Nimbolide as a bioactive compound in food science: inhibition of proliferation and glycolysis in endometriosis cells
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Keywords
apoptosis, endometriosis, glycolysis, nimbolide, phosphoinositide 3-kinase/protein Kinase B (PI3K/AKT) pathway
Abstract
Endometriosis is a common gynecological disorder characterized by the ectopic growth of endometrial-like tissue, often leading to chronic pain and infertility. Despite its high prevalence, the underlying mechanisms are still poorly understood. Nimbolide, a bioactive compound derived from Azadirachta indica (neem), has been shown to possess various biological activities, including anti-malarial, anti-inflammatory, and anti-cancer properties. However, its effects on endometriosis have largely remained unexplored. Human endometriosis cell lines (End1/E6E7) were cultured and treated with varying concentrations of nimbolide for 48 hours. Cell proliferation was assessed using the MTT assay, and apoptosis was analyzed by flow cytometry with annexin V/PI staining. Cellular motility was evaluated using wound healing assays, glycolysis was examined by measuring lactate production, and Western blotting was performed to determine the expression levels of key proteins involved in the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT) signaling pathway. Our findings reveal that nimbolide inhibited the proliferation of human endometriosis cells by inducing apoptosis and suppressing cellular motility. Furthermore, it disrupted abnormal glycolysis. Mechanistic analysis showed that nimbolide exerted its effects by inhibiting the PI3K/AKT signaling pathway, a key regulator of cell growth and metabolism in endometriosis. These findings suggest that nimbolide may serve as a potential therapeutic agent for managing endometriosis by targeting cell proliferation, motility, and glycolytic metabolism through the inhibition of the PI3K/AKT pathway.
References
Bansod, S., Aslam Saifi, M., Khurana, A., & Godugu, C. (2020). Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating beta-catenin/Smad in a sirtuin-dependent way. Pharmacological Research, 156, 104756. 10.1016/j.phrs.2020.104756
Bansod, S., & Godugu, C. (2021). Nimbolide ameliorates pancreatic inflammation and apoptosis by modulating NF-kappaB/SIRT1 and apoptosis signaling in acute pancreatitis model. International Immunopharmacology, 90, 107246. 10.1016/j.intimp.2020.107246
Chen, X., Zhang, H., Pan, Y., Zhu, N., Zhou, L., Chen, G., & Wang, J. (2023). Nimbolide Exhibits Potent Anticancer Activity Through ROS-Mediated ER Stress and DNA Damage in Human Non-small Cell Lung Cancer Cells. Applied Biochemistry and Biotechnology. 10.1007/s12010-023-04507-9
Heydari, S., Kashani, L., & Noruzinia, M. (2021). Dysregulation of Angiogenesis and Inflammatory Genes in Endometrial Mesenchymal Stem Cells and Their Contribution to Endometriosis. Iranian Journal of Allergy, Asthma, and Immunology, 20(6), 740–750. 10.18502/ijaai.v20i6.8025
Huo, J., Ding, Y., Wei, X., Chen, Q., & Zhao, B. (2022). Antiosteoporosis and bone protective effect of nimbolide in steroid-induced osteoporosis rats. Journal of Biochemical and Molecular Toxicology, 36(12), e23209. 10.1002/jbt.23209
Incognito, G. G., Di Guardo, F., Gulino, F. A., Genovese, F., Benvenuto, D., Lello, C., & Palumbo, M. (2023). Interleukin-6 as A Useful Predictor of Endometriosis-Associated Infertility: A Systematic Review. International Journal of Fertility and Sterility, 17(4), 226–230. 10.22074/ijfs.2023.557683.1329
Jaiswara, P. K., & Kumar, A. (2022). Nimbolide retards T cell lymphoma progression by altering apoptosis, glucose metabolism, pH regulation, and ROS homeostasis. Environmental Toxicology, 37(6), 1445–1457. 10.1002/tox.23497
Katola, F. O., & Olajide, O. A. (2023). Nimbolide Targets Multiple Signalling Pathways to Reduce Neuroinflammation in BV-2 Microglia. Molecular Neurobiology, 60(9), 5450–5467. 10.1007/s12035-023-03410-y
