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https://www.readbyqxmd.com/read/28098949/identification-of-cellular-targets-involved-in-cardiac-failure-caused-by-pki-in-oncology-an-approach-combining-pharmacovigilance-and-pharmacodynamics
#1
E Patras de Campaigno, E Bondon-Guitton, G Laurent, F Montastruc, J L Montastruc, M Lapeyre-Mestre, F Despas
AIMS: To evaluate the risk of cardiac failure (CF) of 15 anticancer protein kinase inhibitors (PKIs) through a case/non-case analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. METHODS: To evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the WHO safety report database (VigiBase®). We realised a literature review to identify 21 PK possibly involved in CF caused by PKIs. Pearson's correlation coefficients (r) between aROR and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely involved in PKI-induced CF...
January 18, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28098450/the-serum-amyloid-p-component-sap-interactome-in-human-plasma-containing-physiological-calcium-levels
#2
Ebbe Toftgaard Poulsen, Kata Wolff Pedersen, Anna Maria Marzeda, Jan Johannes Enghild
The pentraxin serum amyloid p component (SAP) is secreted by the liver and found in plasma at a concentration of approximately 30 mg/L. SAP is a 25 kDa homo-pentamer known to bind both protein and non-protein ligands, all in a calcium-dependent manner. The function of SAP is unclear, but likely involves the humoral innate immune system spanning the complement system, inflammation, and coagulation. Also, SAP is known to binding to the generic structure of amyloid deposits and possibly to protect these against proteolysis...
January 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28098336/preclinical-evaluation-of-intravenous-nax-810-2-a-novel-galr2-preferring-analog-for-anticonvulsant-efficacy-and-pharmacokinetics
#3
Cameron S Metcalf, Brian D Klein, Daniel R McDougle, Liuyin Zhang, Dan Kaufmann, Grzegorz Bulaj, H Steve White
OBJECTIVE: Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice...
January 18, 2017: Epilepsia
https://www.readbyqxmd.com/read/28098301/optical-dna-mapping-in-nanofluidic-devices-principles-and-applications
#4
Vilhelm Müller, Fredrik Westerlund
Optical DNA mapping has over the last decade emerged as a very powerful tool for obtaining long range sequence information from single DNA molecules. In optical DNA mapping, intact large single DNA molecules are labeled, stretched out, and imaged using a fluorescence microscope. This means that sequence information ranging over hundreds of kilobasepairs (kbp) can be obtained in one single image. Nanochannels offer homogeneous and efficient stretching of DNA that is crucial to maximize the information that can be obtained from optical DNA maps...
January 18, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/28098263/a-lab-on-a-chip-for-monolith-based-preconcentration-and-electrophoresis-separation-of-phosphopeptides
#5
Monica Araya-Farias, Szymon Dziomba, Benjamin Carbonnier, Mohamed Guerrouache, Ichraf Ayed, Nacera Aboud, Myriam Taverna, N Thuy Tran
A microdevice combining online preconcentration and separation of phosphopeptides was developed in a glass microchip. An ethylene glycol methacrylate phosphate (EGMP), acrylamide (AM) and bisacrylamide (BAA) based monolith was synthesized within microchannels through a photo-driven process. Morphological investigations revealed a homogeneous monolithic structure composed of uniform nodules (∼0.8 μm), with a large pore volume (0.62 cm(3) g(-1)) and sufficiently high specific surface area (34.1 m(2) g(-1))...
January 18, 2017: Analyst
https://www.readbyqxmd.com/read/28098172/structural-diversity-of-anti-pancreatic-cancer-capsimycins-identified-in-mangrove-derived-streptomyces-xiamenensis-318-and-post-modification-via-a-novel-cytochrome-p450-monooxygenase
#6
He-Lin Yu, Shu-Heng Jiang, Xu-Liang Bu, Jia-Hua Wang, Jing-Yi Weng, Xiao-Mei Yang, Kun-Yan He, Zhi-Gang Zhang, Ping Ao, Jun Xu, Min-Juan Xu
Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds-ikarugamycin (1), capsimycin (2) and capsimycin B (3)-two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28097910/purification-and-biochemical-characterization-of-a-novel-thermostable-serine-alkaline-protease-from-aeribacillus-pallidus-c10-a-potential-additive-for-detergents
#7
Vildan Yildirim, Mustafa Ozkan Baltaci, Ilknur Ozgencli, Melda Sisecioglu, Ahmet Adiguzel, Gulsah Adiguzel
An extracellular thermostable alkaline serine protease enzyme from Aeribacillus pallidus C10 (GenBank No: KC333049), was purified 4.85 and 17. 32-fold with a yield of 26.9 and 19.56%, respectively, through DE52 anion exchange and Probond affinity chromatography. The molecular mass of the enzyme was determined through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), with approximately 38.35 kDa. The enzyme exhibited optimum activity at pH 9 and at temperature 60 °C. It was determined that the enzyme had remained stable at the range of pH 7...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28097886/reagent-free-lc-ms-ms-based-pharmacokinetic-quantification-of-polyhistidine-tagged-therapeutic-proteins
#8
Jianxia Shi, Jing Man Wong, Ji Ma, Tiffany Dickerson, Colin Hall, Dan A Rock, Timothy J Carlson
AIM: Immobilized metal ion affinity chromatography is widely employed for purifying polyhistidine-tagged recombinant proteins from cell lysates. The technique can be applied for quantification of therapeutic proteins in biological matrices by LC-MS/MS. RESULTS: A protein reagent-free workflow was developed for quantifying polyhistidine-tagged proteins by LC-MS/MS. The workflow includes target protein enrichment by immobilized metal ion affinity chromatography, on-bead trypsin digestion and quantification of signature peptides by LC-MS/MS...
