Identifying the active compounds and mechanism of action of Banxia Xiexin decoction for treating ethanol-induced chronic gastritis using network pharmacology combined with UPLC–LTQ–Orbitrap MS
Graphical abstract
Introduction
Gastritis is an inflammatory disease that includes injury to the gastric mucosa. It is typically associated with symptoms that include stomach pain, bloating and anorexia. Chronic gastritis has become a major threat to human health and is predominantly characterised by mononuclear inflammatory cells (Estevam et al., 2017). Excessive or chronic drinking of strong alcohol can induce gastric mucosa congestion, oedema and erosion, as well as acute or chronic gastritis (Bode and Bode, 1997; Shin et al., 2013). Alcohol may be converted to acetaldehyde and induce local toxicity in the gastrointestinal tract (Seitz et al., 1994). Meanwhile, inflammatory cytokines including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-2, and IL-8 are induced by ethanol (Ghare et al., 2011; Tanyeli et al., 2017). IL levels significantly increase the production of intercellular adhesion molecules (ICAMs) after alcohol ingestion, and there is a close relationship with serum ICAM-1 levels and alcohol intake (Sacanella et al., 1999). Lactate dehydrogenase (LDH) is significantly activated by aspirin, induces acute gastritis and contributes to the development of gastric lesions (Du et al., 2014). The inhibition of caspase-3 cleavage and the regulation of phosphatidylinositol-3-kinase (PI3K)/protein–serine–threonine kinase (Akt) transduction, nuclear factor-kappa B (NF-κB) activation and mitogen-activated protein kinase (MAPK) signalling play key roles in the process of gastric mucosal injury (Arab et al., 2019).
Banxia Xiexin decoction (BXD) has been used clinically for thousands of years, and it shows the characteristics of an effective multi-component, multi-target therapeutic with few side effects (Chen et al., 2015a,b). This formula is widely used to treat gastric motility disorders, gastritis, colitis and peptic ulcer by acting on the spleen and stomach (Lu et al., 2018). The prescription consists of several medicinal herbs or their parts (Pinellia Rhizoma, Glycyrrhizae Radix et Rhizoma, Scutellaria Radix, Coptidis Rhizoma, Ginseng Radix et Rhizoma, Zingiberis Rhizoma and Jujube Fructus). Previous studies showed that BXD contains multiple active components including berberine, baicalin, baicalein, wogonin, wogonoside, coptisine, palmatine, and ginsenosides (Wang et al., 2014; Yan et al., 2013). Berberine, which attenuates the B cell-activated factor-triggered Th17 response, exerts anti-inflammatory effects on Helicobacter pylori-induced chronic gastritis (Wu and Li, 2018). Baicalin and baicalein promote health by preventing H. pylori infection and interfering with H. pylori growth and virulence (Chen et al., 2018a,b). However, there are many complex ingredients in BXD, and its mechanism of action and targets for treating various diseases remains obscure.
Network pharmacology is a method used to study the regulation of diseases by multi-component drugs (Zhang et al., 2019; Zhu et al., 2018). It integrates system bioinformatics and omics methods to identify target proteins and signalling pathways associated with drug efficacy from an integral perspective and incudes characteristics of completeness, synergy and dynamics (Lim and Xie, 2019; Wu et al., 2018). Furthermore, surface plasmon resonance (SPR) technology may be applied to traditional Chinese Medicine (TCM), and high-throughput screening of bioactive components can be used to identify its multi-component chemicals. The most important advantage of SPR is the ability to monitor the dynamic process of biological macromolecules with compounds in real time (Aristotelous et al., 2015; Lago et al., 2018).
Consequently, the aim of the present study was to use an innovative strategy to identify the molecular mechanisms and potential targets of BXD using a systematic pharmacological approach, SPR, molecular mechanics simulation and experimental verification to gain insight into the therapeutic properties of BXD in treating ethanol-induced chronic gastritis.
Section snippets
Reagents and materials
Pinellia Rhizoma, Scutellaria Radix, Ginseng Radix et Rhizoma, Zingiberis Rhizoma, Coptidis Rhizoma, Glycyrrhizae Radix et Rhizoma and Jujube Fructus were selected based on the standards specified in the Chinese Pharmacopoeia and were purchased from the Shanghai Kang Qiao Chinese Medicine Tablet Co., Ltd. Wogonoside, wogonin, berberine, baicalin, baicalein, and glycyrrhetinic acid were purchased from Yuanye Biological (Shanghai, China). Enzyme-linked immunosorbent assay (ELISA) kits for IL-2,
Effects of BXD on ethanol-induced chronic gastritis in rats
The gastric mucosa of the normal group was not damaged. In contrast, erosion, ulcers and bleeding of the gastric mucosa were observed in the model group. The gastric mucosal damage of the BXD group was lower than that of the model group (Fig. 2A). H&E staining of the stomach tissues revealed that there was inflammation in the infiltrate of immune cells in the model group. Oedema and congestion were also apparent in the submucosal and intrinsic layers as well as incomplete submucosa. However,
Discussion
Chronic gastritis is the result of damage and inflammation in the gastric mucosa. Ethanol may disrupt the gastric mucosal barrier defence system and reduce the ability of the gastric mucosa to defend against the effects of gastric acid, leading to mucosal oedema, erosion, haemorrhage and necrosis (Ning et al., 2012). Treatment for alcoholic gastritis is limited, and some adverse reactions remain a major challenge (Bandyopadhyay et al., 2002). BXD has been used for the treatment of chronic
Conclusions
Based on the analysis of the serum components of BXD by molecular docking and compound–target network analysis, some active ingredients and target proteins were selected for SPR validation. KEGG pathway and PPI network analysis indicated that the NF-κB, HIF-1, PI3K-Akt, and JAK-STAT signalling pathways participate in the occurrence and treatment of ethanol-induced chronic gastritis. Furthermore, molecular docking and SPR methods were used to validate the interactions between key compounds and
Author statement
WJ wrote the original draft. KL performed the experiments. TW and YX analyzed the data. RA revised the manuscript. XW conceived of the study and designed the study. All authors read and approved the final version of the manuscript.
Funding
This work was supported by National Natural Science Foundation of China (grant No.81774183), and sponsored by Scientific Research Foundation of Shanghai University of Medicine and Health Sciences (grant number E3-0200-21-201011-34).
Declaration of Competing Interest
The authors report no declarations of interest.
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