Natural Active Compounds as Cardiovascular Therapeutics: A Gender ViewView this Special Issue
Review Article | Open Access
Flavia Franconi, Ilaria Campesi, Annalisa Romani, "Is Extra Virgin Olive Oil an Ally for Women’s and Men’s Cardiovascular Health?", Cardiovascular Therapeutics, vol. 2020, Article ID 6719301, 33 pages, 2020. https://doi.org/10.1155/2020/6719301
Is Extra Virgin Olive Oil an Ally for Women’s and Men’s Cardiovascular Health?
Noncommunicable diseases are long-lasting and slowly progressive and are the leading causes of death and disability. They include cardiovascular diseases (CVD) and diabetes mellitus (DM) that are rising worldwide, with CVD being the leading cause of death in developed countries. Thus, there is a need to find new preventive and therapeutic approaches. Polyphenols seem to have cardioprotective properties; among them, polyphenols and/or minor polar compounds of extra virgin olive oil (EVOO) are attracting special interest. In consideration of numerous sex differences present in CVD and DM, in this narrative review, we applied “gender glasses.” Globally, it emerges that olive oil and its derivatives exert some anti-inflammatory and antioxidant effects, modulate glucose metabolism, and ameliorate endothelial dysfunction. However, as in prescription drugs, also in this case there is an important gender bias because the majority of the preclinical studies are performed on male animals, and the sex of donors of cells is not often known; thus a sex/gender bias characterizes preclinical research. There are numerous clinical studies that seem to suggest the benefits of EVOO and its derivatives in CVD; however, these studies have numerous limitations, presenting also a considerable heterogeneity across the interventions. Among limitations, one of the most relevant in the era of personalized medicine, is the non-attention versus women that are few and, also when they are enrolled, sex analysis is lacking. Therefore, in our opinion, it is time to perform more long, extensive and lessheterogeneous trials enrolling both women and men.
The Mediterranean diet (MedDiet) includes high consumption of legumes, cereals, fruits, and vegetables; moderate fish and wine consumption; and low consumption of red meat ( and cited literature). The MedDiet also includes the consumption of 25–50 ml/day of extra virgin olive oil (EVOO), which seems to have health benefits [2, 3].
Cardiovascular diseases (CVD) are the main cause of deaths, accounting for >17 million deaths annually . The beneficial effect of MedDiet on CVD is suggested by several randomized clinical trials, although some recent papers stated that the evidence is still uncertain [5, 6]. For example, the Oslo Diet-Heart Study and the Finnish Mental Hospital Study [7–9] tested the effectiveness of low-cholesterol diets, enriched in polyunsaturated fatty acids, showing a decrease in coronary heart diseases (CAD) and blood cholesterol (Chol). Moreover, the Seven Countries Study, enrolling 11,579 middle-aged men from eight nations of seven Mediterranean and non-Mediterranean countries, shows a lower mortality from ischemic heart disease (IHD) in Mediterranean populations compared to those of Northern Europe and America . PREDIMED study proves that EVOO is linked to lower risk of cardiovascular (CV) events . However, a Cochrane Systematic Review proves that elevation in polyunsaturated fatty acids (PUFA) assumption has a small effect, if any, on all-cause mortality or CV deaths although it slightly decreases Chol and probably triglycerides (TG), leaving practically unaltered high density lipoprotein (HDL) .
Beneficial effects of EVOO are also associated with the presence of minor polar compounds (MPCs) that have antioxidant, anti-inflammatory, anti-aggregating, and antimicrobial activities and regulate serum insulin/glucose response [13–21]. A claim of the European Food Safety Authority (EFSA) declared that “consumption of olive oil polyphenols contributes to the protection of blood lipids from oxidative damage” at a daily dose of 5 mg of hydroxytyrosol (HTyr) and its derivatives (e.g., oleuropein complex and tyrosol) .
