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Melatonin in Disease and Health

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 69837

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Prof. Dr. Rita Rezzani

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Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
Interests: antioxidants; sex differences; skin; melatonin; oxidative stress and cancer
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Special Issue Information

Dear Colleagues,

Neurodegeneration, cancer, and cardiovascular diseases will be some of the main hot topics for the health care of the future.

Even more, it will be particularly important to consider the fine, basic mechanisms underlying the chronic dysfunctions towards which the human body gradually moves during the lifespan. In this regard, there are many recently published studies that emphasize the involvement of common general alterations (e.g., oxidative stress, inflammation, angiogenesis, and endothelial function and dysfunction) in the pathogenesis of most chronic diseases. Another point to consider is the progressive aging of the population and the associated increasing number of comorbidities. In this sense, it becomes fundamental to find a therapeutic and/or supplementation strategy that does not weigh on the already compromised functionality of organs and systems.

In this complex context, melatonin (N-acetyl-5-methoxytryptamine) has begun to be and remains the focus of new research works. As a small molecule that is ubiquitously present in all organisms, from cyanobacteria to humans, it has been investigated for its peculiar nocturne production and its role in the regulation of circadian rhythms. It is now recognized for its pleiotropic activity.

Overall, its biosynthesis starts after the uptake of tryptophan by cells; specifically, this essential amino acid is converted to 5-hydroxytryptophan and then to 5-hydroxytryptamine (serotonin) and, ultimately, to melatonin. When it is released in the bloodstream, melatonin regulates physiological functions like circadian rhythm, sleep–wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune modulation, and anticancer effects in the body. On the contrary, it is known that a decrease in melatonin secretion is related to the aging process and leads to tumorigenesis and visceral adiposity.

All these activities are carried out in two different ways: as an amphiphilic molecule, melatonin directly interacts with the intracellular components, but it also acts indirectly through the membrane receptors which are widely distributed in all eukaryotic cells.

Papers dealing with any aspects of melatonin in human health and disease, with special attention paid to new experimental therapeutic applications, will be considered for this Special Issue.

Prof. Dr. Rita Rezzani
Guest Editor

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Keywords

health and pathology
oxidative stress and inflammation
endothelial dysfunction
aging and cancer
skin diseases
neurodegenerative and cardiovascular diseases
metabolic syndromes
sex/gender dimorphism

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Related Special Issue

Melatonin in Disease and Health 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (9 papers)

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Research

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14 pages, 1867 KiB

Open AccessArticle

Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats

by Karsten Peters, David Dahlgren, Péter Pál Egerszegi, Hans Lennernäs and Markus Sjöblom

Int. J. Mol. Sci. 2022, 23(6), 2912; https://doi.org/10.3390/ijms23062912 - 8 Mar 2022

Cited by 4 | Viewed by 2417

Abstract

Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of ⁵¹Cr-labeled EDTA in response to luminal SDS as well as a histological evaluation of the exposed tissue. Melatonin at both 10 and 100 µM reduced SDS-induced increase in permeability by 50%. Misoprostol at 1 and 10 µM reduced the permeability by 50 and 75%, respectively. Combination of the two drugs at their respective highest concentrations had no additive protective effect. These in vivo results support further investigations of melatonin and misoprostol for oral treatments of a dysfunctional intestinal barrier. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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11 pages, 2947 KiB

Open AccessArticle

Topical Melatonin Exerts Immunomodulatory Effect and Improves Dermatitis Severity in a Mouse Model of Atopic Dermatitis

by Yung-Sen Chang, Chih-Chen Tsai, Pang-Yan Yang, Chih-Yu Tang and Bor-Luen Chiang

Int. J. Mol. Sci. 2022, 23(3), 1373; https://doi.org/10.3390/ijms23031373 - 25 Jan 2022

Cited by 9 | Viewed by 3720

Abstract

Oral melatonin supplement has been shown to improve dermatitis severity in children with AD, but the mechanism of the effect is unclear, and it is uncertain whether melatonin has a direct immunomodulatory effect on the dermatitis. Topical melatonin treatment was applied to DNCB-stimulated Balb/c mice, and gross and pathological skin findings, serum IgE, and cytokine levels in superficial lymph nodes were analyzed. Secretion of chemokines and cell proliferative response after melatonin treatment in human keratinocyte HaCaT cells were also studied. We found that in DNCB-stimulated Balb/c mice, topical melatonin treatment improved gross dermatitis severity, reduced epidermal hyperplasia and lymphocyte infiltration in the skin, and decreased IP-10, CCL27, IL-4, and IL-17 levels in superficial skin-draining lymph nodes. Melatonin also reduced cytokine-induced secretion of AD-related chemokines IP-10 and MCP-1 and decreased IL-4-induced cell proliferation in HaCaT cells. Melatonin seems to have an immunomodulatory effect on AD, with IP-10 as a possible target, and topical melatonin treatment is a potentially useful treatment for patients with AD. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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12 pages, 1295 KiB

