Olea europaea as Potential Source of Bioactive Compounds for Diseases Prevention

Chapter 12

Olea europaea as Potential Source of Bioactive Compounds for Diseases Prevention Nassima Talhaoui*, Najla Trabelsi‡, Amani Taamalli‡, Vito Verardo§,1,
rrez* Ana Maria Go´mez-Caravaca*, Alberto Ferna´ndez-Gutie and David Arraez-Roman*,† *

Faculty of Sciences, University of Granada, Granada, Spain Research and Development Functional Food Centre (CIDAF), Health Science Technological Park, Granada, Spain ‡ Laboratoire de Biotechnologie de l’Olivier, Centre de Biotechnologie-Technop^ ole de Borj C
edria, Hammam-Lif, Tunisie § Department of Nutrition and Food Science-University of Granada. Campus of Cartuja, Granada, Spain 1 Corresponding author: e-mail: [email protected] †

Chapter Outline Introduction Olive Oil and Human Health Antiinflammatory Properties Antimicrobial Properties Heart Disease Risk Factors Hypertension Cancer Risk Olive Leaves and Human Health

389 393 393 395 396 397 398 398

Cardioprotective Activity Cancer Risk Antidiabetic Activity Antiinflammatory Activity Antimicrobial and Antiviral Conclusions References Further Reading

404 404 405 405 406 406 406 411

INTRODUCTION The traditional Mediterranean diet (MD) refers to dietary patterns prevailing in olive-growing areas of the Mediterranean region [1]. However, the traditional MD is more than just a diet; it is a whole healthy lifestyle pattern that has been acknowledged by UNESCO in 2010 as an intangible cultural heritage [2]. Olives and olive oil are an inherent part of the Mediterranean culture and diet. The olive tree (Olea europaea L.) is among the oldest known cultivated trees in the world. For more than 6000 years, the cultivated olive has been Studies in Natural Products Chemistry, Vol. 57. https://doi.org/10.1016/B978-0-444-64057-4.00012-0 © 2018 Elsevier B.V. All rights reserved.

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developed alongside Mediterranean civilizations [3]. The tree is typically distributed in the coastal areas of the eastern Mediterranean Basin, the adjoining coastal areas of southeastern Europe and northern Africa as well as northern Iran at the south end of the Caspian Sea [4]. Olive tree continued to spread and new plantings also exist in California, Chile, Argentina, South Africa, and Australia [3]. In several civilizations, the olive tree had and still has a very strong cultural and religious symbolism [5]. The olive fruit, its oil, and the leaves of the olive tree have a rich history of nutritional, medicinal, and ceremonial uses. Olives are rarely used in their natural form due to severe bitterness. However, they are consumed in either one of the two forms, oil or table olives. The chemical compound responsible for bitterness is oleuropein and must be eliminated from olives to make them palatable [6]. The increasing health consciousness of today’s more cosmopolitan society explains the rising consumption of olive oil around the world and, hence, the rapid growth of the olive industry [6]. Actually, more than 11 million hectares of olives are grown in the world, and 98% of the world’s olives are harvested in the Mediterranean region. With the increase in olive oil production, the total world consumption of olive oil has increased from 1876 thousand tons from 1990/1991 to 1995/1996 till 2995 thousand tons from 2009/2010 to 2014/2015. Table olive consumption has also increased from 994 thousand tons from 1990/1991 to 1995/1996 till 2461 thousand tons from 2009/2010 to 2014/2015 [7]. The olive oil industry gives vast amounts of residues in the production line [8]. A number of different by-products are originated during olive oil production, such as pomace residues with olive stones and wastewater. An indirect residue of olive oil production consists of leaves accompanying the olive fruits to the mill, and they suppose around 10% of the total weight of olives [9]. Moreover, it has been estimated that an average of three tons of pruning biomass is obtained each year from one olive tree hectare, making these residues a huge, cheap, and unexploited source of energy or chemicals [10]. The agroindustrial residues generated can become a major environmental issue; however, they have the potential to be used with different purposes, providing economic advantages [11]. The olive tree has a long history of medicinal and nutritional values. In fact, olive oil has been used as a nutritious food, drug, and as cosmetics for centuries by the Mediterranean people, and it has been a subject of much scientific interest in the last few decades, confirming its biological, therapeutic, and functional food applications [4]. Because of the interest in improving the nutritional quality of food and the biological importance of olive oil, continuous attempts have been made to extend the use of the latter in a variety of fatty products such as margarines, reduced-fat mayonnaise, and butter creams [12]. Moreover, olive oil has been added to various meat products instead of animal fat to reduce the saturated fatty acid and cholesterol content of the product [13]. In this sense, a patent