Actually, botanicals are largely used [23, 24], especially by women [25, 26], but rigorous findings regarding their efficacy and safety profiles are still lacking . Besides, the influence of sex on botanicals including EVOO, VOO, OO, and MPCs is also lacking; nevertheless, the individual’s sex and gender is one of the most important modulators of CV health [28–39] and the numerous sex and gender differences at CV level are summarized in Table 1. Previously, we reviewed the sex-gender effect on polyphenols of various origins [25, 26]; here we focus on EVOO and its MPCs because, as already mentioned, EFSA declares their utility in ameliorating low-density lipoproteins (LDL) oxidation and their importance in MedDiet .
2. MedDiet and Sex Differences
The Mediterranean Region includes about 20 nations with different ethnic, historical, and cultural backgrounds; religions (Muslims, Orthodox Christians, Catholic Christians, Jews); and economic status , and the UNESCO declared that MedDiet is an intangible cultural heritage . Importantly, MedDiet also includes social aspects (social integration) and a peculiar way of life (sleeping and nutrition) that may play a role in reducing age-related diseases [58, 59]. However, the transferability of the benefit of MedDiet outside of Mediterranean Region decreases the importance of social aspects [60, 61]. In particular, it has been found that, in US women who are adherent to MedDiet, the CV risk reduced by about 25% over 12 years, having a reduction in myocardial and cerebral infarcts and vascular death .
Mediterranean populations have the lowest prevalence of chronic inflammatory disease and have very high life expectancy . Actually, adherence to this diet is decreased  nevertheless many authors declare that adherence to the MedDiet has beneficial effects on diabetes mellitus (DM), obesity, and CVD [11, 64–70].
High adherence to the MedDiet reduces the overall mortality [71–73] and the risk of CVD (10%) and neoplastic diseases (4%) . Adherence to MedDiet induces small favorable changes in some risk factors for CVD, but its effect on hematic lipids is generally weak . Low-carbohydrate MedDiet reduces glycosylated haemoglobin (HbA1c) levels and delays the use of oral antidiabetic drugs when compared with a low-fat diet [75–77]. Recently, it has been shown that MedDiet can influence the genetics. However, there is not univocal data on health benefits [5, 6]. Importantly, investigating the rs7903146 polymorphism in the transcription factor 7-like 2 gene, Corella and coworkers  proved that in the homozygotes the hypercholesterolemia and hypertriglyceridemia are reduced by MedDiet.
Low adherence to MedDiet and smoking are independent predictors of 10-year CV events in women and in men, respectively . The adherence to the MedDiet, nonsmoking, normal weight, and regular physical activity reduce the mortality in men and in women, but the statistical significance is reached only in women [72, 73, 80]. However, the response to the MedDiet seems to be greater in men than in premenopausal women when cardiometabolic changes are considered [81–84]. MedDiet ameliorates plasma lipid profile and diastolic blood pressure (DBP) without impacting on leptin levels and the leptin-to-adiponectin ratio in both sexes . Only in men, it ameliorates the insulin homeostasis and redistribution of LDL subclasses from smaller to larger LDL, while an opposite trend is observed in women . Finally, MedDiet increased telomere length, a marker of biological age, in women , although no consensus is found about this effect . Finally, men are less adherent to MedDiet than women .
3. EVOO, VOO, OO, and MPC
OO is produced from the fruits of Olea europaea L. evergreen trees, a plant cultivated worldwide, but it is typical cultivation of the Mediterranean area . It mainly contains monounsaturated fats (98-99% of total weight of EVOO), such as oleic acid, followed by a low amount (1-2%) of phenols, phytosterols, tocopherols, and squalene . Importantly, in EVOO only, fatty acids are stabilized by MPCs, with antioxidant activities .
EVOO composition and concentration in MPCs are extremely variable either qualitatively or quantitatively (200–600 mg/kg) . MPCs are dependent on the tree cultivar, the climate, growing, and production procedure . The phenolic cluster of EVOO can be subdivided into several subclasses. In particular, EVOO contains saponifiable compounds (triacylglycerol, partial glycerides, esters of fatty acids or free fatty acids, and phosphatides) and unsaponifiable compounds (hydrocarbons (squalene), phytosterols (β-sitosterol, stigmasterol, and campesterol), tocopherols, carotenoids, pigments (chlorophylls), aliphatic and triterpenic alcohols, triterpenic acids (oleanolic acid), volatile compounds, and polyphenols) .
