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Special Issue "Advances in the Research of Melatonin 2014"

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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 (31 July 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Rudiger Hardeland

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

Special Issue Information

Dear Colleagues,

Considerable progress has been made during recent years in the research of melatonin and melatonergic signaling. This extends from the classic role of melatonin as a regulator of temporal processes in vertebrates to various other fields, such as actions in invertebrate animals, plants and unicellular organisms as well as various aspects of human health. The medicinal perspectives concern areas as different as gerontology, sleep research, mental disorders, immunology, oxidative stress including mitochondrial dysfunction, metabolic disorders and diseases. An increasing number of studies are dealing with the corresponding effects of synthetic melatonergic agonists, which differ with regard to duration of action, receptor affinity and metabolism. In some cases, the melatonergic actions are associated with properties such as serotonergic antagonists. Despite this novel complexity, the effects of melatonin and its synthetic analogs on the circadian system continues to be of particular interest, especially as well-functioning of both central and peripheral circadian oscillators is increasingly perceived to be of significant importance to health. Phasing and coordination of rhythms and support of circadian amplitudes seem to represent an area in which cellular oscillations and melatonergic actions are intertwined, with mutual support and synergism in its physiological outcome. The hope is that maintenance of these time structures might overcome, to a certain degree, pathophysiological changes caused by aging and diseases. Melatonin and its synthetic analogs may represent tools for achieving this objective. The numerous perspectives resulting from new findings justify a continuation of the special issue on Advances in the Research of Melatonin that started in 2013.

Prof. Dr. Rudiger Hardeland
Guest Editor

Submission

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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 refereed through a 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 monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs).

Keywords

  • aging
  • antioxidative protection
  • chronobiotic
  • diabetes
  • immune system
  • melatonergic drugs
  • mental disorders
  • metabolic syndrome
  • phytomelatonin
  • sleep

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Published Papers (28 papers)

