Reduction of VEGF Levels by Phaleria macrocarpa Flavonoids in an Endometriosis Mouse (Mus musculus) Model

Amina Diarsy, Fany Hardiati Amalia, Sutrisno Sutrisno, Tatit Nurseta, Safrina Dewi Ratnaningrum

Abstract


Endometriosis occurs when endometrial-like cells proliferate at ectopic sites outside the uterus. The advancement of endometriotic lesions is strongly influenced by VEGF, as it stimulates the formation of new blood vessels. In contrast, flavonoids derived from Phaleria macrocarpa extract possess inhibitory effects on both pro-inflammatory signaling molecules and pro-angiogenic pathways. This study investigated the effects of flavonoids from Phaleria macrocarpa extract on VEGF levels in the peritoneal fluid of endometriosis mouse models. This research employed a post-test-only control group experimental design. A total of thirty mice (Mus musculus) were assigned to six groups: a healthy control group, an untreated endometriosis group, and four endometriosis groups receiving isolated flavonoids from Phaleria macrocarpa extract at doses of 3.75, 7.5, 15, and 30 mg/mouse/day (n=5). Peritoneal fluid samples were collected from all groups to examine VEGF levels using ELISA. The results were expressed as mean ± SD and subsequently evaluated using a one-way ANOVA with LSD post-hoc test at a significance level of p-value < 0.05. Flavonoids at the dose of 30 mg/day significantly decreased the VEGF levels compared to the group of endometriosis mouse models (p-value=0.001). Flavonoids decreased VEGF levels as an angiogenic factor in peritoneal fluid, which may play a role in the proliferation of endometriosis tissue.

 

Keywords: Flavonoid, Phaleria macrocarpa, VEGF, Endometriosis

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References


Altaf, R., Asmawi, M. Z. Bin, Dewa, A., Sadikun, A., & Umar, M. I. (2013). Phytochemistry and medicinal properties of Phaleria macrocarpa (Scheff.) Boerl. extracts. Pharmacognosy Reviews, 7(13), 73–80. https://doi.org/10.4103/0973-7847.112853

Bo, C., & Wang, Y. (2024). Angiogenesis signaling in endometriosis: Molecules, diagnosis and treatment (Review). Molecular Medicine Reports, 29(3), 1–14. https://doi.org/10.3892/mmr.2024.13167

Chung, M. S., & Han, S. J. (2022). Endometriosis-Associated Angiogenesis and Anti-angiogenic Therapy for Endometriosis. Frontiers in Global Women’s Health, 3(April), 1–11. https://doi.org/10.3389/fgwh.2022.856316

Comalada, M., Ballester, I., Bailón, E., Sierra, S., Xaus, J., Gálvez, J., Medina, F. S. de, & Zarzuelo, A. (2006). Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: Analysis of the structure-activity relationship. Biochemical Pharmacology, 72(8), 1010–1021. https://doi.org/10.1016/j.bcp.2006.07.016

Hämäläinen, M., Nieminen, R., Vuorela, P., Heinonen, M., & Moilanen, E. (2007). Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-κB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κB activation along with their inhibitory effect on i. Mediators of Inflammation, 2007. https://doi.org/10.1155/2007/45673

Hu, W. H., Wang, H. Y., Xia, Y. T., Dai, D. K., Xiong, Q. P., Dong, T. T. X., Duan, R., Chan, G. K. L., Qin, Q. W., & Tsim, K. W. K. (2020). Kaempferol, a Major Flavonoid in Ginkgo Folium, Potentiates Angiogenic Functions in Cultured Endothelial Cells by Binding to Vascular Endothelial Growth Factor. Frontiers in Pharmacology, 11(April), 1–12. https://doi.org/10.3389/fphar.2020.00526

Huang, Z., Fang, F., Wang, J., & Wong, C. W. (2010). Structural activity relationship of flavonoids with estrogen-related receptor gamma. FEBS Letters, 584(1), 22–26. https://doi.org/10.1016/j.febslet.2009.11.026

Ilhan, M., Ali, Z., Khan, I. A., Taştan, H., & Küpeli Akkol, E. (2019). Bioactivity-guided isolation of flavonoids from Urtica dioica L. and their effect on endometriosis rat model. Journal of Ethnopharmacology, 243(July). https://doi.org/10.1016/j.jep.2019.112100

