Tanshinone ⅡA participates in the treatment of endometriosis by regulating adhesion, invasion, angiogenesis and inhibition of PI3K/Akt/mTOR signaling pathway

Zhang,Xiaoxiao; Li,Shumiao; Chen,Zhenzhen; Liang,Wei; Pei,Shuting; Gou,Feiyue; Jia,Zhicheng; Geng,Zhaoyang; Gong,Xin

doi:10.3892/mmr.2023.13108

Tanshinone ⅡA participates in the treatment of endometriosis by regulating adhesion, invasion, angiogenesis and inhibition of PI3K/Akt/mTOR signaling pathway

Authors:
- Xiaoxiao Zhang
- Shumiao Li
- Zhenzhen Chen
- Wei Liang
- Shuting Pei
- Feiyue Gou
- Zhicheng Jia
- Zhaoyang Geng
- Xin Gong
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Affiliations: The Second Clinical School of Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China, Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, P.R. China, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, P.R. China, Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China, Department of Gynecology, Dong Fang Hospital of Beijing University of Chinese Medicine, Beijing 100078, P.R. China
Published online on: September 29, 2023 https://doi.org/10.3892/mmr.2023.13108
Article Number: 221
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Endometriosis (EMs) is a common gynecological disorder characterized by abnormal growth of the endometrial stroma and glands outside the uterus. Tanshinone IIA, the active component of Chinese medicine Danshen (Salvia miltiorrhiza Bge.), has a number of pharmacological effects such as anti‑inflammation and anti‑oxidation and serves a significant role in the treatment of EMs. In the present study, network pharmacology and experimental validation were used to elucidate the potential mechanism of tanshinone IIA for treating EMs. Several databases were used to collect information on EMs and tanshinone IIA and cross‑targets for tanshinone IIA and EMs finally obtained. A total of 64 common targets were found between tanshinone IIA and EMs. Subsequently, a protein‑protein interaction network was constructed, a total of 14 core targets were screened for enrichment analysis. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. The network pharmacology showed that intercellular adhesion molecule (ICAM)‑1, MMP‑9 and VEGF are the core targets while PI3K/AKT pathway and mTOR pathway are the main signaling pathways through which tanshinone IIA regulates relevant biological processes to intervene in EMs. Finally, the therapeutic role and mechanism of tanshinone IIA on EMs was verified in vivo. Female Sprague‑Dawley rats were treated by autologous transplantation to establish EMs. Serum inflammatory factors were detected by enzyme‑linked immunosorbent assay (ELISA). The expression of ICAM‑1, MMP‑9 and VEGF in ectopic endometrial tissues of rats was determined by immunohistochemical. The expression of PI3K/Akt/mTOR pathway‑related proteins and genes was detected by western blotting and quantitative PCR. It was found that tanshinone IIA treatment significantly decreased the formation of ectopic endometrium by reducing serum levels of TNF‑α and IL‑1β, and down regulating the levels of ICAM‑1, MMP‑9 and VEGF in ectopic uterine tissue. In addition, tanshinone IIA can also block the activation of PI3K/Akt/mTOR signaling pathway by reducing the expression of related proteins and genes. In conclusion, tanshinone IIA can regulate adhesion, invasion and angiogenesis, thereby improving the pathological morphology of ectopic endometrium and inhibiting the formation of ectopic lesions. The PI3K/Akt/mTOR signaling pathway may play a key role in controlling this process.

