Melatonin

Melatonin: the placental antioxidant and anti-inflammatory.

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.

A review of sleep disorders and melatonin.

Sleep disorders are a group of conditions that affect the ability to sleep well on a regular basis and cause significant impairments in social and occupational functions. Although currently approved medications are efficacious, they are far from satisfactory. Benzodiazepines, antidepressants, antihistamines and anxiolytics have the potential for dependence and addiction. Moreover, some of these medications can gradually impair cognition. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone produced by the pineal gland and released exclusively at night. Exogenous melatonin supplementation is well tolerated and has no obvious short- or long-term adverse effects. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. It is centrally involved in anti-oxidation, circadian rhythmicity maintenance, sleep regulation and neuronal survival. This narrative review aims to provide a comprehensive overview of various therapeutic functions of melatonin in insomnia, sleep-related breathing disorders, hypersomnolence, circadian rhythm sleep-wake disorders and parasomnias. Melatonin offers an alternative treatment to the currently available pharmaceutical therapies for sleep disorders with significantly less side effects.

5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology.

L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.

Effects of a single dose of N-Acetyl-5-methoxytryptamine (Melatonin) and resistance exercise on the growth hormone/IGF-1 axis in young males and females.

Melatonin and resistance exercise alone have been shown to increase the levels of growth hormone (GH). The purpose of this study was to determine the effects of ingestion of a single dose of melatonin and heavy resistance exercise on serum GH, somatostatin (SST), and other hormones of the GH/insulin-like growth factor 1 (IGF-1) axis. Physically active males (n = 30) and females (n = 30) were randomly assigned to ingest either a melatonin supplement at 0.5 mg or 5.0 mg, or 1.0 mg of dextrose placebo. After a baseline blood sample, participants ingested the supplement and underwent blood sampling every 15 min for 60 min, at which point they underwent a single bout of resistance exercise with the leg press for 7 sets of 7 reps at 85% 1-RM. After exercise, participants provided additional blood samples every 15 min for a total of 120 min. Serum free GH, SST, IGF-1, IGFBP-1, and IGFBP-3 were determined with ELISA. Data were evaluated as the peak pre- and post-exercise values subtracted from baseline and the delta values analyzed with separate three-way ANOVA (p < 0.05). In males, when compared to placebo, 5.0 mg melatonin caused GH to increase (p = 0.017) and SST to decrease prior to exercise (p = 0.031), whereas both 0.5 and 5.0 mg melatonin were greater than placebo after exercise (p = 0.045) and less than placebo for SST. No significant differences occurred for IGF-1; however, males were shown to have higher levels of IGFBP-1 independent of supplementation (p = 0.004). The 5.0 mg melatonin dose resulted in higher IGFBP-3 in males (p = 0.017). In conclusion, for males 5.0 mg melatonin appears to increase serum GH while concomitantly lowering SST levels; however, when combined with resistance exercise both melatonin doses positively impacts GH levels in a manner not entirely dependent on SST.

Melatonin Ameliorates Depressive-Like Behaviors in Ovariectomized Mice by Improving Tryptophan Metabolism via Inhibition of Gut Microbe Alistipes Inops.

Melatonin (N-acetyl-5-methoxytryptamine) is reported to improve mood disorders in perimenopausal women and gut microbiome composition is altered during menopausal period. The possible role of microbiome in the treatment effect of melatonin on menopausal depression remains unknown. Here, it is shown that melatonin treatment reverses the gut microbiota dysbiosis and depressive-like behaviors in ovariectomy (OVX) operated mice. This effect of melatonin is prevented by antibiotic cocktails (ABX) treatment. Transferring microbiota harvested from adolescent female mice to OVX-operated mice is sufficient to ameliorate depressive-like behaviors. Conversely, microbiota transplantation from OVX-operated mice or melatonin-treated OVX-operated mice to na&#xef;ve recipient mice exhibits similar phenotypes to donors. The colonization of Alistipes Inops, which is abundant in OVX-operated mice, confers the recipient with depressive-like behaviors. Further investigation indicates that the expansion of Alistipes Inops induced by OVX leads to the degradation of intestinal tryptophan, which destroys systemic tryptophan availability. Melatonin supplementation restores systemic tryptophan metabolic disorders by suppressing the growth of Alistipes Inops, which ameliorates depressive-like behaviors. These results highlight the previously unrecognized role of Alistipes Inops in the modulation of OVX-induced behavioral disorders and suggest that the application of melatonin to inhibit Alistipes Inops may serve as a potential strategy for preventing menopausal depressive symptoms.

Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders.

