The mechanism and candidate compounds of aged citrus peel (chenpi) preventing chronic obstructive pulmonary disease and its progression to lung cancer - PubMed (original) (raw)

The mechanism and candidate compounds of aged citrus peel (chenpi) preventing chronic obstructive pulmonary disease and its progression to lung cancer

Lin Zhou et al. Food Nutr Res. 2021.

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is an important risk factor for developing lung cancer. Aged citrus peel (chenpi) has been used as a dietary supplement for respiratory diseases in China.

Objective: To explore the mechanism and candidate compounds of chenpi preventing COPD and its progression to lung cancer.

Methods: The active components and potential targets of chenpi were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Disease-associated targets of COPD and lung cancer were collected in the Gene Cards and TTD database. The component-target network and PPI network were constructed using the Cytoscape 3.8.0 software. David database was used for GO and KEGG enrichment analysis. The main active components were verified by using the autodock Vina 1.1.2 software. Mouse lung cancer with COPD was induced by cigarette smoking (CS) combined with urethane injection to confirm preventing the effect of hesperetin (the candidate compound of chenpi) on COPD progression to lung cancer and its underlying mechanisms.

Results: The network analysis revealed that the key active components of chenpi (nobiletin, naringenin, hesperetin) regulate five core targets (AKT1, TP53, IL6, VEGFA, MMP9). In addition, 103 potential pathways of chenpi were identified. Chenpi can prevent COPD and its progression to lung cancer by getting involved in the PI3K-Akt signaling pathway and MAPK signaling pathway. Molecular docking indicated that hesperetin had better binding activity for core targets. In mouse lung cancer with COPD, treatment with hesperetin dose-dependently improved not only lung tissue injury in COPD but also carcinoma lesions in lung cancer. Meanwhile, hesperetin could suppress the protein expression of AKT1, IL6, VEGFA, MMP9 and up-regulate the protein expression of TP53, and thus reduced the risk of COPD progression to lung cancer.

Conclusion: Hesperetin is a candidate compound of chenpi that helps in preventing COPD and its progression to lung cancer by regulating AKT1, IL6, VEGFA, MMP9 and TP53.

Keywords: chenpi; chronic obstructive pulmonary disease (COPD); hesperetin; lung cancer; network pharmacology.

© 2021 Lin Zhou et al.

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Conflict of interest statement

The authors have declared no conflict of interest. This study was supported by the Youth Natural Science Foundation of Henan Province of China. (No. 212300410109), the Postgraduate Education Innovation and Quality Improvement Project of Henan University (No. SYL19060139-140, SYL18060136-137, SYL20060159-160) and the Scientific Research Foundation for Postdoctoral Science Foundation of Henan Province of China.

Figures

Fig. 1

Fig. 1

The research scheme in this experiment.

Fig. 2

Fig. 2

The 2D structure of active components in chenpi. (a) The 2D structure of nobiletin. (b)The 2D structure of hesperetin. (c) The 2D structure of citromitin. (d) The 2D structure of naringenin. (e) The 2D structure of sitosterol.

Fig. 3

Fig. 3

The network of _chenpi_-COPD and lung cancer intersection targets. (a) The components–targets network. A network with 174 nodes and 342 edges linking five compounds in chenpi and 169 target genes. The red nodes represent the targets, the purple nodes represent the compounds. (b) Venn diagram. (c) The PPI network containing 169 nodes and 1,992 edges. The node represents the protein, and the edge represents the interaction between proteins.

Fig. 4

Fig. 4

GO and KEGG pathway enrichment analysis. (a) Histogram of GO enrichment analysis. (b) Histogram of KEGG enrichment analysis. (c)Visualization of KEGG enrichment analysis.

Fig. 5

Fig. 5

Pattern diagram of molecular docking. (a) Hesperetin-AKT1, (b) hesperetin-MMP9, (c) hesperetin-IL6, (d) naringenin-MMP9, (e) nobiletin-AKT1, (f) nobiletin-IL6.

Fig. 6

Fig. 6

The preventive efficacy of hesperetin on urethane and CS-induced lung cancer with COPD. (a) Schematic design of the experimental procedure. (b) Tidal volume (TV) in lung function. (c) The whole lung at 4 and 8 weeks after urethane injection and CS exposure to the naked eye. (d) HE staining of lung tissues. (e) Lung injury score. (f) Lung W/D ratio. (g) The number of lung nodes at 8 weeks. The data are presented as the mean ± SD (n = 10), the experiments were repeated three times and statistical significance was determined by a t test. *P < 0.05, **P < 0.01 vs. normal; #P < 0.05, ##P < 0.01 vs. the model.

Fig. 7

Fig. 7

Hesperetin regulates the core targets of COPD and lung cancer in urethane and CS-induced lung cancer with COPD. (a) Protein expression of core targets examined by western blot in COPD stage. (b) Protein expression of core targets examined by western blot in the lung cancer stage. The data are presented as the mean ± SD (n = 10), the experiments were repeated three times and statistical significance was determined by a t test. *P < 0.05, **P < 0.01 vs. normal; #P < 0.05, ##P < 0.01 vs. the model.

Fig. 8

Fig. 8

Hesperetin regulates the core targets of COPD and lung cancer in urethane and CS-induced lung cancer with COPD examined by immunofluorescence. The data are presented as the mean ± SD (n = 10), the experiments were repeated three times, and statistical significance was determined by a t test. *P < 0.05, **P < 0.01 vs. normal; #P < 0.05, ##P < 0.01 vs. the model.

Fig. 9

Fig. 9

Hesperetin as a candidate compound of chenpi prevents COPD and its progression to lung cancer by regulating AKT1, IL6, VEGFA, MMP9 and TP53 in mouse lung cancer with COPD induced by CS and urethane.

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