Protective Effect of Berberine on Acute Gastric Ulcer by Promotion of Tricarboxylic Acid Cycle-Mediated Arachidonic Acid Metabolism

Abstract

Background and Objective

Peptic ulcer is a high incidence gastrointestinal disease in China. Berberine (BBR) is a natural product isolated from the Chinese herb Coptis chinensis Franch that has protective effects in digestive diseases. We aimed to evaluate the ability of BBR to attenuate acute gastric ulcer induced by one-time administration of ethanol in the rat.

Methods

Tissue pathological morphology, macroscopic score, ulcer healing rate, and serum levels of the inflammatory cytokines nitric oxide (NO), interleukin-6 (IL-6), and prostaglandin E2 (PGE2), and anti-inflammatory interleukin-10 (IL-10) were used to determine the efficacy of BBR and evaluated to identify the optimal dosage. Subsequently, transcriptome and metabolome sequencing were conducted in Control, Model, and optimal dosage groups to explore the pathogenesis of the disease and the mechanism of action of the drug. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), as well as those of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined by enzyme-linked immunosorbent assay to verify the results of transcriptomics and metabolomics analyses.

Results

BBR significantly improved the pathological morphology of gastric ulcers, increased the macroscopic score and healing rate, decreased serum levels of NO, IL-6, and PGE2, and increased serum levels of IL-10, thus effectively alleviating gastric ulcer severity. Transcriptome results showed that the therapeutic effect of BBR was mainly mediated by the arachidonic acid metabolism pathway at the gene level, which is closely associated with inflammation and increased levels of reactive oxygen species (ROS). The differentially accumulated metabolite prostaglandin E1, which is a negative regulator of ROS, was significantly up-regulated after BBR administration. The validation results indicated that BBR pretreatment increased SOD and GSH-Px enzyme activities, while reducing levels of the oxidative products MDA and MPO.

Conclusion

This study demonstrated that BBR exerts a protective effect on acute gastric ulcer by promoting tricarboxylic acid cycle-mediated arachidonic acid metabolism.

Graphical Abstract

Keywords:

• Berberine
• acute gastric ulcer
• transcriptome
• untargeted metabolomics

Abbreviations

AA, arachidonic acid; ANOVA, analysis of Variance; BBR, berberine; COX, cyclooxygenases; CYP, cytochrome P450s; DAMs, Differentially Accumulated Metabolites; DEGs, differentially expressed genes; ELISA, enzyme linked immunosorbent assay; GO, Gene Ontology; GSH-Px, glutathione peroxidase; HE, hematoxylin-eosin; HMDB, human metabolome database; IL-4, interleukin-4; IL-6, interleukin-6; IL-10, interleukin-10; JAK, janus kinase; KEGG, Kyoto Encyclopedia of Genes and Genomes; LOX, lipoxygenases; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MPO, myeloperoxidase; NF-κB, nuclear factor kappa B; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory drugs; PCA, principal components analysis; PGs, prostaglandins; PGE1, prostaglandin E1; PLS-DA, partial least squares discriminant analysis; PUFA, polyunsaturated fatty acid; QC, quality control; R2, R squared; RNA, ribonucleic acid; ROS, reactive oxygen species; SD, standard deviation; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TCA cycle, reactive oxygen species; Th17, T helper cell 17; TXA2, thromboxane A2.

Data Sharing Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The animal study was reviewed and approved by the Institutional Animal Care and Use Committee and Animal Ethics Committee of the Institute of Chinese Materia Medica, with approval number 2023B018. All the applied procedures followed the Chinese guidelines for the welfare of the laboratory animals (GB/T 35823-2018).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors have read and approved the final submitted manuscript.

Disclosure

The authors declare that they have no competing interest.

Additional information

Funding

The authors gratefully acknowledge the financial support from, the National Natural Science Foundation of China (No. 82104480), the Fundamental Research Funds for the Central Public Welfare Research Institutes (Nos. ZZ14-YQ-060, and ZZ16-ND-10-19), and the Young Elite Scientists Sponsorship Program by CAST (NO.2021-QNRC2-B29), and Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A04313).