Melatonin is ubiquitous molecule with wide distribution in nature and is produced by many living organisms. In human beings, pineal gland is the major site for melatonin production and to lesser extent by retina, lymphocytes, bone marrow, gastrointestinal tract, and thymus. Melatonin as a neurohormone is released into circulation wherein it penetrates all tissues of the body. Melatonin synthesis and secretion is supressed by light and enhanced by dark. Melatonin mostly exerts its effect through different pathways with melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) being the predominant type of receptor that are mainly expressed by many mammalian organs. Melatonin helps to regulate sleep patterns and circadian rhythms. In addition, melatonin acts as an antioxidant and scavenges excessive free radicals generated in the body by anti-excitatory and anti-inflammatory properties. A multiple array of other functions are displayed by melatonin that include oncostatic, hypnotic, immune regulation, reproduction, puberty timing, mood disorders, and transplantation. Deficiencies in the production or synthesis of melatonin have been found to be associated with onset of many disorders like breast cancer and neurodegenerative disorders. Melatonin could be used as potential analgesic drug in diseases associated with pain and it has quite promising role there. In the past century, a growing interest has been developed regarding the wide use of melatonin in treating various diseases like inflammatory, gastrointestinal, cancer, mood disorders, and others. Several melatonin agonists have been synthesized and are widely used in disease treatment. In this review, an effort has been made to describe the biochemistry of melatonin along with its therapeutic potential in various diseases of humans.

Phytomelatonin: a review.

Melatonin (N-acetyl-5-methoxytryptamine) has been detected in a number of plant species. Indeed, there exists evidence that this classically-considered animal indole is actually both synthesized in and taken up by plants. Among the actions that melatonin may carry out in plant tissues, its role as an antioxidant or growth promoter is most strongly supported by the experimental evidence. Other suggested functional implications include the co-ordination of photoperiodic responses and regulation of plant reproductive physiology, defence of plant cells against apoptosis induced by harsh environmental conditions, its participation as a free radical scavenging agent and/or up-regulator of certain protective enzymes in the senescent process. This review presents a detailed summary of the investigations that have been performed to date in the plant melatonin (phytomelatonin) field. The purpose of this summary is to bring the reader up to date on what is known about melatonin in plants and to encourage plant scientists to investigate this novel research topic; this would certainly assist in solving the numerous questions that still remain regarding the role of melatonin in plants.

Melatonin and female reproduction.

Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by the pineal gland. After entering the circulation, melatonin acts as an endocrine factor and a chemical messenger of light and darkness. It regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It also affects the brain, immune, gastrointestinal, cardiovascular, renal, bone and endocrine functions and acts as an oncostatic and anti-aging molecule. Many of melatonin's actions are mediated through interactions with specific membrane-bound receptors expressed not only in the central nervous system, but also in peripheral tissues. Melatonin also acts through non-receptor-mediated mechanisms, for example serving as a scavenger for reactive oxygen species and reactive nitrogen species. At both physiological and pharmacological concentrations, melatonin attenuates and counteracts oxidative stress and regulates cellular metabolism. Growing scientific evidence of reproductive physiology supports the role of melatonin in human reproduction. This review was conducted to investigate the effects of melatonin on female reproduction and to summarize our findings in this field.

Melatonergic drugs in development.

Melatonin (N-acetyl-5-methoxytryptamine) is widely known as "the darkness hormone". It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.

Melatonin Target Proteins: Too Many or Not Enough?

The neurohormone N-acetyl-5-methoxytryptamine, better known as melatonin, is a tryptophan derivative with a wide range of biological effects that is present in many organisms. These effects are believed to rely either on the chemical properties of melatonin itself as scavenger of free radicals or on the binding of melatonin to protein targets. More than 15 proteins, including receptors (MT1, MT2, Mel1c, CAND2, ROR, VDR), enzymes (QR2, MMP-9, pepsin, PP2A, PR-10 proteins), pores (mtPTP), transporters (PEPT1/2, Glut1), and other proteins (HBS, CaM, tubulin, calreticuline), have been suggested to interact with melatonin at sub-nanomolar to millimolar melatonin concentrations. In this review we assemble for the first time the available information on proposed melatonin targets and discuss them in a comprehensive manner to evaluate the robustness of these findings in terms of methodology, physiological relevance, and independent replication.

Melatonin for cognitive impairment.

