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Health Effects of Phenolic Compounds Found in Extra-Virgin Olive Oil, By-Products, and Leaf of Olea europaea L

Abstract and Figures

Olea europaea L. fruit is a peculiar vegetal matrix containing high levels of fatty acids (98–99% of the total weight of extra-virgin olive oil, EVOO) and low quantities (1–2%) of phenolics, phytosterols, tocopherols, and squalene. Among these minor components, phenolics are relevant molecules for human health. This review is focused on their beneficial activity, in particular of hydroxytyrosol (HT), oleuropein (OLE), oleocanthal (OLC), and lignans found in EVOO, olive oil by-products and leaves. Specifically, the cardioprotective properties of the Mediterranean diet (MD) related to olive oil consumption, and the biological activities of polyphenols recovered from olive oil by-products and leaves were described. Recent European projects such as EPIC (European Prospective Investigation into Cancer and Nutrition) and EPICOR (long-term follow-up of antithrombotic management patterns in acute coronary syndrome patients) have demonstrated the functional and preventive activities of EVOO showing the relation both between cancer and nutrition and between consumption of EVOO, vegetables, and fruit and the incidence of coronary heart disease. The data reported in this review demonstrate that EVOO, one of the pillars of the MD, is the main product of Olea europaea L. fruits; leaves and by-products are secondary but precious products from which bioactive compounds can be recovered by green technologies and reused for food, agronomic, nutraceutical, and biomedical applications according to the circular economy strategy.
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nutrients
Article
Health Eects of Phenolic Compounds Found in
Extra-Virgin Olive Oil, By-Products, and Leaf of
Olea europaea L.
Annalisa Romani 1, *, Francesca Ieri 1, Silvia Urciuoli 1, Annalisa Noce 2, * , Giulia Marrone 2,3 ,
Chiara Nediani 4and Roberta Bernini 5
1
PHYTOLAB (Pharmaceutical, Cosmetic, Food Supplement, Technology and Analysis)-DiSIA, University of
Florence, Via U. Schi, 6, 50019 Sesto Fiorentino, Italy
2
UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine,
University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
3PhD School of Applied Medical, Surgical Sciences, University of Rome Tor Vergata, via Montpellier 1,
00133 Rome, Italy
4Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence,
Viale Morgagni 50, 50134 Florence, Italy
5Department of Agriculture and Forest Sciences (DAFNE), University of Tuscia, Via San Camillo de Lellis,
01100 Viterbo, Italy
*Correspondence: annalisa.romani@unifi.it (A.R.); annalisa.noce@uniroma2.it (A.N.);
Tel.: +39-055-457377 (A.R.); +39-06-20902188 (A.N.); Fax: +39-055-2751525 (A.R.); +39-06-20902096 (A.N.)
Received: 14 July 2019; Accepted: 28 July 2019; Published: 1 August 2019


Abstract:
Olea europaea L. fruit is a peculiar vegetal matrix containing high levels of fatty acids (98–99%
of the total weight of extra-virgin olive oil, EVOO) and low quantities (1–2%) of phenolics, phytosterols,
tocopherols, and squalene. Among these minor components, phenolics are relevant molecules for
human health. This review is focused on their beneficial activity, in particular of hydroxytyrosol
(HT), oleuropein (OLE), oleocanthal (OLC), and lignans found in EVOO, olive oil by-products and
leaves. Specifically, the cardioprotective properties of the Mediterranean diet (MD) related to olive oil
consumption, and the biological activities of polyphenols recovered from olive oil by-products and
leaves were described. Recent European projects such as EPIC (European Prospective Investigation
into Cancer and Nutrition) and EPICOR (long-term follow-up of antithrombotic management patterns
in acute coronary syndrome patients) have demonstrated the functional and preventive activities of
EVOO showing the relation both between cancer and nutrition and between consumption of EVOO,
vegetables, and fruit and the incidence of coronary heart disease. The data reported in this review
demonstrate that EVOO, one of the pillars of the MD, is the main product of Olea europaea L. fruits;
leaves and by-products are secondary but precious products from which bioactive compounds can
be recovered by green technologies and reused for food, agronomic, nutraceutical, and biomedical
applications according to the circular economy strategy.
Keywords:
Olea europaea L.; extra-virgin olive oil; olive oil by-products; olives leaf; phenolic
compounds; hydroxytyrosol; oleuropein; oleocanthal; lignans; health eects; circular economy
1. Introduction
Olea europaea L. is a fruit tree native to Asia Minor and Syria, which today is cultivated in the entire
Mediterranean area; nowadays, the major producers of olives and olive oil are Spain, Italy, and Greece.
Extra-virgin olive oil (EVOO), extracted physically from the fruit, is known for its nutritional properties
and health eects, especially against cardiovascular diseases (CVDs). These properties are due
Nutrients 2019,11, 1776; doi:10.3390/nu11081776 www.mdpi.com/journal/nutrients
Nutrients 2019,11, 1776 2 of 33
to the presence of high levels of fatty acids (98–99% of the total weight of EVOO), in particular
of monounsaturated acids such as oleic, as well as of other valuable components like phenolics,
phytosterols, tocopherols, and squalene even if present in low percentages (1–2%). Only EVOO,
and not all seed oils, has a high percentage of fatty acids with a correct balance of unsaturated fatty
acids stabilized by minor polar compounds, with an antioxidant character [1].
All components of EVOO may potentially contribute to “health maintenance” [
2
].
Several international organisms regulate the quality and purity of EVOO, namely the European
Union (EU), the International Olive Council (IOC), and the Codex Alimentarius according to data
compiled by the Unaprol Economic Observatory [3].
Tree cultivars, their growing conditions, and the techniques used for EVOO production, are key
factors for the quality of EVOO, aecting both its qualitative and quantitative characteristics, which
can influence the sensorial and health properties of the oil. Advanced analytical techniques, such as
high-performance liquid chromatography coupled to a diode array or a mass detector (HPLC-DAD,
HPLC-MS), have played an important role in identifying and quantifying the bioactive compounds
found in EVOO, which are responsible for its beneficial eects.
Among the minor components, the phenolic ones are relevant for the health eects attributed
to EVOO (Table 1) [
1
]. In particular, epidemiological studies indicate that dietary consumption
of phenol enriched EVOO has a cardioprotective eect in Mediterranean populations. The minor
polar compounds include dierent subclasses among these: secoiridoids that are the dialdehydic
form of decarboxymethyl elenolic acid linked to ortho-diphenolic and/or phenolic alcohols, such
as OLE aglycone and oleacein, deacetoxyoleuropein, oleocanthal (OLC) (tyrosol linked to elenolic
acid), and traces of ligstroside aglycon (tyrosol linked to elenolic acid). Another class is represented
by phenolic alcohols, with hydroxytyrosol (HT), and tyrosol (TYR), together with their secoiridoid
precursors and traces of phenolic acids such as gallic acid, protocatechic acid, p-hydroxybenzoic
acid, vanillic acid, caeic acid, syringic acid, p- and o-coumaric acid, ferulic acid, and cinnamic acid.
The flavonoids class is represented in traces; luteolin and apigenin are the flavones found in greater
amounts. The last class is composed of lignans, and the most representative compounds in EVOO
are acetoxypinoresinol and pinoresinol [
3
]. Among the minor polar compounds, HT and OLE are
widely studied; in addition to the recently investigated OLC, they have been studied for their specific
anti-inflammatory properties. In detail, HT and OLE (Figure 1) are valuable compounds for their high
antioxidant capacity and for metal-chelating and free radical scavenging activities. HT is a molecule
containing an ortho-diphenolic group that plays a significant role in EVOO. Its high antioxidant activity
is due to its ability to scavenge reactive oxygen species (ROS) and stabilize oxygen radicals with an
intramolecular hydrogen bond [
4
]. The above described lignans, pinoresinol and acetoxypinoresinol,
also show antioxidant capacity [5].
Interestingly, during fruit maturation and olive oil production, the enzymatic systems present in
the fruit are able to hydrolyze OLE first into its aglycone form, and then into HT together with glucose
and elenolic acid, as depicted in Figure 2[
6
]. Due to its hydrophilic character, HT is abundant in olive
oil by-products and in particular in olive oil wastewaters, thus representing a precious source from
which to extract this valuable compound [7].
This review is focused on the description of the beneficial eects of the main polyphenols found in
EVOO, olive oil by-products and olive leaf, analyzing the beneficial properties of HT and OLE in detail.
The extraction procedures used to retrieve polyphenols from olive waste, leaf, and the fruit have
recently been improved, and traditional systems have been optimized by newer technologies such
as membrane separation techniques developed to fractionate olive mill wastewaters. The benefits
achieved with the newer methods include lower energy consumption and no necessary additives or
phase change [4,8].
Nutrients 2019,11, 1776 3 of 33
Table 1. Subclasses of EVOO minor polar components
EVOO Minor Polar Components
Secoiridoids
(a) Oleuropein aglycone
(b) Deacetoxy oleuropein
(c) Oleocanthal and oleacin
(d) Ligstroside aglycone
Phenolics
(a) Hydroxytyrosol
(b) Tyrosol
(c) Hydroxytyrosol glycole
Phenolic acids
(a) Gallic acid
(b) Protocatechuic acid
(c) p-Hydroxybenzoic acid
(d) Vanillic acid
(e) Caeic acid
(f) Syringic acid
(g) p- and o-coumaric acid
(h) Ferulic acid
(i) Cinnamic acid
Flavonoids (a) Luteolin
(b) Apigenin
Lignans (a) (+) Pinoresinol
(b) (+) Acetoxypinoresinol
Nutrients 2019, 11, x FOR PEER REVIEW 3 of 32
Figure 1. Chemical structure of the main phenolic compounds found in Olea europaea L.
Interestingly, during fruit maturation and olive oil production, the enzymatic systems present
in the fruit are able to hydrolyze OLE first into its aglycone form, and then into HT together with
glucose and elenolic acid, as depicted in Figure 2 [6]. Due to its hydrophilic character, HT is abundant
in olive oil by-products and in particular in olive oil wastewaters, thus representing a precious source
from which to extract this valuable compound [7].
This review is focused on the description of the beneficial effects of the main polyphenols found
in EVOO, olive oil by-products and olive leaf, analyzing the beneficial properties of HT and OLE in
detail.
The extraction procedures used to retrieve polyphenols from olive waste, leaf, and the fruit have
recently been improved, and traditional systems have been optimized by newer technologies such as
membrane separation techniques developed to fractionate olive mill wastewaters. The benefits
achieved with the newer methods include lower energy consumption and no necessary additives or
phase change [4,8].
This paper envisages the characterization and use of EVOO as a natural functional food, and the
characterization and use of active extracts/ingredients obtained from olive leaf, pitted and de-oiled
olive paste and juices, and from
secondary matrixes (olive biphasic pomace and leaf), through sustainable green technologies.
Fractions enriched in EVOO’s minor polar compounds, in OLE from leaf and in HT from de-oiled
and pitted olive paste and the lipophilic derivatives, will be characterized and described from the
chemical point of view, as quali-quantitative content in bioactive components and for their biological
and nutraceutical activities (Figure 3).
Figure 1. Chemical structure of the main phenolic compounds found in Olea europaea L.
Nutrients 2019,11, 1776 4 of 33
Nutrients 2019, 11, x FOR PEER REVIEW 4 of 32
HO
Hydroxytyrosol
HO
Glucose
+
Elenolic acid
Oleuropein aglycone
OH
HO
Oleuropein
HO
O
O
O
O
OCH3
O
O
HO
OH
OH
OH
HO
HO
O
O
O
O
OCH3
HO
O
O
OCH3
O
O
OH
Figure 2. Enzimatic conversion of oleuropein into hydroxytyrosol.
Figure 3. Circular economy platform based on green technologies, for the recovery of active molecules
from olive leaf and processing by-products, useful in the food, nutraceutical, cosmetic, and
biomedical fields.
Figure 2. Enzimatic conversion of oleuropein into hydroxytyrosol.
This paper envisages the characterization and use of EVOO as a natural functional food, and the
characterization and use of active extracts/ingredients obtained from olive leaf, pitted and de-oiled olive
paste and juices, and from secondary matrixes (olive biphasic pomace and leaf), through sustainable
green technologies. Fractions enriched in EVOO’s minor polar compounds, in OLE from leaf and
in HT from de-oiled and pitted olive paste and the lipophilic derivatives, will be characterized and
described from the chemical point of view, as quali-quantitative content in bioactive components and
for their biological and nutraceutical activities (Figure 3).
The technical, economic, and environmental evaluation of the Olea europaea L. platform requires a
material and energy flow analysis of the production cycle. The methodology used is the Membrane
Filtration Absorption (MFA), which can evaluate the energy and material flows in a well identified
system [
9
,
10
] that is the production process of the polyphenols from Olea europaea L., accounting for the
inputs (consumption of material and energy resources consumption) and the outputs (waste products)
of the process.
