Anti-Acetylcholinesterase and Synergistic Antifungal Activities of Selected Salvia Species: Correlation with Metabolic Profiles

Year 2022, Volume: 5 Issue: 2, 136 - 145, 02.01.2023

Gamze Benli Yardımcı , Nurnehir Baltacı , Çiğdem Kahraman , Ekrem Murat Gönülalan

https://doi.org/10.38093/cupmap.1209073

Abstract

Salvia species are known for their anti-fungal and anti-acetylcholinesterase (AChE) activity. Metabolomics is defined as a comprehensive quantitative and qualitative analysis of large-scale metabolites. In this study, besides determining anti-acetylcholinesterase and synergistic antifungal activities of selected Salvia species (S. cryptantha, S. tchihatcheffii, S. officinalis, S. virgata), the metabolite profiles were clarified and correlation analyzes between the activity results and profiles were carried out. Aerial parts of all plant materials were extracted by methanol to determine the metabolic profile by using GC-MS (Gas Chromatography-Mass Spectrometry) and LC-QTOF-MS (Liquid Chromatography Quadrupole Time of Flight Mass Spectrometry). Also, Ellman's spectrophotometric method for anti-acetylcholinesterase activity and the checkerboard method for synergistic antifungal activity between extracts and fluconazole were performed. 295 known and 1408 unknown metabolites were detected in GC-MS while 346 known and 69008 unknown metabolites in LC-QTOF-MS. S. cryptantha, S. tchihatcheffii, S. officinalis, and S. virgata demonstrated inhibitory activities on AChE with the ratio of 32.72%, 5.9%, 43.96%, and 12.1% at the concentration of 200 µg/m and a synergism was found for all Salvia sp. against Candida tropicalis ATCC 750 strain with the FICI values of 0.28, 0.15, 0.10, 0.5 respectively. In addition, as a result of correlation analysis, 73 metabolites positively and 31 metabolites negatively correlated with anti-acetylcholinesterase activity, while 18 metabolites positively, and 117 metabolites negatively correlated with synergistic activity were found. All Salvia species exhibited synergic activity with fluconazole while having weak AChE inhibitory activity. Combining natural products with synthetic drugs is important in order to increase efficacy. At the same time, herbal products must be used carefully at the point of herb-drug interactions. Further studies are needed to investigate active metabolites according to correlation results.

Keywords

Acetylcholinesterase inhibitory activity, Metabolomics, Salvia, Synergism, Candida

Supporting Institution

Afyonkarahisar Health Sciences University Scientific Research Projects

Project Number

Project No: 19. TEMATİK.007, Project no: 20. GENEL. 018

Thanks

Special thanks to Afyonkarahisar Health Sciences University Scientific Research Projects

