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https://www.readbyqxmd.com/read/29150694/inhibition-of-intimal-hyperplasia-in-murine-aortic-allografts-by-administration-of-a-small-molecule-tlr4-inhibitor-tak-242
#1
Chuangyan Wu, Xiangchao Ding, Cheng Zhou, Ping Ye, Yuan Sun, Jie Wu, Anchen Zhang, Xiaofan Huang, Lingyun Ren, Ke Wang, Peng Deng, Zhang Yue, Jiuling Chen, Sihua Wang, Jiahong Xia
Graft arteriosclerosis (GA) is the leading cause of late cardiac allograft dysfunction. The innate immune system plays a major role in GA, paprticularly Toll-like receptor 4 (TLR4) signaling. Here we characterized the role of TLR4 and its antagonist TAK-242 in a mouse model of GA. BALB/c (H-2d) donor aortas were transplanted into C57BL/6 (H-2b) recipients, and the mice received intraperitoneal injection of 3 or 10 mg/kg of TAK-242 or vehicle every other day for 1, 2, 4, 6, 8 and 12 weeks. With TAK-242 administration, intimal hyperplasia initially appeared at 2 weeks after transplantation, and TAK-242 postponed the progression of neointimal formation in allogeneic aortic grafts...
November 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29150334/a-routinely-used-protein-staining-dye-acts-as-an-inhibitor-of-wild-type-and-mutant-alpha-synuclein-aggregation-and-modulator-of-neurotoxicity
#2
Nuzhat Ahsan, Ibrar Ahmed Siddique, Sarika Gupta, Avadhesha Surolia
Inhibition of amyloid formation along with modulation of toxicity employing small molecules is emerging as a potential therapeutic approach for protein misfolding disorders which includes Parkinson's disease, Alzheimer's disease and Multiple System Atrophy etc. Countless current interventional strategies for treating α-synucleinopathies consider using peptidic and non-peptidic inhibitors for arresting fibrillisation, disrupting existing fibrils and reducing associated toxicity. One group of molecules less exploited in this regard are triphenylmethane dyes...
October 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29150244/proteomic-analysis-of-follicular-fluid-from-tropically-adapted-goats
#3
Alexandre R Paula Junior, Mauricio F van Tilburg, Marina D P Lobo, Ana C O Monteiro-Moreira, Renato A Moreira, Carlos H S Melo, Joanna M G Souza-Fabjan, Airton A Araújo, Luciana M Melo, Dárcio I A Teixeira, Arlindo A Moura, Vicente J F Freitas
The present study was conducted to characterize the major proteome of ovarian follicular fluid from locally-adapted, "Canindé" goats in the northeast of Brazil. Eight estrous cycling goats received a hormonal treatment consisting of medroxyprogesterone acetate, D-cloprostenol and FSH. Fluid was collected by laparoscopy from small (<3mm), medium (3-4mm) and large (>4mm) follicles and then, proteins were analyzed by 2-D SDS-PAGE and tandem mass spectrometry. Thirty-six proteins were identified in the goat follicular fluid, including albumin, immunoglobulins, ceruloplasmin, complement factor B, alpha-1B-glycoprotein precursor, serotransferrin, complement C3 and serpins, among others...
November 6, 2017: Animal Reproduction Science
https://www.readbyqxmd.com/read/29149831/molecular-mechanisms-triggered-by-bile-acids-on-iintestinal-ca2-absorption
#4
Ana Marchionatti, Maria Rivoira, Valeria Rodriguez, Adriana Perez, Nori Tolosa de Talamoni
Bile acids (BAs) are synthesized in the liver and are among the main components of bile. For many years, it was thought that they have only a role as emulsifiers of fat in the small intestine facilitating the absorption of lipids and lipid soluble vitamins. Lately, they are also considered important signaling molecules, not only by regulating their own synthesis, but also having a role in several metabolic diseases. In this review we focus on the effect of deoxycholic, ursodeoxycholic and litocholic acids and their combination upon the intestinal Ca2+ absorption...