Khodarahmian, M., Amidi, F., Moini, A., Kashani, L., Salahi, E., Danaii-mehrabad, S., Nashtaei, M. S., Mojtahedi, M. F., Esfandyari, S., & Sobhani, A. (2021). A randomized exploratory trial to assess the effects of resveratrol on VEGF and TNF-α 2 expression in endometriosis women. Journal of Reproductive Immunology, 143(3). https://doi.org/10.1016/j.jri.2020.103248

Li, C., Zhao, H. L., Li, Y. J., Zhang, Y. Y., Liu, H. Y., Feng, F. Z., & Yan, H. (2021). The expression and significance of leukemia inhibitory factor, interleukin-6 and vascular endothelial growth factor in Chinese patients with endometriosis. Archives of Gynecology and Obstetrics, 304(1), 163–170. https://doi.org/10.1007/s00404-021-05980-5

Liang, Y., Xie, H., Wu, J., Liu, D., & Yao, S. (2018). Villainous role of estrogen in macrophage-nerve interaction in endometriosis. Reproductive Biology and Endocrinology, 16(1), 1–11. https://doi.org/10.1186/s12958-018-0441-z

Lousse, J. C., Van Langendonckt, A., González-Ramos, R., Defrère, S., Renkin, E., & Donnez, J. (2008). Increased activation of nuclear factor-kappa B (NF-κB) in isolated peritoneal macrophages of patients with endometriosis. Fertility and Sterility, 90(1), 217–220. https://doi.org/10.1016/j.fertnstert.2007.06.015

Maharani, M., Lajuna, L., Yuniwati, C., Sabrida, O., & Sutrisno, S. (2021). Phytochemical characteristics from Phaleria macrocarpa and its inhibitory activity on the peritoneal damage of endometriosis. Journal of Ayurveda and Integrative Medicine, 12(2), 229–233. https://doi.org/10.1016/j.jaim.2020.06.002

Mirossay, L., Varinská, L., & Mojžiš, J. (2018). Antiangiogenic effect of flavonoids and chalcones: An update. International Journal of Molecular Sciences, 19(1). https://doi.org/10.3390/ijms19010027

Mohamed Mahzir, K. A., Abd Gani, S. S., Hasanah Zaidan, U., & Halmi, M. I. E. (2018). Development of Phaleria macrocarpa (Scheff.) Boerl Fruits Using Response Surface Methodology Focused on Phenolics, Flavonoids and Antioxidant Properties. Molecules (Basel, Switzerland), 23(4), 1–22. https://doi.org/10.3390/molecules23040724

Mustafida, R. Y., Munawir, A., & Dewi, R. (2014). Efek Antiangiogenik Ekstrak Etanol Buah MAhkota Dewa (Phaleria macrocarpa (Scheff.) Boerl.) pada Membran Korio Alantois (CAM) Embrio Ayam. E-Jurnal Pustaka Kesehatan, 2(1), 4–8. https://jpk.jurnal.unej.ac.id/index.php/JPK/article/view/587/415

Nanda, A., Thangapandi, K., Banerjee, P., Dutta, M., Wangdi, T., Sharma, P., Chaudhury, K., & Jana, S. K. (2020). Cytokines, angiogenesis, and extracellular matrix degradation are augmented by oxidative stress in endometriosis. Annals of Laboratory Medicine, 40(5), 390–397. https://doi.org/10.3343/alm.2020.40.5.390

Rossi, M., Edefonti, V., Parpinel, M., Lagiou, P., Franchi, M., Ferraroni, M., Decarli, A., Zucchetto, A., Serraino, D., Dal Maso, L., Negri, E., & La Vecchia, C. (2013). Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: A case-control study in Italy. British Journal of Cancer, 109(7), 1914–1920. https://doi.org/10.1038/bjc.2013.447

Rowlands, I. J., Abbott, J. A., Montgomery, G. W., Hockey, R., Rogers, P., & Mishra, G. D. (2021). Prevalence and incidence of endometriosis in Australian women: a data linkage cohort study. BJOG: An International Journal of Obstetrics and Gynaecology, 128(4), 657–665. https://doi.org/10.1111/1471-0528.16447