References

• 1. Ahmad, A., Khan, A., & Manzoor, N. (2013). Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole. European Journal of Pharmaceutical Sciences, 48(1-2), 80-86. DOI:10.1016/j.ejps.2012.09.016
• 2. Alkhalifa, B. A., Bulatova, N. R., & Darwish, R. M. (2022). Serotonin reuptake inhibitors effect on fluconazole activity against resistant Candida glabrata strains. Journal of Global Antimicrobial Resistance, 29, 49-54. DOI:10.1016/j.jgar.2022.01.030
• 3. Amaro-Luis, J. M., Herrera, J. R., & Luis, J. G. (1998). Abietane diterpenoids from Salvia chinopeplica. Phytochemistry, 47(5), 895-897.
• 4. Arastehfar, A., Hilmioğlu-Polat, S., Daneshnia, F., Hafez, A., Salehi, M., Polat, F., ... & Lass-Flörl, C. (2020). Recent increase in the prevalence of fluconazole-non-susceptible Candida tropicalis blood isolates in Turkey: Clinical implication of azole-non-susceptible and fluconazole tolerant phenotypes and genotyping. Frontiers in microbiology, 11, 587278. DOI: 10.3389/fmicb.2020.587278
• 5. Bibi, M., Murphy, S., Benhamou, R. I., Rosenberg, A., Ulman, A., Bicanic, T., ... & Berman, J. (2021). Combining colistin and fluconazole synergistically increases fungal membrane permeability and antifungal cidality. ACS infectious diseases, 7(2), 377-389. DOI:10.1021/acsinfecdis.0c00721
• 6. Björkholm, C., & Monteggia, L. M. (2016). BDNF--a key transducer of antidepressant effects. Neuropharmacology, 102, 72-79. DOI:10.1016/j.neuropharm.2015.10.034
• 7. Canturk, Z. (2018). Evaluation of synergistic anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans. journal of food and drug analysis, 26(1), 439-443. DOI: 10.1016/j.jfda.2016.12.014
• 8. Clinical and Laboratory Standards Institute (2008). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts-Third Edition: Approved Standard M27-A3; CLSI: Wayne, PA, USA,; Volume 28.
• 9. Ellman, G. L., Courtney, K. D., Andres Jr, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology, 7(2), 88-95
• 10. Ermenlieva, N., Georgieva, E., Mihaylova, S., Stamova, S., Laleva, K., Tsankova, G., & Tsvetkova, A. (2022). Synergistic Interaction Between Lamiaceae Essential Oils and Antifungal Drugs Against Candida albicans Atcc 10231. biofilms, 70, 4:720-725. DOI: 10.31925/farmacia.2022.4.18
• 11. Gonulalan, E. M., Nemutlu, E., Bayazeid, O., Kocak, E., Yalçın, F. N., & Demirezer, L. O. (2020). Metabolomics and proteomics profiles of some medicinal plants and correlation with BDNF activity. Phytomedicine, 74, 152920. DOI:10.1016/j.phymed.2019.152920.
• 12. Keighley, C., Gall, M., van Hal, S. J., Halliday, C. L., Chai, L. Y. A., Chew, K. L., ... & Chen, S. C. (2022). Whole Genome Sequencing Shows Genetic Diversity, as Well as Clonal Complex and Gene Polymorphisms Associated with Fluconazole Non-Susceptible Isolates of Candida tropicalis. Journal of Fungi, 8(9), 896. DOI:10.3390/ jof8090896
• 13. Kobus-Cisowska, J., Szymanowska, D., Maciejewska, P., Kmiecik, D., Gramza-Michałowska, A., Kulczyński, B., & Cielecka-Piontek, J., (2019). In vitro screening for acetylcholinesterase and butyrylcholinesterase inhibition and antimicrobial activity of chia seeds (Salvia hispanica). Electronic Journal of Biotechnology, 37, 1-10. DOI:10.1016/j.ejbt.2018.10.002
• 14. Kumar, S., Bajwa, B. S., Kuldeep, S., & Kalia, A. N. (2013). Anti-inflammatory activity of herbal plants: a review. Int J Adv Pharm Biol Chem, 2(2), 272-281.
• 15. Lu, Y., & Foo, L. Y. (2002). Polyphenolics of Salvia—a review. Phytochemistry, 59(2), 117-140.
• 16. Mamun-or-Rashid, A. N. M., Hossain, M. S., Hassan, N., Dash, B. K., Sapon, M. A., & Sen, M. K. (2014). A review on medicinal plants with antidiabetic activity. Journal of Pharmacognosy and Phytochemistry, 3(4), 149-159.
• 17. Martins, N., Barros, L., Santos-Buelga, C., Henriques, M., Silva, S., & Ferreira, I. C. (2015). Evaluation of bioactive properties and phenolic compounds in different extracts prepared from Salvia officinalis L. Food chemistry, 170, 378-385. DOI:10.1016/j.foodchem.2014.08.096
