Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) 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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), an endogenously produced indole found throughout the animal kingdom, was recently reported, using a variety of techniques, to be a scavenger of a number of reactive oxygen and reactive nitrogen species both in vitro and in vivo. Initially, melatonin was discovered to directly scavenge the high toxic hydroxyl radical (*OH). The methods used to prove the interaction of melatonin with the *OH included the generation of the radical using Fenton reagents or the ultraviolet photolysis of hydrogen peroxide (H202) with the use of spin-trapping agents, followed by electron spin resonance (ESR) spectroscopy, pulse radiolysis followed by ESR, and several spectrofluorometric and chemical (salicylate trapping in vivo) methodologies. One product of the reaction of melatonin with the *OH was identified as cyclic 3-hydroxymelatonin (3-OHM) using high-performance liquid chromatography with electrochemical (HPLC-EC) detection, electron ionization mass spectrometry (EIMS), proton nuclear magnetic resonance (1H <em>N</em>MR) and COSY 1H <em>N</em>MR. Cyclic 3-OHM appears in the urine of humans and other mammals and in rat urine its concentration increases when melatonin is given exogenously or after an imposed oxidative stress (exposure to ionizing radiation). Urinary cyclic 3-OHM levels are believed to be a biomarker (footprint molecule) of in vivo *OH production and its scavenging by melatonin. Although the data are less complete, besides the *OH, melatonin in cell-free systems has been shown to directly scavenge H2O2, singlet oxygen (1O2) and nitric oxide (<em>N</em>O*), with little or no ability to scavenge the superoxide anion radical (O2*-) In vitro, melatonin also directly detoxifies the peroxynitrite anion (O<em>N</em>OO-) and/or peroxynitrous acid (O<em>N</em>OOH), or the activated form of this molecule, O<em>N</em>OOH*; the product of the latter interaction is proposed to be 6-OHM. How these in vitro findings relate to the in vivo antioxidant actions of melatonin remains to be established. The ability of melatonin to scavenge the lipid peroxyl radical (LOO*) is debated. The weight of the evidence is that melatonin is probably not a classic chain-breaking antioxidant, since its ability to scavenge the LOO* seems weak. Its ability to reduce lipid peroxidation may stem from its function as a preventive antioxidant (scavenging initiating radicals), or yet unidentified actions. In sum, in vitro melatonin acts as a direct free radical scavenger with the ability to detoxify both reactive oxygen and reactive nitrogen species; in vivo, it is an effective pharmacological agent in reducing oxidative damage under conditions in which excessive free radical generation is believed to be involved.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), an indoleamine produced in many organs including the pineal gland, was initially characterized as a hormone primarily involved in circadian regulation of physiological and neuroendocrine function. Subsequent studies found that melatonin and its metabolic derivatives possess strong free radical scavenging properties. These metabolites are potent antioxidants against both ROS (reactive oxygen species) and R<em>N</em>S (reactive nitrogen species). The mechanisms by which melatonin and its metabolites protect against free radicals and oxidative stress include direct scavenging of radicals and radical products, induction of the expression of antioxidant enzymes, reduction of the activation of pro-oxidant enzymes, and maintenance of mitochondrial homeostasis. In both in vitro and in vivo studies, melatonin has been shown to reduce oxidative damage to lipids, proteins and D<em>N</em>A under a very wide set of conditions where toxic derivatives of oxygen are known to be produced. Although the vast majority of studies proved the antioxidant capacity of melatonin and its derivatives, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (μm to mm range) in several tumor and nontumor cells; thus, melatonin functioned as a conditional pro-oxidant. Mechanistically, melatonin may stimulate ROS production through its interaction with calmodulin. Also, melatonin may interact with mitochondrial complex III or mitochondrial transition pore to promote ROS production. Whether melatonin functions as a pro-oxidant under in vivo conditions is not well documented; thus, whether the reported in vitro pro-oxidant actions come into play in live organisms remains to be established.

