Original article
Mechanism of rutaecarpine on ethanol-induced acute gastric ulcer using integrated metabolomics and network pharmacology

https://doi.org/10.1016/j.biopha.2021.111490Get rights and content
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Highlights

  • RUT notably alleviated damage of gastric tissue triggered by ethanol.

  • RUT could remarkably ameliorate the level of GU-related factors.

  • potential metabolites involved in 9 metabolic pathways were identified.

  • 4 key target proteins that may regulate the specific metabolites were obtained.

  • The mechanism may be related to energy metabolism, oxidative stress, and inflammation.

Abstract

This study was aimed to explore the mechanism of rutaecarpine (RUT) on ethanol-induced gastric ulcer (GU) in mice by integrated approaches. At first, the efficacy was determined through the macroscopic and microscopic state of stomach tissue and the expression levels of GU-related factors. Then, the serum metabolomics method based on UPLC-Q-TOF/MS was used to explore the specific metabolites and metabolic pathways. Finally, the upstream key protein targets of these specific metabolites were analyzed by network pharmacology and verified by PCR to explore the potential mechanism. RUT alleviated the histological and pathological damage of gastric tissue caused by ethanol, and could remarkably ameliorate the level of GU-related factors. Subsequently, a total of 7 potential metabolites involved in 9 metabolic pathways were identified by metabolomics analysis. Then, a ‘component-targets-metabolites’ interaction network was constructed, and therefore 4 key target proteins (PLA2G1B, PDE5A, MIF and SRC) that may regulate the specific metabolites were obtained. This case was further verified by the results of PCR. ALL the above results strongly demonstrated that RUT exerted a gastroprotective effect against GU. And it is the first time to combine metabolomics combined with network pharmacology to elucidate the mechanism of RUT on GU, which may be related to the regulation of energy metabolism, oxidative stress, and inflammation, and these pathways may be regulated through the upstream protein PLA2G1B, PDE5A, MIF and SRC.

Abbreviations

GU
gastric ulcer
RUT
rutaecarpine
OME
omeprazole
UPLC–Q-TOF/MS
ultraperformance liquid chromatography with quadrupole time-of flight mass spectrometry
NSAIDs
non-steroidal anti-inflammatory drugs
PPI
proton pump inhibitors
CMC-Na
carboxymethylcellulose sodium
EGF
epidermal growth factor
NO
nitric oxide
ET-1
endothelin-1
UI
ulcer index
H&E
hematoxylin and eosin
ESI
electrospray ionization
PCA
principle component analysis
OPLS-DA
orthogonal projection to latent structures discriminate analysis
KEGG
kyoto encyclopedia of genes of genomes
HMDB
human metabolome database
TCMSP
traditional Chinese medicine systems pharmacology database and analysis platform
SEA
similarity ensemble approach
MBrole
metabolites biological role
RT-PCR
real‑time polymerase chain reaction
PLA2G1B
phospholipase A2 group IB
PDE5A
Phosphodiesterase 5 A
SRC
SRC proto-oncogene, non-receptor tyrosine kinase
MIF
Macrophage migration inhibitory factor

Keywords

Rutaecarpine
Acute gastric ulcer
Metabolomics
UPLC-Q-TOF/MS
Network pharmacology

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