Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health

Molecules

Volumn 24, Issue 10, 2019, Pages

  Marković, Ana Karković ^a   Torić, Jelena ^a   Barbarić, Monika ^a   Brala, Cvijeta Jakobušić ^a  

^a UNIVERSITY OF ZAGREB   (Croatia)

Author keywords

Bioavailability; Biological activities; Hydroxytyrosol; Metabolism; Oleacein; Oleocanthal; Oleuropein; Tyrosol

Indexed keywords

3,4-DIHYDROXYPHENYLETHANOL; 4-HYDROXYPHENYLETHANOL; ANTINEOPLASTIC AGENT; CARDIOTONIC AGENT; NEUROPROTECTIVE AGENT; PHENETHYL ALCOHOL;

CHEMISTRY; HEALTH; HUMAN;

ANTINEOPLASTIC AGENTS; CARDIOTONIC AGENTS; HEALTH; HUMANS; NEUROPROTECTIVE AGENTS; PHENYLETHYL ALCOHOL;

EID: 85066287530     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules24102001     Document Type: Review

References (304)

1. López-Miranda, J.; Pérez-Jiménez, F.; Ros, E.; De Caterina, R.; Badimón, L.; Covas, M. I.; Escrich, E.; Ordovás, J. M.; Soriguer, F.; Abiá, R.; et al. Olive oil and health: Summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008. Nutr. Metab. Cardiovasc. Dis. 2010, 20, 284-294.
2. Estruch, R.; Ros, E.; Salas-Salvadó, J.; Covas, M.-I.; Corella, D.; Arós, F.; Gómez-Gracia, E.; Ruiz-Gutiérrez, V.; Fiol, M.; Lapetra, J.; et al. Primary Prevention of Cardiovascular Disease with A Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N. Engl. J. Med. 2018, 378, e34.
3. Sofi, F.; Macchi, C.; Abbate, R.; Gensini, G. F.; Casini, A. Mediterranean diet and health status: An updated meta-Analysis and A proposal for A literature-based adherence score. Public Health Nutr. 2014, 17, 2769-2782.
4. Covas, M.-I.; de la Torre, R.; Fitó, M. Virgin olive oil: A key food for cardiovascular risk protection. Br. J. Nutr. 2015, 113, S19-S28.
5. Psaltopoulou, T.; Kosti, R. I.; Haidopoulos, D.; Dimopoulos, M.; Panagiotakos, D. B. Olive oil intake is inversely related to cancer prevalence: A systematic review and A meta-Analysis of 13800 patients and 23340 controls in 19 observational studies. Lipids Health Dis. 2011, 10, 127-143.
6. Buckland, G.; Gonzalez, C. A. The role of olive oil in disease prevention: A focus on the recent epidemiological evidence from cohort studies and dietary intervention trials. Br. J. Nutr. 2015, 113, S94-S101.
7. Piroddi, M.; Albini, A.; Fabiani, R.; Giovannelli, L.; Luceri, C.; Natella, F.; Rosignoli, P.; Rossi, T.; Taticchi, A.; Servili, M.; et al. Nutrigenomics of extra-virgin olive oil: A review. BioFactors 2017, 43, 17-41.
8. Menendez, J. A.; Joven, J.; Aragonès, G.; Barrajón-Catalán, E.; Beltrán-Debón, R.; Borrás-Linares, I.; Camps, J.; Corominas-Faja, B.; Cufí, S.; Fernández-Arroyo, S.; et al. Xenohormetic and anti-Aging activity of secoiridoid polyphenols present in extra virgin olive oil: A new family of gerosuppressant agents. Cell Cycle 2013, 12, 555-578.
9. Ghanbari, R.; Anwar, F.; Alkharfy, K. M.; Gilani, A.-H.; Saari, N. Valuable Nutrients and Functional Bioactives in Different Parts of Olive (Olea europaea L.)-A Review. Int. J. Mol. Cell. Med. 2012, 13, 3291-3340.
10. Rodriguez-Morato, J.; Xicota, L.; Fito, M.; Farre, M.; Dierssen, M.; de la Torre, R. Potential Role of Olive Oil Phenolic Compounds in the Prevention of Neurodegenerative Diseases. Molecules 2015, 20, 4655-4680.
11. Rigacci, S.; Stefani, M. Nutraceutical Properties of Olive Oil Polyphenols. An Itinerary from Cultured Cells through Animal Models to Humans. Int. J. Mol. Cell. Med. 2016, 17, 843-871.
12. Parkinson, L.; Cicerale, S. The Health Benefiting Mechanisms of Virgin Olive Oil Phenolic Compounds. Molecules 2016, 21, 1734-1746.
13. Jakobuši Brala, C.; Barbari, M.; Karkovi Markovi, A.; Urši, S. Biomedicinal aspects and activities of olive oil phenolic compounds. In Handbook of olive oil. Phenolic compounds, production and health benefits, 1st ed.; Miloš, J.; Ed.; Nova Science Publishers: New York, USA, 2017; pp. 47-85, 978-1-53612-356-2.
14. Cicerale, S.; Lucas, L.; Keast, R. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr. Opin. Biotech. 2012, 23, 129-135.
15. Fabiani, R. Anti-cancer properties of olive oil secoiridoid phenols: A systematic review of in vivo studies. Food Funct. 2016, 7, 4145-4159.
16. Visioli, F.; Poli, A.; Galli, C. Antioxidant and other biological activities of phenols from olives and olive oil. Med. Res. Rev. 2002, 22, 65-75.
17. Tome-Carneiro, J.; Crespo, M. C.; Iglesias-Gutierrez, E.; Martin, R.; Gil-Zamorano, J.; Tomas-Zapico, C.; Burgos-Ramos, E.; Correa, C.; Gomez-Coronado, D.; Lasuncion, M. A.; et al. Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans. J. Nutr. Biochem. 2016, 34, 146-155.
18. Echeverria, F.; Ortiz, M.; Valenzuela, R.; Videla, L. A. Hydroxytyrosol and Cytoprotection: A Projection for Clinical Interventions. Int. J. Mol. Sci. 2017, 18, 930-944.
19. Robles-Almazan, M.; Pulido-Moran, M.; Moreno-Fernandez, J.; Ramirez-Tortosa, C.; Rodriguez-Garcia, C.; Quiles, J. L.; Ramirez-Tortosa, MC. Hydroxytyrosol: Bioavailability, toxicity, and clinical applications. Food Res. Int. 2018, 105, 654-667.
20. Wani, T. A.; Masoodi, F. A.; Gani, A.; Baba, W. N.; Rahmanian, N.; Akhter, R.; Wani, I. A.; Ahmad, M. Olive oil and its principal bioactive compound: Hydroxytyrosol-A review of the recent literature. Trends Food Sci. Technol. 2018, 77, 77-90.
21. Bayram, B.; Ozcelik, B.; Grimm, S.; Roeder, T.; Schrader, C.; Ernst, I. M. A.; Wagner, A. E.; Grune, T.; Frank, J.; Rimbach, G. A Diet Rich in Olive Oil Phenolics Reduces Oxidative Stress in the Heart of SAMP8 Mice by Induction of Nrf2-Dependent Gene Expression. Rejuvenation Res. 2012, 15, 71-81.
22. Scoditti, E.; Nestola, A.; Massaro, M.; Calabriso, N.; Storelli, C.; De Caterina, R.; Carluccio, M. A. Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKC and PKC1 inhibition. Atheroscler. 2014, 232, 17-24.
23. Bigagli, E.; Cinci, L.; Paccosi, S.; Parenti, A.; D'Ambrosio, M.; Luceri, C. Nutritionally relevant concentrations of resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocytes and monocytes and the production of pro-inflammatory mediators in LPS-stimulated RAW 264. 7 macrophages. Int. Immunopharmacol. 2017, 43, 147-155.
24. Perona, J. S.; Cabello-Moruno, R.; Ruiz-Gutierrez, V. The role of virgin olive oil components in the modulation of endothelial function. J. Nutr. Biochem. 2006, 17, 429-445.
25. Rietjens, S. J.; Bast, A.; Haenen, G. R. M. M. New insights into controversies on the antioxidant potential of the olive oil antioxidant hydroxytyrosol. J. Agric. Food Chem. 2007, 55, 7609-7614.
26. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), (2010). Scientific Opinion on the substantiation of health claims related to vitamin E and protection of DNA, proteins and lipids from oxidative damage. EFSA J. 2010, 8, 1816.
27. Berrougui, H.; Ikhlef, S.; Khalil, A. Extra Virgin Olive Oil Polyphenols Promote Cholesterol Efflux and Improve HDL Functionality. Evid.-based Complement. Altern. Med. 2015, 208062.
28. Calabriso, N.; Gnoni, A.; Stanca, E.; Cavallo, A.; Damiano, F.; Siculella, L.; Carluccio, M. A. Hydroxytyrosol Ameliorates Endothelial Function under Inflammatory Conditions by Preventing Mitochondrial Dysfunction. Oxid. Med. Cell. Longev. 2018, 2018, 9086947.
29. Wu, X.; Li, C.; Mariyam, Z.; Jiang, P.; Zhou, M.; Zeb, F.; ul Haq, I.; Chen, A.; Feng, Q. Acrolein-induced atherogenesis by stimulation of hepatic flavin containing monooxygenase 3 and A protection from hydroxytyrosol. J. Cellr. Physiol. 2019, 234, 475-485.
30. Fuccelli, R.; Fabiani, R.; Rosignoli, P. Hydroxytyrosol Exerts Anti-Inflammatory and Anti-Oxidant Activities in A Mouse Model of Systemic Inflammation. Molecules 2018, 23, 3212.
31. Colica, C.; Di Renzo, L.; Trombetta, D.; Smeriglio, A.; Bernardini, S.; Cioccoloni, G.; Costa de Miranda, R.; Gualtieri, P.; Sinibaldi Salimei, P.; De Lorenzo, A. Antioxidant Effects of A Hydroxytyrosol-Based Pharmaceutical Formulation on Body Composition, Metabolic State, and Gene Expression: A Randomized Double-Blinded, Placebo-Controlled Crossover Trial. Oxid. Med. Cell. Longev. 2017, 2473495.
32. Crespo, M. C.; Tome-Carneiro, J.; Burgos-Ramos, E.; Kohen, V. L.; Espinosa, M. I.; Herranz, J.; Visioli, F. Oneweek administration of hydroxytyrosol to humans does not activate Phase II enzymes. Pharmacol. Res. 2015, 95-96, 132-137.
33. Catalan, U.; Lopez de las Hazas, M.-C.; Pinol, C.; Rubio, L.; Motilva, M.-J.; Fernandez-Castillejo, S.; Sola, R. Hydroxytyrosol and its main plasma circulating metabolites attenuate the initial steps of atherosclerosis through inhibition of the MAPK pathway. J. Funct. Food 2018, 40, 280-291.
34. Gonzalez-Santiago, M.; Martin-Bautista, E.; Carrero, J. J.; Fonolla, J.; Baro, L.; Bartolome, M. V.; Gil-Loyzaga, P.; Lopez-Huertas, E. One-month administration of hydroxytyrosol, A phenolic antioxidant present in olive oil, to hyperlipemic rabbits improves blood lipid profile, antioxidant status and reduces atherosclerosis development. Atheroscler. 2006, 188, 35-42.
35. Tomé-Carneiro, J.; Visioli, F. Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomed. 2016, 23, 1145-1174.
36. Lopez-Huertas, E.; Fonolla, J. Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial. Redox. Biol. 2017, 11, 384-389.
37. Xie, Y.; Xu, Y.; Chen, Z.; Lu, W.; Li, N.; Wang, Q.; Shao, L.; Li, Y.; Yang, G.; Bian, X. A new multifunctional hydroxytyrosol-fenofibrate with antidiabetic, antihyperlipidemic, antioxidant and antiinflammatory action. Biomed. Pharmacother. 2017, 95, 1749-1758.
