Glycyrrhizic Acid Attenuates Pulmonary Fibrosis of Silicosis by Inhibiting the Interaction between HMGB1 and BRG1 through PI3K/Akt/mTOR Pathway

Abstract

Purpose: High mobility group protein 1 (HMGB1) is a highly conserved DNA-binding nuclear protein that participates in the occurrence and development of silicosis. HMGB1 binds to its specific receptor and activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B, (PKB; Akt)/mammalian target of rapamycin (mTOR) pathway. Brahma-related genes 1 (BRG1; SMARCA4) is the core subunit of SWI/SNF. HMGB1 activates the Akt pathway through BRG1 to promote the proliferation of prostate cancer. Glycyrrhizic acid is a new pharmacological inhibitor of HMGB1, which may inhibit the occurrence and development of silicosis. We speculate that glycyrrhizic acid inhibits the interaction between HMGB1 and BRG1 through the PI3K/Akt/mTOR pathway to affect the progression of silicosis. Methods: We carried out an in vitro study and stimulated A549 with TGF-β1 to establish an epithelial–mesenchymal transition (EMT) model, knocked down the HMGB1 and BRG1 genes in cells, observed the expression of EMT markers, and detected the interaction between HMGB1 and BRG1 by co-immunoprecipitation. In vivo, we injected glycyrrhizic acid into the mouse silicosis model to inhibit the expression of HMGB1. Results: Both HMGB1 and BRG1 were highly expressed in the process of EMT. After knocking down HMGB1 and BRG1, the process of EMT was inhibited through the PI3K/Akt/mTOR pathway, and their expressions were influenced by each other. HMGB1 and BRG1 interact with each other in A549 cells. HMGB1 and BRG1 are also highly expressed in the mouse silicosis model, and glycyrrhizic acid can inhibit the expression of HMGB1/BRG1 through the PI3K/Akt/mTOR pathway. Conclusion: Glycyrrhizic acid can inhibit the interaction between HMGB1 and BRG1 through the PI3K/Akt/mTOR pathway to affect the progression of silicosis.

Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis

“…2 ), suggesting that BRG1 may act as a positive mediator of fibrotic responses downstream of TGF-β1. Consistent with our study, Gong et al [ 16 ], Niu et al [ 37 ], Yang et al [ 38 ] have found that BRG1 is a downstream of TGF-β1 in various cell types. Of note, we also notice that the mRNA level of BRG1 cannot be augmented by TGF-β1 stimulation (data not shown), implying that TGF-β1 might regulate the expression of BRG1 in a post-transcriptional pathway manner in peritoneal mesothelial cells.…”

“…2), suggesting that BRG1 may act as a positive mediator of fibrotic responses downstream of TGF-β1. Consistent with our study, Gong et al [16], Niu et al [37], Yang et al [38] have found that BRG1 is a downstream of TGF-β1 in various cell types. Of Co-immunoprecipitation demonstrated that the interaction between BRG1 and H3K14ac was decreased after the mutation of BRG1 N1540.…”

Investigating HMGB1 as a potential serum biomarker for early diabetic nephropathy monitoring by quantitative proteomics

“… 37 When the cell is stimulated by various kinds of damage, it releases itself into the extracellular space as a damage-associated molecular pattern (DAMP) molecule that participates in inflammatory responses, differentiation and migration of cells. 38 , 39 HMGB1, as a pathogenic factor in DN, interacts with TLRs and RAGE, which are its receptors on the cytomembrane, activating innate immune responses by promoting nuclear translocation of transcription factors. 40 , 41 , 42 Interestingly, high levels of HMGB1 in serum from patients with DN can induce podocyte autophagy, apoptosis, and EMT.…”

Integrated network analysis and metabolomics reveal the molecular mechanism of Yinchen Sini decoction in CCl4-induced acute liver injury

“…Phosphorylated AKT enhances the nuclear transcription of NFκB and the release of pro-inflammatory cytokines, and these effects are blocked by PI3K inhibitors, thereby inhibiting hepatocyte apoptosis, reducing inflammation, and alleviating liver damage ( Gong et al, 2020 ). Glycyrrhizic acid ( Niu et al, 2022 ), scoparone ( Liu et al, 2020 ), isorhamnetin ( Li et al, 2015 ), quercetin ( Yang et al, 2020 ), and luteolin ( Jiang et al, 2023 ) have been reported to regulate the PI3K/AKT axis to improve ALI. And these metabolites were detected in YCSND in our study.…”