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https://www.readbyqxmd.com/read/28437629/design-and-development-of-benzoxazole-derivatives-with-toll-like-receptor-9-antagonism
#1
Swarnali Roy, Ayan Mukherjee, Barnali Paul, Oindrila Rahaman, Shounak Roy, Gundaram Maithri, Bandaru Ramya, Sourav Pal, Dipyaman Ganguly, Arindam Talukdar
Toll-like receptor 9 (TLR9) is a major therapeutic target for numerous inflammatory disorders. Development of small molecule inhibitors for TLR9 remains largely empirical due to lack of structural understanding of potential TLR9 antagonism by small molecules and due to the unusual topology of the ligand binding surface of the receptor. To develop a structural model for rational design of small molecule TLR9 antagonists, an enhanced homology model of human TLR9 (hTLR9) was constructed. Binding mode analysis of a series of molecules having characteristic molecular geometry, flexibility and basicity was conducted based on crystal structure of the inhibitory DNA (iDNA) bound to horse and bovine TLR9...
April 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28436304/the-pten-inhibitor-bpv-pic-promotes-neuroprotection-against-amyloid-%C3%AE-peptide-25-35-induced-oxidative-stress-and-neurotoxicity
#2
Xiao-Ying Liu, Li-Jing Zhang, Zhou Chen, Li-Bin Liu
OBJECTIVES: The aim of this study was to elucidate the mechanism underlying the neuroprotective effects of the phosphatase and tensin homolog (PTEN) inhibitor, bisperoxovanadium-pic [bpV(pic)]. METHODS: We determined the effects of bpV(pic) on amyloid-β-peptide-(25-35)-induced neurotoxicity, particularly intracellular reactive oxygen species (ROS) production and mitochondria-mediated apoptotic signaling, in a human neuroblastoma (SH-SY5Y) cell model. RESULTS: We found that exposure of SH-SY5Y cells to amyloid β peptides (Aβ25-35) resulted in a significant reduction in cell viability accompanied by increased lactate dehydrogenase (LDH) release, elevated levels of intracellular ROS, and decreased superoxide dismutase (SOD) activities, all of which were reversed by co-treatment with bpV(pic)...
April 23, 2017: Neurological Research
https://www.readbyqxmd.com/read/28435892/dramatic-improvement-of-crispr-cas9-editing-in-candida-albicans-by-increased-single-guide-rna-expression
#3
Henry Ng, Neta Dean
The clustered regularly interspaced short palindromic repeat system with CRISPR-associated protein 9 nuclease (CRISPR/Cas9) has emerged as a versatile tool for genome editing in Candida albicans. Mounting evidence from other model systems suggests that the intracellular levels of single guide RNA (sgRNA) limit the efficiency of Cas9-dependent DNA cleavage. Here, we tested this idea and describe a new means of sgRNA delivery that improves previously described methods by ~10-fold. The efficiency of Cas9/sgRNA-dependent cleavage and repair of a single-copy yeast enhanced monomeric red fluorescent protein (RFP) gene was measured as a function of various parameters that are hypothesized to affect sgRNA accumulation, including transcriptional and posttranscriptional processing...
March 2017: MSphere
https://www.readbyqxmd.com/read/28435665/a%C3%A2-voltage-dependent-fluorescent-indicator-for-optogenetic-applications-archaerhodopsin-3-structure-and-optical-properties-from-in-silico-modeling
#4
Dmitrii M Nikolaev, Anton Emelyanov, Vitaly M Boitsov, Maxim S Panov, Mikhail N Ryazantsev
It was demonstrated in recent studies that some rhodopsins can be used in optogenetics as fluorescent indicators of membrane voltage. One of the promising candidates for these applications is archaerhodopsin-3. However, the fluorescent signal for wild-type achaerhodopsin-3 is not strong enough for real applications. Rational design of mutants with an improved signal is an important task, which requires both experimental and theoretical studies. Herein, we used a homology-based computational approach to predict the three-dimensional structure of archaerhodopsin-3, and a Quantum Mechanics/Molecular Mechanics (QM/MM) hybrid approach with high-level multireference ab initio methodology (SORCI+Q/AMBER) to model optical properties of this protein...
