Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of its effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases

Pharmacological Research

Volumn 143, Issue , 2019, Pages 58-72

  de Pablos, Rocío M ^a   Espinosa Oliva, Ana María ^a   Hornedo Ortega, Ruth ^b   Cano, Mercedes ^a   Arguelles, Sandro ^a  

^a UNIVERSITY OF SEVILLE   (Spain)

^b UNIVERSITÉ DE BORDEAUX   (France)

Author keywords

Aging; AMPK; Autophagy; Hydroxytyrosol; Mediterranean diet; Senescence; Sirtuin

Indexed keywords

HYDROXYTYROSOL; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE KINASE; SIRTUIN 1; 3,4-DIHYDROXYPHENYLETHANOL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; PHENETHYL ALCOHOL; PROTECTIVE AGENT;

AGING; ALZHEIMER DISEASE; AMPK SIGNALING; ANTIAGING ACTIVITY; AUTOPHAGY; BREAST CANCER; CARDIOVASCULAR DISEASE; DEGENERATIVE DISEASE; DIABETES MELLITUS; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA DAMAGE; DNA REPAIR; EPIGENETICS; HUMAN; HYPERCHOLESTEROLEMIA; IMMUNE MEDIATED INJURY; MALIGNANT NEOPLASM; MEDITERRANEAN DIET; METABOLIC REGULATION; METABOLIC SYNDROME X; MULTIPLE SCLEROSIS; NONHUMAN; OSTEOPOROSIS; OXIDATIVE STRESS; PARKINSON DISEASE; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; WOUND HEALING; ANIMAL; DRUG EFFECT; METABOLISM; NEOPLASM;

AGING; AMP-ACTIVATED PROTEIN KINASES; ANIMALS; AUTOPHAGY; DIET, MEDITERRANEAN; HUMANS; METABOLIC SYNDROME; NEOPLASMS; NEURODEGENERATIVE DISEASES; OSTEOPOROSIS; PHENYLETHYL ALCOHOL; PROTECTIVE AGENTS;

EID: 85062856245     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2019.03.005     Document Type: Review

References (194)

1. Mattson, M.P., Arumugam, T.V., Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27 (2018), 1176–1199, 10.1016/j.cmet.2018.05.011.
2. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., The hallmarks of aging. Cell 153 (2013), 1194–1217, 10.1016/j.cell.2013.05.039.
3. Harman, D., The aging process: major risk factor for disease and death. Proc. Natl. Acad. Sci. U. S. A. 88 (1991), 5360–5363 (accessed December 20, 2018) http://www.ncbi.nlm.nih.gov/pubmed/2052612.
4. Balducci, L., Ershler, W.B., Cancer and ageing: a nexus at several levels. Nat. Rev. Cancer 5 (2005), 655–662, 10.1038/nrc1675.
5. Bishop, N.A., Lu, T., Yankner, B.A., Neural mechanisms of ageing and cognitive decline. Nature 464 (2010), 529–535, 10.1038/nature08983.
6. Berti, A., Caporali, R., Montecucco, C., Paolazzi, G., Monti, S., Aging in primary systemic vasculitis: implications for diagnosis, clinical manifestations, and management. Drugs Aging 36 (2018), 53–63, 10.1007/s40266-018-0617-4.
7. Lewis, E.D., Meydani, S.N., Wu, D., Regulatory role of vitamin E in the immune system and inflammation. IUBMB Life, 2018, 10.1002/iub.1976.
8. Blagosklonny, M.V., From rapalogs to anti-aging formula. Oncotarget 8 (2017), 35492–35507, 10.18632/oncotarget.18033.
9. Davis, C., Bryan, J., Hodgson, J., Murphy, K., Definition of the Mediterranean diet; a literature review. Nutrients 7 (2015), 9139–9153, 10.3390/nu7115459.
10. Vincent-Baudry, S., Defoort, C., Gerber, M., Bernard, M.-C., Verger, P., Helal, O., Portugal, H., Planells, R., Grolier, P., Amiot-Carlin, M.-J., Vague, P., Lairon, D., The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet. Am. J. Clin. Nutr. 82 (2005), 964–971, 10.1093/ajcn/82.5.964.
11. Buckland, G., González, C.A., Agudo, A., Vilardell, M., Berenguer, A., Amiano, P., Ardanaz, E., Arriola, L., Barricarte, A., Basterretxea, M., Chirlaque, M.D., Cirera, L., Dorronsoro, M., Egües, N., Huerta, J.M., Larrañaga, N., Marin, P., Martínez, C., Molina, E., Navarro, C., Quirós, J.R., Rodriguez, L., Sanchez, M.-J., Tormo, M.-J., Moreno-Iribas, C., Adherence to the Mediterranean diet and risk of coronary heart disease in the Spanish EPIC Cohort Study. Am. J. Epidemiol. 170 (2009), 1518–1529, 10.1093/aje/kwp282.
12. Itsiopoulos, C., Brazionis, L., Kaimakamis, M., Cameron, M., Best, J.D., O'Dea, K., Rowley, K., Can the Mediterranean diet lower HbA1c in type 2 diabetes? Results from a randomized cross-over study. Nutr. Metab. Cardiovasc. Dis. 21 (2011), 740–747, 10.1016/j.numecd.2010.03.005.
13. Tresserra-Rimbau, A., Medina-Remón, A., Pérez-Jiménez, J., Martínez-González, M.A., Covas, M.I., Corella, D., Salas-Salvadó, J., Gómez-Gracia, E., Lapetra, J., Arós, F., Fiol, M., Ros, E., Serra-Majem, L., Pintó, X., Muñoz, M.A., Saez, G.T., Ruiz-Gutiérrez, V., Warnberg, J., Estruch, R., Lamuela-Raventós, R.M., Dietary intake and major food sources of polyphenols in a Spanish population at high cardiovascular risk: the PREDIMED study. Nutr. Metab. Cardiovasc. Dis. 23 (2013), 953–959, 10.1016/j.numecd.2012.10.008.
14. Bravo, L., Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev. 56 (1998), 317–333 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/9838798.
15. Castro-Barquero, S., Lamuela-Raventós, R.M., Doménech, M., Estruch, R., Relationship between Mediterranean dietary polyphenol intake and obesity. Nutrients, 10, 2018, 1523, 10.3390/nu10101523.
16. Dai, J., Mumper, R.J., Plant phenolics: extraction, analysis and their antioxidant and anticancer properties. Molecules 15 (2010), 7313–7352, 10.3390/molecules15107313.
17. Del Rio, D., Rodriguez-Mateos, A., Spencer, J.P.E., Tognolini, M., Borges, G., Crozier, A., Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal. 18 (2013), 1818–1892, 10.1089/ars.2012.4581.
18. Pandey, K.B., Rizvi, S.I., Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell. Longev. 2 (2009), 270–278, 10.4161/oxim.2.5.9498.
19. Quideau, S., Deffieux, D., Douat-Casassus, C., Pouységu, L., Plant polyphenols: chemical properties, biological activities, and synthesis. Angew. Chem. Int. Ed. Engl. 50 (2011), 586–621, 10.1002/anie.201000044.
20. Hornedo-Ortega, R., Cerezo, A.B., de Pablos, R.M., Krisa, S., Richard, T., García-Parrilla, M.C., Troncoso, A.M., Phenolic compounds characteristic of the Mediterranean diet in mitigating microglia-mediated neuroinflammation. Front. Cell. Neurosci., 12, 2018, 373, 10.3389/fncel.2018.00373.
21. Brenes, M., García, A., García, P., Rios, J.J., Garrido, A., Phenolic compounds in Spanish olive oils. J. Agric. Food Chem. 47 (1999), 3535–3540 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/10552681.
