GR-mediated anti-inflammation of α-boswellic acid: Insights from in vitro and in silico studies. (September 2021)

• Record Type: Journal Article
• Authors: Zhang, Jie; Zhao, Jiarui; Sun, Yantong; Liang, Yuan; Zhao, Jingqi; Zou, Haoyang; Zhang, Tiehua; Ren, Li
• Is Part Of: Food and chemical toxicology. Volume 155(2021)
• Publication Date: 2021-09
• Subjects: α-Boswellic acid (α-BA) -- Anti-inflammation -- Glucocorticoid receptor (GR) -- Dissociative ligand; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112379
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Although multiple bioactivities of α-boswellic acid have been reported, the molecular mechanism of its anti-inflammatory action is not yet clear. Hence, glucocorticoid receptor (GR)-mediated anti-inflammation of α-boswellic acid was investigated in this work. Fluorescence polarization assay suggested that α-boswellic acid bound to GR with IC50 value of 658.00 ± 0.21 μM. Upon binding to α-boswellic acid, GR translocated from cytoplasm into nucleus of HeLa cells, facilitating sequential transcriptional regulation of GR-related genes. Luciferase reporter assay suggested that α-boswellic acid lacked GR transcriptional activity, indicating its potential as a dissociative GR ligand. Interestingly, α-boswellic acid selectively modulated the anti-inflammatory gene CBG (marker for GR transrepression), while leaving the "side-effect" gene TAT (marker for GR transactivation) unaffected in HepG2 cells. Furthermore, α-boswellic acid inhibited lipopolysaccharide-stimulated cytokines production in U937 macrophages, confirming its anti-inflammation property in vitro . Molecular docking showed that both hydrogen-bonding and hydrophobic interactions helped to stabilize α-boswellic acid-GR binding. Their binding stability was further confirmed in a 70-ns dynamics simulation. In summary, α-boswellic acid could bind to and translocate GR but did not induce glucocorticoid response element-mediated transcription. Since α-boswellic acid showed the dissociated characteristic that separated transrepression from transactivation, it might be a selective GR modulator against inflammatory disorders. Highlights: GR-mediated anti-inflammation of α-boswellic acid was investigated herein. α-Boswellic acid bound to and translocated GR but lacked GR transcriptional activity. α-Boswellic acid was a dissociative ligand that separated transrepression from transactivation. The in vitro anti-inflammation property of α-boswellic acid was confirmed in U937 macrophages. The interaction between α-boswellic acid and GR was explored by computer simulation.