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has been developed on the production of excellent-stability products such as cooked pork meats, sausages, and salamis of contracted meat with direct embodiment of olive oil [14]. With the aim to evaluate the oxidative stability during storage of dry fermented sausages manufactured with partial replacement of pork back fat with olive oil, Ansorena and Astiasara´n showed that the addition of olive oil, especially with antioxidants, was more effective than using vacuum storing methods in avoiding lipid oxidation during storage [15]. In another study, enrichment of refined olive and refined olive-pomace oils with oleuropein, oleuropein aglycone, and hydroxytyrosol extract improved the stability of the oil to oxidation [16]. In addition, frying is a common food preparation method that gives desirable fried flavor to food, golden-brown color and crisp texture. This method affects little or not the protein and mineral content of food. Nevertheless, the high temperature induces thermal stress of polyunsaturated fatty acid (PUFA)-rich culinary oils generating high levels of cytotoxic aldehydic products, arising from the fragmentation of conjugated hydroperoxydiene precursors [17]. Due to its specific features, olive oil can modulate the damages occurred by endogenous and exogenous oxidative stress. Thus, Quiles and coworkers found that the highly unsaturated sunflower oil resisted to a lower extent the stress produced by the frying and led to a higher degree of lipid peroxidation in liver microsomes of rats when compared to virgin olive oil [18]. The potential of olive leaves for the isolation of high-value bioactive components for pharmaceutical, nutraceutical, and food industries is also acknowledged. Over the centuries, olive leaf extracts have been used in folk medicine and mentioned as effective against malaria, hypertension, and diabetes [19]. Nowadays, commercial products in the form of herbal teas or food supplements are available all over the world, as complete dried leaves, powder, extracts, or tablets [19]. Olive tree by-products can be considered as environmental and economic point of view, a promising cosmetic ingredient source. Nevertheless, in order to avoid the presence of irritant constituents stability and toxicity assays should be performed [11]. The use of products derived from the olive tree on human health dates back centuries. The great beneficial effects of olive tree products on health are mainly based on the antioxidant properties of their components. Such antioxidant activities could be directly or indirectly involved in all prevention mechanisms against certain human diseases. In fact, an excess of free radicals can cause oxidative damage to lipids, DNA, and proteins which increases the risk of developing numerous chronic diseases such as atherosclerosis, cancer, chronic inflammation, stroke, and other degenerative diseases [20,21]. Several compounds form olive oil and leaves can deactivate and scavenge the free radicals by donating hydrogen atom or chelating metals, preventing tissue damage and cell death. Phenolic compounds in olive oil exert in vitro and in vivo beneficial effects on lipid oxidation, DNA oxidative damage and in general oxidative

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stress [22]. Low-density lipoprotein (LDL) oxidation is considered to be a major risk factor for the development of atherosclerosis and cardiovascular disease, inducing plaque formation. In vivo human and animal studies demonstrated a decrease in LDL oxidation with an increased ingestion of olive oil phenolic compounds. Three mechanistic studies showed that phenolic compounds bind to LDL and increase the resistance to LDL oxidation [23–25]. Concerning DNA oxidative damage, several researches showed that the intake of phenol-rich olive oil (up to 592 mg/kg) decreases oxidative DNA damage in humans by up to 30% [26,27]. Other studies have shown that hydroxytyrosol and oleuropein, potently at concentrations of 10 6 to 10 4 M, inhibit copper sulfate-induced LDL oxidation in a dose-dependent manner [28,29]. Concerning the antioxidant activity of olive leaves, phenolic compounds, such as oleuropein and related secoiridoids, have repeatedly been tested by common in vitro assays for reactive oxygen and nitrogen species scavenging properties [30–36]. It has been reported that the oxygen radical absorbance capacity, which is a method of measuring antioxidant capacities in biological samples in vitro, is much higher in some extracts of olive leaves than the antioxidant capacities of grape seed and green tea extract [37]. Moreover, it has been claimed that oleuropein and hydroxytyrosol are much more efficient antioxidants than butylated hydroxytoluene or vitamin E and C [38,39]. The genoprotective and antioxidant properties of olive leaves phenolic compounds have been evidenced in vitro by evaluating the effect of these extracts against adrenaline-induced DNA damage in human leukocytes [40]. Moreover, following the same assay, Zukovec Topalovic et al. have found that olive leaves phenolic compounds counteract L-thyroxine-induced genotoxicity in human peripheral blood leukocytes [41]. A recent in vivo study carried out in male Sprague–Dawley rats revealed the enormous antioxidant effect of olive leaves extract (OLE) decreasing the doxorubicin DOX-induced cardiac, hepatic, and renal oxidative stress and injury [42]. Lipid peroxidation is the oxidative degradation of lipids. It involves the formation of lipid radicals, the uptake of oxygen, a rearrangement of the double bonds in unsaturated lipids and the eventual destruction of membrane lipids, with the production of a variety of breakdown products, including alcohols, ketones, alkanes, aldehydes, and ethers. Tocopherols (vitamin E) are considered as the most important lipid soluble natural antioxidants, which prevent lipid peroxidation by scavenging radicals in membranes and lipoprotein particles, and, thus, they slow down the aging process [43,44]. In addition, to remove free radicals, tocopherols in olive oil prevent photooxidation changes, increase the oxidative stability of the oil during storage [44], defend the body against free radical attacks, and prevent atherosclerosis, skin diseases, and certain cancerous diseases [33,45]. Therefore, tocopherols exhibit synergistic effect in antioxidant activity with phenolic compounds. Recent studies proved that the beneficial effects of olive oil are also due to the minor bioactive components such as squalene, a polyunsaturated triterpene

