Mediterranean Diet and Melatonin: A Systematic Review

Citation: Grao-Cruces, E.; Calvo, J.R.; Maldonado-Aibar, M.D.; Millan-Linares, M.d.C.; Montserrat-de la Paz, S. Mediterranean Diet and Melatonin: A Systematic Review. Antioxidants 2023,12, 264. https://doi.org/ 10.3390/antiox12020264 Academic Editor: Mario Allegra Received: 21 December 2022 Revised: 17 January 2023 Accepted: 19 January 2023 Published: 24 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antioxidants Systematic Review Mediterranean Diet and Melatonin: A Systematic Review Elena Grao-Cruces †, Juan Ramon Calvo †, Maria Dolores Maldonado-Aibar, Maria del Carmen Millan-Linares and Sergio Montserrat-de la Paz * Department of Medical Biochemistry, Molecular Biology, and Immunology, School of Medicine, University of Seville, Avenida Sanchez Pizjuan s/n, 41009 Seville, Spain *Correspondence: [email protected]; Tel.: +34-955421051 † These authors contributed equally to this work. Abstract: The Mediterranean diet (MD) has beneficial effects on human health, which is evidenced by the observation of lower incidence rates of chronic diseases in Mediterranean countries. The MD dietary pattern is rich in antioxidants, such as melatonin, which is a hormone produced mainly by the pineal gland and controls several circadian rhythms. Additionally, melatonin is found in foods, such as fruit and vegetables. The purpose of this systematic review was to assess the melatonin content in Mediterranean foods and to evaluate the influence of the MD on melatonin levels in both humans and model organisms. A comprehensive search was conducted in four databases (PubMed, Scopus, Cochrane Library and Web of Science) and data were extracted. A total of 31 records were chosen. MD-related foods, such as tomatoes, olive oil, red wine, beer, nuts, and vegetables, showed high melatonin contents. The consumption of specific MD foods increases melatonin levels and improves the antioxidant status in plasma. Keywords: antioxidant; beer; circadian rhythm; nuts; tomato; olive oil; sleep; wine 1. Introduction The Mediterranean diet (MD) is a nutritional pattern with widely known health properties [ 1 ]. Traditionally, the MD is consumed in geographic areas where olives (Olea europea L.) and grapes (Vitis vinifera L.) are cultivated, and olive oil and wine are regularly produced and consumed [ 2 , 3 ]. Other features are associated with the benefits of the MD. The MD has been declared as part of the intangible heritage of humanity by UNESCO, but including other habits and factors of the Mediterranean countries, the weather and moderate exercise practice [ 4 ]. In terms of the nutritional pattern, the MD is balanced in calories and macro- and micronutrient intake. As essential components, the MD includes whole grains, fruits, vegetables, legumes, nuts, yogurt, fish, and white meat [ 5 , 6 ]. Minerals, vitamins, and other bioactive compounds are included in different foods of the MD, such as fruits, vegetables, and olive oil, among others [ 6 – 8 ]. The MD dietary habits are correlated with a lower incidence of cancer [ 9 , 10 ], cardiovascular [ 11 , 12 ] and neurodegenerative diseases [13–15], when compared to industrialized countries’ dietary patterns [16]. From a phytochemical point of view, the MD is rich in phenylpropanoids, isoprenoids, and alkaloids [ 6 , 17 ], compounds with high antioxidant activity. In fact, the antioxidant properties of the bioactive compounds included in the MD are some of the major contributors to the health properties of the MD [ 18 ]. For example, polyphenols have been widely studied in terms of the antioxidant properties of the MD [ 19 – 22 ]. On the other hand, melatonin has been recently characterized as a phytochemical element in MD foods, which increases the MD’s health potential [23,24]. Melatonin is a hormone that is biosynthesized from tryptophan in four well-defined intracellular steps [ 25 ]. Melatonin synthesis is regulated by the light/dark cycle and the enzymes involved in the process are expressed during the night, because the light inhibits their expression [ 26 ]. It is involved in different plant functions, such as plant Antioxidants 2023,12, 264. https://doi.org/10.3390/antiox12020264 https://www.mdpi.com/journal/antioxidants Antioxidants 2023,12, 