In general, secoiridoids are the most representative followed by phenolic alcohols such as Tyr and HTyr, flavonoids, lignans, and phenolic acids [89, 92]. In general, HTyr, Tyr, and conjugated forms of secoiridoids like oleuropein (which are hydrolyzed to HTyr and Tyr in the stomach) are the most representative . HTyr also originates by the hydrolysis of oleuropein during olive ripening or/and during the storage and elaboration of table olives . It can be found in a free form, such as acetate form, or as part of oleacein, verbascoside, and oleuropein . Also ligstroside, oleacein, and oleocanthal are sources of HTyr and Tyr .
Some of MPCs such as HTyr, Tyr, and their secoiridoid derivatives (oleuropein, oleuropein aglycone, and elenolic acid dialdehydes) are hydrophilic , while other MPCs are lipophilic . Lignans belong to the family of phytoestrogen  and in general the predominant lignan is (+)-1-acetoxypinoresinol . The leaves of the Olea Europaea L. contain higher concentrations of phenols than the olive fruit and derived oils [99–101]. The predominant MPCs in the leaves are verbascoside, apigenin-7-glucoside, luteolin-7-glucoside, HTyr, Tyr, and oleuropein . Notably, a single MPC may possess distinct biological activity [103, 104]. Thus, it is impossible to extrapolate the result of the single EVOO, VOO, and OO to another. For example, Chetoui and Blanqueta cultivars (rich in linoleic acid) induce higher total triacylglycerol (TAG) incorporation into THP-1 cells than Buldiego and Picual (rich in oleic acid), promoting foam cells formation . Further, extracts of Taggiasca and Seggianese, which have different amounts and composition of MPCs, have a different antioxidant activity being higher in Seggianese extract .
4. Pharmacokinetics of MPCs and Influence of Sex
The influence of sex and gender on pharmacokinetics of phenols was recently reviewed . Briefly, in humans, MPCs are well adsorbed (∼40%–95%, using HTyr and Tyr as proxy) [105, 106]. It is important to recall here that, in humans, there is an endogenous synthesis of HTyr during the metabolism of dopamine with its formation being favored by ethanol . In addition, HTyr is a product of oleuropein hydrolysis that can occur in the stomach. Besides, gut microbiota generates HTyr from oleuropein .
In the intestinal tract (both ileum and colon), more than 40% of HTyr is absorbed by bidirectional passive transport , which depends on numerous factors such as food matrix or vehicle. The absorption of HTyr and Tyr is higher when administered as an OO solution than as aqueous solution . In the gastric and intestinal tract MPCs are hydrolyzed , with some exceptions. In particular, oleuropein is degraded by the colon microbiota to HTyr that is then absorbed . HTyr bioavailability seems to be influenced by sex . The maximum plasmatic concentration of HTyr is reached 5–30 min after administration of EVOO and VOO . HTyr and its derivatives cross the blood brain barriers . Finally, HTyr is incorporated in HDL, which is higher in women than in men .
HTyr and Tyr are extensively metabolized by phase I enzymes, such as CYP2D6 and CYP3A4, and by phase II enzymes both at intestinal and hepatic levels [108, 112]. Numerous phase I and II enzymes present numerous sex differences both in animals and in humans . Thus, the metabolism of MPCs can be sex divergent at least in rats . In humans, the biotransformation of HTyr and Tyr mainly occurs through glucuronidation and sulphation, and the main circulating metabolites are both HTyr sulfate and HTyr acetate . HTyr is also metabolized by catechol-O-methyl transferases that are more expressed in men than in women  forming 3-hydroxy-4-methoxyphenyl ethanol (homovanillyl alcohol) . Globally, HTyr and Tyr have lower bioavailability than their metabolites . Inside the cells, the conjugated forms can be deconjugated and thus HTyr and Tyr metabolites can be reformed. Finally, the intestinal microorganisms metabolize HTyr into hydroxylated phenylacetic acid, acetic acid, and benzoic acid . In plasma and urine, 98% of HTyr is recovered as glucuronide form and only 2% is free . Usually, the complete elimination of HTyr and metabolites occurs approximately in 4 and 6 h in rats and humans, respectively . HTyr is mainly excreted by the renal route where it is present both in conjugated and nonconjugated form . Urinary HTyr levels (adjusting for ethyl glucuronide) are higher in men than in women . In addition, through the biliary route they reach the small intestine where they can be retransformed and reabsorbed . Despite the enterohepatic recycling, a small amount (about 5%) of total HTyr is excreted by feces  and the consumption of MPC-rich OO elevates the free HTyr levels in feces of men . Notably, Tyr, HTyr acetate, 3,4-dihydroxyphenylacetic acid, and homovanillyl alcohol administration changes urinary excretion of catecholamines (dopamine, normetanephrine, norepinephrine, and 3-methoxytyramine) in male and female rats, with the excretion being significantly higher in male than in female rats .
