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Stowe SR, Duston A, Robinson W, Diniz Behn C. Analyzing the Interactions of Light and Melatonin Forcing in a Mathematical Model of the Human Circadian Oscillator. J Pineal Res 2025; 77:e70056. [PMID: 40415269 DOI: 10.1111/jpi.70056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Revised: 04/14/2025] [Accepted: 04/28/2025] [Indexed: 05/27/2025]
Abstract
The pineal secretion of the hormone melatonin demonstrates a circadian (~24 h) rhythm with the onset of melatonin production at night and offset each morning under tight circadian control for entrained individuals. Melatonin exerts both acute sleep-promoting effects and phase-shifting effects on the circadian clock. Due to its hypnotic and chronobiotic (phase shifting) effects, exogenous melatonin supplements are increasingly being used as a treatment for a variety of sleep and circadian diseases and disorders. Phase shifting of the circadian clock can also be accomplished through ocular exposure to light. However, the interacting effects of light and melatonin on the circadian clock are not well understood. To analyze the dynamic behavior of both endogenous and exogenous melatonin's influence on the circadian clock, we extend a previously published mathematical model of the circadian clock to account for forcing due to both endogenous melatonin produced by the pineal gland and exogenous melatonin entering the system through ingested oral supplements. We fit model parameters using published melatonin pharmacokinetics, a melatonin suppression illuminance-response curve, and a 3-pulse 3 mg melatonin phase response curve (PRC). Simulated microscopic PRCs to light and melatonin are determined by the model fits and demonstrate a relative phase difference consistent with previous observations in experimental PRC data. Finally, we simulate a phase advancing experimental protocol utilizing both light exposure and exogenous melatonin to generate model predictions for the effects of interacting inputs to the clock. This modeling framework allows for the study of melatonin's dynamic properties and interaction with the circadian clock. Furthermore, it provides a framework for determining optimal light exposure and exogenous melatonin administration schedules to induce desired phase shifting of the circadian clock.
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Affiliation(s)
- Shelby R Stowe
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado, USA
| | - Armelle Duston
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado, USA
| | - Will Robinson
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado, USA
| | - Cecilia Diniz Behn
- Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado, USA
- Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Stapel B, Alvarenga ME, Kahl KG. Pharmacological and psychological approaches to insomnia treatment in cardiac patients: a narrative literature review. Front Psychiatry 2025; 16:1490585. [PMID: 40018681 PMCID: PMC11865029 DOI: 10.3389/fpsyt.2025.1490585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/24/2025] [Indexed: 03/01/2025] Open
Abstract
Sleep disorders are highly prevalent in the general population and are considered a major public health issue. Insomnia constitutes the most frequent sleep disorder in healthy individuals and has been shown to be even more frequent in patients with physical illnesses including cardiovascular diseases. Inadequate sleep quality and short sleep duration, independent of underlying causes, have been linked to the development and progression of cardiometabolic disorders. Additionally, insomnia has been found to be associated with adverse outcome measures, including daytime sleepiness, fatigue, decreased self-reported physical functioning, lower exercise capacity, poor health related quality of life, depressive symptoms, higher rates of hospitalization and increased mortality in patients with cardiovascular diseases. Against this background, comparatively little information is available in the literature regarding the treatment of chronic insomnia in cardiac patient populations. While guidelines for the general population suggest cognitive behavioral therapy for insomnia as a first-line treatment option and preliminary evidence suggests this treatment to be beneficial in cardiac patients with insomnia symptoms, it is often limited by availability and possibly the clinician's poor understanding of sleep issues in cardiac patients. Therefore, pharmacologic treatment remains an important option indicated by the high number of hypnotic drug prescriptions in the general population and in patients with cardiovascular disorders. In this narrative review of the literature, we summarize treatment options for chronic insomnia based on clinical guidelines for the general population and highlight necessary considerations for the treatment of patients with cardiovascular diseases.
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Affiliation(s)
- Britta Stapel
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Marlies E. Alvarenga
- Institute of Health and Wellbeing, Federation University Australia and Victorian Heart Institute, Melbourne, VIC, Australia
| | - Kai G. Kahl
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
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Shi X, Zhang J, Gao J, Guo D, Zhang S, Chen X, Tang H. Melatonin attenuates liver ischemia-reperfusion injury via inhibiting the PGAM5-mPTP pathway. PLoS One 2024; 19:e0312853. [PMID: 39471139 PMCID: PMC11521291 DOI: 10.1371/journal.pone.0312853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 10/14/2024] [Indexed: 11/01/2024] Open
Abstract
Phosphoglycerate mutase/protein phosphatase (PGAM5)-mediated cell death plays an important role in multiple liver diseases. However, few studies have confirmed the regulatory mechanism of melatonin acting on PGAM5-mediated cell death in the context of liver ischemia-reperfusion (I/R) injury. The liver I/R injury model and cell hypoxia-reoxygenation model were established after melatonin pretreatment. Liver injury, cell activity, cell apoptosis, oxidative stress index, and PGAM5 protein expression were detected. To investigate the role of PGAM5 in melatonin-mediated liver protection during I/R injury, PGAM5 silencing, and overexpression were performed before melatonin pretreatment. Our results indicated that PGAM5 was significantly elevated by I/R injury, and predominantly localized in the necrosis area. However, treatment with melatonin blocked PGAM5 activation and conferred a survival advantage of hepatocytes in liver I/R injury, similar to the results achieved by silencing PGAM5. In terms of mechanism, we illustrated that activated PGAM5 promoted mitochondrial permeability transition pore (mPTP) opening, and administration of melatonin inhibited mPTP opening and interrupted hepatocytes death via blocking PGAM5. Our data indicated that the PGAM5-mPTP axis is responsible for I/R-induced liver injury. In contrast, melatonin supplementation blocked the PGAM5-mPTP axis and thus decreased cell death, providing a protective advantage to hepatocytes in I/R. These results established a new paradigm in melatonin-mediated hepatocyte protection under the burden of I/R attack.
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Affiliation(s)
- Xiaoyi Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Jie Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Danfeng Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Xu Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
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Meredith Weiss S, Aydin E, Lloyd-Fox S, Johnson MH. Trajectories of brain and behaviour development in the womb, at birth and through infancy. Nat Hum Behav 2024; 8:1251-1262. [PMID: 38886534 DOI: 10.1038/s41562-024-01896-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 04/04/2024] [Indexed: 06/20/2024]
Abstract
Birth is often seen as the starting point for studying effects of the environment on human development, with much research focused on the capacities of young infants. However, recent imaging advances have revealed that the complex behaviours of the fetus and the uterine environment exert influence. Birth is now viewed as a punctuate event along a developmental pathway of increasing autonomy of the child from their mother. Here we highlight (1) increasing physiological autonomy and perceptual sensitivity in the fetus, (2) physiological and neurochemical processes associated with birth that influence future behaviour, (3) the recalibration of motor and sensory systems in the newborn to adapt to the world outside the womb and (4) the effect of the prenatal environment on later infant behaviours and brain function. Taken together, these lines of evidence move us beyond nature-nurture issues to a developmental human lifespan view beginning within the womb.
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Affiliation(s)
- Staci Meredith Weiss
- University of Cambridge, Department of Psychology, Cambridge, UK.
- University of Roehampton, School of Psychology, London, UK.
| | - Ezra Aydin
- University of Cambridge, Department of Psychology, Cambridge, UK
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Sarah Lloyd-Fox
- University of Cambridge, Department of Psychology, Cambridge, UK
| | - Mark H Johnson
- University of Cambridge, Department of Psychology, Cambridge, UK
- Centre for Brain and Cognitive Development, Birkbeck, University of London, London, UK
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Okamoto HH, Cecon E, Nureki O, Rivara S, Jockers R. Melatonin receptor structure and signaling. J Pineal Res 2024; 76:e12952. [PMID: 38587234 DOI: 10.1111/jpi.12952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/05/2024] [Accepted: 03/24/2024] [Indexed: 04/09/2024]
Abstract
Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.
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Affiliation(s)
- Hiroyuki H Okamoto
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Erika Cecon
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Silvia Rivara
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Ralf Jockers
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
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Joseph TT, Schuch V, Hossack DJ, Chakraborty R, Johnson EL. Melatonin: the placental antioxidant and anti-inflammatory. Front Immunol 2024; 15:1339304. [PMID: 38361952 PMCID: PMC10867115 DOI: 10.3389/fimmu.2024.1339304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/15/2024] [Indexed: 02/17/2024] Open
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is an indolamine hormone with many physiological and biological roles. Melatonin is an antioxidant, anti-inflammatory, free radical scavenger, circadian rhythm regulator, and sleep hormone. However, its most popular role is the ability to regulate sleep through the circadian rhythm. Interestingly, recent studies have shown that melatonin is an important and essential hormone during pregnancy, specifically in the placenta. This is primarily due to the placenta's ability to synthesize its own melatonin rather than depending on the pineal gland. During pregnancy, melatonin acts as an antioxidant and anti-inflammatory, which is necessary to ensure a stable environment for both the mother and the fetus. It is an essential antioxidant in the placenta because it reduces oxidative stress by constantly scavenging for free radicals, i.e., maintain the placenta's integrity. In a healthy pregnancy, the maternal immune system is constantly altered to accommodate the needs of the growing fetus, and melatonin acts as a key anti-inflammatory by regulating immune homeostasis during early and late gestation. This literature review aims to identify and summarize melatonin's role as a powerful antioxidant and anti-inflammatory that reduces oxidative stress and inflammation to maintain a favorable homeostatic environment in the placenta throughout gestation.
