Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) 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 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 single cells to vertebrates and the human. It is one of the most evolutionarily conserved and pleiotropic hormone still active in humans and has been implicated in vital skin functions such as hair growth, fur pigmentation as well as melanoma control. Being a main secretory product of the pineal gland, melatonin regulates seasonal biorhythms, reproductive mechanisms or mammary gland metabolism. Due to its wide range endocrine properties it is also recognized to modulate numerous additional functions ranging from scavenging free radicals, immunomodulation-mediated D<em>N</em>A repair, wound healing, involvement in gene expression connected with circadian clocks and modulation of secondary endocrine signaling including prolactin release. Recently, apart from above mentioned entities, it was shown that melatonin suppresses ultraviolet (UV)-induced damage in human skin and human derived cell lines (e.g., keratinocytes, fibroblasts). The magnitude of UV-induced damage is mediated apparently by various molecular mechanisms related to generation of reactive oxygen species (ROS), apoptosis and mitochondrial-mediated cell death which are all counteracted or modulated by melatonin. We provide here an update of the relevant protective effects and molecular mechanisms of action of melatonin in the skin.

As one popular fresh fruit, banana (Musa acuminata) is cultivated in the world's subtropical and tropical areas. In recent years, pathogen Fusarium oxysporum f. sp. cubense (Foc) has been widely and rapidly spread to banana cultivated areas, causing substantial yield loss. However, the molecular mechanism of banana response to Foc remains unclear, and functional identification of disease-related genes is also very limited. In this study, nine 90 kDa heat-shock proteins (HSP90s) were genomewide identified. Moreover, the expression profile of them in different organs, developmental stages, and in response to abiotic and fungal pathogen Foc were systematically analyzed. <em>N</em>otably, we found that the transcripts of 9 MaHSP90s were commonly regulated by melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) and Foc infection. Further studies showed that exogenous application of melatonin improved banana resistance to Fusarium wilt, but the effect was lost when cotreated with HSP90 inhibitor (geldanamycin, GDA). Moreover, melatonin and GDA had opposite effect on auxin level in response to Foc4, while melatonin and GDA cotreated plants had no significant effect, suggesting the involvement of MaHSP90s in the cross talk of melatonin and auxin in response to fungal infection. Taken together, this study demonstrated that MaHSP90s are essential for melatonin-mediated plant response to Fusarium wilt, which extends our understanding the putative roles of MaHSP90s as well as melatonin in the biological control of banana Fusarium wilt.

The pineal secretory product melatonin (chemically, <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) acts as an effective antioxidant and free-radical scavenger and plays an important role in several physiological functions such as sleep induction, immunomodulation, cardiovascular protection, thermoregulation, neuroprotection, tumor-suppression and oncostasis. Membrane lipid-peroxidation in terms of malondialdehyde (MDA) and intracellular glutathione (GSH) is considered to be a reliable marker of oxidative stress. The present work was undertaken to study the modulating effect of melatonin on MDA and GSH in human erythrocytes during day and night. Our observation shows the modulation of these two biomarkers by melatonin, and this may have important therapeutic implications. In vitro dose-dependent effect of melatonin also showed variation during day and night. We explain our observations on the basis of melatonin's antioxidative function and its effect on the fluidity of plasma membrane of red blood cells. Rhythmic modulation of MDA and GSH contents emphasized the role of melatonin as an antioxidant and its function against oxidative stress.

Melatonin (MLT; <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) exhibits analgesic properties in chronic pain conditions. While researches linking MLT to epigenetic mechanisms have grown exponentially over recent years, very few studies have investigated the contribution of MLT-associated epigenetic modification to pain states. Here, we report that together with behavioral allodynia, spinal nerve ligation (S<em>N</em>L) induced a decrease in the expression of catalytic subunit of phosphatase 2A (PP2Ac) and enhanced histone de<em>acetyl</em>ase 4 (HDAC4) phosphorylation and cytoplasmic accumulation, which epigenetically alleviated HDAC4-suppressed hmgb1 gene transcription, resulting in increased high-mobility group protein B1 (HMGB1) expression selectively in the ipsilateral dorsal horn of rats. Focal knock-down of spinal PP2Ac expression also resulted in behavioral allodynia in association with similar protein expression as observed with S<em>N</em>L. <em>N</em>otably, intrathecal administration with MLT increased PP2Ac expression, HDAC4 dephosphorylation and nuclear accumulation, restored HDAC4-mediated hmgb1 suppression and relieved S<em>N</em>L-sensitized behavioral pain; these effects were all inhibited by spinal injection of 4P-PDOT (a MT2 receptor antagonist, 30 minutes before MLT) and okadaic acid (OA, a PP2A inhibitor, 3 hr after MLT). Our findings demonstrate a novel mechanism by which MLT ameliorates neuropathic allodynia via epigenetic modification. This MLT-exhibited anti-allodynia is mediated by MT2-enhanced PP2Ac expression that couples PP2Ac with HDAC4 to induce HDAC4 dephosphorylation and nuclear import, herein increases HDAC4 binding to the promoter of hmgb1 gene and upregulates HMGB1 expression in dorsal horn neurons.

