Zuojin Pill attenuates Helicobacter pylori-induced chronic atrophic gastritis in rats and improves gastric epithelial cells function in GES-1 cells
Graphical abstract
Introduction
Chronic atrophic gastritis (CAG) is a universal disease of the digestive system and one of the most common health concerns worldwide. Helicobacter pylori (H. pylori) infection is the strongest risk factor for the development of gastric carcinogenesis (Crew and Neugut, 2006). H. pylori infection can induce CAG, which develops during the premalignant periods of intestinal metaplasia and dysplasia, eventually leading to gastric cancer (Correa and Piazuelo, 2012). At present, traditional treatment options for H. pylori, include conventional triple therapy, bismuth-based quadruple therapy and proton pump inhibitors (Wang et al., 2017a). Regardless of the type, these conventional therapies can cause a series of serious adverse reactions, such as abdominal pain and constipation, as well as a decline in eradication rates. Therefore, the discovery of novel and safe drugs for clinical treatment is greatly needed. Copious evidence from China has indicated that traditional Chinese medicine (TCM) possess unlimited potential in treating H. pylori-induced CAG. As alternative therapies, TCMs are gaining increasing attention as clinical treatments worldwide (Wang, 2014). Zuojin pill (ZJP), which was recorded in the Danxi's experiential therapy, has been used for more than 700 years to treat gastrointestinal diseases. However, the underlying mechanism of ZJP in the treatment of H. pylori-induced CAG remains unclear.
ZJP consists of Coptidis Rhizoma (CR) and Euodiae Fructus (EF) in a 6:1 ratio (w/w) and was initially reported as a treatment for gastrointestinal disorders in an ancient medicine treatise during China's Yuan Dynasty. CR is the dried rhizome of Coptis chinensis Franch. (Ranunculaceae), Coptis deltoidea C.Y. Cheng et Hsiao, or Coptis teeta Wall. (Chinese Pharmacopoeia Commission, 2015). In the clinic, it is often utilized to treat diarrhea, abdominal fullness, vomiting, jaundice, toothache, diabetes and eczema (Wang et al., 2019). EF is the dried immature fruit of Euodia rutaecarpa (Juss.) Benth. (Rutaceae), Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang (Chinese Pharmacopoeia Commission, 2015). EF is widely applied for the treatment of inflammation, headache, and hypertension (Xu et al., 2012). Alkaloids are the primary compounds of CR and EF, including berberine, coptisine, palmatine, evodiamine and rutaecarpine (Guo et al., 2019). ZJP is listed in the Chinese Pharmacopoeia (2015 edition) and is commonly prescribed for clinical patients suffering from esophagitis, gastritis, peptic ulcer and other disorders. To date, ZJP has been widely used in clinical applications. The mechanism by which ZJP treats CAG is still unclear. This study elucidates the effects of ZJP on H. pylori-induced CAG and the associated molecular mechanisms.
In this study, a H. pylori-induced CAG model was established to assess the therapeutic effectiveness and safety of ZJP in reducing inflammation and gastric mucosal cell injury. Gastric histopathology and serum inflammatory factors were assessed to evaluate the inflammatory levels and mucosal damage of CAG. The improvement of cell viability and morphology by ZJP was also detected by a cell model. In addition, the relative mRNA and protein expression levels of the JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway were detected to better understand the therapeutic effects and potential mechanism of ZJP on H. pylori-induced CAG.
Section snippets
Materials
Coptidis Rhizoma (Lot: 18011901) and Euodiae Fructus (Lot: 17021602) were purchased from Beijing Lvye Pharmaceutical Co., Ltd. (Beijing, China). Product quality inspection document numbers were CP-18-01-22 (Coptidis Rhizoma) and CP-17-02-11 (Euodiae Fructus). All inspection results demonstrated that the quality of Coptidis Rhizoma and Euodiae Fructus met the quality requirements of the Chinese Pharmacopoeia (2020 Edition). Omeprazole (positive drugs) was purchased from Astrazeneca
Analysis of chemical constituents of ZJP
Firstly, the active chemical composition existed in the aqueous extract of ZJP was comprehensively identified. Positive ES mode of the total ion chromatograms is listed in Fig. 1. Six chemical compounds, including magnoflorine, berberine, coptisine, palmatine, evodiamine and rutaecarpine were totally identified. In addition, the corresponding chemical constituents were also quantitatively analyzed. The results are shown in Table 3.
Effects of ZJP on macroscopic pathological
After the rats were infected with H. pylori for 8 weeks,
Discussion
ZJP is a commonly used traditional Chinese prescription that was first written by Zhu Zhenheng. ZJP has a wide range of pharmacological actions in the digestive system, including bacteriostic, anti-inflammatory and analgesic effects. The protection offered by ZJP against ethanol-induced mucosal lesions is indicative of its outstanding gastroprotective effect, which may be related with the regulation of the NF-кB signaling pathway (Wang et al., 2015a). An increasing number of studies have shown
Conclusion
Taken together, our results confirmed that ZJP exerts a therapeutic effect in the H. pylori-induced CAG model. We also found that histone demethylase plays a vital role in the CAG model. Importantly, ZJP prevented gastric mucosal injury by inhibiting H. pylori-induced inflammation via the JMJD2B/COX-2/VEGF axis and HMGB1/NF-kB signaling pathway. The results of this study suggest a potential role for ZJP in the treatment of CAG, which needs to be further investigated.
Author contributions
JW ([email protected]) conceived the study and wrote the manuscript. SW ([email protected]) collected and prepared the samples. XM ([email protected]) checked the data. YZ ([email protected]) designed the study and amended the paper. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.
Data availability of statement
The datasets used and/or analyzed of this study are from corresponding author upon reasonable request.
Ethics approval and consent to participate
The animal study was reviewed and approved by the Chinese PLA General Hospital. No human studies are presented in this manuscript. No potentially identifiable human images or data is presented in this study.
Declaration of competing interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements and funding
This study was supported by the National Key R&D Program of China, China [No. 2018YFC1704500], Science Foundation of Sichuan Education Department, China [No.18ZA0186], and Xihua University Talent Introduction Project, China (Z211060).
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