Advanced Search

Journal of Traditional Chinese Medicine >

2025 , Vol. 45 >Issue 2: 311 - 325

DOI: https://doi.org/10.19852/j.cnki.jtcm.2025.02.006

Original articles

Xiahuo Pingwei San (夏藿平胃散) attenuated intestinal inflammation in dextran sulfate sodium-induced ulcerative colitis mice through inhibiting the receptor for advanced glycation end-products signaling pathway

  • Jiaen HUANG ,
  • Qing LUO ,
  • Gengting DONG ,
  • Weiwen PENG ,
  • Jianhong HE ,
  • Weibo DAI
Expand
  • 1 Department of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China
    2 State Key Laboratory of Quality Research in Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China
    3 Pharmacology Laboratory, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China
    4 National Bngineering Research Center for Modernization of Traditional Chinese Medicine, Hospital Prepration Transformation Branch, Zhongshan 528400, China

Received date: 2024-06-16

  Accepted date: 2024-11-11

  Online published: 2025-03-10

Supported by

Guangdong Provincial Basic and Applied Basic Research Project: Mechanistic Study on the Regulation of Inflammatory Microenvironment and Improvement of Ulcerative Colitis by Lingnan Traditional Medicine Ficus Pandurata Hance through Wilms' Tumor 1-associating Protein-Mediated RNA Methyltransferase Promoting Toll Like Receptor 4 m6A Modification(2023A1515011699);Zhongshan Medical Research Project: Mechanistic Study on the Action of Xiahuo Pingwei San in the Treatment of Ulcerative Colitis(2022A020446)

Fold

Abstract

OBJECTIVE: To evaluate the therapeutic effects of Xiahuo Pingwei San (夏藿平胃散, XHPWS) on ulcerative colitis (UC) in mice and to explore the underlying mechanisms through a network pharmacology approach.

METHODS: Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was utilized to identify the chemical composition and authenticate the active constituents of XHPWS, ensuring rigorous quality control across batches. A dextran sulfate sodium (DSS)-induced UC model was established in C57BL/6 mice, which were treated with XHPWS in vivo. The efficacy against UC was assessed by measuring parameters such as body weight, disease activity index (DAI) scores, and colon length. Levels of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α), in colonic tissue were evaluated using enzyme-linked immunosorbent assay (ELISA). Histological analysis of colon sections was conducted using hematoxylin and eosin staining. A network pharmacology approach was employed to explore the mechanisms of XHPWS and to predict its potential targets in UC treatment. Predicted protein expressions in colonic tissue were validated using immune-ohistochemistry (IHC) and Western blotting techniques.

RESULTS: XHPWS effectively alle viated DSS-induced UC symptoms in mice, as evidenced by restored body weight, reduced colon shortening, and decreased DAI scores. Histopathological examination revealed that XHPWS significantly reduced intestinal inflammatory infiltration, restored intestinal epithelial permeability, and increased goblet cell count. Network pharmacology analysis identified 63 active compounds in XHPWS and suggested that it might target 35 potential proteins associated with UC treatment. Functional enrichment analysis indicated that the protective mechanism of XHPWS could be related to the advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway. Notably, quercetin, kaempferol, wogonin, and nobiletin, the main components of XHPWS, showed strong correlations with the core targets. Additionally, experimental validation demonstrated that XHPWS significantly decreased levels of inflammatory cytokines interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) in UC mice, while downregulating the expression of proteins related to the AGE-RAGE pathway.

CONCLUSION: Our study demonstrated that XHPWS effectively alle viates colitis symptoms and inflammation in UC mice, potentially through the regulation of the AGE-RAGE pathway. These findings provide strong evidence for the therapeutic potential of XHPWS in UC treatment, thereby broadening its clinical applications.

Key words： colitis, ulcerative; network pharmacology; inflammation; glycation end products, advanced; receptor for advanced glycation end products; signal transduction; Xiahuo Pingwei San

Cite this article

Jiaen HUANG , Qing LUO , Gengting DONG , Weiwen PENG , Jianhong HE , Weibo DAI . Xiahuo Pingwei San (夏藿平胃散) attenuated intestinal inflammation in dextran sulfate sodium-induced ulcerative colitis mice through inhibiting the receptor for advanced glycation end-products signaling pathway[J]. Journal of Traditional Chinese Medicine, 2025 , 45(2) : 311 -325 . DOI: 10.19852/j.cnki.jtcm.2025.02.006