The type of catecholamine receptor involved in the regulation of serotonin <em>N</em>-<em>acetyl</em>transferase (<em>N</em>AT) activity and melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) level in chicken retina was compared to that regulating these parameters in the pineal gland. Systemic administration of apomorphine, a dopamine receptor agonist, resulted in marked inhibition of the nocturnal increase of retinal <em>N</em>AT activity and melatonin content. Apomorphine did not affect <em>N</em>AT activity or melatonin content of the pineal gland. In contrast, clonidine, an alpha-2 adrenergic receptor agonist, inhibited the nocturnal rise in pineal <em>N</em>AT activity and melatonin content although being without effect on these parameters in retina. Apomorphine-induced inhibition of retinal <em>N</em>AT activity was blocked by spiperone, a D2-dopamine receptor antagonist, but not by antagonists of D1-dopamine, alpha-1, alpha-2 and beta adrenergic receptors. Systemic or intraocular injection of quinpirole, a D2-dopamine receptor agonist, in the middle of the dark phase of the light-dark cycle markedly reduced retinal <em>N</em>AT activity and melatonin level, whereas injections of SKF 38393-A, a D1-dopaminergic agonist, had no effect. The inhibitory effect of clonidine on pineal <em>N</em>AT activity was blocked by yohimbine, an alpha-2 adrenergic receptor antagonist. The results presented in this paper demonstrate that <em>N</em>AT activity and melatonin content in chicken retina and pineal gland are differentially modulated in vivo by D2-dopamine and alpha-2 adrenergic receptors, respectively. Despite the different types of receptors involved, both tissues may share a common pathway for catecholamine-mediated inhibition of melatonin biosynthesis, i.e., inhibition of adenylate cyclase activity.

BACKGROUND

In a previous study, we reported a significant and dose-dependent suppression of UV-induced erythema in human skin by a topically applied melatonin preparation.

OBJECTIVE

The present double-blind randomized study was designed to examine the influence of the application time point of topical melatonin on this antierythema effect.

METHODS

Defined small areas on the lower back of 20 volunteers were treated with 0.6 mg/cm2 melatonin dissolved in a nanocolloid gel carrier either 15 min before or 1, 30 or 240 min after UV irradiation with twice the individual minimal erythema dose delivered by a Multiport Solar UV Simulator (UVA and UVB). The erythemata induced were evaluated by visual scoring and chromametry 24 h after irradiation.

RESULTS

Treatment of the skin with melatonin 15 min before UV irradiation proved to almost completely suppress the development of an UV-induced erythema. In contrast, no significant protective effects of melatonin were observed when it was applied after UV irradiation.