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Affiliation(s)
- Tyana T. Joseph
- Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Viviane Schuch
- Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Daniel J. Hossack
- Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Rana Chakraborty
- Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Erica L. Johnson
- Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
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Vlachou M, Siamidi A, Protopapa C, Vlachos M, Kloutsou S, Dreliozi CC, Papanastasiou IP. In vitro Modified Release Studies on Melatoninergic Fluorinated Phenylalkylamides: Circumventing their Lipophilicity for Oral Administration. Curr Pharm Des 2024; 30:1433-1441. [PMID: 38616752 DOI: 10.2174/0113816128304967240328065809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 03/15/2024] [Indexed: 04/16/2024]
Abstract
INTRODUCTION In an attempt to circumvent the lipophilicity burden for the oral administration of new potent synthetic melatoninergic fluorine-substituted methoxyphenylalkyl amides, we conducted in vitro modified release studies using carefully selected matrix tablets' biopolymeric materials in different ratios. METHODS In particular, we sought to attain release profiles of these analogues similar to that of the parent compound, the chronobiotic hormone Melatonin (MLT), and also of the commercially available drug, Circadin®. RESULTS It was found that some of these systems, albeit being more lipophilic than MLT, mimic the in vitro release patterns of melatonin and Circadin®. CONCLUSION Moreover, a number of these derivatives were proven suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance dysfunctions.
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Affiliation(s)
- Marilena Vlachou
- Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
| | - Angeliki Siamidi
- Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
| | - Chrystalla Protopapa
- Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
| | - Michalis Vlachos
- Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
| | - Sophia Kloutsou
- Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
| | - Chrysoula-Christina Dreliozi
- Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
| | - Ioannis P Papanastasiou
- Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, Athens 15784, Greece
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Feng Y, Jiang X, Liu W, Lu H. The location, physiology, pathology of hippocampus Melatonin MT 2 receptor and MT 2-selective modulators. Eur J Med Chem 2023; 262:115888. [PMID: 37866336 DOI: 10.1016/j.ejmech.2023.115888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/06/2023] [Accepted: 10/17/2023] [Indexed: 10/24/2023]
Abstract
Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT1 and MT2 receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT1 receptor, the widely expressed MT2 receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT2 receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT2 receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT2 receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT2 receptor ligands used in psychopharmacology and other MT2-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT2 receptor drug candidates.
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Affiliation(s)
- Yueqin Feng
- Department of Ultrasound, the First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Xiaowen Jiang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Wenwu Liu
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, PR China
| | - Hongyuan Lu
- Department of Clinical Pharmacology, China Medical University, Shenyang, PR China.
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Klymenko A, Lutz D. Melatonin signalling in Schwann cells during neuroregeneration. Front Cell Dev Biol 2022; 10:999322. [PMID: 36299487 PMCID: PMC9589221 DOI: 10.3389/fcell.2022.999322] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/23/2022] [Indexed: 11/13/2022] Open
Abstract
It has widely been thought that in the process of nerve regeneration Schwann cells populate the injury site with myelinating, non–myelinating, phagocytic, repair, and mesenchyme–like phenotypes. It is now clear that the Schwann cells modify their shape and basal lamina as to accommodate re–growing axons, at the same time clear myelin debris generated upon injury, and regulate expression of extracellular matrix proteins at and around the lesion site. Such a remarkable plasticity may follow an intrinsic functional rhythm or a systemic circadian clock matching the demands of accurate timing and precision of signalling cascades in the regenerating nervous system. Schwann cells react to changes in the external circadian clock clues and to the Zeitgeber hormone melatonin by altering their plasticity. This raises the question of whether melatonin regulates Schwann cell activity during neurorepair and if circadian control and rhythmicity of Schwann cell functions are vital aspects of neuroregeneration. Here, we have focused on different schools of thought and emerging concepts of melatonin–mediated signalling in Schwann cells underlying peripheral nerve regeneration and discuss circadian rhythmicity as a possible component of neurorepair.
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Burgess HJ, Emens JS. Drugs Used in Circadian Sleep-Wake Rhythm Disturbances. Sleep Med Clin 2022; 17:421-431. [PMID: 36150804 DOI: 10.1016/j.jsmc.2022.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
This article focuses on melatonin and other melatonin receptor agonists and summarizes their circadian phase shifting and sleep-enhancing properties, along with their associated possible safety concerns. The circadian system and circadian rhythm sleep-wake disorders are described, along with the latest American Academy of Sleep Medicine recommendations for the use of exogenous melatonin in treating them. In addition, the practical aspects of using exogenous melatonin obtainable over the counter in the United States, consideration of the effects of concomitant light exposure, and assessing treatment response are discussed.
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Affiliation(s)
- Helen J Burgess
- Biological Rhythms Research Laboratory, Department of Behavioral Sciences, Rush University Medical Center, 1645 West Jackson Boulevard, Suite 425, Chicago, IL 60612, USA.
| | - Jonathan S Emens
- Department of Psychiatry, Oregon Health & Science University, VA Portland Health Care System, 3710 Southwest US Veterans Hospital, Road P3-PULM, Portland, OR 97239, USA; Department of Medicine, Oregon Health & Science University, VA Portland Health Care System, 3710 Southwest US Veterans Hospital, Road P3-PULM, Portland, OR 97239, USA
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Tsotinis A, Afroudakis PA, Papanastasiou IP, Sakellaropoulou A, Boniakou M, Komiotis D, Garratt PJ, Delagrange P, Bocianowska-Zbrog A, Sugden D. Mapping the Melatonin Receptor. 8. Selective MT2 Agonists derived from 5,6-dihydroindolo[2,1-a]isoquinolines and related systems. ChemMedChem 2022; 17:e202200129. [PMID: 35478275 DOI: 10.1002/cmdc.202200129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/15/2022] [Indexed: 11/10/2022]
Abstract
A series of substituted indolo[2,1- a ]isoquinolines and indolo[1,2- a ]benzoxazines have been prepared, as melatonin analogues, to investigate the nature of the binding site of the melatonin receptor. Agonist and antagonist potency of all the analogues was measured using the [35S]GTPγS binding assay protocol. The binding affinity of the analogues were measured by competition binding studies against the human MT1 (hMT1) and MT2 (hMT2) receptors stably transfected in Chinese Hamster Ovarian (CHO) cells, using 2-[ 125 I]-iodomelatonin, as a ligand. N -Acetyl 2-(10-methoxy-5,6-dihydroindolo[2,1- a ]isoquinolin-12-yl)propyl-1-amine (12a) binds strongly to both the hMT1 and hMT2 receptors, and shows a preference for the hMT2, as does Its propanamido counterpart 12b . The introduction of two methyl groups into their side chain, analogues 15a and 1 5b, leads to antagonism, in the case of the former, and drastically diminishes its hMT1 binding; an analogous profile is seen for 15b , which, however, is a partial agonist.. Introduction of chlorine or methoxyl groups into ring 4 gives compounds, that are weakly binding, with a preference for MT2. Substitution of oxygen for carbon at position 5 gives the indolo[1,2- c ]benzoxazines 33 , 36a and b , that bind strongly to the human receptors, 33 , 36b are potent agonists at the melatonin receptors, but do not discriminate between hMT1 and hMT2.
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Affiliation(s)
- Andrew Tsotinis
- University of Athens: Ethniko kai Kapodistriako Panepistemio Athenon, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Panepistimioupoli-Zografou, 15771, Athens, GREECE
| | - Pandelis A Afroudakis
- National and Kapodistrian University of Athens School of Health Sciences: Ethniko kai Kapodistriako Panepistemio Athenon, Pharmacy, GREECE
| | - Ioannis P Papanastasiou
- National and Kapodistrian University of Athens School of Health Sciences: Ethniko kai Kapodistriako Panepistemio Athenon, Pharmacy, GREECE
| | - Aikaterini Sakellaropoulou
- National and Kapodistrian University of Athens School of Health Sciences: Ethniko kai Kapodistriako Panepistemio Athenon, Pharmacy, GREECE
| | - Marina Boniakou
- National and Kapodistrian University of Athens: Ethniko kai Kapodistriako Panepistemio Athenon, Pharmacy, GREECE
| | - Dimitri Komiotis
- University of Thessaly: Panepistemio Thessalias, Department of Biochemistry & Biotechnology, GREECE
| | | | | | | | - David Sugden
- King's College London, Pharmacology, UNITED KINGDOM
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12
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Vlachou M, Siamidi A, Anagnostopoulou D, Christodoulou E, Bikiaris ND. Modified Release of the Pineal Hormone Melatonin from Matrix Tablets Containing Poly(L-lactic Acid) and Its PLA-co-PEAd and PLA-co-PBAd Copolymers. Polymers (Basel) 2022; 14:polym14081504. [PMID: 35458252 PMCID: PMC9027688 DOI: 10.3390/polym14081504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 12/29/2022] Open
Abstract
In terms of drug delivery, the attractive properties of poly(L-lactic acid) (PLA) and its aliphatic polyesters, poly(ethylene adipate) (PEAd) and poly(butylene adipate) (PBAd), render them ideal co-formulants for the preparation of modified-release pharmaceutical formulations. Furthermore, we have previously demonstrated that by adding a “softer” aliphatic polyester onto the macromolecular chain of PLA, i.e., PEAd or PBAd, resulting in the formation of the PLA’s copolymers (PLA-co-PEAd and PLA-co-PBAd, in 95/5, 90/10, 75/25 and 50/50 weight ratios), the hydrolysis rate is also severely affected, leading to improved dissolution rates of the active pharmaceutical ingredients (API). In the present report, we communicate our findings on the in vitro modified release of the chronobiotic hormone melatonin (MLT), in aqueous media (pH 1.2 and 6.8), from poly(L-lactic acid) and the aforementioned copolymer matrix tablets, enriched with commonly used biopolymers, such as hydroxypropylmethylcellulose (HPMC K15), lactose monohydrate, and sodium alginate. It was found that, depending on the composition and the relevant content of these excipients in the matrix tablets, the release of MLT satisfied the sought targets for fast sleep onset and sleep maintenance. These findings constitute a useful background for pursuing relevant in vivo studies on melatonin in the future.
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Affiliation(s)
- Marilena Vlachou
- Division of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 15784 Athens, Greece; (A.S.); (D.A.)