38. Xie, Y.-D.; Chen, Z.-Z.; Li, N.; Lu, W.-F.; Xu, Y.-H.; Lin, Y.-Y.; Shao, L.-H.; Wang, Q.-T.; Guo, L.-Y.; Gao, Y.-Q. et al. Hydroxytyrosol nicotinate, A new multifunctional hypolipidemic and hypoglycemic agent. Biomed. Pharmacother. 2018, 99, 715-724.
39. Xie, Y.-D.; Chen, Z.-Z.; Shao, L.-H.; Wang, Q.-T.; Li, N.; Lu, W.-F.; Xu, Y.-H.; Gao, Y.-Q.; Guo, L.-Y.; Li, Y.-P.; et al. A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects. Bioorg. Med. Chem. Lett. 2018, 28, 3119-3122.
40. Gonzalez-Correa, J. A.; Navas, M. D.; Munoz-Marin, J.; Trujillo, M.; Fernandez-Bolanos, J.; Pedro de la Cruz, J. Effects of hydroxytyrosol and hydroxytyrosol acetate administration to rats on platelet function compared to acetylsalicylic acid. J. Agric. Food Chem. 2008, 56, 7872-7876.
41. Catalan, U.; Rubio, L.; Lopez de las Hazas, M.-C.; Herrero, P.; Nadal, P.; Canela, N.; Pedret, A.; Motilva, M.-J.; Sola, R. Hydroxytyrosol and its complex forms (secoiridoids) modulate aorta and heart proteome in healthy rats: Potential cardio-protective effects. Mol. Nutr. Food Res. 2016, 60, 2114-2129.
42. Fabiani, R.; Sepporta, M. V.; Rosignoli, P.; De Bartolomeo, A.; Crescimanno, M.; Morozzi, G. Antiproliferative and pro-Apoptotic activities of hydroxytyrosol on different tumour cells: The role of extracellular production of hydrogen peroxide. Eur. J. Nutr. 2012, 51, 455-464.
43. Imran, M.; Nadeem, M.; Gilani, S. A.; Khan, S.; Sajid, M. W.; Amir, R. M. Antitumor Perspectives of Oleuropein and Its Metabolite Hydroxytyrosol: Recent Updates. J. Food Sci. 2018, 83, 1781-1791.
44. Corona, G.; Tzounis, X.; Assunta DessÌ, M.; Deiana, M.; Debnam, E. S.; Visioli, F.; Spencer, J. P. E. The fate of olive oil polyphenols in the gastrointestinal tract: Implications of gastric and colonic microflora-dependent biotransformation. Free Radic. Res. 2006, 40, 647-658.
45. Corona, G.; Deiana, M.; Incani, A.; Vauzour, D.; Dessi, M. A.; Spencer, J. P. E. Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1. Mol. Nutr. Food Res. 2009, 53, 897-903.
46. de las Hazas, M. C. L.; Piñol, C.; Macià, A.; Motilva, M.-J. Hydroxytyrosol and the Colonic Metabolites Derived from Virgin Olive Oil Intake Induce Cell Cycle Arrest and Apoptosis in Colon Cancer Cells. J. Agric. Food Chem. 2017, 65, 6467-6476.
47. Sun, L.; Luo, C.; Liu, J. Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Funct. 2014, 5, 1909-1914.
48. Terzuoli, E.; Giachetti, A.; Ziche, M.; Donnini, S. Hydroxytyrosol, A product from olive oil, reduces colon cancer growth by enhancing epidermal growth factor receptor degradation. Mol. Nut. Food Res. 2016, 60, 519-529.
49. Bernini, R.; Carastro, I.; Palmini, G.; Tanini, A.; Zonefrati, R.; Pinelli, P.; Brandi, M. L.; Romani, A. Lipophilization of Hydroxytyrosol-Enriched Fractions from Olea europaea L. Byproducts and Evaluation of the in Vitro Effects on A Model of Colorectal Cancer Cells. J. Agric. Food Chem. 2017, 65, 6506-6512.
50. Rosignoli, P.; Fuccelli, R.; Sepporta, M. V.; Fabiani, R. In vitro chemo-preventive activities of hydroxytyrosol: The main phenolic compound present in extra-virgin olive oil. Food Funct. 2016, 7, 301-307.
51. Zubair, H.; Bhardwaj, A.; Ahmad, A.; Srivastava, S. K.; Khan, M. A.; Patel, G. K.; Singh, S.; Singh, A. P. Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells. Nutr. Cancer 2017, 69, 932-942.
52. Calahorra, J.; Martínez-Lara, E.; De Dios, C.; Siles, E. Hypoxia modulates the antioxidant effect of hydroxytyrosol in MCF-7 breast cancer cells. PLOS ONE 2018, 13, e0203892.
53. Zhao, B.; Ma, Y.; Xu, Z.; Wang, J.; Wang, F.; Wang, D.; Pan, S.; Wu, Y.; Pan, H.; Xu, D.; et al. Hydroxytyrosol, A natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. Cancer Lett. 2014, 347, 79-87.
54. Tutino, V.; Caruso, M. G.; Messa, C.; Perri, E.; Notarnicola, M.; Antiproliferative, Antioxidant and Antiinflammatory Effects of Hydroxytyrosol on Human Hepatoma HepG2 and Hep3B Cell Lines. Anticancer Res. 2012, 5371-5378.
55. Li, S.; Han, Z.; Ma, Y.; Song, R.; Pei, T.; Zheng, T.; Wang, J.; Xu, D.; Fang, X.; Jiang, H.; et al. Hydroxytyrosol inhibits cholangiocarcinoma tumor growth: An in vivo and in vitro study. Oncol. Rep. 2014, 31, 145-152.
56. Goldsmith, C.; Bond, D.; Jankowski, H.; Weidenhofer, J.; Stathopoulos, C.; Roach, P.; Scarlett, C. The Olive Biophenols Oleuropein and Hydroxytyrosol Selectively Reduce Proliferation, Influence the Cell Cycle, and Induce Apoptosis in Pancreatic Cancer Cells. Int. J. Mol. Sci. 2018, 19, 1937.
57. Toteda, G.; Lupinacci, S.; Vizza, D.; Bonofiglio, R.; Perri, E.; Bonofiglio, M.; Lofaro, D.; La Russa, A.; Leone, F.; Gigliotti, P.; et al. High doses of hydroxytyrosol induce apoptosis in papillary and follicular thyroid cancer cells. J. Endocrinol. Invest. 2017, 40, 153-162.
58. de las Hazas, M. C. L.; Rubio, L.; Macia, A.; Motilva, M. J. Hydroxytyrosol: Emerging Trends in Potential Therapeutic Applications. Curr. Pharml. Desig 2018, 24, 2157-2179.
59. Orsini, F.; Ami, D.; Lascialfari, A.; Natalello, A. Inhibition of lysozyme fibrillogenesis by hydroxytyrosol and dopamine: An Atomic Force Microscopy study. Int. J. Biol. Macromol. 2018, 111, 1100-1105.
60. Goldstein, D. S.; Jinsmaa, Y.; Sullivan, P.; Holmes, C.; Kopin, I. J.; Sharabi, Y. 3, 4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells. Neurochem. Res. 2016, 41, 2173-2178.
61. Hornedo-Ortega, R.; Cerezo, A. B.; Troncoso, A. M.; Garcia-Parrilla, M. C. Protective effects of hydroxytyrosol against alpha-synuclein toxicity on PC12 cells and fibril formation. Food Chem. Toxicol. 2018, 120, 41-49.
62. Funakohi-Tago, M.; Sakata, T.; Fujiwara, S.; Sakakura, A.; Sugai, T.; Tago, K.; Tamura, H. Hydroxytyrosol butyrate inhibits 6-OHDA-induced apoptosis through activation of the Nrf2/HO-1 axis in SH-SY5Y cells. Eur. J. Pharmacol. 2017, 834, 246-256.
63. Zheng, A.; Li, H.; Cao, K.; Xu, J.; Zou, X.; Li, Y.; Chen, C.; Liu, J.; Feng, Z. Maternal hydroxytyrosol administration improves neurogenesis and cognitive function in prenatally stressed offspring. J. Nutr. Biochem. 2015, 26, 190-199.
64. Davinelli, S.; Maes, M.; Corbi, G.; Zarrelli, A.; Willcox, D. C.; Scapagnini, G. Dietary phytochemicals and neuroinflammaging: From mechanistic insights to translational challenges. Immun. Ageing 2016, 13, 16.
65. Priore, P.; Gnoni, A.; Natali, F.; Testini, M.; Gnoni, G. V.; Siculella, L.; Damiano, F. Oleic Acid and Hydroxytyrosol Inhibit Cholesterol and Fatty Acid Synthesis in C6 Glioma Cells. Oxid. Med. Cell Longev. 2017, 9076052.
66. Carito, V.; Ceccanti, M.; Cestari, V.; Natella, F.; Bello, C.; Coccurello, R.; Mancinelli, R.; Fiore, M. Olive polyphenol effects in A mouse model of chronic ethanol addiction. Nutrition 2017, 33, 65-69.
67. Jemai, H.; El Feki, A.; Sayadi, S. Antidiabetic and Antioxidant Effects of Hydroxytyrosol and Oleuropein from Olive Leaves in Alloxan-Diabetic Rats. J. Agric. Food Chem. 2009, 57, 8798-8804.
68. Antonio Lopez-Villodres, J.; Abdel-Karim, M.; Pedro De La Cruz, J.; Dolores Rodriguez-Perez, M.; Julio Reyes, J.; Guzman-Moscoso, R.; Rodriguez-Gutierrez, G.; Fernandez-Bolanos, J.; Antonio Gonzalez-Correa, J. Effects of hydroxytyrosol on cardiovascular biomarkers in experimental diabetes mellitus. J. Nutr. Biochem. 2016, 37, 94-100.
69. Reyes, J. J.; Villanueva, B.; Lopez-Villodres, J. A.; De La Cruz, J. P.; Romero, L.; Rodriguez-Perez, M. D.; Rodriguez-Gutierrez, G.; Fernandez-Bolanos, J.; Gonzalez-Correa, J. A. Neuroprotective Effect of Hydroxytyrosol in Experimental Diabetes Mellitus. J. Agric. Food Chem. 2017, 65, 4378-4383.
70. Suribabu, R.; Pindiprolu, S. S. S.; Talluri, S. V.; Chintamaneni, P.; Samidala, N. Protective Effects of Hydroxytyrosol from Diabetic Peripheral Neuropathy in Rodents: Implications of Antioxidant and Anti-Inflammatory Effects. Lat. Amer. J. Pharm. 2017, 36, 373-379.
71. Carmen Crespo, M.; Tome-Carneiro, J.; Pintado, C.; Davalos, A.; Visioli, F.; Burgos-Ramos, E.; Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease. Biofactors 2017, 43, 540-548.
72. Soto-Alarcon, S. A.; Valenzuela, R.; Valenzuela, A.; Videla, L. A. Liver Protective Effects of Extra Virgin Olive Oil: Interaction between Its Chemical Composition and the Cell-signaling Pathways Involved in Protection. Endocr. Metab. Immune Disord. Drug Targets 2017, 75-84.
73. Pirozzi, C.; Lama, A.; Simeoli, R.; Paciello, O.; Pagano, T. B.; Mollica, M. P.; Di Guida, F.; Russo, R.; Magliocca, S.; Canani, R. B.; et al. Hydroxytyrosol prevents metabolic impairment reducing hepatic inflammation and restoring duodenal integrity in A rat model of NAFLD. J. Nutr. Biochem. 2016, 30, 108-115.
74. Valenzuela, R.; Echeverria, F.; Ortiz, M.; Rincón-Cervera, M. Á.; Espinosa, A.; Hernandez-Rodas, M. C.; Illesca, P.; Valenzuela, A.; Videla, L. A. Hydroxytyrosol prevents reduction in liver activity of 5 and 6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice. Lipids Health Dis. 2017, 64-80.
75. Echeverría, F.; Valenzuela, R.; Bustamante, A.; Álvarez, D.; Ortiz, M.; Soto-Alarcon, S. A.; Muñoz, P.; Corbari, A.; Videla, L. A. Attenuation of High-Fat Diet-Induced Rat Liver Oxidative Stress and Steatosis by Combined Hydroxytyrosol-(HT-) Eicosapentaenoic Acid Supplementation Mainly Relies on HT. Oxid. Med. Cell Longev. 2018, 2018, 1-13.
