Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

/pdf/melatonin-pharmacology-functions-and-therapeutic-benefits-1q6ku6rylm.pdf

Melatonin: Pharmacology, Functions and Therapeutic Benefits

Reactive oxygen species (ROS) serve as cell signaling molecules for normal biologic processes. However, the generation of ROS can also provoke damage to multiple cellular organelles and processes, which can ultimately disrupt normal physiology. An imbalance between the production of ROS and the antioxidant defenses that protect cells has been implicated in the pathogenesis of a variety of diseases, such as cancer, asthma, pulmonary hypertension, and retinopathy. The nature of the injury will ultimately depend on specific molecular interactions, cellular locations, and timing of the insult. This review will outline the origins of endogenous and exogenously generated ROS. The molecular, cellular, pathologic, and physiologic targets will then be discussed with a particular emphasis on aspects relevant to child development. Finally, antioxidant defenses that scavenge ROS and mitigate associated toxicities will be presented, with a discussion of potential therapeutic approaches for the prevention and/or treatment of human diseases using enzymatic and nonenzymatic antioxidants.

/pdf/oxygen-toxicity-and-reactive-oxygen-species-the-devil-is-in-29mvohxtxq.pdf

Oxygen toxicity and reactive oxygen species: the devil is in the details.

Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.

Melatonin as a hormone: new physiological and clinical insights

Many processes in the human body — including brain function — are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep–wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.

/pdf/rhythms-of-life-circadian-disruption-and-brain-disorders-1m0o2384sk.pdf

Rhythms of life: circadian disruption and brain disorders across the lifespan.

The human pineal gland is a neuroendocrine transducer that forms an integral part of the brain. Through the nocturnally elevated synthesis and release of the neurohormone melatonin, the pineal gland encodes and disseminates information on circadian time, thus coupling the outside world to the biochemical and physiological internal demands of the body. Approaches to better understand molecular details behind the rhythmic signalling in the human pineal gland are limited but implicitly warranted, as human chronobiological dysfunctions are often associated with alterations in melatonin synthesis. Current knowledge on melatonin synthesis in the human pineal gland is based on minimally invasive analyses, and by the comparison of signalling events between different vertebrate species, with emphasis put on data acquired in sheep and other primates. Together with investigations using autoptic pineal tissue, a remnant silhouette of premortem dynamics within the hormone's biosynthesis pathway can be constructed. The detected biochemical scenario behind the generation of dynamics in melatonin synthesis positions the human pineal gland surprisingly isolated. In this neuroendocrine brain structure, protein-protein interactions and nucleo-cytoplasmic protein shuttling indicate furthermore a novel twist in the molecular dynamics in the cells of this neuroendocrine brain structure. These findings have to be seen in the light that an impaired melatonin synthesis is observed in elderly and/or demented patients, in individuals affected by Alzheimer's disease, Smith-Magenis syndrome, autism spectrum disorder and sleep phase disorders. Already, recent advances in understanding signalling dynamics in the human pineal gland have significantly helped to counteract chronobiological dysfunctions through a proper restoration of the nocturnal melatonin surge.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2011.00856.x

A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases.

The development of rhythmic 6-sulfatoxymelatonin excretion in urine was studied in healthy full-term and premature infants during the first 12 months of life. There was little evidence of rhythmic 6-sulfatoxymelatonin excretion before 9 to 12 weeks of age in full-term infants. Over this period, excretion increased five to six times compared to the excretion at 6 weeks (08 +/- 103 vs. 2973 +/- 438 pmol/24 h) with the major proportion of the hormone metabolite being excreted between 0200-1000 h. At 24 weeks of age, total 6-sulfatoxymelatonin excretion was 25% of adult levels. Premature infants (51 +/- 4 days premature) had a delay in the appearance of rhythmic 6-sulfatoxymelatonin of approximately 9 weeks. Even after correcting for gestational age or length of time at home, the premature infants were found to have a 2-3 week delay in the development of 6-sulfatoxymelatonin rhythmicity compared to full-term infants. These results provide evidence that neural centers responsible for rhythm generation and/or the pineal gland fail to accelerate their development after premature delivery. This may be due to the environment the infants are exposed to during their stay in hospital, particularly the pattern and intensity of lighting.

Development of melatonin production in infants and the impact of prematurity.

