Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Mar 15, 2023; 15(3): 464-489
Published online Mar 15, 2023. doi: 10.4251/wjgo.v15.i3.464
Xiaojianzhong decoction prevents gastric precancerous lesions in rats by inhibiting autophagy and glycolysis in gastric mucosal cells
Jia-Xiang Zhang, Sheng-Chuan Bao, Juan Chen, Ting Chen, Hai-Liang Wei, Xiao-Yan Zhou, Jing-Tao Li, Shu-Guang Yan
Jia-Xiang Zhang, Sheng-Chuan Bao, Juan Chen, Ting Chen, Shu-Guang Yan, College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
Jia-Xiang Zhang, Sheng-Chuan Bao, Juan Chen, Ting Chen, Hai-Liang Wei, Xiao-Yan Zhou, Shu-Guang Yan, Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
Hai-Liang Wei, Department of General Surgery, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
Xiao-Yan Zhou, Department of Gastroenterology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
Jing-Tao Li, Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
Author contributions: Zhang JX performed the experiments, sample detection, data analysis and wrote the manuscript; Bao SC, Chen J, and Chen T helped with the performing and sample collection of the animal experiment; Yan SG, Li JT, Wei HL, and Zhou XY conceived and supervised the experiments and finalized the manuscript; all authors reviewed the manuscript.
Supported by the Shaanxi Science and Technology overall Planning and Innovation Project, No. 2016KTTSSF01-05; Key R & D projects in Shaanxi Province, No. 2022ZDLSF05-10; and Shaanxi University of Chinese Medicine Discipline Innovation Team Construction Project, No. 2019-YL-05.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Regulations for the Care and Use of Laboratory Animals in Shaanxi University of Chinese Medicine (Approval No. SCXK 2019-0004).
Conflict-of-interest statement: The authors declare that there is no conflict of interest in this study.
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at ysg2002. student@sina.com upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4. 0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shu-Guang Yan, PhD, Professor, College of Basic Medicine, Shaanxi University of Traditional Chinese Medicine, Century Avenue, Qindu District, Xianyang 712046, Shaanxi Province, China. ysg2002.student@sina.com
Received: August 16, 2022
Peer-review started: August 16, 2022
First decision: November 17, 2022
Revised: December 1, 2022
Accepted: January 16, 2023
Article in press: January 16, 2023
Published online: March 15, 2023
Processing time: 210 Days and 17.6 Hours
Abstract
BACKGROUND

Gastric precancerous lesions (GPL) precede the development of gastric cancer (GC). They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation, bacterial infection, and injury. Abnormalities in autophagy and glycolysis affect GPL progression, and their effective regulation can aid in GPL treatment and GC prevention. Xiaojianzhong decoction (XJZ) is a classic compound for the treatment of digestive system diseases in ancient China which can inhibit the progression of GPL. However, its specific mechanism of action is still unclear.

AIM

To investigate the therapeutic effects of XJZ decoction on a rat GPL model and the mechanisms underlying its effects on autophagy and glycolysis regulation in GPLs.

METHODS

Wistar rats were randomly divided into six groups of five rats each and all groups except the control group were subjected to GPL model construction for 18 wk. The rats’ body weight was monitored every 2 wk starting from the beginning of modeling. Gastric histopathology was examined using hematoxylin-eosin staining and Alcian blue-periodic acid-Schiff staining. Autophagy was observed using transmission electron microscopy. The expressions of autophagy, hypoxia, and glycolysis related proteins in gastric mucosa were detected using immunohistochemistry and immunofluorescence. The expressions of the following proteins in gastric tissues: B cell lymphoma/Leukemia-2 and adenovirus E1B19000 interacting protein 3 (Bnip-3), microtubule associated protein 1 light chain 3 (LC-3), moesin-like BCL2-interacting protein 1 (Beclin-1), phosphatidylinositol 3-kimase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), p53, AMP-activated protein kinase (AMPK), and Unc-51 like kinase 1 (ULK1) were detected using western blot. The relative expressions of autophagy, hypoxia, and glycolysis related mRNA in gastric tissues was detected using reverse transcription-polymerase chain reaction.

RESULTS

Treatment with XJZ increased the rats’ body weight and improved GPL-related histopathological manifestations. It also decreased autophagosome and autolysosome formation in gastric tissues and reduced Bnip-3, Beclin-1, and LC-3II expressions, resulting in inhibition of autophagy. Moreover, XJZ down-regulated glycolysis-related monocarboxylate transporter (MCT1), MCT4, and CD147 expressions. XJZ prevented the increase of autophagy level by decreasing gastric mucosal hypoxia, activating the PI3K/AKT/mTOR pathway, inhibiting the p53/AMPK pathway activation and ULK1 Ser-317 and Ser-555 phosphorylation. In addition, XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression.

CONCLUSION

This study demonstrates that XJZ may inhibit autophagy and glycolysis in GPL gastric mucosal cells by improving gastric mucosal hypoxia and regulating PI3K/AKT/mTOR and p53/ AMPK/ULK1 signaling pathways, providing a feasible strategy for the GPL treatment.

Keywords: Xiaojianzhong decoction; Gastric precancerous lesions; Autophagy; Glycolysis; Gastric mucosal cells; Herb

Core Tip: Xiaojianzhong Decoction is a classic compound for the treatment of digestive system diseases in ancient China, and it also shows good curative effect in the treatment of gastric precancerous lesions (GPL). Many studies have shown that the levels of autophagy and glycolysis influence the progression of GPL. Our study found that Xiaojianzhong Decoction can improve the pathological manifestations of gastric mucosa in GPL rats, and inhibits the expression of autophagy, glycolysis-related proteins and mRNA. Xiaojianzhong decoction (XJZ) prevented the increase of autophagy levels by decreasing gastric mucosal hypoxia, activating the phosphatidylinositol 3-kimase/protein kinase B/mammalian target of rapamycin pathway, inhibiting the p53/AMP-activated protein kinase pathway activation and Unc-51 Like kinase 1 (ULK1) Ser-317 and Ser-555 phosphorylation. In addition, XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression.