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

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.

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

“…Several studies have reported that HES can ameliorates anxiety and depression-like behaviors by enhancing Glo-1 and activating the Nrf2/ARE pathway in the brain of diabetic rats and high glucose cultured SH-SY5Y cells [19]. HES is also regarded as a natural product for the prevention and treatment of cancer [20,21]. Moreover, HES and its derivatives may improve complex central nervous system diseases such as Alzheimer's disease (AD) [19,22].…”

Potential Natural Small Molecular Compounds for the Treatment of Chronic Obstructive Pulmonary Disease: An Overview

“…Silibinin, an active constitute of silymarin, could markedly reduce the production of fibrotic mediators in CS + LPS-exposed mice via suppression of TGF-β1/Smad 2/3 signaling ( Ko et al, 2017 ), as well as clearly decrease the pro-inflammatory mediators and airway mucus production expression in CS condensate-stimulated H292 cells and COPD mice model via the inhibition in ERK phosphorylation ( Park et al, 2016 ). Among dihydroflavones, Naringenin, hesperetin, and liquiritin apioside (LA) also exhibited positive effects on COPD, among which hesperetin could not only effectively alleviate inflammation and oxidative stress responses in CES-induced COPD mice by virtue of NAD-dependent protein deacetylase sirtuin-1(SIRT1)/PGC-1α/NF-κB signaling axis ( Wang et al, 2020 ), but also suppress the protein expression of AKT1, IL6, VEGFA, and MMP9 and up-regulate TP53 to reduce the risk of COPD progressing to lung cancer ( Zhou et al, 2021 ). Besides, LA offered protection to lung epithelial cell from CS-induced injuries by inhibiting the transforming growth factor- β (TGF-β) and tumor necrosis factor-α (TNF-α) expression and increasing anti-oxidative levels of glutathione (GSH) ( Guan et al, 2012 ).…”

Hesperidin Reversed Long-Term N-methyl-N-nitro-N-Nitroguanidine Exposure Induced EMT and Cell Proliferation by Activating Autophagy in Gastric Tissues of Rats

“…Hesperidin is a multi-effect citrus flavone, and the most abundant polyphenol in citrus fruits and traditional Chinese medicine [26,27]. Studies have confirmed that hesperidin has minimal or no side effects [28] and has an anti-cancer effect in a variety of cancers, such as gastric cancer [29,30], breast cancer [27], and lung cancer [31,32]. Although the role of hesperidin's anti-cancer activity in different cancer has been studied, limited work has been conducted on its role in MNNG-induced gastric cancer.…”