Chemical composition and cholinesterase, tyrosinase, alpha-amylase and alpha-glucosidase inhibitory activity of the essential oil of Salvia tomentosa

Yıl 2022, Cilt: 2 Sayı: 1, 1 - 16, 15.06.2022

Mustafa Koçer Erman Salih İstifli

Öz

The aim of this study was to determine the chemical composition of Salvia tomentosa (Miller) essential oil and to examine its inhibitory effect on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, α-amylase and α-glucosidase in vitro. In this study, the interaction between the main components of essential oil and the enzymes in question was analyzed through molecular docking analyses. The presence of 60 compounds representing 98.2% of the essential oil was determined. The major compounds of the oil were camphor (9.35%), γ-muurolene (8.37%), α-pinene (7.59%), α-caryophyllene (6.25%), viridiflorol (5.13), δ-cadinene (5.01%), and terpinene-4-ol (5.01 %). The oil exhibited higher inhibitory activity on BChE than on AChE. The BChE inhibitory activity of the oil was determined to be 16.48 mg GALAEs/g. The oil showed 47.13 mg KAEs/g inhibitory activity on tyrosinase. The inhibitory activities of the essential oil on α-glucosidase and α-amylase were determined as 703.29 and 694.75 mg ACEs/g, respectively. Based on docking binding energies, δ-cadinene, viridiflorol, γ-muurolene and α-caryophyllene were determined to be the most promising ligands showing the highest affinity (min. -6.90 kcal/mol; max. -8.40 kcal/mol) against α-amylase, AChE and BChE. However, all four ligands were found to exhibit low affinity (min. -5.50 kcal/mol; max. -5.90 kcal/mol) against tyrosinase. Considering in silico physicochemical properties, drug-like features (Lipinski's rule of 5) and intracellular targets, δ-cadinene, viridiflorol, γ-muurolene and α-caryophyllene possess hit features and do not show non-specific enzyme or protein affinity. Ligand binding assays (LBA) to be performed between the monoterpenes and enzymes in question may constitute the next step in confirming their competitive inhibitory capacity.

Anahtar Kelimeler

Salvia tomentosa, essential oil, enzyme inhibitory activity, molecular docking, ADMET, drug likeness

