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drug screening

Yifan Liu, Eun Ju Yang, Baoyuan Zhang, Zhengqiang Miao, Changjie Wu, Junfang Lyu, Kaeling Tan, Terence Chuen Wai Poon, Joong Sup Shim
PTEN is a tumor suppressor found mutated in many cancers. From a synthetic lethality drug screen with PTEN-isogenic colorectal cancer cells, we found that mutant-PTEN cells were resistant to dual inhibitors of FLT3 and aurora kinase-A, including KW2449 and ENMD-2076. KW2449 significantly reduced the viability of wildtype-PTEN cells causing apoptosis, while little effect was observed in mutant-PTEN counterparts. Transcriptome profiling showed that members of PI3K-AKT signaling pathway were strongly changed in cells after KW2449 treatment, indicating a potential role of the pathway in drug resistance...
August 14, 2018: Cancer Letters
Hajer Dahmani, Kaouthar Louati, Adel Hajri, Senda Bahri, Fathi Safta
Several studies have highlighted that nutritional supplements may contain undeclared anabolic steroids that are banned by the International Olympic Committee/World Anti-Doping Agency. Any kind of abuse with these drugs is extremely dangerous because of their side effects. Thus, the control of food additives in order to protect the best consumer health and to limit fraudulent practices in the field of sports is essential. This paper describes a simple and effective qualitative gas chromatography-mass spectrometry (GC-MS) method to detect anabolic androgenic steroids (AAS): androsterone, nandrolene, dehydroepiandrosterone, 5ɑ-androstane-3β, 17β-diol, dihydrotestosterone, testosterone, methenolone acetate, methandienone, boldenone and fluoxymesterone, in food supplements...
August 14, 2018: Steroids
Priyal Barai, Nisith Raval, Sanjeev Acharya, Ankit Borisa, Hardik Bhatt, Niyati Acharya
Alzheimer's disease (AD) is an enervating and chronic progressive neurodegenerative disorder, occurring frequently in the elderly and adversely affecting intellectual capabilities and the cognitive processes. Bergenin possesses efficacious antioxidant, antiulcerogenic, anti-HIV, hepatoprotective, neuroprotective, anti-inflammatory and immunomodulatory activity along with antinociceptive effect and wound healing properties. Previous studies have shown that bergenin has in vitro bovine adrenal tyrosine hydroxylase inhibitory activity, mushroom tyrosinase inhibitory activities, β-secretase (BACE-1) enzyme inhibitory activity and prevented neuronal death in the primary culture of rat cortical neurons...
August 14, 2018: Behavioural Brain Research
Venkatesan Suryanarayanan, Tamilselvam Rajavel, Kasi Pandima Devi, Sanjeev Kumar Singh
p300/CBP Associated Factor (PCAF), a GNAT family member protein, represent a valid target for therapeutic interventions since its dysfunction has implicated in variety of diseases like cancer, diabetes, inflammatory diseases, etc. Despite its potential for therapeutics, only a small number of PCAF inhibitors were reported. Hence, in this study, the catalytic domain of PCAF was explored to screen novel, potent and cell permeable inhibitor from three small molecule databases like Life Chemical, Maybridge and Chembridge by using Structure Based Virtual Screening (SBVS) method...
August 10, 2018: International Journal of Biological Macromolecules
Bing Cao, Fengfeng Xiao, Da Xing, Xianglong Hu
The increased threat of antibiotic resistance has created an urgent need for new strategies. Herein, polyprodrug antimicrobials are proposed to mimic antimicrobial peptides appended with a concurrent drug release property, exhibiting broad-spectrum antibacterial activity and especially high potency to inhibit methicillin-resistant Staphylococcus aureus (MRSA) without inducing resistance. Two series of polyprodrug antimicrobials are fabricated by facile polymerization of triclosan prodrug monomer (TMA) and subsequent quaternization of hydrophilic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA), affording PDMAEMA-b-PTMA and PQDMA-b-PTMA, respectively...
August 17, 2018: Small
Rhys Salter, Douglas C Beshore, Steven L Colletti, Liam Evans, Yong Gong, Roy Helmy, Yong Liu, Cheri M Maciolek, Gary Martin, Natasa Pajkovic, Richard Phipps, James Small, Jonathan Steele, Ronald de Vries, Headley Williams, Iain J Martin
1. Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. 2. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes, and recombinant human drug metabolizing enzymes. 3...
August 17, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Joseph A Fantuzzo, Ronald P Hart, Jeffrey D Zahn, Zhiping P Pang
Neuropsychiatric disorders have traditionally been difficult to study due to the complexity of the human brain and limited availability of human tissue. Induced pluripotent stem (iPS) cells provide a promising avenue to further our understanding of human disease mechanisms, but traditional 2D cell cultures can only provide a limited view of the neural circuits. To better model complex brain neurocircuitry, compartmentalized culturing systems and 3D organoids have been developed. Early compartmentalized devices demonstrated how neuronal cell bodies can be isolated both physically and chemically from neurites...
