scholarly journals Data-driven discovery of targets for bipotent anticancer drugs identifies Estrogen Related Receptor Alpha

2021 ◽  
Author(s):  
Avinash Sahu ◽  
Xiaoman Wang ◽  
Phillip Munson ◽  
Jan Klomp ◽  
Xiaoqing Wang ◽  
...  
Keyword(s):  
Drug Targets ◽  
Macrophage Polarization ◽  
Data Driven ◽  
Direct Effects ◽  
Receptor Alpha ◽  
Cytokine Induction ◽  
Oncogenic Pathway ◽  
Clinical Benefits ◽  
Metabolic Regulators ◽  
Estrogen Related Receptor

Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at http://bipotentr.dfci.harvard.edu/.

scholarly journals Estrogen-related receptor alpha (ERRα) is a key regulator of intestinal homeostasis and protects against colitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Allan Tran ◽  
Charlotte Scholtes ◽  
Mario Songane ◽  
Claudia Champagne ◽  
Luc Galarneau ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Current Knowledge ◽  
Experimental Colitis ◽  
Protective Effects ◽  
Mitochondrial Energy Metabolism ◽  
Receptor Alpha ◽  
Cell Counts ◽  
Α Diversity ◽  
Estrogen Related Receptor

AbstractThe estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERRα is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERRα in the intestine. We found that mice deficient in ERRα were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERRα lead to a reduction in microbiome α-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERRα mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD.

scholarly journals Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (23) ◽  
pp. 34131-34148 ◽  
Author(s):  
Hiroshi Matsushima ◽  
Taisuke Mori ◽  
Fumitake Ito ◽  
Takuro Yamamoto ◽  
Makoto Akiyama ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Receptor Alpha ◽  
Uterine Endometrial Cancer ◽  
Estrogen Related Receptor

scholarly journals Open-source chemogenomic data-driven algorithms for predicting drug–target interactions

2018 ◽  
Vol 20 (4) ◽  
pp. 1465-1474 ◽  
Author(s):  
Ming Hao ◽  
Stephen H Bryant ◽  
Yanli Wang
Keyword(s):  
Drug Discovery ◽  
Human Genome ◽  
High Throughput Screening ◽  
Drug Target ◽  
Drug Targets ◽  
Drug Repositioning ◽  
Research Field ◽  
Data Driven ◽  
Source Codes ◽  
Novel Technologies

AbstractWhile novel technologies such as high-throughput screening have advanced together with significant investment by pharmaceutical companies during the past decades, the success rate for drug development has not yet been improved prompting researchers looking for new strategies of drug discovery. Drug repositioning is a potential approach to solve this dilemma. However, experimental identification and validation of potential drug targets encoded by the human genome is both costly and time-consuming. Therefore, effective computational approaches have been proposed to facilitate drug repositioning, which have proved to be successful in drug discovery. Doubtlessly, the availability of open-accessible data from basic chemical biology research and the success of human genome sequencing are crucial to develop effective in silico drug repositioning methods allowing the identification of potential targets for existing drugs. In this work, we review several chemogenomic data-driven computational algorithms with source codes publicly accessible for predicting drug–target interactions (DTIs). We organize these algorithms by model properties and model evolutionary relationships. We re-implemented five representative algorithms in R programming language, and compared these algorithms by means of mean percentile ranking, a new recall-based evaluation metric in the DTI prediction research field. We anticipate that this review will be objective and helpful to researchers who would like to further improve existing algorithms or need to choose appropriate algorithms to infer potential DTIs in the projects. The source codes for DTI predictions are available at: https://github.com/minghao2016/chemogenomicAlg4DTIpred.

Estrogen-related receptor alpha (ERRα) is required for PGC-1α-dependent gene expression in the mouse brain

Neuroscience ◽  
2021 ◽  
Author(s):  
L.J. McMeekin ◽  
K.L. Joyce ◽  
L.M. Jenkins ◽  
B.M. Bohannon ◽  
K.D. Patel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Receptor Alpha ◽  
Estrogen Related Receptor

scholarly journals Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development

Theranostics ◽  
2020 ◽  
Vol 10 (24) ◽  
pp. 10874-10891
Author(s):  
Meng Yang ◽  
Qingli Liu ◽  
Tongling Huang ◽  
Wenjuan Tan ◽  
Linbing Qu ◽  
...  
Keyword(s):  
Receptor Alpha ◽  
Vldl Secretion ◽  
Sex Disparity ◽  
Estrogen Related Receptor
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