264 2 of 17 growth regulation, delaying flowering delay, photosynthetic system protection, oxidative stress damage protection, and biotic and abiotic stresses [ 27 – 29 ]. Melatonin was first discovered as a secretory product of the pineal gland. It is the main chronobiotic hormone that regulates the circadian rhythms [ 30 ] and seasonal changes in vertebrate physiology via its daily nocturnal increase in blood [ 31 , 32 ]. However, subsequent studies showed that melatonin is present in bacteria, unicellular eukaryotic organisms, invertebrates and vertebrates, algae, plants, and fungi, and is found in various edibles, such as vegetables, fruit, herbs, and seeds [ 33 , 34 ]. In mammals, melatonin is synthesized in many tissues and organs [ 35 – 40 ], and melatonin shows remarkable functional versatility, exhibiting antioxidant [ 41 ], oncostatic [ 42 ], antiaging [ 43 ], and immunomodulatory [ 44 ] effects. The antioxidant functions of melatonin have been widely described. Melatonin is a free radical scavenger; it directly scavenges reactive oxygen species (ROS) and nitrogen-based species with even more effectivity than vitamin E [ 45 – 49 ]. Additionally, melatonin induces the activity of antioxidant enzymes, such as glutathione reductase and peroxidase [50,51]. The MD is a nutritional pattern rich in many antioxidants and bioactive compounds; therefore, the identification of melatonin in edibles and the multiple functions of melatonin are an interesting perspective. The aim of this systematic review was to assess the melatonin content in Mediterranean foods and to evaluate the influence of the MD on melatonin levels in both humans and model organisms. 2. Materials and Methods This systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) [ 52 , 53 ]. This review was registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration No. CRD42022332235). 2.1. Searching Strategy A comprehensive search was conducted in four databases (PubMed, Scopus, Web of Science and Cochrane Library), searching all years of records up until February 2022. The language restriction was English and Spanish. The search terms were categorized into the following three key concepts: study population, MD (MD-related foods and intervention) and melatonin levels. The specific terms used were “adult” OR “middle-aged” OR “young” OR “m?n” OR “wom?n” OR “food” OR “plant” AND “mediterranean diet” OR “Olive Oil” OR “grape” OR “tomato” OR “nuts” OR “legume” OR “cereal” AND “melatonin”, respectively. In addition, the reference lists of the elected articles were manually searched for relevant publications. To choose which MD-related foods were specifically included in the research algorithm, foods previously described to have melatonin content were used, based on the work of Meng et al. [ 54 ]. In regard to the MD, the foods were selected according to Schwingshackl et al. [6]. 2.2. Selection Criteria The published studies in this review were required to adhere to the following criteria: (1) they must be original research; (2) human adult or animal studies or edible food studies; (3) MD or MD-related food interventions or analyses; (4) must include melatonin measurements. 2.3. Data Extraction and Reliability The PRISMA recommendations were followed [ 52 , 53 ]. First, in order to identify relevant articles, the titles were screened and abstracts were analyzed. Then, the selected articles were fully reviewed for eligibility by two independent researchers. Antioxidants 2023,12, 264 3 of 17 3. Results 3.1. Search and Selection of Studies The searching and selection strategies are detailed in Figure 1. A total of 999 and 7 records were identified through database searching and the search of the reference lists of the retrieved articles, respectively. Duplicates were removed, leaving a set of 617 records, from which 36 records were screened. Finally, 5 records were excluded for not following the selection criteria and 31 records were selected. The records were divided into the following two different categories: foods from the MD with melatonin [ 55 – 80 ] and influence of the MD on melatonin levels [60,72,79–86]. Antioxidants 2023, 12, x FOR PEER REVIEW 3 of 20 3. Results 3.1. Search and Selection of Studies The searching and selection strategies are detailed in Figure 1. A total of 999 and 7 records were identified through database searching and the search of the reference lists of the retrieved articles, respectively. Duplicates were removed, leaving a set of 617 records, from which 36 records were screened. Finally, 5 records were excluded for not following the selection criteria and 31 records were selected. The records were divided into the following two different categories: foods from the MD with melatonin [55–80] and influence of the MD on melatonin levels [60,72,79–86]. Figure 1. Flow diagram of record selection. 