22. El Riachy, M., Priego-Capote, F., León, L., Rallo, L., Luque de Castro, M.D., Hydrophilic antioxidants of virgin olive oil. Part 1: hydrophilic phenols: a key factor for virgin olive oil quality. Eur. J. Lipid Sci. Technol. 113 (2011), 678–691, 10.1002/ejlt.201000400.
23. Obied, H.K., Prenzler, P.D., Omar, S.H., Ismael, R., Servili, M., Esposto, S., Taticchi, A., Selvaggini, R., Urbani, S., Pharmacology of olive biophenols. Adv. Mol. Toxicol., 2012, 10.1016/B978-0-444-59389-4.00006-9.
24. Tripoli, E., Giammanco, M., Tabacchi, G., Di Majo, D., Giammanco, S., La Guardia, M., The phenolic compounds of olive oil: structure, biological activity and beneficial effects on human health. Nutr. Res. Rev., 18, 2005, 98, 10.1079/NRR200495.
25. Keys, A., Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. 1980, Harvard University Press, Cambridge Mass (accessed December 28, 2018) https://www.worldcat.org/title/seven-countries-a-multivariate-analysis-of-death-and-coronary-heart-disease/oclc/5101917.
26. 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. 834 (2018), 246–256, 10.1016/j.ejphar.2018.07.043.
27. Estruch, R., Ros, E., Salas-Salvadó, J., Covas, M.-I., Corella, D., Arós, F., Gómez-Gracia, E., Ruiz-Gutiérrez, V., Fiol, M., Lapetra, J., Lamuela-Raventos, R.M., Serra-Majem, L., Pintó, X., Basora, J., Muñoz, M.A., Sorlí, J.V., Martínez, J.A., Martínez-González, M.A., Retraction and republication: primary prevention of cardiovascular disease with a Mediterranean diet. N. Engl. J. Med. 368 (2013), 1279–1290, 10.1056/NEJMc1806491 N. Engl. J. Med. 378 (2018) 2441–2442.
28. Bulló, M., Casas, R., Portillo, M.P., Basora, J., Estruch, R., García-Arellano, A., Lasa, A., Juanola-Falgarona, M., Arós, F., Salas-Salvadó, J., Dietary glycemic index/load and peripheral adipokines and inflammatory markers in elderly subjects at high cardiovascular risk. Nutr. Metab. Cardiovasc. Dis. 23 (2013), 443–450, 10.1016/j.numecd.2011.09.009.
29. Babio, N., Toledo, E., Estruch, R., Ros, E., Martínez-González, M.A., Castañer, O., Bulló, M., Corella, D., Arós, F., Gómez-Gracia, E., Ruiz-Gutiérrez, V., Fiol, M., Lapetra, J., Lamuela-Raventos, R.M., Serra-Majem, L., Pintó, X., Basora, J., Sorlí, J.V., Salas-Salvadó, J., PREDIMED Study Investigators, Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial. CMAJ 186 (2014), E649–E657, 10.1503/cmaj.140764.
30. Toledo, E., Salas-Salvadó, J., Donat-Vargas, C., Buil-Cosiales, P., Estruch, R., Ros, E., Corella, D., Fitó, M., Hu, F.B., Arós, F., Gómez-Gracia, E., Romaguera, D., Ortega-Calvo, M., Serra-Majem, L., Pintó, X., Schröder, H., Basora, J., Sorlí, J.V., Bulló, M., Serra-Mir, M., Martínez-González, M.A., Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial. JAMA Intern. Med. 175 (2015), 1752–1760, 10.1001/jamainternmed.2015.4838.
31. Trichopoulou, A., Orfanos, P., Norat, T., Bueno-de-Mesquita, B., Ocké, M.C., Peeters, P.H.M., van der Schouw, Y.T., Boeing, H., Hoffmann, K., Boffetta, P., Nagel, G., Masala, G., Krogh, V., Panico, S., Tumino, R., Vineis, P., Bamia, C., Naska, A., Benetou, V., Ferrari, P., Slimani, N., Pera, G., Martinez-Garcia, C., Navarro, C., Rodriguez-Barranco, M., Dorronsoro, M., Spencer, E.A., Key, T.J., Bingham, S., Khaw, K.T., Kesse, E., Clavel-Chapelon, F., Boutron-Ruault, M.C., Berglund, G., Wirfalt, E., Hallmans, G., Johansson, I., Tjonneland, A., Olsen, A., Overvad, K., Hundborg, H.H., Riboli, E., Trichopoulos, D., Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study. Br. Med. J., 330, 2005, 991, 10.1136/bmj.38415.644155.8F.
32. Pérez-López, F.R., Chedraui, P., Haya, J., Cuadros, J.L., Effects of the Mediterranean diet on longevity and age-related morbid conditions. Maturitas 64 (2009), 67–79, 10.1016/j.maturitas.2009.07.013.
33. Buckland, G., Agudo, A., Travier, N., María Huerta, J., Cirera, L., Tormo, M.J., Navarro, C., Dolores Chirlaque, M., Moreno-Iribas, C., Ardanaz, E., Barricarte, A., Etxeberria, J., Marin, P., Ramón Quirós, J., Redondo, M.L., Larrañaga, N., Amiano, P., Dorronsoro, M., Arriola, L., Basterretxea, M., Sanchez, M.J., Molina, E., González, C.A., Adherence to the Mediterranean diet reduces mortality in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). Br. J. Nutr. 106 (2011), 1581–1591, 10.1017/S0007114511002078.
34. Knoops, K.T.B., de Groot, L.C., Fidanza, F., Alberti-Fidanza, A., Kromhout, D., van Staveren, W.A., Comparison of three different dietary scores in relation to 10-year mortality in elderly European subjects: the HALE project. Eur. J. Clin. Nutr. 60 (2006), 746–755, 10.1038/sj.ejcn.1602378.
35. Bamia, C., Trichopoulos, D., Ferrari, P., Overvad, K., Bjerregaard, L., Tjønneland, A., Halkjær, J., Clavel-Chapelon, F., Kesse, E., Boutron-Ruault, M.C., Boffetta, P., Nagel, G., Linseisen, J., Boeing, H., Hoffmann, K., Kasapa, C., Orfanou, A., Travezea, C., Slimani, N., Norat, T., Palli, D., Pala, V., Panico, S., Tumino, R., Sacerdote, C., Bueno-de-Mesquita, H.B., Waijers, P.M.C.M., Peeters, P.H.M., Van Der Schouw, Y.T., Berenguer, A., Martinez-Garcia, C., Navarro, C., Barricarte, A., Dorronsoro, M., Berglund, G., Wirfält, E., Johansson, I., Johansson, G., Bingham, S., Khaw, K.T., Spencer, E.A., Key, T., Riboli, E., Trichopoulou, A., Dietary patterns and survival of older Europeans: the EPIC-elderly study (European prospective investigation into cancer and nutrition). Public Health Nutr. 10 (2007), 590–598, 10.1017/S1368980007382487.
36. Alcalay, R.N., Gu, Y., Mejia-Santana, H., Cote, L., Marder, K.S., Scarmeas, N., The association between Mediterranean diet adherence and Parkinson's disease. Mov. Disord. 27 (2012), 771–774, 10.1002/mds.24918.
37. Gardener, S., Gu, Y., Rainey-Smith, S.R., Keogh, J.B., Clifton, P.M., Mathieson, S.L., Taddei, K., Mondal, A., Ward, V.K., Scarmeas, N., Barnes, M., Ellis, K.A., Head, R., Masters, C.L., Ames, D., Macaulay, S.L., Rowe, C.C., Szoeke, C., Martins, R.N., AIBL Research Group, Adherence to a Mediterranean diet and Alzheimer's disease risk in an Australian population. Transl. Psychiatry, 2, 2012, 10.1038/tp.2012.91 e164.