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formed by the condensation of six units of isoprene. This molecule is well known for its anticancer properties, and several biological activities, with the antioxidant one being similar to that of trans-retinol [46]. Results of in vitro studies indicate that squalene is a quencher of singlet oxygen preventing the corresponding lipid peroxidation in human skin surface. In addition, squalene possesses the capacity to decrease the UV radiations generating the DNA damage of cells, consequently helping in the prevention of human skin photoaging [46]. Oleanolic acid, maslinic acid, uvaol, and erythrodiol are the main triterpenes present in olive leaves [19]. These triterpenes possess antioxidant properties per se, and in different cellular types, they have been found to affect some central proteins of oxidative stress and inflammation (NF-kB and COX-2) [47]. Also, their antioxidant activity are claimed in numerous research [48,49]. The nonenzymatic antioxidant activities of oleanolic acid and ursolic acid in a liposome system have been found to surpass even a-tocopherol activity under certain conditions [50]. Recently, accumulating experimental, clinical, and epidemiological data have provided the beneficial health effects of olive tree derivatives.

OLIVE OIL AND HUMAN HEALTH Olive trees are continuously exposed to environmental stress such as UV radiation and relatively high temperatures, and, thus, they need a variety of compounds, for example, antioxidants, to preserve their integrity [20]. Among the several minor constituents of olive oil, different components can be found: b-carotene (together with chlorophylls are responsible for the oil color), vitamins such as a- and g-tocopherols, phytosterols, terpenic acids, squalene, and phenolic compounds (Fig. 12.1) [20]. Several studies suggested that MD health benefits may be due to a synergistic combination of phytochemicals (including carotenes, tocopherols, and phenolic compounds) and fatty acids such as oleic acid (a monounsaturated fatty acid (MUFA)) which is the main fat of the MD [51].

Antiinflammatory Properties The olive oil triterpenes have recently been studied for the capacity to modulate the inflammatory response. In fact, oleanolic acid is an antiinflammatory molecule exerting in vivo and in vitro activity. This compound induces an antiinflammatory condition inhibiting the activation of nuclear factor-kB (NF-kB) and the production of tumor necrosis factor-a (TNF-a) in human umbilical vein endothelial cells (HUVECs) [51]. In addition, some authors have studied the prevention of lipid peroxidation in the hepatic microsomes of rats fed for 3 weeks with sunflower oil, olive oil, and olive-pomace oil. These oils contain different concentrations of the antioxidants a-tocopherol,

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OH O

HO

OH

H3C O

HO

HO

OH

H

O

HO H

O

CH3 O

H

H

O

H

OH

HO

H

O H

O

O

H OH

O OH

(B) Hydroxytyrosol

(A) Tyrosol

(C) Oleocanthal

O

CH3 CH3

CH3

(E) Oleic acid

CH3

(D) Oleuropein

H3C

CH3

HO

OH

O

CH3

CH3 CH3

CH3

(F) Squalene

O N N− Mg++ N− N

O O

O

O

a-Carotene

Chlorophyll

H

H O H H

H

Erythrodiol

O H

O

H

O

H

H

O H

Maslinic acid

O

H

Oleanolic acid

H O O

H

O

H

O H O

H O

H O

H H

O

b-Carotene

O O O

a-Tocopherol

b-Tocopherol

g-Tocopherol

H

d-Tocopherol

FIG. 12.1 Main olive oil and leaves bioactive compounds.

erythrodiol, and oleanolic acid. As a result, they have found that oleanolic acid and erythrodiol can protect against lipid peroxidation of microsomes in rats fed with olive-pomace oil [51]. The inflammation is strictly associated to the oxidative stress by the NF-kB pathway and on account of other signals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by macrophages and other mediated immune cells [51]. This signal allows to macrophages the capacity to activate other immune cells that will try both to mediate inflammation and revert to the initial health status. This is how, any compound that participates in oxidative stress (directly or indirectly) acts in inflammation and, thus, in the prelude of several diseases. In this context, oleanolic acid is one of the most studied triterpenes in inflammation and oxidative stress. This compound is a powerful inhibitor of cyclo-oxygenase (COX) and of 5-lipoxygenase

