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Special Issue "Advances in the Research of Melatonin"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (28 February 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Rudiger Hardeland

Institute of Zoology and Anthropology, University of Goettingen, Berliner Str. 28, D-37073 Goettingen, Germany
E-Mail
Phone: +49-551-395414

Special Issue Information

Dear Colleagues,

Accumulating evidence indicates an important role of melatonin and melatonergic signaling for the well-functioning of a body. Both physiological and psychological impairments can be associated with decreases of melatonin levels, as observed in the course of aging or as a consequence of various diseases and disorders. The multiplicity of possible changes reflects the extraordinary pleiotropy of this hormone. The association of deviations in melatonergic signaling with mental and metabolic disorders, in particular, diabetes type 2, is supported by knockouts and polymorphisms of genes involved in melatonin biosynthesis or signaling. An overlap with similar findings concerning genes of circadian oscillators indicates a significant chronobiological role of melatonin in the maintenance of health. High nocturnal levels of melatonin, which imply large amplitudes of the melatonin rhythm, synchronize other rhythms with external cycles and within the circadian multioscillator system. They support the maintenance of high amplitudes of peripheral rhythms, as shown by melatonin deficiency. They have also been interpreted as an indicator of youthfulness. Conversely, the decline of nocturnal melatonin leads to numerous undesired changes, including impairments in both detoxification and production of reactive oxygen and nitrogen species, increased susceptibility to these reactive compounds, mitochondrial dysfunction, reductions in immune functions, sleep disturbances and, eventually, mood disorders. To overcome these problems, prolonged-release formulations of melatonin and various synthetic melatonergic agonists have been developed, some of which combine melatonergic signaling with additional properties of possible value in the treatment of depressive symptoms and metabolic disorders.

Prof. Dr. Rudiger Hardeland
Guest Editor

Submission

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Keywords

  • aging
  • antioxidative protection
  • bipolar disorder
  • chronobiotic
  • diabetes
  • immune system
  • melatonergic drugs
  • metabolic syndrome
  • seasonal affective disorder
  • sleep

Related Special Issue

Published Papers (27 papers)

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Research

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Open AccessArticle Does Melatonin Homeostasis Play a Role in Continuous Epigastric Pain Syndrome?
Int. J. Mol. Sci. 2013, 14(6), 12550-12562; doi:10.3390/ijms140612550
Received: 5 March 2013 / Revised: 22 April 2013 / Accepted: 16 May 2013 / Published: 14 June 2013
Cited by 1 | PDF Full-text (604 KB) | HTML Full-text | XML Full-text
Abstract
Two clinical forms of functional dyspepsia (FD) are listed in the Rome III criteria: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), differing in the recurrence of ailments depending on the diet. Continuous EPS (CEPS) is observed in some EPS patients, also
[...] Read more.
Two clinical forms of functional dyspepsia (FD) are listed in the Rome III criteria: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), differing in the recurrence of ailments depending on the diet. Continuous EPS (CEPS) is observed in some EPS patients, also at night, but its cause is still unknown. We showed previously that melatonin (MEL) homeostasis may be associated with FD. In the present work we evaluated selected components of melatonin homeostasis in patients with CEPS. The study included 30 patients with CEPS, 21 women and nine men, aged 21–49 years and 30 control subjects (EPS excluded); organic and mental diseases, as well as Helicobacter pylori infection, were excluded in both groups. The average severity of abdominal pain in the last three months was estimated in a 10-point scale (Visual Analog Scale). The levels of mRNA expression of arylalkylamine-N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT), the main components of MEL homeostasis, were determined in gastric mucosa with real time PCR. The fasting serum level of MEL (at 09:00 a.m.) and circadian urine excretion of 6-sulfatoxymelatonin (6-HMS) were determined with ELISA. AANAT expression in antral mucosa of control subjects was 1.76 ± 0.41, in the gastric body 1.35 ± 0.38, and in the dyspeptic group 1.42 ± 0.38 (p < 0.05) and 0.92 ± 0.55 (p < 0.05), respectively. HIOMT expression in the control was 2.05 ± 0.70 in the antrum and 1.57 ± 0.69 in the body and in the CEPS group, it was: 1.51 ± 0.57 (p < 0.05) and 0.74 ± 0.31 (p < 0.001), respectively. MEL concentration (pg/mL) was 9.41 ± 3.09 in the control group and 5.62 ± 1.34 (p < 0.01) in the CEPS group. Urinary 6-HMS excretion (μg/24 h) was 11.40 ± 4.46 in the controls and 7.68 ± 2.88 (p < 0.05) in the CEPS. Moreover, a negative correlation was found between the tested parameters and severity of epigastric pain. These results indicate that patients with CEPS may display low level of AANAT and HIOMT expression in gastric mucosa, resulting in decreased MEL synthesis. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Open AccessArticle New Evidence for Cross Talk between Melatonin and Mitochondria Mediated by a Circadian-Compatible Interaction with Nitric Oxide
Int. J. Mol. Sci. 2013, 14(6), 11259-11276; doi:10.3390/ijms140611259
Received: 22 March 2013 / Revised: 16 May 2013 / Accepted: 16 May 2013 / Published: 28 May 2013
Cited by 11 | PDF Full-text (868 KB) | HTML Full-text | XML Full-text
Abstract
Extending our previous observations, we have shown on HaCat cells that melatonin, at ~10−9 M concentration, transiently raises not only the expression of the neuronal nitric oxide synthase (nNOS) mRNA, but also the nNOS protein synthesis and the nitric oxide oxidation products,
[...] Read more.
