Hydrophilic phenols are the most abundant natural antioxidants of virgin olive oil (VOO), in which, however, tocopherols and carotenes are also present. The prevalent classes of hydrophilic phenols found in VOO are phenolic alcohols and acids, flavonoids, lignans and secoiridoids. Among these substances the last two classes include the most concentrate phenols of VOO. Secoiridoids, like aglycone derivatives of oleuropein, demethyloleuropein and ligstroside, are present in olive fruit as most abundant VOO phenolic antioxidants. Several important biological properties (antioxidant, anti-inflammatory, chemopreventive and anti-cancer) and the characteristic pungent and bitter tasty properties have been attributed to VOO phenols. Relationships between polyphenols activities and their chemical structures are discussed in this paper.

Our aim in this study was to provide further support to the hypothesis that phenolic compounds may play an important role in the anticarcinogenic properties of olive oil. We measured the effect of olive oil phenols on hydrogen peroxide (H(2)O(2))-induced DNA damage in human peripheral blood mononuclear cells (PBMC) and promyelocytic leukemia cells (HL60) using single-cell gel electrophoresis (comet assay). Hydroxytyrosol [3,4-dyhydroxyphenyl-ethanol (3,4-DHPEA)] and a complex mixture of phenols extracted from both virgin olive oil (OO-PE) and olive mill wastewater (WW-PE) reduced the DNA damage at concentrations as low as 1 micromol/L when coincubated in the medium with H(2)O(2) (40 micromol/L). At 10 micromol/L 3,4-DHPEA, the protection was 93% in HL60 and 89% in PBMC. A similar protective activity was also shown by the dialdehydic form of elenoic acid linked to hydroxytyrosol (3,4-DHPEA-EDA) on both kinds of cells. Other purified compounds such as isomer of oleuropein aglycon (3,4-DHPEA-EA), oleuropein, tyrosol, [p-hydroxyphenyl-ethanol (p-HPEA)] the dialdehydic form of elenoic acid linked to tyrosol, caffeic acid, and verbascoside also protected the cells against H(2)O(2)-induced DNA damage although with a lower efficacy (range of protection, 25-75%). On the other hand, when tested in a model system in which the oxidative stress was induced by phorbole 12-myristate 13-acetate-activated monocytes, p-HPEA was more effective than 3,4-DHPEA in preventing the oxidative DNA damage. Overall, these results suggest that OO-PE and WW-PE may efficiently prevent the initiation step of carcinogenesis in vivo, because the concentrations effective against the oxidative DNA damage could be easily reached with normal intake of olive oil.

Recent epidemiological evidence and animal studies suggest a relationship between the intake of olive oil and a reduced risk of several malignancies. The present study assesses the effect of hydroxytyrosol, a major antioxidant compound of virgin olive oil, on proliferation, apoptosis and cell cycle of tumour cells. Hydroxytyrosol inhibited proliferation of both human promyelocytic leukaemia cells HL60 and colon adenocarcinoma cells HT29 and HT29 clone 19A. The con-centrations of hydroxytyrosol which inhibited 50% of cell proliferation were approximately 50 and approximately 750 micromol/l for HL60 and both HT29 and HT29 clone 19A cells, respectively. At concentrations ranging from 50 to 100 micromol/l, hydroxytyrosol induced an appreciable apoptosis in HL60 cells after 24 h of incubation as evidenced by flow cytometry, fluorescence microscopy and internucleosomal DNA fragmentation. Interestingly, no effect on apoptosis was observed after similar treatment of freshly isolated human lymphocytes and polymorphonuclear cells. The DNA cell cycle analysis, quantified by flow cytometry, showed that the treatment of HL60 cells with hydroxytyrosol 50-100 micromol/l arrested the cells in the G0/G1 phase with a concomitant decrease in the cell percentage in the S and G2/M phases. These results support the hypothesis that hydroxytyrosol may exert a protective activity against cancer by arresting the cell cycle and inducing apoptosis in tumour cells, and suggest that hydroxytyrosol, an important component of virgin olive oil, may be responsible for its anticancer activity.

Nutrigenomics data on the functional components of olive oil are still sparse, but rapidly increasing. Olive oil is the main source of fat and health-promoting component of the Mediterranean diet. Positive effects have been observed on genes involved in the pathobiology of most prevalent age- and lifestyle-related human conditions, such as cancer, cardiovascular disease and neurodegeneration. Other effects on health-promoting genes have been identified for bioactive components of olives and olive leafs. Omics technologies are offering unique opportunities to identify nutritional and health biomarkers associated with these gene responses, the use of which in personalized and even predictive protocols of investigation, is a main breakthrough in modern medicine and nutrition. Gene regulation properties of the functional components of olive oil, such as oleic acid, biophenols and vitamin E, point to a role for these molecules as natural homeostatic and even hormetic factors with applications as prevention agents in conditions of premature and pathologic aging. Therapeutic applications can be foreseen in conditions of chronic inflammation, and particularly in cancer, which will be discussed in detail in this review paper as major clinical target of nutritional interventions with olive oil and its functional components. © 2016 BioFactors, 43(1):17-41, 2017.