References

1. Kirsner JB. Historical origins of current IBD concepts. World J Gastroenterol 2001; 7: 175-84.
2. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol 2015; 12: 720-7.
3. Yao D, Dong M, Dai C, Wu S. Inflammation and inflammatory cytokine contribute to the initiation and development of ulcerative colitis and its associated cancer. Inflamm Bowel Dis 2019; 25: 1595-602.
4. Rubio CA, Langner C, Schmidt PT. Partial to complete abrogation of the subepithelial macrophage barrier against the gut microbiota in patients with ulcerative colitis and Crohn's colitis. Histopathology 2018; 72: 580-97.
5. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 2011; 11: 750-61.
6. Nguyen VQ, Eden K, Morrison HA, et al. Noncanonical NF-κB signaling upregulation in inflammatory bowel disease patients is associated with loss of response to anti-TNF agents. Front Pharmacol 2021; 12: 655887.
7. Bevivino G, Monteleone G. Advances in understanding the role of cytokines in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2018; 12: 907-15.
8. Chen YY, Ma ZB, Xu HY, et al. IL-6/STAT3/SOCS3 signaling pathway playing a regulatory role in ulcerative colitis carcinogenesis. Int J Clin Exp Med 2015; 8: 12009-17.
9. Salas A, Hernandez-Rocha C, Duijvestein M, et al. JAK-STAT pathway targeting for the treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17: 323-37.
10. Zhao Y, Luan H, Gao H, Wu X, Zhang Y, Li R. Gegen Qinlian decoction maintains colonic mucosal homeostasis in acute/chronic ulcerative colitis via bidirectionally modulating dysregulated Notch signaling. Phytomed 2020; 68: 153182.
11. Zhou Y, Dou F, Song H, Liu T. Anti-ulcerative effects of wogonin on ulcerative colitis induced by dextran sulfate sodium via Nrf2/TLR4/NF-κB signaling pathway in BALB/c mice. Environ Toxicol 2022; 37: 954-63.
12. Lu PD, Zhao YH. Targeting NF-κB pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines. Chin Med 2020; 15: 15.
13. Harbord M, Eliakim R, Bettenworth D, et al. Third european evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management. J Crohns Colitis 2017; 11: 769-84.
14. Zhang C, Jiang M, Lu A. Considerations of Traditional Chinese Medicine as adjunct therapy in the management of ulcerative colitis. Clin Rev Allergy Immunol 2012; 44: 274-83.
15. Bai H, Zhou J. Buhuanjin Zhengqi powder in the treatment of ulcerative colitis for 31 cases. Zhong Guo Zhong Yi Yao Xian Dai Yuan Cheng Jiao Yu 2016; 14: 80-2.
16. Du Y, Du B. Discussion on treating diarrheal irritable bowel syndrome with Jiawei Buchangjin Zhengqi powder. Chin J Clin Res 2016; 29: 108-9+14.
17. Wang J. Effect of modified Buhuanjin Zhengqi powder in treatment of ulcerative colitis. Liaoning Zhong Yi Yao Da Xue Xue Bao 2013; 15: 176-8.
18. Wang ZY, Wang X, Zhang DY, Hu YJ, Li S. Traditional Chinese Medicine network pharmacology: development in new era under guidance of network pharmacology evaluation method guidance. Zhong Guo Zhong Yao Za Zhi 2022; 47: 7-17.
19. Zhang P, Zhang D, Zhou W, et al. Network pharmacology: towards the artificial intelligence-based precision Traditional Chinese Medicine. Brief Bioinform 2023; 25: bbad518.
20. Wu L, Wang Y, Li Z, Zhang B, Cheng Y, Fan X. Identifying roles of “Jun-Chen-Zuo-Shi” component herbs of Qishen Yiqi formula in treating acute myocardial ischemia by network pharmacology. Chin Med 2014; 9: 1-9.
21. Zeng L, Yang K. Exploring the pharmacological mechanism of Yanghe Decoction on HER2-positive breast cancer by a network pharmacology approach. J Ethnopharmacol 2017; 199: 68-85.
22. Fang J, Wang L, Wu T, et al. Network pharmacology-based study on the mechanism of action for herbal medicines in Alzheimer treatment. J Ethnopharmacol 2017; 196: 281-92.
23. Wang X, Wu M, Lai X, et al. Network pharmacology to uncover the biological basis of spleen Qi deficiency syndrome and herbal treatment. Oxid Med Cell Longev 2020; 2020: 2974268.
24. Suo T, Liu J, Chen X, et al. Combining chemical profiling and network analysis to investigate the pharmacology of complex prescriptions in Traditional Chinese Medicine. Sci Rep 2017; 7: 40529.
25. Shen H, Zhu L, Yao N, Wu J. The effect of the compatibility of Radix Aconiti Laterlis and radix glycyrrhizae on pharmacokinatic of aconitine, mesaconitine and hypacmitine in rat plasma. Zhong Yao Cai 2011; 34: 937-42.