Oleocanthal constitutes about 10% of the olive’s MPCs (100–300 mg/kg EVOO) . Oleocanthal, as other MPCs, is stable at acid pH and at 37°C and it is biotransformed by phase I and II enzymes, with glucuronidation being the prevalent way . Oleocanthal and other secoiridoids and their metabolites are mainly eliminated by renal route and they are found in human urine 2–6 h after the intake .
Little and nonunivocal data are available on sex influence on bioavailability of chlorogenic acids ( and cited literature) and lignans. After long flaxseed lignan secoisolariciresinol diglycoside exposure, female rats have higher lignan concentrations in heart and thymus than male rats . A strong association between dietary lignan intake and prevalent obesity exists only for boys .
Importantly, pharmacokinetic interactions with other botanicals and prescription drugs have been described. For example, bioavailability of HTyr is enhanced when co-administered with the thyme extracts .
Considering the role of gut microbiota in sex healthcare paradigm [122, 123] and their ability to expand metabolic activity of the host , it important to recall that they could be a modifier of the activity and kinetic of all compounds present in olive and leaves and other matrixes . In turn, OO derivatives may influence the gut microbiome. For example, the dialdehydic form of decarboxymethyl oleuropein aglycone, oleocanthal, HTyr, and Tyr may inhibit the growth of bacteria , including the beneficial ones . Sex-gender differences in the microbiota are recently reviewed by Kim et al. . Here, it is important to recall that microbiota modifications may participate in the pathophysiology of CVD . For example, some metabolites of gut microbiota such as short-chain fatty acids and trimethylamine N-oxide may participate in the modulation of blood pressure through G protein receptors . Further gut microbiota may inhibit HDL-coordinated reverse cholesterol transport .
Globally, the effects of MPCs on microbiota appear to be compound and sex specific, and in consideration of sex differences that characterize the human microbiota, its effects on MPC fate and activity should be accurately studied.
5. Effect of EVOO, VOO, OO, Leaf Extracts, and MPCs on Endothelial Dysfunction: Influence of Sex
Endothelial function is a barometer of vascular health  and it is a predictor and a pathogenic mechanism of atherosclerosis , being also related to the prognosis and severity of CVD [50, 132]. Endothelial dysfunction is more precocious than atherosclerotic plaques and it is a more prominent risk factor in women than in men (Table 1). It is related to oxidative stress, inflammation, platelet activity, an alteration of glucose metabolism, and uric acid levels [133–136], and all these processes present sex differences [34, 136–140].
5.1. Effect of EVOO, VOO, OO, Leaf Extracts, and MPCs on Oxidative Stress: Influence of Sex
The influence of sex on oxidative stress is widely reviewed [34, 137]. However, no univocal results are obtained and this could depend on species, tissues, and cells used and on donor age. For example, Brunelli et al.  report no differences in the plasma antioxidant barrier, although women present a higher oxidative status than men. Moreover, they suggest that premenopausal and postmenopausal women are similar . By contrast, Vassalle and coworkers  report that menopause is a condition that elevates oxidative stress. Further, young men have lower levels of malondialdehyde (MDA) in comparison to fertile women and older men . After correction for body weight (BW), both pre- and postmenopausal women have higher amounts of carbonylated proteins vs men of similar age . Others show that lipid and protein oxidation are increased in peri- and postmenopausal women, whereas superoxide dismutase (SOD) and catalase (CAT) activities are decreased and increased in postmenopause and in perimenopausal women, respectively . Glutathione (GSH) and glutathione peroxidase (GPx) are lower in women aged 32–39 years than in women aged 20–25 years. Meanwhile, 20–25-year old men have higher GSH and lower glutathione disulfide (GSSG) than women of the same age. The SOD and CAT activities are higher in women aged 32–39 years than in men and women of younger age . Moreover, women with CAD seem to have higher oxidative stress than men . Another study shows that African American women with symptomatic peripheral artery disease produce more ROS than men, while Caucasian men and women do not diverge indicating that ethnicities could play a role in sex and gender differences [146–150]. Others report the opposite trend and others do not find any significant sex difference [151–153].
