Plumbagin attenuates high glucose-induced trophoblast cell apoptosis and insulin resistance via activating AKT/mTOR pathway
Main Article Content
Keywords
plumbagin, high glucose, trophoblast cell, insulin resistance, AKT/mTOR
Abstract
Plumbagin, a bioactive phytoconstituent, is isolated from the root of Plumbago zeylanica L. Plumbagin possesses antidiabetic effect to mediate glucose homeostasis, wound healing and diabetic nephropathy. However, the involvement of plumbagin in gestational diabetes mellitus (GDM) has not been reported yet. Trophoblast cell line (HTR8/SVneo) was incubated with high glucose to establish cell model of GDM. Cell viability and proliferation were detected by MTT and EdU staining. Flow cytometry was used to investigate cell apoptosis. Cell viability of HTR8/SVneo was reduced by high glucose or incubation of plumbagin. Plumbagin restored reduced cell viability and proliferation of HTR8/SVneo induced by high glucose. Plumbagin attenuated high glucose-induced cell apoptosis in HTR8/SVneo cells through upregulation of Bcl-2 and down-regulation of Bax, cleaved caspase-3 and cleaved caspase-9. Protein expression of glucose transporter type 4 (GLUT-4), insulin receptor (INSR)-B and INSR substrate (IRS1) was decreased in high glucose-induced HTR8/SVneo but increased by plumbagin. The suppressive effects of high glucose on phosphorylation of AKT and mTOR in HTR8/SVneo were reversed by plumbagin. Plumbagin improved high glucose-induced cell apoptosis and insulin resistance of HTR8/SVneo through activation of AKT/mTOR pathway, suggesting that plumbagin might be used as a potential strategy for the prevention of GDM.
References
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Yong, R., Chen, X.-M., Shen, S., Vijayaraj, S., Ma, Q., Pollock, C.A. and Saad, S., 2013. Plumbagin ameliorates diabetic nephropathy via interruption of pathways that include NOX4 signalling. PloS one 8: e73428. 10.1371/journal.pone.0073428
Yuan, J.-H., Pan, F., Chen, J., Chen, C.-E., Xie, D.-P., Jiang, X.-Z., Guo, S.-J. and Zhou, J., 2017. Neuroprotection by plumbagin involves BDNF-TrkB-PI3K/Akt and ERK1/2/JNK pathways in isoflurane-induced neonatal rats. Journal of Pharmacy and Pharmacology 69: 896–906. 10.1111/jphp.12681
Zhang, L., Zeng, M., Tang, F., Chen, J., Cao, D. and Tang, Z.-N., 2021. Circ-PNPT1 contributes to gestational diabetes mellitus (GDM) by regulating the function of trophoblast cells through miR-889-3p/PAK1 axis. Diabetology & Metabolic Syndrome 13: 58–58. 10.1186/s13098-021-00678-9
Zhou, X., Xiang, C. and Zheng, X., 2019. miR-132 serves as a diagnostic biomarker in gestational diabetes mellitus and its regulatory effect on trophoblast cell viability. Diagnostic pathology 14: 1–7.