- Correspondence: ; Tel.: +30-2107274674
| | - Angeliki Siamidi
- Division of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 15784 Athens, Greece; (A.S.); (D.A.)
| | - Dionysia Anagnostopoulou
- Division of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 15784 Athens, Greece; (A.S.); (D.A.)
| | - Evi Christodoulou
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (E.C.); (N.D.B.)
| | - Nikolaos D. Bikiaris
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (E.C.); (N.D.B.)
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13
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Elisi GM, Scalvini L, Lodola A, Mor M, Rivara S. Free-Energy Simulations Support a Lipophilic Binding Route for Melatonin Receptors. J Chem Inf Model 2021; 62:210-222. [PMID: 34932329 PMCID: PMC8757440 DOI: 10.1021/acs.jcim.1c01183] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
![]()
The effects of the
neurohormone melatonin are mediated by the activation
of the GPCRs MT1 and MT2 in a variety of tissues.
Crystal structures suggest ligand access to the orthosteric binding
site of MT1 and MT2 receptors through a lateral
channel between transmembrane (TM) helices IV and V. We investigated
the feasibility of this lipophilic entry route for 2-iodomelatonin,
a nonselective agonist with a slower dissociation rate from the MT2 receptor, applying enhanced sampling simulations and free-energy
calculations. 2-Iodomelatonin unbinding was investigated with steered
molecular dynamics simulations which revealed different trajectories
passing through the gap between TM helices IV and V for both receptors.
For one of these unbinding trajectories from the MT1 receptor,
an umbrella-sampling protocol with path-collective variables provided
a calculated energy barrier consistent with the experimental dissociation
rate. The side-chain flexibility of Tyr5.38 was significantly different
in the two receptor subtypes, as assessed by metadynamics simulations,
and during ligand unbinding it frequently assumes an open conformation
in the MT1 but not in the MT2 receptor, favoring
2-iodomelatonin egress. Taken together, our simulations are consistent
with the possibility that the gap between TM IV and V is a way of
connecting the orthosteric binding site and the membrane core for
lipophilic melatonin receptor ligands. Our simulations also suggest
that the open state of Tyr5.38 generates a small pocket on the surface
of MT1 receptor, which could participate in the recognition
of MT1-selective ligands and may be exploited in the design
of new selective compounds.
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Affiliation(s)
- Gian Marco Elisi
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy
| | - Laura Scalvini
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy
| | - Alessio Lodola
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy
| | - Marco Mor
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy.,Microbiome Research Hub, University of Parma, I-43124 Parma, Italy
| | - Silvia Rivara
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy
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14
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Ikram M, Park HY, Ali T, Kim MO. Melatonin as a Potential Regulator of Oxidative Stress, and Neuroinflammation: Mechanisms and Implications for the Management of Brain Injury-Induced Neurodegeneration. J Inflamm Res 2021; 14:6251-6264. [PMID: 34866924 PMCID: PMC8637421 DOI: 10.2147/jir.s334423] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/15/2021] [Indexed: 12/29/2022] Open
Abstract
This review covers the preclinical and clinical literature supporting the role of melatonin in the management of brain injury-induced oxidative stress, neuroinflammation, and neurodegeneration, and reviews the past and current therapeutic strategies. Traumatic brain injury (TBI) is a neurodegenerative condition, unpredictably and potentially progressing into chronic neurodegeneration, with permanent cognitive, neurologic, and motor dysfunction, having no standard therapies. Due to its complex and multi-faceted nature, the TBI has highly heterogeneous pathophysiology, characterized by the highest mortality and disability worldwide. Mounting evidence suggests that the TBI induces oxidative and nitrosative stress, which is involved in the progression of chronic and acute neurodegenerative diseases. Defenses against such conditions are mostly dependent on the usage of antioxidant compounds, the majority of whom are ingested as nutraceuticals or as dietary supplements. A large amount of literature is available regarding the efficacy of antioxidant compounds to counteract the TBI-associated damage in animal and cellular models of the TBI and several clinical studies. Collectively, the studies have suggested that TBI induces oxidative stress, by suppressing the endogenous antioxidant system, such as nuclear factor erythroid 2–related factor-2 (Nrf-2) increasing the lipid peroxidation and elevation of oxidative damage. Moreover, elevated oxidative stress may induce neuroinflammation by activating the microglial cells, releasing and activating the inflammatory cytokines and inflammatory mediators, and energy dyshomeostasis. Thus, melatonin has shown regulatory effects against the TBI-induced autophagic dysfunction, regulation of mitogen-activated protein kinases, such as ERK, activation of the NLRP-3 inflammasome, and release of the inflammatory cytokines. The collective findings strongly suggest that melatonin may regulate TBI-induced neurodegeneration, although further studies should be conducted to better facilitate future therapeutic windows.
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Affiliation(s)
- Muhammad Ikram
- Division of Life Science and Applied Life Science (BK21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Hyun Young Park
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands.,School for Mental Health and Neuroscience (MHeNS), Maastricht Medical Center, Maastricht, 6229 ER, the Netherlands
| | - Tahir Ali
- Division of Life Science and Applied Life Science (BK21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Myeong Ok Kim
- Division of Life Science and Applied Life Science (BK21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea.,Alz-Dementia Korea Co., Jinju, 52828, Republic of Korea
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15
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Melatonin: From Neurobiology to Treatment. Brain Sci 2021; 11:brainsci11091121. [PMID: 34573143 PMCID: PMC8468230 DOI: 10.3390/brainsci11091121] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/12/2021] [Accepted: 08/23/2021] [Indexed: 01/12/2023] Open
Abstract
Melatonin, the major regulator of the sleep/wake cycle, also plays important physiological and pharmacological roles in the control of neuronal plasticity and neuroprotection. Accordingly, the secretion of this hormone reaches the maximal extent during brain development (childhood-adolescence) while it is greatly reduced during aging, a condition associated to altered sleep pattern and reduced neuronal plasticity. Altogether, these properties of melatonin have allowed us to demonstrate in both experimental models and clinical studies the great chronobiotic efficacy and sleep promoting effects of exogenous melatonin. Thus, the prolonged release formulation of melatonin, present as a drug in the pharmaceutical market, has been recently recommended for the treatment of insomnia in over 55 years old subjects.
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16
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Valente R, Alves F, Sousa-Pinto I, Ruivo R, Castro LFC. Functional or Vestigial? The Genomics of the Pineal Gland in Xenarthra. J Mol Evol 2021; 89:565-575. [PMID: 34342686 DOI: 10.1007/s00239-021-10025-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/27/2021] [Indexed: 11/28/2022]
Abstract
Vestigial organs are historical echoes of past phenotypes. Determining whether a specific organ constitutes a functional or vestigial structure can be a challenging task, given that distinct levels of atrophy may arise between and within lineages. The mammalian pineal gland, an endocrine organ involved in melatonin biorhythmicity, represents a classic example, often yielding contradicting anatomical observations. In Xenarthra (sloths, anteaters, and armadillos), a peculiar mammalian order, the presence of a distinct pineal organ was clearly observed in some species (i.e., Linnaeus's two-toed sloth), but undetected in other closely related species (i.e., brown-throated sloth). In the nine-banded armadillo, contradicting evidence supports either functional or vestigial scenarios. Thus, to untangle the physiological status of the pineal gland in Xenarthra, we used a genomic approach to investigate the evolution of the gene hub responsible for melatonin synthesis and signaling. We show that both synthesis and signaling compartments are eroded and were probably lost independently among Xenarthra orders. Additionally, by expanding our analysis to 157 mammal genomes, we offer a comprehensive view showing that species with very distinctive habitats and lifestyles have convergently evolved a similar phenotype: Cetacea, Pholidota, Dermoptera, Sirenia, and Xenarthra. Our findings suggest that the recurrent inactivation of melatonin genes correlates with pineal atrophy and endorses the use of genomic analyses to ascertain the physiological status of suspected vestigial structures.
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Affiliation(s)
- Raul Valente
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos, S/N, 4450-208, Matosinhos, Portugal.,FCUP-Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua Do Campo Alegre, Porto, Portugal
| | - Filipe Alves
- MARE-Marine and Environmental Sciences Centre, ARDITI, Madeira, Portugal.,OOM-Oceanic Observatory of Madeira, Funchal, Portugal
| | - Isabel Sousa-Pinto
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos, S/N, 4450-208, Matosinhos, Portugal.,FCUP-Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua Do Campo Alegre, Porto, Portugal
| | - Raquel Ruivo
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos, S/N, 4450-208, Matosinhos, Portugal
| | - L Filipe C Castro
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos, S/N, 4450-208, Matosinhos, Portugal. .,FCUP-Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua Do Campo Alegre, Porto, Portugal.
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17
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Melhuish Beaupre LM, Brown GM, Gonçalves VF, Kennedy JL. Melatonin's neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders. Transl Psychiatry 2021; 11:339. [PMID: 34078880 PMCID: PMC8172874 DOI: 10.1038/s41398-021-01464-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 04/16/2021] [Accepted: 05/14/2021] [Indexed: 02/05/2023] Open
Abstract
Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin's prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin's potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin's ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.
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Affiliation(s)
- Lindsay M Melhuish Beaupre
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Gregory M Brown
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Vanessa F Gonçalves
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - James L Kennedy
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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18
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Hoashi Y, Takai T, Kosugi Y, Nakashima M, Nakayama M, Hirai K, Uchikawa O, Koike T. Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist. J Med Chem 2021; 64:3059-3074. [PMID: 33682410 DOI: 10.1021/acs.jmedchem.0c01836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
To develop potent and orally bioavailable melatonin receptor (MT1 and MT2) agonists, a novel series of 5-6-5 tricyclic derivatives was designed, synthesized, and evaluated. The synthesized indeno[5,4-d][1,3]oxazole, cyclopenta[c]pyrazolo[1,5-a]pyridine, indeno[5,4-d][1,3]thiazole, and cyclopenta[e]indazole derivatives showed potent binding affinities for MT1/MT2 receptors. Further optimization of these derivatives based on their metabolic stability in human hepatic microsomes revealed that (S)-3b ((S)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide) was a potent MT1 and MT2 ligand (MT1, Ki = 0.031 nM; MT2, Ki = 0.070 nM) with good metabolic stability in human hepatic microsomes. Moreover, compound (S)-3b showed good BBB permeability in rats, and its in vivo pharmacological effects were confirmed by its sleep-promotion ability in cats.
