Skip to main content

Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases


The overall health beneficial action of olive oil phenolic components is well established. Recent studies have elucidated the biological effects of two isolated compounds, namely oleuropein and hydroxytyrosol, with particular attention on their antioxidant activity. Thus, a protective action has been demonstrated in preclinical studies against several diseases, especially cardiovascular and metabolic disorders.

The present review will describe the biological effects of oleuropein and hydroxytyrosol, with particular attention on the molecular mechanism underlying the protective action on cardiovascular and metabolic alterations, as demonstrated by in vitro and in vivo experimental studies performed with the isolated compounds.


Several studies have assigned to the virgin olive oil (VOO) most of the beneficial effects on human health attributed to the Mediterranean diet [1]-[6]. Initially, the richness of monounsaturated fatty acids (MUFA), and in particular oleic acid, was considered as the major healthful characteristic of VOO. Later on, after the observation that other aliments rich in MUFA, as rapeseeds, soybean and sunflower, were not comparable with VOO as healthful food [7],[8], the role of some ‘minor components’ has been taken into consideration, also because such compounds are able to maintain their biological action when VOO is consumed in crude form. There are more than 200 ‘minor components’ in the unsaponifiable fraction of olive oil, which represent about 2% of the total weight, and include a number of heterogeneous compounds non-chemically related to fatty acids (Figure 1) [9],[10].

Figure 1
figure 1

Composition of unsaponifiable and saponifiable fractions of olive oil.

Particular attention has been focused on the nutraceutical properties of those compounds provided with antioxidant activity. The most abundant antioxidants in VOO are lipophilic and hydrophilic phenols [11] (Table 1), which are physiologically produced in the plant to react against various pathogen attacks and/or insect injuries [2],[12],[13]. The antioxidant hydrophilic phenolic alcohols of VOO and their secondary metabolites also contribute to the long oil shelf-life and influence several organoleptic characteristics, including taste (e.g. bitter, astringent, pungent, throat-catching) and color [14]-[16].

Table 1 The main phenolic compounds in virgin olive oil

Nutraceutical properties have been attributed to secoiridoid oleuropein (OL) and its derivatives, the main alcohols 3,4-dihydroxyphenyl ethanol, also known as hydroxytyrosol (HT) and p-hydroxyphenyl ethanol or tyrosol [2],[11] (Figure 2). Such compounds are released from the olive fruit to VOO during the extraction process. In particular, OL is abundant in high amounts in unprocessed olive leaves and fruit, while higher concentration of HT may be found in the fruit and in olive oil, owing to chemical and enzymatic reactions that in the plant occur during maturation of the fruit [14],[17]. In addition, many agronomic factors, as cultivar, ripening stage, geographic origin of olive fruit and olive trees irrigation, as well as various oil extraction conditions during crushing, malaxation and VOO separation, may influence their final concentration in VOO [18]-[20].

Figure 2
figure 2

Chemical structure of the best known phenolic compounds in the VOO.

OL and HT represent the molecules of major interest for their biological and pharmacological properties, and, with no doubt, are among the most investigated antioxidant natural compounds [5],[11],[21]. They have been studied as isolated compounds or as components of ‘oil phenolic extracts’, showing a wide variety of beneficial effects, mainly related to their antioxidant activity (Figure 3), in many preclinical models of diseases [5],[22]-[26].

Figure 3
figure 3

Antioxidant activity and related effects of oleuropein and hydroxytyrosol.

In the following sections will be described the biological effects of OL and HT, as resulting by in vitro and in vivo experimental data obtained with isolated compounds.

Antioxidant activity of Oleuropein and Hydroxytyrosol

Defense against reactive oxygen species (ROS) is fundamental to protect cellular molecules as lipids, proteins or DNA and avoid the development of degenerative diseases. When the defensive mechanisms are overtaken by the action of the free radicals, the subsequent cellular damage may lead to several diseases, including atherosclerosis, cardiovascular diseases, skin and neurodegenerative diseases, diabetes mellitus and metabolic syndrome. Finally, physiological processes such as aging have been associated with a disequilibrium between the action of ROS and that of antioxidants [27],[28].

Antioxidant agents are present in various amount in several types of food. In the VOO, phenolic compounds in general, and OL derivatives in particular, act as natural antioxidants. They are important for the food stability and protect against the oxidation occurring naturally during VOO storage owing to reaction with air [29].

The antioxidant activity of OL and HT in vivo is related to their highly bioavailability [23],[24]: various studies have documented a high degree of absorption, fundamental to exert their metabolic and pharmacokinetics properties [23],[24],[30].

OL and HT behave as antioxidant acting as: a. free radical scavengers and radical chain breaking; b. anti-oxygen radicals; c. metal chelators. With their catecholic structure, they are able to scavenge the peroxyl radicals and break peroxidative chain reactions producing very stable resonance structures [2],[31].

A decrease in ROS production, derived by iron or copper induced oxidation of low-density lipoproteins (LDL), was first described after treatment with either OL or HT in an in vitro model, suggesting a chelating action on such metals [25],[32].

However, a strong free-radical scavenging action has been demonstrated also by using metal-independent oxidative systems [33] or measuring stable free radicals, such as 2,2-diphe-1-picrylhydrazyl (DPPH) [34],[35]. The ability to scavenge or reduce the generation of ROS was further confirmed both in leukocytes treated with phorbol 12-myristate 13-acetate (PMA) and in hypoxanthine/xanthine oxidase cell-free system through a chemiluminescence method [36],[37]. Again, a scavenging effect of OL and HT was demonstrated with respect to hypochlorous acid (HOCl) [36], a potent oxidant produced in vivo at the site of inflammation: this activity was demonstrated in a model of HOCl-mediated inactivation of catalase. This last evidence may have important implication in the protection from atherosclerosis, since HOCl can oxidize the apoproteic component of LDL (see next section). Zhu et al. have reported that HT induces simultaneously both phase II detoxifying enzymes (a set of important enzymes for protecting against oxidative damage) and mitochondrial biogenesis, two critical pathways occurring in the fight against oxidative stress [38]. An additional important element that contributes to the accumulation of intracellular ROS is the endoplasmic reticulum (ER) stress [39]: recently, it has been reported that HT is able both to modulate an adaptive signaling pathway activated after ER stress and to ameliorate ER homeostasis [40]. It must be noted that, at higher doses, OL and HT may exert pro-oxidant activity [41]-[44], responsible for the antiproliferative properties on cancer cells (see Section “Other activities”).