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1	Chen LH, Lo WC, Huang HY and Wu HM: A Lifelong impact on endometriosis: Pathophysiology and pharmacological treatment. Int J Mol Sci. 24:75032023. View Article : Google Scholar : PubMed/NCBI
2	Donnez J and Cacciottola L: Endometriosis: An inflammatory disease that requires new therapeutic options. Int J Mol Sci. 23:15182022. View Article : Google Scholar : PubMed/NCBI
3	Abramiuk M, Grywalska E, Małkowska P, Sierawska O, Hrynkiewicz R and Niedźwiedzka-Rystwej P: The role of the immune system in the development of endometriosis. Cells. 11:20282022. View Article : Google Scholar : PubMed/NCBI
4	Vercellini P, Viganò P, Somigliana E and Fedele L: Endometriosis: Pathogenesis and treatment. Nat Rev Endocrinol. 10:261–275. 2014. View Article : Google Scholar : PubMed/NCBI
5	Amro B, Ramirez Aristondo ME, Alsuwaidi S, Almaamari B, Hakim Z, Tahlak M, Wattiez A and Koninckx PR: New understanding of diagnosis, treatment and prevention of endometriosis. Int J Environ Res Public Health. 19:67252022. View Article : Google Scholar : PubMed/NCBI
6	Vallée A, Vallée JN, Le Blanche A and Lecarpentier Y: PPARγ Agonists: Emergent Therapy in Endometriosis. Pharmaceuticals (Basel). 14:5432021. View Article : Google Scholar : PubMed/NCBI
7	Nominato NS, Prates LF, Lauar I, Morais J, Maia L and Geber S: Caesarean section greatly increases risk of scar endometriosis. Eur J Obstet Gynecol Reprod Biol. 152:83–85. 2010. View Article : Google Scholar : PubMed/NCBI
8	Horne AW and Missmer SA: Pathophysiology, diagnosis, and management of endometriosis. Bmj. 14:2022–070750. 2022.
9	Chapron C, Marcellin L, Borghese B and Santulli P: Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 15:666–682. 2019. View Article : Google Scholar : PubMed/NCBI
10	Taylor HS, Kotlyar AM and Flores VA: Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations. Lancet. 397:839–852. 2021. View Article : Google Scholar : PubMed/NCBI
11	Leonardi M, Gibbons T, Armour M, Wang R, Glanville E, Hodgson R, Cave AE, Ong J, Tong YYF, Jacobson TZ, et al: When to Do Surgery and When Not to Do Surgery for Endometriosis: A Systematic Review and Meta-analysis. J Minim Invasive Gynecol. 27:390–407. 2020. View Article : Google Scholar : PubMed/NCBI
12	Yela DA, Vitale SG, Vizotto MP and Benetti-Pinto CL: Risk factors for recurrence of deep infiltrating endometriosis after surgical treatment. J Obstet Gynaecol Res. 47:2713–2719. 2021. View Article : Google Scholar : PubMed/NCBI
13	Guo R, Li L, Su J, Li S, Duncan SE, Liu Z and Fan G: Pharmacological activity and mechanism of Tanshinone IIA in Related Diseases. Drug Des Devel Ther. 14:4735–4748. 2020. View Article : Google Scholar : PubMed/NCBI
14	Zhang X, Wang Q, Wang X, Chen X, Shao M, Zhang Q, Guo D, Wu Y, Li C, Wang W and Wang Y: Tanshinone IIA protects against heart failure post-myocardial infarction via AMPKs/mTOR-dependent autophagy pathway. Biomed Pharmacother. 112:1085992019. View Article : Google Scholar : PubMed/NCBI
15	Miao Q, Wang R, Sun X, Du S and Liu L: Combination of puerarin and tanshinone IIA alleviates ischaemic stroke injury in rats via activating the Nrf2/ARE signalling pathway. Pharm Biol. 60:1022–1031. 2022. View Article : Google Scholar : PubMed/NCBI
16	Ni H, Ruan G, Sun C, Yang X, Miao Z, Li J, Chen Y, Qin H, Liu Y, Zheng L, et al: Tanshinone IIA inhibits gastric cancer cell stemness through inducing ferroptosis. Environ Toxicol. 37:192–200. 2022. View Article : Google Scholar : PubMed/NCBI
