Plant-Derived Multi-Target Modulators for Pre-Gestational Diabetes: Systems Insights into Syzygium cumini for Maternal Health
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Pre-gestational diabetes (PGD), encompassing type 1 and type 2 diabetes diagnosed prior to conception, is a chronic metabolic disorder characterized by persistent hyperglycaemia, insulin resistance, impaired glucose uptake, and dysregulated lipid metabolism, posing substantial risks to maternal and fetal health. Given the multifactorial pathophysiology of PGD and limitations of single-target pharmacotherapy during pregnancy, this study aimed to elucidate the multi-target therapeutic potential of Syzygium cumini (S. cumini) bark phytoconstituents using an integrative network pharmacology and molecular docking approach. Comprehensive phytochemical profiling of the ethanolic bark extract was conducted using GC-MS and LC-HRMS, revealing fatty acids, sterol derivatives, and a flavonoid-dominant metabolite spectrum. Sixteen representative compounds were subjected to target prediction and mapped to PGD-related genes. The Protein–protein interaction analysis and functional enrichment (GO and KEGG) identified central regulatory nodes including PPAR-γ, glucose transporter (GLUT) proteins, and insulin receptor substrates associated with insulin signaling and metabolic homeostasis. Molecular docking against five PGD-relevant proteins (PDB IDs: 2PRG, 5EQI, 7WSN, 4F1D, 4ZW9) demonstrated strong binding affinities for flavonoids (quercetin, myricetin, kaempferol) and phytosterols (-8.1 to -10.4 kcal/mol), supporting the structural plausibility of multi-target interactions. Collectively, this study provides a systems-level mechanistic framework highlighting the potential of S. cumini as a complementary multi-pathway modulator in the management of pre-gestational diabetes.
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[1] I.D.F. (2015). IDF Diabetes Atlas 11th Edition. International Diabetes Federation (IDF), Brussels, Belgium.
[2] McIntyre, H. D., Catalano, P., Zhang, C., Desoye, G., Mathiesen, E. R., & Damm, P. (2019). Gestational diabetes mellitus. Nature Reviews Disease Primers, 5(1), 47. doi:10.1038/s41572-019-0098-8.
[3] Bardenheier, B. H., Imperatore, G., Devlin, H. M., Kim, S. Y., Cho, P., & Geiss, L. S. (2015). Trends in pre-pregnancy diabetes among deliveries in 19 U.S. states, 2000-2010. American Journal of Preventive Medicine, 48(2), 154–161. doi:10.1016/j.amepre.2014.08.031.
[4] Guariguata, L., Linnenkamp, U., Beagley, J., Whiting, D. R., & Cho, N. H. (2014). Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Research and Clinical Practice, 103(2), 176–185. doi:10.1016/j.diabres.2013.11.003.
[5] Baliga, M. S., Bhat, H. P., Baliga, B. R. V., Wilson, R., & Palatty, P. L. (2011). Phytochemistry, traditional uses and pharmacology of Eugenia jambolana Lam. (black plum): A review. Food Research International, 44(7), 1776–1789. doi:10.1016/j.foodres.2011.02.007.
[6] Hasanuzzaman, M., Islam, W., & Islam, M. (2018). Phytochemical screening of Syzygium cumini (L.) extracts in different solvents. Journal of Bio-Science, 24, 11–18. doi:10.3329/jbs.v24i0.37483.
[7] Perera, P. R. D., Ekanayake, S., & Ranaweera, K. K. D. S. (2017). Antidiabetic compounds in Syzygium cumini decoction and ready to serve herbal drink. Evidence-Based Complementary and Alternative Medicine, 2017(1), 1083589. doi:10.1155/2017/1083589.
[8] Saravanan, G., & Pari, L. (2008). Hypoglycaemic and antihyperglycaemic effect of Syzygium cumini bark in streptozotocin-induced diabetic rats. Journal of Pharmacology and Toxicology, 3(1), 1–10. doi:10.3923/jpt.2008.1.10.
[9] Mulkalwar, S., Kulkarni, V., Deshpande, T., Bhide, H., Patel, A., & Tilak, A. V. (2021). Antihyperglycemic activity of Syzygium cumini (Jamun) in diabetic rats. Journal of Pharmaceutical Research International, 33, 12–19. doi:10.9734/jpri/2021/v33i35a31868.
[10] Sharma, S., Pathak, S., Gupta, G., Sharma, S. K., Singh, L., Sharma, R. K., Mishra, A., & Dua, K. (2017). Pharmacological evaluation of aqueous extract of Syzigium cumini for its antihyperglycemic and antidyslipidemic properties in diabetic rats fed a high cholesterol diet—Role of PPARγ and PPARα. Biomedicine and Pharmacotherapy, 89, 447–453. doi:10.1016/j.biopha.2017.02.048.