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Open AccessArticle Melatonin Stimulates Dendrite Formation and Complexity in the Hilar Zone of the Rat Hippocampus: Participation of the Ca++/Calmodulin Complex
Int. J. Mol. Sci. 2015, 16(1), 1907-1927; doi:10.3390/ijms16011907
Received: 31 July 2014 / Accepted: 7 January 2015 / Published: 16 January 2015
Cited by 3 | PDF Full-text (6414 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca [...] Read more.
Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII) by CaM. Previous work showed that MEL increased the synthesis and translocation of CaM, suggesting that MEL activates CaM-dependent enzymes by this pathway. In this work we investigated whether MEL stimulates dendrite formation by CaMKII activation in organotypic cultures from adult rat hippocampus. We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices. Also, PKC inhibition abolished dendritogenesis, while luzindole, an antagonist of MEL receptors (MT1/2), partially blocked the effects of MEL. Moreover, autophosphorylation of CaMKII and PKC was increased in presence of MEL, as well as phosphorylation of ERK1/2. Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction. Dendritogenesis elicited by MEL also required PKC activation, and signaling through MT1/2 receptors was partially involved. Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Melatonin and Female Hormone Secretion in Postmenopausal Overweight Women
Int. J. Mol. Sci. 2015, 16(1), 1030-1042; doi:10.3390/ijms16011030
Received: 26 August 2014 / Accepted: 16 December 2014 / Published: 5 January 2015
Cited by 1 | PDF Full-text (374 KB) | HTML Full-text | XML Full-text
Abstract
Estrogen deficiency is considered to be the main cause of increased appetite and increased weight in postmenopausal women. In this period, reduced secretion of melatonin (MEL) was also observed. The aim of the study was to evaluate the secretion of melatonin, 17-β [...] Read more.
Estrogen deficiency is considered to be the main cause of increased appetite and increased weight in postmenopausal women. In this period, reduced secretion of melatonin (MEL) was also observed. The aim of the study was to evaluate the secretion of melatonin, 17-β estradiol and follicle-stimulating hormone (FSH) in relation to body mass index (BMI) in pre- and postmenopausal women. The study included 90 women divided into three equal groups: group I (control)—women without menstrual disorders, group II—postmenopausal women without change in appetite and body weight, group III—postmenopausal women experiencing increased appetite and weight gain. In each patient, serum melatonin, 17-β-estradiol, FSH and urine a 6-sulfatoxymelatonin (aMT6s) were determined. Compared to the control group, the level of melatonin and estradiol was statistically lower. The FSH level was higher than in the groups of postmenopausal women. No significant correlation was found in all groups between the level of melatonin and the levels of estradiol and FSH. A negative correlation was found between aMT6s excretion and BMI, and a positive correlation between the level of FSH and BMI, mainly in overweight women. The obtained results indicate a significant effect of melatonin deficiency on the process of weight gain in postmenopausal women and justify its use in treatment of these disorders. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Expression of the MT1 Melatonin Receptor in Ovarian Cancer Cells
Int. J. Mol. Sci. 2014, 15(12), 23074-23089; doi:10.3390/ijms151223074
Received: 14 October 2014 / Revised: 20 November 2014 / Accepted: 21 November 2014 / Published: 12 December 2014
Cited by 3 | PDF Full-text (1562 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer (OC) is the leading cause of death among women with genital tract disorders. Melatonin exhibits oncostatic properties which it may effect through binding to its membrane receptor, MT1. The aim of this study was to determine the expression of MT1 [...] Read more.
Ovarian cancer (OC) is the leading cause of death among women with genital tract disorders. Melatonin exhibits oncostatic properties which it may effect through binding to its membrane receptor, MT1. The aim of this study was to determine the expression of MT1 in OC cells and to correlate this with clinical and pathological data. Immunohistochemistry was performed on 84 cases of OC. Normal ovarian epithelial (IOSE 364) and OC (SK-OV-3, OVCAR-3) cell lines were used to examine the MT1 expression at protein level using the western blot and immunofluorescence technique. The expression of MT1 was observed as cytoplasmic-membrane (MT1CM) and membrane (MT1M) reactions. A positive correlation between MT1CM and MT1M was found in all the studied cases. There were no significant differences between the expression of MT1CM, MT1M, and histological type, staging, grading, presence of residual disease, or overall survival time. Immunofluorescence showed both MT1M and MT1CM expression in all the tested cell lines. Western blot illustrated the highest protein level of MT1 in IOSE 364 and the lowest in the OVCAR-3. The results indicate the limited prognostic significance of MT1 in OC cells. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Melatonin as a Signaling Molecule for Metabolism Regulation in Response to Hypoxia in the Crab Neohelice granulata
Int. J. Mol. Sci. 2014, 15(12), 22405-22420; doi:10.3390/ijms151222405
Received: 31 July 2014 / Revised: 1 November 2014 / Accepted: 4 November 2014 / Published: 4 December 2014
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Abstract
Melatonin has been identified in a variety of crustacean species, but its function is not as well understood as in vertebrates. The present study investigates whether melatonin has an effect on crustacean hyperglycemic hormone (CHH) gene expression, oxygen consumption (VO2) [...] Read more.
Melatonin has been identified in a variety of crustacean species, but its function is not as well understood as in vertebrates. The present study investigates whether melatonin has an effect on crustacean hyperglycemic hormone (CHH) gene expression, oxygen consumption (VO2) and circulating glucose and lactate levels, in response to different dissolved-oxygen concentrations, in the crab Neohelice granulata, as well as whether these possible effects are eyestalk- or receptor-dependent. Melatonin decreased CHH expression in crabs exposed for 45 min to 6 (2, 200 or 20,000 pmol·crab−1) or 2 mgO2·L−1 (200 pmol·crab−1). Since luzindole (200 nmol·crab−1) did not significantly (p > 0.05) alter the melatonin effect, its action does not seem to be mediated by vertebrate-typical MT1 and MT2 receptors. Melatonin (200 pmol·crab−1) increased the levels of glucose and lactate in crabs exposed to 6 mgO2·L−1, and luzindole (200 nmol·crab−1) decreased this effect, indicating that melatonin receptors are involved in hyperglycemia and lactemia. Melatonin showed no effect on VO2. Interestingly, in vitro incubation of eyestalk ganglia for 45 min at 0.7 mgO2·L−1 significantly (p < 0.05) increased melatonin production in this organ. In addition, injections of melatonin significantly increased the levels of circulating melatonin in crabs exposed for 45 min to 6 (200 or 20,000 pmol·crab−1), 2 (200 and 20,000 pmol·crab−1) and 0.7 (200 or 20,000 pmol·crab−1) mgO2·L−1. Therefore, melatonin seems to have an effect on the metabolism of N. granulata. This molecule inhibited the gene expression of CHH and caused an eyestalk- and receptor-dependent hyperglycemia, which suggests that melatonin may have a signaling role in metabolic regulation in this crab. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Melatonin-Induced Temporal Up-Regulation of Gene Expression Related to Ubiquitin/Proteasome System (UPS) in the Human Malaria Parasite Plasmodium falciparum
