Diapin®: A food supplement with diverse therapeutic potentials

Abstract

Background and Aims: For many centuries herbs and spices have traditionally been used to treat or manage a variety of dis- eases. The formulation of food supplements containing single or multiple herbs or spices is now popular. These formulations provide biochemical, pharmacological and medicinal benefits due to their diverse phytochemical constituents.
Methods: In the present study, Diapin® – a food supplement containing Olea europaea L. leaves extract, Cinnamomum cassia (L.) J. Presl stem extract, Nigella sativa L. seed oil, Cocos nucifera L. oil and vitamin D3 – dissolved in absolute ethanol was evaluated for α-amylase, α-glucosidase, acetylcholinesterase, elastase, neuraminidase, adenosine deaminase and arginase inhibitory activity.
Results: The supplement strongly inhibited neuraminidase (IC50 = 0.272 ± 0.007 mg/mL), while adenosine deaminase, ace- tylcholinesterase, elastase and arginase were moderately inhibited (with an IC50 of 4.562 ± 0.052, 5.396 ± 0.563, 5.783 ± 0.058 and 6.800 ± 0.067 mg/mL respectively). The less inhibition activity was on α-amylase and α-glucosidase (IC50 = 9.593 ± 0.582 and 14.010 ± 2.280 mg/mL respectively).
Conclusion: The pharmacological activities of Diapin® can be attributed to its opulent phytochemical composition. The pres- ent findings support the folkloric claim of Diapin® supplement having antidiabetic, anticancer, anti-inflammatory, antimicro- bial, anti-ageing, and immune bolstering properties, in addition to the mitigation of Alzheimer’s disease and the alleviation of neurological dysfunction.

Keywords

• Diapin®
• Olea europaea
• Cinnamomum cassia
• Nigella sativa
• Cocos nucifera
• enzyme inhibition
• extracts

References

1. Adekola, K.A., Salleh, A.B., Zaidan U.H., Azlan A., Chiavaro E., Paci- ulli M. & Marikkar J.M.N. (2017). Total phenolic content, antioxi- dative and antidiabetic properties of coconut (Cocos nucifera L.) testa and selected bean seed coats. Italian Journal of Food Science, 29,741–753. https://doi.org/10.14674/IJFS-941
2. Ahmad, A., Husain, A., Mujeeb, M., Khan, S.A., Najmi, A.K., SiddiqueN.A. & Anwar F. (2013). A review on therapeutic potential of Nige- lla sativa: A miracle herb. Asian Pacific Journal of Tropical Biomedi- cine, 3, 337–352. https://doi.org/10.1016/S2221-1691(13)60075-1
3. Akilen, R., Tsiami, A., Devendra, D. & Robinson, N. (2012). Cinnamon in glycaemic control: Systematic review and metaanalysis. Clinical Nutrition, 31, 609–615. https://doi.org/10.1016/j.clnu.2012.04.003
4. Alam, S.R., Newby, D.E. & Henriksen, P.A. (2012). Role of the endog- enous elastase inhibitor, elafin, in cardiovascular injury: From epi- thelium to endothelium. Biochemical Pharmacology, 83, 695–704. https://doi.org/10.1016/j.bcp.2011.11.003
5. Al-Bukhari, M.I. (1976). In: The collection of authentic sayings of Prophet Mohammad (peace be upon him), division 71 on medi- cine. 2nd ed. Al-Bukhari Sahi., editor. Ankara, Turkey: Hilal Yayinlari.
