Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a molecule known to be produced in multiple cells and organs. It acts at the level of the biological clock, the suprachiasmatic nuclei, to modulate their activity, thereby influencing circadian rhythms, and also sleep processes. The clinical application of melatonin in the treatment of human mental disorders is still in its infancy. Until now, melatonin only has been used in psychiatry because of its hypnotic, resynchronizing and antioxidant actions. In this review, we hypothesized that melatonin might play an important role as an adjuvant therapy, in mental disturbances, due to other properties including its anti-inflammatory, antinociceptive, anxiolytic, drug detoxification properties, protective actions against osteoporosis, etc. Complex interactions occur between the brain and the immune system and currently is accepted that psychological and psychiatric illness can compromise immune and hormonal functions. Altered psychological states often influence the susceptibility of an individual to illness or modify the course of the illness and its prognosis. The present review discusses on the advantages of the co-treatment with melatonin and recent patents in three major psychiatric disorders: depression, bipolar syndrome and schizophrenia. The findings suggest new vistas in both the pathophysiology and the pharmacology of mental disorders.

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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) 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.

OBJECTIVE

Anti-cancer effects of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, an indole-amine), have been widely reported, however, little has been known, regarding its mechanism(s) of action in lung cancer. Thus, we investigated its induction of apoptosis through biomolecular changes (lipid, protein and nucleic acid/D<em>N</em>A) in the SK-LU-1 human lung cancer cell line.

METHODS

We used Fourier transform infrared (FTIR) microspectroscopy, and conventional methods, to confirm changes in lipid (annexin V/PI staining for membrane alteration), protein (caspase-3/7 protein activity) and DNA (DAPI staining for DNA fragmentation).

RESULTS

We observed from FTIR data that melatonin increased lipid content and reduced intensity of nucleic acid/D<em>N</em>A, confirmed by annexin V/PI and DAPI respectively. Secondary protein structure at 16<em>5</em>6 cm(-1) (α-helix) was reduced and peak position of β-sheet structure (1637 cm(-1) ) was shifted to lower frequency. Alteration in apoptotic proteins was demonstrated via caspase-3/7 activity induction.

CONCLUSIONS

High melatonin concentration exerted anti-cancer effects by changing biomolecular structure of lipids, nucleic acids and proteins, supporting its enhancement of apoptotic induction.

delta-Aminolevulinic acid (ALA) is a precursor of haem. The increased concentration of ALA is typically related to acute intermittent porphyria, hereditary tyrosinemia, and lead poisoning. delta-Aminolevulinic acid produced in excess accumulates in a number of organs, causes oxidative damage, and often leads to cancer. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a well-known antioxidant, free radical scavenger, and exhibits anticarcinogenic properties. It protects D<em>N</em>A, lipids, and proteins from oxidative damage. The protective effects of melatonin against ALA-induced oxidation of guanine bases, lipid peroxidation, and alterations in membrane fluidity in several organs have been documented. There is an inverse relationship between melatonin and ALA concentrations in both experimental and clinical conditions of porphyria. The marked efficacy of melatonin in protecting against ALA-related oxidative stress, its oncostatic properties, and low toxicity constitute reasons to consider the use of this indoleamine as a co-treatment in patients suffering from disturbances related to ALA accumulation.

<em>N</em>umerous classes of chemicals have been considered as regulators of various aspects of plant growth and development. In evaluating these putative regulatory molecules, plant biologists have encountered a number of challenges, including: the problem of quantifying substances present at trace levels in extremely complex mixtures; difficulty in obtaining and interpreting phenotypic responses to exogenous applications; and, until recently, the inability to selectively alter endogenous levels of these substances. Melatonin (<em>N</em>-<em>acetyl</em> <em>5</em>-<em>methoxytryptamine</em>), a methoxylated indoleamine, is a potential regulatory molecule found in plants. Although no specific phenotype is currently associated with melatonin or its analogs in higher plants, it has important and unique biological activity in many other taxa, from algae to primates. In these organisms, melatonin functions as a night signal, coordinating responses to diurnal and photoperiodic environmental cues. We assess the process by which melatonin has been evaluated in plants so far and find that many of the methods for melatonin analysis, which have been adopted from animal studies, are inappropriate for use with plant materials. Thus, despite some interesting preliminary reports, research supporting the case for melatonin as a plant regulator is still in its infancy.