Although epidemiologic evidence and animal studies suggest that olive oil may prevent the onset of cancer, the components responsible for such an effect and their mechanisms of action remain largely unknown. In the present study, we investigated the effect of a virgin olive oil phenol extract (PE) on proliferation, the cell cycle distribution profile, apoptosis, and differentiation of the human promyelocytic cell line HL60. PE inhibited HL60 cell proliferation in a time- and concentration-dependent manner, as demonstrated by the viable cell count and 3-[4,5-dimethyl(thiazol-2-yl)]-3,5-diphenyltetrazolium bromide (MTT) metabolism. Cell growth was completely blocked at a PE concentration of 13.5 mg/L; apoptosis was also induced as detected by fluorescence microscopy and flow cytometry. Determination of the cell cycle distribution by flow cytometry revealed an accumulation of cells in the G(0)/G(1) phase. Two compounds isolated from PE, the dialdehydic forms of elenoic acid linked to hydroxytyrosol (3,4-DHPEA-EDA) and to tyrosol (pHPEA-EDA), were shown to possess properties similar to those of PE; they account for a part of the powerful effects exerted by the complex mixture of compounds present in PE. The concentrations of the different compounds in PE were determined by HPLC, and the purity of 3,4-DHPEA-EDA and pHPEA-EDA was ascertained by NMR. Treatment with PE induced a differentiation in HL60 cells, which subsequently acquired the ability to produce superoxide ions and reduce nitroblue tetrazolium to formazan. These results support the hypothesis that polyphenols play a critical role in the anticancer activity of olive oil.

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Metabolic Syndrome (MetS) constitutes a relevant public health burden. Several studies have demonstrated the association between diet and MetS. We performed a systematic review and meta-analysis to provide an estimate of the association between dietary patterns defined through a posteriori methods and MetS. A literature search on PubMed, Web of Science, and Scopus databases, up to March 2019, was conducted to identify all eligible case-control, prospective, or cross-sectional studies involving adult subjects of both sexes. Random-effects models were used. Heterogeneity and publication bias were evaluated. Stratified analyses were conducted on study characteristics. Forty observational studies were included in the meta-analysis, which identified the “Healthy” and the “Meat/Western” dietary patterns. The “Healthy” pattern was associated with reduced MetS risk (OR = 0.85; 95% confidence interval (CI): 0.79–0.91) and significantly decreased the risk in both sexes and in Eastern countries, particularly in Asia. Adherence to the “Meat/Western” pattern increased MetS risk (OR = 1.19; 95% CI: 1.09–1.29) and the association persisted in the stratified analysis by geographic area (Asia, Europe, America) and study design. Lifestyle is linked to risk of developing MetS. The “Healthy” and “Meat/Western” patterns are significantly associated with reduced and increased MetS risk, respectively. Nutrition represents an important modifiable factor affecting MetS risk.

Recent evidence indicates that the cancer preventive activity of olive oil can be mediated by the presence of minor components, such as antioxidant phenolic compounds. However, their mechanisms of action remain largely unknown. In this study, we investigated the in vitro effects of one of the main olive oil phenols, hydroxytyrosol [3,4-dihydroxyphenylethanol (3,4-DHPEA)], on proliferation, cell cycle progression, apoptosis, and differentiation of HL60 human promyelocytic leukemia cells. 3,4-DHPEA showed a potent inhibitory activity on DNA synthesis, as evidenced by a 92% reduction of [3H]-thymidine incorporation at 100 micromol/L, and an induced apoptosis, as evidenced by the release of cytosolic nucleosomes and flow cytometry. This phenol, 3,4-DHPEA, was also able to inhibit the progression of the cell cycle in synchronized HL60 cells, which accumulated in the G0/G1 phase of the cell cycle after 25 h of treatment. Furthermore, 3,4-DHPEA induced differentiation on HL60 cells with a maximum effect (22% of cells) at 100 micromol/L after 72 h of treatment. Among the different proteins involved in the regulation of the cell cycle, 3,4-DHPEA reduced the level of cyclin-dependent kinase (CDK) 6 and increased that of cyclin D3. With regard to the CDK inhibitors, p15 was not altered by 3,4-DHPEA treatment, whereas the expression of p21(WAF1/Cip1) and p27(Kip1) was increased at both protein and mRNA levels. To our knowledge, these results provide the first evidence that 3,4-DHPEA may effect the expression of genes involved in the regulation of tumor cell proliferation and differentiation.