Allergologia et Immunopathologia

Allergologia et Immunopathologia

Volume 48, Issue 5, September–October 2020, Pages 441-449
Allergologia et Immunopathologia

Original Article
Network pharmacology-based study of the protective mechanism of conciliatory anti-allergic decoction on asthma

https://doi.org/10.1016/j.aller.2019.12.011Get rights and content

Abstract

Background

This study aimed to explore the underlying anti-asthma pharmacological mechanisms of conciliatory anti-allergic decoction (CAD) with a network pharmacology approach.

Methods

Traditional Chinese medicine related databases were utilized to screen the active ingredients of CAD. Targets of CAD for asthma treatment were also identified based on related databases. The protein-protein interaction network, biological function and KEGG pathway enrichment analysis, and molecular docking of the targets were performed. Furthermore, an asthma mouse model experiment involving HE staining, AB-PAS staining, and ELISA was also performed to assess the anti-asthma effect of CAD.

Results

There were 77 active ingredients in CAD, including quercetin, kaempferol, stigmasterol, luteolin, cryptotanshinone, beta-sitosterol, acacetin, naringenin, baicalin, and 48 related targets for asthma treatment, mainly including TNF, IL4, IL5, IL10, IL13 and IFN-γ, were identified with ideal molecular docking binding scores by network pharmacology analysis. KEGG pathway analysis revealed that these targets were directly involved in the asthma pathway, Th1 and Th2 cell differentiation, and signaling pathways correlated with asthma (NF-κB, IL17, T cell receptor, TNF, JAK-STAT signaling pathways, etc.). Animal experiments also confirmed that CAD could attenuate inflammatory cell invasion, goblet cell hyperplasia and mucus secretion. The levels of the major targets TNF-α, IL4, IL5, and IL13 can also be regulated by CAD in an asthma mouse model.

Conclusion

The anti-asthma mechanism of CAD possibly stemmed from the active ingredients targeting asthma-related targets, which are involved in the asthma pathway and signaling pathways to exhibit therapeutic effects.

Introduction

Asthma is a common chronic respiratory disease especially endemic among children. According to the epidemiological survey by the World Health Organization in 2015, there were approximately 334 million people (4.9% of the world's population) suffering from asthma, and 250,000 people die of asthma prematurely each year.1 Recent years have witnessed a rising tendency of the morbidity and mortality of asthma worldwide, which poses a serious threat to human health and medical resources.2, 3 Studies have shown that many risk factors, including genetic susceptibility, allergens, air pollution, climate change, and respiratory virus infection are closely related to asthma.4 The pathogenesis of asthma is complex and has not been clearly elucidated, but the airway inflammation, accompanied by airway hyperresponsiveness and airway remodeling, are well-acknowledged characteristics of asthma. In the allergic reaction of asthma, allergens or pathogens that enter through body surfaces (e.g., the skin or lungs) are phagocytized by antigen-presenting cells, such as dendritic cells, which come to mature with the help of different cytokines.5 Th2 cells can produce pro-inflammatory cytokines, including IL4, IL5, and IL13 to exert their effects on many other cell types, including B cells, eosinophils, mast cells, epithelial cells, and airway goblet cells, and can also induce immunoglobulin E (IgE) production by B cells, resulting in the regulation of inflammation in asthma. Some drugs such as glucocorticoids, β2 receptor agonists, anti-cholinergic drugs, theophylline and leukotriene receptor antagonists, have also been approved for asthma treatment; however, the side effects and acquired resistance limit their clinical application.6, 7, 8 Thus, developing more safe and effective drugs for asthma therapy remains urgent and crucial.

Over thousands of years, traditional Chinese medicine has provided excellent therapeutic effects for asthma treatment in clinical practice.9 Traditional Chinese medicine possesses the advantages of “simple, convenient, economic, effective and individualized therapy”, which is in good accordance with the concept of modern medicine.10 Conciliatory anti-allergic decoction (CAD), a modified decoction comprising 10 herbs originating from the classical formula Xiao Chai Hu Tang by the well-known Chinese physician Zhang Zhongjing, has been widely used for asthma treatment in hospitals. Our former clinical research revealed that CAD can effectively reduce the frequency of asthma attacks and respiratory tract infection in children with asthma, enhance the immune function and anti-allergic ability of respiratory mucosa, and alleviate airway inflammation.11 However, the therapeutic mechanism of CAD in asthma still remains unclear.

Our current study was designed to explore the anti-asthma mechanisms of CAD. Network pharmacology study was applied in this work since it can provide a novel strategy to uncover the bioactive ingredients and underlying mechanisms of CAD from a systemic and holistic perspective.12 With the approach of network pharmacology, the active ingredients and related targets relevant to asthma were screened out, an ingredients-targets network and a protein–protein interaction (PPI) network were constructed, gene functional enrichment analysis, and molecular docking of the targets were conducted to clarify the pharmacological mechanisms of the targets and ingredients in CAD. Furthermore, animal experiments were also performed to validate the pharmacological mechanisms of CAD in an asthma mouse model.

Section snippets

Screening of the active ingredients of CAD

The CAD is composed of ten traditional Chinese herbs, including Radix Bupleuri (Chinese pinyin name Chaihu), Scutellariae Radix (Chinese pinyin name Huangqin), Pseudostellariae Radix (Chinese pinyin name Taizishen), Arum Ternatum Thunb. (Chinese pinyin name Banxia), Radix Salviae (Chinese pinyin name Danshen), Ephedra Herba (Chinese pinyin name Mahuang), Fritillariae Thunbrgii Bulbus (Chinese pinyin name Zhebeimu), Farfarae Flos (Chinese pinyin name Kuandonghua), Cicadae Periostracum (Chinese

Active ingredients and candidate targets in CAD

A total of 77 active ingredients were screened from the TCMSP database according to the ADME criteria, with six compounds in Radix Bupleuri, 13 compounds in Scutellariae Radix, three compounds in Pseudostellariae Radix, five compounds in Arum Ternatum Thunb., 27 compounds Radix Salviae, nine compounds in Ephedra Herba, one compound in Fritillariae Thunbrgii Bulbus, four compounds in Farfarae Flos, two compounds in Cicadae Periostracum, and 27 compounds in Licorice. Although the ingredients in

Discussion

Asthma is a chronic inflammatory disease of the airway with high morbidity and mortality globally. Numerous traditional Chinese medicines have excellent therapeutic effects for asthma, including CAD. Compared with the well-applied treatments in the clinic, the pharmacological mechanisms of CAD have not been researched clearly. In the present study, we applied network pharmacology to explore the anti-asthma mechanisms of CAD. A total of 77 active ingredients and 48 asthma-related targets of CAD

Funding

This work was funded by Zhejiang Provincia Natural Science Foundation of China (grant number LY15H270006).

Conflict of interest

The authors have no conflict of interest to declare.

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    1

    Xiaobo Xuan and Ziyan Sun contributed equally to this work.

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