Int. J. Mol. Sci. 2014, 15(12), 22320-22330; doi:10.3390/ijms151222320
Received: 25 August 2014 / Revised: 11 September 2014 / Accepted: 16 October 2014 / Published: 3 December 2014
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Abstract
There is an increasing understanding that melatonin and the ubiquitin/ proteasome system (UPS) interact to regulate multiple cellular functions. Post-translational modifications such as ubiquitination are important modulators of signaling processes, cell cycle and many other cellular functions. Previously, we reported a melatonin-induced [...] Read more.
There is an increasing understanding that melatonin and the ubiquitin/ proteasome system (UPS) interact to regulate multiple cellular functions. Post-translational modifications such as ubiquitination are important modulators of signaling processes, cell cycle and many other cellular functions. Previously, we reported a melatonin-induced upregulation of gene expression related to ubiquitin/proteasome system (UPS) in Plasmodium falciparum, the human malaria parasite, and that P. falciparum protein kinase 7 influences this process. This implies a role of melatonin, an indolamine, in modulating intraerythrocytic development of the parasite. In this report we demonstrate by qPCR analysis, that melatonin induces gene upregulation in nine out of fourteen genes of the UPS, consisting of the same set of genes previously reported, between 4 to 5 h after melatonin treatment. We demonstrate that melatonin causes a temporally controlled gene expression of UPS members. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
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Open AccessArticle Effects of Melatonin on the Proliferation and Apoptosis of Sheep Granulosa Cells under Thermal Stress
Int. J. Mol. Sci. 2014, 15(11), 21090-21104; doi:10.3390/ijms151121090
Received: 30 July 2014 / Revised: 3 November 2014 / Accepted: 3 November 2014 / Published: 14 November 2014
Cited by 4 | PDF Full-text (1401 KB) | HTML Full-text | XML Full-text
Abstract
The cross-talk between oocyte and somatic cells plays a crucial role in the regulation of follicular development and oocyte maturation. As a result, granulosa cell apoptosis causes follicular atresia. In this study, sheep granulosa cells were cultured under thermal stress to induce [...] Read more.
The cross-talk between oocyte and somatic cells plays a crucial role in the regulation of follicular development and oocyte maturation. As a result, granulosa cell apoptosis causes follicular atresia. In this study, sheep granulosa cells were cultured under thermal stress to induce apoptosis, and melatonin (MT) was examined to evaluate its potential effects on heat-induced granulosa cell injury. The results demonstrated that the Colony Forming Efficiency (CFE) of granulosa cells was significantly decreased (heat 19.70% ± 1.29% vs. control 26.96% ± 1.81%, p < 0.05) and the apoptosis rate was significantly increased (heat 56.16% ± 13.95% vs. control 22.80% ± 12.16%, p < 0.05) in granulosa cells with thermal stress compared with the control group. Melatonin (10−7 M) remarkably reduced the negative effects caused by thermal stress in the granulosa cells. This reduction was indicated by the improved CFE and decreased apoptotic rate of these cells. The beneficial effects of melatonin on thermal stressed granulosa cells were not inhibited by its membrane receptor antagonist luzindole. A mechanistic exploration indicated that melatonin (10−7 M) down-regulated p53 and up-regulated Bcl-2 and LHR gene expression of granulosa cells under thermal stress. This study provides evidence for the molecular mechanisms of the protective effects of melatonin on granulosa cells during thermal stress. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Distinct Expression Profiles of Three Melatonin Receptors during Early Development and Metamorphosis in the Flatfish Solea senegalensis
Int. J. Mol. Sci. 2014, 15(11), 20789-20799; doi:10.3390/ijms151120789
Received: 29 July 2014 / Revised: 31 October 2014 / Accepted: 3 November 2014 / Published: 13 November 2014
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Abstract
Melatonin actions are mediated through G protein-coupled transmembrane receptors. Recently, mt1, mt2, and mel1c melatonin receptors were cloned in the Senegalese sole. Here, their day-night and developmental expressions were analyzed by quantitative PCR. These results revealed distinct expression patterns of [...] Read more.
Melatonin actions are mediated through G protein-coupled transmembrane receptors. Recently, mt1, mt2, and mel1c melatonin receptors were cloned in the Senegalese sole. Here, their day-night and developmental expressions were analyzed by quantitative PCR. These results revealed distinct expression patterns of each receptor through development. mel1c transcripts were more abundant in unfertilized ovulated oocytes and declined during embryonic development. mt1 and mt2 expression was higher at the earliest stages (2–6 days post-fertilization), decreasing before (mt2) or during (mt1) metamorphosis. Only mt1 and mel1c expression exhibited day-night variations, with higher nocturnal mRNA levels. These results suggest different roles and transcriptional regulation of these melatonin receptors during flatfish development and metamorphosis. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Melatonin Attenuates Intermittent Hypoxia-Induced Lipid Peroxidation and Local Inflammation in Rat Adrenal Medulla
Int. J. Mol. Sci. 2014, 15(10), 18437-18452; doi:10.3390/ijms151018437
Received: 15 July 2014 / Revised: 26 September 2014 / Accepted: 2 October 2014 / Published: 13 October 2014
Cited by 1 | PDF Full-text (4700 KB) | HTML Full-text | XML Full-text
Abstract
Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested [...] Read more.
Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague–Dawley rats were exposed to air (normoxic control) or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg) or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD)-1 and SOD-2) were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) and mediators (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Effect of Melatonin on Human Dental Papilla Cells
Int. J. Mol. Sci. 2014, 15(10), 17304-17317; doi:10.3390/ijms151017304
Received: 23 July 2014 / Revised: 10 September 2014 / Accepted: 11 September 2014 / Published: 26 September 2014
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Abstract