2017: F1000Research
https://www.readbyqxmd.com/read/28435300/the-identification-of-protein-domains-that-mediate-functional-interactions-between-rab-gtpases-and-rabgaps-using-3d-protein-modeling
#5
Jeremiah J Davie, Silviu L Faitar
Currently, time-consuming serial in vitro experimentation involving immunocytochemistry or radiolabeled materials is required to identify which of the numerous Rab-GTPases (Rab) and Rab-GTPase activating proteins (RabGAP) are capable of functional interactions. These interactions are essential for numerous cellular functions, and in silico methods of reducing in vitro trial and error would accelerate the pace of research in cell biology. We have utilized a combination of three-dimensional protein modeling and protein bioinformatics to identify domains present in Rab proteins that are predictive of their functional interaction with a specific RabGAP...
2017: Advances and Applications in Bioinformatics and Chemistry: AABC
https://www.readbyqxmd.com/read/28434914/full-length-oligomeric-structure-of-wzz-determined-by-cryoelectron-microscopy-reveals-insights-into-membrane-bound-states
#6
Richard F Collins, Vasileios Kargas, Brad R Clarke, C Alistair Siebert, Daniel K Clare, Peter J Bond, Chris Whitfield, Robert C Ford
Wzz is an integral inner membrane protein involved in regulating the length of lipopolysaccharide O-antigen glycans and essential for the virulence of many Gram-negative pathogens. In all Wzz homologs, the large periplasmic domain is proposed to be anchored by two transmembrane helices, but no information is available for the transmembrane and cytosolic domains. Here we have studied purified oligomeric Wzz complexes using cryoelectron microscopy and resolved the transmembrane regions within a semi-continuous detergent micelle...
April 11, 2017: Structure
https://www.readbyqxmd.com/read/28434763/computer-aided-discovery-of-two-novel-chalcone-like-compounds-active-and-selective-against-leishmania-infantum
#7
Marcelo N Gomes, Laura M Alcântara, Bruno J Neves, Cleber C Melo-Filho, Lucio H Freitas-Junior, Carolina B Moraes, Rui Ma, Scott G Franzblau, Eugene Muratov, Carolina Horta Andrade
Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28433418/binge-alcohol-alters-pnpla3-levels-in-liver-through-epigenetic-mechanism-involving-histone-h3-acetylation
#8
REVIEW
Ricardo J Restrepo, Robert W Lim, Ronald J Korthuis, Shivendra D Shukla
The human PNPLA3 (patatin-like phospholipase domain-containing 3) gene codes for a protein which is highly expressed in adipose tissue and liver, and is implicated in lipid homeostasis. While PNPLA3 protein contains regions homologous to functional lipolytic proteins, the regulation of its tissue expression is reflective of lipogenic genes. A naturally occurring genetic variant of PNPLA3 in humans has been linked to increased susceptibility to alcoholic liver disease. We have examined the modulatory effect of alcohol on PNPLA3 protein and mRNA expression as well as the association of its gene promoter with acetylated histone H3K9 by chromatin immunoprecipitation (ChIP) assay in rat hepatocytes in vitro, and in vivo in mouse and rat models of acute binge, chronic, and chronic followed by acute binge ethanol administration...
March 12, 2017: Alcohol
https://www.readbyqxmd.com/read/28433110/animal-models-of-wilson-disease
#9
Valentina Medici, Dominik Huster
Wilson disease (WD) is caused by ATPase copper-transporting beta (ATP7B) mutations and results in copper toxicity in liver and brain. Although the defective gene was identified in 1993, the specific mechanisms underlying copper toxicity and the remarkable phenotypic diversity of the disease are still poorly understood. Animal models harboring defects in the ATP7B homolog have helped to reveal new insights into pathomechanisms of WD. Four rodent models with ATP7B gene defects have been described - the Long-Evans Cinnamon (LEC) rat, inbred mouse models (toxic milk (tx), the Jackson Laboratory toxic milk (tx-j)), and the genetically engineered ATP7B(-/-) (knockout) mouse - all of which develop liver disease to different extents...
