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Special Issue "Melatonin from an Antioxidant to a Classic Hormone or a Tissue Factor: Experimental and Clinical Aspects 2019"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editors

Prof. Dr. Juan Carlos Mayo
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Guest Editor
Department of Morphology and Cell Biology, Redox Biology Unit. University Institute of Oncology of Asturias (IUOPA), University of Oviedo. Facultad de Medicina, Julián Clavería 6, 33006 Oviedo, Spain
Interests: redox regulation of cell proliferation and differentiation; oxidative stress, antioxidants and cancer; redox regulation of glucose metabolism
Special Issues and Collections in MDPI journals
Prof. Dr. Rosa M. Sainz
E-Mail
Guest Editor
Departamento de Morfologia y Biologia Celular, Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Melatonin, the primary product of the pineal gland, was discovered in the late 1950s as a hormonal factor that lightens the skin of tadpoles. This effect, the first reported biological function of melatonin, is far from revealing the actual role of the indole. In the mid-1960s, Hoffman and Reiter found that seasonal fluctuations of melatonin synchronize reproductive activities in seasonal breeding animals. Since then, researchers’ knowledge about the indole has changed dramatically. Not only is the essential function of the cell questioned, but also where the indole can be found, and how it is synthesized.

Melatonin is released at night with a duration inverse to that of the photoperiod, participating in the transmission of the circadian and seasonal message to the organism. In humans, the pineal hormone is also used to readjust the circadian phases, after time shifts derived from jet lag or maladapted shift work, in sleep disorders, blind people or in circadian-related mood disorders. Additionally, melatonin was found to be an endogenous potent-free radical scavenger and enhancer of the antioxidant system, thus protecting cells from the harmful effect of pro-oxidants. This protecting effect should be added to the immunomodulatory and anti-proliferative actions widely reported in many cell and animal models. More recently, the physiological interaction between melatonin and glucose metabolism has been the focus of attention of several research groups. Melatonin controls the daily rhythms of glucose levels by altering insulin release, or by inhibiting glucose uptake. Melatonin functions are mediated by membrane receptors MT1 and MT2, intracellular binding sites or as a consequence of receptor-independent actions.

All papers related to any aspect of melatonin physiology, biochemistry and molecular biology, as well as clinical reports, will be considered for this Special Issue.

Prof. Dr. Juan C. Mayo
Prof. Dr. Rosa M. Sainz
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • animal
  • plant
  • microbiota
  • metabolism
  • glucose
  • cancer
  • diabetes
  • insulin resistance
  • stem cells
  • genomics, metabolomics, proteomics
  • cell growth
  • cell death
  • differentiation
  • apoptosis
  • oxidative stress
  • redox signalling

Published Papers (6 papers)