CONCLUSIONS

Topically applied melatonin has a clear-cut protective effect against UV-induced erythema. Free radical scavenging of UV-generated hydroxyl radicals and interference with the arachidonic acid metabolism are possible mechanisms of the melatonin action.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is documented as a hormone involved in the circadian regulation of physiological and neuroendocrine function in mammals. Herein, the effects of melatonin on the functions of porcine granulosa cells in vitro were investigated. Porcine granulosa cells were cultivated with variable concentrations of melatonin (0, 0.001, 0.01, 0.1, 1.0, and 10ng/mL) for 48h. Melatonin receptor agonist (IIK7) and antagonist (Luzindole, 4P-PDOT) were used to further examine the action of melatonin. The results showed optimum cell viability and colony-forming efficiency of porcine granulosa cells at 0.01ng/mL melatonin for 48-h incubation period. The percentage of apoptotic granulosa cells was significantly reduced by 0.01 and 0.1ng/mL melatonin within the 48-h incubation period as compared with the rest of the treatments. Estradiol biosynthesis was significantly stimulated by melatonin supplementation and suppressed for the progesterone secretion; the minimum ratio of progesterone to estradiol was 1.82 in 0.01ng/mL melatonin treatment after 48h of cultivation. Moreover, the expression of BCL-2, CYP17A1, CYP19A1, SOD1, and GPX4 were up-regulated by 0.01ng/mL melatonin or combined with IIK7, but decreased for the mR<em>N</em>A levels of BAX, P<em>5</em>3, and CASPASE-3, as compared with control or groups treated with Luzindole or 4P-PDOT in the presence of melatonin. In conclusion, the study demonstrated that melatonin mediated proliferation, apoptosis, and steroidogenesis in porcine granulosa cells predominantly through the activation of melatonin receptor MT2 in vitro, which provided evidence of the beneficial role of melatonin as well as its functional mechanism in porcine granulosa cells in vitro.

The complex process of carcinogenesis is, to a large extent, due to oxidative stress. <em>N</em>umerous indicators of oxidative damage are enhanced in the result of the action of carcinogens. Several antioxidants protect, with different efficacy, against oxidative abuse, exerted by carcinogens. Recently, melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) and some other indoleamines have gained particular meaning in the defense against oxidative stress and, consequently, carcinogenesis. Some antioxidants, like ascorbic acid, play a bivalent role in the antioxidative defense, revealing, under specific conditions, prooxidative effects. Among known antioxidants, melatonin is particularly frequently applied in experimental models of anticarcinogenic action. In the numerous studies, examining several parameters of oxidative damage and using several in vitro and in vivo models, this indoleamine has been shown to protect D<em>N</em>A and cellular membranes from the oxidative abuse caused by carcinogens. When either preventing or decreasing the oxidative damage to macromolecules, melatonin also protects against the initiation of cancer. The protection provided by melatonin and some other antioxidants against cellular damage, due to carcinogens, make them potential therapeutic supplements in the conditions of increased cancer risk.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, MT) is a molecule with pleiotropic effects including antioxidant activity, regulated plant growth, development, and reduced environmental stress in plants. However, only a few studies have analyzed the effect of exogenous MT on drought stress in naked oat seedlings. Therefore, in this study, we studied the effects of exogenous MT on the antioxidant capacity of naked oat under drought stress to understand the possible antioxidant mechanism. The results showed that a pretreatment of 100 μM MT reduced the hydrogen peroxide (H₂O₂) and superoxide anion (O2−•) contents. MT also enhanced superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) activities in the leaves of naked oat seedlings under 20% PEG-6000 drought stress. MT upregulated the expression levels of the mitogen-activated protein kinases (MAPKs) Asmap1 and Aspk11, and the transcription factor (TF) genes (except for <em>N</em>AC), WRKY1, DREB2, and MYB increased in drought with MT pretreatment seedlings when compared with seedlings exposed to drought stress alone. These data indicated that the MT-mediated induction of the antioxidant response may require the activation of reactive oxygen species (ROS) and MAPK, followed by triggering a downstream MAPK cascade such as Asmap1 and Aspk11, to regulate the expression of antioxidant-related genes. This study demonstrated that MT could induce the expression of MAPKs and TFs and regulate the expression of downstream stress-responsive genes, thereby increasing the plant’s tolerance. This may provide a new idea for MT modulation in the regulation of plant antioxidant defenses. These results provide a theoretical basis for MT to alleviate drought stress in naked oat.