Data and methods concern the extraction of polyphenols from olive oil by-products based on
new sustainable technologies with a water extraction and membrane separation system. Previously,
scientific reports considered the same procedure for olive-oil waste-water polyphenol purification
at a laboratory scale [
11
,
12
]. This innovative industrial process has instead been implemented at
an industrial level by using physical technologies defined as BAT (Best Available Technology) and
recognized by the EPA (Environmental Protection Agency) [13,14].
In the production process, the yield in quality EVOO, stands near 10–14%. Generally, the recovery
process is based on membrane technologies applied to aqueous extracts obtained in a pneumatic
extractor and then purified by filtration. The first phase of olive-oil production, from olives to oil and
wet pomace, has only been considered in the material data (as Figure 2shows) and it emerges that
from the processed olives, by the use of a two-phases system, the wet-pomace can be extracted at
the rate of 80% [
15
]. The remaining share represents the EVOO and olive oil (near 20%). Regarding
the process, from wet olive pomace to the main output, the yield is very low and approximately
4.4%. The Olea by-products recovery process includes demineralized/pure water production and
a final reverse osmosis (RO) phase. The chemical recovery and the production of energy should
be a continuous process of interaction between green technology and environmental and economic
sustainability, making this integrated platform highly innovative and consistent with the principles of
Nutrients 2019,11, 1776 5 of 33
the circular economy, with the development of new business activities. The results have highlighted
that this platform can produce up to 6000 kg of standardized polyphenol fractions, useful in food
and nutraceutical application; moreover, each residue of the process (water, olive cores, destoned
pulp) comes into an innovative use in the same and/or other processes according to the circular
economy models. The conclusion underlines the main positive features of this sustainable model,
the eco-innovation of the process and the economic and environmental advantages consisting in
reducing waste, water, and energy consumption. Operating plants that produce standardized natural
fractions in HT and OLE contents, are in Spain and Italy and commercial fractions, in sharp increase
in consumption are, for example, Phenolea Active, and OleaFit
standardized in various bio-active
compounds content.
Nutrients 2019, 11, x FOR PEER REVIEW 4 of 32
HO
Hydroxytyrosol
HO
Glucose
+
Elenolic acid
Oleuropein aglycone
OH
HO
Oleuropein
HO
O
O
O
O
OCH3
O
O
HO
OH
OH
OH
HO
HO
O
O
O
O
OCH3
HO
O
O
OCH3
O
O
OH
Figure 2. Enzimatic conversion of oleuropein into hydroxytyrosol.
Figure 3. Circular economy platform based on green technologies, for the recovery of active molecules
from olive leaf and processing by-products, useful in the food, nutraceutical, cosmetic, and
biomedical fields.
Figure 3.
Circular economy platform based on green technologies, for the recovery of active
molecules from olive leaf and processing by-products, useful in the food, nutraceutical, cosmetic,
and biomedical fields.
2. Methods
Current literature analyzing the beneficial eects of the minor polar compounds of EVOO has
been contextualized in this review. Specifically, the search was conducted using digital libraries such
as Medline (Pubmed) and Scopus. The search examined studies published until May 2019, utilizing
the words: Olea europaea L. minor polar compounds of extra-virgin olive oil, HT, OLE, OLC, lignans,
biological activities of extra-virgin olive oil, and Olea by-products. Specific research related to the topic
of this review carried out by all authors was also described.
3. Health Eects of Phenolic Compounds Found in Extra-Virgin Olive Oil (EVOO)
The cardioprotective properties of the Mediterranean diet (MD), related mostly to the beneficial
eects of EVOO, were demonstrated for the first time in the Seven Country Study of Cardiovascular
Disease (SCSCD) [
16
]. The MD consists of a balanced consumption of fruit, vegetables, legumes,
and cereals, associated with a large assumption of bluefish and EVOO (the last as the main source of
fats), reduced consumption of red meat and dairy products, and moderate intake of alcohol, mainly
Nutrients 2019,11, 1776 6 of 33
red wine. The MD has an important eect on maintaining health and increasing longevity, as cited by
the United Nations Educational Scientific and Cultural Organization (UNESCO) in 2010 [17,18].
In the last few decades, numerous epidemiological studies [
19
] and meta-analyses [
20
], as well as
intervention trials [
21
23
], confirmed this observation, pointing out the protective role of the MD on
primary [24] and secondary [25] prevention of CVDs (Figure 4).
Nutrients 2019, 11, x FOR PEER REVIEW 6 of 32
increase in consumption are, for example, Phenolea Active, and OleaFit™ standardized in various
bio-active compounds content.
2. Methods
Current literature analyzing the beneficial effects of the minor polar compounds of EVOO has
been contextualized in this review. Specifically, the search was conducted using digital libraries such
as Medline (Pubmed) and Scopus. The search examined studies published until May 2019, utilizing the
words: Olea europaea L. minor polar compounds of extra-virgin olive oil, HT, OLE, OLC, lignans,
biological activities of extra-virgin olive oil, and Olea by-products. Specific research related to the
topic of this review carried out by all authors was also described.
3. Health Effects of Phenolic Compounds Found in Extra-Virgin Olive Oil (EVOO)
The cardioprotective properties of the Mediterranean diet (MD), related mostly to the beneficial
effects of EVOO, were demonstrated for the first time in the Seven Country Study of Cardiovascular
Disease (SCSCD) [16]. The MD consists of a balanced consumption of fruit, vegetables, legumes, and
cereals, associated with a large assumption of bluefish and EVOO (the last as the main source of fats),
reduced consumption of red meat and dairy products, and moderate intake of alcohol, mainly red
wine. The MD has an important effect on maintaining health and increasing longevity, as cited by the
United Nations Educational Scientific and Cultural Organization (UNESCO) in 2010 [17,18].
In the last few decades, numerous epidemiological studies [19] and meta-analyses [20], as well
as intervention trials [21–23], confirmed this observation, pointing out the protective role of the MD
on primary [24] and secondary [25] prevention of CVDs (Figure 4).
Figure 4. EVOO and its cardioprotective action on the CV system. EVOO, Extra-virgin olive oil; HT,
hydroxytyrosol; OxLDL, oxidized LDL; OS, oxidative stress.
The PREDIMED study investigated, on 7477 subjects at high risk of CVDs, the protective effect
of the MD supplemented with EVOO or nuts on major cardiovascular (CV) events (such as stroke,
myocardial infarction, or death from CV causes). The authors highlighted that the incidence of major
CV events was significantly decreased in subjects following the MD supplemented with EVOO or
nuts compared to those following a reduced-fat diet, confirming the beneficial effects of the MD for
primary CV prevention [24].
Figure 4.
EVOO and its cardioprotective action on the CV system. EVOO, Extra-virgin olive oil; HT,
hydroxytyrosol; OxLDL, oxidized LDL; OS, oxidative stress.
The PREDIMED study investigated, on 7477 subjects at high risk of CVDs, the protective eect
of the MD supplemented with EVOO or nuts on major cardiovascular (CV) events (such as stroke,
myocardial infarction, or death from CV causes). The authors highlighted that the incidence of major
CV events was significantly decreased in subjects following the MD supplemented with EVOO or nuts
compared to those following a reduced-fat diet, confirming the beneficial eects of the MD for primary
CV prevention [24].
A prospective randomized trial [
25
] compared a MD enriched with alpha-linoleic acid to a
prudent diet, in regards to their respective eects on secondary prevention after myocardial infarction,
concluding that the alpha-linoleic acid-enriched MD was more eective in secondary prevention of
acute coronary events and death, since it has been hypothesized that linoleic acid reduces the incidence
of fatal arrhythmias [26].
In our study, we observed for the first time the health eects of the Italian Mediterranean diet
(IMD) and the Italian Mediterranean organic diet (IMOD) in healthy subjects and in stage II–III chronic
kidney disease (CKD) patients, staged according to the Kidney-Disease Outcomes Quality Initiative
(K-DOQI) guidelines [
27
]. Specifically, we demonstrated a significant reduction of phosphorus, total
homocysteine (Hcy), and albuminuria, as well as an improvement of body composition (a significant
increase in lean mass percentage and a decrease in fat mass both in kg and in percentage) after two
weeks of IMOD treatment. The improvement of all these clinical parameters is associated with lower
CV risk, highlighting the role of the IMOD in the prevention of CVDs [
22
]. The IMOD would seem to
induce a slowing down of CKD progression.
In our study, we subsequently confirmed that the IMOD in CKD patients on conservative therapy
represents a useful tool for the prevention of CVDs, inducing a significant reduction of serum Hcy
influenced by the methylenetetrahydrofolate reductase (MTHFR) genotype [
23
]. Hcy causes endothelial
Nutrients 2019,11, 1776 7 of 33
dysfunction through production of ROS, which occurs during the autoxidation process, accelerating
atherosclerosis [28,29].
In 2011, the European Food Safety Authority approved some claims reported by the Commission
Regulation no. 432/2012 concerning the benefits of bioactive compounds found in foods including
EVOO phenols and, in particular, of HT and OLE, supporting their relevant role for human health [
30
].
The health eects are protection of LDL from oxidative damage, maintenance of normal blood HDL
cholesterol concentrations, maintenance of normal blood pressure, anti-inflammatory properties,
contribution to upper respiratory tract health, maintenance of normal gastrointestinal tract function,
and contribution to body defenses against external agents. These beneficial eects are obtained with a
daily intake of 20 g of EVOO, containing 5 mg of HT and its derivatives [
31
]. Indeed, the oxidized LDLs
(OxLDLs) binding with the receptor LOX-1 (receptor OxLDL-lectin-similar to receptor-1), stimulate
endothelial expression and secretion of pro-atherogenic enzymes. This bond induces the production of
superoxide and the reduction in local nitric oxide (NO) concentration. LOX-1, which causes a rapid rise
in ROS levels through membrane-bound NADPH oxidase (NOX), is a specific endothelial scavenger
receptor involved in the initial process of atherosclerotic plaque formation [32].
EVOO extracts were tested
in vitro
on human endothelial cells (HUVEC) to evaluate their
antioxidant capacity [
33
] and their ability to modulate the cellular expression of ICAM-1 and VCAM-1
in a pro-inflammatory environment, in order to investigate their anti-atherogenic eects [
34
]. In order
to better understand the dierences among the
in vitro
and
in vivo
eects of EVOO, it will be necessary
to compare various monocultivar in phenolic content.
Despite the biological activities of dietary phenolics, only a few studies have been carried out to
investigate their absorption in humans after ingestion. A specific study on olive oil phenolics was
performed by Visioli et al. [
35
], demonstrating that they were absorbed in humans and excreted in the
urine as glucuronide.
As far as the biological activities of olive oil are concerned, a review by Covas et al. [
36
] examined 15
human studies and the majority indicate that olive oil (rich in phenols) is superior to seed oils and olive
oil with low-phenol content. This superiority was attributed to the reduction of CV risk factors, such
as reduced plasma LDL, improved endothelial function and a decreased prothrombotic environment.
Polyphenolic metabolites of EVOO after ingestion were methylated, sulfonated, or glucorinated;
in vitro
studies [
37
,
38
] have shown that these metabolic modifications do not inhibit their biological
activities in humans. Moreover, the parent compounds and the metabolites derived from EVOO are
capable of reaching a concentration at tissue level (mainly in the gastrointestinal and CV systems) able
to exert antioxidant and anti-inflammatory actions, by modulating intracellular signaling [39].
Pharmacological studies concerning the activities of phenolic compounds are increasing, since
they seem to have potential cardioprotective and chemopreventive actions.
HT and OLE are able to inhibit copper-induced LDL oxidation at low concentrations and show
a powerful ability to chelate metals and scavenge free radicals [
26
,
27
]. In particular, a specific
study carried out by Franconi et al. [
40
] demonstrated that the concentration capable of reducing
copper-induced LDL is similar to that measured in human plasma after EVOO intake [40,41].
A study on 10 healthy postmenopausal women compared the eects of high-phenol EVOO (592
mg total phenols/kg) with a low-phenol EVOO (147 mg total phenols/kg). Daily dose of EVOO was 50
g per day for a period of 8 weeks. Oxidative DNA damage was evaluated by monitoring peripheral
blood lymphocytes. Subjects who took high-phenol EVOO had oxidative DNA damage reduced by
30% compared to subjects treated with low-phenol EVOO. This study demonstrated a protective role
of EVOO phenols on oxidative damage in healthy postmenopausal women. Moreover, subjects who
consumed high-phenol EVOO had a significantly increased urinary excretion of HT compared to
low-phenol EVOO [42].
