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https://www.readbyqxmd.com/read/28922596/privileged-substructures-to-modulate-protein-protein-interactions
#1
Nicolas Bosc, Mélaine A Kuenemann, Jérome Bécot, Marek Vavrusa, Adrien H Cerdan, Olivier Sperandio
Given the difficulties to identify chemical probes that can modulate protein-protein interactions (PPIs), actors in the field start to agree on the necessity to use PPI-tailored screening chemical collections. However, which type of scaffolds may promote the binding of compounds to PPI targets remains unclear. In this big data analysis, we have identified a list of privileged chemical substructures that are most often observed within inhibitors of PPIs. Using molecular frameworks as a way to perceive chemical substructures with the combination of an experimental and a machine-learning based predicted dataset of iPPI compounds, we propose a list of privileged substructures in the form of scaffolds and chemical moieties that can be substantially chemically functionalized and do not present any toxicophore nor Pan-assay interference (PAINS) alerts...
September 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28922553/programmable-nucleic-acid-based-polygons-with-controlled-neuroimmunomodulatory-properties-for-predictive-qsar-modeling
#2
Morgan Brittany Johnson, Justin R Halman, Emily Satterwhite, Alexey V Zakharov, My N Bui, Kheiria Benkato, Victoria Goldsworthy, Taejin Kim, Enping Hong, Marina A Dobrovolskaia, Emil F Khisamutdinov, Ian Marriott, Kirill A Afonin
In the past few years, the study of therapeutic RNA nanotechnology has expanded tremendously to encompass a large group of interdisciplinary sciences. It is now evident that rationally designed programmable RNA nanostructures offer unique advantages in addressing contemporary therapeutic challenges such as distinguishing target cell types and ameliorating disease. However, to maximize the therapeutic benefit of these nanostructures, it is essential to understand the immunostimulatory aptitude of such tools and identify potential complications...
September 18, 2017: Small
https://www.readbyqxmd.com/read/28922238/primary-central-nervous-system-lymphoma-time-for-diagnostic-biomarkers-and-biotherapies
#3
Louis Royer-Perron, Khê Hoang-Xuan, Agusti Alentorn
PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare cancer with a somber prognosis in older patients, which it affects predominantly. Only in recent years have molecular alterations characterizing PCNSL been thoroughly described. This opens possibilities for the use of targeted therapies. Developments in imaging and biomarkers have also great potential to help clinicians faced with diagnostic and prognostic uncertainties. RECENT FINDINGS: Several biomarkers for PCNSL, such as different microRNAs, which could be tested in cerebrospinal fluid and vitreous fluid, and IL-10, which has been shown to have excellent sensitivity and specificity in the cerebrospinal fluid, have emerged in the last years...
September 15, 2017: Current Opinion in Neurology
https://www.readbyqxmd.com/read/28922161/comorbidity-analysis-between-alzheimer-s-disease-and-type-2-diabetes-mellitus-t2dm-based-on-shared-pathways-and-the-role-of-t2dm-drugs
#4
Reagon Karki, Alpha Tom Kodamullil, Martin Hofmann-Apitius
BACKGROUND: Various studies suggest a comorbid association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. OBJECTIVE: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. METHOD: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28922156/soluble-oligomers-require-a-ganglioside-to-trigger-neuronal-calcium-overload
#5
Roberta Cascella, Elisa Evangelisti, Alessandra Bigi, Matteo Becatti, Claudia Fiorillo, Massimo Stefani, Fabrizio Chiti, Cristina Cecchi
An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28922023/fatty-acid-synthase-fasn-as-a-therapeutic-target-in-breast-cancer
#6
Javier A Menendez, Ruth Lupu
Ten years ago, we put forward the metabolo-oncogenic nature of fatty acid synthase (FASN) in breast cancer. Since the conception of this hypothesis, which provided a model to explain how FASN is intertwined with various signaling networks to cell-autonomously regulate breast cancer initiation and progression, FASN has received considerable attention as a therapeutic target. However, despite the ever-growing evidence demonstrating the involvement of FASN as part of the cancer-associated metabolic reprogramming, translation of the basic science-discovery aspects of FASN blockade to the clinical arena remains a challenge...