There are a number of studies that suggest a relationship between decline of melatonin function and the symptoms of dementia. The review assessed the evidence of clinical efficacy and safety of melatonin in the treatment of manifestations of dementia or cognitive impairment (CI). The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched for trials involving melatonin on 5 October 2005. The search terms used were MELATONIN, and N-ACETYL-5-METHOXYTRYPTAMINE. This Register contains records from all major health care databases as well as many ongoing trials databases and is updated regularly. All relevant, randomized controlled trials in which orally administered melatonin in any dosage was compared with a control group for the effect on managing cognitive, behavioural (excluding sleep), and/or affective disturbances of people with dementia of any degree of severity. Two to three reviewers independently assessed the retrieved articles for relevance and methodological quality, and extracted data from the selected studies. Statistically significant differences in changes in outcomes from baseline to end of treatment between the melatonin and control groups were examined. Each study was summarized using a measure of effect (e.g. mean difference) and meta-analyses were conducted when appropriate. Three studies met the inclusion criteria. This review revealed non-significant effects from the pooled estimates of MMSE cognitive, and ADAS-cognitive change scores. Individual study estimates for treatment effect demonstrated a significant improvement for melatonin compared with placebo in behavioural and affective symptoms as measured by the ADAS non-cognitive scale in a study of 20 patients, and the Neuropsychiatric Inventory (NPI) following treatment with 2.5 mg/day (SR) melatonin, but not with 10mg/day (IR) melatonin in a larger study of 157 patients. The remainder of the treatment effects for affect, behaviour and activities of daily living were non-significant. There is insufficient evidence to support the effectiveness of melatonin in managing the cognitive and non-cognitive sequelae of dementia.

Alternative Ligands at Melatonin Receptors.

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that possesses a wide range of biological effects. Most of the main recognized effects of this hormone in mammals are due to its interaction with two G protein-coupled receptors, MT1 and MT2. Ligand-binding studies have been based on the use of its radioligand analog, 2[125I]-iodomelatonin, a super agonist discovered in the early 1990s. This compound has been used in most of the binding studies reported in the literature. Nevertheless, more recently other possibilities arose. This chapter is a brief summary of those alternative radioligands and of their benefits one can find in using them.

Melatonin: a multitasking molecule.

Melatonin (N-acetyl-5-methoxytryptamine) has revealed itself as an ubiquitously distributed and functionally diverse molecule. The mechanisms that control its synthesis within the pineal gland have been well characterized and the retinal and biological clock processes that modulate the circadian production of melatonin in the pineal gland are rapidly being unravelled. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. While many of these actions are mediated by well-characterized, G-protein coupled melatonin receptors in cellular membranes, other actions of the indole seem to involve its interaction with orphan nuclear receptors and with molecules, for example calmodulin, in the cytosol. Additionally, by virtue of its ability to detoxify free radicals and related oxygen derivatives, melatonin influences the molecular physiology of cells via receptor-independent means. These uncommonly complex processes often make it difficult to determine specifically how melatonin functions to exert its obvious actions. What is apparent, however, is that the actions of melatonin contribute to improved cellular and organismal physiology. In view of this and its virtual absence of toxicity, melatonin may well find applications in both human and veterinary medicine.

Melatonin in aging women.

Melatonin is a neurohormone secreted mainly by the pineal gland that controls circadian rhythm, which is primarily regulated by light. Although melatonin levels are known to be altered in individuals with sleep disorders, melatonin also has modulatory effects on other body systems, including the skeletal and immune systems. In addition, melatonin has been shown to interfere with carbohydrate and lipid metabolism and to have significant antioxidant effects, both directly and via its metabolites. Melatonin levels vary throughout human life and are known to decrease with age but the effects of declining melatonin levels are poorly understood. In women, this age-related decrease in melatonin levels coincides with the menopause. This review aims to summarize the impact of altered melatonin levels in aging women and the outcomes of exogenous replacement therapies.

Human hepatocellular carcinoma: Protection by melatonin.

Despite great scientific breakthroughs toward understanding the identity of human hepatocellular carcinoma (HCC) mechanistically, there are still no clinically efficient therapeutic methods for this cancer. Melatonin (N-acetyl-5-methoxytryptamine) is a multi-tasking hormone that has long been known for its anti-cancer activity against various human cancers including HCC, which is a focus of this review. PubMed database was searched for relevant articles with the keywords: hepatocellular carcinoma (HCC), melatonin, apoptosis, proliferation, invasion, angiogenesis, autophagy, oxidative stress, tumor immunity, and mitogen-activated protein kinase (MAPK) focusing on just human cell lines and English language articles. Melatonin inhibits apoptosis resistance and activates both extrinsic and intrinsic pathways of apoptosis in HCC. Melatonin induces ensoplasmic reticulum (ER)- and autophagy-mediated apoptosis in cancer cells. Melatonin works against cancer cell proliferation, motility, and invasiveness by modulating actions of a variety of transcription factors and related pathways. Melatonin also relieves an immunosuppressive state in HCC cancer cells through making a control over tumor-derived exosomes. Both pro-and anti-oxidative functions of melatonin are necessary for combating HCC. Combination of melatonin with chemotherapy could also provide cumulative effects on cancer cells. Melatonin exerts most of these roles by acting on the members of MAPK family.

