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Journal of Traditional Chinese Medicine >

2024 , Vol. 44 >Issue 5: 991 - 999

DOI: https://doi.org/10.19852/j.cnki.jtcm.20240806.004

Network-based pharmacology and experimental validation to explore the mechanism of action of the Jiawei Pentongling formula (加味盆痛灵方) for the treatment of endometriosis-related pain

  • Siyun YU ,
  • Shiwen ZHANG ,
  • Yu XIA ,
  • Xiaoqing LIU ,
  • Yajie LIU ,
  • Jinrong FU
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  • Department of Gynecology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China

Received date: 2023-07-22

  Accepted date: 2023-11-07

  Online published: 2024-08-06

Supported by

Exploring the Molecular Mechanism of Reversal of Pain in Endometriosis by Pentongling Formula based on Nerve Growth Factor/p38 mitogen-activated Protein Kinase Signaling Pathway(81674009);Construction of Traditional Chinese Medicine Inheritance and Innovation Development Demonstration Pilot Projects in Pudong New area-high-level Research-oriented Traditional Chinese Medicine Hospital Construction(YC-2023-0901)

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Abstract

OBJECTIVE: To investigate the effects and mechanisms of the Jiawei Pentongling formula (加味盆痛灵方, JWPTL) in treating endometriosis-related pain using network pharmacology study and experimental validation.

METHODS: Active ingredients and relevant targets of JWPTL, as well as genes for endometriosis-related pain, were collected from public databases. Prediction of core targets and pathways of JWPTL against pain associated with endometriosis by protein-protein interaction (PPI) network work, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis. The Sprague-Dawley rat endo-metriosis model was constructed using the autologous endosomal transplantation method, and the successfully modeled rats were randomly divided into the model group and the JWPTL group, with 8 rats in each group. Another 8 rats were set up in the sham group. Rats in the JWPTL group used the rectal delivery method with the addition of JWPTL (7.77 g·kg-1·d-1) once a day for 28 d. Rats in the model and sham-operated groups were given equal amounts of saline using the same administration method. The 50% paw withdrawal threshold (PWT) of the rats was measured at different time points. After the intervention, the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) proteins and mRNA in endometriotic tissues was detected by immune-ohistochemistry and reverse transcription-polymerase chain reaction.

RESULTS: From GeneCards, Online Mendelian Inheritance in Man and other databases, a total of 964 endometriosis (EMs) -related pain targets were screened, 142 active ingredients of JWPTL, 605 targets, and 221 potential targets were obtained by intersection of Venn diagram; 44 core targets were identified by constructing PPI network. KEGG enrichment analysis showed that JWPTL mainly involves the PI3K-Akt signaling pathway, estrogen signaling pathway, hypoxia inducible factor-1 signaling pathway, tumour necrotizing factor signaling pathway, and other signaling pathways in the treatment of EMs-related pain. Animal experiments showed that JWPTL could up-regulate the mechanical pain threshold and reduce the expression of PI3K and Akt proteins and mRNA in ectopic endometrial tissues of model rats.

CONCLUSIONS: The present study preliminarily analyzed the pharmacological mechanism of the formula, and molecular docking and animal experiments showed the feasibility of this study, suggesting that the formula may inhibit the release of inflammatory factors and reverse the pain associated with EMs by downregulating the PI3K/Akt signaling pathway.

Key words： Endometriosis-related pain; phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; Signal Transduction; Jiawei Pentongling formula; network pharmacology

Cite this article

Siyun YU , Shiwen ZHANG , Yu XIA , Xiaoqing LIU , Yajie LIU , Jinrong FU . Network-based pharmacology and experimental validation to explore the mechanism of action of the Jiawei Pentongling formula (加味盆痛灵方) for the treatment of endometriosis-related pain[J]. Journal of Traditional Chinese Medicine, 2024 , 44(5) : 991 -999 . DOI: 10.19852/j.cnki.jtcm.20240806.004