Destekleyen Kurum

Kilis 7 Aralik University

Proje Numarası

2128LTP1

Kaynakça

• Aghajari, N., Feller, G., Gerday, C., Haser, R., 2002. Structural basis of alpha-amylase activation by chloride. Protein Science, 11, 1435-1441.
• Ak, G., Zengin, G., Ceylan, R., Fawzi Mahomoodally, M., Jugreet, S., Mollica, A., Stefanucci, A., 2021. Chemical composition and biological activities of essential oils from Calendula officinalis L. flowers and leaves. Flavour and Fragrance Journal, 36, 554-563.
• Askun, T., Baser, K.H.C., Tumen, G., Kurkcuoglu, M., 2010. Characterization of essential oils of some Salvia species and their antimycobacterial activities. Turkish Journal of Biology, 34, 89-95.
• Ballante, F., 2018. Protein-Ligand Docking in Drug Design: Performance Assessment and Binding-Pose Selection. Methods in Molecular Biology, 1824, 67-88.
• Bardakci, H., Servi, H., Polatoglu, K., 2019. Essential Oil Composition of Salvia candidissima Vahl. occidentalis Hedge, S. tomentosa Miller and S. heldreichiana Boiss. Ex Bentham from Turkey. Journal of Essential Oil Bearing Plants, 22, 1467-1480.
• Bonesi, M., Menichini, F., Tundis, R., Loizzo, M.R., Conforti, F., Passalacqua, N.G., Statti, G.A., Menichini, F., 2010. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of Pinus species essential oils and their constituents. Journal of Enzyme Inhibition and Medicinal Chemistry, 25, 622-628.
• Bouyahya, A., Lagrouh, F., El Omari, N., Bourais, I., El Jemli, M., Marmouzi, I., Salhi, N., Faouzi, M.E., Belmehdi, O., Dakka, N., Bakri, Y., 2020. Essential oils of Mentha viridis rich phenolic compounds show important antioxidant, antidiabetic, dermatoprotective, antidermatophyte and antibacterial properties. Biocatalysis and Agricultural Biotechnology, 23, 101471.
• Brayer, G.D., Luo, Y., Withers, S.G., 1995. The structure of human pancreatic α‐amylase at 1.8 Å resolution and comparisons with related enzymes. Protein Science, 4, 1730-1742.
• Burlando, B., Clericuzio, M., Cornara, L., 2017. Moraceae plants with tyrosinase inhibitory activity: A review. Mini Reviews in Medicinal Chemistry, 17, 108-121.
• Chang, T.S., 2009. An updated review of tyrosinase inhibitors. International Journal of Molecular Sciences, 10, 2440-2475.
• Chang, T.S., 2012. Natural melanogenesis inhibitors acting through the down-regulation of tyrosinase activity. Materials, 5, 1661-1685.
• Chaudhury, A., Duvoor, C., Reddy Dendi, V.S., Kraleti, S., Chada, A., Ravilla, R., Marco, A., Shekhawat, N.S., Montales, M.T., Kuriakose, K., 2017. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Frontiers in Endocrinology, 8, 6.
• da Silva Barbosa, D.C., Holanda, V.N., de Assis, C.R.D., de Oliveira Farias, J.C.R., Henrique da Nascimento, P., da Silva, W.V., Navarro, D.M.D.A.F., da Silva, M.V., de Menezes Lima, V.L., dos Santos Correia, M.T., 2020. Chemical composition and acetylcholinesterase inhibitory potential, in silico, of Myrciaria floribunda (H. West ex Willd.) O. Berg fruit peel essential oil. Industrial Crops and Products, 151, 112372.
• Daina, A., Michielin, O., Zoete, V., 2017. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 1-13.
• 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, W357-W364.
• Davis, E.C., Callender, V.D., 2010. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. The Journal of Clinical and Aesthetic Dermatology, 3, 20.
• Delaney, J.S., 2004. ESOL: estimating aqueous solubility directly from molecular structure. Journal of Chemical Information and Modeling, 44, 1000-1005.
• Dos Santos, R.N., Ferreira, L.G., Andricopulo, A.D., 2018. Practices in Molecular Docking and Structure-Based Virtual Screening. Methods in Molecular Biology, 1762, 31-50.