Extending our previous observations, we have shown on HaCat cells that melatonin, at ~10−9 M concentration, transiently raises not only the expression of the neuronal nitric oxide synthase (nNOS) mRNA, but also the nNOS protein synthesis and the nitric oxide oxidation products, nitrite and nitrate. Interestingly, from the cell bioenergetic point of view, the activated NO-related chemistry induces a mild decrease of the oxidative phosphorylation (OXPHOS) efficiency, paralleled by a depression of the mitochondrial membrane potential. The OXPHOS depression is apparently balanced by glycolysis. The mitochondrial effects described have been detected only at nanomolar concentration of melatonin and within a time window of a few hours’ incubation; both findings compatible with the melatonin circadian cycle. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessArticle New Radioligands for Describing the Molecular Pharmacology of MT1 and MT2 Melatonin Receptors
Int. J. Mol. Sci. 2013, 14(5), 8948-8962; doi:10.3390/ijms14058948
Received: 16 March 2013 / Revised: 14 April 2013 / Accepted: 15 April 2013 / Published: 25 April 2013
Cited by 10 | PDF Full-text (378 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin receptors have been studied for several decades. The low expression of the receptors in tissues led the scientific community to find a substitute for the natural hormone melatonin, the agonist 2-[125I]-iodomelatonin. Using the agonist, several hundreds of studies were conducted,
[...] Read more.
Melatonin receptors have been studied for several decades. The low expression of the receptors in tissues led the scientific community to find a substitute for the natural hormone melatonin, the agonist 2-[125I]-iodomelatonin. Using the agonist, several hundreds of studies were conducted, including the discovery of agonists and antagonists for the receptors and minute details about their molecular behavior. Recently, we attempted to expand the panel of radioligands available for studying the melatonin receptors by using the newly discovered compounds SD6, DIV880, and S70254. These compounds were characterized for their affinities to the hMT1 and hMT2 recombinant receptors and their functionality in the classical GTPS system. SD6 is a full agonist, equilibrated between the receptor isoforms, whereas S70254 and DIV880 are only partial MT2 agonists, with Ki in the low nanomolar range while they have no affinity to MT1 receptors. These new tools will hopefully allow for additions to the current body of information on the native localization of the receptor isoforms in tissues. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessArticle Melatonin Inhibits GnRH-1, GnRH-3 and GnRH Receptor Expression in the Brain of the European Sea Bass, Dicentrarchus labrax
Int. J. Mol. Sci. 2013, 14(4), 7603-7616; doi:10.3390/ijms14047603
Received: 11 March 2013 / Revised: 24 March 2013 / Accepted: 26 March 2013 / Published: 8 April 2013
Cited by 11 | PDF Full-text (590 KB) | HTML Full-text | XML Full-text
Abstract
Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 µg/g body mass) in male specimens.
[...] Read more.
Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 µg/g body mass) in male specimens. The brain mRNA transcript levels of the three GnRH forms and the five GnRH receptors present in this species were determined by real time quantitative PCR. Our findings revealed day–night variations in the brain expression of GnRH-1, GnRH-3 and several GnRH receptors (dlGnRHR-II-1c, -2a), which exhibited higher transcript levels at mid-light compared to mid-dark phase of the photocycle. Moreover, an inhibitory effect of melatonin on the nocturnal expression of GnRH-1, GnRH-3, and GnRH receptors subtypes 1c, 2a and 2b was also demonstrated. Interestingly, the inhibitory effect of melatonin affected the expression of hypophysiotrophic GnRH forms and GnRH receptors that exhibit day–night fluctuations, suggesting that exogenous melatonin reinforce physiological mechanisms already established. These interactions between melatoninergic and GnRH systems could be mediating photoperiod effects on reproductive and other rhythmic physiological events in the European sea bass. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Open AccessArticle Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2
Int. J. Mol. Sci. 2013, 14(3), 6345-6358; doi:10.3390/ijms14036345
Received: 7 January 2013 / Revised: 13 March 2013 / Accepted: 13 March 2013 / Published: 19 March 2013
Cited by 5 | PDF Full-text (531 KB) | HTML Full-text | XML Full-text
Abstract
The defect of the melatonin signaling pathway has been proposed to be one of the key etiopathogenic factors in adolescent idiopathic scoliosis (AIS). A previous report showed that melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate
[...] Read more.
The defect of the melatonin signaling pathway has been proposed to be one of the key etiopathogenic factors in adolescent idiopathic scoliosis (AIS). A previous report showed that melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate whether the abnormal MT2 expression in AIS is quantitative or qualitative. Cultured osteoblasts were obtained from 41 AIS girls and nine normal controls. Semi-quantification of protein expression by Western blot and mRNA expression by TaqMan real-time PCR for both MT1 and MT2 were performed. Anthropometric parameters were also compared and correlated with the protein expression and mRNA expression of the receptors. The results showed significantly lower protein and mRNA expression of MT2 in AIS girls compared with that in normal controls (p = 0.02 and p = 0.019, respectively). No differences were found in the expression of MT1. When dichotomizing the AIS girls according to their MT2 expression, the group with low expression was found to have a significantly longer arm span (p = 0.036). The results of this study showed for the first time a quantitative change of MT2 in AIS that was also correlated with abnormal arm span as part of abnormal systemic skeletal growth. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessArticle A Comparison of B16 Melanoma Cells and 3T3 Fibroblasts Concerning Cell Viability and ROS Production in the Presence of Melatonin, Tested Over a Wide Range of Concentrations
Int. J. Mol. Sci. 2013, 14(2), 3901-3920; doi:10.3390/ijms14023901
Received: 22 January 2013 / Revised: 31 January 2013 / Accepted: 4 February 2013 / Published: 14 February 2013
Cited by 5 | PDF Full-text (954 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is a pleiotropic molecule with many cellular and systemic actions, including chronobiotic effects. Beneficial effects are widely documented concerning the treatment of neoplastic diseases in vivo as well as reductions in viability of cultured cells from melanoma, one of the most aggressive
[...] Read more.
Melatonin is a pleiotropic molecule with many cellular and systemic actions, including chronobiotic effects. Beneficial effects are widely documented concerning the treatment of neoplastic diseases in vivo as well as reductions in viability of cultured cells from melanoma, one of the most aggressive cancers in humans. However, studies of its effects on non-tumor cells in vitro have not focused on viability, except for experiments aiming to protect against oxidotoxicity or other toxicological insults. Furthermore, there is no agreement on the range of effective melatonin concentrations in vitro, and the mechanisms that reduce cell viability have remained unclear. Tumor cell-specific increases in the production of reactive oxygen and nitrogen species (ROS/RNS) may provide a possible explanation. Our aim was to analyze the potential inhibition of tumor (B16 melanoma 4A5) and non-tumor cell (3T3 Swiss albino) viability using a wide range of melatonin concentrations (10−11–10−2 M), and to determine whether intracellular ROS enhancement was involved in this process. In the absence of fetal bovine serum (FBS), low melatonin concentrations (10−9–10−5 M) reduced the proliferation of melanoma cells with no effect in fibroblasts, whereas, in the presence of FBS, they had no effect or even increased the proliferation of both fibroblast and melanoma cells. Melatonin concentrations in the upper millimolar range increased ROS levels and reduced the viability of both cell types, but more markedly so in non-tumor cells. Thus, low melatonin concentrations reduce proliferation in this specific melanoma cell line, whereas high concentrations affect the viability of both tumor (B16 4A5 melanoma) and non-tumor (3T3 fibroblasts) cells. Increased ROS levels in both lines indicate a role for ROS production in the reduction of cell viability at high—but not low—melatonin concentrations, although the mechanism of action still remains to be elucidated. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessArticle Out of the Lab and into the Bathroom: Evening Short-Term Exposure to Conventional Light Suppresses Melatonin and Increases Alertness Perception
Int. J. Mol. Sci. 2013, 14(2), 2573-2589; doi:10.3390/ijms14022573
Received: 23 November 2012 / Revised: 23 December 2012 / Accepted: 16 January 2013 / Published: 28 January 2013
Cited by 19 | PDF Full-text (595 KB) | HTML Full-text | XML Full-text
Abstract
Life in 24-h society relies on the use of artificial light at night that might disrupt synchronization of the endogenous circadian timing system to the solar day. This could have a negative impact on sleep–wake patterns and psychiatric symptoms. The aim of the
[...] Read more.