Melatonin mitigates mitochondrial malfunction.

Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.

Melatonin and Its Effects on Plant Systems.

Melatonin (N-acetyl-5-methoxytryptamine) is a nontoxic biological molecule produced in a pineal gland of animals and different tissues of plants. It is an important secondary messenger molecule, playing a vital role in coping with various abiotic and biotic stresses. Melatonin serves as an antioxidant in postharvest technology and enhances the postharvest life of fruits and vegetables. The application of exogenous melatonin alleviated reactive oxygen species and cell damage induced by abiotic and biotic stresses by means of repairing mitochondria. Additionally, the regulation of stress-specific genes and the activation of pathogenesis-related protein and antioxidant enzymes genes under biotic and abiotic stress makes it a more versatile molecule. Besides that, the crosstalk with other phytohormones makes inroads to utilize melatonin against non-testified stress conditions, such as viruses and nematodes. Furthermore, different strategies have been discussed to induce endogenous melatonin activity in order to sustain a plant system. Our review highlighted the diverse roles of melatonin in a plant system, which could be useful in enhancing the environmental friendly crop production and ensure food safety.

Melatonin as an Antioxidant for Stroke Neuroprotection.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin-based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (-)-epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke.

Guidelines for prescribing melatonin.

Although compelling logic suggests that melatonin may be effective for a variety of disorders, there are few empirical clinical studies. The optimal dose of melatonin is not clear; most studies have used doses that produce supraphysiological blood levels. The timing of melatonin administration is important. Melatonin has few immediate side-effects except drowsiness, but the effects of chronic administration are unclear. Melatonin may be effective in reducing jet lag. In elderly patients with poor sleep and documented low melatonin production, melatonin may be helpful. In several studies, melatonin has been shown to shorten sleep latency. Further studies are needed to clarify the efficacy and safety of melatonin.

Role of melatonin in respiratory diseases (Review).

Melatonin, primarily secreted by the pineal gland, is an anthracemal compound. Its chemical name is N-acetyl-5-methoxytryptamine. Great advances in melatonin-related research have been made, including the understanding of its roles in the rhythm of the sleep/wake cycle, retardation of aging processes, as well as antioxidant and/or anti-inflammatory effects. Melatonin exerts a wide range of physiological effects related to the high lipophilicity of melatonin itself. Melatonin has strong radical scavenging activity, which serves an important role in pulmonary disorders. Pulmonary disorders are among the diseases that threaten human health. Especially in developing countries, due to environmental factors such as smoke and dust, the incidences of pulmonary disorders are high. Melatonin has been reported to have great potential to treat patients with pulmonary disorders. The present review discusses the relationship between melatonin and pulmonary disorders, including coronavirus disease-2019, chronic obstructive pulmonary disease, non-small cell lung cancer and pulmonary fibrosis.

Melatonin: reproductive effects.

N-acetyl-5-methoxytryptamine, melatonin, is synthesized within and secreted from the pineal gland. Although the concentration of this constituent in the blood is diminished after surgical removal of the pineal gland it does not completely disappear. Other potential contributors to blood titers of melatonin include the retinas, the Harderian glands and the gastro-intestinal tract. Melatonin has a potent antigonadotrophic action in the Syrian hamster ( a highly photosensitive species) provided the indole is given during a restricted portion of the light phase of the light-dark cycle. This so-called sensitive period falls late in the light phase; melatonin acutely administered at other times has virtually no inhibitory influence on the reproductive physiology of hamsters. When melatonin is continuously available (from a subcutaneous deposit) it counteracts the antigonadotrophic influence of the pineal gland in light restricted or blinded hamsters, i.e., it causes a "functional pinealectomy". Furthermore, chronically available melatonin negates the antigonadotrophic capability of acute melatonin injections.

Melatonin in animal husbandry: functions and applications.

Melatonin (N-acetyl-5-methoxytryptamine) is an essential small molecule with diverse biological functions. It plays several key roles, including regulating the secretion of reproductive hormones and the reproductive cycle, enhancing the functionality of reproductive organs, improving the quality of sperm and eggs, and mitigating oxidative stress in the reproductive system. Melatonin effectively inhibits and scavenges excess free radicals while activating the antioxidant enzyme system and reduces the production of inflammatory factors and alleviates tissue damage caused by inflammation by regulating inflammatory pathways. Additionally, melatonin contributes to repairing the intestinal barrier and regulating the gut microbiota, thereby reducing bacterial and toxin permeation. The use of melatonin as an endogenous hormone in animal husbandry has garnered considerable attention because of its positive effects on animal production performance, reproductive outcomes, stress adaptation, disease treatment, and environmental sustainability. This review explores the characteristics and biological functions of melatonin, along with its current applications in animal production. Our findings may serve as a reference for the use of melatonin in animal farming and future developmental directions.