Melatonin regulates a variety of biological processes, which are the control of circadian rhythms, regulation of seasonal reproductive function and body temperature, free radical scavenging and so on. Our previous studies have shown that various cells exist in human and mouse tooth [...] Read more.
Melatonin regulates a variety of biological processes, which are the control of circadian rhythms, regulation of seasonal reproductive function and body temperature, free radical scavenging and so on. Our previous studies have shown that various cells exist in human and mouse tooth germs that express the melatonin 1a receptor (Mel1aR). However, little is known about the effects of melatonin on tooth development and growth. The present study was performed to examine the possibility that melatonin might exert its influence on tooth development. DP-805 cells, a human dental papilla cell line, were shown to express Mel1aR. Expression levels of mRNA for Mel1aR in DP-805 cells increased until 3 days after reaching confluence and decreased thereafter. Real-time reverse transcription-polymerase chain reaction showed that melatonin increased the expression of mRNAs for osteopontin (OPN), osteocalcin (OCN), bone sialoprotein (BSP), dentin matrix protein-1 (DMP-1) and dentin sialophosphoprotin (DSPP). Melatonin also enhanced the mineralized matrix formation in DP-805 cell cultures in a dose-dependent manner. These results strongly suggest that melatonin may play a physiological role in tooth development/growth by regulating the cellular function of odontogenic cells in tooth germs. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Abnormal Response of the Proliferation and Differentiation of Growth Plate Chondrocytes to Melatonin in Adolescent Idiopathic Scoliosis
Int. J. Mol. Sci. 2014, 15(9), 17100-17114; doi:10.3390/ijms150917100
Received: 31 July 2014 / Revised: 2 September 2014 / Accepted: 19 September 2014 / Published: 25 September 2014
Cited by 4 | PDF Full-text (546 KB) | HTML Full-text | XML Full-text
Abstract
Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. [...] Read more.
Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects. Although the MT2 receptor was identified in GPCs from both AIS and controls, its mRNA expression was significantly lower in AIS patients than the controls. GPCs were cultured in the presence of either the vehicle or various concentrations of melatonin, with or without the selective MT2 melatonin receptor antagonist 4-P-PDOT (10 µM). Then the cell viability and the mRNA expression of collagen type X (COLX) and alkaline phosphatase (ALP) were assessed by MTT and qPCR, respectively. In the control GPCs, melatonin at the concentrations of 1, 100 nM and 10 µM significantly reduced the population of viable cells, and the mRNA level of COLX and ALP compared to the vehicle. Similar changes were not observed in the presence of 4-P-PDOT. Further, neither proliferation nor differentiation of GPCs from AIS patients was affected by the melatonin treatment. These findings support the presence of a functional abnormality of the melatonin signaling pathway in AIS GPCs, which might be associated with the abnormal endochondral ossification in AIS patients. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Methylphenidate Ameliorates Depressive Comorbidity in ADHD Children without any Modification on Differences in Serum Melatonin Concentration between ADHD Subtypes
Int. J. Mol. Sci. 2014, 15(9), 17115-17129; doi:10.3390/ijms150917115
Received: 1 August 2014 / Revised: 15 September 2014 / Accepted: 17 September 2014 / Published: 25 September 2014
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Abstract
The vast majority of Attention-deficit/hyperactivity disorder (ADHD) patients have other associated pathologies, with depressive symptoms as one of the most prevalent. Among the mediators that may participate in ADHD, melatonin is thought to regulate circadian rhythms, neurological function and stress response. To [...] Read more.
The vast majority of Attention-deficit/hyperactivity disorder (ADHD) patients have other associated pathologies, with depressive symptoms as one of the most prevalent. Among the mediators that may participate in ADHD, melatonin is thought to regulate circadian rhythms, neurological function and stress response. To determine (1) the serum baseline daily variations and nocturnal excretion of melatonin in ADHD subtypes and (2) the effect of chronic administration of methylphenidate, as well as the effects on symptomatology, 136 children with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: DSM-IV-TR criteria) were divided into subgroups using the “Children’s Depression Inventory” (CDI). Blood samples were drawn at 20:00 and 09:00 h, and urine was collected between 21:00 and 09:00 h, at inclusion and after 4.61 ± 2.29 months of treatment. Melatonin and its urine metabolite were measured by radioimmunoassay RIA. Factorial analysis was performed using STATA 12.0. Melatonin was higher predominantly in hyperactive-impulsive/conduct disordered children (PHI/CD) of the ADHD subtype, without the influence of comorbid depressive symptoms. Methylphenidate ameliorated this comorbidity without induction of any changes in the serum melatonin profile, but treatment with it was associated with a decrease in 6-s-melatonin excretion in both ADHD subtypes. Conclusions: In untreated children, partial homeostatic restoration of disrupted neuroendocrine equilibrium most likely led to an increased serum melatonin in PHI/CD children. A differential cerebral melatonin metabolization after methylphenidate may underlie some of the clinical benefit. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Synthesis and Characterization of New Bivalent Agents as Melatonin- and Histamine H3-Ligands
Int. J. Mol. Sci. 2014, 15(9), 16114-16133; doi:10.3390/ijms150916114
Received: 1 August 2014 / Revised: 3 September 2014 / Accepted: 4 September 2014 / Published: 12 September 2014
Cited by 2 | PDF Full-text (1567 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is an endogenous molecule involved in many pathophysiological processes. In addition to the control of circadian rhythms, its antioxidant and neuroprotective properties have been widely described. Thus far, different bivalent compounds composed by a melatonin molecule linked to another neuroprotective agent [...] Read more.
Melatonin is an endogenous molecule involved in many pathophysiological processes. In addition to the control of circadian rhythms, its antioxidant and neuroprotective properties have been widely described. Thus far, different bivalent compounds composed by a melatonin molecule linked to another neuroprotective agent were synthesized and tested for their ability to block neurodegenerative processes in vitro and in vivo. To identify a novel class of potential neuroprotective compounds, we prepared a series of bivalent ligands, in which a prototypic melatonergic ligand is connected to an imidazole-based H3 receptor antagonist through a flexible linker. Four imidazolyl-alkyloxy-anilinoethylamide derivatives, characterized by linkers of different length, were synthesized and their binding affinity for human MT1, MT2 and H3 receptor subtypes was evaluated. Among the tested compounds, 14c and 14d, bearing a pentyl and a hexyl linker, respectively, were able to bind to all receptor subtypes at micromolar concentrations and represent the first bivalent melatonergic/histaminergic ligands reported so far. These preliminary results, based on binding affinity evaluation, pave the way for the future development of new dual-acting compounds targeting both melatonin and histamine receptors, which could represent promising therapeutic agents for the treatment of neurodegenerative pathologies. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
