Identification and Network Analyses of Salicylic Acid-Induced Overexpression of P-Glycoprotein Inhibitors in Sesamum indicum and Coriandrum sativum
Abstract
Background: Plants are major sources of bioactive metabolites, contributing to over one-third of modern pharmaceuticals. These metabolites arise from primary and secondary metabolic pathways essential for plant growth and defense. Salicylic acid, a phytohormone, acts as an elicitor that enhances secondary metabolite biosynthesis. Such metabolites may help overcome multidrug resistance, particularly through inhibition of the efflux transporter P-glycoprotein. Objectives: Building on previous identification of P-glycoprotein inhibitors via molecular docking, this study investigated their biosynthetic pathways and evaluated the impact of salicylic acid elicitation on the phytochemical profiles of selected medicinal plants. Methods: Biosynthetic pathways of identified inhibitor compounds were retrieved from the Plant Metabolic Network database and analyzed to identify common enzymes. Protein–protein interaction analysis was conducted using the STRING database. For elicitation studies, Sesamum indicum and Coriandrum sativum were treated with salicylic acid on alternate days. Harvested seeds were subjected to GC-MS profiling to assess phytochemical changes. Results and Conclusion: Twelve of 33 inhibitors were mapped to phytosterol, tocopherol, sesamin, and cis-abienol biosynthesis pathways, involving 14 common enzymes. Among these, 3β-hydroxysteroid-4α-carboxylate 3-dehydrogenase (decarboxylating) showed the highest connectivity, highlighting its role in sterol biosynthesis. GC-MS analysis revealed that elicited Sesamum indicum showed an increase in phytochemicals from 22 to 50, with potential P-glycoprotein inhibitor candidates increasing from 4 to 19. In Coriandrum sativum, compounds increased from 42 to 44. Salicylic acid elicitation enhanced phytochemical diversity and increased the occurrence of compounds previously reported as potential P-glycoprotein inhibitors, particularly in Sesamum indicum, highlighting its utility as an elicitor for modulating secondary metabolite production.
Keywords:
GC-MS, P-Glycoprotein Inhibitors, S`esamum Indicum, Salicylic Acid
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References
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Kianersi, F., Amin Azarm, D., Fatemi, F., Pour-Aboughadareh, A., &Poczai, P. (2022). Methyl jasmonate induces genes involved in linalool accumulation and increases the content of phenolics in two Iranian coriander (Coriandrum sativum L.) Ecotypes. Genes, 13(10), 1717. https://doi.org/10.3390/genes13101717
Kumar, K., Debnath, P., Singh, S., & Kumar, N. (2023). An overview of plant phenolics and their involvement in abiotic stress tolerance. Stresses, 3(3), 570-585. https://doi.org/10.3390/stresses3030040
Mukhopadhyay, S., Roy, C., & Ghosh, P. (2024). Spice components as modulating agents of P-glycoprotein–An in-silico study. Indian Journal of Pharmacology, 56(3), 214-219. https://doi.org/10.4103/ijp.ijp_299_23
Munir, S., Shahzad, A. N., Rai, A., Petrov, V., Gechev, T., Shokat, S., & Qureshi, M. K. (2025). Reactive oxygen species production and signal transduction in response to stress triggered by Alternaria elicitors in Brassicaceae. Plant Molecular Biology, 115, 113. https://doi.org/10.1007/s11103-025-01639-w
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Pham, T. H., Lee, G. H., Jin, S. W., Lee, S. Y., Han, E. H., Kim, N. D., ... & Jeong, H. G. (2023). Sesamin ameliorates lipotoxicity and lipid accumulation through the activation of the estrogen receptor alpha signaling pathway. Biochemical Pharmacology, 216, 115768. https://doi.org/10.1016/j.bcp.2023.115768
