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Nediani, C. Oleuropein in Non-Communicable Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/14579 (accessed on 08 December 2023).
Nediani C. Oleuropein in Non-Communicable Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/14579. Accessed December 08, 2023.
Nediani, Chiara. "Oleuropein in Non-Communicable Diseases" Encyclopedia, https://encyclopedia.pub/entry/14579 (accessed December 08, 2023).
Nediani, C.(2021, September 26). Oleuropein in Non-Communicable Diseases. In Encyclopedia. https://encyclopedia.pub/entry/14579
Nediani, Chiara. "Oleuropein in Non-Communicable Diseases." Encyclopedia. Web. 26 September, 2021.
Oleuropein in Non-Communicable Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/antiox8120578

Growing scientific literature data suggest that the intake of natural bioactive compounds plays a critical role in preventing or reducing the occurrence of human chronic non-communicable diseases (NCDs), such as neuro- and cardiovascular diseases, diabetes mellitus and cancer. Oleuropein, the main phenolic component of Olea europaea L., has attracted scientific attention for its several health beneficial properties such as antioxidant, anti-inflammatory, cardio- and neuro-protective, and anti-cancer. This entry contains data from the current literature concerning the effect of oleuropein in NCDs not only due to its putative antioxidant and anti-inflammatory activities, but also to its other peculiar actions such as autophagy inducer and amyloid fibril growth inhibitor and, finally, as anti-cancer agent. Despite the increasing number of published studies, looking at the health effects of oleuropein, there is limited clinical evidence focused on the benefits of this polyphenol as a nutraceutical product in humans, and many problems are still to be resolved about its bioavailability, bioaccessibility, and dosage. Thus, future clinical randomized trials are needed to establish the relation between the beneficial effects and the mechanisms of action occurring in the human body in response to the intake of oleuropein.

Olea europaea L. oleuropein extra-virgin olive oil health effects non-communicable diseases oxidative stress inflammation autophagy amyloid

