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Chemical screen beta cell

Arpita Kulshrestha, Gajendra K Katara, Safaa A Ibrahim, Renukadevi Patil, Shivaputra A Patil, Kenneth D Beaman
In ovarian cancer (OVCA), treatment failure due to chemo-resistance is a serious challenge. It is therefore critical to identify new therapies that are effective against resistant tumors and have reduced side effects. We recently identified 4-H-chromenes as tubulin depolymerizing agents that bind to colchicine site of beta-tubulin. Here, we screened a chemical library of substituted 4-H-chromenes and identified SP-6-27 to exhibit most potent anti-proliferative activity towards a panel of human cisplatin sensitive and resistant OVCA cell lines with 50% inhibitory concentration (IC50; mean ± SD) ranging from 0...
May 2, 2017: Oncotarget
Olivier Laroche, Susanna A Wood, Louis A Tremblay, Gavin Lear, Joanne I Ellis, Xavier Pochon
Sequencing environmental DNA (eDNA) is increasingly being used as an alternative to traditional morphological-based identification to characterize biological assemblages and monitor anthropogenic impacts in marine environments. Most studies only assess eDNA which, compared to eRNA, can persist longer in the environment after cell death. Therefore, eRNA may provide a more immediate census of the environment due to its relatively weaker stability, leading some researchers to advocate for the use of eRNA as an additional, or perhaps superior proxy for portraying ecological changes...
2017: PeerJ
J M Bravo-San Pedro, F Pietrocola, V Sica, V Izzo, A Sauvat, O Kepp, M C Maiuri, G Kroemer, L Galluzzi
Macroautophagy is a specific variant of autophagy that involves a dedicated double-membraned organelle commonly known as autophagosome. Various methods have been developed to quantify the size of the autophagosomal compartment, which is an indirect indicator of macroautophagic responses, based on the peculiar ability of microtubule-associated protein 1 light chain 3 beta (MAP1LC3B; best known as LC3) to accumulate in forming autophagosomes upon maturation. One particularly convenient method to monitor the accumulation of mature LC3 within autophagosomes relies on a green fluorescent protein (GFP)-tagged variant of this protein and fluorescence microscopy...
2017: Methods in Enzymology
Vibha Pathak, Corinne Elizabeth Augelli-Szafran, Han-Xun Wei, Yonghe Li, Patsy G Oliver, Wenyan Lu, Donald J Buchsbaum, Mark J Suto
Wnt/beta-Catenin signaling pathway has a very important role in pancreatic ductal adenocarcinoma (PDAC) initiation and progression. This signaling pathway has been implicated in angiogenesis, maintenance of resistant CICs (cancer-initiating cells), metastasis, regulation of cell cycle, apoptosis and chemoresistance. We investigated the activity of a chemical series of phenyl benzimidazoles, small molecule inhibitors of Wnt signaling in LRP6-expressing HEK 293 cells against PDAC cells. Several benzimidazoles were designed, synthesized and screened under adherent and CIC conditions...
February 23, 2017: Journal of Medicinal Chemistry
Chun Shi, Keith Viccaro, Hyoung-Gon Lee, Kavita Shah
Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2)...
May 1, 2016: Journal of Cell Science
David T White, Arife Unal Eroglu, Guohua Wang, Liyun Zhang, Sumitra Sengupta, Ding Ding, Surendra K Rajpurohit, Steven L Walker, Hongkai Ji, Jiang Qian, Jeff S Mumm
The zebrafish has emerged as an important model for whole-organism small-molecule screening. However, most zebrafish-based chemical screens have achieved only mid-throughput rates. Here we describe a versatile whole-organism drug discovery platform that can achieve true high-throughput screening (HTS) capacities. This system combines our automated reporter quantification in vivo (ARQiv) system with customized robotics, and is termed 'ARQiv-HTS'. We detail the process of establishing and implementing ARQiv-HTS: (i) assay design and optimization, (ii) calculation of sample size and hit criteria, (iii) large-scale egg production, (iv) automated compound titration, (v) dispensing of embryos into microtiter plates, and (vi) reporter quantification...
December 2016: Nature Protocols
Ankur Singh, Rajniti Prasad, Aditya Kumar Gupta, Anil Sharma, Sandra Alves, Maria Francisca Coutinho, Seema Kapoor, Om Prakash Mishra
Mucopolysaccharidosis (MPS) and Mucolipidosis (ML) share common phenotypes (coarse facial features, organomegaly, dysostosis multiplex) despite having different molecular basis. Thus, they pose great diagnostic challenge to treating clinicians. Differentiating between the two conditions requires a battery of tests from screening to molecular diagnosis. Besides discussing differential diagnosis of MPS like features with negative urinary Glycosaminoglycans (GAG), the authors also discuss the utility of p-nitrocatechol sulphate based chemical test as an important screening tool, besides establishing molecular basis in index case...
