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https://www.readbyqxmd.com/read/28088556/regulation-of-docetaxel-sensitivity-in-prostate-cancer-cells-by-hsa-mir-125a-3p-via-modulation-of-mta1-signaling
#1
Jian-Zhou Liu, Feng-Yan Yin, Chang-You Yan, Hui Wang, Xiao-Hui Luo
OBJECTIVE: To identify the potential down-stream targets of hsa-miR-125a-3p, a mature form of miR-125a, during the pathogenesis of chemoresistance in prostate cancer (PCa). METHODS: Expression levels of hsa-miR-125a-3p was assessed in chemoresistant PCa tissues and experimentally-established chemoresistant cells using quantitative RT-PCR (qRT-PCR). The effect of hsa-miR-125a-3p knockdown or hsa-miR-125a-3p overexpression on the Dox-induced cell death was evaluated using apoptosis ELISA in chemosensitive PC-3 cells or in chemoresistant PC-3 cells (PC-3R)...
January 11, 2017: Urology
https://www.readbyqxmd.com/read/28088086/design-and-synthesis-of-new-raf-kinase-inhibiting-antiproliferative-quinoline-derivatives-part-2-diarylurea-derivatives
#2
Mohammed I El-Gamal, Mohammad Ashrafuddin Khan, Hamadeh Tarazi, Mohammed S Abdel-Maksoud, Mahmoud M Gamal El-Din, Kyung Ho Yoo, Chang-Hyun Oh
This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 cancer cell lines of nine cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC50 and total growth inhibition (TGI) values against the cell lines...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28087697/development-of-high-affinity-and-high-specificity-inhibitors-of-metalloproteinase-14-through-computational-design-and-directed-evolution
#3
Valeria Arkadash, Gal Yosef, Jason Shirian, Itay Cohen, Yuval Horev, Moran Grossman, Irit Sagi, Evette S Radisky, Julia M Shifman, Niv Papo
Degradation of the extracellular matrices in the human body is controlled by matrix metalloproteinases (MMPs), a family of more than 20 homologous enzymes. Imbalance in MMP activity can result in many diseases, such as arthritis, cardiovascular diseases, neurological disorders, fibrosis, and cancers. Thus, MMPs present attractive targets for drug design and have been a focus for inhibitor design for as long as three decades. Yet, to date, all MMP inhibitors have failed in clinical trials because of their broad activity against numerous MMP family members and the serious side effects of the proposed treatment...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28087315/assessing-light-independent-effects-of-hypericin-on-cell-viability-ultrastructure-and-metabolism-in-human-glioma-and-endothelial-cells
#4
Veronika Huntosova, Marta Novotova, Zuzana Nichtova, Lucia Balogova, Maria Maslanakova, Dana Petrovajova, Katarina Stroffekova
Cell exposure to light-independent effects of photosensitizers (PS) used in PDT is clinically relevant when PS affect the pro-apoptotic cascade.In many malignant cells, Hypericin (Hyp) has PS displayed light-dependent anti-proliferative and cytotoxic effects with no cytotoxicity in the dark. Recent studies have shown that Hyp also exhibited light-independent cytotoxic effects in a wide range of concentrations. The molecular mechanisms underlying Hyp light-independent (dark) toxicity may be due to its interaction with different molecules at the Hyp accumulation sites including mitochondria, and these mechanisms are not understood in detail...
January 10, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28087313/an-m2-v27a-channel-blocker-demonstrates-potent-in-vitro-and-in-vivo-antiviral-activities-against-amantadine-sensitive-and-resistant-influenza-a-viruses
#5
Yanmei Hu, Rami Musharrafieh, Chunlong Ma, Jiantao Zhang, Donald F Smee, William F DeGrado, Jun Wang
Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target...
January 10, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28087265/myocardial-relaxation-is-accelerated-by-fast-stretch-not-reduced-afterload
#6
Charles S Chung, Charles W Hoopes, Kenneth S Campbell
Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction...
January 10, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28081127/transient-in-vivo-resistance-mechanisms-of-burkholderia-pseudomallei-to-ceftazidime-and-molecular-markers-for-monitoring-treatment-response
#7
Jason E Cummings, Richard A Slayden
Much is known about the mode of action of drugs and resistance mechanisms under laboratory growth conditions, but research on the bacterial transcriptional response to drug pressure in vivo or efficacious mode of action and transient resistance mechanisms of clinically employed drugs is limited. Accordingly, to assess active alternative metabolism and transient resistance mechanisms, and identify molecular markers of treatment response, the in vivo transcriptional response of Burkholderia pseudomallei 1026b to treatment with ceftazidime in infected lungs was compared to the in vitro bacterial response in the presence of drug...