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(5-LOX). COX is an enzyme responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin. Besides, 5-LOX is an enzyme that catalyzes the oxidation of fatty acids or other alkenes. The COX and 5-LOX enzymes catalyze steps in the biochemical inflammation pathways derived from arachidonic acid [51]. The antiinflammatory effects of suppressing COX-2 action, like the reduction of several proinflammatory cytokines such as IL-6, IL-1b, and TNF-a, are well known. Besides, maslinic acid has the capacity to suppress COX-2 and inducible nitric oxide synthase expression at protein and mRNA, likewise in the translocation of NF-kB to the nucleus (and IkBa phosphorylation), depending to their concentration in cultured cortical astrocytes. Moreover, maslinic acid reduces IL-6, IL-1b, and TNF-a, produced in mouse macrophages [51]. Olive oil phenolic compounds have been reported to possess significant antiinflammatory capacity. Several in vivo and in vitro researches have reported that the dietary intake of olive oil, containing significant amount of phenolic compounds, may attenuate inflammatory responses in the body and, therefore, reduces the risk of chronic inflammatory diseases development [22]. For example, Dell’Agli and coworkers proved that oleuropein aglycone prevented the stimulation of metalloproteinases MMP-9 expression and secretion in tumor necrosis factor R-treated THP-1 cells. This effect on MMP-9 is due to impaired NF-kB signaling [52]. Consequently, these results supported the hypothesis that inhibition of proteolytic activity by olive oil phenolic compounds might be responsible for the reduction of invasiveness of tumor cells. This study elucidates some of the molecular mechanisms through which olive oil, a source of phenolic compounds, contributes to the antiinflammatory and the antiatherosclerotic actions. In addition, hydroxytyrosol showed significant antiinflammatory actions in an animal model (rats) of inflammation, and it attenuated the proinflammatory cytokines (TNFa and IL-1b) expression, often observed in inflammatory disease [53]. Furthermore, in 2005, Beauchamp and coworkers showed that the phenolic compound oleocanthal possesses the same mechanistic antiinflammatory pathway as the nonsteroidal antiinflammatory drug, ibuprofen [54]. In fact, an in vitro test confirmed that oleocanthal inhibits in a dose-dependent manner the two inflammatory enzymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). This study demonstrated that oleocanthal is more potent than ibuprofen in inhibiting these enzymes at equimolar concentrations [54], and it also showed to attenuate markers of inflammation implicated in Alzheimer’s disease [55,56]. In this sense, oleocanthal may be a potential pharmacological agent used for the treatment of neurogenerative disease.

Antimicrobial Properties Infectious diseases are the leading cause of death world-wide, and antibiotic resistance has become a global concern. Therefore, researchers are increasingly

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turning their attention to folk medicine to discover new compounds with antimicrobial properties inhibiting the growth of microorganisms and acting as therapeutic agents with diverse chemical structures and novel mechanisms of action. Phenolic compounds of olive oil such as oleuropein aglycone, oleocanthal, hydroxytyrosol and tyrosol have potent antimicrobial efficacy against several strains of bacteria [22]. In this context, Romero and coworkers demonstrated that oleocanthal escaped hydrolysis under stomach-simulated conditions and inhibited the growth of Helicobacter pylori bacteria, which is associated with peptic ulcer and gastric cancer development [128]. Karaosmanoglu and coworkers tested the in vitro antimicrobial activities of olive oil phenolics against: Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella enteritidis, and the study demonstrated a synergistic interaction between various olive oil phenolic compounds [57]. This synergism seemed to increase antimicrobial capacity compared to individual compounds. The authors concluded that the use of olive oil in foods may prevent food-borne disease.

Heart Disease Risk Factors Olive oil phenolic content intake has shown to be beneficial in the prevention and/or treatment of cardiovascular diseases (such as high blood pressure, high low-density cholesterol, or low high-density cholesterol). Most of these diseases were characterized by the development of atherosclerotic plaque in the subendothelial space of the blood vessels [21]. Briefly, the accumulation of cholesterol inside the macrophages that reside in the intima induces an inflammatory response triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death, ischemic heart disease, gangrene, and loss of function in the extremities [58,59]. The oxidation of LDL and high-density lipoprotein (HDL) influences the charge of cholesterol inside macrophages; hence, oxidized LDL is able to load cholesterol into the macrophages [60,61]. Several human trials have demonstrated that the administration of olive oil induced the decrease of oxidized LDL in augmenting the phenolic content in oil from 0 to 800 mg/kg [21]. For instance, in 40 women suffering from stable coronary heart disease, Fito´ and coworkers showed that olive oil enriched with olive oil phenolic compounds (161 mg/kg) decreased the levels of oxidized LDL in plasma as compared to another olive oil with a smaller amount of phenolic compounds (15 mg/kg) [62]. In fact, hydroxytyrosol and its glucuronidated metabolites reduce the oxidative damage caused by various ROS such as H2O2, which is a major cause of endothelial dysfunction [63–66]. Olive oil phenolic compounds also influence the platelet aggregation, which is a key factor in the development of thrombus and myocardial infarction. In this sense, it has been demonstrated that hydroxytyrosol can interfere with platelet aggregation in vitro in a concentration of 400 mM [67]. Nevertheless, the presence of large amount of MUFAs, such as oleic acid, is strongly linked with the reduced prevalence of cardiovascular