Protection against cardiovascular diseases

Several studies have emphasized the importance of a regular use of olive oil in the benefits of traditional mediterranean diet on cardiovascular diseases [6],[45]-[47]. In particular, beside the antioxidant activity, vasodilatatory, anti-platelet aggregation and anti-inflammatory effects have been assigned to olive oil phenolic compounds such as OL and HT [5],[22],[23],[48].

Several reports have described the protective effects against atherosclerosis of OL and HT in preclinical experimental models. Visioli et al. [25] have demonstrated that OL and HT inhibit copper sulphate-induced oxidation of LDL. As previously mentioned, OL and HT exert a scavenging effect towards HOCl, which acts through chlorination of apoB-100 as an initiating agent in LDL lipid peroxidation [49], and this effect determines a retard in the onset of the atherosclerotic damage. In addition, Jemai et al. demonstrated that in rats fed with a cholesterol-rich diet, the same compounds were able to promote hypocholesterolemia, lowering LDL plasma levels and total cholesterol; also, they increased the levels of high-density lipoproteins (HDL) and the activity of antioxidant enzymes reducing LDL oxidation [50],[51]. Recently, the European Food Safety Authority (EFSA) has recognized protective effects of the olive oil phenolic compounds on LDL oxidation, in particular of HT [52].

Effects other than the reduction of LDL and cholesterol may explain the anti-atherogenic action of OL and HT, too (see Table 2). Carluccio et al. described the inhibition of endothelial activation, an early step in atherogenesis, by OL and HT, able to reduce lipopolysaccharide (LPS)-stimulated expression of vascular adhesion molecule-1 (VCAM-1) in human vascular endothelial cells by inhibition of its mRNA levels, thus decreasing monocyte cell adhesion to endothelial cells [53]. Two additional mechanisms involved in the vascular damages, platelet aggregation and proliferation of smooth muscle cells, are also antagonized by the olive oil phenolic compounds. It has been observed that HT inhibits in vitro platelet aggregation induced by thromboxane B2 production and collagen [54]. The same effect was observed in healthy rats assigned to diet supplemented with HT [55]: in this study was proposed that both an inhibition of cyclooxygenase (COX)-2 with a related decrease of thromboxane A2 blood levels and an increase of vascular nitric oxide production may contribute to this effect [55]. Inhibition of vascular smooth muscle cell proliferation has been demonstrated after treatment with OL, associated with a reduction of the extracellular regulated kinase-1/2 activity [56].

Table 2 Effects and mechanisms involved in the cardiovascular protection of oleuropein and hydroxytyrosol

Some data exist also abut direct cardioprotective effects of these molecules. Manna et al. [57] analyzed OL effects in myocardial injury induced by ischemia; in isolated rat heart perfused with OL before induction of ischemia, were measured the levels of creatine kinase, a biochemical marker of cellular damage, and those of oxidize glutathione, a marker of heart exposure to oxidative stress and a key factor in the pathogenesis of atherosclerosis. OL significantly decreased levels of both markers suggesting a cardioprotective effect in the acute events that follow coronary occlusion. Recently, it has been observed that OL is able to prevent cardiomyopathy in rats treated with doxorubicin (DXR) [58]. In addition, Granados et al. have reported that HT attenuated DXR-associated chronic cardiac toxicity in rats with breast cancer ameliorating mitochondrial dysfunction [59].

The impact of OL was studied also in vivo in normal and hypercholesterolemic rabbits subjected to ischemia and reperfusion [62]. Treatment with OL for 3 or 6 weeks considerably reduced the infarct size in normal rabbits and, at higher doses, in hypercholesterolemic rabbits. Moreover, OL protection of re-perfused myocardium was associated with decreased total cholesterol and triglyceride levels [62].

The cardioprotective effects of HT have been confirmed in a study conducted with cardiomyocytes extracted from rats treated with this phenol. In these animals, administration of HT reduced the expression of proteins related to ageing as well as the infarct size and cardiomyocyte apoptosis [60].

In another study, a reduced infarct size with improvement in the myocardial function was shown in tyrosol-treated rats compared to non-treated controls [61].

Protection against diabetes and metabolic disorders

In the early 90s, Gonzalez et al., using an animal model of alloxan-induced diabetes mellitus, first postulated a protective role of OL extracted by olive leaves [63]. Subsequent studies evidenced a strong link of the antidiabetic action with the antioxidant effects of OL. By treating alloxan-diabetic rabbits with OL, Al-Azzawie and Alhamdani obtained a significant hypoglycemic effect as compared with diabetic control animals, associated with restoration of the levels of malondialdehyde and most of the enzymatic and non-enzymatic endogenous antioxidants [64]. Similar data were reported in alloxan-diabetic rats treated with OL and HT from olive leaves [65] or using purified HT from olive mill waste both in vitro and in rats [66].

A close relationship between antioxidant and hypoglycemic activity of olive leaf extracts (OLE) was confirmed by Poudyal et al. [67] in rats with a diet-induced model of the metabolic syndrome. Supplementation of the diet with OLE enriched with OL and HT attenuated the metabolic alterations, including plasma glucose, triglyceride and total cholesterol concentrations. Such effects were paralleled by reduced plasmatic malondialdehyde and uric acid levels, therefore suggesting again a role for the antioxidant activity.