November 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29149821/statins-therapy-for-connective-tissue-diseases-new-therapeutic-opportunities
#5
Przemyslaw J Kotyla, Eugene J Kucharz
Background and Objective Statins, 3-hydroxyl-3-methyl-glutharyl Coenzyme A reductase inhibitors showed their therapeutic potential in the treatment of atherosclerosis-related diseases. Recently, the properties of statins, separate from their lipid lowering activity have attracted much attention. These properties that cover a wide area of physiopathological activities including cell maturation, immune response regulation, tissue fibrosis, endothelial activity and are called pleiotropic activity. Many in vitro studies demonstrated significant, statins-dependent regulation of immune system reactivity, reduction of pro-inflammatory and pro-fibrotic cytokines as well as suppression of endothelial activity and damage...
November 15, 2017: Endocrine, Metabolic & Immune Disorders Drug Targets
https://www.readbyqxmd.com/read/29149763/formulation-and-anti-neurotoxic-activity-of-baicalein-incorporating-neutral-nanoliposome
#6
Farhang Aliakbari, Ali Akbar Shabani, Hassan Bardania, Hossein Mohammad-Beigi, Amir Tayaranian Marvian, Faezeh Dehghani Esmatabad, Abbas Ali Vafaei, Seyed Abbas Shojaosadati, Ali Akbar Saboury, Gunna Christiansen, Daniel E Otzen, Dina Morshedi
Despite extensive studies of the effects of herbal-derived small molecules in the biopharmaceutical and biomedical sciences, their low solubility and stability remain a challenge. Here we focus on baicalein, a small molecule showing potential against neurodegenerative diseases such as Parkinson's and Alzheimer's. However, therapeutic usage in vivo is challenged by low solubility and stability. To address this we have applied neutrally-charged nanoliposome (NLP) as carrier for baicalein. Baicalein was incorporated into NLP to form NLP-Ba at molar baicalain:lipid ratios of up to 1:3, giving a drug entrapment efficiency of 96...
November 11, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/29149726/protein-structure-based-drug-design-from-docking-to-molecular-dynamics
#7
REVIEW
Paweł Śledź, Amedeo Caflisch
Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 10(6) small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics...
November 14, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/29149720/a-robust-strategy-for-preparation-of-sequential-stimuli-responsive-block-copolymer-prodrugs-via-thiolactone-chemistry-to-overcome-multiple-anticancer-drug-delivery-barriers
#8
Wendong Ke, Wei Yin, Zengshi Zha, Jean Felix Mukerabigwi, Weijian Chen, Yuheng Wang, Chuanxin He, Zhishen Ge
Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release...
November 9, 2017: Biomaterials
https://www.readbyqxmd.com/read/29149532/exploitation-of-micrornas-by-japanese-encephalitis-virus-in-human-microglial-cells
#9
Meghana Rastogi, Neha Srivastava, Sunit K Singh
JEV infection in CNS leads to the JE neuroinflammation. Children and old age individual have been reported to be more prone to JEV infection. MicroRNAs are endogenous, small non-coding RNAs, which regulate the gene expression. These are ∼22 nucleotide long, conserved RNA sequence that binds at the 3'UTR of a target mRNA and regulate the post-transcriptional gene expression. The role of microRNAs has been reported in several diseases like cancer, viral infection, neuro-degeneration, diabetes etc. In the present study, the human microglial cells were infected with JEV (JaOAr strain)...
November 17, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/29149495/a-redox-activated-g-quadruplex-dna-binder-based-on-a-platinum-iv-salphen-complex
#10
Ramon Vilar, Stephane Bandeira, Jorge Gonzalez Garcia, Evangelina Pensa, Tim Albrecht
There has been increasing interest in the development of small molecules that can selectively bind to G-quadruplex DNA structures. The latter have been associated to a number of key biological processes and therefore are proposed to be potential targets for drug development. In this paper we report the first example of a reduction-activated G-quadruplex DNA binder. We show that a new octahedral platinum(IV)-salphen complex does not interact with DNA in aqueous media at pH 7.4; however, upon addition of bio-reductants such as ascorbic acid or glutathione, the compound readily reduces to the corresponding square planar platinum(II) complex...