References

1. Dyson MT, Roqueiro D, Monsivais D, et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLOS Genet 2014; 10: e1004158.
2. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012; 98: 511-19.
3. Zhang H, Zhou C, Zhang Z, et al. Network pharmacology and experimental validation to reveal the pharmacological mechanisms of Liuwei Dihuang decoction against intervertebral disc degeneration. Drug Des Devel Ther 2021; 15: 4911-24.
4. Fu JR, Zheng J, Hu XM, Yang ZQ. Clinical observation of “Pentongling decoction” in treating pelvic pain following endometriosis. Shanghai Zhong Yi Yao Za Zhi 2007; 3: 35-6.
5. Fu JR, Shen YF, Zhang JJ, et al. Clinical evaluation on chronic pelvic pain of different diseases treated with Pentongling formula coloclysis. Shanghai Zhong Yi Yao Da Xue Xue Bao 2018; 32: 34-9.
6. Ge M, Fu JR, Tang H, Jiang H. Effects of “Jiawei Pentongling” on IL-1β and NGF in serum and peritoneal fluid in EMs rats. Shanghai Zhong Yi Yao Za Zhi 2013; 47: 79-81.
7. Zhu B, Zhang W, Lu Y, et al. Network pharmacology-based identification of protective mechanism of Panax Notoginseng Saponins on aspirin induced gastrointestinal injury. Biomed Pharmacother 2018; 105: 159-66.
8. Xiang SY, Zhao J, Lu Y. et al. Network pharmacology-based identification for the-rapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs. Comput Biol Med 2019; 110: 1-7.
9. He S, Wang T, Shi C, Wang Z, Fu X. Network pharmacology based approach to understand the effect and mechanism of Danshen against anemia. J Ethnopharmacology 2021; 282: 114615-45.
10. Wei Y, Ren S, Wang R, et al. Based on Network pharmacology to explore the potential bioactive compounds and mechanisms of Zuojin pill for the treatment of ulcerative colitis. Evid Based Complement Alternat Med 2021; 2021: 7567025-37.
11. Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6: 1-6.
12. Wang Y, Xing J, Xu Y, et al. In silico ADME/T modelling for rational drug design. Q Rev Biophys 2015; 48: 488-515.
13. Demchak B, Hull T, Reich M, et al. Cytoscape: the network visualization tool for GenomeSpace workflows. F1000Res 2014; 3: 151-64.
14. Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci USA 2004; 101: 11094-8.
15. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63.
16. Bulun SE. Endometriosis. N Engl J Med 2009; 360: 268-79.
17. Vercellini P, Vigan`o P, Somigliana E. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014; 10: 261-75.
18. Li X, Wu C, Chen N, et al. PI3K/AKT/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 2016; 7: 33440-50.
19. Calabriso N, Scoditti E, Massaro M, et al. Multiple anti-inflammatory and antiatherosclerotic properties of red wine polyphenolic extracts: differential role of hydroxycinnamic acids, flavonols and stilbenes on endothelial inflammatory gene expression. Eur J 2016; 55: 477-89.
20. Karuppagounder V, Arumugan S, Thandavarayan RA. Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis. Drug Discov 2016; 21: 632-9.
21. Anjaneyulu M, Chopra K. Quercetin attenuates thermal hyperalgesia and cold allod-ynia in STZ-induced diabetic rats. Indian J Exp Biol 2004; 42: 766-9.
22. Comalada M, Camuesco D, Sierra S, et al. In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappa B pathway. Eur J Immunol 2005; 35: 584-92.
23. Valério DA, Georgetti SR, Magro DA, et al. Quercetin reduces inflammatory pain: inhibition of oxidative stress and cytokine production. J Nat Prod 2009; 72: 1975-9.
24. Suou K, Taniguchi F, Tagashira Y, Kiyama T, Terakawa N, Harada T. Apigenin inhibits tumor necrosis factor α-induced cell proliferation and prostaglandin E2 synthesis by inactivating NF-κB in endometriotic stromal cells. Fertil Steril 2011; 95: 1518-21.
25. Park S, Lim W, Bazer FW. Apigenin induces ROS dependent apoptosis and ER stress in human endometriosis cells. J Cell Physiol 2018; 233: 3055-65.
26. Aziz N, Kim MY, Cho JY. Anti-inflammatory effects of luteolin: a review of in vitro, in vivo, and in silico studies. J Ethnopharmacol 2018; 225: 342-58.
27. Hyam SR, Jang SE, Jeong JJ, Joh EH, Han MJ, Kim DH. Echinocystic acid, a metabolite of lancemaside A, inhibits TNBS-induced colitis in mice. Int Immunopharmacol 2013; 15: 433-41.
28. Joh EH, Gu W, Kim DH. Echinocystic acid ameliorates lung inflammation in mice and alveolar macrophages by inhibiting the binding of LPS to TLR4 in NF-κB and MAPK pathways. Biochemical Pharmacology 2012; 84: 331-40.
29. Liu B, Piao X, Niu W, et al. Kuijieyuan decoction improved intestinal barrier injury of ulcerative colitis by affecting TLR4-dependent PI3K/AKT/NF-κB oxidative and inflammatory signaling and gut microbiota. Front Pharmacol 2020; 11: 1036-54.
30. Wang HY, Zhang CY, Xu L, et al. Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway. Oncotarget 2016; 7: 20193-208.
31. Li X, Liu H, Yao Q. Quercetin protects mice from ConA-induced hepatitis by inhibiting HMGB1-TLR expression and down-regulating the nuclear factor Kappa B pathway. Inflammation 2016; 39: 96-106.
32. Madanes D, Bilotas MA, Bastón JI, et al. PI3K/AKT pathway is altered in the endometriosis patient's endometrium and presents differences according to severity stage. Gynecol Endocrinol 2020; 36: 22:1-5.
33. Kim TH, Yu Y, Luo L, Lydon JP, Jeong JW, Kim JJ. Activated AKT pathway promotes establishment of endometriosis. Endocrinology 2014; 155: 1921-30.
34. Bedaiwy MA, Falcone T, Sharma RK, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002; 17: 426-31.
35. Machairiotis N, Vasilakaki S, Thomakos N. Inflammatory mediators and pain in endometriosis: a systematic review. Biomedicines 2021; 9: 54-72.
36. Wu J, Xie H, Yao S. Macrophage and nerve interaction in endometriosis. J Neur-oinflammation 2017; 14: 53-64.
37. Liu Y, Qin XY, Lu XF, Jiang J. Effects of inhibiting the PI3K/AKT/mTOR signaling pathway on the pain of sciatic endometriosis in a rat model. Can J Physiol Pharmacol 2019; 97: 963-70.
38. Ge M, Tang H, Fu JR, Yang ZQ. Comparison of analgesic effects of Pentongling and Jiawei Pengtongling. Heilongjiang Zhong Yi Yao 2013; 42: 24-5.
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