Parkinson's disease (PD) is a movement disorder characterized by the selective degeneration of nigrostriatal dopaminergic neurons. Both familial and sporadic cases present tremor, rigidity, slowness of movement, and postural instability. Although major insights into the genes responsible for some rare hereditary cases have arisen, the etiology of sporadic cases remains unknown. Epidemiological studies have suggested an association with environmental toxins, mainly mitochondrial complex I inhibitors such as the widely used pesticide rotenone. In recent years, Drosophila melanogaster has been used as a model of several neurodegenerative diseases, including a genetic model of PD. Here, we studied the neurodegenerative and behavioral effects of a sublethal chronic exposure to rotenone in Drosophila. After several days, the treated flies presented characteristic locomotor impairments that increased with the dose of rotenone. Immunocytochemistry analysis demonstrated a dramatic and selective loss of dopaminergic neurons in all of the brain clusters. The addition of l-dopa (3,4-dihydroxy-L-phenylalanine) into the feeding medium rescued the behavioral deficits but not neuronal death, as is the case in human PD patients. In contrast, the antioxidant melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) alleviated both symptomatic impairment and neuronal loss, supporting the idea that this agent may be beneficial in the treatment of PD. Therefore, chronic exposure to pesticides recapitulates key aspects of PD in Drosophila and provides a new in vivo model for studying the mechanisms of dopaminergic neurodegeneration.

Melatonin, or <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, 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 mtD<em>N</em>A 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.

It has been historically assumed that the pineal gland is the major source of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) in vertebrates. Melatonin plays a central role in fine-tuning circadian rhythms in vertebrate physiology. In addition, melatonin shows a remarkable functional versatility exhibiting antioxidant, oncostatic, antiaging, and immunomodulatory properties. Melatonin has been identified in a wide range of organisms from bacteria to human beings. Its biosynthesis from tryptophan involves four well-defined intracellular steps catalyzed by tryptophan hydroxylase, aromatic amino acid decarboxylase, serotonin-<em>N</em>-<em>acetyl</em>transferase, and hydroxyindole-O-methyltransferase. Here, for the first time, we document that both resting and phytohemagglutinin-stimulated human lymphocytes synthesize and release large amounts of melatonin, with the melatonin concentration in the medium increasing up to five times the nocturnal physiological levels in human serum. Moreover, we show that the necessary machinery to synthesize melatonin is present in human lymphocytes. Furthermore, melatonin released to the culture medium is synthesized in the cells, because blocking the enzymes required for its biosynthesis or inhibiting protein synthesis in general produced a significant reduction in melatonin release. Moreover, this inhibition caused a decrease in IL-2 production, which was restored by adding exogenous melatonin. These findings indicate that in addition to pineal gland, human lymphoid cells are an important physiological source of melatonin and that this melatonin could be involved in the regulation of the human immune system, possibly by acting as an intracrine, autocrine, and/or paracrine substance.

Experiments were undertaken to characterize pharmacologically a neuronal receptor to <em>5</em>-HT in guinea pig ileum. Segments of longitudinal muscle myenteric plexus preparations were treated with phenoxybenzamine and exposed to submaximal electrical field stimulation to evoke the cholinergically mediated "twitch" response. The ability of <em>5</em>-HT to enhance the submaximal twitch response was investigated. Results using several antagonists (metergoline, spiperone, cyanopindolol, <em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptophyl-<em>5</em>-hydroxytryptophan amide, <em>N</em>-hexanoyl-<em>5</em>-hydroxytryptophyl-<em>5</em>-hydroxytryptophan amide, ICS 20<em>5</em>-930, GR 38032F, MDL 72222 and cocaine) indicate that <em>5</em>-HT (3 X 10(-10) to 1 x 10(-7) M) agonizes a novel <em>5</em>-HT receptor site distinct from the <em>5</em>-HT1, <em>5</em>-HT2, <em>5</em>-HT3 and <em>5</em>-HT1P subtypes as well as the M receptor. The receptor site is located neuronally and is characterized positively by a low affinity for ICS 20<em>5</em>-930 (pA2 = 6.