3.2. Melatonin in Mediterranean Diet Foods 3.2.1. Melatonin Content in Fruit and Vegetables Melatonin is present in different MD-associated foods and drinks, with grapes and olive oil being the first two products of the MD in which melatonin was detected (Table 1). Wine is a grape by-product drink associated with the nutritional pattern of the MD and is rich in phytochemicals, such as polyphenols and melatonin. Red wines are richer in melatonin (7.44–0.24 ng/mL) compared to white wines (3.93–0.16 ng/mL), which is similar to grapes [55,56,58]. However, Rodriguez-Naranjo et al. showed that the melatonin content of different wines from Spain was between 423.01 and 74.14 ng/mL, with no differences being observed between white and red wines [57]. It is important to consider that different factors, such as environmental factors, agricultural practices, vintage, and winemaking procedures, may influence the melatonin levels in wine. For example, the melatonin content was different among different brands that produce the same wine [56]. Additionally, Albana grape-derived wine showed a lower content of melatonin compared to the Albana grape itself (the melatonin level of which is 1.2 ng/g), supporting the hypothesis that part of melatonin is lost during the wine-making process [55]. Beer is other typical beverage in the MD; however, the melatonin content in beer was lower when compared to wines [60]. Figure 1. Flow diagram of record selection. 3.2. Melatonin in Mediterranean Diet Foods 3.2.1. Melatonin Content in Fruit and Vegetables Melatonin is present in different MD-associated foods and drinks, with grapes and olive oil being the first two products of the MD in which melatonin was detected (Table 1). Wine is a grape by-product drink associated with the nutritional pattern of the MD and is rich in phytochemicals, such as polyphenols and melatonin. Red wines are richer in melatonin (7.44–0.24 ng/mL) compared to white wines (3.93–0.16 ng/mL), which is similar to grapes [ 55 , 56 , 58 ]. However, Rodriguez-Naranjo et al. showed that the melatonin content of different wines from Spain was between 423.01 and 74.14 ng/mL, with no differences being observed between white and red wines [ 57 ]. It is important to consider that different factors, such as environmental factors, agricultural practices, vintage, and wine-making procedures, may influence the melatonin levels in wine. For example, the melatonin content was different among different brands that produce the same wine [ 56 ]. Additionally, Albana grape-derived wine showed a lower content of melatonin compared to the Albana grape itself (the melatonin level of which is 1.2 ng/g), supporting the hypothesis that part of melatonin is lost during the wine-making process [ 55 ]. Beer is other typical beverage in the MD; however, the melatonin content in beer was lower when compared to wines [60]. Antioxidants 2023,12, 264 4 of 17 Table 1. Melatonin content in grapes, wine, beer, and oils of the MD. Variety Melatonin (ng/g; ng/mL) Melatonin Extraction Melatonin Measure Reference Grape Sangiovese grape 1.5 MEPS with methanol HPLC-FLD [55] Albana grape 1.2 Albana must 1.1 Albana grape juice 0.5 White wine Albana 0.6 MEPS with methanol HPLC-FLD [55] Multivarietal 0.63 DLLME with acetonitrile, chloroform and NaCl HPLC-FLD [56] Moscatel Graudo 3.93 Palomino fino 390.82 SPE with methanol and water LC-ESI-MS/MS [57] Sauvignon blanc 0.32 Methanol and sonication Electrochromatography [58] Chardonnay 0.16 Red wine Malbec 0.24 Methanol and sonication Electrochromatography [58] Cabernet Sauvignon 0.23 SPE with methanol and water ELISA [59] Jaen tinto 0.16 Merlot 0.21 Palomino negro 0.28 Petit verlot 0.22 Prieto picudo 0.19 Syrah 