38. Scarmeas, N., Stern, Y., Mayeux, R., Manly, J.J., Schupf, N., Luchsinger, J.A., Mediterranean diet and mild cognitive impairment. Arch. Neurol. 66 (2009), 216–225, 10.1001/archneurol.2008.536.
39. Casamenti, F., Stefani, M., Olive polyphenols: new promising agents to combat aging-associated neurodegeneration. Expert Rev. Neurother. 17 (2017), 345–358, 10.1080/14737175.2017.1245617.
40. Féart, C., Samieri, C., Allès, B., Barberger-Gateau, P., Potential benefits of adherence to the Mediterranean diet on cognitive health. Proc. Nutr. Soc. 72 (2013), 140–152, 10.1017/S0029665112002959.
41. Nooyens, A.C.J., Bueno-De-Mesquita, H.B., Van Boxtel, M.P.J., Van Gelder, B.M., Verhagen, H., Verschuren, W.M.M., Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Br. J. Nutr. 106 (2011), 752–761, 10.1017/S0007114511001024.
42. Scarmeas, N., Stern, Y., Tang, M.-X., Mayeux, R., Luchsinger, J.A., Mediterranean diet and risk for Alzheimer's disease. Ann. Neurol. 59 (2006), 912–921, 10.1002/ana.20854.
43. Tangney, C.C., Kwasny, M.J., Li, H., Wilson, R.S., Evans, D.A., Morris, M.C., Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population. Am. J. Clin. Nutr. 93 (2011), 601–607, 10.3945/ajcn.110.007369.
44. Visioli, F., Caruso, D., Plasmati, E., Patelli, R., Mulinacci, N., Romani, A., Galli, G., Galli, C., Hydroxytyrosol, as a component of olive mill waste water, is dose- dependently absorbed and increases the antioxidant capacity of rat plasma. Free Radic. Res. 34 (2001), 301–305 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/11264904.
45. Tuck, K.L., Hayball, P.J., Major phenolic compounds in olive oil: metabolism and health effects. J. Nutr. Biochem. 13 (2002), 636–644 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/12550060.
46. Romero, C., Brenes, M., Analysis of total contents of hydroxytyrosol and tyrosol in olive oils. J. Agric. Food Chem. 60 (2012), 9017–9022, 10.1021/jf3026666.
47. Piñeiro, Z., Cantos-Villar, E., Palma, M., Puertas, B., Direct liquid chromatography method for the simultaneous quantification of hydroxytyrosol and tyrosol in red wines. J. Agric. Food Chem. 59 (2011), 11683–11689, 10.1021/jf202254t.
48. Dickinson, J.R., Salgado, L.E.J., Hewlins, M.J.E., The catabolism of amino acids to long chain and complex alcohols in Saccharomyces cerevisiae. J. Biol. Chem. 278 (2003), 8028–8034, 10.1074/jbc.M211914200.
49. Hornedo-Ortega, R., Cerezo, A.B., Troncoso, A.M., Garcia-Parrilla, M.C., Protective effects of hydroxytyrosol against α-synuclein toxicity on PC12 cells and fibril formation. Food Chem. Toxicol. 120 (2018), 41–49, 10.1016/j.fct.2018.06.059.
50. Vissers, M.N., Zock, P.L., Roodenburg, A.J.C., Leenen, R., Katan, M.B., Olive oil phenols are absorbed in humans. J. Nutr. 132 (2002), 409–417, 10.1093/jn/132.3.409.
51. 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. 58 (2014), 1809–1819, 10.1002/mnfr.201400124.
52. Cotrim, B.A., Joglar, J., Rojas, M.J.L., del Olmo, J.M.D., Macias-González, M., Cuevas, M.R., Fitó, M., Muñoz-Aguayo, D., Planells, M.I.C., Farré, M., de Fonseca, F.R., de la Torre, R., Unsaturated fatty alcohol derivatives of olive oil phenolic compounds with potential low-density lipoprotein (LDL) antioxidant and antiobesity properties. J. Agric. Food Chem. 60 (2012), 1067–1074, 10.1021/jf203814r.
53. Schröder, H., de la Torre, R., Estruch, R., Corella, D., Martínez-González, M.A., Salas-Salvadó, J., Ros, E., Arós, F., Flores, G., Civit, E., Farré, M., Fiol, M., Vila, J., Fernandez-Crehuet, J., Ruiz-Gutiérrez, V., Lapetra, J., Sáez, G., Covas, M.-I., PREDIMED Study Investigators, alcohol consumption is associated with high concentrations of urinary hydroxytyrosol. Am. J. Clin. Nutr. 90 (2009), 1329–1335, 10.3945/ajcn.2009.27718.
54. 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. 29 (2001), 1492–1498 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/11602527.
55. Tuck, K.L., Freeman, M.P., Hayball, P.J., Stretch, G.L., Stupans, I., The in vivo fate of hydroxytyrosol and tyrosol, antioxidant phenolic constituents of olive oil, after intravenous and oral dosing of labeled compounds to rats. J. Nutr. 131 (2001), 1993–1996, 10.1093/jn/131.7.1993.
56. Miro-Casas, E., Covas, M.-I., Farre, M., Fito, M., Ortuño, J., Weinbrenner, T., Roset, P., de la Torre, R., Hydroxytyrosol disposition in humans. Clin. Chem. 49 (2003), 945–952 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/12765992.
57. Visioli, F., Galli, C., Bornet, F., Mattei, A., Patelli, R., Galli, G., Caruso, D., Olive oil phenolics are dose-dependently absorbed in humans. FEBS Lett. 468 (2000), 159–160 (accessed December 28, 2018) http://www.ncbi.nlm.nih.gov/pubmed/10692578.
58. 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. Nutr. 133 (2003), 2612–2615, 10.1093/jn/133.8.2612.
59. García-Villalba, R., Carrasco-Pancorbo, A., Nevedomskaya, E., Mayboroda, O.A., Deelder, A.M., Segura-Carretero, A., Fernández-Gutiérrez, A., Exploratory analysis of human urine by LC-ESI-TOF MS after high intake of olive oil: understanding the metabolism of polyphenols. Anal. Bioanal. Chem. 398 (2010), 463–475, 10.1007/s00216-010-3899-x.
60. Caruso, D., Visioli, F., Patelli, R., Galli, C., Galli, G., Urinary excretion of olive oil phenols and their metabolites in humans. Metabolism 50 (2001), 1426–1428, 10.1053/meta.2001.28073.
61. 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. 134 (2012), 1132–1136, 10.1016/j.foodchem.2012.02.192.
62. Rodríguez-Morató, J., Boronat, A., Kotronoulas, A., Pujadas, M., Pastor, A., Olesti, E., Pérez-Mañá, C., Khymenets, O., Fitó, M., Farré, M., de la Torre, R., Metabolic disposition and biological significance of simple phenols of dietary origin: hydroxytyrosol and tyrosol. Drug Metab. Rev. 48 (2016), 218–236, 10.1080/03602532.2016.1179754.
63. 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. 125 (2011), 865–872, 10.1016/J.FOODCHEM.2010.09.054.
64. Khymenets, O., Crespo, M.C., Dangles, O., Rakotomanomana, N., Andres-Lacueva, C., Visioli, F., Human hydroxytyrosol's absorption and excretion from a nutraceutical. J. Funct. Foods 23 (2016), 278–282, 10.1016/J.JFF.2016.02.046.
65. 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. 56 (2012), 486–496, 10.1002/mnfr.201100436.