February 2017: Indian Journal of Pediatrics
Weixi Liu, Hang Ma, Nicholas A DaSilva, Kenneth N Rose, Shelby L Johnson, Lu Zhang, Chunpeng Wan, Joel A Dain, Navindra P Seeram
Medicinal plants are promising candidates for Alzheimer's disease (AD) research but there is lack of systematic algorithms and procedures to guide their selection and evaluation. Herein, we developed a Neuroprotective Potential Algorithm (NPA) by evaluating twenty-three standardized and chemically characterized Ayurvedic medicinal plant extracts in a panel of bioassays targeting oxidative stress, carbonyl stress, protein glycation, amyloid beta (Aβ) fibrillation, acetylcholinesterase (AChE) inhibition, and neuroinflammation...
September 29, 2016: Neurochemistry International
Coraline Simon, Matthias Onghena, Adrian Covaci, Els Van Hoeck, Joris Van Loco, Tara Vandermarken, Kersten Van Langenhove, Heidi Demaegdt, Birgit Mertens, Karin Vandermeiren, Marie-Louise Scippo, Marc Elskens
Endocrine activity of 65 compounds migrating from polycarbonate replacement plastic baby bottles was assessed using in vitro cell based assays (reporter gene assays) involving 7 nuclear receptors, i.e. human steroid hormones receptors (oestrogen, androgen, progesterone and glucocorticoid receptors), human thyroid beta and peroxisome proliferator-activated gamma receptors, and the mouse aryl hydrocarbon receptor. The chemicals were tested at 4 concentrations ranging from 0.001mM to 1mM. Only twelve chemicals did not show any activity towards any of the nuclear receptors, while fifty three compounds showed a possible endocrine activity...
December 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Diana A Stavreva, Lyuba Varticovski, Ludmila Levkova, Anuja A George, Luke Davis, Gianluca Pegoraro, Vicki Blazer, Luke Iwanowicz, Gordon L Hager
Even though the presence of endocrine disrupting chemicals (EDCs) with thyroid hormone (TH)-like activities in the environment is a major health concern, the methods for their efficient detection and monitoring are still limited. Here we describe a novel cell assay, based on the translocation of a green fluorescent protein (GFP)-tagged chimeric molecule of glucocorticoid receptor (GR) and the thyroid receptor beta (TRβ) from the cytoplasm to the nucleus in the presence of TR ligands. Unlike the constitutively nuclear TRβ, this GFP-GR-TRβ chimera is cytoplasmic in the absence of hormone while translocating to the nucleus in a time- and concentration-dependent manner upon stimulation with triiodothyronine (T3) and thyroid hormone analogue, TRIAC, while the reverse triiodothyronine (3,3',5'-triiodothyronine, or rT3) was inactive...
August 10, 2016: Toxicology
Hui Zeng, Min Guo, Ting Zhou, Lei Tan, Chi Nok Chong, Tuo Zhang, Xue Dong, Jenny Zhaoying Xiang, Albert S Yu, Lixia Yue, Qibin Qi, Todd Evans, Johannes Graumann, Shuibing Chen
Genome-wide association studies (GWASs) have increased our knowledge of loci associated with a range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human ESCs (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic beta-like cells differentiated from these lines, we found that mutations in CDKAL1, KCNQ1, and KCNJ11 led to impaired glucose secretion in vitro and in vivo, coinciding with defective glucose homeostasis...
September 1, 2016: Cell Stem Cell
Chia-Wen Amy Hsu, Jinghua Zhao, Menghang Xia
The farnesoid X receptor (FXR) is a nuclear receptor responsible for homeostasis of bile acids, lipids, and glucose. Compounds that alter endogenous FXR signaling can be used as therapeutic candidates or identified as potentially hazardous compounds depending on exposure doses and health states. Therefore, there is an increasing need for high-throughput screening assays of FXR activity to profile large numbers of environmental chemicals and drugs. This chapter describes a workflow of FXR modulator identification and characterization...