6. Al-Jassir, M.S. (1992). Chemical composition and microflora of black cumin (Nigella sativa L.) seeds growing in Saudi Arabia. Food Chemistry, 45, 239–242. https://doi.org/10.1016/0308- 8146(92)90153-S
7. Angelidi, A.M., Kokkinos, A., Katechaki, E., Ros, E. & Mantzoros, C.S. (2021). Mediterranean diet as a nutritional approach for CO- VID-19. Metabolism,114, 154407. https://doi.org/10.1016/j.me-tabol.2020.154407
8. Angelis, A., Mavros, P., Nikolaou, P.E., Mitakou, S., Halabalaki, M. & Skaltsounis, L. (2020). Phytochemical analysis of olive flowers’ hydroalcoholic extract and in vitro evaluation of tyrosinase, elas- tase and collagenase inhibition activity. Fitoterapia, 153, 104602. https://doi.org/10.1016/j.fitote.2020.104602

9. Annweiler, C., Karras, S.N., Anagnostis, P. & Beauchet, O. (2014). Vitamin D supplements: a novel therapeutic approach for Al- zheimer patients. Frontiers in Pharmacology, 5, 6. https://doi. org/10.3389/fphar.2014.00006
10. Baeta, C., Bagina, R. & Canilhas, N. (2020). Relationship and psy- chological effects between food, Mediterranean diet and CO- VID-19. CPQ Nutrition, 4, 01-16. Retrieved from https://www.cient- periodique.com
11. Bakathir, H.A. & Abbas, N.A. (2011). Detection of the antibacterial effect of Nigella sativa ground seeds with water. African Journal of Traditional, Complementary and Alternative Medicines, 8, 159-164. https://doi.org/10.4314/ajtcam.v8i2.63203
12. Battinelli, L., Daniele, C., Cristiani, M., Bisignano, G., Saija, A. & Maz- zanti, G. (2006). In vitro antifungal and anti-elastase activity of some aliphatic aldehydes from Olea europaea L. fruit. Phytomedi- cine, 13, 558-563. https://doi.org/10.1016/j.phymed.2005.09.009
13. Bhutkar, M.A. & Bhise, S.B. (2012). In vitro assay of alpha amylase inhibitory activity of some indigenous plants. International Jour- nal of Chemical Science, 10, 457–462. Retrieved from https://www. tsijournals.com
14. Bieth, J.G. (2001). The elastases. Journal de la Société de Biologie, (in French). 195, 173–179. Retrieved from https://pubmed.ncbi.nlm. nih.gov
15. Blackburn, M.R. & Kellems R.E. (2005). Adenosine deaminase de- ficiency: metabolic basis of immune deficiency and pulmonary inflammation. Advances in Immunology, 86,1–41. doi: https://doi. org/10.1016/S0065-2776(04)86001-2
16. Blum, U. & Schwedt, G. (1998). Inhibition behavior of phospha- tase, phosphodiesterase I and adenosine deaminase as tools for trace metal analysis and speciation. Analytica Chimica Acta, 360, 101-108.https://doi.org/10.1016/S0003-2670(97)00717-4
17. Cama, E., Colleluori, D.M., Emig, F.A., Shin, H., Kim, S.W., Kim, N.N., Traish, A.M.… Christianson, D.W. (2003). Human arginase II: crystal structure and physiological role in male and female sexual arous- al. Biochemistry, 42, 8445–8451.https://doi.org/10.1021/bi034340j
18. Christianson, D.W. (2005). Arginase: Structure, mechanism, and physiological role in male and female sexual arousal. Accounts of Chemical Research, 38, 191-201. https://doi.org/10.1021/ ar040183k
19. Cordero, J.G., Garcia-Escudero, R., Avila, J., Gargini R. & Garcia- Escudero, V. (2018). Benefit of oleuropein aglycone for Al- zheimer’s disease by promoting autophagy. Oxidative Medicine and Cellular Longevity, Article ID 5010741, 12 pages. https://doi. org/10.1155/2018/5010741
20. Corraliza, I.M., Campo, M.L., Soler, G. & Modolell M. (1994). Deter- mination of arginase activity in macrophages: A micromethod. Journal of Immunological Methods, 174, 231–235.https://doi. org/10.1016/0022-1759(94)90027-2