The antioxidant activity of EVOO, VOO, and MPCs is extensively reviewed [154, 155] (Table 2). It is based on their scavenger, chain breaking, and chelating activities . Moreover, they favor the resistance over oxidation . High dose of oleuropein and HTyr may exert prooxidant activity [267, 268], and this paradoxically could be one of the mechanisms of their antioxidant activity because it can activate the translocation of nuclear factor E2-related factor 2 (Nrf2) to the nucleus  in a sex-specific manner [270, 271] that leads to modifications of proteins expression and activity such as γ-glutamylcysteine ligase, which is expressed less in female rat livers than in male ones . After trauma and hemorrhage, HTyr elevates liver Nrf2 modulating heme oxygenase-1 (OH-1) especially in rat females (proestrous phase) compared to males . Through Nrf2, MPCs can also activate phase II detoxifying enzymes and mitochondrial biogenesis, two critical pathways in reducing the negative effect of oxidative stress . Oleuropein and HTyr seem to be scavengers of HOCl , which starts LDL lipid peroxidation and oxidizes the apolipoprotein (Apo) B-100 . However this is not a univocal result . Finally, in animals and in humans, HTyr may interact with several microRNAs [218, 276] that regulate numerous cellular function including DICER function that is relevant to the redox state [277, 278].
5.2. Effect of EVOO, VOO, OO, Leaf Extracts, and MPCs on Inflammatory Response: Influence of Sex
The effect of sex on inflammatory response has been recently reviewed [138, 139, 279]. Women and men have a different immune system  and arachidonic acid (AA) cascade . This last generates numerous compounds with proinflammatory and anti-inflammatory activities. Interestingly, females seem to be protected against endothelial dysfunction induced by systemic inflammation . In particular, COX2 and COX1 female knockout mice have less inflammatory edema and joint destruction than male mice . Consistently, expression of COX2 is more elevated in male than in female cells . More PGE2 is produced by human male neutrophils vs female ones . In male coronary rat arteries, PGF2α exerts a major contraction in male arteries than in female ones for the presence of more PG receptors . Also the lipoxygenase (LOX) system presents some sexual dimorphism. 5-LOX and its 5-lipoxygenase-activating protein (FLAP) are downregulated by androgens . Thus, the bigger production of leukotrienes in monocytes and neutrophils of women is not surprising . In human neutrophils and monocytes, the synthesis of lipoxin A4 (LXA4), a proresolving molecule , is reduced by estradiol . Further, a positive and a negative correlation exist between age and aspirin triggered 15-epi-LXA4 in women and men, respectively . Resolvins, protectins, and maresins activities may be influenced by sex . For example, D-resolvin is higher in women exudate whereas chemoattractant leukotriene B4 is higher in men . The precursors of oxylipins are higher in the female urine than in male one .
