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https://www.readbyqxmd.com/read/29165709/structural-basis-for-the-gtp-specificity-of-the-rna-kinase-domain-of-fungal-trna-ligase
#1
Barbara S Remus, Yehuda Goldgur, Stewart Shuman
Fungal tRNA ligase (Trl1) is an essential enzyme that repairs RNA breaks with 2',3'-cyclic-PO4 and 5'-OH ends inflicted during tRNA splicing and non-canonical mRNA splicing in the fungal unfolded protein response. Trl1 is composed of C-terminal cyclic phosphodiesterase and central polynucleotide kinase domains that heal the broken ends to generate the 3'-OH,2'-PO4 and 5'-PO4 termini required for sealing by an N-terminal ligase domain. Trl1 enzymes are found in all human fungal pathogens and are promising targets for antifungal drug discovery because their domain compositions and biochemical mechanisms are unique compared to the mammalian RtcB-type tRNA splicing enzyme...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29165391/micrornas-associated-with-von-hippel-lindau-pathway-in-renal-cell-carcinoma-a-comprehensive-review
#2
REVIEW
Lisa-Maria Schanza, Maximilian Seles, Michael Stotz, Johannes Fosselteder, Georg C Hutterer, Martin Pichler, Verena Stiegelbauer
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time...
November 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29165360/dynamic-docking-a-paradigm-shift-in-computational-drug-discovery
#3
REVIEW
Dario Gioia, Martina Bertazzo, Maurizio Recanatini, Matteo Masetti, Andrea Cavalli
Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD) have emerged as a valid alternative for simulating macromolecular complexes...
November 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29165068/identifying-candidates-for-breast-cancer-using-interactions-of-chemicals-and-proteins
#4
Jing Lu, Kangle Shang, Yi Bi
Breast cancer is one of the major cause of cancer death in women worldwide. Therefore, it is urgent to discovery novel drugs or design effective treatments for this disease. However, the research and development of drugs by using only experimental methods is always time-consuming and expensive. With the development of computer science, some advanced computational methods can make full use of known knowledge to design candidate drugs, thereby reducing the cost and time of experimental testing. In this study, a computational method was proposed to identify novel candidates for breast cancer...
November 20, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/29164889/comparison-of-quantitative-mass-spectrometry-platforms-for-monitoring-kinase-atp-probe-uptake-in-lung-cancer
#5
Melissa A Hoffman, Bin Fang, Eric B Haura, Uwe Rix, John M Koomen
Recent developments in instrumentation and bioinformatics have led to new quantitative mass spectrometry platforms including LC-MS/MS with data-independent acquisition (DIA) and targeted analysis using parallel reaction monitoring mass spectrometry (LC-PRM), which provide alternatives to well-established methods, such as LC-MS/MS with data-dependent acquisition (DDA) and targeted analysis using multiple reaction monitoring mass spectrometry (LC-MRM). These tools have been used to identify signaling perturbations in lung cancers and other malignancies, supporting the development of effective kinase inhibitors and, more recently, providing insights into therapeutic resistance mechanisms and drug repurposing opportunities...
November 22, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/29164815/application-of-kartogenin-for-musculoskeletal-regeneration
#6
REVIEW
Gun-Il Im
Kartogenin (KGN) is a recently characterized small molecule that promotes the selective differentiation of mesenchymal stem cells into chondrocytes, and thus, KGN stimulates cartilage regeneration. KGN also possess chondro-protective effect. Furthermore, because it is highly stable small molecule, KGN can be stored and transported at room temperature. These obvious superiorities over peptide growth factors make KGN a desirable chondrogenic agent for cartilage regeneration. Since its discovery, KGN has drawn much attention as a new chondrogenic drug for intraarticular (IA) treatment...
November 22, 2017: Journal of Biomedical Materials Research. Part A
https://www.readbyqxmd.com/read/29163887/a-novel-peptide-stapling-strategy-enables-the-retention-of-ring-closing-amino-acid-side-chains-for-the-wnt-%C3%AE-catenin-signalling-pathway
#7
Ye Wu, Ye-Hua Li, Xiang Li, Yan Zou, Hong-Li Liao, Lei Liu, Ye-Guang Chen, Donald Bierer, Hong-Gang Hu
The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry. We incorporate the new amino acids into a β-catenin-binding domain of Axin (469-482) and develop a new category of stapled peptides with the retention of the native side chains...