Potential benefits of melatonin in organ transplantation: a review.

Organ transplantation is a useful therapeutic tool for patients with end-stage organ failure; however, graft rejection is a major obstacle in terms of a successful treatment. Rejection is usually a consequence of a complex immunological and nonimmunological antigen-independent cascade of events, including free radical-mediated ischemia-reperfusion injury (IRI). To reduce the frequency of this outcome, continuing improvements in the efficacy of antirejection drugs are a top priority to enhance the long-term survival of transplant recipients. Melatonin (N-acetyl-5-methoxytryptamine) is a powerful antioxidant and ant-inflammatory agent synthesized from the essential amino acid l-tryptophan; it is produced by the pineal gland as well as by many other organs including ovary, testes, bone marrow, gut, placenta, and liver. Melatonin has proven to be a potentially useful therapeutic tool in the reduction of graft rejection. Its benefits are based on its direct actions as a free radical scavenger as well as its indirect antioxidative actions in the stimulation of the cellular antioxidant defense system. Moreover, it has significant anti-inflammatory activity. Melatonin has been found to improve the beneficial effects of preservation fluids when they are enriched with the indoleamine. This article reviews the experimental evidence that melatonin is useful in reducing graft failure, especially in cardiac, bone, otolaryngology, ovarian, testicular, lung, pancreas, kidney, and liver transplantation.

Melatonin Confers Plant Cadmium Tolerance: An Update.

Cadmium (Cd) is one of the most injurious heavy metals, affecting plant growth and development. Melatonin (N-acetyl-5-methoxytryptamine) was discovered in plants in 1995, and it is since known to act as a multifunctional molecule to alleviate abiotic and biotic stresses, especially Cd stress. Endogenously triggered or exogenously applied melatonin re-establishes the redox homeostasis by the improvement of the antioxidant defense system. It can also affect the Cd transportation and sequestration by regulating the transcripts of genes related to the major metal transport system, as well as the increase in glutathione (GSH) and phytochelatins (PCs). Melatonin activates several downstream signals, such as nitric oxide (NO), hydrogen peroxide (H2O2), and salicylic acid (SA), which are required for plant Cd tolerance. Similar to the physiological functions of NO, hydrogen sulfide (H2S) is also involved in the abiotic stress-related processes in plants. Moreover, exogenous melatonin induces H2S generation in plants under salinity or heat stress. However, the involvement of H2S action in melatonin-induced Cd tolerance is still largely unknown. In this review, we summarize the progresses in various physiological and molecular mechanisms regulated by melatonin in plants under Cd stress. The complex interactions between melatonin and H2S in acquisition of Cd stress tolerance are also discussed.

The metabolism of melatonin (N-acetyl-5-methoxytryptamine) and 5-methoxytryptamine.

Melatonin as a Potential Multitherapeutic Agent.

Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone produced by the pineal gland that was discovered many years ago. The physiological roles of this hormone in the body are varied. The beneficial effects of MEL administration may be related to its influence on mitochondrial physiology. Mitochondrial dysfunction is considered an important factor in various physiological and pathological processes, such as the development of neurodegenerative and cardiovascular diseases, diabetes, various forms of liver disease, skeletal muscle disorders, and aging. Mitochondrial dysfunction induces an increase in the permeability of the inner membrane, which leads to the formation of a permeability transition pore (mPTP) in the mitochondria. The long-term administration of MEL has been shown to improve the functional state of mitochondria and inhibit the opening of the mPTP during aging. It is known that MEL is able to suppress the initiation, progression, angiogenesis, and metastasis of cancer as well as the sensitization of malignant cells to conventional chemotherapy and radiation therapy. This review summarizes the studies carried out by our group on the combined effect of MEL with chemotherapeutic agents (retinoic acid, cytarabine, and navitoclax) on the HL-60 cells used as a model of acute promyelocytic leukemia. Data on the effects of MEL on oxidative stress, aging, and heart failure are also reported.