66. Arguelles, S., Guerrero-Castilla, A., Cano, M., Muñoz, M., Ayala, A., Advantages and disadvantages of apoptosis in the aging process. Ann. NY. Acad. Sci., 2019, 10.1111/nyas.14020.
67. Arriola Apelo, S.I., Lamming, D.W., Rapamycin: an InhibiTOR of aging emerges from the soil of Easter Island. J. Gerontol. A. Biol. Sci. Med. Sci. 71 (2016), 841–849, 10.1093/gerona/glw090.
68. Swindell, W.R., Meta-analysis of 29 experiments evaluating the effects of rapamycin on life span in the laboratory mouse, journals gerontol. Ser. A Biol. Sci. Med. Sci., 2016, 10.1093/gerona/glw153 glw153.
69. Garcia, D., Shaw, R.J., AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66 (2017), 789–800, 10.1016/j.molcel.2017.05.032.
70. Zheng, A., Li, H., Xu, J., Cao, K., Li, H., Pu, W., Yang, Z., Peng, Y., Long, J., Liu, J., Feng, Z., Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: role of AMP-activated protein kinase activation. Br. J. Nutr. 113 (2015), 1667–1676, 10.1017/S0007114515000884.
71. Priore, P., Siculella, L., Gnoni, G.V., Extra virgin olive oil phenols down-regulate lipid synthesis in primary-cultured rat-hepatocytes. J. Nutr. Biochem. 25 (2014), 683–691, 10.1016/j.jnutbio.2014.01.009.
72. Hao, J., Shen, W., Yu, G., Jia, H., Li, X., Feng, Z., Wang, Y., Weber, P., Wertz, K., Sharman, E., Liu, J., Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes. J. Nutr. Biochem. 21 (2010), 634–644, 10.1016/j.jnutbio.2009.03.012.
73. Priore, P., Gnoni, A., Natali, F., Testini, M., Gnoni, G.V., Siculella, L., Damiano, F., Acid, Oleic, Hydroxytyrosol inhibit cholesterol and fatty acid synthesis in C6 glioma cells. Oxid. Med. Cell. Longev. 2017 (2017), 1–10, 10.1155/2017/9076052.
74. Zrelli, H., Matsuoka, M., Kitazaki, S., Zarrouk, M., Miyazaki, H., Hydroxytyrosol reduces intracellular reactive oxygen species levels in vascular endothelial cells by upregulating catalase expression through the AMPK–FOXO3a pathway. Eur. J. Pharmacol. 660 (2011), 275–282, 10.1016/J.EJPHAR.2011.03.045.
75. Wang, W., Jing, T., Yang, X., He, Y., Wang, B., Xiao, Y., Shang, C., Zhang, J., Lin, R., Hydroxytyrosol regulates the autophagy of vascular adventitial fibroblasts through the SIRT1-mediated signaling pathway. Can. J. Physiol. Pharmacol. 96 (2018), 88–96, 10.1139/cjpp-2016-0676.
76. 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. 15 (2012), 71–81, 10.1089/rej.2011.1245.
77. Ding, Y.-W., Zhao, G.-J., Li, X.-L., Hong, G.-L., Li, M.-F., Qiu, Q.-M., Wu, B., Lu, Z.-Q., SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro. Int. J. Mol. Med. 37 (2016), 1049–1058, 10.3892/ijmm.2016.2503.
78. Cetrullo, S., D'Adamo, S., Guidotti, S., Borzì, R.M., Flamigni, F., Hydroxytyrosol prevents chondrocyte death under oxidative stress by inducing autophagy through sirtuin 1-dependent and -independent mechanisms. Biochim. Biophys. Acta 1860 (2016), 1181–1191, 10.1016/j.bbagen.2016.03.002.
79. D'Adamo, S., Cetrullo, S., Guidotti, S., Borzì, R.M., Flamigni, F., Hydroxytyrosol modulates the levels of microRNA-9 and its target sirtuin-1 thereby counteracting oxidative stress-induced chondrocyte death. Osteoarthr. Cartil. 25 (2017), 600–610, 10.1016/j.joca.2016.11.014.
80. Liu, D., Xu, L., Zhang, X., Shi, C., Qiao, S., Ma, Z., Yuan, J., Liu, D., Xu, L., Zhang, X., Shi, C., Qiao, S., Ma, Z., Yuan, J., Snapshot: implications for mTOR in aging-related ischemia/reperfusion injury. Aging Dis. 10 (2019), 116–133, 10.14336/AD.2018.0501.
81. Pei, Y., Chen, J., Xie, L., Cai, X., Yang, R.-H., Wang, X., Gong, J., Hydroxytyrosol protects against myocardial ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Mediators Inflamm. 2016 (2016), 1–9, 10.1155/2016/1232103.
82. Johnson, S.C., Rabinovitch, P.S., Kaeberlein, M., mTOR is a key modulator of ageing and age-related disease. Nature 493 (2013), 338–345, 10.1038/nature11861.
83. Zhao, B., Ma, Y., Xu, Z., Wang, J., Wang, F., Wang, D., Pan, S., Wu, Y., Pan, H., Xu, D., Liu, L., Jiang, H., 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. 347 (2014), 79–87, 10.1016/j.canlet.2014.01.028.
84. Sun, L., Luo, C., Liu, J., Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Funct. 5 (2014), 1909–1914, 10.1039/c4fo00187g.
85. Echeverría, F., Ortiz, M., Valenzuela, R., Videla, L.A., Hydroxytyrosol and cytoprotection: a projection for clinical interventions. Int. J. Mol. Sci., 18, 2017, 10.3390/ijms18050930.
86. 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 (2017), 1–14, 10.1155/2017/2473495.
87. 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-γ and NF-κB. Biomed. Pharmacother. 109 (2019), 2472–2481, 10.1016/j.biopha.2018.11.120.
88. Avola, R., Graziano, A.C.E., Pannuzzo, G., Bonina, F., Cardile, V., Hydroxytyrosol from olive fruits prevents blue-light-induced damage in human keratinocytes and fibroblasts. J. Cell. Physiol. 234 (2019), 9065–9076, 10.1002/jcp.27584.
89. 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), 1–14, 10.1155/2018/9086947.
90. Soni, M., Prakash, C., Sehwag, S., Kumar, V., Protective effect of hydroxytyrosol in arsenic-induced mitochondrial dysfunction in rat brain. J. Biochem. Mol. Toxicol., 31, 2017, 10.1002/jbt.21906 e21906.
91. Sarsour, E.H., Kumar, M.G., Kalen, A.L., Goswami, M., Buettner, G.R., Goswami, P.C., MnSOD activity regulates hydroxytyrosol-induced extension of chronological lifespan. Age (Dordr). 34 (2012), 95–109, 10.1007/s11357-011-9223-7.
92. Granados-Principal, S., El-azem, N., Pamplona, R., Ramirez-Tortosa, C., Pulido-Moran, M., Vera-Ramirez, L., Quiles, J.L., Sanchez-Rovira, P., Naudí, A., Portero-Otin, M., Perez-Lopez, P., Ramirez-Tortosa, Mc., Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem. Pharmacol. 90 (2014), 25–33, 10.1016/j.bcp.2014.04.001.
93. 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. 26 (2015), 190–199, 10.1016/j.jnutbio.2014.10.006.
94. Meschini, R., D'Eliseo, D., Filippi, S., Bertini, L., Bizzarri, B.M., Botta, L., Saladino, R., Velotti, F., Tyrosinase-treated hydroxytyrosol-enriched olive vegetation waste with increased antioxidant activity promotes autophagy and inhibits the inflammatory response in human THP-1 monocytes. J. Agric. Food Chem. 66 (2018), 12274–12284, 10.1021/acs.jafc.8b03630.
