Cited by 883Circadian rhythm and melatoninmelanin and skin pigmentationImpact of Light on Environment and Health

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Melatonin: Nature’s most versatile biological signal?

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Pandi‐Perumal, S. R., Srinivasan, V., Maestroni, G. J. M., Cardinali, D. P., Poeggeler, B., Hardeland, R.·2006·The FEBS Journal

DOI 10.1111/j.1742-4658.2006.05322.x

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Abstract

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.

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N 1 ‐acetyl‐ N 2 ‐formyl‐5‐methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant
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Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFκB activation
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The immunotherapeutic potential of melatonin
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Daily Melatonin Administration at Middle Age Suppresses Male Rate Visceral Fat, Plasma Leptin, and Plasma Insulin to Youthful Levels
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Transcriptional activation of the nuclear receptor RZRα by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand
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Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum
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Double Blind Study of Melatonin Effects on the Sleep-wake Rhythm, Cognitive and Non-cognitive Functions in Alzheimer Type Dementia
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An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease
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Melatonin, immune function and aging
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Melatonin effects on bone: experimental facts and clinical perspectives
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Putting Cancer to Sleep at Night: The Neuroendocrine/Circadian Melatonin Signal
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Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction
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Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro
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Melatonin and circadian control in mammals
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The Mitochondrial Production of Reactive Oxygen Species in Relation to Aging and Pathology
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Melatonin as an antioxidant: physiology versus pharmacology
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Role of melatonin in neurodegenerative diseases
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Melatonin and the Circadian Regulation of Sleep Initiation, Consolidation, Structure, and the Sleep EEG
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Melatonin mediates two distinct responses in vascular smooth muscle
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Melatonin as a cytoskeletal modulator: implications for cell physiology and disease
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The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration
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Seasonal Changes in Adiposity: the Roles of the Photoperiod, Melatonin and Other Hormones, and Sympathetic Nervous System
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Delayed sleep phase syndrome: A placebo‐controlled cross‐over study on the effects of melatonin administered five hours before the individual dim light melatonin onset
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Diminished Melatonin Secretion in the Elderly Caused by Insufficient Environmental Illumination1
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Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome
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Basic aspects of melatonin action
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Impaired nocturnal secretion of melatonin in coronary heart disease
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Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical
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Circadian Rhythm Sleep Disorders
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Five years survival in metastatic non‐small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial
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Functional Melatonin Receptors in Rat Ovaries at Various Stages of the Estrous Cycle
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Rhythms of glutathione peroxidase and glutathione reductase in brain of chick and their inhibition by light
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Melatonin as a hypnotic: Pro
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Melatonin reduces nitric oxide synthase activity in rat hypothalamus
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The role of melatonin in immuno‐enhancement: potential application in cancer
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Sleep-Promoting Effects of Melatonin: At What Dose, in Whom, Under What Conditions, and by What Mechanisms?
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Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans
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Inverse Seasonal Relationship Between Melatonin and Ovarian Activity in Humans in a Region With a Strong Seasonal Contrast in Luminosity*
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Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men
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The Mitochondrial Production of Reactive Oxygen Species in Relation to Aging and Pathology
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Melatonin's unique radical scavenging properties – roles of its functional substituents as revealed by a comparison with its structural analogs
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Reactive Oxygen Intermediates, Molecular Damage, and Aging: Relation to Melatonin
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Melatonin: Role in Gating Nocturnal Rise in Sleep Propensity
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Functional Expression of MT2 (Mel1b) Melatonin Receptors in Human PAZ6 Adipocytes
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The use of melatonin in Alzheimer's disease.
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Glucocorticoid-Induced Osteoporosis
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Melatonin and its precursors scavenge nitric oxide
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AMPLIFICATION OF NOCTURNAL MELATONIN SECRETION IN WOMEN WITH FUNCTIONAL HYPOTHALAMIC AMENORRHEA
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Direct Effect of Melatonin on Syrian Hamster Testes: Melatonin Subtype 1a Receptors, Inhibition of Androgen Production, and Interaction with the Local Corticotropin-Releasing Hormone System