In another animal model of high-fat-diet (HFD)-induced obesity, hyperglycemia, hyperlipidemia, and insulin resistance, Cao et al. demonstrated the protective effect of HT, showing its ability to decrease HFD-induced lipid deposits through inhibition of the SREBP-1c/FAS pathway in liver and skeletal muscle tissues, enhance antioxidant enzyme activities, normalize expression of mitochondrial complex subunits and mitochondrial fission marker Drp1, and eventually inhibit apoptosis activation [68]. In addition, in mutant diabetic (db/db) mice, HT significantly decreased fasting glucose, and lipid serum levels, the latter effects obtained when treatment with metformin failed. As in the HFD model, muscle mitochondrial carbonyl protein levels and improved mitochondrial complex activities were also observed in db/db mice treated with HT [68]. Thus, at least for HT, the metabolic effects may be not limited to the action against the oxidative stress [68]. Moreover, in diabetic rats treated with HT, a reduction of the content of triglycerides and LDL-cholesterol and an increase of HDL-cholesterol levels has been reported [26]. Recently, El et al. suggested that improvement of glucose-induced insulin release as well as increased peripheral uptake of glucose are both involved in the hypoglycemic effect of OL [22].

The effects of OL and HT on insulin action have recently been demonstrated by De Bock et al. in overweight middle-aged men: administration of a diet supplemented with olive leaf polyphenols (51.1 mg OL, 9.7 mg HT for day) determined both amelioration of insulin action and secretion, two aspects of glucose regulation. Such an effect was independent of fat distribution, dietary intakes and physical activity and was comparable to that seen with drugs used to treat diabetes [69].

Interesting results have come from elucidation of the gene expression profile performed in the liver of obese mice treated with OL [70]. In particular, the mRNA levels of lipocalin 2 (LCN2) (0.33-fold) resulted down-regulated after OL treatment [70]. Since LCN2 deficiency in mice has been associated with protection from developing aging-and obesity-associated insulin resistance and hyperglycemia [71], the effect on this protein may represent an additional target of OL action.

Other activities

OL and HT displayed protective effects against several other diseases, mainly dependent on their antioxidant activity. Protection against the genotoxic action of the ROS is one of the mechanisms explaining the anticancer effects of these compounds [72]-[74]. In addition, OL and HT may act also through the modulation of pro- and anti-oncogenic signaling pathways, leading to cell apoptosis and growth arrest of several tumor cell lines in vitro[73]-[80]. It has been recently suggested that the antiproliferative and pro-apoptotic effects of OL and HT on tumor cells, may be mediated by their capability to induce the accumulation of hydrogen peroxide in the culture medium [41]-[44].

At present, there are few studies demonstrating the block of tumor growth in vivo[24],[79]. Results from a recent work by Sepporta et al. [81] demonstrated that OL was able to inhibit the MCF-7 human breast cells xenograft growth and their invasiveness into the lung.

Protective properties against infections are attributed to olive oil extracts or isolated compounds, as confirmed by many studies reporting anti-microorganisms and anti-virus activity [82]-[86].

By acting against oxidation, inflammation and atherosclerosis, HT, OL and derivatives result effective also in age-related disorders, as neurodegenerative diseases [48],[87],[88]. Neuroprotection may derive by interference with amyloid beta peptide (Aβ) and Tau protein aggregation [87]-[90]. Furthermore the potential neuroprotective effects of HT and OL have also been reported against brain damages such as brain hypoxia-reoxygenation, cerebral ischemia and spinal cord injury [91],[92].

At the skin level, HT conjugates with fatty acids showed optimal topical delivery features through the human stratum corneum and viable epidermis membranes [93]. Moreover, co-administration of HT and hydrocortisone in the co-loaded nanoparticles provide additional anti-inflammatory and antioxidant benefits in atopic dermatitis treatment [94]. OL intra-dermal injection also reduced cell infiltration in the wound site and forwards collagen fibers deposition and more advanced re-epithelialization in vivo[95].

Finally, OL has demonstrated beneficial antioxidant properties even against ethanol-induced gastric damages in vivo[96].

Table 3 summarizes the main results regarding the effects of isolated OL and HT in preclinical models of neoplastic, neurodegenerative and skin diseases.

Table 3 Effects of oleuropein and hydroxytyrosol in neoplastic, neurodegenerative and skin diseases

Conclusions and remarks

The large number of preclinical studies described herein has revealed the molecular basis of the beneficial actions of single components of the phenolic fraction of olive oil. Although some of these effects may derive from the interaction of the various VOO components generated by enzymatic hydrolysis of the phenolic extracts when used as a mixture, OL and HT are considered the major candidates for a pharmacological use, both as single drug or after enrichment of olive oil or other food components. Moreover, OL and HT possess high bioavailability [23],[24], together with an absolute absence of either acute or sub-chronic toxicity, at least as shown in animal experimental models [100],[101]. In view of a possible use of OL and HT in human pathology, more than one approach is under investigation. The high stability and bioavailability of these compounds has encouraged attempts to enrich the olive oil or other food components with isolated/purified phenolic compounds [102],[103]. In addition, implementation of the preparation process by the food industry and modification of the molecules to obtain more active derivatives are also promising strategies. Noteworthy, recent results obtained with OL aglycone or some semisynthetic derivatives [80],[97],[102],[104]-[107] suggest that it is possible to improve the pharmacological properties of these compounds. Further studies will better clarify the in vivo effects of OL, HT and their semisynthetic derivatives, to use as individual agents or in combination, with particular attention to their safety profile on humans, and open the way to a wide utilization in human pharmacology.









European food safety authority


Endoplasmic reticulum


Low-density lipoproteins






Hypochlorous acid


Low-density lipoproteins


Lipocalin 2




Matrix metalloproteinases


Monounsaturated fatty acids


Phorbol 12-myristate 13-acetate




Olive leaf extracts


Reactive oxygen species


Vascular adhesion molecule-1


Virgin olive oil


  1. 1.

    Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E, Trichopoulos D: Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr. 1995, 61 (Suppl 6): 1402S-1406S.

    CAS  PubMed  Google Scholar 

  2. 2.

    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. 2005, 18: 98-112.

    CAS  PubMed  Google Scholar 

  3. 3.