21. Costello, R.B., Dwyer, J.T., Saldanha, L., Bailey, R.L., Merkel, J. & Wambogo, E. (2016). Do Cinnamon supplements have a role in glycemic control in type 2 diabetes? A Narrative Review. Journal of the Academy of Nutrution and Diet,116, 1794–1802. https://doi. org/10.1016/j.jand.2016.07.015
22. Cubukcu, H. C., Durak, Z. E., Kocaoglu, E. H. & Durak I. (2018). Dif- ferent effects of olive leaf on purine metabolizing enzymes of hu- man gastric tissues in vitro. Cancer Therapy & Oncology International Journal, 12, 555826. Retrieved from https://juniperpublishers.com
23. Cumaoglu, A., Rackova, L., Stefek, M., Kartal, M., Maechler, P. & Karasu C. (2011). Effects of olive leaf polyphenols against H₂O₂ toxicity in insulin secreting β-cells. Acta Biochimica Polinica, 58, 45-50. Retrieved from http://www.actabp.pl
24. de Bock, M., Derraik, J.G., Brennan, C.M., Biggs, J.B., Morgan, P.E., Hodg- kinson, S.C., Hofman, P.L….. Cutfield W.S. (2013). Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged over- weight men: a randomized, placebo-controlled, crossover trial. PloS One, 8, e57622. https://doi.org/10.1371/journal.pone.0057622
25. Farhan, A.M., Mehde, A.A., Mehdi, W.A., Jassim, R.A., Kadhim, N.J. & Jasim N.A. (2016). Synthesis of silver nanoparticles from leaf extract of olive and fig with silver nitrate and effect on ECTO-5’- nucleotidase (5’-NT), ADA and AMPDA enzymes in sera of ath- erosclerosis patients. International Journal of Chemical Sciences, 14, 1805-1817. Retrieved from https://www.tsijournals.com
26. Frydman-Marom, A., Levin, A., Farfara, D., Benromano, T., Scherzer- Attali, R., Peled, S., Vassar, R., Segal, D….. Ovadia, M. (2011). Orally administrated cinnamon extract reduces β-amyloid oligomeriza- tion and corrects cognitive impairment in Alzheimer’s disease animal models. PLoS One, 6, e16564. https://doi.org/10.1371/jour- nal.pone.0016564
27. Garcia-Alvarez, A., Egan, B., de Klein, S., Dima, L., Maggi, F., Isonie- mi, M…..Serra-Majem, L. (2014). Usage of plant food supplements across six european countries: findings from the plant LIBRA con- sumer survey. PLoS One, 9, e92265. https://doi.org/10.1371/jour- nal.pone.0092265
28. Gholamnezhad, Z., Rafatpanah, H., Sadeghnia, H.R. & Boskabady, M.H. (2015). Immunomodulatory and cytotoxic effects of Nigella sativa and thymoquinone on rat splenocytes. Food and Chemi- cal Toxicology, 86, 72–80. https://doi.org/10.1016/j.fct.2015.08.028
29. Girish, K.S., Kemparaju, K., Nagaraju, S. & Vishwanath, B.S. (2009). Hyaluronidase inhibitors: a biological and therapeutic perspec- tive. Current Medicinal Chemistry, 16, 2261–2288. https://doi. org/10.2174/092986709788453078
30. Gray, E.W. & Miller, J.I. (1970). The spice trade of the Roman Em- pire 29 B.C. to A.D. 641. The Journal of Roman Studies, 60, 222-224. http://doi.org/10.1017/S0075435800043537
31. Guo, Z., Jia, X., Zheng, Z., Lu, X., Zheng, Y., Zheng, B. & Xiao J. (2018). Chemical composition and nutritional function of olive (Olea europaea L.): A review. Phytochemistry Reviews, 17, 1091-1110. https://doi.org/10.1007/s11101-017-9526-0.
32. Hardy, G. (2000). Nutraceuticals and functional foods: introduc- tion and meaning. Nutrition, 16, 688-689. https://doi.org/10.1016/ s0899-9007(00)00332-4
33. Hasler, C.M. (2005). Regulation of functional foods and nutraceuti- cals: a global perspective. USA, IFT Press and Blackwell Publishing.