• 18. Meirelles, G. C., Pippi, B., Hatwig, C., Barros, F., de Oliveira, L. F., Poser, G. L. V., & Fuentefria, A. M. (2017). Synergistic antifungal activity of the lipophilic fraction of Hypericum carinatum and fluconazole. Revista Brasileira de Farmacognosia, 27, 118-123. DOI:10.1016/j.bjp.2016.08.001
• 19. Mirghani, M. (2022). A Review of Antifungal Activity of Combined Plant Extracts or Plant Exudates from Medicinal Plants either together or with Known Antifungal Agents. European Journal of Medicinal Plants, 33(8): 16-47. DOI: 10.9734/EJMP/2022/v33i830483
• 20. Muflihah, Y. M., Gollavelli, G., & Ling, Y. C. (2021). Correlation study of antioxidant activity with phenolic and flavonoid compounds in 12 Indonesian indigenous herbs. Antioxidants, 10(10), 1530. DOI: 10.3390/antiox10101530
• 21. Nemutlu, E., Zhang, S., Juranic, N. O., Terzic, A., Macura, S., & Dzeja, P. (2012). 18 O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases. Croatian medical journal, 53(6), 529-534. DOI: 10.3325/cmj.2012.53.529
• 22. Ng’uni, T. L., dos Santos Abrantes, P. M., McArthur, C., Klaasen, J. A., & Fielding, B. C. (2022). Evaluation of synergistic anticandidal activity of Galenia africana extract and fluconazole against Candida albicans and Candida glabrata. Journal of Herbal Medicine, 32, DOI: 10.1016/j.hermed.2021.100503
• 23. Nikmehr, B., Ghaznavi, H., Rahbar, A., Sadr, S., & Mehrzadi, S. (2014). In vitro anti-leishmanial activity of methanolic extracts of Calendula officinalis flowers, Datura stramonium seeds, and Salvia officinalis leaves. Chinese Journal of Natural Medicines, 12(6), 423-427.
• 24. Nóbrega, J. R., Sousa, P. M. S., de Lira Mota, K. S., Cordeiro, L. V., de Andrade Júnior, F. P., & de Oliveira, W. A. (2019). Antifungal activity of carvacrol and antifungal agent combinations against non-albicans Candida species. Scientia Plena, 15(10). DOI:10.14808/sci.plena.2019.104601
• 25. Pozzatti, P., Scheid, L. A., Spader, T. B., Atayde, M. L., Santurio, J. M., & Alves, S. H. (2008). In vitro activity of essential oils extracted from plants used as spices against fluconazole-resistant and fluconazole-susceptible Candida spp. Canadian journal of microbiology, 54(11), 950-956. DOI: 10.1139/W08-097
• 26. Rao, R. V., Descamps, O., John, V., & Bredesen, D. E. (2012). Ayurvedic medicinal plants for Alzheimer's disease: a review. Alzheimer's research & therapy, 4(3), 1-9. DOI:10.1186/alzrt125
• 27. Rus, C.F., Pop, G., Alexa, E., Șumălan, R.M., & Copolovıcı, D.M., (2015). Antifungal activity and chemical composition of Salvia officinalis L. essential oil. Research Journal of Agricultural Science, 47(2),186-193.
• 28. Samber, N., Khan, A., Varma, A., & Manzoor, N. (2015). Synergistic anti-candidal activity and mode of action of Mentha piperita essential oil and its major components. Pharmaceutical biology, 53(10), 1496-1504. DOI:10.3109/13880209.2014.989623
• 29. Tsugawa, H., Cajka, T., Kind, T., Ma, Y., Higgins, B., Ikeda, K., Kanazaw, M., VanderGheynst, J., Fiehn, O, Arita, M., (2015). MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat. Methods 12, 523–526. DOI:10.1038/nmeth.3393
• 30. Tullio, V., Roana, J., Scalas, D., & Mandras, N., (2019). Evaluation of the antifungal activity of Mentha x piperita (Lamiaceae) of Pancalieri (Turin, Italy) essential oil and its synergistic interaction with azoles. Molecules, 24(17), 3148. DOI:10.3390/molecules24173148
• 31. Verpoorte, R., Choi, Y. H., & Kim, H. K. (2005). Ethnopharmacology and systems biology: a perfect holistic match. Journal of ethnopharmacology, 100(1-2), 53-56. DOI:10.1016/j.jep.2005.05.033
• 32. Waris, M., Koçak, E., Gonulalan, E. M., Demirezer, L. Ö., Kır, S., & Nemutlu, E. (2022). Metabolomics analysis insight into medicinal plant science. TrAC Trends in Analytical Chemistry, 116795. DOI: 10.1016/j.trac.2022.116795
• 33. Williamson, E. M. (2001). Synergy and other interactions in phytomedicines. Phytomedicine, 8(5), 401-409. DOI:10.1078/0944-7113-00060