Mechanisms of genipin-induced hepatotoxicity by using network pharmacology and transcriptomics

doi:10.19803/j.1672-8629.20210700

Abstract

Abstract: Objective To explore the mechanism of genipin-induced hepatotoxicity by network pharmacology and transcriptomics. Methods Network pharmacology: Potential targets of genipin were screened by searching TCMSP, Pharmapper, Stitch and CTD databases. Meanwhile, disease-related targets were retrieved from Disgenet, CTD, PharmGKB, GeneCards and NCBI Gene databases using “Chemical and drug-induced liver injury” as the keywords. STRING was used for target interaction analysis, while Cytoscape software was used to construct a genipin-hepatotoxic target-disease network model. Finally, DAVID was used to perform GO enrichment and KEGG pathway analysis of targets of genipin-induced hepatotoxicity. Transcriptomics: Human HepaRG cells were subjected to interventions by blank and genipin medium respectively for 24 h. The Illumina high-throughput sequencing platform was used for transcriptome sequencing and bioinformatics analysis. Results Network pharmacological screening showed that genipin could act on 142 targets, 112 of which were related to hepatotoxicity. According to the protein-protein interaction (PPI) network map, there were 92 nodes and 382 edges. Enriched analysis showed that the targets of genipin-induced hepatotoxicity were mainly concentrated in PI3K/Akt signaling pathway, TNF signaling pathway, FOXO signaling pathway and NF-κB signaling pathway. Differential genes of the genipin group and control group were compared with those of the gene database, and a false discovery rate (FDR) <0.01 and Fc (fold change) ≥4 were selected as screening conditions. A total of 1 160 differential gene were found. KEGG enrichment analysis showed that the differential genes were mainly involved in TNF signaling pathway, transcription disorders, and ribosome metabolism. TNF signaling pathway played a key role in genipin-induced hepatotoxicity as was evidenced by network pharmacological results. Conclusion Genipin-induced hepatotoxicity may be related to the TNF signaling pathway, which induces inflammation, oxidative stress and cell apoptosis.

Key words: genipin, hepatotoxicity, network pharmacology, transcriptomics

CLC Number:

WANG Xiaohui, ZHANG Fan, XIA Wenbin, WEI Yuhui. Mechanisms of genipin-induced hepatotoxicity by using network pharmacology and transcriptomics[J]. Chinese Journal of Pharmacovigilance, 2023, 20(2): 177-180.

References

[1] REN YQ, TIAN YR, LI C, et al.Cytotoxic effect of geniposide and its metabolite genipin on HepG2 cells and mechanism[J]. Chinese Pharmacological Bulletin(中国药理学通报),2016,32(12): 1755-1761.
[2] WEI LG, ZHANG HH, LI HF, et al.A comparative study on hepatotoxicity of geniposide,genipin,gardenia blue in vivo and vitro[J]. Chinese Archives of Traditional Chinese Medicine(中华中医药学刊),2019,37(2):311-314.
[3] CHEN GQ, GOEDDEL DV.TNF-R1 signaling: a beautiful pathway[J]. Science, 2002, 296(5573): 1634-1635
[4] FAN XF, LIN L, CUI BX, et al.Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: more friend than foe[J]. Pharmacol Res, 2020, (159): 104945.
[5] WANG JJ, CHEN L, LIANG ZB, et al.Genipin inhibits LPS-induced inflammatory response in BV2 microglial cells[J]. Neurochem Res, 2017, 42(10): 2769-2776.
[6] LI YW, LI L, HOLSCHER CH.Therapeutic potential of genipin in central neurodegenerative diseases[J]. CNS Drugs, 2016, 30(10): 889-897.
[7] XIA ZS, WEI M, WEI YT, et al.Genipin induces developmental toxicity through oxidative stress and apoptosis in zebrafish[J]. Comp Biochem Phys C, 2020,(241): 108951.
[8] LI C, LAN M, LU J, et al.Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells[J]. Molecules, 2019, 24(21): 3920.
[9] WANG WS, FU LX, YE JJ.Research progress of TNF-α signaling pathway[J]. Journal of Fujian Medical University(福建医科大学学报), 2005, 39(B08): 27-31.
[10] QIU CH, HOU G, HUANG DN.Molecular mechanism of TNF-α signaling pathway[J]. Chinese Journal of Biochemistry and Molecular Biology(中国生物化学与分子生物学报), 2007(6): 430-435.
[11] SHA L, HONG M, TAN HY, et al.Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases[J]. Oxid Med Cell Longev, 2016, 2016(1-3): 1-21.
[12] IDRISS HT, NAISMITH JH.TNF alpha and the TNF receptor superfamily: structure-function relationship(s)[J]. Microsc Res Techniq, 2000, 50(3): 184-195.
[13] SETHU S, MELENDEZ AJ .New developments on the TNFα-mediated signalling pathways[J]. Bioscience Rep, 2010, 31(1): 63-76.
[14] YANG SS, LIAN GJ.ROS and diseases: role in metabolism and energy supply[J]. Mol Cell Biochem, 2019, 467(1): 7-19.
[15] DIDONATO JA, MERCURIO F, Karin M.NF-κB and the link between inflammation and cancer[J]. Immunol Rev, 2012, 246(1): 379-400.