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https://www.readbyqxmd.com/read/27923201/synthesis-and-biological-evaluation-of-a-new-class-of-benzothiazines-as-neuroprotective-agents
#1
Alessandra Mancini, Alessia Chelini, Angela Di Capua, Loretta Castelli, Simone Brogi, Marco Paolino, Germano Giuliani, Andrea Cappelli, Maria Frosini, Lorenzo Ricci, Erminia Leonelli, Gianluca Giorgi, Antonio Giordani, Jacopo Magistretti, Maurizio Anzini
Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival...
November 27, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27922681/cxcr4-promotes-cisplatin-resistance-of-non-small-cell-lung-cancer-in-a-cyp1b1-dependent-manner
#2
Songping Xie, Zhenbo Tu, Jie Xiong, Ganjun Kang, Lina Zhao, Weidong Hu, Haiyan Tan, Kingsley Miyanda Tembo, Qianshan Ding, Xinzhou Deng, Jie Huang, Qiuping Zhang
Chemoresistance is the main cause of treatment failure and high mortality in advanced lung cancer. Cisplatin, an important chemotherapeutic agent for lung cancer, has been observed to show enormously reduced chemotherapeutic efficacy owing to the development of chemoresistance. CXCR4, a stromal-derived-factor-1 specific chemokine receptor, is highly expressed in non-small cell lung cancer (NSCLC) tissues and participates in cancer progression by regulating cell growth, apoptosis or invasion. In this study, we therefore investigated whether CXCR4 plays a role in the cisplatin associated resistance in NSCLC...
December 2, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27922667/pituitary-sex-hormones-enhance-the-pro%C3%A2-metastatic-potential-of-human-lung-cancer-cells-by-downregulating-the-intracellular-expression-of-heme-oxygenase%C3%A2-1
#3
Ahmed Abdelbaset-Ismail, Daniel Pedziwiatr, Gabriela Schneider, Jacek Niklinski, Radoslaw Charkiewicz, Marcin Moniuszko, Magda Kucia, Mariusz Z Ratajczak
We report that human lung cancer cell lines express functional receptors for pituitary sex hormones (SexHs) and respond to stimulation by follicle‑stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). Expression of these receptors has also been confirmed in patient lung cancer samples at the mRNA level. Stimulation of human lung cancer cell lines with FSH, LH, or PRL stimulated migration and chemotaxis, and some cell lines responded by enhanced proliferation. Moreover, priming of human lung cancer cells by exposing them to pituitary SexHs resulted in enhanced seeding efficiency of injected human lung cancer cells into bone marrow, liver, and lungs in an immunodeficient mouse model...
December 2, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27922604/common-variants-on-2p16-1-6p22-1-and-10q24-32-are-associated-with-schizophrenia-in-han-chinese-population
#4
H Yu, H Yan, J Li, Z Li, X Zhang, Y Ma, L Mei, C Liu, L Cai, Q Wang, F Zhang, N Iwata, M Ikeda, L Wang, T Lu, M Li, H Xu, X Wu, B Liu, J Yang, K Li, L Lv, X Ma, C Wang, L Li, F Yang, T Jiang, Y Shi, T Li, D Zhang, W Yue
Many schizophrenia susceptibility loci have been identified through genome-wide association studies (GWASs) in European populations. However, until recently, schizophrenia GWASs in non-European populations were limited to small sample sizes and have yielded few loci associated with schizophrenia. To identify genetic risk variations for schizophrenia in the Han Chinese population, we performed a two-stage GWAS of schizophrenia comprising 4384 cases and 5770 controls, followed by independent replications of 13 single-nucleotide polymorphisms in an additional 4339 schizophrenia cases and 7043 controls of Han Chinese ancestry...
December 6, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27922200/a-fluorescence-lifetime-based-binding-assay-for-class-iia-histone-deacetylases
#5
Christian Meyners, Monique Mertens, Pablo Wessig, Franz-Josef Meyer-Almes
Class IIa HDACs show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as "Readers" of acetyl marks, whereas enzymatically active HDACs from class I or IIb are called "Erasers" to highlight their capability to remove acetyl groups from acetylated histones or other proteins...
December 6, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27922192/evidence-for-pipecolate-oxidase-in-mediating-protection-against-hydrogen-peroxide-stress
#6
Sathish Kumar Natarajan, Ezhumalai Muthukrishnan, Oleh Khalimonchuk, Justin L Mott, Donald F Becker
Pipecolate, an intermediate of the lysine catabolic pathway, is oxidized to Δ(1) -piperideine-6-carboxylate (P6C) by the flavoenzyme L-pipecolate oxidase (PIPOX). P6C spontaneously hydrolyzes to generate α-aminoadipate semialdehyde, which is then converted into α-aminoadipate acid by α-aminoadipatesemialdehyde dehydrogenase. L-pipecolate was previously reported to protect mammalian cells against oxidative stress. Here, we examined whether PIPOX is involved in the mechanism of pipecolate stress protection...