• Edwin, E., Sheeja, E., Chaturvedi, M., Sharma, S., Gupta, V., 2006. A comparative study on antihyperglycemic activity of fruits and barks of Ficus bengalensis (L.). Advances in Pharmacology and Toxicology, 7, 69-71.
• Elgamal, A.M., Ahmed, R.F., Abd-ElGawad, A.M., El Gendy, A.G., Elshamy, A.I., Nassar, M.I., 2021. Chemical Profiles, Anticancer, and Anti-Aging Activities of Essential Oils of Pluchea dioscoridis (L.) DC. and Erigeron bonariensis L. Plants-Basel, 10, 667.
• 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, 88-95.
• Erdogan-Orhan, I., Baki, E., Senol, S., Yilmaz, G., 2010. Sage-called plant species sold in Turkey and their antioxidant activities. Journal of the Serbian Chemical Society, 75, 1491-1501.
• Ertas, A., Goren, A.C., Boga, M., Yesil, Y., Kolak, U., 2014. Essential oil compositions and anticholinesterase activities of two edible plants Tragopogon latifolius var. angustifolius and Lycopsis orientalis. Natural Product Research, 28, 1405-1408.
• Es-Safi, I., Mechchate, H., Amaghnouje, A., El Moussaoui, A., Cerruti, P., Avella, M., Grafov, A., Bousta, D., 2021. Marketing and legal status of phytomedicines and food supplements in Morocco. Journal of Complementary and Integrative Medicine, 18, 279-285.
• Ferrante, C., Zengin, G., Menghini, L., Diuzheva, A., Jeko, J., Cziaky, Z., Recinella, L., Chiavaroli, A., Leone, S., Brunetti, L., Lobine, D., Senkardes, I., Mahomoodally, M.F., Orlando, G., 2019. Qualitative Fingerprint Analysis and Multidirectional Assessment of Different Crude Extracts and Essential Oil from Wild Artemisia santonicum L. Processes, 7, 522.
• Ferreira, L.G., Dos Santos, R.N., Oliva, G., Andricopulo, A.D., 2015. Molecular docking and structure-based drug design strategies. Molecules, 20, 13384-13421.
• Fukai, T., Oku, Y., Hou, A.J., Yonekawa, M., Terada, S., 2005. Antimicrobial activity of isoprenoid-substituted xanthones from Cudrania cochinchinensis against vancomycin-resistant enterococci. Phytomedicine, 12, 510-513.
• Hanlidou, E., Karousou, R., Lazari, D., 2014. Essential‐Oil Diversity of Salvia tomentosa Mill. in Greece. Chemistry & Biodiversity, 11, 1205-1215.
• Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vandermeersch, T., Zurek, E., Hutchison, G.R., 2012. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4, 1-17.
• Haznedaroglu, M.Z., Karabay, N.U., Zeybek, U., 2001. Antibacterial activity of Salvia tomentosa essential oil. Fitoterapia, 72, 829-831.
• Ho, J.C., 2010. Chemical Composition and Bioactivity of Essential Oil of Seed and Leaf from Alpinia speciosa Grown in Taiwan. Journal of the Chinese Chemical Society, 57, 758-763.
• Huang, S.Y., Zou, X., 2010. Advances and challenges in protein-ligand docking. International Journal of Molecular Sciences, 11, 3016-3034.
• Hussein, B.A., Karimi, I., Yousofvand, N., 2019. Computational insight to putative anti-acetylcholinesterase activity of Commiphora myrrha (Nees), Engler, Burseraceae: a lessen of archaeopharmacology from Mesopotamian Medicine I. In Silico Pharmacology, 7, 1-17.
• Istifli, E.S., Tepe, A.Ş., Sarikürkcü, C., Tepe, B., 2020. Interaction of certain monoterpenoid hydrocarbons with the receptor binding domain of 2019 novel coronavirus (2019-nCoV), transmembrane serine protease 2 (TMPRSS2), cathepsin B, and cathepsin L (CatB/L) and their pharmacokinetic properties. Turkish Journal of Biology, 44, 242-264.
• Jugreet, B.S., Mahomoodally, M.F., Sinan, K.I., Zengin, G., Abdallah, H.H., 2020. Chemical variability, pharmacological potential, multivariate and molecular docking analyses of essential oils obtained from four medicinal plants. Industrial Crops and Products, 150, 112394.