September 18, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28921929/tumor-suppressive-mir-145-co-repressed-by-tcf4-%C3%AE-catenin-and-prc2-complexes-forms-double-negative-regulation-loops-with-its-negative-regulators-in-colorectal-cancer
#7
Wei Wang, Xin Xiao, Xu Chen, Yi Huo, Wen-Jin Xi, Zhi-Feng Lin, Dan Zhang, Yu-Fang Li, Fan Yang, Wei-Hong Wen, An-Gang Yang, Tao Wang
The frequently dysregulated Wnt/β-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In the present study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-in-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistances
#8
Vania Bernardes Genisson, Julie Laborde, Céline Deraeve
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens, namely ethionamide (ETH), prothionamide (PTH), p-aminosalicylic acid (PAS), thiacetazone (TAC), isoxyl (ISO) and the recently approved delamanid. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy...
September 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28921867/polymer-cancerostatics-targeted-with-an-antibody-fragment-bound-via-a-coiled-coil-motif-in-vivo-therapeutic-efficacy-against-murine-bcl1-leukemia
#9
Michal Pechar, Robert Pola, Olga Janoušková, Irena Sieglová, Vlastimil Král, Milan Fábry, Barbora Tomalová, Marek Kovář
A BCL1 leukemia-cell-targeted polymer-drug conjugate with a narrow molecular weight distribution consisting of an N-(2-hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal-free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer-pirarubicin conjugate and the targeting protein...
September 15, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28921848/interconversion-rates-between-conformational-states-as-rationale-for-the-membrane-permeability-of-cyclosporines
#10
Jagna Witek, Max Mühlbauer, Bettina G Keller, Markus Blatter, Axel Meissner, Trixie Wagner, Sereina Riniker
Cyclic peptides have regained interest as potential inhibitors of challenging targets, but have often a low bioavailability. The natural product cyclosporine A (CsA) is the textbook exception. Despite its size and polar backbone it is able to passively cross membranes. This ability is hypothesized to be due to a conformational change from the low-energy conformation in water to a "congruent" conformation that is populated both in water and inside the membrane. Here, we use a combination of NMR measurements and kinetic models based on molecular dynamics simulations to rationalize the difference in the membrane permeability of cyclosporine E (CsE) and CsA...
September 17, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
https://www.readbyqxmd.com/read/28921745/transcription-factor-ccaat-enhancer-binding-protein-%C3%AE-upregulates-microrna-let-7f-1-in-human-endocervical-cells
#11
Kanchana Ayyar, Kudumula Venkata Rami Reddy
PROBLEM: In endocervical epithelial cells (End1/E6E7), miRNA let-7f plays an important role in the control of innate immunity. The underlying molecular mechanism for let-7f regulation in these cells remains largely unclear. METHODS OF STUDY: let-7f was knocked down in End1/E6E7 cells using siRNA, and differential gene expression was analyzed by microarray. Differentially expressed genes were validated by qPCR and Western blot. Expression of let-7f was studied by qPCR after inhibition of C/EBPβ with betulinic acid (BA) and pCMVβ plasmid and after overexpression of C/EBPβ with pCMVβ+ plasmid...
September 16, 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/28921700/low-dose-fractionated-irradiation-promotes-axonal-regeneration-beyond-reactive-gliosis-and-facilitates-locomotor-function-recovery-after-spinal-cord-injury-in-beagle-dogs
#12
Qiang Zhang, Ying Xiong, Bo Zhu, Bifeng Zhu, Daishi Tian, Wei Wang
Injury to the adult central nervous system (CNS) results in the formation of glial scar tissues. Glial scar-induced failure of regenerative axon pathfinding may limit axon regrowth beyond the lesion site and cause incorrect reinnervation and dystrophic appearance of stalled growth after CNS trauma. Glial scars also upregulate chondroitin sulfate proteoglycans (CSPGs) and expression of proinflammatory factor(s) that form a barrier to axonal regeneration. Therefore, interventions for glial scarring are an attractive strategy for augmenting axonal sprouting and regeneration and overcoming the physical and molecular barriers impeding functional repair...