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Open AccessArticle Melatonin Suppresses Hypoxia-Induced Migration of HUVECs via Inhibition of ERK/Rac1 Activation
Int. J. Mol. Sci. 2014, 15(8), 14102-14121; doi:10.3390/ijms150814102
Received: 5 April 2014 / Revised: 31 July 2014 / Accepted: 7 August 2014 / Published: 13 August 2014
Cited by 4 | PDF Full-text (3673 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved [...] Read more.
Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Diurnal Profiles of Melatonin Synthesis-Related Indoles, Catecholamines and Their Metabolites in the Duck Pineal Organ
Int. J. Mol. Sci. 2014, 15(7), 12604-12630; doi:10.3390/ijms150712604
Received: 5 June 2014 / Revised: 1 July 2014 / Accepted: 3 July 2014 / Published: 16 July 2014
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Abstract
This study characterizes the diurnal profiles of ten melatonin synthesis-related indoles, the quantitative relations between these compounds, and daily variations in the contents of catecholamines and their metabolites in the domestic duck pineal organ. Fourteen-week-old birds, which were reared under a 12L:12D [...] Read more.
This study characterizes the diurnal profiles of ten melatonin synthesis-related indoles, the quantitative relations between these compounds, and daily variations in the contents of catecholamines and their metabolites in the domestic duck pineal organ. Fourteen-week-old birds, which were reared under a 12L:12D cycle, were killed at two-hour intervals. The indole contents were measured using HPLC with fluorescence detection, whereas the levels of catecholamines and their metabolites were measured using HPLC with electrochemical detection. All indole contents, except for tryptophan, showed significant diurnal variations. The 5-hydroxytryptophan level was approximately two-fold higher during the scotophase than during the photophase. The serotonin content increased during the first half of the photophase, remained elevated for approximately 10 h and then rapidly decreased in the middle of the scotophase. N-acetylserotonin showed the most prominent changes, with a more than 15-fold increase at night. The melatonin cycle demonstrated only an approximately 5-fold difference between the peak and nadir. The 5-methoxytryptamine content was markedly elevated during the scotophase. The 5-hydroxyindole acetic acid, 5-hydroxytryptophol, 5-methoxyindole acetic acid and 5-methoxytryptophol profiles were analogous to the serotonin rhythm. The norepinephrine and dopamine contents showed no significant changes. The DOPA, DOPAC and homovanillic acid levels were higher during the scotophase than during the photophase. Vanillylmandelic acid showed the opposite rhythm, with an elevated level during the daytime. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
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Open AccessArticle Melatonin Promotes Superovulation in Sika Deer (Cervus nippon)
Int. J. Mol. Sci. 2014, 15(7), 12107-12118; doi:10.3390/ijms150712107
Received: 21 May 2014 / Revised: 19 June 2014 / Accepted: 30 June 2014 / Published: 8 July 2014
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Abstract
In this study, the effects of melatonin (MT) on superovulation and reproductive hormones (melatonin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and PRL) were investigated in female sika deer. Different doses (40 or 80 mg/animal) of melatonin were subcutaneously implanted into deer before [...] Read more.
In this study, the effects of melatonin (MT) on superovulation and reproductive hormones (melatonin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and PRL) were investigated in female sika deer. Different doses (40 or 80 mg/animal) of melatonin were subcutaneously implanted into deer before the breeding season. Exogenous melatonin administration significantly elevated the serum FSH levels at the time of insemination compared with levels in control animals. During superovulation, the serum LH levels in donor sika deer reached their highest values (7.1 ± 2.04 ng/mL) at the point of insemination, compared with the baseline levels (4.98 ± 0.07 ng/mL) in control animals. This high level of LH was sustained until the day of embryo recovery. In contrast, the serum levels of PRL in the 80 mg of melatonin-treated group were significantly lower than those of control deer. The average number of corpora lutea in melatonin-treated deer was significantly higher than that of the control (p < 0.05). The average number of embryos in the deer treated with 40 mg of melatonin was higher than that of the control; however, this increase did not reach significant difference (p > 0.05), which may be related to the relatively small sample size. In addition, embryonic development in melatonin-treated groups was delayed. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessArticle Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin
Int. J. Mol. Sci. 2014, 15(7), 11941-11956; doi:10.3390/ijms150711941
Received: 7 May 2014 / Revised: 13 June 2014 / Accepted: 18 June 2014 / Published: 4 July 2014
Cited by 5 | PDF Full-text (1637 KB) | HTML Full-text | XML Full-text
Abstract
A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand [...] Read more.
A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell apoptosis under hypoxic conditions. Melatonin inhibits cell proliferation in many cancer types and induces apoptosis in some particular cancer types. Here, we examined the effects of melatonin on hypoxic resistant cells against TRAIL-induced apoptosis and the possible mechanisms of melatonin in the hypoxic response. Melatonin treatment increased TRAIL-induced A549 cell death under hypoxic conditions, although hypoxia inhibited TRAIL-mediated cell apoptosis. In a mechanistic study, hypoxia inducible factor-1α and prolyl-hydroxylase 2 proteins, which increase following exposure to hypoxia, were dose-dependently down-regulated by melatonin treatment. Melatonin also blocked the hypoxic responses that reduced pro-apoptotic proteins and increased anti-apoptotic proteins including Bcl-2 and Bcl-xL. Furthermore, melatonin treatment reduced TRAIL resistance by regulating the mitochondrial transmembrane potential and Bax translocation. Our results first demonstrated that melatonin treatment induces apoptosis in TRAIL-resistant hypoxic tumor cells by diminishing the anti-apoptotic signals mediated by hypoxia and also suggest that melatonin could be a tumor therapeutic tool by combining with other apoptotic ligands including TRAIL, particularly in solid tumor cells exposed to hypoxia. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