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diseases. Oleic acid (C18:1), the principal fatty acid in olive oil, has been claimed to increase the plasma HDL cholesterol and apoprotein A1 and decrease LDL cholesterol and apoprotein B. For this reason, this fatty acid prevents cardiovascular diseases that are the major cause of mortality in industrialized countries [4]. On the other hand, some studies have reported that cardiovascular alterations and periodontal disease are very associated. In this respect, nutrition may be of great importance in oral health affecting the development and integrity of the oral cavity as well as the progression of oral diseases. In this context, Bullon et al. have evaluated the influence of squalene, hydroxytyrosol, and coenzyme Q10 on gingival tissues of rabbits fed with an atherosclerotic diet [68]. Rabbits fed with atherosclerotic diet presented higher fibrosis and endothelial activation and lower cellularity in gingival mucosa than controls. However, hydroxytyrosol reduced endothelial activation, and the squalene decreased fibrosis. These findings suggest that gingival vascular changes induced by the atherosclerotic diet have been reversed by the natural products from the minor fraction of virgin olive oil: hydroxytyrosol and squalene. In addition, aging increases the frequency of chronic diseases like cardiovascular or periodontal disease. Bullon et al. reproduced an age-dependent model of the periodontium, a fully physiological approach to periodontal conditions, to evaluate the impact of dietary fat type on gingival tissue of young (6 months old) and old (24 months old) rats [69]. Different diets based on MUFA as virgin olive oil, n-6 polyunsaturated fatty acids (n-6PUFA), as sunflower oil, or n-3PUFA, as fish oil have been accorded lifelong to animals. The main finding is that the enhanced alveolar bone loss (a feature of periodontal disease) associated to age may be conditioned by dietary fat. Thus, MUFA or n-3PUFA might allow mitochondrial maintaining turnover through biogenesis or autophagy. They can induce the corresponding antioxidant systems to avoid oxidative stress age-related without inhibit mitochondrial electron transport chain. From the nutritional and clinical point of view, it is interesting to note that the potential treatments to reduce the alveolar bone loss associated to age are similar to some of the proposed for the prevention and treatment of cardiovascular diseases recently associated with age-related periodontitis.

Hypertension There is a reduced incidence of hypertension in populations that consume the MD which is inversely related to systolic and diastolic blood pressure [70,71]. Several studies have demonstrated the antihypertensive properties of olive oil. Epidemiological data from studies in Mediterranean countries (Italy, Greece, and Spain) suggest the protective effect of MUFAs or olive oil, whereas these effects are small or absent in non-Mediterranean countries [72]. In addition, Ferrara and coworkers compared in patients taking antihypertensive medications, a diet rich in polyunsaturated fatty acids from sunflower oil with a diet high in MUFAs from

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olive oil and proved that individuals who consumed an olive oil-rich diet were able to reduce the dosage of antihypertensive medication [73]. RodrίguezRodrίguez and coworkers evaluated the vasodilatory effects of oleanolic acid and erythrodiol, two triterpenoids contained in olive oil in rat thoracic aorta [74]. They found that oleanolic acid and erythrodiol, accumulatively added, evoke an endothelium-dependent vasorelaxation in rat aorta. Thus, they concluded that these two triterpenoids may possess an interesting therapeutic virtue as new vasodilator drugs for the protection of cardiovascular system.

Cancer Risk Epidemiological studies have shown that the consumption of olive oil was inversely associated with the occurrence of different types of cancer [75–78]. Olive oil phenolic content interferes with basic cell functions that are able to modify the cell cycle. In this context, Fabiani et al. demonstrated that hydroxytyrosol interfered with the G1 cell cycle and apoptosis in human colon adenocarcinoma cells and promyelocytic leukemia cells at concentrations ranging from 50 to 100 mM [79]. In addition, this molecule inhibited the p38/CREB phosphorylation and COX-2 expression in human adenocarcinoma cell at 50 mg/mL, and arrested at G2/M and inhibited cell growth in a dose-dependent manner (5–200 mM) [80,81]. Squalene, ubiquitous in nature, is a triterpene hydrocarbon and a major intermediate in the biosynthesis of cholesterol. Olive oil is composed of approximately 0.7% of squalene [82]. Due to the structure of this molecule, it is more likely to scavenge singlet oxygen species than hydroxyl radicals [83]. Exposure to high levels of ultraviolet radiation causes the formation of carcinogenic singlet oxygen species within the skin, where a high concentration of squalene may provide a chemoprotective effect [83]. The MD is rich in squalene which is believed to be responsible for the lower incidence of skin cancer seen in epidemiological studies of populations consuming this diet [82].

