# Systematic Review and Meta-Analysis of Melatonin Quantification in Wine
## 1 Introduction  
Melatonin is an essential indoleamine hormone produced in the pineal gland involved in modulating several physiological processes [1]. For example, it suppresses prooxidant enzymes, stimulates the activity of antioxidant enzymes, reduces radical formation and metal-induced toxicity due to improving mitochondrial function [2], and can be a powerful direct free radical scavenger [3], twice more effective than vitamin E [4]. It was considered a characteristic compound of vertebrates [5], but in recent decades, it has been found in a variety of medicinal and food plants [6]. Melatonin is present in drinks, including wine [7, 8, 9], as one of its dietary components [10], even if its acceptable daily intake is very difficult to estimate. Because melatonin can cross physiological barriers [11], the intake of drinks containing melatonin increases its concentration in plasma and the number of melatonin-derived metabolites [12]. After the identification of melatonin in grapes [13], studies were carried out to quantify it in wines [14]. Melatonin is naturally present in wines because it is contained in wine grapes. Also, in some stages of the winemaking process, melatonin is biosynthesized by yeasts from its precursors, tryptophanand serotonin [15; 16; 17], mainly during alcoholic fermentation [18]. The final amount can be affected by environmental conditions during vine cultivation [19]. The presence of the melatonin in wines offers an exciting perspective related to moderate red wine consumption associated with potential health benefits, strengthening the premise that health benefits of the Mediterranean diet are due in part to wine [20]. The implication of melatonin as a potential health benefit is firstly due to its endogenous antioxidant capacity. Likewise, its additive and synergistic effects with other natural antioxidants in the winemaking process, such as resveratrol [21], can lead to the enhancement of polyphenic compounds [22]. However, studies are still in the early stages [23], and it is not fully understood how melatonin changes the profile of phenolic compounds in wines. The low amounts of melatonin in wines necessitate complex analytical techniques for their quantification. Many proper methods have been developed, such as the voltammetry of immobilized particles methodology [24]; the capillary electrochromatography (CEC) method [25]; the enzyme-linked immunosorbent assay (ELISA) method [26]; and the methods of HPLC with different detectors, diode array detection (DAD) [27], FL [28; 29; 30], and tandem MS [31; 32]. HPLC is most affordable and suitable for assaying melatonin in wines since it enables unambiguous identification, it has a large capacity for discrimination and performs one of the most precise analyses. Because wine represents a complex matrix and melatonin concentrations are in the ng mL\({}^{-1}\) range, these methods require the pretreatment of sample. Several extraction and concentration methods were evaluated, such as solid-phase extraction (SPE) [14; 29; 33], dispersive liquid-liquid micro-extraction (DLLME) [27; 30], and microextraction by packed sorbent (MEPS) [28]. Although melatonin can modify the phenolic profile and antioxidant activity via phenylpropanol metabolism, only one systematic review has been reported on the melatonin content of foods in the Mediterranean diet, such as tomatoes, olive oil, red wine, beer, nuts, and vegetables [34]. It highlighted that the consumption of these foods could have an impact on antioxidant status and that components of food matrix may play a role in the effect of melatonin intake. Taking into consideration the potential health benefits of melatonin with regard to regular moderate wine consumption, several reviews have focused on the presence of melatonin in wine [7; 20; 35], but to date, no systematic review and meta-analysis regarding melatonin quantification in wine has been performed.