95. Yang, X., Jing, T., Li, Y., He, Y., Zhang, W., Wang, B., Xiao, Y., Wang, W., Zhang, J., Wei, J., Lin, R., Hydroxytyrosol attenuates LPS-Induced acute lung injury in mice by regulating autophagy and sirtuin expression. Curr. Mol. Med. 17 (2017), 149–159, 10.2174/1566524017666170421151940.
96. Warleta, F., Quesada, C.S., Campos, M., Allouche, Y., Beltrán, G., Gaforio, J.J., Hydroxytyrosol protects against oxidative DNA damage in human breast cells. Nutrients 3 (2011), 839–857, 10.3390/nu3100839.
97. 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. 138 (2008), 1411–1416, 10.1093/jn/138.8.1411.
98. 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. 35 (2007), 137–152, 10.1016/J.BIOORG.2006.09.003.
99. Zhang, X., Cao, J., Jiang, L., Geng, C., Zhong, L., Protective effect of hydroxytyrosol against acrylamide-induced cytotoxicity and DNA damage in HepG2 cells. Mutat. Res. Mol. Mech. Mutagen. 664 (2009), 64–68, 10.1016/J.MRFMMM.2009.02.013.
100. Guo, W., An, Y., Jiang, L., Geng, C., Zhong, L., The protective effects of hydroxytyrosol against UVB-induced DNA damage in HaCaT cells. Phyther. Res. 24 (2010), 352–359, 10.1002/ptr.2943.
101. Aymerich, M.S., Aso, E., Abellanas, M.A., Tolon, R.M., Ramos, J.A., Ferrer, I., Romero, J., Fernández-Ruiz, J., Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system. Biochem. Pharmacol. 157 (2018), 67–84, 10.1016/j.bcp.2018.08.016.
102. Di Francesco, A., Falconi, A., Di Germanio, C., Micioni Di Bonaventura, M.V., Costa, A., Caramuta, S., Del Carlo, M., Compagnone, D., Dainese, E., Cifani, C., Maccarrone, M., D'Addario, C., Extravirgin olive oil up-regulates CB1 tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms. J. Nutr. Biochem. 26 (2015), 250–258, 10.1016/J.JNUTBIO.2014.10.013.
103. Albayram, O., Bilkei-Gorzo, A., Zimmer, A., Loss of CB1 receptors leads to differential age-related changes in reward-driven learning and memory. Front. Aging Neurosci., 4, 2012, 34, 10.3389/fnagi.2012.00034.
104. Zhu, W.-W., Xiao, F., Tang, Y.-Y., Zou, W., Li, X., Zhang, P., Wang, A.-P., Tang, X.-Q., Spermidine prevents high glucose-induced senescence in HT-22 cells by upregulation of CB1 receptor. Clin. Exp. Pharmacol. Physiol. 45 (2018), 832–840, 10.1111/1440-1681.12955.
105. Falandry, C., Bonnefoy, M., Freyer, G., Gilson, E., Biology of cancer and aging: a complex association with cellular senescence. J. Clin. Oncol. 32 (2014), 2604–2610, 10.1200/JCO.2014.55.1432.
106. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136 (2015), E359–86, 10.1002/ijc.29210.
107. Mehra, K., Berkowitz, A., Sanft, T., Diet, physical activity, and body weight in cancer survivorship. Med. Clin. North Am. 101 (2017), 1151–1165, 10.1016/j.mcna.2017.06.004.
108. Zhang, F., Shi, J.-J., Thakur, K., Hu, F., Zhang, J.-G., Wei, Z.-J., Anti-cancerous potential of polysaccharide fractions extracted from peony seed dreg on various human cancer cell lines via cell cycle arrest and apoptosis. Front. Pharmacol., 8, 2017, 102, 10.3389/fphar.2017.00102.
109. Zhang, Q., Zhang, F., Thakur, K., Wang, J., Wang, H., Hu, F., Zhang, J.-G., Wei, Z.-J., Molecular mechanism of anti-cancerous potential of Morin extracted from mulberry in Hela cells. Food Chem. Toxicol. 112 (2018), 466–475, 10.1016/j.fct.2017.07.002.
110. Wang, J., Zhang, Y.-S., Thakur, K., Hussain, S.S., Zhang, J.-G., Xiao, G.-R., Wei, Z.-J., Licochalcone A from licorice root, an inhibitor of human hepatoma cell growth via induction of cell apoptosis and cell cycle arrest. Food Chem. Toxicol. 120 (2018), 407–417, 10.1016/j.fct.2018.07.044.
111. Zhang, Y.-S., Ma, Y.-L., Thakur, K., Hussain, S.S., Wang, J., Zhang, Q., Zhang, J.-G., Wei, Z.-J., Molecular mechanism and inhibitory targets of dioscin in HepG2 cells. Food Chem. Toxicol. 120 (2018), 143–154, 10.1016/j.fct.2018.07.016.
112. Amin, A., Hamza, A.A., Daoud, S., Khazanehdari, K., Al Hrout, A., Baig, B., Chaiboonchoe, A., Adrian, T.E., Zaki, N., Salehi-Ashtiani, K., Saffron-based crocin prevents early lesions of liver cancer: in vivo, in vitro and network analyses. Recent Pat. Anticancer Drug Discov. 11 (2016), 121–133 (accessed February 22, 2019) http://www.ncbi.nlm.nih.gov/pubmed/26522014.
113. Amin, A.R.M.R., Karpowicz, P.A., Carey, T.E., Arbiser, J., Nahta, R., Chen, Z.G., Dong, J.-T., Kucuk, O., Khan, G.N., Huang, G.S., Mi, S., Lee, H.-Y., Reichrath, J., Honoki, K., Georgakilas, A.G., Amedei, A., Amin, A., Helferich, B., Boosani, C.S., Ciriolo, M.R., Chen, S., Mohammed, S.I., Azmi, A.S., Keith, W.N., Bhakta, D., Halicka, D., Niccolai, E., Fujii, H., Aquilano, K., Ashraf, S.S., Nowsheen, S., Yang, X., Bilsland, A., Shin, D.M., Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds. Semin. Cancer Biol. 35 (2015), S55–S77, 10.1016/j.semcancer.2015.02.005.
114. Yaswen, P., MacKenzie, K.L., Keith, W.N., Hentosh, P., Rodier, F., Zhu, J., Firestone, G.L., Matheu, A., Carnero, A., Bilsland, A., Sundin, T., Honoki, K., Fujii, H., Georgakilas, A.G., Amedei, A., Amin, A., Helferich, B., Boosani, C.S., Guha, G., Ciriolo, M.R., Chen, S., Mohammed, S.I., Azmi, A.S., Bhakta, D., Halicka, D., Niccolai, E., Aquilano, K., Ashraf, S.S., Nowsheen, S., Yang, X., Therapeutic targeting of replicative immortality. Semin. Cancer Biol. 35 (2015), S104–S128, 10.1016/j.semcancer.2015.03.007.
115. 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. 83 (2018), 1781–1791, 10.1111/1750-3841.14198.
116. Schwingshackl, L., Hoffmann, G., Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis of observational studies. Cancer Med. 4 (2015), 1933–1947, 10.1002/cam4.539.
117. Vilaplana-Pérez, C., Auñón, D., García-Flores, L.A., Gil-Izquierdo, A., Hydroxytyrosol and potential uses in cardiovascular diseases, cancer, and AIDS. Front. Nutr., 1, 2014, 18, 10.3389/fnut.2014.00018.
118. Fabiani, R., Anti-cancer properties of olive oil secoiridoid phenols: a systematic review of in vivo studies. Food Funct. 7 (2016), 4145–4159, 10.1039/C6FO00958A.
