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https://www.readbyqxmd.com/read/28340475/irinotecan-upregulates-fibroblast-growth-factor-receptor-3-expression-in-colorectal-cancer-cells-which-mitigates-irinotecan-induced-apoptosis
#1
Zeynep N Erdem, Stefanie Schwarz, Daniel Drev, Christine Heinzle, Andrea Reti, Petra Heffeter, Xenia Hudec, Klaus Holzmann, Bettina Grasl-Kraupp, Walter Berger, Michael Grusch, Brigitte Marian
BACKGROUND: Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI. METHODS: We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed...
March 21, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28340378/current-fda-approved-treatments-for-non-small-cell-lung-cancer-and-potential-biomarkers-for-its-detection
#2
REVIEW
Karla A Ruiz-Ceja, Yolanda I Chirino
BACKGROUND: Lung cancer is the leading worldwide cancer with almost 1.5 million deaths every year. Some drugs for lung cancer treatment have been available on the market for decades, but novel drugs have emerged promising better outcomes, especially for Non-Small Cell Lung Cancer (NSCLC), which represents 75% of lung cancer cases. However, how much do drugs have evolved for NSCLC treatment? Are they sharing the same mechanism of action? AIM: In this review we analyzed how the approved drugs by Federal Drug Agency for NSCLC have advanced in the last four decades identifying shared mechanism of action of medicines against NSCLC treatment and some of the potential biomarkers for early detection...
March 21, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28340340/selective-chemical-inhibition-of-pgc-1%C3%AE-gluconeogenic-activity-ameliorates-type-2-diabetes
#3
Kfir Sharabi, Hua Lin, Clint D J Tavares, John E Dominy, Joao Paulo Camporez, Rachel J Perry, Roger Schilling, Amy K Rines, Jaemin Lee, Marc Hickey, Melissa Bennion, Michelle Palmer, Partha P Nag, Joshua A Bittker, José Perez, Mark P Jedrychowski, Umut Ozcan, Steve P Gygi, Theodore M Kamenecka, Gerald I Shulman, Stuart L Schreiber, Patrick R Griffin, Pere Puigserver
Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes...
March 23, 2017: Cell
https://www.readbyqxmd.com/read/28340334/advances-in-phase-plate-cryo-em-imaging-of-dna-and-nucleosomes
#4
Eugene Y D Chua, Sara Sandin
Contrast in electron cryo-microscopy (cryo-EM) is limited by the weak phase and radiation sensitive nature of biologic samples embedded in vitrified ice. We have recently shown that a new contrast enhancement technique utilizing the Volta phase plate can be combined with single particle analysis to determine the structure of a small chromatin complex, the nucleosome core particle, at near-atomic resolution. Here, we discuss advantages and limitations of the technique in terms of data collection, particle detection, and visualization of individual DNA molecules and higher-order chromatin structure...
February 7, 2017: Nucleus
https://www.readbyqxmd.com/read/28339780/adverse-kidney-effects-of-epidermal-growth-factor-receptor-inhibitors
#5
Hassan Izzedine, Mark A Perazella
The epidermal growth factor receptor (EGFR) is implicated in various malignancies. The past decade has seen the development and widespread use of EGFR inhibitors for the successful treatment of such cancers. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents...
February 23, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28339196/discovery-of-a-small-molecule-degrader-of-bromodomain-and-extra-terminal-bet-proteins-with-picomolar-cellular-potencies-and-capable-of-achieving-tumor-regression
#6
Bing Zhou, Jiantao Hu, Fuming Xu, Zhuo Chen, Longchuan Bai, Ester Fernandez-Salas, Mei Lin, Liu Liu, Chao-Yie Yang, Yujun Zhao, Donna McEachern, Sally Przybranowski, Bo Wen, Duxin Sun, Shaomeng Wang
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders...
March 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28339191/allosteric-activation-of-cytochrome-p450-3a4-via-progesterone-bioconjugation
#7
Vanja Polic, Karine Auclair
Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of the majority of drugs. As such, it is implicated in many adverse drug-drug and food-drug interactions, and is of significant interest to the pharmaceutical industry. This enzyme is known to simultaneously bind multiple ligands and display atypical enzyme kinetics, suggestive of allostery and cooperativity. As well, evidence of a postulated peripheral allosteric binding site has provoked debate around its significance and location. We report the use of bioconjugation to study the significance of substrate binding at the proposed allosteric site and its effect on CYP3A4 activity...