Review

Jump to: Research, Other

Open AccessReview Agomelatine beyond Borders: Current Evidences of Its Efficacy in Disorders Other than Major Depression
Int. J. Mol. Sci. 2015, 16(1), 1111-1130; doi:10.3390/ijms16011111
Received: 31 July 2014 / Accepted: 23 December 2014 / Published: 5 January 2015
Cited by 7 | PDF Full-text (722 KB) | HTML Full-text | XML Full-text
Abstract
Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine’s antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic [...] Read more.
Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine’s antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Protecting the Melatonin Rhythm through Circadian Healthy Light Exposure
Int. J. Mol. Sci. 2014, 15(12), 23448-23500; doi:10.3390/ijms151223448
Received: 3 September 2014 / Revised: 2 November 2014 / Accepted: 9 November 2014 / Published: 17 December 2014
Cited by 5 | PDF Full-text (3393 KB) | HTML Full-text | XML Full-text
Abstract
Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay [...] Read more.
Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Transcriptional Regulation of Programmed Hypertension by Melatonin: An Epigenetic Perspective
Int. J. Mol. Sci. 2014, 15(10), 18484-18495; doi:10.3390/ijms151018484
Received: 13 July 2014 / Revised: 4 September 2014 / Accepted: 25 September 2014 / Published: 14 October 2014
Cited by 5 | PDF Full-text (679 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is an endogenously produced indoleamine and secreted by the pineal gland. Melatonin has pleiotropic bioactivities and is involved in epigenetic regulation. Suboptimal conditions during maternal and perinatal phases can elicit epigenetic regulation of genes for nephrogenesis and reset physiological responses to [...] Read more.
Melatonin is an endogenously produced indoleamine and secreted by the pineal gland. Melatonin has pleiotropic bioactivities and is involved in epigenetic regulation. Suboptimal conditions during maternal and perinatal phases can elicit epigenetic regulation of genes for nephrogenesis and reset physiological responses to develop programmed hypertension. This review discusses the early utility of melatonin to prevent programmed hypertension in later life by epigenetic regulation in the kidney, with an emphasis on: (1) the role of melatonin in epigenetic regulation; (2) the beneficial effects of melatonin on programmed hypertension; (3) epigenetic regulation of maternal melatonin therapy in different developmental windows of offspring kidneys analyzed by whole-genome RNA next-generation sequencing; and (4) current blocks in the application of melatonin in preventing programmed hypertension. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Melatonin, Noncoding RNAs, Messenger RNA Stability and Epigenetics—Evidence, Hints, Gaps and Perspectives
Int. J. Mol. Sci. 2014, 15(10), 18221-18252; doi:10.3390/ijms151018221
Received: 23 April 2014 / Revised: 21 September 2014 / Accepted: 24 September 2014 / Published: 10 October 2014
Cited by 5 | PDF Full-text (850 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is a highly pleiotropic regulator molecule, which influences numerous functions in almost every organ and, thus, up- or down-regulates many genes, frequently in a circadian manner. Our understanding of the mechanisms controlling gene expression is actually now expanding to a previously [...] Read more.
Melatonin is a highly pleiotropic regulator molecule, which influences numerous functions in almost every organ and, thus, up- or down-regulates many genes, frequently in a circadian manner. Our understanding of the mechanisms controlling gene expression is actually now expanding to a previously unforeseen extent. In addition to classic actions of transcription factors, gene expression is induced, suppressed or modulated by a number of RNAs and proteins, such as miRNAs, lncRNAs, piRNAs, antisense transcripts, deadenylases, DNA methyltransferases, histone methylation complexes, histone demethylases, histone acetyltransferases and histone deacetylases. Direct or indirect evidence for involvement of melatonin in this network of players has originated in different fields, including studies on central and peripheral circadian oscillators, shift work, cancer, inflammation, oxidative stress, aging, energy expenditure/obesity, diabetes type 2, neuropsychiatric disorders, and neurogenesis. Some of the novel modulators have also been shown to participate in the control of melatonin biosynthesis and melatonin receptor expression. Future work will need to augment the body of evidence on direct epigenetic actions of melatonin and to systematically investigate its role within the network of oscillating epigenetic factors. Moreover, it will be necessary to discriminate between effects observed under conditions of well-operating and deregulated circadian clocks, and to explore the possibilities of correcting epigenetic malprogramming by melatonin. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Peripheral and Central Effects of Melatonin on Blood Pressure Regulation
Int. J. Mol. Sci. 2014, 15(10), 17920-17937; doi:10.3390/ijms151017920
Received: 3 July 2014 / Revised: 17 September 2014 / Accepted: 17 September 2014 / Published: 8 October 2014
Cited by 15 | PDF Full-text (700 KB) | HTML Full-text | XML Full-text
Abstract
The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled [...] Read more.
The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Local Melatoninergic System as the Protector of Skin Integrity
Int. J. Mol. Sci. 2014, 15(10), 17705-17732; doi:10.3390/ijms151017705
Received: 15 August 2014 / Revised: 9 September 2014 / Accepted: 16 September 2014 / Published: 30 September 2014
Cited by 24 | PDF Full-text (4397 KB) | HTML Full-text | XML Full-text
Abstract
The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin [...] Read more.
The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a “guardian” of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Melatonin Regulates Aging and Neurodegeneration through Energy Metabolism, Epigenetics, Autophagy and Circadian Rhythm Pathways
Int. J. Mol. Sci. 2014, 15(9), 16848-16884; doi:10.3390/ijms150916848
Received: 25 July 2014 / Revised: 3 September 2014 / Accepted: 12 September 2014 / Published: 22 September 2014