The emergence of melatonin rhythmicity was studied in 163 infants between 46-55 weeks postconception by monitoring the excretion of the urinary melatonin metabolite 6-sulfatoxymelatonin (aMT.6S). From this population, we examined the effects of gender, season, multiple birth, home birth, previous sudden infant death syndrome in the family, premature labor, spontaneous rupture of membranes, preeclampsia, intrauterine growth restriction, and nursery lighting on pineal rhythmicity. As previously reported, rhythmic excretion of aMT.6S appeared between 49-55 weeks postconception (9-15 weeks of age) in singleton babies born at term in the hospital. Full-term infants who had a sibling die of sudden infant death syndrome had a pattern of melatonin rhythm development no different from that of the control full-term infants. In contrast, full-term infants born at home and full-term twins born in the hospital had significantly lower aMT.6S excretion than hospital-born singleton infants at the same ages despite similar body weights (e.g. at 52 weeks postconception; 1.8 +/- 0.4, 1.1 +/- 0.3, and 3.6 +/ -0.5 nmol/day, respectively). In full-term infants, there was no difference in the development of melatonin rhythmicity between the sexes, with season or method of delivery (vaginal vs. caesarean). The premature infants were divided into 5 groups (babies born after premature labor, premature rupture of membranes, preeclampsia, intrauterine growth restriction, and fetal distress). All premature infants had a delay in the appearance of aMT.6S rhythms in the urine in relation to chronological age. When the infants were compared on the basis of weeks since conception, those infants born after spontaneous premature labor excreted amounts of aMT.6S no different from those of full-term singleton infants during the period of study. In contrast, the premature rupture of membranes, preeclampsia, and fetal distressed infants excreted 50% less aMT.6S, and intrauterine growth restricted infants excreted 67% less at the same postconceptional ages. These differences were due to reduced nocturnal excretion of the metabolite. In an attempt to accelerate the development of melatonin rhythmicity, premature labor and premature rupture of membranes infants were randomly assigned to be totally deprived of light (using phototherapy eye shields) or partially deprived of light by moving them to a dimly lit room each night for the last 3-8 weeks of their stay in the hospital nursery. Babies born after premature labor produced normal amounts of aMT.6S between 46-52 weeks postconception, and this pattern was not affected by the nocturnal light deprivation. Infants born after premature rupture of membranes and totally deprived of light at night had aMT.6S excretion rhythms at 52 weeks postconception no different from those of full-term hospital-born infants or premature labor infants, whereas those in infants placed in dim light were similar to those in untreated premature rupture of membranes infants. These results suggest that premature birth alone is not the sole cause of altered rhythm development; other factors, such as preeclampsia, growth restriction, and nursery lighting, play an important role. The consequences of the delayed appearance of melatonin in infants are not known, but deserve further study.

/pdf/factors-influencing-the-development-of-melatonin-rhythmicity-fvkl1du2qi.pdf

Factors influencing the development of melatonin rhythmicity in humans

Clinical Review 36: Cardiovascular Manifestationsof Endocrine DiseaseEditorial: Non-Thyrotropin-Dependent ThyroidSecretionLevothyroxine Dose Requirements for ThyrotropinSuppression in the Treatment of DifferentiatedThyroid CancerEffects of Low-Protein Diets on Protein Metabolismin Insulin-Dependent Diabetes Mellitus Patientswith Early NephropathyPeculiar Distribution of Adipose Tissue in Patientswith Congenital Generalized LipodystrophyStudies in a Kindred with Parathyroid CarcinomaDevelopment of Melatonin Production in Infants andthe Impact of PrematurityEffect of Deltorphin on Pituitary-Adrenal Responseto Insulin-Induced Hypoglycemia and OvineCorticotropin-Releasing Hormone in Healthy ManFood Contains the Bioactive Peptide, Cyclo(His-Pro)I Klein and K Ojamaa 339J T Nicoloff and C A Spencer 343L A Burmeister, M 0 Goumaz, 344C N Mariash, andJ H OppenheimerI G Brodsky, D C Robbins, 351E Hiser, S P Fuller, M Fillyaw,and J T DevlinA Garg, J L Fleckenstein, 358R M Peshock, and S M GrundyE A Streeten, L S Weinstein, 362J A Norton, J J Mulvihill,B J White, E Friedman, G Jaffe,M L Brandi, K Stewart,M B Zimering, A M Spiegel,G D Aurbach, and S J MarxD J Kennaway, G E  Stamp, and 367F C GobleE C Degli Uberti, S Salvadori, 370G Trasforini, A Margutti,M R Ambrosio, R Rossi,F Portaluppi an, d R PansiniC W Hilton, C Prasad, P Vo, and 375C MoutonTHE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM (ISSN 0021-972X is The) Official Journa of Thl eEndocrine Society, published monthl by The Endocriny e Society, 9650 Rockville Pike M, BethesdaD 20814 Secon, d classpostage paid at Bethesda, MD and at additional mailing offices Subscription rates $11500 ($15500 foreign); institutions $16500($20500 foreign); in-training $7500 ($11500 foreign); single copy $1500 ($1800 foreign) Annua fol duer journas includl e $60subscription Subscription prices subjec to changet  All subscriptions start with the January issue To order call (301) 571-1802Japanese yen price is available from ou exclusivr e agen itn Japan, Igaku Shoin Ltd, 1-28-3 6 Hongo , Bunko-ku Toyk 113oJapan POSTMASTER: send address change to Thse Journal of Clinical Endocrinology and Metabolism, 9650 Rockville Pike,Bethesda, MD 20814 Indexed by Index Medicus, Current Contents, BIOSIS and Curren, t Awarenes ins Biological SciencesCopyright © 1992 by The Endocrine SocietyContents continued on page 10A9A

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Development of melatonin production in infants and the impact of prematurity.

Factors influencing the development of melatonin rhythmicity in humans

Clinical endocrinology & metabolism