Open access peer-reviewed chapter
Abstract
Melatonin is a neurohormone produced and released by the pineal gland. Neurons placed in the eye surface send a signal when the person is exposed to darkness to the suprachiasmatic nuclei and that prompts melatonin release. This biomolecule is in charge of synchronizing body circadian rhythms such as sleep or hunger. Intense light exposure can avoid its release or healthy rhythm. Apart from that, the scientific literature has suggested that melatonin influences immune system, antioxidant capacity, or cell preservation. Moreover, melatonin can be supplied by dietary food such as grapes, dairy or fermented products. Interestingly, some foods contain a significant amount of melatonin and can be considered as good sources of that bioactive molecule. The information in this chapter will cover melatonin dietary sources, biological capacity, related metabolites, and proven benefits in the human body.
Keywords
- melatonin
- diet sources
- foods
- antioxidant
- immune system
- cell preservation
1. Introduction
The neurohormone melatonin (MEL) (N-acetyl-5-methoxytyramine) is produced in the pineal gland and can be also found as metabolite in plants. Moreover, the synthesis of MEL derives from the aminoacid tryptophan, leading to 5-hydroxytryptophan, serotonin, and finally, N-acetylserotonin. Moreover, MEL can also be produced by
MEL content has been reported in seeds, for example, rice or corn and roots, leaves, or fruits of a significant range of plants. The occurrence of MEL has also been reported in olive oil, especially in extra virgin olive oil, and in sunflower oil [3]. Moreover, the content of MEL has also been reported in grapes and wines [4]. Scientific literature has revealed that MEL is formed after fermentation with wine yeast, mainly due to
MEL is a key modulator of human health, showing antioxidant, anticarcinogenic, or neuroprotective capacity between others [6]. The biological capacity of their main metabolites as N-1-acetyl-N-2-formyl-5-methoxyquinuramine (AFMK) and N-1-acetyl-5-methoxyquinuramine (AMK) is also significant. AFMK is considered a potent antioxidant compound, and AMK is also a potent antioxidant being able to inhibit the biosynthesis of prostaglandins related to diazepam receptors [7]. As other secondary metabolites, MEL can promote antioxidant enzymes and/or neutralize free radicals [1]. In vivo studies have also reported the antioxidant capacity of MEL, which decreases chronic oxidative stress related to aging [8] and reduces blood pressure in men with chronic hypertension [9]. MEL has been successfully used for sleep disorders restoring circadian rhythm and is especially effective in population with neurodegenerative illnesses.
The amphipathic property of MEL allows it to cross some physiological barriers, being present in the cytosol, mitochondria, and different biological membranes [10]. Therefore, MEL provides biological properties where it is needed.
2. Bioavailability, absorption, and adjuvant interactions of melatonin
Its amphiphilic character allows melatonin to penetrate all compartments of a cell because, helped by its small size, conferring a good solubility in both water and lipids. Melatonin and its derivatives have antioxidant ability and can start a radical scavenger cascade creating oxidation products (e.g., hydroxymelatonin) that help to eliminate oxygen reactive species [11]. Due to this, melatonin is effective and bioable in organisms [12]. Herbs that have been used in traditional Chinese medicine have up to several thousands of melatonin nanograms in their tissues [13], implying a decent source of the neurohormone. It was also measured in several parts, however, in seeds where the highest levels have been found, probably related with the needs of reproductive organs (e.g., defend from adversarial attacks), fluctuations of melatonin concentration are even in varieties of the same species [14]. While animals can only obtain melatonin from food, plants can synthesize it or absorb and accumulate it from the environment [15]. Eating foodstuffs rich in melatonin can increase melatonin serum concentration [16]. Organs that produce melatonin (e.g., pineal gland, retina [17], and gastrointestinal tract) can also process it from foodstuffs [18].
2.1 Bioavailability
Melatonin bioavailability from formulations and food ranges from 2.5% to 33% [19, 20] and with protein binding of 60% measured
Regarding oral bioavailability in the experiments with chicks, we know that when feeding them with edible plants rich in melatonin, circulating melatonin levels increase, and it is proven that this melatonin is functional as it competed with melatonin binding sites in the brain.
In humans, serum melatonin levels have been assessed after beer intake. This study assessed 18 brands of beer, containing up to 170 pg/mL, males (n = 7) received 660 mL, and females (n = 3) 330 mL. Consumption resulted in an increase of 112 ng and 56 ng of melatonin, respectively, related to the volume taken, confirmed by serum analysis by ELISA prior and 45 min after the beverage [25]. Also in humans, serum melatonin raised from 10 to 12 pg/ml 60 min after a glass of 100 ml of red wine was drunk [26]. Melatonin bioavailability is also high in case of taking fruits, as a study with 12 volunteers consuming for breakfast a juice from either orange, pineapple, or bananas containing 302 ng, 150 ng, and 1.7 ng of melatonin, respectively, increasing melatonin in serum. Blood tests were carried out before juice and then hourly the next 3 hours. ELISA proved that serum melatonin concentration nadir was at hour 2 after breakfast. All values were significantly increased from time zero for pineapples (146 vs. 48 pg/mL, p = 0.002), oranges (151 vs. 40 pg/mL, p = 0.005), and bananas (140 vs. 32 pg/mL, p = 0.008) [27]. Further, an across ages study with three groups of participants (20 ± 10, 45 ± 10, and 75 ± 10 years old) reported after 5-day intake of 200 ml/day of grape juicehigher antioxidant capacity [28], as well as 6-sulfatoxymelatonin in urine [29].