2016: Methods in Molecular Biology
LaQueta K Hudson, Meghan E Dancho, Jianhua Li, Johanna B Bruchfeld, Ahmed A Ragab, Mingzhu M He, Meaghan Bragg, Delaney Lenaghan, Michael D Quinn, Jason R Fritz, Matthew V Tanzi, Harold A Silverman, William M Hanes, Yaakov A Levine, Valentin A Pavlov, Peder S Olofsson, Jesse Roth, Yousef Al-Abed, Ulf Andersson, Kevin J Tracey, Sangeeta S Chavan
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by beta cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice...
June 10, 2016: Molecular Medicine
Danciu Corina, Florina Bojin, Rita Ambrus, Delia Muntean, Codruta Soica, Virgil Paunescu, Mirabela Cristea, Iulia Pinzaru, Cristina Dehelean
BACKGROUND: Fisetin,quercetin and kaempferol are among the important representatives of flavonols, biological active phytocomounds, with low water solubility. OBJECTIVE: To evaluate the antimicrobial effect, respectively the antiproliferative and pro apoptotic activity on the B164A5 murine melanoma cell line of pure flavonols and their beta cyclodextrins complexes. METHOD: Incorporation of fisetin, quercetin and kaempferol in beta cyclodextrins was proved by scanning electron microscopy (SEM), differencial scanning calorimetry (DSC) and X-ray powder diffraction (XRPD)...
2017: Anti-cancer Agents in Medicinal Chemistry
Nivedita Lahiri, Rupal R Shah, Emilie Layre, David Young, Chris Ford, Megan B Murray, Sarah M Fortune, D Branch Moody
Global control of tuberculosis has become increasingly complicated with the emergence of multidrug-resistant strains of Mycobacterium tuberculosis First-line treatments are anchored by two antibiotics, rifampin and isoniazid. Most rifampin resistance occurs through the acquisition of missense mutations in the rifampin resistance-determining region, an 81-base pair region encoding the rifampin binding site on the β subunit of RNA polymerase (rpoB). Although these mutations confer a survival advantage in the presence of rifampin, they may alter the normal process of transcription, thereby imposing significant fitness costs...
July 1, 2016: Journal of Biological Chemistry
Lingling Feng, Brandoch Cook, Su-Yi Tsai, Ting Zhou, Brooke LaFlamme, Todd Evans, Shuibing Chen
Sorely missing from the "toolkit" for directed differentiation of stem/progenitor cells are agonists of the BMP-signaling pathway. Using a high-throughput chemical screen, we discovered that PD407824, a checkpoint kinase 1 (CHK1) inhibitor, increases the sensitivity of cells to sub-threshold amounts of BMP4. We show utility of the compound in the directed differentiation of human embryonic stem cells toward mesoderm or cytotrophoblast stem cells. Blocking CHK1 activity using pharmacological compounds or CHK1 knockout using single guide RNA (sgRNA) confirmed that CHK1 inhibition increases the sensitivity to BMP4 treatment...
May 31, 2016: Cell Reports
Carina Lotz-Jenne, Urs Lüthi, Sabine Ackerknecht, François Lehembre, Tobias Fink, Manuel Stritt, Matthias Wirth, Simona Pavan, Ruben Bill, Urs Regenass, Gerhard Christofori, Nathalie Meyer-Schaller
An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG)...
May 3, 2016: Oncotarget
Scott Auerbach, Dayne Filer, David Reif, Vickie Walker, Alison C Holloway, Jennifer Schlezinger, Supriya Srinivasan, Daniel Svoboda, Richard Judson, John R Bucher, Kristina A Thayer
BACKGROUND: Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U...
August 2016: Environmental Health Perspectives
Ajit Singh Rathore, Neha Keshri, Devi Charan Shetty, Saurabh Juneja
BACKGROUND: Increased iron overload is frequent problem in thalassemia patients, and this is monitored by serum ferritin levels or chemical assessment of the iron levels in liver tissue. However, repeated monitoring of serum ferritin levels to assess the iron overload is an invasive procedure associated with practical problems. AIMS: To use Perl's Prussian blue reaction to evaluate the iron overload in beta-thalassemia patients by staining the oral cytosmears. MATERIALS AND METHODS: The study comprised 35 patients diagnosed with beta-thalassemia...
January 2016: International Journal of Applied and Basic Medical Research
Michael S Boosalis, Jose I Sangerman, Gary L White, Roman F Wolf, Ling Shen, Yan Dai, Emily White, Levi H Makala, Biaoru Li, Betty S Pace, Mehdi Nouraie, Douglas V Faller, Susan P Perrine
High-level fetal (γ) globin expression ameliorates clinical severity of the beta (β) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- and functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions...
2015: PloS One
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