76. Lemonakis, N.; Poudyal, H.; Halabalaki, M.; Brown, L.; Tsarbopoulos, A.; Skaltsounis, A.-L.; Gikas, E. The LC-MS-based metabolomics of hydroxytyrosol administration in rats reveals amelioration of the metabolic syndrome. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2017, 1041, 45-59.
77. Warnke, I.; Goralczyk, R.; Fuhrer, E.; Schwager, J. Dietary constituents reduce lipid accumulation in murine C3H10 T1/2 adipocytes: A novel fluorescent method to quantify fat droplets. Nutrit. Metabol. 2011, 8, 30.
78. Dagla, I.; Benaki, D.; Baira, E.; Lemonakis, N.; Poudyal, H.; Brown, L.; Tsarbopoulos, A.; Skaltsounis, A.-L.; Mikros, E.; Gikas, E. Alteration in the liver metabolome of rats with metabolic syndrome after treatment with Hydroxytyrosol. A Mass Spectrometry And Nuclear Magnetic Resonance-based metabolomics study. Talanta 2018, 178, 246-257.
79. Stefanon, B.; Colitti, M. Original Research: Hydroxytyrosol, an ingredient of olive oil, reduces triglyceride accumulation and promotes lipolysis in human primary visceral adipocytes during differentiation. Exp Biol Med 2016, 241, 1796-1802.
80. Wang, N.; Liu, Y.; Ma, Y.; Wen, D. Hydroxytyrosol ameliorates insulin resistance by modulating endoplasmic reticulum stress and prevents hepatic steatosis in diet-induced obesity mice. J. Nutrit. Biochem. 2018, 57, 180-188.
81. Illesca, P.; Valenzuela, R.; Espinosa, A.; Echeverría, F.; Soto-Alarcon, S.; Ortiz, M.; Videla, L. A. Hydroxytyrosol supplementation ameliorates the metabolic disturbances in white adipose tissue from mice fed A high-fat diet through recovery of transcription factors Nrf2, SREBP-1c, PPAR- and NF-B. Biomed. Pharmacother. 2019, 109, 2472-2481.
82. Valenzuela, R.; Illesca, P.; Echeverria, F.; Espinosa, A.; Rincon-Cervera, M. A.; Ortiz, M.; Hernandez-Rodas, M. C.; Valenzuela, A.; Videla, L. A. Molecular adaptations underlying the beneficial effects of hydroxytyrosol in the pathogenic alterations induced by A high-fat diet in mouse liver: PPAR-Alpha and Nrf2 activation, and NF-kappa B down-regulation. Food Funct. 2017, 8, 1526-1537.
83. Bisignano, G.; Tomaino, A.; Lo Cascio, R.; Crisafi, G.; Uccella, N.; Saija, A. On the in-vitro antimicrobial activity of oleuropein and hydroxytyrosol. J. Pharm. Pharmacol. 1999, 51, 971-974.
84. Medina, E.; De Castro, A.; Romero, C.; Brenes, M. Comparison of the concentrations of phenolic compounds in olive oils and other plant oils: Correlation with antimicrobial activity. J. Agric. Food Chem. 2006, 54, 4954-4961.
85. Wu, H.; Jiang, K.; Zhang, T.; Zhao, G.; Deng, G. Hydroxytyrosol exerts an anti-inflammatory effect by suppressing Toll-like receptor 2 and TLR 2 downstream pathways in Staphylococcus aureus-induced mastitis in mice. J. Funct. Food 2017, 35, 595-604.
86. Ghalandari, M.; Naghmachi, M.; Oliverio, M.; Nardi, M.; Shirazi, H. R. G.; Eilami, O. Antimicrobial effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Hydroxytyrosol Oleate on Staphylococcus Aureus and Staphylococcus Epidermidis. Elect. J. Gen. Med. 2018, 15, UNSP em46.
87. Sogawa, K.; Kobayashi, M.; Suzuki, J.; Sanda, A.; Kodera, Y.; Fukuyama, M. Inhibitory Activity of Hydroxytyrosol against Streptolysin O-Induced Hemolysis. Biocontrol Sci 2018, 23, 77-80.
88. Eilami, O.; Oliverio, M.; Hosseinian, S.; Motlagh, A. H.; Naghmachi, M. Antimicrobial Effects of Hydroxytyrosol Extracted From Olive Leaves, on Propionibacterium Acnes. World Family Medicine 2017, 15, 187-191.
89. Furneri, P. M.; Piperno, A.; Sajia, A.; Bisignano, G. Antimycoplasmal activity of hydroxytyrosol. Antimicrob Agents Chemother. 2004, 48, 4892-4894.
90. Medina-Martinez, M. S.; Truchado, P.; Castro-Ibanez, I.; Allende, A. Antimicrobial activity of hydroxytyrosol: A current controversy. Biosci. Biotechnol. Biochem. 2016, 80, 801-810.
91. Bedoya, L. M.; Beltran, M.; Obregon-Calderon, P.; Garcia-Perez, J.; de la Torre, H. E.; Gonzalez, N.; Perez-Olmeda, M.; Aunon, D.; Capa, L.; Gomez-Acebo, E.; et al. Hydroxytyrosol: A new class of microbicide displaying broad anti-HIV-1 activity. Aids 2016, 30, 2767-2776.
92. Yamada, K.; Ogawa, H.; Hara, A.; Yoshida, Y.; Yonezawa, Y.; Karibe, K.; Nghia, V. B.; Yoshimura, H.; Yamamoto, Y.; Yamada, M.; et al. Mechanism of the antiviral effect of hydroxytyrosol on influenza virus appears to involve morphological change of the virus. Antiviral Resear. 2009, 83, 35-44.
93. Diallinas, G.; Rafailidou, N.; Kalpaktsi, I.; Komianou, A. C.; Tsouvali, V.; Zantza, I.; Mikros, E.; Skaltsounis, A. L.; Kostakis, I. K. Hydroxytyrosol (HT) Analogs Act as Potent Antifungals by Direct Disruption of the Fungal Cell Membrane. Front Microbiol. 2018, 9, 2624.
94. Belmonte-Reche, E.; Martinez-Garcia, M.; Penalver, P.; Gomez-Perez, V.; Lucas, R.; Gamarro, F.; Maria Perez-Victoria, J.; Carlos Morales, J. Tyrosol and hydroxytyrosol derivatives as antitrypanosomal and antileishmanial agents. Eur. J. Med. Chem. 2016, 119, 132-140.
95. Fernandez-Pastor, I.; Martinez-Garcia, M.; Medina-O'Donnell, M.; Rivas, F.; Martinez, A.; Perez-Victoria, J. M.; Parra, A. Semisynthesis of omega-Hydroxyalkylcarbonate Derivatives of Hydroxytyrosol as Antitrypanosome Agents. J Nat Prod 2018, 81, 2075-2082.
96. Yonezawa, Y.; Miyashita, T.; Nejishima, H.; Takeda, Y.; Imai, K.; Ogawa, H. Anti-inflammatory effects of olive-derived hydroxytyrosol on lipopolysaccharide-induced inflammation in RAW264. 7 cells. J. Vet. Med. Sci. 2018, 80, 1801-1807.
97. Angeles Rosillo, M.; Sanchez-Hidalgo, M.; Castejon, M. L.; Montoya, T.; Gonzalez-Benjumea, A.; Fernandez-Bolanos, J. G.; Alarcon-de-la-Lastra, C. Extra-virgin olive oil phenols hydroxytyrosol and hydroxytyrosol acetate, down-regulate the production of mediators involved in joint erosion in human synovial cells. J. Funct. Food 2017, 36, 27-33.
98. Cetrullo, S.; D'Adamo, S.; Guidotti, S.; Borzi, R. M.; Flamigni, F. Hydroxytyrosol prevents chondrocyte death under oxidative stress by inducing autophagy through sirtuin 1-dependent and-independent mechanisms. Biochim. Biophys. Acta-Gen. Subj. 2016, 1860, 1181-1191.
99. Aparicio-Soto, M.; Sanchez-Hidalgo, M.; Cardeno, A.; Gonzalez-Benjumea, A.; Fernandez-Bolanos, J. G.; Alarcon-de-la-Lastra, C. Dietary hydroxytyrosol and hydroxytyrosyl acetate supplementation prevent pristane-induced systemic lupus erythematous in mice. J. Funct. Food 2017, 29, 84-92.
100. Sánchez-Fidalgo, S.; Villegas, I.; Aparicio-Soto, M.; Cárdeno, A.; Rosillo, Ma. Á.; González-Benjumea, A.; Marset, A.; López, Ó.; Maya, I.; Fernández-Bolaños, J. G.; et al. Effects of dietary virgin olive oil polyphenols: Hydroxytyrosyl acetate and 3, 4-dihydroxyphenylglycol on DSS-induced acute colitis in mice. J. Nutr. Biochem. 2015, 26, 513-520.
101. Yang, X.; Jing, T.; Li, Y.; He, Y.; Zhang, W.; Wang, B.; Zhang, J.; Wei, J.; Li, R. Hydroxytyrosol Attenuates LPS-Induced Acute Lung Injury in Mice by Regulating Autophagy and Sirtuin Expression. Currt. Mol. Med. 2017, 17, 149-159.
102. Hagiwara, K.; Goto, T.; Araki, M.; Miyazaki, H.; Hagiwara, H. Olive polyphenol hydroxytyrosol prevents bone loss. Eur. J. Pharmacol. 2011, 662, 78-84.
103. García-Martínez, O.; De Luna-Bertos, E.; Ramos-Torrecillas, J.; Ruiz, C.; Milia, E.; Lorenzo, M. L.; Jimenez, B.; Sánchez-Ortiz, A.; Rivas, A. Phenolic Compounds in Extra Virgin Olive Oil Stimulate Human Osteoblastic Cell Proliferation. PLoS ONE 2016, 11, e0150045.
104. Bonura, A.; Vlah, S.; Longo, A.; Bulati, M.; Melis, M. R.; Cibella, F.; Colombo, P. Hydroxytyrosol modulates Par j 1-induced IL-10 production by PBMCs in healthy subjects. Immunobiol. 2016, 221, 1374-1377.
105. Salucci, S.; Burattini, S.; Battistelli, M.; Buontempo, F.; Canonico, B.; Martelli, A. M.; Papa, S.; Falcieri, E. Tyrosol prevents apoptosis in irradiated keratinocytes. J Dermatol Sci 2015, 80, 61-68.
106. Avola, R.; Graziano ACE.; Pannuzzo, G.; Bonina, F.; Cardile, V. Hydroxytyrosol from olive fruits prevents blue-light-induced damage in human keratinocytes and fibroblasts. J. Cell Physiol. 2019, 234, 9065-9076.
107. Martinez-Lara, E.; Pena, A.; Calahorra, J.; Canuelo, A.; Siles, E. Hydroxytyrosol decreases the oxidative and nitrosative stress levels and promotes angiogenesis through HIF-1 independent mechanisms in renal hypoxic cells. Food Funct. 2016, 7, 540-548.
108. Visioli, F.; Galli, C.; Bornet, F.; Mattei, A.; Patelli, R.; Galli, G.; Caruso, D. Olive oil phenolics are dosedependently absorbed in humans. FEBS Letters 2000, 468, 159-160.
109. de las Hazas, M. C. L.; Godinho-Pereira, J.; Macia, A.; Almeida, A. F.; Ventura, M. R.; Motilva, M.-J.; Santos, C. J. Brain uptake of hydroxytyrosol and its main circulating metabolites: Protective potential in neuronal cells. J. Funct. Food 2018, 46, 110-107.
110. Domínguez-Perles, R.; Auñón, D.; Ferreres, F.; Gil-Izquierdo, A. Gender differences in plasma and urine metabolites from Sprague-Dawley rats after oral administration of normal and high doses of hydroxytyrosol, hydroxytyrosol acetate, and DOPAC. Eur. J. Nutr. 2017, 56, 215-224.