0.22 Tempranillo 0.14 Castelao 7.44 DLLME with acetonitrile, chloroform and NaCl HPLC-FLD [28] [56] Syrah 4.29–2.61 Trincadeira 1.90 Aragonez 4.27 Touriga Nacional 2.71–2.81 Touriga Franca 1.05 Alicante Bouschet 1.92 Cabernet Sauvignon 2.85–3.06 Syrah 423.01 Methanol and sonication LC-ESI-MS/MS [57] Cabernet Sauvignon 74.13 Merlot 245.46 Tempranillo 306.86 Tintilla de Rota 322.68 Beer Volt-Damm 0.1697 NS ELISA [60] Murphy’s 0.1427 Mahou Negra 0.1386 Amstel 0.1281 Coronita 0.1276 Budweisser 0.1198 Guiness 0.1181 Cruzcampo 0.1119 Calsberg 0.1044 Mahou 5 estrellas 0.1019 Heineken 0.0981 San Miguel Sp 0.0976 Mahou Clasica 0.0846 Laiker Sin 0.0686 San Miguel 0.0 0.0616 Buckler Sin 0.0616 Kaliber Sin 0.0527 Buckler 0.0 0.0518 Antioxidants 2023,12, 264 5 of 17 Table 1. Cont. Variety Melatonin (ng/g; ng/mL) Melatonin Extraction Melatonin Measure Reference Olive oil D.O Sierra Magina 0.107 Liquid–liquid extraction with methanol and chloroform ELISA [61] D.O. Siurana 0.095 D.O. Bajo Aragon 0.071 D.O Montes de Toledo 0.108 D.O. Baena 0.119 D.O. Sierra de Segura 0.089 D.O. Les Garrigues 0.098 D.O. Toscano 0.109 Refined olive oil 0.053–0.075 DLLME, dispersive liquid–liquid microextraction; ELISA, enzyme-linked immunoassay; HPLC-FLD, highprecision liquid chromatography with fluorescence detection; LC-ESI-MS/MS, liquid chromatography electrospray ionization tandem mass spectrometry; MEPS, microextraction by packed sorbent or packaged syringe. Olive oil is a by-product of olive that is known worldwide for its anti-inflammatory and antioxidant properties, while virgin olive oil is the main oil used in the MD. De la Puerta et al. measured the melatonin content of different virgin olive oils and reported values that ranged between 71 and 119 pg/mL, with the highest amount of melatonin being detected in virgin olive oils produced via the cold process. Additionally, the refinement process reduces the melatonin content in olive oil, even though refined olive oil showed a higher content of melatonin than sunflower oil [61]. The highest melatonin content was detected in fruit and vegetables (Table 2), but the melatonin quantity in the same fruit varies depending on the harvest conditions, such as the time of day, year, maturity, and variety. For example, tomato is one of most consumed fruit in the MD and its melatonin content has been widely studied, with wide differences being observed between varieties. Stürtz et al. studied different tomato varieties, including Lycopersicon esculentum from Spain, and the highest content of melatonin was detected in the Raf and Bond varieties, with 50 and 25 ng/g, respectively [ 62 ]. It is important to highlight that Dubbels et al. [ 64 ] and Pape et al. [ 63 ] measured the melatonin content of other varieties of Lycopersicon esculentum grown in Germany, showing a 10–100-times lower content when compared with that described by Stürtz et al. Pape et al. measured melatonin content using ELISA and HPLC-PD and different organic solvents to extract melatonin, and the melatonin content was between 0.5984 and 1.0685 ng/g [ 63 ], which was similar to the findings of Dubbles et al. [ 64 ]. Despite the fact that Pape et al. [ 63 ] and Stürtz et al. [ 62 ] used the same tomato species (L. esculentum) and HPLC to measure the melatonin content, the solvents for the extraction and the harvest processes were different. Additionally, Stürtz et al. studied the melatonin content in L. esculentum and found that it differed within the same tomato variety because of the different harvests [62]. In regard to Solanum lycopersicum, the melatonin content found by all authors [ 66 – 68 ] was lower compared to that of Lycopersicum esculentum determined by Stürtz et al. [ 62 ]. However, Spanish Solanum lycopersicum [ 68 ] showed the highest melatonin content, when compared to the same species grown in other countries [66,67]. Antioxidants 2023,12, 264 6 of 17 Table 2. Melatonin content in fruit and vegetables. Food Melatonin ng/g Melatonin Extraction Melatonin Measure Reference Species Variety Tomato L. esculentum Bond 23.87 Methanol and water LC-FL [62] Borsalina 8.2 Catalina 4.1 Gordal 17.10 Lucinda 4.45 Marbone 18.13–114.5 Myriade 8.0 Pitenza 14.0–14.2 Santonio ND Perlino ND Platero 13.6 Raf 50.1 NS 0.9821 Na2CO3ether HPLC-PD [63] 1.0685 ELISA [63] 0.6169 SPE with PCA HPLC-PD [63] 0.5984 ELISA [63] 0.8963 SPE with acetone HPLC-PD [63] 0.9363 ELISA [63] Mill. Cultivar Sweet 100 0.506 Na2CO3and diethyl ether Radioimmunoassay [64] Mill. Cultivar Rutgers California supreme 0.166 NS Crystal 0.029 Initial extraction with ethyl acetate, followed by SPE with methanol and water UHPLC-q-Orbitrap MS [65] Raspberry 0.0323 Oxheart 0.0151 GiantPaste 0.0493 Beorange 0.0232 Hurma 0.0181 Lemon 0.0299 Raspberry 0.0492 Yellow plum 0.0324 Azoycka <0.01 Giant <0.01 Better Boy 0.0174 Ox’s Forehead 0.0418 Yellow Plum 0.0157 Roma 0.0594 Mini Plums 0.0219 Cherry 0.0788 Cherry Red 0.0149 Kiwi 0.024 Green Pepper 0.0141 Black Moor 0.0242 Black Broken Heart 0.0141 Kumato 0.0242 Mojito 0.0209 Acrobat Tom 0.0453 Beauty Lottringa 0.0138 Raspberry 0.0246 Plum 0.0251 Solanum lycopersicum Cerasiforme 1.618 SPE and methanol HPLC-FLD [66] Micro-Tom 0.001–0.003 SPE with acetone and methanol ELISA [67] Ciliegia 0.64 Methanol UHPLC-QqQ- MS/MS [68] Isis 1.5 Jack 1.5 Prico 3 Jesus 4 NKT 072 6 Optima 14.77 L. pimpinellifolium 0.112 Na2CO3and diethyl ether Radioimmunoassay [64] Sweet cherry Prunus avium L. 60 Methanol and ultrasonication HPLC-FLD [69] Antioxidants 2023,12, 264 7 of 17 Table 2. Cont. Food Melatonin ng/g Melatonin Extraction Melatonin Measure Reference Species Variety Strawberries Fragaria ananassa Camarosa 1.4–5.58 SPE with methanol and acetone LC-FL [62] Candonga 2.1–5.5 Festival 3.28–11.26 Primoris 4.2–8.5 Fragaria magna 0.136 Na2CO3and diethyl ether GC/MS [70] Banana Musa ensete 0.655 Na2CO3and diethyl ether GC/MS [70] Musa sapitentum 0.41 Diethyl ether Radioimmuno assay [64] 1.741 SPE with methanol HPLC-FLD [66] Pineapple Ananas comosus 1.693 SPE with methanol HPLC-FLD [66] 0.278 Na2CO3and diethyl ether GC/MS [70] Apple Malus domestia 0.161 Na2CO3and diethyl ether GC/MS [70] Pomegranate Punica granatum 0.16.8 Na2CO3and diethyl ether GC/MS [70] Watermelon Cirtullus lanatus ND SPE with methanol HPLC-FLD [66] Orange Citrus sinensis 1.704 SPE with methanol HPLC-FLD [66] Bell pepper NS Green 0.0255–0.5214 Methanol and ethyl acetate HPLC-FLD [71] Orange 0.045– 0.0495 Ethyl acetate HPLC-FLD [71] 0.5811 Methanol HPLC-FLD [71] Red 0.0243–0.0664 Ethyl acetate HPLC-FLD [71] 0.1795 Methanol HPLC-FLD [71] C. anuum Barranca Green 2 Methanol UHPLC-QqQ- MS/MS [68] Red 4 Derio Green 3.5 Red 6 Velero Green 10 Red 4 F26 Green 2 Red 11 NC9 Green 2.5 Red 4 Cucumber NS 0.009 Diethyl ether Radioimmuno assay [64] Cucumis sativus 0.592 Na2CO3and diethyl ether GS/MS [70] Onion Allium cepa 29.9 Na2CO3and diethyl ether GS/MS [70] Garlic Allium sativum 58.7 Na2CO3and diethyl ether GS/MS [70] Cabbage Brassica oleraceae Capitata 30.9 Na2CO3and diethyl ether GS/MS [70] Cauliflower Brassica oleraceae Botrytis 82.4 Na2CO3and diethyl ether GS/MS [70] Turnip Brassica rapa 50.1 Na2CO3and diethyl ether GS/MS [70] Carrot Daucus carota 49.2 Na2CO3and diethyl ether GS/MS [70] Barley Hordeum vulgare 87.3 Na2CO3and diethyl ether GS/MS [70] Radish Raphnus sativus 75.8 Na2CO3and diethyl ether GS/MS [70] Beetroot 0.0001 Diethyl ether Radioimmuno assay [64] Potato ND Diethyl ether Radioimmuno assay [64] ND Na2CO3and diethyl ether GC/MS [70] ELISA, enzyme-linked immunoassay; GC/MS, gas chromatography–mass spectrometry; LC-FL, liquid chromatography with fluorescence detection; PCA; SPE, solid-phase extraction; UHPLC, ultra-high-performance liquid chromatography; ND, not detected; NS, not specified. Antioxidants 2023,12, 264 8 of 17 3.2.2. Melatonin Content in Nuts, Legumes, and Animal-Derived Products Different types of nuts, including almonds, pistachios, nuts, and chestnuts, which grow in Mediterranean countries, are included in the nutritional pattern of the MD and have approximately 1 ng/g of melatonin (Table 3). The nut variety influences melatonin levels in nuts, with different varieties of almonds (Prunus dulcis L.) and pistachios (Pistacia vera L.) showing melatonin content values between 600–2000 pg/g and 1000–12,000 pg/g, respectively [ 73 , 74 ]. Verde et al. measured melatonin in almonds and pistachios by HPLCFLD after extraction with a combination of organic solvents and found a similar quantity of melatonin to Paroni et al., who measured melatonin content by LC-MS/MS after SPE extraction in both