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in silico prediction

Naeim Ehtesham, Fariborz Khorvash, Majid Kheirollahi
MicroRNAs (miRNAs) are crucial to the immunopathogenesis of multiple sclerosis (MS). The mechanism of action of interferon beta (IFN-β) in relapsing-remitting (RR) MS patients is largely unknown. miR-145 and miR-20a-5p previously reported as diagnosis biomarker in treatment naïve RRMS patients and their expression after IFN-β therapy might be indicative of molecular mechanism of IFN-β. Cross-talking between JAK/STAT pathway and complementary pathways like MAPK is important in IFN-β signaling. Here, in order to clarify the ambiguous molecular mechanism of IFN-β and evaluate the potential use of them as a biomarker for monitoring of therapy, we investigated the expression of miR-145 and miR-20a-5p in blood sample of 15 treatment naïve RRMS patients, 15 IFN-β-treated RRMS patients, and 15 healthy volunteers (HVs)...
October 17, 2016: Journal of Molecular Neuroscience: MN
Sufyan Ahmad, Fatima Iftikhar, Farhat Ullah, Abdul Sadiq, Umer Rashid
Based on the pharmacological importance of dihydropyrimidine (DHPM) scaffold, substituted DHPMs linked with acetamide linker to substituted aromatic anilines were synthesized and evaluated for their potency as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The good AChE inhibitory activity of 4-dihydropyrimidine-2-thione (4a-h) and 2-amino-1,4-dihyropyrimidines (5a-h) series was observed with compound 4a and 4d identified as the most potent compounds with IC50 values of 0.17±0.01 and 0...
October 11, 2016: Bioorganic Chemistry
Chiguru Vishnuvardhan, Saibaba Baikadi, Roshan M Borkar, R Srinivas, N Satheeshkumar
Silodosin (SLD) is a novel α1-adrenoceptor antagonist which has shown promising clinical efficacy and safety in patients with benign prostatic hyperplasia (BPH). However, lack of information about metabolism of SLD prompted us to investigate metabolic fate of SLD in rats. To identify in vivo metabolites of SLD, urine, feces and plasma were collected from Sprague-Dawley rats after its oral administration. The samples were prepared using an optimized sample preparation approach involving protein precipitation followed by solid-phase extraction and then subjected to LC/HR-MS/MS analysis...
October 2016: Journal of Mass Spectrometry: JMS
Jenny M Pedersen, Yoo-Sik Shim, Vaibhav Hans, Martin B Phillips, Jeffrey M Macdonald, Glenn Walker, Melvin E Andersen, Harvey J Clewell, Miyoung Yoon
Accurate prediction of metabolism is a significant outstanding challenge in toxicology. The best predictions are based on experimental data from in vitro systems using primary hepatocytes. The predictivity of the primary hepatocyte-based culture systems, however, is still limited due to well-known phenotypic instability and rapid decline of metabolic competence within a few hours. Dynamic flow bioreactors for three-dimensional cell cultures are thought to be better at recapitulating tissue microenvironments and show potential to improve in vivo extrapolations of chemical or drug toxicity based on in vitro test results...
2016: Frontiers in Bioengineering and Biotechnology
José E Belizário, Beatriz A Sangiuliano, Marcela Perez-Sosa, Jennifer M Neyra, Dayson F Moreira
With multiple omics strategies being applied to several cancer genomics projects, researchers have the opportunity to develop a rational planning of targeted cancer therapy. The investigation of such numerous and diverse pharmacogenomic datasets is a complex task. It requires biological knowledge and skills on a set of tools to accurately predict signaling network and clinical outcomes. Herein, we describe Web-based in silico approaches user friendly for exploring integrative studies on cancer biology and pharmacogenomics...
2016: Frontiers in Pharmacology
A Paini, M Mennecozzi, T Horvat, K Gerloff, T Palosaari, J V Sala Benito, A Worth
The Virtual Cell Based Assay (VCBA) was applied to simulate the long-term (repeat dose) toxic effects of chemicals, including substances in cosmetics and personal care products. The presented model is an extension of the original VCBA for simulation of single exposure and is implemented in a KNIME workflow. This work illustrates the steps taken to simulate the repeat dose effects of two reference compounds. i) Using caffeine, in vitro experimental viability data in single and repeated exposure from two human liver cell lines, HepG2 and HepaRG, were measured and used to optimize the VCBA...