34. Heinrich, M. & Teoh, H.L. (2004). Galanthamine from snowdrop- the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. Journal of Ethnopharmacology, 92,147–162. http://doi: 10.1016/j.jep.2004.02.012
35. Hovorková, P., Laloučková, K. & Skřivanová, E. (2018). Determi- nation of in vitro antibacterial activity of plant oils containing medium-chain fatty acids against Gram-positive pathogenic and gut commensal bacteria. Czech Journal of Animal Science, 63, 119–125. https://doi.org/10.17221/70/2017-CJAS
36. Ingkaninan, K., Temkitthawon, P., Chuenchon, K., Yuyaem, T. & Thongnoi, W. (2003). Screening for acetylcholinesterase inhibi- tory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. Journal of Ethnopharmacology, 89, 261–264. https://doi.org/10.1016/j.jep.2003.08.008
37. Jayaprakasha, G.K. & Rao L.J. (2011). Chemistry, biogenesis, and biological activities of Cinnamomum zeylanicum. Critical Re- views in Food Science and Nutrition, 51, 547-562. https://doi. org/10.1080/10408391003699550
38. Jilani, H., Cilla, A., Barberá, R. & Hamdi, M. (2016). Improved bio-accessibility and antioxidant capacity of olive leaf (Olea euro- paea L.) polyphenols through biosorption on Saccharomyces cerevisiae. Industrial Crops and Products, 84, 131–138. https://doi. org/10.1016/j.indcrop.2016.02.002
39. Johansson, P., Almqvist, E.G., Johansson, J.O., Mattsson, N., An- dreasson, U., Hansson, O., Wallin, A……Svensson, J. (2013). Ce- rebrospinal fluid (CSF) 25-hydroxyvitamin D concentration and CSF acetylcholinesterase activity are reduced in patients with Alzheimer’s disease. PloS One, 8, e81989. https://doi.org/10.1371/ journal.pone.0081989
40. Kacem, R. & Meraihi, Z. (2006). Effects of essential oil extracted from Nigella sativa (L.) seeds and its main components on hu- man neutrophil elastase activity. Yakugaku Zasshi., 126, 301-305. https://doi.org/10.1248/yakushi.126.301
41. Kalra, E.K. (2003). Nutraceutical-definition and introduction. Amer- ican Association of Pharmaceutical Scientists, 5, 27–28. https://doi. org/10.1208/ps050325
42. Kannan, R., Ittiyavirah, S.P. & Harindran, Y. (2019). Acetylcholines- terase and growth inhibitory effects - various grades of N. sativa oils. International Journal of Pharmaceutical Sciences and Research, 10, 245-250.Retrieved from https://ijpsr.com
43. Kanter, M., Meral, I., Yener, Z., Ozbek, H. & Demir, H. (2003). Partial regeneration/proliferation of the beta-cells in the islets of langer- hans by Nigella sativa L. in streptozotocin-induced diabetic rats. The Tohoku Journal Experimental Medicine, 201, 213-219. https:// doi.org/10.1620/tjem.201.213
44. Kerimi, A., NyambeSilavwe, H., Pyner, A., Oladele, E., Gauer, J.S. & Stevens, Y. (2019). Nutritional implications of olives and sugar: at- tenuation of postprandial glucose spikes in healthy volunteers by inhibition of sucrose hydrolysis and glucose transport by oleu- ropein. European Journal of Nutrition, 58, 1315–1330. https://doi. org/10.1007/s00394-018-1662-9
45. Kim, J.H., Bugaj, L.J., Oh, Y.J., Bivalacqua, T.J., Ryoo, S., Soucy, K.G. & Berkowitz, D.E. (2009). Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. Journal of Appleid Physiology, 107,1249–1257. https://doi. org/10.1152/japplphysiol.91393.2008