    Huang C, Sumpio B: Olive oil, the mediterranean diet, and cardiovascular health. J Am Coll Surg. 2008, 207: 407-416.

    PubMed  Google Scholar 

  4. 4.

    García-González DL, Aparicio-Ruiz R, Aparicio R: Virgin olive oil – chemical implications on quality and health. Eur J Lipid Sci Technol. 2008, 110: 602-607.

    Google Scholar 

  5. 5.

    Omar SH: Oleuropein in olive and its pharmacological effects. Sci Pharm. 2010, 78: 133-154.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. 6.

    Sofi F, Macchi C, Abbate R, Gensini GF, Casini A: Mediterranean diet and health. Biofactors. 2013, 39 (4): 335-342.

    CAS  PubMed  Google Scholar 

  7. 7.

    Harper CR, Edwards MC, Jacobson TA: Flaxseed oil supplementation does not affect plasma lipoprotein concentration or particle size in human subjects. J Nutr. 2006, 136: 2844-2848.

    CAS  PubMed  Google Scholar 

  8. 8.

    Aguilera CM, Mesa MD, Ramirez-Tortosa MC, Nestares MT, Ros E, Gil A: Sunflower oil does not protect against LDL oxidation as virgin olive oil does in patients with peripheral vascular disease. Clin Nutr. 2004, 23: 673-681.

    CAS  PubMed  Google Scholar 

  9. 9.

    Boskou D: Olive Oil: Chemistry and Technology. 1996, AOCS Press, Champaign

    Google Scholar 

  10. 10.

    Beltran G, Aguilera MP, Del-Rio C, Sanchez S, Martinez L: Influence of fruit ripening on the natural antioxidant content of Hojiblanca virgin olive oils. Food Chem. 2005, 89: 207-215.

    CAS  Google Scholar 

  11. 11.

    Bendini A, Cerretani L, Carrasco-Pancorbo A, Gómez-Caravaca AM, Segura-Carretero A, Fernández-Gutiérrez A, Lercker G: Phenolic molecules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical methods: an overview of the last decade. Molecules. 2007, 12: 1679-1719.

    CAS  PubMed  Google Scholar 

  12. 12.

    Carluccio MA, Massaro M, Scoditti E, De Caterina R: Vasculoprotective potential of olive oil components. Mol Nutr Food Res. 2007, 51: 1225-1234.

    CAS  PubMed  Google Scholar 

  13. 13.

    Servili M, Montedoro G: Contribution of phenolic compound to virgin olive oil quality. Eur J Lipid Sci Technol. 2002, 104: 602-613.

    CAS  Google Scholar 

  14. 14.

    Morello JR, Motilva MJ, Tovar MJ, Romero MP: Changes in commercial virgin olive oil (cv. Arbequina) during storage, with special emphasis on the phenolic fraction. Food Chem. 2004, 85: 357-364.

    CAS  Google Scholar 

  15. 15.

    Servili M, Taticchi A, Esposto S, Urbani S, Selvaggini R, Montedoro G: Influence of the decrease in oxygen during malaxation of olive paste on the composition of volatiles and phenolic compounds in virgin olive oil. J Agric Food Chem. 2008, 56: 10048-10055.

    CAS  PubMed  Google Scholar 

  16. 16.

    Angerosa F: Sensory Quality of Olive Oils. Handbook of Olive Oil: Analysis and Properties. Edited by: Harwood J, Aparicio R. 2000, Aspen Publication, Gaithenburg, 355-392.

    Google Scholar 

  17. 17.

    Brenes M, García A, García P, Garrido A: Acid hydrolysis of secoiridoid aglycons during storage of virgin olive oil. J Agric Food Chem. 2001, 49: 5609-5614.

    CAS  PubMed  Google Scholar 

  18. 18.

    Servili M, Selvaggini R, Esposto S, Taticchi A, Montedoro G, Morozzi G: Health and sensory properties of virgin olive oil hydrophilic phenols: agronomic and technological aspect of production that affect their occurence in the oil. J Chromatogr. 2004, 1054: 113-127.

    CAS  Google Scholar 

  19. 19.

    Servili M, Taticchi A, Esposto S, Urbani S, Selvaggini R, Montedoro G: Effect of olive stoning on the volatile and phenolic composition of virgin olive oil. J Agric Food Chem. 2007, 55: 7028-7035.

    CAS  PubMed  Google Scholar 

  20. 20.

    Servili M, Esposto S, Lodolini E, Selvaggini R, Taticchi A, Urbani S, Montedoro G, Serravalle M, Gucci R: Irrigation effects on quality, phenolic composition, and selected volatiles of virgin olive oils cv. Leccino. J Agric Food Chem. 2007, 55: 6609-6618.

    CAS  PubMed  Google Scholar 

  21. 21.

    Soler-Rivas C, Espı’n JC, Wichers H: Oleuropein and related compounds. J Sci Food Agric. 2000, 80: 1013-1023.

    CAS  Google Scholar 

  22. 22.

    El SN, Karakaya S: Olive tree (Olea europaea) leaves: potential beneficial effects on human health. Nutr Rev. 2009, 67: 632-638.

    PubMed  Google Scholar 

  23. 23.

    Cicerale S, Lucas LJ, Keast RS: Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr Opin Biotechnol. 2012, 23: 129-135.

    CAS  PubMed  Google Scholar 

  24. 24.

    Cicerale S, Lucas L, Keast R: Biological activities of phenolic compounds present in virgin olive oil. Int J Mol Sci. 2010, 11: 458-479.

    PubMed Central  CAS  PubMed  Google Scholar 

  25. 25.

    Visioli F, Poli A, Gall C: Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev. 2002, 22: 65-75.

    CAS  PubMed  Google Scholar 

  26. 26.

    Hu T, He XW, Jiang JG, Xu XL: Hydroxytyrosol and its potential therapeutic effects. J Agric Food Chem. 2014, 62 (7): 1449-1455.

    CAS  PubMed  Google Scholar 

  27. 27.

    Halliwell B: Oxidative stress and cancer: have we moved forward?. Biochem J. 2007, 401: 1-11.