November 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29149416/history-of-histamine-releasing-factor-hrf-translationally-controlled-tumor-protein-tctp-including-a-potential-therapeutic-target-in-asthma-and-allergy
#11
Susan M MacDonald
Histamine-releasing factor (HRF) also known as translationally controlled tumor protein (TCTP) is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here we will highlight the subcloning of the molecule, its clinical implications, as well as an inducible-transgenic mouse. Particular attention will be paid to its extracellular functioning and its potential role as a therapeutic target in asthma and allergy. The cells and the cytokines that are produced when stimulated or primed by HRF/TCTP will be detailed as well as the downstream signaling pathway that HRF/TCTP elicits...
2017: Results and Problems in Cell Differentiation
https://www.readbyqxmd.com/read/29149402/structural-insights-into-tctp-and-its-interactions-with-ligands-and-proteins
#12
Nadine Assrir, Florian Malard, Ewen Lescop
The 19-24 kDa Translationally Controlled Tumor Protein (TCTP) is involved in a wide range of molecular interactions with biological and nonbiological partners of various chemical compositions such as proteins, peptides, nucleic acids, carbohydrates, or small molecules. TCTP is therefore an important and versatile binding platform. Many of these protein-protein interactions have been validated, albeit only few received an in-depth structural characterization. In this chapter, we will focus on the structural analysis of TCTP and we will review the available literature regarding its interaction network from a structural perspective...
2017: Results and Problems in Cell Differentiation
https://www.readbyqxmd.com/read/29149330/s101-an-inhibitor-of-proliferating-t-cells-rescues-mice-from-superantigen-induced-shock
#13
Alexei Shir, Shoshana Klein, Idit Sagiv-Barfi, Tamar Geiger, Maya Zigler, Yael Langut, Nufar Edinger, Alexander Levitzki
Superantigens (SAg) are extremely potent bacterial toxins, which evoke a virulent immune response, inducing non-specific T-cell proliferation, rapid cytokine release and lethal toxic shock, for which there is no effective treatment. We previously developed a small molecule, S101, which potently inhibits proliferating T-cells (Sagiv-Barfi et al, Bioorg Med Chem (2010) 18:6404-6413). In a severe mouse model of toxic shock, a single injection of S101 given together with superantigen challenge, rescued 100% of the mice...
November 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29149299/twj-screen-an-isothermal-screening-assay-to-assess-ligand-dna-junction-interactions-in-vitro
#14
Ludivine Guyon, Marc Pirrotta, Katerina Duskova, Anton Granzhan, Marie-Paule Teulade-Fichou, David Monchaud
The quest for chemicals able to operate at selected genomic loci in a spatiotemporally controlled manner is desirable to create manageable DNA damages. Mounting evidence now shows that alternative DNA structures, including G-quadruplexes and branched DNA (or DNA junctions), might hamper proper progression of replication fork, thus triggering DNA damages and genomic instability. Therefore, small molecules that stabilize these DNA structures are currently scrutinized as a promising way to create genomic defects that cannot be dealt with properly by cancer cells...
November 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29149297/dna-knots-occur-in-intracellular-chromatin
#15
Antonio Valdés, Joana Segura, Sílvia Dyson, Belén Martínez-García, Joaquim Roca
In vivo DNA molecules are narrowly folded within chromatin fibers and self-interacting chromatin domains. Therefore, intra-molecular DNA entanglements (knots) might occur via DNA strand passage activity of topoisomerase II. Here, we assessed the presence of such DNA knots in a variety of yeast circular minichromosomes. We found that small steady state fractions of DNA knots are common in intracellular chromatin. These knots occur irrespective of DNA replication and cell proliferation, though their abundance is reduced during DNA transcription...