46. Kim, J.S., Kwon, C.S. & Son, K.H. (2000). Inhibition of alpha-glucosidase and amylase by luteolin, a flavonoid. Bioscience, Biotechnology, and Biochemistry, 64, 2458–2461. https://doi.org/10.1271/bbb.64.2458
47. Kiss, A., Tratsiakovich, Y., Gonon, A., Fedotovskaya, O., Lanner, J., Andersson, D., Yang, J…. Pernow, J. (2014). The role of arginase and Rho kinase in cardioprotection from remote ischemic per- conditioning in non-diabetic and diabetic rat in vivo. PLoS One, 9, e104731. https://doi.org/10.1371/journal.pone.0104731
48. Komaki, S., Yamaguchi, I., Maru, M., Kinoshita, K., Kakehi, Y., Ohta, Y….Tsukada, Y. (2003). Identification of anti-α-amylase compo- nents from olive leaf extracts. Food Science and Technology Re- search, 9, 35-39. https://doi.org/10.3136/fstr.9.35
49. Kontogianni, V.G., Charisiadis, P., Margianni, E., Lamari, F.N., Gerothanassis, I.P. & Tzakos A.G. (2013). Olive leaf extracts are a natural source of advanced glycation end product inhibitors. Journal of Medicinal Food, 16, 817-822. https://doi.org/10.1089/ jmf.2013.0016
50. Korkmaz, S., Sarimahmut, M., Ozel, M. & Ulukaya, E. (2016). Ol- ive leaf extract containing oleuropein modulates the cytotoxic effect of epirubicin on breast cancer cells depending on the cell line. Turkish Journal of Biochemistry, 41, 385-392. https://doi. org/10.1515/tjb-2016-0117
51. Korukluoglu, M., Sahan, Y., Yigit, A., Ozer, E.T. & Gucer, S. (2010). Antibacterial activity and chemical constitutions of Olea euro- paea L. leaf extracts. Journal of Food Processing and Preservation, 34, 383–396. https://doi.org/10.1111/j.1745-4549.2008.00318.x
52. Leach, M. J. & Kumar, S. (2012). Cinnamon for diabetes mellitus. Cochrane Database Systamic Reviews, 2012,CD007170. https://doi. org/10.1002/14651858
53. Lebrun, P., Grivet, L. & Baudouin, L. (2013). Use of RFLP markers to study the diversity of the coconut palm. In Oropeza, C., Verdeil, J.K., Ash- burner, G.R., Cardena, R. & Santamaria, J.M. (eds.). Current Advances in Coconut Biotechnology. Springer Science & Business Media. 83–85.
54. Liu, Y., McKeever, C.L. & Malik, N.S.A. (2017). Assessment of the antimicrobial activity of olive leaf extract against foodborne bacterial pathogens. Frontiers in Microbiology, 8, 113.https://doi. org/10.3389/fmicb.2017.00113
55. Losey, H.C., Ruthenburg, A.J. & Verdine, G.L. (2006). Crystal struc- ture of Staphylococcus aureus tRNA adenosine deaminase TadA in complex with RNA. Nature Structural and Molecular Biology, 13, 153–159. https://doi.org/10.1038/nsmb1047.
56. Maarsingh, H., Pera, T. & Meurs, H. (2008). Arginase and pulmonary diseases. Naunyn-Schmiedberg’s Archives of Pharmacology,378, 171-184. https://doi.org/10.1007/s00210-008-0286-7
57. Maierean, S.M., Serban, M.C., Sahebkar, A., Ursoniu, S., Serban, A., Penson, P. & Banach, M. (2017). The effects of cinnamon supple- mentation on blood lipid concentrations: A systematic review and meta-analysis. Journal of Clinical Lipidology, 11, 1393–1406. https://doi.org/10.1016/j.jacl.2017.08.004
