Study on the Mechanism of Fufang E'Jiao Jiang on Precancerous Lesions of Gastric Cancer Based on Network Pharmacology and Metabolomics

Abstract

Ethnopharmacological relevance: Fufang E'jiao Jiang (FEJ) is a prominent traditional Chinese medicine prescription, which consists of Colla corii Asini (Donkey-hide gelatin prepared by stewing and concentrating from the hide of Equus asinus Linnaeus.), Radix Codonopsis Pilosulae (the dried root of Codonopsis pilosula (Franch.) Nannf.), Radix Ginseng Rubra (the steamed and dried root of Panax ginseng C.A. Mey.), Fructus Crataegi (the ripe fruits of Crataegus pinnatifida Bunge) and Radix Rehmanniae Preparata (the steamed and sun dried tuber of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & C.A. Mey.). It is a popularly used prescription for 'nourishing Qi and nourishing blood'.

Aim of the study: To explore the potential mechanism of FEJ on rats with precancerous lesion of gastric cancer with Qi and blood deficiency by combining network pharmacology and metabolomics.

Methods: Traditional Chinese Medicine Systems Pharmacology and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine were used to identify the ingredients and potential targets of FEJ. GeneCards database was used to define PLGC-associated targets. We built a herb-component-disease-target network and analyzed the protein-protein interaction network. Underlying mechanisms were identified using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. In addition, 40% ethanol, N-methyl-N'-nitro-N-nitroguanidine and irregular eating were used to establish PLGC rats model. We also evaluated the efficacy of FEJ on MNNG-induced PLGC rats by body weight, histopathology, blood routine and cytokine levels, while the predicted pathway was determined by the Western blot. Ultra-performance liquid chromatography-tandem mass spectrometry-based serum non-targeted metabolomics was used to select potential biomarkers and relevant pathways for FEJ in the treatment of PLGC.

Results: Network pharmacology showed that FEJ exhibited anti-PLGC effects through regulating ALB, TNF, VEGFA, TP53, AKT1 and other targets, and the potential pathways mainly involved cancer-related, TNF, PI3K-AKT, HIF-1, and other signaling pathways. Animal experiments illustrated that FEJ could suppress inflammation, regulate gastrointestinal hormones, and inhibit the expression of PI3K/AKT/HIF-1α pathway-related proteins. Based on serum non-targeted metabolomics analysis, 12 differential metabolites responding to FEJ treatment were identified, and metabolic pathway analysis showed that the role of FEJ was concentrated in 6 metabolic pathways.

Conclusion: Based on network pharmacology, animal experiments and metabolomics, We found that FEJ might ameliorate gastric mucosal injury in PLGC rats by regulating gastrointestinal hormones and inhibiting inflammation, and its mechanism of action is related to the inhibition of excessive activation of PI3K/AKT/HIF-1α signaling pathway and regulation of disorders of body energy metabolism. This comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in Traditional Chinese Medicine .

Note:
Funding Information: This work was supported by the National Key Research and Development Program of China (2018YFC1706300,2018YFC17063003), the Major Projects in Gansu Province (21ZD4FA013), the Talent Innovation and Entrepreneurship Project of Lanzhou (2017-RC115, 2020-RC-41), the Taishan Industry Leading Talents (TSCY20180234).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All procedures were performed according to the code of ethics of the World Medical Association and approved by the Ethics Committee of School of Pharmacy, Lanzhou University.

Keywords: Fufang E'jiao Jiang, Precancerous lesions of gastric cancer, Network pharmacology, metabolomics