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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
#1
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 modelling, PLIF (protein ligand interaction fingerprint), docking, pharmacophore and dynamic simulation...
May 20, 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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
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
#9
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
#10
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
#11
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...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28258298/complement-factor-5-blockade-reduces-porcine-myocardial-infarction-size-and-improves-immediate-cardiac-function
#12
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-nonphagocytic-cells-by-bacterial-pathogens-burkholderia-and-klebsiella
#13
Yi Han Tan, Akshamal M Gamage, Yunn-Hwen Gan
Burkholderia pseudomallei is a serum-resistant Gram-negative bacterium capable of causing disseminated infections with metastatic complications. However, its interaction with nonphagocytic 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
#14
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
#15
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
#16
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...
March 10, 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
#17
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
#18
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
#19
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
#20
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
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