58. McAuley, J.L., Corcilius, L., Tan, H.X., Payne, R.J., McGuckin, M.A. & Brown, L.E. (2017). The cell surface mucin MUC1 limits the sever- ity of influenza A virus infection. Mucosal Immunology, 10, 1581- 1593. https://doi.org/10.1038/mi.2017.16
59. Meddah, B., Ducroc, R., El Abbes Faouzi, M., Eto, B., Mahraoui, L., Benhaddou-Andaloussi, A., Martineau, L.C….Haddad, P.S. (2009). Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. Journal of Ethnopharmacology, 121, 419- 424. https://doi.org/10.1016/j.jep.2008.10.040
60. Mirzaei, F., Khazaei, M., Komaki, A., Amiri, I. & Jalili, C. (2019). Multi- target effects of coconut oil (virgin type) on Aβ-induced Alzheim- er’s disease animal model. Archives of Neuroscience, 6, e85715. https://doi.org/10.5812/ans.85715
61. Mohammed, A., Luka, C.D., Gyang, S.D. & Ngwen, A.L. (2017). Evaluation of the effect of coconut oil (Cocos nucifera) on some biochemical parameters in alloxan-induced diabetic rats. Saudi Journalof Medical and Pharmaceutical Sciences, 3, 318-322. https:// doi.org/10.21276/sjmps
62. Moon, J., Yim, E., Song, G., Lee, N.H. & Hyun, C. (2010). Screening of elastase and tyrosinase inhibitory activity from Jeju Island plants. EurAsian Journal of Biosciences, 4, 41-53. https://doi.org/10.5053/ ejobios.2010.4.0.6
63. Moriwaki, Y., Yamamoto, T. & Higashino, K. (1999). Enzymes in- volved in purine metabolism--a review of histochemical localiza- tion and functional implications. Histology and Histopathology, 14, 1321–1340. https://doi.org/10.14670/HH-14.1321
64. Moroy, G., Alix, A.J.P., Sapi, J., Hornebeck, W. & Bourguet, E. (2012). Neutrophil elastase as a target in lung cancer. Anti- cancer Agents in Medicinal Chemistry, 12, 565-579. https://doi. org/10.2174/187152012800617696
65. Morris, M.C., Tangney, C.C., Wang, Y., Sacks, F.M., Bennett, D.A. & Ag- garwal N.T. (2015). MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimer’s and Dementia, 11, 1007–1014. https://doi.org/10.1016/j.jalz.2014.11.009
66. Morris, S.M. (2002). Regulation of enzymes of the urea cycle and arginine metabolism. Annual Review of Nutrition, 22, 87–105. https://doi.org/10.1146/annurev.nutr.22.110801.140547.
67. Munazza, F., Najam-us-Sahar, S. Z., Deeba, A. & Farhan, A. (2016). In vitro antiviral activity of Cinnamomumcassia and its nanoparticles against H7N3 influenza A virus. Journal of Microbiology and Bio- technology, 26, 151-159. https://doi.org/10.4014/jmb.1508.08024
68. Myers, R.W., Lee, R.T., Lee, Y.C., Thomas, G.H., Reynolds, L.W. & Uchi- da, Y. (1980). The synthesis of 4-methylumbelliferyl α-ketoside of N-acetylneuraminic acid and its use in a fluorometric assay for neuraminidase. Analytical Biochemistry, 101, 166-174. https://doi. org/10.1016/0003-2697(80)90056-1
69. Nafar, F. & Mearow K.M. (2014). Coconut oil attenuates the effects of amyloid-β on cortical neurons in vitro. Journal of Alzheimer’s Disease, 39, 233–237.https://doi.org/10.3233/JAD-131436
70. Naik, A., Raghavendra, S.N. & Raghavarao, K.S. (2012). Production of coconut protein powder from coconut wet processing waste and its characterization. Applied Biochemistry and Biotechnology 167, 1290–1302. https://doi.org/10.1007/s12010-012-9632-9.