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Affiliation(s)
- Yasutaka Hoashi
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Takafumi Takai
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Yohei Kosugi
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Masato Nakashima
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Masaharu Nakayama
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Keisuke Hirai
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Osamu Uchikawa
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Tatsuki Koike
- Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
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19
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Kinker GS, Ostrowski LH, Ribeiro PAC, Chanoch R, Muxel SM, Tirosh I, Spadoni G, Rivara S, Martins VR, Santos TG, Markus RP, Fernandes PACM. MT1 and MT2 melatonin receptors play opposite roles in brain cancer progression. J Mol Med (Berl) 2021; 99:289-301. [PMID: 33392634 DOI: 10.1007/s00109-020-02023-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 11/19/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023]
Abstract
Primary brain tumors remain among the deadliest of all cancers. Glioma grade IV (glioblastoma), the most common and malignant type of brain cancer, is associated with a 5-year survival rate of < 5%. Melatonin has been widely reported as an anticancer molecule, and we have recently demonstrated that the ability of gliomas to synthesize and accumulate this indolamine in the surrounding microenvironment negatively correlates with tumor malignancy. However, our understanding of the specific effects mediated through the activation of melatonin membrane receptors remains limited. Thus, here we investigated the specific roles of MT1 and MT2 in gliomas and medulloblastomas. Using the MT2 antagonist DH97, we showed that MT1 activation has a negative impact on the proliferation of human glioma and medulloblastoma cell lines, while MT2 activation has an opposite effect. Accordingly, gliomas have a decreased mRNA expression of MT1 (also known as MTNR1A) and an increased mRNA expression of MT2 (also known as MTNR1B) compared to the normal brain cortex. The MT1/MT2 expression ratio negatively correlates with the expression of cell cycle-related genes and is a positive prognostic factor in gliomas. Notably, we showed that functional selective drugs that simultaneously activate MT1 and inhibit MT2 exert robust anti-tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in glioma stem-like cells. Overall, we provided the first evidence regarding the differential roles of MT1 and MT2 in brain tumor progression, highlighting their relevance as druggable targets. KEY MESSAGES: • MT1 impairs while MT2 promotes the proliferation of glioma and medulloblastoma cell lines. • Gliomas have a decreased expression of MT1 and an increased expression of MT2 compared to normal brain cortex. • Tumors with a high MT1/MT2 expression ratio have significantly better survival rates. • Functional selective drugs that simultaneously activate MT1 and inhibit MT2 downregulate the expression of cell cycle and energy metabolism genes in glioma stem-like cells and exert robust anti-tumor effects in vivo.
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MESH Headings
- Animals
- Brain/metabolism
- Brain Neoplasms/genetics
- Brain Neoplasms/metabolism
- Brain Neoplasms/mortality
- Brain Neoplasms/pathology
- Cell Line, Tumor
- Cell Proliferation
- Disease Progression
- Female
- Glioma/genetics
- Glioma/metabolism
- Glioma/mortality
- Glioma/pathology
- Humans
- Kaplan-Meier Estimate
- Male
- Mice, Inbred BALB C
- Mice, Nude
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/genetics
- Receptor, Melatonin, MT2/metabolism
- Mice
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Affiliation(s)
- G S Kinker
- Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil.
| | - L H Ostrowski
- Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil
| | - P A C Ribeiro
- International Research Center, A.C. Camargo Cancer Center, Sao Paulo, Brazil
| | - R Chanoch
- Department of Molecular Cell Biology, Weizmann Institute, Rehovot, Israel
| | - S M Muxel
- Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil
| | - I Tirosh
- Department of Molecular Cell Biology, Weizmann Institute, Rehovot, Israel
| | - G Spadoni
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - S Rivara
- Department of Food and Drug, University of Parma, Parma, Italy
| | - V R Martins
- International Research Center, A.C. Camargo Cancer Center, Sao Paulo, Brazil
- National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation - INCITO-INOTE, Sao Paulo, Brazil
| | - T G Santos
- International Research Center, A.C. Camargo Cancer Center, Sao Paulo, Brazil
- National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation - INCITO-INOTE, Sao Paulo, Brazil
| | - R P Markus
- Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil
| | - P A C M Fernandes
- Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil.
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20
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Probing the release of the chronobiotic hormone melatonin from hybrid calcium alginate hydrogel beads. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2020; 70:527-538. [PMID: 32412433 DOI: 10.2478/acph-2020-0037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/17/2019] [Indexed: 01/19/2023]
Abstract
A variety of commonly used hydrogels were utilized in the preparation of calcium alginate beads, which incorporate the chronobiotic hormone melatonin (MLT). The in vitro release of the hormone in aqueous media at pH 1.2 and 6.8 was probed in the conjunction with the swelling of the beads and their thermal degradation properties. It has been found that the release of MLT from the beads was reversibly proportional to the extent of their expansion, which depends on the molecular mass/viscosity of the biopolymers present in the beads; the higher the molecular mass/viscosity of the hydrogels the greater the beads swelling and the less the MLT's release. Thermogravimetric analysis (TGA) data support the presence of the components in the hybrid hydrogel beads and elucidate their effects on the thermal stability of the systems. Thus, the physicochemical properties of the biopolymers used, along with their stereoelectronic features modulate the release of MLT from the beads, providing formulations able to treat sleep onset related problems or dysfunctions arising from poor sleep maintenance.
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21
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Abstract
This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.
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Affiliation(s)
- Helen J Burgess
- Biological Rhythms Research Laboratory, Department of Behavioral Sciences, Rush University Medical Center, 1645 West Jackson Boulevard, Suite 425, Chicago, IL 60612, USA.
| | - Jonathan S Emens
- Department of Psychiatry, Oregon Health & Science University, VA Portland Health Care System, 3710 Southwest US Veterans Hospital, Road P3-PULM, Portland, OR 97239, USA; Department of Medicine, Oregon Health & Science University, VA Portland Health Care System, 3710 Southwest US Veterans Hospital, Road P3-PULM, Portland, OR 97239, USA
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22
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Li Y, Lv Y, Bian C, You X, Shi Q. Molecular evolution of melatonin receptor genes (mtnr) in vertebrates and its shedding light on mtnr1c. Gene 2020; 769:145256. [PMID: 33164759 DOI: 10.1016/j.gene.2020.145256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/05/2020] [Accepted: 10/20/2020] [Indexed: 12/15/2022]
Abstract
Melatonin receptors (MTNRs) play important roles in regulation of circadian rhythms and seasonal reproduction. However, their origin and evolution in vertebrates have not been investigated. Here, we performed a comprehensive examination by comparative genome mining of MTNRs in vertebrates. We successfully extracted 164 putative encoding sequences for MTNRs (including 57 mtnr1a, 59 mtnr1b and 48 mtnr1c) from 45 high-quality representative genomes. Interestingly, the putative expansions of mtnr1a and mtnr1b in zebrafish were also identified in other Cyprinifomes, but not in other orders of teleost. Using phylogenetic interference, we observed this expansion to be clustered into a primitive position of the Actinopterygii, which may be resulted from teleost-specific genome duplication. The C-terminal extension of MTNR1C, predicted to be proteoglycan 4 (PRG4), originated after the speciation of Monotremata or Marsupialia. Our present genomics survey provides novel insights into the evolution of MTNRs in vertebrates and updates our understanding of these proteins.
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Affiliation(s)
- Yanping Li
- Key Laboratory of Sichuan Province for Fishes Conservation and Utilization in the Upper Reaches of the Yangtze River, College of Life Sciences, Neijiang Normal University, Neijiang 641100, China; Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China
| | - Yunyun Lv
- Key Laboratory of Sichuan Province for Fishes Conservation and Utilization in the Upper Reaches of the Yangtze River, College of Life Sciences, Neijiang Normal University, Neijiang 641100, China
| | - Chao Bian
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China
| | - Xinxin You
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China
| | - Qiong Shi
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China.
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23
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Khan S, Khurana M, Vyas P, Vohora D. The role of melatonin and its analogues in epilepsy. Rev Neurosci 2020; 32:/j/revneuro.ahead-of-print/revneuro-2019-0088/revneuro-2019-0088.xml. [PMID: 32950966 DOI: 10.1515/revneuro-2019-0088] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 04/01/2020] [Indexed: 12/31/2022]
Abstract
Extensive research has gone into proposing a promising link between melatonin administration and attenuation of epileptic activity, the majority of which suggest its propensity as an antiseizure with antioxidant and neuroprotective properties. In the past few years, a number of studies highlighting the association of the melatonergic ligands with epilepsy have also emerged. In this context, our review is based on discussing the recent studies and various mechanisms of action that the said category of drugs exhibit in the context of being therapeutically viable antiseizure drugs. Our search revealed several articles on the four major drugs i.e. melatonin, agomelatine, ramelteon and piromelatine along with other melatonergic agonists like tasimelteon and TIK-301. Our review is suggestive of antiseizure effects of both melatonin and its analogues; however, extensive research work is still required to study their implications in the treatment of persons with epilepsy. Further evaluation of melatonergic signaling pathways and mechanisms may prove to be helpful in the near future and might prove to be a significant advance in the field of epileptology.