Life in 24-h society relies on the use of artificial light at night that might disrupt synchronization of the endogenous circadian timing system to the solar day. This could have a negative impact on sleep–wake patterns and psychiatric symptoms. The aim of the study was to investigate the influence of evening light emitted by domestic and work place lamps in a naturalistic setting on melatonin levels and alertness in humans. Healthy subjects (6 male, 3 female, 22–33 years) were exposed to constant dim light (<10 lx) for six evenings from 7:00 p.m. to midnight. On evenings 2 through 6, 1 h before habitual bedtime, they were also exposed to light emitted by 5 different conventional lamps for 30 min. Exposure to yellow light did not alter the increase of melatonin in saliva compared to dim light baseline during (38 ± 27 pg/mL vs. 39 ± 23 pg/mL) and after light exposure (39 ± 22 pg/mL vs. 44 ± 26 pg/mL). In contrast, lighting conditions including blue components reduced melatonin increase significantly both during (office daylight white: 25 ± 16 pg/mL, bathroom daylight white: 24 ± 10 pg/mL, Planon warm white: 26 ± 14 pg/mL, hall daylight white: 22 ± 14 pg/mL) and after light exposure (office daylight white: 25 ± 15 pg/mL, bathroom daylight white: 23 ± 9 pg/mL, Planon warm white: 24 ± 13 pg/mL, hall daylight white: 22 ± 26 pg/mL). Subjective alertness was significantly increased after exposure to three of the lighting conditions which included blue spectral components in their spectra. Evening exposure to conventional lamps in an everyday setting influences melatonin excretion and alertness perception within 30 min. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Open AccessArticle Melatonin May Curtail the Metabolic Syndrome: Studies on Initial and Fully Established Fructose-Induced Metabolic Syndrome in Rats
Int. J. Mol. Sci. 2013, 14(2), 2502-2514; doi:10.3390/ijms14022502
Received: 24 December 2012 / Revised: 15 January 2013 / Accepted: 22 January 2013 / Published: 25 January 2013
Cited by 15 | PDF Full-text (708 KB) | HTML Full-text | XML Full-text
Abstract
To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood
[...] Read more.
To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c) concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 μg/mL drinking solution) counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phases. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Review

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Open AccessReview Advances in the Research of Melatonin in Autism Spectrum Disorders: Literature Review and New Perspectives
Int. J. Mol. Sci. 2013, 14(10), 20508-20542; doi:10.3390/ijms141020508
Received: 6 August 2013 / Revised: 3 September 2013 / Accepted: 13 September 2013 / Published: 14 October 2013
Cited by 18 | PDF Full-text (301 KB) | HTML Full-text | XML Full-text
Abstract
Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with
[...] Read more.
Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity
Int. J. Mol. Sci. 2013, 14(9), 18385-18406; doi:10.3390/ijms140918385
Received: 2 June 2013 / Revised: 16 July 2013 / Accepted: 26 August 2013 / Published: 6 September 2013
Cited by 5 | PDF Full-text (1366 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by
[...] Read more.
Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT1 and MT2 transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules. Both MT1 and MT2 receptors are widely expressed in the central nervous system as well as many peripheral tissues, but each receptor subtype can be linked to specific functional responses at the target tissue. Given the broad therapeutic implications of melatonin receptors in chronobiology, immunomodulation, endocrine regulation, reproductive functions and cancer development, drug discovery and development programs have been directed at identifying chemical molecules that bind to the two melatonin receptor subtypes. However, all of the melatoninergics in the market act on both subtypes of melatonin receptors without significant selectivity. To facilitate the design and development of novel therapeutic agents, it is necessary to understand the intrinsic differences between MT1 and MT2 that determine ligand binding, functional efficacy, and signaling specificity. This review summarizes our current knowledge in differentiating MT1 and MT2 receptors and their signaling capacities. The use of homology modeling in the mapping of the ligand-binding pocket will be described. Identification of conserved and distinct residues will be tremendously useful in the design of highly selective ligands. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Melatonin Signaling and Its Modulation of PfNF-YB Transcription Factor Expression in Plasmodium falciparum
Int. J. Mol. Sci. 2013, 14(7), 13704-13718; doi:10.3390/ijms140713704
Received: 19 May 2013 / Revised: 23 June 2013 / Accepted: 25 June 2013 / Published: 1 July 2013
Cited by 5 | PDF Full-text (765 KB) | HTML Full-text | XML Full-text
Abstract
Malaria is one of the most severe tropical infectious diseases. More than 220 million people around the world have a clinical malaria infection and about one million die because of Plasmodium annually. This parasitic pathogen replicates efficiently in its human host making it
[...] Read more.
Malaria is one of the most severe tropical infectious diseases. More than 220 million people around the world have a clinical malaria infection and about one million die because of Plasmodium annually. This parasitic pathogen replicates efficiently in its human host making it difficult to eradicate. It is transmitted by mosquito vectors and so far mosquito control programs have not effectively eliminated this transmission. Because of malaria’s enormous health and economic impact and the need to develop new control and eventual elimination strategies, a big research effort has been made to better understand the biology of this parasite and its interactions with its vertebrate host. Determination of the genome sequence and organization, the elucidation of the role of key proteins, and cell signaling studies have helped to develop an understanding of the molecular mechanisms that provide the parasite’s versatility. The parasite can sense its environment and adapt to benefit its survival, indeed this is essential for it to complete its life cycle. For many years we have studied how the Plasmodium parasite is able to sense melatonin. In this review we discuss the melatonin signaling pathway and its role in the control of Plasmodium replication and development. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview The Melatonergic System in Mood and Anxiety Disorders and the Role of Agomelatine: Implications for Clinical Practice
Int. J. Mol. Sci. 2013, 14(6), 12458-12483; doi:10.3390/ijms140612458
Received: 17 March 2013 / Revised: 22 May 2013 / Accepted: 22 May 2013 / Published: 13 June 2013
Cited by 27 | PDF Full-text (279 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of the body either as single ones or together.
[...] Read more.
Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of the body either as single ones or together. A growing literature suggests that the melatonergic system may be involved in the pathophysiology of mood and anxiety disorders. In fact, some core symptoms of depression show disturbance of the circadian rhythm in their clinical expression, such as diurnal mood and other symptomatic variation, or are closely linked to circadian system functioning, such as sleep-wake cycle alterations. In addition, alterations have been described in the circadian rhythms of several biological markers in depressed patients. Therefore, there is interest in developing antidepressants that have a chronobiotic effect (i.e., treatment of circadian rhythm disorders). As melatonin produces chronobiotic effects, efforts have been aimed at developing agomelatine, an antidepressant with melatonin agonist activity. The present paper reviews the role of the melatonergic system in the pathophysiology of mood and anxiety disorders and the clinical characteristics of agomelatine. Implications of agomelatine in “real world” clinical practice will be also discussed. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Diseases
Int. J. Mol. Sci. 2013, 14(6), 11742-11766; doi:10.3390/ijms140611742
Received: 28 February 2013 / Revised: 15 May 2013 / Accepted: 16 May 2013 / Published: 31 May 2013
Cited by 17 | PDF Full-text (532 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the
[...] Read more.
Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Melatonin Receptor Genes in Vertebrates
Int. J. Mol. Sci. 2013, 14(6), 11208-11223; doi:10.3390/ijms140611208
Received: 27 February 2013 / Revised: 28 April 2013 / Accepted: 20 May 2013 / Published: 27 May 2013
Cited by 18 | PDF Full-text (319 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while
[...] Read more.
Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Melatonin Effects on Hard Tissues: Bone and Tooth
Int. J. Mol. Sci. 2013, 14(5), 10063-10074; doi:10.3390/ijms140510063
Received: 22 March 2013 / Revised: 29 April 2013 / Accepted: 2 May 2013 / Published: 10 May 2013
Cited by 16 | PDF Full-text (250 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole plays an important role in many physiological processes including circadian entrainment, blood pressure regulation, seasonal reproduction, ovarian physiology,
[...] Read more.
Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole plays an important role in many physiological processes including circadian entrainment, blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. Recently, the investigation and applications of melatonin in the hard tissues bone and tooth have received great attention. Melatonin has been investigated relative to bone remolding, osteoporosis, osseointegration of dental implants and dentine formation. In the present review, we discuss the large body of published evidence and review data of melatonin effects on hard tissues, specifically, bone and tooth. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Neuroprotective Effect of Melatonin: A Novel Therapy against Perinatal Hypoxia-Ischemia
Int. J. Mol. Sci. 2013, 14(5), 9379-9395; doi:10.3390/ijms14059379
Received: 28 February 2013 / Revised: 15 April 2013 / Accepted: 16 April 2013 / Published: 29 April 2013
Cited by 19 | PDF Full-text (2530 KB) | HTML Full-text | XML Full-text
Abstract
One of the most common causes of mortality and morbidity in children is perinatal hypoxia-ischemia (HI). In spite of the advances in neonatology, its incidence is not diminishing, generating a pediatric population that will require an extended amount of chronic care throughout their
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One of the most common causes of mortality and morbidity in children is perinatal hypoxia-ischemia (HI). In spite of the advances in neonatology, its incidence is not diminishing, generating a pediatric population that will require an extended amount of chronic care throughout their lifetime. For this reason, new and more effective neuroprotective strategies are urgently required, in order to minimize as much as possible the neurological consequences of this encephalopathy. In this sense, interest has grown in the neuroprotective possibilities of melatonin, as this hormone may help to maintain cell survival through the modulation of a wide range of physiological functions. Although some of the mechanisms by which melatonin is neuroprotective after neonatal asphyxia remain a subject of investigation, this review tries to summarize some of the most recent advances related with its use as a therapeutic drug against perinatal hypoxic-ischemic brain injury, supporting the high interest in this indoleamine as a future feasible strategy for cerebral asphyctic events. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Open AccessReview Melatonin-Based Therapeutics for Neuroprotection in Stroke
Int. J. Mol. Sci. 2013, 14(5), 8924-8947; doi:10.3390/ijms14058924
Received: 8 March 2013 / Revised: 10 April 2013 / Accepted: 11 April 2013 / Published: 25 April 2013
Cited by 10 | PDF Full-text (308 KB) | HTML Full-text | XML Full-text
Abstract
The present review paper supports the approach to deliver melatonin and to target melatonin receptors for neuroprotection in stroke. We discuss laboratory evidence demonstrating neuroprotective effects of exogenous melatonin treatment and transplantation of melatonin-secreting cells in stroke. In addition, we describe a novel
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The present review paper supports the approach to deliver melatonin and to target melatonin receptors for neuroprotection in stroke. We discuss laboratory evidence demonstrating neuroprotective effects of exogenous melatonin treatment and transplantation of melatonin-secreting cells in stroke. In addition, we describe a novel mechanism of action underlying the therapeutic benefits of stem cell therapy in stroke, implicating the role of melatonin receptors. As we envision the clinical entry of melatonin-based therapeutics, we discuss translational experiments that warrant consideration to reveal an optimal melatonin treatment strategy that is safe and effective for human application. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Role of Melatonin in Schizophrenia
Int. J. Mol. Sci. 2013, 14(5), 9037-9050; doi:10.3390/ijms14059037
Received: 19 February 2013 / Revised: 9 April 2013 / Accepted: 10 April 2013 / Published: 25 April 2013
Cited by 11 | PDF Full-text (195 KB) | HTML Full-text | XML Full-text
Abstract
Schizophrenia is a chronic mental disease that disturbs several cognitive functions, such as memory, thought, perception and volition. Schizophrenia’s biological etiology is multifactorial and is still under investigation. Melatonin has been involved in schizophrenia since the first decades of the twentieth century. Research
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Schizophrenia is a chronic mental disease that disturbs several cognitive functions, such as memory, thought, perception and volition. Schizophrenia’s biological etiology is multifactorial and is still under investigation. Melatonin has been involved in schizophrenia since the first decades of the twentieth century. Research into melatonin regarding schizophrenia has followed two different approaches. The first approach is related to the use of melatonin as a biological marker. The second approach deals with the clinical applications of melatonin as a drug treatment. In this paper, both aspects of melatonin application are reviewed. Its clinical use in schizophrenia is emphasized. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Melatonin: Buffering the Immune System