The neurohormone <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, 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 1<em>5</em> proteins, including receptors (MT₁, MT₂, Mel1c, CA<em>N</em>D2, 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.

As a well-known animal hormone, melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is also involved in multiple plant biological processes, especially in various stress responses. Rice is one of the most important crops, and melatonin is taken in by many people everyday from rice. However, the transcriptional profiling of melatonin-related genes in rice is largely unknown. In this study, the expression patterns of 11 melatonin related genes in rice in different periods, tissues, in response to different treatments were synthetically analyzed using published microarray data. These results suggest that the melatonin-related genes may play important and dual roles in rice developmental stages. We highlight the commonly regulation of rice melatonin-related genes by abscisic acid (ABA), jasmonic acid (JA), various abiotic stresses and pathogen infection, indicating the possible role of these genes in multiple stress responses and underlying crosstalks of plant hormones, especially ABA and JA. Taken together, this study may provide insight into the association among melatonin biosynthesis and catabolic pathway, plant development and stress responses in rice. The profile analysis identified candidate genes for further functional characterization in circadian rhythm and specific stress responses.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) was first purified and characterized from the bovine pineal gland extract by Aron Lerner and co-workers in 19<em>5</em>8. Since then, a plethora of information has piled up on its biosynthesis, metabolism, time-bound periodicity, physiological and patho-physiological functions, as well as its interactions with other endocrine or neuro-endocrine organs and tissues in the body. Melatonin has wide range of applications in physiology and biomedical fields. In recent years, a significant progress has been made in the understanding mechanism of its actions at the cellular and molecular levels. Consistent efforts have uncovered the mystery of this indoleamine, and demonstrated its role in regulation of a large as well as diverse body functions in different groups of animals in general, and in humans in particular. Current review, in commemoration of <em>5</em>0 years of discovery of melatonin, while revisiting the established dogmas, summarizes current information on biosynthesis, secretion, metabolism and molecular mechanism of action of melatonin at cellular level and highlights the recent research on its role in human physiology and clinical biology.

