Healthy Effects of Plant Polyphenols: Molecular Mechanisms.

1. Introduction

Human beings in advanced countries are experiencing an increasing extension in life expectancy, yet at the cost of a progressively greater prevalence of a number of diseases associated with lifestyle and age. The latter include widespread pathologies such as cancer, metabolic disease such as type 2 diabetes mellitus (T2DM), hepatitis and the metabolic syndrome (MetS), cardiovascular diseases (CVDs), and amyloid diseases, both systemic and neurodegenerative, particularly Alzheimer’s (AD) and Parkinson (PD) diseases. Among the latter pathologies, amyloid diseases, both the sporadic and the early onset familial forms, are substantially intractable. In particular, most sporadic amyloidoses are characterized by slow progression, often covering several decades, and their clinical signs appear only at mid- or old age, when they are irreversible due to conspicuous cell loss. It is then evident that the absence of fully reliable early diagnostic tools and of resolutive therapies, particularly in the case of amyloid diseases, calls for prevention in the role of best approach to face these pathological conditions.

Following the considerations reported above, it is not surprising that research has progressively shifted from a “cure” to “prevention” focus, in addition to the “drugs”, and the “lifestyle” concept, including “diet”, and hence “food”. Many epidemiological and observational studies support the idea that the Mediterranean diet (MD) and the Asian diet are associated with “safe” aging, with a reduced prevalence of diseases associated with aging including CVDs, cancer, and cognitive decline [ 1 ]. The MD is the result of a complex socio-economic development of the Mediterranean populations in which agricultural, social, territorial, and environmental practices represent a heritage intimately associated with their culture and lifestyle that has been passed through several generations over many centuries. The great value of the MD and the associated lifestyle has been recognized by the “Organizzazione delle Nazioni Unite per l’Educazione, la Scienza e la Cultura“ (UNESCO) that, since November 2010, has inscribed the MD in the list of the intangible cultural heritage of humanity ( https/ich.unesco.org/ ). Recently, the “Mediterranean Diet Foundation Expert Group” has proposed a new MD pyramid [ 2 ]; the latter, besides confirming the importance of the daily assumption of substantial amounts of vegetables, fruits, legumes, grains, nuts, seeds, and, in particular, of a moderate intake of red wine and of extra virgin olive oil (EVOO) as the main lipid source, also emphasizes a healthy lifestyle where, in addition to caloric restriction (CR), frugality, moderation, adequate rest, conviviality, culinary activities, and physical exercise play an important role.

A key aspect of the MD is the high assumption of phytonutrients (particularly vitamins and plant phenols) that, by themselves, interfere with multiple signaling pathways involved in protein homeostasis, DNA repair, metabolism regulation, and antioxidant defenses that, in most cases, recall CR [ 3 , 4 ]. Many available data and population studies suggest that greater adherence to the MD reduces metabolic pathologies and aging-associated deterioration; these data have been further supported by a number of clinical trials carried out by administering foods enriched in specific polyphenols to patients at cardiovascular or neurodegeneration risk, suffering from metabolic diseases, or affected by some forms of cancers (see below). Biophenols are found in many foods of plant origin that are key components of the MD and the Asian diet; these include red wine, EVOO, green tea, spices, berries, and aromatic herbs that ensure a continuous daily moderate intake of these substances during lifespan. Hence, the presence of substantial amounts of polyphenols in the diet may provide a rationale for the results of the large number of population studies and clinical trials supporting the idea that an association does exist between dietary practices, their content in polyphenols, and a significant reduction of the incidence of many aging-associated diseases [ 5 ].

The studies carried out during the last decade have highlighted the fact that, in the case of amyloid diseases and several other aging-associated pathologies, plant polyphenols do not simply affect a single step of the pathogenesis of these diseases such as the aggregation path of the involved protein/peptide, the inflammatory response, the alteration of the proteostatic network, and/or the oxidative stress; rather, the biological and functional features of their positive outcomes result from multi-target effects that restore several altered homeostatic systems in the cells and tissues where impaired metabolism or protein/peptide aggregation occur. Moreover, these molecules share key chemical features that, at least in part, explain why most of them, although chemically different, induce similar effects. Recent research is increasingly shedding light in the biochemical, cellular, and epigenetic modifications produced by a number of investigated plant polyphenols, with special emphasis on the olive ones, and the ensuing modulation of key cellular processes such as metabolic/energetic/redox homeostasis, proteostasis, signaling, and control of oxidative stress and of gene expression. These data are providing the knowledge needed to fully understand the beneficial effects of the MD and the Asian diet and the importance of plant polyphenols for human wellness and as possible tools useful in disease prevention and, possibly, therapy.

Here, we summarize the results of the studies on a number of plant polyphenols, with particular emphasis on those found in the olive leaves and drupes and in the EVOO, particularly oleuropein aglycone (OLE) and hydroxytyrosol (HT). We also provide data on the population surveys and clinical trials supporting the beneficial effects of the MD, its content in fruit, vegetables, herbs, and EVOO, and the intake of these molecules. We also focus the main molecular mechanisms by which plant polyphenols ensure protection against a number of age-related pathologies, in light of the recently proposed hormetic theory (see below); the molecular determinants underlying such protection both in biological models such as cultured cells and animals and the most recent advances towards their possible use in prevention and, possibly, as co-adjuvants in clinical treatment of neurodegenerative diseases, CVDs, cancer, T2DM, and the MetS are also discussed.

2. Polyphenols: Important Players of the Mediterranean/Asian Diets

Natural biophenols are a wide group of molecules (over 8000 described so far) found only in the plant kingdom; their molecules display one or more aromatic rings carrying one or more hydroxyl groups; these molecules display remarkable antioxidant power and are produced as secondary metabolites by the plant for protection against the attack by bacteria, fungi, and insects (phytoalexins) [ 1 ]. Plant polyphenols include non-flavonoids or flavonoids; the latter are further divided into flavonols, flavononols, flavones, anthocyanins, procyanidins, phenolic acids, stilbenes, and tannins depending on the number of hydroxyls in the molecule and on the nature and the position of other substituents [ 6 ]. The natural phenols most studied for their healthy properties ar curcumin, a phenolic acid found in the rhizome of Curcuma longa Linn (family Zingiberaceae) and a component of the curry; epigallocathechins, notably epigallocatechin-3-gallate (EGCG), the flavanol found in green tea; resveratrol (3,5,4′-trihydroxy- trans -stilbene), a stilbene found in grapes and in red wine; quercetin and myricetin, flavonols present in tea, onions, cocoa, red wine, and in Ginkgo biloba extracts. Many other plant phenols or their metabolic derivatives have also been investigated, yet with variable results; these include tannic, ellagic, ferulic, nordihydroguaiaretic and caffeic acid, morin, rutin, apigenin, baicalein, kaempferol, fisetin, luteolin, rottlerin, malvidin, piceatannol, and silibinin.

More recently, particular interest has been dedicated to the polyphenols present abundantly in the leaves and in the ripening fruits of the olive tree ( Olea europaea ); including flavonols, lignans iridoids, and their glycosides. Iridoids are monoterpenes containing a cyclopentane ring fused to a six-atom heterocycle with an oxygen atom, whereas the molecules where the cyclopentane ring is interrupted are indicated as secoiridoids. The most abundant polyphenols found in the EVOO include the secoiridoids oleuropein and ligstroside, both in the glycated and in the aglycone forms, and their main metabolites: The phenolic alcohols tyrosol (p-hydroxyphenylethanol, p-HPEA) and hydroxytyrosol (3,4-dihydroxyphenylethanol, 3,4-DHPEA), oleacein, and oleocanthal. Oleuropein confers the bitter taste to the olive leaves, drupes, and EVOO, whereas oleocanthal produces the burning sensation in the back of the throat when consuming EVOO [ 7 , 8 ]. Phenolic concentration in plants depends on several variables; in the olive tree, and hence in the EVOO, these include (i) olive cultivar and stage of ripening [ 9 ]; (ii) environmental cues (altitude, cultivation practices, meteorological factors, and irrigation); (iii) technological aspects such as extraction conditions (temperature and others) and systems to separate oil from olive pastes; and (iv) storage conditions and time, due to spontaneous oxidation, and deposition of suspended water droplets with their content of polyphenols [ 10 ]. At the best, polyphenol content in the EVOO can exceed 60 mg/100 g.

Plant polyphenols have been considered for their remarkable antioxidant properties; however, their effects go well beyond this property. In fact, plant polyphenols have been shown to possess beneficial effects against aggregation of peptides/proteins into amyloid assemblies, a process involved in several amyloid diseases, particularly T2DM, AD, and PD, thus reducing the load of intra- or extracellular deposits [ 1 ]. T2DM is characterized by aggregates of the peptide amylin in insulin-secreting pancreatic β-cells; AD results from the extracellular amyloid aggregation of the Aβ peptide (mostly Aβ 1–42 ) in senile and neuritic plaques and the intracellular aggregation into neurofibrillary tangles of tau protein; these aggregates are found in specific brain areas, notably the hippocampus and the pre-frontal cortex. PD results mostly from the aggregation of α-synuclein into intracellular Lewy bodies found in the neurons of the mesencephalic substantia nigra . Actually, olive polyphenols, notably OLE and its main metabolite, HT, have been reported to be effective against amyloid aggregation and the ensuing pathologic effects in T2DM [ 11 , 12 ], AD [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ] and, possibly, in PD [ 20 , 21 ] and other amyloidoses. Plant polyphenols, including those enriched in EVOO, have also been reported to reduce insulin resistance and to improve impaired glucose homeostasis, two main signs of T2DM. Considering that increasing evidence supports a strong link between diabetes (mainly T2DM) and neurodegeneration associated with AD [ 22 , 23 ], it is conceivable that many plant polyphenols can interfere with both pathologies at similar molecular levels.

The beneficial effects of plant preparations and derivatives, including, in the case of olive, oil and leaf extracts, have already been known for the last couple of centuries and have been scientifically investigated over the recent several decades; these researches have progressively led to a focus on the multi-target activity and health properties of plant polyphenols, including the anti-amyloid aggregation, antioxidant, antimicrobial, antihypertensive, hypoglycemic, and vasodilator effects. The antioxidant power has been shown to involve modulation of oxidative pathways [ 2 ], direct action on enzymes, proteins, receptors, and several types of signaling paths [ 3 , 4 ], as well as the interference with epigenetic modifications of chromatin [ 24 ] (see below). The clinical significance of the beneficial properties of plant polyphenols was first reported in 1950 [ 25 ], leading to the inclusion in the European Pharmacopoeia (Ph. Eur.) of the 80% alcoholic extract of olive leaves, containing oleuropein, HT, caffeic acid, tyrosol, apigenin, and verbascoside [ 26 , 27 ]. Biophenols can also be used to develop new drugs useful to combat chronic inflammatory conditions, the risk of thrombosis, CVD-related states such as atherosclerosis [ 28 ], cancer [ 29 ], also in combination with anti-cancer drugs [ 30 ], as well as to reduce amyloid deposition associated with T2DM and aging-related states such as neurodegeneration [ 1 , 31 ] ( Figure 1 ). Finally, the molecular scaffolds of plant polyphenols are also investigated to develop new molecules potentially exploitable in disease prevention and therapy [ 32 ].

The beneficial effects of olive and other plant polyphenols can be hindered by the reduced bioavailability of the latter following reduced intestinal absorption and their rapid biotransformation in the organism; in addition, chemical modifications of many polyphenols by gut microbiota further reduces their bioavailability and biological efficacy [ 33 ]. Several strategies to overcome reduced bioavailability have been proposed, including encapsulation within nanoparticles [ 34 ], self-microemulsifying formulations [ 35 ], and others (reviewed in [ 36 ]). Yet, several studies have shown that many plant polyphenols, including EVOO polyphenols, are absorbed, although in reduced amount, by humans and distributed, in part, to organs and tissues before completion of their secondary metabolism, degradation, and excretion [ 37 , 38 , 39 ]. Moreover, some OLE metabolites, notably HT, arising mainly from acid hydrolysis in the stomach, have been found in the brain of TgCRND8 mice and rats after an acute oral administration of either OLE or HT, which supports the ability of OLE and some of its derivatives, including HT, to cross the blood–brain barrier [ 40 , 41 ]. In particular, convincing evidence indicates that HT is dose-dependently bioavailable; it is substantially (40%) absorbed and reaches maximum concentration in plasma after 5–30 min from EVOO ingestion, with a calculated total bioavailability around 10% due to metabolic modifications in the gut and in the organism through phase II conjugation reactions [ 42 ]. Thus, in spite of reduced information on many aspects of their pharmacokinetics, pharmacodynamics, and metabolic modifications by gut microbiota and in the organism, oral assumption of plant polyphenols results in partial absorption and distribution to the whole organism (reviewed in [ 43 ]).

3. The Beneficial Effects of Plant Polyphenols Are Supported by Population Studies and Clinical Trials

A wealth of currently available data arising from population studies suggest that greater adherence to the MD improves healthy aging by reducing the risk of cardiovascular diseases (CVDs), metabolic pathologies, cancer, and aging-associated mental deterioration; in particular, it enhances cognitive function and reduces both the risk of developing mild cognitive impairment and of its conversion to AD [ 44 , 45 ]. The beneficial effects of the MD have been related to the presence, in the latter, of many polyphenols, particularly those enriched in fruits and vegetables, in red wine, and in EVOO (reviewed in [ 1 , 43 ]). The importance of the content of polyphenols (EGCG, OLE, HT, resveratrol, curcumin, quercetin, morin, myricetin, and many others) in the MD has been confirmed by many population studies and clinical trials.

Over 60 years ago, the first large-population study on the diet–health relation, the “Seven Countries Study”, reported quite a low rate of cardiovascular mortality in Crete farmers, though in the presence of a large intake of lipids, and related that finding to their MD (reviewed in [ 46 ]). Some years later, other studies confirmed and extended these results. The “Lyon Diet Heart Study” further supported the MD–myocardial infarction relation, leading to the conclusion that the MD may delay considerably, up to 46 months, the rate of recurrence [ 47 ]. The “Three-City Study”, conducted on 7000 elderly subjects, is one of the most cited studies on the protection by olive oil against neurodegeneration and cognitive decline. The results of the study, published in 2009, showed a lower rate of cognitive deficit in subjects whose diet was characterized by the presence of variable amounts of olive oil with respect to the subjects using other lipids [ 48 ].

More recently, the randomized “PREvención con DIeta MEDiterránea” (PREDIMED) and PREDIMED-NAVARRA studies have been conducted in Spain on subjects at high cardiovascular risk (477 and 522 participants, respectively) [ 49 , 50 , 51 ]. In particular, the PREDIMED-NAVARRA study was originally carried out on high-cardiovascular-risk asymptomatic subjects (187 people, 67 years mean age) on MD supplemented with olive oil, with nuts, or at control diet to test the effect of the two types of MD on the progression of subclinical carotid atherosclerosis. The results showed significant improvement in mean intima-media thickness with regression of carotid atherosclerosis after one year in people on either MD [ 52 ]. The PREDIMED study was a primary prevention trial originally designed to test the long-term effects of the MD on the incidence of CVDs in people at high cardiovascular risk; the trial suggested that olive oil consumption matches reduced risk and mortality for CVDs [ 53 , 54 ]. The same cohort was also checked for cognition, which was significantly improved in people following an EVOO-enriched MD [ 49 , 51 ]. The study also investigated breast cancer incidence in the same cohort, leading to the conclusion that the risk of developing cancer was reduced by 68% in the EVOO group [ 55 ]. Finally, data from a subsample ( n = 990) of the PREDIMED study showed that the MD significantly decreased low-density lipoproteins (LDL) oxidation only when it was enriched in EVOO with medium-high phenolic content [ 56 ].

More recently, a cross-sectional sampling population study was carried out among Spanish people in 100 health centers, where 4572 individuals aged > 18 years, representative of the Spanish population, were analyzed on the basis of their use of olive or sunflower oil. According to the study, the intake of olive oil resulted as beneficial against several cardiovascular risk factors, particularly in obese people with a sedentary lifestyle, impaired glucose tolerance, and insulin resistance [ 57 ]. Another study carried out in the USA investigated the relation between intake of olive oil and incidence of T2DM; the study followed 59,930 women (35–65 years) for 22 years from the Nurses’ Health Study and 85,157 women (26–45 years) from the NHS II with no diabetes, CVDs, or cancer at baseline. The results indicated that a slightly lower risk of T2DM was associated with higher olive oil intake, whereas an increased risk was associated with the assumption of other lipids in place of olive oil [ 58 ].

A very recent crossover study carried out with 25 healthy subjects randomly distributed to a MD without EVOO or supplemented with 10 g EVOO/day concluded that EVOO reduces post-prandial levels of LDL-cholesterol and glucose, further supporting the positive effects of the MD against atherosclerosis [ 59 ]. Moreover, a small crossover trial (Trial number: ISRCTN09220811) was conducted in the context of the “EUROLIVE” study with 200 participants who, after a two-week washout, assumed 25 mL of olive oil with different phenolic content three times in a day for three weeks. The results indicated a linear decrease of the oxidative stress markers ratio and of the total cholesterol/HDL-cholesterol matching the content of polyphenols in olive oil [ 60 ]. A subset of the same trial suggested protection against atherosclerosis [ 61 ]. Another subset of the study confirmed that the phenolic content in olive oil increases human HDL functionality by favoring HDL-mediated efflux of cholesterol from macrophages [ 62 ]. In another multicenter trial in Spain, 7447 participants (55–80 years) at high cardiovascular risk, but with no CVD at enrollment, were assigned to a MD supplemented with EVOO, a MD supplemented with mixed nuts, or a control diet (with reduced fat). The authors reported that the incidence of major cardiovascular events was lower in the participants on an EVOO- or nut-supplemented MD than in those at a diet with reduced fat. [ 63 ].

In 2010, a study with 20 patients with the MetS showed that the acute intake of olive oil fortified with olive polyphenols resulted in positive changes of the postprandial expression of disease-involved genes in mononuclear cells from peripheral blood [ 64 ]. Studies were also carried out to determine the effects of an acute administration of olive oil, particularly in the case of protection against postprandial hyperlipidemia and the associated inflammation. Another research conducted on 20 obese subjects showed that oils rich in phenols reduced postprandial inflammation by lowering the levels of pro-inflammatory cytokines and by activating nuclear factor κB (NF-κB) [ 65 ]. Some other studies reported a remarkable delay in living day activities decline together with improved cognition, psychopathology, and quality of life of the involved people [ 66 , 67 , 68 ]. Recently, a study carried out on 62 institutionalized elderly humans fed with EVOO showed a significant improvement of their redox status, with positive effects on lipid profiles and total antioxidant capacity, significantly increased activity of catalase in erythrocytes, and decreased activity of superoxide dismutase and glutathione peroxidase [ 69 ]. Finally, a systematic review evaluated the effect of the intake of olive oil with high or low polyphenol content on CVDs risk factors, as emerged in a number of clinical trials; the study concluded that polyphenol-rich olive oil confers some benefits resulting in reduction of CVD-risk, even though the authors claimed that more prolonged studies in non-Mediterranean populations were needed to better validate the data [ 70 ].

The reported observational studies, population surveys, and randomized controlled trials on the MD–cardiovascular health relation have been critically reviewed very recently. The study included the five most comprehensive meta-analyses published in the 2014–2018 period together with additional prospective studies for a total of 45 reports. The authors concluded that higher conformity to the traditional MD matches better cardiovascular health outcomes in terms of reduced rates of coronary heart disease, ischemic stroke, and CVD [ 71 ]. In spite of the existence of remarkable differences among the investigated populations, the results of other studies substantially confirmed the studies reported above and also highlighted a beneficial effect of the MD against cognitive deterioration, particularly in AD and PD (reviewed in [ 72 ]) and against cancer. In particular, a study carried out in Australia and New Zealand (ACTRN12613000602729) showed that a cause–effect relationship does exist between MD and aging-dependent impairment of cognition [ 73 ]; these results were confirmed by a study carried out with a cohort of aged people, the “Prevenciòn con Dieta Mediterrànea Nutrition Intervention Trial” (ISRCTN35739639), where a significant improvement of cognitive behavior following MD supplementation with olive oil or nuts was reported [ 74 ].

