Ursolic and oleanolic acids suppress MNNG induced malignant transformation of human gastric mucosal epithelium by regulating the PI3 K/AKT pathway.

Berberine hydrochloride (Ber) is the primary active compound in the traditional Chinese medicine 'Huanglian'. Ursolic acid (UA) and oleanolic acid (OA) are the main triterpenoids extracted from 'Tengligen'. Notably, both Ber and UA/OA exhibit antitumour activity. This study aimed to investigate the role of Ber and UA/OA in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced malignant transformation of the human gastric mucosal epithelium and explore the underlying mechanism. Using network pharmacology and molecular docking, we analysed the molecular mechanisms of Ber and UA/OA in treating precancerous lesions of gastric cancer (PLGC). Our results revealed that Ber and UA/OA regulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. To simulate PLGC, we established malignant cells (MCs) as an in vitro cellular model using MNNG. Our results showed that Ber and UA/OA significantly inhibited the epithelial-mesenchymal transition in MCs. Notably, UA/OA more effectively inhibited MC-colony formation and cell invasion and induced MC apoptosis than Ber. Mechanistically, UA/OA significantly suppressed the PI3K/AKT/nuclear factor-kappa B (NF-κB) p65/NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) pathway. However, the PI3K/AKT agonist 740YP reversed these effects and attenuated UA/OA-induced apoptosis. In conclusion, UA/OA significantly inhibited cell-clone formation and invasion, induced apoptosis, and inhibited the malignant transformation of MCs by regulating the PI3K/AKT/NF-κB p65/NLRP3 pathway.