A plant‐derived glucocorticoid receptor modulator with potency to attenuate the side effects of glucocorticoid therapy. (13th October 2022)

• Record Type: Journal Article
• Authors: Wang, Yixuan; Gao, Jian; Yu, Ying; Zhou, Lin; Wang, Miao; Xue, Wenwen; Liu, Bo; Wu, Xudong; Wu, Xuefeng; Gao, Huiyuan; Shen, Yan; Xu, Qiang
• Is Part Of: British journal of pharmacology. Volume 180:Number 2(2023)
• Page Start: 194
• Page End: 213
• Publication Date: 2022-10-13
• Subjects: ant‐inflammation -- caesaldekarin e -- dimerization -- EED -- glucocorticoid receptor -- side effects; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15957
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and purpose: Continuous efforts have been made to move towards maintaining the beneficial anti‐inflammatory functions of glucocorticoids (GCs) while minimizing side effects. Here, we investigated the selective glucocorticoid receptor (GR) modulator‐like properties of a plant‐derived compound caesaldekarin e (CA‐e). Experimental approach: The therapeutic efficacy of CA‐e was evaluated in several mouse models, including dextran sulfate sodium‐induced colitis, ovalbumin‐induced lung allergic inflammation, imiquimod‐induced psoriasis‐like skin inflammation and skin atrophy. The action of CA‐e targeting the GR was analysed using molecular docking, cellular thermal shift assays and microscale thermophoresis. Other methods included DNA–protein pull‐down assays and mass spectrometry. Key results: CA‐e selectively inhibited positive GC response element ((+) GRE)‐mediated direct transactivation while maintaining and even enhancing the anti‐inflammatory effects of treatment with dexamethasone. CA‐e, alone and in combination with dexamethasone, efficiently alleviated inflammation in several mouse models with milder side effects compared with dexamethasone alone. Mechanistically, CA‐e inhibited the formation of dimers by binding to the dimerization interface located in the ligand‐binding domain of GR and facilitated embryonic ectoderm development that is involved in the regulation of transcriptional repression to compete for binding to (+) GRE, eventually leading to the repression of (+) GRE‐regulated genes. In addition, CA‐e repressed NF‐κB‐dependent genes by enhancing the interaction between GR and p65. Conclusions and implications: Our results reveal that CA‐e is a novel GR modulator with strong potency to attenuate the side effects of GC therapy and can be used as a potential molecular tool for deciphering GR signalling.