Open AccessArticle

Melatonin-Activated Receptor Signaling Pathways Mediate Protective Effects on Surfactant-Induced Increase in Jejunal Mucosal Permeability in Rats

by Karsten Peters, David Dahlgren, Hans Lennernäs and Markus Sjöblom

Int. J. Mol. Sci. 2021, 22(19), 10762; https://doi.org/10.3390/ijms221910762 - 5 Oct 2021

Cited by 7 | Viewed by 2434

Abstract

A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants. Currently, there are no approved drugs targeting a dysfunctional intestinal barrier, which emphasizes a significant medical need. One candidate drug reported to regulate intestinal mucosal permeability is melatonin. However, it is still unclear if its effect is primarily receptor mediated or antioxidative, and if it is associated with enteric neural pathways. The aim of this rat intestinal perfusion study was to investigate the mechanisms of melatonin and nicotinic acetylcholine receptors on the increase in intestinal mucosal clearance of ⁵¹Cr-labeled ethylenediaminetetraacetate induced by 15 min luminal exposure to the anionic surfactant, sodium dodecyl sulfate. Our results show that melatonin abolished the surfactant-induced increase in intestinal permeability and that this effect was inhibited by luzindole, a melatonin receptor antagonist. In addition, mecamylamine, an antagonist of nicotinic acetylcholine receptors, reduced the surfactant-induced increase in mucosal permeability, using a signaling pathway not influenced by melatonin receptor activation. In conclusion, our results support melatonin as a potentially potent candidate for the oral treatment of a compromised intestinal mucosal barrier, and that its protective effect is primarily receptor-mediated. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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Review

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20 pages, 1321 KiB

Open AccessReview

Melatonin as the Cornerstone of Neuroimmunoendocrinology

by Igor Kvetnoy, Dmitry Ivanov, Ekaterina Mironova, Inna Evsyukova, Ruslan Nasyrov, Tatiana Kvetnaia and Victoria Polyakova

Int. J. Mol. Sci. 2022, 23(3), 1835; https://doi.org/10.3390/ijms23031835 - 6 Feb 2022

Cited by 40 | Viewed by 11764

Abstract

Much attention has been recently drawn to studying melatonin – a hormone whose synthesis was first found in the epiphysis (pineal gland). This interest can be due to discovering the role of melatonin in numerous physiological processes. It was the discovery of melatonin synthesis in endocrine organs (pineal gland), neural structures (Purkinje cells in the cerebellum, retinal photoreceptors), and immunocompetent cells (T lymphocytes, NK cells, mast cells) that triggered the evolution of new approaches to the unifield signal regulation of homeostasis, which, at the turn of the 21st century, lead to the creation of a new integral biomedical discipline — neuroimmunoendocrinology. While numerous hormones have been verified over the last decade outside the “classical” locations of their formation, melatonin occupies an exclusive position with regard to the diversity of locations where it is synthesized and secreted. This review provides an overview and discussion of the major data regarding the role of melatonin in various physiological and pathological processes, which affords grounds for considering melatonin as the “cornerstone” on which neuroimmunoendocrinology has been built as an integral concept of homeostasis regulation. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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23 pages, 3456 KiB

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Mechanisms of Melatonin in Obesity: A Review

by Qingyun Guan, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen

Int. J. Mol. Sci. 2022, 23(1), 218; https://doi.org/10.3390/ijms23010218 - 25 Dec 2021

Cited by 69 | Viewed by 10164

Abstract

Obesity and its complications have become a prominent global public health problem that severely threatens human health. Melatonin, originally known as an effective antioxidant, is an endogenous hormone found throughout the body that serves various physiological functions. In recent decades, increasing attention has been paid to its unique function in regulating energy metabolism, especially in glucose and lipid metabolism. Accumulating evidence has established the relationship between melatonin and obesity; nevertheless, not all preclinical and clinical evidence indicates the anti-obesity effect of melatonin, which makes it remain to conclude the clinical effect of melatonin in the fight against obesity. In this review, we have summarized the current knowledge of melatonin in regulating obesity-related symptoms, with emphasis on its underlying mechanisms. The role of melatonin in regulating the lipid profile, adipose tissue, oxidative stress, and inflammation, as well as the interactions of melatonin with the circadian rhythm, gut microbiota, sleep disorder, as well as the α7nAChR, the opioidergic system, and exosomes, make melatonin a promising agent to open new avenues in the intervention of obesity. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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14 pages, 667 KiB

Open AccessReview

Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders

by Adam Wichniak, Aleksander Kania, Mariusz Siemiński and Wiesław Jerzy Cubała

Int. J. Mol. Sci. 2021, 22(16), 8623; https://doi.org/10.3390/ijms22168623 - 11 Aug 2021