These data were confirmed in a randomized trial in 200 healthy male subjects that evaluated the
eects of olive oil phenol content on lipid oxidative damage and plasma lipid levels. The enrolled
subjects were randomized into three groups based on the content of phenols in olive oil and took 25 mL
Nutrients 2019,11, 1776 8 of 33
of oil per day for a total of 3 weeks. The three types of olive oil were the following: low-phenol olive
oil (2.7 mg/kg of olive oil), medium-phenol olive oil (164 mg/kg of olive oil), and high-phenol olive oil
(666 mg/kg of olive oil). The authors highlighted that the biomarkers of oxidative stress were reduced
proportionally to the phenol content, while the HDL-cholesterol levels increased directly to the phenol
content of the olive oil. Triglycerides were reduced in all the three groups examined. Therefore, this
study confirmed that phenolic content improves lipid oxidative damage and lipid profile [
43
]. Several
studies showed that a constant consumption of EVOO is associated with a reduction in the molecules
involved in inflammatory processes related to atherosclerosis, by the downregulation of NF-kB [
44
,
45
].
The close correlation between inflammation, endothelial dysfunction, and CVDs is well
known [
46
,
47
]. In the study conducted by Brunelleschi et al. [
48
], phenolic-rich EVOO inhibits,
in a concentration-dependent manner, the nuclear translocation of the p50 and p65 subunits of the
NF-
κ
B complex within monocytes and monocyte-derived macrophages (MDM) of healthy subjects.
This inhibitory eect was especially evident when the cells were stimulated by phorbol-myristate
acetate (PMA) and obtained at EVOO extract concentrations similar to those measured in human
plasma after a daily ingestion of EVOO. This inhibitory action is comparable to the eect exerted by
ciglitazone, a PPAR-γligand.
Moreover, OLE, the most abundant polyphenol in EVOO, has shown to significantly increase
lipopolysaccharide (LPS)-induced NO production, a bactericidal and cytostatic agent whose heightened
expression increases macrophages’ functional activity [49].
Western blot analysis of cell homogenates, and coincubation of bacterial LPS challenged cells with
L-nitromethylarginine methylester (a nitric oxide synthase, iNOS inhibitor), showed how OLE directly
stimulates the inducible form of the iNOS enzyme, leading to the above-mentioned enhancement of
macrophage function [49].
The incidence of chronic illnesses related to aging and unhealthy lifestyles is on the rise, but
increasing data are showing how the intake of secoiridoid-rich EVOO may help to prevent or even
treat chronic non-communicable diseases (NCDs), in which the inflammatory component is directly
involved in their onset and progression [50,51].
Another secoiridoid of considerable interest is OLC because recent studies have highlighted its
pharmacological properties and its mechanisms of action, showing the preventive eect on inflammation,
oxidative stress, specific types of cancer, neurodegenerative and rheumatic diseases. OLC is one of
the components of EVOO and it is responsible for the pungent character of this food. This perception
seems to be due to the presence of a specific OLC receptor present in the oropharyngeal region [
52
].
This receptor seems to be the transient receptor potential channel, subfamily A, member 1 (TRPA1) [
53
].
It is hypothesized that the dierent sensitivity in the perception of the pungent taste of OLC may be
related to the inter-individual variations in the expression of the TRPA1 receptor in the oropharynx [
53
].
This sensation is similar to that observed after taking ibuprofen (non-steroidal anti-inflammatory
drug), and from this observation, some authors have hypothesized that the two substances could
have the same biological activity [
54
]. Despite the structural dierences, both molecules inhibit the
same cyclooxygenase enzymes involved in the biosynthesis of prostaglandins. In detail, both OLC
enantiomers induce the inhibition of cyclooxygenase (COX) 1 and 2, but
in vitro
have no eect on
lipoxygenase. The inhibition of COX 1 and 2 is dose-dependent: an OLC concentration equal to 25
µ
M
inhibits COX activity by 41% and 57% vs. 25
µ
M of ibuprofen which inhibits COX by 13% to 18%,
respectively [55].
Therefore, the authors have hypothesized that the long-term consumption of OLC may
protect against the onset of certain pathological conditions, due to its biological action similar
to
ibuprofen [56,57]
. The dosage that seems to be active is 9 mg per day, which corresponds to 10% of
the dose of ibuprofen taken by adults to counteract pain. In the literature, it is known that a constant
low dose of aspirin (another COX -inhibitor) induces CV protection [
54
]. Therefore, it is hypothesized
that a long-term OLC consumption may also exert a cardioprotective action.
Nutrients 2019,11, 1776 9 of 33
To date, the OLC-induced cardioprotective action has been little investigated. In fact, a single
study highlights the possible protective eects of OLC in atherosclerotic CV disease [
58
]. This disease is
a chronic inflammatory process that aects the vessel walls and begins with damage to the endothelium.
Endothelial damage mainly involves platelets [
58
,
59
]. Recently, Agrawal K. et al. [
60
] have shown,
in a randomized clinical trial, that the intake of 40 mL per week of EVOO rich in OLC can influence
platelet aggregation responses in healthy male adults, confirming previous data obtained from animal
studies [
61
]. Currently, the analytical methods for the OLC assay are not standardized and, in literature,
not all the studies reporting the content of EVOO minor polar compounds show this data. Therefore,
the value of 9 mg per day is probable but not yet defined. The concentration of OLC is usually low in
fresh EVOO and increases during EVOO storage due to hydrolysis of secoiridoids that enhance HT [
39
].
A study carried out by Carrrasco-Pancorbo et al. [
62
] has demonstrated the antioxidant activity
of pinoresinol and acetoxypinoresinol using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method
and evidenced that the absence of the acetyl group in pinoresinol is relevant for its activity [
5
,
62
].
Further studies demonstrated that pinoresinol also shows
in vitro
anti-inflammatory activity [
63
].
In vitro
studies show that both acetoxypinoresinol and pinoresinol have chemopreventive activity in
breast cancer by decreasing the levels of fatty acids synthase in the HER2 gene that is over-expressed
in breast cancer cells [
64
]. A study conducted in 2008 [
65
] demonstrated the capacity of pinoresinol,
in synergy with other phenolic compounds present in olive oil extracts, in decreasing proliferation and
inducing apoptosis of human colon cancer cells.
A limited number of available randomized controlled trials (RCTs), show EVOO’s action
in secondary prevention of diseases related to atherosclerosis and there are no RCTs aimed at
assessing the minimum daily EVOO intake required in order to have an anti-inflammatory and
cardioprotective action [66].
Evidence indicates that regular consumption of EVOO is associated with a reduced risk of
developing NCDs. In the field of NCDs, disorders like cancer, CKD, arterial hypertension, and metabolic
syndrome deserve a special mention [67].
The European Prospective Investigation into Cancer and Nutrition (EPIC) study has indicated
the possible correlation between cancer and nutrition, examining lifestyle, nutritional status, type of
diet, medical history, anthropometric parameters, and biological samples. This study was conducted
on 521,000 subjects (one of the largest cohort studies in the world) enrolled from 23 centers in 10
western European countries. Following enrollment, the participants were contacted at regular intervals
every 3–5 years (depending on the country or center) to obtain information on various aspects of their
lifestyle, which may have changed over time. To date, the data collected indicates that the MD is the
most eective food model in cancer prevention. There is also evidence that consumption of flavonoids
reduces the risk of gastric cancer [68,69].
The EPIC study Italian cohort, composed of 47.749 volunteers, was evaluated for eating habits
and lifestyle. The authors concluded that the food pattern “Olive oil and Salad” food pattern, mainly
based on the consumption of raw vegetables, EVOO and legumes is associated with lower mortality in
the elderly and a lower risk of developing colorectal cancer. The latter has a lower incidence in regular
yogurt consumers for the probable protective action exerted by probiotics against NCDs [70,71].
These data were confirmed in a cohort of 5,611 Italian elderly subjects (aged
60 years), where
a Cox model showed that a high consumption of olive oil, fresh vegetables, soup, and poultry was
inversely correlated with mortality from all causes. On the other hand, the food pattern “Pasta and
Meat” characterized by a high content of pasta, tomato sauce, red and processed meat, added animal
fats, white bread, and wine was associated with an increase in mortality from all causes. The authors
recommend a high consumption of olive oil, fresh vegetables, and poultry in the geriatric population
due to its eects on health [72].
In the EPICOR (long-term follow-up of antithrombotic management patterns in acute coronary
syndrome patients) study, the authors enrolled 29,689 Italian women from northern, central,
and southern cities, evaluating the possible associations between assumption of EVOO, vegetables
Nutrients 2019,11, 1776 10 of 33
and fruit, and incidents of coronary heart disease (CHD). The mean follow-up period was 7.85 years.
They demonstrated that women who consumed vegetables and olive oil in the highest quartile had a
reduced risk of developing CHD. This study confirms the protective eect for CVDs in primary and
secondary prevention, related to the consumption of vegetables and olive oil [73].
Our project called EXTRANUTRAOILS is evaluating the impact of EVOO with health claims
(natural functional food) in CKD patients, to investigate the eects of high-phenol EVOO on the
progression of CKD and its complications (Table 2).
Impact of Olive Oil and Its Derivatives on Gut Microbiota Composition
One of the most densely populated human ecosystems is the gastrointestinal tract. It boasts the
presence of about 1013 microbial species within it, and is called the “gut microbiota” [74].
The study of the link between human gut microbiota and health status has attracted considerable
interest in the scientific community over the past 15 years. It is essential to understand how dierent
nutrients impact the gut microbiota composition which in turn influences the onset and progression of
chronic non-communicable diseases [
75
]. Currently, the knowledge on the gut microbiota indicates
that it can interact with the host both directly and indirectly. In fact, it is able to release bioactive
molecules that modulate numerous biological responses, involving several systems and functions such
as the immune system and/or energy homeostasis [
76
]. Some nutrients can influence the composition
of gut microbiota; among these, we find olive oil and its derivatives [77].
Pallara G. et al. [
78
] evaluated the polyunsatured fatty acid (FA) profile derived from ruminant
livestock, after the administration of feed supplemented with stoned olive pomace (SOP), which
represents a waste deriving from the processes of conversion from olive or olive oil. They concluded
that feeds supplemented with SOP decreased the production of unsaturated FA in a dose-dependent
manner through the modification of gut microbiota composition. Therefore, functional lipids can be
produced from meat and dairy products through animal feed supplementation.
N. Martinez et al. [
79
] performed an animal study to compare the eects of standard diets
versus high fat diets (enriched with EVOO, refined olive oil or butter) diets, on gut microbiota
composition. In order to evaluate the possible variations on gut microbiota caused by dierent diets,
they sequenced mice fecal 16S rRNA. The group fed with a high fat-diet enriched with refined olive oil,
showed significantly higher levels of total cholesterol compared to the EVOO diet group. Moreover,
the high-fat diet enriched with refined oil group showed a greater presence of Desulfovibrionaceae,
Spiroplasmataceae, and Helicobacteraceae families. The authors showed a direct relation between
the quality of fats in the diet (in this case refined olive oil and EVOO), some laboratory parameters,
and the presence of certain taxa. For this reason, it becomes increasingly clear that the minor polar
compounds present in EVOO are able to positively modulate the gut microbiota.
Nutrients 2019,11, 1776 11 of 33
Table 2. Studies on extra virgin olive oil.
Extra Virgin Olive Oil
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
In vitro cell
models
Manna, C.
[41]
2002
Evaluation of eects of phenolic fraction
extract from EVOO on oxidative damage
in human erythrocytes and Caco-2 cells
Protective eects of EVOO phenolic
fractions
Linear relationship between antioxidant
capacity of EVOO phenolic fraction and
o-phenolic content.
R2=0.999
Beauchamp, G.K.
[54]
2005
Evaluation of eects of oleocanthal as
modulator of inflammation and
analgesia
Oleocanthal caused dose-dependent
inhibition of COX-1 and COX-2 activities.
- N.A.
Carrasco-
Pancorbo, A.
[62]
2005
Electrochemical study on the resistance
of oxidative deterioration of VOO
correlated to the presence of phenolic
compounds
Ability of compounds isolated from
VOO by measuring the radical
scavenging eect on
1,1-diphenyl-2-picrylhydrazyl radical
- N.A.
Vuorela, S.
[63]
2005
Phenolic extracts isolated from bioactive
sources have been studied for their
antioxidant, antimicrobial,
anti-inflammatory, and antimutagenic
properties.
Phenolic extracts from oils, induced a
decrease of proinflammatory mediators
(prostaglandin E2).
All tested extracts were safe. In fact, they
did not stimulate mutagenic nor toxic
action on Caco-2 cells or macrophages.
- N.A.
Dell’Agli, M.
[34]
2006
Evaluation of HT and OleA form EVOO
in HUVEC
Expression of
- ICAM-1 VCAM-1 at concentration
(IC50 <1 micro M)
- -HVA
- -E-selectin cell surface expression
- Downregulation of adhesion
molecules associated with
early atherosclerosis
Franconi, F.