• Karimi, I., Yousofvand, N., Hussein, B.A., 2021. In vitro cholinesterase inhibitory action of Cannabis sativa L. Cannabaceae and in silico study of its selected phytocompounds. In Silico Pharmacology, 9, 1-15.
• Ko, H.H., Chiang, Y.C., Tsai, M.H., Liang, C.J., Hsu, L.F., Li, S.Y., Wang, M.C., Yen, F.L., Lee, C.W., 2014. Eupafolin, a skin whitening flavonoid isolated from Phyla nodiflora, downregulated melanogenesis: Role of MAPK and Akt pathways. Journal of Ethnopharmacology, 151, 386-393.
• Li, B., Duysen, E.G., Carlson, M., Lockridge, O., 2008. The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency. Journal of Pharmacology and Experimental Therapeutics, 324, 1146-1154.
• Lien, C.Y., Chen, C.Y., Lai, S.T., Chan, C.F., 2014. Kinetics of mushroom tyrosinase and melanogenesis inhibition by N-acetyl-pentapeptides. The Scientific World Journal, 2014.
• Lohning, A.E., Levonis, S.M., Williams-Noonan, B., Schweiker, S.S., 2017. A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists. Current Topics in Medicinal Chemistry, 17, 2023-2040.
• Lopez-Vallejo, F., Caulfield, T., Martinez-Mayorga, K., Giulianotti, M.A., Nefzi, A., Houghten, R.A., Medina-Franco, J.L., 2011. Integrating virtual screening and combinatorial chemistry for accelerated drug discovery. Combinatorial Chemistry & High Throughput Screening, 14, 475-487.
• Lopez, M.D., Campoy, F.J., Pascual-Villalobos, M.J., Munoz-Delgado, E., Vidal, C.J., 2015. Acetylcholinesterase activity of electric eel is increased or decreased by selected monoterpenoids and phenylpropanoids in a concentration-dependent manner. Chemico-Biological Interactions, 229, 36-43.
• Majouli, K., Hlila, M.B., Hamdi, A., Flamini, G., Ben Jannet, H., Kenani, A., 2016. Antioxidant activity and alpha-glucosidase inhibition by essential oils from Hertia cheirifolia (L.). Industrial Crops and Products, 82, 23-28.
• Mechchate, H., Es-safi, I., Bari, A., Grafov, A., Bousta, D., 2020. Ethnobotanical survey about the management of diabetes with medicinal plants used by diabetic patients in region of FezMeknes, Morocco. Journal of Ethnobotany Research and Applications, 19, 1-28.
• Mechchate, H., Es-Safi, I., Haddad, H., Bekkari, H., Grafov, A., Bousta, D., 2021a. Combination of Catechin, Epicatechin, and Rutin: optimization of a novel complete antidiabetic formulation using a mixture design approach. The Journal of Nutritional Biochemistry, 88, 108520.
• Mechchate, H., Es-Safi, I., Louba, A., Alqahtani, A.S., Nasr, F.A., Noman, O.M., Farooq, M., Alharbi, M.S., Alqahtani, A., Bari, A., 2021b. In vitro alpha-amylase and alpha-glucosidase inhibitory activity and in vivo antidiabetic activity of Withania frutescens L. Foliar extract. Molecules, 26, 293.
• Meng, X.-Y., Zhang, H.-X., Mezei, M., Cui, M., 2011. Molecular docking: a powerful approach for structure-based drug discovery. Current Computer-Aided Drug Design, 7, 146-157.
• Murata, K., Takahashi, K., Nakamura, H., Itoh, K., Matsuda, H., 2014. Search for skin-whitening agent from Prunus plants and the molecular targets in melanogenesis pathway of active compounds. Natural Product Communications, 9, 185-188.
• Nagy, G., Günther, G., Máthé, I., Blunden, G., Yang, M.-h., Crabb, T.A., 1999. Diterpenoids from Salvia glutinosa, S. austriaca, S. tomentosa and S. verticillata roots. Phytochemistry, 52, 1105-1109.
• Noh, H., Lee, S.J., Jo, H.-J., Choi, H.W., Hong, S., Kong, K.-H., 2020. Histidine residues at the copper-binding site in human tyrosinase are essential for its catalytic activities. Journal of Enzyme Inhibition and Medicinal Chemistry, 35, 726-732.