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Affiliation(s)
- Sumaira Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mallika Khurana
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Preeti Vyas
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
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Melatonin and Mesenchymal Stem Cells as a Key for Functional Integrity for Liver Cancer Treatment. Int J Mol Sci 2020; 21:ijms21124521. [PMID: 32630505 PMCID: PMC7350224 DOI: 10.3390/ijms21124521] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common hepatobiliary malignancy with limited therapeutic options. On the other hand, melatonin is an indoleamine that modulates a variety of potential therapeutic effects. In addition to its important role in the regulation of sleep–wake rhythms, several previous studies linked the biologic effects of melatonin to various substantial endocrine, neural, immune and antioxidant functions, among others. Furthermore, the effects of melatonin could be influenced through receptor dependent and receptor independent manner. Among the other numerous physiological and therapeutic effects of melatonin, controlling the survival and differentiation of mesenchymal stem cells (MSCs) has been recently discussed. Given its controversial interaction, several previous reports revealed the therapeutic potential of MSCs in controlling the hepatocellular carcinoma (HCC). Taken together, the intention of the present review is to highlight the effects of melatonin and mesenchymal stem cells as a key for functional integrity for liver cancer treatment. We hope to provide solid piece of information that may be helpful in designing novel drug targets to control HCC.
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Lee BH, Bussi IL, de la Iglesia HO, Hague C, Koh DS, Hille B. Two indoleamines are secreted from rat pineal gland at night and act on melatonin receptors but are not night hormones. J Pineal Res 2020; 68:e12622. [PMID: 31715643 PMCID: PMC7007382 DOI: 10.1111/jpi.12622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 11/28/2022]
Abstract
INTRODUCTION At night, the pineal gland produces the indoleamines, melatonin, N-acetylserotonin (NAS), and N-acetyltryptamine (NAT). Melatonin is accepted as a hormone of night. Could NAS and NAT serve that role too? METHODS Concentration-response measurements with overexpressed human melatonin receptors MT1 and MT2 ; mass spectrometry analysis of norepinephrine-stimulated secretions from isolated rat pineal glands; analysis of 24-hour periodic samples of rat blood. RESULTS We show that NAT and NAS do activate melatonin receptors MT1 and MT2 , although with lower potency than melatonin, and that in vitro, melatonin and NAS are secreted from stimulated, isolated pineal glands in roughly equimolar amounts, but secretion of NAT was much less. All three were found at roughly equal concentrations in blood during the night. However, during the day, serum melatonin fell to very low values creating a high-amplitude circadian rhythm that was absent after pinealectomy, whereas NAS and NAT showed only small or no circadian variation. CONCLUSION Blood levels of NAS and NAT were insufficient to activate peripheral melatonin receptors, and they were invariant, so they could not serve as circulating hormones of night. However, they could instead act in paracrine circadian fashion near the pineal gland or via other higher-affinity receptors.
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Affiliation(s)
- Bo Hyun Lee
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
| | - Ivana L. Bussi
- Department of Biology, University of Washington School, Seattle, WA 98195-1800 USA
| | | | - Chris Hague
- Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
| | - Duk-Su Koh
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
- Co-corresponding authors: Bertil Hille; , Phone: 206-543-6661, Duk-Su Koh; , Phone: 206-407-6690
| | - Bertil Hille
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
- Co-corresponding authors: Bertil Hille; , Phone: 206-543-6661, Duk-Su Koh; , Phone: 206-407-6690
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26
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Xu Z, You W, Liu J, Wang Y, Shan T. Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes. Adv Nutr 2020; 11:447-460. [PMID: 31355852 PMCID: PMC7442421 DOI: 10.1093/advances/nmz070] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/28/2019] [Accepted: 06/13/2019] [Indexed: 12/15/2022] Open
Abstract
The high prevalence of obesity and its associated metabolic diseases has heightened the importance of understanding control of adipose tissue development and energy metabolism. In mammals, 3 types of adipocytes with different characteristics and origins have been identified: white, brown, and beige. Beige and brown adipocytes contain numerous mitochondria and have the capability to burn energy and counteract obesity, while white adipocytes store energy and are closely associated with metabolic disorders and obesity. Thus, regulation of the development and function of different adipocytes is important for controlling energy balance and combating obesity and related metabolic disorders. Melatonin is a neurohormone, which plays multiple roles in regulating inflammation, blood pressure, insulin actions, and energy metabolism. This article summarizes and discusses the role of melatonin in white, beige, and brown adipocytes, especially in affecting adipogenesis, inducing beige formation or white adipose tissue browning, enhancing brown adipose tissue mass and activities, improving anti-inflammatory and antioxidative effects, regulating adipokine secretion, and preventing body weight gain. Based on the current findings, melatonin is a potential therapeutic agent to control energy metabolism, adipogenesis, fat deposition, adiposity, and related metabolic diseases.
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Affiliation(s)
- Ziye Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Wenjing You
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Jiaqi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Yizhen Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Tizhong Shan
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China,Address correspondence to TS (E-mail: )
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27
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Colunga Biancatelli RML, Berrill M, Mohammed YH, Marik PE. Melatonin for the treatment of sepsis: the scientific rationale. J Thorac Dis 2020; 12:S54-S65. [PMID: 32148926 DOI: 10.21037/jtd.2019.12.85] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sepsis affects 30 million people worldwide, leading to 6 million deaths every year (WHO), and despite decades of research, novel initiatives are drastically needed. According to the current literature, oxidative imbalance and mitochondrial dysfunction are common features of septic patients that can cause multiorgan failure and death. Melatonin, alongside its traditionally accepted role as the master hormonal regulator of the circadian rhythm, is a promising adjunctive drug for sepsis through its anti-inflammatory, antiapoptotic and powerful antioxidant properties. Several animal models of sepsis have demonstrated that melatonin can prevent multiorgan dysfunction and improve survival through restoring mitochondrial electron transport chain (ETC) function, inhibiting nitric oxide synthesis and reducing cytokine production. The purpose of this article is to review the current evidence for the role of melatonin in sepsis, review its pharmacokinetic profile and virtual absence of side effects. While clinical data is limited, we propose the adjunctive use of melatonin is patients with severe sepsis and septic shock.
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Affiliation(s)
- Ruben Manuel Luciano Colunga Biancatelli
- Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.,Policlinico Umberto I, La Sapienza University of Rome, Rome, Italy
| | - Max Berrill
- Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.,St. Peter's Hospital, Department of Respiratory Medicine, London, UK
| | - Yassen H Mohammed
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Paul E Marik
- Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
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28
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Skarlis C, Anagnostouli M. The role of melatonin in Multiple Sclerosis. Neurol Sci 2019; 41:769-781. [PMID: 31845043 DOI: 10.1007/s10072-019-04137-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/31/2019] [Indexed: 12/20/2022]
Abstract
Melatonin is a neurohormone mainly produced by the pineal gland following a circadian rhythm. It is characterized as a pleiotropic factor because it not only regulates the wake-sleep rhythm but also exerts antinociceptive, antidepressant, anxiolytic, and immunomodulating properties. Recent studies suggest that dysregulation of melatonin secretion is associated with the pathogenesis of various autoimmune diseases, such as, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). MS is an autoimmune disorder characterized by an abnormal immune response directed against the myelin sheath in the central nervous system, demyelination, oligodendrocyte death, and axonal degeneration. Recent evidence reveals that melatonin secretion is dysregulated in MS patients, suggesting that melatonin could be a potential target for therapeutic intervention. Here, we summarize the available literature regarding the role of melatonin in immune processes relevant for experimental autoimmune encephalomyelitis (EAE), MS, and the current clinical trials of melatonin supplementation in MS patients.
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Affiliation(s)
- Charalampos Skarlis
- Immunogenetics Laboratory, 1st Department of Neurology, Medical School of National and Kapodistrian University of Athens, Aeginition Hospital, Vas. Sophias, 74, 115 28, Athens, Greece.
| | - Maria Anagnostouli
- Immunogenetics Laboratory, 1st Department of Neurology, Medical School of National and Kapodistrian University of Athens, Aeginition Hospital, Vas. Sophias, 74, 115 28, Athens, Greece. .,Demyelinating Diseases Clinic, 1st Department of Neurology, Medical School of National and Kapodistrian University of Athens, Aeginition Hospital, Athens, Greece.
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29
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Espino J, Rodríguez AB, Pariente JA. Melatonin and Oxidative Stress in the Diabetic State: Clinical Implications and Potential Therapeutic Applications. Curr Med Chem 2019; 26:4178-4190. [PMID: 29637854 DOI: 10.2174/0929867325666180410094149] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023]
Abstract
All living organisms exhibit circadian rhythms, which govern the majority of biological functions, including metabolic processes. Misalignment of these circadian rhythms increases the risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect the onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of the human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species (ROS) since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.
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Affiliation(s)
- Javier Espino
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - Ana B Rodríguez
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - José A Pariente
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
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30
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Han D, Wang Y, Chen J, Zhang J, Yu P, Zhang R, Li S, Tao B, Wang Y, Qiu Y, Xu M, Gao E, Cao F. Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin-conferred cardioprotection against myocardial ischemia/reperfusion injury. J Pineal Res 2019; 67:e12571. [PMID: 30903623 DOI: 10.1111/jpi.12571] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/01/2019] [Accepted: 03/17/2019] [Indexed: 12/14/2022]
Abstract
Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin-conferred cardioprotection remains unclear. In this study, we employed both loss-of-function and gain-of-function approaches to reveal the answer. Mice (wild-type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild-type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R-initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2-silenced heart, but not the MT1 subtype. Furthermore, AAV9-mediated cardiomyocyte-specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.