26. Wang XM, Xu WJ, Xu LK, Song S, Xing XF, Luo JB. Antipyretic effect of Herba ephedrae-ramulus cinnamomi herb pair on yeast-induced pyrexia rats: a metabolomics study. Chin J Integr Med 2018; 24: 676-82.
27. Liu X, Shi Y, Hu Y, et al. Bupleurum marginatum Wall. ex DC in liver fibrosis: pharmacological evaluation, differential proteomics, and network pharmacology. Front Pharmacol 2018; 9: 524.
28. Zhou Y, Wu R, Cai FF, et al. Xiaoyaosan decoction alle via ted rat liver fibrosis via the TGFβ/Smad and Akt/FoxO 3 signaling pathways based on network pharmacology analysis. J Ethnopharmacol 2021; 10: 113021.
29. MacArthur Clark JA, Sun D. Guidelines for the ethical review of laboratory animal welfare People's Republic of China National Standard GB/T 35892-2018 [Issued 6 February 2018 Effective from 1 September 2018]. Animal Model Exp Med 2020; 3: 103-13.]
30. Chen XQ, Lyu XY, Liu SJ. Baitouweng decoction alle via tes dextran sulfate sodium-induced ulcerative colitis by regulating intestinal microbiota and the IL-6/STAT3 signaling pathway. J Ethnopharmacol 2021; 265: 113357.
31. Low D, Nguyen DD, Mizoguchi E. Animal models of ulcerative colitis and their application in drug research. Drug Des, Dev Ther 2013; 7: 1341-57.
32. Yuan JM, Lu DN, Wang JJ, et al. Effect and mechanism of Bovis Calculus on ulcerative colitis by inhibiting IL-17/IL-17RA/Act1 signaling pathway. Zhong Guo Zhong Yao Za Zhi 2023; 48: 2500-11.
33. Duan ZL, Wang YJ, Lu ZH, et al. Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: network pharmacology analysis and experimental evidence. Phytomed 2023; 111: 154658.
34. Zou M, Huang X, Chen Y, Ning X. Molecular mechanisms of Tripterygium Wilfordii in treatment of ulcerative colitis explored by GEO chip analysis combined with network pharmacology. Zhong Guo Yao Li Xue Tong Bao 2021; 37: 1743-9.
35. Wang Y, Tang W, Gao Q, et al. Exploring the mechanism of acanthopanax senticosus in the treatment of Alzheimer’s disease based on GEO data mining and network pharmacology. Chin J Mod Appl Pharm 2023; 40: 2192-202.
36. Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6: 13.
37. UniProt C. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res 2021; 49: D480-9.
38. Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498-504.
39. Li K, Strauss R, Ouahed J, et al. Molecular comparison of adult and pediatric ulcerative colitis indicates broad similarity of molecular pathways in disease tissue. J Pediatr Gastroenterol Nutr 2018; 67: 45-52.
40. Keir ME, Fuh F, Ichikawa R, et al. Regulation and role of αE integrin and gut homing integrins in migration and retention of intestinal lymphocytes during inflammatory bowel disease. J Immunol 2021; 207: 2245-54.
41. Ren C, Li M, Du W, et al. Comprehensive bioinformatics analysis reveals hub genes and inflammation state of rheumatoid arthritis. Biomed Res Int 2020; 2020: 6943103.
42. Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43: e47.
43. LI D, Chen G, Tan Q, et al. The potential mechanism of Xuebijing injection in treatment of severe acute pancreatitis based on network pharmacology and molecular docking. Zhong Yi Xue 2023; 12: 291.
44. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021:customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49: D60512.
45. Tang Y, Li M, Wang J, Pan Y, Wu F-X. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems 2015; 127: 67-72.
46. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci 2005; 102: 15545-50.
47. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012; 16: 284-7.
48. Trott O, Olson AJJJocc. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-61.
49. Zhang J, Lei H, Hu X, Dong W. Hesperetin ameliorates DSS-induced colitis by maintaining the epithelial barrier via blocking RIPK3/MLKL necroptosis signaling. Eur J Pharmacol 2020; 873: 172992.
50. Quiroga R, Villarreal MA. Vinardo: a scoring function based on autodock vina improves scoring, docking, and virtual screening. PLoS One 2016; 11: e0155183.
51. Di Muzio E, Toti D, Polticelli F. DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina. J Comput Aided Mol Des 2017; 31: 213-8.
52. Li C, Wang L, Zhao J, et al. Lonicera rupicola Hook.f.et Thoms flavonoids ameliorated dysregulated inflammatory responses, intestinal barrier, and gut microbiome in ulcerative colitis via PI3K/AKT pathway. Phytomedicine 2022; 104: 154284.
