Mini-review Received: 9 October 2014

Revised: 9 December 2014

Accepted article published: 15 December 2014

Published online in Wiley Online Library:

(wileyonlinelibrary.com) DOI 10.1002/jsfa.7051

Melatonin in Mediterranean diet, a new perspective Marcello Iritia* and Elena Maria Varonib Abstract The health-promoting properties of the Mediterranean diet have been attributed, at least in part, to the chemical diversity of plant foods. Among phytochemicals, polyphenols represent the paradigm of the relationship between healthy foods and reduced risk of chronic-degenerative diseases, although, in the past few years, a new element has enriched this scenario. Melatonin, and possibly other indoleamines recently discovered in some relevant Mediterranean foods, may represent a new factor contributing to the elucidation of the protective effects of diets rich in plant products. Therefore, in synergy with polyphenols and other bioactive phytochemicals (e.g. carotenoids and glucosinolates), melatonin may contribute to maximizing the benefits of healthy dietary styles. This brief survey deals with the occurrence of melatonin in the Mediterranean diet, with an emphasis on grape products, and focuses on the biological significance of dietary melatonin, an emerging and exciting topic in the field of nutritional sciences. © 2014 Society of Chemical Industry Keywords: Mediterranean diet; melatonin; grapes; wine; indoleamines; melatonin isomers

INTRODUCTION The healthy properties of the Mediterranean diet have been attributed to the phytochemical diversity of this traditional dietary style. In the past two decades, a plethora of in vitro and in vivo studies have emphasized the many biological activities of non-nutrient components of plant foods, with polyphenols representing the archetype of bioactive phytochemicals. Because of many confounding factors that make it difficult to differentiate between causal or casual relationships, however, epidemiological and human studies have failed to unquestionably associate adequate plant food consumption with reduced risk of chronic-degenerative diseases. A new element has recently contributed to improving the phytochemical diversity of typical Mediterranean foods and, possibly, their healthy potential. This new factor is melatonin (Fig. 1); among typical Mediterranean food plants, it was first discovered in grapes and then in grape products.1,2 In animals, particularly in vertebrates, melatonin is a hormonal, endogenous molecule that modulates circadian and circannual physiological functions, such as the sleep/wake cycle, reproductive function, bone metabolism and turnover, via cell receptor-mediated mechanisms. Receptor-independent processes have also been reported, mainly because of melatonin’s powerful antioxidant activity. Melatonin can directly scavenge free radical species (both reactive oxygen and nitrogen species) and stimulate the activity of antioxidant enzymes; thus it is involved in immune response and the pathogenesis of chronic-degenerative disorders. Melatonin biosynthesis was first described in the pineal gland (epiphysis), but it also occurs in other tissues outside the central nervous system, such as the gastrointestinal tract, bone marrow and lymphocytes. The aromatic amino acid tryptophan is the precursor of melatonin and other indoleamines, including serotonin (Fig. 2).3 J Sci Food Agric (2015)

Outside the animal kingdom, melatonin was first discovered in the photosynthesizing unicellular alga Lingulodinium polyedrum (Stein) J.D. Dodge syn. Gonyaulax polyedra Stein, belonging to the phylum Dinoflagellata.4 Since then, the presence of melatonin in food plants and medicinal herbs has been extensively reported. The first complete publications reporting melatonin in tracheophytes (vascular or higher plants) were independently provided by two research groups, which found this indoleamine in a number of edible plants.5,6 So far, melatonin has been detected and quantified in roots, shoots, leaves, flowers, fruits and seeds of a considerable variety of spermatophyte species, and its presence in plants has been unequivocally confirmed.7 In flowering plants (angiosperms), the occurrence of melatonin in a number of families belonging to both the mono- and dicotyledons, which are relevant as food and medicinal plants, has been described.8

MELATONIN IN THE MEDITERRANEAN DIET The traditional Mediterranean diet originated in areas where olives (Olea europaea L.) and grapevines (Vitis vinifera L.) were cultivated and where olive oil and wine are produced and regularly consumed. In addition to these foodstuffs, other main components of the Mediterranean diet include whole grains, fruits, vegetables, legumes and nuts; yogurt and ricotta cheese as dairy products;



Correspondence to: Marcello Iriti, Department of Agricultural and Environmental Sciences, Milan State University, Via G. Celoria 2, I-20133 Milan, Italy. E-mail: [email protected]

a Department of Agricultural and Environmental Sciences, Milan State University, Milan, Italy b Department of Biomedical, Surgical and Dental Sciences, Milan State University, Milan, Italy