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MESH Headings
- Animals
- Apoptosis
- Disease Models, Animal
- Endoplasmic Reticulum Stress/genetics
- Humans
- Male
- Mice
- Myocardial Reperfusion Injury/genetics
- Myocardial Reperfusion Injury/metabolism
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/prevention & control
- Myocardium/metabolism
- Myocardium/pathology
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Oxidative Stress/genetics
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/genetics
- Receptor, Melatonin, MT2/metabolism
- Signal Transduction
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Affiliation(s)
- Dong Han
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yongjun Wang
- Department of Cardiovascular Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiangwei Chen
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jibin Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Peng Yu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Ran Zhang
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Shuang Li
- Department of Cardiology, Chengdu Military General Hospital, Chengdu, China
| | - Bo Tao
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yabin Wang
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ya Qiu
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Mengqi Xu
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Erhe Gao
- Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Feng Cao
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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31
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Lok R, van Koningsveld MJ, Gordijn MCM, Beersma DGM, Hut RA. Daytime melatonin and light independently affect human alertness and body temperature. J Pineal Res 2019; 67:e12583. [PMID: 31033013 PMCID: PMC6767594 DOI: 10.1111/jpi.12583] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 04/17/2019] [Accepted: 04/19/2019] [Indexed: 12/01/2022]
Abstract
Light significantly improves alertness during the night (Cajochen, Sleep Med Rev, 11, 2007 and 453; Ruger et al., AJP Regul Integr Comp Physiol, 290, 2005 and R1413), but results are less conclusive at daytime (Lok et al., J Biol Rhythms, 33, 2018 and 589). Melatonin and core body temperature levels at those times of day may contribute to differences in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body temperature, and skin temperature was studied. The goal was to assess whether (a) alerting effects of light are melatonin dependent, (b) soporific effects of melatonin are mediated via the thermoregulatory system, and (c) light can improve alertness after melatonin-induced sleepiness during daytime. 10 subjects (5 females, 5 males) received melatonin (5 mg) in dim (10 lux) and, on a separate occasion, in bright polychromatic white light (2000 lux). In addition, they received placebo both under dim and bright light conditions. Subjects participated in all four conditions in a balanced order, yielding a balanced within-subject design, lasting from noon to 04:00 pm. Alertness and performance were assessed half hourly, while body temperature and skin temperature were measured continuously. Saliva samples to detect melatonin concentrations were collected half hourly. Melatonin administration increased melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change subjective alertness scores, but body temperature and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (a) exogenous melatonin administration during daytime increases subjective sleepiness, confirming a role for melatonin in sleepiness regulation, (b) bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness, therefore temperature changes seem nonessential for melatonin-induced sleepiness, (c) subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin-induced sleepiness feelings nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during daytime and nighttime.
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Affiliation(s)
- Renske Lok
- Chronobiology Unit, Groningen Institute for Evolutionary Life SciencesUniversity of GroningenGroningenThe Netherlands
| | - Minke J. van Koningsveld
- Chronobiology Unit, Groningen Institute for Evolutionary Life SciencesUniversity of GroningenGroningenThe Netherlands
| | - Marijke C. M. Gordijn
- Chronobiology Unit, Groningen Institute for Evolutionary Life SciencesUniversity of GroningenGroningenThe Netherlands
- Chrono@WorkGroningenThe Netherlands
| | - Domien G. M. Beersma
- Chronobiology Unit, Groningen Institute for Evolutionary Life SciencesUniversity of GroningenGroningenThe Netherlands
| | - Roelof A. Hut
- Chronobiology Unit, Groningen Institute for Evolutionary Life SciencesUniversity of GroningenGroningenThe Netherlands
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32
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Abstract
For many years now a treatment mitigating the debilitating effects of jet lag has been sought. Rapid travel across time zones leads, in most people, to temporary symptoms, in particular poor sleep, daytime alertness and poor performance. Mis-timed circadian rhythms are considered to be the main factor underlying jet-lag symptoms, together with the sleep deprivation from long haul flights. Virtually all aspects of physiology are rhythmic, from cells to systems, and circadian rhythms are coordinated by a central pacemaker or clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN adapts slowly to changes in time zone, and peripheral clocks or oscillators adapt at different rates, such that the organism is in a state of desynchrony from the external environment and internally. Light exposure is the main factor controlling the circadian system and needs to be considered together with any pharmacological interventions. This review covers the relatively new chronobiotic drugs, which can hasten adaptation of the circadian system, together with drugs directly affecting alertness and sleep propensity. No current treatment can instantly shift circadian phase to a new time zone; however, adaptation can be hastened. The melatoninergic drugs are promising but larger trials in real-life situations are needed. For short stopovers it is recommended to preserve sleep and alertness without necessarily modifying the circadian system. New research suggests that modification of clock function via genetic manipulation may one day have clinical applications.
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Affiliation(s)
- Josephine Arendt
- Faculty of Health and Medical Sciences (FHMS), University of Surrey, Guildford, Surrey, GU2 7XH, UK.
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Mirza-Aghazadeh-Attari M, Mohammadzadeh A, Adib A, Darband SG, Sadighparvar S, Mihanfar A, Majidinia M, Yousefi B. Melatonin-mediated regulation of autophagy: Making sense of double-edged sword in cancer. J Cell Physiol 2019; 234:17011-17022. [PMID: 30859580 DOI: 10.1002/jcp.28435] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 02/09/2019] [Accepted: 02/14/2019] [Indexed: 12/19/2022]
Abstract
Much research has been conducted to discover novel techniques to reverse the process of tumorigenesis and, cure already stablished malignancies. One well-stablished approach has been the use of organic compounds and naturally found agents such as melatonin whose anticancer effects have been shown in multiple studies, signaling a unique opportunity regarding cancer prevention and treatment. Various agents use a variety of methods to exert their anticancer effects. Two of the most important of these methods are interfering with cell signaling pathways and changing cellular functions, such as autophagy, which is essential in maintaining cellular stability against multiple exogenous and endogenous sources of stress, and is a major tool to evade early cell death. In this study, the importance of melatonin and autophagy are discussed, and the effects of melatonin on autophagy, and its contribution in the process of tumorigenesis are then noted.
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Affiliation(s)
- Mohammad Mirza-Aghazadeh-Attari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mohammadzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Adib
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saber Ghazizadeh Darband
- Danesh Pey Hadi Co., Health Technology Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Shirin Sadighparvar
- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Ainaz Mihanfar
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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34
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The Singularity of Cetacea Behavior Parallels the Complete Inactivation of Melatonin Gene Modules. Genes (Basel) 2019; 10:genes10020121. [PMID: 30736361 PMCID: PMC6410235 DOI: 10.3390/genes10020121] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/01/2019] [Accepted: 02/01/2019] [Indexed: 12/26/2022] Open
Abstract
Melatonin, the hormone of darkness, is a peculiar molecule found in most living organisms. Emerging as a potent broad-spectrum antioxidant, melatonin was repurposed into extra roles such as the modulation of circadian and seasonal rhythmicity, affecting numerous aspects of physiology and behaviour, including sleep entrainment and locomotor activity. Interestingly, the pineal gland—the melatonin synthesising organ in vertebrates—was suggested to be absent or rudimentary in some mammalian lineages, including Cetacea. In Cetacea, pineal regression is paralleled by their unique bio-rhythmicity, as illustrated by the unihemispheric sleeping behaviour and long-term vigilance. Here, we examined the genes responsible for melatonin synthesis (Aanat and Asmt) and signalling (Mtnr1a and Mtnr1b) in 12 toothed and baleen whale genomes. Based on an ample genomic comparison, we deduce that melatonin-related gene modules are eroded in Cetacea.
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35
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Feng NY, Marchaterre MA, Bass AH. Melatonin receptor expression in vocal, auditory, and neuroendocrine centers of a highly vocal fish, the plainfin midshipman (Porichthys notatus). J Comp Neurol 2019; 527:1362-1377. [PMID: 30620047 DOI: 10.1002/cne.24629] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/31/2018] [Accepted: 01/02/2019] [Indexed: 11/07/2022]
Abstract
Melatonin plays a central role in entraining activity to the day-night cycle in vertebrates. Here, we investigate neuroanatomical substrates of melatonin-dependent vocal-acoustic behavior in the nocturnal and highly vocal teleost fish, the plainfin midshipman (Porichthys notatus). Using in situ hybridization (ISH) and quantitative real-time PCR (qPCR), we assess the mRNA distribution and transcript abundance of melatonin receptor subtype 1B (mel1b), shown to be important for vocalization in midshipman fish and songbirds. ISH shows robust mel1b expression in major nodes of the central vocal and auditory networks in the subpallium, preoptic area (POA), anterior hypothalamus, dorsal thalamus, posterior tuberculum, midbrain torus semicircularis and periaqueductal gray, and hindbrain. Mel1b label is also abundant in secondary targets of the olfactory, visual, and lateral line systems, as well as telencephalic regions that have been compared to the amygdala, extended amygdala, striatum, septum, and hippocampus of tetrapods. Q-PCR corroborates mel1b abundance throughout the brain and shows significant increases in the morning compared with nighttime in tissue samples inclusive of the telencephalon and POA, but remains stable in other brain regions. Plasma melatonin levels show expected increase at night. Our findings support the hypothesis that melatonin's stimulatory effects on vocal-acoustic mechanisms in midshipman is mediated, in part, by melatonin binding in vocal, auditory, and neuroendocrine centers. Together with robust mel1b expression in multiple telencephalic nuclei and sensory systems, the results further indicate an expression pattern comparable to that in birds and mammals that is indicative of melatonin's broad involvement in the modulation of physiology and behavior.
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Affiliation(s)
- Ni Y Feng
- Department of Neurobiology and Behavior, Cornell University, Ithaca, New York
| | | | - Andrew H Bass
- Department of Neurobiology and Behavior, Cornell University, Ithaca, New York.,Bodega Marine Laboratory, University of California, Davis, Bodega Bay, California
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36
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Singh SS, Deb A, Sutradhar S. Effect of melatonin on arsenic-induced oxidative stress and expression of MT1 and MT2 receptors in the kidney of laboratory mice. BIOL RHYTHM RES 2019. [DOI: 10.1080/09291016.2019.1566993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Shiv Shankar Singh
- Molecular Endocrinology Research Lab, Department of Zoology, Tripura University, Suryamaninagar, India
| | - Anindita Deb
- Molecular Endocrinology Research Lab, Department of Zoology, Tripura University, Suryamaninagar, India
| | - Sangita Sutradhar
- Molecular Endocrinology Research Lab, Department of Zoology, Tripura University, Suryamaninagar, India
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Abstract
This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.