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Monozygotic twins with Alzheimer's disease treated with melatonin: Case report
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Melatonin for the Treatment of Sleep Disturbances in Major Depressive Disorder
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Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease
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Antioxidant properties of melatonin: a pulse radiolysis study
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Nitrosation of melatonin by nitric oxide and peroxynitrite
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Overview: clinical and physiological comparison of meditation with other self-control strategies
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Melatonin activates Th1 lymphocytes by increasing IL-12 production
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Melatonin as a hydroxyl radical scavenger
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Melatonin and cancer risk: does light at night compromise physiologic cancer protection by lowering serum melatonin levels?
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Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans
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A Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effect of Exogenous Melatonin on Delayed Sleep Phase Syndrome
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Melatonin for treatment of sundowning in elderly persons with dementia – a preliminary study
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Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease
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Anticarcinogenic actions of melatonin which involve antioxidative processes: comparison with other antioxidants
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Serum melatonin and urinary 6-sulfatoxymelatonin in major depression
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Melatonin Reverses the Profibrillogenic Activity of Apolipoprotein E4 on the Alzheimer Amyloid Aβ Peptide
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Senescence, sleep, and circadian rhythms
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GLUCOCORTICOID-INDUCED OSTEOPOROSIS
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Acute increases in night-time plasma melatonin levels following a period of meditation
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How to Trick Mother Nature into Letting You Fly Around or Stay Up All Night
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Chronobiotics—drugs that shift rhythms
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Ubiquitous melatonin-presence and effects in unicells, plants and animals
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Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and Apoptosis in Alzheimer’s Disease
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Improvement of sleep quality by melatonin
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Melatonin Receptor Activation Regulates GnRH Gene Expression and Secretion in GT1–7 GnRH Neurons
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Melatonin
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Mitochondrial regulation by melatonin And its metabolites
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DNA oxidatively damaged by chromium(III) and H2O2 is protected by the antioxidants melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, resveratrol and uric acid
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Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system
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Melatonin, Sleep, and Shift Work Adaptation
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Gene Regulation by Melatonin
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Some Effects of Melatonin and the Control of its Secretion in Humans
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Serum Melatonin in Central Precocious Puberty Is Lower than in Age-Matched Prepubertal Children*
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The pineal, a tranquillizing organ?
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Melatonin receptor (MT1) knockout mice display depression-like behaviors and deficits in sensorimotor gating
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The 2004 Aschoff/Pittendrigh Lecture: Theory of the Origin of the Pineal Gland— A Tale of Conflict and Resolution
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Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells
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Neuroendocrine Aspects of Primary Endogenous Depression
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Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar
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Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod
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Reactions of the melatonin metabolite AMK (N1‐acetyl‐5‐methoxykynuramine) with reactive nitrogen species: Formation of novel compounds, 3‐acetamidomethyl‐6‐methoxycinnolinone and 3‐nitro‐AMK
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Authors: Pandi‐Perumal, S. R., Srinivasan, V., Maestroni, G. J. M., Cardinali, D. P., Poeggeler, B., & Hardeland, R.
Affiliations: Universiti Sains Malaysia (MY)
Istituto Cantonale di Patologia (CH)
Universidad de Buenos Aires (AR)
University of Göttingen (DE)
ORCID: Cardinali, D. P.
Hardeland, R.
Venue: The FEBS Journal
Publisher: Wiley
Published: 2006-06-15
Volume: 273
Issue: 13
Pages: 2813-2838
ISSN: 1742-464X (ISSN-L)
1742-4658
DOI: 10.1111/j.1742-4658.2006.05322.x
OpenAlex: W2049985521
Cited by: 875
References: 293
Citations by year: 2026: 15 · 2025: 29 · 2024: 33 · 2023: 33 · 2022: 42 · 2021: 56 · 2020: 47 · 2019: 49 · 2018: 42 · 2017: 45 · 2016: 34 · 2015: 38 · 2014: 53 · 2013: 53 · 2012: 51
FWCI: 5.54
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: FEBS Journal (publishedVersion)
PubMed (publishedVersion)
GRO (submittedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
Physical Sciences › Environmental Science › Global and Planetary Change › Impact of Light on Environment and Health
Keywords: melatonin, pineal gland, suprachiasmatic nucleus, circadian rhythm, sleep regulation, antioxidant activity, anti-apoptotic signaling, neuroprotection, neurodegenerative diseases, immunomodulation, circadian rhythm sleep disorders, jet lag, shift work disorder, insomnia, agomelatine, photoperiodism, seasonal reproduction, melatonin analogues
MeSH terms: Animals, Antioxidants, Chronobiology Phenomena, Depression, Humans, Melatonin, Models, Chemical, Plant Proteins, Sleep, Signal Transduction, Free Radical Scavengers, Apoptosis, Receptors, Melatonin

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