types of nuts. However, Bronte DOP pistachio and cv. Palo almond showed higher contents of melatonin when compared to other varieties. These differences are greater when comparing pistachio varieties [ 74 ]. It is important to highlight that Oladi et al. determined the melatonin content in four different varieties of pistachio from Iran, which was 1000–10,000-times higher than that of other nuts and pistachio varieties [ 75 ]. In contrast, Manchester et al. measured the melatonin content in almonds derived from another species referred to as Prunus amygdalus [ 76 ], showing 10-times higher levels compared to that of Prunus Dulcis. Additionally, it is important to consider that nuts can be eaten raw or roasted, and the processing of foods influences melatonin bioavailability. In fact, it was reported that roasting decreased melatonin content in most nuts, while this was increased in roasted peanuts [73]. Table 3. Melatonin content in nuts and seeds. Food Melatonin pg/g Melatonin Extraction Melatonin Measure Reference Species Variety Walnut Junglans regia L. Bulk 3500 Liquid–liquid extraction with methanol and chloroform HPLC [72] Pizarro 1191 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Franquette 1600 Hartley 3301 Native 2000 Pistachio Pistacia vera L. NS 1000 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Bronte DOP 12,000 First extraction with ethanol, followed by SPE with water and methanol LC-MS/MS [74] Noberasco 1000 Italy 1000 Italy 1000 Ahmed Aghaes 233,000,000 UASLE with methanol GC/MS [75] 230,700,000 Spectrofluorometry [75] Akbari 226,900,000 GC/MS [75] 229,200,000 Spectrofluorometry [75] Karle Qouchi 231,400,000 GC/MS [75] 229,100,000 Spectrofluorometry [75] Fandoghi 130,700,000 GC/MS [75] 228,400,000 Spectrofluorometry [75] Hazelnut Corylus avellana L. 350 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Antioxidants 2023,12, 264 9 of 17 Table 3. Cont. Food Melatonin pg/g Melatonin Extraction Melatonin Measure Reference Species Variety Almond Prunus dulcis L. NS 1100 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] cv. Palo 2000 First extraction with ethanol, followed by SPE with water and methanol LC-MS/MS [74] cv. Collepasso 600 cv. Barletta 1500 cv. Cassano 1300 cv. Minervino 600 Prunus amygdalus 39,000 Ethanol HPLC [76] Peanut Arachis hypogaea L. 83 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] 39,430 Organic solvents and sonication HPLC-FD [77] Pine nuts Pinus pinea L. 1000 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Pumpkin seed Cucurbita pepo L. 500 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Sunflower Helianthus annuus L. Seed 500 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] NS 67,450 First extraction with ethanol, followed by water and dichloromethane HPLC-FD [77] Cashew nut Anacardium occidentale L. 200 (roasted) First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Macadamia nut Macadamia intergriogolia Maiden y Betche 300 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Brazil nut Bertholleita excels Humb and Bonpl 100 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] Chestnut Castanea sativa Miller 1417 First extraction with hexane–methanol–water, followed by SPE with acetonitrile and 0.1 % formic acid HPLC-FLD [73] GC/MS, gas chromatography–mass spectrometry; HPLC, high-performance liquid chromatography; SPE, solidphase extraction; NS, not specified. Legumes and grains are one of the main components of the MD and are very rich in melatonin, in contrast with animal-derived products, such as meat, fish and eggs, in which melatonin content is very low (Table 4). Lentils showed the highest amount of melatonin, which was doubled in sprouts, compared to raw lentils [ 80 ]. However, comparison with other studies cannot be made, because there are no multiple records regarding the melatonin content in the same legume. 