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https://www.readbyqxmd.com/read/28088086/design-and-synthesis-of-new-raf-kinase-inhibiting-antiproliferative-quinoline-derivatives-part-2-diarylurea-derivatives
#1
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/28087752/deficient-retinoid-driven-angiogenesis-may-contribute-to-failure-of-adult-human-lung-regeneration-in-emphysema
#2
John-Poul Ng-Blichfeldt, Joana Alçada, M Angeles Montero, Charlotte H Dean, Uta Griesenbach, Mark J Griffiths, Matthew Hind
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema...
January 13, 2017: Thorax
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/28087659/plant-parasitic-nematodes-towards-understanding-molecular-players-in-stress-responses
#4
REVIEW
François-Xavier Gillet, Caroline Bournaud, Jose Dijair Antonino de Souza Júnior, Maria Fatima Grossi-de-Sa
BACKGROUND: Plant-parasitic nematode interactions occur within a vast molecular plant immunity network. Following initial contact with the host plant roots, plant-parasitic nematodes (PPNs) activate basal immune responses. Defence priming involves the release in the apoplast of toxic molecules derived from reactive species or secondary metabolism. In turn, PPNs must overcome the poisonous and stressful environment at the plant-nematode interface. The ability of PPNs to escape this first line of plant immunity is crucial and will determine its virulence...
January 13, 2017: Annals of Botany
https://www.readbyqxmd.com/read/28087641/molecular-pathways-targeting-protein-tyrosine-phosphatases-in-cancer
#5
Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I Savage, Powel H Brown
The aberrant activation of oncogenic signaling pathways is a universal phenomenon in cancer and drives tumorigenesis and malignant transformation. This abnormal activation of signaling pathways in cancer is due to the altered expression of protein kinases and phosphatases. In response to extra cellular signals, protein kinases activate downstream signaling pathways through a series of protein phosphorylation events, ultimately producing a signal response. Protein tyrosine phosphatases (PTPs) are a family of enzymes that hydrolytically remove phosphate groups from proteins...
January 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28087598/bayesian-network-inference-modeling-identifies-trib1-as-a-novel-regulator-of-cell-cycle-progression-and-survival-in-cancer-cells
#6
Rina Gendelman, Heming Xing, Olga K Mirzoeva, Preeti Sarde, Christina Curtis, Heidi Feiler, Paul McDonagh, Joe W Gray, Iya Khalil, W Michael Korn
Molecular networks governing cellular responses to targeted therapies are complex dynamic systems with non-intuitive behaviors. Here we applied a novel computational strategy to infer probabilistic causal relationships between network components based on gene expression. We constructed a model comprised of an ensemble of networks using multidimensional data from cell line models of cell cycle arrest caused by inhibition of MEK1/2. Through simulation of reverse-engineered Bayesian network modeling, we generated predictions of G1-S transition...
January 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28087532/establishment-and-validation-of-rna-based-predictive-models-for-understanding-survival-of-vibrio-parahaemolyticus-in-oysters-stored-at-low-temperatures
#7
Chao Liao, Yong Zhao, Luxin Wang
: This study developed RNA-based predictive models describing the survival of Vibrio parahaemolyticus in Eastern oysters (Crassostrea virginica) during storage at 0, 4, and 10°C. Post-harvested oysters were inoculated with a cocktail of five V. parahaemolyticus strains and were then stored at 0, 4, and 10°C for 21 or 11 days. A real-time RT-PCR assay targeting expression of tlh gene was used to evaluate the number of surviving V. parahaemolyticus, which was then used to establish primary molecular models (MMs)...
January 13, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28087462/impact-of-disease-linked-mutations-targeting-the-oligomerization-interfaces-of-aldehyde-dehydrogenase-7a1
#8
David A Korasick, John J Tanner, Michael T Henzl
Aldehyde dehydrogenase 7A1 (ALDH7A1) is involved in lysine catabolism, catalyzing the oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Certain mutations in the ALDH7A1 gene, which are presumed to reduce catalytic activity, cause an autosomal recessive seizure disorder known as pyridoxine-dependent epilepsy (PDE). Although the genetic association between ALDH7A1 and PDE is well established, little is known about the impact of PDE-mutations on the structure and catalytic function of the enzyme. Herein we report the first study of the molecular consequences of PDE mutations using purified ALDH7A1 variants...
January 10, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28087428/polycomb-complexes-prc1-and-their-function-in-hematopoiesis
#9
REVIEW
Miguel Vidal, Katharzina Starowicz
Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated to reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repressive complexes (PRC) endowed with distinct histone tail modifying activities...
January 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28087344/up-regulation-of-the-active-form-of-small-gtpase-rab13-promotes-macroautophagy-in-vascular-endothelial-cells
#10
Lu Zhang, Fang Dai, LiuQing Cui, Bo Zhou, YuQi Guo
The importance of macroautophagy (hereafter referred to as autophagy) in vascular endothelial cell (VEC) biology and dysfunction is increasingly recognized, but the molecular mechanisms of autophagy in VECs in the presence of serum are still poorly understood. Previously, we identified pterostilbene as a potent autophagy inducer of VECs in the presence of serum. In this study, we used pterostilbene as a tool to induce VEC autophagy and identified the differentially expressed genes using high-throughput DAN microarray...