[40]
2006
Whole virgin olive extracts studied to
determine whether they maintain the
antioxidant activity and whether this last
is linked to MPC composition of a single
virgin oil
Evaluation of oils derived from Taggiasca
and Seggianese olive on human LDL
- In both tests, the oil extracts
dose-dependently reduced
malondialdehyde and conjugated
diene generation
-
Seggianese extract was more active
with respect to Taggiasca extract.
Nutrients 2019,11, 1776 12 of 33
Table 2. Cont.
Extra Virgin Olive Oil
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
Brunelleschi, S.
[48]
2007
Evaluation of EVOO extracts rich in
minor polar compounds (MPC-OOE) on
human cells
NF-kB translocation in monocytes and
monocyte-derived macrophages
sampled from healthy subjects
- MPC-OOE extracts inhibits NF-kB
translocation in human monocytes
and MPC does not aect PPAR-
γ
in
human monocytes and MDM
p<0.001
Menendez, J.A.
[64]
2008
Evaluation of EVOO phenolic eects on
the expression of FASN in human breast
cancer epithelial cell lines.
EVOO phenols: lignans, flavonoids,
and secoiridoids suppress FASN protein
expression in HER2 gene amplificated
SKBR3 breast cancer cells
- Extracts from EVOO can induce
anti-cancer eects in breast
cancer cells
Fini, L.
[65]
2008
Evaluation of anti-cancer eects of
EVOO phenolic extracts in cells lines for
two EVOOs.
(1). EVOO (A) pinoresinol as main
phenol
(2). EVOO (B) oleocanthal as main
phenol
EVOO (A) has powerful
chemopreventive actions and
upregulates the ATM-p53 cascade
EVOO (A) inhibits cell proliferation in a
dependent manner. The comparison
between eects of EVOO (A) and (B)
demonstrates significant powerful eects
of EVOO (A) respect to EVOO (B)
p<0.0001
Zambonin, L.
[33]
2012
Evaluation of the antioxidant activity of
phenolic acids in HEL cells Proapoptotic eects in leukemia cells
In HEL cells:
- Induce apoptosis
- Increase caspases 3,8,9 activity
- Increase ratio Bax/Bcl2
- Reduce Akt activation
Nutrients 2019,11, 1776 13 of 33
Table 2. Cont.
Extra Virgin Olive Oil
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
Incani, A.
[38]
2016
Evaluation of two monovarietal EVOO
phenolic extracts (Bosana and Nera) on
Caco-2 cells
Modulation of enterocyte response to
oxidative and inflammatory stimuli after
absorption of EVOO
- Protection of Caco-2 cell
monolayers against TBH and
oxysterols oxidative injury
- ROS production inversely
correlated to decrease of
GSH levels
- Attenuation of TBH-induced
oxidative damage (Bosana type the
most active)
Animal Priora, R.
[61]
2008
Randomized study in 6 groups for
dierent treatments (10 rats x group).
They tested 3 types of oil characterized
by dierent MPC concentration: refined
olive oil with trace MPC (control),
low-MPC EVOO, and high-MPC EVOO
Eect of EVOO in relation to MPC on
platelet aggregation and plasma
concentration of Hcy redox form
- MPC of EVOO inhibits platelet
aggregation and decreases the
concentration of Hcy redox form
Humans
Keys, A.
[16]
1986
Study among 15 dierent cohorts
(n=11.579 healthy males) on mortality
from all causes, follow-up period 15
years
All cause and coronary disease death
during 15-year follow-up was
significantly lower in cohorts with olive
oil as main fat
- N.A.
De Lorgeril, M.
[25]
1994
MD alpha-linolenic acid rich
vs.
prudent diet in secondary prevention of
CHD patients
Secondary prevention of coronary events
and deaths
- Coronary events:
- R.R. 0.27 (95% CI, 0.12–0.59)
-p=0.001
- Death:
- R.R. 0.30 (95% CI, 0.11–0.82)
-p=0.082
Visioli, F.
[35]
2000
Six male volunteers 50 mL of olive oil
samples accompanied by 40 g of bread,
four times
Olive oil phenolics are dose-dependently
absorbed in humans - N.A.
Nutrients 2019,11, 1776 14 of 33
Table 2. Cont.
Extra Virgin Olive Oil
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
Riboli, E.
[68]
2002
Multicenter prospective cohort study on
521.000 subjects investigation on the
relationship between nutrition and
cancer
Evaluation of the possible correlation
between the incidence of cancer and
nutrition
- Data collected indicates that the
MD is the most eective food
model in cancer prevention
Salvini, S.
[42]
2006
Randomized Cross over trial 10
postmenopausal women about the eect
of high-phenol EVOO vs. low-phenol
EVOO on oxidative DNA damage
Two types of olive oil were assumed for 8
weeks (50 g/day) and were tested in
peripheral blood lymphocytes
- Oxidative DNA damage during
assumption of high-phenol EVOO
was 30% lower respect to mean
values observed during low-phenol
EVOO consumption (p=0.02)
Covas, M.I.
[43]
2006
Evaluated, in 200 healthy male
volunteers, the eects of polyphenol
content in olive oil on oxidative lipid
damage and plasma lipid levels
Crossover study, enrolled subjects
assumed randomly 3 types of olive oils
daily administration (25 mL/day).
One type was low-phenols (2.7 mg/kg of
olive oil), medium-phenols (164 mg/kg),
or high-phenols (366 mg/kg) content.
Intervention periods were 3 weeks.
- Values of oxidative stress
biomarkers were inversely related
to phenolic content
Masala, G.
[72]
2007
Evaluation of dietary patterns on overall
mortality in Italian elderly population
(aged >60 years)
“Olive oil and salad” type is inversely
associated with all-cause mortality.
While the pasta and meat pattern have
an increased mortality for all causes.
-
All-cause mortality was reduced by
about 50% in the highest quartile of
the “Olive Oil and Salad” model.
-p=0.008
De Lorenzo, A.
[22]
2010
IMD and IMOD vs.
usual diet in patients with CKD stage
II–III
Eect of diet treatment on laboratory and
body composition parameters
- Reduction of:
- Hcy (p=0.0116)
-p(p<0.001)
- Microalbuminuria (p=0.0086)
- hs-CRP (p<0.05)
- FM (kg), FM (%), (p= <0.001)
Nutrients 2019,11, 1776 15 of 33
Table 2. Cont.
Extra Virgin Olive Oil
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
Bendinelli, B.
[73]
2011
Association between fruit, vegetable,
and olive oil consumption and the
incidence of CHD in Italian women
8-year follow-up in which the possible
relationships between dietary habits,
lifestyle, anthropometric measures,
and the development of CHD major
events were evaluated.
- Reverse association between
consumption of leafy vegetables
and olive oil and risk of
developing CHD.
Leaf vegetables:
H.R. 0.54 (95% CI 0.33–0.90, p=0.03
Olive oil:
H.R. 0.56 (95% CI 0.31–0.99, p=0.04)
Perez-Herrera, A.
[44]
2012
Study randomized crossover of 20 obese
subjects that received four breakfasts
constituted by milk and mun prepared
with one of four dierent oils: virgin
olive oil, sunflower oil, mixture seeds oil
with added dimethylpolyxiloxane, or
natural antioxidants from olive mill
wasterwater alperujo
Evaluations of postprandial
inflammatory status in 20 obese subjects
by the activation of nuclear NF-kB,
the cytoplasmatic concentration of
NF-kB inhibitor, the mRNA levels of
NF-kB subunits and activators,
inflammatory molecules, and LPS levels
- Virgin olive oil and olive mill
wasterwater alperujo reduced
NF-kB activation, increased NF-kB
inhibitor, and decreased LPS
plasma concentration
- Seed oil increases mRNA
expression of NF-kB subunit,
inflammatory molecules, and LPS
Di Daniele, N.
[23]
2014
IMD and IMOD in patients with CKD
stage II–III vs.
low-protein diet
according to MTHFR genotypes
Eect of diet treatment on laboratory and
body composition parameters
- Reduction of Hcy in T
(+) genotypes: -IMD: 3.08 mol/L,
95% CI, 4.94–1.23), p=0.001
-IMOD: 9.18 mol/L, 95% CI,
11.04–7.33), p<0.001
Nutrients 2019,11, 1776 16 of 33
Table 2. Cont.
Extra Virgin Olive Oil
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
Agrawal, K.
[60]
2017
Double-blind, randomized controlled
crossover study on 9 healthy subjects.
They assumed 40 mL/week of tree
dierent phenolic content EVOO.
Evaluation of EVOO assumption on
inhibition of platelet aggregation pre and
2 h post-EVOO intake
- Decline of Pmax is related to
oleocanthal intake (r=0.56
p=0.002)
Estruch, R.
[24]
2018
Mediterranean Diet supplements with
EVOO or nuts vs. reduced-fat diet in
7447 Spanish subjects
Major CV events
- MD+EVOO
- H. R. 0.69 (95% CI, 0.53–0.91)
- MD+NUTS
- H.R. 0.72 (95% CI, 0.54–0.95)
Akt, protein kinase B; ATM, ataxia–telangectasia mutated; Bax, (Bcl-2)-associated X protein; Bcl-2, B-cell lymphoma protein 2; Caco-2, heterogeneous human epithelial colorectal
adenocarcinoma cell lines; CHD, coronary heart disease; CKD, chronic kidney disease; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; CV, cardiovascular; EVOO, extra virgin
olive oil; FASN, inhibitors of fatty acid synthase; FM, fat mass; GSH, glutathione; Hcy, homocysteine; HEL, human erythroleukemia cell lines; HER2, receptor tyrosine-protein kinase
erbB-2; hs-CRP, high sensitivity-C reactive protein; HT, hydroxytyrosol; HUVEC, human umbilical vein endothelial cell lines; HVA, homovanillyl alcohol; ICAM-1, intercellular adhesion
molecule 1; IMD, Italian Mediterranean diet; IMOD, Italian Mediterranean organic diet; LDL, low-density lipoprotein; LPS, lipopolysaccharide; MD, Mediterranean diet; MDM,
monocytes-derived macrophages; MPC-OOE, minor polar compounds olive oil extract; MPC, minor polar compounds; MTHFR, methylene tetrahydrofolate reductase; NF-kB, nuclear
factor kappa-light-chain-enhancer of activated B cells; OleA, oleuropein aglycone; P, phosphorus; Pmax, maximum platelet aggregation; ROS, reactive oxygen species; SKBR3, human
breast cancer cell lines; TBH, tert-butyl hydroperoxide; VCAM-1, vascular cell adhesion molecule 1; VOO, virgin olive oil.
Nutrients 2019,11, 1776 17 of 33
Prieto et al. [
80
] investigated, in Swiss Webster mice, the eects (on hormonal, physiological,
and metabolic parameters) of a diet having EVOO as the main source of fat, compared to a diet enriched
with butter. Moreover, the authors analyzed fecal DNA e 16S rRNA genes. In the mice with butter
diets, there were higher values of systolic blood pressure and a greater percentage of Desulfovibrio
sequences compared to the mice on EVOO diet. In addition, in mice with EVOO diet, the authors
observed reduced plasma levels of insulin and leptin. The concentration of leptin was inversely related
to Sutterellaceae, Marispirillum, and Mucilaginibacter dageonensis. Therefore, the intake of EVOO would
seem to influence the composition of the intestinal microbiota, which in turn can positively aect
health status.
In spontaneous hypertension rats, M. Hidalgo et al. [
81
] investigated the eects of EVOO on gut
microbiota composition and blood pressure levels. After 12 weeks, the rats fed with the diet enriched
with EVOO had significant dierence in Lactobacillus and Clostridia XIV percentage with respect to rats
fed with a standard diet. Moreover, the abundance of Clostridia XIV was inversely related to systolic
blood pressure values.
In a randomized, double blind cross-over human study [
82
] conducted on 10 hypercholesterolemic
subjects, the authors evaluated the eects of the consumption of 25 mL/day of olive oil for three weeks
on human intestinal immune function. The authors studied the eects of three olive oils (OO) diering
in their content of phenolic compounds: OO varieties containing 80 mg phenolic compounds/kg, OO
containing 500 mg phenolic compounds/kg from OO and OO containing a mixture of 500 mg PC/kg
from OO and thyme. The authors concluded that the consumption of olive oil with a high content of
phenolic compounds induces an increased stimulation of the intestinal immune system.
4. Health Eects of Phenolic Compounds Present in Olea By-Products and Waste
Olea by-products and waste are precious sources of bioactive compounds that could be selectively
recovered and reused for industrial applications. These principles are the pillars of the circular
economy, a model of economy where by-products are not waste but resources to be valorized and
reused (Figure 3).