Several clinical studies, mostly carried out with a limited number of patients, sought to unravel the role played by specific polyphenols in the MD against the same pathological conditions, yet with variable results. The effects of curcumin against AD have been investigated in four clinical trials (reviewed in [ 75 ]); two studies reported that no significant differences were found between placebo- and curcumin-treated groups where cognition, plasma, and cerebrospinal fluid (CSF) biomarkers were concerned [ 76 , 77 ]; these data were confirmed by other, more recent, trials with no solid results on protection by lipidated curcumin against neurodegeneration in AD [ 78 ]. Over 244 clinical trials, with an additional 27 clinical trials currently ongoing, investigated the healthy effects, safety, and pharmacokinetics of resveratrol. Resveratrol administration gave positive results in patients suffering from diabetes mellitus, obesity, MetS, hypertension, stroke, CVDs, colorectal and breast cancer, multiple myeloma, AD, inflammatory diseases, and others, as summarized in a very recent review [ 79 ]. Other clinical trials reported a positive modulation by resveratrol of enzyme systems involved in carcinogen activation and detoxification together with some improvement of cerebral blood flow (reviewed in [ 80 ]). Recently, a clinical trial with trans -resveratrol was conducted on 28 obese men with the MetS and insulin resistance in the metabolic unit of the Rockefeller University Hospital. The subjects randomly received 1 g resveratrol orally twice a day for 35 days while consuming a Western-style diet. The subjects were tested for glucose tolerance, energy expenditure at rest, blood pressure, and abdominal adipose tissue. The results indicated that resveratrol altered glucose homeostasis only slightly except in a small group of Caucasians, where it improved insulin resistance and glucose homeostasis [ 81 ]. The beneficial effects of green tea, particularly of epigallocatechins, have been largely investigated even in clinical trials addressing their anti-cancer properties; however, the reported data do not permit to draw solid conclusions indicating a decreased risk of breast cancer by green tea consumption, due to the high heterogeneity of case-control and cohort studies (reviewed in [ 82 ]). Recently it has been suggested that green tea and/or green tea extracts inhibit the progression of cardiac amyloidoses [ 83 ]; however, currently, reduced information is available in humans on the protection against amyloidoses and amyloid-associated neurodegeneration specifically attributable to EGCG. Finally, Ginkgo biloba extracts were administered in several clinical trials carried out in aged people, both healthy, demented, or after ischemic stroke. Some of these studies yielded positive outcomes for what protection against cognitive decline was concerned (reviewed in [ 84 ]). The positive effects of plant polyphenols against breast, colon, and colorectal cancer, as emerged from clinical trials, preclinical studies, and primary research, have been recently reviewed critically [ 85 , 86 , 87 , 88 ].

Clinical studies involving specific olive polyphenols are still in their infancy. In 2012, the efficacy of an olive leaf extract as a hypoglycemic agent both in diabetic rats and in humans with improved glucose homeostasis, reduction of fasting plasma levels of insulin and glycated hemoglobin was reported [ 89 ]. Soon after, the antidiabetic properties of this polyphenol were further supported by the results of a randomized, placebo-controlled, crossover trial carried out with 46 middle-aged overweight men; the study confirmed the improvement of glucose homeostasis with a reduction of glycated hemoglobin and fasting plasma insulin levels in the enrolled patients [ 90 ]. More recently, the results of a randomized controlled clinical trial carried out with 60 pre-hypertensive males fed for six weeks with an olive leaf extract containing 136 mg of OLE and 6 mg of HT agreed with previous data, indicating the hypotensive and lipid-lowering effects associated with OLE intake [ 91 ]. Olive leaf extracts also improve human vascular function, as indicated by a randomized, double-blind, placeb-controlled, crossover trial carried out with nine healthy males and nine healthy females on a normal diet or on a diet supplemented with 51 mg of OLE and 10 mg of HT (four-week washout) [ 92 ]. A recent study aimed at identifying modifications of gene and miRNAs expression following intake of high- or low-polyphenols EVOO was carried out in 12 healthy subjects and 12 patients with the MetS by using microarray and real-time PCR (RT-PCR). Gene and miRNAs expression analysis in PBMCs prior of after EVOO administration showed that high-polyphenols EVOO induced modifications of the transcriptome in the investigated cells; in particular, a number of pathways associated with pathophysiological alterations of CVDs, metabolic diseases, and cancer were modulated. In healthy subjects, the acute intake of EVOO enriched in polyphenols not only resulted in improved glycaemia and decreased insulin resistance, but also modulated the transcription of genes and miRNAs involved in metabolism, inflammation, and cancer, inducing a less severe inflammatory phenotype in peripheral blood mononuclear cells (PBMCs); weaker effects were described in patients with the MetS as well as in healthy subjects administered with low-polyphenol EVOO [ 93 ]. Comparable results were reported in a study where the effects of HT on the expression of inflammation-related genes were investigated by RT-PCR in Simpson Golabi Behmel Syndrome (SGBS) adipocytes in terms of mRNA and microRNA levels. The results indicated that HT modulates the expression of adipocyte genes through oxidative stress reduction and inhibition of NF-κB, thus hindering macrophage recruitment and reducing the deregulation of signaling pathways involved in pathologies associated with obesity, with overall improvement of the inflammatory state of the adipose tissue [ 94 ]. Another recent randomized controlled trial was carried out with 22 healthy volunteers at post-prandial assumption of 25 g of polyphenols-enriched EVOO. After 2 h from the intake, a significant improvement of the redox, inflammatory, and metabolic status was detected, with decrease of oxidized LDL, malonyldialdehyde, triglicerides, and visceral adiposity index, resulting from upregulation of superoxide dismutase 1, catalase, and upstream transcription factor 1 [ 95 ]. Finally, a systematic review of randomized controlled trials aimed at focusing the state of the art of the relation between daily polyphenol consumption, circulating CVD biomarkers, and iron level has been undertaken very recently. The reported results involved seven studies that agreed with the inclusion criteria, and indicated that the intake of polyphenols results in a significant improvement of the inflammatory biomarkers and lipid profile without any interference with iron levels [ 96 ].

Many other trials carried out with a number of other plant biophenols, in most cases, gave positive outcomes against the same pathologies as those reported above. Taken together, the clinical trials data appear encouraging, yet in the absence of definitive results on the effective benefits of the various investigated polyphenols against a number of pathologies, and on the effective doses at which these effects are fully reached. In particular, large clinical trials aimed at evaluating effective protection by specific polyphenols against the most widespread neurodegenerative diseases are still lacking. In conclusion, clinical trials and population studies support consistent and effective protection by the MD and Asian diet, particularly associated with the prolonged intake of their polyphenols, against the insurgence of aging-associated pathologies, notably neurodegeneration, CVDs and metabolic diseases, and, possibly, cancer ( Table 1 ). In particular, taking into consideration the positive results of the large number of clinical and population studies supporting the healthy power of olive polyphenols, in November 2011, the European EFSA authorized a claim stating the benefits of the assumption of olive oil polyphenols, suggesting a daily intake of 5 mg ( http://www.efsa.europa.eu/ ).

4. Hormesis: A New General Concept Supporting Polyphenol Benefits

Hormesis is defined as any process in a cell or an organism characterized by a biphasic response to the exposure to increasing amounts of a stressing condition or substance (stressor) [ 98 ]. Generally, a favorable biological response to low exposure to any stressor is found within the hormetic zone, whereas cell damage occurs at higher doses ( Figure 2 ). Plant polyphenols are produced by plants to defend themselves against pests such as bacteria, fungi, and insects, to which they are toxic. Such toxicity is not seen in higher animals at the maximal doses so far used experimentally, reaching 10 g/day in the case of resveratrol. However, these polyphenols act as stressors to the exposed animal cells, with the result of activating various cell defense systems aimed at controlling the redox environment, the proteostatic and metabolic homeostasis, organelle turnover, the inflammatory response, and others, thus making cells more resistant to subsequent toxic stimuli, particularly in aged people.

In addition to many substances, including alcohol and many plant molecules, notably polyphenols, most stressors include physical agents and lifestyle such as physical exercise, CR, and, possibly, mild oxidative stress, while the role of low doses of ionizing radiations is debated. When assessed over a broad dose–response range, all these agents display a hormetic-biphasic dose–response relation. The biphasic dose–response results in low dose stimulation and high dose inhibition. Typically, the highest stimulatory responses are only about 30%–60% greater than in the control group [ 99 , 100 , 101 ]. It is within the low-dose stimulatory range where health benefits associated with polyphenols occur. While maximum stimulatory responses have been shown to be highly consistent in the 30%–60% stimulatory range, the hormetic stimulatory dose range can be quite valuable, depending on the agent, model, and endpoint agent, with the stimulatory dose zone typically being in the 5–50-fold dose range below the threshold. However, it is not uncommon for the stimulatory dose range to be in the 100- to 1000-fold dose range. These quantitative features can have important public health implications since a primary goal is to optimize the beneficial response while avoiding toxicity at higher doses. A more extensive assessment of the occurrence of hormesis [ 102 ] and its mechanistic foundations [ 103 ] is provided in these references. Several examples of hormetic dose responses for constituents of olive oil/olive leaf extracts are provided in [ 104 , 105 , 106 , 107 ] and in Figure 3 .

5. Plant Polyphenols Rescue Altered Homeostatic Systems in Cells

5.1. Redox Homeostasis and the Inflammatory Response

Emerging research has recently focused on biological relevance for cell protection in many degenerative diseases and for neuroprotection in several neurodegenerative disorders, particularly AD and PD, of the redox homeostasis elicited by plant polyphenols through the activation of vitagene signaling pathways. The latter involves redox sensitive genes such as the Hsp70, heme-oxygenase-1 (HO-1), thioredoxin/thioredoxin reductase, and sirtuins system [ 108 ]. All these cytoprotective genes can be transcriptionally modulated by the nuclear factor erythroid 2–related factor 2 (Nrf2) as a part of the electrophile counterattack, defined phase 2 response. Nrf2 is a key transcription effector for the activation of wide range of cytoprotective genes (>500). The Nrf2 activity induces a mild stress response, providing a healthy physiological steady state and extending lifespan in different cells and animal models. On the other hand, a chronic long-term Nrf2 stimulation may lead to pathophysiological events, therefore the Nrf2 signaling can be considered as a hormetic-like pathway [ 109 , 110 ]. Increasing evidences show that plant polyphenols activate the phase 2 response leading to the expression of various Nrf2-dependent antioxidant vitagenes. These effects represent a powerful instrument supporting redox homeostasis under stressful conditions [ 111 ] and support the assumptions that the helpful properties of polyphenols carry out through adaptive stress response vitagenes. Within this context, both heme oxygenase-1 (HO-1) and Hsp70 have received considerable attention for their recognized antioxidative function needed to maintain cell homeostasis [ 112 ]. Moreover, the well-known principle of hormesis may be applied also to HO-1. In fact, although several studies have shown the crucial role of HO-1 activity against oxidative and nitrosative stress [ 113 , 114 ], excessive upregulation of HO-1 system may be deleterious for cells, because of accumulation of its by-products such as carbon monoxide (CO), iron, and the bilirubin precursor, biliverdin [ 115 ]; in light of the concept of hormesis, it is reasonable to look at these by-products of HO1 activity in terms of their positive effects obtained at very low concentrations.

As reported by Naviaux and coworkers [ 116 ], the hormetic response is activated when chemical-physical or biological hazards surpass the cellular capacity for homeostasis. The ensuing disruption of homeostasis induces a cascade of deleterious molecular changes in cells involving electron flow, oxygen consumption, and redox potential, that result in alterations of cellular structures and processes, including membrane fluidity, bioenergetics, protein folding, and misfolding. An increasing body of evidence shows that most chronic diseases arise from the biological response to a stress factor, not from the initial injury, or from the agent of the injury itself. The initial components of this cascade elicit the release of ATP, ADP, metabolic intermediates of Krebs cycle, oxygen, and reactive oxygen species (ROS) that is sustained by purinergic signaling pathway [ 116 ]. The anti-inflammatory and resilience phenotypes arise from these initial adaptive processes eventually mediate protection from a variety of potential injuries.

Dietary plant polyphenols that act as powerful antioxidants may block/abolish the anti-inflammatory phenotype that results from a redox regulatory signaling pathway [ 117 , 118 , 119 , 120 ]. More recent findings suggest that the biphasic dose responses of hormetic type are common effects of plant polyphenols. Interestingly, plant polyphenols are considered as a “preventive treatment of disease” inducing biological effects with important therapeutic applications to in vitro and in vivo models through the activation of adaptive responses [ 121 ]. Currently, increasing evidence suggests that plant polyphenols such as curcumin, sulforaphane, resveratrol, HT, and OLE may offer beneficial effects acting in a hormetic-like manner by activating adaptive stress-response pathways and making the hormesis concept fully applicable to the field of nutrition. Moreover, it has been considered that plant polyphenols may be protective through hormetic processes that involve the stress-activated “vitagenes” [ 117 , 122 ].

Chronic neuroinflammation is a prominent feature shared by several neurodegenerative diseases, such as AD and PD. Microglial activation, the hallmark of brain neuroinflammation, results in the production of highly pro-inflammatory cytokines (i.e., TNF-α, IL-β, prostaglandin E2, cyclooxygenases, and iNOS through the modulation of signal transduction pathways), ROS, and NO, leading to cellular modifications including mitochondrial dysfunction, impaired energy metabolism, altered redox homeostasis, lipid peroxidation, DNA fragmentation, neuronal inflammation, and cell death; recently, these alterations have been associated with the pathogenesis of neurological disorders [ 123 , 124 ]. Inflammasomes are multiprotein signaling complexes that regulate cells of the innate immune system, mainly microglial cells in the brain. Notably, a considerable amount of information has provided evidence on the existence of inflammasome-mediated inflammatory pathways in neurological diseases. In particular, the NLR family, pyrin domain-containing-3 (NLRP3) inflammasome has been shown to play a pathogenic role in the development of neuroinflammatory disorders, such as AD [ 125 ] and PD [ 126 ].

In vivo and in vitro studies have highlighted a direct relationship between inflammasome activation and AD pathogenesis, suggesting that inflammasome inhibition represents a potential therapeutic approach for AD treatment. This concept was confirmed in APP/PS1mice (transgenic mice with chronic deposition of Aβ) where a deficiency of NLRP3 inflammasome and caspase-1 activity were found [ 127 ]. Moreover, in these mice models, the production of microglia with phenotype M2 induced by NLRP3 inflammasome deficiency was observed, resulting in reduced deposition of Aβ [ 127 ]. In addition, in humans, enhanced caspase-1 activation was found mainly in the hippocampal area of human brain tissue of patients with AD, [ 127 ]. Moreover, in an AD mouse model, administration of cathepsin-B (produced by microglia after Aβ phagocytosis) inhibitors significantly decreased the load of amyloid plaques in the mouse brain tissue and resulted in substantial improvement in memory deficit. In PD patient brains, the inflammasome pathway can potentially be activated by oxidative stress and by insoluble α-synuclein aggregates [ 128 ]. The pathophysiological link between inflammasome responses and Aβ-plaque spreading indicates that pharmacological targeting of inflammasomes may represent a novel, potential treatment strategy for AD and PD.

In light of the data reported above, the activities of plant polyphenols against neuroinflammation appear to target activated microglia resulting in low-level production of pro-inflammatory molecules induced by the NRLP3 inflammasome. In particular, many recent data suggest the key role played by phenolic components of EVOO in counteracting protein misfolding and proteotoxicity, with a particular emphasis on the mechanisms leading to the onset and progression of AD and PD, including APP processing, Aβ peptide and tau amyloid aggregation, autophagy impairment, disruption of redox homeostasis, α-synuclein neurotoxicity, and neuroinflammation [ 48 , 72 ]. Additionally, several data indicate that OLE interferes with APP processing [ 129 ] and with the amyloid aggregation of Aβ and tau protein, escaping the growth of toxic Aβ oligomers both in vitro [ 17 , 19 , 130 , 131 ], in C. elegans [ 132 ], and in TgCRND8 mice, a transgenic model of Aβ deposition [ 40 ]. In accordance with these data, a recent study has reported that rats fed with OLE display significant improvement of cognitive performance; in fact, OLE diet decreases the apoptosis and oxidative stress levels and prevents the impairment of spatial learning and memory resulting from morphine-induced neurotoxicity to the hippocampus [ 133 ].

It is noteworthy that HT, a dopamine metabolite, is present in the brain [ 134 ]. Monoamine oxidase (MAO) catalyzes oxidative deamination of dopamine in a toxic metabolite, DOPAL (3,4-dihydroxyphenylaldehyde), that can be oxidized by aldehyde dehydrogenase (ALDH) to DOPAC (3,4-dihydroxyphenylacetic acid), the major metabolite of dopamine in the brainor may be reduced to HT by alcohol dehydrogenase (ADH). At the same time, DOPAC reductase can transform DOPAC in HT [ 135 ]. DOPAL is a highly reactive metabolite, suggesting that it might be a neurotoxic dopamine metabolite with a role in the pathogenesis of PD [ 136 , 137 ].

HT removes soluble oligomeric Aβ 1–42 plus ibotenic acid-induced neurobehavioral dysfunction following intracerebroventricular injection of Aβ 1–42 [ 130 ]. In hippocampal neurons, HT treatment rescues, to a significant extent, negatively altered spatial reference and working memory induced by Aβ, an effect associated with reduced activation of death kinases such as JNK and p38-MAPK, while concomitantly increasing the survival-signaling pathways such as ERK-MAPK/RSK2, PI3K/Akt1, and JAK2/STAT3 [ 130 ].

In human trials, a higher adherence to the MD was associated with reduced cognitive decline and the risk of AD [ 138 ]. In transgenic AD mice, the positive effects of EVOO in preventing and delaying the onset of AD and declining the severity of its symptoms have been reported [ 139 ]. However, in spite of the reported biological effects, it has not been clear how efficiently HT acts against AD progression. Six-month HT administration to three-month-old female transgenic APP/PS1 mice at 5 mg/kg/day improved the electroencephalographic activity and cognitive function and reduced mitochondrial oxidative stress and neuroinflammation [ 140 ]. Moreover, HT was shown to dose-dependently inhibit toxicity of α-synuclein aggregation in PD [ 141 ] and HT and OLE improved spatial working memory and energetic metabolism in the brain of aged mice [ 142 ]. Notably, HT efficiently neutralizes free radicals and protects biomolecules from ROS-induced oxidative damage. In this regard, HT activates the Nrf2–antioxidant response element (ARE) pathway, leading to the activation of phase II detoxifying enzymes and the protection of dopaminergic neurons exposed to hydrogen peroxide or to 6-hydroxydopamine [ 20 , 143 ]. In addition, HT improved mitochondrial function and induced phase II antioxidative enzymes, which decreased oxidative stress in the brain of db/db mice [ 144 ]. Recently, it has also been shown that OLE improves mitochondrial performance through activation of the Nrf2-mediated signaling pathway protecting the hypothalamus from oxidative stress [ 145 ]. In conclusion, HT is being considered with interest for possible use in pharmacological mitigation of neurodegenerative processes as a potent antioxidant and a novel small molecule that can upregulate the Nrf2-ARE pathway.

Interestingly, plant polyphenols upregulate the vitagene signaling pathway that represents a potential therapeutic target in the crosstalk of inflammatory response process and oxidative stress in neurodegeneration. Accordingly, recent in vitro and in vivo studies have indicated that HT attenuates the NLRP3 inflammasome pathway by reducing pro-inflammatory interleukin (IL)-1β and IL-18 cytokine levels, oxidative stress, neuronal apoptosis, via activation of the Nrf-2/HO-1 signaling pathway and suppression of NF-κB [ 146 , 147 , 148 ]. Previous research revealed that HT and OLE activate the signaling pathway from Sirt1, an important member of the vitagene family that catalyzes the deacetylation of various substrates, by utilizing nicotinamide (NAD + ) as a substrate, to restore adaptive homeostasis under stress conditions [ 149 ]. By regulating cellular redox homeostasis, Sirt1 plays a critical role in neuron survival, insulin sensitivity, mitochondrial biogenesis, neurogenesis, and inflammation [ 114 ]. Sirt1 has been shown to be essential for synaptic plasticity, cognitive functions [ 150 ], modulation of learning, and the preservation of memory processes that deteriorate during aging, in the brain [ 151 ]. Recently, in vitro and in vivo studies suggest that HT and OLE inhibit the inflammatory response through different pathways regulated by several members of the sirtuin family (e.g., Sirt1, Sirt2, Sirt6) [ 140 , 152 , 153 , 154 , 155 , 156 ].