<em>5</em> vs. <em>5</em>-HT) and by the following order of agonist potency: <em>5</em>-HT greater than <em>5</em>-<em>methoxytryptamine</em> greater than BRL 24924 greater than alpha-methyl-<em>5</em>-hydroxytryptamine greater than zacopride = cisapride = <em>5</em>-carboxamidotryptamine. Agonist-independent pA2 estimates for ICS 20<em>5</em>-930 (6.3-6.6) suggest a single site of agonism. 2-Methyl-<em>5</em>-hydroxytryptamine and <em>5</em>-hydroxyindalpine were inactive at 1 x 10(-<em>5</em>) M either as agonists or antagonists. Thus, the receptor site exhibits a pharmacological profile similar to that characterizing the recently described <em>5</em>-HT4 [corrected] receptor. Unlike Gaddum's M receptor, which equates with the <em>5</em>-HT3 [corrected] receptor, the putative <em>5</em>-HT4 [corrected] receptor site exhibits a higher sensitivity to agonism by <em>5</em>-HT and is resistant to antagonism by cocaine.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a well-known animal hormone, is also involved in plant development and abiotic stress responses. In this study, it is shown that exogenous application of melatonin conferred improved salt, drought, and cold stress resistances in bermudagrass. Moreover, exogenous melatonin treatment alleviated reactive oxygen species (ROS) burst and cell damage induced by abiotic stress; this involved activation of several antioxidants. Additionally, melatonin-pre-treated plants exhibited higher concentrations of <em>5</em>4 metabolites, including amino acids, organic acids, sugars, and sugar alcohols, than non-treated plants under abiotic stress conditions. Genome-wide transcriptomic profiling identified 3933 transcripts (2361 up-regulated and 1<em>5</em>72 down-regulated) that were differentially expressed in melatonin-treated plants versus controls. Pathway and gene ontology (GO) term enrichment analyses revealed that genes involved in nitrogen metabolism, major carbohydrate metabolism, tricarboxylic acid (TCA)/org transformation, transport, hormone metabolism, metal handling, redox, and secondary metabolism were over-represented after melatonin pre-treatment. Taken together, this study provides the first evidence of the protective roles of exogenous melatonin in the bermudagrass response to abiotic stresses, partially via activation of antioxidants and modulation of metabolic homeostasis. <em>N</em>otably, metabolic and transcriptomic analyses showed that the underlying mechanisms of melatonin could involve major reorientation of photorespiratory and carbohydrate and nitrogen metabolism.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) was initially thought to be produced exclusively in the pineal gland. Subsequently its synthesis was demonstrated in other organs, for example, the retinas, and very high concentrations of melatonin are found at other sites, for example, bone marrow cells and bile. The origin of the high level of melatonin in these locations has not been definitively established, but it is likely not exclusively of pineal origin. Melatonin has been shown to possess anti-inflammatory effects, among a number of actions. Melatonin reduces tissue destruction during inflammatory reactions by a number of means. Thus melatonin, by virtue of its ability to directly scavenge toxic free radicals, reduces macromolecular damage in all organs. The free radicals and reactive oxygen and nitrogen species known to be scavenged by melatonin include the highly toxic hydroxyl radical (.OH), peroxynitrite anion (O<em>N</em>OO-), and hypochlorous acid (HOCl), among others. These agents all contribute to the inflammatory response and associated tissue destruction. Additionally, melatonin has other means to lower the damage resulting from inflammation. Thus, it prevents the translocation of nuclear factor-kappa B (<em>N</em>F-kappa B) to the nucleus and its binding to D<em>N</em>A, thereby reducing the upregulation of a variety of proinflammatory cytokines, for example, interleukins and tumor neurosis factor-alpha. Finally, there is indirect evidence that melatonin inhibits the production of adhesion molecules that promote the sticking of leukocytes to endothelial cells. By this means melatonin attenuates transendothelial cell migration and edema, which contribute to tissue damage.