甘草酸通过抑制 HMGB1 与 BRG1 的相互作用，抑制 PI3K/Akt/mTOR 通路，减轻矽肺肺纤维化。
Glycyrrhizic Acid Attenuates Pulmonary Fibrosis of Silicosis by Inhibiting the Interaction between HMGB1 and BRG1 through PI3K/Akt/mTOR Pathway.
机构信息
Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
出版信息
Int J Environ Res Public Health. 2022 Jul 18;19(14):8743. doi: 10.3390/ijerph19148743.
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.
目的
高迁移率族蛋白 1（HMGB1）是一种高度保守的 DNA 结合核蛋白，参与矽肺的发生和发展。HMGB1 与特定受体结合并激活磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（PKB；Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）途径。Brahma 相关基因 1（BRG1；SMARCA4）是 SWI/SNF 的核心亚基。HMGB1 通过 BRG1 激活 Akt 途径，促进前列腺癌的增殖。甘草酸是 HMGB1 的一种新型药理学抑制剂，可能抑制矽肺的发生和发展。我们推测，甘草酸通过 PI3K/Akt/mTOR 途径抑制 HMGB1 与 BRG1 的相互作用，从而影响矽肺的进展。
方法
我们进行了一项体外研究，用 TGF-β1 刺激 A549 细胞建立上皮-间充质转化（EMT）模型，敲低细胞中的 HMGB1 和 BRG1 基因，观察 EMT 标志物的表达，并通过共免疫沉淀检测 HMGB1 和 BRG1 之间的相互作用。在体内，我们向矽肺模型小鼠注射甘草酸以抑制 HMGB1 的表达。
结果
在 EMT 过程中，HMGB1 和 BRG1 均高表达。敲低 HMGB1 和 BRG1 后，通过 PI3K/Akt/mTOR 途径抑制 EMT 过程，且两者相互影响。HMGB1 和 BRG1 在 A549 细胞中相互作用。HMGB1 和 BRG1 在小鼠矽肺模型中也高表达，甘草酸可通过 PI3K/Akt/mTOR 途径抑制 HMGB1/BRG1 的表达。
结论
甘草酸可通过 PI3K/Akt/mTOR 途径抑制 HMGB1 与 BRG1 的相互作用，从而影响矽肺的进展。
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