119. Cruz-Lozano, M., González-González, A., Marchal, J.A., Muñoz-Muela, E., Molina, M.P., Cara, F.E., Brown, A.M., García-Rivas, G., Hernández-Brenes, C., Lorente, J.A., Sanchez-Rovira, P., Chang, J.C., Granados-Principal, S., Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple-negative breast cancer cell lines by the simultaneous targeting of epithelial-to-mesenchymal transition, Wnt/β-catenin and TGFβ signaling pathways. Eur. J. Nutr., 2018, 10.1007/s00394-018-1864-1.
120. Martínez, N., Herrera, M., Frías, L., Provencio, M., Pérez-Carrión, R., Díaz, V., Morse, M., Crespo, M.C., A combination of hydroxytyrosol, omega-3 fatty acids and curcumin improves pain and inflammation among early stage breast cancer patients receiving adjuvant hormonal therapy: results of a pilot study. Clin. Transl. Oncol., 2018, 10.1007/s12094-018-1950-0.
121. Goldsmith, C.D., Bond, D.R., Jankowski, H., Weidenhofer, J., Stathopoulos, C.E., Roach, P.D., Scarlett, C.J., The olive biophenols oleuropein and hydroxytyrosol selectively reduce proliferation, influence the cell cycle, and induce apoptosis in pancreatic Cancer cells. Int. J. Mol. Sci., 19, 2018, 1937, 10.3390/ijms19071937.
122. Ng, S.-F., Tan, S.-L., Development and in vitro assessment of alginate bilayer films containing the olive compound hydroxytyrosol as an alternative for topical chemotherapy. Int. J. Pharm. 495 (2015), 798–806, 10.1016/j.ijpharm.2015.09.057.
123. Herrera, A.J., Espinosa-Oliva, A.M., Oliva-Martin, M.J., Carrillo-Jimenez, A., Venero, J.L., de Pablos, R.M., Collateral damage: contribution of peripheral inflammation to neurodegenerative diseases. Curr. Top. Med. Chem. 15 (2015), 2193–2210 (accessed December 20, 2018) http://www.ncbi.nlm.nih.gov/pubmed/26059357.
124. De Miranda, B.R., Rocha, E.M., Bai, Q., El Ayadi, A., Hinkle, D., Burton, E.A., Timothy Greenamyre, J., Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson's disease. Neurobiol. Dis. 115 (2018), 101–114, 10.1016/j.nbd.2018.04.008.
125. Scudamore, O., Ciossek, T., Increased oxidative stress exacerbates α-Synuclein aggregation in vivo. J. Neuropathol. Exp. Neurol. 77 (2018), 443–453, 10.1093/jnen/nly024.
126. Zeng, X.-S., Geng, W.-S., Jia, J.-J., Chen, L., Zhang, P.-P., Cellular and molecular basis of neurodegeneration in parkinson disease. Front. Aging Neurosci., 10, 2018, 109, 10.3389/fnagi.2018.00109.
127. Omar, S.H., Scott, C.J., Hamlin, A.S., Obied, H.K., The protective role of plant biophenols in mechanisms of Alzheimer's disease. J. Nutr. Biochem. 47 (2017), 1–20, 10.1016/j.jnutbio.2017.02.016.
128. Peng, Y., Hou, C., Yang, Z., Li, C., Jia, L., Liu, J., Tang, Y., Shi, L., Li, Y., Long, J., Liu, J., Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1 mice. Mol. Nutr. Food Res. 60 (2016), 2331–2342, 10.1002/mnfr.201600332.
129. St-Laurent-Thibault, C., Arseneault, M., Longpré, F., Ramassamy, C., Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling. Curr. Alzheimer Res. 8 (2011), 543–551 (accessed December 20, 2018) http://www.ncbi.nlm.nih.gov/pubmed/21605049.
130. Crespo, M.C., Tomé-Carneiro, J., Pintado, C., Dávalos, A., Visioli, F., Burgos-Ramos, E., Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease. Biofactors 43 (2017), 540–548, 10.1002/biof.1356.
131. Li, J., Cesari, M., Liu, F., Dong, B., Vellas, B., Effects of diabetes mellitus on cognitive decline in patients with alzheimer disease: a systematic review. Can. J. Diabetes 41 (2017), 114–119, 10.1016/j.jcjd.2016.07.003.
132. Olanow, C.W., Schapira, A.H.V., Agid, Y., Neuroprotection for Parkinson's disease: prospects and promises. Ann. Neurol. 53:Suppl 3 (2003), S1–S2, 10.1002/ana.10566.
133. Yu, G., Deng, A., Tang, W., Ma, J., Yuan, C., Ma, J., Hydroxytyrosol induces phase II detoxifying enzyme expression and effectively protects dopaminergic cells against dopamine- and 6-hydroxydopamine induced cytotoxicity. Neurochem. Int. 96 (2016), 113–120, 10.1016/j.neuint.2016.03.005.
134. 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. 41 (2016), 2173–2178, 10.1007/s11064-016-1959-0.
135. Conde, C., Escribano, B.M., Luque, E., Aguilar-Luque, M., Feijóo, M., Ochoa, J.J., LaTorre, M., Giraldo, A.I., Lillo, R., Agüera, E., Santamaría, A., Túnez, I., The protective effect of extra-virgin olive oil in the experimental model of multiple sclerosis in the rat. Nutr. Neurosci., 2018, 1–12, 10.1080/1028415X.2018.1469281.
136. Liuzzi, G.M., Latronico, T., Branà, M.T., Gramegna, P., Coniglio, M.G., Rossano, R., Larocca, M., Riccio, P., Structure-dependent inhibition of gelatinases by dietary antioxidants in rat astrocytes and sera of multiple sclerosis patients. Neurochem. Res. 36 (2011), 518–527, 10.1007/s11064-010-0373-2.
137. Santangelo, C., Vari, R., Scazzocchio, B., De Sanctis, P., Giovannini, C., D'Archivio, M., Masella, R., Anti-inflammatory activity of extra virgin olive oil polyphenols: which role in the prevention and treatment of immune-mediated inflammatory diseases?. Endocr. Metab. Immune Disord. Drug Targets 18 (2018), 36–50, 10.2174/1871530317666171114114321.
138. NIH consensus development panel on osteoporosis prevention, diagnosis, and therapy, osteoporosis prevention, diagnosis, and therapy. JAMA 285 (2001), 785–795 (accessed December 20, 2018) http://www.ncbi.nlm.nih.gov/pubmed/11176917.
139. Vidal, M., Thibodaux, R.J., Neira, L.F.V., Messina, O.D., Osteoporosis: a clinical and pharmacological update. Clin. Rheumatol., 2018, 10.1007/s10067-018-4370-1.
140. Delmas, P.D., Treatment of postmenopausal osteoporosis. Lancet (London, England) 359 (2002), 2018–2026, 10.1016/S0140-6736(02)08827-X.
141. Rivas, A., Romero, A., Mariscal-Arcas, M., Monteagudo, C., Feriche, B., Lorenzo, M.L., Olea, F., Mediterranean diet and bone mineral density in two age groups of women. Int. J. Food Sci. Nutr. 64 (2013), 155–161, 10.3109/09637486.2012.718743.
142. Romero Pérez, A., Rivas Velasco, A., Adherence to Mediterranean diet and bone health. Nutr. Hosp. 29 (2014), 989–996, 10.3305/nh.2014.29.5.7332.
143. 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, 11, 2016, 10.1371/journal.pone.0150045 e0150045.
144. Hagiwara, K., Goto, T., Araki, M., Miyazaki, H., Hagiwara, H., Olive polyphenol hydroxytyrosol prevents bone loss. Eur. J. Pharmacol. 662 (2011), 78–84, 10.1016/j.ejphar.2011.04.023.