The thioredoxin system (Trx/TrxR) is a meaningful thiol/disulphide redox controller ensuring the cellular redox homeostasis [ 157 , 158 ]. In addition to the regulation of the expression of the encoding genes, TrxR activity is also regulated post-translationally by the thioredoxin inhibitory protein (TxNIP). In this context, a recent study has reported that HT induces neuroprotection and cellular antioxidant defenses via upregulation of the Keap1-Nrf2-TRXR1 pathway [ 159 ]. Sulforaphane is an herbal isothiocyanate enriched in cruciferous vegetables obtained in high concentrations from broccoli seeds and sprouts; myrosinase, an enzyme segregated in plant cells and released when the latter are masticated and ingested, produces sulphoraphane by glucoraphanin hydrolysis. This molecule has been shown to be active by fostering cellular defenses against a broad spectrum of cellular stresses. Evidence has shown that sulforaphane in the CNS activates Hsps and related mechanisms central to multiple cellular processes, including synaptic transmission, and improves cortical connectivity [ 160 ]. In addition, sulforaphane can also decrease STAT-1 and NLRP3 inflammasome activation by the Nrf2/HO-1 signaling pathway in human microglia-like THP-1 cells [ 161 ]. Finally, a recent in vivo study showed that sulforaphane modulates Hsp70 upregulating C-terminus of Hsp70-interacting protein (CHIP) and has the potential to reduce the deposition of Aβ and tau in a mouse models of AD [ 162 ].

Several studies have reported the antioxidant and anti-inflammatory properties of resveratrol, presently under clinical trial against neurodegenerative disorders. Recent compelling evidence indicated that resveratrol at micromolar concentrations can effectively scavenge free radicals and is an importantallosteric activator of the vitagene signaling pathway. In addition, resveratrol is involved in the neuroprotective mechanisms by increasing the Nrf2 pathway and reducing NF-κB activity, and therefore exerts a positive effect against a neuroinflammatory state and counteracts the progression of brain aging [ 163 ]. Some studies have also shown that resveratrol improves the learning and memory deficit in neurodegenerative disorders and, through its antioxidant activity, protects against memory decline in AD [ 164 ]. One of the major mechanisms of resveratrol as neuroprotective molecule is the activation of Sirt1 that is expressed in the adult mammalian brain, predominantly in neurons [ 165 ]. Moreover, resveratrol upregulates the Sirt1 pathway, thus preventing Aβ-induced microglial death and contributing to improve cognitive function [ 166 ] and induces the SIRT-1 and TRX signaling pathways with reduction of Aβ-stimulated NF-κB signaling, that contributes to its strong neuroprotection in AD [ 167 , 168 , 169 , 170 ].

Some preclinical studies have also suggested a positive role of curcumin as an adjuvant therapeutic strategy in free radical-based disorders, particularly neurodegenerative disorders. Some studies have reported the key role played by HO-1 as a target for neuroprotection by curcumin [ 117 , 171 ]. Several studies showed that resveratrol and curcumin increase HO-1 expression in PC12 cells and endothelial cells, among other cell lines [ 168 , 170 , 172 ]. Moreover, it has been suggested that curcumin inhibits IL-1β secretion and NLRP3 inflammasome activation in macrophages, reduces soluble tau oligomers, and improves cognition by increasing HSP70, HSP90, and HSC70, in aged human tau transgenic mice [ 173 , 174 ].

Taken together, all these data indicate that the activation of stress responsive mechanisms following moderate and chronic consumption of low doses of plant polyphenols induces the vitagene signaling pathway, thus activating antioxidant and neuroprotective cascades that could be effective to prevent neuroinflammation in aging-associated cognitive decline, and thereby improves health-life and longevity in animals and humans ( Table 2 ).

5.2. Metabolic Homeostasis

Traditionally, the main aim of nutrition is to provide correct amounts of dietary principles to prevent and, when needed, to treat, nutritional deficiencies. However, when nutrition is inadequate or excessive, the body faces the problem of controlling the amount of nutrients absorbed and stored, with the ensuing emergence of diet-associated pathologies, including MetS. The latter is a complex of symptoms and pathological conditions appearing in people over 65, particularly in females [ 175 ], induced by insulin resistance; MetS includes T2DM, cardiovascular diseases, obesity, non-alcoholic liver steatosis, and cancer [ 176 ]. Growing evidence indicates a significant reduction of the incidence of T2DM and MetS by the intake of plant polyphenols [ 177 ], particularly those found in the EVOO [ 57 , 178 ]. MetS treatment include lifestyle modifications such as physical activity, weight control, and intake of plant food products, such as whole grains, berries, fruits, and vegetables, all known to be sources of many polyphenols [ 179 , 180 ].

The regulation of blood glucose levels is dependent on the liver, in coordination with muscle and adipose tissue. Particularly, in the postprandial state, the liver involves several enzymes such as glucokinase and glycogen synthase to store glucose via the glycogenesis pathway. Moreover, the produced glucose by the liver, via glycogenolysis or gluconeogenesis pathways, depends by pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase activities [ 181 ]. In abnormal conditions, the increased post-prandial Apo-B48 levels correlate with the blood glucose levels and lipid profile [ 58 ], promoting and/or worsening the atherosclerotic process [ 182 ]. A correlation between oxidative stress and incidence of cardiovascular events was observed in diabetic vs. non-diabetic patients with post-prandial glycaemia [ 183 ]. Indeed, a recent study in patients with diabetes mellitus (DM) reported a correlation between a high-fat meal and enhanced circulating levels of gut-derived bacteria lipopolysaccharide (LPS) [ 184 ]; this modification may represent an important activator step for systemic post-prandial oxidative stress as LPS is responsible for activation of Nox2, a most important ROS producer [ 185 ]; overall, data obtained in animal models and in human studies highlight the beneficial effects on postprandial blood glucose levels of natural polyphenols derived from food fractions and beverages. It has been observed that OLE and HT in diabetic rats modulate activities of hepatic antioxidant enzymes, superoxide dismutase, and catalase, attenuating the oxidative stress associated with diabetes [ 186 ]. Other data reported that EVOO consumption is associated with down-regulation of Nox-2-derived oxidative stress [ 187 ], indicating its ability to mitigate post-prandial oxidative stress via lowering post-prandial LPS also in patients with impaired fasting glucose [ 188 ]. Another study highlighted the different pattern of postprandial glycaemia induced by consumption of cranberry juice sweetened with high-fructose corn syrup with respect to comparable amount of a sweetener in water [ 189 ]. Finally, a very recent study carried out on stroke-affected mice fed with HT-supplemented diet showed a remarkable recovery of motor and cognitive functions, and of magnetic resonance imaging parameters, together with improvement in neuroinflammation and neurogenesis with respect to controls mice fed with normal diet [ 190 ].

Plant polyphenols influence glucose metabolism through several mechanisms such as reduction of intestine carbohydrate digestion and glucose absorption, stimulation of pancreatic β-cells to secret insulin, modulation of liver glucose release, activation of insulin-sensitive tissues in terms of insulin receptors, and glucose uptake. In this context, different polyphenols have been shown to inhibit the enzymes involved in digestion to glucose of dietary carbohydrates, α-amylase and α-glucosidase [ 180 ], reducing the rate of glucose release and absorption, thus suppressing post-prandial hyperglycemia [ 191 , 192 ]. The polyphenols for which these inhibitory effects have been reported include quercetin, myricetin, luteolin, EGCG theaflavin, and resveratrol [ 193 , 194 , 195 ]. Moreover, several flavonoids and phenolic acids, such as tannic acids, quercetin, and myricetin, have been reported to inhibit the sodium-dependent SGLT1 and the sodium-independent GLUT2 glucose transporters in cultured intestinal cells [ 196 , 197 ]. Furthermore, it has been reported that in vitro catechins of green tea [ 198 ], procyanidins derived from grape seed [ 199 ], bitter melon [ 200 ], phenols of EVOO [ 11 ], and black soybean [ 201 ] act on a GLUT4-mediated process to enhance insulin-mediated glucose uptake. Otherwise, data obtained from T2DM mice model demonstrated that black soybean seeds, rich in anthocyanins and procyanidins, reduced glucose levels and increased insulin sensitivity activating the PI3K and 5′-adenosine monophosphate-activated protein kinase (AMPK) pathways in the skeletal muscle and liver [ 202 ]. Moreover, AMPK activation was also observed in OLE-treated C2C12 cells and in high-fat-diet mice and resulted as being correlated with the up-regulation of GLUT4 in skeletal muscle and with the down-regulation of liver gluconeogenesis [ 203 , 204 , 205 ]. The increased GLUT4 expression induced by OLE treatment, particularly in association with insulin, reduced oxidative stress and enhanced glucose consumption, improving insulin sensitivity [ 206 ]. Differently, in pancreatic β-cells, the glucose-stimulated insulin secretion resulted from glucose entrance via GLUT2, glycolysis, and tricarboxylic acid cycle with increased ATP production and inactivation of ATP-sensitive K + membrane channels [ 207 ]. Treatment with EGCG and buckwheat, the flavonoid rutin, resulted in reduced glucotoxicity to β-cells by activation of insulin receptor substrate 2 (IRS2) and AMPK signaling, and increased ATP levels [ 208 , 209 ]. Other data obtained with the RINmF5 cell model indicated that polyphenols such as quercetin, apigenin, and luteolin inhibit β-cell damage through suppression of NF-κB activity [ 210 ]. Moreover, the glucose-stimulated insulin secretion in β-cells was promoted by OLE treatment, but not its moiety HT, by activating ERK/MAPK signaling [ 211 ]. Other studies reported that HT reduces the oxidative stress in adipocytes, increasing the activity of AMPK, acetyl CoA carboxylase, hormone- sensitive lipase, and lipase phosphorylation, thus reducing the risk of obesity, a condition that correlates positively with the MetS [ 209 , 210 ] ( Figure 4 ). Many of the reported metabolic and cellular physiologic effects elicited by plant polyphenols share a common upstream mechanism involving AMPK activation/mTORC inhibition. The serine/threonine kinases AMPK and mTORC are key co-ordinators and controllers of many molecular routines including those regulating cell metabolism (anabolism or catabolism) autophagy and proteostasis, cell proliferation, and the redox condition [ 210 , 212 ]. In turn, AMPK and mTORC activities are under control of several factors. AMPK, a regulator of cellular energy homeostasis [ 213 ], is triggered by energy stress signalled by reduced ATP and increased AMP levels [ 211 ]. AMPK is also activated by phosphorylation of two regulatory subunits by several kinases, including the energy stress-sensitive LKB [ 214 ], PKA [ 215 ], and the CAMM-GSK3β axis [ 216 ] as well as by other factors, including PPARα, associated with lipid metabolism [ 217 ] and hypoxia [ 218 ]. AMPK triggers the expression of antioxidant enzymes, notably HO-1, through Nrf2 [ 219 , 220 ], and improves the control of proteostasis [ 221 ] through direct activation of FOXO3 [ 222 ] and ULK1 [ 223 ] and by indirect activation of TFEB [ 224 ]; AMPK activation also improves both glucose metabolism by favoring GLUT4 translocation to the membrane [ 225 , 226 ] and lipid metabolism through PPARα. Finally, AMPK activation results in inhibition of mTORC following both direct phosphorylation and phosphorylation of the mTORC controller TSC [ 227 ].

Some of the mechanisms reported above are also triggered by plant polyphenols. In particular, it has been reported that OLE increases intracellular free Ca 2+ levels from the internal stores with ensuing activation of the calcium-CAMMK-GSK3β pathway [ 216 ] and reduces oxidative stress through AMPK-dependent activation of HO-1 [ 219 ], whereas in aged rats, resveratrol protects against high-fat diet-induced muscle atrophy counteracting PKA/LKB1/AMPK-mediated mitochondrial dysfunction and oxidative stress [ 215 ]. Finally, plant polyphenols including quercetin, resveratrol, and catechins activate SIRT1, a class-3 histone deacetylase involved in several aging-related pathologies, including neurodegeneration [ 228 ]. Recent data with TgCRND1 mice indicate that SIRT1 is activated by OLE, with concomitant inhibition of PARP1 in a crosstalk affecting apoptosis and autophagy [ 40 ]. It is remarkable that some of these effects by several plant polyphenols are shared with the well-known antidiabetic drug metformin [ 229 ]. These molecules have different ways of accomplishing their functions and work in different cell types; however, taken together, the vast amount of research and preclinical data provide a convincing, yet still incomplete, explanation of the cellular protection by these substances that underlies their hormetic behaviour (see Figure 4 ).

5.3. Proteostasis

Proteostasis is a key biological process under strict cellular control by maintaining the equilibrium between protein synthesis and protein degradation by different protein degradation machineries (the chaperone–ubiquitin–proteasome and various forms of autophagy), whose homeostasis is needed for a healthy life span. The proteostasis network needs the coordinated action of both chaperones and the ubiquitin–proteasome system (UPS), and several types of autophagy, notably macro-autophagy and chaperone-mediated autophagy. Molecular chaperones, in particular the heat shock proteins (HSPs), are the prime line of defense to counteract protein misfolding and the ensuing protein deposition; they recognize hydrophobic regions of proteins and promote either their refolding or their transfer to the UPS or autophagy systems [ 230 ]. The small HSPs are ATP-independent chaperones, a particular class of HSPs that bind misfolded and aggregation-prone proteins, avoiding undesired intermolecular interactions and preventing their aggregation with ensuing loss of function [ 231 , 232 ]. The UPS is localized both in the cytoplasm and in the nuclei; it provides rapid degradation of proteins following their polyubiquitination and subsequent delivery to the proteasome. The misfolded proteins of the secretory pathway are managed by the endoplasmic reticulum-associated protein degradation (ERAD) pathway.

Differently from the UPS and the ERAD pathways, autophagy, a self-digestive process triggered by nutrient deprivation, aging, and other stressful conditions including energy shortage, heath shock, and oxidative stress, is important for long-lived proteins and organelles clearance. It requires the participation of a number of proteins encoded by autophagy-related genes (Atg) that are necessary to the formation of autophagosomes, double membrane vesicles, where the cargo material is engulfed and their subsequent delivery to lysosomes for degradation [ 233 ]. In addition to the proteostasis network, the cells can also alleviate intracellular accumulation of misfolded proteins through a selective secretion of damaged proteins and RNAs into vesicles of endosomal origin, called exosomes. Several evidences have stressed a crosstalk between the autophagic pathway and the exososomes [ 234 ].

The proteostasis network can decline permanently or transiently following development, aging, and exposure to environmental stress, and this decline may contribute to adult-onset proteotoxic disorders and their progression. In particular, a continuous reduction of the efficiency of the proteostasis network may induce pathological aging with accumulation of abnormal proteins, a common feature of many oncological, neurodegenerative, metabolic, and cardiovascular disorders. Proteostasis deregulation at the level of the ER is one of the major contributors to aging and cancer as well [ 235 ]. Indeed, harmful stimuli, such as oxidative stress and disruptions of the secretory process may contribute to deposition of unfolded or misfolded proteins at the ER lumen, thus upregolating the endoplasmic reticuluym (ER) stress response [ 236 ]. Finally, cancer cells accumulate genetic changes resulting in the presence of mutated proteins; accordingly, most cancer cells are closely dependent on the proteostasis network for survival.

Scientific evidence shows that natural molecules, such as polyphenols, exhibit healthy and protective effects as consequence of their ability not only to maintain the proper oxidant/antioxidant balance in cells, but also for their anti-inflammatory power together with their ability to control the activity of signaling pathways responsible with cell survival, proliferation, and migration. Moreover, the pleiotropic anti-amyloid properties of the polyphenols indicate that these molecules may be useful for treatment of several amyloidosis, notably T2DM and several neurodegenerative diseases. Indeed, many plant polyphenols can reduce the aggregation of some proteins/peptides involved in metabolic and neurodegenerative diseases and can directly or indirectly enhance the clearance of misfolded proteins by modulating the activity of the proteostasis network. However, recent data indicate that increased efficiency of proteostasis and stress resistance may also favor cancer progression. The stresses accomplished by cancer cells require active chaperone platforms to limit protein misfolding and aggregation; the latter, in these cells, may result from high levels of protein synthesis and metabolic requests, oxidative stress, growth under hypoxic and acidic conditions, and protein expression in altered stoichiometries resulting from aneuploidy [ 237 ]. The modulation of the proteostasis network by small regulatory molecules can provide a previously unexploited and potentially powerful approach to improve proteome balance.

Resveratrol, one of the most investigated plant polyphenols, displays eclectic biochemical behavior; in fact, it acts upstream of several signaling cascades, likely upon binding to membrane receptor(s); actually, potential binding sites were detected in the plasma membrane of neuronal cells and, to a lesser extent, in nuclear and cellular fractions of rat brain homogenates [ 238 ]. In addition, resveratrol mimics some aspects of the CR by inhibiting cAMP phosphodiesterase with activation of AMPK, with reduced fat accumulation, increased glucose tolerance, insulin sensitivity, mitochondrial biogenesis, and physical endurance. Besides its antioxidant activity [ 239 ], resveratrol reduces both intracellular and secreted Aβ in cell culture by activating chaperones such as Hsp70 and by inducing proteasome-dependent Aβ degradation [ 240 ]. In addition, resveratrol activates SIRT-1, increases AMPK activity, thus reducing Aβ-induced death signals, such as NF-κB signaling and p53 activity [ 240 ] and triggering the degradation of Aβ aggregates by autophagy [ 239 ]. The anti-cancer property of resveratrol occurs by inducing caspase 8- and caspase 3-dependent apoptosis via ROS-induced autophagy in human colon cancer cells [ 241 ]. In androgen-independent prostate cancer cells, resveratrol induces autophagy-mediated cell death through regulation of store-operated Ca 2+ entry (SOCE) mechanisms, and down-regulation of stromal interaction molecule 1 (STIM1) expression. In addition, resveratrol triggers ER stress by depleting the pool of ER calcium [ 242 ]. Resveratrol has also been shown to decrease the proliferation of breast cancer stem-like cells by inhibiting Wnt/β-catenin signaling pathway [ 243 ]. Finally, resveratrol has been shown to act as an inhibitor of global protein synthesis in the H4-II-E rat hepatoma cell line. This effect was reached through modulation of mTOR self-phosphorylation and hence of mTOR-dependent and mTOR-independent signaling by reduced formation of the eIF4F translation initiation complex and increased phosphorylation of eIF2α with inhibition of translation [ 244 ]. Other findings in renal tissues of rats fed with resveratrol after unilateral uretral obstruction point to the reduced expression of eIF2α and the ensuing reduced levels of ATF4 [ 245 ].

Other plant polyphenols have been investigated for their ability to control the proteostasis system at several levels. Curcumin displays several beneficial effects in different in vivo models of aging, ischemia, trauma, and neurodegeneration. In in vivo models of proteinopathies, curcumin reduces plaque burden and improves cognitive function [ 246 ]. In addition, curcumin has been shown to induce the expression of Hsp genes and the nuclear translocation of Hsf1, a master regulator of Hsp expression [ 247 ]. Green tea catechins show conformational similarities to chaperones and a chaperone-like activity [ 248 ]. Phenolic and flavonoid components present in bee pollen activate the chymotrypsin-like activity of the proteasome in HFL-1 human embryonic fibroblasts [ 249 ]. OLE displays neuroprotection by increasing proteasome activity, and extending the life span of human IMR90 and WI-38 embryonic fibroblasts [ 250 ]. The administration of OLE to the C. elegans C2006 strain expressing Aβ42 in muscle cells induced a significant reduction of amyloid plaque and toxic oligomer formation, with reduction of the extent of paralysis and increased lifespan [ 132 ]. The dietary administration of OLE also improved the cognitive performance of the TgCRND8 mouse model of Aβ deposition resulting from reduced plaque deposits, increased microglia migration to the plaques for phagocytosis, and an intense autophagic reaction followed by modulation of the mTOR/AMPK pathways [ 14 , 40 ]. Recent data with cardiomyocytes indicate that OLE counteracts MAO-A cytotoxicity and that this effect results from restoration of restoration of the defective autophagic flux, as indicated by the increase of autolysosomes, indicative of autophagosome–lysosome fusion. Interestingly, autophagy induction involved nuclear translocation and activation of the master gene for lysosomal biogenesis TFEB, suggesting a role of OLE as a TFEB activator [ 251 ].

