessen, M A Nunn, H Scott, H Skulstad, A Barratt-Due, T E Mollnes
Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction...
May 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28186697/complement-activated-vitronectin-enhances-the-invasion-of-non-phagocytic-cells-by-bacterial-pathogens-burkholderia-and-klebsiella
#7
Yi Han Tan, Akshamal Gamage, Yunn-Hwen Gan
Burkholderia pseudomallei is a serum-resistant Gram-negative bacterium capable of causing disseminated infections with metastatic complications. However, their interaction with non-phagocytic cells is poorly understood. We observed that exposure of B. pseudomallei and the closely related yet avirulent B. thailandensis to human plasma increased epithelial cell invasion by >20 fold. Enhanced invasion was primarily driven by a plasma factor which required a functional complement cascade, but surprisingly, was downstream of C3 mediated opsonisation...
February 10, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28185538/synthesis-and-biological-evaluation-of-hybrid-1-5-and-2-5-disubstituted-indoles-as-potentially-new-antitubercular-agents
#8
Ana Soares, Mónica S Estevão, M Manuel B Marques, Vasily Kovalishyn, Diogo A R S Latino, João Aires-de-Sousa, Jorge Ramos, Miguel Viveiros, Filomena Martins
BACKGROUND: Tuberculosis (TB) is the second leading cause of mortality worldwide being a highly contagious and insidious illness caused by Mycobacterium tuberculosis, Mtb. Additionally, the emergence of multidrug-resistant and extensively drug-resistant strains of Mtb, together with significant levels of co-infection with HIV and TB (HIV/TB) makes the search for new antitubercular drugs urgent and challenging. METHODS: This work was based on the hypothesis that an active compound could be obtained if substituents present in some other active compounds were attached on a core of an important structure, in this case the indole scaffold, thus generating a hybrid compound...
February 9, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28185110/foxm1-mediated-rfc5-expression-promotes-temozolomide-resistance
#9
Wan-Xin Peng, Xiu Han, Chun-Li Zhang, Lu Ge, Feng-Yi Du, Jie Jin, Ai-Hua Gong
Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter...
February 9, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/28131777/synthesis-of-c5-tethered-indolyl-3-glyoxylamide-derivatives-as-tubulin-polymerization-inhibitors
#10
Sravanthi Devi Guggilapu, Guntuku Lalita, T Srinivasa Reddy, Santosh Kumar Prajapti, Atulya Nagarsenkar, Shymala Ramu, Uma Rani Brahma, Uppa Jaya Lakshmi, Ganga Modi Naidu Vegi, Suresh K Bhargava, Bathini Nagendra Babu
A series of C5-tethered Indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 7f displayed cytotoxicity of IC50 = 140 nM towards DU145 cancer cell line. The treatment of DU145 cells with 7f led to inhibition of cell migration ability...
January 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28092952/total-synthesis-of-zaragozic-acid-c-implementation-of-photochemical-c-sp-3-h-acylation
#11
Takahiro Kawamata, Masanori Nagatomo, Masayuki Inoue
Zaragozic acid C (1) was isolated as a potent squalene synthase inhibitor. The 2,8-dioxabicyclo[3.2.1]octane core of 1 is decorated with the three hydroxycarbonyl (C3,4,5), two hydroxy (C4,7), one acyloxy (C6), and one alkyl (C1) groups. Installation of the contiguous C4- and C5-fully substituted carbons presents a formidable synthetic challenge. Our approach to address this problem used a two-step photochemical C(sp(3))-H acylation. Persilylated d-gluconolactone 4 was derivatized into 3 with the 1,2-diketone moiety at the C5-tetrasubstituted center...
January 25, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28077967/integrated-omics-analyses-reveal-the-details-of-metabolic-adaptation-of-clostridium-thermocellum-to-lignocellulose-derived-growth-inhibitors-released-during-the-deconstruction-of-switchgrass
#12
Suresh Poudel, Richard J Giannone, Miguel Rodriguez, Babu Raman, Madhavi Z Martin, Nancy L Engle, Jonathan R Mielenz, Intawat Nookaew, Steven D Brown, Timothy J Tschaplinski, David Ussery, Robert L Hettich
BACKGROUND: Clostridium thermocellum is capable of solubilizing and converting lignocellulosic biomass into ethanol. Although much of the work-to-date has centered on characterizing this microbe's growth on model cellulosic substrates, such as cellobiose, Avicel, or filter paper, it is vitally important to understand its metabolism on more complex, lignocellulosic substrates to identify relevant industrial bottlenecks that could undermine efficient biofuel production. To this end, we have examined a time course progression of C...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/28058212/complement-related-kidney-diseases-recurrence-after-transplantation
#13
REVIEW
Maurizio Salvadori, Elisabetta Bertoni
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement...