Cited by 24 | Viewed by 8091

Abstract

Melatonin is registered to treat circadian rhythm sleep–wake disorders and insomnia in patients aged 55 years and over. The essential role of the circadian sleep rhythm in the deterioration of sleep quality during COVID-19 confinement and the lack of an adverse effect of melatonin on respiratory drive indicate that melatonin has the potential to be a recommended treatment for sleep disturbances related to COVID-19. This review article describes the effects of melatonin additional to its sleep-related effects, which make this drug an attractive therapeutic option for treating patients with COVID-19. The preclinical data suggest that melatonin may inhibit COVID-19 progression. It may lower the risk of the entrance of the SARS-CoV-2 virus into cells, reduce uncontrolled hyper-inflammation and the activation of immune cells, limit the damage of tissues and multiorgan failure due to the action of free radicals, and reduce ventilator-induced lung injury and the risk of disability resulting from fibrotic changes within the lungs. Melatonin may also increase the efficacy of COVID-19 vaccination. The high safety profile of melatonin and its potential anti-SARS-CoV-2 effects make this molecule a preferable drug for treating sleep disturbances in COVID-19 patients. However, randomized clinical trials are needed to verify the clinical usefulness of melatonin in the treatment of COVID-19. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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21 pages, 1254 KiB

Open AccessReview

Melatonin and Myo-Inositol: Supporting Reproduction from the Oocyte to Birth

by Michele Russo, Gianpiero Forte, Mario Montanino Oliva, Antonio Simone Laganà and Vittorio Unfer

Int. J. Mol. Sci. 2021, 22(16), 8433; https://doi.org/10.3390/ijms22168433 - 5 Aug 2021

Cited by 28 | Viewed by 9674

Abstract

Human pregnancy is a sequence of events finely tuned by several molecular interactions that come with a new birth. The precise interlocking of these events affecting the reproductive system guarantees safe embryo formation and fetal development. In this scenario, melatonin and myo-inositol seem to be pivotal not only in the physiology of the reproduction process, but also in the promotion of positive gestational outcomes. Evidence demonstrates that melatonin, beyond the role of circadian rhythm management, is a key controller of human reproductive functions. Similarly, as the most representative member of the inositol’s family, myo-inositol is essential in ensuring correct advancing of reproductive cellular events. The molecular crosstalk mediated by these two species is directly regulated by their availability in the human body. To date, biological implications of unbalanced amounts of melatonin and myo-inositol in each pregnancy step are growing the idea that these molecules actively contribute to reduce negative outcomes and improve the fertilization rate. Clinical data suggest that melatonin and myo-inositol may constitute an optimal dietary supplementation to sustain safe human gestation and a new potential way to prevent pregnancy-associated pathologies. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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11 pages, 486 KiB

Open AccessReview

Melatonin, Its Beneficial Effects on Embryogenesis from Mitigating Oxidative Stress to Regulating Gene Expression

by Dmitry Ivanov, Gianluigi Mazzoccoli, George Anderson, Natalia Linkova, Anastasiia Dyatlova, Ekaterina Mironova, Victoria Polyakova, Igor Kvetnoy, Inna Evsyukova, Annalucia Carbone and Ruslan Nasyrov

Int. J. Mol. Sci. 2021, 22(11), 5885; https://doi.org/10.3390/ijms22115885 - 30 May 2021

Cited by 22 | Viewed by 6576

Abstract

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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40 pages, 6831 KiB

Open AccessReview

Thymus-Pineal Gland Axis: Revisiting Its Role in Human Life and Ageing

by Rita Rezzani, Caterina Franco, Rüdiger Hardeland and Luigi Fabrizio Rodella

Int. J. Mol. Sci. 2020, 21(22), 8806; https://doi.org/10.3390/ijms21228806 - 20 Nov 2020

Cited by 15 | Viewed by 13065

Abstract

For years the thymus gland (TG) and the pineal gland (PG) have been subject of increasingly in-depth studies, but only recently a link that can associate the activities of the two organs has been identified. Considering, on the one hand, the well-known immune activity of thymus and, on the other, the increasingly emerging immunological roles of circadian oscillators and the rhythmically secreted main pineal product, melatonin, many studies aimed to analyse the possible existence of an interaction between these two systems. Moreover, data confirmed that the immune system is functionally associated with the nervous and endocrine systems determining an integrated dynamic network. In addition, recent researches showed a similar, characteristic involution process both in TG and PG. Since the second half of the 20th century, evidence led to the definition of an effectively interacting thymus-pineal axis (TG-PG axis), but much has to be done. In this sense, the aim of this review is to summarize what is actually known about this topic, focusing on the impact of the TG-PG axis on human life and ageing. We would like to give more emphasis to the implications of this dynamical interaction in a possible therapeutic strategy for human health. Moreover, we focused on all the products of TG and PG in order to collect what is known about the role of peptides other than melatonin. The results available today are often unclear and not linear. These peptides have not been well studied and defined over the years. In this review we hope to awake the interest of the scientific community in them and in their future pharmacological applications. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health)

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