Quercetin has been shown to have neuroprotective effect in various in vitro and in vivo systems. In malignant mesothelioma, quercetin inhibits cell growth and increases the levels of Nrf2, with the transcriptional activation of genes involved in the control of the cellular redox status [ 252 ]. In addition, quercetin may induce the expression of chaperones and of proteasome subunits through the Nrf2 pathway [ 253 ]. In primary effusion B cell lymphoma, quercetin induces apoptosis and autophagy by inhibiting the PI3K/AKT/mTOR and STAT3 signaling pathways, with the ensuing down-regulation of the expression of pro-survival cellular proteins such as c-FLIP, cyclin D1, and cMyc [ 254 ].

6. Epigenetic Implications

The pivotal mechanisms of genetic regulation, that induce or repress the expression of genes, include genetic mutations and epigenetic modifications, the last include DNA methylation, histone acetylation, methylation or phosphorylation, and RNA interference (RNAi). When aberrant, these modifications influence the onset and worsening of diseases and these alterations are considered as essential hallmarks for distinct types of cancer, neurodegenerative diseases, metabolic disorders, bone, and skeletal diseases [ 2 ]. In principle, drugs are able to reverse epigenetic defects on the contrary to genetic alterations [ 255 ]. In this regard, promising results for cancer treatment have been obtained from two groups of drugs with inhibitory activities on DNA methyl transferase (DNMT) and histone deacethylase (HDAC) [ 256 ]. Recently, most studies demonstrated epigenetic modifications induced by natural polyphenols treatment, allowing the introduction of the term “epigenetic diet” [ 257 , 258 , 259 ]. As an example, several polyphenols, including curcumin, resveratrol, and catechins, are reported to act on the NF-κB expression and chromatin remodeling through modulation of HDACs and DNMTs activity [ 260 ] ( Figure 5 ). Below, several studies supporting plant polyphenols effects on epigenetic are reported with possible clues for treatment of specific diseases.

6.1. DNA Methylation

The presence or the absence of 5-methylcytosine define DNA methylated regions of DNA template. The methylation on cytosine residues depends on DNMTs or 10 or 11 translocation methyl-cytosine dioxygenases (TETs) activity. In this way, the gene expression is regulated by DNA methylation in a region-specific manner, and occurs predominantly at cytosines preceding a guanine nucleotide (CpG sites). Usually, DNA hypermethylation occurs at promoter CpG islands and is a major epigenetic mechanism to silence gene expressions [ 261 ]. However, at present, the methylation process must establish a relationship between of intronic, exonic, or untranslated regions and the expression pattern of the encoded proteins [ 262 ]. The acetylation and methylation mechanisms reverse the epigenetic modifications of genes that include chemical modification, e.g., the methylation at CpG dinucleotides, and the ensuing transcriptional activation of histone complexes [ 263 ]. The DNA methylation of some developmental genes is a highly controlled mechanism that involved the NAD-dependent deacetylase SIRT1 that selectively prevents abnormal methylation process [ 264 ]. Sirtuins, NAD + -dependent enzymes, are considered amongst the most promising anti-aging targets, leading to define these deacetylases as “the enzymes of youth”. Sirtuins depend on AMPK via stimulation of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme involved in NAD + synthesis that regulates cellular metabolism in several mammalian organs and tissues [ 265 ] and whose inhibition worsens diet-induced hepatic steatosis in mice [ 266 ].

Recent studies have provided a lot of data to support that plant polyphenols and other phytochemicals remarkable impact on DNA methylation by causing direct or indirect modifications of DNMTs levels and activity. For example, genistein, one of the phytoestrogens found in soybeans, reduces DNMT activity, forming a complex with it, and activates tumor suppressor genes, with possible significance for cancer prevention and therapy [ 267 ]. Other data indicate that resveratrol activates both the PGC1α/SIRT1/AMPK axis and DNMTs, with beneficial effects for cancer prevention and treatment [ 268 ]. Similar results have been reported for quercetin [ 269 ] and EVOO polyphenols; the latter were shown to activate the Sirt1 path, with possible relevance for AD prevention/treatment [ 40 ]. Furthermore, studies performed on esophageal, oral, skin, regulatory T-cells, lung, breast, and prostate cancer cells reported alterations induced by bioactive compounds from green tea, including EGCG, on DNMT activity in studies performed on esophageal, oral, skin, regulatory T-cells, lung, breast, and prostate cancer cells [ 270 ]. In detail, Fang et al. suggested an EGCG inhibitory effect on DNMT and reactivation of methylation-silenced genes in human colon, esophageal, and prostate cancer cells [ 271 ]. Finally, it appears that the inhibition of DNMT is a chemopreventive effect on cancer cell growth by genistein, suggesting its use as anti-neoplastic drug in some malignancies [ 272 ].

6.2. Histone Modifications

The primary components of the epigenome are the post-translational modifications (PTMs) of histones often leading to charge-induced changes in the nucleosome, with major influence on gene expression. Histone PTMs also regulate several biological processes by chemical alterations of chromatin and the ensuing modulation of gene expression that contributes significantly to aging-associated dysfunctions and to tumor development and carcinogenesis [ 273 ]. Histone modifications can result from the activity of various enzymes, including histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs). The histone acetylation is a process involved in the regulation of different cellular processes such as transcription, gene silencing, apoptosis, DNA repair, and cell differentiation [ 274 ]. Differently, HDACs catalyze histone de-acetylation, signal transduction, apoptosis, and cell growth [ 275 ].

As modulators of histone modifications, many dietary polyphenols hold promise to be effective for prevention and therapy of neurodegeneration and some cancers. For example, the inhibition of HDAC activity is due to the interaction between sulforaphane complexes with the active sites of HDACs [ 276 ]. EGCG not only modifies DNA methylation, but also acts as a histone modifier, interfering with the HDAC and HAT activities [ 277 ]. Quercetin behaves as an HAT inhibitor and suppresses HAT activity in human endothelial cells [ 278 ]; moreover, a recent study suggests that it can also inhibit HDAC [ 279 ]. Recently, it has been reported that the co-treatment with suberoylanilidehydroxamic acid (SAHA), an HDAC inhibitor, and naringenin, a flavone present in citrus, synergistically induces cytotoxic effects in neuroblastoma with respect to non-malignant neuronal cells [ 280 ]. Genistein is the polyphenol with the highest ability to modify histone activity compared to other isoflavones; indeed, it was reported an increased HATs and decreased HDACs activity after treatment with this compound of precancerous and cancer breast cells [ 281 , 282 , 283 ]. Otherwise, clinical benefits in cancer cells have been obtained after curcumin treatment, resulting in down-regulation of HATs activity [ 284 ].

Recent data indicate that the protective effects of OLE in the diet of a Tg murine model of Aβ deposition could be traced bask, at least in part, to the increased acetylation of histone 3 and 4, that matched the reduced expression of HDAC-2 [ 40 ], whose levels are increased in the AD brain [ 285 , 286 ] and of glutaminyl cyclase (GC), the enzyme responsible for the generation of pE3Aβ, the most aggregating pyroglutamylated derivative of the Aβ 1–42 peptide in AD [ 287 ]. Interestingly, GC is significantly increased in the brain of AD patients [ 288 ]. Similar epigenetic effects have been reported in cancer cells [ 289 ]. Oleacein, another EVOO polyphenol, also induces a strong increase of histone and α-acetyl-tubulin acetylation [ 290 ].

6.3. Noncoding RNAs

MicroRNAs (miRNAs) are small non-coding RNA molecules, 20–22 nucleotides in length, organized in a single-strand structure, with the function of RNA silencing and post-transcriptional regulation of gene expression [ 291 ]. miRNAs significantly participate in epigenetic regulation; in fact, they perform catalytic functions related to RNA splicing and significantly contribute to post-translational gene regulations. Accordingly, miRNAs regulate many cellular processes, including cell proliferation, apoptosis, cell differentiation, and any alterations of their expression correlate with different disease progression. Many studies support a direct association between alterations of miRNAs expression and cancer [ 292 ]. Indeed, bladder, lung, and breast cancer onset correlates with different mechanisms of regulation of miRNAs expression including chromosomal abnormalities, single nucleotide polymorphisms (SNPs), mutations in primary transcripts [ 293 ], altered activity of transcription factors, such as the miR-17-92 cluster, and modifications in the miR-34 family such as consequence of p53 activation [ 294 , 295 ].

Recently, EGCG has been found to decrease the expression of oncogenic miRNAs (miR-92, miR-93, and miR-106b) and to increase the expression of tumor-suppressor miRNAs (miR-7-1, miR-34a, and miR-99a) in human cancer cells [ 296 , 297 ]. Another study in apolipoprotein E-deficient mice reported that the treatment with one of nine different polyphenols including hesperidin and naringenin affected the expression of five miRNA in vivo [ 298 ]. Curcumin also regulates pancreatic cancer symptoms by up-regulation of miR-22 and down-regulation of miR-199a [ 299 ]. However, the potential use of curcumin and other polyphenols against cancer cells trough modulation of miRNAs is very prominent, but at the same time, limited because of the reduced bioavailability of these substances. In spite of these limitations, the data currently available contribute to explaining the healthy effects of flavonones [ 298 ].

7. Conclusions

A growing number of population surveys and clinical trials increasingly support the use of plant polyphenols, possibly in association with more specific drugs, to prevent and/or to treat several aging-associated pathologies [ 300 ]. However, in a number of cases, contradictory results have been reported possibly due to different experimental settings in terms of dose, length of treatment, clinical conditions of the enrolled patients at the onset of treatment, and other unknown variables. In fact, the low bioavailability of polyphenols must be taken into account, as well as the fact that the latter could be further affected by specific physiological features of different patients, also taking into account the role played by the gut microbiota. Moreover, data are still lacking that properly focus the pharmacodynamics and pharmacokinetics of these molecules in different clinical settings. However, the overall picture that emerges from the body of the data currently available strongly suggests the nutraceutical value of these substances, yet with differences from each other.

The positive results arising from population surveys and clinical trials are increasingly supported at the molecular/cellular/tissue level by the large body of studies carried out recently that have, at least in part, unraveled the molecular basis and the cellular correlates of the healthy effects recorded at the organismal level. What emerges from these studies is the ability of plant polyphenolsthese to interact with many regulatory molecules modulating a number of signaling paths that maintain proteostasis as well as the redox and metabolic homeostasis or restore any disequilibrium of these conditions. In this sense, the data on the modulation of several epigenetic modifications by some of these molecules, although still limited, are of importance, providing clues as to how plant polyphenols can produce so many heterogeneous effects at the cellular level, integrating and extending the hormetic theory.

In conclusion, the rising interest in the nutraceutical/pharmacological exploitment of plant polyphenols or their molecular scaffolds holds promise that in the near future, the knowledge of the molecular/cellular determinants of the beneficial effects of these molecules, together with their pharmacokinetics and pharmacodynamics, will increase. It is also expected that results from more extended and convincing clinical trials will be reported, better focusing on benefits and, possibly, caveats associated with the use of these molecules or their chemical derivatives. Such increased information, provided it will further confirm the potential of plant polyphenols in the prevention/treatment of metabolic-, aging-, or lifestyle-associated pathologies presently without resolutive therapies, will allow a more general use of these molecules as an important tool to prevent or to reduce the incidence of these increasingly widespread pathologies, ensuring safer aging.

Acknowledgments

M.L. was supported by ANCC-COOP/Airalzh ONLUS [Reg. n° 0043966.30-10-359 2014-u] through University of Florence [D.R.595/2016].

Author Contributions

M.L., M.S., M.L.O., V.C., E.J.C., M.B., M.S. writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by “Fondo di ricerca University of Catania” n. 20130143005.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Stefani M. Rigacci S. Beneficial properties of natural phenols: Highlight on protection against pathological conditions associated with amyloid aggregation BioFactors 2014 40 482 493 10.1002/biof.1171 24890399

2. Bach-Faig A. Berry E.M. Lairon D. Reguant J. Trichopoulou A. Dernini S. Medina F.X. Battino M. Belahsen R. Miranda G. Mediterranean diet pyramid today. Science and cultural updates. Mediterranean Diet Foundation Expert Group Public Health Nutr. 2011 14 2274 2284 10.1017/S1368980011002515 22166184

3. Williams R.J. Spencer J.P. Rice-Evans C. Flavonoids: Antioxidants or signalling molecules? Free Radic. Biol. Med. 2004 36 838 849 10.1016/j.freeradbiomed.2004.01.001 15019969

4. Halliwell B. Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment Drugs Aging 2001 18 685 716 10.2165/00002512-200118090-00004 11599635

5. Tangney C.C. Kwasny M.J. Li H. Wilson R.S. Evans D.A. Morris M.C. Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population Am. J. Clin. Nutr. 2011 93 601 607 10.3945/ajcn.110.007369 21177796 PMC3041601

6. Bravo L. Polyphenols: Chemistry, dietary sources, metabolism and nutritional significance Nutr. Rev. 1998 56 313 333 10.1111/j.1753-4887.1998.tb01670.x 9838798

7. Dinda B. Debnath S. Banik R. Naturally Occurring Iridoids and Secoiridoids. An Updated Review, Part 4 Chem. Pharm. Bull. (Tokyo) 2011 59 803 833 10.1248/cpb.59.803 21720031

8. Dinda B. Dubnath S. Harigaya Y. Naturally Occurring Iridoids. A Review, Part 1 Chem. Pharm. Bull. (Tokyo) 2007 55 159 222 10.1248/cpb.55.159 17268091

9. Ranalli A. Marchegiani D. Contento S. Girardi F. Nicolosi M.P. Brullo M.D. Variations of the iridoid oleuropein in Italian olive varieties during growth and maturation Eur. J. Lipid Sci. Technol. 2009 111 678 687 10.1002/ejlt.200800268

10. Servili M. Montedoro G.F. Contribution of phenolic compounds in virgin olive oil quality Eur. J. Lipid Sci. Technol. 2002 104 602 613 10.1002/1438-9312(200210)104:9/10<602::AID-EJLT602>3.0.CO;2-X

11. Fujiwara Y. Tsukahara C. Ikeda N. Sone Y. Ishikawa T. Ichi I. Koike T. Aoki Y. Oleuropein improves insulin resistance in skeletal muscle by promoting the translocation of GLUT4 J. Clin. Biochem. Nutr. 2017 61 196 202 10.3164/jcbn.16-120 29203961 PMC5703779

12. Wu L. Velander P. Liu D. Xu B. Olive Component Oleuropein Promotes β-Cell Insulin Secretion and Protects β-Cells from Amylin Amyloid-Induced Cytotoxicity Biochemistry 2017 56 5035 5039 10.1021/acs.biochem.7b00199 28829122

13. Abuznait A.H. Qosa H. Busnena B.A. El Sayed K.A. Kaddoumi A. Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: In vitro and in vivo studies ACS Chem. Neurosci. 2013 4 973 982 10.1021/cn400024q 23414128 PMC3689195

14. Grossi C. Rigacci S. Ambrosini S. Ed Dami T. Luccarini I. Traini C. Failli P. Berti A. Casamenti F. Stefani M. The polyphenol oleuropein aglycone protects TgCRNDmice against Aβ plaque pathology PLoS ONE 2013 8 e71762 10.1371/journal.pone.0071702 23951225 PMC3738517

15. Monti M.C. Margarucci L. Riccio R. Casapullo A. Modulation of tau protein fibrillization by oleocanthal J. Nat. Prod. 2012 75 1584 1588 10.1021/np300384h 22988908

16. Rigacci S. Guidotti V. Bucciantini M. Parri M. Nediani C. Cerbai E. Stefani M. Berti A. Oleuropein aglycon prevents cytotoxic amyloid aggregation of human amylin J. Nutr. Biochem. 2010 8 726 735 10.1016/j.jnutbio.2009.04.010 19616928

17. Daccache A. Lion C. Sibille N. Gerard M. Slomianny C. Lippens G. Cotelle P. Oleuropein and derivatives from olives as Tau aggregation inhibitors Neurochem. Int. 2011 58 700 707 10.1016/j.neuint.2011.02.010 21333710

18. Qosa H. Mohamed L.A. Batarseh Y.S. Alqahtani S. Ibrahim B. LeVine H. III Keller J.N. Kaddoumi A. Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice J. Nutr. Biochem. 2015 26 1479 1490 10.1016/j.jnutbio.2015.07.022 26344778 PMC4679638

19. Leri M. Natalello A. Bruzzone E. Stefani M. Bucciantini M. Oleuriopein aglycone and hydroxytyrosol interfere differently with toxic Aβ1-aggregation Food Chem. Toxicol. 2019 129 1 12 10.1016/j.fct.2019.04.015 30995514

20. Yu G. Deng A. Tang W. Ma J. Yuan C. Ma J. Hydroxytyrosol induces phase II detoxifying enzyme expression and effectively protects dopaminergic cells against dopamine- and 6-hydroxydopamine induced cytotoxicity Neurochem. Int. 2016 96 113 120 10.1016/j.neuint.2016.03.005 26970393

21. Nardiello P. Pantano D. Lapucci A. Stefani M. Casamenti F. Diet supplementation with hydroxytyrosol ameliorates brain pathology and restores cognitive functions in a mouse model of amyloid-β deposition J. Alzheimers Dis. 2018 63 1161 1172 10.3233/JAD-171124 29710709

22. Biessels G.J. Reagan L.P. Hippocampal insulin resistance and cognitive dysfunction Nat. Rev. Neurol. 2015 16 660 671 10.1038/nrn4019 26462756

23. Bedse G. Di Domenico F. Serviddio G. Cassano T. Aberrant insulin signaling in Alzheimer’s disease: Current knowledge Front. Neurosci. 2015 9 204 10.3389/fnins.2015.00204 26136647 PMC4468388

24. Ayissi V.B.O. Ebrahimi A. Schluesenner H. Epigenetic effects of natural polyphenols: A focus on SIRT1-mediated mechanisms Mol. Nutr. Food Res. 2014 58 22 32 10.1002/mnfr.201300195 23881751

25. Bartolini G. Petruccelli R. Classifications, Origins, Diffusion and History of the Olive Rome Food and Agricolture Organisation in the United Nations Roma, Italy 2002

26. Flemmig J. Rusch D. Czerwinska M.E. Ruwald H.W. Arnhold J. Components of a standardized olive leaf dry extract (Ph. Eur.) promote hypothiocyanate production by lactoperoxidase Arch. Biochem. Biophys. 2014 549 17 25 10.1016/j.abb.2014.03.006 24657078

27. Flemming J. Kuchta K. Arnhold J. Rauwald H.W. Olea europaea leaf (Ph. Eur.) extract as well as several of its isolated phenolics inhibit the gout-related enzyme xanthine oxidase Phytomedicine 2011 18 561 566 10.1016/j.phymed.2010.10.021 21144719

28. Calixto J.B. Campos M.M. Otuki M.F. Santos A.R. Anti-inflammatory compounds of plant origin. Part II. Modulation of pro-inflammatory cytokines, chemokines and adhesion molecules Planta Med. 2004 70 93 103 14994184 10.1055/s-2004-815483

29. Colomer R. Sarrats A. Lupu R. Puig T. Natural Polyphenols and their Synthetic Analogs as Emerging Anticancer Agents Curr. Drug Targets 2017 18 147 159 10.2174/1389450117666160112113930 26758667