17	Jin J, Hu QY, Xu WW, Zhu WJ, Liu B, Liu J, Wang W and Zhou HF: Tanshinone IIA attenuates estradiol-induced polycystic ovarian syndrome in mice by ameliorating FSHR expression in the ovary. Exp Ther Med. 17:3501–3508. 2019.PubMed/NCBI
18	Luo Y, Li ZM, Li LP, Zou Y, Xu XY, Zhang ZY, Liu FY, Xiong Y and Wan L: ITRAQ-based proteomics analysis of tanshinone IIA on human ectopic endometrial stromal cells of adenomyosis. Arch Gynecol Obstet. 303:1501–1511. 2021. View Article : Google Scholar : PubMed/NCBI
19	Luo M, Cai X, Yan D, Liu X and Guo SW: Sodium tanshinone IIA sulfonate restrains fibrogenesis through induction of senescence in mice with induced deep endometriosis. Reprod Biomed Online. 41:373–384. 2020. View Article : Google Scholar : PubMed/NCBI
20	Zhang Q, Liu X and Guo SW: Progressive development of endometriosis and its hindrance by anti-platelet treatment in mice with induced endometriosis. Reprod Biomed Online. 34:124–136. 2017. View Article : Google Scholar : PubMed/NCBI
21	Zhou ZH, Weng Q, Zhou JH and Zhou J: Extracts of Salvia miltiorrhiza Bunge on the cytokines of rat endometriosis models. Afr J Tradit Complement Altern Med. 9:303–314. 2012. View Article : Google Scholar : PubMed/NCBI
22	Chen ZZ and Gong X: Tanshinone IIA contributes to the pathogenesis of endometriosis via renin angiotensin system by regulating the dorsal root ganglion axon sprouting. Life Sci. 240:1170852020. View Article : Google Scholar : PubMed/NCBI
23	Jiashuo WU, Fangqing Z, Zhuangzhuang LI, Weiyi J and Yue S: Integration strategy of network pharmacology in traditional Chinese medicine: A narrative review. J Tradit Chin Med. 42:479–486. 2022.PubMed/NCBI
24	Li X, Wei S, Niu S, Ma X, Li H, Jing M and Zhao Y: Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis. Comput Biol Med. 144:1053892022. View Article : Google Scholar : PubMed/NCBI
25	Zhang R, Zhu X, Bai H and Ning K: Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment. Front Pharmacol. 10:1232019. View Article : Google Scholar : PubMed/NCBI
26	Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, et al: TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 6:1758–2946. 2014. View Article : Google Scholar : PubMed/NCBI
27	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
28	Ding J, Tan X, Song K, Ma W, Xiao J, Song Y and Zhang M: Bushen huoxue recipe alleviates implantation loss in mice by enhancing estrogen-progesterone signals and promoting decidual angiogenesis through FGF2 during early pregnancy. Front Pharmacol. 9:4372018. View Article : Google Scholar : PubMed/NCBI
29	Saunders PTK and Horne AW: Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 184:2807–2824. 2021. View Article : Google Scholar : PubMed/NCBI
30	Casper RF: Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril. 107:533–536. 2017. View Article : Google Scholar : PubMed/NCBI
31	Qin Z, Dong Z, Liu J, Zhong A, Bao M, Wang H, Yu H, Zhang S, Zhang W, Shen L, et al: A Preliminary study on the effects of black cohosh preparations on bone metabolism of rat models With GnRH-a-Induced Peri-Menopausal symptoms. Front Endocrinol. 13:8543452022. View Article : Google Scholar : PubMed/NCBI
32	Zhao L, Zhang H, Li N, Chen J, Xu H, Wang Y and Liang Q: Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol. 309:1163062023. View Article : Google Scholar : PubMed/NCBI
33	Han Y, Xiao Y, Yu L, Chen J, Yang X, Cui H and Liang J: Advances in the mechanism of luteolin against hepatocellular carcinoma based on bioinformatics and network pharmacology. J Cancer. 14:966–980. 2023. View Article : Google Scholar : PubMed/NCBI