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) has been implicated in abiotic and biotic stress tolerance in plants. However, information on the effects of melatonin in cold-stress tolerance in vivo is limited. In this study, the effect of melatonin was investigated in the model plant Arabidopsis thaliana challenged with a cold stress at 4⁰C for 72 and 120 hr. Melatonin-treated plants (10 and 30 μm) had significantly higher fresh weight, primary root length, and shoot height compared with the nontreated plants. To aid in the understanding of the role of melatonin in alleviating cold stress, we investigated the effects of melatonin treatment on the expression of cold-related genes. Melatonin up-regulated the expression of C-repeat-binding factors (CBFs)/Drought Response Element Binding factors (DREBs), a cold-responsive gene, COR1<em>5</em>a, a transcription factor involved in freezing and drought-stress tolerance CAMTA1 and transcription activators of reactive oxygen species (ROS)-related antioxidant genes, ZAT10 and ZAT12, following cold stress. The up-regulation of cold signaling genes by melatonin may stimulate the biosynthesis of cold-protecting compounds and contribute to the increased growth of plants treated with exogenous melatonin under cold stress.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a molecule with a very wide phylogenetic distribution from plants to man. In vertebrates, melatonin was initially thought to be exclusively of pineal origin recent studies have shown, however, that melatonin synthesis may occur in a variety of cells and organs. The concentration of melatonin within body fluids and subcellular compartments varies widely, with blood levels of the indole being lower than those at many other sites. Thus, when defining what constitutes a physiological level of melatonin, it must be defined relative to a specific compartment. Melatonin has been shown to have a variety of functions, and research in the last decade has proven the indole to be both a direct free radical scavenger and indirect antioxidant. Because of these actions, and possibly others that remain to be defined, melatonin has been shown to reduce the toxicity and increase the efficacy of a large number of drugs whose side effects are well documented. Herein, we summarize the beneficial effects of melatonin when combined with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin, <em>acetyl</em>salicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol, caposide-<em>5</em>0, morphine, cyclophosphamide and L-cysteine. While the majority of these studies were conducted using animals, a number of the investigations also used man. Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the efficacy of these drugs, its use as a combination therapy with these agents seems important and worthy of pursuit.

The present study was designed to characterize an "atypical" <em>5</em>-hydroxytryptamine (<em>5</em>-HT) receptor mediating relaxation of the rat oesophageal tunica muscularis mucosae. All experiments were performed under equilibrium conditions, using pargyline to inhibit the oxidative deamination of indoleamines, and cocaine and corticosterone to inhibit neuronal and extraneuronal uptake. Under these conditions <em>5</em>-HT (0.3-1000 nmol/l) produced a concentration-dependent relaxation of carbachol-induced tension. The concentration-effect curve to <em>5</em>-HT was unaffected by potent antagonists for <em>5</em>-HT1, <em>5</em>-HT2, <em>5</em>-HT3 and so called <em>5</em>-HT1P receptors (metergoline, methysergide, ketanserin, ondansetron, <em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptophyl-<em>5</em>-hydroxytryptophan amide), but was antagonized competitively by ICS 20<em>5</em>-930 (pA2 = 6.7). Responses to <em>5</em>-HT were mimicked by other indoleamines and substituted benzamides with the following order of potency: <em>5</em>-HT greater than or equal to <em>5</em>-<em>methoxytryptamine</em> greater than cisapride = alpha-methyl-<em>5</em>-HT = (S)-zacopride = renzapride greater than (RS)-zacopride greater than <em>5</em>-carboxamido-tryptamine = metoclopramide = (R)-zacopride greater than tryptamine greater than 2-methyl-<em>5</em>-HT. ICS 20<em>5</em>-930 afforded similar pA2 values (6.0-6.7) against each agonist, indicating a common site of action. Concentration-effect curves to <em>5</em>-HT were not affected by tetrodotoxin or indomethacin, suggesting that <em>5</em>-HT-induced relaxation of the tunica muscularis mucosae was mediated via a post-junctional receptor, independent of endogenous prostanoids. The pharmacological profile of the <em>5</em>-HT receptor in the rat oesophageal tunica muscularis mucosae correlates well with the <em>5</em>-HT4 receptor characterized recently in both the C<em>N</em>S and gastro-intestinal tract.