 1. Introduction

The great progress of medical research has highly contributed to decrease mortality due to severe pathologies. But, on the other hand, a longer life expectancy has been associated with a greater incidence of illness and disability.
Non-communicable diseases (NCDs) are a group of long-lasting and slowly progressive chronic disorders. The World Health Organization (WHO) recently reported that NCDs are the leading causes of death and disability for the general population, regardless of age, region, or gender. NCDs have been deeply studied and some common key features have been identified; these include the intracellular presence of oxidative stress due to abnormal production of reactive oxidative species (ROS), inadequate antioxidant defense, and dysregulation of the autophagy pathway, responsible for the maintenance of cellular proteostasis [1] . Also inflammation is implicated in NCDs [2], since its level in an organism is closely related to cellular redox and an autophagic state [3] [4].
Moreover, the health care costs associated with NCDs highlight the importance of finding new therapies for these pathological conditions, and it has been shown that healthy and equilibrated dietary patterns are useful in the prevention of NCDs [5] .
The consumption of extra virgin olive oil (EVOO) is common in the Mediterranean Diet, which is largely known to have several health benefits and to increase longevity, as reported by the United Nations Educational Scientific and Cultural Organization (UNESCO) in 2010 [6]. As recently reported in the III International Conference on Virgin Olive Oil and Health Consensus Report, EVOO intake is also associated with reduced risk of most ageing-related diseases including cardiovascular and neurodegenerative diseases (CVD and NDD), and some types of cancer [7]. Initially, the beneficial properties of EVOO were attributed to functional components such as monounsaturated and polyunsaturated fatty acids, like oleic acid,  linoleic acid and linolenic acid. However, recent epidemiological and experimental studies also show that minor bioactive compounds, including phenolic alcohols, such as hydroxytyrosol (HT, 3,4-dihydroxyphenylethanol, 3,4-DHPEA) and tyrosol (p-hydroxyphenylethanol, p-HPEA), secoiridoid derivatives, phenolic acids, lignans, and flavonoids contribute to the beneficial effects of EVOO [8]. A high biophenol content confers a high stability to EVOOs, preventing EVOO autoxidation and contributing to a long shelf-life.
Oleuropein (Ole) is the major phenolic compound, belonging to the secoiridoids, in the olive tree, Olea europaea L., and is particularly abundant in unprocessed olive fruit and leaves, with concentrations up to 140 mg g−1 on a dry matter basis in young olives [9]  , and 60–90 mg g−1 of dry matter in the leaves [10] . 
Ole is an ester of elenolic acid and HT, and has a oleosidic skeleton that is common to the secoiridoid glucosides of Oleaceae (Figure 1)
Antioxidants 08 00578 g001 550
Figure 1. Chemical structure of oleuropein.
Ole present in green olives, during the oil mechanical extraction process, is hydrolysed by the activity of endogenous β-glucosidases to form oleuropein aglycone (OleA), responsible for the bitter and pungent taste of EVOO. OleA, whose content is dependent on the oil production process, together with other derivative secoiridoid species, represents the minor polar compounds that determine the antioxidant capacity of EVOO.
The relevance of bioactive components in EVOO has been strengthened by the European Food Safety Authority (EFSA), that in 2011, released a health claim on the efficacy of oil phenols (5 mg/day per 20 g of EVOO, HT and OleA) in protecting low-densitiy lipoprotein (LDL) from oxidation, the initial event of atherosclerotic plaque formation. This is of interest because it is unique as a health claim that associates a specific dosage of a natural bioactive component of food with cardiovascular risk (LDL cholesterol oxidation) reduction [11] .
Leaves of olive tree are an hystorical Mediterranean herbal drug, used as a traditional remedy for health promotion and a therapy for chronic conditions. The differences in Ole content depend on the cultivar, production area, and leaf tissue conditions (fresh, frozen, dried, or lyophilized). Commercial Olea leaf extracts, standardized in Ole content, were used to obtain food supplements with specific biological and biomedical properties [12].
Recently, both oleuropein isoforms, glycosidic form and aglycones, have attracted scientific attention by virtue of their health benefits, such as antioxidant, anti-inflammatory, cardio- and neuro-protective, and anti-cancer effects. These pharmacological activities are mainly due to their putative radical scavenging features, due to the ortho-diphenolic group. Mechanistic studies indicate that these compounds are also able to act at different sites, interfering with protein function and gene expression, or modifying cellular pathways relevant to the NCDs pathological processes [13] , suggesting that oleuropein actions in various disorders may result from shared molecular mechanisms. As reported above, dysregulated autophagy is a common feature of NCDs. This dysregulation seems to be due to increased oxidative stress, so, although these mechanisms are generally viewed as cell autonomous, recent evidence suggests an occurrence of an interplay between autophagy and oxidative stress that influences the inflammatory state of tissues, linked with NCD development [1] (Figure 2). 
Antioxidants 08 00578 g002 550
Figure 2. Effect of oleuropein on interplay between oxidative stress, autophaghy and inflammation in non-communicable diseases. AMPK, 5’ adenosine monophosphate-activated protein kinase; Beclin-1 autophagy-specific marker; COX, Cyclooxygenase; CRP, C Reactive Protein; Hcy, homocysteine; ICAM-1, Intercellular Adhesion Molecule 1; IL-1β, interleukin-1β; IL-6, interleukin-6; iNOS, inducible form of nitric oxide synthase; LC3 autophagy-specific marker; MMP-9, metalloproteinases-9; mTOR, mammalian target of rapamycin; NF-kB, Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells; oxLDL, oxidized low-density lipoprotein; p62 autophagy-specific marker; PARP1, Poly (ADP-ribose) polymerase; ROS, Reactive Oxygen Species; SIRT-1, NAD-dependent deacetylase sirtuin-1; TFEB, Transcription factor EB; TNF-α, tumour necrosis factor-α; VCAM-1, Vascular Cell Adhesion Molecule 1.
In this entry are reported data available in the literature concerning the effect of oleuropein isoforms, Ole and OleA, in NCDs by their putative antioxidant and anti-inflammatory activities, but also through their other peculiar actions as autophagy inducers and amyloid fibril growth inhibitors and, finally, as anti-cancer agents with ability to sensitize and potentiate the action of current therapies.