The material balance of the process is equal to a total of 73,200 kg as input and output, of which
2,940 kg are the main outputs. It should be noted how this multifunctional platform is highly innovative
and in line with circular economy principles. Each residue of the process (water, olive stones, destoned
pulp) would come into new use in the same and/or external processes, according to the “zero waste”
model. Indeed, after the extraction of the bioactive fractions, residues of the olive oil mill can be used
as animal feed, compost, or other agricultural or agro-industrial products and/or be exploited as energy
sources in the same biorefinery or sold for other economic activities.
Olive tree cultivation is particularly widespread in the Mediterranean Basin and provides a
strong contribution as a source of polyphenols. After the production of olive oil, olive pulp and olive
oil wastewaters are obtained as by-products in large quantities, representing a great environmental
problem in consideration of their high toxicity [
83
]. Olive oil by-products such as olive mill and leaves
are allowed for production of feed, cosmetics, food, and nutraceuticals, whereas waste and olive
oil waste waters are only allowed for use in agronomy. The importance and use of waste from the
production of oil, as a resource and source of polyphenols, has been described by Cecchi et al. in a
recent study [
84
], which showed that only 0.5% of the total polyphenols present in olives is found in
the extracted oil, while the remainder is waste that can be used for the formulation of supplements for
the nutraceutical sector.
Regarding the recovery of waste from oil production, there are studies in literature concerning the
treatment of wastewater. A recent study demonstrated that the retentates obtained after microfiltration,
ultrafiltration, nanofiltration, and reverse osmosis are stable; HT recovered was stable for 24 months
and the process showed a good reproducibility [85].
Among the wastes from oil production, in addition to olive mill wastewaters, there is pat
è
, a
particular dried olive pomace containing high amounts of HT and OLE. It has been estimated that 1.0 g
Nutrients 2019,11, 1776 18 of 33
of pat
è
contains the same amount of polyphenols as 200 g of EVOO, thus representing a good source to
be used for industrial applications [
86
]. A recent study indicated that extracts obtained from olive mill
wastewater exhibited cytoprotective eects in PC12 cells [
87
]. Similarly, they showed antibacterial
activity [88].
HT is a small phenol that can be recovered from olive oil by-products and used as starting materials
for the preparation of novel bioactive compounds [
89
92
]. Thanks to the presence of the alcoholic
group, it is possible to prepare the corresponding alkyl derivatives showing better lipophilicity and
bioavailability than HT. Figure 5describes some examples of saturated and unsaturated lipophilic
HT derivatives. These compounds could be obtained by a selective esterification of HT with acyl
chlorides of dierent chain length in order to modulate their lipophilicity [
89
,
93
]. Interestingly, the same
functionalization has been introduced in Olea europaea L. extracts enriched in HT recovered by olive
oil by-products, and their antiproliferative activity on the human colon cancer cell line HCT8-
β
8 was
evaluated [
7
]. The experimental results indicated that both the presence and the length of the alkyl
chain exert a relevant role on the antiproliferative activity [
94
]. In a similar manner, HT stearate and
HT oleate showed anti-inflammatory activity [
95
]. To date, it appears that experiments on animal and
human models are lacking (Table 3) [96].
Nutrients 2019, 11, x FOR PEER REVIEW 18 of 32
Figure 5. Lipophilic HT derivatives.
5. Health Effects of Phenolic Compounds Present in Olea Leaf and Olea Leaf Extracts
Olive leaves, deriving both from the processing of olives and from pruning practices, can be
definitely considered a waste of the olive supply chain. These vegetal tissues are a valuable source of
bioactive compounds including phenols with low molecular weight [97]. In olive leaf, the prominent
constituent is the secoiridoid OLE, which by enzymatic or chemical hydrolysis produces the
aglyconic form present in the oil, HT, elenolic acid, and glucose [6,49].
In a 2016 study, several extracts from olive leaf were analyzed. Qualitative differences in total
polyphenols and in OLE content were found. In particular, polyphenols varied from 7.87 to 34.21
mg/g, while OLE varied from 2.79 to 21.03 mg/g depending on the kind of leaf (fresh, refrigerated,
dried, frozen, or lyophilized), cultivar, sampling time, and production area. This study has pointed
out that OLE and stability are related to the extraction temperature and drying process [7].
Many benefits are related to the properties and chemical characteristics of olive leaf. For this
reason, many studies are focused on the use of olive leaf for human consumption. In the last few
years, olive leaf extracts have been used by the food industry as foodstuffs or food additives [98]
producing functional foods with health properties. In a 2017 review, all the studies carried out on the
benefits of olive leaves and their extracts were collected [99]. To date, olive leaf extracts have been
sold as dried leaves, powders, extracts, or tablets used as herbal teas or food supplements, available
all over the world. Extracts of hot fresh water leaves are eaten to increase diuresis and treat
hypertension and bronchial asthma [99]. Olive leaves also affect metabolism, so they have been used
as a traditional herbal medicine for years. Many studies, both in vitro and in vivo, demonstrated their
important biological properties, including radio-protective, anti-proliferative, and cytotoxic effects
on cancer cells; anti-fungal activity; and anti-atherosclerotic, hypoglycemic, and cardioprotective
effects [99]. As reported above, the olive leaves antioxidant activity is ascribed to secondary
metabolites, in particular OLE and its ability to chelate Cu and Fe metal ions, which catalyze free
radical generation reactions [100]. Janahmadi et al. [101] showed that OLE intake in rats with a
permanent ligation of left main coronary attenuated heart failure progression through antioxidative
and anti-inflammatory effects. In alloxan-diabetic rats, the intake of olive leaf extract in a
concentration of 16 mg/kg body weight influences their lipid profile, improving
hypercholesterolemia associated with hyperglycemia [102]. A recent study reported that 20 healthy
subjects after an intake of 20 mg of OLE before lunch showed an improved post prandial glycemic
profile by reducing glucose and increasing insulin and GPL-1 [103]. In overweight middle-aged men
at risk of developing diabetes, supplementation with olive leaf polyphenols for 12 weeks significantly
improved insulin sensitivity and pancreatic β-cell secretory capacity [104].
Figure 5. Lipophilic HT derivatives.
Nutrients 2019,11, 1776 19 of 33
Table 3. Biological activity of Olea europaea L. by-products.
By-Products of EVOO Process
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
In vitro cell models
Obied, H.K.
[88]2007
Olive mill waste waters tested against
Staphylococcus aureus,Bacillus subtilis,
Escherichia coli,Pseudomonas aeruginosa,
Candida albicans,Aspergillus niger.
Antibacterial activity
against S. aureus,B.
subtilis,E. coli, and P.
aeruginosa
At lower concentrations, the extracts
exhibited dierential antibacterial action,
but at 5 mg/disc extracts were active
against all the challenge bacteria
Schaer, S.
[87]2010
OMWW extracts and HT were evaluated
for their cytoprotective eects in an
in vitro
model of neuronal-like PC12 cells
Cytoprotective eects in
PC12 cells subjected to
oxidative or nitrosative
stress by adding either
ferrous iron or sodium
nitroprusside to the cell
culture medium for 18 h
Incubating PC12 cells with wastewater
extract protect from nitrosative stress.
The extract was able to maintain ATP
levels but not MMP.
Bernini, R.
[93]2017
Lipophilic fractions from Olea
by-products were tested on human colon
cancer cell line HCT8-β8 engineered to
overexpress estrogen receptor β(ERβ)
Antiproliferative eect
HT and lipophilic fractions significantly
reduced the proliferation of
HCT8-β8-expressing cells in a
concentration-dependent manner.
HT oleate showed the greater eect.
Plastina, P.
[95]2019
Phenolic extracts from OMWW were
tested for their ability to reduce NO
production by LPS-stimulated
RAW-264.7 macrophages
Anti-inflammatory
activity
HT stearate and HT oleate decrease NO
production in a concentration-dependent
manner
Humans Visioli, F.
[96]2009 OMWW extracts were tested on human
volunteers 1 h after ingestion
Plasma antioxidant
capacity and total reduced
glutathione
No dierence in plasma antioxidant
capacity; a significant increase in total
plasma glutathione concentration
ATP, adenosine triphosphate; ER
β
, estrogen receptor beta; HT, hydroxytyrosol; LPS, lipopolysaccharide; MMP, mitochondrial membrane potential; NO, nitric oxide; OMWW, olive mill
wastewater; RAW-264.7, Abelson murine leukemia virus transformed.
Nutrients 2019,11, 1776 20 of 33
5. Health Eects of Phenolic Compounds Present in Olea Leaf and Olea Leaf Extracts
Olive leaves, deriving both from the processing of olives and from pruning practices, can be
definitely considered a waste of the olive supply chain. These vegetal tissues are a valuable source of
bioactive compounds including phenols with low molecular weight [
97
]. In olive leaf, the prominent
constituent is the secoiridoid OLE, which by enzymatic or chemical hydrolysis produces the aglyconic
form present in the oil, HT, elenolic acid, and glucose [6,49].
In a 2016 study, several extracts from olive leaf were analyzed. Qualitative dierences in total
polyphenols and in OLE content were found. In particular, polyphenols varied from 7.87 to 34.21 mg/g,
while OLE varied from 2.79 to 21.03 mg/g depending on the kind of leaf (fresh, refrigerated, dried,
frozen, or lyophilized), cultivar, sampling time, and production area. This study has pointed out that
OLE and stability are related to the extraction temperature and drying process [7].
Many benefits are related to the properties and chemical characteristics of olive leaf. For this
reason, many studies are focused on the use of olive leaf for human consumption. In the last few years,
olive leaf extracts have been used by the food industry as foodstus or food additives [
98
] producing
functional foods with health properties. In a 2017 review, all the studies carried out on the benefits of
olive leaves and their extracts were collected [
99
]. To date, olive leaf extracts have been sold as dried
leaves, powders, extracts, or tablets used as herbal teas or food supplements, available all over the world.
Extracts of hot fresh water leaves are eaten to increase diuresis and treat hypertension and bronchial
asthma [
99
]. Olive leaves also aect metabolism, so they have been used as a traditional herbal medicine
for years. Many studies, both
in vitro
and
in vivo
, demonstrated their important biological properties,
including radio-protective, anti-proliferative, and cytotoxic eects on cancer cells; anti-fungal activity;
and anti-atherosclerotic, hypoglycemic, and cardioprotective eects [
99
]. As reported above, the olive
leaves antioxidant activity is ascribed to secondary metabolites, in particular OLE and its ability to
chelate Cu and Fe metal ions, which catalyze free radical generation reactions [
100
]. Janahmadi et
al. [
101
] showed that OLE intake in rats with a permanent ligation of left main coronary attenuated
heart failure progression through antioxidative and anti-inflammatory eects. In alloxan-diabetic
rats, the intake of olive leaf extract in a concentration of 16 mg/kg body weight influences their lipid
profile, improving hypercholesterolemia associated with hyperglycemia [
102
]. A recent study reported
that 20 healthy subjects after an intake of 20 mg of OLE before lunch showed an improved post
prandial glycemic profile by reducing glucose and increasing insulin and GPL-1 [
103
]. In overweight
middle-aged men at risk of developing diabetes, supplementation with olive leaf polyphenols for 12
weeks significantly improved insulin sensitivity and pancreatic β-cell secretory capacity [104].
What is of translational importance is that OLE was found to be a powerful sensitizer of doxorubicin
(DXR)-mediated killing of prostate and breast cancer cells. In fact, in a first study, 200
µ
g/mL of
OLE, was able to inhibit cell proliferation at very low doses of DXR (3–12.5 nM). In a second study
in a breast tumor xenograft in mice, the intraperitoneal injection of the combination of 1.5 mg/kg
of, followed by 50 mg/kg of OLE, decreased the volume of the tumor threefold [
105
,
106
]. A recent
investigation demonstrated that olive-leaf ingredients, such as HT, are good antioxidants for food
lipids even at very low doses (<100 mg kg
1
), without cytotoxic eects, nor do they inhibit probiotic
lactating producing bacteria.
Furthermore, olive leaf-derived phenolic compounds have shown significant antimicrobial
properties, thus playing an important role in the control of food processing and preservation during
storage, as well as in counteracting pathological microorganisms like Helicobacter pylori and other
food-borne pathogens [
107
]. As a consequence of their recognized nutraceutical activities, olive-leaf
extracts containing polyphenols can be used as foodstuingredients. OLE, and in particular its aglycone
obtained by enzymatic hydrolysis of pure extracts from olive leaves, as previously reported [
108
],
also showed an anti-amyloid eect, resulting in protection against the cytotoxic eects of amyloid
aggregates [
109
,
110
], as well as having an autophagy inducer eect by modulating the AMPK/mTOR
pathway and by activating autophagy gene expression mediated through sirtuins or EB transcription
factor [108,111,112]. These last actions suggest that OLE aglycone may have a neuroprotective action
Nutrients 2019,11, 1776 21 of 33
in diseases such as Alzheimer’s, characterized by amyloid deposition and autophagy impairment,
contributing to a decrease in aggregated protein and to a reduction in cognitive impairment in
in vivo
models [
113
]. Another interesting eect of OLE aglycone is its modulation in the tumor
microenvironment to control tumor angiogenesis as reported by Margheri et al. in 2019 [
114
]. They
showed that the treatment with OLE aglycone of “senescence-associated-secretory-phenotype” (SASP)
fibroblasts, an accepted cellular senescence model decreased the release of SASP pro-angiogenic
factors in cell media, inhibited dependent cell invasion, and inhibited formation of capillary-like
structures of endothelial cells exposed to the same media, suggesting a mechanistic interpretation of
the anti-angiogenic activities for cancer prevention by olive oil polyphenols.