Also the nuclear factor-kappa b (NF-kB) pathway, which is crucial for inflammatory response , is sex-dependent with its activation being mediated by the adaptor molecule MyD88, which interacts with cytoplasmic estrogen receptor-α . The NF-kB activation is higher in female human umbilical cord vein endothelial cells (HUVEC) than in male ones, under hyperoxic conditions . Also the tumor necrosis factor-α (TNF-α) pathway exhibits sex differences. For example, the human female adult cardiac progenitor cells appear to be more responsive to TNF-α when migration and cell cycle progression are considered . Young men have lower levels of TNF-α when compared to fertile women . Also the interleukin systems present some sex differences, with IL-6 being significantly higher in postmenopausal women than in premenopausal women , and in young women with CAD either in basal condition or after stress than men . The anti-inflammatory effects of OO and its derivatives are summarized in Tables 2 and 3. In general, female animals and women are less studied and OO with a high content of MPCs is more active in the control inflammation, redox status, and lipid metabolism than OO with low content of MPCs. For example, EVOO with high MPCs reduces peripheral blood mononuclear cells (PBMC) activation of the CD40/CD40 ligand (CD40L) and LDLox and modifies numerous genes . Some MPCs like HTyr exert anti-inflammatory activity with multiple mechanisms attenuating iNOS, COX2, and IL-1β expression and TNF-α and inhibiting the activation of granulocytes and monocytes . Also oleocanthal and Tyr inhibit COX [246, 360].
5.3. Effects of EVOO, VOO, OO, Leaf Extracts, and MPCs on Platelets Function: Influence of Sex
Human platelets are sexually divergent; women have more platelets, longer bleeding time, and more activatable glycoprotein IIb/IIIa than men whereas platelet spreading and adherence are higher in men than in women . The already described sex differences in AA pathways may induces sex differences in platelet aggregation. Adenosine diphosphate (ADP) and collagen-induced aggregation are higher in women, and women and men respond differently to antiaggregating agents [135, 361]. Both preclinical and clinical studies (Tables 2 and 3) show that EVOO and some of its MPCs (HTyr, oleuropein aglycone, luteolin, and oleocanthal) reduce platelet aggregation [13, 180], interfering either with AA pathways  or with other mechanisms such as calcium mobilization and attenuating iNOS activity [247, 363]. In hypercholesterolemic patients, MPCs decrease platelet aggregation inhibiting procoagulant factors, such as plasminogen activator inhibitor-1 and factor VII . Small crossover trial proves that oleocanthal is the most active in inhibiting collagen-induced aggregation at least in men , probably because it is a nonselective inhibitor of COX. HTyr antiaggregant activity seems to be agonist specific . However, in vivo, it remains difficult to discriminate EVOO associated effects of specific MPCs and phenols. Tables 2 and 3 show that, globally, the majority of the studies are performed on males and even when females are recruited no sex analysis is performed.
5.4. Effect of EVOO, VOO, OO, Leaf Extracts, and MPCs on Glucose Metabolism: Influence of Sex
Their effects are summarized in Tables 2 and 3. Briefly, the antidiabetic actions may reside in the inhibition of α-amylase and α-glucosidase [166, 167, 214, 365], which might lead to less effective absorption of glucose . Some authors suggest that HTyr is a better inhibitor of α-amylase than of α-glucosidase . Also oleuropein inhibits these enzymes . Beyond the inhibition of these enzymes, other mechanisms have been proposed for the antidiabetic activity including antioxidant and anti-inflammatory action (see above) and activation of AMP-activated protein kinase and of incretin release [197, 205–207, 341]. In particular, the antidiabetic activity of HTyr and oleuropein is recently reviewed [367, 368]. Again it emerges that the antidiabetic activity has been mainly studied in males; nevertheless, it clearly shows that DM presents numerous sex differences , including the relative risk for CVD associated with hyperglycaemia that is higher in women than in men (Table 1).
5.5. Effects of EVOO, VOO, OO, Leaf Extracts, and MPCs on Uric Acid: Influence of Sex
It is related to CV events both in women and in men [140, 369, 370], but it is a higher risk in women . However, these are not univocal data because others sustain that this association is present only in women [372–374], who have lower plasma levels that men . Leaf extracts of olive tree and HTyr inhibit xanthine oxidase reducing uric acid synthesis . In male rats, HTyr also regulates transcription of some renal transporters that favor uric acid excretion .