Melatonin, also known as <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, is a ubiquitously acting molecule that is produced by the pineal gland and other organs of animals, including humans. As melatonin and its metabolites are potent antioxidants and free radical scavengers, they are protective against a variety of disorders. Moreover, multiple molecular targets of melatonin have been identified, and its actions are both receptor-mediated and receptor-independent. Recent studies have shown that melatonin may be useful in fighting against sepsis and septic injury due to its antioxidative and anti-inflammatory actions; the results generally indicate a promising therapeutic application for melatonin in the treatment of sepsis. To provide a comprehensive understanding regarding the protective effects of melatonin against septic injury, in the present review we have evaluated the published literature in which melatonin has been used to treat experimental and clinical sepsis. Firstly, we present the evidence from studies that have used melatonin to resist bacterial pathogens. Secondly, we illustrate the protective effect of melatonin against septic injury and discuss the possible mechanisms. Finally, the potential directions for future melatonin research against sepsis are summarized.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is widely known as "the darkness hormone". It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. <em>N</em>umerous 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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a molecule implicated in multiple biological functions. Its level decreases with age, and the intake of foods rich in melatonin has been considered an exogenous source of this important agent. Orange is a natural source of melatonin. Melatonin synthesis occurs during alcoholic fermentation of grapes, malt and pomegranate. The amino acid tryptophan is the precursor of all <em>5</em>-<em>methoxytryptamines</em>. Indeed, melatonin appears in a shorter time in wines when tryptophan is added before fermentation. The aim of the study was to measure melatonin content during alcoholic fermentation of orange juice and to evaluate the role of the precursor tryptophan. Identification and quantification of melatonin during the alcoholic fermentation of orange juice was carried out by UHPLC-QqQ-MS/MS. Melatonin significantly increased throughout fermentation from day 0 (3.1<em>5</em> ng/mL) until day 1<em>5</em> (21.80 ng/mL) reaching larger amounts with respect to other foods. Melatonin isomer was also analysed, but its content remained stable ranging from 11.<em>5</em>9 to 14.18 ng/mL. The enhancement of melatonin occurred mainly in the soluble fraction. Tryptophan levels significantly dropped from 13.80 mg/L (day 0) up to 3.19 mg/L (day 1<em>5</em>) during fermentation. Melatonin was inversely and significantly correlated with tryptophan (r = 0.907). Therefore, the enhancement in melatonin could be due to both the occurrence of tryptophan and the new synthesis by yeast. In summary, the enhancement of melatonin in novel fermented orange beverage would improve the health benefits of orange juice by increasing this bioactive compound.

Hormones are a class of molecules, which mediate their effects by regulating a variety of signalling pathways. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a pineal gland hormone, is one among the categories of compounds having various therapeutic and pharmacological effects. Melatonin has many intracellular as well as extracellular targets including apoptosis, metastasis, angiogenesis and inflammatory pathways. Gene-profile studies have further established its antagonist effect on the various genes involved in the tumour progression, neurodegeneration and ageing. It has also been known to reduce the toxicity induced by chemotherapeutic agents in advanced stages of tumour. The present review extensively describes the molecular interactions of melatonin with various recognized cellular targets, which may lead the scientific community to propose novel therapeutic strategies.

The transduction of seasonal information from the environment (i.e., photoperiod and water temperature) into melatonin rhythms was studied in sea bass. Plasma and ocular melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) was determined in autumn, winter, spring and summer (experiment 1) under natural culture conditions, and in the summer and winter solstices under both natural and "6-month out-of-phase" photoperiods (experiment 2). At each sampling, 48 sea bass were sacrificed at a rate of 6 fish every 3 hr and the level of melatonin was determined in plasma and eye cup samples by ELISA. In experiment 1, significant diel changes were observed in plasma melatonin, with nocturnal melatonin varying from 144 pg/mL (summer) to 23 pg/mL (autumn), while diurnal melatonin remained low, around 8 pg/mL throughout the year. In experiment 2, the photoperiod length was shown to control the duration of the nocturnal melatonin rise, while the water temperature determined the amplitude of the melatonin rhythm. Ocular melatonin peaked during daytime in autumn and winter, but no significant changes were detected in summer and spring. In conclusion, plasma melatonin rhythms in sea bass reflect the pineal capacity to integrate seasonal information and supply precise calendar information, which may synchronize different physiological processes such as annual reproduction and feeding rhythms.