Cai, Z., He, S., Li, T., Zhao, L. and Zhang, K., 2020. Plumbagin inhibits proliferation and promotes apoptosis of ovarian granulosa cells in polycystic ovary syndrome by inactivating PI3K/Akt/mTOR pathway. Animal Cells and Systems 24: 197–204. 10.1080/19768354.2020.1790416
Carrasco-Wong, I., Moller, A., Giachini, F.R., Lima, V.V., Toledo, F., Stojanova, J., Sobrevia, L. and San Martín, S., 2020. Placental structure in gestational diabetes mellitus. Biochimica et Biophysica Acta (BBA)–Molecular Basis of Disease 1866: 165535. 10.1016/j.bbadis.2019.165535
Chang, S.-C. and Vivian Yang, W.-C., 2013. Hyperglycemia induces altered expressions of angiogenesis associated molecules in the trophoblast. Evidence-Based Complementary and Alternative Medicine: eCAM 2013: 457971–457971. 10.1155/2013/457971
Chen, X.-J., Zhang, J.-G. and Wu, L., 2018. Plumbagin inhibits neuronal apoptosis, intimal hyperplasia and also suppresses TNF-α/NF-κB pathway-induced inflammation and matrix metalloproteinase-2/9 expression in rat cerebral ischemia. Saudi Journal of Biological Sciences 25: 1033–1039. 10.1016/j.sjbs.2017.03.006
Han, N., Fang, H.-Y., Jiang, J.-X. and Xu, Q., 2020. Downregulation of microRNA-873 attenuates insulin resistance and myocardial injury in rats with gestational diabetes mellitus by upregulating IGFBP2. American Journal of Physiology-Endocrinology and Metabolism 318: E723–E735. 10.1152/ajpendo.00555.2018
Ilekis, J.V., Tsilou, E., Fisher, S., Abrahams, V.M., Soares, M.J., Cross, J.C., Zamudio, S., Illsley, N.P., Myatt, L., Colvis, C., Costantine, M.M., Haas, D.M., Sadovsky, Y., Weiner, C., Rytting, E. and Bidwell, G., 2016. Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. American Journal of Obstetrics and Gynecology 215: S1–S46. 10.1016/j.ajog.2016.03.001
Kaiser, J., 2014. Gearing up for a closer look at the human placenta. Science 344: 1073. 10.1126/science.344.6188.1073
Lee, J.-H., Yeon, J.-H., Kim, H., Roh, W., Chae, J., Park, H.-O. and Kim, D.-M., 2012. The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation. PloS One 7: e45023. 10.1371/journal.pone.0045023
Li, J., Li, Y., Zhou, X., Wei, L., Zhang, J., Zhu, S., Zhang, H., Gao, X., Sharifu, L.M., Wang, S., Xi, L. and Feng, L., 2021. Upregulation of IL-15 in the placenta alters trophoblasts behavior contributing to gestational diabetes mellitus. Cell & Bioscience 11: 33. 10.1186/s13578-021-00533-4
Madazlı, R., Tuten, A., Calay, Z., Uzun, H., Uludag, S. and Ocak, V., 2008. The incidence of placental abnormalities, maternal and cord plasma malondialdehyde and vascular endothelial growth factor levels in women with gestational diabetes mellitus and nondiabetic controls. Gynecologic and Obstetric Investigation 65: 227–232. 10.1159/000113045
Malaeb, D., Hallit, S., Sacre, H., Hallit, R. and Salameh, P., 2020. Factors associated with wheezing among Lebanese children: results of a cross-sectional study. Allergologia et Immunopathologia 48: 523–529. 10.1016/j.aller.2020.02.003
Pai, S.A., Munshi, R.P., Panchal, F.H., Gaur, I.-S., Mestry, S.N., Gursahani, M.S. and Juvekar, A.R., 2019. Plumbagin reduces obesity and nonalcoholic fatty liver disease induced by fructose in rats through regulation of lipid metabolism, inflammation and oxidative stress. Biomedicine & Pharmacotherapy 111: 686–694. 10.1016/j.biopha.2018.12.139
Paul, A., Viswanathan, G.K., Mahapatra, S., Balboni, G., Pacifico, S., Gazit, E. and Segal, D., 2019. Antagonistic activity of naphthoquinone-based hybrids toward amyloids associated with Alzheimer’s disease and type-2 diabetes. ACS Chemical Neuroscience 10: 3510–3520. 10.1021/acschemneuro.9b00123
Peng, H.-Y., Li, H.-P. and Li, M.-Q., 2020. Downregulated ABHD5 aggravates insulin resistance of trophoblast cells during gestational diabetes mellitus. Reproductive Sciences 27: 233–245. 10.1007/s43032-019-00010-x