Melatonin Interplay in Physiology and Disease-The Fountain of Eternal Youth Revisited.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone associated with the regulation of biological rhythms. The indoleamine is secreted by the pineal gland during the night, following a circadian rhythm. The highest plasmatic levels are reached during the night, whereas the lowest levels are achieved during the day. In addition to the pineal gland, other organs and tissues also produce melatonin, like, for example, the retina, Harderian glands, gut, ovaries, testes, skin, leukocytes, or bone marrow. The list of organs is extensive, including the cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, carotid body, placenta, and endometrium. At all these locations, the availability of melatonin is intended for local use. Interestingly, a decline of the circadian amplitude of the melatonin secretion occurs in old subjects in comparison to that found in younger subjects. Moreover, genetic and environmental factors are the primary causes of diseases, and oxidative stress is a key contributor to most pathologies. Numerous studies exist that show interesting effects of melatonin in different models of disease. Impairment in its secretion might have deleterious consequences for cellular physiology. In this regard, melatonin is a natural compound that is a carrier of a not yet completely known potential that deserves consideration. Thus, melatonin has emerged as a helpful ally that could be considered as a guard with powerful tools to orchestrate homeostasis in the body, majorly based on its antioxidant effects. In this review, we provide an overview of the widespread actions of melatonin against diseases preferentially affecting the elderly.

Distinct roles of N-acetyl and 5-methoxy groups in the antiproliferative and neuroprotective effects of melatonin.

Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353&#xa0;cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.

Melatonin: An Anti-Tumor Agent in Hormone-Dependent Cancers.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland mainly during the night, since light exposure suppresses its production. Initially, an implication of this indoleamine in malignant disease was described in endocrine-responsive breast cancer. Data from several clinical trials and multiple experimental studies performed both in vivo and in vitro have documented that the pineal hormone inhibits endocrine-dependent mammary tumors by interfering with the estrogen signaling-mediated transcription, therefore behaving as a selective estrogen receptor modulator (SERM). Additionally, melatonin regulates the production of estradiol through the control of the enzymes involved in its synthesis, acting as a selective estrogen enzyme modulator (SEEM). Many more mechanisms have been proposed during the past few years, including signaling triggered after activation of the membrane melatonin receptors MT-1 and MT-2, or else intracellular actions targeting molecules such as calmodulin, or binding intranuclear receptors. Similar results have been obtained in prostate (regulation of enzymes involved in androgen synthesis and modulation of androgen receptor levels and activity) and ovary cancer. Thus, tumor metabolism, gene expression, or epigenetic modifications are modulated, cell growth is impaired and angiogenesis and metastasis are inhibited. In the last decade, many more reports have demonstrated that melatonin is a promising adjuvant molecule with many potential beneficial consequences when included in chemotherapy or radiotherapy protocols designed to treat endocrine-responsive tumors. Therefore, in this state-of-the-art review, we aim to compile the knowledge about the oncostatic actions of the indoleamine in hormone-dependent tumors, and the latest findings concerning melatonin actions when administered in combination with radio- or chemotherapy in breast, prostate, and ovary cancers. As melatonin has no toxicity, it may be well deserve to be considered as an endogenously generated agent helpful in cancer prevention and treatment.

A Review of Melatonin, Its Receptors and Drugs.

After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/ROR&#x3b1;: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future.

Phytomelatonin: From Intracellular Signaling to Global Horticulture Market.

Melatonin (N-acetyl-5-methoxytryptamine), a well-known mammalian hormone, has been having a great relevance in the Plant World in recent years. Many of its physiological actions in plants are leading to possible features of agronomic interest, especially those related to improvements in tolerance to stressors and in the postharvest life of fruits and vegetables. Thus, through the exogenous application of melatonin or by modifying the endogenous biosynthesis of phytomelatonin, some change can be made in the functional levels of melatonin in tissues and their responses. Also, acting in the respective phytomelatonin biosynthesis enzymes, regulating the expression of tryptophan decarboxylase (TDC), tryptamine 5-hydroxylase (T5H), serotonin N-acetyltransferase (SNAT), N-acetylserotonin O-methyltransferase (ASMT), and caffeic acid O-methyltransferase (COMT), and recently the possible action of deacetylases on some intermediates offers promising opportunities for improving fruits and vegetables in postharvest and its marketability. Other regulators/effectors such as different transcription factors, protein kinases, phosphatases, miRNAs, protein-protein interactions, and some gasotransmitters such as nitric oxide or hydrogen sulfide were also considered in an exhaustive vision. Other interesting aspects such as the role of phytomelatonin in autophagic responses, the posttranslational reprogramming by protein-phosphorylation, ubiquitylation, SUMOylation, PARylation, persulfidation, and nitrosylation described in the phytomelatonin-mediated responses were also discussed, including the relationship of phytomelatonin and several plant hormones, for chilling injury and fungal decay alleviating. The current data about the phytomelatonin receptor in plants (CAND2/PMTR1), the effect of UV-B light and cold storage on the postharvest damage are presented and discussed. All this on the focus of a possible new action in the preservation of the quality of fruits and vegetables.