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), the chief secretory product of the pineal gland in the brain, is well known for its functional versatility. In hundreds of investigations, melatonin has been documented as a direct free radical scavenger and an indirect antioxidant, as well as an important immunomodulatory agent. The radical scavenging ability of melatonin is believed to work via electron donation to detoxify a variety of reactive oxygen and nitrogen species, including the highly toxic hydroxyl radical. It has long been recognized that the damaging effects of ionizing radiation are brought about by both direct and indirect mechanisms. The direct action produces disruption of sensitive molecules in the cells, whereas the indirect effects ( approximately 70%) result from its interaction with water molecules, which results in the production of highly reactive free radicals such as *OH, *H, and e(aq)- and their subsequent action on subcellular structures. The hydroxyl radical scavenging ability of melatonin was used as a rationale to determine its radioprotective efficiency. Indeed, the results from many in vitro and in vivo investigations have confirmed that melatonin protects mammalian cells from the toxic effects of ionizing radiation. Furthermore, several clinical reports indicate that melatonin administration, either alone or in combination with traditional radiotherapy, results in a favorable efficacy:toxicity ratio during the treatment of human cancers. This article reviews the literature from laboratory investigations that document the ability of melatonin to scavenge a variety of free radicals (including the hydroxyl radical induced by ionizing radiation) and summarizes the evidence that should be used to design larger translational research-based clinical trials using melatonin as a radioprotector and also in cancer radiotherapy. The potential use of melatonin for protecting individuals from radiation terrorism is also considered.

Ionizing radiation is classified as a potent carcinogen, and its injury to living cells is, to a large extent, due to oxidative stress. The molecule most often reported to be damaged by ionizing radiation is D<em>N</em>A. Hydroxyl radicals (*OH), considered the most damaging of all free radicals generated in organisms, are often responsible for D<em>N</em>A damage caused by ionizing radiation. Melatonin, <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, is a well-known antioxidant that protects D<em>N</em>A, lipids, and proteins from free-radical damage. The indoleamine manifests its antioxidative properties by stimulating the activities of antioxidant enzymes and scavenging free radicals directly or indirectly. Among known antioxidants, melatonin is a highly effective scavenger of *OH. Melatonin is distributed ubiquitously in organisms and, as far as is known, in all cellular compartments, and it quickly passes through all biological membranes. The protective effects of melatonin against oxidative stress caused by ionizing radiation have been documented in in vitro and in vivo studies in different species and in in vitro experiments that used human tissues, as well as when melatonin was given to humans and then tissues collected and subjected to ionizing radiation. The radioprotective effects of melatonin against cellular damage caused by oxidative stress and its low toxicity make this molecule a potential supplement in the treatment or co-treatment in situations where the effects of ionizing radiation are to be minimized.

It is commonly accepted that melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), the most relevant pineal secretory product, has oncostatic properties in a wide variety of tumors and, especially, in those identified as being hormonedependent. The objective of the present article is to offer a global and integrative view of the mechanisms involved in the oncostatic actions of this indoleamine. Due to the wide spectrum of melatonin's actions, the mechanisms that may be involved in its ability to counteract tumor growth are varied. These include: a) antioxidant effects; b) regulation of the estrogen receptor expression and transactivation; c) modulation of the enzymes involved in the local synthesis of estrogens; d) modulation of cell cycle and induction of apoptosis; e) inhibition of telomerase activity; f) inhibition of metastasis; g) prevention of circadian disruption; h) antiangiogenesis; i) epigenetic effects; j) stimulation of cell differentiation; and k) activation of the immune system. The data supporting each of these oncostatic actions of melatonin are summarized in this review. Moreover, the list of actions described may not be exhaustive in terms of how melatonin modulates tumor growth.