    CAS  PubMed  Google Scholar 

  28. 28.

    Duracková Z: Some current insights into oxidative stress. Physiol Res. 2010, 59: 459-469.

    PubMed  Google Scholar 

  29. 29.

    Carrasco-Pancorbo A, Cerretani L, Bendini A, Segura-Carretero A, Lercker G, Fernández-Gutiérrez A: Evaluation of the influence of thermal oxidation on the phenolic composition and on the antioxidant activity of extra-virgin olive oils. J Agric Food Chem. 2007, 13,55: 1771-1780.

    Google Scholar 

  30. 30.

    Lavelli V: Comparison of the antioxidant activities of extra virgin olive oils. J Agric Food Chem. 2002, 50: 7704-7708.

    CAS  PubMed  Google Scholar 

  31. 31.

    Bulotta S, Oliverio M, Russo D, Procopio A: Biological Activity of Oleuropein and its Derivatives. Natural Products. Edited by: Ramawat KG, Mérillon JM. 2013, Heidelberg Springer-Verlag, Berlin, 3605-3638.

    Google Scholar 

  32. 32.

    Andrikopoulos NK, Kaliora AC, Assimopoulou AN, Papageorgiou VP: Inhibitory activity of minor polyphenolic and nonpolyphenolic constituents of olive oil against in vitro low-density lipoprotein oxidation. J Med Food. 2002, 5: 1-7.

    CAS  PubMed  Google Scholar 

  33. 33.

    Aruoma OI, Deiana M, Jenner A, Halliwell B, Kaur H, Banni S, Corongiu FP, Dessì MA, Aeschbach R: Effect of hydroxytyrosol found in extra virgin olive oil on oxidative DNA damage and on low-density lipoprotein oxidation. J Agric Food Chem. 1998, 46: 5181-5187.

    CAS  Google Scholar 

  34. 34.

    Visioli F, Galli C: The effect of minor constituents of olive oil on cardiovascular disease: new findings. Nutr Rev. 1998, 56: 142-147.

    CAS  PubMed  Google Scholar 

  35. 35.

    Carrasco-Pancorbo A, Cerretani L, Bendini A, Segura-Carretero A, Del Carlo M, Gallina-Toschi T, Lercker G, Compagnone D, Fernández-Gutiérrez A: Evaluation of the antioxidant capacity of individual phenolic compounds in virgin olive oil. J Agric Food Chem. 2005, 53: 8918-8925.

    CAS  PubMed  Google Scholar 

  36. 36.

    Visioli F, Bellomo G, Galli C: Free radical-scavenging properties of olive oil poliphenols. Biochem Biophys Res Commun. 1998, 247: 60-64.

    CAS  PubMed  Google Scholar 

  37. 37.

    de la Puerta R, Ruiz Gutierrez V, Hoult JR: Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem Pharmacol. 1999, 57: 445-449.

    CAS  PubMed  Google Scholar 

  38. 38.

    Zhu L, Liu Z, Feng Z, Hao J, Shen W, Li X, Sun L, Sharman E, Wang Y, Wertz K, Weber P, Shi X, Liu J: Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J Nutr Biochem. 2010, 21: 1089-1098.

    CAS  PubMed  Google Scholar 

  39. 39.

    Malhi H, Kaufman RJ: Endoplasmic reticulum stress in liver disease. J Hepatol. 2011, 54: 795-809.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. 40.

    Giordano E, Davalos A, Nicod N, Visioli F: Hydroxytyrosol attenuates tunicamycin-induced endoplasmic reticulum stress in human hepatocarcinoma cells. Mol Nutr Food Res. 2014, 58 (5): 954-962.

    CAS  PubMed  Google Scholar 

  41. 41.

    Fabiani R, Fuccelli R, Pieravanti F, De Bartolomeo A, Morozzi G: Production of hydrogen peroxide is responsible for the induction of apoptosis by hydroxytyrosol on HL60 cells. Mol Nutr Food Res. 2009, 53 (7): 887-896.

    CAS  PubMed  Google Scholar 

  42. 42.

    Fabiani R, Sepporta MV, Rosignoli P, De Bartolomeo A, Crescimanno M, Morozzi G: Anti-proliferative and pro-apoptotic activities of hydroxytyrosol on different tumour cells: the role of extracellular production of hydrogen peroxide. Eur J Nutr. 2012, 51 (4): 455-464.

    CAS  PubMed  Google Scholar 

  43. 43.

    Odiatou EM, Skaltsounis AL, Constantinou AI: Identification of the factors responsible for the in vitro pro-oxidant and cytotoxic activities of the olive polyphenols oleuropein and hydroxytyrosol. Cancer Lett. 2013, 330 (1): 113-121.

    CAS  PubMed  Google Scholar 

  44. 44.

    Luo C, Li Y, Wang H, Cui Y, Feng Z, Li H, Li Y, Wang Y, Wurtz K, Weber P, Long J, Liu J: Hydroxytyrosol promotes superoxide production and defects in autophagy leading to anti-proliferation and apoptosis on human prostate cancer cells. Curr Cancer Drug Targets. 2013, 13 (6): 625-639.

    CAS  PubMed  Google Scholar 

  45. 45.

    Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Keys MH, Kromhout D, Nedeljkovic S, Punsar S, Seccareccia F, Toshima H: The diet and 15-year death rate in the seven countries study. Am J Epidemiol. 1986, 124: 903-915.

    CAS  PubMed  Google Scholar 

  46. 46.

    Martín-Peláez S, Covas MI, Fitó M, Kušar A, Pravst I: Health effects of olive oil polyphenols: recent advances and possibilities for the use of health claims. Mol Nutr Food Res. 2013, 57 (5): 760-771.

    PubMed  Google Scholar 

  47. 47.

    Visioli F, Bernardini E: Extra virgin olive oil’s polyphenols: biological activities. Curr Pharm Des. 2011, 17: 786-804.

    CAS  PubMed  Google Scholar 

  48. 48.