2.2 Pharmacokinetics
Melatonin suffers great hepatic metabolism upon oral intake, with high hepatic first-pass effect [30, 31], which explains its low bioavailability [31]. Animal and human studies describe that melatonin metabolism mainly occurs through CYP1A2 and CYP2C19 hepatic enzymes [30, 32]. 6-Hydroxy-melatonin is conjugated with sulfate and forms the most abundant metabolite (80%): the 6-sulfatoxymelatonin (6-SM) [30, 33]. Then 6-SM metabolite can be measured in urine as an inactive metabolite [34]. Hence, further research is needed in human metabolites as some works have described the existence of active metabolites excreted [30].
2.3 Adjuvant interactions
The co-ingestion of melatonin-rich food with phenolic compounds (caffeic acid or quercetin) could increase its bioavailability [35]. When analyzing the relation of cherries with sleep cycle and urinary 6-hidroxymelatonin sulfate (MT6), it was observed that regardless of melatonin absence in some cherry varieties (Ambrunes had only 37.6 ± 1.4 ng of serotonin in 100 g fresh fruit [36]), an increase of urinary MT6s was detected [37, 38]. Thus, it was possible to infer that both MEL and serotonin present in cherries may have contributed to improvements in sleep parameters and MT6 excretion [37, 38].
3. Functions and effects described for melatonin
In this chapter, authors introduce MEL as a dietary source and its role in human health.
3.1 Antioxidant capacity
MEL promotes the synthesis of antioxidant enzymes as glutathione peroxidase or glutathione reductase [39, 40], improving the reducing capacity in the organism [41], neutralizes the nitrogenous toxins responsible for nitrosamine damage [42, 43], being able to chelate metals [44]. MEL and related metabolites have scavenging capacity [12] being able to neutralize up to 10 types of free radicals [18].
Limson et al. showed that MEL chelates zinc, lead, copper, iron, aluminum, and cadmium ion in a dose-dependent manner [44]. MEL is able to chelate Fe3+ and Fe2+, preventing the formation of the hydroxyl radical. Moreover, MEL and its metabolites are also capable of chelating Cu2+, preventing the first step in the Haber-Weiss reaction, and neutralizing the formation of hydroxyl radical.
Additionally, MEL modulates the activity of certain enzymes, limiting the emission of electrons from the mitochondrial respiratory chain, which reduces the formation of superoxide anion [45]. Due to the anti-inflammatory capacity of MEL and considering that inflammation promotes the generation of free radicals [17], oxidative processes with lower production of oxidant molecules can be regulated by the supplementation of MEL [46].
3.2 Cardiovascular protection
The benefits to cardiovascular health related to Mediterranean diet are widely reported and can be partially attributed to the high intake of MEL-rich foods [47].
Most of the studies reporting the effect of MEL on cardiovascular system are focused on ischemia-reperfusion and have been accomplished administrating high doses of MEL (between 1 and 50 μM). Moreover, other studies reported the cardioprotective capacity of MEL using similar concentrations than those found in foods. For example, related to the intake of as red wine [48], MEL at physiological concentration is able to significantly decrease the infarct size after ischemia-reperfusion accident. The mechanism responsible of these effects is related to the activation of the surviving activator factor enhancement (SAFE) pathway, which involves the stimulation of TNF-α and its receptor, leading to the activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). That fact leads to downregulation of reactive oxygen species (ROS) in the mitochondria and the electron chain transport [49].
Despite MEL being found in foods, more investigation is needed to determine if the consumption of MEL-rich foods is determinant to observe the cardiovascular benefits reported for the administration of MEL or if higher concentration are needed.
3.3 Neuroprotective capacity
The different neurodegenerative diseases are characterized by a rapid and progressive deterioration of the different structures that make up the central nervous system and the compromise of proper brain function. In addition, the degeneration of different parts of the neurons can increase the frequency of symptoms observed in the course of Alzheimer's disease, dementia, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease [50].