6. Clinical Studies
Results of clinical studies are summarized in Table 3. The beneficial aspects of regular use of OO on CVD has been suggested by numerous authors [2, 154, 306, 310, 378–380], through the biological activities discussed above and summarized in Table 2. However, clinical studies have common limitations: (a) despite the numerosity of studies, the size of samples is very small and they do not take into account the high interindividual variability; (b) they are relatively limited or of questionable quality; (c) with some exceptions they are very short in duration; (d) they are mainly performed on Mediterranean populations; (e) they have heterogeneous designs, with variation in control diets and in the type of oil used. Therefore, to overcome these limitations we focus on meta-analyses.
Schwingshackl and Hoffmann  reported that the use of OO is associated with a 20–40% lower risk of stroke and CHD. Another meta-analysis of case-control, prospective cohort studies and randomized controlled trials proves a negative relationship between OO consumption and stroke (and stroke and CHD combined), but the association is not significant for CHD . A successive meta-analysis proves that high EVOO MPCs ameliorate surrogate end points such as lipid peroxidation, oxLDL, Chol, and HDL . In addition, the subgroup analysis indicates an improvement in inflammatory biomarkers and in BP . After pooling oil interventions, PCR and IL-6 are lowered compared to baseline . Others show that the regular dietary intake of OO reduces CRP, IL-6, and TNF-α . The comparison of the effect of different types of OO (refined, mixed, low, and high MPC EVOO) shows no significant effects on Chol, HDL, TG, or DBP . However, in secondary analyses, EVOO may reduce oxLDL vs refined OO in a dose-dependent manner. Finally, one meta-analysis that includes 1089 participants shows that OO increases HDL reducing LDL and TG, while ApoA1 and ApoB are not significantly changed .
Another crucial risk factor for CVD is hypertension , a condition that presents numerous sex differences . After 4 years of follow-up, results of interventional and randomized PREDIMED study show no significant variations in systolic blood pressure (SBP), whereas DBP is decreased in EVOO and EVOO + nuts MedDiet . The 1-year trial that examines 235 subjects (56.5% women) proves that MedDiet supplemented with either EVOO or mixed nuts reduces SBP and DBP . A meta-analysis, which includes primary and secondary prevention trials proves that high MPC OO slightly reduces SBP and oxLDL compared to low MPC OO, leaving Chol, TG, MDA, and DBP unchanged . A very small decrease in blood pressure is observed in MedDiet + EVOO or nut vs a low-fat control group . Finally, the meta-analysis of RTC of PREDIMED shows that the MedDiet lowers SBP by 3.02 mm Hg and DBP by 1.99 mm Hg . Importantly, a systemic review that includes primary prevention proves the importance of pharmaceutical form because only liquid oil but not capsule with oil significantly reduces DBP .
OO impacts on glucose metabolism, two meta-analyses, which include cohort and interventional studies in prevention and care of DM2 [380, 393], prove that there is a 16% risk reduction in people that consume more OO with high amount of MPCs vs those who consume OO with small amounts of MPCs. In patients with DM2, OO supplementation reduces HbA1c, fasting plasma glucose and inflammatory biomarkers, compared to controls . In addition, MedDiet and MedDiet + EVOO + nuts reduce metabolic syndrome and insulin resistance in the postpartum [394, 395].
Indeed, a systemic review and meta-analysis, which includes RC trials that examine lipid profile, inflammation, and oxidative stress biomarkers in individuals that consume low MPC OO and high MPC OO, observed the improvement in MDA, oxLDL, Chol, and HDL. The subgroup analyses and individual studies measure additional improvements in inflammatory markers and blood pressure. Nevertheless, the authors conclude that there is a need for longer-term studies in non-Mediterranean populations because most studies were rated as having low-to-moderate risk of bias . A recent meta-analysis, including RC trials for more than 3 weeks and examining at least two of the following OO: refined OO, mixed OO, low MPC EVOO, and high MPC EVOO, suggests that it is not possible to reach any clear conclusion for the beneficial effects . Moreover, in line with what was observed with prescription drugs , a gender gap exists because the majority of clinical studies are performed mainly on males, and if they include females, results are not stratified for sex. This leads to low scientific value of the results in consideration of the numerous sex differences observed in CVD, DM, and hypertension (Table 1).