Puthusseri, B., Divya, P., Lokesh, V., &Neelwarne, B. (2013). Salicylic acid-induced elicitation of folates in coriander (Coriandrum sativum L.) improves bioaccessibility and reduces pro-oxidant status. Food Chemistry, 136(2), 569-575. https://doi.org/10.1016/j.foodchem.2012.09.005
Qadir, A., Ali, A., Arif, M., Al-Rohaimi, A. H., Singh, S. P., Ahmad, U., ... & Kumar, A. (2018). Solvent extraction and GC-MS analysis of sesame seeds for determination of bioactive antioxidant fatty acid/fatty oil components. Drug Research, 68(06), 344-348. https://doi.org/10.1055/s-0043-123466
Rao, M. J., Duan, M., Zhou, C., Jiao, J., Cheng, P., Yang, L., ... & Zheng, B. (2025). Antioxidant defense system in plants: reactive oxygen species production, signaling, and scavenging during abiotic stress-induced oxidative damage. Horticulturae, 11(5), 477. https://doi.org/10.3390/horticulturae11050477
Singh, S. (2023). Salicylic acid elicitation improves antioxidant activity of spinach leaves by increasing phenolic content and enzyme levels. Food Chemistry Advances, 2, 100156. https://doi.org/10.1016/j.focha.2022.100156
Srivastava, S. (2024). A review on biosynthetic pathways in plants. International Journal of Research Publication and Reviews, 5(2), 668-673. https://doi.org/10.55248/gengpi.5.0224.0422
Szklarczyk, D., Gable, A. L., Nastou, K. C., Lyon, D., Kirsch, R., Pyysalo, S., ... & von Mering, C. (2021). The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Research, 49(D1), D605-D612. https://doi.org/10.1093/nar/gkaa1074
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Veiga-Matos, J., Morales, A. I., Prieto, M., Remião, F., & Silva, R. (2023). Study models of drug–drug interactions involving P-glycoprotein: the potential benefit of P-glycoprotein modulation at the kidney and intestinal levels. Molecules, 28(22), 7532. https://doi.org/10.3390/molecules28227532
Wu, L., Wang, S., Liu, H., Pei, M., Shi, Q., Guo, D., & Wei, T. (2026). Research progress on the synthesis, signal transduction, and functions of plant hormones in potassium deficiency responses. Journal of Plant Growth Regulation, 1-21. https://doi.org/10.1007/s00344-026-12241-9
Yeasmin, S., Chowdhury, T. A., Rana, G. M., Rahman, M. M., & Ferdousi, L. (2021). Characteristics of Sesame (Sesamum Indi-cum L.) seed meal grown in the Northern region of Bangladesh. Biomedical Journal of Scientific & Technical Research, 38(1), 29944-29949. http://dx.doi.org/10.26717/BJSTR.2021.38.006083
Yruela, I. (2015). Plant development regulation: Overview and perspectives. Journal of Plant Physiology, 182, 62-78. https://doi.org/10.1016/j.jplph.2015.05.006
Yu, J., Zhou, P., Asenso, J., Yang, X. D., Wang, C., & Wei, W. (2016). Advances in plant-based inhibitors of P-glycoprotein. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(6), 867-881. https://doi.org/10.3109/14756366.2016.1149476
Abdallah, H. M., Al-Abd, A. M., El-Dine, R. S., & El-Halawany, A. M. (2015). P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review. Journal of Advanced Research, 6(1), 45-62. https://doi.org/10.1016/j.jare.2014.11.008
Ali, B. (2021). Salicylic acid: An efficient elicitor of secondary metabolite production in plants. Biocatalysis and Agricultural Biotechnology, 31, 101884. https://doi.org/10.1016/j.bcab.2020.101884
Dar, A. A., Kancharla, P. K., Chandra, K., Sodhi, Y. S., & Arumugam, N. (2019). Assessment of variability in lignan and fatty acid content in the germplasm of Sesamum indicum L. Journal of Food Science and Technology, 56(2), 976-986. https://doi.org/10.1007/s13197-018-03564-x