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Hazlerigg D, Lomet D, Lincoln G, Dardente H. Neuroendocrine correlates of the critical day length response in the Soay sheep. J Neuroendocrinol 2018; 30:e12631. [PMID: 29972606 DOI: 10.1111/jne.12631] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/20/2018] [Accepted: 06/30/2018] [Indexed: 12/19/2022]
Abstract
In mammals, melatonin is the hormone responsible for synchronisation of seasonal physiological cycles of physiology to the solar year. Melatonin is secreted by the pineal gland with a profile reflecting the duration of the night and acts via melatonin-responsive cells in the pituitary pars tuberalis (PT), which in turn modulate hypothalamic thyroid hormone status. Recent models suggest that the actions of melatonin in the PT depend critically on day length-dependent changes in the expression of eyes absent 3 (Eya3), which is a coactivator for thyrotrophin β-subunit (Tshβ) gene transcription. According to this model, short photoperiods suppress Eya3 and hence Tshβ expression, whereas long photoperiods produce the inverse effect. Studies underpinning this model have relied on step changes in photoperiod (from 8 to 16 hours of light/24 hours) and have not compared the sensitive ranges of photoperiods for changes in Eya3 and Tshβ expression with those for relevant downstream molecular and endocrine responses. We therefore performed a "critical day length" experiment in Soay sheep, in which animals acclimated to 8 hours of light/24 hours (SP) were exposed to a range of increased photoperiods spanning the range 11.75 to 16 hours (LP) and then responses at the level of the PT, hypothalamus and hormonal output were assessed. Although Eya3 and Tshβ both showed the predicted SP vs LP differences, they responded quite differently to intermediate photoperiods within this range and, at the individual animal level, no clear Eya3-Tshβ relationship could be seen. This result is inconsistent with a simple coactivator model for EYA3 action in the PT. Further downstream layers of nonlinearity were also seen in terms of the Tshβ-dio2 and the dio2-testosterone relationships. We conclude that the transduction of progressive changes in photoperiod into transitions in endocrine output is an emergent property of a multistep signalling cascade within the mammalian neuroendocrine system.
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Affiliation(s)
- David Hazlerigg
- Department of Arctic and Marine Biology, University of Tromsø, Tromsø, Norway
| | - Didier Lomet
- PRC, INRA, CNRS, IFCE, Université de Tours, Nouzilly, France
| | - Gerald Lincoln
- Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Hugues Dardente
- PRC, INRA, CNRS, IFCE, Université de Tours, Nouzilly, France
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39
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Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 2018; 175:3263-3280. [PMID: 28707298 PMCID: PMC6057902 DOI: 10.1111/bph.13950] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 07/05/2017] [Accepted: 07/10/2017] [Indexed: 12/15/2022] Open
Abstract
Melatonin, N-acetyl-5-methoxytryptamine, an evolutionally old molecule, is produced by the pineal gland in vertebrates, and it binds with high affinity to melatonin receptors, which are members of the GPCR family. Among the multiple effects attributed to melatonin, we will focus here on those that are dependent on the activation of the two mammalian MT1 and MT2 melatonin receptors. We briefly summarize the latest developments on synthetic melatonin receptor ligands, including multi-target-directed ligands, and the characterization of signalling-biased ligands. We discuss signalling pathways activated by melatonin receptors that appear to be highly cell- and tissue-dependent, emphasizing the impact of system bias on the functional outcome. Different proteins have been demonstrated to interact with melatonin receptors, and thus, we postulate that part of this system bias has its molecular basis in differences of the expression of receptor-associated proteins including heterodimerization partners. Finally, bias at the level of the receptor, by the expression of genetic receptor variants, will be discussed to show how a modified receptor function can have an effect on the risk for common diseases like type 2 diabetes in humans. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.
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Affiliation(s)
- Erika Cecon
- Institut CochinInserm, U1016ParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Atsuro Oishi
- Institut CochinInserm, U1016ParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Ralf Jockers
- Institut CochinInserm, U1016ParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
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40
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Oliveira-Abreu K, Ferreira-da-Silva FW, Silva-Alves KSD, Silva-Dos-Santos NM, Cardoso-Teixeira AC, Amaral FGD, Cipolla-Neto J, Leal-Cardoso JH. Melatonin decreases neuronal excitability in a sub-population of dorsal root ganglion neurons. Brain Res 2018; 1692:1-8. [PMID: 29702086 DOI: 10.1016/j.brainres.2018.04.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 04/10/2018] [Accepted: 04/23/2018] [Indexed: 12/29/2022]
Abstract
Melatonin, a powerful antioxidant, participates in the regulation of important physiological and pathological processes. We investigated the actions of melatonin on neuronal excitability of intact dorsal root ganglions (DRG) from rats using intracellular recording techniques in current clamps. Melatonin blocked the generation of action potentials in a concentration-dependent manner. Bath applied melatonin (1.0-1000.0 nM) hyperpolarized the resting membrane potential, and increased the input resistance and rheobase. Melatonin also altered the active electrophysiological properties of the action potential, amplitude and maximum descendant inclination, in a statistically significant way. In order to provide evidence on the mechanism of action of melatonin in the DRG, quantitative PCR (qPCR) was performed. Analyses were performed for melatonin membrane receptors, MT1 and MT2, and it was observed that the DRG expresses MT1 receptors. In addition, we noted that the melatonin-induced effects were blocked in the presence of luzindole, a melatonin receptor antagonist. The minimal effective concentrations of melatonin (10.0 nM) and the blockade of effects caused by luzindole suggest that the effects of melatonin are hormonal, and are induced when it binds to MT1 receptors.
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Affiliation(s)
- Klausen Oliveira-Abreu
- Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brazil
| | | | - Kerly Shamyra da Silva-Alves
- Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brazil
| | - Nathalia Maria Silva-Dos-Santos
- Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brazil
| | - Ana Carolina Cardoso-Teixeira
- Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brazil
| | - Fernanda Gaspar do Amaral
- Laboratório de Neurobiologia, Instituto de Ciências Biomédicas 1, Universidade de São Paulo, São Paulo, SP, Brazil
| | - José Cipolla-Neto
- Laboratório de Neurobiologia, Instituto de Ciências Biomédicas 1, Universidade de São Paulo, São Paulo, SP, Brazil
| | - José Henrique Leal-Cardoso
- Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brazil.
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41
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Advances of Melatonin-Based Therapies in the Treatment of Disturbed Sleep and Mood. Handb Exp Pharmacol 2018; 253:305-319. [PMID: 31123831 DOI: 10.1007/164_2018_139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Melatonin and melatonin agonists offer novel treatments for sleep and mood disorders, particularly where circadian misalignment is also present. The therapies offer both phase-shifting and sleep-promoting effects and have shown potential to treat advanced and delayed sleep-wake phase disorder, non-24-h sleep-wake cycle, jetlag, shift work disorder, insomnia, seasonal affective disorder and major depressive disorder.
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42
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Alkozi HA, Sánchez Montero JM, Doadrio AL, Pintor J. Docking studies for melatonin receptors. Expert Opin Drug Discov 2017; 13:241-248. [PMID: 29271261 DOI: 10.1080/17460441.2018.1419184] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Melatonin is a neurohormone that controls many relevant physiological processes beyond the control of circadian rhythms. Melatonin's actions are carried out by two main types of melatonin receptors; MT1 and MT2. These receptors are important, and not just because of the biological actions of its natural agonist; but also, because melatonin analogues can improve or antagonize their biological effect. Area covered: The following article describes the importance of melatonin as a biologically relevant molecule. It also defines the receptors for this substance, as well as the second messengers coupled to these receptors. Lastly, the article describes the amino acid residues involved in the docking process in both MT1 and MT2 melatonin receptors. Expert opinion: The biological actions of melatonin and their interpretations are becoming more relevant and therefore require the development of new pharmacological tools. Understanding the second messenger mechanisms involved in melatonin actions, as well as the characteristics of the docking of this molecule to MT1 and MT2 melatonin receptors, will permit the development of more selective agonists and antagonists which will help us to better understand this molecule as well to develop new therapeutic compounds.
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Affiliation(s)
- Hanan Awad Alkozi
- a Department of Biochemistry and Molecular Biology IV, Faculty of Optometry , Universidad Complutense de Madrid , Madrid , Spain
| | - José Maria Sánchez Montero
- b Department of Organic Chemistry and Pharmaceutical, Faculty of Pharmacy , Ciudad Universitaria , Madrid , Spain
| | - Antonio Luis Doadrio
- c Department of Inorganic Chemistry and Bioorganic, Faculty of Pharmacy , University Complutense of Madrid , Ciudad Universitaria, Madrid , Spain
| | - Jesus Pintor
- a Department of Biochemistry and Molecular Biology IV, Faculty of Optometry , Universidad Complutense de Madrid , Madrid , Spain
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43
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Abstract
The Melatonin (MLT), secreted rhythmically by the pineal, is an efferent hormonal signal of the circadian clock. MLT presents overall pleitropic effects but it is the role of MLT as a hormonal circadian signal which is the best documented. MLT-receptors are present in numerous structures/organs and the MLT is now considered as an endogenous synchronizer within the circadian system. The presence of MLT-receptors within the circadian clock, explains that exogenous MLT is a chronobiotic drug. Trials in humans, have confirmed the efficacy of MLT in circadian rhythm disorders. Subtypes of MLT-receptors have been characterized (MT1 and MT2). Striking differences are observed in the distribution pattern of these 2 subtypes. Up to now, MTL-analogues commercialized as drugs, are all non-specific MT1/MT2 agonists acting on the SCN. The development of new specific agonists/antagonists for both subtypes, the identification of the link between MLT target sites within different parts of the brain or the body and the association of specific MLT receptor subtypes and particular physiological effects open great therapeutic potential.
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Affiliation(s)
- P Pevet
- Institute for Cellular and Integrative Neurosciences (UPR 3212), CNRS and University of Strasbourg, Strasbourg France.
| | - P Klosen
- Institute for Cellular and Integrative Neurosciences (UPR 3212), CNRS and University of Strasbourg, Strasbourg France.
| | - M P Felder-Schmittbuhl
- Institute for Cellular and Integrative Neurosciences (UPR 3212), CNRS and University of Strasbourg, Strasbourg France.