3.3. Melatonin Levels and Mediterranean Diet Despite the fact that different foods of the MD contain melatonin, the influence of their intake is not clear. All the records that show data of melatonin levels after the intake of the MD are shown in Table 5. The consumption of melatonin-rich foods, such as fruit and legumes, increased melatonin levels in humans and animal models. However, the available data are not comparable, because different foods were used in all the records of the different study populations. Antioxidants 2023,12, 264 16 of 17 70. Badria, F.A. Melatonin, serotonin, and tryptamine in some egyptian food and medicinal plants. J. Med. Food 2002 ,5, 153–157. [CrossRef] 71. Huang, X.; Mazza, G. Simultaneous analysis of serotonin, melatonin, piceid and resveratrol in fruits using liquid chromatography tandem mass spectrometry. J. Chromatogr. A 2011,1218, 3890–3899. [CrossRef] 72. Reiter, R.J.; Manchester, L.C.; Tan, D.X. Melatonin in walnuts: Influence on levels of melatonin and total antioxidant capacity of blood. Nutrition 2005,21, 920–924. [CrossRef] [PubMed] 73. Verde, A.; Minguez, J.M.; Leao-Martins, J.M.; Gago-Martinez, A.; Gallardo, M. Melatonin content in walnuts and other commercial nuts. Influence of cultivar, ripening and processing (roasting). J. Food Compos. Anal. 2022,105, 104180. [CrossRef] 74. Paroni, R.; Dei Cas, M.; Rizzo, J.; Ghidoni, R.; Montagna, M.T.; Rubino, F.M.; Iritri, M. Bioactive phytochemicals of tree nuts. Determination of the melatonin and sphingolipid content in almonds and pistachios. J. Food Compos. Anal. 2019 ,82, 103227. [CrossRef] 75. Oladi, E.; Mohamadi, M.; Shamspur, T.; Mostafavi, A. Spectrofluorimetric determination of melatonin in kernels of four different Pistacia varieties after ultrasound-assisted solid-liquid extraction. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2014 ,132, 326–329. [CrossRef] 76. Manchester, L.C.; Tan, D.X.; Reiter, R.J.; Park, W.; Monis, K.; Qi, W. High levels of melatonin in the seeds of edible plants. Life Sci. 2000,67, 3023–3029. [CrossRef] 77. Sangsopha, J.; Johns, N.P.; Johns, J.; Moongngarm, A. Dietary sources of melatonin and benefits from production of high melatonin pasteurized milk. J. Food Sci. Technol. 2020,57, 2026–2037. [CrossRef] 78. Tan, D.X.; Zanghi, B.M.; Manchester, L.C.; Reiter, R.J. Melatonin identified in meats and other food stuffs: Potentially nutritional impact. J. Pineal Res. 2014,57, 213–218. [CrossRef] 79. Sae-Teaw, M.; Johns, J.; Johns, N.P.; Subongkot, S. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers. J. Pineal Res. 2013,55, 58–64. [CrossRef] 80. Rebollo-Hernanz, M.; Aguilera, Y.; Herrera, T.; Cayuelas, L.T.; Dueñas, M.; Rodriguez-Rodriguez, P.; Ramiro-Cortijo, D.; Arribas, S.M.; Martin-Cabrejas, M.A. Bioavailability of Melatonin from Lentil Sprouts and Its Role in the Plasmatic Antioxidant Status in Rats. Foods 2020,9, 330. [CrossRef] 81. Yang, T.H.; Chen, Y.C.; Ou, T.H.; Chien, Y.W. Dietary supplement of tomato can accelerate urinary aMT6s level and improve sleep quality in obese postmenopausal women. Clin. Nutr. 2020,39, 291–297. [CrossRef] [PubMed] 82. Varoni, E.M.; Paroni, R.; Antognetti, J.; Lodi, G.; Sardella, A.; Carrassi, A.; Iritri, M. Effect of red wine intake on serum and salivary melatonin levels: A randomized, placebo-controlled clinical trial. Molecules 2018,23, 2474. [CrossRef] [PubMed] 83. Johns, N.P.; Johns, J.; Porasuphatana, S.; Plaimee, P.; Sae-Teaw, M. Dietary Intake of Melatonin from Tropical Fruit Altered Urinary Excretion of 6-sulfatoxymelatonin in Healthy Volunteers. J. Agric. Food Chem. 2013,61, 913–919. [CrossRef] [PubMed] 84. Ribas-Latre, A.; del Bas, J.M.; Baselga-Escudero, L.; Casanova, E.; Arola-Arnal, A.; Salvado, M.J.; Arola, L.; Blade, C. Dietary proanthocyanidins modulate melatonin levels in plasma and the expression pattern of clock genes in the hypothalamus of rats. Mol. Nutr. Food Res. 2015,59, 865–878. [CrossRef] [PubMed] 85. Garcia, C.P.; Lamarque, A.L.; Comba, A.; Berra, M.A.; Silva, R.A.; Labuckas, D.O.; Das, U.N.; Eynard, A.R.; Pasqualini, M.E. Synergistic anti-tumor effects of melatonin and PUFAs from walnuts in a murine mammary adenocarcinoma model. Nutrition 2015,31, 570–577. [CrossRef] [PubMed] 86. Aguilera, Y.; Rebollo-Hernanz, M.; Herrera, T.; Cayuelas, L.T.; Rodriguez-Rodriguez, P.; Lopez de Pablo, A.L.; Arribas, S.M.; Martin-Cabrejas, M.A. Intake of bean sprouts influences melatonin and antioxidant capacity biomarker levels in rats. Food Funct. 2016,7, 1438–1445. [CrossRef] 87. Rzepka-Migut, B.; Paprocka, J. Melatonin-Measurement Methods and the Factors Modifying the Results. A Systematic Review of the Literature. Int. J. Environ. Res. Public Health 2020,17, 1916. [CrossRef] 88. Bal, E. Physicochemical changes in ‘Santa Rosa’ plum fruit treated with melatonin during cold storage. J. Food Meas. Charact. 