Moreover, as recently reported in a review that summarized the existing
in vitro
and
in vivo
studies [
115
] on OLE and its metabolite HT [
116
], these compounds not only exert a chemopreventive
action “per se” (by increasing apoptosis and decreasing proliferation and viability), but they may also
be used as adjuvants to conventional antitumoral therapies [
117
,
118
]. OLE, at non-toxic doses, blocks
the AKT pathway and may act synergistically with several current chemotherapies used against BRAF
melanoma cells, allowing a decrease in drug dosage that can lower the adverse eects on non-target
cells and reverse resistance towards conventional agents such as 42-O-(2-hydroxyethyl) rapamycin
(RAD001) and dacarbazine (DTIC).
In the context of anticancer therapy, the anthracycline DXR has a limited use as a chemotherapeutic
agent due to its cardio-toxic eects. Consequently, sustained research has been focused on identifying
eective drugs and strategies in order to reduce DXR toxicity without compromising its antitumor
ecacy. Some studies reported that OLE prevented cardiomyopathy caused by chronic DXR toxicity
and, by attenuating inflammatory development and the degenerative myocardial lesions, preserved
left ventricle contractility and/or [119] acted as a sensitizer of DXD-induced death of cancer cells.
In addition, [
118
] reported that leaf extract enriched in OLE was even more eective than OLE
alone against melanoma cells, probably because of the co-presence of other polyphenols, suggesting
that the combination of several components (rather than any single one alone) might be the ultimate
chemopreventive agent (Table 4).
Nutrients 2019,11, 1776 22 of 33
Table 4. Biological activity olive leaf extracts.
Olive Leaf Extracts
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
In vitro cell models
Andrikopoulos,
N.K.
[100]
2002 Eects against copper ion-induced
low-density lipoprotein (LDL) oxidation LDL mean protection activity
Quercetin, luteolin, and rutin, activities
46.8%, 49.5%, and 53.7% MP, respectively,
comparable to oleuropein the 49.0% MP
Sudjana, A.N.
[107]2009 Antimicrobical activity
Role in regulating the composition of the
gastric flora
Specific activity, in reducing levels of H.
pylori and C. jejuni.
Rigacci, S.
[109,110]
2010
2011
Eects on amylin and peptide
aggregation and cytotoxicity
Hindering amylin and Aβ-peptide
aggregation, preventing their
cytotoxicity
Increased viability of β-pancreatic and
neuroblastoma cells decreasing caspase-3
activity
Rigacci, S.
[111]2015 Neuroprotection eect
Autophagy induction both in vitro in
neuronal cells and in in vivo Aβmodel
deposition (TgCRND8 mice) by
Ca2+/CaMKKβ/AMPK/mTOR axis
Cytosolic Ca2+increase activates
CaMKK
β
and pAMPK concomitant with
increased beclin1/LC3II and decreased
phospho-mTOR and phospho-p70S6K
expression
Papachristodoulou,
A.
[105]
2016 Anticancer eect and adjuvant to
antitumoral therapies
Lowering of the cytotoxic dose in
doxorubicin to obtain the same
antiproliferative eect in prostate cancer
Remarkable induction of autophagy
correlated to significant metabolite
alterations
Luccarini, I.
[112]2016 Neuroprotection eect
Counteracting neuronal damage through
modulation of the PARP1–SIRT1
interplay both in neuronal cells and in
TgCRND8 mice
In vitro reduction of PARP1 activation
and paralleled overexpression of Sirtuin1.
In vivo, (in addition to above reported
eects), a decrease of NF-kB and of the
pro-apoptotic marker p53 expression
Miceli, C.
[108]2018 Cardioprotective eect
Cardioprotection on MAO-A
overexpressed cardiomyocytes by
restoring the defective autophagic flux
due to oxidative stress
Reduction of MAO-induced
cardiotoxicity through MTT.
Autophagy induction by TFEB nuclear
translocation.
Ruzzolini, J.
[118]2018 Anticancer eect and adjuvant to
antitumoral therapies
Reduction of viability of BRAF
melanoma cells. Enhanced eects with
chemotherapic drugs (dacarbazina and
everolimus) at no toxic dose.
High dose induced cell death by
apoptosis, while no toxic dose aected
viability through the inhibition of
phosphorylation of AKT and the S6
pathway
Nutrients 2019,11, 1776 23 of 33
Table 4. Cont.
Olive Leaf Extracts
Type of Study Reference Year Type of Intervention Primary Outcome p-Value for Primary Endpoint
Margheri,
F.M.B.
[114]
2019 Eect on tumor microenvironment
Anti-angiogenic activity in
senescence-associated-secretory-phenotype
(SASP) fibroblast cultured media
Decrease of pro-angiogenic factors
release in SASP fibroblasts cultured
media and inhibition of cell-dependent
invasion and of capillary-like structure
formation of endothelial cells exposed to
the above media
Animals
Jemai, H.
[102]2009 Eects in alloxan-diabetic rats Hypoglycemic and antioxidant activity
Andreadou, I.
[119]2014 Eect on chronic doxorubicin induced
cardiomyopathy
Prevention of the structural, functional,
and histopathological cardiac eects
Activation of AMPK and suppression of
iNOS.
Reduction of pro-apoptotic mediators
and modulation of myocardial
metabolism.
Rigacci, S.
[111]2015 See above
Luccarini, I.
[112]2016 See above
Janahmadi, Z.
[101]2017 Cardioprotection in rats with heart
failure
Antioxidative and
anti-inflammatory eects
Increase of SV, EF, FS, and CO (p<0.05),
serum SOD and GRx.
Reduction of serum MDA, IL-1βor
TNF-α(p<0.05).
Humans
De Bock, M.
[104]2013
46 Participants (aged 46.465.5 years and
BMI 28.062.0 kg/m
2
) were randomized to
receive capsules with olive leaf extract
(OLE) or placebo for 12 weeks
Improvement in insulin sensitivity and
β-pancreatic cell secretory capacity
Insulin sensitivity (p=0.024).
β-pancreatic cell responsiveness
(p=0.013).
Carnevale, R.
[103]2018
Twenty healthy subjects were
randomized to receive 20 mg oleuropein
or 20 mg placebo before lunch
Improvement in postprandial
glycemic profile
Lower blood glucose, DPP-4 activity,
and higher insulin and glucagon-like
peptide-1 vs. placebo
AKT, protein kinase B; AMPK, 5
0
adenosine monophosphate-activated protein kinase; BMI, body mass index; BRAF, B-Raf proto-oncogene; CaMKK
β
, Ca2+/calmodulin-dependent
protein kinase kinase
β
; CO, cardiac output; DPP-4, dipeptidyl peptidase-4; EF, ejection fraction; FS, fractional shortening; GRx, glutathione reductase; HT, Hydroxytyrosol; IL-1
β
,
interleukin-1β; iNOS, nitric oxide inducible isoform; LDL, low-density lipoprotein; MAO-A, monoamine oxidase A; MDA, malondialdehyde; MP, mean protection; mTOR, mammalian
target of rapamycin; MTT assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NF-KB, nuclear factor kappa-light-chain-enhancer of activated B cells; OLE, oleuropein;
ORAC, oxygen radical absorbance capacity; PARP1, poly[ADP-ribose] polymerase 1; SASP, senescence associated secretory phenotype; SIRT1, NAD-dependent deacetylase sirtuin-1; SV,
stroke volume; TEAC, Trolox equivalent antioxidant capacity; TFEB, transcription factor EB; TNF-α, tumor necrosis factor-α.
Nutrients 2019,11, 1776 24 of 33
6. Bioaccessibility and Bioavailability of Olea Minor Compounds
Among the minor polar compounds of Olea products HT, Tyr, and OLE have dierent
bioaccessibility and bioavailability. One of the first studies on the bioavailability of the minor
polar compounds was conducted by Visioli et al. from 2000, which showed that HT and Tyr are
dose-dependently absorbed [
35
]. In a recent review, studies on the bioavailability of principal Olea
minor compounds—such as HT, Tyr, and OLE—in olive oil were collected [
120
]. In a 2016 study,
the plasma levels of HT were evaluated after ingestion of olive oil and EVOO. The pharmacokinetic
results show that it was not possible to detect HT in the blood after the ingestion of ordinary olive oil,
unlike the results obtained after the ingestion of EVOO [121].
As many authors reported, the bioaccessibility regards the amount of component(s) of interest
that is (are) released from the food matrix into the gastrointestinal (GI) tract, whereas the bioavailability
is the quantity of the same digested compound(s) that is(are) absorbed and metabolized within the
human body. As for OLE, some authors reported that, under
in vitro
gastrointestinal conditions, it was
the most resistant compound among those present in olive leaves, varying its content between 26%
and 61%, depending on the type of extract during the first hour [
122
]. The same authors found that the
intestinal phase aected OLE more than the gastric one probably due to pancreatic enzymatic activity
and alkaline pH contributing to a reduction of its bioaccessibility, so that at the end of the digestion
processes only 10% of OLE was present.
HT and OLE bioaccessibility has been investigated
in vitro
by Jilani H et al. [
123
] in relationship
to the potential use of Saccharomyces cerevisiae as a new carrier of OLE as means to protect their lasting
antioxidant capacity during simulated gastrointestinal digestion.
Using an
in vivo
digestion condition, de Bock et al. [
124
] found that after ingestion of dierent
doses of OLE and HT in capsule or liquid form, the plasma of subjects receiving liquid doses (2.74 ng/mL)
showed detectable peak concentrations that were higher compared to those who consumed capsules
(0.47 ng/mL). In fact, previous results showed the influence of the dose and formulation taken by the
subjects, in addition to gender, in plasma concentrations. In the same study, the authors also noticed
that the primary metabolites identified in urine and plasma were the conjugated metabolites of HT,
mainly consisting of HT sulphated and glucuronidated compounds [
125
]. The gut microbiota is another
factor that may influence the bioavailability and bioaccessibility of olive phenolic compounds by
performing biotransformation to other active metabolites with interesting beneficial health properties
in bowel diseases [
126
]. Using human fecal microbiota, an
in vitro
model [
127
] observed that OLE was
rapidly deglycosylated until 6 h of incubation producing oleuropein OLE aglycone, that, on the other
hand, was degradated into elenolic acid and HT by microbial esterase activity, until it disappeared after
48 h. On the contrary, HT, the main metabolite of OLE ester hydrolysis constantly increased during
the same fermentation period. The same authors combined the
in vitro
colon fermentation studies
with an
in vivo
intervention and found, after 3 weeks’ intake of phenol-rich olive oil, a significant
increase in the concentration of free HT in the feces of the all participants in the study, confirming the
in vitro findings.
Interestingly, Santos et al. [
128
] showed that conversion of OLE into HT was performed by lactic
acid bacteria, in particular by Lactobacillus plantarum, and on the basis of this evidence, some authors
recently developed oral granules for co-delivery of L. plantarum and a standardized olive leaf extract
(Phenolea®Active F) in order to foster OLE metabolism and provide high levels of HT [129].
7. Conclusions
Olea europaea L. fruits and leaves are a matrix rich in bioactive compounds such as unsaturated
acids, phenolics, phytosterols, tocopherols, and squalene. The main components are fatty acids,
in particular oleic and linoleic acids, while secoiridoids, polyphenols, phenols, and lignans turned out
to be minor polar compounds. HT and OLE are the most active compounds; HT is present mainly
in fruits, olive oil, and olive oil by-products, while OLE is present in Olea leaves. Despite their low
concentration, they are responsible for numerous health eects in humans. The chemical characteristics,
Nutrients 2019,11, 1776 25 of 33
functional or medical food properties, biological and biomedical activities of these compounds were
described in this review with the aim to demonstrate how the olive tree can be a food species of great
scientific and health interest.
EVOO is a functional food with legal health claims, certified as cardioprotective.
These characteristics are related to the content of minor polar compounds, in particular to HT
and its various derivatives. Therefore, among all dietary plans, a MD based on the daily consumption
of EVOO as a source of fat, is an ideal dietary model for its beneficial cardioprotective eects, longevity,
and prevention of NCDs.