    Omar SH: Cardioprotective and neuroprotective roles of oleuropein in olive. Saudi Pharm J. 2010, 18 (3): 111-121.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. 49.

    Carr AC, Tijerina T, Frei B: Vitamin C protects against and reverses specific hypochlorous acid- and chloramine-dependent modifications of low-density lipoprotein. Biochem J. 2000, 346: 491-499.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. 50.

    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.

    CAS  PubMed  Google Scholar 

  51. 51.

    Jemai H, Fki I, Bouaziz M, Bouallagui Z, El Feki A, Isoda H, Sayadi S: Lipid-lowering and antioxidant effects of hydroxytyrosol and its triacetylated derivative recovered from olive tree leaves in cholesterol-fed rats. J Agric Food Chem. 2008, 56: 2630-2636.

    CAS  PubMed  Google Scholar 

  52. 52.

    Scientific Opinion on the substantiation of health claims related to polyphenols in olive and protection of LDL particles from oxidative damage (ID 1333, 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). EFSA J. 2009, 9: 2033-2058.

  53. 53.

    Carluccio MA, Siculella L, Ancora MA, 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.

    CAS  PubMed  Google Scholar 

  54. 54.

    Petroni A, Blasevich M, Salami M, Papini N, Montedoro GF, Galli C: Inhibition of platelet aggregation and eicosanoid production by phenolic components of olive oil. Thromb Res. 1995, 78 (2): 151-160.

    CAS  PubMed  Google Scholar 

  55. 55.

    González-Correa JA, Navas MD, Muñoz-Marín J, Trujillo M, Fernández-Bolaños J, de la Cruz JP: Effects of hydroxytyrosol and hydroxytyrosol acetate administration to rats on platelet function compared to acetylsalicylic acid. J Agric Food Chem. 2008, 56 (17): 7872-7876.

    PubMed  Google Scholar 

  56. 56.

    Abe R, Beckett J, Abe R, Nixon A, Rochier A, Yamashita N, Sumpio B: Olive oil polyphenol oleuropein inhibits smooth muscle cell proliferation. Eur J Vasc Endovasc Surg. 2011, 41: 814-820.

    CAS  PubMed  Google Scholar 

  57. 57.

    Manna C, Migliardi V, Golino P, Scognamiglio A, Galletti P, Chiariello M, Zappia V: Oleuropein prevents oxidative myocardial injury by ischemia and reperfusion. J Nutr Biochem. 2004, 15: 461-468.

    CAS  PubMed  Google Scholar 

  58. 58.

    Andreadou I, Mikros E, Ioannidis K, Sigala F, Naka K, Kostidis S, Farmakis D, Tenta R, Kavantzas N, Bibli SI, Gikas E, Skaltsounis L, Kremastinos DT, Iliodromitis EK: Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism. J Mol Cell Cardiol. 2014, 69: 4-16.

    CAS  PubMed  Google Scholar 

  59. 59.

    Granados-Principal S, El-Azem N, Pamplona R, Ramirez-Tortosa C, Pulido-Moran M, Vera-Ramirez L, Quiles JL, Sanchez-Rovira P, Naudí A, Portero-Otin M, Perez-Lopez P, Ramirez-Tortosa M: Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem Pharmacol. 2014, 90 (1): 25-33.

    CAS  PubMed  Google Scholar 

  60. 60.

    Mukherjee S, Lekli I, Gurusamy N, Bertelli AA, Das DK: Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol. Free Radic Biol Med. 2009, 46: 573-578.

    CAS  PubMed  Google Scholar 

  61. 61.

    Samuel SM, Thirunavukkarasu M, Penumathsa SV, 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 (20): 9692-9698.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. 62.

    Andreadou I, Iliodromitis EK, Mikros E, Constantinou M, Agalias A, Magiatis P, Skaltsounis AL, Kamber E, Tsantili-Kakoulidou A, Kremastinos DT: The olive constituent oleuropein exhibits anti-ischemic, antioxidative, and hypolipidemic effects in anesthetized rabbits. J Nutr. 2006, 136: 2213-2219.

    CAS  PubMed  Google Scholar 

  63. 63.

    Gonzalez M, Zarzuelo A, Gamez MJ, Utrilla MP, Jimenez J, Osuna I: Hypoglycemic activity of olive leaf. Planta Med. 1992, 58: 513-515.

    CAS  PubMed  Google Scholar 

  64. 64.

    Al-Azzawie HF, Alhamdani MS: Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits. Life Sci. 2006, 78: 1371-1377.

    CAS  PubMed  Google Scholar 

  65. 65.

    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.

    CAS  PubMed  Google Scholar 

  66. 66.

    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. 2009, 180: 421-432.

    CAS  PubMed  Google Scholar 

  67. 67.

    Poudyal H, Campbell F, Brown L: Olive leaf extract attenuates cardiac, hepatic, and metabolic changes in high carbohydrate, high fat-fed rats. J Nutr. 2010, 140: 946-953.

    CAS  PubMed  Google Scholar 

  68. 68.

    Cao K, Xu J, Zou X, Li Y, Chen C, Zheng A, Li H, Li H, Szeto IM, Shi Y, Long J, Liu J, Feng Z: Hydroxytyrosol prevents diet-induced metabolic syndrome and attenuates mitochondrial abnormalities in obese mice. Free Radic Biol Med. 2014, 67: 396-407.

    CAS  PubMed  Google Scholar 

  69. 69.

    de Bock M, Derraik JG, Brennan CM, Biggs JB, Morgan PE, Hodgkinson SC, Hofman PL, Cutfield WS: Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, placebo-controlled, crossover trial. PLoS One. 2013, 8 (3): e57622-

    PubMed Central  CAS  PubMed  Google Scholar 

  70. 70.

    Kim Y, Choi Y, Park T: Hepatoprotective effect of oleuropein in mice: mechanisms uncovered by gene expression profiling. Biotechnol J. 2010, 5: 950-960.

    CAS  PubMed  Google Scholar 

  71. 71.

