Health-promoting properties of oleocanthal and oleacein: Two secoiridoids from extra-virgin olive oil.

Extra virgin olive oil (EVOO) polyphenols, including the secoiridoids oleocanthal (OLC) and oleacein (OLE), are attracting attention because of their beneficial effects on health. Data on OLC and OLE bioavailability are scarce, as most research on EVOO polyphenols has concentrated on hydroxytyrosol, tyrosol, and oleuropein. Consequently, relevant goals for future research are the elucidation of OLC and OLE bioavailability and finding evidence for their beneficial effects through pre-clinical and clinical studies. The aim of this review is to shed light on OLC and OLE, focusing on their precursors in the olive fruit and the impact of agronomic and processing factors on their presence in EVOO. Also discussed are their bioavailability and absorption, and finally, their bioactivity and health-promoting properties.


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Extra virgin olive oil (EVOO) is a staple of the Mediterranean diet and is highly appreciated 39 for its unique nutritional and organoleptic attributes (Polari et al. 2018). A Mediterranean diet 40 rich in EVOO may prevent type 2 diabetes, cancer, neurodegenerative and cardiovascular 41 diseases (Anna Tresserra-Rimbau et al. 2011;A. Tresserra-Rimbau et al. 2014;Martínez-alcohols (Muriana et al. 2017) released into the aqueous phase and becoming available for 188 absorption. SEC remain highly stable during digestion in the mouth, whereas in the gastric, 189 duodenal and colonic regions they undergo important losses; their recovery index in the 190 duodenal step was found to oscillate between 7 and 34% (Quintero-Flórez et al. 2017). 191 Studies indicate that SEC, which are apparently not absorbed in the small intestine, are likely 192 to reach the large intestine to be degraded by the colonic microflora (Corona et al. 2006). 193 Some authors suggest that the breakdown of the ester bond of OLC is relatively probable, 194 either in acidic or alkaline conditions or by esterases located in the small intestine or the liver 195 (Rubió et al. 2012) (Fig 2). 196 The absorption of SEC is not well elucidated, a possible mechanism being passive 197 diffusion (Scalbert and Williamson 2000). SEC are a group of coumarin-like compounds, 198 which are usually glycosidically bound (Corona et al. 2006). The absorption of SEC through 199 passive diffusion would therefore require the removal of the attached glycosyl moiety 200 (Vissers et al. 2002) by enzymes (glycosidases), which can be present in the gastrointestinal 201 mucosa or secreted by the colon microflora (Scalbert and Williamson 2000). 202 Another pathway of polyphenol absorption is the one supported by Hollman et al. 203 (1999), who described how glucosides can promote polyphenol absorption across the 204 intestinal epithelium. They suggested this occurs by interaction with the sodium-dependent 205 glucose transporter SGLT1 or, as mentioned above, by the action of glycosidases (Hollman et 206 al. 1999).

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The metabolism of SEC can be carried out by phase I (hydrogenation, hydroxylation, hydration, etc.) or phase II reactions (glucuronidation, methylation, sulphation, etc.). The 213 OLC metabolites found in plasma and urine are the result of hydrogenation, hydration (Silva 214 et al. 2017a;García-Villalba et al. 2010), hydroxylation and glucuronidation (García-Villalba 215 et al. 2010) and are formed mainly in the small intestine and liver. 216 Although the liver appears to be the major organ involved in glucuronidation, high 217 levels of some UGT isoforms are found in the kidney and intestine, suggesting that  conjugates have been identified in one study (Suárez et al. 2011) in plasma samples, 230 suggesting the presence of enzymatic activity able to methylate tyrosol-like molecules such as 231 OLC.

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Sulfotransferases catalyze the transfer of a sulfate moiety from 3'-phosphoadenosine-233 5'-phosphosulfate to a hydroxyl group on various substrates (steroids, bile acids, polyphenols, 234 etc.), and the reaction occurs mainly in the liver rather than in the small intestine (64). These 235 enzymes could sulfate OLC and OLE, but no sulfate metabolites of OLC have been identified 236 in any study in humans to date (Silva et al. 2017a;García-Villalba et al. 2010). A possible reason for the absence of such metabolites is that OLC inhibits the sulfotransferases by 238 mimicking the activity of other polyphenols (Gee et al. 1998;Burchell and Coughtrie 1997).

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Another plausible explanation is that sulfation is generally a higher-affinity, lower-capacity 240 pathway than glucuronidation in the same substrate, which if ingested at higher doses results 241 in a shift from sulfation toward glucuronidation (Koster et al. 1981 (Goldring and Otero 2011). The down-regulating effect of OLC on these cytokines and mediators has been determined (Iacono et al. 2010;287 Morena Scotece et al. 2012).

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In a study carried out by Iacono and co-workers (Iacono et al. 2010

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Cancer is a multifactorial disease characterized by uncontrolled cell proliferation with 307 the potential to invade or spread to other parts of the body. To control this abnormal cell 308 growth, anti-cancer drugs are designed to reduce cell proliferation and to promote cell death 309 (Thurston 2006). Studies have shown that OLC exhibits anti-cancer activity in both processes Cancer proliferation can be controlled by tyrosine-protein kinase Met (c-Met) 312 phosphorylation. In vitro studies have shown that OLC is able to reduce the expression of the 313 c-Met receptor, which seems to be involved in tumor growth, survival and angiogenesis (Akl 314 et al. 2014;Elnagar, Sylvester, and El Sayed 2011). OLC also inhibits the heat shock protein 315 (Hsp90), which leads to an improper folding of the tumor cell proteins and finally to a 316 decrease in tumor growth (Margarucci et al. 2013). Another target of OLC is the transcription 317 factor STAT3, whose downregulation blocks its products, resulting in an inhibition of 318 hepatocellular carcinoma cell growth and metastasis, both in vitro and in vivo (Pei et al. 2016; 319 Gu, Wang, and Peng 2017). OLC also has the ability to downregulate the extracellular signal- The OLC neuroprotective effect has been mainly studied in Alzheimer's disease (AD), 355 due to the latter's prevalence in current society, but it has also been found useful for treating 356 traumatic brain injury. The major effect of OLC on neurological diseases is linked to a 357 capacity to reduce oxidative stress and prevent apoptosis in neuronal cells (Mete et al. 2017).

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AD is a slow-progressing neurodegenerative disorder characterized by the misfolding, 359 aggregation and increased toxicity of the β-amyloid peptide and tau protein in the brain. The 360 misfolded protein and peptide act as a prion inside the brain, causing aggregation and inducing neuronal apoptosis and inflammatory signals (Nussbaum, Seward, and Bloom 2013).

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OLC reduces AD symptoms by acting on both β-amyloid and tau, and lessening their toxicity. 363 Firstly, OLC inhibits mTOR, which is involved in the synthesis of β-amyloid and tau 364 (Khanfar et al. 2015). Secondly, it is able to change the β-amyloid structure, resulting in a 365 protein that is easier to eliminate, less reactive and less toxic (Qosa et al. 2015;Abuznait et al. 366 2013; Pitt et al. 2009;Batarseh et al. 2017). Thirdly, OLC can inhibit the fibrillation of the tau 367 protein, modifying it to a conformationally more stable secondary structure, hence preventing 368 its abnormal functionality (Monti et al. 2012;Li et al. 2009). OLC induces P-glycoprotein 369 expression and functionality, which is responsible for β-amyloid clearance (Shinde et al.