Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies

Siyu Zhao, Zhenli Liu, Menglei Wang, Dan He, Linlin Liu, Yisong Shu, Zhiqian Song, Hui Li, Yuanyan Liu*, Aiping Lyu

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

41 Citations (Scopus)


Background: The inflammatory response has a complex pathogenesis; thus, it is a critical contributor to the development and complication of many diseases. Zhishi and Zhiqiao are famous Citrus herbal medicines that are rich in bioactive phenolic constituents with multiple anti-inflammatory activities. Purpose: Establishment of a multi-component-target-pathway network strategy to investigate the usage of Zhishi and Zhiqiao on inflammatory diseases can provide a reference for mechanisms of traditional Chinese medicine (TCM). Study Design: A multi-component-target-pathway network strategy was constructed to elucidate the various antiinflammatory effects of Zhishi and Zhiqiao by integrating multi-constituent determination, network pharmacology, molecular mechanisms in cells and integrated metabolomics in animals. Methods: Based on the quantitatively determined global and characteristic chemical profiles of Zhishi and Zhiqiao, the component-target-pathway network was predicted by network pharmacology coupled with text mining and docking. The potential antiinflammatory mechanism of the various components in Zhishi and Zhiqiao were verified using LPS-induced inflammatory responses in RAW 264.7 cells. The different metabolic regulating effects of Zhishi and Zhiqiao against an LPS-induced inflammation model were investigated using a plasma metabolomics strategy. Results: The molecular mechanism of Zhishi mainly suppressed the MAPK signaling pathway, whereas Zhiqiao emphasized the PPAR-AKT signaling pathways simultaneously to block the inflammatory process. Meanwhile, Zhishi and Zhiqiao both exhibited an anti-inflammatory effect by inhibiting the NF-κB signaling pathway to reduce the production of inflammatory mediators. In the metabolomics study, Zhishi and Zhiqiao exhibited variant corrections of the disordered metabolic pathways through amino acid metabolism, glycometabolism and lipid metabolism. Conclusion: All of these results indicate that Zhishi and Zhiqiao, in a diversified mixture, exert their anti-inflammatory effect through variant pathways. These findings can assist in developing the use of Zhishi and Zhiqiao for inflammatory diseases.

Original languageEnglish
Pages (from-to)61-72
Number of pages12
Publication statusPublished - 15 Nov 2018

Scopus Subject Areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

User-Defined Keywords

  • Anti-inflammatory mechanism
  • Metabolomics
  • Network pharmacology
  • Zhiqiao
  • Zhishi


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