Dichloromethane extract from aerial parts of Ferula sinkiangensis prevents anhydrous ethanol-induced acute gastric ulcer by regulating PI3K-Akt/JNK/Nrf2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula sinkiangensis K.M.Shen (F. sinkiangensis) is a local medicinal material unique to Xinjiang, China, and has been used in traditional Chinese medicine, Xinjiang Uyghur medicine, and Kazakh medicine. According to the Pharmacopoeia of the People's Republic of China, it has the functions of eliminating accumulation, resolving symptoms, dispersing lumps and killing insects, and is often used in the treatment of gastrointestinal diseases.

AIM OF THE STUDY: To investigate the protective effect of the aerial parts of F. sinkiangensis on acute gastric ulcer by UHPLC-Q-Orbitrap-MS/MS technology, pharmacodynamic evaluation, network pharmacology and molecular biology experiments, and to explore its pharmacodynamic material basis and potential molecular mechanism against gastric ulcers.

MATERIALS AND METHODS: UHPLC/MS technology was used to identify the common compounds in F. sinkiangensis resin (EEFR) and its aerial parts (DEAF) in order to detect the similarity of their components. After 7 days of pre-administration, the mouse model of acute gastric ulcer was established. The effects of DEAF on anti gastric ulcer activity were systematically evaluated by injury index analysis, histopathological examination, and changes in cytokine levels and enzyme activities. At the same time, network pharmacology research was carried out for the identified compounds, and the core targets and pathways of DEAF anti-gastric ulcer were screened, and the combination of compounds and targets was simulated by molecular docking. Finally, Western blot was used to verify the core pathway.

RESULTS: 20 identical chemical constituents, including Ferulic acid, Coumarin, Isoferulic acid and Farnesiferol A, etc. were identified in EEFR and DEAF by UHPLC/MS, and the potential active ingredients of the anti-gastric ulcer activity of DEAF was preliminarily identified. The pharmacodynamic results showed that DEAF significantly reduced the content of MDA, inhibited MPO activity, and increased SOD activity, while reducing the content of GAS, IL-6 and TNF-α and increasing the content of IL-10. This indicates that DEAF has excellent anti-gastric ulcer activity, and the anti-gastric ulcer effect of DEAF was comparable to that of EEFR. The network pharmacology analysis showed that PI3K-Akt and MAPK signaling pathway played an important role in the treatment of gastric ulcer by DEAF. Further molecular biological experiments confirmed that DEAF could inhibit the expression of p-Akt/Akt, p-JNK/JNK and Keap-1, and promote the expression of Bcl-2/Bax, Nrf2 and HO-1, revealing the potential anti gastric ulcer mechanism of DEAF.

CONCLUSION: This study systematically evaluated the pharmacological effect of DEAF against gastric ulcers, preliminarily identified the potential active ingredients of DEAF against gastric ulcers, and revealed that it can exert an anti-gastric ulcer effect by regulating the PI3K-Akt/JNK/Nrf2 signaling pathway. The research results provide a theoretical basis for the anti-gastric ulcer activity of the aerial parts of F. sinkiangensis, which is conducive to the subsequent research on the aerial parts.