The effect that MEL has on the mitochondria is decisive in explaining its role as a neuroprotective agent. MEL is capable of reducing different metabolic pathways that lead to neuronal death, such as chronic inflammation, increased oxidative stress, changes in the circadian rhythm, decreased autophagy, and increased mitochondrial damage. All these processes can lead to a lower adenosine triphosphate (ATP) production capacity and the consequent neuronal death. Various experimental models of the aforementioned diseases show the efficacy of MEL to slow down or even stop the progression of the disease, in addition to mitigating some of the related symptoms. In fact, it has been reported that the endogenous synthesis of MEL could be altered in diseases such as Alzheimer's and Parkinson's.
There is currently evidence that oxidative damage is decisive in favoring the development and progression of most neurodegenerative diseases. Similarly, the generation of free radicals is crucial in the development of the pathophysiology of these diseases, as well as all neurodegenerative diseases [51]. Thus, current evidence suggests the neuroprotective capacity of MEL in different neurodegenerative disorders, in addition to presenting little or no side effects, even at high doses and higher than those found in food [52].
3.4 Anticancer capacity
MEL can also play the role of anticancer molecule. In fact, MEL has scavenging capacity, which can prevent oxidative injury to nuclear DNA [53] leading to a possible way to prevent and treat some kinds of cancer as other bioactive compounds with similar scavenging ability. Interestingly, MEL can prevent cancer at its first stages, lessening the side effects because of its chronobiotic effects, reducing complications related with radio and chemotherapy used for the treatment of cancer [54].
MEL has reported to have a link with sirtuin 1 (Sirt1) and circadian rhythms as previously reported [53]. It was reported that the disturbance on the synthesis of MEL in the pineal gland decontrols the correct circadian rhythm, increasing the occurrence of cancer. Moreover, MEL is able to reduce the production of Sirt1 protein, reducing the proliferative potential of cancer cells. That fact was not observed in normal cells. Additionally, MEL has antiestrogenic capacity, which could reduce some kinds of cancers such as breast or prostate cancer, which are hormone-related cancers [55].
Furthermore, MEL can be effective in the decrease of brain-related endothelin-1 concentration in stroked patients. Endothelin-1 is considered a relevant compound for the advancement of angiogenesis, being related with regulation of cancer expansion [56]. Angiogenesis is a main cause of tumor growth, providing oxygen and nutrients to dividing cells for the continuation of cell division. Remarkably, the suppression of angiogenesis seems to be assisted by the reduction of endothelin-1 [57].
Therefore, the scientific literature has reported enough information to consider MEL as a promising molecule for the treatment and prevention of cancer particularly through its anti-gonadotropin and anti-estrogenic ability. Because of its low toxicity and the variety of health benefits reported for MEL, it can be concluded that MEL could be considered as a complementary treatment of different types of cancer [58].
3.5 Circadian rhythm
The endogenous production of MEL is restricted to the night, regardless of the activity or resting. In fact, MEL was described as the “chemical expression of darkness” [59], being reduced during the night blocks with light. Moreover, a usual consideration used as indicator of the circadian rhythm is the “dim light MEL onset,” which specifies the initiation of the endogenous production of MEL. Just then, the concentration of plasmatic MEL exceeds 10 pg/mL, compared with daytime levels (1 pg/mL).
After its spreading in the organism, MEL binds to MEL-membrane receptors (MT1 and MT2). The membrane receptors of MEL are situated in the brain (principally the MT2) but also in other peripheral tissues. The expected outcome varies depending on the target organ. For example, in pancreatic islet cells, the binding of MEL with its receptors leads to insulin release to glucose stimulation. Moreover, the MT1 activation in β-cells leads to the phosphorylation of the insulin receptor that controls its release [60]. Therefore, MEL can be determinant for circadian insulin stimulation and is synchronized with the activity-feeding/rest-fasting periods.
Related to this, MEL can act as a central regulator of the cycles of wakefulness, feeding, and rest, being decisive for the correct regulation of the circadian cycle in the different metabolic pathways. MEL links and regulates the sleep-wake cycle with energy metabolism. In fact, during the active phase of the day when low plasma levels of MEL are found, the use and storage of available energy by tissues and cells controlled by MEL can be observed. On the contrary, an increased sensitivity to insulin and glucose by the tissues can be seen, in addition to the synthesis of glycogen and glycolysis or the increase in lipogenesis. During the rest phase, by not eating food, the resulting fasting period means that energy has to be obtained from reserves and used to maintain the different physiological functions. This metabolic phase is characterized by increased insulin resistance, gluconeogenesis and glycogenolysis, lipolysis, and further leptin secretion [61].
4. Melatonin content in foods
The melatonin hormone exists in different types of food, although its content can be very different from one to another, being in nuts and some medicinal plants where it has been found the most [62].
In edible plants, the fruits seem to be the part that contains the least melatonin, while the roots and leaves contain the most [63]. It also depends on the environment where the plants grow, how they are cultivated, temperature, sun exposure, agricultural treatments, etc. [64].