December 6, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27921184/chemotherapeutic-drug-selectivity-between-wild-type-and-mutant-braf-kinases-in-colon-cancer
#7
Jianchun Zhang, Tao Ji
Oncogenic BRaf V600E mutation is involved in the development, invasion and metastasis of colon cancer. Selective inhibition of BRaf(V600E) mutant has been recognized as a therapeutic strategy for the cancer. Here, we carried out atomistic molecular dynamics (MD) simulations to characterize the structural basis, energetic property, and dynamics behavior of conformational change in BRaf activation loop upon the mutation. It is found that V600E mutation destabilizes inactive DFG-out conformation of activation loop and promotes its conversion to the active DFG-in conformation, thus conferring constitutive activity for BRaf kinase...
January 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/27920890/mesoporous-silica-nanoparticles-equipped-with-surface-nanovalves-for-ph-controlled-liberation-of-doxorubicin
#8
N V Roik, L A Belyakova
Silica carriers equipped with molecular and supramolecular pH-sensitive nanovalves were designed by combination of sol-gel synthesis and selective postsynthetic modification. Mesoporous structure of synthesized materials was characterized by low-temperature nitrogen adsorption-desorption, small-angle X-ray diffraction and transmission electron microscopy. Chemical immobilization of N-[N'-(N'-phenyl)-2-aminophenyl]aminoalkyl groups was confirmed by IR spectral and chemical analyses of surface layer. Loading and release behaviour of synthesized drug carriers was studied in phosphate buffer solutions with pH 5...
December 6, 2016: Interface Focus
https://www.readbyqxmd.com/read/27920719/bile-acids-in-neurodegenerative-disorders
#9
REVIEW
Hayley D Ackerman, Glenn S Gerhard
Bile acids, a structurally related group of molecules derived from cholesterol, have a long history as therapeutic agents in medicine, from treatment for primarily ocular diseases in ancient Chinese medicine to modern day use as approved drugs for certain liver diseases. Despite evidence supporting a neuroprotective role in a diverse spectrum of age-related neurodegenerative disorders, including several small pilot clinical trials, little is known about their molecular mechanisms or their physiological roles in the nervous system...
2016: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/27920664/investigation-of-snp-rs2060546-immediately-upstream-to-ntn4-in-a-danish-gilles-de-la-tourette-syndrome-cohort
#10
Shanmukha S Padmanabhuni, Rayan Houssari, Ann-Louise Esserlind, Jes Olesen, Thomas M Werge, Thomas F Hansen, Birgitte Bertelsen, Fotis Tsetsos, Peristera Paschou, Zeynep Tümer
Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC, and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 (NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27920501/three-generations-of-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-developed-to-revolutionize-the-therapy-of-lung-cancer
#11
REVIEW
Haijun Zhang
Lung cancer, ~80%-85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm(+)), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27920426/crystal-structure-based-discovery-of-a-novel-synthesized-parp1-inhibitor-ol-1-with-apoptosis-inducing-mechanisms-in-triple-negative-breast-cancer
#12
Leilei Fu, Shuya Wang, Xuan Wang, Peiqi Wang, Yaxin Zheng, Dahong Yao, Mingrui Guo, Lan Zhang, Liang Ouyang
Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors...
December 2016: Scientific Reports
https://www.readbyqxmd.com/read/27920157/two-serk-receptor-like-kinases-interact-with-the-receptor-like-kinase-ems1-in-anther-cell-fate-determination
#13
Zhiyong Li, Yao Wang, Jian Huang, Nagib Ahsan, Gabriel Biener, Joel Paprocki, Jay J Thelen, Valerica Raicu, Dazhong Zhao
Cell signaling pathways mediated by leucine-rich repeat receptor-like kinases (LRR-RLK) are essential for plant growth, development and defense. The EMS1 (EXCESS MICROSPOROCYTES1) LRR-RLK and its small protein ligand TPD1 (TAPETUM DETERMINANT1) play a fundamental role in somatic and reproductive cell differentiation during early anther development in Arabidopsis (Arabidopsis thaliana). However, it is unclear whether other cell surface molecules serve as co-regulators of EMS1. Here, we show that SERK1 (SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1) and SERK2 LRR-RLKs act redundantly as co-regulatory and physical partners of EMS1...
December 5, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27920086/a-role-for-mitotic-bookmarking-of-sox2-in-pluripotency-and-differentiation
#14
Cédric Deluz, Elias T Friman, Daniel Strebinger, Alexander Benke, Mahé Raccaud, Andrea Callegari, Marion Leleu, Suliana Manley, David M Suter
Mitotic bookmarking transcription factors remain bound to chromosomes during mitosis and were proposed to regulate phenotypic maintenance of stem and progenitor cells at the mitosis-to-G1 (M-G1) transition. However, mitotic bookmarking remains largely unexplored in most stem cell types, and its functional relevance for cell fate decisions remains unclear. Here we screened for mitotic chromosome binding within the pluripotency network of embryonic stem (ES) cells and show that SOX2 and OCT4 remain bound to mitotic chromatin through their respective DNA-binding domains...