Shah, M.A., Keach, J.E. and Panichayupakaranant, P., 2018. Antidiabetic naphthoquinones and their plant resources in Thailand. Chemical and Pharmaceutical Bulletin 66: 483–492. 10.1248/cpb.c17-00529
Shao, Y., Dang, M., Lin, Y. and Xue, F., 2019. Evaluation of wound healing activity of plumbagin in diabetic rats. Life Sciences 231: 116422. 10.1016/j.lfs.2019.04.048
Sun, D.-G., Tian, S., Zhang, L., Hu, Y., Guan, C.-Y., Ma, X. and Xia, H.-F., 2020. The miRNA-29b Is downregulated in placenta during gestational diabetes mellitus and may alter placenta development by regulating trophoblast migration and invasion through a HIF3A-dependent mechanism. Frontiers in Endocrinology 11: 169. 10.3389/fendo.2020.00169
Sunil, C., Duraipandiyan, V., Agastian, P. and Ignacimuthu, S., 2012. Antidiabetic effect of plumbagin isolated from Plumbago zeylanica L. root and its effect on GLUT4 translocation in streptozotocin-induced diabetic rats. Food and Chemical Toxicology 50: 4356–4363. 10.1016/j.fct.2012.08.046
Tanase-Nakao, K., Arata, N., Kawasaki, M., Yasuhi, I., Sone, H., Mori, R. and Ota, E., 2017. Potential protective effect of lactation against incidence of type 2 diabetes mellitus in women with previous gestational diabetes mellitus: a systematic review and meta-analysis. Diabetes/Metabolism Research and Reviews 33: e2875. 10.1002/dmrr.2875
Tang, L., Li, P. and Li, L., 2020. Whole transcriptome expression profiles in placenta samples from women with gestational diabetes mellitus. Journal of Diabetes Investigation 11: 1307–1317. 10.1111/jdi.13250
Tsai, K., Tullis, B., Jensen, T., Graff, T., Reynolds, P. and Arroyo, J., 2021. Differential expression of mTOR related molecules in the placenta from gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR) and preeclampsia patients. Reproductive Biology 21: 100503. 10.1016/j.repbio.2021.100503
Vince, K., Perković, P. and Matijević, R., 2020. What is known and what remains unresolved regarding gestational diabetes mellitus (GDM). Journal of Perinatal Medicine 48: 757-763. 10.1515/jpm-2020-0254
Yan, B., Yu, Y., Lin, M., Li, Z., Wang, L., Huang, P., Song, H., Shi, X., Yang, S., Li, X. and Li, X., 2019. High, but stable, trend in the prevalence of gestational diabetes mellitus: a population-based study in Xiamen, China. Journal of Diabetes Investigation 10: 1358–1364. 10.1111/jdi.13039
Yin, Z., Zhang, J., Chen, L., Guo, Q., Yang, B., Zhang, W. and Kang, W., 2020. Anticancer Effects and Mechanisms of Action of Plumbagin: review of research advances. BioMed Research International 2020: 6940953–6940953. 10.1155/2020/6940953
Yong, R., Chen, X.-M., Shen, S., Vijayaraj, S., Ma, Q., Pollock, C.A. and Saad, S., 2013. Plumbagin ameliorates diabetic nephropathy via interruption of pathways that include NOX4 signalling. PloS one 8: e73428. 10.1371/journal.pone.0073428
Yuan, J.-H., Pan, F., Chen, J., Chen, C.-E., Xie, D.-P., Jiang, X.-Z., Guo, S.-J. and Zhou, J., 2017. Neuroprotection by plumbagin involves BDNF-TrkB-PI3K/Akt and ERK1/2/JNK pathways in isoflurane-induced neonatal rats. Journal of Pharmacy and Pharmacology 69: 896–906. 10.1111/jphp.12681
Zhang, L., Zeng, M., Tang, F., Chen, J., Cao, D. and Tang, Z.-N., 2021. Circ-PNPT1 contributes to gestational diabetes mellitus (GDM) by regulating the function of trophoblast cells through miR-889-3p/PAK1 axis. Diabetology & Metabolic Syndrome 13: 58–58. 10.1186/s13098-021-00678-9
Zhou, X., Xiang, C. and Zheng, X., 2019. miR-132 serves as a diagnostic biomarker in gestational diabetes mellitus and its regulatory effect on trophoblast cell viability. Diagnostic pathology 14: 1–7.
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