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https://www.readbyqxmd.com/read/28231254/rapid-generation-of-drug-resistance-alleles-at-endogenous-loci-using-crispr-cas9-indel-mutagenesis
#1
Jonathan J Ipsaro, Chen Shen, Eri Arai, Yali Xu, Justin B Kinney, Leemor Joshua-Tor, Christopher R Vakoc, Junwei Shi
Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel) mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28231052/review-the-role-of-peroxisome-proliferator-activated-receptor-in-the-treatment-of-non-alcoholic-fatty-liver-disease
#2
Xin Sun, Yan Zhang, Meilin Xie
Non-alcoholic fatty liver disease (NAFLD) has been defined as a spectrum of histological abnormalities and is characterized by significant and excessive accumulation of triglycerides in the hepatocytes in patients without alcohol consumption or other diseases. Current studies are targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. Many therapeutic targets have been found and used in clinical studies. Peroxisome proliferator-activated receptors (PPARs) are among the potential targets and have been demonstrated to exert a pivotal role in modulation of NAFLD...
March 1, 2017: Acta Pharmaceutica
https://www.readbyqxmd.com/read/28230866/oridonin-induces-autophagy-via-inhibition-of-glucose-metabolism-in-p53-mutated-colorectal-cancer-cells
#3
Zhuo Yao, Fuhua Xie, Min Li, Zirui Liang, Wenli Xu, Jianhua Yang, Chang Liu, Hongwangwang Li, Hui Zhou, Liang-Hu Qu
The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28230790/influence-of-chitosan-swelling-behaviour-on-controlled-release-of-tenofovir-from-mucoadhesive-vaginal-systems-for-prevention-of-sexual-transmission-of-hiv
#4
Fernando Notario-Pérez, Araceli Martín-Illana, Raúl Cazorla-Luna, Roberto Ruiz-Caro, Luis-Miguel Bedoya, Aitana Tamayo, Juan Rubio, María-Dolores Veiga
The main challenges facing efforts to prevent the transmission of human immunodeficiency virus (HIV) are the lack of access to sexual education services and sexual violence against young women and girls. Vaginal formulations for the prevention of sexually transmitted infections are currently gaining importance in drug development. Vaginal mucoadhesive tablets can be developed by including natural polymers that have good binding capacity with mucosal tissues, such as chitosan or guar gum, semisynthetic polymers such as hydroxypropylmethyl cellulose, or synthetic polymers such as Eudragit(®) RS...
February 21, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28228973/duchenne-regulatory-science-consortium-meeting-on-disease-progression-modeling-for-duchenne-muscular-dystrophy
#5
Jane Larkindale, Richard Abresch, Enrique Aviles, Abby Bronson, Janice Chin, Pat Furlong, Heather Gordish-Dressman, Elizabeth Habeeb-Louks, Erik Henricson, Hans Kroger, Charles Lynn, Stephen Lynn, Dana Martin, Glen Nuckolls, William Rooney, Klaus Romero, Lee Sweeney, Krista Vandenborne, Glenn Walter, Jodi Wolff, Brenda Wong, Craig M McDonald, Members Of The Duchenne Regulatory Science Consortium Imaging-Dmd Consortium And The Cinrg Investigators
The Duchenne Regulatory Science Consortium (D-RSC) was established to develop tools to accelerate drug development for DMD.  The resulting tools are anticipated to meet validity requirements outlined by qualification/endorsement pathways at both the U.S. Food and Drug Administration (FDA) and European Medicines Administration (EMA), and will be made available to the drug development community. The initial goals of the consortium include the development of a disease progression model, with the goal of creating a model that would be used to forecast changes in clinically meaningful endpoints, which would inform clinical trial protocol development and data analysis...
January 12, 2017: PLoS Currents
https://www.readbyqxmd.com/read/28228926/antibody-h3-structure-prediction
#6
REVIEW
C Marks, C M Deane
Antibodies are proteins of the immune system that are able to bind to a huge variety of different substances, making them attractive candidates for therapeutic applications. Antibody structures have the potential to be useful during drug development, allowing the implementation of rational design procedures. The most challenging part of the antibody structure to experimentally determine or model is the H3 loop, which in addition is often the most important region in an antibody's binding site. This review summarises the approaches used so far in the pursuit of accurate computational H3 structure prediction...
2017: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/28228363/efficient-synthesis-of-%C3%AE-fluoromethylhistidine-di-hydrochloride-and-demonstration-of-its-efficacy-as-a-glutathione-s-transferase-inhibitor
#7
Kelly L Considine, Lazaros Stefanidis, Karl G Grozinger, Joseph Audie, Benjamin J Alper
Histidine decarboxylase (HDC) is an enzyme that converts histidine to histamine. Inhibition of HDC has several medical applications, and HDC inhibitors are of considerable interest for the study of histidine metabolism. (S)-α-Fluoromethylhistidine di-hydrochloride (α-FMH) is a potent HDC inhibitor that is commercially available at high cost in small amounts only. Here we report a novel, inexpensive, and efficient method for synthesis of α-FMH using methyl 2-aziridinyl-3-(N-triphenylmethyl-4-imidazolyl) propionate and HF/pyridine, with experimental yield of 57%...