To have a clear conclusion, it is important to harmonize study design. For example, it will be important to declare whether the goal is the use of OO as a supplement or as a part of dietary pattern. If it is given as a supplement, it is important to consider the pharmaceutical form (liquid, capsule, and excipients) because this could modify both the pharmacokinetics and pharmacodynamics. Furthermore, considering the prevention and therapy of noncommunicable diseases such as CVD and DM, there is a need for long-term studies that consider also a sufficient number of extra-Mediterranean people and low-risk populations (most of the trials are conducted on high-risk populations and this could result in underestimation of possible benefits on low-risk populations ).
Considering the great sex differences observed in CVD (Table 1) and in DM [32, 39, 397] and the possible sex-divergent effects of MPCs [25, 26, 398, 399], it is necessary to enroll males and females in studies, to overcome the sex and gender gap that pervades all the research in the field of the OO, VOO, EVOO, leaf extracts, and MPCs. In the era of personalized medicine, it is mandatory to consider the sex and gender aspects to answer a multiplicity of questions regarding the effects of diet and specific diet components on health and to relieve consumer uncertainty and promote health, comprehensive cross-demographic studies using the latest technologies, which include foodomics, integrated omics approaches, personomics, and appropriate study design.
|ACE:||Angiotensin converting enzyme|
|PI3 kinase:||Phosphatidylinositol 3-kinase/Akt|
|ADAMTS:||A disintegrin and metalloproteinase with thrombospondin motifs (aggrecanase)|
|AMPK:||AMP-activated protein kinase|
|CRP:||C reactive protein|
|ERK:||Extracellular regulated mitogen-activated protein kinase|
|EDHF:||Endothelium-derived hyperpolarization factor|
|EFSA:||The European Food Safety Authority|
|eNOS:||Endothelial nitric oxide synthase|
|EGFR:||Epidermal growth factor receptor|
|ERK, PI3K/Akt/FOXO3a:||Phosphoinositide 3-kinase/Akt/Forkhead box O3|
|FAS:||Fatty acid synthase|
|FPPS:||Farnesyl diphosphate synthase|
|GIP:||Glucose-dependent insulinotropic polypeptide|
|GPx-1:||Glutathione peroxidase 1|
|HEL60:||Promyelocytic leukemia cells|
|HMEC-1:||Human microvascular endothelial cell line|
|ICAM:||Intercellular adhesion molecule-1|
|iNOS:||Inducible nitric oxide synthase|
|JNK:||c-Jun N-terminal kinase|
|IRF-1:||Interferon regulatory factor-1|
|MIF:||Macrophage migration inhibitory factor|
|MAPK:||Mitogen-activated protein kinases|
|MCP-1:||Monocyte chemoattractant protein|
|MIP-1α:||Macrophage inflammatory protein-1α|
|MPC:||Minor polar compound|
|EGFR:||Epidermal growth factor receptor|
|NADPH oxidase:||Nicotinamide adenine dinucleotide phosphate oxidase|
|NF-κB:||Nuclear factor-kappa B|
|Nrf2:||Nuclear factor E2-related factor 2|
|oxLDL:||Oxidized low-density lipoprotein|
|PAI-I:||Plasminogen activator inhibitor-1|
|PMA:||Phorbol myristate acetate|
|PPAR:||Peroxisome proliferator activated receptor|
|PPARγ coactivator-1α:||Peroxisome proliferator activated receptor coactivator γ-1α|
|ROS:||Reactive oxygen species|
|mTOR:||Mammalian target of rapamycin|
|TRPA1:||Transient receptor potential cation channel subtype A1|
|SREBP-1c:||Sterol regulatory element binding protein 1c|
|VCAM-1:||Vascular cell adhesion molecule-1|
|VEGF:||Vascular endothelial growth factor|
|VSMC:||Vascular smooth muscle cells|
|Akt:||Protein kinase B|
|CD:||Cluster of differentiation|
|EGFR:||Epidermal growth factor receptor|
|FMO3:||Flavin containing monooxygenase 3|
Conflicts of Interest
The authors confirm that there are no conflicts of interest.
This work was supported by EXTRANUTRAOILS, MIPAF Project, 2019, and BIOSINOILS Project, PEI-AGRI, GO2017, Tuscany Region, Italy.
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