Sutrisno, S., Andarini, S., Wiyasa, I. W. A., Kulsum, U., Noerhamdani, N., Suyuti, H., & Hendarto, H. (2019). The effect of implant origin differences on peritoneal endometriosis in an endometriosis mouse model. International Journal of Women’s Health and Reproduction Sciences, 7(1), 34–40. https://doi.org/10.15296/ijwhr.2019.06

Sutrisno, S., & Maharani, M. (2024). Genistein Ameliorated Vascular Endothelial Growth Factor-A (VEGF-A) and Estrogen Receptor-Alpha (ER- α) in Endometriosis Mice Model, in Vivo and in Silico. Scientific World Journal, 2024. https://doi.org/10.1155/2024/5338212

Sutrisno, S., Noeraini, A. R., Khumairoh, R., Maharani, M., Nurseta, T., Handono, K., Wahyuni, E. S., & Khotimah, H. (2023). The Effect of Flavonoid Isolates from Extract of Phaleria macrocarpa (Scheff.) boerl on Peritoneal Fluid of Endometriosis Mice. https://pubs.aip.org/aip/acp/article-abstract/2634/1/020072/2871015/The-effect-of-flavonoid-isolates-from-extract-of?redirectedFrom=fulltext

Sutrisno, S., Wulandari, R. C. L., Sulistyowati, D. W. W., Wulandari, R. F., Wahyuni, E. S., Yueniwati, Y., & Santoso, S. (2015). Effect of genistein on proinflammatory cytokines and estrogen receptor-β in mice model of endometriosis. Asian Pacific Journal of Reproduction, 4(2), 96–99. https://doi.org/10.1016/S2305-0500(15)30003-8

Tandrasasmita, O. M., Sutanto, A. M., Arifin, P. F., & Tjandrawinata, R. R. (2015). Anti-inflammatory, antiangiogenic, and apoptosis-inducing activity of DLBS1442, a bioactive fraction of phaleria macrocarpa, in a RL95-2 cell line as a molecular model of endometriosis. International Journal of Women’s Health, 7, 161–169. https://doi.org/10.2147/IJWH.S74552

Wei, Q., & Zhang, Y. H. (2024). Flavonoids with Anti-Angiogenesis Function in Cancer. Molecules, 29(7). https://doi.org/10.3390/molecules29071570

Woo, J. H., Jang, D. S., & Choi, J. H. (2021). Luteolin promotes apoptosis of endometriotic cells and inhibits the alternative activation of endometriosis-associated macrophages. Biomolecules and Therapeutics, 29(6), 678–684. https://doi.org/10.4062/BIOMOLTHER.2021.045

World Health Organization. (2023). Endometriosis. https://doi.org/ https://www.who.int/news-room/fact-sheets/detail/endometriosis

Xi, X., Wang, J., Qin, Y., You, Y., Huang, W., & Zhan, J. (2022). The Biphasic Effect of Flavonoids on Oxidative Stress and Cell Proliferation in Breast Cancer Cells. Antioxidants, 11(4). https://doi.org/10.3390/antiox11040622

Yoshida, T., Hashimura, M., Mastumoto, T., Tazo, Y., Inoue, H., Kuwata, T., & Saegusa, M. (2013). Transcriptional upregulation of HIF-1α by NF-κB/p65 and its associations with β-catenin/p300 complexes in endometrial carcinoma cells. Laboratory Investigation, 93(11), 1184–1193. https://doi.org/10.1038/labinvest.2013.111

Young, V. J., Ahmad, S. F., Brown, J. K., Duncan, W. C., & Horne, A. W. (2015). Peritoneal VEGF-A expression is regulated by TGF-β1 through an ID1 pathway in women with endometriosis. Scientific Reports, 5(July), 1–9. https://doi.org/10.1038/srep16859

Zondervan, Krina T., D.Phil., Christian M. Becker, M. D., & and Stacey A. Missmer, S. D. (2020). Endometriosis, Review Article. The New England Journal of Medicine, 382(1244), 56. https://doi.org/10.1056/NEJMra1810764

Zondervan, K. T., Becker, C. M., Koga, K., Missmer, S. A., Taylor, R. N., & Viganò, P. (2018). Endometriosis. Nature Reviews Disease Primers, 4(1). https://doi.org/10.1038/s41572-018-0008-5




DOI: http://dx.doi.org/10.30829/contagion.v7i3.25355

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