February 14, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28228225/-advances-in-classification-and-research-methods-of-lung-epithelial-stem-%C3%A2-and-progenitor-cells
#8
Minhua Deng, Jinhua Li, Ye Gan, Ping Chen
Isolation and characterization of lung epithelial stem and progenitor cells and understanding of their specific role in lung physiopathology are critical for preventing and controlling lung diseases including lung cancer. In this review, we summarized recent advances in classification and research methods of lung epithelial stem and progenitor cells. Lung epithelial stem and progenitor cells were region-specific, which primarily included basal cells and duct cells in proximal airway, Clara cells, variant Clara cells, bronchioalveolar stem cells and induced krt5+ cells in bronchioles, type II alveolar cells and type II alveolar progenitor cells in alveoli...
February 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28225907/characterisation-of-iunh-gene-knockout-strain-from-mycobacterium-tuberculosis
#9
Anne Drumond Villela, Valnês da Silva Rodrigues, Antônio Frederico Michel Pinto, Priscila Lamb Wink, Zilpa Adriana Sánchez-Quitian, Guilherme Oliveira Petersen, Maria Martha Campos, Luiz Augusto Basso, Diógenes Santiago Santos
BACKGROUND: Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis. The better understanding of important metabolic pathways from M. tuberculosis can contribute to the development of novel therapeutic and prophylactic strategies to combat TB. Nucleoside hydrolase (MtIAGU-NH), encoded by iunH gene (Rv3393), is an enzyme from purine salvage pathway in M. tuberculosis. MtIAGU-NH accepts inosine, adenosine, guanosine, and uridine as substrates, which may point to a pivotal metabolic role...
March 2017: Memórias do Instituto Oswaldo Cruz
https://www.readbyqxmd.com/read/28225764/cynomolgus-macaques-naturally-infected-with-trypanosoma-cruzi-i-exhibit-an-overall-mixed-pro-inflammatory-modulated-cytokine-signature-characteristic-of-human-chagas-disease
#10
Danielle Marquete Vitelli-Avelar, Renato Sathler-Avelar, Armanda Moreira Mattoso-Barbosa, Nicolas Gouin, Marcelo Perdigão-de-Oliveira, Leydiane Valério-Dos-Reis, Ronaldo Peres Costa, Silvana Maria Elói-Santos, Matheus de Souza Gomes, Laurence Rodrigues do Amaral, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Edward J Dick, Gene B Hubbard, Jane F VandeBerg, John L VandeBerg
BACKGROUND: Non-human primates have been shown to be useful models for Chagas disease. We previously reported that natural T. cruzi infection of cynomolgus macaques triggers clinical features and immunophenotypic changes of peripheral blood leukocytes resembling those observed in human Chagas disease. In the present study, we further characterize the cytokine-mediated microenvironment to provide supportive evidence of the utility of cynomolgus macaques as a model for drug development for human Chagas disease...
February 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28224764/tak1-inhibitor-suppresses-the-proliferation-in-triple-negative-breast-cancer-through-tgf-%C3%AE-tgfr-pathway
#11
Liangyu Zhang, Zelong Fu, Xia Li, Haitao Tang, Jiesi Luo, Dehui Zhang, Yongzhi Zhang, Zhiyang Han, Mingzhu Yin
Breast cancer is one for the most invasive cancer type in female population. The functional activity of transformation growth factor-activated factor 1 (TAK1) in breast cancer progression increasingly attracts attention since it provides a potential target for anti-breast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells...
February 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28224120/oncolytic-virotherapy-including-rigvir-and-standard-therapies-in-malignant-melanoma
#12
REVIEW
Hani M Babiker, Irbaz Bin Riaz, Muhammad Husnain, Mitesh J Borad
The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients...
2017: Oncolytic Virotherapy
https://www.readbyqxmd.com/read/28223228/drug-discovery-using-induced-pluripotent-stem-cell-models-of-neurodegenerative-and-ocular-diseases
#13
REVIEW
Sandy S C Hung, Shahnaz Khan, Camden Y Lo, Alex W Hewitt, Raymond C B Wong
The revolution of induced pluripotent stem cell (iPSC) technology provides a platform for development of cell therapy, disease modeling and drug discovery. Recent technological advances now allow us to reprogram a patient's somatic cells into induced pluripotent stem cells (iPSCs). Together with methods to differentiate these iPSCs into the disease-relevant cell types, we are now able to model disease in vitro using iPSCs. Importantly, this represents a robust in vitro platform using patient-specific cells, providing opportunity for personalized precision medicine...