Neuroprotective Mechanisms of Melatonin in Hemorrhagic Stroke.

Hemorrhagic stroke which consists of subarachnoid hemorrhage and intracerebral hemorrhage is a dominant cause of death and disability worldwide. Although great efforts have been made, the physiological mechanisms of these diseases are not fully understood and effective pharmacological interventions are still lacking. Melatonin (N-acetyl-5-methoxytryptamine), a neurohormone produced by the pineal gland, is a broad-spectrum antioxidant and potent free radical scavenger. More importantly, there is extensive evidence demonstrating that melatonin confers neuroprotective effects in experimental models of hemorrhagic stroke. Multiple molecular mechanisms such as antioxidant, anti-apoptosis, and anti-inflammation, contribute to melatonin-mediated neuroprotection against brain injury after hemorrhagic stroke. This review article aims to summarize current knowledge regarding the beneficial effects of melatonin in experimental models of hemorrhagic stroke and explores the underlying mechanisms. We propose that melatonin is a promising neuroprotective candidate that is worthy of further evaluation for its potential therapeutic applications in hemorrhagic stroke.

Melatonin - This is important to know.

MEL (N-acetyl-5-methoxytryptamine) is a well-known natural compound that controls cellular processes in both plants and animals and is primarily found in plants as a neurohormone. Its roles have been described very broadly, from its antioxidant function related to the photoperiod and determination of seasonal rhythms to its role as a signalling molecule, imitating the action of plant hormones (or even being classified as a prohormone). MEL positively affects the yield and survival of plants by increasing their tolerance to unfavourable biotic and abiotic conditions, which makes MEL widely applicable in ecological farming as a stimulant of growth and development. Thus, it is called a phytobiostimulator. In this review, we discuss the genesis of MEL functions, the presence of MEL at the cellular level and its effects on gene expression and plant development, which can ensure the survival of plants under the conditions they encounter. Moreover, we consider the future application possibilities of MEL in agriculture.

Melatonin and the Cardiovascular System.

Melatonin (N-acetyl-5-methoxytryptamine) is a neuroendocrine hormone primarily secreted by the pineal gland and also produced in extrapineal tissues such as the retina, lymphocytes, and the cardiovascular (CV) system. This hormone possesses amphiphilic properties, allowing it to penetrate most biological barriers and exert its effects at the subcellular level; it plays an important role in controlling the body's response to circadian rhythms and adjusting to internal and external environmental cues. It also has antioxidant, anti-inflammatory, and antiaging properties. Melatonin's secretion is controlled by daily and seasonal environmental light cycles. Its production is strictly occurs during the night and is inhibited by light. Besides these chronobiotic actions, this hormone possesses vasoactive properties mediated by the plasma membrane melatonin receptors (MT1/MT2) and ion channels expressed in the CV system. The responses triggered by melatonin in the CV system vary depending on the vascular bed analyzed and hormone concentration. Also, MT1 receptors likely mediate vasoconstrictor effects, whereas MT2 receptors mediate vasorelaxant effects. Furthermore, there is a gap in the literature, as very few studies have addressed the effects of circadian variations on the expression of these receptors, pointing to an important area for further investigation. In summary, melatonin is a robust antioxidant agent and free radical scavenger, guarding cells from oxidative damage. Within its wide spectrum of diverse physiological roles, such as maintaining the functional integrity of endothelial cells, thus averting atherosclerosis, a major contributor to CVD, melatonin exhibits antioxidant and free radical scavenging properties, potentially ameliorating cardiometabolic disorders, and, as herein detailed, it has a unique adjunctive therapeutic potential for managing various CVDs via several mechanisms by which melatonin interacts with the CV system. All these issues are herein reviewed, the results of relevant meta-analyses are tabulated and discussed, and the actions and influences of melatonin on the CV system are detailed and pictorially illustrated.

Microbial melatonin metabolism in the human intestine as a therapeutic target for dysbiosis and rhythm disorders.

Melatonin (MT) (N-acetyl-5-methoxytryptamine) is an indoleamine recognized primarily for its crucial role in regulating sleep through circadian rhythm modulation in humans and animals. Beyond its association with the pineal gland, it is synthesized in various tissues, functioning as a hormone, tissue factor, autocoid, paracoid, and antioxidant, impacting multiple organ systems, including the gut-brain axis. However, the mechanisms of extra-pineal MT production and its role in microbiota-host interactions remain less understood. This review provides a comprehensive overview of MT, including its production, actions sites, metabolic pathways, and implications for human health. The gastrointestinal tract is highlighted as an additional source of MT, with an examination of its effects on the intestinal microbiota. This review explores whether the microbiota contributes to MT in the intestine, its relationship to food intake, and the implications for human health. Due to its impacts on the intestinal microbiota, MT may be a valuable therapeutic agent for various dysbiosis-associated conditions. Moreover, due to its influence on intestinal MT levels, the microbiota may be a possible therapeutic target for treating health disorders related to circadian rhythm dysregulation.