[11] Mujawah, A., Rauf, A., Bawazeer, S., Wadood, A., Hemeg, H. A., & Bawazeer, S. (2023). Isolation, structural elucidation, in vitro anti-α-glucosidase, anti-β-secretase, and in silico studies of bioactive compound isolated from Syzygium cumini L. Processes, 11(3), 880. doi:10.3390/pr11030880.
[12] Prasad, M. D., & Naik, J. M. (2014). Ameliorative potential of aqueous leaves extract of Syzygium cumini (L) associated metabolic alterations in alloxan induced diabetic rats. Journal of Pharmacognosy and Phytochemistry, 3(3), 168–172.
[13] Bhuyan, Z. A., Rokeya, B., Masum, N., Hossain, S., & Mahmud, I. (1970). Antidiabetic effect of Syzygium cumini L. seed on type 2 diabetic rats. Dhaka University Journal of Biological Sciences, 19(2), 157–164. doi:10.3329/dujbs.v19i2.8959.
[14] Dubey, V., Kansagra, J., Kamani, B., & Sureja, V. (2025). Network pharmacology study to identify molecular pathways involved in the anti-diabetic activity of Syzygium cumini seed constituents. AIMS Molecular Science, 12(3), 255–271. doi:10.3934/molsci.2025016.
[15] Soundaryalakshmi, S., Thirunavukkarasu, M. K., & Vasanthi, M. (2026). Integrative network pharmacology and glucose uptake studies identify potential phytochemicals from Syzygium cumini as promising antidiabetic agents. Chemistry and Biodiversity, 23(1), 1602. doi:10.1002/cbdv.202501602.
[16] Santy, P., Sutriana, A., Nizwan Siregar, T., & Sofyan, H. (2025). Phytochemical profiling of Syzygium cumini L.: A comparative study of extraction efficiency using n-hexane, ethyl acetate, and ethanol. IOP Conference Series: Earth and Environmental Science, 1510(1), 12022. doi:10.1088/1755-1315/1510/1/012022.
[17] Sitio, R., Akmal, M., Marlina, M., & Gholib, G. (2024). Investigating ethanolic extract from Acehnese lime (Citrus aurantifolia) peel as potential anti-hypercholesterolemia agent. Journal of Human, Earth, and Future, 5(3), 348–365. doi:10.28991/hef-2024-05-03-04.
[18] Maulydia, N. B., Khairan, K., Tallei, T. E., & Idroes, R. (2025). Metabolomic profiling and anti-inflammatory activity of Blumea balsamifera: Insights from in silico and in vitro studies. Pharmacia, 72, 1–15. doi:10.3897/pharmacia.72.e146995.
[19] Daina, A., Michielin, O., & Zoete, V. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research, 47(W1), W357–W3664. doi:10.1093/nar/gkz382.
[20] Stelzer, G., Rosen, N., Plaschkes, I., Zimmerman, S., Twik, M., Fishilevich, S., & Lancet, D. (2016). The GeneCards suite: from gene data mining to disease genome sequence analyses. Current Protocols in Bioinformatics, 54(1), 1-30. doi:10.1002/cpbi.5.
[21] Hamosh, A., Scott, A. F., Amberger, J. S., Bocchini, C. A., & McKusick, V. A. (2005). Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Research, 33, 514–517. doi:10.1093/nar/gki033.
[22] Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2023). PubChem 2023 update. Nucleic Acids Research, 51(D1), D1373–D1380. doi:10.1093/nar/gkac956.
[23] Maulydia, N. B., Khairan, K., Tallei, T. E., & Idroes, R. (2025). Unveiling metabolite compounds and anti-inflammatory properties from Chromolaena odorata in three geothermal areas. Indonesian Journal of Pharmacy, 646–660. doi:10.22146/ijp.15973.
[24] Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: An overview. Journal of Nutritional Science, 5. doi:10.1017/jns.2016.41.
[25] Williamson, G., Kay, C. D., & Crozier, A. (2018). The bioavailability, transport, and bioactivity of dietary flavonoids: A review from a historical perspective. Comprehensive Reviews in Food Science and Food Safety, 17(5), 1054–1112. doi:10.1111/1541-4337.12351.
[26] Illsley, N. P. (2000). Glucose transporters in the human placenta. Placenta, 21(1), 14–22. doi:10.1053/plac.1999.0448.
[27] Sciullo, E., Cardellini, G., Baroni, M., Torresi, P., Mazziotti, F., Pozzilli, P., & Fallucca, F. (1997). Glucose transporters (GLUT 1, GLUT 3) mRNA in human placenta of diabetic and non-diabetic pregnancies. Annali Dell’Istituto Superiore Di Sanita, 33(3), 361–365.