71. Nayar, N.M. (2017). The Coconut: Phylogeny, Origins, and Spread. Academic Press. 10–21. ISBN 978-0-12-809778-6.
72. Neelakantan, N., Seah, J.Y.H. & van Dam, R.M. (2020). The effect of coconut oil consumption on cardiovascular risk factors (System- atic review). Circulation 141, 803–814. https://doi.org/10.1161/ circulationaha.119.043052
73. Ngoc, T. M., Nhiem, N. X., Khoi, N. M., Son, D. C., Hung, T. V. & Van Kiem, P. (2014). A new coumarin and cytotoxic activities of constitu- ents from Cinnamomum cassia. Natural Product Communications, 9, 487-488. Retrieved from https://pubmed.ncbi.nlm.nih.gov
74. Nickavar, B. & Yousefian, N. (2011). Evaluation of α-amylase inhibi- tory activities of selected antidiabetic medicinal plants. Journal of Verbraucherschutz und Lebensmittelsicherheit, 6, 191-195. https:// doi.org/10.1007/s00003-010-0627-6
75. Nickavar, B., Mojab, F., Javidnia, K. & Amoli, M. A. (2003). Chemi- cal composition of the fixed and volatile oils of Nigella sativa L. from Iran. Zeitschrift für Naturforschung C, Journal of Biosciences, 58, 629–631. https://doi.org/10.1515/znc-2003-9-1004
76. Obied, H.K., Prenzler, P.D., Omar, S.H., Ismael, R., Servili, M., Esposto, S. & Urbani, S. (2012). Pharmacology of olive biophenols. Advanc- es in Molecular Toxicology, 6, 195–242. https://doi.org/10.1016/ B978-0-444-59389-4.00006-9
77. Omar, S.H., Scott, C.J., Hamlin, A.S. & Obied, H.K. (2018). Biophe- nols: enzymes (β-secretase, cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.). Fitotera- pia, 128,118–129. https://doi.org/10.1016/j.fitote.2018.05.011
78. Park, S.B., Lee, J.H., Kim, H.D., Soe, K.H., Jeong, H.S., Kim, D.H. & Lee S.E. (2018). Screening of plant extracts with cholinesterase inhibi- tion activity. Korean Journal of Plant Resources, 31, 433-452. https:// doi.org/10.7732/kjpr.2018.31.5.433
79. Peng, X., Zhang, G. & Zen, L. (2016). Inhibition of α-glucosidase by vitamin D3 and the effect of vitamins B1 and B2. Food & Function, 7, 982–991. https://doi.org/10.1039/c5fo00992h
80. Pereira, A.P., Ferreira, I.C., Marcelino, F., Valentao, P., Andrade, P.B., Seabra, R., Estevinho, L…..Pereira, J.A. (2007). Phenolic com- pounds and antimicrobial activity of olive (Olea europaea L. Cv. Cobrançosa) leaves. Molecules, 12, 1153-1162. https://doi. org/10.3390/12051153
81. Ramasubbu, N., Paloth, V., Luo, Y., Brayer, G.D. & Levine, M.J. (1996). Structure of human salivary alpha-amylase at 1.6 a resolution: implications for its role in the oral cavity. Acta Crystallographica. Section D, Biological Crystallography, 52, 435-346. https://doi. org/10.1107/S0907444995014119
82. Rao, A.A., Sridhar, G.R. & Das, U.N. (2007). Elevated butyrylcholines- terase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer’s disease. Medical Hypoth- eses, 69, 1272–1276. https://doi.org/10.1016/j.mehy.2007.03.032
83. Roman, G.C., Jackson, R.E., Gadhia, R., Roman, A.N. & Reis, J. (2019). Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease. Revue Neurologique (Paris), 175, 724-741. https://doi.org/10.1016/j.neurol.2019.08.005
84. Rothe, B., Rothe, B., Roggentin, P. & Schauer, R. (1991). The sialidasegene from Clostridium septicum: cloning, sequencing, expres- sion in Escherichia coli and identification of conserved sequences in sialidases and other proteins. Molecular and General Genetics, 226, 190-197.https://doi.org/10.1007/BF00273603
85. Shafiq, H., Ahmad A., Masud, T. & Kaleem, M. (2014). Cardio-pro- tective and anti-cancer therapeutic potential of Nigella sativa. Iranian Journal of Basic Medical Sciences, 17, 967.Retrieved from http://ncbi.nlm.nih.gov