September 18, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28921644/clinical-pharmacology-considerations-for-the-development-of-immune-checkpoint-inhibitors
#13
Jennifer Sheng, Shivani Srivastava, Kinjal Sanghavi, Zheng Lu, Brian J Schmidt, Akintunde Bello, Manish Gupta
Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921643/bridging-adult-experience-to-pediatrics-in-oncology-drug-development
#14
Ruby Leong, Hong Zhao, Gregory Reaman, Qi Liu, Yaning Wang, Clinton F Stewart, Gilbert Burckart
Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921641/pharmacokinetic-guided-dosing-of-new-oral-cancer-agents
#15
Catherine J Lucas, Jennifer H Martin
Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921639/standing-in-the-shifting-sands-of-molecular-targeting-and-precision-medicine-is-the-oasis-of-21st-century-oncology-therapeutics
#16
Lucy Lee, Lionel D Lewis
No abstract text is available yet for this article.
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921619/alcohol-reduces-arterial-remodeling-by-inhibiting-sonic-hedgehog-stimulated-sca1-progenitor-stem-cell-expansion
#17
Emma Fitzpatrick, Xu Han, Weimin Liu, Eoin Corcoran, Denise Burtenshaw, Maryam Alshamrani, David Morrow, Jay-Christian Helt, Paul A Cahill, Eileen M Redmond
BACKGROUND: Cell and molecular mechanisms mediating the cardiovascular effects of alcohol are not fully understood. Our aim was to determine the effect of moderate Ethanol (EtOH) on Sonic Hedgehog (SHh) signaling in regulating possible Sca1(+) progenitor stem cell involvement during pathologic arterial remodeling. METHODS AND RESULTS: Partial ligation or sham-operation of the left carotid artery was performed in transgenic Sca1-eGFP mice gavaged with or without 'daily moderate' EtOH...
September 18, 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28921381/pentachlorophenol-molecule-design-with-lower-bioconcentration-through-3d-qsar-associated-with-molecule-docking
#18
Xiaolei Wang, Zhenhua Chu, Jiawen Yang, Yu Li
A three-dimensional quantitative structure activity relationship (3D-QSAR) model is built by using a comparative molecular similarity indices analysis (CoMSIA) technique with an experimentally determined logarithm of bioconcentration factors (logBCFs) for 36 phenols in fish. Meanwhile, with the pentachlorophenol (PCP) molecule as target molecules, contributions of the molecular fields indicate that the electrostatic fields are the main influences on the bioconcentration of the PCP molecule. Based on the analytical results of CoMSIA contour map of PCP and PCP molecular docking with SOD protease (PDB ID: 4A7T), the R6 substituent positions of PCP were modified to give seven new modified PCP molecules with low bioconcentration in this paper...
September 18, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28921309/lung-cancer-associated-brain-metastasis-molecular-mechanisms-and-therapeutic-options
#19
REVIEW
Meysam Yousefi, Tayyeb Bahrami, Arash Salmaninejad, Rahim Nosrati, Parisa Ghaffari, Seyed H Ghaffari
BACKGROUND: Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease...
September 18, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28921079/identification-of-a-new-isoindole-2-yl-scaffold-as-a-qo-and-qi-dual-inhibitor-of-cytochrome-bc-1-complex-virtual-screening-synthesis-and-biochemical-assay
#20
Homa Azizian, Kowsar Bagherzadeh, Sophia Shahbazi, Niusha Sharifi, Massoud Amanlou
Respiratory chain ubiquinol-cytochrome (cyt) c oxidoreductase (cyt bc 1 or complex III) has been demonstrated as a promising target for numerous antibiotics and fungicide applications. In this study, a virtual screening of NCI diversity database was carried out in order to find novel Qo/Qi cyt bc 1 complex inhibitors. Structure-based virtual screening and molecular docking methodology were employed to further screen compounds with inhibition activity against cyt bc 1 complex after extensive reliability validation protocol with cross-docking method and identification of the best score functions...
September 18, 2017: Interdisciplinary Sciences, Computational Life Sciences
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