2. Oleuropein As an Antioxidant

The strong antioxidant property of oleuropein is shared with other phenols present in olive leaves and olive oil. In its chemical structure oleuropein contains an ortho-diphenolic group able to scavenge ROS through hydrogen donation, and to stabilize oxygen radicals with an intramolecular hydrogen bond [14]. Many evidence in vitro and in vivo showed a direct antioxidant effect of Ole [15] [16]. In humans, Visioli et al. [17] proved that Ole supplementation in healthy volunteers decreased, in a dose-dependent manner, the urinary excretion of 8-iso-PGF2α, suggesting a lower lipid peroxidation. The first experimental evidence of Ole direct antioxidant cardioprotective effect against the post-ischemic oxidative burst after coronary occlusion, was reported by Manna et al.[18]. They observed that an Ole pretreatment, in isolated rat hearts subjected to global ischemia and then reperfused, decreased the level of creatine kinase and of glutathione release in the perfusate, as well as the content of oxidized glutathione and of the lipid peroxidation level. Ole was also able to exert, in an indirect way, its antioxidant action by stimulating the expression of intracellular antioxidant enzymes via the activaction of Nuclear factor erythroid 2-related factor 2  transcription [19], as well as by increasing the level of non enzymatic antioxidants such as glutathione, α-tocoferol, β-carotene, and ascorbic acid [20] [21] .

3. Oleuropein As an Anti-Inflammatory and CVD Protective Agent

Inflammation is a crucial and defensive response induced by tissue damage or infection, and represents the “common soil” of multi-factorial diseases, playing a crucial role in promoting many disabling illnesses, such as atherosclerosis, diabetes mellitus, metabolic syndrome, cancer, and neurodegenerative diseases [22]. It is correlated with the production of ROS that may cause oxidative damage and the depletion of antioxidants [23]. Macrophages, one of the main factors in the inflammatory response, produce ROS, but also pro-inflammatory cytokines and chemokines, including IL-1, IL-6, TNF-a, and IFN-γ. IL-6 seems to be the central mediator of the inflammatory response and an index of increased frailty [24][25]. Therefore, besides the release of several inflammatory cytokines or mediators, damaged tissues also release monocyte chemoattractant proteins, cyclooxygenase, inducible form of nitric oxide synthase, metalloproteinases (MMP), and adhesion molecules. In addition, nuclear factor Kappa β (NF-kβ) occupies a key upstream position in a complex signal transduction pathway, controlling the production of countless pro-inflammatory mediators [26] .
In 2006, the PREDIMED trial first showed the anti-inflammatory effect of the Mediterranean Diet (MD) supplemented with EVOO for three months (compared with a low fat diet), through a remarkable decrease of serum C-Reactive Protein, IL-6, endothelial and monocytary adhesion molecules, and chemokines, in a group of 722 partecipants [27]. Many other sub-studies of the PREDIMED trial have supported that adherence to the MD with EVOO can modify inflammation, regardless of shared genetic and environmental factors [28][29][30][31]. In this context, many scientists have focused their attention on the possibility of using individual EVOO polyphenolic compounds, like oleuropein, in vitro as a promising alternative anti-inflammatory agent, due to its capability to inhibit the synthesis of pro-inflammatory cytokines [32][33][34] and lipoxygenase activity [2], or to modulate inflammatory parameters [35][36] and tumor microevironment[37]. The anti-inflammatory effect of Ole is also recognised by studies using in vivo animal models [38][39][40][41][42].

Lipid-Regulating, Anti-Hypertensive and Antidiabetic Effects of Oleuropein

CVD is a group of disorders, affecting heart and/or blood vessels, including coronary  cerebrovascular and peripheral arterial diseases. The cardiovascular protective effect of oleuropein is supported by many in vivo animal studies and human clinical trials that showed, in addition to its antioxidant and anti-inflammatory properties, its lipid-lowering activity, anti-hypertensive, and hypoglycemic action [43][44][45][46][47].