OLIVE LEAVES AND HUMAN HEALTH As mentioned in Section 1, historically, olive leaves have widely been used in folk medicine combating diseases such as inflammatory disorders, bacterial infections, hypertension, and including malaria [4,84]. Nowadays, modern science has devoted greater interest in the healing powers of olive leaves, prompting wide chemical and pharmacological research. Thus, the healthy benefits of olive leaves have been attributed to different bioactive phytochemical compounds such as tocopherols, triterpenoids, pigments, and phenolic compounds (Fig. 12.1). Several studies have shown that OLE exhibits a large spectrum of in vitro and in vivo properties, including antioxidant activity, radioprotective effects, antiproliferative, anticancer, antiHIV, antifungal, gastroprotective and antidiabetic activities [85]. The main researches related to olive leaves healthy proprieties are summarized in Table 12.1.

TABLE 12.1 The Main Recent Researches Related to the Bioactivity of Olive Leaves

In vitro

Biological Effect

Extract/Compounds

Observations

References

Nonenzymatic antioxidative and antiglycative

Oleanolic acid and ursolic acid

Liposome system

[50]

Antioxidant

Olive leaf extract

Human peripheral blood leukocytes

[40]

Antioxidant

Olive leaf extract

Human peripheral blood leukocytes

[41]

Radical scavenging

Oleuropein

Reduced the toxicity of TAM by ninefold

[86]

Anticancer, antiproliferative, and apoptotic

Oleuropein and hydroxytyrosol

MCF-7 (breast cancer cells)

[87]

Anticancer

Olive leaf extract

MCF-7, SKBR3, and JIMT-1 cells (breast cancer)

[88]

Anticancer and apoptosis

Hydroxytyrosol

Human keratinocytes (FEP-1811), CEM-CCRF, R100, and K562

[89]

Prooxidant and cytotoxic

Oleuropein and hydroxytyrosol

Human breast cancer MDA-MB231 cells

[90]

Chemopreventive or anticancer

Hydroxytyrosol, oleuropein, verbascoside, tyrosol, and caffeic acid

Recombinant wild-type human topoisomerase IIa, topoisomerase IIb, and Top2aD1175

[91]

Continued

TABLE 12.1 The Main Recent Researches Related to the Bioactivity of Olive Leaves—Cont’d Biological Effect

Extract/Compounds

Observations

References

Cytotoxic activities and antiproliferation

Uvaol and erythrodiol

Human breast cancer cells (MDAMB-231) and human epithelial breast cells (MCF10A)

[92]

Antiadipogenic

Oleuropein

Murine 3T3-L1 preadipocytes

[93]

Antiinflammatory

Oleuropein, apigenin, luteolin, luteolin-7-O-beta-D-glucoside, and caffeic acid, individually

Inhibit the gout-related enzyme xanthine oxidase

[94]

Antiinflammatory

Oleuropein

RAW264 mouse macrophages cells

[95]

Antiinflammatory and immunomodulatory

Olive leaf extract

RAW264 mouse macrophages cells

[96]

Antimicrobial

Olive leaf extract

Gram-positive bacteria: Bacillus cereus (KCCM 40935) and Salmonella aureus (KCCM 40907), and the Gram-negative bacteria: Escherichia coli (KCCM 11234) and S. enteritidis (KCCM 12021)

[97]

Antimicrobial

Olive leaves volatiles

Staphylococcus aureus strains, two specific pathogenic strains (hemorrhagic Escherichia coli O157:H7 and Klebsiella pneumoniae) and one Pseudomonas aeruginosa strain

[98]

Antimicrobial

Olive leaf extract

Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 27950, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27950. In the case of yeasts, Candida glabrata ATCC 90030, C. kreusei ATCC 6258, C. parapsilosis ATCC 22019 and C. albicans ATCC 90028.