Recent circular economy models promoting green technologies for the recovery of active
compounds from by-products and waste are already operational in the olive-oil industry. Biological
and biomedical activities of many secondary metabolites from Olea europaea L. have been scientifically
demonstrated. Studies on the innovative use of standardized fractions in HT content as precursors
for the synthesis of new biologically active molecules with rich bioavailability have already been
processed. For this reason, the olive tree is an unmatched sustained resource for unique bioactive
compounds with diverse health benefits.
Author Contributions:
Conceptualization A.R., A.N., and R.B.; Writing—Original Draft Preparation F.I., S.U., G.M.,
and C.N.; Writing—Review and Editing A.R., A.N., and R.B. All authors read and approved the final manuscript.
Funding: This research received no external funding.
Acknowledgments:
The authors thank EXTRANUTRAOILS Project (DM n.30311, October 31st 2018, Ministero
delle Politiche Agricole e Forestali–MIPAF) and Federazione Medico Sportiva Italiana for financial support;
Caterina Gola for the revision of the English language.
Conflicts of Interest: The authors declare no conflicts of interest.
Abbreviation List
CKD Chronic kidney disease
COX-1 Ciclooxygenase-1
COX-2 Ciclooxygenase-2
CV Cardiovascular
CVD Cardiovascular disease
DXR Doxorubicin
EFSA European Food Safety Authority
EPIC European Prospective Investigation into Cancer and Nutrition
EPICOR
Long-term follow-up of antithrombotic management patterns on acute coronary syndrome
patients
EU European Union
EVOO Extra-virgin olive oil
Hcy Homocysteine
HDL High density lipoproteins
HPLC-DAD High performance liquid chromatography-diode array detector
HPLC-MS High performance liquid chromatography-mass detector
HT Hydroxytyrosol
HUVEC Human endothelial cells
IMD Italian Mediterranean diet
IMOD Italian Mediterranean organic diet
IOC International Olive Council
K-DOQI Kidney-Disease Outcomes Quality Initiative
LDL Low density lipoprotein
LOX-1 Lectin-like oxidized LDL receptor-1
MD Mediterranean diet
Nutrients 2019,11, 1776 26 of 33
MDM Monocyte- derived macrophages
MFA Membrane Filtration Absorption
MTHFR Methylenetetrahydrofolate reductase
NCD Chronic non-communicable disease
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells
NO Nitric oxide
OLC Oleocanthal
OLE Oleuropein
OO Olive oil
OxLDL Oxidized low density lipoprotein
PMA Phorbol-myristate acetate
PPAR-γPeroxisome proliferator-activated receptor gamma
RCT Randomized controlled trial
ROS Reactive oxygen species
SASP Senescence-associated-secretory-phenotype
SCSCD Seven Country Study of Cardiovascular Disease
SOP Stoned Olive Pomace
TRPA1 Transient receptor potential channel, subfamily A, member 1
Tyr Tyrosol
UNESCO United Nations Educational Scientific and Cultural Organization
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©
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... Over the ages, Olive Oil has been widely produced and consumed in Mediterranean countries, while it is also considered to be the main lipid source in the Mediterranean diet. Its beneficial properties are associated with fatty acid composition, phenolic antioxidants and other minor compounds that make olive oil a very interesting option among heating oils and fats [6,7]. Extra Virgin Olive Oil exhibits high resistance to oxidation, in comparison with other vegetable oils, and it is well known for its very good sensory and health properties [8,9]. ...
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Fresh potatoes were deep-fried in olive oil (OO) & extra virgin olive oil (EVOO) and their blends with 5%, 10% and 20% v/v sesame oil (SO). This is the first report on the use of sesame oil as natural source of antioxidant for olive oil deep-frying. Oil was evaluated for Peroxide Value (PV), Free Fatty Acids (FFA), K232, K270, Trolox Equivalent Antioxidant Capacity (TEAC) and Total Phenols (TP) until Total Polar Compounds (TPCs) reached 25%. Sesame lignan transformations were monitored through Reverse-phase HPLC. While TPCs in olive oils increased at a steady rate, the addition of 5%, 10% and 20% v/v SO created a time window lasting 1, 2 and 3 hours, respectively, where TPCs were constant. SO addition to OO increased the total frying time. Furthermore, the addition of SO reduced the peroxides formation rate for both OO and EVOO. EVOO was more resistant to oxidation than OO as measured by TPCs and TEAC, while frying time raised from 21.5 to 25.25 h when EVOO replaced OO. The increase in frying time for olive oil but not for extra virgin olive oil, after SO addition, is pointing out a niche market for extra virgin olive oil in deep-frying.
... The olive tree contains phenolic compounds, such as HT, tyrosol (Tyr) and oleuropein (Ole) [12][13], which have key roles in plant physiology such as enhancing resistance to insects and microorganisms [14]. The oil obtained from the pressing of olive fruits contains phenolic compounds that contribute to the protection of LDL from oxidation. ...
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In the present study we report the efficacy of food matrices derived from olives in preventing oxidation of low-density lipoprotein cholesterol (LDL) and lipid peroxidation. To this end, 12 healthy volunteers were divided into 3 groups and cross-received a single dose of olive phenolics, mainly hydroxytyrosol (HT), provided as a liquid dietary supplement (30.6 or 61.5 mg HT), or as fortified extra virgin olive oil (12.19 mg HT + tyrosol). Blood and urine samples were collected at baseline and up to 12 hours after ingestion. Plasma oxidized LDL levels were measured by ELISA using a monoclonal antibody, while F2-isoprostanes were quantified in urine by UHPLC-MS/MS. Despite the great variability between individuals, a tendency to reduce lipoxidation reactions has been observed after olive phenolics intake in both, blood and urine. In addition, the subgroup of individuals with the highest baseline lipoxidation level showed a decrease in F2-isoprostanes (p < 0.05) after taking the food supplements, as well as a marked decrease in oxidized LDL levels (p < 0.01) after intake of the food supplement with the lowest HT dose. These promising results suggest that HT supplementation could be a useful aid in preventing lipoxidation. Additionally, people with a redox imbalance could benefit even more from supplementing with bioavailable HT.
... Extra virgin olive oil (EVOO) is a highly valued product in the Mediterranean Diet (MED), and its consumption is increasing around the world, including in countries far from the Mediterranean basin [1][2][3]. In MED, EVOO is the main source of fat since it is composed of a major fatty acid fraction (98-99%), which comprises oleic acid (55-83%) and linoleic acid (2.5-21%) predominantly, and certain minor constituents that include phenolic and volatile compounds, which offer both a multitude of bioactive functions and distinctive organoleptic properties [4][5][6][7][8]. In order to be classified in commercial categories, a sensory analysis of each EVOO is mandatory. ...
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Extra virgin olive oil (EVOO) is the best vegetable oil worldwide but, at the same time, is one of the product victims of fraud in the agri-food sector, and the differences in quality within the extra-virgin olive oil category are often missed. Several scientific techniques were applied in order to guarantee the authenticity and quality of this EVOO. In the present study, the volatile compounds (VOCs) by gas chromatography-mass spectrometry with solid-phase micro-extraction detection (GC-MS SPME), organoleptic analysis by the official Slow Food panel, and the detection by a Small Sensor System (S3) were applied. Ten EVOOs from Umbria, a central Italian region, were selected from the 2021 Slow Food Italian extra virgin olive oil official guide, which includes hundreds of high-quality olive oils. The results demonstrated the possibility to discriminate the ten EVOOs, even if they belong to the same Italian region, by all three techniques. The result of GC-MS SPME detection was comparable at the discrimination level to the organoleptic test with few exceptions, while the S3 was able to better separate some EVOOs, which were not discriminated perfectly by the other two methods. The correlation analysis performed among and between the three methodologies allowed us to identify 388 strong associations with a p-value less than 0.05. This study has highlighted how much the mix of VOCs was different even among few and localized EVOOs. The correlation with the sensor detection, which is faster and cheaper compared to the other two techniques, elucidated the similarities and discrepancies between the applied methods.
... Interest in new areas in the field of pharmaceutical and dietary strategies has started to minimize CVD risk as much as possible. Epidemiological studies have indicated that a high flavonoid content diet is positively related to lower incidence of coronary artery disease, hypertension, stroke, and other vascular diseases [60][61][62][63]. ...
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Abstract: The prevalence of cardiovascular disease, oxidative stress-related complications, and chronic age-related illnesses is gradually increasing worldwide. Several causes include the ineffectiveness of medicinal treatment therapies, their toxicity, their inability to provide radical solutions in some diseases, and the necessity of multiple drug therapy in certain chronic diseases. It is therefore necessary for alternative treatment methods to be sought. In this review, polyphenols were identified and classified according to their chemical structure, and the sources of these polyphenol molecules are indicated. The cardioprotective, ROS scavenging, anti-aging, anticancer properties of polyphenolic compounds have been demonstrated by the results of many studies, and these natural antioxidant molecules are potential alternative therapeutic agents.
... Oleu is characterized as a nontoxic natural secoiridoid comprising the main phenolic compound in Olea europea L. (Oleaceae) and is found in almost all olive products and by-products, with the exception of OO, in which it is detected in traces [97]. Oleu is a glucoside ester of EA and HTyr with diverse, extensively studied health benefits, such as antioxidant, cholesterol lowering, cardioprotective, anti-inflammatory, hypoglycemic and antimicrobial properties [24,[98][99][100][101]. Despite Oleu being determined in plasma [102,103], this compound undergoes extensive metabolism to HTyr and other products, such as EA, HTyr, Tyr and glucose [104]. ...
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Consumption of olive products has been established as a health-promoting dietary pattern due to their high content in compounds with eminent pharmacological properties and well-described bioactivities. However, their metabolism has not yet been fully described. The present critical review aimed to gather all scientific data of the past two decades regarding the absorption and metabolism of the foremost olive compounds, specifically of the phenylalcohols hydroxytyrosol (HTyr) and tyrosol (Tyr) and the secoiridoids oleacein (Olea), oleocanthal (Oleo) and oleuropein (Oleu). A meticulous record of the in vitro assays and in vivo (animals and humans) studies of the characteristic olive compounds was cited, and a critical discussion on their bioavailability and metabolism was performed taking into account data from their gut microbial metabolism. The existing critical review summarizes the existing knowledge regarding the bioavailability and metabolism of olive-characteristic phenylalchohols and secoiridoids and spotlights the lack of data for specific chemical groups and compounds. Critical observations and conclusions were derived from correlating structure with bioavailability data, while results from in vitro, animal and human studies were compared and discussed, giving significant insight to the future design of research approaches for the total bioavailability and metabolism exploration thereof.
... The regular consumption of virgin olive oil (VOO) has been associated with a lower incidence of diseases related to oxidative damage, such as coronary heart disease Covas, de la Torre, and Fitó 2015;Gaforio et al. 2019;López-Miranda et al. 2010;Parkinson and Cicerale 2016;Romani et al. 2019;Tresserra-Rimbau et al. 2014;Widmer et al. 2015) some types of cancer (Casaburi et al. 2013;Emma et al. 2021;Fabiani 2016;Psaltopoulou et al. 2011), and age-related cognitive decline (De La Cruz et al. 2015;Mete et al. 2018;Parkinson and Cicerale 2016;Solfrizzi, Panza, and Capurso 2003). The high content in oleic acid by itself, brings benefits to consumer health but several studies have shown that the consumption of olive oil rich in polyphenols produce higher antioxidant and anti-inflammatory effects than the consumption of low-polyphenol olive oils López-Miranda et al. 2010;Parkinson and Cicerale 2016;Tresserra-Rimbau et al. 2014;. ...
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The chemistry of the phenolic compounds found in virgin olive oil (VOO) is very complex due, not only to the different classes of polyphenols that can be found in it, but, above all, due to the existence of a very specific phenol class found only in oleaceae plants: the secoiridoids. Searching in the Scopus data base the keywords flavonoid, phenolic acid, lignin and secoiridoid, we can find a number of 148174, 79435, 11326 and 1392 research articles respectively, showing how little is devote to the latter class of compounds. Moreover, in contrast with other classes, that include only phenolic compounds, secoiridoids may include phenolic and non-phenolic compounds, being the articles concerning phenolic secoiridoids much less than the half of the abovementioned articles. Therefore, it is important to clarify the structures of these compounds and their chemistry, as this knowledge will help understand their bioactivity and metabolism studies, usually performed by researchers with a more health science's related background. In this review, all the structures found in many research articles concerning VOO phenolic compounds chemistry and metabolism was gathered, with a special attention devoted to the secoiridoids, the main phenolic compound class found in olives, VOO and olive leaf.