2017: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/28432873/conditional-deletion-of-bmal1-accentuates-microvascular-and-macrovascular-injury
#10
Ashay D Bhatwadekar, Eleni Beli, Diao Yanpeng, Jonathan Chen, Qianyi Luo, Alpha Alex, Sergio Caballero, James M Dominguez, Tatiana E Salazar, Julia V Busik, Mark S Segal, Maria B Grant
The brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1 constitutes a major transcriptional regulator of the circadian clock. Here, we explored the impact of conditional deletion of Bmal1 in endothelium and hematopoietic cells in murine models of microvascular and macrovascular injury. We used two models of Bmal1(fx/fx);Tek-Cre mice, a retinal ischemia/reperfusion model and a neointimal hyperplasia model of the femoral artery. Eyes were enumerated for acellular capillaries and were stained for oxidative damage markers using nitrotyrosine immunohistochemistry...
April 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28432778/cross-species-studies-of-cognition-relevant-to-drug-discovery-a-translational-approach
#11
REVIEW
T W Robbins
This Review advances the case that bidirectional, cross-species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross-species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenergic reuptake blocker atomoxetine...
April 22, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28432456/deregulated-bcl-2-family-proteins-impact-on-repair-of-dna-double-strand-breaks-and-are-targets-to-overcome-radioresistance-in-lung-cancer
#12
Sarah A Wieczorek, Frank Breitenbuecher, Aashish Soni, Katja Paul-Konietzko, Sophie Ziegler, Ali Sak, George Iliakis, Martin Schuler
PURPOSE: DNA damage-induced cell death is a major effector mechanism of radiotherapy. Aberrant expression of anti-apoptotic BCL-2 family proteins is frequently observed in lung cancers. Against this background, we studied radioresistance mediated by BCL-2 family proteins at the mechanistic level and its potential as target for radiochemotherapy. METHODS: Lung cancer models stably expressing BCL-xL or MCL-1 were irradiated to study cell death, clonogenic survival, and DNA repair kinetics in vitro, and growth suppression of established tumors in vivo...
April 21, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28432363/joint-based-description-of-protein-structure-its-application-to-the-geometric-characterization-of-membrane-proteins
#13
Jayaraman Thangappan, Sangwook Wu, Sun-Gu Lee
A macroscopic description of a protein structure allows an understanding of the protein conformations in a more simplistic manner. Here, a new macroscopic approach that utilizes the joints of the protein secondary structures as a basic descriptor for the protein structure is proposed and applied to study the arrangement of secondary structures in helical membrane proteins. Two types of dihedral angle, Ω and λ, were defined based on the joint points of the transmembrane (TM) helices and loops, and employed to analyze 103 non-homologous membrane proteins with 3 to 14 TM helices...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28430892/anti-arrhythmic-potential-of-the-late-sodium-current-inhibitor-gs-458967-in-murine-scn5a-1798insd-and-human-scn5a-1795insd-ipsc-derived-cardiomyocytes
#14
Vincent Portero, Simona Casini, Maaike Hoekstra, Arie O Verkerk, Isabella Mengarelli, Luiz Belardinelli, Sridharan Rajamani, Arthur A M Wilde, Connie R Bezzina, Marieke W Veldkamp, Carol Ann Remme
AIM: Selective inhibition of cardiac late sodium current (INaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of INaL, in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from both human SCN5A-1795insD+/- induced pluripotent stem cells (hiPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD+/-...