October 13, 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Marion A David, Stéphane Orlowski, Roger K Prichard, Shaima Hashem, François André, Anne Lespine
Macrocyclic lactones (ML) are important anthelmintics used in animals and humans against parasite nematodes, but their therapeutic success is compromised by the spread of ML resistance. Some ABC transporters, such as p-glycoproteins (Pgps), are selected and overexpressed in ML-resistant nematodes, supporting a role for some drug efflux proteins in ML resistance. However, the role of such proteins in ML transport remains to be clarified at the molecular level. Recently, Caenorhabditis elegans Pgp-1 (Cel-Pgp-1) has been crystallized, and its drug-modulated ATPase function characterized in vitro revealed Cel-Pgp-1 as a multidrug transporter...
September 15, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Kayoko Kanamitsu, Ryosuke Arakawa, Yuichi Sugiyama, Tetsuya Suhara, Hiroyuki Kusuhara
The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in humans. The occupancy of the dopamine D2 receptor and the plasma concentrations of the antipsychotic drugs quetiapine and perospirone in humans were collected from the literature or produced experimentally...
July 30, 2016: Drug Metabolism and Pharmacokinetics
Raquib Alam, Divya Wahi, Raja Singh, Devapriya Sinha, Vibha Tandon, Abhinav Grover, Rahisuddin
In an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes...
October 5, 2016: Bioorganic Chemistry
Mohammad Uzzal Hossain, Arafat Rahman Oany, Shah Adil Ishtiyaq Ahmad, Md Anayet Hasan, Md Arif Khan, Md Al Ahad Siddikey
Chagas is a parasitic disease with major threat to public health due to its resistance against commonly available drugs. Trypanothione reductase (TryR) is the key enzyme to develop this disease. Though this enzyme is well thought-out as potential drug target, the accurate structure of enzyme-inhibitor complex is required to design a potential inhibitor which is less available for TryR. In this research, we aimed to investigate the advanced drug over the available existing drugs by designing inhibitors as well as to identify a new enzyme-inhibitor complex that may act as a template for drug design...
October 7, 2016: Computational Biology and Chemistry
I Velázquez-López, E León-Cruz, J P Pardo, A Sosa-Peinado, M González-Andrade
Eight new fluorescent biosensors of human calmodulin (hCaM) using Alexa Fluor(®) 350, 488, 532, and 555 dyes were constructed. These biosensors are thermodynamically stable, functional, and highly sensitive to ligands of the CaM. They resolve the problem of CaM ligands with similar spectroscopic properties to the intrinsic and extrinsic fluorophores of other biosensors previously reported. Additionally, they can be used in studies of protein-protein interaction through Förster resonance energy transfer (FRET)...
October 12, 2016: Analytical Biochemistry
Takahiro Yamamoto, Wakaba Endo, Hidenori Ohnishi, Kazuo Kubota, Norio Kawamoto, Takehiko Inui, Atsushi Imamura, Jun-Ichi Takanashi, Masaaki Shiina, Hirotomo Saitsu, Kazuhiro Ogata, Naomichi Matsumoto, Kazuhiro Haginoya, Toshiyuki Fukao
BACKGROUND: Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures. METHODS: Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions...
October 12, 2016: Brain & Development
Shulin Zhuang, Xuan Lv, Liumeng Pan, Liping Lu, Zhiwei Ge, Jiaying Wang, Jingpeng Wang, Jinsong Liu, Weiping Liu, Chunlong Zhang
Benzotriazole ultraviolet stabilizers (BUVSs) are prominent chemicals widely used in industrial and consumer products to protect against ultraviolet radiation. They are becoming contaminants of emerging concern since their residues are frequently detected in multiple environmental matrices and their toxicological implications are increasingly reported. We herein investigated the antiandrogenic activities of eight BUVSs prior to and after human CYP3A4-mediated metabolic activation/deactivation by the two-hybrid recombinant human androgen receptor yeast bioassay and the in vitro metabolism assay...