The bi<em>n</em>di<em>n</em>g a<em>n</em>d pharmacological characteristics of the melato<em>n</em>i<em>n</em> site labeled by the radioliga<em>n</em>d 2-[12<em>5</em>I]iodomelato<em>n</em>i<em>n</em> i<em>n</em> chicke<em>n</em> brai<em>n</em> membra<em>n</em>es were determi<em>n</em>ed a<em>n</em>d compared with those of the melato<em>n</em>i<em>n</em> site of chicke<em>n</em> reti<em>n</em>al membra<em>n</em>es. The specific bi<em>n</em>di<em>n</em>g of 2-[12<em>5</em>I]iodomelato<em>n</em>i<em>n</em> to chicke<em>n</em> brai<em>n</em> membra<em>n</em>es was fou<em>n</em>d to be stable, saturable, reversible a<em>n</em>d of high affi<em>n</em>ity. Scatchard a<em>n</em>alysis of the bi<em>n</em>di<em>n</em>g revealed a<em>n</em> affi<em>n</em>ity co<em>n</em>sta<em>n</em>t (Kd) of 344 +/- 24 pM (<em>n</em> = 4) a<em>n</em>d a total <em>n</em>umber of bi<em>n</em>di<em>n</em>g sites (Bmax) of <em>5</em>7.6 +/- 10.1 fmol/mg protei<em>n</em> (<em>n</em> = 4). The Kd value correspo<em>n</em>d closely with that fou<em>n</em>d i<em>n</em> ki<em>n</em>etic studies (Kd = 407 pM) a<em>n</em>d that reported i<em>n</em> chicke<em>n</em> reti<em>n</em>al membra<em>n</em>es. Competitio<em>n</em> experime<em>n</em>ts were carried out with various compou<em>n</em>ds reveali<em>n</em>g the followi<em>n</em>g order of pharmacological affi<em>n</em>ities: 6-chloromelato<em>n</em>i<em>n</em> greater tha<em>n</em> or equal to 2-iodomelato<em>n</em>i<em>n</em> greater tha<em>n</em> melato<em>n</em>i<em>n</em> greater tha<em>n</em> 2-methyl-6,7-dichloromelato<em>n</em>i<em>n</em> greater tha<em>n</em> 6-hydroxymelato<em>n</em>i<em>n</em> greater tha<em>n</em> <em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptami<em>n</em>e greater tha<em>n</em> luzi<em>n</em>dole greater tha<em>n</em> <em>N</em>-<em>acetyl</em>-<em>5</em>-methoxyky<em>n</em>ure<em>n</em>ami<em>n</em>e greater tha<em>n</em> 6-methoxymelato<em>n</em>i<em>n</em> greater tha<em>n</em> <em>N</em>-<em>acetyl</em>tryptami<em>n</em>e greater tha<em>n</em> <em>5</em>-<em>methoxytryptamine</em> greater tha<em>n</em> <em>5</em>-hydroxytryptami<em>n</em>e greater tha<em>n</em> <em>5</em>-methoxy-<em>N</em>,<em>N</em>-dimethyltryptami<em>n</em>e greater tha<em>n</em> <em>5</em>-methoxytryptophol. This order of pharmacological affi<em>n</em>ities is ide<em>n</em>tical to that fou<em>n</em>d i<em>n</em> chicke<em>n</em> reti<em>n</em>al membra<em>n</em>es. Correlatio<em>n</em> betwee<em>n</em> affi<em>n</em>ity co<em>n</em>sta<em>n</em>ts for various melato<em>n</em>i<em>n</em> receptor ago<em>n</em>ists a<em>n</em>d putative melato<em>n</em>i<em>n</em> receptor a<em>n</em>tago<em>n</em>ists obtai<em>n</em>ed i<em>n</em> chicke<em>n</em> brai<em>n</em> a<em>n</em>d reti<em>n</em>al membra<em>n</em>es yielded a correlatio<em>n</em> coefficie<em>n</em>t (r) of 0.966 (slope = 0.6<em>5</em>2, <em>n</em> = 14, P less tha<em>n</em> 0.01). We co<em>n</em>clude that the high affi<em>n</em>ity site labeled by 2-[12<em>5</em>I]iodomelato<em>n</em>i<em>n</em> i<em>n</em> chicke<em>n</em> brai<em>n</em> membra<em>n</em>es has ide<em>n</em>tical bi<em>n</em>di<em>n</em>g a<em>n</em>d pharmacological characteristics to the ML-1 melato<em>n</em>i<em>n</em> receptor site previously described i<em>n</em> chicke<em>n</em> reti<em>n</em>al membra<em>n</em>es.

The present study investigates the possible direct actions of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) on intestinal motility in goldfish (Carassius auratus) using an in vitro system of isolated intestine in an organ bath engaged to an isometric transducer. The longitudinal strips from goldfish intestine in the organ bath showed a resting spontaneous myogenic rhythmic activity which is not altered by melatonin. The addition of <em>acetyl</em>choline (1 nmol l(-1)-10 mmol l(-1)) to the organ bath induces a significant contraction of the intestinal strips in a concentration-dependent manner. The addition of melatonin and its agonist, 2-iodomelatonin, induced a concentration-dependent attenuation of <em>acetyl</em>choline-induced contractile response. The specificity of this effect is tested by the preincubation of the intestine strips in the presence of two melatoninergic antagonists, luzindole (a non-selective MT(1)/MT(2) melatonin receptor antagonist) and 4-P-PDOT (preferred antagonist of MT2 receptor subtype), which counteracted the melatonin-induced relaxation in a concentration-dependent manner. Finally, present results demonstrate that this melatoninergic effect on intestinal strips is a process highly dependent on extracellular calcium. In conclusion, this is the first study demonstrating the role of melatonin in the control of gut motility in a non-mammalian vertebrate. The melatonin effects on isolated intestine from goldfish are mediated by melatoninergic membrane receptors, and could suggest a delay in food transit time, supporting its anorectic effect reported on in vivo studies.