In animals, melatonin has been found mainly in eggs and fish and to a lesser extent in meat. Melatonin has been found in human breast milk, and that of other animals, to vary with circadian rhythms, being lower during the day and higher at night [65, 66]. Regarding plants, melatonin has been found in cereals, although they are still being investigated in different species such as corn, black rice, barley, and oats, among others [67]. In fruits, melatonin has been found in grapes [68], cherries [69], and strawberries [68], other fruits seem to have relatively lower levels of melatonin.
We found melatonin in different vegetables, being undetectable in beets and potatoes [70], and instead we found higher concentrations in mushrooms, tomatoes, and peppers [68]. It has been found in seeds and legumes with relatively high levels; in addition, it has been seen that in the germination process it can increase melatonin levels. Highest levels of melatonin have been found in walnuts [62].
Melatonin has also been searched for in different medicinal plants and high values have been found, above 1000 ng/g [13], for example, it is the case of St. John's Wort, (
4.1 Fermented food
Melatonin concentration can range from picograms to nanograms per mL of product in fermented beverages such as wine and beer. Although the content of melatonin can vary in different unfermented products, it has been proven that the alcoholic fermentation process is important for the melatonin formation process, since it is generated after the addition of yeasts, the role of
4.1.1 Wine
Melatonin concentration is modified with fermentation, presenting its highest value between the first and second days of fermentation [73, 74]. Different factors can affect the concentration of MEL in red wine, such as the agrochemicals used, winemaking practices, fermenting microorganisms, or even the composition of the grapes that has been used to produce wine [74, 75, 76].
The presence of melatonin in wines has been described by different authors. In Sangiovese red wines and Trebbiano white wine, Mercolini et al. found values of 0.4 and 0.5 ng/mL [77] and found 0.3 and 0.5 ng/mL in varieties of Albana grappa and grape juice [78]. Stege et al. found values of 0.24 ng/mL for Cabernet Sauvignon red wine, 0.16 ng/mL for Malbec red wine, and 0.32 ng/mL for Chardonnay white wine [79]. For Gropello and Merlot wine varieties, Vitalini et al. [80] found values of 4.1 and 8.1 ng/mL, respectively. Rodriguez-Naranjo et al. found values between 74 and 322 ng/mL for pressed wines (Tempranillo, Merlot, Sauvignon, Syrah, and Tintilla de Rota) and between 250 and 340 ng/mL for racked wines (Merlot, Sauvignon, Tempranillo, Syrah, and Tintilla de Rota [5]). For monovarietal red wines, Vitalini et al. found values between 0.14 and 0.62 ng/mL, for multivarietal red wines 0.05–0.31 ng/mL, for white wine 0.18 ng/mL, for dessert wines between 0 and 0.31 ng/mL, and for balsamic vinegar of Modena 0.11–0.13 ng/mL [81].
In a study in which tryptophan and certain metabolites, including melatonin, were analyzed simultaneously in various types of red wine, melatonin values ranged from 0.038 ± 0.001 g/L to 0.063 ± 0.004 g/L [81]. It should be noted that the presence of melatonin in the grape is not always reflected later in the wine, as shown in a study by Gómez et al [82], where the melatonin concentration of the grape was 120–160 ng/g; however, in the wine from these grapes there was no longer melatonin but a melatonin isomer that decreased its concentration with values from 18 to 24 ng/g.
It is important to note that the oral bioavailability of melatonin after ingesting a glass of wine is not known, which is not the case with polyphenols where it is known, perhaps due to the complex process that can influence the absorption of active metabolites [80]. However, it is known when it is consumed in supplement form since it is consumed in high doses and has been known for years [77, 83]. In addition, the presence of ethanol seems to improve the amount of melatonin, since it acts as a solvent, improving the permeability of the membranes [84].
In humans, Varoni et al. evaluated the serum levels of melatonin after administering a melatonin-enriched wine versus a placebo wine, and it was observed that the maximum concentrations were within 60 min, being 8.7 ± 2.2 pg/min for the melatonin group and 6.7 ± 0.6 pg/min for placebo wine, the results showed an area under the curve of 993 ± 162 vs. 745 ± 88 pg/min for the melatonin group versus placebo, respectively. No significant significant differences were observed between the concentration in saliva, the peak was reached at 45 minutes after melatonin intake, also without statistically significant differences, showing placebo levels after 120 min [80].
4.1.2 Beer
Beer is regularly consumed by a large number of people and is characterized by having a wide variety of bioactive nutraceutical and phytochemical compounds such as polyphenols and antioxidants [85]. In addition, they contain B complex vitamins, ascorbic acid, citric acid, etc. A study of 18 commercial brands of beer investigated the content of melatonin, with different degrees of alcohol, and showed that all the beers that participated in the study had melatonin, being directly proportional to the alcohol content. Thus, the higher the alcohol content, the higher the concentration of melatonin, with values ranging from 51.8 ± 2.2 pg/ml in nonalcoholic beer to 169.7 ± 8.7 pg/ml in normal beer [82]. This finding could be due to the fact that alcohol acts as a solvent for melatonin.