Update on melatonin receptors: IUPHAR Review 20.

Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

Functions and prospects of melatonin in plant growth, yield, and quality.

Melatonin (N-acetyl-5-methoxytryptamine) is an indole molecule widely found in animals and plants. It is well known that melatonin improves plant resistance to various biotic and abiotic stresses due to its potent free radical scavenging ability while being able to modulate plant signaling and response pathways through mostly unknown mechanisms. In recent years, an increasing number of studies have shown that melatonin plays a crucial role in improving crop quality and yield by participating in the regulation of various aspects of plant growth and development. Here, we review the effects of melatonin on plant vegetative growth and reproductive development, and systematically summarize its molecular regulatory network. Moreover, the effective concentrations of exogenously applied melatonin in different crops or at different growth stages of the same crop are analysed. In addition, we compare endogenous phytomelatonin concentrations in various crops and different organs, and evaluate a potential function of phytomelatonin in plant circadian rhythms. The prospects of different approaches in regulating crop yield and quality through exogenous application of appropriate concentrations of melatonin, endogenous modification of phytomelatonin metabolism-related genes, and the use of nanomaterials and other technologies to improve melatonin utilization efficiency are also discussed.

Melatonin utility in neonates and children.

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenously produced indoleamine secreted by the pineal gland and the secretion is suppressed by light. Melatonin is a highly effective antioxidant, free radical scavenger, and has anti-inflammatory effect. Plenty of evidence supports the utility of melatonin in adults for cancer, neurodegenerative disorders, and aging. In children and neonates, melatonin has been used widely, including for respiratory distress syndrome, bronchopulmonary dysplasia, periventricular leukomalacia (PVL), hypoxia-ischemia encephalopathy and sepsis. In addition, melatonin can be used in childhood sleep and seizure disorders, and in neonates and children receiving surgery. This review article discusses the utility of melatonin in neonates and children.

The Therapeutic Potential of Melatonin and Its Novel Synthetic Analogs in Circadian Rhythm Sleep Disorders, Inflammation-Associated Pathologies, and Neurodegenerative Diseases.

Melatonin, N-acetyl-5-methoxytryptamine, is a tryptophan-derived hormone mostly produced in the pineal gland, despite being synthesized locally at several tissues and organs. This production is rhythmically controlled by complex clock gene networks in the master pacemaker located in the suprachiasmatic nucleus of the hypothalamus. Melatonin is usually secreted only during the dark phase of the day and is essential to synchronize circadian rhythms and neuroendocrine physiological processes. Its main clinical use is associated with the treatment of jet lag and other circadian rhythm sleep disorders, with a growing number of other promising therapeutic applications due to the diverse physiological roles of melatonin. In this review, we explore melatonin and its receptors and provide an updated overview on research concerning the role of melatonin, either as an endogenous molecule or as a drug, in: sleep-wake cycle regulation; circadian rhythms; inflammatory processes that may compromise cardiovascular, respiratory, gastrointestinal, renal, and reproductive system functions; and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The most recent and promising research findings concerning melatonin synthetic analogs such as agomelatine and ramelteon are highlighted, pointing toward new compounds with promising pharmacological activity while emphasizing their structural differences and advantages when compared to melatonin.

Melatonin: pharmacological aspects and clinical trends.

Melatonin, N-acetyl-5-methoxytryptamine, the major hormone produced by the pineal gland under the influence of the dark/light cycle, has been shown to have a large number of therapeutic possibilities. It has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep-wake cycle disturbances in blind people, and shift workers. In our mechanism of act, the G(i) protein-coupled metabotropic melatonin receptors MT1 and MT2 are the primary mediators of the physiological actions of melatonin. This hormone plays an important role in the regulation of physiological and neuroendocrine functions, such as synchronization of seasonal reproductive rhythms and entrainment of circadian cycles. In addition to its chronobiological role, several pharmacological effects of melatonin have been reported in mammals including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities. There is some evidence from clinical trials that melatonin can be helpful in that event. Current trends of pharmacological functions of melatonin pointed out its use in the treatment of neurodegenerative and neoplastic diseases. These effects and uses of melatonin are mentioned but further confirmatory studies are needed in most of them.