Day-night levels of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) were determined in different organs of adult female crickets (Gryllus bimaculatus) exposed to a 12/12 light/dark cycle, using reversed-phase high performance liquid chromatography coupled with fluorometric detection. Melatonin levels in the compound eye, brain, and palp were significantly higher during the dark period than during the light period, suggesting that a diurnal rhythm of melatonin levels exists in these organs of crickets, with a peak during the dark period. Conversely, melatonin levels were significantly higher during the light period than the dark period in the cercus, ovipositor, antenna, hind-leg and ovary. <em>N</em>o significant day-night difference was found in the fore- and mid-legs, Malpighian tube, and digestive tube. Thus, these organs may have different melatonin-metabolizing systems compared to those found in the compound eye, brain, and palp. Differences in the phasing of the melatonin rhythm in various organs of the cricket suggest possible differences in melatonin function in these organs.

<em>N</em>aphthalene is a bicyclic aromatic compound that is widely used in various domestic and commercial applications. Previous studies in our laboratory have demonstrated enhanced production of reactive oxygen species, lipid peroxidation and D<em>N</em>A fragmentation in both in vitro and in vivo models following treatment with naphthalene. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), an indole hormone, is the chief secretory product of the pineal gland and is an efficient free radical scavenger and antioxidant, both in vitro and in vivo. In this study, we have investigated the ability of 1 mM melatonin to protect against naphthalene-induced oxidative stress and D<em>N</em>A damage in cultured macrophage J774A.1 cells. <em>N</em>o significant changes were observed when these macrophage cells were treated with 100 microM naphthalene. Approximately 2.0-, 4.2- and 4.4-fold increases in cytochrome c reduction were observed at 200, 400 and <em>5</em>00 mM concentrations of naphthalene, demonstrating the increased production of superoxide anion. At 24 h, lipid peroxidation increased by approximately 1.4-, 2.1- and 2.2-fold following treatment of these cells with 200, 400 and <em>5</em>00 mM concentrations of naphthalene, respectively, while 1.6-, 2.8- and 2.8-fold increases in D<em>N</em>A fragmentation were observed at these same concentrations. Two hour pretreatment of these cultured cells with 1 mM melatonin provided approximately 26-44% decreases in lipid peroxidation, superoxide anion production and D<em>N</em>A fragmentation in cells treated with 400 and <em>5</em>00 microM naphthalene. Cellular viability decreased significantly when cells were incubated with concentrations of naphthalene greater than 100 microM, while preincubation with melatonin significantly increased the cellular viability. These results demonstrate that naphthalene may induce toxic manifestations by enhanced production of reactive oxygen free radicals, resulting in lipid peroxidation and D<em>N</em>A damage, while preincubation with melatonin significantly suppressed cytoxicity in J774A.1 macrophage cells.

