Integrating Systematic Pharmacology-based Strategy and Experimental Validation to Explore Mechanism of Glycoside on Cholangiocyte-related Liver Injury

Overview

Journal Chin Herb Med

Publisher Elsevier

Date 2022 Nov 21

PMID 36405068

Authors

Yajing Li

Sen Li

Xiaoyong Xue

Ting Wang

Xiaojiaoyang Li

Affiliations

Soon will be listed here.

Abstract

Objective: glycoside (TG) is widely used in clinical practice for its multiple bioactivities including anti-inflammatory and immunosuppressive effects. However, emerging studies have frequently reported TG-induced adverse reactions to multiple organs, especially liver. Here, this study aimed to investigate the mechanism of liver damage induced by TG and explore representative components to reflect TG hepatotoxicity.

Methods: Network pharmacology was used to determine the potential targets of bile duct injury caused by TG. Next, the hepatotoxic effects of TG, triptolide (TP) and celastrol (CEL) were investigated and compared and . Liver function was determined by measuring serum transaminase and histopathology staining. The cell proliferation and apoptosis were determined by cell viability assay, scratch assay and flow cytometry. The expression of gene of interest was determined by qPCR and Western blot.

Results: Based on the network pharmacological analysis of 12 bioactive ingredients found in TG, a total of 35 targets and 15 pathways related to bile duct injury were obtained. Both TG and TP resulted in cholangiocyte damage and liver injury, as illustrated by increased levels of serum transaminase and oxidative stress, stimulated portal edema and lymphocytic infiltration and decreased expression of cholangiocyte marker, cytoskeletal 19. In addition, TG and TP inhibited cell proliferation and migration, arrested cell cycle and promoted Caspase-dependent apoptosis of cholangiocytes suppressing the phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) and protein kinase B (AKT). While, CEL at equivalent dosage had no obvious hepatotoxicity.

Conclusion: We revealed that TG-stimulated liver injury was specifically characterized by cholangiocyte damage and TP might be the decisive ingredient to reflect TG hepatotoxicity. Our results not only provide novel insights into the mechanism underlying the hepatotoxicity effects of TG but also offer reference for clinical rational use of TG.

Citing Articles

Bioinformatics based exploration of the anti-NAFLD mechanism of Wang's empirical formula via TLR4/NF-κB/COX2 pathway.

Chen S, Zhou C, Huang J, Qiao Y, Wang N, Huang Y Mol Med. 2024; 30(1):278.

PMID: 39730994 PMC: 11673956. DOI: 10.1186/s10020-024-01022-3.

extracts prevent liver fibrosis via targeting CTCF-c-MYC-H19 pathway.

Li Y, Li F, Ding M, Ma Z, Li S, Qu J Chin Herb Med. 2024; 16(1):82-93.

PMID: 38375042 PMC: 10874761. DOI: 10.1016/j.chmed.2023.07.003.

Interaction of (Gaertn.) Desr. and Drugs as a Possible Mechanism of Liver Injury: The Case of Montelukast.

Di Giacomo S, Di Sotto A, Percaccio E, Scuotto E, Battistelli C, Mazzanti G Antioxidants (Basel). 2023; 12(9).

PMID: 37760074 PMC: 10525400. DOI: 10.3390/antiox12091771.

References

Beroske L, Van den Wyngaert T, Stroobants S, Van der Veken P, Elvas F . Molecular Imaging of Apoptosis: The Case of Caspase-3 Radiotracers. Int J Mol Sci. 2021; 22(8). PMC: 8069194. DOI: 10.3390/ijms22083948. View

Wang J, Miao M, Zhang Y, Liu R, Li X, Cui Y . Quercetin ameliorates liver injury induced with Tripterygium glycosides by reducing oxidative stress and inflammation. Can J Physiol Pharmacol. 2015; 93(6):427-33. DOI: 10.1139/cjpp-2015-0038. View

Du X, He X, Huang Y, Fu B, Liang B, Lv C . Simultaneous determination of seven effective components of Tripterygium glycosides in human biological matrices by ultra performance liquid chromatography-triple quadrupole mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2019; 1113:1-13. DOI: 10.1016/j.jchromb.2019.02.024. View

Visentin M, Lenggenhager D, Gai Z, Kullak-Ublick G . Drug-induced bile duct injury. Biochim Biophys Acta Mol Basis Dis. 2017; 1864(4 Pt B):1498-1506. DOI: 10.1016/j.bbadis.2017.08.033. View