• Orhan, D.D., Senol, F.S., Hosbas, S., Orhan, I.E., 2014. Assessment of cholinesterase and tyrosinase inhibitory and antioxidant properties of Viscum album L. samples collected from different host plants and its two principal substances. Industrial Crops and Products, 62, 341-349.
• Orhan, I.E., Jedrejek, D., Senol, F.S., Salmas, R.E., Durdagi, S., Kowalska, I., Pecio, L., Oleszek, W., 2018. Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives. Phytomedicine, 42, 25-33.
• Orhan, I.E., Kucukboyaci, N., Calis, I., Cerón-Carrasco, J.P., den-Haan, H., Peña-García, J., Pérez-Sánchez, H., 2017. Acetylcholinesterase inhibitory assessment of isolated constituents from Salsola grandis Freitag, Vural & Adıgüzel and molecular modeling studies on N-acetyltryptophan. Phytochemistry Letters, 20, 373-378.
• Özcan, M., Akgül, A., Chalchat, J., 2002. Volatile constituents of essential oils of Salvia aucheri Benth. var. canescens Boiss. et Heldr. and S. tomentosa Mill. grown in Turkey. Journal of Essential Oil Research, 14, 339-341.
• Palanisamy, U.D., Ling, L.T., Manaharan, T., Appleton, D., 2011. Rapid isolation of geraniin from Nephelium lappaceum rind waste and its anti-hyperglycemic activity. Food Chemistry, 127, 21-27.
• Pérez Gutierrez, R., Hernández Luna, H., Hernández Garrido, S., 2006. Antioxidant activity of Tagetes erecta essential oil. Journal of the Chilean Chemical Society, 51, 883-886.
• Perry, E., Howes, M.J.R., 2011. Medicinal plants and dementia therapy: herbal hopes for brain aging? CNS Neuroscience & Therapeutics, 17, 683-698.
• Perry, N.S.L., Houghton, P.J., Theobald, A., Jenner, P., Perry, E.K., 2000. In-vitro inhibition of human erythrocyte acetylcholinesterase by Salvia lavandulaefolia essential oil and constituent terpenes. Journal of Pharmacy and Pharmacology, 52, 895-902.
• Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., Ferrin, T.E., 2004. UCSF Chimera--a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25, 1605-1612.
• Pinho, B.R., Ferreres, F., Valentão, P., Andrade, P.B., 2013. Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment. Journal of Pharmacy and Pharmacology, 65, 1681-1700.
• Pires, D.E., Blundell, T.L., Ascher, D.B., 2015. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. Journal of Medicinal Chemistry, 58, 4066-4072.
• Politeo, O., Bektašević, M., Carev, I., Jurin, M., Roje, M., 2018. Phytochemical composition, antioxidant potential and cholinesterase inhibition potential of extracts from Mentha pulegium L. Chemistry & Biodiversity, 15, e1800374.
• Rosenberry, T.L., Brazzolotto, X., Macdonald, I.R., Wandhammer, M., Trovaslet-Leroy, M., Darvesh, S., Nachon, F., 2017. Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study. Molecules, 22, 2098.
• Sacks, D.B., 1997. Implications of the revised criteria for diagnosis and classification of diabetes mellitus. Oxford University Press.
• Salleh, W., Ahmad, F., Yen, K.H., 2015. Chemical compositions and biological activities of the essential oils of Beilschmiedia madang Blume (Lauraceae). Archives of Pharmacal Research, 38, 485-493.
• Sarikurkcu, C., Zengin, G., Oskay, M., Uysal, S., Ceylan, R., Aktumsek, A., 2015. Composition, antioxidant, antimicrobial and enzyme inhibition activities of two Origanum vulgare subspecies (subsp. vulgare and subsp. hirtum) essential oils. Industrial Crops and Products, 70, 178-184.
• Savelev, S., Okello, E., Perry, N.S.L., Wilkins, R.M., Perry, E.K., 2003. Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil. Pharmacology Biochemistry and Behavior, 75, 661-668.