August 17, 2018: Developmental Dynamics: An Official Publication of the American Association of Anatomists
J Parrish, K S Lim, K Baer, G J Hooper, T B F Woodfield
Traditional 2D monolayer cell cultures and submillimeter 3D tissue construct cultures used widely in tissue engineering are limited in their ability to extrapolate experimental data to predict in vivo responses due to their simplistic organization and lack of stimuli. The rise of biofabrication and bioreactor technologies has sought to address this through the development of techniques to spatially organize components of a tissue construct, and devices to supply these tissue constructs with an increasingly in vivo-like environment...
August 17, 2018: Lab on a Chip
Denis V Abramochkin, Minna Hassinen, Matti Vornanen
Zebrafish are increasingly used as a model for human cardiac electrophysiology, arrhythmias, and drug screening. However, K+ ion channels of the zebrafish heart, which determine the rate of repolarization and duration of cardiac action potential (AP) are still incompletely known and characterized. Here, we provide the first evidence for the presence of the slow component of the delayed rectifier K+ channels in the zebrafish heart and characterize electrophysiological properties of the slow component of the delayed rectifier K+ current, IKs ...
August 16, 2018: Pflügers Archiv: European Journal of Physiology
Dominik R Bach, Christoph W Korn, Johanna Vunder, Antonia Bantel
Valproate is an anticonvulsant drug with strong preclinical evidence for reducing anxiety behaviour in rodents but no clear clinical evidence. To motivate clinical trials, we here investigate the use of valproate in a translational human model of anxiety behaviour. In a double-blind, randomised, placebo-controlled trial, n = 118 healthy participants played a previously validated approach/avoidance conflict computer game to measure anxiety-like behaviour, while under 400 mg valproate, under 200 mg of the established anxiolytic/anticonvulsant pregabalin, or under placebo...
August 16, 2018: Translational Psychiatry
Sjors M Kas, Julian de Ruiter, Eva Schut, Lorenzo Bombardelli, Ellen Wientjens, Anne Paulien Drenth, Renske de Korte-Grimmerink, Sunny Mahakena, Chris Phillips, Paul D Smith, Sjoerd Klarenbeek, Koen van de Wetering, Anton Berns, Lodewyk F A Wessels, Jos Jonkers, Koen Schipper
In human cancers, fibroblast growth factor receptor (FGFR) signaling is frequently hyperactivated by deregulation of FGF ligands or by activating mutations in the FGFR receptors such as gene amplifications, point mutations and gene fusions. As such, FGFR inhibitors are considered an attractive therapeutic strategy for patients with mutations in FGFR family members. We previously identified Fgfr2 as a key driver of invasive lobular carcinoma (ILC) in an in vivo insertional mutagenesis screen using the Sleeping Beauty (SB) transposon system...
August 16, 2018: Cancer Research
Hiroki Matsuda, Sri Teja Mullapudi, Yu Hsuan Carol Yang, Hideki Masaki, Daniel Hesselson, Didier Y R Stainier
β cell loss and dysfunction play a critical role in the progression of type 1 and type 2 diabetes. Identifying new molecules and/or molecular pathways that improve β cell function and/or increase β cell mass should significantly contribute to the development of new therapies for diabetes. Using the zebrafish model, we screened 4640 small molecules to identify modulators of β cell function. This in vivo strategy identified 84 stimulators of insulin expression which simultaneously reduced glucose levels. The insulin promoter activation kinetics for 32 of these stimulators were consistent with a direct mode of action...
August 16, 2018: Diabetes
Shyam Sundhar Bale, Jeffrey T Borenstein
Animal models such as rats and primates provide body-wide information for drug and metabolite responses, including organ-specific toxicity and any unforeseen side effects on other organs. While effective in the drug screening process, their translatability to humans is limited due to the lack of high concordance and correlation between enzymatic mechanisms, cellular mechanisms and resulting toxicities. A significant mode of failure for safety prediction in drug screening is hepatotoxicity, resulting in ~30% of all safety-related drug failures and withdrawals from the market...
August 16, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Naila Ismayilova, Yael Hacohen, Andrew D MacKinnon, Frances Elmslie, Antonia Clarke
Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels...