[99]

Antimicrobial

Olive leaf extract

Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC®27853), Klebsiella pneumoniae, (ATCC 15380), Salmonella typhimurium (ATCC®14028), Enterococcus faecalis (ATCC®49452), Staphylococcus aureus (ATCC®6538), Listeria monocytogenes (ATCC®13932), and Bacillus subtlis

[100]

Antiviral against HIV-1

Olive leaf extract

HIV-1 infection and replication infected H9 cells

[101]

Continued

TABLE 12.1 The Main Recent Researches Related to the Bioactivity of Olive Leaves—Cont’d

In vitro and in vivo

In vivo

Biological Effect

Extract/Compounds

Observations

References

Antiviral against VHSV

Olive leaf extract

Cell monolayers infected by the viral hemorrhagic septicemia virus (VHSV)

[102]

Antiviral against laryngotracheitis virus (ILTV)

Olive leaf extract

CER cells infected by ILTV virus

[103]

Antihyperglycemic

Oleanolic acid

Chinese hamster ovary (CHO) cells, COS1 (ATCC) cells, and male C57BL/6J mice

[104]

Antidiabetic neuropathic pain

Olive leaf extract

Pheochromo-cytoma (PC12) cells and streptozotocin-induced diabetic rats

[105]

Hypoglycemic and antioxidant

Oleuropein

Male New Zealand rabbit

[106]

Lipid-lowering and antioxidant

Triacetylated hydroxytyrosol and hydroxytyrosol

Wistar rats

[107]

Antioxidant

Oleuropein

Male Sprague–Dawley rats

[108]

Antioxidant agent against oxidative stress

Olive leaf extract containing 94% oleuropein

Male Sprague–Dawley

[109]

Antioxidant activities against TAA toxicity

Olive leaf extract

Male Wistar rats

[36]

Protective effect against oxidative stress

Olive leaf extract

Wistar rats

[110]

Antioxidant

Olive leaf extract

Male Sprague–Dawley rats

[42]

Antiatherosclerotic and antiinflammatory

Olive leaf extract

Male New Zealand rabbits

[111]

Therapeutic agents against hepatotoxicity, cardiotoxicity, nephrotoxicity, and metabolic disorders induced by diazinon

Olive leaf aqueous extract

Male albino mice of MF1 strain

[112]

Antiatherosclerotic

Olive leaf extract

Male Wistar rats

[113]

Chemopreventive role in tongue squamous cell carcinoma

Oleuropein

Male F344 rats

[114]

Antidiabetic

Olive leaf extract

Male Wistar rats

[115]

Chronic inflammation and oxidative stress

Oleuropein and hydroxytyrosol

Male Wistar rats

[116]

Antiinflammatory

Oleuropein and hydroxytyrosol

Healthy male and female human volunteers

[117]

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Cardioprotective Activity Natural antioxidants, including oleuropein from olive leaves, may play a role in the prevention of cardiovascular diseases through a decreased formation of atherosclerotic plaques by inhibiting LDL oxidation [28,111]. In vitro and in vivo studies related to the efficient protection of hydroxytyrosol against LDL oxidation have widely been reviewed [35,118]. Moreover, it has also been found that olive compounds have vasodilating effects, seemingly independent of vascular endothelia integrity [119]. The same observation has already been observed in in vivo studies [87]. One of the most recent in vivo studies has showed that phenolic compounds have significantly decreased the levels of total cholesterol and LDL cholesterol levels, suggesting its beneficial effects on atherosclerosis [113].

Cancer Risk The antitumoral effects of triterpenes are also evidenced. A recent in vitro research showed that triterpenes as uvaol possessed an apoptotic effect on human breast cancer cells (MDA-MB-231) and human epithelial breast cells (MCF10A). In fact, uvaol has shown a protective effect against DNA damage in both cell lines [92]. In vitro studies with individual phenols or whole leaf phenolic extracts have suggested that olive phenols are capable of significantly affecting the overall process of carcinogenesis by their abilities to inhibit the cell cycle, cell proliferation, or oxidative stress, improve the efficacy of detoxification enzymes, induce apoptosis, and stimulate the immune system [79,120]. Besides, the anticancer properties of oleuropein and hydroxytyrosol have been confirmed by in vitro studies with different cell lines [87]. These phenols have also been found to inhibit cell proliferation of human urinary bladder carcinoma (T-24) and bovine brain capillary endothelial [79], human breast adenocarcinoma (MCF-7) [121], and human breast carcinoma cell line JIMT-1 [122]. Moreover, hydroxytyrosol has shown to have anticancer effect on human colon adenocarcinoma HT-29 cells and human promyelocytic leukemia HL-60 cells [87], and in numerous series of human cell lines: human keratinocytes (FEP-1811), CEMCCRF, R100, and K562 [89]. A thorough study related to the activity of olive leaves phenols against human topoisomerase IIa, an enzyme which alters the supercoiled form of a DNA molecule, has demonstrated the ability of hydroxytyrosol, oleuropein, and verbascoside to act as covalent topoisomerase II poison [91]. All of those metabolites have induced cell cycle arrest, displayed antiproliferative effects, and showed beneficial activity against in vivo tumor models. In in vivo animal studies, oleuropein has rapidly and completely induced tumor regression when it has been administered to mice orally [123]. Similarly, after the oral administration of OLE, oleuropein reportedly prevented chronic ultraviolet B radiation-induced skin damage and carcinogenesis in hairless mice. In fact, oleuropein could inhibit increases in skin thickness and reductions

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in skin elasticity, and, consequently, it could reduce skin carcinogenesis and tumor growth [124]. Likewise, an inhibition of 4-nitroquinoline-1-oxide (4-NQO)-induced F433 rat tongue carcinogenesis by oleuropein ingestion has recently been reported [114].