111. Bernini, R.; Montani, M. S. G.; Merendino, N.; Romani, A.; Velotti, F. Hydroxytyrosol-Derived Compounds: A Basis for the Creation of New Pharmacological Agents for Cancer Prevention and Therapy. J. Med. Chem. 2015, 58, 9089-9107.
112. Mateos, R.; Pereira-Caro, G.; Saha, S.; Cert, R.; Redondo-Horcajo, M.; Bravo, L.; Kroon, P. A. Acetylation of hydroxytyrosol enhances its transport across differentiated Caco-2 cell monolayers. Food Chem. 2011, 125, 865-872.
113. Pereira-Caro, G.; Mateos, R.; Shikha, S.; Andres, M.; José Luis, E.; Laura, B.; Paul, A. K. Transepithelial transport and metabolism of new lipophilic ether derivatives of hydroxytyrosol by enterocyte-like Caco-2/TC7 cells. J. Agric. Food Chem. 2010, 58, 11501-11509.
114. Pereira-Caro, G.; Madrona, A.; Bravo, L.; Espartero, J. L.; Alcudia, F.; Cert, A.; Mateos, R. Antioxidant activity evaluation of alkyl hydroxytyrosyl ethers, A new class of hydroxytyrosol derivatives. Food Chem. 2009, 115, 86-91.
115. Grasso, S.; Siracusa, L.; Spatafora, C.; Renis, M.; Tringali, C. Hydroxytyrosol lipophilic analogues: Enzymatic synthesis, radical scavenging activity and DNA oxidative damage protection. Bioorg. Chem. 2007, 35, 137-152.
116. Manna, C.; Galletti, P.; Maisto, G.; Cucciolla, V.; D'Angelo, S.; Zappia, V. Transport mechanism and metabolism of olive oil hydroxytyrosol in Caco-2 cells. FEBS Lett. 2000, 470, 341-344.
117. Pastor, A.; Rodríguez-Morató, J.; Olesti, E.; Pujadas, M.; Pérez-Mañá, C.; Khymenets, O.; Fitó, M.; Covas, M.-I.; Solá, R.; Motilva, M.-J.; et al. Analysis of free hydroxytyrosol in human plasma following the administration of olive oil. J. Chromatogr. A 2016, 1437, 183-190.
118. Tuck, K. L.; Hayball, P. J.; Stupans, I. Structural Characterization of the Metabolites of Hydroxytyrosol, the Principal Phenolic Component in Olive Oil, in Rats. J. Agric. Food Chem. 2002, 50, 2404-2409.
119. Visioli, F.; Galli, C.; Grande, S.; Colonnelli, K.; Patelli, C.; Galli, G.; Caruso, D. Hydroxytyrosol Excretion Differs between Rats and Humans and Depends on the Vehicle of Administration. J. Nutrit. 2003, 133, 2612-2615.
120. González-Santiago, M.; Fonollá, J.; Lopez-Huertas, E. Human absorption of A supplement containing purified hydroxytyrosol, A natural antioxidant from olive oil, and evidence for its transient association with low-density lipoproteins. Pharmacoll. Res. 2010, 61, 364-370.
121. D'Angelo, S.; Manna, C.; Migliardi, V.; Mazzoni, O.; Morrica, P.; Capasso, G.; Pontoni, G.; Galletti, P.; Zappia, V. Pharmacokinetics and metabolism of hydroxytyrosol, A natural antioxidant from olive oil. Drug Metab. Dispos. 2001, 29, 1492-1498.
122. Fernandez-Avila, C.; Montes, R.; Castellote, A. I.; Chisaguano, A. M.; Fito, M.; Covas, M. I.; Munoz-Aguallo, D.; Nyyssonen, K.; Zunft, H. J.; Lopez-Sabater, M. C. Fast determination of virgin olive oil phenolic metabolites in human high-density lipoproteins. Biomed. Chromatogr. 2015, 29, 1035-1041.
123. Serra, A.; Rubió, L.; Borràs, X.; Macià, A.; Romero, M.-P.; Motilva, M.-J. Distribution of olive oil phenolic compounds in rat tissues after administration of A phenolic extract from olive cake. Mol. Nutr. Food Res. 2012, 56, 486-496.
124. Schaffer, S.; Asseburg, H.; Kuntz, S.; Muller, W. E.; Eckert, G. P. Effects of Polyphenols on Brain Ageing and Alzheimer's Disease: Focus on Mitochondria. Mol. Neurobiol. 2012, 46, 161-178.
125. Schaffer, S.; Müller, W. E.; Eckert, G. P. Cytoprotective effects of olive mill wastewater extract and its main constituent hydroxytyrosol in PC12 cells. Pharmacol. Res. 2010, 62, 322-327.
126. Rodríguez-Morató, J.; Boronat, A.; Kotronoulas, A.; Pujadas, M.; Pastor, A.; Olesti, E.; Pérez-Mañá, C.; Khymenets, O.; Fitó, M.; Farré, M.; et al. Metabolic disposition and biological significance of simple phenols of dietary origin: Hydroxytyrosol and tyrosol. Drug Metabol. Rev. 2016, 48, 218-236.
127. de la Torre, R.; Covas, M. I.; Pujadas, M. A.; Fitó, M.; Farré, M. Is dopamine behind the health benefits of red wine Eur. J. Nutr. 2006, 45, 307-310.
128. Xu, C. L.; Sim, M. K. Reduction of dihydroxyphenylacetic acid by A novel enzyme in the rat brain. Biochem. Pharmacol. 1995, 50, 1333-1337.
129. Perez-Mana, C.; Farre, M.; Pujadas, M.; Mustata, C.; Menoyo, E.; Pastor, A.; Langohr, K.; de la Torre, R. Ethanol induces hydroxytyrosol formation in humans. Pharmacol. Res. 2015, 95-96, 27-33.
130. Davis, V. E.; Walsh, M. J. Alcohol, amines, and alkaloids: A possible biochemical basis for alcohol addiction. Science 1970, 167, 1005-1007.
131. Davis, V. E.; Walsh, M. J.; Yamanaka, Y. Augmentation of alkaloid formation from dopamine by alcohol and acetaldehyde in vitro. J. Pharmacol. Exp. Ther. 1970, 174, 401-412.
132. Tank, A. W.; Weiner, H. Ethanol-induced alteration of dopamine metabolism in rat liver. Biochem. Pharmacol. 1979, 28, 3139-3147.
133. Marchitti, S. A.; Deitrich, R. A.; Vasiliou, V. Neurotoxicity and Metabolism of the Catecholamine-Derived 3, 4-Dihydroxyphenylacetaldehyde and 3, 4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase. Pharmacol. Rev. 2007, 59, 125-150.
134. Rubió, L.; Macià, A.; Valls, R. M.; Pedret, A.; Romero, M.-P.; Solà, R.; Motilva, M.-J. A new hydroxytyrosol metabolite identified in human plasma: Hydroxytyrosol acetate sulphate. Food Chem. 2012, 134, 1132-1136.
135. de las Hazas, M. C. L.; Rubió, L.; Kotronoulas, A.; de la Torre, R.; Solà, R.; Motilva, M.-J. Dose effect on the uptake and accumulation of hydroxytyrosol and its metabolites in target tissues in rats. Mol. Nutr. Food Res. 2015, 59, 1395-1399.
136. de las Hazas, M. C. L.; Piñol, C.; Macià, A.; Romero, M.-P.; Pedret, A.; Solà, R.; Rubió, L.; Motilva, M.-J. Differential absorption and metabolism of hydroxytyrosol and its precursors oleuropein and secoiridoids. J. Func. Food 2016a, 22, 52-63.
137. de las Hazas, M. C. L.; Motilva, M. J.; Piñol, C.; Macià, A. Application of dried blood spot cards to determine olive oil phenols (hydroxytyrosol metabolites) in human blood. Talanta 2016, 159, 189-193.
138. Caruso, D.; Visioli, F.; Patelli, R.; Galli, C.; Galli, G. Urinary excretion of olive oil phenols and their metabolites in humans. Metabolism 2001, 50, 1426-1428.
139. Kotronoulas, A.; Pizarro, N.; Serra, A.; Robledo, P.; Joglar, J.; Rubió, L.; Hernaéz, Á.; Tormos, C.; Motilva, M. J.; Fitó, M.; et al. Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats. Pharmacol. Res. 2013, 77, 47-56.
140. Wu, Y.-T.; Lin, L.-C.; Tsai, T.-H. Measurement of free hydroxytyrosol in microdialysates from blood and brain of anesthetized rats by liquid chromatography with fluorescence detection. J. Chromatogr. A 2009, 1216, 3501-3507.
141. Mateos, R.; Martínez-López, S.; Baeza Arévalo, G.; Amigo-Benavent, M.; Sarriá, B.; Bravo-Clemente, L. Hydroxytyrosol in functional hydroxytyrosol-enriched biscuits is highly bioavailable and decreases oxidised low density lipoprotein levels in humans. Food. Chem. 2016, 205, 248-256.
142. Serreli, G.; Deiana, M. Biological Relevance of Extra Virgin Olive Oil Polyphenols Metabolites. Antioxidants 2018, 7, 170.
143. García-Villalba, R.; Larrosa, M.; Possemiers, S.; Tomás-Barberán, F. A.; Espín, J. C. Bioavailability of phenolics from an oleuropein-rich olive (Olea europaea) leaf extract and its acute effect on plasma antioxidant status: Comparison between pre-And postmenopausal women. Eur. J. Nutr. 2014, 53, 1015-1027.
144. Mosele, J. I.; Martín-Peláez, S.; Macià, A.; Farràs, M.; Valls, R.-M.; Catalán, Ú.; Motilva, M.-J. Faecal microbial metabolism of olive oil phenolic compounds: In vitro and in vivo approaches. Mol. Nutr. Food Res. 2014, 58, 1809-1819.
145. Mosele, J.; Macià, A.; Motilva, M.-J. Metabolic and Microbial Modulation of the Large Intestine Ecosystem by Non-Absorbed Diet Phenolic Compounds: A Review. Molecules 2015, 20, 17429-17468.
146. Ozdal, T.; Sela, D. A.; Xiao, J.; Boyacioglu, D.; Chen, F.; Capanoglu, E. The Reciprocal Interactions between Polyphenols and Gut Microbiota and Effects on Bioaccessibility. Nutrients 2016, 8, 78.
147. Parkar, S. G.; Trower, T. M.; Stevenson, D. E. Fecal microbial metabolism of polyphenols and its effects on human gut microbiota. Anaerobe 2013, 23, 12-19.
148. Suárez, M.; Valls, R. M.; Romero, M.-P.; Macià, A.; Fernández, S.; Giralt, M.; Solà, R.; Motilva, M.-J. Bioavailability of phenols from A phenol-enriched olive oil. Br. J. Nutr. 2011, 106, 1691-1701.
149. Chashmi, N. A.; Emadi, S.; Khastar, H. Protective effects of hydroxytyrosol on gentamicin induced nephrotoxicity in mice. Biochem. Biophys. Res. Commun. 2017, 482, 1427-1429.
150. Miró-Casas, E.; Farré Albaladejo, M.; Covas, M.-I.; Rodriguez, J. O.; Menoyo Colomer, E.; Lamuela Raventós, R. M.; de la Torre, R. Capillary Gas Chromatography-Mass Spectrometry Quantitative Determination of Hydroxytyrosol and Tyrosol in Human Urine after Olive Oil Intake. Anal. Biochem. 2001, 294, 63-72.
151. Miró-Casas, E.; Covas, M.-I.; Fitó, M.; Farré-Albadalejo, M.; Marrugat, J.; de la Torre, R. Tyrosol and hydroxytyrosol are absorbed from moderate and sustained doses of virgin olive oil in humans. Eur, J. Clin Nutr. 2003, 57, 186-190.
152. Khymenets, O.; Fito, M.; Tourino, S.; Munoz-Aguayo, D.; Pujadas, M.; Torres, J. L.; Joglar, J.; Farre, M.; Covas, M.-I.; de la Torre, R. Antioxidant Activities of Hydroxytyrosol Main Metabolites Do Not Contribute to Beneficial Health Effects after Olive Oil Ingestion. Drug Metab. Dispos. 2010, 38, 1417-1421.