Jing X, Cheng W, Guo S, Zou Y, Zhang T, He L . Toxic effects of Tripterygium wilfordii Hook F on the reproductive system of adolescent male rats. Biomed Pharmacother. 2017; 95:1338-1345. DOI: 10.1016/j.biopha.2017.09.038. View

Ma B, Li X . Resveratrol extracted from Chinese herbal medicines: A novel therapeutic strategy for lung diseases. Chin Herb Med. 2020; 12(4):349-358. PMC: 7498443. DOI: 10.1016/j.chmed.2020.07.003. View

Estaphan S, Abdel-Malek R, Rashed L, Mohamed E . Cimetidine a promising radio-protective agent through modulating Bax/Bcl2 ratio: An in vivo study in male rats. J Cell Physiol. 2020; 235(11):8495-8506. DOI: 10.1002/jcp.29692. View

Li X, Jiang Z, Zhang L . Triptolide: progress on research in pharmacodynamics and toxicology. J Ethnopharmacol. 2014; 155(1):67-79. DOI: 10.1016/j.jep.2014.06.006. View

Ma B, Qi H, Li J, Xu H, Chi B, Zhu J . Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: A GC-MS based metabolomics study. Toxicology. 2015; 336:84-95. DOI: 10.1016/j.tox.2015.07.008. View

10.

Li Y, Liu R, Wu J, Li X . Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Theranostics. 2020; 10(18):7993-8017. PMC: 7381749. DOI: 10.7150/thno.47826. View

11.

Hu T, Shi C, Liu L, Li P, Sun Y, An Z . A single-injection targeted metabolomics profiling method for determination of biomarkers to reflect tripterygium glycosides efficacy and toxicity. Toxicol Appl Pharmacol. 2020; 389:114880. DOI: 10.1016/j.taap.2020.114880. View

12.

Li X, Liu R, Huang Z, Gurley E, Wang X, Wang J . Cholangiocyte-derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans. Hepatology. 2018; 68(2):599-615. PMC: 6085159. DOI: 10.1002/hep.29838. View

13.

Zhang S, Lu Y, Chen W, Shi W, Zhao Q, Zhao J . Network Pharmacology and Experimental Evidence: PI3K/AKT Signaling Pathway is Involved in the Antidepressive Roles of Chaihu Shugan San. Drug Des Devel Ther. 2021; 15:3425-3441. PMC: 8353879. DOI: 10.2147/DDDT.S315060. View

14.

Dai W, Tang T, Dai Z, Shi D, Mo L, Zhang Y . Probing the Mechanism of Hepatotoxicity of Hexabromocyclododecanes through Toxicological Network Analysis. Environ Sci Technol. 2020; 54(23):15235-15245. DOI: 10.1021/acs.est.0c03998. View

15.

Osterreicher C, Trauner M . Xenobiotic-induced liver injury and fibrosis. Expert Opin Drug Metab Toxicol. 2012; 8(5):571-80. DOI: 10.1517/17425255.2012.674511. View

16.

Miao Y, Luo L, Shu T, Wang H, Jiang Z, Zhang L . [Study on difference of liver toxicity and its molecular mechanisms caused by Tripterygium wilfordii multiglycoside and equivalent amount of triptolid in rats]. Zhongguo Zhong Yao Za Zhi. 2019; 44(16):3468-3477. DOI: 10.19540/j.cnki.cjcmm.20190301.002. View

17.

Kaliyaperumal K, Grove J, Delahay R, Griffiths W, Duckworth A, Aithal G . Pharmacogenomics of drug-induced liver injury (DILI): Molecular biology to clinical applications. J Hepatol. 2018; 69(4):948-957. DOI: 10.1016/j.jhep.2018.05.013. View

18.

Huang W, Liu C, Xie L, Wang Y, Xu Y, Li Y . Integrated network pharmacology and targeted metabolomics to reveal the mechanism of nephrotoxicity of triptolide. Toxicol Res (Camb). 2020; 8(6):850-861. PMC: 7017871. DOI: 10.1039/c9tx00067d. View

19.

Liu R, Li X, Zhu W, Wang Y, Zhao D, Wang X . Cholangiocyte-Derived Exosomal Long Noncoding RNA H19 Promotes Hepatic Stellate Cell Activation and Cholestatic Liver Fibrosis. Hepatology. 2019; 70(4):1317-1335. PMC: 6783323. DOI: 10.1002/hep.30662. View

20.

Li S, Wang Y, Li C, Yang N, Yu H, Zhou W . Study on Hepatotoxicity of Rhubarb Based on Metabolomics and Network Pharmacology. Drug Des Devel Ther. 2021; 15:1883-1902. PMC: 8106470. DOI: 10.2147/DDDT.S301417. View