March 24, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28339166/pharmacokinetics-pharmacodynamics-pharmacogenomics-safety-and-tolerability-of-avatrombopag-in-healthy-japanese-and-white-subjects
#8
Maiko Nomoto, Gina Pastino, Bhaskar Rege, Jagadeesh Aluri, Jim Ferry, David Han
Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects...
March 24, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28339149/effect-of-food-intake-on-the-pharmacodynamics-of-tenapanor-a-phase-1-study
#9
Susanne A Johansson, Mikael Knutsson, Maria Leonsson-Zachrisson, David P Rosenbaum
Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of tenapanor. Eighteen volunteers completed a randomized sequence of three 4-day treatments with tenapanor hydrochloride 15 mg twice daily: before food, after food, and while fasting. Participants received a diet standardized for sodium content...
March 24, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28339120/accessing-structurally-diverse-near-infrared-cyanine-dyes-for-folate-receptor-targeted-cancer-cell-staining
#10
Sandra G König, Roland Krämer
Folate receptor (FR) targeting is one of the most promising strategies for the development of small-molecule based cancer imaging agents since the FR is highly overexpressed on the surface of many cancer cell types. FR-targeted conjugates of NIR emissive cyanine dyes are in advanced clinical trials for fluorescence-guided surgery and are valuable research tools for optical molecular imaging in animal models. Only a small number of promising conjugates has been evaluated so far. Analysis of structure-performance relations to identify critical factors modulating the performance of targeted conjugates is essential for successful further optimization...
March 24, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28338920/dendritic-cell-expression-of-the-signaling-molecule-traf6-is-required-for-immune-tolerance-in-the-lung
#11
Daehee Han, Matthew C Walsh, Kwang Soon Kim, Sung-Wook Hong, Junyoung Lee, Jaeu Yi, Gloriany Rivas, Yongwon Choi, Charles D Surh
Immune tolerance in the lung is important for preventing hypersensitivity, such as allergic asthma. Maintenance of tolerance in the lung is established by coordinated activities of poorly understood cellular and molecular mechanisms, including participation of dendritic cells (DCs). We have previously identified DC expression of the signaling molecule TRAF6 as a non-redundant requirement for the maintenance of immune tolerance in the small intestine of mice. Because mucosal tissues share similarities in how they interact with exogenous antigens, we examined the role of DC-expressed TRAF6 in the lung...
March 11, 2017: International Immunology
https://www.readbyqxmd.com/read/28338898/the-hematopoietic-cell-specific-transcription-factor-pu-1-is-critical-for-expression-of-cd11c
#12
Takuya Yashiro, Kazumi Kasakura, Yoshihito Oda, Nao Kitamura, Akihito Inoue, Shusuke Nakamura, Hokuto Yokoyama, Kanako Fukuyama, Mutsuko Hara, Hideoki Ogawa, Ko Okumura, Makoto Nishiyama, Chiharu Nishiyama
PU.1 is a hematopoietic cell-specific transcription factor belonging to the Ets-family, which plays an important role in the development of dendritic cells (DCs). CD11c (encoded by Itgax) is well established as a characteristic marker of hematopoietic lineages including DCs. In the present study, we analyzed the role of PU.1 (encoded by Spi-1) in the expression of CD11c. When small interfering RNA (siRNA) for Spi-1 was introduced into bone marrow-derived (BM) DCs, the mRNA level and cell surface expression of CD11c were dramatically reduced...
February 24, 2017: International Immunology
https://www.readbyqxmd.com/read/28338896/rapid-evolution-of-microrna-loci-in-the-brown-algae
#13
J Mark Cock, Fuli Liu, Delin Duan, Simon Bourdareau, Agnieszka Lipinska, Susana M Coelho, James E Tarver
Stringent searches for microRNAs (miRNAs) have so far only identified these molecules in animals, land plants, chlorophyte green algae, slime molds and brown algae. The identification of miRNAs in brown algae was based on analysis of a single species, the filamentous brown alga Ectocarpus sp. Here we have used deep sequencing of small RNAs and a recently published genome sequence to identify miRNAs in a second brown alga, the kelp Saccharina japonica. S. japonica possesses a large number of miRNAs (117) and these miRNAs are highly diverse, falling into 98 different families...
March 3, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/28338772/chemical-strategies-for-pancreatic-%C3%AE-cell-differentiation-reprogramming-and-regeneration
#14
Xiaojie Ma, Saiyong Zhu
Generation of unlimited functional pancreatic β cells is critical for the study of pancreatic biology and treatment of diabetes mellitus. Recent advances have suggested several promising directions, including directed differentiation of pancreatic β cells from pluripotent stem cells, reprogramming of pancreatic β cells from other types of somatic cells, and stimulated proliferation and enhanced functions of existing pancreatic β cells. Small molecules are useful in generating unlimited numbers of functional pancreatic cells in vitro and could be further developed as drugs to stimulate endogenous pancreatic regeneration...