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© 2014 Society of Chemical Industry

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A

B H H

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O N H

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Figure 1. Structures of (A) melatonin and (B) 6-sulfatoxymelatonin, the main urinary metabolite of melatonin in mammals.

and fish and white meat as sources of protein. Among typical Mediterranean products, melatonin was first reported in grapes and then in olive oil. In the berry exocarp (skin) of different Italian and French wine grape cultivars grown in northwestern Italy, the highest melatonin concentrations were detected in Nebbiolo and Croatina varieties (0.9 and 0.8 ng g−1 respectively), whereas the lowest concentration occurred in the Cabernet Franc cultivar (0.005 ng g−1 ).9 Differences were also found when comparing refined olive oils and extra virgin olive oils with designation of origin (DO), as well as among DO oils (e.g. 71 pg mL−1 in DO Bajo Aragón and 119 pg mL−1 in DO Baena). Diversities in heat treatment or chemical processing of the products may explain the diverse concentrations measured.10 Interestingly, black olives contained 5.3 pg g−1 melatonin.11 Besides grapevine and olive products, high levels of this indoleamine were detected in other typical Mediterranean foods, including fish (3.7 ng g−1 in salmon), white meat (2.3 ng g−1 in chicken and 1.6 ng g−1 in lamb), bread (341 pg g−1 in crumb and 138 pg g−1 in crust) and yogurt (126 pg g−1 ).11,12

MELATONIN IN GRAPE PRODUCTS A huge disproportion between studies of the melatonin content in grapevine products and in other Mediterranean plant foodstuffs exists. As previously mentioned, an intraspecific variation of the melatonin content in berry skin tissue of different cultivars (Nebbiolo, Croatina, Barbera, Cabernet Sauvignon, Sangiovese, Merlot, Marzemino and Cabernet Franc) was found, with levels ranging from 0.005 to 0.96 ng g−1 .9 Similar results (from 0.6 to 1.2 ng g−1 ) were reported by Stege et al.13 for the same tissue of Malbec, Cabernet Sauvignon and Chardonnay varieties cultivated in Argentina. In Merlot berry skin, we found 17.5 and 9.3 ng g−1 melatonin at prevéraison and véraison respectively, the two main phenological stages of grapes.14 Conversely, the transition from prevéraison to véraison increased the melatonin content in both Merlot berry seeds (from 3.5 to 10 ng g−1 ) and flesh (from 0.2 to 3.9 ng g−1 ).14 In berry skin of the Malbec variety cultivated in Argentina, melatonin concentration showed similar values during the night (∼10 ng g−1 ), reaching a strong peak in the morning (159 ng g−1 ).15 However, much higher melatonin concentrations – between 100 and 150 μg g−1 , depending on the phenological stage – were measured in the whole berry (i.e. skin, flesh and seeds analysed together) of a Merlot cultivar grown in Canada.16 Melatonin was recently found at 1.5 and 1.2 ng g−1 in the whole berry of Sangiovese red and Albana white grapes respectively from central Italy.17,18

