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Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update

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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 August 2021) | Viewed by 23066

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Prof. Dr. Amnon Brzezinski

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Dept. of Obstetrics & Gynecology, Former Academic Faculty Chair of Obstetrics & Gynecology, The Hebrew University Medical School, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Interests: Melatonin in humans; circadian rhythms; Menopause; Hormone replacement therapy

Special Issue Information

Dear Colleagues,

Melatonin, the pineal gland hormone, is a biological time domain-acting molecule. Cumulative evidence indicates that melatonin has a wide range of roles in the biological regulation of circadian rhythms, sleep, mood, reproduction, tumor growth, immune response, and neurodegenerative processes. However, uncertainties and doubts still surround the pathophysiological mechanisms of action of the hormone.

This Special Issue will present current knowledge about melatonin and its underlying molecular mechanisms and signaling pathways (e.g., antioxidant and antiproliferation activity, induction of apoptosis). We will focus on its main in vivo and in vitro functions as uncovered in both humans and in animal models.

This Special Issue on “Melatonin: Molecular Mechanisms and Biologica Functions” will include manuscripts representing the recent advancements in molecular biological and cellular research in the field of melatonin. Papers aiming to improve our understanding of the mechanisms of action of this hormone and its signaling pathways are welcome. Original research and reviews on these and related topics are invited.

Prof. Dr. Amnon Brzezinski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

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Keywords

melatonin
circadian rhythms
antioxidant activity
antiproliferation
induction of apoptosis
immune response
neurodegenerative processes

Published Papers (5 papers)

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Review

9 pages, 1165 KiB

Open AccessReview

Melatonin, Clock Genes, and Mammalian Reproduction: What Is the Link?

by Amnon Brzezinski, Seema Rai, Adyasha Purohit and Seithikurippu R. Pandi-Perumal

Int. J. Mol. Sci. 2021, 22(24), 13240; https://doi.org/10.3390/ijms222413240 - 08 Dec 2021

Cited by 20 | Viewed by 8550

Abstract

Physiological processes and behaviors in many mammals are rhythmic. Recently there has been increasing interest in the role of circadian rhythmicity in the control of reproductive function. The circadian rhythm of the pineal hormone melatonin plays a role in synchronizing the reproductive responses of animals to environmental light conditions. There is some evidence that melatonin may have a role in the biological regulation of circadian rhythms and reproduction in humans. Moreover, circadian rhythms and clock genes appear to be involved in optimal reproductive performance. These rhythms are controlled by an endogenous molecular clock within the suprachiasmatic nucleus (SCN) in the hypothalamus, which is entrained by the light/dark cycle. The SCN synchronizes multiple subsidiary oscillators (clock genes) existing in various tissues throughout the body. The basis for maintaining the circadian rhythm is a molecular clock consisting of transcriptional/translational feedback loops. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance. This mini review summarizes the current knowledge regarding the interrelationships between melatonin and the endogenous molecular clocks and their involvement in reproductive physiology (e.g., ovulation) and pathophysiology (e.g., polycystic ovarian syndrome). Full article

(This article belongs to the Special Issue Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update)

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15 pages, 1687 KiB

Open AccessReview

Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense

by Regina P. Markus, Kassiano S. Sousa, Sanseray da Silveira Cruz-Machado, Pedro A. Fernandes and Zulma S. Ferreira

Int. J. Mol. Sci. 2021, 22(22), 12143; https://doi.org/10.3390/ijms222212143 - 10 Nov 2021

Cited by 21 | Viewed by 3723

Abstract

Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune–pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues. Full article

(This article belongs to the Special Issue Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update)

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21 pages, 2194 KiB

Open AccessReview

Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders

by Annia Galano, Eduardo G. Guzmán-López and Russel J. Reiter

Int. J. Mol. Sci. 2021, 22(21), 11584; https://doi.org/10.3390/ijms222111584 - 27 Oct 2021

Cited by 6 | Viewed by 3290

Abstract

Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives. Full article

(This article belongs to the Special Issue Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update)

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14 pages, 931 KiB

Open AccessReview

Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved

by Sepideh Bastani, Moloud Akbarzadeh, Yeganeh Rastgar Rezaei, Ali Farzane, Mohammad Nouri, Mahsa Mollapour Sisakht, Amir Fattahi, Maryam Akbarzadeh and Russel J. Reiter

Int. J. Mol. Sci. 2021, 22(19), 10874; https://doi.org/10.3390/ijms221910874 - 08 Oct 2021

Cited by 14 | Viewed by 2522

Abstract

Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis. Full article

(This article belongs to the Special Issue Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update)

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17 pages, 1153 KiB

Open AccessReview

Melatonin and Microglia

by Rüdiger Hardeland

Int. J. Mol. Sci. 2021, 22(15), 8296; https://doi.org/10.3390/ijms22158296 - 02 Aug 2021

Cited by 32 | Viewed by 3975

Abstract

Melatonin interacts in multiple ways with microglia, both directly and, via routes of crosstalk with astrocytes and neurons, indirectly. These effects of melatonin are of relevance in terms of antioxidative protection, not only concerning free-radical detoxification, but also in prevention of processes that cause, promote, or propagate oxidative stress and neurodegeneration, such as overexcitation, toxicological insults, viral and bacterial infections, and sterile inflammation of different grades. The immunological interplay in the CNS, with microglia playing a central role, is of high complexity and includes signaling toward endothelial cells and other leukocytes by cytokines, chemokines, nitric oxide, and eikosanoids. Melatonin interferes with these processes in multiple signaling routes and steps. In addition to canonical signal transduction by MT₁ and MT₂ melatonin receptors, secondary and tertiary signaling is of relevance and has to be considered, e.g., via the upregulation of sirtuins and the modulation of pro- and anti-inflammatory microRNAs. Many details concerning the modulation of macrophage functionality by melatonin are obviously also applicable to microglial cells. Of particular interest is the polarization toward M2 subtypes instead of M1, i.e., in favor of being anti-inflammatory at the expense of proinflammatory activities, which is well-documented in macrophages but also applies to microglia. Full article

(This article belongs to the Special Issue Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update)

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Melatonin: Molecular Mechanisms and Biological Functions. A 2021 Update

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