Xiaojianzhong decoction attenuates aspirin-induced gastric mucosal injury via the PI3K/AKT/mTOR/ULK1 and AMPK/ULK1 pathways

Pharm Biol. 2023 Dec;61(1):1234-1248. doi: 10.1080/13880209.2023.2243998.

Abstract

Context: Xiaojianzhong decoction (XJZD), classically prescribed in Chinese medicine, has protective and healing effects on gastric mucosal injury. However, the exact mechanism behind this effect remains unclear.

Objective: To investigate the effect of XJZD on gastric mucosal injury and explore its underlying mechanisms.

Materials and methods: C57BL/6 mice were randomized into six groups (n = 10): the control group receiving sterile water, the model (aspirin 300 mg/kg), the XJZD high-dose (12 g/kg), XJZD medium-dose (6 g/kg), XJZD low-dose (3 g/kg) and omeprazole (20 mg/kg) groups, by gavage daily for 14 days. The area of gastric mucosal injury, mucosal injury index and degree of histopathological damage were analysed. Gastric mucosal epithelial cell apoptosis was detected. Epithelial cell autophagy was observed. The expression levels of tight junction proteins and proteins related to apoptosis, autophagy and the pentose phosphate pathway were analysed.

Results: The results showed that after treatment with XJZD (12, 6 and 3 g/kg), the mucosal injury area was reduced (83.4%, 22.6% and 11.3%), the expression level of ZO-1 and occludin was up-regulated, the apoptosis rate of epithelial cells was reduced (40.8%, 25.4% and 8.7%), the expression of autophagy-related proteins LC3 and Beclin1 was decreased and the expression of p62 was increased, the PI3K/AKT/mTOR/ULK1(ser757) signalling pathway was activated, and the AMPK/ULK1(ser317) signalling pathway was inhibited. In addition, XJZD can antagonize the imbalance of redox homeostasis caused by aspirin and protect the gastric mucosa.

Discussion and conclusions: XJZD protects against aspirin-induced gastric mucosal injury, implying it to be a potential therapeutic agent.

Keywords: Traditional Chinese medicine; apoptotic; autophagy; drug-induced gastric injury; redox homeostasis.

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Aspirin* / toxicity
  • Drugs, Chinese Herbal* / pharmacology
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Stomach Diseases* / chemically induced
  • Stomach Diseases* / drug therapy
  • TOR Serine-Threonine Kinases

Substances

  • AMP-Activated Protein Kinases
  • Aspirin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Drugs, Chinese Herbal

Grants and funding

This work was supported by the Shaanxi Science and Technology overall Planning and Innovation Project (Project number: 2016KTTSSF01-05), the Key R&D projects in Shaanxi Province (Project number: 2022ZDLSF05-10) and the Shaanxi University of Chinese Medicine Discipline Innovation Team Construction Project (Grant No. 2019-YL-05), Innovation Team of Shaanxi Science and Technology Department (Project number: 2022TD-55), Innovation Team of Shaanxi Provincial Administration of Traditional Chinese Medicine (No. 2022-SLRH-LJ-002) and the Qin Chuangyuan Traditional Chinese Medicine Innovation Research and Development Transformation Project (Project number: 2022-QCYZH-024).