Atopic dermatitis (AD) is a common disease in children, and epicutaneous treatment with a chemical hapten such as 2,4-dinitrofluorobenzene (D<em>N</em>FB) evokes an AD-like reaction in <em>N</em>C/<em>N</em>ga mice under specific pathogen-free conditions. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is synthesized by the pineal gland, has several different physiologic functions, which include seasonal reproduction control, immune system modulation, free radical scavenging, and inflammatory suppression. In the present study, we investigated whether melatonin suppresses D<em>N</em>FB-induced AD-like skin lesions in <em>N</em>C/<em>N</em>ga mice. The topical administration of melatonin to D<em>N</em>FB-treated <em>N</em>C/<em>N</em>ga mice was found to inhibit ear thickness increases and the skin lesions induced by D<em>N</em>FB. Furthermore, interleukin (IL)-4 and interferon (IF<em>N</em>)-gamma secretion by activated CD4(+) T cells from the draining lymph nodes of D<em>N</em>FB-treated <em>N</em>C/<em>N</em>ga mice were significantly inhibited by melatonin, and total IgE levels in serum were reduced. Our findings suggest that melatonin suppresses the development of AD-like dermatitis in D<em>N</em>FB-treated <em>N</em>C/<em>N</em>ga mice by reducing total IgE in serum, and IL-4 and IF<em>N</em>-gamma production by activated CD4(+) T cells.

It is believed that oxidative stress is a key causing factor of liver damage induced by a variety of agents, and it is a major contributing factor in almost all conditions compromising liver function, including ischemia-reperfusion injury (IRI), nonalcoholic fatty liver disease (<em>N</em>AFLD), nonalcoholic steatohepatitis (<em>N</em>ASH), liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). Liver is the organ that high concentration of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) accumulates, and it is the sole organ where circulating melatonin is metabolized. Melatonin is one of the best antioxidants that protects liver, and its metabolites also have antioxidative function. Melatonin exerts its antioxidative function directly through its radical scavenging ability and indirectly through stimulation of antioxidant enzymes. The antioxidative response from melatonin in liver affects from various factors, including its dosage, route, time and duration of administration, the type of oxidative-induced agent and species aging. This indoleamine is also an effective and promising antioxidative choice for targeting liver IRI, <em>N</em>AFLD, <em>N</em>ASH, fibrosis, cirrhosis, and HCC.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an efficient free radical scavenger and antioxidant, both in vitro and in vivo. The role of melatonin as an immunomodulator is, in some cases, contradictory. In this study we have investigated the therapeutic efficacy of melatonin in rats subjected to Pelagia noctiluca crude venom (of the familia Pelaguiidae; and genus Pelagia) induced acute paw inflammation. In particular, injection of the venom into the paw of rats elicited an acute inflammatory response characterized by accumulation of fluid containing a large number of polymorphonuclear neutrophils in the paw and subsequent lipid peroxidation. Furthermore, the venom promoted an expression of i<em>N</em>OS, nitrotyrosine and the activation of the nuclear enzyme poly (ADP-ribose) polymerase as determined by immunohistochemical analysis of paw tissues. Administration of melatonin 30 min, 1 and 6 hr after the challenge with the venom, caused a significant reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that melatonin may be useful a treatment of local acute inflammation induced by P. noctiluca crude venom.

The pineal hormone melatonin (<em>N</em>-<em>acetyl</em>, <em>5</em>-<em>methoxytryptamine</em>) was recently accepted to act as an antioxidant under both in vivo and in vitro conditions. In this study, we examined the possible preventive effect of melatonin on ascorbate-Fe(2+) lipid peroxidation of rat testis microsomes and mitochondria. Special attention was paid to the changes produced on the highly polyunsaturated fatty acids C20:4 n6 and C22:<em>5</em> n6. The lipid peroxidation of testis microsomes or mitochondria produced a significant decrease of C20:4 n6 and C22:<em>5</em> n6. The light emission (chemiluminescence) used as a marker of lipid peroxidation was similar in both kinds of organelles when the control and peroxidized groups were compared. Both long chain polyunsaturated fatty acids were protected when melatonin was incorporated either in microsomes or mitochondria. The melatonin concentration required to inhibit by 100% the lipid peroxidation process was <em>5</em>.0 and 1.0mM in rat testis microsomes and mitochondria, respectively. IC <em>5</em>0 values calculated from the inhibition curve of melatonin on the chemiluminescence rates were higher in microsomes (4.98 mM) than in mitochondria (0.67 mM). The protective effect observed by melatonin in rat testis mitochondria was higher than that observed in microsomes which could be explained if we consider that the sum of C20:4 n6+C22:<em>5</em> n6 in testis microsomes is two-fold greater than present in mitochondria.