    Law IK, Xu A, Lam KS, Berger T, Mak TW, Vanhoutte PM, Liu JT, Sweeney G, Zhou M, Yang B, Wang Y: Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes. 2010, 59: 872-882.

    PubMed Central  CAS  PubMed  Google Scholar 

  72. 72.

    Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Servili M, Montedoro GF, 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 (8): 1411-1416.

    CAS  PubMed  Google Scholar 

  73. 73.

    Warleta F, Quesada CS, Campos M, Allouche Y, Beltrán G, Gaforio JJ: Hydroxytyrosol protects against oxidative DNA damage in human breast cells. Nutrients. 2011, 3: 839-857.

    PubMed Central  CAS  PubMed  Google Scholar 

  74. 74.

    Casaburi I, Puoci F, Chimento A, Sirianni R, Ruggiero C, Avena P, Pezzi V: Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies. Mol Nutr Food Res. 2013, 57 (1): 71-83.

    CAS  PubMed  Google Scholar 

  75. 75.

    Goulas V, Exarchou V, Troganis AN, Psomiadou E, Fotsis T, Briasoulis E, Gerothanassis IP: Phytochemicals in olive-leaf extracts and their antiproliferative activity against cancer and endothelial cells. Mol Nutr Food Res. 2009, 53: 600-608.

    CAS  PubMed  Google Scholar 

  76. 76.

    Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Morozzi G: Inhibition of cell cycle progression by hydroxytyrosol is associated with upregulation of cyclin-dependent protein kinase inhibitors p21(WAF1/Cip1) and p27(Kip1) and with induction of differentiation in HL60 cells. J Nutr. 2008, 138 (1): 42-48.

    CAS  PubMed  Google Scholar 

  77. 77.

    Menendez JA, Vazquez-Martin A, Colomer R, Brunet J, Carrasco-Pancorbo A, Garcia-Villalba R, Fernandez-Gutierrez A, Segura-Carretero A: Olive oil’s bitter principle reverses acquired autoresistance to trastuzumab (Herceptin™) in HER2-overexpressing breast cancer cells. BMC Cancer. 2007, 7: 80-

    PubMed Central  PubMed  Google Scholar 

  78. 78.

    Bouallagui Z, Han J, Isoda H, Sayadi S: Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food Chem Toxicol. 2011, 49: 179-184.

    CAS  PubMed  Google Scholar 

  79. 79.

    Hamdi HK, Castellon R: Oleuropein, a non-toxic olive iridoid, is an anti-tumor agent and cytoskeleton disruptor. Biochem Biophys Res Commun. 2005, 334: 769-778.

    CAS  PubMed  Google Scholar 

  80. 80.

    Bulotta S, Corradino R, Celano M, Maiuolo J, D’Agostino M, Oliverio M, Procopio A, Filetti S, Russo D: Antioxidant and antigrowth action of peracetylated oleuropein in thyroid cancer cells. J Mol Endocrinol. 2013, 51: 181-189.

    CAS  PubMed  Google Scholar 

  81. 81.

    Sepporta MV, 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 Func Food. 2014, 8: 269-273.

    CAS  Google Scholar 

  82. 82.

    Sudjana AN, D’Orazio C, Ryan V, Rasool N, Ng J, Islam N, Riley TV, Hammer KA: Antimicrobial activity of commercial Olea europaea (olive) leaf extract. Int J Antimicrob Agents. 2009, 33: 461-463.

    CAS  PubMed  Google Scholar 

  83. 83.

    Fleming HP, Walter WM, Etchells JL: Antimicrobial properties of oleuropein and products of its hydrolysis from green olives. Appl Microbiol. 1973, 26: 777-782.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. 84.

    Aziz NH, Farag SE, Mousa LA, Abo-Zaid MA: Comparative antibacterial and antifungal effects of some phenolic compounds. Microbios. 1998, 93: 43-54.

    CAS  PubMed  Google Scholar 

  85. 85.

    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.

    CAS  PubMed  Google Scholar 

  86. 86.

    Zhao G, Yin Z, Dong J: Antiviral efficacy against hepatitis B virus replication of oleuropein isolated from Jasminum officinale L. var. grandiflorum. J Ethnopharmacol. 2009, 125: 265-268.

    CAS  PubMed  Google Scholar 

  87. 87.

    Galanakis PA, Bazoti FN, Bergquist J, Markides K, Spyroulias GA, Tsarbopoulos A: Study of the interaction between the amyloid beta peptide (1–40) and antioxidant compounds by nuclear magnetic resonance spectroscopy. Biopolymers. 2011, 96: 316-327.

    CAS  PubMed  Google Scholar 

  88. 88.

    Bazoti FN, Bergquist J, Markides KE, Tsarbopoulos A: Noncovalent interaction between amyloid-β-peptide (1–40) and Oleuropein studied by electrospray ionization mass spectrometry. J Am Soc Mass Spectrom. 2006, 17: 568-575.

    CAS  PubMed  Google Scholar 

  89. 89.

    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. 2011, 8: 543-551.

    CAS  PubMed  Google Scholar 

  90. 90.

    Daccache A, Lion C, Sibille N, Gerard M, Slomianny C, Lippens G, Cotelle P: Oleuropein and derivatives from olives as Tau aggregation inhibitors. Neurochem Int. 2011, 58: 700-707.

    CAS  PubMed  Google Scholar 

  91. 91.

    Khalatbary AR, Ahmadvand H: Neuroprotective effect of oleuropein following spinal cord injury in rats. Neurol Res. 2012, 34: 44-51.

    CAS  PubMed  Google Scholar 

  92. 92.

    Cabrerizo S, De La Cruz JP, López-Villodres JA, Muñoz-Marín J, Guerrero A, Reyes JJ, Labajos MT, González-Correa JA: Role of the inhibition of oxidative stress and inflammatory mediators in the neuroprotective effects of hydroxytyrosol in rat brain slices subjected to hypoxia reoxygenation. J Nutr Biochem. 2013, 24: 2152-2157.

    CAS  PubMed  Google Scholar 

  93. 93.