Kumar, K., Narvekar, N. N., & Maslin, K. (2023). Self-managed dietary changes and functional gut symptoms in endometriosis: A qualitative interview study. European Journal of Obstetrics & Gynecology and Reproductive Biology X, 19, 100219. 10.1016/j.eurox.2023.100219
Luan, Y., Luan, Y., Feng, Q., Chen, X., Ren, K. D., & Yang, Y. (2021). Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases. Oxidative Medicine and Cellular Longevity, 2021, 3259963. 10.1155/2021/3259963
Mahmoud, N., Dawood, M., Huang, Q., Ng, J. P. L., Ren, F., Wong, V. K. W., & Efferth, T. (2022). Nimbolide inhibits 2D and 3D prostate cancer cells migration, affects microtubules and angiogenesis and suppresses B-RAF/p.ERK-mediated in vivo tumor growth. Phytomedicine, 94, 153826. 10.1016/j.phymed.2021.153826
Ngernprom, P., Klangsin, S., Suwanrath, C., & Peeyananjarassri, K. (2023). Risk factors for recurrent endometriosis after conservative surgery in a quaternary care center in southern Thailand. PLoS One, 18(8), e0289832. 10.1371/journal.pone.0289832
Pooladanda, V., Thatikonda, S., Bale, S., Pattnaik, B., Sigalapalli, D. K., Bathini, N. B., Singh, S. B., & Godugu, C. (2019). Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-alpha mediated NF-kappaB and HDAC-3 nuclear translocation. Cell Death & Disease, 10(2), 81. 10.1038/s41419-018-1247-9
Shin, S. S., Hwang, B., Muhammad, K., Gho, Y., Song, J. H., Kim, W. J., Kim, G., & Moon, S. K. (2019). Nimbolide Represses the Proliferation, Migration, and Invasion of Bladder Carcinoma Cells via Chk2-Mediated G2/M Phase Cell Cycle Arrest, Altered Signaling Pathways, and Reduced Transcription Factors-Associated MMP-9 Expression. Evidence-Based Complementary and Alternative Medicine, 2019, 3753587. 10.1155/2019/3753587
Singh, D., Mohapatra, P., Kumar, S., Behera, S., Dixit, A., & Sahoo, S. K. (2022). Nimbolide-encapsulated PLGA nanoparticles induces Mesenchymal-to-Epithelial Transition by dual inhibition of AKT and mTOR in pancreatic cancer stem cells. Toxicology In Vitro, 79, 105293. 10.1016/j.tiv.2021.105293
Suzuki, S., Ota, Y., Sano, R., Morimoto, Y., Moriya, T., & Shiota, M. (2022). Growing teratoma syndrome after surgery for ovarian immature teratoma. European Journal of Gynaecological Oncology, 43(1), 115-122. 10.31083/j.ejgo4301017
Szukiewicz, D. (2023). Insight into the Potential Mechanisms of Endocrine Disruption by Dietary Phytoestrogens in the Context of the Etiopathogenesis of Endometriosis. International Journal of Molecular Sciences, 24(15). 10.3390/ijms241512195
Teng, Y., Huang, Y., Yu, H., Wu, C., Yan, Q., Wang, Y., Yang, M., Xie, H., Wu, T., Yang, H., & Zou, J. (2023). Nimbolide targeting SIRT1 mitigates intervertebral disc degeneration by reprogramming cholesterol metabolism and inhibiting inflammatory signaling. Acta Pharmaceutica Sinica B, 13(5), 2269–2280. 10.1016/j.apsb.2023.02.018
Wan, Q.-Y., Liu, R.-F., Zou, Y., Luo, Y., Zhou, J.-Y., Deng, Y.-H., Zeng, X., Gao, G.-D., & Huang, O.-P. (2022). A rare variant in the MARVELD2 gene is associated with Chinese samples with ovarian endometriosis. EJGO, 43(1), 42–47. 10.31083/j.ejgo4301012
Xia, D., Chen, D., Cai, T., Zhu, L., Lin, Y., Yu, S., Zhu, K., Wang, X., Xu, L., & Chen, Y. (2022). Nimbolide attenuated the inflammation in the liver of autoimmune hepatitis’s mice through regulation of HDAC3. Toxicology and Applied Pharmacology, 434, 115795. 10.1016/j.taap.2021.115795
Zhang, J., Jung, Y. Y., Mohan, C. D., Deivasigamani, A., Chinnathambi, A., Alharbi, S. A., Rangappa, K. S., Hui, K. M., Sethi, G., & Ahn, K. S. (2022). Nimbolide enhances the antitumor effect of docetaxel via abrogation of the NF-kappaB signaling pathway in prostate cancer preclinical models. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1869(12), 119344. 10.1016/j.bbamcr.2022.119344
Zhang, L., Li, Y., Sun, D., & Bai, F. (2022). Protective Effect of Nimbolide against High Fat Diet-induced Obesity in Rats via Nrf2/HO-1 Pathway. Journal of Oleo Science, 71(5), 709–720. 10.5650/jos.ess21389
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