Furthermore, another study measured the concentration of melatonin in the different craft beer production processes, obtaining a final value of 333 pg/mL in a 5% vol. of alcohol after the second fermentation; these values are three times higher than that of commercial beers [86]. In terms of composition, in concentrated worth barley were found high levels of melatonin (339 ± 9 pg/mL) while low amounts were found in hops 33 ± 10 pg/mL [86]. The concentration of melatonin in beer can be attributed to the amount of melatonin in the barley, while in the case of wine, it seems to depend on the fermentation processes rather than the original amount in the grape.
5. Conclusions
Current literature highlights the high bioavailability of melatonin in human studies. The different MEL supplements are available for the treatment of sleep disorders or the effects derived from jet lag and are mainly used to reset the circadian clock. In addition, melatonin acts as a central synchronizer, capable of regulating a wide range of physiological functions, such as glucose and body lipid metabolism. Additionally, human clinical trials have shown that melatonin treatment can help improve or alleviate some of the most dangerous cardiovascular events. Similarly, melatonin has antioxidant capacity and is capable of neutralizing a wide variety of reactive oxygen and nitrogen molecules and indirectly modulates the activity of the endogenous enzymatic antioxidant system. Due to this cardioprotective capacity against oxidative stress, and taking into account the inhibition of different inflammatory and apoptotic pathways, melatonin is capable of exerting neuroprotective capacity. These findings reveal the great capacity and therapeutic potential of this molecule to combat different neurodegenerative pathologies.
Appendices and nomenclature
N-1-acetyl-N-2-formyl-5-methoxyquinuramine N-1-acetyl-5-methoxyquinuramine adenosine triphosphate cytochrome P-450 1A2 cytochrome P-450 2C19 enzyme immunoassay adsorption assay deoxyribonucleic acid melatonin melatonin receptor 1 melatonin receptor 2 6-hydroxymelatonin sulfate reactive oxygen species surviving activator factor enhancement signal transducer and activator of transcription 3 tumor necrosis tumoral alpha 6-sulfatoxymelatonin
References
- 1.
Hardeland R, Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutrition & Metabolism (London). 2005; 2 :22 - 2.
Sprenger J, Hardeland R, Fuhrberg B, et al. Melatonin and other 5-methoxylated indoles in yeast: Presence in high concentrations and dependence on tryptophan availability. Cytologia (Tokyo). 1999; 64 :209-213 - 3.
de la Puerta C, Carrascosa-Salmoral MP, García-Luna PP, et al. Melatonin is a phytochemical in olive oil. Food Chemistry. 2007; 104 :609-612 - 4.
Iriti M, Rossoni M, Borgo M, et al. Benzothiadiazole enhances resveratrol and anthocyanin biosynthesis in grapevine, meanwhile improving resistance to Botrytis cinerea. Journal of Agricultural and Food Chemistry. 2004; 52 :4406-4413 - 5.
Rodriguez-Naranjo MI, Gil-Izquierdo A, Troncoso AM, et al. Melatonin is synthesised by yeast during alcoholic fermentation in wines. Food Chemistry. 2011; 126 :1608-1613 - 6.
Fernández-Mar MI, Mateos R, García-Parrilla MC, et al. Bioactive compounds in wine: Resveratrol, hydroxytyrosol and melatonin: A review. Food Chemistry. 2012; 130 :797-813 - 7.
Schaefer M, Hardeland R. The melatonin metabolite N-acetyl-5-methoxykynuramine is a potent singlet oxygen scavenger. Journal of Pineal Research. 2009; 46 :49-52 - 8.
Nogués MR, Giralt M, Romeu M, et al. Melatonin reduces oxidative stress in erythrocytes and plasma of senescence-accelerated mice. Journal of Pineal Research. 2006; 41 :142-149 - 9.
Scheer FAJL, Van Montfrans GA, van Someren EJW, et al. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertens (Dallas, Tex 1979). 2004; 43 :192-197 - 10.
Karbownik M, Lewinski A, Reiter RJ. Anticarcinogenic actions of melatonin which involve antioxidative processes: Comparison with other antioxidants. The International Journal of Biochemistry & Cell Biology. 2001; 33 :735-753 - 11.
Rosen J, Than NN, Koch D, et al. Interactions of melatonin and its metabolites with the ABTS cation radical: Extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones. Journal of Pineal Research. 2006; 41 :374-381 - 12.
Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. Journal of Pineal Research. 2013; 54 :245-257 - 13.
Chen G, Huo Y, Tan D-X, et al. Melatonin in Chinese medicinal herbs. Life Sciences. 2003; 73 :19-26 - 14.
Tan D-X, Hardeland R, Manchester LC, et al. Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. Journal of Experimental Botany. 2012; 63 :577-597 - 15.