<em>5</em>-Hydroxytryptamine (<em>5</em>-HT) is a mediator of chloride ion (Cl-) secretion in the intestine which can be seen as a rise in short circuit current (Isc) in the Ussing chamber model. We investigated the <em>5</em>-HT receptor mediating <em>5</em>-HT-induced Cl- secretion in the human jejunum in vitro. Jejunal segments obtained from patients having gastric bypass surgery for obesity, were stripped of muscularis and mounted in Ussing chambers and short-circuited. The <em>5</em>-HT receptor agonist-induced change (delta) in Isc was recorded in the presence and and absence of <em>5</em>-HT receptor antagonists. The rank order of agonist potency was: <em>5</em>-HT>> <em>5</em>-<em>methoxytryptamine</em>>> renzapride (BRL 24924>> alpha-methyl-<em>5</em>-HT>>) 2-methyl-<em>5</em>-HT. In the presence of Cl(-)-free media or 100 microM furosemide, <em>5</em>-HT-induced delta Isc was significantly reduced. It was also antagonized by>> or = 1 microM tropisetron (a <em>5</em>-HT 3/<em>5</em>-HT4 receptor antagonist) and>> or = 10 nM GR 113808 (a selective <em>5</em>-HT4 receptor antagonist) with pA2 values of 6.<em>5</em> and 7.9, respectively. Another <em>5</em>-HT4 receptor antagonist, SC <em>5</em>3606 (0.1 microM), antagonized the <em>5</em>-HT-induced response with a pA2 of 7.3 <em>5</em>-HT1-like/<em>5</em>-HT2 (methysergide), <em>5</em>-HT1P [<em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptophyl <em>5</em>-hydroxytryptophan amide (<em>5</em>-HT-DP], <em>5</em>-HT2A (ketanserin) and <em>5</em>-HT3 (ondansetron) receptor antagonists and tetrodotoxin, had no significant effect on the EC<em>5</em>0 for <em>5</em>-HT. In conclusion, this study demonstrates that in the human muscle-stripped jejunum in vitro, <em>5</em>-HT induced change in short circuit current is mediated by a <em>5</em>-HT4 receptor via a non-neural pathway.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is the chief secretory product of the pineal gland and synthesized enzymatically from serotonin (<em>5</em>-hydroxytryptamine). These indoleamine derivatives play an important role in the prevention of oxidative damage. In the present study, DMPD radical scavenging and cupric ion (Cu(2+)) reducing ability of melatonin and serotonin as trolox equivalent antioxidant activity (TEAC) was investigated. Melatonin and serotonin demonstrated 73.<em>5</em> and 127.4 microg/mL trolox equivalent DMPD( radical+) scavenging activity at the concentration of 100 microg/mL. Also, at the same concentration, melatonin and serotonin showed 14.41 and 116.09 microg/mL trolox equivalent cupric ion (Cu(2+)) reducing ability. These results showed that melatonin and serotonin had marked DMPD(radical+) radical scavenging and cupric ions (Cu(2+)) reducing ability. Especially, serotonin had higher DMPD radical scavenging and cupric ions (Cu(2+)) reducing activity than melatonin because of its phenolic group.

In the rat distal colon, <em>5</em>-hydroxytryptamine (<em>5</em>-HT)-induced Cl- secretion is seen as a rise in short circuit current (Isc). We investigated the <em>5</em>-HT receptor mediating <em>5</em>-HT-induced Cl- secretion in the rat distal colon. Rat distal colon was prepared either by stripping away the muscularis propria with the neural ganglia, or by leaving it intact. The tissue was mounted in Ussing chambers and short circuited. <em>5</em>-HT receptor agonist-induced changes (delta) in Isc were recorded in the presence and absence of <em>5</em>-HT receptor antagonists. In stripped preparations, the rank order of potency of agonists was: <em>5</em>-HT>> <em>5</em>-<em>methoxytryptamine</em>>> alpha-methyl-<em>5</em>-HT>>) 2-methyl-<em>5</em>-HT. <em>5</em>-HT and <em>5</em>-<em>methoxytryptamine</em>-induced changes in Isc were antagonized by>> or = 0.3 microM tropisetron with pA2 values 6.<em>5</em> and 6.4, respectively. The <em>5</em>-HT4 antagonist, SC <em>5</em>3606, antagonized the <em>5</em>-HT-induced response with a pA2 of 7.2. <em>5</em>-HT1-like (methysergide), <em>5</em>-HT1P (<em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptophyl <em>5</em>-hydroxytryptophan amide (<em>5</em>-HTP-DP)), <em>5</em>-HT2A (ketanserin) and <em>5</em>-HT3 (ondansetron) receptor antagonists had no significant effect on the <em>5</em>-HT response in stripped tissue. 3 microM forskolin, or 10 microM 3-isobutyl-1-methyl-xanthine (IBMX), decreased the EC<em>5</em>0 and increased the maximum <em>5</em>-HT response. The 2-methyl-<em>5</em>-HT and <em>5</em>-HT-induced delta Isc in the unstripped colon preparation were antagonized by the <em>5</em>-HT3 antagonist, ondansetron (0.3 nM), and 2-methyl-<em>5</em>-HT activity was abolished by pretreatment with tetrodotoxin. In conclusion, <em>5</em>-HT-induced delta Isc is neurally mediated via a <em>5</em>-HT3 receptor, and non-neurally mediated via a <em>5</em>-HT4 receptor in the rat distal colon.