145. 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. 56 (2008), 9417–9422, 10.1021/jf801794q.
146. Chen, Q., Yang, L., Zhang, G., Wang, F., Bioactivity-guided Isolation of antiosteoporotic compounds from Ligustrum lucidum. Phytother. Res. 27 (2013), 973–979, 10.1002/ptr.4820.
147. Mahmoudi, A., Ghorbel, H., Feki, I., Bouallagui, Z., Guermazi, F., Ayadi, L., Sayadi, S., Oleuropein and hydroxytyrosol protect rats’ pups against bisphenol A induced hypothyroidism. Biomed. Pharmacother. 103 (2018), 1115–1126, 10.1016/j.biopha.2018.03.004.
148. Wang, X., Yuan, Y., Han, Z., Yu, Y., Xu, Z., Cai, B., Potential applications of induced pluripotent stem cells for cardiovascular diseases. Curr. Drug Targets, 20, 2018, 10.2174/1389450120666181211164147.
149. 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. 1041–1042 (2017), 45–59, 10.1016/j.jchromb.2016.12.020.
150. 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 178 (2018), 246–257, 10.1016/j.talanta.2017.09.029.
151. Poudyal, H., Lemonakis, N., Efentakis, P., Gikas, E., Halabalaki, M., Andreadou, I., Skaltsounis, L., Brown, L., Hydroxytyrosol ameliorates metabolic, cardiovascular and liver changes in a rat model of diet-induced metabolic syndrome: pharmacological and metabolism-based investigation. Pharmacol. Res. 117 (2017), 32–45, 10.1016/j.phrs.2016.12.002.
152. 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., Liu, H.-L., Li, Y.-P., Yang, G.-D., Bian, X.-L., A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects. Bioorg. Med. Chem. Lett. 28 (2018), 3119–3122, 10.1016/j.bmcl.2018.06.010.
153. Tshongo Muhindo, C., Ahn, S.A., Rousseau, M.F., Dierckxsens, Y., Hermans, M.P., Efficacy and safety of a combination of red yeast rice and olive extract in hypercholesterolemic patients with and without statin-associated myalgia. Complement. Ther. Med. 35 (2017), 140–144, 10.1016/j.ctim.2017.10.014.
154. Lee, Y.Y., Crauste, C., Wang, H., Leung, H.H., Vercauteren, J., Galano, J.-M., Oger, C., Durand, T., Wan, J.M.-F., Lee, J.C.-Y., Extra virgin olive oil reduced polyunsaturated fatty acid and cholesterol oxidation in rodent liver: is this accounted for hydroxytyrosol-fatty acid conjugation?. Chem. Res. Toxicol. 29 (2016), 1689–1698, 10.1021/acs.chemrestox.6b00214.
155. Fki, I., Sahnoun, Z., Sayadi, S., Hypocholesterolemic effects of phenolic extracts and purified hydroxytyrosol recovered from olive mill wastewater in rats fed a cholesterol-rich diet. J. Agric. Food Chem. 55 (2007), 624–631, 10.1021/jf0623586.
156. Tabernero, M., Sarriá, B., Largo, C., Martínez-López, S., Madrona, A., Espartero, J.L., Bravo, L., Mateos, R., Comparative evaluation of the metabolic effects of hydroxytyrosol and its lipophilic derivatives (hydroxytyrosyl acetate and ethyl hydroxytyrosyl ether) in hypercholesterolemic rats. Food Funct. 5 (2014), 1556–1563, 10.1039/C3FO60677E.
157. 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 pro-oxidant effect in Caco-2 human enterocyte-like cells. Food Funct. 7 (2016), 337–346, 10.1039/C5FO00074B.
158. Santos-López, J.A., Garcimartín, A., Bastida, S., Bautista-Ávila, M., González-Muñoz, M.J., Benedí, J., Sánchez-Muniz, F.J., Lipoprotein profile in aged rats fed chia oil- or hydroxytyrosol-enriched pork in high cholesterol/high saturated fat diets. Nutrients, 10, 2018, 1830, 10.3390/nu10121830.
159. Santos-López, J.A., Garcimartín, A., Merino, P., López-Oliva, M.E., Bastida, S., Benedí, J., Sánchez-Muniz, F.J., Effects of silicon vs. hydroxytyrosol-enriched restructured pork on liver oxidation status of aged rats fed high-saturated/high-cholesterol diets. PLoS One, 11, 2016, 10.1371/journal.pone.0147469 e0147469.
160. 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. 57 (2009), 8798–8804, 10.1021/jf901280r.
161. Hamden, K., Allouche, N., Damak, M., Elfeki, A., Hypoglycemic and antioxidant effects of phenolic extracts and purified hydroxytyrosol from olive mill waste in vitro and in rats. Chem. Biol. Interact. 180 (2009), 421–432, 10.1016/j.cbi.2009.04.002.
162. Reyes, J.J., Villanueva, B., López-Villodres, J.A., De La Cruz, J.P., Romero, L., Rodríguez-Pérez, M.D., Rodriguez-Gutierrez, G., Fernández-Bolaños, J., González-Correa, J.A., Neuroprotective Effect of Hydroxytyrosol in Experimental Diabetes Mellitus. J. Agric. Food Chem. 65 (2017), 4378–4383, 10.1021/acs.jafc.6b02945.
163. Ristagno, G., Fumagalli, F., Porretta-Serapiglia, C., Orrù, A., Cassina, C., Pesaresi, M., Masson, S., Villanova, L., Merendino, A., Villanova, A., Cervo, L., Lauria, G., Latini, R., Bianchi, R., Hydroxytyrosol attenuates peripheral neuropathy in streptozotocin-induced diabetes in rats. J. Agric. Food Chem. 60 (2012), 5859–5865, 10.1021/jf2049323.
164. Lutfi, E., Babin, P.J., Gutiérrez, J., Capilla, E., Navarro, I., Caffeic acid and hydroxytyrosol have anti-obesogenic properties in zebrafish and rainbow trout models. PLoS One, 12, 2017, 10.1371/journal.pone.0178833 e0178833.
165. 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. Nutr. Biochem. 57 (2018), 180–188, 10.1016/j.jnutbio.2018.03.018.
166. López-Villodres, J.A., Abdel-Karim, M., De La Cruz, J.P., Rodríguez-Pérez, M.D., Reyes, J.J., Guzmán-Moscoso, R., Rodriguez-Gutierrez, G., Fernández-Bolaños, J., González-Correa, J.A., Effects of hydroxytyrosol on cardiovascular biomarkers in experimental diabetes mellitus. J. Nutr. Biochem. 37 (2016), 94–100, 10.1016/j.jnutbio.2016.07.015.
167. Catalán, Ú., Rubió, L., López de Las Hazas, M.-C., Herrero, P., Nadal, P., Canela, N., Pedret, A., Motilva, M.-J., Solà, R., Hydroxytyrosol and its complex forms (secoiridoids) modulate aorta and heart proteome in healthy rats: potential cardio-protective effects. Mol. Nutr. Food Res. 60 (2016), 2114–2129, 10.1002/mnfr.201600052.
168. Tejada, S., Pinya, S., Del Mar Bibiloni, M., Tur, J.A., Pons, A., Sureda, A., Cardioprotective effects of the polyphenol hydroxytyrosol from olive oil. Curr. Drug Targets 18 (2017), 1477–1486, 10.2174/1389450117666161005150650.
169. Peyrol, J., Riva, C., Amiot, M.J., Hydroxytyrosol in the prevention of the metabolic syndrome and related disorders. Nutrients, 9, 2017, 306, 10.3390/nu9030306.