February 13, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28223123/proarrhythmia-liability-assessment-and-the-comprehensive-in-vitro-proarrhythmia-assay-cipa-an-industry-survey-on-current-practice
#14
Simon Authier, Michael K Pugsley, John E Koerner, Bernard Fermini, William S Redfern, Jean-Pierre Valentin, Hugo M Vargas, Derek J Leishman, Krystle Correll, Michael J Curtis
INTRODUCTION: The Safety Pharmacology Society (SPS) has conducted a survey of its membership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA). METHODS: Survey topics included nonclinical approaches to address proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay...
February 18, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28222334/a-quantification-method-for-determination-of-racemate-praziquantel-and-r-enantiomer-in-rat-plasma-for-comparison-of-their-pharmacokinetics
#15
Danlu Zhang, Haina Wang, Jianbo Ji, Lei Nie, Dequn Sun
Praziquantel is the drug of first choice for the control and treatment of all forms of schistosomiasis. Praziquantel is administered as a racemate, including R-enantiomer and S-enantiomer. Among them, R-enantiomer has main contribution to schistosomicidal activity. In this study, a sensitive and rapid liquid chromatography with tandem mass spectrometry was established and validated to determine the concentration of racemate praziquantel and R-enantiomer in rat plasma after oral administration. Chromatographic separation was performed on an Agilent Zorbax SB-C18 column...
February 14, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28220535/interaction-of-approved-drugs-with-synaptic-vesicle-protein-2a
#16
Azeem Danish, Vigneshwaran Namasivayam, Anke C Schiedel, Christa E Müller
Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [(3) H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM...
February 21, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28219316/from-disorder-to-mis-order-structural-aspects-of-pathogenic-oligomerization-in-conformational-diseases
#17
Chin Pang Benny Yiu, Yu Wai Chen
Proteins implicated in neurological conformational diseases contain substantial amounts of "intrinsic disorder". These native monomeric functional states may transit into some oligomeric states that have high β-sheet contents and seed the formation of insoluble amyloid fibrils. The prevailing view is that these "toxic" oligomers should be targeted for drug development. Here, an overview of the diseases was presented, within the general framework of the oligomerization of intrinsically disordered proteins. These systems pose some specific challenges to structural studies: the toxic oligomers are transient, low in concentration, and often need to be studied in a heterogeneous environment...
February 20, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28218837/rapid-and-efficient-genome-editing-in-staphylococcus-aureus-by-using-an-engineered-crispr-cas9-system
#18
Weizhong Chen, Yifei Zhang, Won-Sik Yeo, Taeok Bae, Quanjiang Ji
Staphylococcus aureus, a major human pathogen, has been the cause of serious infectious diseases with a high mortality rate. Although genetics is a key means to study S. aureus physiology, such as drug resistance and pathogenesis, genetic manipulation in S. aureus is always time consuming and labor intensive. Here, we report a CRISPR/Cas9 system (pCasSA) for rapid and efficient genome editing, including gene deletion, insertion and single-base substitution mutation in S. aureus. The designed pCasSA system is amenable to assembly of spacers and repair arms by Golden Gate assembly and Gibson assembly, respectively, enabling rapid construction of the plasmids for editing...
February 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28218733/integrating-pharmacoproteomics-into-early-phase-clinical-development-state-of-the-art-challenges-and-recommendations
#19
REVIEW
Savita Nandal, Tal Burt
Pharmacoproteomics is the study of disease-modifying and toxicity parameters associated with therapeutic drug administration, using analysis of quantitative and temporal changes to specific, predetermined, and select proteins, or to the proteome as a whole. Pharmacoproteomics is a rapidly evolving field, with progress in analytic technologies enabling processing of complex interactions of large number of unique proteins and effective use in clinical trials. Nevertheless, our analysis of clinicaltrials.gov and PubMed shows that the application of proteomics in early-phase clinical development is minimal and limited to few therapeutic areas, with oncology predominating...
February 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28218430/stepwise-assembly-of-functional-c-terminal-rest-nrsf-transcriptional-repressor-complexes-as-a-drug-target
#20
Ken Inui, Zongpei Zhao, Juan Yuan, Sakthidasan Jayaprakash, Le T M Le, Srdja Drakulic, Bjoern Sander, Monika M Golas
In human cells, thousands of predominantly neuronal genes are regulated by the repressor element 1 (RE1)-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF). REST/NRSF represses transcription of these genes in stem cells and non-neuronal cells by tethering corepressor complexes. Aberrant REST/NRSF expression and intracellular localization are associated with cancer and neurodegeneration in humans. To date, detailed molecular analyses of REST/NRSF and its C-terminal repressor complex have been hampered largely by the lack of sufficient amounts of purified REST/NRSF and its complexes...
February 20, 2017: Protein Science: a Publication of the Protein Society
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