30. Toric J. Markovic A.K. Brala C.J. Barbaric M. Anticancer effects of olive oil polyphenols and their combinations with anticancer drugs Acta Pharm. 2019 69 461 482 10.2478/acph-2019-0052 31639094

31. Rigacci S. Stefani M. Nutraceuticals and amyloid neurodegenerative diseases: A focus on natural polyphenols Exp. Rev. Neurother. 2014 15 41 52 10.1586/14737175.2015.986101 25418871

32. Tomaselli S. La Vitola P. Pagano K. Brandi E. Santamaria G. Galante D. D’Arrigo C. Moni L. Lambruschini C. Banfi L. Biophysical and in vivo studies identify a new natural-based polyphenol, counteracting Aβ oligomerization in vitro and Aβ oligomer-mediated memory impairment and neuroinflammation in an acute mouse model of Alzheimer’s disease ACS Chem. Neurosci. 2019 10 4452 4465 10.1021/acschemneuro.9b00241 31603646

33. Curti V. Zaccaria V. Tsetegho Sokeng A.J. Dacrema M. Masiello I. Mascaro A. D’Antona G. Daglia M. Bioavailability and In Vivo Antioxidant Activity of a Standardized Polyphenol Mixture Extracted from Brown Propolis Int. J. Mol. Sci. 2019 20 1250 10.3390/ijms20051250 30871097 PMC6429100

34. Gumireddy A. Christman R. Kumari D. Tiwari A. North E.J. Chauhan H. Preparation, Characterization, and In vitro Evaluation of Curcumin- and Resveratrol-Loaded Solid Lipid Nanoparticles AAPS Pharm. Sci. Tech. 2019 20 145 10.1208/s12249-019-1349-4 30887133

35. Jaisamut P. Wiwattanawongsa K. Wiwattanapatapee R. A Novel Self-Microemulsifying System for the Simultaneous Delivery and Enhanced Oral Absorption of Curcumin and Resveratrol Planta Med. 2017 83 461 467 10.1055/s-0042-108734 27280934

36. Chimento A. De Amicis F. Sirianni R. Sinicropi M.S. Puoci F. Casaburi I. Saturnino C. Pezzi V. Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol Int. J. Mol. Sci. 2019 20 1381 10.3390/ijms20061381 PMC6471659 30893846

37. Vissers M.N. Zock P.L. Roodenburg A.J.C. Leenen R. Katan M.B. Olive oil phenols are absorbed in humans J. Nutr. 2002 132 409 417 10.1093/jn/132.3.409 11880564

38. De Bock M. Thorstensen E.B. Derraik J.G.B. Henderson H.V. Hofman P.L. Cutfield W.S. Human absorption and metabolism of oleuropein and hydroxytyrosol ingested as olive ( Olea europaea L.) leaf extract Mol. Nutr. Food Res. 2013 57 2079 2085 10.1002/mnfr.201200795 23766098

39. Garcia-Villalba R. Larrosa M. Possemiers S. Tomás-Barberán F.A. Espín J.C. Bioavailability of phenolics from an oleuropein-rich olive ( Olea europaea ) leaf extract and its acute effect on plasma antioxidant status: Comparison between pre- and postmenopausal women Eur. J. Nutr. 2014 53 1015 1027 10.1007/s00394-013-0604-9 24158653

40. Luccarini I. Grossi C. Rigacci S. Coppi E. Pugliese A.M. Pantano D. la Marca G. ed Dami T. Berti A. Stefani M. Oleuropein aglycone protects against pyroglutamylated-amyloid-β toxicity: Biochemical, epigenetic and functional correlates Neurobiol. Aging 2015 36 648 663 10.1016/j.neurobiolaging.2014.08.029 25293421

41. Lòpez de las Hazas M.-C. Godinho-Pereira J. Macià A. Filipa Almeida A. Ventura M.R. Motilva M.-J. Santos C.N. Brain uptake of hydroxytyrosol and its main circulating metabolites: Protective potential in neuronal cells J. Funct. Foods 2018 46 110 117 10.1016/j.jff.2018.04.028

42. De Pablos R.M. Espinosa-Oliva A.M. Hornado-Ortega R. Cano M. Arguelles S. Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of ots effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases Pharm. Res. 2019 143 58 72 10.1016/j.phrs.2019.03.005 30853597

43. Casamenti F. Stefani M. Olive polyphenols: New promising agents to combat aging-associated neurodegeneration Exp. Rev. Neurother. 2017 17 345 358 10.1080/14737175.2017.1245617 27762153

44. Scarmeas N. Stern Y. Mayeux R. Manly J.J. Schupf N. Luchsinger J.A. Mediterranean diet and mild cognitive impairment Arch. Neurol. 2009 66 216 225 10.1001/archneurol.2008.536 19204158 PMC2653223

45. Cheng K.K. Yeung C.F. Ho S.W. Chow S.F. Chow A.H. Baum L. Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer’s disease Tgmice AAPS J. 2013 15 324 336 10.1208/s12248-012-9444-4 23229335 PMC3675736

46. Keys Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease Harvard University Press Cambridge, MA, USA 1980

47. De Lorgeril M. Salen P. Martin J.L. Monjaud I. Delaye J. Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study Circulation 1999 99 779 785 10.1161/01.CIR.99.6.779 9989963

48. Berr C. Portet F. Carriere I. Akbaraly T.N. Feart C. Gourlet V. Combe N. Barberger-Gateau P. Ritchie K. Olive oil and cognition: Results from the three-city study Dement. Geriatr. Cogn. Disord. 2009 28 357 364 10.1159/000253483 19887798 PMC2796327

49. Martínez-Lapiscina E.H. Clavero P. Toledo E. Estruch R. Salas-Salvadó J. San Julián B. Sanchez-Tainta A. Ros E. Valls-Pedret C. Martinez-Gonzalez M.Á. Mediterranean diet improves cognition: The PREDIMED-NAVARRA randomised trial J. Neurol. Neurosurg. Psychiatry 2013 84 1318 1325 10.1136/jnnp-2012-304792 23670794

50. Martínez-Lapiscina E.H. Galbete C. Corella D. Toledo E. Buil-Cosiales P. Salas-Salvado J. Ros E. Martinez-Gonzalez M.A. Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: The PREDIMED-NAVARRA trial Genes Nutr. 2014 9 393 10.1007/s12263-014-0393-7 24643340 PMC4026432

51. Valls-Pedret C. Lamuela-Raventós R.M. Medina-Remón A. Quintana M. Corella D. Pintó X. Martínez-González M.Á. Estruch R. Ros E. Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk J. Alzheimers Dis. 2012 29 773 782 10.3233/JAD-2012-111799 22349682

52. Murie-Fernandez M. Irimia P. Toledo E. Martínez-Vila E. Buil-Cosiales P. Serrano-Martínez M. Ruiz-Gutiérrez V. Ros E. Estruch R. Martínez-González M.Á. PREDIMED Investigators. Carotid intima-media thickness changes with Mediterranean diet: A randomized trial (PREDIMED-Navarra) Atherosclerosis 2011 219 158 162 10.1016/j.atherosclerosis.2011.06.050 21802081

53. Guasch-Ferré M. Hu F.B. Martínez-González M.A. Fitó M. Bulló M. Estruch R. Ros E. Corella D. Recondo J. Gómez-Gracia E. Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study BMC Med. 2014 12 78 10.1186/1741-7015-12-78 24886626 PMC4030221

54. Guo X. Tresserra-Rimbau A. Estruch R. Martínez-González M.A. Medina-Remón A. Castañer O. Corella D. Salas-Salvadó J. Lamuela-Raventós R.M. Effects of Polyphenol, Measured by a Biomarker of Total Polyphenols in Urine, on Cardiovascular Risk Factors After a Long-Term Follow-Up in the PREDIMED Study Oxid. Med. Cell Longev. 2016 2016 2572606 10.1155/2016/2572606 26881019 PMC4736321

55. Toledo E. Salas-Salvadó J. Donat-Vargas C. Buil-Cosiales P. Estruch R. Ros E. Corella D. Fitó M. Hu F.B. Arós F. Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial: A Randomized Clinical Trial JAMA Int. Med. 2015 175 1752 1760 10.1001/jamainternmed.2015.4838 26365989

56. Fitó M. Estruch R. Salas-Salvadò J. Martínez-Gonzalez M.A. Arós F. Vila J. Corella D. Díaz O. Sáez G. de la Torre R. Effect of the Mediterranean diet on heart failure biomarkers: A randomized sample from the PREDIMED trial Eur. J. Heart Fail. 2014 16 543 550 10.1002/ejhf.61 24574190

57. Soriguer F. Rojo-Martinez G. Goday A. Bosch-Comas A. Bordiu E. Caballero-Diaz F. Calle-Pascual A. Carmena R. Casamitjana R. Castaño L. Olive oil has a beneficial effect on impaired glucose regulation and other cardiometabolic risk factors. Di@bet.es study Eur. J. Clin. Nutr. 2013 67 911 916 10.1038/ejcn.2013.130 23859999

58. Guasch-Ferré M. Hruby A. Salas-Salvadò J. Martinez-Gonzàlez M.A. Sun Q. Willett W.C. Hu F.B. Olive oil consumption and risk of type diabetes in US women Am. J. Clin. Nutr. 2015 102 479 486 10.3945/ajcn.115.112029 26156740 PMC4515873

59. Violi F. Loffredo L. Pignatelli P. Angelico F. Bartimoccia S. Nocella C. Cangemi R. Petruccioli A. Monticolo R. Pastori D. Extra virgin olive oil use is associated with improved post-prandial blood glucose and LDL-cholesterol in healthy subjects Nutr. Diabetes 2015 5 e172 10.1038/nutd.2015.23 26192450 PMC4521177

60. Covas M.I. Nyyssönen K. Poulsen H.E. Kaikkonen J. Zunft H.J. Kiesewetter H. Gaddi A. de la Torre R. Mursu J. Bäumler H. The effect of polyphenols in olive oil on heart disease risk factors: A randomized trial Ann. Int. Med. 2006 145 333 341 10.7326/0003-4819-145-5-200609050-00006 16954359

61. Hernáez Á. Remaley A.T. Farràs M. Fernández-Castillejo S. Subirana I. Schröder H. Fernández-Mampel M. Muñoz-Aguayo D. Sampson M. Solà R. Olive Oil Polyphenols Decrease LDL Concentrations and LDL Atherogenicity in Men in a Randomized Controlled Trial J. Nutr. 2015 145 1692 1697 10.3945/jn.115.211557 26136585 PMC4516770

62. Hernáez Á. Fernàndez-Castillejo S. Farràs M. Catalán Ú. Subirana I. Montes R. Solà R. Muñoz-Aguayo D. Gelabert-Gorgues A. Díaz-Gil Ó. Olive oil polyphenols enhance high-density lipoprotein function in humans. A randomized controlled trial Arterioscler. Thromb. Vasc. Biol. 2014 34 2115 2119 10.1161/ATVBAHA.114.303374 25060792

63. Estruch R. Ros E. Salas-Salvadó J. Covas M.I. Corella D. Arós F. Gómez-Gracia E. Ruiz-Gutiérrez V. Fiol M. Lapetra J. PREDIMED Study Investigators. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts N. Engl. J. Med. 2018 378 e34 10.1056/NEJMoa1800389 29897866

64. Camargo A. Ruano J. Fernandez J.M. Parnell L.D. Jimenez A. Santos-Gonzalez M. Marin C. Perez-Martinez P. Uceda M. Lopez-Miranda J. Gene expression changes in mononuclear cells in patients with metabolic syndrome after acute intake of phenol-rich virgin olive oil BMC Genom. 2010 11 253 10.1186/1471-2164-11-253 20406432 PMC2874810

65. Perez-Herrera A. Delgado-Lista J. Torres-Sanchez L.A. Rangel-Zuñiga O.A. Camargo A. Moreno-Navarrete J.M. Garcia-Olid B. Quintana-Navarro G.M. Alcala-Diaz J.F. Muñoz-Lopez C. The postprandial inflammatory response after ingestion of heated oils in obese persons is reduced by the presence of phenol compounds Mol. Nutr. Food Res. 2012 56 510 514 10.1002/mnfr.201100533 22162245

66. Rainer M. Mucke H. Schlaefke S. Ginkgo biloba extract EGb in the treatment of dementia: A pharmacoeconomic analysis of the Austrian setting Wien Klin. Wochenschr. 2013 125 8 15 10.1007/s00508-012-0307-x 23292640

67. Herrschaft H. Nacu A. Likhachev S. Sholomov I. Hoerr R. Schlaefke S. Ginkgo biloba extract EGb 761 ® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of mg J. Psychiatr. Res. 2012 46 716 723 10.1016/j.jpsychires.2012.03.003 22459264

68. Bachinskaya N. Hoerr R. Ihl R. Alleviating neuropsychiatric symptoms in dementia: The effects of Ginkgo biloba extract EGb 761. Findings from a randomized controlled trial. Neuropsychiatr Dis. Treat. 2011 7 209 215 10.2147/NDT.S18741 PMC3090284 21573082

69. Oliveras-López M.J. Molina J.J. Mir M.V. Rey E.F. Martin F. de la Serrana H.L. Extra virgin olive oil (EVOO) consumption and antioxidant status in healthy institutionalized elderly humans Arch. Gerontol. Geriatr. 2013 57 234 242 10.1016/j.archger.2013.04.002 23642776

70. George E.S. Marshall S. Mayr H.L. Trakman G.L. Tatucu-Babet O.A. Lassemillante A.M. Bramley A. Reddy A.J. Forsyth A. Tierney A.C. The effect of high-polyphenol extra virgin olive oil on cardiovascular risk factors: A systematic review and meta-analysis Crit. Rev. Food Sci. Nutr. 2019 59 2772 2795 10.1080/10408398.2018.1470491 29708409

71. Martínez-González M.A. Gea A. Ruiz-Canela M. The Mediterranean Diet and Cardiovascular Health Circ. Res. 2019 124 779 798 10.1161/CIRCRESAHA.118.313348 30817261

72. Féart C. Samieri C. Allès B. Barberger-Gateau P. Potential benefits of adherence to the Mediterranean diet on cognitive health Proc. Nutr. Soc. 2013 72 140 152 10.1017/S0029665112002959 23228285

73. Knight A. Bryan J. Wilson C. Hodgson J. Murphy K. A randomised controlled intervention trial evaluating the efficacy of a Mediterranean dietary pattern on cognitive function and psychological wellbeing in healthy older adults: The MedLey study BMC Geriatr. 2015 15 5 10.1186/s12877-015-0054-8 25928696 PMC4506625

74. Valls-Pedret C. Sala-Vila A. Serra-Mir M. Corella D. de la Torre R. Martínez-González M.Á. Martínez-Lapiscina E.H. Fitó M. Pérez-Heras A. Salas-Salvadó J. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial JAMA Int. Med. 2015 175 1094 1103 10.1001/jamainternmed.2015.1668 25961184

75. Hamaguchi T. Ono K. Yamada M. Curcumin and Alzheimer’s Disease CNS Neurosci. Ther. 2010 16 285 297 10.1111/j.1755-5949.2010.00147.x 20406252 PMC6493893

76. Baum L. Lam C.W. Cheung S.K. Kwok T. Lui V. Tsoh J. Lam L. Leung V. Hui E. Ng C. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease J. Clin. Psychopharmacol. 2008 28 110 113 10.1097/jcp.0b013e318160862c 18204357

77. Ringman J.M. Frautschy S.A. Teng E. Begum A.N. Bardens J. Beigi M. Gylys K.H. Badmaev V. Heath D.D. Apostolova L.G. Oral curcumin for Alzheimer’s disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study Alzheimers Res. Ther. 2012 4 43 10.1186/alzrt146 23107780 PMC3580400

78. DiSilvestro R.A. Joseph E. Zhao S. Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people Nutr. J. 2012 11 79 10.1186/1475-2891-11-79 23013352 PMC3518252

79. Singh A.P. Singh R. Verma S.S. Rai V. Kaschula C.H. Maiti P. Gupta S.C. Health benefits of resveratrol: Evidence from clinical studies Med. Res. Rev. 2019 39 1851 1891 10.1002/med.21565 30741437

80. Patel K.R. Scott E. Brown V.A. Gescher A.J. Steward W.P. Brown K. Clinical trials of resveratrol Ann. N. Y. Acad. Sci. 2011 1215 161 169 10.1111/j.1749-6632.2010.05853.x 21261655

81. Walker J.M. Eckardt P. Aleman J.O. da Rosa J.C. Liang Y. Iizumi T. Etheve S. Blaser M.J.L. Breslow J. Holt P.R. The effects of trans-resveratrol on insulin resistance, inflammation, and microbiota in men with the metabolic syndrome: A pilot randomized, placebo-controlled clinical trial J. Clin. Transl. Res. 2018 4 122 135 30873501 PMC6412609

82. Najaf Najafi M. Salehi M. Ghazanfarpour M. Hoseini Z.S. Khadem-Rezaiyan M. The association between green tea consumption and breast cancer risk: A systematic review and meta-analysis Phytother. Res. 2018 32 1855 1864 10.1002/ptr.6124 29876987

83. Kristen A.V. Lehrke S. Buss S. Mereles D. Steen H. Ehlermann P. Hardt S. Giannitsis E. Schreiner R. Haberkorn U. Green tea halts progression of cardiac transthyretin amyloidosis: An observational report Clin. Res. Cardiol. 2012 101 805 813 10.1007/s00392-012-0463-z 22584381 PMC3445797

84. Howes M.J. Perry E. The role of phytochemicals in the treatment and prevention of dementia Drugs Aging 2011 28 439 468 10.2165/11591310-000000000-00000 21639405

85. Gu H.F. Mao X.Y. Du M. Prevention of breast cancer by dietary polyphenols-role of cancer stem cells Crit. Rev. Food Sci. Nutr. 2019 11 1 16 10.1080/10408398.2018.1551778 30632783 PMC6625949

86. Gardeazabal I. Romanos-Nanclares A. Martínez-González M.A. Sánchez-Bayona R. Vitelli-Storelli F. Gaforio J.J. Aramendía-Beitia J.M. Toledo E. Total polyphenol intake and breast cancer risk in the SUN cohort Br. J. Nutr. 2018 27 1 23 10.1017/S0007114518003811 30588893

87. Afshari K. Haddadi N.S. Haj-Mirzaian A. Farzaei M.H. Rohani M.M. Akramian F. Naseri R. Sureda A. Ghanaatian N. Abdolghaffari A.H. Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies J. Cell Physiol. 2019 234 21519 21546 10.1002/jcp.28777 31087338

88. Alam M.N. Almoyad M. Huq F. Polyphenols in Colorectal Cancer: Current State of Knowledge including Clinical Trials and Molecular Mechanism of Action Biomed. Res. Int. 2018 2018 4154185 10.1155/2018/4154185 29568751 PMC5820674

89. Wainstein J. Ganz T. Boaz M. Bar Dayan Y. Dolev E. Kerem Z. Madar Z. Olive leaf extract as a hypoglycemic agent in both human diabetic subjects and in rats J. Med. Food 2012 15 605 610 10.1089/jmf.2011.0243 22512698

90. De Bock M. Derraik J.G.B. Brennan C.M. Biggs J.B. Morgan P.E. Hodgkinson S.C. Hofman P.L. Cutfield W.S. Olive ( Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: A randomized, placebo-controlled, crossover trial PLoS ONE 2013 8 e57622 10.1371/journal.pone.0057622 23516412 PMC3596374

91. Lockyer S. Rowland I. Spencer J.P.E. Yaqoob P. Stonehouse W. Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: A randomized controlled trial Eur. J. Nutr. 2017 56 1421 1432 10.1007/s00394-016-1188-y 26951205 PMC5486627

92. Lockyer S. Corona G. Yaqoob P. Spencer J.P. Rowland I. Secoiridoids delivered as olive leaf extract onduce acute improvements in human vascular function and reduction of an inflammatory cytokine: A randomized, double-blind, placebo-controlled, crioss over trial Br. J. Nutr. 2015 114 75 83 10.1017/S0007114515001269 26051429