Int. J. Mol. Sci. 2013, 14(4), 8638-8683; doi:10.3390/ijms14048638
Received: 1 March 2013 / Revised: 6 April 2013 / Accepted: 7 April 2013 / Published: 22 April 2013
Cited by 94 | PDF Full-text (567 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an
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Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Homology Models of Melatonin Receptors: Challenges and Recent Advances
Int. J. Mol. Sci. 2013, 14(4), 8093-8121; doi:10.3390/ijms14048093
Received: 7 March 2013 / Revised: 28 March 2013 / Accepted: 28 March 2013 / Published: 12 April 2013
Cited by 10 | PDF Full-text (3810 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of
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Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compounds will be commented upon. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Open AccessReview Influence of Melatonin on the Immune System of Fish: A Review
Int. J. Mol. Sci. 2013, 14(4), 7979-7999; doi:10.3390/ijms14047979
Received: 15 January 2013 / Revised: 26 March 2013 / Accepted: 27 March 2013 / Published: 11 April 2013
Cited by 7 | PDF Full-text (218 KB) | HTML Full-text | XML Full-text
Abstract
Endocrine-immune system interactions have been widely demonstrated in mammals, whereas in fish, these relationships remain unclear. Of the organs that constitute the endocrine system, the pineal gland and its secretory product melatonin act in the synchronization of daily and seasonal rhythms in most
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Endocrine-immune system interactions have been widely demonstrated in mammals, whereas in fish, these relationships remain unclear. Of the organs that constitute the endocrine system, the pineal gland and its secretory product melatonin act in the synchronization of daily and seasonal rhythms in most vertebrates, including fish. Seasonal differences in immunocompetence and disease prevalence have been well documented in humans. Seasonality also strongly influences the life history of fish by controlling the timing of physiological events, such as reproduction, food intake, locomotor activity, and growth performance. Apart from its synchronizing capabilities, the role of melatonin in physiological processes in fish is not thoroughly understood. The purpose of this review is to summarize current studies on the effects of melatonin on the fish immune system. These studies suggest that melatonin represents an important component of fish endocrine-immune system interactions. The elucidation of the defense mechanisms of fish will facilitate the development of health management tools to support the growing finfish aquaculture industry as well as address questions concerning the origins and evolution of the immune system in vertebrates. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Peripheral Reproductive Organ Health and Melatonin: Ready for Prime Time
Int. J. Mol. Sci. 2013, 14(4), 7231-7272; doi:10.3390/ijms14047231
Received: 25 February 2013 / Accepted: 27 March 2013 / Published: 2 April 2013
Cited by 41 | PDF Full-text (3236 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin has a wide variety of beneficial actions at the level of the gonads and their adnexa. Some actions are mediated via its classic membrane melatonin receptors while others seem to be receptor-independent. This review summarizes many of the published reports which confirm
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Melatonin has a wide variety of beneficial actions at the level of the gonads and their adnexa. Some actions are mediated via its classic membrane melatonin receptors while others seem to be receptor-independent. This review summarizes many of the published reports which confirm that melatonin, which is produced in the ovary, aids in advancing follicular maturation and preserving the integrity of the ovum prior to and at the time of ovulation. Likewise, when ova are collected for in vitro fertilization-embryo transfer, treating them with melatonin improves implantation and pregnancy rates. Melatonin synthesis as well as its receptors have also been identified in the placenta. In this organ, melatonin seems to be of particular importance for the maintenance of the optimal turnover of cells in the villous trophoblast via its ability to regulate apoptosis. For male gametes, melatonin has also proven useful in protecting them from oxidative damage and preserving their viability. Incubation of ejaculated animal sperm improves their motility and prolongs their viability. For human sperm as well, melatonin is also a valuable agent for protecting them from free radical damage. In general, the direct actions of melatonin on the gonads and adnexa of mammals indicate it is an important agent for maintaining optimal reproductive physiology. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon
Int. J. Mol. Sci. 2013, 14(4), 6981-7015; doi:10.3390/ijms14046981
Received: 21 February 2013 / Revised: 7 March 2013 / Accepted: 11 March 2013 / Published: 27 March 2013
Cited by 26 | PDF Full-text (572 KB) | HTML Full-text | XML Full-text
Abstract
The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon
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The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