December 5, 2016: Genes & Development
https://www.readbyqxmd.com/read/27919952/molecular-factors-associated-with-pemetrexed-sensitivity-according-to-histological-type-in-non-small-cell-lung-cancer
#15
Tsukihisa Yoshida, Tatsuro Okamoto, Tokujiro Yano, Kazuki Takada, Mikihiro Kohno, Kenichi Suda, Mitsuhiro Takenoyama, Yoshinao Oda, Yoshihiko Maehara
BACKGROUND: This study was designed to investigate potential molecules that predict chemosensitivity to pemetrexed (Alimta®) in surgically resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Chemosensitivity to ALM and other drugs was assessed by succinate dehydrogenase inhibition (SDI) test in 69 NSCLC samples (55 adenocarcinomas, and 14 squamous cell carcinomas). The mRNA expression levels of Alimta®-target enzymes [thymidylate synthase (TYMS); dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT)], Alimta®-metabolizing enzymes [γ-glutamyl hydrase (GGH) and folylpolyglutamate synthase] and an Alimta® transporter [reduce folate carrier (RFC)] were measured and examined for potential correlations to chemosensitivity...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27919951/rho-associated-protein-kinase-rock-inhibitors-inhibit-survivin-expression-and-sensitize-pancreatic-cancer-stem-cells-to-gemcitabine
#16
Hiroyuki Takeda, Masashi Okada, Shuhei Suzuki, Kenta Kuramoto, Hirotsugu Sakaki, Hikaru Watarai, Tomomi Sanomachi, Shizuka Seino, Takashi Yoshioka, Chifumi Kitanaka
BACKGROUND: Targeting pathways regulating survivin expression, which has been implicated in multidrug resistance of cancer cells, is a promising strategy to overcome cancer chemoresistance. To date, the role of rho-associated protein kinases (ROCKs) in survivin expression remains largely unknown. MATERIALS AND METHODS: The effects of ROCK inhibitors Y-27632 and fasudil on survivin expression and cell viability were determined by immunoblot analysis and dye exclusion, respectively, in PANC-1 CSLC, a cancer stem cell line derived from a serum-cultured, gemcitabine-sensitive pancreatic cancer cell line, PANC-1...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27919782/understanding-zebrafish-cognition
#17
REVIEW
Darya A Meshalkina, Marina N Kizlyk, Elana V Kysil, Adam D Collier, David J Echevarria, Murilo S Abreu, Leonardo J G Barcellos, Cai Song, Allan V Kalueff
Zebrafish (Danio rerio) are rapidly becoming a popular model organism in translational and cognitive neuroscience research. Both larval and adult zebrafish continue to increase our understanding of cognitive mechanisms and their genetic and pharmacological modulation. Here, we discuss the developing utility of zebrafish in understanding cognitive phenotypes and their deficits, relevant to a wide range human brain disorders. We also discuss the potential of zebrafish models for high-throughput genetic mutant and small molecule screening (e...
December 2, 2016: Behavioural Processes
https://www.readbyqxmd.com/read/27919695/metabolomics-identifies-perturbations-in-amino-acid-metabolism-in-the-prefrontal-cortex-of-the-learned-helplessness-rat-model-of-depression
#18
Xinyu Zhou, Lanxiang Liu, Yuqing Zhang, Juncai Pu, Lining Yang, Chanjuan Zhou, Shuai Yuan, Hanping Zhang, Peng Xie
Major depressive disorder is a serious psychiatric condition associated with high rates of suicide and is a leading cause of health burden worldwide. However, the underlying molecular mechanisms of major depression are still essentially unclear. In our study, a non-targeted gas chromatography-mass spectrometry-based metabolomics approach was used to investigate metabolic changes in the prefrontal cortex of the learned helplessness rat model of depression. Body-weight measurements and behavioral tests including the active escape test, sucrose preference test, forced swimming test, elevated plus-maze and open field test were used to assess changes in the behavioral spectrum after inescapable footshock stress...
December 2, 2016: Neuroscience
https://www.readbyqxmd.com/read/27919658/quinolizinium-as-a-new-fluorescent-lysosomotropic-probe
#19
Emmanouil Zacharioudakis, Tatiana Cañeque, Raúl Custodio, Sebastian Müller, Ana M Cuadro, Juan J Vaquero, Raphaël Rodriguez
We have synthesized a collection of quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown that different functional groups appended to the cationic quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While quinolizinium probes are known nuclear staining reagents, we have identified a particular quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919612/an-in-tether-sulfoxide-chiral-center-influences-the-biophysical-properties-of-the-n-capped-peptides
#20
Jingxu Li, Yuan Tian, Dongyuan Wang, Yujie Wu, Xiyang Ye, Zigang Li
Thanks to their large binding interfaces, peptides are attractive ligands targeting protein-protein interactions compared with small molecules. Various strategies to improve peptides' pharmaceutical properties have been developed to constrain peptides into their functional three-dimensional structures. In our previous work, we reported that an in-tether chiral center could modulate peptides' biophysical properties. Herein, we applied this concept to construct a chiral sulfoxide center into the N-terminal end-cap system...
November 25, 2016: Bioorganic & Medicinal Chemistry
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