170. Hotamisligil, G.S., Inflammation and metabolic disorders. Nature 444 (2006), 860–867, 10.1038/nature05485.
171. Calder, P.C., Ahluwalia, N., Brouns, F., Buetler, T., Clement, K., Cunningham, K., Esposito, K., Jönsson, L.S., Kolb, H., Lansink, M., Marcos, A., Margioris, A., Matusheski, N., Nordmann, H., O'Brien, J., Pugliese, G., Rizkalla, S., Schalkwijk, C., Tuomilehto, J., Wärnberg, J., Watzl, B., Winklhofer-Roob, B.M., Dietary factors and low-grade inflammation in relation to overweight and obesity. Br. J. Nutr., 106(Suppl 3), 2011, 10.1017/S0007114511005460 S5-78.
172. Oliviero, F., Scanu, A., Zamudio-Cuevas, Y., Punzi, L., Spinella, P., Anti-inflammatory effects of polyphenols in arthritis. J. Sci. Food Agric. 98 (2018), 1653–1659, 10.1002/jsfa.8664.
173. Silva, S., Sepodes, B., Rocha, J., Direito, R., Fernandes, A., Brites, D., Freitas, M., Fernandes, E., Bronze, M.R., Figueira, M.E., Protective effects of hydroxytyrosol-supplemented refined olive oil in animal models of acute inflammation and rheumatoid arthritis. J. Nutr. Biochem. 26 (2015), 360–368, 10.1016/j.jnutbio.2014.11.011.
174. Rosillo, M.A., Sánchez-Hidalgo, M., González-Benjumea, A., Fernández-Bolaños, J.G., Lubberts, E., Alarcón-de-la-Lastra, C., Preventive effects of dietary hydroxytyrosol acetate, an extra virgin olive oil polyphenol in murine collagen-induced arthritis. Mol. Nutr. Food Res. 59 (2015), 2537–2546, 10.1002/mnfr.201500304.
175. Cheng, Y., Qu, Z., Fu, X., Jiang, Q., Fei, J., Hydroxytyrosol contributes to cell proliferation and inhibits apoptosis in pulsed electromagnetic fields treated human umbilical vein endothelial cells in vitro. Mol. Med. Rep. 16 (2017), 8826–8832, 10.3892/mmr.2017.7701.
176. Zrelli, H., Kusunoki, M., Miyazaki, H., Role of hydroxytyrosol-dependent regulation of HO-1 expression in promoting wound healing of vascular endothelial cells via Nrf2 de novo synthesis and stabilization. Phytother. Res. 29 (2015), 1011–1018, 10.1002/ptr.5339.
177. Auñon-Calles, D., Giordano, E., Bohnenberger, S., Visioli, F., Hydroxytyrosol is not genotoxic in vitro. Pharmacol. Res. 74 (2013), 87–93, 10.1016/j.phrs.2013.06.002.
178. Kirkland, D., Edwards, J., Woehrle, T., Beilstein, P., Investigations into the genotoxic potential of olive extracts. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 777 (2015), 17–28, 10.1016/j.mrgentox.2014.10.012.
179. Cayero-Otero, M.D., Espinosa-Oliva, A.M., Herrera, A.J., Garcia-Dominguez, I., Fernandez-Arevalo, M., Martin-Banderas, L., de Pablos, R.M., Potential use of nanomedicine for the anti-inflammatory treatment of neurodegenerative diseases. Curr. Pharm. Des. 24 (2018), 1589–1616, 10.2174/1381612824666180403113015.
180. Siddique, M.I., Katas, H., Jamil, A., Mohd Amin, M.C.I., Ng, S.-F., Zulfakar, M.H., Nadeem, S.M., Potential treatment of atopic dermatitis: tolerability and safety of cream containing nanoparticles loaded with hydrocortisone and hydroxytyrosol in human subjects. Drug Deliv. Transl. Res., 2017, 10.1007/s13346-017-0439-7.
181. Chashmi, N.A., Emadi, S., Khastar, H., Protective effects of hydroxytyrosol on gentamicin induced nephrotoxicity in mice. Biochem. Biophys. Res. Commun. 482 (2017), 1427–1429, 10.1016/j.bbrc.2016.12.052.
182. 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, 5109503, 10.1155/2018/5109503.
183. El-Azem, N., Pulido-Moran, M., Ramirez-Tortosa, C.L., Quiles, J.L., Cara, F.E., Sanchez-Rovira, P., Granados-Principal, S., Ramirez-Tortosa, Mc., Modulation by hydroxytyrosol of oxidative stress and antitumor activities of paclitaxel in breast cancer. Eur. J. Nutr., 2018, 10.1007/s00394-018-1638-9.
184. Terzuoli, E., Nannelli, G., Frosini, M., Giachetti, A., Ziche, M., Donnini, S., Inhibition of cell cycle progression by the hydroxytyrosol-cetuximab combination yields enhanced chemotherapeutic efficacy in colon cancer cells. Oncotarget 8 (2017), 83207–83224, 10.18632/oncotarget.20544.
185. 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. 95 (2017), 1749–1758, 10.1016/j.biopha.2017.09.073.
186. Serreli, G., Deiana, M., Biological relevance of extra virgin olive oil polyphenols metabolites. Antioxidants (Basel, Switzerland), 7, 2018, 170, 10.3390/antiox7120170.
187. 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., 9, 2018, 2624, 10.3389/fmicb.2018.02624.
188. Officioso, A., Panzella, L., Tortora, F., Alfieri, M.L., Napolitano, A., Manna, C., Comparative analysis of the effects of olive oil hydroxytyrosol and its 5-S-lipoyl conjugate in protecting human erythrocytes from mercury toxicity. Oxid. Med. Cell. Longev., 2018, 2018, 9042192, 10.1155/2018/9042192.
189. Amorati, R., Valgimigli, L., Panzella, L., Napolitano, A., d'Ischia, M., 5-S-lipoylhydroxytyrosol, a multidefense antioxidant featuring a solvent-tunable peroxyl radical-scavenging 3-thio-1,2-dihydroxybenzene motif. J. Org. Chem. 78 (2013), 9857–9864, 10.1021/jo401522q.
190. Fernandez-Pastor, I., Fernandez-Hernandez, A., Rivas, F., Martinez, A., Garcia-Granados, A., Parra, A., Synthesis and antioxidant activity of hydroxytyrosol alkyl-carbonate derivatives. J. Nat. Prod. 79 (2016), 1737–1745, 10.1021/acs.jnatprod.6b00124.
191. Sakakura, A., Pauze, M., Namiki, A., Funakoshi-Tago, M., Tamura, H., Hanaya, K., Higashibayashi, S., Sugai, T., Chemoenzymatic synthesis of hydroxytyrosol monoesters and their suppression effect on nitric oxide production stimulated by lipopolysaccharides. Biosci. Biotechnol. Biochem., 2018, 1–7, 10.1080/09168451.2018.1530970.
192. Panzella, L., Verotta, L., Goya, L., Ramos, S., Martín, M.A., Bravo, L., Napolitano, A., d'Ischia, M., Synthesis and bioactivity profile of 5-s-lipoylhydroxytyrosol-based multidefense antioxidants with a sizeable (poly)sulfide chain. J. Agric. Food Chem. 61 (2013), 1710–1717, 10.1021/jf302690c.
193. Bernini, R., Gilardini Montani, M.S., 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. 58 (2015), 9089–9107, 10.1021/acs.jmedchem.5b00669.
194. 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., Yang, G.-D., Li, Y.-P., Bian, X.-L., Hydroxytyrosol nicotinate, a new multifunctional hypolipidemic and hypoglycemic agent. Biomed. Pharmacother. 99 (2018), 715–724, 10.1016/j.biopha.2018.01.123.