January 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28080986/clinical-implications-of-globally-emerging-azole-resistance-in-aspergillus-fumigatus
#8
REVIEW
Jacques F Meis, Anuradha Chowdhary, Johanna L Rhodes, Matthew C Fisher, Paul E Verweij
Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides...
December 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28079973/a-regulatory-bmi1-let-7i-erk3-pathway-controls-the-motility-of-head-and-neck-cancer-cells
#9
Lobna Elkhadragy, Minyi Chen, Kennon Miller, Muh-Hwa Yang, Weiwen Long
Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells...
November 9, 2016: Molecular Oncology
https://www.readbyqxmd.com/read/28079302/molecular-basis-for-covalent-inhibition-of-glyceraldehyde-3-phosphate-dehydrogenase-by-a-2-phenoxy-1-4-naphthoquinone-small-molecule
#10
Stefano Bruno, Elisa Uliassi, Mirko Zaffagnini, Federica Prati, Christian Bergamini, Riccardo Amorati, Gianluca Paredi, Marilena Margiotta, Paola Conti, Maria Paola Costi, Marcel Kaiser, Andrea Cavalli, Romana Fato, Maria Laura Bolognesi
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has recently gained attention as an anti-protozoan and anti-cancer drug target. We have previously identified 2-phenoxy-1,4-naphthoquinone as an inhibitor of both Trypanosoma brucei and human GAPDH. Herein, through multiple chemical, biochemical, and biological studies, and through the design of analogs, we confirmed the formation of a covalent adduct, we clarified the inhibition mechanism and we demonstrated antitrypanosomal, antiplasmodial and cytotoxic activities in cell cultures...
January 12, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28076845/molecular-dynamics-simulation-reveals-how-phosphorylation-of-tyrosine-26-of-phosphoglycerate-mutase-1-upregulates-glycolysis-and-promotes-tumor-growth
#11
Yan Wang, Wen-Sheng Cai, Luonan Chen, Guanyu Wang
Phosphoglycerate mutase 1 (PGAM1) catalyzes the eighth step of glycolysis and is often found upregulated in cancer cells. To test the hypothesis that the phosphorylation of tyrosine 26 residue of PGAM1 greatly enhances its activity, we performed both conventional and steered molecular dynamics simulations on the binding and unbinding of PGAM1 to its substrates, with tyrosine 26 either phosphorylated or not. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, binding free energy, etc...
January 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28076791/mll-af4-spreading-identifies-binding-sites-that-are-distinct-from-super-enhancers-and-that-govern-sensitivity-to-dot1l-inhibition-in-leukemia
#12
Jon Kerry, Laura Godfrey, Emmanouela Repapi, Marta Tapia, Neil P Blackledge, Helen Ma, Erica Ballabio, Sorcha O'Byrne, Frida Ponthan, Olaf Heidenreich, Anindita Roy, Irene Roberts, Marina Konopleva, Robert J Klose, Huimin Geng, Thomas A Milne
Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076324/poly-c-binding-protein-1-mediates-drug-resistance-in-colorectal-cancer
#13
Jiani Guo, Changli Zhu, Kangqun Yang, Jin Li, Nan Du, Mingzhu Zong, Jianwei Zhou, Jingdong He
Oxaliplatin (L-OHP) is standard treatment for colorectal cancer. However, resistance to L-OHP often leads to treatment failure or cancer relapse. Understanding of the mechanism underlying L-OHP resistance is important to overcome the resistance and improve colorectal cancer treatment. This study aimed to identify new proteins that mediates L-OHP resistance in colorectal cancer and elucidate their mode of function. HT-29 cells were exposed to gradually increased concentration of L-OHP to select L-OHP resistant HT-29/L-OHP cell line...
January 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28075551/cucurbit-n-uril-based-microcapsules-self-assembled-within-microfluidic-droplets-a-versatile-approach-for-supramolecular-architectures-and-materials
#14
Ji Liu, Yang Lan, Ziyi Yu, Cindy S Y Tan, Richard M Parker, Chris Abell, Oren A Scherman
Microencapsulation is a fundamental concept behind a wide range of daily applications ranging from paints, adhesives, and pesticides to targeted drug delivery, transport of vaccines, and self-healing concretes. The beauty of microfluidics to generate microcapsules arises from the capability of fabricating monodisperse and micrometer-scale droplets, which can lead to microcapsules/particles with fine-tuned control over size, shape, and hierarchical structure, as well as high reproducibility, efficient material usage, and high-throughput manipulation...