October 12, 2016: Environmental Pollution
M Hirschvogel, M Bassilious, L Jagschies, S M Wildhirt, M W Gee
A model for patient-specific cardiac mechanics simulation is introduced, incorporating a 3-dimensional finite element model of the ventricular part of the heart which is coupled to a reduced-order 0-dimensional closed-loop vascular system, heart valve and atrial chamber model.The ventricles are modeled by a nonlinear orthotropic passive material law. The electrical activation is mimicked by a prescribed parametrized active stress acting along a generic muscle fiber orientation. Our activation function is constructed such that the start of ventricular contraction and relaxation as well as the active stress curve's slope are parameterized...
October 15, 2016: International Journal for Numerical Methods in Biomedical Engineering
Juan Francisco Morales, Sebastián Scioli Montoto, Pietro Fagilino, María Esperanza Ruiz
The blood brain barrier (BBB) is a physical and biochemical barrier that restricts the entry of certain drugs to the Central Nervous System (CNS), while allowing the passage of others. The ability to predict the permeability of a given molecule through the BBB is a key aspect in CNS drug discovery and development, since neurotherapeutic agents with molecular targets in the CNS should be able to cross the BBB, whereas peripherally acting agents should not, to minimize the risk of CNS adverse effects. In this review we examine and discuss QSAR approaches and current availability of experimental data for the construction of BBB permeability predictive models, focusing on the modeling of the biorelevant parameter unbound partitioning coefficient (Kp,uu) ...
October 13, 2016: Mini Reviews in Medicinal Chemistry
Michael Welter, Heiko Rieger
Tumor vasculature, the blood vessel network supplying a growing tumor with nutrients such as oxygen or glucose, is in many respects different from the hierarchically organized arterio-venous blood vessel network in normal tissues. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature. Integrative models, based on detailed experimental data and physical laws, implement, in silico, the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature...
2016: Advances in Experimental Medicine and Biology
A Mercuri, S Wu, S Stranzinger, S Mohr, S Salar-Behzadi, M Bresciani, E Fröhlich
This work aims to better understand the in vivo behaviour of modified release (MR) formulations (Envarsus(®) tablets and Advagraf(®) capsules) using in vitro properties of tacrolimus and in silico simulations. The in silico concentration profiles of tacrolimus released from the MR formulations were predicted after building a three compartments PK model with GastroPlus™, and using the experimentally determined in vitro physico-chemical properties as input parameters. In vitro-in vivo correlations (IVIVC) were obtained after deconvolution of in vivo data from a clinical trial...
October 10, 2016: International Journal of Pharmaceutics
Qinchang Chen, Xiaoxiang Wang, Wei Shi, Hongxia Yu, Xiaowei Zhang, John P Giesy
Some hydroxylated polybrominated diphenyl ethers (HO-PBDEs), that have been widely detected in the environment and tissues of humans and wildlife, bind to thyroid hormone (TH) receptor (TR) and can disrupt functioning of systems modulated by the TR. However, the mechanism of TH disrupting effect is still equivocal. Here, disruption of functions of TH modulated pathways by HO-PBDEs were evaluated by use of assays of competitive binding, coactivator recruitment and proliferation of GH3 cells. In silico simulations considering effects of co-regulators were carried out to investigate molecular mechanisms and predict potencies for disrupting functions of the TH...
October 14, 2016: Environmental Science & Technology
Henry Reyer, Siriluck Ponsuksili, Ellen Kanitz, Ralf Pöhland, Klaus Wimmers, Eduard Murani
The glucocorticoid receptor (GR) is a central player in the neuroendocrine stress response; it mediates feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis and physiological actions of glucocorticoids in the periphery. Despite intensive investigations of GR in the context of receptor-ligand interaction, only recently the first naturally occurring gain-of-function substitution, Ala610Val, of the ligand binding domain was identified in mammals. We showed that this mutation underlies a major quantitative trait locus for HPA axis activity in pigs, reducing cortisol production by about 40-50 percent...
2016: PloS One
Pratyush Kumar Das, Laura Puusepp, Finny S Varghese, Age Utt, Tero Ahola, Dzmitry G Kananovich, Margus Lopp, Andres Merits, Mati Karelson
Chikungunya virus (CHIKV, genus Alphavirus) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome. Active forms of replicase enzymes are generated using the autoproteolytic activity of nsP2...
October 10, 2016: Antimicrobial Agents and Chemotherapy
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