January 18, 2017: Bioanalysis
https://www.readbyqxmd.com/read/28097868/development-of-phenothiazine-based-theranostic-compounds-that-act-both-as-inhibitors-of-%C3%AF-amyloid-aggregation-and-imaging-probes-for-amyloid-plaques-in-alzheimer-s-disease
#9
Pascal Dao, Feifei Ye, Yan Liu, Zhiyun Du, Kun Zhang, Chang-Zhi Dong, Bernard Meunier, Huixiong Chen
Early detection of Alzheimer's disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting Aβ plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near infrared fluorescent imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early stages. In the present study, we report the design, synthesis and evaluation of a series of new near-infrared fluorescent probes...
January 18, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28097817/revisiting-regulation-of-potassium-homeostasis-in-escherichia-coli-the-connection-to-phosphate-limitation
#10
Hannah Schramke, Vera Laermann, Halina E Tegetmeyer, Andreas Brachmann, Kirsten Jung, Karlheinz Altendorf
Two-component signal transduction constitutes the predominant strategy used by bacteria to adapt to fluctuating environments. The KdpD/KdpE system is one of the most widespread, and is crucial for K(+) homeostasis. In Escherichia coli, the histidine kinase KdpD senses K(+) availability, whereas the response regulator KdpE activates synthesis of the high-affinity K(+) uptake system KdpFABC. Here we show that, in the absence of KdpD, kdpFABC expression can be activated via phosphorylation of KdpE by the histidine kinase PhoR...
January 17, 2017: MicrobiologyOpen
https://www.readbyqxmd.com/read/28097765/a-false-positive-screening-hit-in-fragment-based-lead-discovery-watch-out-for-the-red-herring
#11
Jonathan Cramer, Johannes Schiebel, Tobias Wulsdorf, Kristof Grohe, Eszter Eva Najbauer, Frederik R Ehrmann, Nedyalka Radeva, Nina Zitzer, Uwe Linne, Rasmus Linser, Andreas Heine, Gerhard Klebe
With the rising popularity of fragment-based approaches in drug development, more and more attention has to be devoted to the detection of false-positive screening results. In particular, the small size and low affinity of fragments drives screening techniques to their limit. The pursuit of a false-positive hit can cause significant loss of time and resources. Here, we present an instructive and intriguing investigation into the origin of misleading assay results for a fragment that emerged as the most potent binder for the aspartic protease endothiapepsin (EP) across multiple screening assays...
January 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28097628/erratum-to-optimal-affinity-of-a-monoclonal-antibody-guiding-principles-using-mechanistic-modeling
#12
Abhinav Tiwari, Anson K Abraham, John M Harrold, Anup Zutshi, Pratap Singh
No abstract text is available yet for this article.
January 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28097528/pharmacology-and-toxicology-of-n-benzylphenethylamine-nbome-hallucinogens
#13
Adam L Halberstadt
Serotonergic hallucinogens induce profound changes in perception and cognition. The characteristic effects of hallucinogens are mediated by 5-HT2A receptor activation. One class of hallucinogens are 2,5-dimethoxy-substituted phenethylamines, such as the so-called 2C-X compounds 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I). Addition of an N-benzyl group to phenethylamine hallucinogens produces a marked increase in 5-HT2A-binding affinity and hallucinogenic potency...
January 18, 2017: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/28097460/synthesis-spectral-characterization-dna-protein-binding-dna-cleavage-cytotoxicity-antioxidative-and-molecular-docking-studies-of-cu-ii-complexes-containing-schiff-base-bpy-phen-ligands
#14
Berelli Anupama, Airva Aruna, Vijjulatha Manga, Sreekanth Sivan, Madamsetty Vijay Sagar, Ravula Chandrashekar
Ternary Cu(II) complexes [Cu(II)(L)(bpy)Cl] 1, [Cu(II)(L)(Phen)Cl] 2 [L = 2,3-dimethyl-1-phenyl-4(2 hydroxy-5-methyl benzylideneamino)-pyrazol-5-one, bpy = 2,2(') bipyridine, phen =1,10 phenanthroline) were synthesized and characterized by elemental analyses, UV-Visible, FT-IR, ESR, Mass, thermogravimetric and SEM EDAX techniques. The complexes exhibit octahedral geometry. The interaction of the Cu(II) with cailf thymus DNA (CT-DNA) was explored by using absorption and fluorescence spectroscopic methods...