34	Wang Y, Dragovic RA, Greaves E, Becker CM and Southcombe JH: Macrophages and small extracellular vesicle mediated-intracellular communication in the peritoneal microenvironment: Impact on endometriosis development. Front Reprod Health. 5:11308492023. View Article : Google Scholar : PubMed/NCBI
35	Kim KH, Lee EN, Park JK, Lee JR, Kim JH, Choi HJ, Kim BS, Lee HW, Lee KS and Yoon S: Curcumin attenuates TNF-α-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and proinflammatory cytokines in human endometriotic stromal cells. Phytother Res. 26:1037–1047. 2012. View Article : Google Scholar : PubMed/NCBI
36	Chopyak VV, Koval HD, Havrylyuk AM, Lishchuk-Yakymovych KA, Potomkina HA and Kurpisz MK: Immunopathogenesis of endometriosis-a novel look at an old problem. Cent Eur J Immunol. 47:109–116. 2022. View Article : Google Scholar : PubMed/NCBI
37	Cheng J, Li C, Ying Y, Lv J, Qu X, McGowan E, Lin Y and Zhu X: Metformin alleviates endometriosis and potentiates endometrial receptivity via decreasing VEGF and MMP9 and increasing leukemia inhibitor factor and HOXA10. Front Pharmacol. 13:7502082022. View Article : Google Scholar : PubMed/NCBI
38	Zhang F, Liu XL, Wang W, Dong HL, Xia YF, Ruan LP and Liu LP: Expression of MMIF, HIF-1α and VEGF in Serum and Endometrial Tissues of Patients with Endometriosis. Curr Med Sci. 38:499–504. 2018. View Article : Google Scholar : PubMed/NCBI
39	Ansariniya H, Hadinedoushan H, Javaheri A and Zare F: Vitamin C and E supplementation effects on secretory and molecular aspects of vascular endothelial growth factor derived from peritoneal fluids of patients with endometriosis. J Obstet Gynaecol. 39:1137–1142. 2019. View Article : Google Scholar : PubMed/NCBI
40	Hattori K, Ito Y, Honda M, Sekiguchi K, Hosono K, Shibuya M, Unno N and Majima M: Lymphangiogenesis induced by vascular endothelial growth factor receptor 1 signaling contributes to the progression of endometriosis in mice. J Pharmacol Sci. 143:255–263. 2020. View Article : Google Scholar : PubMed/NCBI
41	Chang KK, Liu LB, Jin LP, Meng YH, Shao J, Wang Y, Mei J, Li MQ and Li DJ: NME1 suppression of endometrial stromal cells promotes angiogenesis in the endometriotic milieu via stimulating the secretion of IL-8 and VEGF. Int J Clin Exp Pathol. 6:2030–2038. 2013.PubMed/NCBI
42	Samimi M, Pourhanifeh MH, Mehdizadehkashi A, Eftekhar T and Asemi Z: The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression. J Cell Physiol. 234:19384–19392. 2019. View Article : Google Scholar : PubMed/NCBI
43	Madanes D, Bilotas MA, Bastón JI, Singla JJ, Meresman GF, Barañao RI and Ricci AG: PI3K/AKT pathway is altered in the endometriosis patient's endometrium and presents differences according to severity stage. Gynecol Endocrinol. 36:436–440. 2020. View Article : Google Scholar : PubMed/NCBI
44	Liu Y, Qin X, Lu X and 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. 97:963–970. 2019. View Article : Google Scholar : PubMed/NCBI
45	Peiris AN, Chaljub E and Medlock D: Endometriosis. JAMA. 320:26082018. View Article : Google Scholar : PubMed/NCBI
46	Jin X, Feng J and Cheng X: LncRNA IGF2-AS promotes endometriosis progression through targeting miR-370-3p/IGF2 axis and activating PI3K/AKT/mTOR signaling pathway. J Assist Reprod Genet. 39:2699–2710. 2022. View Article : Google Scholar : PubMed/NCBI
47	Qin R, Zheng F, Qin W, Wang J, Ma N, Tian W, Li J, Liao M and Qin A: Progranulin promotes proliferation, migration and invasion via the PI3K/Akt signalling pathway in a model of endometriosis. Reprod Biomed Online. 46:425–435. 2023. View Article : Google Scholar : PubMed/NCBI