February 22, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28338770/response-of-human-non-small-cell-lung-cancer-cells-to-the-influence-of-wogonin-with-sgk1-dynamics
#15
Guanglin Shi, Qian Wang, Xiaoyu Zhou, Jun Li, Hua Liu, Jun Gu, Haiying Wang, Yi Wu, Liang Ding, Songshi Ni, Zhiyuan Tang
A number of significant studies in the field of cell biology have revealed another pattern of intracellular signal transduction in which cells transmit information through the dynamics of key signaling molecules. Dynamical properties of p53 have been demonstrated to be the key factor in dictating cell fate, including cell cycle arrest, permanent cell cycle arrest, and cell death. Previous studies showed a negative feedback regulation pathway between SGK1 and p53, but the dynamics of SGK1 have never been reported before...
February 18, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28338680/real-time-molecular-scale-observation-of-crystal-formation
#16
Roy E Schreiber, Lothar Houben, Sharon G Wolf, Gregory Leitus, Zhong-Ling Lang, Jorge J Carbó, Josep M Poblet, Ronny Neumann
How molecules in solution form crystal nuclei, which then grow into large crystals, is a poorly understood phenomenon. The classical mechanism of homogeneous crystal nucleation proceeds via the spontaneous random aggregation of species from liquid or solution. However, a non-classical mechanism suggests the formation of an amorphous dense phase that reorders to form stable crystal nuclei. So far it has remained an experimental challenge to observe the formation of crystal nuclei from five to thirty molecules...
April 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28338621/optimized-4-5-diarylimidazoles-as-potent-selective-inhibitors-of-protein-kinase-ck1%C3%AE-and-their-structural-relation-to-p38%C3%AE-mapk
#17
Jakob Halekotte, Lydia Witt, Chiara Ianes, Marc Krüger, Mike Bührmann, Daniel Rauh, Christian Pichlo, Elena Brunstein, Andreas Luxenburger, Ulrich Baumann, Uwe Knippschild, Joachim Bischof, Christian Peifer
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications...
March 24, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28338387/comparison-of-the-effects-of-curcumin-and-rg108-on-ngf-induced-pc-12%C3%A2-adh-cell-differentiation-and-neurite-outgrowth
#18
Miriş Dikmen
DNA methyltransferases (DNMTs) are promising epigenetic targets for the development of novel drugs, especially for neurodegenerative disorders. In recent years, there has been increased interest in small molecules that can cross the blood-brain barrier for the treatment of neurodegenerative diseases. Therefore, comparing the neuronal differentiative effects of a natural compound curcumin and a synthetic small molecule RG108 was the aim of this study. The effects of curcumin and RG108 on neuronal differentiation and neurite outgrowth were investigated in the PC-12 Adh cell line...
March 24, 2017: Journal of Medicinal Food
https://www.readbyqxmd.com/read/28338139/adsorption-of-small-inorganic-molecules-on-a-defective-mos2-monolayer
#19
César González, Blanca Biel, Yannick J Dappe
We present a theoretical study of molecular adsorption on defects on a MoS2 monolayer. Based on Density Functional Theory, our calculations confirm that small inorganic molecules, such as CO2, CO, H2O, NO, NO2, H2 and N2, remain bonded to the pristine monolayer through weak van der Waals interactions, suggesting that the molecules may easily diffuse over the clean monolayer. On the other hand, the introduction of defects can lead to three different situations, depending on the defect and the molecule considered: physisorption, chemical (strong) bonding to the metallic defects, namely the Mo substitutional atoms on the S vacancies, and dissociation, that can take place spontaneously at 0 K in some specific cases or by the effect of thermal agitation in molecules such as CO2 or NO2 on the S vacancy...
March 24, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28338042/simulating-electric-field-interactions-with-polar-molecules-using-spectroscopic-databases
#20
Alec Owens, Emil J Zak, Katy L Chubb, Sergei N Yurchenko, Jonathan Tennyson, Andrey Yachmenev
Ro-vibrational Stark-associated phenomena of small polyatomic molecules are modelled using extensive spectroscopic data generated as part of the ExoMol project. The external field Hamiltonian is built from the computed ro-vibrational line list of the molecule in question. The Hamiltonian we propose is general and suitable for any polar molecule in the presence of an electric field. By exploiting precomputed data, the often prohibitively expensive computations associated with high accuracy simulations of molecule-field interactions are avoided...
March 24, 2017: Scientific Reports
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