Tan D-X, Manchester LC, Helton P, et al. Phytoremediative capacity of plants enriched with melatonin. Plant Signaling & Behavior. 2007; 2 :514-516 - 16.
Iriti M, Varoni EM. The good health of Bacchus: Melatonin in grapes, the unveiled myth. LWT- Food Science and Technology. 2016; 65 :758-761 - 17.
Pandi-Perumal SR, Srinivasan V, Maestroni GJM, et al. Melatonin: Nature’s most versatile biological signal? The FEBS Journal. 2006; 273 :2813-2838 - 18.
Reiter RJ, Mayo JC, Tan D-X, et al. Melatonin as an antioxidant: Under promises but over delivers. Journal of Pineal Research. 2016; 61 :253-278 - 19.
Harpsøe NG, Andersen LPH, Gögenur I, et al. Clinical pharmacokinetics of melatonin: A systematic review. European Journal of Clinical Pharmacology. 2015; 71 :901-909 - 20.
Andersen LPH, Werner MU, Rosenkilde MM, et al. Pharmacokinetics of high-dose intravenous melatonin in humans. Journal of Clinical Pharmacology. 2016; 56 :324-329 - 21.
Lalanne S, Fougerou-Leurent C, Anderson GM, et al. Melatonin: From pharmacokinetics to clinical use in autism spectrum disorder. International Journal of Molecular Sciences. 2021; 22 :1490 - 22.
Salehi B, Sharopov F, Fokou PVT, et al. Melatonin in medicinal and food plants: Occurrence, bioavailability, and health potential for humans. Cell. 2019; 8 :681 - 23.
Ng KY, Leong MK, Liang H, et al. Melatonin receptors: Distribution in mammalian brain and their respective putative functions. Brain Structure & Function. 2017; 222 :2921-2939 - 24.
World Health Organization. WHO Consultation on Selected Medicinal Plants. 2nd ed. Ravello-Salerno, Italy; 1999 - 25.
Maldonado MD, Moreno H, Calvo JR. Melatonin present in beer contributes to increase the levels of melatonin and antioxidant capacity of the human serum. Clinical Nutrition. 2009; 28 :188-191 - 26.
Iriti M, Varoni EM, Vitalini S. Melatonin in traditional Mediterranean diets. Journal of Pineal Research. 2010; 49 :101-105 - 27.
Sae-Teaw M, Johns J, Johns NP, et al. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers. Journal of Pineal Research. 2013; 55 :58-64 - 28.
González-Flores D, Gamero E, Garrido M, et al. Urinary 6-sulfatoxymelatonin and total antioxidant capacity increase after the intake of a grape juice cv. Tempranillo stabilized with HHP. Food Functionals. 2012; 3 :34-39 - 29.
Schernhammer ES, Feskanich D, Niu C, et al. Dietary correlates of urinary 6-sulfatoxymelatonin concentrations in the Nurses’ Health Study cohorts. The American Journal of Clinical Nutrition. 2009; 90 :975-985 - 30.
Andersen LPH, Gögenur I, Rosenberg J, et al. Pharmacokinetics of melatonin: The missing link in clinical efficacy? Clinical Pharmacokinetics. 2016; 55 :1027-1030 - 31.
Di W-L, Kadva A, Johnston A, et al. Variable bioavailability of oral melatonin. The New England Journal of Medicine. 1997; 336 :1028-1029 - 32.
Von Bahr C, Ursing C, Yasui N, et al. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects–an indication that cytochrome P 450 CYP1A2 and CYP2C19 hydroxylate melatonin. European Journal of Clinical Pharmacology. 2000; 56 :123-127 - 33.
European Medicines Agency. Assessment Report for Circadin. 2007. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/circadin [Accessed: August 03, 2018] - 34.
Tordjman S, Chokron S, Delorme R, et al. Melatonin: Pharmacology, functions and therapeutic benefits. Current Neuropharmacology. 2017; 15 :434-443 - 35.
Jana S, Rastogi H. Effects of caffeic acid and quercetin on in vitro permeability, metabolism and in vivo pharmacokinetics of melatonin in rats: Potential for herb-drug interaction. European Journal of Drug Metabolism and Pharmacokinetics. 2017; 42 :781-791 - 36.
González-Flores D, Velardo B, Garrido M, et al. Ingestion of Japanese plums (Prunus salicina Lindl. cv. Crimson Globe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content. Journal of Food Nutritional Research. 2011; 50 :229-236 - 37.
Garrido M, Paredes SD, Cubero J, et al. Jerte Valley cherry-enriched diets improve nocturnal rest and increase 6-sulfatoxymelatonin and total antioxidant capacity in the urine of middle-aged and elderly humans. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2010; 65 :909-914 - 38.
Garrido M, González-Gómez D, Lozano M, et al. A Jerte valley cherry product provides beneficial effects on sleep quality. Influence on aging. The Journal of Nutrition, Health & Aging. 2013; 17 :553-560 - 39.
