scholarly journals Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 841 ◽  
Author(s):  
Caitlin Lynch ◽  
Jinghua Zhao ◽  
Srilatha Sakamuru ◽  
Li Zhang ◽  
Ruili Huang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
High Throughput ◽  
High Throughput Screening ◽  
Biological Properties ◽  
Environmental Chemicals ◽  
Hek293 Cells ◽  
Peroxisome Proliferator ◽  
Receptor Alpha ◽  
Screening Assays ◽  
Estrogen Related Receptor

The nuclear receptor, estrogen-related receptor alpha (ERRα; NR3B1), plays a pivotal role in energy homeostasis. Its expression fluctuates with the demands of energy production in various tissues. When paired with the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the PGC/ERR pathway regulates a host of genes that participate in metabolic signaling networks and in mitochondrial oxidative respiration. Unregulated overexpression of ERRα is found in many cancer cells, implicating a role in cancer progression and other metabolism-related diseases. Using high throughput screening assays, we screened the Tox21 10K compound library in stably transfected HEK293 cells containing either the ERRα-reporter or the reporter plus PGC-1α expression plasmid. We identified two groups of antagonists that were potent inhibitors of ERRα activity and/or the PGC/ERR pathway: nine antineoplastic agents and thirteen pesticides. Results were confirmed using gene expression studies. These findings suggest a novel mechanism of action on bioenergetics for five of the nine antineoplastic drugs. Nine of the thirteen pesticides, which have not been investigated previously for ERRα disrupting activity, were classified as such. In conclusion, we demonstrated that high-throughput screening assays can be used to reveal new biological properties of therapeutic and environmental chemicals, broadening our understanding of their modes of action.

scholarly journals Development of Novel Cell Lines for High-Throughput Screening to Detect Estrogen-Related Receptor Alpha Modulators

2017 ◽  
Vol 22 (6) ◽  
pp. 720-731 ◽  
Author(s):  
Christina T. Teng ◽  
Jui-Hua Hsieh ◽  
Jinghua Zhao ◽  
Ruili Huang ◽  
Menghang Xia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
High Throughput ◽  
High Throughput Screening ◽  
Environmental Chemicals ◽  
Screening Tools ◽  
Receptor Alpha ◽  
Pharmacologically Active ◽  
Estrogen Related Receptor

Estrogen-related receptor alpha (ERRα), the first orphan nuclear receptor discovered, is crucial for the control of cellular energy metabolism. ERRα and its coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), are required for rapid energy production in response to environmental challenges. They have been implicated in the etiology of metabolic disorders such as type 2 diabetes and metabolic syndrome. ERRα also plays a role in the pathogenesis of breast cancer. Identification of compounds that modulate ERRα signaling may elucidate environmental factors associated with these diseases. Therefore, we developed stable cell lines containing an intact ERRα signaling pathway, with and without the coactivator PGC-1α, to use as high-throughput screening tools to detect ERRα modulators. The lentiviral PGC-1α expression constructs and ERRα multiple hormone response element (MHRE) reporters were introduced into HEK293T cells that express endogenous ERRα. A cell line expressing the reporter alone was designated “ERR.” A second cell line expressing both reporter and PGC-1α was named “PGC/ERR.” Initial screenings of the Library of Pharmacologically Active Compounds (LOPAC) identified 33 ERR and 22 PGC/ERR agonists, and 54 ERR and 15 PGC/ERR antagonists. Several potent ERRα agonists were dietary plant compounds (e.g., genistein). In conclusion, these cell lines are suitable for high-throughput screens to identify environmental chemicals affecting metabolic pathways and breast cancer progression.

scholarly journals Bioactivity Signatures of Drugs vs. Environmental Chemicals Revealed by Tox21 High-Throughput Screening Assays

2019 ◽  
Vol 2 ◽  
Author(s):  
Deborah K. Ngan ◽  
Lin Ye ◽  
Leihong Wu ◽  
Menghang Xia ◽  
Anna Rossoshek ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Environmental Chemicals ◽  
Screening Assays

scholarly journals Design of High-Throughput Screening Assays and Identification of a SUMO1-Specific Small Molecule Chemotype Targeting the SUMO-Interacting Motif-Binding Surface

2015 ◽  
Vol 17 (4) ◽  
pp. 239-246 ◽  
Author(s):  
Aileen Y. Alontaga ◽  
Yifei Li ◽  
Chih-Hong Chen ◽  
Chen-Ting Ma ◽  
Siobhan Malany ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Binding Surface ◽  
Screening Assays

scholarly journals Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β

Biopolymers ◽  
2014 ◽  
Vol 102 (5) ◽  
pp. 396-406 ◽  
Author(s):  
Franck Madoux ◽  
Claudia Tredup ◽  
Timothy P. Spicer ◽  
Louis Scampavia ◽  
Peter S. Chase ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Screening Assays

scholarly journals Clarifying intact 3D tissues on a microfluidic chip for high-throughput structural analysis

2016 ◽  
Vol 113 (52) ◽  
pp. 14915-14920 ◽  
Author(s):  
Yih Yang Chen ◽  
Pamuditha N. Silva ◽  
Abdullah Muhammad Syed ◽  
Shrey Sindhwani ◽  
Jonathan V. Rocheleau ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Three Dimensional ◽  
Microfluidic System ◽  
High Throughput Drug Screening ◽  
Image Analysis Algorithm ◽  
Screening Assays ◽  
On Chip ◽  
Tissue Models

On-chip imaging of intact three-dimensional tissues within microfluidic devices is fundamentally hindered by intratissue optical scattering, which impedes their use as tissue models for high-throughput screening assays. Here, we engineered a microfluidic system that preserves and converts tissues into optically transparent structures in less than 1 d, which is 20× faster than current passive clearing approaches. Accelerated clearing was achieved because the microfluidic system enhanced the exchange of interstitial fluids by 567-fold, which increased the rate of removal of optically scattering lipid molecules from the cross-linked tissue. Our enhanced clearing process allowed us to fluorescently image and map the segregation and compartmentalization of different cells during the formation of tumor spheroids, and to track the degradation of vasculature over time within extracted murine pancreatic islets in static culture, which may have implications on the efficacy of beta-cell transplantation treatments for type 1 diabetes. We further developed an image analysis algorithm that automates the analysis of the vasculature connectivity, volume, and cellular spatial distribution of the intact tissue. Our technique allows whole tissue analysis in microfluidic systems, and has implications in the development of organ-on-a-chip systems, high-throughput drug screening devices, and in regenerative medicine.

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