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M Iriti, EM Varoni

Further studies ascertained the occurrence of melatonin in wine (Table 1). Mercolini et al.17,18 detected this indoleamine at 0.6, 0.5 and 0.4 ng mL−1 in Albana white, Sangiovese red and Trebbiano white wines respectively. Stege et al.13 reported melatonin at 0.16, 0.24 and 0.32 ng mL−1 in Chardonnay, Malbec and Cabernet Sauvignon wines respectively. Our results showed that the levels of melatonin in Groppello and Merlot red wines varied between 5.2 and 8.1 ng mL−1 , depending on agrochemical treatments,19 whereas Rodriguez-Naranjo et al.20,21 measured higher melatonin concentrations (up to 150 and 400 ng mL−1 ) in racked wines. In a recent screening of Italian mono- and polyvarietal red, white and dessert wines from different geographical areas, we measured melatonin at concentrations around or less than 0.5 ng mL−1 .22 Intriguingly, in this study the linear correlation coefficient between the melatonin content in wines and their antiradical capacity was higher compared with the weak correlation found between trans-resveratrol-3-O-glucoside (trans-piceid) and the same activity, even though the levels of stilbenes (around or less than 1 mg mL−1 ) were three orders of magnitude higher than the levels of indoleamine.22 In these terms, it can be hypothesized that melatonin possesses a higher antioxidant activity than resveratrol. In other grapevine products, the presence of melatonin was reported in traditional balsamic vinegars of Modena DO (∼0.1 ng mL−1 ), in grape juice (0.5 ng mL−1 ) and in Albana grappa (0.3 ng mL−1 ) (Table 1).17,22 Three melatonin isomers were recently detected in different grape products: Italian mono- and polyvarietal red, white and dessert wines from different geographical areas; Modena balsamic vinegars; and grape juices. In particular, isomer 1 and isomer 2 were the most recurring and abundant in all wines and vinegars assayed respectively, with levels much higher than those of melatonin and maximum concentrations of 68.4 and 40.3 ng mL−1 in red wine and vinegar respectively.22 Recently, one of these isomers has been identified as tryptophan-ethylester, a compound with the same molecular weight as melatonin.23 The emergence of naturally occurring melatonin isomers has opened a new, exciting and fascinating topic in the field of melatonin research, as recently emphasized in the excellent review article by Tan et al.24 Certainly, it would be of great interest to ascertain in the near future the nutritional significance of these isomers, comparing their biological activity with that of melatonin, particularly in terms of interaction with melatonin receptors. Many endogenous and external factors may noticeably influence the melatonin levels in grapes and their products; these factors include the genetic traits of the cultivars and their geographic origin, the berry tissues/plant organs analysed, the difference between thin- and thick-skinned grapes, the phenological stages, day/night fluctuations, pathogen (mainly fungal) infections and agrochemical treatments, agro-meteorological conditions and environmental stresses, altitude, ultraviolet radiation and high light irradiance, the vintage, and winemaking procedures.15,16,19,20 However, the exact contribution of grapes to melatonin and its isomers in wine has not entirely been elucidated yet, and a pivotal role of yeasts in the production of these metabolites in wine has been suggested. Melatonin production by yeasts in synthetic grape must was demonstrated,25 and the ability of yeasts to enrich fermented foods and beverages different from wine, such as bread and beer, with indoleamines is corroborated by a number of studies.26,27

© 2014 Society of Chemical Industry

J Sci Food Agric (2015)

Melatonin in Mediterranean diet

www.soci.org

Tryptophan NH2

N H

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Tryptophan decarboxylase (TDC) or AADC

OH

Tryptophan-5-hydroxylase (TPH) HO

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5-Hydroxytryptophan H2N

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Tryptamine

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Aromatic L-aminoacid decarboxylase (AADC)

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5-Hydroxytriptamine (serotonin) Tryptamine-5-hydroxylase (T5H)

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Arylalchylamine N-acetyltransferase (AANAT)

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N-Acetil-5-hydroxytriptamine (N-acetylserotonin)

N H

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N-Acetylserotonin methyltransferase (ASMT)

N-Acetylserotonin N H

H N HN

O

O

N-Acetyl-5-methoxytriptamine (melatonin)

Figure 2. Biosynthetic pathway of melatonin in living organisms.

BIOLOGICAL SIGNIFICANCE OF MELATONIN IN PLANT FOODS The possibility of modulating the circulating levels of melatonin in mammals, which are basically very low (∼200 pg mL−1 at the maximum night-time peak and lower than 10 pg mL−1 during the day)28 compared with melatonin in grape products (near 1 ng g−1 and 0.5 ng mL−1 in berry skin and wine respectively), through the intake of plant foods represents an exciting and relevant topic. Efficient uptake and bioavailability of dietary melatonin have been demonstrated in both animals and humans. In a pioneering study, feeding chicks with plant foods rich in melatonin increased their serum melatonin levels, and melatonin extracted from plants inhibited the binding of labelled melatonin to cell membrane receptors in rabbit brain.6 In rats fed 3 g of walnuts (Juglans regia L.) containing about 10.5 ng of melatonin, the serum concentration of indoleamine was augmented from 11.5 to 38.0 pg mL−1 , as was the serum antioxidant capacity.29 The effects of melatonin-rich plant foods were also studied in humans. Both melatonin levels and total antioxidant status of serum samples from healthy volunteers were increased 45 min after drinking beer.30 Likewise, consumption of tropical fruits (including oranges) increased the serum melatonin concentration and antioxidant capacity in healthy subjects.31 In premenopausal J Sci Food Agric (2015)

Table 1. Melatonin content in some typical Mediterranean plant foods

Mediterranean product Grape products Red wines White wines Dessert wines Grape juice (undisclosed cultivar) Albana grappa Modena balsamic vinegar (DO) Olive oils Extra virgin (DO) Refined

Melatonin content

Reference(s)

Melatonin in Mediterranean diet, a new perspective.

The health-promoting properties of the Mediterranean diet have been attributed, at least in part, to the chemical diversity of plant foods. Among phyt...
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