January 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28087315/assessing-light-independent-effects-of-hypericin-on-cell-viability-ultrastructure-and-metabolism-in-human-glioma-and-endothelial-cells
#11
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
#12
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/28087272/synthesis-and-evaluation-of-5-1h-indol-3-yl-n-aryl-1-3-4-oxadiazol-2-amines-as-bcl-2-inhibitory-anticancer-agents
#13
Rania Hamdy, Noha I Ziedan, Samia Ali, Cinzia Bordoni, Mohamed El-Sadek, Elsaid Lashin, Andrea Brancale, Arwyn T Jones, Andrew D Westwell
A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin...
December 27, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28087265/myocardial-relaxation-is-accelerated-by-fast-stretch-not-reduced-afterload
#14
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/28086948/is-there-still-a-role-for-cytotoxic-chemotherapy-after-targeted-therapy-and-immunotherapy-in-metastatic-melanoma-a-case-report-and-literature-review
#15
Aurélien Simon, Hampig Raphael Kourie, Joseph Kerger
Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations...
January 13, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/28086840/evidence-of-multiple-insecticide-resistance-mechanisms-in-anopheles-gambiae-populations-in-bangui-central-african-republic
#16
Marina Lidwine Olé Sangba, Aboubakar Sidick, Renaud Govoetchan, Christian Dide-Agossou, Razaki A Ossè, Martin Akogbeto, Mamadou Ousmane Ndiath
BACKGROUND: Knowledge of insecticide resistance status in the main malaria vectors is an essential component of effective malaria vector control. This study presents the first evaluation of the status of insecticide resistance in Anopheles gambiae populations from Bangui, the Central African Republic. METHODS: Anopheles mosquitoes were reared from larvae collected in seven districts of Bangui between September to November 2014. The World Health Organisation's bioassay susceptibility tests to lambda-cyhalothrin (0...
January 13, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28086757/a-combination-of-genetic-and-biochemical-analyses-for-the-diagnosis-of-pi3k-akt-mtor-pathway-associated-megalencephaly
#17
Yutaka Negishi, Fuyuki Miya, Ayako Hattori, Yoshikazu Johmura, Motoo Nakagawa, Naoki Ando, Ikumi Hori, Takao Togawa, Kohei Aoyama, Kei Ohashi, Shinobu Fukumura, Seiji Mizuno, Ayako Umemura, Yoko Kishimoto, Nobuhiko Okamoto, Mitsuhiro Kato, Tatsuhiko Tsunoda, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Makoto Nakanishi, Shinji Saitoh
BACKGROUND: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder...
January 13, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28086748/genetic-mechanisms-of-bone-digestion-and-nutrient-absorption-in-the-bone-eating-worm-osedax-japonicus-inferred-from-transcriptome-and-gene-expression-analyses
#18
Norio Miyamoto, Masa-Aki Yoshida, Hiroyuki Koga, Yoshihiro Fujiwara
BACKGROUND: Bone-eating worms of the genus Osedax (Annelida, Siboglinidae) have adapted to whale fall environments by acquiring a novel characteristic called the root, which branches and penetrates into sunken bones. The worms lack a digestive tract and mouth opening, and it has been suggested that Osedax degrade vertebrate bones and uptake nutrients through acidification and secretion of enzymes from the root. Symbiotic bacteria in the root tissue may have a crucial role in the metabolism of Osedax...
January 13, 2017: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28081246/nitrosothiol-trapping-based-proteomic-analysis-of-s-nitrosylation-in-human-lung-carcinoma-cells
#19
Shani Ben-Lulu, Tamar Ziv, Pnina Weisman-Shomer, Moran Benhar
Nitrosylation of cysteines residues (S-nitrosylation) mediates many of the cellular effects of nitric oxide in normal and diseased cells. Recent research indicates that S-nitrosylation of certain proteins could play a role in tumor progression and responsiveness to therapy. However, the protein targets of S-nitrosylation in cancer cells remain largely unidentified. In this study, we used our recently developed nitrosothiol trapping approach to explore the nitrosoproteome of human A549 lung carcinoma cells treated with S-nitrosocysteine or pro-inflammatory cytokines...
2017: PloS One
https://www.readbyqxmd.com/read/28081156/generation-of-a-stable-transgenic-swine-model-expressing-a-porcine-histone-2b-egfp-fusion-protein-for-cell-tracking-and-chromosome-dynamics-studies
#20
Renan B Sper, Sehwon Koh, Xia Zhang, Sean Simpson, Bruce Collins, Jeff Sommer, Robert M Petters, Ignacio Caballero, Jeff L Platt, Jorge A Piedrahita
Transgenic pigs have become an attractive research model in the field of translational research, regenerative medicine, and stem cell therapy due to their anatomic, genetic and physiological similarities with humans. The development of fluorescent proteins as molecular tags has allowed investigators to track cell migration and engraftment levels after transplantation. Here we describe the development of two transgenic pig models via SCNT expressing a fusion protein composed of eGFP and porcine Histone 2B (pH2B)...
2017: PloS One
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