Antidiabetic Activity The triterpene oleanolic acid has shown to be an agonist for TGR5 in an interesting in vitro and in vivo study. The latter has been identified as the first cell surface receptor activated by bile acids, and this receptor is reported to mediate some of the endocrine functions of bile acids. The finding suggested that oleanolic acid is involved in the antidiabetic effect of olive leaves and further emphasize the potential role of TGR5 agonists to improve metabolic disorders [104]. Besides, numerous studies have demonstrated the effect of the whole or individual phenolic compounds of olive leaves in combating different types of diabetes and their different mechanisms. For instance, the inhibitor effect on the high glucose-induced neural damage and the diabetes-induced thermal hyperalgesia on in vitro and in vivo models of diabetic pain neuropathy has been shown [105]. Moreover, phenolic compounds have revealed big efficiency in attenuating insulin resistance in rats with type 2 diabetes induced by streptozotocin and high-fat diet-induced diabetes, by suppressing mRNA expression of proinflammatory cytokines and elevating of insulin receptor substrate 1 expression [115].

Antiinflammatory Activity The antiinflammatory effects of olive leaves phenolic compounds have extensively been tested [116,125,126]; however, oleanolic acid, maslinic acid, uvaol, and erythrodiol, the most described triterpenes in olive leaves, have also been studied because of their antiinflammatory activity [47]. A recent in vitro evidence has pointed to the antiinflammatory properties of oleuropein and other phenolic compounds, demonstrating its ability to inhibit the release of the proinflammatory mediator nitric oxide in LPS-stimulated RAW264.7 macrophage cells [95,96]. The inhibition of inflammatory response and oxidation is supposed to be potential targets for atherosclerosis prevention. In an in vivo study, it has been proved that the administration of phenolic compounds to rabbit not only decreased the levels of blood lipid but also inhibited inflammatory response [111]. The antiinflammatory effect of oleuropein and hydroxytyrosol from olive leaves has also been shown in human assays. In fact, the oral administration of OLE (basically, oleuropein and hydroxytyrosol) to 18 healthy volunteers has positively modulated vascular function and lipopolysaccharide-stimulated of the cytokine (IL-8) production. The latter is considered as one of the most important proinflammatory cytokines for the development of atherosclerosis [117].

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Antimicrobial and Antiviral Volatiles such as (E)-3-hexenol, 3-ethenylpyridine, (E)-b-damascenone and phenylethyl alcohol from olive leaves have been the object of an in vitro study where they have been evaluated against four bacterial and four fungal strains. The volatile fractions have shown significant antibacterial and antifungal effect inhibiting most bacteria and fungi growth [99]. Cyclotrisiloxanehexamethyl, cyclotetrasiloxaneoctamethyl, and cyclopentasiloxanedecamethyl extracted from olive leaves have also demonstrated antimicrobial activity against Gram-positive and Gram-negative bacteria [98]. Moreover, individual and combine phenolic compounds have revealed clear evidence of the antimicrobial activity of olive leaves. Oleuropein and caffeic acid have shown inhibitor effect against many strains of microorganisms (Gram-positive and Gram-negative bacteria) [97]. The same results have been confirmed by other authors for the whole olive leaves phenolic compounds [100,127], showing that olive leaves have antibacterial activities against some of the Gram-positive and Gram-negative bacterial strains. This matrix has also been investigated for their antiviral activity against HIV-1 infection and replication. In fact, cell-to-cell transmission of HIV has been inhibited in a dose-dependent manner, and HIV replication has been inhibited in an in vitro experiment [101], against viral hemorrhagic septicemia virus (VHSV) [102], and against laryngotracheitis virus (ILTV) [103].

CONCLUSIONS This chapter is far from being exhausted of the thousand studies found in the literature about the healthy benefits of olive oil and leaves. However, it gives an overview of the most recent and important in vivo studies related to olive oil and leaves bioactivities. A high oleic acid intake is known for the healthful properties of olive oil; however, minor components of olive oil also show properties that can account for benefits in human health. In the case of olive leaves, the majority of studies deals with phenolic compounds proprieties rather than other minor constituents such as triterpenes or tocopherols. Finally, the huge number of studies related to the valuable effect of olive leaves phenolic compounds on health in last decade should encourage the industry to assess these leaves as a source of antioxidants to produce medicines, cosmetics, nutraceuticals, and functional foods.

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FURTHER READING [1] S. Cicerale, X.A. Conlan, A.J. Sinclair, R.S.J. Keast, Crit. Rev. Food Sci. Nutr. 49 (2009) 218–236.