<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, 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.

The mammalia<em>n</em> pi<em>n</em>eal gla<em>n</em>d is a promi<em>n</em>e<em>n</em>t secretory orga<em>n</em> with a high metabolic activity. Melato<em>n</em>i<em>n</em> (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), the mai<em>n</em> secretory product of the pi<em>n</em>eal gla<em>n</em>d, efficie<em>n</em>tly scave<em>n</em>ges both the hydroxyl a<em>n</em>d peroxyl radicals cou<em>n</em>teracti<em>n</em>g lipid peroxidatio<em>n</em> i<em>n</em> biological membra<em>n</em>es. Approximately 2<em>5</em>% of the total fatty acids prese<em>n</em>t i<em>n</em> the rat pi<em>n</em>eal lipids are represe<em>n</em>ted by arachido<em>n</em>ic acid (20:4<em>n</em>-6) a<em>n</em>d docosahexae<em>n</em>oic acid (22:6<em>n</em>-3). These very lo<em>n</em>g chai<em>n</em> polyu<em>n</em>saturated fatty acids play importa<em>n</em>t roles i<em>n</em> the pi<em>n</em>eal gla<em>n</em>d. I<em>n</em> additio<em>n</em> to the productio<em>n</em> of melato<em>n</em>i<em>n</em>, the mammalia<em>n</em> pi<em>n</em>eal gla<em>n</em>d is able of co<em>n</em>vert these polyu<em>n</em>saturated fatty acids i<em>n</em>to bioactive lipid mediators. Lipoxyge<em>n</em>atio<em>n</em> is the pri<em>n</em>cipal lipoxyge<em>n</em>ase (LOX) activity observed i<em>n</em> the rat pi<em>n</em>eal gla<em>n</em>d. Lipoxyge<em>n</em>atio<em>n</em> i<em>n</em> the pi<em>n</em>eal gla<em>n</em>d is exceptio<em>n</em>al because <em>n</em>o other brai<em>n</em> regio<em>n</em>s express sig<em>n</em>ifica<em>n</em>t LOX activities u<em>n</em>der <em>n</em>ormal physiological co<em>n</em>ditio<em>n</em>s. The rat pi<em>n</em>eal gla<em>n</em>d expresses both 12- a<em>n</em>d 1<em>5</em>-lipoxyge<em>n</em>ase (LOX) activities, produci<em>n</em>g 12- a<em>n</em>d 1<em>5</em>-hydroperoxyeicosatetrae<em>n</em>oic acid (12- a<em>n</em>d 1<em>5</em>-HpETE) from arachido<em>n</em>ic acid a<em>n</em>d 14- a<em>n</em>d 17-hydroxydocosahexae<em>n</em>oic acid (14- a<em>n</em>d 17-HdoHE) from docosahexae<em>n</em>oic acid, respectively. The rat pi<em>n</em>eal also produces hepoxili<em>n</em>s via LOX pathways. The hepoxili<em>n</em>s are bioactive epoxy-hydroxy products of the arachido<em>n</em>ic acid metabolism via the 12S-lipoxyge<em>n</em>ase (12S-LOX) pathway. The two key pi<em>n</em>eal biochemical fu<em>n</em>ctio<em>n</em>s, lipoxyge<em>n</em>atio<em>n</em> a<em>n</em>d melato<em>n</em>i<em>n</em> sy<em>n</em>thesis, may be sy<em>n</em>ergistically regulated by the status of <em>n</em>-3 esse<em>n</em>tial fatty acids.