93. D’Amore S. Vacca M. Cariello M. Graziano G. D’Orazio A. Salvia R. Sasso R.C. Sabbà C. Palasciano G. Moschetta A. Genes and miRNA expression signatures in peripheral blood mononuclear cells in healthy subjects and patients with metabolic syndrome after acute intake of extra virgin olive oil Biochim. Biophys. Acta 2016 1861 1671 1680 10.1016/j.bbalip.2016.07.003 27422371

94. Scoditti E. Carpi S. Massaro M. Pellegrino M. Polini B. Carluccio M.A. Wabitsch M. Verri T. Nieri P. De Caterina R. Hydroxytyrosol modulates adipocyte gene and miRNA expression under inflammatory condition Nutrients 2019 11 2493 10.3390/nu11102493 31627295 PMC6836288

95. Perrone M.A. Gualtieri P. Gratteri S. Ali W. Sergi D. Muscoli S. Cammarano A. Bernardini S. Di Rienzo L. Romeo E. Effects of postprandial hydroxytyrosol and derivates on oxidation of LDL, cardiometabolic state and gene expression: A nurtrigenomic approach for cardiovascular prevention J. Cardiovasc. Med. 2019 20 419 426 10.2459/JCM.0000000000000816 31593559

96. Speer H. D’Cunha N.M. Botek M. McKune A.J. Sergi D. Georgousopoulou E. Mellor D.D. Naumovski N. The effect of dietary polyphenols on circulating cardiovascular disease biomarkers and iron status: A systematic review Nutr. Metab. Insights 2019 12 1178638819882739 10.1177/1178638819882739 31673228 PMC6804354

97. Carlos S. De La Fuente-Arrillaga C. Bes-Rastrollo M. Razquin C. Rico-Campà A. Martínez-González M. Ruiz-Canela A. Mediterranean Diet and Health Outcomes in the SUN Cohort Nutrients 2018 10 E439 10.3390/nu10040439 29614726 PMC5946224

98. Mattson M.P. Hormesis Defined Ageing Res. Rev. 2008 7 1 7 10.1016/j.arr.2007.08.007 18162444 PMC2248601

99. Calabrese E.J. Hormesis and Ginkgo biloba (GB): Numerous biological effects of GB are mediated via hormesis Ageing Res. Rev. 2019 10.1016/j.arr.2020.101019 31931153

100. Calabrese E.J. Mattson M.P. Calabrese V. Resveratrol commonly displays hormesis: Occurrence and biomedical significance Hum. Exp. Toxicol. 2010 29 980 1015 10.1177/0960327110383625 21115559

101. Calabrese E.J. Dhawan D. Kapoor R. Mattson M.P. Rattan S.I.S. Curcumin and hormesis with particular emphasis on neural cells Food Chem. Toxicol. 2019 129 399 404 10.1016/j.fct.2019.04.053 31047936

102. Calabrese E.J. Blain R.B. The hormesis database: The occurrence of hormetic dose responses in the toxicological literature Reg. Toxicol. Pharmacol. 2011 61 73 81 10.1016/j.yrtph.2011.06.003 21699952

103. Calabrese E.J. Hormetic mechanisms Crit. Rev. Toxicol. 2013 43 580 606 10.3109/10408444.2013.808172 23875765

104. Abbasi N. Akhavan M.M. Rohbar-Roshandel N. Shafiei M. The effects of low and high concentrations of luteolin on cultured human endothelial cells under normal and glucotoxic conditions: Involvement of integrin-linked kinase and cyclooxygenase-2 Phtyother. Res. 2014 28 1301 1307 10.1002/ptr.5128 25201753

105. Abbasi N. Khosravi A. Aidy A. Shafiei M. Biphasic response to luteolin in MG-osteobalst-like cells under high glucose-induced oxidative stress IJMS 2016 41 118 125 26989282 PMC4764961

106. Moghadam F.H. Mesbah-Artdakani M. Nasr-Esfahani M.H. Ferulic acid exerts concentration-dependent anti-apoptotic and neuronal differentiation-inducing effects in PCand mouse neural stem cells Eur. J. Pharmacol. 2018 741 104 112 10.1016/j.ejphar.2018.10.003 30332611

107. Woo S.M. Choi W.R. Jang D. Yi C.S. Kim H.L. Kim K.H. Kim J.T. Choi W.H. Hang S.H. Kim M.J. Immune enhancement effect of an herb complex extract through the activation of natural killer cells and the regulation of cytokine levels in a cyclophosphamide-induced immunosuppression rat model Asian Pacif. J. Trop. Med. 2018 11 653 658

108. Trovato Salinaro A. Cornelius C. Koverech G. Koverech A. Scuto M. Lodato F. Fronte V. Muccilli V. Reibaldi M. Longo A. Cellular stress response, redox status, and vitagenes in glaucoma: A systemic oxidant disorderlinked to Alzheimer’s disease Front. Pharmacol. 2014 5 129 10.3389/fphar.2014.00129 24936186 PMC4047681

109. Wakabayashi N. Itoh K. Wakabayashi J. Motohashi H. Noda S. Takahashi S. Imakado S. Kotsuji T. Otsuka F. Roop D.R. Keap1-null mutation leads to post-natal lethality due to constitutive Nrfactivation Nat. Genet. 2003 35 238 245 10.1038/ng1248 14517554

110. Calabrese V. Cornelius C. Dinkova-Kostova A.T. Calabrese E.J. Mattson M.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders Antioxid. RedoxSignal. 2010 13 1763 1811 10.1089/ars.2009.3074 PMC2966482 20446769

111. Trovato Salinaro A. Pennisi M. Di Paola R. Scuto M. Crupi R. Cambria M.T. Ontario M.L. Tomasello M. Uva M. Maiolino L. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: Modulation by nutritional mushrooms Immun. Ageing 2018 15 8 10.1186/s12979-017-0108-1 29456585 PMC5813410

112. Scuto M. Di Mauro P. Ontario M.L. Amato C. Modafferi S. Ciavardelli D. Trovato Salinaro A. Maiolino L. Calabrese V. Nutritional Mushroom Treatment in Meniere’s Disease with Coriolus versicolor: A Rationale for Therapeutic Intervention inNeuroinflammation and Antineurodegeneration Int. J. Mol. Sci. 2019 21 E284 10.3390/ijms21010284 31906226 PMC6981469

113. Mattson M.P. Hormesis and disease resistance: Activation of cellular stressresponse pathways Hum. Exp. Toxicol. 2008 27 155 162 10.1177/0960327107083417 18480142

114. Cornelius C. Trovato Salinaro A. Scuto M. Fronte V. Cambria M.T. Pennisi M. Bella R. Milone P. Graziano A. Crupi R. Cellular stress response, sirtuins and UCP proteins in Alzheimer disease: Role of vitagenes Immun. Ageing 2013 10 41 10.1186/1742-4933-10-41 24498895 PMC3842652

115. Mancuso C. Santangelo R. Calabrese V. The hemeoxygenase/biliverdin reductase system: A potential drug target in Alzheimers disease J. Biol. Regul. Homeost. Agents 2013 27 Suppl. 2 75 87 24813317

116. Naviaux R.K. Metabolic features and regulation of the healing cycle-A new modelfor chronic disease pathogenesis and treatment Mitochondrion 2019 46 278 297 10.1016/j.mito.2018.08.001 30099222

117. Scuto M.C. Mancuso C. Tomasello B. Laura Ontario M. Cavallaro A. Frasca F. Maiolino L. Trovato Salinaro A. Calabrese E.J. Calabrese V. Curcumin, Hormesis and the Nervous System Nutrients 2019 11 2417 10.3390/nu11102417 PMC6835324 31658697

118. Frey B. Hehlgans S. Rodel F. Gaipl U.S. Modulation of inflamma- tion by low and high doses of ionizing radiation: Implications for benign and malign diseases Cancer Lett. 2015 368 230 237 10.1016/j.canlet.2015.04.010 25888451

119. Large M. Hehlgans S. Reichert S. Gaipl U.S. Fournier C. Rodel C. Weiss C. Rodel F. Study of the anti- inflammatory effect of low-dose radiation. The contribution of biphasic regulation of the antioxidative system in endothelial cells Strahlenther. Onkol. 2015 191 742 749 10.1007/s00066-015-0848-9 26051282

120. Wunderlich R. Ernst A. Roedel F. Fietkau R. Ott O. Lauber K. Frey B. Gaipl U.S. Low and moderate doses of ionizing radiation up to Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function Clin. Exp. Immunol. 2015 179 50 61 10.1111/cei.12344 24730395 PMC4260896

121. Trovato A. Siracusa R. Di Paola R. Scuto M. Ontario M.L. Bua O. Di Mauro P. Toscano M.A. Petralia C.C.T. Maiolino L. Redox modulation of cellular stress response and lipoxin Aexpression by Hericium Erinaceus in rat brain: Relevance to Alzheimer’s disease pathogenesis Immun. Ageing 2016 13 23 10.1186/s12979-016-0078-8 27398086 PMC4938991

122. Trovato A. Siracusa R. Di Paola R. Scuto M. Fronte V. Koverech G. Luca M. Serra A. Toscano M.A. Petralia A. Redox modulation of cellular stress response and lipoxin Aexpression by Coriolus versicolor in rat brain: Relevance to Alzheimer’s disease pathogenesis Neurotoxicology 2016 53 350 358 10.1016/j.neuro.2015.09.012 26433056

123. Calabrese V. Santoro A. Monti D. Crupi R. Di Paola R. Latteri S. Cuzzocrea S. Zappia M. Giordano J. Calabrese E.J. Aging and Parkinson’s Disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis Free Radic. Biol. Med. 2018 115 80 91 10.1016/j.freeradbiomed.2017.10.379 29080843

124. Liu B. Hong J.S. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention J. Pharmacol. Exp. Ther. 2003 304 1 7 10.1124/jpet.102.035048 12490568

125. Tan M.S. Yu J.T. Jiang T. Zhu X.C. Tan L. The NLRPinflammasome in Alzheimer’s disease Mol. Neurobiol. 2013 48 875 882 10.1007/s12035-013-8475-x 23686772

126. Freeman D. Cedillos R. Choyke S. Lukic Z. McGuire K. Marvin S. Burrage A.M. Sudholt S. Rana A. O’Connor C. Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxy-gen species following endocytosis PLoS ONE 2013 8 e62143 10.1371/journal.pone.0062143 23634225 PMC3636263

127. Heneka M.T. Kummer M.P. Stutz A. Delekate A. Schwartz S. Vieira-Saecker A. Griep A. Axt D. Remus A. Tzeng T.C. NLRPis activated in Alzheimer’s disease and contributes to pathology in APP/PSmice Nature 2013 493 674 678 10.1038/nature11729 23254930 PMC3812809

128. Codolo G. Plotegher N. Pozzobon T. Brucale M. Tessari I. Bubacco L. de Bernard M. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies PLoS ONE 2013 8 e55375 10.1371/journal.pone.0055375 23383169 PMC3561263

129. Kostomoiri M. Fragkouli A. Sagnou M. Skaltsounis L.A. Pelecanou M. Tsilibary E.C. Tzinia A.K. Oleuropein, an anti-oxidant polyphenol constituent of olivepromotes α-secretase cleavage of the amyloid precursor protein (AβPP) Cell. Mol. Neurobiol. 2013 33 147 154 10.1007/s10571-012-9880-9 23053546 PMC11497865

130. Ladiwala A.R. Mora-Pale M. Lin J.C. Bale S.S. Fishman Z.S. Dordick J.S. Tessier P.M. Polyphenolic glycosides and aglycones utilize opposing pathways to selectively remodel and inactivate toxic oligomers of amyloid β Chembiochem 2011 12 1749 1758 10.1002/cbic.201100123 21671331 PMC4145403

131. Kim M.H. Min J.S. Lee J.Y. Chae U. Yang E.J. Song K.S. Lee H.S. Lee H.J. Lee S.R. Lee D.S. Oleuropein isolated from Fraxinus rhynchophylla inhibits glutamate-induced neuronal cell death by attenuating mitochondrial dysfunction Nutr. Neurosci. 2018 21 520 528 10.1080/1028415X.2017.1317449 28448247

132. Diomede L. Rigacci S. Romeo M. Stefani M. Salmona M. Oleuropein Aglycone Protects Transgenic, C. elegans Strains Expressing Aβby Reducing Plaque Load and Motor Deficit PLoS ONE 2013 8 e58893 10.1371/journal.pone.0058893 23520540 PMC3592812

133. Shibani F. Sahamsizadeh A. Fatemi I. Allahtavakoli M. Hasanshahi J. Rahmani M. Azin M. Hassanipour M. Mozafari N. Kaeidi A. Effect of oleuropein on morphine-induced hippocampus neurotoxicity and memory impairments in rats Naunyn Schmiedebergs Arch. Pharmacol. 2019 392 1383 1391 10.1007/s00210-019-01678-3 31236657

134. De la Torre R. Covas M.I. Pujadas M.A. Fito M. Farre M. Is dopamine behind the health benefits of red wine? Eur. J. Nutr. 2006 45 307 310 10.1007/s00394-006-0596-9 16586149

135. Xu C.L. Sim M.K. Reduction of dihydroxyphenylacetic acid by a novel enzyme in the rat brain Biochem. Pharmacol. 1995 50 1333 1337 10.1016/0006-2952(95)02092-6 7503780

136. Goldstein D.S. Jinsmaa Y. Sullivan P. Holmes C. Kopin I.J. Sharabi Y. 3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PCCells Neurochem. Res. 2016 41 2173 2178 10.1007/s11064-016-1959-0 27220335 PMC5125943

137. Jinsmaa Y. Isonaka R. Sharabi Y. Goldstein D. 3,4-Dihydroxyphenylacetaldehyde is more efficient than dopamine in oligomerizing and quinonizing alpha-synuclein J. Pharmacol. Exp. Ther. 2019 10.1124/jpet.119.262246 PMC6978699 31744850

138. Safouris A. Tsivgoulis G. Sergentanis T.N. Psaltopoulou T. Mediterranean Diet and Risk of Dementia Curr. Alzheimer Res. 2015 12 736 744 10.2174/1567205012666150710114430 26159192

139. Psaltopoulou T. Sergentanis T.N. Mediterranean diet may reduce Alzheimer’s risk Evid. Based. Med. 2015 20 202 10.1136/ebmed-2015-110237 26337936

140. Peng Y. Hou C. Yang Z. Li C. Jia L. Liu J. Tang Y. Shi L. Li Y. Long J. Hydroxytyrosol mildly improve cognitive function independent of APP processing inAPP/PSmice Mol. Nutr. Food Res. 2016 60 2331 2342 10.1002/mnfr.201600332 27287957

141. Palazzi L. Leri M. Cesaro S. Stefani M. Bucciantini M. Polverino de Laureto P. Insight into the molecular mechanism underlying the inhibition of α-synuclein aggregation by hydroxytyrosol Biochem. Pharmacol. 2019 in press 10.1016/j.bcp.2019.113722 31756328

142. Reutzel M. Grewal R. Silaidos C. Zotzel J. Marx S. Tretzel J. Eckert G.P. Effects of Long-Term Treatment with a Blend of Highly Purified Olive Secoiridoids on Cognition and Brain ATP Levels in Aged NMRI Mice Oxid. Med. Cell. Longev. 2018 2018 4070935 10.1155/2018/4070935 30510619 PMC6232801

143. Funakohi-Tago M. Sakata T. Fujiwara S. Sakakura A. Sugai T. Tago K. Tamura H. Hydroxytyrosol butyrate inhibits 6-OHDA-induced apoptosis through activation of the Nrf2/HO-axis in SH-SY5Y cells Eur. J. Pharmacol. 2018 834 246 256 10.1016/j.ejphar.2018.07.043 30053409

144. Zheng A. Li H. Xu J. Cao K. Li H. Pu W. Yang Z. Peng Y. Long J. Liu J. Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: Role of AMP-activated protein kinase activation Br. J. Nutr. 2015 113 1667 1676 10.1017/S0007114515000884 25885653

145. Sun W. Wang X. Hou C. Yang L. Li H. Guo J. Huo C. Wang M. Miao Y. Liu J. Oleuropein improves mitochondrial function to attenuate oxidative stress by activating the Nrfpathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats Neuropharmacology 2017 113 556 566 10.1016/j.neuropharm.2016.11.010 27847271

146. Zrelli H. Kusunoki M. Miyazaki H. Role of Hydroxytyrosol-dependent Regulation of HO-Expression in Promoting Wound Healing of Vascular Endothelial Cells via NrfDe Novo Synthesis and Stabilization Phytother. Res. 2015 29 1011 1018 10.1002/ptr.5339 25870947

147. Wei Y. Jia J. Jin X. Tong W. Tian H. Resveratrol ameliorates inflammatory damage and protects against osteoarthritis in a rat model of osteoarthritis Mol. Med. Rep. 2018 17 1493 1498 10.3892/mmr.2017.8036 29138829 PMC5780088

148. Montoya T. Aparicio-Soto M. Castejón M.L. Rosillo M.Á. Sánchez-Hidalgo M. Begines P. Fernández-Bolaños J.G. Alarcón-de-la-Lastra C. Peracetylated hydroxytyrosol, a new hydroxytyrosol derivate, attenuates LPS-induced inflammatory response in murine peritoneal macrophages via regulation of non-canonical inflammasome, Nrf2/HOand JAK/STAT signaling pathways J. Nutr. Biochem. 2018 57 110 120 10.1016/j.jnutbio.2018.03.014 29694939

149. Kumar R. Nigam L. Singh A.P. Singh K. Subbarao N. Dey S. Design, synthesis of allosteric peptide activator for human SIRTand its biological evaluation in cellular model of Alzheimer’s disease Eur. J. Med. Chem. 2017 127 909 916 10.1016/j.ejmech.2016.11.001 27836195

150. Herskovits A.Z. Guarente L. SIRTin neurodevelopment and brain senescence Neuron 2014 81 471 483 10.1016/j.neuron.2014.01.028 24507186 PMC4040287

151. Gao J. Wang W.Y. Mao Y.W. Gräff J. Guan J.S. Pan L. Mak G. Kim D. Su S.C. Tsai L.H. A novel pathway regulates memory and plasticity via SIRTand miR-134 Nature 2010 466 1105 1109 10.1038/nature09271 20622856 PMC2928875

152. Zhi L.Q. Yao S.X. Liu H.L. Li M. Duan N. Ma J.B. Hydroxytyrosol inhibits the inflammatory response of osteoarthritis chondrocytes via SIRT6-mediated autophagy Mol. Med. Rep. 2018 17 4035 4042 10.3892/mmr.2017.8353 29286133

153. Sun T. Chen Q. Zhu S.Y. Wu Q. Liao C.R. Wang Z. Wu X.H. Wu H.T. Chen J.T. Hydroxytyrosol promotes autophagy by regulating SIRTagainst advanced oxidation protein product-induced NADPH oxidase and inflammatory response Int. J. Mol. Med. 2019 44 1531 1540 31432093 10.3892/ijmm.2019.4300

154. Gallardo-Fernández M. Hornedo-Ortega R. Cerezo A.B. Troncoso A.M. García-Parrilla M.C. Melatonin, protocatechuic acid and hydroxytyrosol effects on vitagenes system against alpha-synuclein toxicity Food Chem. Toxicol. 2019 134 110817 10.1016/j.fct.2019.110817 31521636

155. Wang W. Jing T. Yang X. He Y. Wang B. Xiao Y. Shang C. Zhang J. Lin R. Hydroxytyrosol regulates the autophagy of vascular adventitial fibroblasts through the SIRT1-mediated signaling pathway Can. J. Physiol. Pharmacol. 2018 96 88 96 10.1139/cjpp-2016-0676 28772080

156. Yang X. Jing T. Li Y. He Y. Zhang W. Wang B. Xiao Y. Wang W. Zhang J. Wei J. Hydroxytyrosol Attenuates LPS-Induced Acute Lung Injury in Mice by Regulating Autophagy and Sirtuin Expression Curr. Mol. Med. 2017 17 149 159 10.2174/1566524017666170421151940 28429673