January 17, 2017: Journal of Fluorescence
https://www.readbyqxmd.com/read/28096461/differential-contribution-of-transmembrane-domains-iv-v-vi-and-vii-to-human-angiotensin-ii-type-1-receptor-homomer-formation
#15
Brent M Young, Elaine Nguyen, Matthew A J Chedrawe, Jan K Rainey, Denis J Dupré
G protein-coupled receptors (GPCRs) play an important role in drug therapy, and represent one of the largest families of drug targets. The angiotensin II type 1 receptor (AT1R) is notable as it has a central role in the treatment of cardiovascular disease. Blockade of AT1R signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. Despite this, it has become apparent that our initial understanding of AT1R signaling is over-simplified. There is considerable evidence to suggest that AT1R signaling is highly modified in the presence of receptor-receptor interactions, but there is very little structural data available to explain this phenomenon even with the recent elucidation of the AT1R crystal structure...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28096460/occupancy-of-the-zinc-binding-site-by-transition-metals-decreases-the-substrate-affinity-of-the-human-dopamine-transporter-by-an-allosteric-mechanism
#16
Yang Li, Felix P Mayer, Peter S Hasenhuetl, Verena Burtscher, Klaus Schicker, Harald H Sitte, Michael Freissmuth, Walter Sandtner
The human dopamine transporter (DAT) has a tetrahedral Zn(2+)-binding site. Zn(2+)-binding sites are also recognized by other first row transition metals. Excessive accumulation of manganese or of copper can lead to Parkinsonism due to dopamine deficiency. Accordingly, we examined the effect of Mn(2+), Co(2+), Ni(2+) and Cu(2+)on transport-associated currents through DAT and DAT-H193K, a mutant with a disrupted Zn(2+)-binding site. All transition metals - but Mn(2+) - modulated the transport cycle of wild type DAT with affinities in the low µM range...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28096387/kinetic-assay-shows-that-increasing-red-cell-volume-could-be-a-treatment-for-sickle-cell-disease
#17
Quan Li, Eric R Henry, James Hofrichter, Jeffrey F Smith, Troy Cellmer, Emily B Dunkelberger, Belhu B Metaferia, Stacy Jones-Straehle, Sarah Boutom, Garrott W Christoph, Terri H Wakefield, Mary E Link, Dwayne Staton, Erica R Vass, Jeffery L Miller, Matthew M Hsieh, John F Tisdale, William A Eaton
Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort ("sickle") the cells...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28096233/role-of-the-constant-region-domain-in-the-structural-diversity-of-human-antibody-light-chains
#18
Emi Hifumi, Hiroaki Taguchi, Ryuichi Kato, Taizo Uda
Issues regarding the structural diversity (heterogeneity) of an antibody molecule have been the subject of discussion along with the development of antibody drugs. Research on heterogeneity has been extensive in recent years, but no clear solution has been reached. Heterogeneity is also observed in catalytic antibody κ light chains (CLs). In this study, we investigated how the constant region domain of CLs concerns structural diversity because it is a simple and good example for elucidating heterogeneity. By means of cation-exchange chromatography, SDS-PAGE, and 2-dimensional electrophoresis for the CL, multimolecular forms consisting of different electrical charges and molecular sizes coexisted in the solution, resulting in the similar heterogeneity of the full length of CLs...
January 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28096202/hasf-c3orf58-is-a-novel-ligand-of-the-insulin-like-growth-factor-1-receptor
#19
Akshay Bareja, Conrad Hodgkinson, Alan Payne, Richard Pratt, Victor Dzau
We have recently shown that Hypoxia and Akt induced Stem cell Factor (HASF) protects the heart from ischemia-induced damage and promotes cardiomyocyte proliferation. While we have identified certain signaling pathways responsible for these protective effects, the receptor mediating these effects was unknown. Here, we undertook studies to identify the HASF receptor. A yeast two-hybrid screen identified a partial fragment of Insulin-like Growth Factor 1 Receptor (IGF1R) as a binding partner of HASF. Subsequent co-immunoprecipitation experiments showed that HASF bound to full-length IGF1R...
January 17, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28096188/erk1-2-phosphorylate-gab2-to-promote-a-negative-feedback-loop-that-attenuates-pi3k-akt-signaling
#20
Xiaocui Zhang, Geneviève Lavoie, Antoine Méant, Léo Aubert, Marie Cargnello, André Haman, Trang Hoang, Philippe P Roux
The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells as it is required for PI3K (phosphoinositide 3-kinase) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function...
January 17, 2017: Molecular and Cellular Biology
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