86. Shah I., Petroczi A., Tabet N., Klugman A., Isaac M. & Naughton D.P. (2012). Low 25OH vitamin D2 levels found in untreated Alzheim- er’s patients, compared to acetylcholinesterase-inhibitor treated and controls. Current Alzheimer Research, 9, 1069-1076. https:// doi.org/10.2174/156720512803568975
87. Silva R.R., e Silva D.O., Fontes H.R., Alviano C.S., Fernandes P.D. &Alviano D.S. (2013). Anti-inflammatory, antioxidant, and anti- microbial activities of Cocos nucifera var. typica. BioMed Central Complementary and Alternative Medicine, 13, 107. https://doi. org/10.1186/1472-6882-13-107
88. Tamer, A.A., Fayed, A.K.M., Ayman, E.E. & Ibrahim, E.E. (2020). Ef- ficiency of mixture of olives oil and figs as an antiviral agent: a review and perspective. International Journal of Medical Science and Health Research, 4, 107-111. Retrieved from http://ijmshr.com
89. Tao, Y., Zhang, Y., Cheng, Y. & Wang, Y. (2013). Rapid screening and identification of α-glucosidase inhibitors from mulberry leaves using enzyme-immobilized magnetic beads coupled with HPLC/ MS and NMR. Biomedical Chromatography, 27, 148–155. https:// doi.org/10.1002/bmc.2761
90. Temiz, M.A. & Temur, A. (2019). The effect of olive leaf extract on digestive enzyme inhibition and insulin production in strepto- zotocin-induced diabetic rats. Ankara Üniversitesi Veteriner Fakül- tesi Dergisi, 66, 163-169. https://doi.org/10.33988/auvfd.423491
91. van den Berg, M.P.M., Meurs, H. & Gosens, R. (2018). Targeting argi- nase and nitric oxide metabolism in chronic airway diseases and their co-morbidities. Current Opinion in Pharmacology, 40, 126-133. https://doi.org/10.1016/j.coph.2018.04.010
92. Vanschoonbeek, K., Thomassen, B.J., Senden, J.M., Wodzig, W.K. & van Loon, L.J. (2006). Cinnamon supplementation does not improve glycemic control in postmenopausal type 2 diabe- tes patients. The Journal of Nutrition, 136, 977–980https://doi. org/10.1093/jn/136.4.977
93. Villarreal, A., Reyes, R.X.A., Angelo, M.F., Reines, A.G. & Ramo, A.J. (2011). S100B alters neuronal survival and dendrite extension via RAGE-mediated NF-KB signaling. Journal of Neurochemistry, 117,321–332. https://doi.org/10.1111/j.1471-4159.2011.07207.x
94. Vogel, P., Kasper, Machado, I., Garavaglia, J., Zani, V.T., de Souza, D. & Morelo Dal Bosco, S. (2014). Polyphenols benefits of olive leaf (Olea europaea L) to human health. Nutriciόn Hospitalaria, 31, 1427-1433. https://doi.org/10.3305/nh.2015.31.3.8400
95. von Itzstein, M. (2007). The war against influenza: discovery and development of sialidase inhibitors. Nature Reviews Drug Discov- ery, 6, 967–974. Retrieved from https://www.nature.com
96. Waterman, E. & Lockwood, B. (2007). Active components and clini- cal applications of olive oil. Alternative Medicine Review: A Journal of Clinical Therapy, 12, 331–342.Retrieved from http://altmedrev.com
97. Wu, G. & Morris, S.M. (1998). Arginine metabolism: nitric oxide and beyond. The Biochemical Journal, 336, 1–17. https://doi. org/10.1042/bj3360001
98. Zakaria, Z.A., Reezal, I., Mat Jais, A.M., Somchit, M.N., Sulaiman, M.R., Marmin, A.H.I., Sidek, H……Abdul Rahman, L. (2006). The anti-inflammatory, anti-pyretic and wound healing activities of Cocos nucifera (MATAG Types) fresh juice and kernel extract in experimental animals. Journal of Pharmacology and Toxicology, 1, 516-526. https://doi.org/10.3923/jpt.2006.516.526
99. Zhen, J., Dai, Y., Villani, T., Giurleo, D., Simon, J.E. & Wu, Q. (2017). Synthesis of novel flavonoid alkaloids as a-glucosidase inhibitors. Bioorganic and Medicinal Chemistry 25, 5355–5364. https://doi. org/10.1016/j.bmc.2017.07.055