Insulin resistance is a systemic disorder, in which there is a reduced action of insulin despite an “hyperinsulinaemia” condition, that affects many organs, in particular the liver and adipose tissue, and leads to development of two NCDs, type 2 diabetes mellitus (T2DM) and metabolic syndrome, well known cardiovascular risk factors. Recent research has described the beneficial properties of OleA and Ole-enriched olive leaf extracts against T2DM, and other metabolic syndrome associated conditions. Therefore, many studies conducted in animal and cell models have reported that Ole has the property of decreasing blood glucose and cholesterol levels, and improving oral glucose tolerance and insulin sensitivity [48][49][50]. These findings were confirmed by human clinical trial results showing that Ole treatment improved glucose homeostasis, reduced glycated hemoglobin and fasting insulin levels, suggesting a significant anti-diabetic effect [51][52][53]. Interestingly, in the context of these latter metabolic disorders, both characterized by insulin-resistance, de BocK et al. [52] showed a recovery of insulin sensitivity and pancreatic β-cell secretion capacity, in a group of overweight middle-aged men that received capsules of oleuropein-leaf extracts for 12 weeks, corroborating previous findings on the hypoglycemic effect of oleuropein [48][45][54]. Non-alcoholic fatty liver disease is another disease highly associated with insulin resistance and the metabolic syndrome, that affects about 25% of the world population, and leads non-alcoholic steatohepatitis. Research on cell and animal models have reported that oleuropein may counteract these conditions through different actions, including (i) an anti-lipidemic activity [55], (ii) protection and prevention of liver damage [56][57][58], and (iii) by interfering with signaling pathways involved in lipogenesis and in the onset of fatty liver disease [43]. Unfortunately, today these findings are not adequately supported by human studies, and remains unproven.

Therefore, in addition to the above reported properties, the ability of oleuropein to inhibit endothelial activation, monocyte cell adhesion and platelet aggregation within the concentration range expected after the nutritional intake from MD, suggest that oleuropein may also be considered an anti-atherogenic agent, reflecting its CVD protective activity [59][60][61][62][63].

4. Oleuropein As an Autophagy Inducer

Autophagy is a process by which the cells remove damaged organelles, malformed proteins or amyloid aggregate accumulation through lysosomal degradation. This is a process highly conserved and is required to maintain cellular homeostasis. Dysregulated autophagy is a common feature in NCDs implicated in NDD, metabolic syndrome, diabetes, CVDs, gastrointestinal diseases, and cancer [1]. As a master regulator of protein, lipid and carbohydrate metabolism, altered autophagy may concomitantly promote metabolic disorders and diseases associated with ageing, unhealthy diets, and inflammation [64][65][66][67][68][69][70]. In the context of CDV, several studies show that autophagy might have beneficial or detrimental roles depending on the stage and type of the considered cardiovascular disease [2]. However, the majority of studies on cardiac disorders show that autophagy may be a common cellular pathway that can be targeted for therapeutic gain, and the growing number of cardioprotective therapies affecting autophagic activity confirms this evidence [1][71][72]. In cancer cells, it is still debated whether autophagy induction or inhibition may represent the most promising approach for future cancer treatments. Interestingly, cancer cells may also use autophagy as a resistance mechanism against chemotherapy [73]. Also in the contest of NDD, such as Alzheimer’s disease (AlzD) many studies reported that the autophagy process was impaired with accumulation of extracellular protein aggregates, mainly composed by polymeric Aβ42 peptide, a product of proteolysis of APP, one of the main responsible for neurological damage and cognitive deficit [74].