Cited by 19 | PDF Full-text (1065 KB) | HTML Full-text | XML Full-text
Abstract
Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor [...] Read more.
Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview A Review of Pinealectomy-Induced Melatonin-Deficient Animal Models for the Study of Etiopathogenesis of Adolescent Idiopathic Scoliosis
Int. J. Mol. Sci. 2014, 15(9), 16484-16499; doi:10.3390/ijms150916484
Received: 23 July 2014 / Revised: 8 September 2014 / Accepted: 10 September 2014 / Published: 18 September 2014
Cited by 1 | PDF Full-text (1536 KB) | HTML Full-text | XML Full-text
Abstract
Adolescent idiopathic scoliosis (AIS) is a common orthopedic disorder of unknown etiology and pathogenesis. Melatonin and melatonin pathway dysfunction has been widely suspected to play an important role in the pathogenesis. Many different types of animal models have been developed to induce [...] Read more.
Adolescent idiopathic scoliosis (AIS) is a common orthopedic disorder of unknown etiology and pathogenesis. Melatonin and melatonin pathway dysfunction has been widely suspected to play an important role in the pathogenesis. Many different types of animal models have been developed to induce experimental scoliosis mimicking the pathoanatomical features of idiopathic scoliosis in human. The scoliosis deformity was believed to be induced by pinealectomy and mediated through the resulting melatonin-deficiency. However, the lack of upright mechanical spinal loading and inherent rotational instability of the curvature render the similarity of these models to the human counterparts questionable. Different concerns have been raised challenging the scientific validity and limitations of each model. The objectives of this review follow the logical need to re-examine and compare the relevance and appropriateness of each of the animal models that have been used for studying the etiopathogenesis of adolescent idiopathic scoliosis in human in the past 15 to 20 years. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Fundamental Issues Related to the Origin of Melatonin and Melatonin Isomers during Evolution: Relation to Their Biological Functions
Int. J. Mol. Sci. 2014, 15(9), 15858-15890; doi:10.3390/ijms150915858
Received: 11 July 2014 / Revised: 15 August 2014 / Accepted: 27 August 2014 / Published: 9 September 2014
Cited by 22 | PDF Full-text (1107 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin and melatonin isomers exist and/or coexist in living organisms including yeasts, bacteria and plants. The levels of melatonin isomers are significantly higher than that of melatonin in some plants and in several fermented products such as in wine and bread. Currently, [...] Read more.
Melatonin and melatonin isomers exist and/or coexist in living organisms including yeasts, bacteria and plants. The levels of melatonin isomers are significantly higher than that of melatonin in some plants and in several fermented products such as in wine and bread. Currently, there are no reports documenting the presence of melatonin isomers in vertebrates. From an evolutionary point of view, it is unlikely that melatonin isomers do not exist in vertebrates. On the other hand, large quantities of the microbial flora exist in the gut of the vertebrates. These microorganisms frequently exchange materials with the host. Melatonin isomers, which are produced by these organisms inevitably enter the host’s system. The origins of melatonin and its isomers can be traced back to photosynthetic bacteria and other primitive unicellular organisms. Since some of these bacteria are believed to be the precursors of mitochondria and chloroplasts these cellular organelles may be the primary sites of melatonin production in animals or in plants, respectively. Phylogenic analysis based on its rate-limiting synthetic enzyme, serotonin N-acetyltransferase (SNAT), indicates its multiple origins during evolution. Therefore, it is likely that melatonin and its isomer are also present in the domain of archaea, which perhaps require these molecules to protect them against hostile environments including extremely high or low temperature. Evidence indicates that the initial and primary function of melatonin and its isomers was to serve as the first-line of defence against oxidative stress and all other functions were acquired during evolution either by the process of adoption or by the extension of its antioxidative capacity. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Therapeutic Effects of Melatonin Receptor Agonists on Sleep and Comorbid Disorders
Int. J. Mol. Sci. 2014, 15(9), 15924-15950; doi:10.3390/ijms150915924
Received: 21 July 2014 / Revised: 20 August 2014 / Accepted: 27 August 2014 / Published: 9 September 2014
Cited by 9 | PDF Full-text (722 KB) | HTML Full-text | XML Full-text
Abstract
Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. [...] Read more.
Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
Open AccessReview Melatonin and Atopy: Role in Atopic Dermatitis and Asthma
Int. J. Mol. Sci. 2014, 15(8), 13482-13493; doi:10.3390/ijms150813482
Received: 26 June 2014 / Revised: 22 July 2014 / Accepted: 22 July 2014 / Published: 4 August 2014
Cited by 8 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme [...] Read more.
Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme activities in several inflammatory diseases. Many skin disorders, including atopic dermatitis, are accompanied by infiltration and activation of mast cells, which release vasoactive and proinflammatory mediators. Experimental data suggest that melatonin inhibits development of atopic eczema and reduces serum total IgE and IL-4. Allergic asthma is a condition characterized by bronchial hyperresponsiveness and the presence of IgE antibodies in response to inhaled allergens; often there is also enhanced total serum IgE levels. Melatonin regulates smooth muscle tone and influences the immune response. Melatonin may, however, act as a pro-inflammatory agent in asthma leading to bronchial constriction. The safety of melatonin as a sleep-inducing agent has been confirmed in asthmatic subjects, but its routine use is not recommended in bronchial asthma. This review summarizes what is known about the role of melatonin as an immunomodulatory agent in asthma and atopic eczema. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

