Diapin®: A food supplement with diverse therapeutic potentials

Year 2022, Volume: 52 Issue: 3, 302 - 310, 30.12.2022

Umar Faruk Magaji , Selahattin Boyacı Umut Bulbul Sadettin Akça Özlem Saçan , Refiye Yanardağ

https://doi.org/10.26650/IstanbulJPharm.2022.980682

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

• 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
• 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
• 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
• 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
• 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.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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.
• 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
• Hasler, C.M. (2005). Regulation of functional foods and nutraceuti- cals: a global perspective. USA, IFT Press and Blackwell Publishing.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Kalra, E.K. (2003). Nutraceutical-definition and introduction. Amer- ican Association of Pharmaceutical Scientists, 5, 27–28. https://doi. org/10.1208/ps050325
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Leach, M. J. & Kumar, S. (2012). Cinnamon for diabetes mellitus. Cochrane Database Systamic Reviews, 2012,CD007170. https://doi. org/10.1002/14651858
• 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.
• 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
• 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.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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.
• 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
• 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
• 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
• 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.
• Nayar, N.M. (2017). The Coconut: Phylogeny, Origins, and Spread. Academic Press. 10–21. ISBN 978-0-12-809778-6.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Wu, G. & Morris, S.M. (1998). Arginine metabolism: nitric oxide and beyond. The Biochemical Journal, 336, 1–17. https://doi. org/10.1042/bj3360001
• 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
• 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