ReferenceID 5911
Discovery of oridonin as a novel agonist for BRS-3
Phytomedicine
Background: Bombesin Receptor Subtype-3 (BRS-3, Bombesin-like receptor, BB 3 ) is an orphan G-protein coupled receptor (GPCR). Recent studies have shown that BRS-3 played a vital role in glucose regulation, insulin secre
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Record Fields
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- Reference Id
- 5911
- Evidence Id
- 22501
- Core Evidence Id
- 22501
- Source Reference Id
- 5079
- Herb2 Reference Id
- HBREF005876
- Subject Paper Key
- HBIN038254_35405616
- Pubmed Id
- 35405616
- Doi
- 10.1016/j.phymed.2022.154085
- Paper Title
- Discovery of oridonin as a novel agonist for BRS-3
- Paper Abstract
- Background: Bombesin Receptor Subtype-3 (BRS-3, Bombesin-like receptor, BB 3 ) is an orphan G-protein coupled receptor (GPCR). Recent studies have shown that BRS-3 played a vital role in glucose regulation, insulin secretion, and energy homeostasis. Therefore, discovering more novel exogenous ligands with diverse structures for BRS-3 will be of great importance for target validation and drug development. Purpose: In this study, we aim to discover new agonists of BRS-3 from our natural compound libraries, providing a new probe to study the function of BRS-3. Study design: Multiple cell-based assays and in vivo experiments were performed to identify the new ligand. Methods: BRS-3 overexpression cells were coupled with FLIPR assay, homogeneous time-resolved fluorescence (HTRF) IP-ONE assay, dynamic mass redistribution (DMR) assay, β-arrestin2 recruitment assay, and western blot to determine receptor activation and downstream signaling events. To further validate the target of BRS-3, a series of in vitro and in vivo experiences were conducted, including glucose uptake, glucose transporter type 4 (GLUT4) transportation in C2C12, and oral glucose tolerance test (OGTT) in mice. Results: We discovered and identified oridonin as a novel small molecule agonist of BRS-3, with a moderate affinity (EC 50 of 2.236 × 10 -7 M in calcium mobilization assay), specificity, and subtype selectivity. Further in vitro and in vivo tests demonstrated that oridonin exerted beneficial effects in glucose homeostasis through activating BRS-3. Conclusions: Oridonin, as the discovered new ligand of BRS-3, provides a valuable tool compound to investigate BRS-3's function, especially for target validation in type 2 diabetes and obesity. Oridonin is promising as a lead compound in the treatment of metabolic disorders. Compared to the known agonists of BRS-3, we can take advantage of the multiple reported pharmacological activities of ODN as a natural product and assess whether these pharmacological activities are regulated by BRS-3. This may facilitate the discovery of novel functions of BRS-3.
- Journal
- Phytomedicine
- Publish Year
- 2022
- Experiment Subject
- mouse; brs-3 overexpression cells
- Experiment Type
- Animal Experiment
- Phenotype Related
- Obesity; Metabolic Disorders; Type 2 Diabetes
- Paper Title Cn
- Paper Title En
- Discovery of oridonin as a novel agonist for BRS-3
- Bilingual Status
- semi_complete