Melatonin is a well-known agent that plays multiple roles in animals. Its possible function in plants is less clear. In the present study, we tested the effect of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) on soybean growth and development. Coating seeds with melatonin significantly promoted soybean growth as judged from leaf size and plant height. This enhancement was also observed in soybean production and their fatty acid content. Melatonin increased pod number and seed number, but not 100-seed weight. Melatonin also improved soybean tolerance to salt and drought stresses. Transcriptome analysis revealed that salt stress inhibited expressions of genes related to binding, oxidoreductase activity/process, and secondary metabolic processes. Melatonin up-regulated expressions of the genes inhibited by salt stress, and hence alleviated the inhibitory effects of salt stress on gene expressions. Further detailed analysis of the affected pathways documents that melatonin probably achieved its promotional roles in soybean through enhancement of genes involved in cell division, photosynthesis, carbohydrate metabolism, fatty acid biosynthesis, and ascorbate metabolism. Our results demonstrate that melatonin has significant potential for improvement of soybean growth and seed production. Further study should uncover more about the molecular mechanisms of melatonin's function in soybeans and other crops.

In spite of the fact that radiotherapy is a common and effective tool for cancer treatment; the radio sensitivity of normal tissues adjacent to the tumor which are unavoidably exposed to radiation limits therapeutic gain. For the sake of improvement in radiation therapy, radiobiology- the study of the action of ionizing radiation on living things- plays a crucial role through explaining observed phenomena, and suggesting improvements to existing therapies. Due to the damaging effects of ionizing radiation, radiobiologists have long been interested in identifying novel, nontoxic, effective, and convenient compounds to protect humans against radiation induced normal tissue injuries. In hundreds of investigations, melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), the chief secretory product of the pineal gland in the brain, has been documented to ameliorate the oxidative injuries due to ionizing radiation. This article reviews different features that make melatonin a potentially useful radioprotector. Moreover, based on radiobiological models we can hypothesize that melatonin may postpone the saturation of repair enzymes which leads to repairing more induced damage by repair system and more importantly allows the use of higher doses of radiation during radiotherapy to get a better therapeutic ratio. The implications of the accumulated observations suggest by virtue of melatonin's radioprotective and anticancer effects; it is time to use it as a radioprotector both for radiation workers and patients suffering from cancer either alone for cancer inhibition or in combination with traditional radiotherapy for getting a favorable efficacy/toxicity ratio during the treatment. Although compelling evidence suggests that melatonin may be effective for a variety of disorders, the optimum dose of melatonin for human radioprotection is yet to be determined. We propose that, in the future, melatonin improve the therapeutic ratio in radiation oncology.

In its role as a pineal hormone, melatonin is a pleiotropic, nocturnally peaking and systemically acting chronobiotic. These effects are largely explained by actions via G protein-coupled membrane receptors found in the suprachiasmatic nucleus, but also in numerous other sites. <em>N</em>uclear (ROR/RZR), cytoplasmic (quinone reductase-2, calmodulin, calreticulin) and mitochondrial binding sites and radical-scavenging properties contribute to the actions of melatonin. Regulation of pineal melatonin biosynthesis is largely explained by control mechanisms acting on arylalkylamine <em>N</em>-<em>acetyl</em>transferase, at the levels of gene expression and/or enzyme stability influenced by phosphorylation and interaction with 14-3-3 proteins. Melatonin is not only a hormone but is also synthesized in numerous extrapineal sites, in which it sometimes attains much higher quantities than in the pineal and the circulation. It is also present in many taxonomically distant groups of organisms, including bacteria, fungi, and plants. Moreover, melatonin is a source of bioactive metabolites, such as <em>5</em>-<em>methoxytryptamine</em>, <em>N</em>(1)-<em>acetyl</em>-<em>N</em>(2)-formyl-<em>5</em>-methoxykynuramine and <em>N</em>(1)-<em>acetyl</em>-<em>5</em>-methoxykynuramine.

