Therapeutic Effects of Qingchang Tongluo Decoction on Intestinal Fibrosis in Crohn's Disease: Network Pharmacology, Molecular Docking and Experiment Validation

Overview

Journal Drug Des Devel Ther

Specialty Pharmacology

Date 2024 Jul 31

PMID 39081706

Authors

Yanan Li

Jingyi Hu

Ryan Au

Cheng Cheng

Feng Xu

Weiyang Li

Yuguang Wu

Yuan Cui

Lei Zhu

Hong Shen

Affiliations

Soon will be listed here.

Abstract

Background: Qingchang Tongluo Decoction (QTF) is clinically used for the treatment of intestinal fibrosis in Crohn's Disease (CD). However, the role of QTF in CD-associated fibrosis and its potential pharmacological mechanism remains unclear.

Purpose: The objective of this study was to elucidate the potential mechanism of QTF in treating CD-associated fibrosis, employing a combination of bioinformatics approaches - encompassing network pharmacology and molecular docking - complemented by experimental validation.

Methods: To investigate the material basis and potential protective mechanism of QTF, a network pharmacology analysis was conducted. The core components and targets of QTF underwent molecular docking analysis to corroborate the findings obtained from network pharmacology. In vitro, a colon fibrotic model was established by stimulating IEC-6 cells with 10 ng/mL of transforming growth factor(TGF-β1). In vivo, an intestinal fibrosis model was induced in BALB/c mice by TNBS. The role of QTF in inhibiting the TGF-β1/Smad signaling pathway was investigated through RT-qPCR, Western blotting, immunohistochemistry staining, and immunofluorescence staining.

Results: Network pharmacology analysis revealed that QTF could exert its protective effect. Bioinformatics analysis suggested that Flavone and Isoflavone might be the key components of the study. Additionally, AKT1, IL-6, TNF, and VEGFA were identified as potential therapeutic targets. Furthermore, experimental validation and molecular docking were employed to corroborate the results obtained from network pharmacology. RT-qPCR, Immunofluorescence, and Western blotting results demonstrated that QTF significantly improved colon function and inhibited pathological intestinal fibrosis in vivo and in vitro.

Conclusion: Through the application of network pharmacology, molecular docking, and experimental validation, QTF could be confirmed to inhibit the proliferation of intestinal fibroblasts associated with CD and reduce the expression of Collagen I and VEGFA. This effect is achieved through the attenuation of ECM accumulation, primarily via the inhibition of the TGF-β1/Smad signaling pathway.

References

Rieder F, Fiocchi C . Intestinal fibrosis in IBD--a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol. 2009; 6(4):228-35. DOI: 10.1038/nrgastro.2009.31. View

Wang R, Wang D, Wang H, Wang T, Weng Y, Zhang Y . Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis. Front Immunol. 2021; 12:670159. PMC: 8387595. DOI: 10.3389/fimmu.2021.670159. View

Huang S, He J, Chen Y, Wang X, Li Y, Su Y . Effect of Huangqin decoction on regulating intestinal flora in colitis mice characterized as inhibition of the NOD2-dependent pathway. Pharm Biol. 2021; 60(1):108-118. PMC: 8725945. DOI: 10.1080/13880209.2021.2017981. View

Powell D, Pinchuk I, Saada J, Chen X, Mifflin R . Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol. 2010; 73:213-37. PMC: 3754809. DOI: 10.1146/annurev.physiol.70.113006.100646. View

Seeliger D, de Groot B . Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des. 2010; 24(5):417-22. PMC: 2881210. DOI: 10.1007/s10822-010-9352-6. View

Baumgart D, Sandborn W . Crohn's disease. Lancet. 2012; 380(9853):1590-605. DOI: 10.1016/S0140-6736(12)60026-9. View

Liu X . Transporter-Mediated Drug-Drug Interactions and Their Significance. Adv Exp Med Biol. 2019; 1141:241-291. DOI: 10.1007/978-981-13-7647-4_5. View

Henderson N, Rieder F, Wynn T . Fibrosis: from mechanisms to medicines. Nature. 2020; 587(7835):555-566. PMC: 8034822. DOI: 10.1038/s41586-020-2938-9. View

Stenke E, Bourke B, Knaus U . Crohn's Strictures-Moving Away from the Knife. Front Pediatr. 2017; 5:141. PMC: 5472668. DOI: 10.3389/fped.2017.00141. View

10.

Owen S, Doak A, Ganesh A, Nedyalkova L, McLaughlin C, Shoichet B . Colloidal drug formulations can explain "bell-shaped" concentration-response curves. ACS Chem Biol. 2014; 9(3):777-84. PMC: 3985758. DOI: 10.1021/cb4007584. View

11.

Zhao Z, Zhu C, Huang J, Li X, Zhang Y, Liang J . Efficacy and safety of Fuzheng Huayu tablet on persistent advanced liver fibrosis following 2 years entecavir treatment: A single arm clinical objective performance criteria trial. J Ethnopharmacol. 2022; 298:115599. DOI: 10.1016/j.jep.2022.115599. View

12.

Li S, Zhang B . Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med. 2013; 11(2):110-20. DOI: 10.1016/S1875-5364(13)60037-0. View

13.

DAlessio S, Ungaro F, Noviello D, Lovisa S, Peyrin-Biroulet L, Danese S . Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol. 2021; 19(3):169-184. DOI: 10.1038/s41575-021-00543-0. View

14.

Hu J, Huang H, Che Y, Ding C, Zhang L, Wang Y . Qingchang Huashi Formula attenuates DSS-induced colitis in mice by restoring gut microbiota-metabolism homeostasis and goblet cell function. J Ethnopharmacol. 2020; 266:113394. DOI: 10.1016/j.jep.2020.113394. View

15.

Imai J, Hozumi K, Sumiyoshi H, Yazawa M, Hirano K, Abe J . Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis. Biochem Biophys Res Commun. 2015; 468(4):554-60. DOI: 10.1016/j.bbrc.2015.10.123. View

16.

Cheng C, Hu J, Li Y, Ji Y, Lian Z, Au R . Qing-Chang-Hua-Shi granule ameliorates DSS-induced colitis by activating NLRP6 signaling and regulating Th17/Treg balance. Phytomedicine. 2022; 107:154452. DOI: 10.1016/j.phymed.2022.154452. View

17.

Wang K, Chen Q, Shao Y, Yin S, Liu C, Liu Y . Anticancer activities of TCM and their active components against tumor metastasis. Biomed Pharmacother. 2020; 133:111044. DOI: 10.1016/j.biopha.2020.111044. View

18.

Malik T . Inflammatory Bowel Disease: Historical Perspective, Epidemiology, and Risk Factors. Surg Clin North Am. 2015; 95(6):1105-22, v. DOI: 10.1016/j.suc.2015.07.006. View

19.

Yun S, Kim S, Kim E . The Molecular Mechanism of Transforming Growth Factor-β Signaling for Intestinal Fibrosis: A Mini-Review. Front Pharmacol. 2019; 10:162. PMC: 6400889. DOI: 10.3389/fphar.2019.00162. View

20.

Liu J, Deng T, Wang Y, Zhang M, Zhu G, Fang H . Calycosin Inhibits Intestinal Fibrosis on CCD-18Co Cells via Modulating Transforming Growth Factor-β/Smad Signaling Pathway. Pharmacology. 2019; 104(1-2):81-89. DOI: 10.1159/000500186. View