*2.1. Cardioprotection*

Most pharma-nutritional studies with olive oil biophenols are being carried out in the cardiovascular arena (note that we will use the term "biophenols" throughout the text because extra virgin olive oil contains a large variety of molecules, many of which are non-phenolic in nature). In vitro experiments with pure HT started 25 years ago [9] and led to the European Food Safety Authority (EFSA, Parma, Italy) granting HT a (somewhat debated) health claim based on this activity [10]. This is—in part—the result of many animal and human studies that have been performed in various experimental conditions; the vast majority indicate that olive oil biophenols do modulate a variety of surrogate markers of cardiovascular disease (CVD) [3]. We discuss the molecular actions below, but it is worth underscoring that investigation on the healthful potential of olive oil biophenols, namely HT, is very advanced and includes nutrigenomic [11] and proteomic studies [12] (vide infra). In terms of surrogate marker modulation, the effects of HT on cholesterol concentrations are apparently modest, ye<sup>t</sup> other risk factors of CVD are positively modulated by olive biophenols [3]. One lipid-related example is that of HDL particles, for which functionality is improved by EVOO biophenols [13].

#### *2.2. Chemprevention of Cancer*

With regard to chemoprevention of cancer, the situation is fairly complex in that animal models and surrogate markers in humans are scant and impede firm conclusions from being drawn [14]. However, epidemiological studies consistently report an inverse association between adherence to the Mediterranean diet and incidence of breast cancer [15]. This association is stronger for postmenopausal breast cancer prevention [16].

In this respect, targeting inflammation as one of the major players in tumor incidence and recurrence appears to be a sensible strategy [17]. As mentioned above, olive biophenols have anti-inflammatory activities and might play protective roles in this area [18]. Also, an increase in nucleophilic tone would contribute toward chemoprevention and accelerated recovery from cancer, as shown for e.g., curcumin [19].

In addition to inflammation, some mechanistic studies have been performed to explain the potential preventive actions of olive oil biophenols on cancer. Mechanisms of action might include inhibition of cell proliferation and tumor progression as well as increased rates of apoptosis (see for example [20,21]).

Finally, it is worth mentioning that a secondary analysis from the Prevention with Mediterranean Diet (PREDIMED) study assessed the effect of a dietary intervention encouraging the adherence to a Mediterranean diet on the incidence of postmenopausal breast cancer among 4152 women aged from 60 to 80 years of age [22]. The results showed that women who consumed at least 15% of EVOO in terms of total energy intake exhibited a significant reduction in breast cancer risk when compared to women for which extra-virgin olive oil consumption was lower than 5% of total caloric intake. Whether the preventive effects of olive oil are due to its biophenols or to other unknown confounders is a matter for further investigation.