November 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29163380/focused-review-cytotoxic-and-antioxidant-potentials-of-mangrove-derived-streptomyces
#8
REVIEW
Hooi-Leng Ser, Loh Teng-Hern Tan, Jodi Woan-Fei Law, Kok-Gan Chan, Acharaporn Duangjai, Surasak Saokaew, Priyia Pusparajah, Nurul-Syakima Ab Mutalib, Tahir Mehmood Khan, Bey-Hing Goh, Learn-Han Lee
Human life expectancy is rapidly increasing with an associated increasing burden of chronic diseases, such as neurodegenerative diseases and cancer. However, there is limited progress in finding effective treatment for these conditions. For this reason, members of the genus Streptomyces have been explored extensively over the past decades as these filamentous bacteria are highly efficient in producing bioactive compounds with human health benefits. Being ubiquitous in nature, streptomycetes can be found in both terrestrial and marine environments...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29163150/targeting-dna-repair-through-podophyllotoxin-and-rutin-formulation-in-hematopoietic-radioprotection-an-in-silico-in-vitro-and-in-vivo-study
#9
M H Yashavarddhan, Sandeep K Shukla, Pankaj Chaudhary, Nitya N Srivastava, Jayadev Joshi, Mrutyunjay Suar, Manju L Gupta
Drug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podophyllotoxin and rutin combination (henceforth referred as G-003M) in the hematopoietic radioprotection and its involvement in the DNA damage and repair signaling pathways. Using in silico study, we identified the binding sites and structural components of G-003M and validated in vitro...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29163089/the-bachd-rat-model-of-huntington-disease-shows-specific-deficits-in-a-test-battery-of-motor-function
#10
Giuseppe Manfré, Erik K H Clemensson, Elisavet I Kyriakou, Laura E Clemensson, Johanneke E van der Harst, Judith R Homberg, Huu Phuc Nguyen
Rationale: Huntington disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and neuropsychiatric symptoms. HD is usually diagnosed by the appearance of motor deficits, resulting in skilled hand use disruption, gait abnormality, muscle wasting and choreatic movements. The BACHD transgenic rat model for HD represents a well-established transgenic rodent model of HD, offering the prospect of an in-depth characterization of the motor phenotype. Objective: The present study aims to characterize different aspects of motor function in BACHD rats, combining classical paradigms with novel high-throughput behavioral phenotyping...
2017: Frontiers in Behavioral Neuroscience
https://www.readbyqxmd.com/read/29163051/young-human-cholinergic-neurons-respond-to-physiological-regulators-and-improve-cognitive-symptoms-in-an-animal-model-of-alzheimer-s-disease
#11
Annamaria Morelli, Erica Sarchielli, Giulia Guarnieri, Elisabetta Coppi, Daniela Pantano, Paolo Comeglio, Pamela Nardiello, Anna M Pugliese, Lara Ballerini, Rosanna Matucci, Stefano Ambrosini, Giuseppe Castronovo, Rosa Valente, Benedetta Mazzanti, Sandra Bucciantini, Mario Maggi, Fiorella Casamenti, Pasquale Gallina, Gabriella B Vannelli
The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain (BF) is associated to the cognitive decline of Alzheimer's disease (AD) patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, this study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs) in order to study their phenotypic, maturational and functional properties...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29162848/mirddcr-a-mirna-based-method-to-comprehensively-infer-drug-disease-causal-relationships
#12
Hailin Chen, Zuping Zhang, Wei Peng
Revealing the cause-and-effect mechanism behind drug-disease relationships remains a challenging task. Recent studies suggested that drugs can target microRNAs (miRNAs) and alter their expression levels. In the meanwhile, the inappropriate expression of miRNAs will lead to various diseases. Therefore, targeting specific miRNAs by small-molecule drugs to modulate their activities provides a promising approach to human disease treatment. However, few studies attempt to discover drug-disease causal relationships through the molecular level of miRNAs...
November 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29162614/discovery-and-validation-of-pyridoxic-acid-and-homovanillic-acid-as-novel-endogenous-plasma-biomarkers-of-organic-anion-transporter-oat-1-and-oat3-in-cynomolgus-monkeys
#13
Hong Shen, David M Nelson, Regina V Oliveira, Yueping Zhang, Colleen A Mcnaney, Xiaomei Gu, Weiqi Chen, Ching Su, Michael D Reily, Petia A Shipkova, Jinping Gan, Yurong Lai, Punit Marathe, W Griffith Humphreys
Perturbation of OAT1- and OAT3-mediated transport can alter the exposure, efficacy, and safety of drugs. Although these have been reports of the endogenous biomarkers for OAT1/3, none of these have all of the characteristics required for a clinical useful biomarker. Cynomolgus monkeys were treated with intravenous probenecid (PROB) at a dose of 40 mg/kg in this study. As expected, PROB increased the AUC of co-administered furosemide (FSM), a known substrate of OAT1 and OAT3, by 4.1-fold, consistent with the values reported in humans (3...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29162433/triptonide-potently-suppresses-pancreatic-cancer-cell-mediated-vasculogenic-mimicry-by-inhibiting-expression-of-ve-cadherin-and-chemokine-ligand-2-genes
#14
Hongyan Han, Longsheng Du, Zhifei Cao, Bing Zhang, Quansheng Zhou
Various aggressive cancers, including pancreatic cancer, produce functional blood vessels by neovascularization. Tumor vasculogenic mimicry (VM) promotes cancer progression and is closely associated with the poor prognosis of the cancer patients. Therefore, tumor VM is a sensible target for novel anti-cancer drug discovery. However, there is a lack of effective anti-tumor VM drugs in the clinical setting. In this study, we aim to explore novel agents to effectually inhibit pancreatic cancer cell-mediated tumor VM for anti-cancer therapy...