• Schepetkin, I.A., Özek, G., Özek, T., Kirpotina, L.N., Khlebnikov, A.I., Quinn, M.T., 2021. Chemical Composition and Immunomodulatory Activity of Essential Oils from Rhododendron albiflorum. Molecules, 26, 3652.
• Sinan, K.I., Etienne, O.K., Stefanucci, A., Mollica, A., Mahomoodally, M.F., Jugreet, S., Rocchetti, G., Lucini, L., Aktumsek, A., Montesano, D., 2021. Chemodiversity and biological activity of essential oils from three species from the Euphorbia genus. Flavour and Fragrance Journal, 36, 148-158.
• Solano, F., 2018. On the Metal Cofactor in the Tyrosinase Family. International Journal of Molecular Sciences, 19, 633.
• Soltanbeigi, A., Sakartepe, E., 2020. Chemical specification of Wild Salvia tomentosa Mill. collected From Inner Aegean Region of Turkey. Zeitschrift fur Arznei-& Guwerzpflanzen, 25, 31-35.
• Tepe, B., Daferera, D., Sokmen, A., Sokmen, M., Polissiou, M., 2005. Antimicrobial and antioxidant activities of the essential oil and various extracts of Salvia tomentosa Miller (Lamiaceae). Food Chemistry, 90, 333-340.
• Trott, O., Olson, A.J., 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31, 455-461.
• Tsai, C.-C., Chan, C.-F., Huang, W.-Y., Lin, J.-S., Chan, P., Liu, H.-Y., Lin, Y.-S., 2013. Applications of Lactobacillus rhamnosus spent culture supernatant in cosmetic antioxidation, whitening and moisture retention applications. Molecules, 18, 14161-14171.
• Ulubelen, A., Miski, M., Mabry, T., 1981a. Further flavones and triterpenes and the new 6-hydroxyluteolin 5-β-D-glucoside from Salvia tomentosa. Journal of Natural Products, 44, 586-587.
• Ulubelen, A., Miski, M., Mabry, T., 1981b. A new diterpene acid from Salvia tomentosa. Journal of Natural Products, 44, 119-124.
• Ulukanli, Z., Karaborklu, S., Cenet, M., Sagdic, O., Ozturk, I., Balcilar, M., 2013. Essential oil composition, insecticidal and antibacterial activities of Salvia tomentosa Miller. Medicinal Chemistry Research, 22, 832-840.
• Usman, L.A., Oguntoye, O.S., Ismaeel, R.O., 2020. Effect of Seasonal Variation on Chemical Composition, Antidiabetic and Antioxidant Potentials of Leaf Essential Oil of Eucalyptus globulus L. Journal of Essential Oil Bearing Plants, 23, 1314-1323.
• Valdes-Tresanco, M.S., Valdes-Tresanco, M.E., Valiente, P.A., Moreno, E., 2020. AMDock: a versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4. Biology Direct, 15, 1-12.
• Wang, Z., Sun, H., Shen, C., Hu, X., Gao, J., Li, D., Cao, D., Hou, T., 2020. Combined strategies in structure-based virtual screening. Physical Chemistry Chemical Physics, 22, 3149-3159.
• Wild, S., Roglic, G., Green, A., Sicree, R., King, H., 2004. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 27, 1047-1053.
• Yang, C.H., Huang, Y.C., Tsai, M.L., Cheng, C.Y., Liu, L.L., Yen, Y.W., Chen, W.L., 2015. Inhibition of melanogenesis by beta-caryophyllene from lime mint essential oil in mouse B16 melanoma cells. International Journal of Cosmetic Science, 37, 550-554.
• Yang, Y., Meng, J., Liu, C., Zhang, Y., Tian, J., Gu, D., 2019. GC-MS profiling, bioactivities and in silico theoretical explanation of cone oil from Pinus thunbergii Parl. Industrial Crops and Products, 141, 111765.
• Yilar, M., Kadioglu, I., Telci, I., 2018. Chemical composition and antifungal activity of Salvia Officinalis (L.), S. Cryptantha (Montbret et aucher ex Benth.), S. Tomentosa (MILL.) plant essential oils and extracts. Fresenius Environmental Bulletin, 27, 1695-1706.
• Zengin, G., Sarikurkcu, C., Aktumsek, A., Ceylan, R., 2014. Sideritis galatica Bornm.: A source of multifunctional agents for the management of oxidative damage, Alzheimer's and diabetes mellitus. Journal of Functional Foods, 11, 538-547.