Importance of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) in the regulation of oocyte maturation has been studied in a carp Catla catla. Melatonin secretory cells were immunocytochemically localized only in the end vesicle. Diurnal and seasonal studies indicated that the serum levels of melatonin exhibit a minimum diurnal value in the mid-day of all seasons, but the peak value is attained either at mid-night or just before the onset of light. Moreover, highest seasonal value of melatonin was noted in the post-spawning phase. Administration of melatonin at different doses (2<em>5</em>, <em>5</em>0, or 100 mug/100 g body weight) for 1, 1<em>5</em>, or 30 days resulted in either pro- or anti-gonadal effects depending on the reproductive seasons. In vitro study revealed that incubation of oocytes with melatonin 4h prior to addition of MIH in the medium led to an accelerated rate of oocyte maturation through the formation of a complex of two proteins (MPF), cyclin B and cyclin dependant kinase, Cdc2. Moreover, melatonin pre-incubation considerably increased MIH stimulation of histone H1 phosphorylation as compared to MIH alone. Taken together, gathered information promotes the idea of a physiological role of melatonin in the maturation of oocytes in Catla catla.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) has been shown by several workers to protect the heart against ischaemia/reperfusion damage. Melatonin, both in the picomolar and micromolar range, significantly reduces infarct size and improves functional recovery during reperfusion. This may be due to its free radical scavenging and anti-oxidant effects, while the melatonin receptor and its marked anti-adrenergic actions may also be involved. The latter is mediated by nitric oxide (<em>N</em>O), guanylyl cyclase and protein kinase C (PKC). Melatonin-induced cardioprotection is associated with activation of protein kinase B (PKB), extracellular signal-regulated kinase (ERK1/2) (the Reperfusion Injury Salvage Kinase (RISK) pathway) and signal activator and transducer 3 (STAT-3) (the Survivor Activating Factor Enhancement (SAFE) pathway) during reperfusion and inhibition of the mitochondrial permeability transition pore (MPTP). Very little is known about the effect of melatonin on myocardial substrate metabolism. Melatonin was demonstrated to be involved in the regulation of whole body glucose homeostasis via its effects on pancreatic insulin secretion and may thus indirectly affect myocardial substrate metabolism in a circadian manner.