157. Calabrese V. Scapagnini G. Davinelli S. Koverech G. Koverech A. De Pasquale C. Salinaro A.T. Scuto M. Calabrese E.J. Genazzani A.R. Sex hormonal regulation and hormesis in aging and longevity: Role of vitagenes J. Cell. Commun. Signal. 2014 8 369 384 10.1007/s12079-014-0253-7 25381162 PMC4390801

158. Amara I. Timoumi R. Annabi E. Di Rosa G. Scuto M. Najjar M.F. Calabrese V. Abid-Essefi S. Di (2-ethylhexyl) phthalate targets the thioredoxin system and the oxidative branch of the pentose phosphate pathway in liver of Balb/c mice Environ Toxicol. 2020 35 78 86 10.1002/tox.22844 31486570

159. Peng S. Zhang B. Yao J. Duan D. Fang J. Dual protection of hydroxytyrosol, an olive oil polyphenol, against oxidative damage in PCcells Food Funct. 2015 6 2091 2100 10.1039/C5FO00097A 26037629

160. Zhang Y. Ahn Y.H. Benjamin I.J. Honda T. Hicks R.J. Calabrese V. Cole P.A. Dinkova-Kostova A.T. HSF1-dependent upregulation of Hspby sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway Chem. Biol. 2011 18 1355 1361 10.1016/j.chembiol.2011.09.008 22118669 PMC3302153

161. An Y.W. Jhang K.A. Woo S.Y. Kang J.L. Chong Y.H. Sulforaphane exerts its anti-inflammatory effect against amyloid-β peptide via STAT-dephosphorylation and activation of Nrf2/HO-cascade in human THP-macrophages Neurobiol. Aging 2016 38 1 10 10.1016/j.neurobiolaging.2015.10.016 26827637

162. Lee S. Choi B.R. Kim J. La Ferla F.M. Park J.H.Y. Han J.S. Lee K.W. Kim J. Sulforaphane Upregulates the Heat Shock Protein Co-Chaperone CHIP and Clears Amyloid-β and Tau in a Mouse Model of Alzheimer’s Disease Mol. Nutr. Food Res. 2018 62 e1800240 10.1002/mnfr.201800240 29714053

163. Moussa C. Hebron M. Huang X. Ahn J. Rissman R.A. Aisen P.S. Turner R.S. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease J. Neuroinflamm. 2017 14 1 10.1186/s12974-016-0779-0 28086917 PMC5234138

164. Zhao Y.N. Li W.F. Li F. Zhang Z. Dai Y.D. Xu A.L. Qi C. Gao J.M. Gao J. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway Biochem. Biophys. Res. Commun. 2013 435 597 602 10.1016/j.bbrc.2013.05.025 23685142

165. Laudati G. Mascolo L. Guida N. Sirabella R. Pizzorusso V. Bruzzaniti S. Serani A. Di Renzo G. Canzoniero L.M.T. Formisano L. Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1/DREAM/PDYN pathway Neurotoxicology 2019 71 6 15 10.1016/j.neuro.2018.11.009 30503815

166. Zhang S. Gao L. Liu X. Lu T. Xie C. Jia J. Resveratrol Attenuates Microglial Activation via SIRT1-SOCSPathway Evid. Based. Complement Alternat. Med. 2017 2017 8791832 10.1155/2017/8791832 28781601 PMC5525071

167. Ma S. Feng J. Zhang R. Chen J. Han D. Li X. Yang B. Li X. Fan M. Li C. SIRTActivation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice Oxid. Med. Cell. Longev. 2017 2017 4602715 10.1155/2017/4602715 28883902 PMC5572590

168. Hui Y. Chengyong T. Cheng L. Haixia H. Yuanda Z. Weihua Y. Resveratrol attenuates the cytotoxicity induced by amyloid-β 1–in PCcells by upregulating heme oxygenase-via the PI3K/Akt/Nrfpathway Neurochem. Res. 2018 43 297 305 10.1007/s11064-017-2421-7 29090409

169. Zhou Y. Jin Y. Yu H. Shan A. Shen J. Zhou C. Zhao Y. Fang H. Wang X. Wang J. Resveratrol inhibits aflatoxin B1-induced oxidative stress and apoptosis in bovine mammary epithelial cells and is involved the Nrfsignaling pathway Toxicon 2019 164 10 15 10.1016/j.toxicon.2019.03.022 30946912

170. Feng L. Zhang L. Resveratrol Suppresses Aβ-Induced Microglial Activation Through the TXNIP/TRX/NLRPSignaling Pathway DNA Cell Biol. 2019 38 874 879 10.1089/dna.2018.4308 31215797

171. Mhillaj E. Cuomo V. Trabace L. Mancuso C. The HemeOxygenase/Biliverdin Reductase System as Effector of the Neuroprotective Outcomes of Herb-BasedNutritionalSupplements Front. Pharmacol. 2019 10 1298 10.3389/fphar.2019.01298 31780933 PMC6859463

172. Xu J. Zhou L. Weng Q. Xiao L. Li Q. Curcumin analogues attenuate Aβ 25—Induced oxidative stress in PCcells via Keap1/Nrf2/HO-signaling pathways Chem. Biol. Interact. 2019 305 171 179 10.1016/j.cbi.2019.01.010 30946834

173. Yin H. Guo Q. Li X. Tang T. Li C. Wang H. Sun Y. Feng Q. Ma C. Gao C. Curcumin Suppresses IL-1β Secretion and Prevents Inflammation through Inhibition of the NLRPInflammasome J. Immunol. 2018 200 2835 2846 10.4049/jimmunol.1701495 29549176

174. Ma Q.L. Zuo X. Yang F. Ubeda O.J. Gant D.J. Alaverdyan M. Teng E. Hu S. Chen P.P. Maiti P. Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice J. Biol. Chem. 2013 288 4056 4065 10.1074/jbc.M112.393751 23264626 PMC3567657

175. Maggi S. Noale M. Gallina P. Bianchi D. Marzari C. Limongi F. Crepaldi G. ILSA Working Group. Metabolic syndrome, diabetes, and cardiovascular disease in an elderly Caucasian cohort: The Italian Longitudinal Study on Aging J. Gerontol. A Biol. Sci. Med. Sci. 2006 61 505 510 10.1093/gerona/61.5.505 16720749

176. Schnack L.L. Romani A.M.P. The Metabolic Syndrome and the Relevance of Nutrients for its Onset Recent Pat. Biotechnol. 2017 11 101 119 10.2174/1872208311666170227112013 28245777

177. Trichopoulou A. Naska A. DAFNE III Group European food availability databank based on household budget surveys: The Data Food Networking initiative Eur. J. Public Health 2003 13 Suppl. 3 24 28 10.1093/eurpub/13.suppl_1.24 14533745

178. Tuomilehto J. Lindström J. Eriksson J.G. Valle T.T. Hämäläinen H. Ilanne-Parikka P. Keinänen-Kiukaanniemi S. Laakso M. Louheranta A. Rastas M. Prevention of type diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance N. Engl. J. Med. 2001 344 1343 1350 10.1056/NEJM200105033441801 11333990

179. Lindström J. Peltonen M. Eriksson J.G. Louheranta A. Fogelholm M. Uusitupa M. Tuomilehto J. High-fibre, low-fat diet predicts long-term weight loss and decreased type diabetes risk: The Finnish Diabetes Prevention Study Diabetologia 2006 49 912 920 10.1007/s00125-006-0198-3 16541277

180. Hanhineva K. Torronen R. Bondia-Pons I. Pekkinen J. Kolehmainen M. Mykkanen H. Poutanen K. Impact of dietary polyphenols on carbohydrate metabolism Int. J. Mol. Sci. 2010 11 1365 1402 10.3390/ijms11041365 20480025 PMC2871121

181. Valdivielso P. Puerta S. Rioja J. Alonso I. Ariza M.J. Sánchez-Chaparro M.A. Palacios R. González-Santos P. Postprandial apolipoprotein Bis associated with asymptomatic peripheral arterial disease: A study in patients with type diabetes and controls Clin. Chim. Acta 2010 411 433 437 10.1016/j.cca.2009.12.022 20059992

182. O’Keefe J.H. Bell D.S.H. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor Am. J. Cardiol. 2007 100 899 904 10.1016/j.amjcard.2007.03.107 17719342

183. Meigs J.B. Nathan D.M. D’Agostino R.B. Sr. Wilson P.W. Framingham Offspring Study Fasting and postchallenge glycemia and cardiovascular disease risk: The Framingham offspring study Diabetes Care 2002 25 1845 1850 10.2337/diacare.25.10.1845 12351489

184. Harte A.L. Varma M.C. Tripathi G. McGee K.C. Al-Daghri N.M. Al-Attas O.S. Sabico S. O’Hare J.P. Ceriello A. Saravanan P. High fat intake leads to acute postprandial exposure to circulating endotoxin in type diabetic subjects Diabetes Care 2012 35 375 382 10.2337/dc11-1593 22210577 PMC3263907

185. Nocella C. Carnevale R. Bartimoccia S. Novo M. Cangemi R. Pastori D. Calvieri C. Pignatelli P. Violi F. Lipopolysaccharide as trigger of platelet aggregation via eicosanoid over-production Thromb. Haemost. 2017 117 1558 1570 10.1160/TH16-11-0857 28492699

186. El-Amin M. Virk P. Elobeid M.A. Almarhoon Z.M. Hassan Z.K. Omer S.A. Merghani N.M. Daghestani M.H. Al-Olayan E.M. Anti-diabetic effect of Murraya koenigii (L) and Olea europaea (L) leaf extracts on streptozotocin induced diabetic rats Pak. J. Pharm. Sci. 2013 26 359 365 23455208

187. Carnevale R. Pignatelli P. Nocella C. Loffredo L. Pastori D. Vicario T. Petruccioli A. Bartimoccia S. Violi F. Extra virgin olive oil blunt postprandial oxidative stress via NOXdown-regulation Atherosclerosis 2014 35 649 658 10.1016/j.atherosclerosis.2014.05.954 24980290

188. Carnevale R. Pastori D. Nocella C. Cammisotto V. Bartimoccia S. Novo M. Del Ben M. Farcomeni A. Angelico F. Violi F. Gut-derived lipopolysaccharides increase post-prandial oxidative stress via Noxactivation in patients with impaired fasting glucose tolerance: Effect of extra-virgin olive oil Eur. J. Nutr. 2019 58 843 851 10.1007/s00394-018-1718-x 29766292

189. Wilson T. Singh A.P. Vorsa N. Goettl C.D. Kittleson K.M. Roe C.M. Kastello G.M. Ragsdale F.R. Human glycemic response and phenolic content of unsweetened cranberry juice J. Med. Food 2008 11 46 54 10.1089/jmf.2007.531 18361737

190. Calahorra J. Shenk J. Wielanga V.H. Verweij V. Geenen B. Dederen P.J. Peinado M.A. Siles E. Wiesmann M. Kiliaan A.J. Hydroxytyroaol, the major phenolic compound of olive oil, as as acute therapeutic strategy after ischemic stroke Nutrients 2019 11 2430 10.3390/nu11102430 PMC6836045 31614692

191. Thilagam E. Parimaladevi B. Kumarappan C. Mandal S.C. α-Glucosidase and α-amylase inhibitory activity of Senna surattensis J. Acupunct. Meridian Stud. 2013 6 24 30 10.1016/j.jams.2012.10.005 23433052

192. Hiyoshi T. Fujiwara M. Yao Z. Postprandial hyperglycemia and postprandial hypertriglyceridemia in type diabetes J. Biomed. Res. 2019 33 1 16 10.7555/JBR.31.20160164 PMC6352876 29089472

193. Tadera K. Minami Y. Takamatsu K. Matsuoka T. Inhibition of alpha-glucosidase and alpha-amylase by flavonoids J. Nutr. Sci. Vitaminol. (Tokyo) 2006 52 149 153 10.3177/jnsv.52.149 16802696

194. Matsui T. Tanaka T. Tamura S. Toshima A. Tamaya K. Miyata Y. Tanaka K. Matsumoto K. alpha-Glucosidase inhibitory profile of catechins and theaflavins J. Agric. Food Chem. 2007 55 99 105 10.1021/jf0627672 17199319

195. Park C.E. Kim M.J. Lee J.H. Min B.I. Bae H. Choe W. Kim S.S. Ha J. Resveratrol stimulates glucose transport in C2Cmyotubes by activating AMP-activated protein kinase Exp. Mol. Med. 2007 39 222 229 10.1038/emm.2007.25 17464184

196. Song J. Kwon O. Chen S. Daruwala R. Eck P. Park J.B. Levine M. Flavonoid inhibition of sodium-dependent vitamin C transporter (SVCT1) and glucose transporter isoform (GLUT2), intestinal transporters for vitamin C and Glucose J. Biol. Chem. 2002 277 15252 15260 10.1074/jbc.M110496200 11834736

197. Johnston K. Sharp P. Clifford M. Morgan L. Dietary polyphenols decrease glucose uptake by human intestinal Caco-cells FEBS Lett. 2005 579 1653 1657 10.1016/j.febslet.2004.12.099 15757656

198. Calabrese V. Santoro A. Trovato Salinaro A. Modafferi S. Scuto M. Albouchi F. Monti D. Giordano J. Zappia M. Franceschi C. Hormetic approaches to the treatment of Parkinson’s disease: Perspectives and possibilities J. Neurosci. Res. 2018 96 1641 1662 10.1002/jnr.24244 30098077

199. Montagut G. Onnockx S. Vaqué M. Bladé C. Blay M. Fernández-Larrea J. Pujadas G. Salvadó M.J. Arola L. Pirson I. Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin J. Nutr. Biochem. 2010 21 476 481 10.1016/j.jnutbio.2009.02.003 19443198

200. Cummings E. Hundal H.S. Wackerhage H. Hope M. Belle M. Adeghate E. Singh J. Momordica charantia fruit juice stimulates glucose and amino acid uptakes in Lmyotubes Mol. Cell. Biochem. 2004 261 99 104 10.1023/B:MCBI.0000028743.75669.ab 15362491

201. Kurimoto Y. Shibayama Y. Inoue S. Soga M. Takikawa M. Ito C. Nanba F. Yoshida T. Yamashita Y. Ashida H. Black soybean seed coat extract ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase in diabetic mice J. Agric. Food Chem. 2013 61 5558 5564 10.1021/jf401190y 23683106

202. Babu P.V. Liu D. Gilbert E.R. Recent advances in understanding the anti-diabetic actions of dietary flavonoids J. Nutr. Biochem. 2013 24 1777 1789 10.1016/j.jnutbio.2013.06.003 24029069 PMC3821977

203. Zhang Z.F. Li Q. Liang J. Dai X.Q. Ding Y. Wang J.B. Li Y. Epigallocatechin-3-O-gallate (EGCG) protects the insulin sensitivity in rat lmuscle cells exposed to dexamethasone condition Phytomedicine 2010 17 14 18 10.1016/j.phymed.2009.09.007 19819682

204. Hadrich F. Mahmoudi A. Bouallagui Z. Feki I. Isoda H. Feve B. Sayadi S. Evaluation of hypocholesterolemic effect of oleuropein in cholesterol-fed rats Chem. Biol. Interact. 2016 252 54 60 10.1016/j.cbi.2016.03.026 27019295

205. Henquin J.C. Triggering and amplifying pathways of regulation of insulin secretion by glucose Diabetes 2000 49 1751 1760 10.2337/diabetes.49.11.1751 11078440

206. Cai E.P. Lin J.K. Epigallocatechin gallate (EGCG) and rutin suppress the glucotoxicity through activating IRSand AMPK signaling in rat pancreatic beta cells J. Agric. Food Chem. 2009 57 9817 9827 10.1021/jf902618v 19803520

207. Rutter G.A. da Silva X.G. Leclerc I. Roles of -AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis Biochem. J. 2003 375 1 16 10.1042/bj20030048 12839490 PMC1223661

208. Kim E.K. Kwon K.B. Song M.Y. Han M.J. Lee J.H. Lee Y.R. Lee J.H. Ryu D.G. Park B.H. Park J.W. Flavonoids protect against cytokine-induced pancreatic beta-cell damage through suppression of nuclear factor κB activation Pancreas 2007 35 e1 e9 10.1097/mpa.0b013e31811ed0d2 18090225

209. Drira R. Chen S. Sakamoto K. Oleuropein and hydroxytyrosol inhibit adipocyte differentiation in T3-Lcells Life Sci. 2011 89 708 716 10.1016/j.lfs.2011.08.012 21945192

210. Hao J. Shen W. Yu G. Jia H. Li X. Feng Z. Wang Y. Weber P. Wertz K. Sharman E. Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-Ladipocytes J. Nutr. Biochem. 2010 21 634 644 10.1016/j.jnutbio.2009.03.012 19576748

211. Hardie D.G. AMP-activated/SNFprotein kinases: Conserved guardians of cellular energy Nat. Rev. Mol. Cell Biol. 2007 8 774 785 10.1038/nrm2249 17712357

212. Sabatini D.M. mTOR and cancer: Insights into a complex relationship Nat. Rev. Cancer 2006 6 729 734 10.1038/nrc1974 16915295

213. Gwinn D.M. Shackelford D.B. Egan D.F. Mihaylova M.M. Mery A. Vasquez D.S. Turk B.E. Shaw R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint Mol. Cell. 2008 30 214 226 10.1016/j.molcel.2008.03.003 18439900 PMC2674027

214. Lee J.H. Koh H. Kim M. Kim Y. Lee S.Y. Karess R.E. Lee S.H. Shong M. Kim J.M. Kim J. Energy-dependent regulation of cell structure by AMP-activated protein kinase Nature 2007 447 1017 1020 10.1038/nature05828 17486097

215. Huang Y. Zhu X. Chen K. Lang H. Zhang Y. Hou P. Ran L. Zhou M. Zheng J. Yi L. Resveratrol prevents sarcopenic obesity by reversing mitochondrial dysfunction and oxidative stress via the PKA/LKB1/AMPK pathway Aging (Albany N. Y.) 2019 11 2217 2240 10.18632/aging.101910 30988232 PMC6519996

216. Rigacci S. Miceli C. Nediani C. Berti A. Cascella R. Pantano D. Nardiello P. Luccarini I. Casamenti F. Stefani M. Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: A mechanistic insight Oncotarget 2015 6 35344 35357 10.18632/oncotarget.6119 26474288 PMC4742109

217. Bronner M. Hertz R. Bar-Tana J. Kinase-independent transcriptional co-activation of peroxisome proliferator-activated receptor alpha by AMP-activated protein kinase Biochem. J. 2004 384 295 305 10.1042/BJ20040955 15312046 PMC1134113

218. Marsin A.S. Bouzin C. Bertrand L. Hue L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase J. Biol. Chem. 2002 277 30778 30783 10.1074/jbc.M205213200 12065600

219. Campbell N.K. Fitzgerald H.K. Fletcher J.M. Dunne A. Plant-Derived Polyphenols Modulate Human Dendritic Cell Metabolism and Immune Function via AMPK-Dependent Induction of Heme Oxygenase-1 Front. Immunol. 2019 10 345 10.3389/fimmu.2019.00345 30881359 PMC6405514

220. Kundu J. Kim D.H. Kundu J.K. Chun K.S. Thymoquinone induces heme oxygenase-expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKα as upstream targets Food Chem. Toxicol. 2014 65 18 26 10.1016/j.fct.2013.12.015 24355171

221. Garza-Lombó C. Schroder A. Reyes-Reyes E.M. Franco R. mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival Curr. Opin. Toxicol. 2018 8 102 110 10.1016/j.cotox.2018.05.002 30417160 PMC6223325

222. Li X.N. Song J. Zhang L. LeMaire S.A. Hou X. Zhang C. Coselli J.S. Chen L. Wang X.L. Zhang Y. Activation of the AMPK-FOXOpathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin Diabetes 2009 58 2246 2257 10.2337/db08-1512 19592618 PMC2750236

223. Egan D.F. Shackelford D.B. Mihaylova M.M. Gelino S. Kohnz R.A. Mair W. Vasquez D.S. Joshi A. Gwinn D.M. Taylor R. Phosphorylation of ULK(hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy Science 2011 331 456 461 10.1126/science.1196371 21205641 PMC3030664