Fischer TW, Kleszczyński K, Hardkop LH, et al. Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2’-deoxyguanosine) in ex vivo human skin. Journal of Pineal Research. 2013; 54 :303-312 - 40.
Rodriguez C, Mayo JC, Sainz RM, et al. Regulation of antioxidant enzymes: A significant role for melatonin. Journal of Pineal Research. 2004; 36 :1-9 - 41.
Gitto E, Tan DX, Reiter RJ, et al. Individual and synergistic antioxidative actions of melatonin: Studies with vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) in rat liver homogenates. The Journal of Pharmacy and Pharmacology. 2001; 53 :1393-1401 - 42.
Gilad E, Cuzzocrea S, Zingarelli B, et al. Melatonin is a scavenger of peroxynitrite. Life Sciences. 1997; 60 :PL169-74 - 43.
Noda Y, Mori A, Liburdy R, et al. Melatonin and its precursors scavenge nitric oxide. Journal of Pineal Research. 1999; 27 :159-163 - 44.
Limson J, Nyokong T, Daya S. The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: An adsorptive voltammetric study. Journal of Pineal Research. 1998; 24 :15-21 - 45.
Hardeland R. Antioxidative protection by melatonin: Multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005; 27 :119-130 - 46.
Mauriz JL, Collado PS, Veneroso C, et al. A review of the molecular aspects of melatonin’s anti-inflammatory actions: Recent insights and new perspectives. Journal of Pineal Research. 2013; 54 :1-14 - 47.
Meng X, Li Y, Li S, et al. Dietary sources and bioactivities of melatonin. Nutrients. 2017; 9 :367 - 48.
Lamont KT, Somers S, Lacerda L, et al. Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol-and melatonin-induced cardioprotection. Journal of Pineal Research. 2011; 50 :374-380 - 49.
Hadebe N, Cour M, Lecour S. The SAFE pathway for cardioprotection: Is this a promising target? Basic Research in Cardiology. 2018; 113 :9 - 50.
Spinedi E, Cardinali DP. Neuroendocrine-metabolic dysfunction and sleep disturbances in neurodegenerative disorders: Focus on Alzheimer’s disease and melatonin. Neuroendocrinology. 2019; 108 :354-364 - 51.
Escames G, Lopez A, Antonio Garcia J, et al. The role of mitochondria in brain aging and the effects of melatonin. Current Neuropharmacology. 2010; 8 :182-193 - 52.
Weishaupt JH, Bartels C, Pölking E, et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. Journal of Pineal Research. 2006; 41 :313-323 - 53.
Jung-Hynes B, Schmit TL, Reagan-Shaw SR, et al. Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. Journal of Pineal Research. 2011; 50 :140-149 - 54.
Gil-Martín E, Egea J, Reiter RJ, et al. The emergence of melatonin in oncology: Focus on colorectal cancer. Medicinal Research Reviews. 2019; 39 :2239-2285 - 55.
Sánchez-Barceló E, Cos S, Mediavillla D, et al. Melatonin–estrogen interactions in breast cancer. Journal of Pineal Research. 2005; 38 :217-222 - 56.
Ahmed M, Rghigh A. Polymorphism in Endothelin-1 Gene: An Overview. Current Clinical Pharmacology. 2016; 11 :191-210 - 57.
Rosanò L, Spinella F, Bagnato A. Endothelin 1 in cancer: Biological implications and therapeutic opportunities. Nature Reviews. Cancer. 2013; 13 :637-651 - 58.
Kubatka P, Zubor P, Busselberg D, et al. Critical Reviews in Oncology / Hematology Melatonin and breast cancer: Evidences from preclinical and human studies. Critical Reviews in Oncology/Hematology. 2018; 122 :133-143 - 59.
Reiter RJ. Melatonin: The chemical expression of darkness. Molecular and Cellular Endocrinology. 1991; 79 :C153-C158 - 60.
Picinato MC, Hirata AE, Cipolla-Neto J, et al. Activation of insulin and IGF-1 signaling pathways by melatonin through MT1 receptor in isolated rat pancreatic islets. Journal of Pineal Research. 2008; 44 :88-94 - 61.
Cipolla-Neto J, Amaral FG, Afeche SC, et al. Melatonin, energy metabolism, and obesity: A review. Journal of Pineal Research. 2014; 56 :371-381 - 62.
Oladi E, Mohamadi M, Shamspur T, et al. Spectrofluorimetric determination of melatonin in kernels of four different Pistacia varieties after ultrasound-assisted solid-liquid extraction. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy. 2014; 132 :326-329 - 63.
Reiter RJ, Tan DX, Burkhardt S, et al. Melatonin in plants. Nutrition Reviews. 2001; 59 :286-290 - 64.
Iriti M, Rossoni M, Faoro F. Melatonin content in grape: Myth or panacea? Journal of the Science of Food and Agriculture. 2006; 86 :1432-1438 - 65.