Other

Jump to: Research, Review

Open AccessHypothesis Cancer Stem Cell Theory and the Warburg Effect, Two Sides of the Same Coin?
Int. J. Mol. Sci. 2014, 15(5), 8893-8930; doi:10.3390/ijms15058893
Received: 23 March 2014 / Revised: 28 April 2014 / Accepted: 12 May 2014 / Published: 19 May 2014
Cited by 11 | PDF Full-text (596 KB) | HTML Full-text | XML Full-text
Abstract
Over the last 100 years, many studies have been performed to determine the biochemical and histopathological phenomena that mark the origin of neoplasms. At the end of the last century, the leading paradigm, which is currently well rooted, considered the origin of [...] Read more.
Over the last 100 years, many studies have been performed to determine the biochemical and histopathological phenomena that mark the origin of neoplasms. At the end of the last century, the leading paradigm, which is currently well rooted, considered the origin of neoplasms to be a set of genetic and/or epigenetic mutations, stochastic and independent in a single cell, or rather, a stochastic monoclonal pattern. However, in the last 20 years, two important areas of research have underlined numerous limitations and incongruities of this pattern, the hypothesis of the so-called cancer stem cell theory and a revaluation of several alterations in metabolic networks that are typical of the neoplastic cell, the so-called Warburg effect. Even if this specific “metabolic sign” has been known for more than 85 years, only in the last few years has it been given more attention; therefore, the so-called Warburg hypothesis has been used in multiple and independent surveys. Based on an accurate analysis of a series of considerations and of biophysical thermodynamic events in the literature, we will demonstrate a homogeneous pattern of the cancer stem cell theory, of the Warburg hypothesis and of the stochastic monoclonal pattern; this pattern could contribute considerably as the first basis of the development of a new uniform theory on the origin of neoplasms. Thus, a new possible epistemological paradigm is represented; this paradigm considers the Warburg effect as a specific “metabolic sign” reflecting the stem origin of the neoplastic cell, where, in this specific metabolic order, an essential reason for the genetic instability that is intrinsic to the neoplastic cell is defined. Full article
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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