April 18, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28429728/a-formulated-tlr7-8-agonist-is-a-flexible-highly-potent-and-effective-adjuvant-for-pandemic-influenza-vaccines
#15
Neal Van Hoeven, Christopher B Fox, Brian Granger, Tara Evers, Sharvari W Joshi, Ghislain I Nana, Sarah C Evans, Susan Lin, Hong Liang, Li Liang, Rie Nakajima, Philip L Felgner, Richard A Bowen, Nicole Marlenee, Airn Hartwig, Susan L Baldwin, Rhea N Coler, Mark Tomai, James Elvecrog, Steven G Reed, Darrick Carter
Since 1997, highly pathogenic avian influenza viruses of the H5N1 subtype have been transmitted from avian hosts to humans. The severity of H5N1 infection in humans, as well as the sporadic nature of H5N1 outbreaks, both geographically and temporally, make generation of an effective vaccine a global public health priority. An effective H5N1 vaccine must ultimately provide protection against viruses from diverse clades. Toll-like receptor (TLR) agonist adjuvant formulations have a demonstrated ability to broaden H5N1 vaccine responses in pre-clinical models...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28429004/binding-site-opening-by-loop-c-shift-and-chloride-ion-pore-interaction-in-the-gabaa-receptor-model
#16
M A Michałowski, S Kraszewski, J W Mozrzymas
GABAA receptors (GABAARs) are crucial in mediating inhibition in the adult mammalian brain. Although the kinetics of this receptor has been extensively studied, the molecular picture of interactions occurring at various channel conformations remains elusive. While electrophysiology combined with mutagenesis sheds light on the role of specific residues, ultrastructural studies reveal static structures which, in the case of GABAARs, are limited to the β3 homomer. To take advantage of the newest crystal structures of cys-loop receptors, a homology model of α1β2γ2 GABAAR in the unbound closed state was built using a template of the homomeric glycine receptor in the closed state...
April 21, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28427225/enhancing-synthetic-lethality-of-parp-inhibitor-and-cisplatin-in-brca-proficient-tumour-cells-with-hyperthermia
#17
Arlene L Oei, Caspar M van Leeuwen, Vidhula R Ahire, Hans M Rodermond, Rosemarie Ten Cate, Anneke M Westermann, Lukas J A Stalpers, Johannes Crezee, H Petra Kok, Przemek M Krawczyk, Roland Kanaar, Nicolaas A P Franken
BACKGROUND: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28426764/structural-characterization-of-core-bradavidin-in-complex-with-biotin
#18
Nitin Agrawal, Juha A E Määttä, Markku S Kulomaa, Vesa P Hytönen, Mark S Johnson, Tomi T Airenne
Bradavidin is a tetrameric biotin-binding protein similar to chicken avidin and bacterial streptavidin, and was originally cloned from the nitrogen-fixing bacteria Bradyrhizobium diazoefficiens. We have previously reported the crystal structure of the full-length, wild-type (wt) bradavidin with 138 amino acids, where the C-terminal residues Gly129-Lys138 ("Brad-tag") act as an intrinsic ligand (i.e. Gly129-Lys138 bind into the biotin-binding site of an adjacent subunit within the same tetramer) and has potential as an affinity tag for biotechnological purposes...
2017: PloS One
https://www.readbyqxmd.com/read/28426370/pin-formed-protein-a-door-to-reveal-the-mechanism-for-auxin-triggered-initiation-of-cotton-fiber
#19
Mi Zhang, Yuehua Xiao, Jianyan Zeng, Yan Pei
Cotton fibers are differentiated ovule epidermal cells that provide an ideal model to study cell differentiation and elongation. Establishment of auxin maximum in fiber cells is crucial for cotton-fiber protrusion from ovule surface. However, it is unclear where the auxin originates from and how the auxin accumulates in fiber cells. Our recent results indicate that the auxin is mainly imported from the outside of ovules, and transported to fiber cells through GhPIN (homolog of PIN-formed proteins in cotton) -mediated polar auxin transport, rather than in situ synthesis...
April 20, 2017: Plant Signaling & Behavior
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#20
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
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