All these data support that autophagy is a key factor in the pathogenesis and regulation of various kinds of diseases, serving as a potential and effective target for their intervention. Therefore, the use of substances, such as polyphenols, including OleA, that modulate autophagy and minimize the collateral effect, may be a valid therapeutic approach [75]. Indeed, several studies, some of which conducted in our laboratory, contributed to demonstrating the healthful actions of oleuropein against pathologies involving autophagy dysfunction, acting as an autophagy enhancer through several mechanisms, In our previous study performed in neuroblastoma cell lines, we found that OleA induced autophagy by activation of the Ca2+/Calmodulin Protein Kinase Kinase β (CaMKKβ)/AMPK/mTOR signalling axis [76].The effects of OleA as an autophagy inducer have also been investigated in animal transgenic models. Grossi et al.[77] using a wildtype and TgCRND8 transgenic mouse model for human Aβ pathology, demonstrated that a diet supplemented with OleA restored the defective autophagic flux by inhibition of the mTOR pathway, resulting in a remarkable cortex plaque reduction, and a recovery of the mice cognitive performance. Another mechanism through which OleA may modulate autophagy is activation of NAD-dependent deacetylase sirtuin-1 (SIRT-1). SIRT-1 influences autophagy directly (but also oxidative stress and apoptosis), via deacetylation of key components of this pathway. It showed a functional crosstalk with Poly (ADP-ribose) polymerase-1 (PARP-1) through NAD+ cofactor availability, and so any changes in levels of intracellular NAD+ and/or PARP-1 activity may influence SIRT-1 activity [78]. Luccarini et al.[79] found that PARP-1 activation matched with a significant accumulation of PAR polymers in the cortex of TgCRND8 mice at the early (3.5 month) and intermediate (six month) stages of Aβ deposition. The same TgCRND8 mice fed with a supplementation of OleA showed a rescue of both PARP-1 activation, the accumulation of its product, and increased SIRT-1 expression. Miceli et al. [80] studied the effect of OleA as an autophagy enhancer in a cardiomyocyte model, characterized by autophagy dysfunction induced by oxidative stress due to a monoamine oxidase-A (MAO-A) overexpression. They found that OleA conferred cardioprotection, not simply by its antioxidant action, but also through restoration of defective autophagic flux autophagy, due to translocation of transcriptional factor EB (TFEB) to the nucleus; this latter modulated the transcription of autophagy genes, prevented by MAO-A activation, reducing its transcriptional activity. Interestingly, TFEB translocation and autophagy recovery induced by OleA did not affect ROS status in cardiomyocytes, further highlighting its peculiarity as an autophagy inducer.

5. Oleuropein as Anti–Amyloid Tool

Many neurodegenerative pathologies, among which AlzD and Parkinson’ disease (PD), together with T2DM, are amyloid diseases (AD), and belong to the NCD group. In general, AD are diseases potentially fatal, defined by the occurrence of deposition of insoluble fibrillar polymeric material, grown from misfolded proteins (amyloid) in several organs. The core of these amyloids is made of unbranched polymeric fibrils of characteristic protein or peptides, typical for each disease, such as Aß peptides for AlzD, a-synuclein for PD, amylin (hIAPP) for T2DM, and transthyretin (TTR) for familial amyloid cardiomyopathy [81][82][83]. Amyloidogenic process involves the formation of an intermediate (soluble) oligomer form, following insoluble protofibril growth. Recently, some authors have demonstrated that the cytotoxicity of different amyloidogenic proteins is due to soluble, intermediate oligomeric species, rather than to insoluble fibrillary amyloids [84]. Their cytotoxicity involves the disruption of calcium homeostasis, destabilization of membranes, ROS production, and apoptosis induction, all factors that determine cell suffering and death [85]. So, the research of compounds interfering with aggregation of amyloid proteins is recognized as a valuable approach to build new therapeutic molecules. OleA has been found, in vitro experiments, to decrease toxic oligomers formation of Aß peptide, hIAPP and α-synuclein amyloid aggregation, as well as to promote fibril and plaque disaggregation [86][87][88][89]. These actions reflect Ole beneficial effects against amyloid toxicity to cultured cells [86][90] and in transgenic model organisms [91][92]suggesting its possible use as a novel and promising pharmacological tool, acting directly on amyloid formation via protein self-assembly pathway, for prevention and therapy of systemic amyloidosis

6. Oleuropein as an Anticancer Agent and Chemotherapy Enhancer

Current protocols for cancer treatment are dependent on the condition of the tumor at time of diagnosis. If diagnosed early, the tumor mass may be removed by surgery, but if it has spread to lymph nodes, surgery will be more intensive, and chemotherapy and immunotherapy will likely be added to the treatment. Up-to-now, chemotherapy and immunotherapy represent a promising route for a more effective, life-saving cure for most human cancers. Despite advancements in these therapies, many patients with metastatic lesions still face a significant mortality risk. Furthermore, chemotherapy and immunotherapy may result in patient resistance, and generate host side effects. Therefore, new strategies that target cancer cells and also reduce resistance and patient side effects, may help the development of new treatments.

