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3. Functions and effects described for melatonin
In this chapter, authors introduce MEL as a dietary source and its role in human health.
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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 reac- tion, and neutralizing the formation of hydroxyl radical.
Additionally, MEL modulates the activity of certain enzymes, limiting the emis- sion of electrons from the mitochondrial respiratory chain, which reduces the forma- tion 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 supple- mentation 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 cardio- protective 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 concen- tration 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 stimula- tion 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 down- regulation 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 pro- gressive 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) produc- tion 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 disor- ders, 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 pro- tein, 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 expan- sion [56]. Angiogenesis is a main cause of tumor growth, providing oxygen and nutrients to dividing cells for the continuation of cell division. Remarkably, the sup- pression 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 particu- larly 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
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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 (prin- cipally 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 con- trolled 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 character- ized by increased insulin resistance, gluconeogenesis and glycogenolysis, lipolysis, and further leptin secretion [61].