    Procopio A, Celia C, Nardi M, Oliverio M, Paolino D, Sindona G: Lipophilic hydroxytyrosol esters: fatty acid conjugates for potential topical administration. J Nat Prod. 2011, 74: 2377-2381.

    CAS  PubMed  Google Scholar 

  94. 94.

    Hussain Z, Katas H, Mohd Amin MC, Kumolosasi E, Buang F, Sahudin S: Self-assembled polymeric nanoparticles for percutaneous co-delivery of hydrocortisone hydroxytyrosol: an ex vivo and in vivo study using an NC/Nga mouse model. Int J Pharm. 2013, 444: 109-119.

    CAS  PubMed  Google Scholar 

  95. 95.

    Mehraein F, Sarbishegi M, Aslani A: Evaluation of effect of oleuropein on skin wound healing in aged male BALB/c mice. Cell J. 2014, 16: 25-30.

    PubMed Central  CAS  PubMed  Google Scholar 

  96. 96.

    Alirezaei M, Dezfoulian O, Neamati S, Rashidipour M, Tanideh N, Kheradmand A: Oleuropein prevents ethanol-induced gastric ulcers via elevation of antioxidant enzyme activities in rats. J Physiol Biochem. 2012, 68 (4): 583-592.

    CAS  PubMed  Google Scholar 

  97. 97.

    Bulotta S, Corradino R, Celano M, D’Agostino M, Maiuolo J, Oliverio M, Procopio A, Iannone M, Rotiroti D, Russo D: Antiproliferative and antioxidant effects of oleuropein and its semisynthetic peracetylated derivatives on breast cancer cells. Food Chem. 2011, 127: 1609-1614.

    CAS  Google Scholar 

  98. 98.

    Kimura Y, Sumiyoshi M: Olive leaf extract and its main component oleuropein prevent chronic ultraviolet B radiation-induced skin damage and carcinogenesis in hairless mice. J Nutr. 2009, 139: 2079-2086.

    CAS  PubMed  Google Scholar 

  99. 99.

    Sumiyoshi M, Kimura Y: Effects of olive leaf extract and its main component oleuroepin on acute ultraviolet B irradiation-induced skin changes in C57BL/6 J mice. Phytother Res. 2010, 24: 995-1003.

    CAS  PubMed  Google Scholar 

  100. 100.

    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.

    PubMed  Google Scholar 

  101. 101.

    Soni MG, Burdock GA, Christian MS, Bitler CM, Crea R: Safety assessment of aqueous olive pulp extract as an antioxidant or antimicrobial agent in foods. Food Chem Toxicol. 2006, 44: 903-915.

    CAS  PubMed  Google Scholar 

  102. 102.

    Achat S, Tomao V, Madani K, Chibane M, Elmaataoui M, Dangles O, Chemat F: Direct enrichment of olive oil in oleuropein by ultrasound-assisted maceration at laboratory and pilot plant scale. Ultrason Sonochem. 2012, 19: 777-786.

    CAS  PubMed  Google Scholar 

  103. 103.

    Zoidou E, Magiatis P, Melliou E, Constantinou M, Haroutounian S, Skaltsounis AL: Oleuropein as a bioactive constituent added in milk and yogurt. Food Chem. 2014, 158: 319-324.

    CAS  PubMed  Google Scholar 

  104. 104.

    Impellizzeri D, Esposito E, Mazzon E, Paterniti I, Di Paola R, Bramanti P, Morittu VM, Procopio A, Britti D, Cuzzocrea S: The effects of oleuropein aglycone, an olive oil compound, in a mouse model of carrageenan-induced pleurisy. Clin Nutr. 2011, 30: 533-540.

    CAS  PubMed  Google Scholar 

  105. 105.

    Impellizzeri D, Esposito E, Mazzon E, Paterniti I, Di Paola R, Morittu VM, Procopio A, Britti D, Cuzzocrea S: Oleuropein aglycone, an olive oil compound, ameliorates development of arthritis caused by injection of collagen type II in mice. J Pharmacol Exp Ther. 2011, 339: 859-869.

    CAS  PubMed  Google Scholar 

  106. 106.

    Impellizzeri D, Esposito E, Mazzon E, Paterniti I, Di Paola R, Bramanti P, Morittu VM, Procopio A, Perri E, Britti D, Cuzzocrea S: The effects of a polyphenol present in olive oil, oleuropein aglycone, in an experimental model of spinal cord injury in mice. Biochem Pharmacol. 2012, 83: 1413-1426.

    CAS  PubMed  Google Scholar 

  107. 107.

    Campolo M, Di Paola R, Impellizzeri D, Crupi R, Morittu VM, Procopio A, Perri E, Britti D, Peli A, Esposito E, Cuzzocrea S: Effects of a polyphenol present in olive oil, oleuropein aglycone, in a murine model of intestinal ischemia/reperfusion injury. J Leukoc Biol. 2013, 93 (2): 277-287.

    CAS  PubMed  Google Scholar 

Download references


DR is supported by MIUR (grant 2010NFEB9L_003); MC is supported by MIUR (grant RBFR12FI27_003).

Author information



Corresponding authors

Correspondence to Arturo Pujia or Diego Russo.

Additional information

Competing interests

The authors declare that there are no competing interests.

Authors’ contributions

DR and AP contributed to the conception of the idea, drafted the manuscript and critically reviewed the final manuscript; DR elaborated the sections Introduction and Conclusion and editing the manuscript; SB elaborated the section Antioxidant activity of Oleuropein and Hydroxytyrosol, the figures, the tables and editing the manuscript; TM and AP elaborated the section Protection against Cardiovascular Diseases; MC elaborated the section Protection against Diabetes and Metabolic disorders and the figures; SL elaborated the section Other Activities. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Authors’ original file for figure 3

Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit

The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bulotta, S., Celano, M., Lepore, S.M. et al. Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases. J Transl Med 12, 219 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Oleuropein
  • Hydroxytyrosol
  • Virgin olive oil
  • Phenols
  • Antioxidant
  • Cardiovascular disease
  • Diabetes mellitus