153. Giordano, E.; Dangles, O.; Rakotomanomana, N.; Baracchini, S.; Visioli, F. 3-O-Hydroxytyrosol glucuronide and 4-O-hydroxytyrosol glucuronide reduce endoplasmic reticulum stress in vitro. Food Funct. 2015, 6, 3275-3281.
154. Atzeri, A.; Lucas, R.; Incani, A.; Peñalver, P.; Zafra-Gómez, A.; Melis, M. P.; Pizzala, R.; Morales, J. C.; Deiana, M. Hydroxytyrosol and tyrosol sulfate metabolites protect against the oxidized cholesterol prooxidant effect in Caco-2 human enterocyte-like cells. Food Funct. 2016, 7, 337-346.
155. Paiva-Martins, F.; Silva, A.; Almeida, V.; Carvalheira, M.; Serra, C.; Rodrígues-Borges, J. E.; Fernandes, J.; Belo, L.; Santos-Silva, A. Protective Activity of Hydroxytyrosol Metabolites on Erythrocyte Oxidative-Induced Hemolysis. J. Agric. Food Chem. 2013, 61, 6636-6642.
156. Deiana, M.; Incani, A.; Rosa, A.; Atzeri, A.; Loru, D.; Cabboi, B.; Paola Melis, M.; Lucas, R.; Morales, J. C.; Assunta Dessì, M. Hydroxytyrosol glucuronides protect renal tubular epithelial cells against H2O2 induced oxidative damage. Chem. Biol. Interact. 2011, 193, 232-239.
157. Di Benedetto, R.; Varì, R.; Scazzocchio, B.; Filesi, C.; Santangelo, C.; Giovannini, C.; Matarrese, P.; D'Archivio, M.; Masella, R. Tyrosol, the major extra virgin olive oil compound, restored intracellular antioxidant defences in spite of its weak antioxidative effectiveness. Nutr. Metab. Cardiovasc. Dis. 2007, 17, 535-545.
158. Lee, K. M.; Hur, J.; Lee, Y.; Yoon, B.-R.; Choi, S. Y. Protective Effects of Tyrosol Against Oxidative Damage in L6 Muscle Cells. Food Sci. Tech. Res. 2018, 24, 943-947.
159. Chang, C.-Y.; Huang, I.-T.; Shih, H.-J.; Chang, Y.-Y.; Kao, M.-C.; Shih, P.-C.; Huang, C.-J. Cluster of differentiation 14 and toll-like receptor 4 are involved in the anti-inflammatory effects of tyrosol. J. Funct. Food 2019, 53, 93-104.
160. Samuel, S. M.; Thirunavukkarasu, M.; Penumathsa, S. V.; Paul, D.; Maulik, N. Akt/FOXO3a/SIRT1-Mediated Cardioprotection by n-Tyrosol against Ischemic Stress in Rat in Vivo Model of Myocardial Infarction: Switching Gears toward Survival and Longevity. J. Agric. Food Chem. 2008, 56, 9692-9698.
161. Plotnikov, M. B.; Aliev, O.; Sidekhmenova, A.; Shamanaev, A. Y.; Anishchenko, A. M.; Fomina, T.; Plotnikova, T. M.; Arkhipov, A. M. Effect of p-tyrosol on hemorheological parameters and cerebral capillary network in young spontaneously hypertensive rats. Microvasc. Res. 2018, 119, 91-97.
162. Osipenko, A. N.; Plotnikova, T. M.; Chernysheva, G. A.; Smolyakova, V. I. The mechanisms of neuroprotective action of p-tyrosol after the global cerebral ischemia in rats. Byulleten Sibirskoy Meditsiny 2017, 16, 65-72.
163. Chandramohan, R.; Pari, L. Anti-inflammatory effects of tyrosol in streptozotocin-induced diabetic Wistar rats. J. Funct. Food 2016, 27, 17-28.
164. Lee, H.; Im, S. W.; Jung, C. H.; Jang, Y. J.; Ha, T. Y.; Ahn, J. Tyrosol, an olive oil polyphenol, inhibits ER stressinduced apoptosis in pancreatic beta-cell through JNK signaling. Biochem. Biophys. Res. Commun. 2016, 469, 748-752.
165. Priore, P.; Siculella, L.; Gnoni, G. V. Extra virgin olive oil phenols down-regulate lipid synthesis in primarycultured rat-hepatocytes. J. Nutr. Biochem. 2014, 25, 683-691.
166. Sarna, L. K.; Sid, V.; Wang, P.; Siow, Y. L.; House, J. D.; O.; K. Tyrosol Attenuates High Fat Diet-Induced Hepatic Oxidative Stress: Potential Involvement of Cystathionine Synthase and Cystathionine Lyase. Lipids 2016, 51, 583-590.
167. St-Laurent-Thibault, C.; Arseneault, M.; Longpré, F.; Ramassamy, C. Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-induced toxicity. Involvement of the NF-B signaling. Curr. Alzheimer Res. 2011, 8, 543-551.
168. Amini, A.; Liu, M.; Ahmad, Z. Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase. Int. J. Biol. Macromol. 2017, 101, 153-164.
169. Puel, C.; Mardon, J.; Agalias, A.; Davicco, M.-J.; Lebecque, P.; Mazur, A.; Horcajada, M.-N.; Skaltsounis, A.-L.; Coxam, V. Major phenolic compounds in olive oil modulate bone loss in an ovariectomy/inflammation experimental model. J. Agric. Food Chem. 2008, 56, 9417-9422.
170. Cañuelo, A.; Gilbert-López, B.; Pacheco-Liñán, P.; Martínez-Lara, E.; Siles, E.; Miranda-Vizuete, A. Tyrosol, A main phenol present in extra virgin olive oil, increases lifespan and stress resistance in Caenorhabditis elegans. Mech Ageing Dev. 2012, 133, 563-574.
171. Lee, D.-H.; Kim, Y.-J.; Kim, M.; Ahn, J.; Ha, T.-Y.; Lee, S.; Jang, Y.; Jung, C. Pharmacokinetics of Tyrosol Metabolites in Rats. Molecules 2016, 21, 128.
172. Tacker, M.; Creaven, P. J.; McIsaac, W. M. Alteration in tyramine metabolism by ethanol. Biochem. Pharmacol. 1970, 19, 604-607.
173. Perez-Mana, C.; Farré, M.; Rodríguez-Morató, J.; Papaseit, E.; Pujadas, M.; Fitó, M.; Robledo, P.; Covas, M.-I.; Cheynier, V.; Meudec, E.; et al. Moderate consumption of wine, through both its phenolic compounds and alcohol content, promotes hydroxytyrosol endogenous generation in humans. A randomized controlled trial. Mol. Nutr. Food Res. 2015b, 59, 1213-1216.
174. Rodríguez-Morató, J.; Robledo, P.; Tanner, J.-A.; Boronat, A.; Pérez-Mañá, C.; Oliver Chen, C.-Y.; Tyndale, R. F.; de la Torre, R. CYP2D6 and CYP2A6 biotransform dietary tyrosol into hydroxytyrosol. Food Chem 2017, 217, 716-725.
175. Mateos, R.; Goya, L.; Bravo, L. Metabolism of the Olive Oil Phenols Hydroxytyrosol, Tyrosol, and Hydroxytyrosyl Acetate by Human Hepatoma HepG2 Cells. J. Agric. Food Chem. 2005, 53, 9897-9905.
176. Muriana, F. J. G.; Montserrat-de la Paz, S.; Lucas, R.; Bermudez, B.; Jaramillo, S.; Morales, J. C.; Abia, R.; Lopez, S. Tyrosol and its metabolites as antioxidative and anti-inflammatory molecules in human endothelial cells. Food Funct. 2017, 8, 2905-2914.
177. Hassen, I.; Casabianca, H.; Hosni, K. Biological activities of the natural antioxidant oleuropein: Exceeding the expectation-A mini-review. J. Funct. Food 2015, 18, 926-940.
178. Visioli, F.; Bellomo, G.; Galli, C. Free Radical-Scavenging Properties of Olive Oil Polyphenols. Biochem. Biophys. Res. Commun. 1998, 247, 60-64.
179. Fabiani, R.; Rosignoli, P.; De Bartolomeo, A.; Fuccelli, R.; Servili, M.; Montedoro, G. F.; Morozzi, G. Oxidative DNA Damage Is Prevented by Extracts of Olive Oil, Hydroxytyrosol, and Other Olive Phenolic Compounds in Human Blood Mononuclear Cells and HL60 Cells. J. Nutr. 2008, 138, 1411-1416.
180. Miles, E. A.; Zoubouli, P.; Calder, P. C. Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures. Nutrition 2005, 21, 389-394.
181. Dell'Agli, M.; Fagnani, R.; Galli, G. V.; Maschi, O.; Gilardi, F.; Bellosta, S.; Crestani, M.; Bosisio, E.; De Fabiani, E.; Caruso, D. Olive Oil Phenols Modulate the Expression of Metalloproteinase 9 in THP-1 Cells by Acting on Nuclear Factor-B Signaling. J. Agric. Food Chem. 2010, 58, 2246-2252.
182. Giner, E.; Andújar, I.; Recio, M. C.; Ríos, J. L.; Cerdá-Nicolás, J. M.; Giner, R. M. Oleuropein Ameliorates Acute Colitis in Mice. J. Agric. Food Chem. 2011, 59, 12882-12892.
183. Giner, E.; Recio, M.-C.; Ríos, J.-L.; Giner, R.-M. Oleuropein Protects against Dextran Sodium Sulfate-Induced Chronic Colitis in Mice. J. Nat. Prod. 2013, 76, 1113-1120.
184. Larussa, T.; Oliverio, M.; Suraci, E.; Greco, M.; Placida, R.; Gervasi, S.; Marasco, R.; Imeneo, M.; Paolino, D.; Tucci, L.; et al. Oleuropein Decreases Cyclooxygenase-2 and Interleukin-17 Expression and Attenuates Inflammatory Damage in Colonic Samples from Ulcerative Colitis Patients. Nutrients 2017, 9, 391-402.
185. Domitrovi, R.; Jakovac, H.; Marchesi, V. V.; Šain, I.; Romi, Ž.; Raheli, D. Preventive and therapeutic effects of oleuropein against carbon tetrachloride-induced liver damage in mice. Pharmacol. Res. 2012, 65, 451-464.
186. Shi, C.; Chen, X.; Liu, Z.; Meng, R.; Zhao, X.; Liu, Z.; Guo, N. Oleuropein protects L-02 cells against H2O2-induced oxidative stress by increasing SOD1, GPx1 and CAT expression. Biomed. Pharmacother. 2017, 85, 740-748.
187. Potonjak, I.; Škoda, M.; Pernjak-Pugel, E.; Perši, M. P.; Domitrovi, R. Oral administration of oleuropein attenuates cisplatin-induced acute renal injury in mice through inhibition of ERK signaling. Mol. Nutr. Food Res. 2016, 60, 530-541.
188. Maalej, A.; Forte, M.; Bouallagui, Z.; Donato, S.; Mita, L.; Mita, D. G.; Filosa, S.; Crispi, S.; Sayadi, S. Olive compounds attenuate oxidative damage induced in HEK-293 cells via MAPK signaling pathway. J. Functl. Food 2017, 39, 18-27.
189. Castejón, M. L.; Rosillo, M. Á.; Montoya, T.; González-Benjumea, A.; Fernández-Bolaños, J. M.; Alarcón-dela-Lastra, C. Oleuropein down-regulated IL-1induced inflammation and oxidative stress in human synovial fibroblast cell line SW982. Food Funct. 2017, 8, 1890-1898.
190. Kim, Y.-H.; Choi, Y.-J.; Kang, M.-K.; Lee, E.-J.; Kim, D. Y.; Oh, H.; Kang, Y.-H. Oleuropein Curtails Pulmonary Inflammation and Tissue Destruction in Models of Experimental Asthma and Emphysema. J. Agric. Food Chem. 2018, 66, 7643-7654.
191. Lou-Bonafonte, J. M.; Arnal, C.; Navarro, M. A.; Osada, J. Efficacy of bioactive compounds from extra virgin olive oil to modulate atherosclerosis development. Mol. Nutr. Food Res. 2012, 56, 1043-1057.