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Research

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Open AccessArticle
Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation
Int. J. Mol. Sci. 2020, 21(2), 548; https://doi.org/10.3390/ijms21020548 - 15 Jan 2020
Abstract
Neuroindole melatonin, a hormone synthesized during the night mainly—but not exclusively—by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of [...] Read more.
Neuroindole melatonin, a hormone synthesized during the night mainly—but not exclusively—by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of the most common carcinomas among developed countries and a type of tumor particularly difficult to fight back in medium/advanced stages. In contrast to other types of cancer, influence of melatonin on melanoma has been scarcely investigated. Thus, we have chosen the murine melanoma model B16-F10 cell line to study antiproliferative and antitumoral actions of melatonin. For this purpose, we combined both, cell culture and in vivo models. Melatonin reduced either, growth rate or migration of B16-F10 cells. Furthermore, melanin synthesis was altered by melatonin, promoting its synthesis. Melatonin also induced a G2/M cell cycle arrest and altered the cytoskeletal organization. To corroborate these results, we tested the effect of melatonin in the in vivo model of B16-F10 cell injection in the tail vein, which causes numerous lung metastases. Two different strategies of melatonin administration were used, namely, in drinking water, or daily intraperitoneal injection. However, contrary to what occurred in cell culture, no differences were observed between control and melatonin treated groups. Results obtained led us to conclude that melatonin exerts an antiproliferative and anti-migrating effect on this melanoma model by interfering with the cytoskeleton organization, but this pharmacological effect cannot be translated in vivo as the indole did not prevent metastasis in the murine model, suggesting that further insights into the effects of the indole in melanoma cells should be approached to understand this apparent paradox. Full article
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Open AccessArticle
Embryonic Ontogeny of 5-Hydroxyindoles and 5-Methoxyindoles Synthesis Pathways in the Goose Pineal Organ
Int. J. Mol. Sci. 2019, 20(16), 3948; https://doi.org/10.3390/ijms20163948 - 14 Aug 2019
Abstract
The aim of this study was to characterize the embryonic ontogeny of 5-hydroxyindoles and 5-methoxyindoles synthesis pathways in the goose pineal organ. The study was performed on embryos aged 14–28 days, which have been incubated under a 12L:12D cycle. The pineal organs were [...] Read more.
The aim of this study was to characterize the embryonic ontogeny of 5-hydroxyindoles and 5-methoxyindoles synthesis pathways in the goose pineal organ. The study was performed on embryos aged 14–28 days, which have been incubated under a 12L:12D cycle. The pineal organs were collected for measurements of indole content by HPLC every 6 h on embryonic day (ED) 14, ED 16, ED 18 and ED 22 or every 2 h on ED 24, ED 26 and ED 28. The level of tryptophan showed no significant changes during development and no day-night variations. The content of 5-hydroxytryptophan increased between ED 14 and ED 26. It was significantly higher during scotophase than during photophase starting from ED 14. The serotonin content was low during the early stages of development (ED 14–ED 18) and prominently increased from ED 20. The serotonin levels also showed day-night differences; however, they were less conspicuous than those of 5-hydroxytryptophan. The changes in the level of 5-hydroxyindole acetic acid were similar to those of serotonin. 5-Hydroxytryptophol was measurable from ED 18. Levels of N-acetylserotonin, which were detectable for the first time on ED 16, prominently increased between ED 22 and ED 28 and showed significant day–night differences from ED 20. Melatonin was detectable from ED 18. Like N-acetylserotonin, its content increased rapidly between ED 22 and ED 28, and from ED 20 showed diurnal variations. 5-Methoxyindole acetic acid and 5-methoxytryptophol occurred at measurable levels from ED 18 and ED 26, respectively. The obtained results showed that embryonic development of indole metabolism in the goose pineal organ starts with the beginning of serotonin synthesis. The processes of serotonin acetylation and 5-hydroxyindoles methylation were turned on later. Diurnal rhythmicity develops very early in the embryonic pineal organ of the goose when the eggs are incubated under a 12 h light: 12 h dark schedule. Two processes are responsible for generation of the diurnal rhythms of 5-hydroxyindoles and 5-methoxyindoles: (i) hydroxylation of tryptophan and (ii) acetylation of serotonin. Full article
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Open AccessArticle
Melatonin Abrogates the Anti-Developmental Effect of the AKT Inhibitor SH6 in Bovine Oocytes and Embryos
Int. J. Mol. Sci. 2019, 20(12), 2956; https://doi.org/10.3390/ijms20122956 - 17 Jun 2019
Cited by 2
Abstract
Melatonin, a nighttime-secreted antioxidant hormone produced by the pineal gland, and AKT, a serine/threonine-specific protein kinase, have been identified as regulators for several cellular processes essential for reproduction. The current study aimed to investigate the potential interplay between melatonin and AKT in bovine [...] Read more.
Melatonin, a nighttime-secreted antioxidant hormone produced by the pineal gland, and AKT, a serine/threonine-specific protein kinase, have been identified as regulators for several cellular processes essential for reproduction. The current study aimed to investigate the potential interplay between melatonin and AKT in bovine oocytes in the context of embryo development. Results showed that the inclusion of SH6, a specific AKT inhibitor, during in vitro maturation (IVM) significantly reduced oocyte maturation, cumulus cell expansion, cleavage, and blastocyst development that were rescued upon addition of melatonin. Oocytes treated with SH6 in the presence of melatonin showed lower levels of reactive oxygen species (ROS) and blastocysts developed exhibited low apoptosis while the mitochondrial profile was significantly improved compared to the SH6-treated group. The RT-qPCR results showed up-regulation of the mRNA of maturation-, mitochondrial-, and cumulus expansion-related genes including GDF-9, BMP-15, MARF1, ATPase, ATP5F1E, POLG2, HAS2, TNFAIP6, and PTGS2 and down-regulation of Bcl-2 associated X apoptosis regulator (BAX), caspase 3, and p21 involved in apoptosis and cell cycle arrest in melatonin-SH6 co-treated group compared to SH6 sole treatment. The immunofluorescence showed high levels of caspase 3 and caspase 9, and low AKT phosphorylation in the SH6-treated group compared to the control and melatonin-SH6 co-treatment. Taken together, our results showed the importance of both melatonin and AKT for overall embryonic developmental processes and, for the first time, we report that melatonin could neutralize the deleterious consequences of AKT inhibition, suggesting a potential role in regulation of AKT signaling in bovine oocytes. Full article
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Open AccessArticle
Melatonin Reduces Excitability in Dorsal Root Ganglia Neurons with Inflection on the Repolarization Phase of the Action Potential
Int. J. Mol. Sci. 2019, 20(11), 2611; https://doi.org/10.3390/ijms20112611 - 28 May 2019
Cited by 1
Abstract
Melatonin is a neurohormone produced and secreted at night by pineal gland. Many effects of melatonin have already been described, for example: Activation of potassium channels in the suprachiasmatic nucleus and inhibition of excitability of a sub-population of neurons of the dorsal root [...] Read more.
Melatonin is a neurohormone produced and secreted at night by pineal gland. Many effects of melatonin have already been described, for example: Activation of potassium channels in the suprachiasmatic nucleus and inhibition of excitability of a sub-population of neurons of the dorsal root ganglia (DRG). The DRG is described as a structure with several neuronal populations. One classification, based on the repolarizing phase of the action potential (AP), divides DRG neurons into two types: Without (N0) and with (Ninf) inflection on the repolarization phase of the action potential. We have previously demonstrated that melatonin inhibits excitability in N0 neurons, and in the present work, we aimed to investigate the melatonin effects on the other neurons (Ninf) of the DRG neuronal population. This investigation was done using sharp microelectrode technique in the current clamp mode. Melatonin (0.01–1000.0 nM) showed inhibitory activity on neuronal excitability, which can be observed by the blockade of the AP and by the increase in rheobase. However, we observed that, while some neurons were sensitive to melatonin effect on excitability (excitability melatonin sensitive—EMS), other neurons were not sensitive to melatonin effect on excitability (excitability melatonin not sensitive—EMNS). Concerning the passive electrophysiological properties of the neurons, melatonin caused a hyperpolarization of the resting membrane potential in both cell types. Regarding the input resistance (Rin), melatonin did not change this parameter in the EMS cells, but increased its values in the EMNS cells. Melatonin also altered several AP parameters in EMS cells, the most conspicuously changed was the (dV/dt)max of AP depolarization, which is in coherence with melatonin effects on excitability. Otherwise, in EMNS cells, melatonin (0.1–1000.0 nM) induced no alteration of (dV/dt)max of AP depolarization. Thus, taking these data together, and the data of previous publication on melatonin effect on N0 neurons shows that this substance has a greater pharmacological potency on Ninf neurons. We suggest that melatonin has important physiological function related to Ninf neurons and this is likely to bear a potential relevant therapeutic use, since Ninf neurons are related to nociception. Full article
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Open AccessArticle
Melatonin Levels in Preterm and Term Infants and Their Mothers
Int. J. Mol. Sci. 2019, 20(9), 2077; https://doi.org/10.3390/ijms20092077 - 27 Apr 2019
Cited by 1
Abstract
The prevention of perinatal brain damage following preterm birth remains a public health priority. Melatonin has been shown to be a promising neuroprotectant in neonatal preclinical models of brain damage, but few studies have investigated melatonin secretion in newborns. We hypothesized that melatonin [...] Read more.
The prevention of perinatal brain damage following preterm birth remains a public health priority. Melatonin has been shown to be a promising neuroprotectant in neonatal preclinical models of brain damage, but few studies have investigated melatonin secretion in newborns. We hypothesized that melatonin circulating levels would be lower in preterm compared to term infants. We conducted a prospective, longitudinal, multicenter study to assess melatonin, and 6-sulfatoxy-melatonin (aMT6s) concentrations, measured by radioimmunoassay. Among 209 neonates recruited, 110 were born before 34 gestational weeks (GW) and 99 born after 34 GW. Plasma melatonin concentrations, measured at birth and on Day 3 were below detectable levels (≤7 pg/mL) in 78% and 81%, respectively, of infants born before 34 GW compared to 57% and 34%, respectively, of infants born after 34 GW. The distribution of plasma melatonin concentrations was found to be correlated with gestational age at both time-points (p < 0.001). Median urine aMT6s concentrations were significantly lower in infants born before 34 GW, both on Day 1 (230 ng/L vs. 533 ng/L, p < 0.0001) and on Day 3 (197 ng/L vs. 359 ng/L, p < 0.0001). In conclusion, melatonin secretion appears very low in preterm infants, providing the rationale for testing supplemental melatonin as a neuroprotectant in clinical trials. Full article
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Review