A specific and sensitive double-antibody radioimmunoassay for melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) has been developed utilizing rabbit antisera to a bovine serum albumin conjugate of <em>N</em>-succinyl-<em>5</em>-<em>methoxytryptamine</em> and utilizing <em>N</em>-3-(4-hydroxyphenl)-propionyl-<em>5</em>-<em>methoxytryptamine</em> for radioiodination. The least detectable concentration of melatonin standard was 10 pmolar (2.3 pg/tube) with <em>5</em>0% inhibition resultinhibition curves obtained with increasing quantities of melatonin or increasing quantities of chloroform extracts of ovine sera were parallel. The immunoreactivity found in ovine sera c-migrated with [3H]melatonin on silica gel G when developed with chloroform:methanol (9:1). <em>N</em>-Acetylserotonin, <em>5</em>-<em>methoxytryptamine</em>, serotonin, tryptophan, 6-hydroxymelatonin, 6-methoxytetrahydroharmalan, and several other indole and beta-carboline compounds do not influence the estimation of melatonin in the radioimmunoassay. Concentrations of melatonin could be accurately determined when 31 to 1000 pg were added to 1 ml ovine serum. Serum samples with melatonin concentrations of 1000 pg/ml, <em>5</em>00 pg/ml and 7<em>5</em> pg/ml had intra-assay coefficients of variation of 9.1%, 8.6%, and 17.4%, respectively. The respective inter-assay coefficients of variation were 22.7%, 18.1%, and 37.1%. Ewes exposed to a 12 h light: 12 h dark lighting regimen demonstrated a circadian rhythm in serum concentrations of melatonin. Concentrations ranged from 10-30 pg/ml during periods of light to 100-300 pg/ml during periods of dark. During exposure to continuous light, the circadian rhythm was abolished and concentrations of melatonin were maintained at 10-<em>5</em>0 pg/ml. When exposed to conditions of continuous dark the circadian rhythm persisted. A precipitous drop in serum concentrations of melatonin resulted when ewes experiencing peak melatonin concentrations were exposed to light. Concentrations returned to peak levels when the lights were turned off 3.<em>5</em> h later.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a highly conserved molecule whose presence is not exclusive to the animal kingdom. Indeed, numerous studies have demonstrated its presence in plants, where the possible role(s) of this indoleamine is (are) under active investigation. The present work aims to further our knowledge in this respect and presents the results of a study of the effect that melatonin has on foliar senescence. Barley leaves treated with melatonin solutions clearly slowed down the senescence process, as estimated from the chlorophyll lost in leaves. This effect of melatonin was concentration dependent, with an optimal response being obtained at 1 mm melatonin, after 48 hr of incubation in darkness. The already known effects of the phytohormones, kinetin, and abscisic acid, were also assayed. Of the phytohormone and melatonin combinations assayed, 1 mm melatonin presented the best protection against senescence. The levels of endogenous melatonin in control leaves were measured by liquid chromatography with fluorescence detection and in leaves treated with different exogenous melatonin concentrations (to demonstrate the absorption capacity of leaves). The possible physiological implications of this newly revealed action of melatonin in foliar senescence are discussed.

In a recent study melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a well-investigated animal molecule but minimally studied in plants, was seen to have a physiological role as growth-promoting molecule in lupin hypocotyls. In the present study, the role of melatonin as a growth promoter is extended to coleoptiles of canary grass, wheat, barley and oat, in which it shows a relative auxinic activity [with respect to indole-3-acetic acid (IAA), the main auxin in plants] of between 10 and <em>5</em><em>5</em>%. In addition, melatonin is seen to have an important inhibitory growth effect on roots similar to that played by auxin. The quantitation by liquid chromatography with electrochemical detection and identification by tandem mass spectrometry of melatonin and IAA in etiolated coleoptiles of the monocots assayed showed that both compounds are present in similar levels in these tissues. These results point to the co-existence of auxin and melatonin in tissues and raises the possibility of their co-participation in some physiological actions as auxinic hormones in plants.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) 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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a well-known animal hormone, was discovered in plants in 199<em>5</em> but very little research into it has been carried out since. It is present in different parts of all the plant species studied, including leaves, stems, roots, fruits and seeds. This brief review will attempt to provide an overview of melatonin (its discovery, presence and functions in different organisms, biosynthetic route, etc.) and to compile a practically complete bibliography on this compound in plants. The common biosynthetic pathways shared by the auxin, indole-3-acetic, and melatonin suggest a possible coordinated regulation in plants. More specifically, our knowledge to date of the role of melatonin in the vegetative and reproductive physiology of plants is presented in detail. The most interesting aspects for future physiological studies are presented.