Ejtahed, R. S., Radjabian, T., &Hoseini Tafreshi, S. A. (2015). Expression analysis of phenylalanine ammonia lyase gene and rosmarinic acid production in Salvia officinalis and Salvia virgata shoots under salicylic acid elicitation. Applied Biochemistry and Biotechnology, 176(7), 1846-1858. https://doi.org/10.1007/s12010-015-1682-3
Fahey, J. W., & Liu, H. (2026). Sulforaphane Synergies with Phytochemicals and Pharmaceuticals: Implications for Healthspan. Medicines, 13(2), 16. https://doi.org/10.3390/medicines13020016
Gandla, K., Islam, F., Zehravi, M., Karunakaran, A., Sharma, I., Haque, M. A., ... & Khandaker, M. U. (2023). Natural polymers as potential P-glycoprotein inhibitors: Pre-ADMET profile and computational analysis as a proof of concept to fight multidrug resistance in cancer. Heliyon, 9(9). https://doi.org/10.1016/j.heliyon.2023.e19454
Guo, M., Lv, H., Chen, H., Dong, S., Zhang, J., Liu, W., ... & Luo, H. (2024). Strategies on biosynthesis and production of bioactive compounds in medicinal plants. Chinese Herbal Medicines, 16(1), 13-26. https://doi.org/10.1016/j.chmed.2023.01.007
Harish, A., Deepika, N., Joshi, V., &Goudanavar, P. S. (2025). Advanced strategies to overcome multidrug resistance in cancer therapy: Progress in P-glycoprotein inhibitors, drug delivery, and personalized medicine. Investigational new Drugs, 43(4), 1086-1108. https://doi.org/10.1007/s10637-025-01562-3
Hatta, M. H.M., Amran, N., Kamisan, F. H., Daud, M. H., Manaf, M. F. A., Chelilah, K. K., & Karim, N. A. (2026). Recent Progress on Polyphenols of Malaysian Honey and Their Molecular Mechanism Pathways in Cancer—A Comprehensive Review. International Journal of Molecular Sciences, 27(7), 3074. https://doi.org/10.3390/ijms27073074
Karalija, E., Macanović, A., &Ibragić, S. (2025). Revisiting traditional medicinal plants: integrating multiomics, in vitro culture, and elicitation to unlock bioactive potential. Plants, 14(13), 2029. https://doi.org/10.3390/plants14132029
Khan, M. I. R., Fatma, M., Per, T. S., Anjum, N. A., & Khan, N. A. (2015). Salicylic acid-induced abiotic stress tolerance and underlying mechanisms in plants. Frontiers in Plant Science, 6, 462. https://doi.org/10.3389/fpls.2015.00462
Khan, M. I. R., Iqbal, N., Masood, A., Per, T. S., & Khan, N. A. (2013). Salicylic acid alleviates adverse effects of heat stress on photosynthesis through changes in proline production and ethylene formation. Plant Signaling&Behavior, 8(11), e26374. https://doi.org/10.4161/psb.26374
Kianersi, F., Amin Azarm, D., Fatemi, F., Pour-Aboughadareh, A., &Poczai, P. (2022). Methyl jasmonate induces genes involved in linalool accumulation and increases the content of phenolics in two Iranian coriander (Coriandrum sativum L.) Ecotypes. Genes, 13(10), 1717. https://doi.org/10.3390/genes13101717
Kumar, K., Debnath, P., Singh, S., & Kumar, N. (2023). An overview of plant phenolics and their involvement in abiotic stress tolerance. Stresses, 3(3), 570-585. https://doi.org/10.3390/stresses3030040
Mukhopadhyay, S., Roy, C., & Ghosh, P. (2024). Spice components as modulating agents of P-glycoprotein–An in-silico study. Indian Journal of Pharmacology, 56(3), 214-219. https://doi.org/10.4103/ijp.ijp_299_23
Munir, S., Shahzad, A. N., Rai, A., Petrov, V., Gechev, T., Shokat, S., & Qureshi, M. K. (2025). Reactive oxygen species production and signal transduction in response to stress triggered by Alternaria elicitors in Brassicaceae. Plant Molecular Biology, 115, 113. https://doi.org/10.1007/s11103-025-01639-w
Ni, J., Dong, L., Jiang, Z., Yang, X., Sun, Z., Li, J., ... & Xu, M. (2018). Salicylic acid-induced flavonoid accumulation in Ginkgo biloba leaves is dependent on red and far-red light. Industrial Crops and Products, 118, 102-110. https://doi.org/10.1016/j.indcrop.2018.03.044