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Open AccessReview Mechanisms Involved in the Pro-Apoptotic Effect of Melatonin in Cancer Cells
Int. J. Mol. Sci. 2013, 14(4), 6597-6613; doi:10.3390/ijms14046597
Received: 5 March 2013 / Revised: 18 March 2013 / Accepted: 20 March 2013 / Published: 25 March 2013
Cited by 31 | PDF Full-text (1623 KB) | HTML Full-text | XML Full-text
Abstract
It is well established that melatonin exerts antitumoral effects in many cancer types, mostly decreasing cell proliferation at low concentrations. On the other hand, induction of apoptosis by melatonin has been described in the last few years in some particular cancer types. The
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It is well established that melatonin exerts antitumoral effects in many cancer types, mostly decreasing cell proliferation at low concentrations. On the other hand, induction of apoptosis by melatonin has been described in the last few years in some particular cancer types. The cytotoxic effect occurs after its administration at high concentrations, and the molecular pathways involved have been only partially determined. Moreover, a synergistic effect has been found in several cancer types when it is administered in combination with chemotherapeutic agents. In the present review, we will summarize published work on the pro-apoptotic effect of melatonin in cancer cells and the reported mechanisms involved in such action. We will also construct a hypothesis on how different cell signaling pathways may relate each other on account for such effect. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Chronobiology of Melatonin beyond the Feedback to the Suprachiasmatic Nucleus—Consequences to Melatonin Dysfunction
Int. J. Mol. Sci. 2013, 14(3), 5817-5841; doi:10.3390/ijms14035817
Received: 17 February 2013 / Revised: 1 March 2013 / Accepted: 4 March 2013 / Published: 12 March 2013
Cited by 8 | PDF Full-text (347 KB) | HTML Full-text | XML Full-text
Abstract
The mammalian circadian system is composed of numerous oscillators, which gradually differ with regard to their dependence on the pacemaker, the suprachiasmatic nucleus (SCN). Actions of melatonin on extra-SCN oscillators represent an emerging field. Melatonin receptors are widely expressed in numerous peripheral and
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The mammalian circadian system is composed of numerous oscillators, which gradually differ with regard to their dependence on the pacemaker, the suprachiasmatic nucleus (SCN). Actions of melatonin on extra-SCN oscillators represent an emerging field. Melatonin receptors are widely expressed in numerous peripheral and central nervous tissues. Therefore, the circadian rhythm of circulating, pineal-derived melatonin can have profound consequences for the temporal organization of almost all organs, without necessarily involving the melatonin feedback to the suprachiasmatic nucleus. Experiments with melatonin-deficient mouse strains, pinealectomized animals and melatonin receptor knockouts, as well as phase-shifting experiments with explants, reveal a chronobiological role of melatonin in various tissues. In addition to directly steering melatonin-regulated gene expression, the pineal hormone is required for the rhythmic expression of circadian oscillator genes in peripheral organs and to enhance the coupling of parallel oscillators within the same tissue. It exerts additional effects by modulating the secretion of other hormones. The importance of melatonin for numerous organs is underlined by the association of various diseases with gene polymorphisms concerning melatonin receptors and the melatonin biosynthetic pathway. The possibilities and limits of melatonergic treatment are discussed with regard to reductions of melatonin during aging and in various diseases. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Roles of Melatonin in Fetal Programming in Compromised Pregnancies
Int. J. Mol. Sci. 2013, 14(3), 5380-5401; doi:10.3390/ijms14035380
Received: 17 February 2013 / Revised: 25 February 2013 / Accepted: 25 February 2013 / Published: 6 March 2013
Cited by 22 | PDF Full-text (304 KB) | HTML Full-text | XML Full-text
Abstract
Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may
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Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may affect development at a later stage. Melatonin is an oxidant scavenger that reverses oxidative stress during the prenatal period. Moreover, the role of melatonin in epigenetic modifications in the field of developmental programming has been studied extensively. Here, we describe the physiological function of melatonin in pregnancy and discuss the roles of melatonin in fetal programming in compromised pregnancies, focusing on its involvement in redox and epigenetic mechanisms. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)
Open AccessReview Melatonin Anticancer Effects: Review
Int. J. Mol. Sci. 2013, 14(2), 2410-2430; doi:10.3390/ijms14022410
Received: 5 December 2012 / Revised: 14 January 2013 / Accepted: 15 January 2013 / Published: 24 January 2013
Cited by 27 | PDF Full-text (747 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet
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Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin)

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