224. Collodet C. Foretz M. Deak M. Bultot L. Metairon S. Viollet B. Lefebvre G. Raymondm F. Parisi A. Civiletto G. AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR FASEB J. 2019 33 12374 12391 10.1096/fj.201900841R 31404503 PMC6902666

225. Furtado L.M. Somwar R. Sweeney G. Niu W. Klip A. Activation of the glucose transporter GLUTby insulin Biochem. Cell Biol. 2002 80 569 578 10.1139/o02-156 12440698

226. Watson R.T. Kanzaki M. Pessin J.E. Regulated membrane trafficking of the insulin-responsive glucose transporter in adipocytes Endocr. Rev. 2004 25 177 204 10.1210/er.2003-0011 15082519

227. Inoki K. Zhu T. Guan K.L. TSCmediates cellular energy response to control cell growth and survival Cell 2003 115 577 590 10.1016/S0092-8674(03)00929-2 14651849

228. Chung S. Yao H. Caito S. Hwang J.W. Arunachalam G. Rahman I. Regulation of SIRTin cellular functions: Role of polyphenols Arch. Biochem. Biophys. 2010 501 79 90 10.1016/j.abb.2010.05.003 20450879 PMC2930135

229. Zhao W. Li A. Feng X. Hou T. Liu K. Liu B. Zhang N. Metformin and resveratrol ameliorate muscle insulin resistance through preventing lipolysis and inflammation in hypoxic adipose tissue Cell Signal. 2016 28 1401 1411 10.1016/j.cellsig.2016.06.018 27343375

230. Chen C.Y. Chen H.F. Gi S.J. Chi T.H. Cheng C.K. Hsu C.F. Ma Y.S. Wei Y.H. Liu C.S. Hsieh M. Decreased heat shock protein expression and altered autophagy in human cells harboring A8344G mitochondrial DNA mutation Mitochondrion 2011 11 739 749 10.1016/j.mito.2011.05.014 21679777

231. Carra S. Rusmini P. Crippa V. Giorgetti E. Boncoraglio A. Cristofani R. Naujock M. Meister M. Minoia M. Kampinga H.H. Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders Philos. Trans. R. Soc. Lond. B Biol. Sci. 2013 368 20110409 10.1098/rstb.2011.0409 23530259 PMC3638395

232. Vos M.J. Zijlstra M.P. Carra S. Sibon O.C. Kampinga H.H. Small heat shock proteins, protein degradation and protein aggregation diseases Autophagy 2011 7 101 103 10.4161/auto.7.1.13935 21045566

233. Korolchuk V.I. Mansilla A. Menzies F.M. Rubinsztein D.C. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates Mol. Cell 2009 33 517 527 10.1016/j.molcel.2009.01.021 19250912 PMC2669153

234. Baixauli F. López-Otín C. Mittelbrunn M. Exosomes and autophagy: Coordinated mechanisms for the maintenance of cellular fitness Front. Immunol. 2014 5 403 10.3389/fimmu.2014.00403 25191326 PMC4138502

235. Labbadia J. Morimoto R.I. The Biology of Proteostasis in Aging and Disease Annu. Rev. Biochem. 2015 84 435 464 10.1146/annurev-biochem-060614-033955 25784053 PMC4539002

236. Hetz C. The unfolded protein response: Controlling cell fate decisions under ER stress and beyond Nat. Rev. Mol. Cell Biol. 2012 13 89 102 10.1038/nrm3270 22251901

237. Joshi S. Wang T. Araujo T.L.S. Sharma S. Brodsky J.L. Chiosis G. Adapting to stress—Chaperome networks in cancer Nat. Rev. Cancer 2018 18 562 575 10.1038/s41568-018-0020-9 29795326 PMC6108944

238. Han Y.S. Bastianetto S. Dumont Y. Quirion R. Specific plasma membrane binding sites for polyphenols, including resveratrol, in the rat brain J. Pharmacol. Exp. Ther. 2006 318 238 245 10.1124/jpet.106.102319 16574779

239. Chung J.H. Manganiello V. Dyck J.R. Resveratrol as a calorie restriction mimetic: Therapeutic implications Trends Cell Biol. 2012 22 546 554 10.1016/j.tcb.2012.07.004 22885100 PMC3462230

240. Lan F. Weikel K.A. Cacicedo J.M. Ido Y. Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application Nutrients 2017 9 751 10.3390/nu9070751 PMC5537865 28708087

241. Miki H. Uehara N. Kimura A. Tsubura A. Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells Int. J. Oncol. 2012 40 1020 1028 10.3892/ijo.2012.1325 22218562 PMC3584586

242. Selvaraj S. Sun Y. Sukumaran P. Singh B.B. Singh Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIMand the mTOR pathway Mol. Carcinog. 2016 55 818 831 10.1002/mc.22324 25917875 PMC4624064

243. Fu Y. Chang H. Peng X. Bai Q. Yi L. Zhou Y. Zhu J. Mi M. Resveratrol Inhibits Breast Cancer Stem-Like Cells and Induces Autophagy via Suppressing Wnt/β-catenin Signaling Pathway PLoS ONE 2014 9 e102535 10.1371/journal.pone.0102535 25068516 PMC4113212

244. Villa-Cuesta E. Boylan J.N.M. Tatar M. Gruppuso P.A. Resveratrol inhibits protein translation in hepatic cells PLoS ONE 2011 6 e29513 10.1371/journal.pone.0029513 22242130 PMC3248458

245. Zhang C. Zhou Y. Zhou Y. Lu Y. Wang D. Regulation of eIF”α expression and renal interstitial fibrosis by resveratrol in rat renal tissue after unilateral uretral obstruction Ren. Fail. 2016 38 622 628 10.3109/0886022X.2016.1149774 26923138

246. Maiti P. Dunbar G.L. Use of Curcumin, a Natural Polyphenol for Targeting Molecular Pathways in Treating Age-Related Neurodegenerative Diseases Int. J. Mol. Sci. 2018 19 1637 10.3390/ijms19061637 PMC6032333 29857538

247. Teiten M.H. Reuter S. Schmucker S. Dicato M. Diederich M. Induction of heat shock response by curcumin in human leukemia cells Cancer Lett. 2009 279 145 154 10.1016/j.canlet.2009.01.031 19246153

248. Graikou K. Kapeta S. Aligiannis N. Sotiroudis G. Chondrogianni N. Gonos E. Chinou I. Chemical analysis of Greek pollen—Antioxidant, antimicrobial and proteasome activation properties Chem. Cent. J. 2011 5 33 10.1186/1752-153X-5-33 21699688 PMC3135496

249. Kuzuhara T. Suganuma M. Fujiki H. Green tea catechin as a chemical chaperone in cancer prevention Cancer Lett. 2008 261 12 20 10.1016/j.canlet.2007.10.037 18068893

250. De Rijk M.C. Breteler M.M. den Breeijen J.H. Launer L.J. Grobbee D.E. van der Meche F.G. Hofman A. Dietary antioxidants and Parkinson disease. The Rotterdam Study Arch. Neurol. 1997 54 762 765 10.1001/archneur.1997.00550180070015 9193212

251. Miceli C. Santin Y. Manzella N. Coppini R. Berti A. Stefani M. Parini A. Mialet-Perez J. Nediani C. Oleuropein aglycone protects against MAO-A-induced autophagy impairment and cardiomyocyte death through activation of TFEB Oxid. Med. Cell. Long. 2018 2018 8067592 10.1155/2018/8067592 PMC5892212 29765503

252. Lee Y.J. Lee D.M. Lee S.H. NrfExpression and Apoptosis in Quercetin-treated Malignant Mesothelioma Cells Mol. Cells 2015 38 416 425 10.14348/molcells.2015.2268 25896339 PMC4443283

253. Kwak M.K. Wakabayashi N. Greenlaw J.L. Yamamoto M. Kensler T.W. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrfsignaling pathway Mol. Cell. Biol. 2003 23 8786 8794 10.1128/MCB.23.23.8786-8794.2003 14612418 PMC262680

254. Granato M. Rizzello C. Gilardini Montani M.S. Cuomo L. Vitillo M. Santarelli R. Gonnella R. D’Orazi G. Faggioni A. Cirone M. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT signaling pathways J. Nutr. Biochem. 2017 41 124 136 10.1016/j.jnutbio.2016.12.011 28092744

255. Korzus E. Manipulating the brain with epigenetics Nat. Neurosci. 2010 13 405 406 10.1038/nn0410-405 20348936

256. Miyamoto K. Ushijima T. Diagnostic and therapeutic applications of epigenetics Jap. J. Clin. Oncol. 2005 35 293 301 10.1093/jjco/hyi088 15930038

257. Peedicayil J. Epigenetic therapy: A new development in pharmacology Indian J. Med. Res. 2006 123 17 24 16567863

258. Rahman I. Chung S. Dietary polyphenols, deacetylases and chromatin remodeling in inflammation J. Nutrigenet. Nutrigenom. 2010 3 220 230 10.1159/000324358 PMC3085527 21474953

259. Schneider-Stock R. Ghantous A. Bajbouj K. Saikali M. Darwiche N. Epigenetic mechanisms of plant-derived anticancer drugs Front. Biosci. 2012 17 129 173 10.2741/3919 22201736

260. Hardy T.M. Tollefsbol T.O. Epigenetic diet: Impact on the epigenome and cancer Epigenomics 2011 3 503 518 10.2217/epi.11.71 22022340 PMC3197720

261. Herman J.G. Baylin S.B. Gene silencing in cancer in association with promoter hypermethylation N. Engl. J. Med. 2003 349 2042 2054 10.1056/NEJMra023075 14627790

262. Esteller M. Epigenetics in cancer N. Engl. J. Med. 2008 358 1148 1159 10.1056/NEJMra072067 18337604

263. Hellebrekers D.M. Griffioen A.W. van Engeland M. Dual targeting of epigenetic therapy in cancer Biochim. Biophys. Acta 2007 1775 76 91 10.1016/j.bbcan.2006.07.003 16930846

264. Heo J. Lim J. Lee S. Jeong J. Kang H. Kim Y. Kang J.W. Yu H.Y. Jeong E.M. Kim K. SirtRegulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l Cell Rep. 2017 18 1930 1945 10.1016/j.celrep.2017.01.074 28228259

265. Fulco M. Sartorelli V. Comparing and contrasting the roles of AMPK and SIRTin metabolic tissues Cell Cycle 2008 7 3669 3679 10.4161/cc.7.23.7164 19029811 PMC2607479

266. Wang L.F. Wang X.N. Huang C.C. Hu L. Xiao Y.F. Guan X.H. Qian Y.S. Deng K.Y. Xin H.B. Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1/AMPKα/SREBPsignaling pathway Lipids Health Dis. 2017 16 82 10.1186/s12944-017-0464-z 28449683 PMC5408374

267. Xie Q. Bai Q. Zou L.Y. Zhang Q.Y. Zhou Y. Chang H. Yi L. Zhu J.D. Mi M.T. Genistein inhibits DNA methylation and increases expression of tumor suppressor genes in human breast cancer cells Geneschromosomes Cancer 2014 53 422 431 10.1002/gcc.22154 24532317

268. Kala R. Shah H.N. Martin S.L. Tollefsbol T.O. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRTand DNMT enzyme expression, including SIRT1-dependent γ-H2AX and telomerase regulation in triple-negative breast cancer BMC Cancer 2015 15 672 10.1186/s12885-015-1693-z 26459286 PMC4603342

269. Heger V. Tyni J. Hunyadi A. Horáková L. Lahtela-Kakkonen M. Rahnasto-Rilla M. Quercetin based derivatives as sirtuin inhibitors Biomed. Pharmacother. 2019 111 1326 1333 10.1016/j.biopha.2019.01.035 30841446

270. Henning S.M. Wang P. Carpenter C.L. Heber D. Epigenetic effects of green tea polyphenols in cancer Epigenomics 2013 5 729 741 10.2217/epi.13.57 24283885 PMC3970408

271. Fang M.Z. Wang Y. Ai N. Hou Z. Sun Y. Lu H. Welsh W. Yang C.S. Tea polyphenol (–)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines Cancer Res. 2003 63 7563 7570 14633667

272. Fenaux P. Mufti G.J. Hellstrom-Lindberg E. Santini V. Finelli C. Giagounidis A. Schoch R. Gattermann N. Sanz G. List A. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study Lancet Oncol. 2009 10 223 232 10.1016/S1470-2045(09)70003-8 19230772 PMC4086808

273. Kouzarides T. Chromatin modifications and their function Cell 2007 128 693 705 10.1016/j.cell.2007.02.005 17320507

274. Utley R.T. Ikeda K. Grant P.A. Côté J. Steger D.J. Eberharter A. John S. Workman J.L. Transcriptional activators direct histone acetyltransferase complexes to nucleosomes Nature 1998 394 498 10.1038/28886 9697775

275. Yang X. Seto E. HATs and HDACs: From structure, function and regulation to novel strategies for therapy and prevention Oncogene 2007 26 5310 10.1038/sj.onc.1210599 17694074

276. Okonkwo A. Mitra J. Johnson G.S. Li L. Dashwood W.M. Hegde M.L. Yue C. Dashwood R.H. Rajendran P. Heterocyclic analogs of sulforaphane trigger DNA damage and impede DNA repair in colon cancer cells: Interplay of HATs and HDACs Mol. Nutr. Food Res. 2018 62 1800228 10.1002/mnfr.201800228 29924908 PMC6553464

277. Choi K.C. Jung M.G. Lee Y.H. Yoon J.C. Kwon S.H. Kang H.B. Kim M.J. Cha J.H. Kim Y.J. Jun W.J. Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation Cancer Res. 2009 69 583 592 10.1158/0008-5472.CAN-08-2442 19147572

278. Xiao X. Shi D. Liu L. Wang J. Xie X. Kang T. Deng W. Quercetin suppresses cyclooxygenase-expression and angiogenesis through inactivation of Psignaling PLoS ONE 2011 6 e22934 10.1371/journal.pone.0022934 21857970 PMC3152552

279. Lee W.J. Chen Y.R. Tseng T.H. Quercetin induces FasL-related apoptosis, in part, through promotion of histone Hacetylation in human leukemia HL-cells Oncol. Rep. 2011 25 583 591 21165570 10.3892/or.2010.1097

280. Ling D. Marshall G.M. Liu P.Y. Xu N. Nelson C.A. Iismaa S.E. Liu T. Enhancing the anticancer effect of the histone deacetylase inhibitor by activating transglutaminase Eur. J. Cancer 2012 48 3278 3287 10.1016/j.ejca.2012.02.067 22459762

281. Li Y. Meeran S.M. Patel S.N. Chen H. Hardy T.M. Tollefsbol T.O. Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer Mol. Cancer 2013 4 12 19 10.1186/1476-4598-12-9 PMC3577460 23379261

282. Majid S. Dar A.A. Shahryari V. Hirata H. Ahmad A. Saini S. Tanaka Y. Dahiya A.V. Dahiya R. Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-Cell translocation gene in prostate cancer Cancer 2010 116 66 76 10.1002/cncr.24662 19885928 PMC3954042

283. Majid S. Dar A.A. Ahmad A.E. Hirata H. Kawakami K. Shahryari V. Saini S. Tanaka Y. Dahiya A.V. Khatri G. BTGtumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer Carcinogenesis 2009 30 662 670 10.1093/carcin/bgp042 19221000 PMC2664457

284. Wang S.L. Li Y. Wen Y.F. Chen Y.F. Na L.X. Li S.T. Sun C.H. Curcumin, a potential inhibitor of up-regulation of TNF-alpha and IL-induced by palmitate in 3T3-Ladipocytes through NF-kappa B and JNK pathway Biomed. Environ. Sci. 2009 22 32 39 10.1016/S0895-3988(09)60019-2 19462685

285. Gräff J. Rei D. Guan J.S. Wang W.Y. Seo J. Hennig K.M. Nieland T.J. Fass D.M. Kao P.F. Kahn M. An epigenetic blockade of cognitive functions in the neurodegenerating brain Nature 2012 483 222 226 10.1038/nature10849 22388814 PMC3498952

286. Lithner C.U. Lacor P.N. Zhao W.Q. Mustafiz T. Klein W.L. Sweatt J.D. Hernandez C.M. Disruption of neocortical histone Hhomeostasis by soluble Aβ: Implications for Alzheimer’s disease Neurobiol. Aging 2013 34 2081 2090 10.1016/j.neurobiolaging.2012.12.028 23582659

287. Frost J.L. Le K.X. Cynis H. Ekpo E. Kleinschmidt M. Palmour R.M. Ervin F.R. Snigdha S. Cotman C.W. Saido T.C. Pyroglutamate-amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models Am. J. Pathol. 2013 183 369 381 10.1016/j.ajpath.2013.05.005 23747948 PMC3730768

288. Schilling S. Zeitschel U. Hoffmann T. Heiser U. Francke M. Kehlen A. Holzer M. Hutter-Paier B. Prokesch M. Windisch M. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology Nat. Med. 2008 14 1105 1111 10.1038/nm.1872 18836460

289. Kikuno N. Shiina H. Urakami S. Kawamoto K. Hirata H. Tanaka Y. Majid S. Igawa M. Dahiya R. Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells Int. J. Cancer 2008 123 552 560 10.1002/ijc.23590 18431742

290. Juli G. Oliverio M. Bellizzi D. Gallo Cantafio M.E. Grillone K. Passarino G. Colica C. Nardi M. Rossi M. Procopio A. Anti-tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma Cancers 2019 11 990 10.3390/cancers11070990 PMC6679356 31315220

291. Lu J. Getz G. Miska E.A. Alvarez-Saavedra E. Lamb J. Peck D. Sweet-Cordero A. Ebert B.L. Mak R.H. Ferrando A.A. MicroRNA expression profiles classify human cancers Nature 2005 435 834 10.1038/nature03702 15944708

292. Lopez-Serra P. Esteller M. DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer Oncogene 2012 31 1609 10.1038/onc.2011.354 21860412 PMC3325426

293. Calin G.A. Ferracin M. Cimmino A. Di Leva G. Shimizu M. Wojcik S.E. Iorio M.V. Visone R. Sever N.I. Fabbri M. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia N. Engl. J. Med. 2005 353 1793 1801 10.1056/NEJMoa050995 16251535

294. Chang T.-C. Wentzel E.A. Kent O.A. Ramachandran K. Mullendore M. Lee K.H. Feldmann G. Yamakuchi M. Ferlito M. Lowenstein C.J. Transactivation of miR-34a by pbroadly influences gene expression and promotes apoptosis Mol. Cell 2007 26 745 752 10.1016/j.molcel.2007.05.010 17540599 PMC1939978

295. Raver-Shapira N. Marciano E. Meiri E. Spector Y. Rosenfeld N. Moskovits N. Bentwich Z. Oren M. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis Mol. Cell 2007 26 731 743 10.1016/j.molcel.2007.05.017 17540598

296. Tsang W.P. Kwok T.T. Epigallocatechin gallate up-regulation of miR-and induction of apoptosis in human cancer cells J. Nutr. Biochem. 2010 21 140 146 10.1016/j.jnutbio.2008.12.003 19269153

297. Chakrabarti M. Khandkar M. Banik N.L. Ray S.K. Alterations in expression of specific microRNAs by combination of 4-HPR and EGCG inhibited growth of human malignant neuroblastoma cells Brain Res. 2012 1454 1 13 10.1016/j.brainres.2012.03.017 22498172 PMC3335959

298. Milenkovic D. Deval C. Gouranton E. Landrier J.F. Scalbert A. Morand C. Mazur A. Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: A new mechanism of the action of polyphenols PLoS ONE 2012 7 e29837 10.1371/journal.pone.0029837 22253797 PMC3254631

299. Sun M. Estrov Z. Ji Y. Coombes K.R. Harris D.H. Kurzrock R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells Mol. Cancer Ther. 2008 7 464 473 10.1158/1535-7163.MCT-07-2272 18347134

300. Pilipenko V. Narbute K. Amara I. Trovato A. Scuto M. Pupure J. Janson B. Poikans J. Bisenieks E. Klusa V. GABA-containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture J. Neurosci. Res. 2019 97 708 726 10.1002/jnr.24396 30742328