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Background: Bombesin Receptor Subtype-3 (BRS-3, Bombesin-like receptor, BB) 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 of 2.236 × 10 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.
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http://dx.doi.org/10.1016/j.phymed.2022.154085 | DOI Listing |
Front Public Health
January 2025
Department of Psychiatry, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
J Am Med Dir Assoc
November 2024
Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand; Waitematā District Health Board/Te Whatu Ora Waitematā, Auckland, New Zealand.
Objectives: Housing quality has significant impact on the wider determinants of health and quality of life (QoL). Retirement villages are considered age-friendly accommodation for community-dwelling older people, offering a variable range of services and supports. We wished to explore the relationship among frailty, QoL, and resilience in older people residing in retirement villages.
View Article and Find Full Text PDFbioRxiv
July 2024
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA 20892.
Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production. While many neural circuits underlying feeding and parenting behaviors are well characterized, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger.
View Article and Find Full Text PDFCell Rep
August 2024
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Guangzhou University of Chinese Medicine, Zhongshan Institute for Drug Discovery, Guangdong 510000, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:
Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, the lack of known endogenous ligands and high-resolution structure has hindered the understanding of BRS3 signaling and function. We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric G protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046.
View Article and Find Full Text PDFJ Orthop Trauma
May 2024
Department of Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, AL.
Objectives: To analyze the relationship between patient resilience and patient-reported outcomes after orthopaedic trauma.
Design: Retrospective analysis of prospectively collected data.
Setting: Single Level 1 Trauma Center.
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