53. Ye BD. Introducing Traditional herbal medicine into conventional health care in treating ulcerative colitis: primum non nocere. Gastroenterol 2018; 154: 792-5.
54. Zhang Z, Shen P, Xie W, et al. Pingwei San ameliorates dextran sulfate sodium-induced chronic colitis in mice. J Ethnopharmacol 2019; 236: 91-9.
55. Chen G, Yang Y, Liu M, et al. Banxia xiexin decoction protects against dextran sulfate sodium-induced chronic ulcerative colitis in mice. J Ethnopharmacol 2015; 166: 149-56.
56. Dong M, Liu H, Cao T, et al. Huoxiang Zhengqi alle via tes azoxymethane/dextran sulfate sodium-induced colitis-associated cancer by regulating Nrf2/NF-κB/NLRP 3 signaling. Front Pharmacol 2022; 13: 1002269.
57. Lyu YL, Zhou HF, Yang J, et al. Biological activities underlying the therapeutic effect of quercetin on inflammatory bowel disease. Mediators Inflamm 2022; 2022: 5665778.
58. Wang X, Xie X, Li Y, et al. Quercetin ameliorates ulcerative colitis by activating aryl hydrocarbon receptor to improve intestinal barrier integrity. Phytother Res 2024; 38: 253-64.
59. Bian Y, Dong Y, Sun J, et al. Protective effect of kaempferol on LPS-induced inflammation and barrier dysfunction in a coculture model of intestinal epithelial cells and intestinal microvascular endothelial cells. J Agric Food Chem 2020; 68: 160-7.
60. Qu Y, Li X, Xu F, et al. Kaempferol alle via tes murine experimental colitis by restoring gut microbiota and inhibiting the LPS-TLR4-NF-κB axis. Front Immunol 2021; 12: 679897.
61. Wu Q, Xie S, Zhu Y, et al. Wogonin strengthens the therapeutic effects of mesenchymal stem cells in DSS-induced colitis via promoting IL-10 production. Oxid Med Cell Longev 2021; 2021: 5527935.
62. He W, Liu M, Li Y, et al. Flavonoids from Citrus aurantium ameliorate TNBS-induced ulcerative colitis through protecting colonic mucus layer integrity. Eur J Pharmacol 2019; 857: 172456.
63. Goh JXH, Tan LT, Goh JK, et al. Nobiletin and derivatives: functional compounds from citrus fruit peel for colon cancer chemoprevention. Cancers 2019; 11: 867.
64. Nakase H, Sato N, Mizuno N, Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev 2022; 21: 103017.
65. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16: 448-57.
66. Kaminsky LW, Al-Sadi R, Ma TY. IL-1β and the intestinal epithelial tight junction barrier. Front Immunol 2021; 12: 767456.
67. Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. J Immunity 2019; 50: 992-1006.
68. Pugliese D, Felice C, Papa A, et al. Anti TNF-α therapy for ulcerative colitis: current status and prospects for the future. Expert Rev Clin Immunol 2017; 13: 223-33.
69. Kalea Anastasia Z, Schmidt Ann M, Hudson Barry I. RAGE: a novel biological and genetic marker for vascular disease. Clin Sci 2009; 116: 621-37.
70. Hudson BI, Lippman ME. Targeting RAGE signaling in inflammatory disease. Annu Rev Med 2018; 69: 349-64.
71. Sabbagh MN, Agro A, Bell J, Aisen PS, Schweizer E, Galasko D. PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis Assoc Disord 2011; 25: 206.
72. Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurol 2014; 82: 1536-42.
73. Hong Y, Shen C, Yin Q, Sun M, Ma Y, Liu X. Effects of RAGE-specific inhibitor FPS-ZM1 on amyloid-β metabolism and AGEs-induced inflammation and oxidative stress in rat hippocampus. Neurochem Res 2016; 41: 1192-9.
74. Manigrasso MB, Pan J, Rai V, et al. Small molecule inhibition of ligand-stimulated RAGE-DIAPH 1 signal transduction. Sci Rep 2016; 6: 22450.
75. Zen K, Chen CX, Chen YT, Wilton R, Liu Y. Receptor for advanced glycation endproducts mediates neutrophil migration across intestinal epithelium. J Immunol 2007; 178: 2483-90.
76. Body-Malapel M, Djouina M, Waxin C, et al. The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for inflammatory bowel diseases. Mucosal Immunol 2019; 12: 468-78.
77. Khanna D, Sethi G, Ahn K, et al. Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol 2007; 7: 344-51.
78. Costa DVS, Moura-Neto V, Bolick DT, et al. S100B inhibition attenuates intestinal damage and diarrhea severity during clostridioides difficile infection by modulating inflammatory response. Front Cell Infect Microbiol 2021; 11: 739874.
79. Shi Y, Qian J, Zhang Q, Hu Y, Sun D, Jiang L. Advanced glycation end products increased placental vascular permeability of human BeWo cells via RAGE/NF-kB signaling pathway. Eur J Obstet Gynecol Reprod Biol 2020; 250: 93-100.
Options
Outlines

/

〈 〉