January 11, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28075486/highly-expandable-human-ips-cell-derived-neural-progenitor-cells-npc-and-neurons-for-central-nervous-system-disease-modeling-and-high-throughput-screening
#15
Chialin Cheng, Daniel M Fass, Kat Folz-Donahue, Marcy E MacDonald, Stephen J Haggarty
Reprogramming of human somatic cells into induced pluripotent stem (iPS) cells has greatly expanded the set of research tools available to investigate the molecular and cellular mechanisms underlying central nervous system (CNS) disorders. Realizing the promise of iPS cell technology for the identification of novel therapeutic targets and for high-throughput drug screening requires implementation of methods for the large-scale production of defined CNS cell types. Here we describe a protocol for generating stable, highly expandable, iPS cell-derived CNS neural progenitor cells (NPC) using multi-dimensional fluorescence activated cell sorting (FACS) to purify NPC defined by cell surface markers...
January 11, 2017: Current Protocols in Human Genetics
https://www.readbyqxmd.com/read/28074539/ritterostatin-gn1n-a-cephalostatin-ritterazine-bis-steroidal-pyrazine-hybrid-selectively-targets-grp78
#16
Andrew J Ambrose, Evelyne A Santos, Paula C Jimenez, Danilo D Rocha, Diego V Wilke, Paolo Beuzer, Josh Axelrod, Ananda Kumar Kanduluru, Philip L Fuchs, Hu Cang, Letícia V Costa-Lotufo, Eli Chapman, James J La Clair
Natural products discovered using agnostic approaches, unlike rationally designed or HTS obtained leads, offer the ability to reveal new biological pathways, and hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent anti-tumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we use comparative cellular and molecular biological methods to uncover the ritterazine/cephalostatin mode of cytotoxic action (MOA) in human tumor cells...
January 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28074024/whole-genome-sequencing-of-invasion-resistant-cells-identifies-laminin-%C3%AE-2-as-a-host-factor-for-bacterial-invasion
#17
Xander M van Wijk, Simon Döhrmann, Björn M Hallström, Shangzhong Li, Bjørn G Voldborg, Brandon X Meng, Karen K McKee, Toin H van Kuppevelt, Peter D Yurchenco, Bernhard O Palsson, Nathan E Lewis, Victor Nizet, Jeffrey D Esko
: To understand the role of glycosaminoglycans in bacterial cellular invasion, xylosyltransferase-deficient mutants of Chinese hamster ovary (CHO) cells were created using clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (CRISPR-cas9) gene targeting. When these mutants were compared to the pgsA745 cell line, a CHO xylosyltransferase mutant generated previously using chemical mutagenesis, an unexpected result was obtained. Bacterial invasion of pgsA745 cells by group B Streptococcus (GBS), group A Streptococcus, and Staphylococcus aureus was markedly reduced compared to the invasion of wild-type cells, but newly generated CRISPR-cas9 mutants were only resistant to GBS...
January 10, 2017: MBio
https://www.readbyqxmd.com/read/28073755/advanced-boolean-modeling-of-biological-networks-applied-to-systems-pharmacology
#18
Itziar Irurzun-Arana, José Martín Pastor, Iñaki F Trocóniz, José David Gómez-Mantilla
MOTIVATION: Literature on complex diseases is abundant but not always quantitative. Many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. Tools for analysis of discrete networks are useful to capture the available information in the literature but have not been efficiently integrated by the pharmaceutical industry. We propose an expansion of the usual analysis of discrete networks that facilitates the identification/validation of therapeutic targets...
January 10, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28073680/rationale-and-design-of-pemvitastart-an-open-label-randomized-trial-comparing-simultaneous-versus-standard-initiation-of-vitamin-b12-and-folate-supplementation-in-nonsquamous-non-small-cell-lung-cancer-patients-undergoing-first-line-pemetrexed-based-chemotherapy
#19
Milind Baldi, Digambar Behera, Jyotdeep Kaur, Rakesh Kapoor, Navneet Singh
Pemetrexed is the preferred chemotherapeutic drug for nonsquamous, non-small-cell lung cancer patients whenever the predictive molecular biomarkers for targeted therapy have either not been assessed or are absent. As per manufacturers' instructions, supplementation with folic acid (FA; folate) at a dose of 350 to 1000 μg daily should be started seven days before the first dose of pemetrexed-based chemotherapy and continued during therapy and for 21 days after therapy cessation. Vitamin B12 injections (1000 μg intramuscularly) should also be started one week before the first dose of chemotherapy...
December 2, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28073102/cancer-resistance-to-therapies-against-the-egfr-ras-raf-pathway-the-role-of-mek
#20
REVIEW
Erika Martinelli, Floriana Morgillo, Teresa Troiani, Fortunato Ciardiello
The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC)...
December 30, 2016: Cancer Treatment Reviews
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