December 24, 2016: World Journal of Transplantation
https://www.readbyqxmd.com/read/28028023/incomplete-inhibition-by-eculizumab-mechanistic-evidence-for-residual-c5-activity-during-strong-complement-activation
#14
Markus J Harder, Nadine Kuhn, Hubert Schrezenmeier, Britta Höchsmann, Inge von Zabern, Christof Weinstock, Thomas Simmet, Daniel Ricklin, John D Lambris, Arne Skerra, Markus Anliker, Christoph Q Schmidt
Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete...
February 23, 2017: Blood
https://www.readbyqxmd.com/read/27988521/inhibitors-of-acetylcholinesterase-derived-from-7-methoxytacrine-and-their-effects-on-the-choline-transporter-cht1
#15
Zdenka Kristofikova, Jan Ricny, Ondrej Soukup, Jan Korabecny, Eugenie Nepovimova, Kamil Kuca, Daniela Ripova
BACKGROUND: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. METHODS: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. RESULTS: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA...
2017: Dementia and Geriatric Cognitive Disorders
https://www.readbyqxmd.com/read/27977428/breaking-down-the-complement-system-a-review-and-update-on-novel-therapies
#16
Yuvaram N V Reddy, Andrew M Siedlecki, Jean M Francis
PURPOSE OF REVIEW: The complement system represents one of the more primitive forms of innate immunity. It has increasingly been found to contribute to pathologies in the native and transplanted kidney. We provide a concise review of the physiology of the complement cascade, and discuss current and upcoming complement-based therapies. RECENT FINDINGS: Current agents in clinical use either bind to complement components directly or prevent complement from binding to antibodies affixed to the endothelial surface...
March 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27939824/pulmonary-platelet-accumulation-induced-by-catecholamines-its-involvement-in-lipopolysaccharide-induced-anaphylaxis-like-shock
#17
Zhiqian Yu, Hiroko Saito, Hirotada Otsuka, Yosuke Shikama, Hiromi Funayama, Mai Sakai, Shigeo Murai, Masanori Nakamura, Takashi Yokochi, Haruhiko Takada, Shunji Sugawara, Yasuo Endo
Intravenously injected lipopolysaccharides (LPS) rapidly induce pulmonary platelet accumulation (PPA) and anaphylaxis-like shock (ALS) in mice. Macrophages reportedly release catecholamines rapidly upon stimulation with LPS. Here, we examined the involvement of macrophage-derived catecholamines in LPS-induced PPA and ALS. A catecholamine or Klebsiella O3 (KO3) LPS was intravenously injected into mice, with 5-hydroxytryptamine in the lung being measured as a platelet marker. The tested catecholamines induced PPA, leading to shock...
February 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/27932157/belatacept-and-eculizumab-for-treatment-of-calcineurin-inhibitor-induced-thrombotic-microangiopathy-after-kidney-transplantation-case-report
#18
J Merola, P S Yoo, J Schaub, J D Smith, M I Rodriguez-Davalos, E Tichy, D C Mulligan, W Asch, R Formica, M Kashgarian, S Kulkarni
Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome...
November 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27914802/synthesis-and-in-vitro-antiproliferative-activity-of-c5-benzyl-substituted-2-amino-pyrrolo-2-3-d-pyrimidines-as-potent-hsp90-inhibitors
#19
Ju-Hyeon Lee, Sang Chul Shin, Seon Hee Seo, Young Ho Seo, Nakcheol Jeong, Chan-Wha Kim, Eunice EunKyeong Kim, Gyochang Keum
A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50 of 36nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27909956/docking-and-three-dimensional-quantitative-structure-activity-relationship-analyses-of-imidazole-and-thiazolidine-derivatives-as-aurora-a-kinase-inhibitors
#20
Chaeuk Im
Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q(2) value of 0...
December 2016: Archives of Pharmacal Research
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