Pham, T. H., Lee, G. H., Jin, S. W., Lee, S. Y., Han, E. H., Kim, N. D., ... & Jeong, H. G. (2023). Sesamin ameliorates lipotoxicity and lipid accumulation through the activation of the estrogen receptor alpha signaling pathway. Biochemical Pharmacology, 216, 115768. https://doi.org/10.1016/j.bcp.2023.115768
Puthusseri, B., Divya, P., Lokesh, V., &Neelwarne, B. (2013). Salicylic acid-induced elicitation of folates in coriander (Coriandrum sativum L.) improves bioaccessibility and reduces pro-oxidant status. Food Chemistry, 136(2), 569-575. https://doi.org/10.1016/j.foodchem.2012.09.005
Qadir, A., Ali, A., Arif, M., Al-Rohaimi, A. H., Singh, S. P., Ahmad, U., ... & Kumar, A. (2018). Solvent extraction and GC-MS analysis of sesame seeds for determination of bioactive antioxidant fatty acid/fatty oil components. Drug Research, 68(06), 344-348. https://doi.org/10.1055/s-0043-123466
Rao, M. J., Duan, M., Zhou, C., Jiao, J., Cheng, P., Yang, L., ... & Zheng, B. (2025). Antioxidant defense system in plants: reactive oxygen species production, signaling, and scavenging during abiotic stress-induced oxidative damage. Horticulturae, 11(5), 477. https://doi.org/10.3390/horticulturae11050477
Singh, S. (2023). Salicylic acid elicitation improves antioxidant activity of spinach leaves by increasing phenolic content and enzyme levels. Food Chemistry Advances, 2, 100156. https://doi.org/10.1016/j.focha.2022.100156
Srivastava, S. (2024). A review on biosynthetic pathways in plants. International Journal of Research Publication and Reviews, 5(2), 668-673. https://doi.org/10.55248/gengpi.5.0224.0422
Szklarczyk, D., Gable, A. L., Nastou, K. C., Lyon, D., Kirsch, R., Pyysalo, S., ... & von Mering, C. (2021). The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Research, 49(D1), D605-D612. https://doi.org/10.1093/nar/gkaa1074
Tian, Y., Lei, Y., Wang, Y., Lai, J., Wang, J., & Xia, F. (2023). Mechanism of multidrug resistance to chemotherapy mediated by P-glycoprotein. International Journal of Oncology, 63(5), 119. https://doi.org/10.3892/ijo.2023.5567
Veiga-Matos, J., Morales, A. I., Prieto, M., Remião, F., & Silva, R. (2023). Study models of drug–drug interactions involving P-glycoprotein: the potential benefit of P-glycoprotein modulation at the kidney and intestinal levels. Molecules, 28(22), 7532. https://doi.org/10.3390/molecules28227532
Wu, L., Wang, S., Liu, H., Pei, M., Shi, Q., Guo, D., & Wei, T. (2026). Research progress on the synthesis, signal transduction, and functions of plant hormones in potassium deficiency responses. Journal of Plant Growth Regulation, 1-21. https://doi.org/10.1007/s00344-026-12241-9
Yeasmin, S., Chowdhury, T. A., Rana, G. M., Rahman, M. M., & Ferdousi, L. (2021). Characteristics of Sesame (Sesamum Indi-cum L.) seed meal grown in the Northern region of Bangladesh. Biomedical Journal of Scientific & Technical Research, 38(1), 29944-29949. http://dx.doi.org/10.26717/BJSTR.2021.38.006083
Yruela, I. (2015). Plant development regulation: Overview and perspectives. Journal of Plant Physiology, 182, 62-78. https://doi.org/10.1016/j.jplph.2015.05.006
Yu, J., Zhou, P., Asenso, J., Yang, X. D., Wang, C., & Wei, W. (2016). Advances in plant-based inhibitors of P-glycoprotein. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(6), 867-881. https://doi.org/10.3109/14756366.2016.1149476
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Mukhopadhyay, S., Ganguli, S. and Ghosh, P. (2026) “Identification and Network Analyses of Salicylic Acid-Induced Overexpression of P-Glycoprotein Inhibitors in Sesamum indicum and Coriandrum sativum”, International Journal of Advancement in Life Sciences Research, 9(3), pp. 123-135. doi: https://doi.org/10.31632/ijalsr.2026.v09i03.010.
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