192. Carluccio, M. A.; Siculella, L.; Ancora, M. A.; Massaro, M.; Scoditti, E.; Storelli, C.; Visioli, F.; Distante, A.; De Caterina, R. Olive Oil and Red Wine Antioxidant Polyphenols Inhibit Endothelial Activation: Antiatherogenic Properties of Mediterranean Diet Phytochemicals. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 622-629.
193. Dell'Agli, M.; Fagnani, R.; Mitro, N.; Scurati, S.; Masciadri, M.; Mussoni, L.; Galli, G. V.; Bosisio, E.; Crestani, M.; De Fabiani, E.; et al. Minor Components of Olive Oil Modulate Proatherogenic Adhesion Molecules Involved in Endothelial Activation. J. Agric. Food Chem. 2006, 54, 3259-3264.
194. Lockyer, S.; Corona, G.; Yaqoob, P.; Spencer, J. P. E.; Rowland, I. Secoiridoids delivered as olive leaf extract induce acute improvements in human vascular function and reduction of an inflammatory cytokine: A randomised, double-blind, placebo-controlled, cross-over trial. Br. J. Nutr. 2015, 114, 75-83.
195. de Bock, M.; Derraik, J. G. B.; Brennan, C. M.; Biggs, J. B.; Morgan, P. E.; Hodgkinson, S. C.; Hofman, P. L.; Cutfield, W. S. Olive (Olea europaea L.) Leaf Polyphenols Improve Insulin Sensitivity in Middle-Aged Overweight Men: A Randomized, Placebo-Controlled, Crossover Trial. PLoS ONE 2013, 8, e57622.
196. Lockyer, S.; Rowland, I.; Spencer, J. P. E.; Yaqoob, P.; Stonehouse, W. Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: A randomised controlled trial. Eur. J. Nutr. 2017, 56, 1421-1432.
197. Susalit, E.; Agus, N.; Effendi, I.; Tjandrawinata, R. R.; Nofiarny, D.; Perrinjaquet-Moccetti, T.; Verbruggen, M. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: Comparison with Captopril. Phytomed. 2011, 18, 251-258.
198. Dell'Agli, M.; Maschi, O.; Galli, G. V.; Fagnani, R.; Dal Cero, E.; Caruso, D.; Bosisio, E. Inhibition of platelet aggregation by olive oil phenols via cAMP-phosphodiesterase. Br. J. Nutr. 2008, 99.
199. Manna, C.; Migliardi, V.; Golino, P.; Scognamiglio, A.; Galletti, P.; Chiariello, M.; Zappia, V. Oleuropein prevents oxidative myocardial injury induced by ischemia and reperfusion. J. Nutr. Biochem. 2004, 15, 461-466.
200. Andreadou, I.; Iliodromitis, E. K.; Mikros, E.; Constantinou, M.; Agalias, A.; Magiatis, P.; Skaltsounis, A. L.; Kamber, E.; Tsantili-Kakoulidou, A.; Kremastinos, D. T. The Olive Constituent Oleuropein Exhibits Anti-Ischemic, Antioxidative, and Hypolipidemic Effects in Anesthetized Rabbits. J. Nutr. 2006, 136, 2213-2219.
201. Zhao, Q.; Bai, Y.; Li, C.; Yang, K.; Wei, W.; Li, Z.; Pan, L.; Li, X.; Zhang, X. Oleuropein Protects Cardiomyocyte against Apoptosis via Activating the Reperfusion Injury Salvage Kinase Pathway In Vitro. J. Evid.-Based Complementary Altern. Med. 2017, 2017, 1-9.
202. Jin, H.-X.; Zhang, Y.-H.; Guo, R.-N.; Zhao, S.-N. Inhibition of MEK/ERK/STAT3 signaling in oleuropein treatment inhibits myocardial ischemia/reperfusion. Int. J. Mol. Med. 2018, 42, 1034-1043.
203. Andreadou, I.; Benaki, D.; Efentakis, P.; Bibli, S.-I.; Milioni, A.-I.; Papachristodoulou, A.; Zoga, A.; Skaltsounis, A.-L.; Mikros, E.; Iliodromitis, E. The Natural Olive Constituent Oleuropein Induces Nutritional Cardioprotection in Normal and Cholesterol-Fed Rabbits: Comparison with Preconditioning. Planta Med. 2015, 81, 655-663.
204. Zhang, J.-Y.; Yang, Z.; Fang, K.; Shi, Z.-L.; Ren, D.-H.; Sun, J. Oleuropein prevents the development of experimental autoimmune myocarditis in rats. Internat. Immunopharmacol. 2017, 48, 187-195.
205. Shamshoum, H.; Vlavcheski, F.; Tsiani, E. Anticancer effects of oleuropein. BioFactors 2017, 43, 517-528.
206. Liu, L.; Ahn, K. S.; Shanmugam, M. K.; Wang, H.; Shen, H.; Arfuso, F.; Chinnathambi, A.; Alharbi, S. A.; Chang, Y.; Sethi, G.; et al. Oleuropein induces apoptosis via abrogating NF-B activation cascade in estrogen receptor-negative breast cancer cells: J. Cell Biochem. 2019, 120, 4504-4513.
207. Hassan, Z. K.; Elamin, M. H.; Daghestani, M. H.; Omer, S. A.; Al-Olayan, E. M.; Elobeid, M. A.; Virk, P.; Mohammed, O. B. Oleuropein Induces Anti-metastatic Effects in Breast Cancer. Asian Pac. J. Cancer Prev. 2012, 13, 4555-4559.
208. Sepporta, M. V.; Fuccelli, R.; Rosignoli, P.; Ricci, G.; Servili, M.; Morozzi, G.; Fabiani, R. Oleuropein inhibits tumour growth and metastases dissemination in ovariectomised nude mice with MCF-7 human breast tumour xenografts. J. Functl. Food 2014, 8, 269-273.
209. Sherif, I. O.; Al-Gayyar, M. M. H. Oleuropein potentiates anti-tumor activity of cisplatin against HepG2 through affecting proNGF/NGF balance. Life Sciences 2018, 198, 87-93.
210. Bakir, M.; Geyikoglu, F.; Koc, K.; Cerig, S. Therapeutic effects of oleuropein on cisplatin-induced pancreas injury in rats. J. Cancer Res. The. 2018, 14, 671-678.
211. Ruzzolini, J.; Peppicelli, S.; Andreucci, E.; Bianchini, F.; Scardigli, A.; Romani, A.; la Marca, G.; Nediani, C.; Calorini, L. Oleuropein, the Main Polyphenol of Olea europaea Leaf Extract, Has an Anti-Cancer Effect on Human BRAF Melanoma Cells and Potentiates the Cytotoxicity of Current Chemotherapies. Nutrients 2018, 10, 1950-1967.
212. Al-Azzawie, H. F.; Alhamdani, M.-S. S. Hypoglycemic and antioxidant effect of oleuropein in alloxandiabetic rabbits. Life Sciences 2006, 78, 1371-1377.
213. Murotomi, K.; Umeno, A.; Yasunaga, M.; Shichiri, M.; Ishida, N.; Koike, T.; Matsuo, T.; Abe, H.; Yoshida, Y.; Nakajima, Y. Oleuropein-Rich Diet Attenuates Hyperglycemia and Impaired Glucose Tolerance in Type 2 Diabetes Model Mouse. J. Agric. Food Chem. 2015, 63, 6715-6722.
214. Alkhateeb, H.; Al-Duais, M.; Qnais, E. Beneficial effects of oleuropein on glucose uptake and on parameters relevant to the normal homeostatic mechanisms of glucose regulation in rat skeletal muscle. Phytother. Res. 2018, 32, 651-656.
215. Wu, L.; Velander, P.; Liu, D.; Xu, B. Olive Component Oleuropein Promotes Cell Insulin Secretion and Protects Cells from Amylin Amyloid-Induced Cytotoxicity. Biochem. 2017, 56, 5035-5039.
216. Liu, Y.-N.; Jung, J.-H.; Park, H.; Kim, H. Olive leaf extract suppresses messenger RNA expression of proinflammatory cytokines and enhances insulin receptor substrate 1 expression in the rats with streptozotocin and high-fat diet-induced diabetes. Nutrit. Res. 2014, 34, 450-457.
217. Wainstein, J.; Ganz, T.; Boaz, M.; Bar Dayan, Y.; Dolev, E.; Kerem, Z.; Madar, Z. Olive Leaf Extract as A Hypoglycemic Agent in Both Human Diabetic Subjects and in Rats. J. Med. Food 2012, 15, 605-610.
218. Carnevale, R.; Silvestri, R.; Loffredo, L.; Novo, M.; Cammisotto, V.; Castellani, V.; Bartimoccia, S.; Nocella, C.; Violi, F. Oleuropein, A component of extra virgin olive oil, lowers postprandial glycaemia in healthy subjects. Br. J. Clin. Pharmacol. 2018, 84, 1566-1574.
219. Jemai, H.; Bouaziz, M.; Fki, I.; El Feki, A.; Sayadi, S. Hypolipidimic and antioxidant activities of oleuropein and its hydrolysis derivative-rich extracts from Chemlali olive leaves. Chem Biol Interact. 2008, 176, 88-98.
220. Paiva-Martins, F.; Barbosa, S.; Silva, M.; Monteiro, D.; Pinheiro, V.; Mourão, J. L.; Fernandes, J.; Rocha, S.; Belo, L.; Santos-Silva, A. The effect of olive leaf supplementation on the constituents of blood and oxidative stability of red blood cells. J. Functl. Food. 2014, 9, 271-279.
221. Kim, S. W.; Hur, W.; Li, T. Z.; Lee, Y. K.; Choi, J. E.; Hong, S. W.; Lyoo, K.-S.; You, C. R.; Jung, E. S.; Jung, C. K.; et al. Oleuropein prevents the progression of steatohepatitis to hepatic fibrosis induced by A high-fat diet in mice. Exp. Molec. Med. 2014, 46, e92-e92.
222. Porcu, C.; Sideri, S.; Martini, M.; Cocomazzi, A.; Galli, A.; Tarantino, G.; Balsano, C. Oleuropein Induces AMPK-Dependent Autophagy in NAFLD Mice, Regardless of the Gender. Int. J. Mol. Cell Med. 2018, 19, e3948.
223. Drira, R.; Chen, S.; Sakamoto, K. Oleuropein and hydroxytyrosol inhibit adipocyte differentiation in 3 T3-L1 cells. Life Sciences 2011, 89, 708-716.
224. Svobodova, M.; Andreadou, I.; Skaltsounis, A.-L.; Kopecky, J.; Flachs, P. Oleuropein as an inhibitor of peroxisome proliferator-Activated receptor gamma. Genes Nutr. 2014, 9, 376.
225. Malliou, F.; Andreadou, I.; Gonzalez, F. J.; Lazou, A.; Xepapadaki, E.; Vallianou, I.; Lambrinidis, G.; Mikros, E.; Marselos, M.; Skaltsounis, A.-L.; et al. The olive constituent oleuropein, as A PPAR agonist, markedly reduces serum triglycerides. J. Nutr. Biochem. 2018, 59, 17-28.
226. Kuem, N.; Song, S. J.; Yu, R.; Yun, J. W.; Park, T. Oleuropein attenuates visceral adiposity in high-fat dietinduced obese mice through the modulation of WNT10b-And galanin-mediated signalings. Mol. Nutr. Food Res. 2014, 58, 2166-2176.
227. van der Stelt, I.; Hoek-van den Hil, E. F.; Swarts, H. J. M.; Vervoort, J. J. M.; Hoving, L.; Skaltsounis, L.; Lemonakis, N.; Andreadou, I.; van Schothorst, E. M.; Keijer, J. Nutraceutical oleuropein supplementation prevents high fat diet-induced adiposity in mice. J. Funct. Food 2015, 14, 702-715.
228. Oi-Kano, Y.; Iwasaki, Y.; Nakamura, T.; Watanabe, T.; Goto, T.; Kawada, T.; Watanabe, K.; Iwai, K. Oleuropein aglycone enhances UCP1 expression in brown adipose tissue in high-fat-diet-induced obese rats by activating adrenergic signaling. J. Nutr. Biochem. 2017, 40, 209-218.