February 9, 2018: European Journal of Paediatric Neurology: EJPN
Lisa M Rice, Julio C Mantero, Eric A Stratton, Rod Warburton, Kari Roberts, Nicholas Hill, Robert W Simms, Robyn Domsic, Harrison W Farber, Robert Layfatis
BACKGROUND: Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of death in SSc. Identification of a serum-based proteomic diagnostic biomarker for SSc-PAH would allow for rapid non-invasive screening and could positively impact patient survival. Identification and validation of novel proteins could potentially facilitate the identification of SSc-PAH, and might also point to important protein mediators in pathogenesis. METHODS: Thirteen treatment-naïve SSc-PAH patients had serum collected at time of diagnosis and were used as the discovery cohort for the protein-expression biomarker...
August 16, 2018: Arthritis Research & Therapy
Jaykant Vora, Shivani Patel, Sonam Sinha, Sonal Sharma, Anshu Srivastava, Mahesh Chhabria, Neeta Shrivastava
The transmission of mosquito-borne Chikungunya virus (CHIKV) has large epidemics worldwide. Till date, there are neither anti-viral drugs nor vaccines available for the treatment of Chikungunya. Accumulated evidences suggest that some natural compounds i.e. Epigallocatechin gallate, Harringtonine, Apigenin, Chrysin, Silybin etc. have the capability to inhibit CHIKV replication in vitro. Natural compounds are known to possess less or no side effects. Therefore, natural compound in its purified or crude extracts form could be the preeminent and safe mode of therapies for Chikungunya...
August 16, 2018: Journal of Biomolecular Structure & Dynamics
Mohamed-Elamir F Hegazy, Ahmed R Hamed, Ali M El-Halawany, Taha A Hussien, Sara Abdelfatah, Shinji Ohta, Paul W Paré, Essam Abdel-Sattar, Thomas Efferth
Diterpenoids salvimulticanol (1) and salvimulticaoic acid (2) together with known diterpenoid (3-6) were isolated from Salvia multicaulis. Structures were elucidated by spectroscopic techniques including HRESIMS as well as 1D-, and 2D-NMR. In-vitro cytotoxicity was assayed against human cancer cell lines. As several metabolites exhibited activity against drug-resistance lines, compounds were screened against a panel of human drug-sensitive and multidrug-resistant cancer lines. A proposed biosynthetic pathway for these new diterpenoids (1-2) as well as the cytotoxic structure-activity relationship of all identified compounds were discussed...
August 13, 2018: Fitoterapia
Daniel P Potaczek, Sebastian D Unger, Nan Zhang, Styliani Taka, Sven Michel, Nesibe Akdağ, Feng Lan, Markus Helfer, Christoph Hudemann, Markus Eickmann, Chrysanthi Skevaki, Spyridon Megremis, Anne Sadewasser, Bilal Alashkar Alhamwe, Fahd Alhamdan, Mübeccel Akdis, Michael R Edwards, Sebastian L Johnston, Cezmi A Akdis, Stephan Becker, Claus Bachert, Nikolaos G Papadopoulos, Holger Garn, Harald Renz
BACKGROUND: Infections with human rhinoviruses (RVs) are responsible for millions of common cold episodes and the majority of asthma exacerbations, especially in childhood. No drugs specifically targeting RVs are available. OBJECTIVE: To identify specific anti-rhinoviral molecules based on DNAzyme technology as candidates to a clinical study. METHODS: A total of 226 candidate DNAzymes were designed against two regions of RV RNA genome identified to be sufficiently highly conserved between virus strains, i...
August 13, 2018: Journal of Allergy and Clinical Immunology
Guangzhong Ma, Guan-Da Syu, Xiaonan Shan, Brandon Henson, Shaopeng Wang, Prashant Desai, Heng Zhu, Nongjian Tao
Membrane proteins play vital roles in cellular signaling processes and serve as the most popular drug targets. A key task in studying cellular functions and developing drugs is to measure the binding kinetics of ligands with the membrane proteins. However, this has been a long-standing challenge because one must perform the measurement in a membrane environment to maintain the conformations and functions of the membrane proteins. Here we report a new method to measure ligand binding kinetics to membrane proteins using self-assembled virion-oscillators...
August 16, 2018: Journal of the American Chemical Society
Jianming Liang, Caifang Gao, Ying Zhu, Chengli Ling, Qi Wang, Yongzhuo Huang, Jing Qin, Jue Wang, Weigen Lu, Jianxin Wang
The unsatisfactory therapeutic outcome for glioma is mainly due to the poor BBB permeability and inefficient accumulation in the glioma area of chemotherapeutic agents. The existing drug delivery strategies can increase drug transport to the brain but are restricted by side effects and/or poor delivery efficiency. In this study, potent brain penetration enhancers were screened from the active components of aromatic resuscitation drugs used in traditional Chinese medicine. A novel glioma-targeting system based on enhancer-modified albumin nanoparticles was developed to safely and efficiently deliver drugs to the glioma regions in the brain...
August 16, 2018: ACS Applied Materials & Interfaces
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