Tiao‐Bu‐Fei‐Shen Formula Improves Glucocorticoid Resistance of Chronic Obstructive Pulmonary Disease via Downregulating the PI3K‐Akt Signaling Pathway and Promoting GRα Expression

Abstract

Objective. To predict and determine the mechanism through which Tiao-Bu-Fei-Shen (TBFS) formula improves glucocorticoid resistance in chronic obstructive pulmonary disease (COPD), using network pharmacology, molecular docking technology, and in vitro studies. Methods. The main active components and associated targets of TBFS were screened using the systems pharmacology database of traditional Chinese medicine database (TCMSP). The main COPD targets were retrieved from the Human Gene (GeneCards) and DrugBank databases. A protein-protein interaction (PPI) network was constructed using the protein interaction platform STRING and Cytoscape 3.6.1. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genome Pathway (KEGG) analyses were performed using the biological information annotation database Metascape. Molecular docking was performed using the AutoDock Vina software. THP-1 monocytes were treated with TBFS-containing serum and cigarette smoke extract (CSE) for 48 h, and cell proliferation in each group was determined using cell counting kit-8 (CCK-8). A COPD cell model was constructed by stimulating THP-1 monocytes with CSE for 12 h. A lentivirus vector for RNA interference of histone deacetylase 2 (HDAC2) gene was constructed and transfected into the THP-1 monocytes, and the transfection efficiency was verified using quantitative polymerase chain reaction (qPCR) and western blotting (WB). The expression of HDAC2 in each group of cells was detected using qPCR, and the expression of HDAC2, phosphoinositide-3 kinase (PI3K) p85α, glucocorticoid receptor α (GRα), and P-AKT1 in each group of cells was detected through WB. Results. A total of 344 TBFS active components, 249 related drug targets, 1,171 COPD target proteins, and 138 drug and disease intersection targets were obtained. Visual analysis of the PPI network map revealed that the core COPD targets of TBFS were AKT1, IL-6, TNF, TP53, and IL1-β. KEGG pathway enrichment analysis resulted in the identification of 20 signaling pathways as the main pathways involved in the action of TBFS against COPD, including the PI3K-Akt, TNF, and IL-17 signaling pathways. Molecular docking experiments revealed a strong binding capacity of kaempferol, luteolin, and quercetin to the ATK1 protein in TBFS, with quercetin performing the best. PCR results showed that treatment with TBFS significantly increased the expression levels of HDAC2 in the COPD model. WB results showed that TBFS treatment significantly increased the expression levels of GRα and HDAC2 in the COPD model, while reducing the expression levels of P-AKT1. Conclusion. TBFS treatment improves glucocorticoid resistance observed in COPD through downregulation of the PI3K-Akt signaling pathway and promotion of GRα expression.

Modulation of PI3K/AKT Signaling Pathway by Chinese Medicine Research Progress in Treating Chronic Obstructive Pulmonary Disease

“…Most of the Chinese medicines used in the treatment of COPD through the regulation of PI3K/Akt signaling pathway are based on "warming the lungs and kidneys, expelling drinks and removing blood stasis", which reflects the concept of "combination of tonic and tonic" in Chinese medicine, warming the kidneys and boosting yang, transforming the cold drinks and removing the stasis of blood, and then all the symptoms will be relieved. The Chinese medicines that are used more frequently are Huang Qin, Dang Shen, Ban Xia, Fu Ling, Chen Pi, Gan Cao, Huang Qi et al [54][55][56][57][58][59][60] which are of good application value and prospect in the prevention and control of COPD, providing the direction of the use of Chinese medicine in the treatment of COPD, providing new ideas and methods for the treatment of COPD, which is of certain significance, and providing theoretical foundations for the use of medicines in the future clinic and the direction of the research of COPD. However, the clinical effectiveness of Chinese medicine in treating COPD has been confirmed and widely accepted, but the research on the mechanism of PI3K/Akt signaling pathway on COPD is still in the early stage, and there are fewer clinical studies on the treatment of COPD through this pathway, and the intervention in the PI3K/Akt signaling pathway in the treatment of COPD is mostly confined to the animal experiments and the cellular level, so the development of related clinical research is the direction of future research.…”

“…↑ expression levels of GRα and HDAC2, ↓expression of PAKT1 [60] It is suggested that Qingfei Huatan decoction can treat COPD by regulating the expression of inflammatory factors and related proteins in PI3K/ Akt/mTOR pathway. Zhang et al [47] used CSE combined with repeated bacterial infections to establish a stable COPD rat model.…”

Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease

“…Xuefu Zhuyu Decoction (XFZYD) is also widely used in the treatment of COPD, and ( Hu et al, 2022 ) and others have found that XFZYD is effective in the treatment of COPD by interfering with the PI3K/Akt signaling pathway, improving oxidative stress and inflammatory responses, and relieving airway remodeling and ventilation disorders through web-based pharmacology and molecular docking experiments. In addition, Tiaobu Feishen (TBFS) was observed to reverse lung inflammation and airway remodeling ( Li et al, 2012 ), Zhou et al (2023) observed that TBFS has more effective in glucocorticoid-resistant COPD patients by modulating PI3K/Akt signaling to improve glucocorticoid resistance.…”