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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), 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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) has been reported to participate in plant development and abiotic stress responses. The main objective of this study was to investigate the role of melatonin in the cold-sensitive (S) and the cold-tolerant (T) bermudagrass genotypes' response to cold stress. The genotypes were treated with 100 μM melatonin and exposed to 4 °C temperature for 3 days. In both genotypes, cold stress increased the endogenous melatonin levels, and more prominently in T than S. Physiological responses indicated that exogenous melatonin triggered antioxidant activities in both genotypes, while it alleviated cell damage in the T genotype response to cold stress. Melatonin treatment under cold stress increased fluorescence curve levels for both genotypes, and higher in T than S genotypes. In both genotypes, the alterations in photosynthetic fluorescence parameters after melatonin treatment highlighted the participation of melatonin in improving photosystem response to cold stress, particularly for the cold-tolerant genotype. The metabolic analyses revealed the alterations of 44 cold-responsive metabolites in the two genotypes, mainly including carbohydrates, organic acids and amino acids. After exogenous melatonin treatment under cold condition, there was high accumulation of metabolites in the cold-tolerant regimes than their cold-sensitive counterparts. Collectively, the present study revealed differential modulations of melatonin between the cold-sensitive and the cold-tolerant genotypes in response to cold stress. This was mainly by impacting antioxidant system, photosystem II, as well as metabolic homeostasis.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is involved in many developmental processes and responses to various abiotic stresses in plants. Most of the studies on melatonin focus on its functions and physiological responses in plants, while its regulation mechanism remains unknown. Caffeic acid 3-O-methyltransferase (COMT) functions at a key step of the biosynthesis process of melatonin. In this study, a COMT-like gene, <i>TaCOMT</i> (Traes_1AL_D903<em>5</em>D<em>5</em>E0.1) was identified in common wheat (<i>Triticum aestivum</i> L.). Transient transformation in wheat protoplasts determined that TaCOMT is localized in cytoplasm. <i>TaCOMT</i> in wheat was induced by drought stress, gibberellin (GA)3 and 3-Indoleacetic acid (IAA), but not by ABA. In <i>TaCOMT</i> transgenic <i>Arabidopsis</i>, melatonin contents were higher than that in wild type (WT) plants. Under D-Mannitol treatment, the fresh weight of the transgenic <i>Arabidopsis</i> was significantly higher than WT, and transgenic lines had a stronger root system compared to WT. Drought tolerance assays in pots showed that the survival rate of <i>TaCOMT</i>-overexpression lines was significantly higher than that of WT lines. this phenotype was similar to that the WT lines treated with melatonin under drought condition. In addition, the <i>TaCOMT</i> transgenic lines had higher proline content and lower malondialdehyde (MDA) content compared to WT lines after drought treatment. These results indicated that overexpression of the wheat <i>TaCOMT</i> gene enhances drought tolerance and increases the content of melatonin in transgenic <i>Arabidopsis</i>. It could be one of the potential genes for agricultural applications.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) has a diverse range of functions, including the control of neuroendocrine events. A number of studies have shown that melatonin may be of potential benefit for the treatment of insomnia, as well as neurodegenerative disorders. At present, there are numerous dosage forms of melatonin, with the oral route of administration being most popular. Presently, there is little information on the stability of melatonin over a pH range. With the changes in pH in the gastro-intestinal tract, as well as in different experimental conditions, information on the stability of melatonin would be important. We used a high-performance liquid chromatography method to determine the stability of melatonin solutions over a pH range (1.2-12) at room temperature and at 37 degrees C over a period of 21 days. The results show that no melatonin degradation occurred in the first 2 days. From days 3 to 21, there was a gradual decline in melatonin at all pHs, with the decline not exceeding 30%. <em>N</em>o decline in melatonin levels occurred in the first 2 days at 37 degrees C. From days 3 to 21, melatonin levels declined gradually, with the decline not exceeding 29%.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a circadian-regulating hormone, has been reported to exert a protective role during acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (I/R). High-mobility group box 1 (HMGB1) is a novel member of the damage-associated molecular pattern (DAMP) family, and has been verified to be an inflammatory cytokine mediating AKI induced by I/R and cisplatin. However, the effect of melatonin on HMGB1, as well as the relationship of these two with folic acid induced AKI are elusive. In this study, we sought to identify the role of melatonin on folic acid induced AKI and its association with HMGB1. Pretreatment with melatonin significantly attenuated folic acid-induced increase in serum creatinine and BU<em>N</em> levels, renal tubular epithelial cell (TEC) apoptosis, and the infiltration of inflammatory cells and secretion of cytokines. Moreover, melatonin pretreatment promoted renal tubular proliferation and improved cell cycle arrest of TECs after folic acid-induced renal damage. This protective role of melatonin was closely related to the inhibition of nucleocytoplasmic translocation of HMGB1 in TECs. These data provide a strong proof that administering melatonin prior to folic acid insult may shed light on a potential treatment for AKI.