229. Poudyal, H.; Campbell, F.; Brown, L. Olive Leaf Extract Attenuates Cardiac, Hepatic, and Metabolic Changes in High Carbohydrate-, High Fat-Fed Rats. The Journal of Nutrition 2010, 140, 946-953.
230. Casamenti, F.; Grossi, C.; Rigacci, S.; Pantano, D.; Luccarini, I.; Stefani, M. Oleuropein Aglycone: A Possible Drug against Degenerative Conditions. In Vivo Evidence of its Effectiveness against Alzheimer's Disease. J. Alzheimers Di. s 2015, 45, 679-688.
231. Yu, H.; Liu, P.; Tang, H.; Jing, J.; Lv, X.; Chen, L.; Jiang, L.; Xu, J.; Li, J. Oleuropein, A natural extract from plants, offers neuroprotection in focal cerebral ischemia/reperfusion injury in mice. Eur. J. Pharmacol. 2016, 775, 113-119.
232. Sun, W.; Wang, X.; Hou, C.; Yang, L.; Li, H.; Guo, J.; Huo, C.; Wang, M.; Miao, Y.; Liu, J.; et al. Oleuropein improves mitochondrial function to attenuate oxidative stress by activating the Nrf2 pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Neuropharmacology 2017, 113, 556-566.
233. Alirezaei, M.; Rezaei, M.; Hajighahramani, S.; Sookhtehzari, A.; Kiani, K. Oleuropein attenuates cognitive dysfunction and oxidative stress induced by some anesthetic drugs in the hippocampal area of rats. J. Physiol. Sci. 2017, 67, 131-139.
234. Simsek, T.; Erbas, M.; Buyuk, B.; Pala, C.; Sahin, H.; Altinisik, B. Prevention of rocuronium induced mast cell activation with prophylactic oleuropein rich diet in anesthetized rabbits. Acta Cir. Bras. 2018, 33, 954-963.
235. Achour, I.; Arel-Dubeau, A.-M.; Renaud, J.; Legrand, M.; Attard, E.; Germain, M.; Martinoli, M.-G. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in A Dopaminergic Cellular Model. Int. J. Mol. Sci. 2016, 17, 1293-1310.
236. Palazzi, L.; Bruzzone, E.; Bisello, G.; Leri, M.; Stefani, M.; Bucciantini, M.; Polverino de Laureto, P. Oleuropein aglycone stabilizes the monomeric synuclein and favours the growth of non-toxic aggregates. Sci. Rep. 2018, 8, 8337-8354.
237. Leri, M.; Oropesa-Nuñez, R.; Canale, C.; Raimondi, S.; Giorgetti, S.; Bruzzone, E.; Bellotti, V.; Stefani, M.; Bucciantini, M. Oleuropein aglycone: A polyphenol with different targets against amyloid toxicity. Biochim Biophys. Acta Gen. Subj. 2018, 1862, 1432-1442.
238. Shi, J.; Wu, G.; Zou, X.; Jiang, K. Oleuropein protects intracerebral hemorrhage-induced disruption of blood-brain barrier through alleviation of oxidative stress. Pharmacol. Rep. 2017, 69, 1206-1212.
239. Zhang, W.; Liu, X.; Li, Q. Protective Effects of Oleuropein Against Cerebral Ischemia/Reperfusion by Inhibiting Neuronal Apoptosis. Med. Sci. Monit. 2018, 24, 6587-6598.
240. Lee, B.; Shim, I.; Lee, H.; Hahm, D.-H. Effect of oleuropein on cognitive deficits and changes in hippocampal brain-derived neurotrophic factor and cytokine expression in A rat model of post-traumatic stress disorder. J. Nat. Med. 2018, 72, 44-56.
241. Lee, B.; Shim, I.; Lee, H.; Hahm, D.-H. Oleuropein reduces anxiety-like responses by activating of serotonergic and neuropeptide Y (NPY)-ergic systems in A rat model of post-traumatic stress disorder. Anim. Cells Syst. 2018, 22, 109-117.
242. Rabiei, Z.; Jahanbazi, S.; Alibabaei, Z. Antidepressant Effects of Oleuropein in Male Mice by Forced Swim Test and Tail Suspension Test. World Fam. Med. J. Middle East. J. Fam. Med. 2018, 16, 132-144.
243. Lee, O.-H.; Lee, B.-Y. Antioxidant and antimicrobial activities of individual and combined phenolics in Olea europaea leaf extract. Bioresour. Bioprocess. 2010, 101, 3751-3754.
244. Obied, H. K.; Bedgood, D. R.; Prenzler, P. D.; Robards, K. Bioscreening of Australian olive mill waste extracts: Biophenol content, antioxidant, antimicrobial and molluscicidal activities. Food Chem. Toxicol. 2007, 45, 1238-1248.
245. Sudjana, A. N.; D'Orazio, C.; Ryan, V.; Rasool, N.; Ng, J.; Islam, N.; Riley, T. V.; Hammer, K. A. Antimicrobial activity of commercial Olea europaea (olive) leaf extract. J. Antimicrob. Agents 2009, 33, 461-463.
246. Lee-Huang, S.; Huang, P. L.; Zhang, D.; Lee, J. W.; Bao, J.; Sun, Y.; Chang, Y.-T.; Zhang, J.; Huang, P. L. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part, I. Integrase inhibition. Biochem. Biophys. Res. Commun. 2007, 354, 872-878.
247. Chin, K.-Y.; Ima-Nirwana, S. Olives and Bone: A Green Osteoporosis Prevention Option. Int. J. Environ. Res. Public Health 2016, 13, 755.
248. Puel, C.; Mathey, J.; Agalias, A.; Kati-coulibaly, S.; Mardon, J.; Obled, C.; Davicco, M.-J.; Lebecque, P.; Horcajada, M.-N.; Skaltsounis, A. L.; et al. Dose-response study of effect of oleuropein, an olive oil polyphenol, in an ovariectomy/inflammation experimental model of bone loss in the rat. Clin. Nutrit. 2006, 25, 859-868.
249. Santiago-Mora, R.; Casado-Díaz, A.; De Castro, M. D.; Quesada-Gómez, J. M. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: The effect on differentiation in stem cells derived from bone marrow. Osteoporos Int 2011, 22, 675-684.
250. Casado-Díaz, A.; Anter, J.; Müller, S.; Winter, P.; Quesada-Gómez, J. M.; Dorado, G. Transcriptomic analyses of the anti-Adipogenic effects of oleuropein in human mesenchymal stem cells. Food Funct. 2017, 8, 1254-1270.
251. Feng, Z.; Li, X.; Lin, J.; Zheng, W.; Hu, Z.; Xuan, J.; Ni, W.; Pan, X. Oleuropein inhibits the IL-1induced expression of inflammatory mediators by suppressing the activation of NF-B and MAPKs in human osteoarthritis chondrocytes. Food Funct. 2017, 8, 3737-3744.
252. Mehraein, F.; Sarbishegi, M.; Aslani, A. Therapeutic Effects of Oleuropein on Wounded Skin in Young Male Balb/c Mice. Wounds 2014, 26, 7.
253. Bharathy, H.; Fathima, N. N. Exploiting oleuropein for inhibiting collagen fibril formation. Int. J. Biol. Macromol. 2017, 101, 179-186.
254. Ji, S. T.; Kim, Y.-J.; Jung, S. Y.; Kim, D. Y.; Kang, S.; Park, J. H.; Jang, W. B.; Ha, J.; Yun, J.; Kwon, S.-M. Oleuropein attenuates hydrogen peroxide-induced autophagic cell death in human adipose-derived stem cells. Biochem. Biophys. Res. Commun. 2018, 499, 675-680.
255. Margheri, F.; Menicacci, B.; Laurenzana, A.; Del Rosso, M.; Fibbi, G.; Cipolleschi, M. G.; Ruzzolini, J.; Nediani, C.; Mocali, A.; Giovannelli, L. Oleuropein aglycone attenuates the pro-Angiogenic phenotype of senescent fibroblasts: A functional study in endothelial cells. J. Functl. Food 2019, 53, 219-226.
256. Vissers, M. N.; Zock, P. L.; Roodenburg, A. J. C.; Leenen, R.; Katan, M. B. Olive Oil Phenols Are Absorbed in Humans. J. Nutrit. 2002, 132, 409-417.
257. Gikas, E.; Papadopoulos, N.; Tsarbopoulos, A. Kinetic Study of the Acidic Hydrolysis of Oleuropein, the Major Bioactive Metabolite of Olive Oil. J. Liq. Chromatogr. Relat. Technol. 2006, 29, 497-508.
258. Carrera-González, M. P.; Ramírez-Expósito, M. J.; Mayas, M. D.; Martínez-Martos, J. M. Protective role of oleuropein and its metabolite hydroxytyrosol on cancer. Trends Food Sci. Technol. 2013, 31, 92-99.
259. Briante, R.; Patumi, M.; Terenziani, S.; Bismuto, E.; Febbraio, F.; Nucci, R. Olea europaea L. Leaf Extract and Derivatives: Antioxidant Properties. J. Agricul and Food Chem 2002, 50, 4934-4940.
260. Beauchamp, G. K.; Keast, R. S. J.; Morel, D.; Lin, J.; Pika, J.; Han, Q.; Lee, C.-H.; Smith, A. B.; Breslin, P. A. S. Ibuprofen-like activity in extra-virgin olive oil: Phytochemistry. Nature 2005, 437, 45-46.
261. Iacono, A.; Gómez, R.; Sperry, J.; Conde, J.; Bianco, G.; Meli, R.; Gómez-Reino, J. J.; Smith, A. B.; Gualillo, O. Effect of oleocanthal and its derivatives on inflammatory response induced by lipopolysaccharide in A murine chondrocyte cell line. Arthritis Rheum. 2010, 62, 1675-1682.
262. Scotece, M.; Conde, J.; Abella, V.; Lopez, V.; Francisco, V.; Ruiz, C.; Campos, V.; Lago, F.; Gomez, R.; Pino, J.; et al. Oleocanthal Inhibits Catabolic and Inflammatory Mediators in LPS-Activated Human Primary Osteoarthritis (OA) Chondrocytes Through MAPKs/NF-kappa B Pathways. Cell Phys. Biochem. 2018, 49, 2414-2426.
263. Segura Palacios, J. M.; Blazquez Sanchez, N.; Rivas Ruiz, F.; Aguilar Bernier, M.; Ramirez Lopez, B.; Fernandez Sanchez, M. E.; de Troya Martin, M. Topical treatment with oleocanthal extract in reducing inflammatory reactions after photodynamic therapy: A prospective quasi-experimental pilot study. Complement. Med. Res. 2019, 42, 298-301.
264. Agrawal, K.; Melliou, E.; Li, X.; Pedersen, T. L.; Wang, S. C.; Magiatis, P.; Newman, J. W.; Holt, R. R. Oleocanthal-rich extra virgin olive oil demonstrates acute anti-platelet effects in healthy men in A randomized trial. J. Funct. Food 2017, 36, 84-93.
265. Abuznait, A. H.; Qosa, H.; Busnena, B. A.; El Sayed, K. A.; Kaddoumi, A. Olive-Oil-Derived Oleocanthal Enhances Amyloid Clearance as A Potential Neuroprotective Mechanism against Alzheimer's Disease: In Vitro and in Vivo Studies. ACS Chem. Neurosci. 2013, 4, 973-982.
266. Parkinson, L.; Keast, R. Oleocanthal, A Phenolic Derived from Virgin Olive Oil: A Review of the Beneficial Effects on Inflammatory Disease. Int. J. Mol. Sci. 2014, 15, 12323-12334.
267. Batarseh, Y. S.; Mohamed, L. A.; Al Rihani, S. B.; Mousa, Y. M.; Siddique, A. B.; El Saved, K. A.; Kaddoumi, A. Oleocanthal ameliorates amyloid-beta oligomers' toxicity on astrocytes and neuronal cells: In vitro studies. Neurosci. 2017, 352, 204-215.