2019,13, 1713–1720. [CrossRef] 89. Bal, E. Effect of melatonin treatments on biochemical quality and postharvest life of nectarines. J. Food Meas. Charact. 2021 ,15, 288–295. [CrossRef] 90. Bose, S.K.; Howlader, P. Melatonin plays multifunctional role in horticultural crops against environmental stresses: A review. Environ. Exp. Bot. 2020,176, 104063. [CrossRef] 91. Tan, D.X.; Manchester, L.C.; Mascio, P.D.; Martinez, G.R.; Prado, F.M.; Reiter, R.J. Novel rhythms of N 1-acetyl-N 2-formyl- 5-methoxykynuramine and its precursor melatonin in water hyacinth: Importance of phytoremediation. FASEB J. 2007 ,21, 1724–1729. [CrossRef] [PubMed] 92. Vitalini, S.; Gardana, C.; Zanzotto, A.; Simonetti, P.; Faoro, R.; Fico, G.; Iritri, M. The presence of melatonin in grapevine (Vitis vinifera L.) Berry tissues. J. Pineal Res. 2001,51, 331–337. [CrossRef] [PubMed] 93. Murch, S.J.; Hall, B.A.; Le, C.H.; Saxena, P.K. Changes in the levels of indoleamine phytochemicals during veraison and ripening of wine grapes. J. Pineal Res. 2010,49, 95–100. [CrossRef] [PubMed] 94. Boccalandro, H.E.; Gonzalez, C.V.; Wunderlin, D.A.; Silva, M.F. Melatonin levels, determined by LC-ESI-MS/MS, fluctuate during the day/night cycle in Vitis vinifera cv Malbec: Evidence of its antioxidant role in fruits. J. Pineal Res. 2011 ,31, 226–232. [CrossRef] [PubMed] Antioxidants 2023,12, 264 17 of 17 95. Li, J.; Somers, V.K.; Xu, H.; Lopez-Jimenez, F.; Covassin, N. Trends in Use of Melatonin Supplements Among US Adults, 1999-2018. JAMA 2022,327, 483–485. [CrossRef] [PubMed] 96. Li, C.; Li, G.; Tan, D.X.; Li, F.; Ma, X. A novel enzyme-dependent melatonin metabolite in humans. J. Pineal Res. 2013 ,54, 100–106. [CrossRef] 97. Di Domenico, M.; Feola, A.; Ambrosio, P.; Pinto, F.; Galasso, G.; Zarrelli, A.; Di Fabio, G.; Porcelli, M.; Scacco, S.; Inchingolo, F.; et al. Antioxidant Effect of Beer Polyphenols and Their Bioavailability in Dental-Derived Stem Cells (D-dSCs) and Human Intestinal Epithelial Lines (Caco-2) Cells. Stem Cells Int. 2020,2020, 8835813. [CrossRef] 98. Habschied, K.; Loncaric, A.; Mastanjevic, K. Screening of Polyphenols and Antioxidative Activity in Industrial Beers. Foods 2020 , 9, 238. [CrossRef] 99. Paterniti, I.; Impellizzeri, D.; Cordaro, M.; Siracusa, R.; Bisignano, C.; Gugliandolo, E.; Carughi, A.; Esposito, E.; Mandalari, G.; Cuzzocrea, S. The Anti-Inflammatory and Antioxidant Potential of Pistachios (Pistacia vera L.) In Vitro and In Vivo. Nutrients 2017,9, 915. [CrossRef] 100. Sheng, J.; Yang, X.; Chen, J.; Peng, T.; Yin, X.; Liu, W.; Liang, M.; Wan, J.; Yang, X. Antioxidative Effects and Mechanism of Study of Bioactive Peptides from Defatted Walnut (Junglans regia L.) Meal Hydrolysate. J. Agric. Food Chem. 2019 ,67, 3305–3312. [CrossRef] 101. Hong, M.Y.; Groven, S.; Marx, A.; Rasmussen, C.; Beidler, J. Anti-Inflammatory, Antioxidant, and hypolipidemic Effects of Mixed Nuts in Atherogenic Diet-Fed Rats. Molecules 2018,23, 3126. [CrossRef] [PubMed] 102. Tikhonova, M.A.; Tikhonova, N.G.; Tendinik, M.V.; Ovsyukova, M.V.; Akopyan, A.A.; Dubrovina, N.I.; Amstislavskaya, T.G.; Khlestkina, E.K. Effects of Grape Polyphenols on the Life Span and Neuroinflammatory Alterations Related to Neurodegenerative Partkinson Disease-Like Disturbances in Mice. Molecules 2020,25, 5339. [CrossRef] [PubMed] 103. Legua, P.; Modica, G.; Porras, I.; Conesa, A.; Continella, A. Bioactive compounds, antioxidant activity and fruit quality evaluation of eleven blood orange cultivars. J. Sci. Food Agric. 2022,102, 2960–2971. [CrossRef] [PubMed] 104. Ghanavati, M.; Clark, C.C.T.; Bahrami, A.; Teymoori, F.; Movahed, M.; Sohrab, G.; Hejazi, E. Dietary intake of polyphenols and total antioxidant capacity and risk of prostate cancer: A case-control study in Iranian men. Eur. J. Cancer Care 2021 ,30, e13364. [CrossRef] [PubMed] 105. Rickards, L.; Lynn, A.; Harrop, D.; Barker, M.E.; Russel, M.; Ranchordas, M.K. Effect of Polyphenol-Rich Foods, juices, and Concentrates on Recovery from Exercise Induced Muscle Damage: A Systematic Review and Meta-Analysis. Nutrients 2021 ,13, 2988. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.