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Improvement of plant adaptation by beneficial bacteria (PGPB) may be achieved by triggering multiple pathways to overcome the environmental stress on plant’s growth cycle, activating plant’s metabolism. The present work reports the differential ability of three Bacillus strains to trigger olive tree metabolism, among which, only H47 was outstanding increasing iridoid and flavonol concentration. One-year old olive seedlings grown open air, under harsh conditions of water shortage in saline soils, were root-inoculated with three Bacillus PGPB strains throughout a 12-month period after which, photosynthesis was determined; photosynthetic pigments and bioactive secondary metabolites (iridoids and flavonols) were analyzed, and a study of gene expression of both pathways involved was undertaken to unravel molecular targets involved in the activation. All three strains increased plant fitness based on photosynthetic values, increasing energy dissipation capacity to lower oxidative stress; only H47 increased CO2 fixation and transpiration. Bacillus H47 was found to trigger synthases in the DOXP pathway (up to 5-fold in DOXP-synthase, 3.5-fold in Iridoid synthase, and 2-fold in secologanin synthase) associated to a concomitant increase in iridoids (up to 5-fold in oleuropein and 2-fold in its precursor secologanin). However, despite the 2-fold increases detected in the two predominant flavonols, gene expression was not enhanced, suggesting involvement of a pulse activation model proposed for innate immunity. Furthermore, the activity of leaf extracts to inhibit Angiotensin Converting Enzyme was evaluated, to explore further uses of plant debris with higher added value. Despite the increases in iridoids, leaf extracts from H47 did not increase ACE inhibition, and still, increased antihypertensive potential in oil obtained with this strain is to be explored, as leaves are the source for these metabolites which further translocate to fruits. In summary, Bacillus H47 is an effective strain to increase plant adaptation to dry and saline environments, activates photosynthesis and secondary metabolism in olive tree.
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Full-text available
In the present study we report the efficacy of food matrices derived from olives in preventing oxidation of low-density lipoprotein cholesterol (LDL) and lipid peroxidation. To this end, 12 healthy volunteers were divided into 3 groups and cross-received a single dose of olive phenolics, mainly hydroxytyrosol (HT), provided as a liquid dietary supplement (30.6 or 61.5 mg HT), or as fortified extra virgin olive oil (12.19 mg HT + tyrosol). Blood and urine samples were collected at baseline and up to 12 hours after ingestion. Plasma oxidized LDL levels were measured by ELISA using a monoclonal antibody, while F2-isoprostanes were quantified in urine by UHPLC-MS/MS. Despite the great variability between individuals, a tendency to reduce lipoxidation reactions has been observed after olive phenolics intake in both, blood and urine. In addition, the subgroup of individuals with the highest baseline lipoxidation level showed a decrease in F2-isoprostanes (p < 0.05) after taking the food supplements, as well as a marked decrease in oxidized LDL levels (p < 0.01) after intake of the food supplement with the lowest HT dose. These promising results suggest that HT supplementation could be a useful aid in preventing lipoxidation. Additionally, people with a redox imbalance could benefit even more from supplementing with bioavailable HT.
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The bioactive compounds present in the edible products of the olive tree have been extensively studied and their favorable effects on various disease risk factors have been demonstrated. The aim of this study was to perform a comparative analysis of the anti-leishmanial effects of total phenolic fractions (TPFs) derived from extra virgin olive oil with different phenolic contents and diverse quantitative patterns. Moreover, the present study investigated their association with miltefosine, a standard anti-leishmanial drug, against both extracellular promastigotes and intracellular amastigotes of a viscerotropic and a dermotropic Leishmania strain. The chemical compositions of TPFs were determined by high performance liquid chromatography with diode array detection (HPLC-DAD). Analysis of parasite growth kinetics, reactive oxygen species production and apoptotic events were determined by microscopy and flow cytometry. Our results revealed that the presence of oleacein (OLEA) and oleocanthal (OLEO) secoiridoids enhances the anti-leishmanial effect of TPF. The association between TPFs and miltefosine was suggested as being additive in Leishmania infantum and Leishmania major promastigotes, and as antagonistic in intracellular amastigotes, as was evaluated with the modified isobologram method. The obtained data verified that TPFs are bioactive dietary extracts with a strong anti-leishmanial activity and highlighted that fractions that are richer in OLEA and OLEO phenolic compounds possess stronger inhibitory effects against parasites. This study may contribute to improving the therapeutic approaches against leishmaniasis.
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This report aims to provide complete knowledge on the polyphenol composition and biological activities of the olive tree. The extraction of the root bark and wood of Olea europaea. L (Chemlali cultivar) was realized by solid-liquid ethanolic extraction, whose analysis was conducted via high-performance liquid chromatography equipped with photodiode array detection and mass spectrometry (HPLC-ESI-DAD and MS/MS). Moreover, radical scavenging and antibacterial activities were determined. The results present a total of 14 phenolic compounds belonging mainly to secoiridoid and flavonoid subclasses. Oleuropein was found to be the most abundant compound at an amount of up to 7000 mg/kg followed by ligstroside and oleuropein derivatives. In addition, we found oleocanthal at a great amount (2115 mg/kg). Higher individual polyphenolic concentrations were recorded in root wood extracts compared to bark ones, except for the flavonoid group. Likewise, the total phenolic compound contents increased in the olive root wood. This trend was reflected in biological activities. In fact, root wood extracts exert more important antioxidant and antibacterial activities than bark extracts due to their high bioactive compounds.
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Low-molecular weight phenols such as tyrosol, homovanillyl alcohol and hydroxytyrosol are valuable compounds that exhibit a high number of health-promoting effects such as antioxidant, anti-inflammatory and anticancer activity. Despite these remarkable properties, their applications such as dietary supplements and stabilizers of foods and cosmetics in non-aqueous media are limited for the hydrophilic character. With the aim to overcome this limitation, the paper describes a simple and low-cost procedure for the synthesis of lipophilic esters of tyrosol, homovanillyl alcohol and hydroxytyrosol. The reactions were carried out under mild and green chemistry conditions, at room temperature, solubilizing the phenolic compounds in dimethyl carbonate, an eco-friendly solvent, and adding a little excess of the appropriate C2–C18 acyl chloride. The final products were isolated in good yields. Finally, according to the “circular economy” strategy, the procedure was applied to hydroxytyrosol-enriched extracts obtained by Olea europaea by-products to prepare a panel of lipophilic extracts that are useful for applications where solubility in lipid media is required.
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The Mediterranean diet and olive oil as its quintessential part are almost synonymous with a healthy way of eating and living nowadays. This kind of diet has been highly appreciated and is widely recognized for being associated with many favorable effects, such as reduced incidence of different chronic diseases and prolonged longevity. Although olive oil polyphenols present a minor fraction in the composition of olive oil, they seem to be of great importance when it comes to the health benefits, and interest in their biological and potential therapeutic effects is huge. There is a growing body of in vitro and in vivo studies, as well as intervention-based clinical trials, revealing new aspects of already known and many new, previously unknown activities and health effects of these compounds. This review summarizes recent findings regarding biological activities, metabolism and bioavailability of the major olive oil phenolic compounds—hydroxytyrosol, tyrosol, oleuropein, oleocanthal and oleacein—the most important being their antiatherogenic, cardioprotective, anticancer, neuroprotective and endocrine effects. The evidence presented in the review concludes that these phenolic compounds have great pharmacological potential, however, further studies are still required.
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In recent years, mounting scientific evidence has emerged regarding the evaluation of the putative correlation between the gut microbiota composition and the presence of chronic non-communicable diseases (NCDs), such as diabetes mellitus, chronic kidney disease, and arterial hypertension. The aim of this narrative review is to examine the current literature with respect to the relationship between intestinal dysbiosis and the insurgence/progression of chronic NCDs, analyzing the physiopathological mechanisms that can induce microbiota modification in the course of these pathologies, and the possible effect induced by microbiota alteration upon disease onset. Therapy based on probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplant can represent a useful therapeutic tool, as has been highlighted on animal studies. To this moment, clinical studies that intended to demonstrate the beneficial effect induced by this kind of oral supplementation on the gut microbiota composition, and subsequent amelioration of signs and symptoms of chronic NCDs have been conducted on limited sample populations for a limited follow-up period. Therefore, to fully evaluate the therapeutic value of this kind of intervention, it would be ideal to design ample population; randomized clinical trials with a lengthy follow up period.
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The gut microbiota is a highly complex community which evolves and adapts to its host over a lifetime. It has been described as a virtual organ owing to the myriad of functions it performs, including the production of bioactive metabolites, regulation of immunity, energy homeostasis and protection against pathogens. These activities are dependent on the quantity and quality of the microbiota alongside its metabolic potential, which are dictated by a number of factors, including diet and host genetics. In this regard, the gut microbiome is malleable and varies significantly from host to host. These two features render the gut microbiome a candidate ‘organ’ for the possibility of precision microbiomics – the use of the gut microbiome as a biomarker to predict responsiveness to specific dietary constituents to generate precision diets and interventions for optimal health. With this in mind, this two-part review investigates the current state of the science in terms of the influence of diet and specific dietary components on the gut microbiota and subsequent consequences for health status, along with opportunities to modulate the microbiota for improved health and the potential of the microbiome as a biomarker to predict responsiveness to dietary components. In particular, in Part I, we examine the development of the microbiota from birth and its role in health. We investigate the consequences of poor-quality diet in relation to infection and inflammation and discuss diet-derived microbial metabolites which negatively impact health. We look at the role of diet in shaping the microbiome and the influence of specific dietary components, namely protein, fat and carbohydrates, on gut microbiota composition.
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Extra virgin olive oil (EVOO) has been reported to have a distinct influence on gut microbiota in comparison to other fats, with its physiological benefits widely studied. However, a large proportion of the population consumes olive oil after a depurative process that not only mellows its taste, but also deprives it of polyphenols and other minority components. In this study, we compare the influence on the intestinal microbiota of a diet high in this refined olive oil (ROO) with other fat-enriched diets. Swiss Webster mice were fed standard or a high-fat diet enriched with EVOO, ROO, or butter (BT). Physiological parameters were also evaluated. At the end of the feeding period, DNA was extracted from feces and the 16S rRNA was pyrosequenced. The group fed ROO behaved differently to the EVOO group in half the families with statistically significant differences among the diets, with higher comparative levels in three families—Desulfovibrionaceae, Spiroplasmataceae, and Helicobacteraceae—correlating with total cholesterol. These results are again indicative of a link between specific diets, certain physiological parameters and the prevalence of some taxa, but also support the possibility that polyphenols and minor components of EVOO are involved in some of the proposed effects of this fat through the modulation of the intestinal microbiota
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Extra virgin olive oil (EVOO) is the main source of fat in the Mediterranean diet. Phenolic compounds of EVOO, in particular, secoiridoids, are minor components that have generated special interest due to their positive effects on human health, supported by several clinical trials. This review summarizes the most recent findings on the pharmacological properties and action's mechanisms of secoiridoid oleocanthal focusing attention on inflammation, oxidative stress, cancer, neurodegenerative processes, and rheumatic diseases. Being of relevance to the clinical effects of EVOO intake, the bioavailability and biotransformation of EVOO polyphenols are addressed. Moreover, this review summarizes the factors that may influence the oleocanthal concentration in EVOO. With the growing incidence of age- and lifestyle-related diseases, the current data indicated that the administration of EVOO rich in secoiridoids may be helpful in the prevention or treatment of different pathologies with an inflammatory component. Although promising, the future raises several questions and challenges, that are discussed here. The real beneficial effects of olive oil phenols on human health need to be clarified in new well-designed clinical studies.
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Background: There is an increasing trend in the consumption of olive oil due to its health benefits, which are mainly correlated to its health-promoting compounds, such as polyphenols, tocopherols, carotenoids, etc. Additionally, some positive effects on the inhibition of foodborne pathogens as well as stimulation of growth of beneficial microorganism besides the antioxidant activity make it as one of the leading edible oils worldwide. Scope and approach: The current study takes an overview regarding the effects of olive on gut microbiota through reviewing the recently published reports in this area of the science. In addition, the potential mechanism involved in the prevention of cardiovascular diseases (CVD) of olive oil was discussed. Key findings and conclusions: This review showed that olive oils originated from various regions of the world can pose some positive effects on gut microbiota. Moreover, this edible oil (especially the extra virgin type) can prevent CVD due to the high levels of valuable bioactive compounds including polyphenols, especially oleocanthal, tyrosol, hydroxytyrosol, oleuropein, and oleuropein aglycone or the presence of highly bioavailable health-promoting carotenoids, like the provitamin A β-carotene of lutein. Therefore, the consumption of olive oil can be recommended not only because of its healthy fatty acid profile (particularly oleic acid) but also due to valuable positive effects on human health.
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Phenolic secoiridoids from olive, including oleocanthal, oleuropein and related derivatives, are bioactive natural products with documented anticancer activities, that have mainly been attributed to their antioxidant, anti-inflammatory and antiproliferative effects. This review summarizes the results of the preclinical studies on the natural secoiridoids of olive used as single agents or in combination with other chemotherapeutics against cancer cells. The molecular targets of their action are described. A critical analysis of the importance of the experimental studies in view of the possible use in humans is also discussed.