268. Giusti, L.; Angeloni, C.; Barbalace, M. C.; Lacerenza, S.; Ciregia, F.; Ronci, M.; Urbani, A.; Manera, C.; Digiacomo, M.; Macchia, M.; et al. A Proteomic Approach to Uncover Neuroprotective Mechanisms of Oleocanthal against Oxidative Stress. Int. J. Mol. Cell Med. 2018, 19, 2329.
269. Qosa, H.; Batarseh, Y. S.; Mohyeldin, M. M.; El Sayed, K. A.; Keller, J. N.; Kaddoumi, A. Oleocanthal Enhances Amyloid-beta Clearance from the Brains of TgSwDI Mice and in Vitro across A Human Blood-Brain Barrier Model. ACS Chem. Neurosci. 2015, 6, 1849-1859.
270. Khanal, P.; Oh, W.-K.; Yun, H. J.; Namgoong, G. M.; Ahn, S.-G.; Kwon, S.-M.; Choi, H.-K.; Choi, H. S. p-HPEA-EDA, A phenolic compound of virgin olive oil, activates AMP-Activated protein kinase to inhibit carcinogenesis. Carcinogen. 2011, 32, 545-553.
271. Elnagar, A.; Sylvester, P.; El Sayed, K. Oleocanthal as A c-Met Inhibitor for the Control of Metastatic Breast and Prostate Cancers. Planta Med. 2011, 77, 1013-1019.
272. Akl, M. R.; Ayoub, N. M.; Mohyeldin, M. M.; Busnena, B. A.; Foudah, A. I.; Liu, Y.-Y.; Sayed, K. A. E. Olive Phenolics as c-Met Inhibitors: Oleocanthal Attenuates Cell Proliferation, Invasiveness, and Tumor Growth in Breast Cancer Models. PLoS ONE 2014, 9, e97622.
273. Busnena, B. A.; Foudah, A. I.; Melancon, T.; El Sayed, K. A. Olive secoiridoids and semisynthetic bioisostere analogues for the control of metastatic breast cancer. Bioorg. Med. Chem. 2013, 21, 2117-2127.
274. Mohyeldin, M. M.; Akl, M. R.; Ebrahim, H. Y.; Dragoi, A. M.; Dykes, S.; Cardelli, J. A.; Sayed, K. A. E. The oleocanthal-based homovanillyl sinapate as A novel c-Met inhibitor. Oncotarget. 2016, 7, 32247-32273.
275. Khanfar, M. A.; Bardaweel, S. K.; Akl, M. R.; El Sayed, K. A. Olive Oil-derived Oleocanthal as Potent Inhibitor of Mammalian Target of Rapamycin: Biological Evaluation and Molecular Modeling Studies: Oleocanthal Is A Potent mTOR Inhibitor. Phytother. Res. 2015, 29, 1776-1782.
276. Ayoub, N. M.; Siddique, A. B.; Ebrahim, H. Y.; Mohyeldin, M. M.; El Sayed, K. A. The olive oil phenolic oleocanthal modulates estrogen receptor expression in luminal breast cancer in vitro and in vivo and synergizes with tamoxifen treatment. Eur. J. Pharmacol. 2017, 810, 100-111.
277. Diez-Bello, R.; Jardin, I.; Lopez, J. J.; El Haouari, M.; Ortega-Vidal, J.; Altarejos, J.; Salido, G. M.; Salido, S.; Rosado, J. A. Oleocanthal inhibits proliferation and migration by modulating Ca2+ entry through TRPC6 in breast cancer cells. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 474-485.
278. Fogli, S.; Arena, C.; Carpi, S.; Polini, B.; Bertini, S.; Digiacomo, M.; Gado, F.; Saba, A.; Saccomanni, G.; Breschi, M. C.; et al. Cytotoxic Activity of Oleocanthal Isolated from Virgin Olive Oil on Human Melanoma Cells. Nutr. Cancer 2016, 68, 873-877.
279. Gu, Y.; Wang, J.; Peng, L. Oleocanthal exerts anti-melanoma activities and inhibits STAT3 signaling pathway. Oncol. Rep. 2017, 37, 483-491.
280. Polini, B.; Digiacomo, M.; Carpi, S.; Bertini, S.; Gado, F.; Saccomanni, G.; Macchia, M.; Nieri, P.; Manera, C.; Fogli, S. Oleocanthal and oleacein contribute to the in vitro therapeutic potential of extra virgin oil-derived extracts in non-melanoma skin cancer. Oxicol. In Vitro 2018, 52, 243-250.
281. Pei, T.; Meng, Q.; Han, J.; Sun, H.; Li, L.; Song, R.; Sun, B.; Pan, S.; Liang, D.; Liu, L. Oleocanthal inhibits growth and metastasis by blocking activation of STAT3 in human hepatocellular carcinoma. Oncotarget. 2016, 7, 43475-43491.
282. Cusimano, A.; Balasus, D.; Azzolina, A.; Augello, G.; Emma, M. R.; Di Sano, C.; Gramignoli, R.; Strom, S. C.; McCubery, J. A.; Montalto, G.; et al. Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation. Int. J. Oncol. 2017, 51, 533-544.
283. Scotece, M.; Gómez, R.; Conde, J.; Lopez, V.; Gómez-Reino, J. J.; Lago, F.; Smith, A. B.; Gualillo, O. Oleocanthal Inhibits Proliferation and MIP-1 Expression in Human Multiple Myeloma Cells. Curr. Med. Chem. 2013, 20, 2467-2475.
284. Pang, K.-L.; Chin, K.-Y. The Biological Activities of Oleocanthal from A Molecular Perspective. Nutrients 2018, 10, e570.
285. García-Villalba, R.; Carrasco-Pancorbo, A.; Oliveras-Ferraros, C.; Vázquez-Martín, A.; Menéndez, J. A.; Segura-Carretero, A.; Fernández-Gutiérrez, A. Characterization and quantification of phenolic compounds of extra-virgin olive oils with anticancer properties by A rapid and resolutive LC-ESI-TOF MS method. J. Pharm. Biomed. Anal. 2010, 51, 416-429.
286. Paiva-Martins, F.; Santos, V.; Mangericão, H.; Gordon, M. H. Effects of Copper on the Antioxidant Activity of Olive Polyphenols in Bulk Oil and Oil-in-Water Emulsions. J. Agric. Food Chem. 2006, 54, 3738-3743.
287. Czerwiska, M.; Kiss, A. K.; Naruszewicz, M. A comparison of antioxidant activities of oleuropein and its dialdehydic derivative from olive oil, oleacein. Food Chemy. 2012, 131, 940-947.
288. Naruszewicz, M.; Czerwinska, M. E.; Kiss, A. K. Oleacein. Translation from Mediterranean Diet to Potential Antiatherosclerotic Drug. Curr. Pharm. Design. 2015, 21, 1205-1212.
289. Filipek, A.; Czerwinska, M. E.; Kiss, A. K.; Wrzosek, M.; Naruszewicz, M. Oleacein enhances antiinflammatory activity of human macrophages by increasing CD163 receptor expression. Phytomed. 2015, 22, 1255-1261.
290. Segade, M.; Bermejo, R.; Silva, A.; Paiva-Martins, F.; Gil-Longo, J.; Campos-Toimil, M. Involvement of endothelium in the vasorelaxant effects of 3, 4-DHPEA-EA and 3, 4-DHPEA-EDA, two major functional bioactives in olive oil. J. Funct. Food. 2016, 23, 637-646.
291. Filipek, A.; Czerwinska, M. E.; Kiss, A. K.; Polanski, J. A.; Naruszewicz, M. Oleacein may inhibit destabilization of carotid plaques from hypertensive patients. Impact on high mobility group protein-1. Phytomed. 2017, 32, 68-73.
292. Czerwiska, M. E.; Kiss, A. K.; Naruszewicz, M. Inhibition of human neutrophils NEP activity, CD11b/CD18 expression and elastase release by 3, 4-dihydroxyphenylethanol-elenolic acid dialdehyde, oleacein. Food. Chem. 2014, 153, 1-8.
293. Lombardo, G. E.; Lepore, S. M.; Morittu, V. M.; Arcidiacono, B.; Colica, C.; Procopio, A.; Maggisano, V.; Bulotta, S.; Costa, N.; Mignogna, C.; et al. Effects of Oleacein on High-Fat Diet-Dependent Steatosis, Weight Gain, and Insulin Resistance in Mice. Front. Endocrinol. 2018, 9, 116.
294. Cicero, A. F. G.; Nascetti, S.; López-Sabater, M. C.; Elosua, R.; Salonen, J. T.; Nyyssönen, K.; Poulsen, H. E.; Zunft, H. J.; Kiesewetter, H.; de la Torre, K.; et al. Changes in LDL fatty acid composition as A response to olive oil treatment are inversely related to lipid oxidative damage: The EUROLIVE study. J. Am. Coll. Nutr. 2008, 27, 314-320.
295. Scientific Opinion on the substantiation of health claims related to polyphenols in olive and protection of LDL particles from oxidative damage (ID 1333, 1638, 1639, 1696, 2865), maintenance of normal blood HDL cholesterol concentrations (ID 1639), mainte. EFSA J. 2011, 9, 2033.
296. Valls, R.,-M.; Farràs, M.; Suárez, M.; Fernández-Castillejo, S.; Fitó, M.; Konstantinidou, V.; Fuentes, F.; López-Miranda, J.; Giralt, M.; Covas, M., I et al. Effects of functional olive oil enriched with its own phenolic compounds on endothelial function in hypertensive patients. A randomised controlled trial. Food. Chem. 2015, 167, 30-35.
297. Hohmann, C., D.; Cramer, H.; Michalsen, A.; Kessler, C.; Steckhan, N.; Choi, K.; Dobos, G., Effects of high phenolic olive oil on cardiovascular risk factors: A systematic review and meta-Analysis. Phytomedicine 2015, 22, 631-640.
298. Buckland, G.; Travier, N.; Agudo, A.; Fonseca-Nunes, A.; Navarro, C.; Lagiou, P.; Demetriou, C.; Amiano, P.; Dorronsoro, M.; Chirlaque, M. D.; et al. Olive oil intake and breast cancer risk in the Mediterranean countries of the European Prospective Investigation into Cancer and Nutrition study. Int. J. Cancer 2012, 131, 2465-2469.
299. Medina-Remon, A.; Casas, R.; Tressserra-Rimbau, A.; Ros, E.; Martinez-Gonzalez, M., A.; Fito, M.; Corella, D.; Salas-Salvadó, J.; Lamuela-Raventos, R., M.; Estruch, R. Polyphenol intake from A Mediterranean diet decreases inflammatory biomarkers related to atherosclerosis: A substudy of the PREDIMED trial. Brit. J. Clin. Pharmacol. 2017, 83, 114-128.
300. Toledo, E.; Salas-Salvadó, J.; Donat-Vargas, C.; Buil-Cosiales, P.; Estruch, R.; Ros, E.; Corella, D.; Fitó, M.; Hu, F. B.; Arós, F.; et al. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial. JAMA Intern. Med. 2015, 175, 1752-1760.
301. Valls-Pedret, C.; Sala-Vila, A.; Serra-Mir, M.; Corella, D.; de la Torre, R.; Martínez-González, M., Á.; Martínez-Lapiscina, E., H.; Fitó, M.; Pérez-Heras, A.; Salas-Salvadó, J.; et al. Mediterranean diet and agerelated cognitive decline. JAMA Intern. Med. 2015, 175, 1094-1103.
302. Martínez-Lapiscina, E., H.; Clavero, P.; Toledo, E.; San Julián, B.; Sanchez-Tainta, A.; Corella, D.; Lamuela-Raventós, R., M.; Martínez, J., A.; Martínez-Gonzalez, M., Á. Virgin olive oil supplementation and long-term cognition: The PREDIMEDNAVARRA randomized, trial. J. Nutr. Health Aging. 2013, 17, 544-552.
303. ClinicalTrials. gov. Available online: https://clinicaltrials. gov/ct2/show/NCT02842567 (accessed on 5/13/2019).
304. ClinicalTrials. gov. Available online: https://clinicaltrials. gov/ct2/show/NCT02068092 (accessed on 5/13/2019).