Ole has been deeply investigated in oncology for its anti-neoplastic properties; it may contribute to therapy in several ways, including its inhibitory role in some crucial cancer cell activities, which are summarized in the Figure3.

Figure 3. Effect of oleuropein (Ole) on the factors contributing to cancer development.

This polyphenol was found to inhibit two of the most important features of cancer cells, uncontrolled proliferation and resistance to apoptosis, in many types of cancers, as breast, prostate, cervical, hepatoma, neuroblastoma, colon and leukemia[93][94][95][96][97][98][99][100][101].

The main cellular pathways affected by Ole are the same implicated in cellular survival, ERK 1/2 (148), JAKs/STATs and AKT/S6 [102][103]; but they are not the only to be targeted by Ole. Ca2+ channels are very important to mantain  cellular homeostasis, and Ole is able to affect them in mesothelioma [104]. Tumor invasiveness is a marker of tumor malignancy and its is closely linked with tumor dissemination and metastatization; Ole was reported to express a potent inhibitory activity on tumor xenografts, disrupting actin filaments, thus abrogating proliferation, motility, and invasiveness [105] and to inhibit angiogenesis and lymphangiogenesis in mouse melanoma cells [106]. Ole effects resulted also in decreasing the activity of MMPs, implicated in invading extracellular tissues [107][108].

Ole was found to reduce dysplasia and genome instability in colon [109], to modulate tumor suppressor genes, such as onco-miRNAs (miRNA-21 and miR-155 in breast cancer [110] and miR-137, -145, and -153, in glioblastoma multiforme cancer stem cells [111] and to enhance p53 activity in human colon cells [112].

Another aspect to consider about tumor arising and development is inflammation; Elamin et al. [113] demonstrated Ole ability to abrogate NF-kB expression in breast cancer cells and this evidence was also confirmed by Liu et al. [114].

Finally Ole exerts its anti-cancer activity by acting as autophagy disregulator, as found in breast [115] and in prostate [116] cancer cells, and by epigenetic changes through histone deacetylases (HDAC2 and HDAC3) inhibition [117].

The use of nutraceutics in oncology is also aimed to enhance the efficacy of conventional treatments and to reduce drug resistance through the combination of standard treatments with biological agents (the so called complementary therapies). Due to the several anticancer properties of Ole, it might represent an effective agent for complementary cancer therapy. This new therapeutical approach has been tested on several types of cancer with  encourageous results [116][118][119][120][121][122].

Data from our laboratory [103] demonstrated that Ole enhances chemotherapy of BRAF melanoma cells, by downregulating the pAKT/pS6 pathway. Of a particular significance, the finding that Ole was able to promote the death effect of Everolimus, a mTOR inhibitor, in Vemurafenib-resistant BRAF melanoma cells, points to a possibility for its use in treating resistant melanoma cells. Ole also contributed to the cytotoxic effect of dacarbazine against BRAF melanoma cells. Furthemore in resistant melanoma cells, exposure to Ole was found to reverse trastuzumab resistance in HER2-overexpressing breast cancer cells[123].

7. Conclusions

In conclusion, several in vitro and in vivo studies have showed the ability of oleuropein (and its derivatives) to counteract oxidative stress and inflammation, to modulate the autophagy pathway, to act as amyloid inhibitor and anticancer agent suggesting its use, not only in the prevention, but also as a complementary therapy of NCD. Despite the low bioavailabilty of oleuropein [124], some clinical trials reported several beneficial effects after administration of this compound, confirming the results obtained in vitro and in vivo studies. The effective daily dose of oleuropein to be administered in humans to achieve a theraputic effect is not known, but clinical and experimental evidence suggest that regular intake of this compound can be effective in the long term, representing a continuous low-intensity stimulus to the cellular defence against NCDs [125]

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Subjects: Biochemistry & Molecular Biology
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Chiara Nediani
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