November 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29149024/the-role-of-the-mammalian-prion-protein-in-the-control-of-sleep
#16
REVIEW
Amber Roguski, Andrew C Gill
Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the "eponymous" fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrP(C)), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease...
November 17, 2017: Pathogens
https://www.readbyqxmd.com/read/29148976/small-molecule-photoregulin3-prevents-retinal-degeneration-in-the-rho-p23h-mouse-model-of-retinitis-pigmentosa
#17
Paul A Nakamura, Andy A Shimchuk, Shibing Tang, Zhizhi Wang, Kole DeGolier, Sheng Ding, Thomas A Reh
Regulation of rod gene expression has emerged as a potential therapeutic strategy to treat retinal degenerative diseases like retinitis pigmentosa (RP). We previously reported on a small molecule modulator of the rod transcription factor Nr2e3, Photoregulin1 (PR1), that regulates the expression of photoreceptor-specific genes. Although PR1 slows the progression of retinal degeneration in models of RP in vitro, in vivo analyses were not possible with PR1. We now report a structurally unrelated compound, Photoregulin3 (PR3) that also inhibits rod photoreceptor gene expression, potentially though Nr2e3 modulation...
November 17, 2017: ELife
https://www.readbyqxmd.com/read/29148850/atad2-in-cancer-a-pharmacologically-challenging-but-tractable-target
#18
Muzammal Hussain, Yang Zhou, Yu Song, H M Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a "difficult to drug" or "least druggable" target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding...
November 17, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29148835/2017-white-paper-on-recent-issues-in-bioanalysis-aren-t-bmv-guidance-guidelines-scientific-part-1-lcms-small-molecules-peptides-and-small-molecule-biomarkers
#19
Jan Welink, Eric Yang, Nicola Hughes, Brian Rago, Eric Woolf, Jens Sydor, Laura Coppola, Brad Ackermann, Wenkui Li, Stephen C Alley, Mark Arnold, Isabella Berger, Chad Briscoe, Michael Buonarati, Mark Bustard, Mark Cancilla, Seongeun Julia Cho, Jeff Duggan, Daniela Fraier, Fabio Garofolo, Rachel Green, Sam Haidar, Lucinda Hittle, Akiko Ishii-Watabe, Rafiq Islam, Rand Jenkins, Barry Jones, John Kadavil, Sean Kassim, Olga Kavetska, Olivier Le Blaye, Anita Lee, Hanlan Liu, John Mehl, Gustavo Mendes Lima Santos, Adrien Musuku, Ragu Ramanathan, Yoshiro Saito, Natasha Savoie, Scott Summerfield, Sekhar Surapaneni, Matthew Szapacs, Nilufer Tampal, Tom Verhaeghe, Stephen Vinter, Emma Whale
The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand-binding assay (LBA) approaches...
November 17, 2017: Bioanalysis
https://www.readbyqxmd.com/read/29148763/discovery-of-n-3-carbamoyl-5-5-7-7-tetramethyl-5-7-dihydro-4h-thieno-2-3-c-pyran-2-yl-lh-pyrazole-5-carboxamide-glpg1837-a-novel-potentiator-which-can-open-class-iii-mutant-cystic-fibrosis-transmembrane-conductance-regulator-cftr-channels-to-a-high-extent
#20
Steven Emiel Van der Plas, Hans Kelgtermans, Tom De Munck, Sébastien Laurent Xavier Martina, Sébastien Dropsit, Evelyne Quinton, Ann De Blieck, Caroline Joannesse, Linda Tomaskovic, Mia Jans, Thierry Christophe, Ellen Van der Aar, Monica Borgonovi, Luc Nelles, Maarten Gees, Pieter Fw Stouten, Jan Van Der Schueren, Oscar Mammoliti, Katja Conrath, Martin J Andrews
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837 which shows enhanced efficacy on CFTR mutants harboring Class III mutations compared to Ivacaftor, the first marketed potentiator...
November 17, 2017: Journal of Medicinal Chemistry
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