Tan D, Zanghi BM, Manchester LC, et al. Melatonin identified in meats and other food stuffs: Potentially nutritional impact. Journal of Pineal Research. 2014; 57 :213-218 - 66.
Milagres MP, Minim VPR, Minim LA, et al. Night milking adds value to cow’s milk. Journal of the Science of Food and Agriculture. 2014; 94 :1688-1692 - 67.
Yılmaz C, Kocadağlı T, Gokmen V. Formation of melatonin and its isomer during bread dough fermentation and effect of baking. Journal of Agricultural and Food Chemistry. 2014; 62 :2900-2905 - 68.
Stürtz M, Cerezo AB, Cantos-Villar E, et al. Determination of the melatonin content of different varieties of tomatoes ( Lycopersicon esculentum ) and strawberries (Fragaria ananassa ). Food Chemistry. 2011;127 :1329-1334 - 69.
González-Gómez D, Lozano M, Fernández-León MF, et al. Detection and quantification of melatonin and serotonin in eight sweet cherry cultivars ( Prunus avium L.). European Food Research and Technology. 2009;229 :223-229 - 70.
Badria FA. Melatonin, serotonin, and tryptamine in some Egyptian food and medicinal plants. Journal of Medicinal Food. 2002; 5 :153-157 - 71.
Murch SJ, Simmons CB, Saxena PK. Melatonin ateşli ve diğer şifalı bitkilerde bulunur. Lancet. 1997; 350 :1598-1599 - 72.
Rodriguez-Naranjo MI, Torija MJ, Mas A, et al. Production of melatonin by Saccharomyces strains under growth and fermentation conditions. Journal of Pineal Research. 2012; 53 :219-224 - 73.
Waldhauser F, Waldhauser M, Lieberman HR, et al. Bioavailability of oral melatonin in humans. Neuroendocrinology. 1984; 39 :307-313 - 74.
Zhdanova IV, Wurtman RJ, Morabito C, et al. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep. 1996; 19 :423-431 - 75.
Vitalini S, Gardana C, Simonetti P, et al. Melatonin, melatonin isomers and stilbenes in Italian traditional grape products and their antiradical capacity. Journal of Pineal Research. 2013; 54 :322-333 - 76.
Guardiola-Lemaitre B. Toxicology of melatonin. Journal of Biological Rhythms. 1997; 12 :697-706 - 77.
Mercolini L, Addolorata Saracino M, Bugamelli F, et al. HPLC-F analysis of melatonin and resveratrol isomers in wine using an SPE procedure. Journal of Separation Science. 2008; 31 :1007-1014 - 78.
Hornedo-Ortega R, Cerezo AB, Troncoso AM, et al. Melatonin and other tryptophan metabolites produced by yeasts: Implications in cardiovascular and neurodegenerative diseases. Frontiers in Microbiology. 2016; 6 :1565 - 79.
Stege PW, Sombra LL, Messina G, et al. Determination of melatonin in wine and plant extracts by capillary electrochromatography with immobilized carboxylic multi-walled carbon nanotubes as stationary phase. Electrophoresis. 2010; 31 :2242-2248 - 80.
Vitalini S, Gardana C, Zanzotto A, et al. From vineyard to glass: Agrochemicals enhance the melatonin and total polyphenol contents and antiradical activity of red wines. Journal of Pineal Research. 2011; 51 :278-285 - 81.
Vitalini S, Gardana C, Simonetti P, et al. Melatonin, melatonin isomers and stilbenes in I talian traditional grape products and their antiradical capacity. Journal of Pineal Research. 2013; 54 :322-333 - 82.
Gomez FJV, Raba J, Cerutti S, et al. Monitoring melatonin and its isomer in Vitis vinifera cv. Malbec by UHPLC-MS/MS from grape to bottle. Journal of Pineal Research. 2012; 52 :349-355 - 83.
Fracassetti D, Vigentini I, Lo Faro AFF, et al. Assessment of Tryptophan, Tryptophan Ethylester, and Melatonin Derivatives in Red Wine by SPE-HPLC-FL and SPE-HPLC-MS Methods. Foods (Basel, Switzerland). 2019; 8 :99-111 - 84.
Mercolini L, Mandrioli R, Raggi MA. Content of melatonin and other antioxidants in grape-related foodstuffs: Measurement using a MEPS-HPLC-F method. Journal of Pineal Research. 2012; 53 :21-28 - 85.
Meng J-F, Shi T-C, Song S, et al. Melatonin in grapes and grape-related foodstuffs: A review. Food Chemistry. 2017; 231 :185-191 - 86.
Varoni EM, Paroni R, Antognetti J, et al. Effect of red wine intake on serum and salivary melatonin levels: A Randomized, Placebo-Controlled Clinical Trial. Molecules. 2018; 23 :2472-2482