Chemical Screening of Nuclear Receptor Modulators

Ishigami‐Yuasa, Mari; Kagechika, Hiroyuki

doi:10.3390/ijms21155512

Cited by 10 publications

(7 citation statements)

References 157 publications

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“…The AR gene is located on the long arm of the X-chromosome and is expressed in several tissues, including the prostate, breast, testes, skeletal muscle, uterus, and bladder [ 11 ]. The AR belongs to the family of transcription factors that homodimerize after ligand-binding, while RXR receptors may heterodimerize, and monomeric orphan receptors do not require dimerization [ 12 , 13 ].…”

Section: Structure Of Androgens and Androgen Receptorsmentioning

confidence: 99%

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

et al. 2021

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Bladder cancer (urothelial carcinoma) is one of the most frequently diagnosed neoplasms, with an estimated half a million new cases and 200,000 deaths per year worldwide. This pathology mainly affects men. Men have a higher risk (4:1) of developing bladder cancer than women. Cigarette smoking and exposure to chemicals such as aromatic amines, and aniline dyes have been established as risk factors for bladder cancer and may contribute to the sex disparity. Male internal genitalia, including the urothelium and prostate, are derived from urothelial sinus endoderm; both tissues express the androgen receptor (AR). Several investigations have shown evidence that the AR plays an important role in the initiation and development of different types of cancer including bladder cancer. In this article, we summarize the available data that help to explain the role of the AR in the development and progression of bladder cancer, as well as the therapies used for its treatment.

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Section: Structure Of Androgens and Androgen Receptorsmentioning

confidence: 99%

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

et al. 2021

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“…Nuclear receptors (NRs) are transcription factors that are induced by ligands and widely exist in metazoans to participate in various biological processes [6]. NRs can bind to ligands and 24 NRs have established ligands.…”

Section: Interaction Of Dehp With the Nuclear Receptor Pparγmentioning

confidence: 99%

Effects of Exposure to Phthalate Plasticizers in Food on Obesity

Yi¹

2022

Proceedings of the 2022 6th International Seminar on Education, Management and Social Sciences (ISEMSS 2022)

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Phthalate (PAEs) is an environmental pollutant and can enter the human body through respiratory tract inhalation, skin contact, and food intake. As one of the food plasticizers, PAEs are seriously harming human health. They migrate into the food and enter the human body through the food packaging materials to affect the normal physiological metabolism of the human body. In this paper, we mainly describe how PAEs can induce obesity by interacting with nuclear receptors, inhibiting the expression of genetic epigenetic factor sirtuin, increasing the content of Bifidobacteria in the intestinal tract, and reducing the secretion of thyroid hormones (TH).Then, two feasible solutions were introduced. One was to control obesity by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) through celery oil seeds, and the other was to control obesity by supplementing Bifidobacterium longum APC1472 to improve intestinal microorganism. In conclusion, this article summarizes the latest progress in the mechanism of PAEs exposure to obesity.

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“…This standard model of nuclear receptor regulation has been validated in many receptors through structural and functional studies − and represents a rigorously tested, well-accepted regulatory model for this group of transcription factors. Based on this standard model, high-throughput compound screens have demonstrated outstanding effectiveness. − These screens monitor the physical interaction between a nuclear receptor LBD and an LXXLL-motif containing peptide from biologically relevant transcriptional coregulators. ,− Drugs developed with the aid of these standard screens remain first-line therapies in human diseases such as cancer, obesity, and diabetes. , …”

Section: Introductionmentioning

confidence: 99%

New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1

et al. 2023

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Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is a lipid-regulated transcription factor and an important drug target for several liver diseases. Advances toward LRH-1 therapeutics have been driven recently by structural biology, with fewer contributions from compound screening. Standard LRH-1 screens detect compound-induced interaction between LRH-1 and a transcriptional coregulator peptide, an approach that excludes compounds that regulate LRH-1 through alternative mechanisms. Here, we developed a FRET-based LRH-1 screen that simply detects compound binding to LRH-1, applying it to discover 58 new compounds that bind the canonical ligand-binding site in LRH-1 (2.5% hit rate), also supported by computational docking. Four independent functional screens identified 15 of these 58 compounds to also regulate LRH-1 function in vitro or in living cells. Although one of these 15 compounds, abamectin, directly binds LRH-1 and regulates full-length LRH-1 in cells, abamectin failed to regulate the isolated ligand-binding domain in standard coregulator peptide recruitment assays using PGC1α, DAX-1, or SHP. Abamectin treatment of human liver HepG2 cells selectively regulated endogenous LRH-1 ChIP-seq target genes and pathways associated with known LRH-1 functions in bile acid and cholesterol metabolism. Thus, the screen reported here can discover compounds not likely to have been identified in standard LRH-1 compound screens but which bind and regulate full-length LRH-1 in cells.

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Chemical Screening of Nuclear Receptor Modulators

Cited by 10 publications

References 157 publications

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

Effects of Exposure to Phthalate Plasticizers in Food on Obesity

New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1

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