November 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29162237/inter-individual-gene-variants-associated-with-trabecular-bone-plasticity-a-step-forward-in-the-personal-genomics-of-degenerative-bone-disease
#15
Enrique Caso, Cristina C Sabiers, Daniel López-Guillén, Jaime Caso, Manuel Toledano, Raquel Osorio, Estrella Osorio, Carmen Lozano, Enrique Guerado
Continuing tissue destruction in osteoarthrosis is maintained by molecular pathways related to an unbalanced chondrocyte metabolism, the loss of reactive oxygen species (ROS) homeostasis, increase catabolism in a degraded matrix and the limited response to growth factors due to cell aging. Rare deleterious gene variants driving relevant molecular pathways may play a key role in the pathogenesis and genetic control of common diseases and may also influence the common gene variants observed in GWAS. We use molecular profiling technologies based on massive sequencing of genes to interrogate clinical samples for a variety of molecules involved in the pathogenesis pathways of OA and also to derive new insights for drug targeting discovery at an early stage of the disease...
November 2017: Injury
https://www.readbyqxmd.com/read/29162230/preface-drug-discovery-in-neurodegenerative-disorders-a-defeat-for-pharmacology
#16
EDITORIAL
Filippo Caraci, Aletta Kraneveld, Mojca Krzan, Monica Di Luca
No abstract text is available yet for this article.
December 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29162092/applying-systems-biology-to-biomedical-research-and-health-care-a-pr%C3%A3-cising-definition-of-systems-medicine
#17
Sebastian Schleidgen, Sandra Fernau, Henrike Fleischer, Christoph Schickhardt, Ann-Kristin Oßa, Eva C Winkler
BACKGROUND: Systems medicine has become a key word in biomedical research. Although it is often referred to as P4-(predictive, preventive, personalized and participatory)-medicine, it still lacks a clear definition and is open to interpretation. This conceptual lack of clarity complicates the scientific and public discourse on chances, risks and limits of Systems Medicine and may lead to unfounded hopes. Against this background, our goal was to develop a sufficiently precise and widely acceptable definition of Systems Medicine...
November 21, 2017: BMC Health Services Research
https://www.readbyqxmd.com/read/29161390/thiopental-to-desflurane-an-anaesthetic-journey-where-are-we-going-next
#18
J R Sneyd
Development targets in anaesthetic pharmacology have evolved from minimizing harm caused by unwanted effects through an era in which rapid onset and offset of drug effect were prioritised. Today's anaesthetists have access to a library of effective drugs whose characteristics offer controllable hypnosis, analgesia and paralysis with manageable off-target effects. The availability of these agents at generic prices inhibits commercial interest and this is reflected in the limited number of current anaesthetic drug development projects...
December 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29161369/pace-capture-guided-ablation-after-contact-force-guided-pulmonary-vein-isolation-results-of-the-randomized-controlled-dragon-trial
#19
Masaharu Masuda, Masashi Fujita, Osamu Iida, Shin Okamoto, Takayuki Ishihara, Kiyonori Nanto, Takashi Kanda, Akihiro Sunaga, Takuya Tsujimura, Yasuhiro Matsuda, Takuya Ohashi, Masaaki Uematsu
Aims: Before the discovery of contact-force guidance, eliminating pacing capture along the pulmonary vein (PV) isolation line had been reported to improve PV isolation durability and rhythm outcomes. DRAGON (UMIN-CTR, UMIN000015332) aimed to elucidate the efficacy of pace-capture-guided ablation following contact-force-guided PV isolation ablation in paroxysmal atrial fibrillation (AF) patients. Methods and results: A total of 156 paroxysmal AF patients with AF-trigger ectopies from any of the four PVs induced by isoproterenol were randomly assigned to undergo pace-capture-guided ablation along a contact-force-guided isolation line around AF-trigger PVs (PC group, n = 76) or contact-force-guided PV isolation ablation alone (control group, n = 80)...
November 17, 2017: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/29161298/controlled-placement-of-multiple-cns-cell-populations-to-create-complex-neuronal-cultures
#20
D Soscia, A Belle, N Fischer, H Enright, A Sales, J Osburn, W Benett, E Mukerjee, K Kulp, S Pannu, E Wheeler
In vitro brain-on-a-chip platforms hold promise in many areas including: drug discovery, evaluating effects of toxicants and pathogens, and disease modelling. A more accurate recapitulation of the intricate organization of the brain in vivo may require a complex in vitro system including organization of multiple neuronal cell types in an anatomically-relevant manner. Most approaches for compartmentalizing or segregating multiple cell types on microfabricated substrates use either permanent physical surface features or chemical surface functionalization...
2017: PloS One
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