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Open AccessReview
Melatonin Mediates Enhancement of Stress Tolerance in Plants
Int. J. Mol. Sci. 2019, 20(5), 1040; https://doi.org/10.3390/ijms20051040 - 27 Feb 2019
Cited by 10
Abstract
Melatonin is a multifunctional signaling molecule, ubiquitously distributed in different parts of plants and responsible for stimulating several physiological responses to adverse environmental conditions. In the current review, we showed that the biosynthesis of melatonin occurred in plants by themselves, and accumulation of [...] Read more.
Melatonin is a multifunctional signaling molecule, ubiquitously distributed in different parts of plants and responsible for stimulating several physiological responses to adverse environmental conditions. In the current review, we showed that the biosynthesis of melatonin occurred in plants by themselves, and accumulation of melatonin fluctuated sharply by modulating its biosynthesis and metabolic pathways under stress conditions. Melatonin, with its precursors and derivatives, acted as a powerful growth regulator, bio-stimulator, and antioxidant, which delayed leaf senescence, lessened photosynthesis inhibition, and improved redox homeostasis and the antioxidant system through a direct scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS) under abiotic and biotic stress conditions. In addition, exogenous melatonin boosted the growth, photosynthetic, and antioxidant activities in plants, confirming their tolerances against drought, unfavorable temperatures, salinity, heavy metals, acid rain, and pathogens. However, future research, together with recent advancements, would support emerging new approaches to adopt strategies in overcoming the effect of hazardous environments on crops and may have potential implications in expanding crop cultivation against harsh conditions. Thus, farming communities and consumers will benefit from elucidating food safety concerns. Full article
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