[28] Feng, C., Jin, Z., Sun, L., Wang, X., Chi, X., Zhang, X., & Lian, S. (2019). Endogenous SHBG levels correlate with that of glucose transporters in insulin resistance model cells. Molecular Biology Reports, 46(5), 4953–4965. doi:10.1007/s11033-019-04946-w.
[29] Garvey, W. T., Maianu, L., Zhu, J. H., Hancock, J. A., & Golichowski, A. M. (1993). Multiple defects in the adipocyte glucose transport system cause cellular insulin resistance in gestational diabetes: Heterogeneity in the number and a novel abnormality in subcellular localization of GLUT4 glucose transporters. Diabetes, 42(12), 1773–1785. doi:10.2337/diab.42.12.1773.
[30] Armoni, M., Harel, C., & Karnieli, E. (2007). Transcriptional regulation of the GLUT4 gene: from PPAR-γ and FOXO1 to FFA and inflammation. Trends in Endocrinology and Metabolism, 18(3), 100–107. doi:10.1016/j.tem.2007.02.001.
[31] Liao, W., Nguyen, M. T. A., Yoshizaki, T., Favelyukis, S., Patsouris, D., Imamura, T., Verma, I. M., & Olefsky, J. M. (2007). Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes. American Journal of Physiology - Endocrinology and Metabolism, 293(1), 219-227. doi:10.1152/ajpendo.00695.2006.
[32] Khairan, K., Maulydia, N. B., Faddillah, V., Tallei, T. E., Fauzi, F. M., & Idroes, R. (2024). Uncovering anti-inflammatory potential of Lantana camara Linn: Network pharmacology and in vitro studies. Narra J, 4(2), 1–16. doi:10.52225/narra.v4i2.894.
[33] Saltiel, A. R., & Kahn, C. R. (2001). Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 414(6865), 799–806. doi:10.1038/414799a.
[34] Huang, S., & Czech, M. P. (2007). The GLUT4 Glucose Transporter. Cell Metabolism, 5(4), 237–252. doi:10.1016/j.cmet.2007.03.006.
[35] Mueckler, M., & Thorens, B. (2013). The SLC2 (GLUT) family of membrane transporters. Molecular Aspects of Medicine, 34(2–3), 121–138. doi:10.1016/j.mam.2012.07.001.
[36] Simpson, I. A., Dwyer, D., Malide, D., Moley, K. H., Travis, A., & Vannucci, S. J. (2008). The facilitative glucose transporter GLUT3: 20 Years of distinction. American Journal of Physiology - Endocrinology and Metabolism, 295(2), 242–253. doi:10.1152/ajpendo.90388.2008.
[37] Ren, L., Qin, X., Cao, X., Wang, L., Bai, F., Bai, G., & Shen, Y. (2011). Structural insight into substrate specificity of human intestinal maltase-glucoamylase. Protein and Cell, 2(10), 827–836. doi:10.1007/s13238-011-1105-3.
[38] Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., & Kliewer, S. A. (1995). An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). Journal of Biological Chemistry, 270(22), 12953–12956. doi:10.1074/jbc.270.22.12953.
[39] Zhabinskii, V. N., Drasar, P., & Khripach, V. A. (2022). Structure and biological activity of ergostane-type steroids from fungi. Molecules, 27(7), 1–53. doi:10.3390/molecules27072103.
[40] Dhanya, R. (2022). Quercetin for managing type 2 diabetes and its complications, an insight into multitarget therapy. Biomedicine and Pharmacotherapy, 146, 112560. doi:10.1016/j.biopha.2021.112560.
[41] Jump, D. B. (2002). The biochemistry of n-3 polyunsaturated fatty acids. Journal of Biological Chemistry, 277(11), 8755–8758. doi:10.1074/jbc.R100062200.
[42] Ajiboye, B. O., Ojo, O. A., Akuboh, O. S., Abiola, O. M., Idowu, O., & Amuzat, A. O. (2018). Anti-hyperglycemic and anti-inflammatory activities of polyphenolic-rich extract of Syzygium cumini linn leaves in alloxan-induced diabetic rats. Journal of Evidence-Based Integrative Medicine, 23, 1–8. doi:10.1177/2515690X18770630.
[43] Sidana, S., Singh, V. B., Meena, B. L., Beniwal, S., Singh, K., Kumar, D., & Singla, R. (2017). Effect of Syzygium cumini (Jamun) seed powder on glycemic control: A double-blind randomized controlled trial. JMS - Journal of Medical Society, 31(3), 185–189. doi:10.4103/jms.jms_62_16.
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