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44
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Choi JY, Choe JR, Lee TH, Choi CY. Effects of bisphenol A and light conditions on the circadian rhythm of the goldfish Carassius auratus. BIOL RHYTHM RES 2017. [DOI: 10.1080/09291016.2017.1385977] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Ji Yong Choi
- Division of Marine BioScience, Korea Maritime and Ocean University, Busan, Republic of Korea
| | - Jong Ryeol Choe
- Division of Marine BioScience, Korea Maritime and Ocean University, Busan, Republic of Korea
| | - Tae Ho Lee
- Division of Marine BioScience, Korea Maritime and Ocean University, Busan, Republic of Korea
| | - Cheol Young Choi
- Division of Marine BioScience, Korea Maritime and Ocean University, Busan, Republic of Korea
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45
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Jang H, Na Y, Hong K, Lee S, Moon S, Cho M, Park M, Lee OH, Chang EM, Lee DR, Ko JJ, Lee WS, Choi Y. Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27 Kip1 promoter in primordial follicles. J Pineal Res 2017; 63. [PMID: 28658519 DOI: 10.1111/jpi.12432] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 06/23/2017] [Indexed: 12/31/2022]
Abstract
Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27Kip1 , which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients.
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Affiliation(s)
- Hoon Jang
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
| | - Younghwa Na
- College of Pharmacy, CHA University, Gyeonggi, Korea
| | - Kwonho Hong
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Korea
| | - Sangho Lee
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
| | - Sohyeon Moon
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
| | - Minha Cho
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
| | - Miseon Park
- Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, Seoul, Korea
| | - Ok-Hee Lee
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
| | - Eun Mi Chang
- Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, Seoul, Korea
| | - Dong Ryul Lee
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
| | - Jung Jae Ko
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
- Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, Seoul, Korea
| | - Woo Sik Lee
- Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, Seoul, Korea
| | - Youngsok Choi
- Department of Biomedical Science, CHA University, Gyeonggi, Korea
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46
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Lo Sardo F, Muti P, Blandino G, Strano S. Melatonin and Hippo Pathway: Is There Existing Cross-Talk? Int J Mol Sci 2017; 18:ijms18091913. [PMID: 28878191 PMCID: PMC5618562 DOI: 10.3390/ijms18091913] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/30/2017] [Accepted: 09/01/2017] [Indexed: 12/16/2022] Open
Abstract
Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy.
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Affiliation(s)
- Federica Lo Sardo
- Oncogenomic and Epigenetic Unit, Molecular Chemoprevention Group, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
| | - Paola Muti
- Department of Oncology, Juravinski Cancer Center, McMaster University, Hamilton, ON L8S 4L8, Canada.
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, Molecular Chemoprevention Group, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
| | - Sabrina Strano
- Oncogenomic and Epigenetic Unit, Molecular Chemoprevention Group, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
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47
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Nogueira RC, Sampaio LDFS. Eye and heart morphogenesis are dependent on melatonin signaling in chick embryos. ACTA ACUST UNITED AC 2017; 220:3826-3835. [PMID: 28839011 DOI: 10.1242/jeb.159848] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 08/18/2017] [Indexed: 12/15/2022]
Abstract
Calmodulin is vital for chick embryos morphogenesis in the incubation time 48-66 h when the rudimentary C-shaped heart attains an S-shaped pattern and the optic vesicles develop into optic cups. Melatonin is in the extraembryonic yolk sac of the avian egg; melatonin binds calmodulin. The aim of this study was to investigate the function of melatonin in the formation of the chick embryo optic cups and S-shaped heart, by pharmacological methods and immunoassays. Mel1a melatonin receptor immunofluorescence was distributed in the optic cups and rudimentary hearts. We separated embryonated chicken eggs at 48 h of incubation into basal, control and drug-treated groups, with treatment applied in the egg air sac. At 66 h of incubation, embryos were excised from the eggs and analyzed. Embryos from the basal, control (distilled water), melatonin and 6-chloromelatonin (melatonin receptor agonist) groups had regular optic cups and an S-shaped heart, while those from the calmidazolium (calmodulin inhibitor) group did not. Embryos from the luzindole (melatonin receptor antagonist) and prazosin (Mel1c melatonin receptor antagonist) groups did not have regular optic cups. Embryos from the 4-P-PDOT (Mel1b melatonin receptor antagonist) group did not have an S-shaped heart. Previous application of the melatonin, 6-chloromelatonin or forskolin (adenylate cyclase enhancer) prevented the abnormal appearance of chick embryos from the calmidazolium, luzindole, prazosin and 4-P-PDOT groups. However, 6-chloromelatonin and forskolin only partially prevented the development of defective eye cups in embryos from the calmidazolium group. The results suggested that melatonin modulates chick embryo morphogenesis via calmodulin and membrane receptors.
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Affiliation(s)
- Renato C Nogueira
- Laboratório de Bioquímica do Desenvolvimento do Sistema Nervoso, Instituto de Ciências Biológicas, Universidade Federal do Pará. Av. Augusto Corrêa 1, CEP: 66075-110 Belém, PA, Brazil
| | - Lucia de Fatima S Sampaio
- Laboratório de Bioquímica do Desenvolvimento do Sistema Nervoso, Instituto de Ciências Biológicas, Universidade Federal do Pará. Av. Augusto Corrêa 1, CEP: 66075-110 Belém, PA, Brazil
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48
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Yeh CM, Su SC, Lin CW, Yang WE, Chien MH, Reiter RJ, Yang SF. Melatonin as a potential inhibitory agent in head and neck cancer. Oncotarget 2017; 8:90545-90556. [PMID: 29163852 PMCID: PMC5685773 DOI: 10.18632/oncotarget.20079] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 07/26/2017] [Indexed: 12/29/2022] Open
Abstract
Melatonin is a molecule secreted by the pineal gland; it is an important regulator of sleep and circadian rhythms. Through multiple interrelated mechanisms, melatonin exhibits various inhibitory properties at different stages of tumor progression. Many studies have explored the oncostatic effects of melatonin on hormone-dependent tumors. In this review, we highlight recent advances in understanding the effects of melatonin on the development of head and neck cancers, including molecular mechanisms identified through experimental and clinical observations. Because melatonin exerts a wide range of effects, melatonin may influence many mechanisms that influence the development of cancer. These include cell proliferation, apoptosis, angiogenesis, extracellular matrix remodeling through matrix metalloproteinases, and genetic polymorphism. Thus, the evidence discussed in this article will serve as a basis for basic and clinical research to promote the use of melatonin for understanding and controlling the development of head and neck cancers.
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Affiliation(s)
- Chia-Ming Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wei-En Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
| | - Russel J Reiter
- Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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49
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Geng CA, Huang XY, Ma YB, Hou B, Li TZ, Zhang XM, Chen JJ. (±)-Uncarilins A and B, Dimeric Isoechinulin-Type Alkaloids from Uncaria rhynchophylla. JOURNAL OF NATURAL PRODUCTS 2017; 80:959-964. [PMID: 28225280 DOI: 10.1021/acs.jnatprod.6b00938] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
(±)-Uncarilins A and B (1a/1b and 2a/2b), two pairs of unusual dimeric isoechinulin-type enantiomers with a symmetric four-membered core, were isolated from Uncaria rhynchophylla driven by LCMS-IT-TOF analyses. Their structures were elucidated by extensive 1D and 2D NMR spectra, X-ray diffraction, and ECD spectroscopic data. (-)-Uncarilin B (2a) showed activities on MT1 and MT2 receptors with agonistic rates of 11.26% and 52.44% at a concentration of 0.25 mM.
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Affiliation(s)
- Chang-An Geng
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
| | - Xiao-Yan Huang
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
| | - Yun-Bao Ma
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
| | - Bo Hou
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
| | - Tian-Ze Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
| | - Xue-Mei Zhang
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
| | - Ji-Jun Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China
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50
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Ren W, Liu G, Chen S, Yin J, Wang J, Tan B, Wu G, Bazer FW, Peng Y, Li T, Reiter RJ, Yin Y. Melatonin signaling in T cells: Functions and applications. J Pineal Res 2017; 62. [PMID: 28152213 DOI: 10.1111/jpi.12394] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Accepted: 01/27/2017] [Indexed: 12/21/2022]
Abstract
Melatonin affects a variety of physiological processes including circadian rhythms, cellular redox status, and immune function. Importantly, melatonin significantly influences T-cell-mediated immune responses, which are crucial to protect mammals against cancers and infections, but are associated with pathogenesis of many autoimmune diseases. This review focuses on our current understanding of the significance of melatonin in T-cell biology and the beneficial effects of melatonin in T-cell response-based diseases. In addition to expressing both membrane and nuclear receptors for melatonin, T cells have the four enzymes required for the synthesis of melatonin and produce high levels of melatonin. Meanwhile, melatonin is highly effective in modulating T-cell activation and differentiation, especially for Th17 and Treg cells, and also memory T cells. Mechanistically, the influence of melatonin in T-cell biology is associated with membrane and nuclear receptors as well as receptor-independent pathways, for example, via calcineurin. Several cell signaling pathways, including ERK1/2-C/EBPα, are involved in the regulatory roles of melatonin in T-cell biology. Through modulation in T-cell responses, melatonin exerts beneficial effects in various inflammatory diseases, such as type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. These findings highlight the importance of melatonin signaling in T-cell fate determination, and T cell-based immune pathologies.
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Affiliation(s)
- Wenkai Ren
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
- University of the Chinese Academy of Sciences, Beijing, China
| | - Gang Liu
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
| | - Shuai Chen
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
| | - Jie Yin
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
| | - Jing Wang
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
| | - Bie Tan
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Yuanyi Peng
- Chongqing Key Laboratory of Forage & Herbivore, College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Tiejun Li
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
- Hunan Co-Innovation Center of Animal Production Safety, CICAPS, Changsha, Hunan, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Yulong Yin
- Laboratory of Animal Nutrition and Health and Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China
- College of Animal Science, South China Agricultural University, Guangzhou, China
- School of Life Science, Hunan Normal University, Changsha, China
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