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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) 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 (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) was identified in the head and hemolymph of the silkworm, Bombyx mori, using reversed-phase high-performance liquid chromatography coupled with fluorometric detection and radioimmunoassay. In addition, evidence of arylakylamine (serotonin) <em>N</em>-<em>acetyl</em>transferase (<em>N</em>AT) a key enzyme controlling the synthesis of melatonin in vertebrates, was found in the head of the silkworm. Melatonin levels in the head and hemolymph and the <em>N</em>AT activity in the head were significantly higher during the dark period than during the light period of a 12-h light/12-h dark cycle. The day-night changes persisted in constant darkness but were suppressed by constant light. The results suggest that the synthesis and release of melatonin in the silkworm head occur as a circadian rhythm that is entrained by environmental light/dark cycles, as it is in the pineal gland of vertebrates. Melatonin in the silkworm head may function as a neurochemical mediator of photoperiodic control of developmental events such as molting, eclosion and diapause.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), an indole hormone, regulates various biological functions through three different receptor subtypes (Mel-1a, Mel-1b, and Mel-1c). However, the distribution of different melatonin receptor subtypes in chicken reproductive tissues was not known. In the present investigation, the partial sequences of ovarian melatonin receptor subtypes (Mel-1a, Mel-1b, and Mel-1c) were characterized. Further, the expression profile of melatonin receptor subtypes in the granulosa and theca layers of different preovulatory and postovulatory follicles (POF) were studied by semi-quantitative RT-PCR. The expression of all three subtypes of melatonin receptors were observed in the ovary of domestic chicken. Analysis of partial sequences of ovarian melatonin receptors revealed that the melatonin subtypes were identical to the brain receptors. In small white ovary follicles, we observed only the expression of mel-1b receptors, but not mel-1a or mel-1c receptors. In yellow follicles, all the three subtypes of receptors expression were noticed. Interestingly, we observed the expression of mel-1a receptor only in thecal layer, but not in granulosa layer. In contrast, mel-1b and -1c receptors were expressed in both granulosa and thecal layer. During the regression of POF, we observed significant upregulation of melatonin receptors (mel-1a and 1c) expression, that downregulated in the later stages of regression. We assume that the expression of melatonin receptors might have been influenced by the atresia or apoptosis of different follicular layers in POF. Our findings suggest that the differential distribution of melatonin receptor subtypes might have distinct downstream cellular functions in the ovarian tissues.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is the main secretory product of the pineal gland in all mammals including humans, but it is also produced in other organs. It has been previously demonstrated to be a powerful organ-protective substance under oxidative stress conditions. The aim of this study was to evaluate the protective effect of melatonin in several organs such as heart, lung, kidney, and of the reproductive system, such as testis and epididymis in animals exposed to intermittent hypobaric hypoxia and therefore exposed to oxidative stress and analyzed by lipid peroxidation. Ten-week-old male Wistar rats were divided into 6 groups for 96 hours during 32 days under: 1) <em>N</em>ormobaric conditions, 2) plus physiologic solution, 3) plus melatonin, 4) intermittent hypobaric hypoxia, <em>5</em> plus physiologic solution and 6) plus melatonin. The animals were injected with melatonin (10 mg/kg body weight) at an interval of 96 hours during 32 days. Results indicated that melatonin decreased lipid peroxidation in heart, kidneys and lung under intermittent hypobaric hypoxia conditions. However, it did not exhibit any protective effect in liver, testis, epididymis and sperm count.

The pineal hormone melatonin (<em>N</em> -<em>acetyl</em>, <em>5</em>-<em>methoxytryptamine</em>) was recently accepted to act as an antioxidant under both in vivo and in vitro conditions. In this study, we examined the possible preventive effect of melatonin on ethanol-induced lipid peroxidation in rat testes. Thirty-seven male Wistar albino rats, <em>5</em>.<em>5</em>--6 months old, were randomly divided into four groups (9--10 animals in each). The first group (control animals) received 4% ethanol at similar intervals to the experimental groups to equalize the stress effect. The second group received only melatonin i.p. 7 mg kg(-1)bw three times over 1.<em>5</em> h intervals. The third group received only 30% alcohol 3 g kg(-1)bw twice daily. The fourth group were treated with melatonin and ethanol according to the above protocol, melatonin injections preceding ethanol treatments. The product of lipid peroxidation, malondialdehyde (MDA) and antioxidant enzymes, superoxide dismutase (Cu--Zn SOD), glutathione peroxidase (GPx) and catalase (CAT) were measured in the post-mitochondrial fraction of the testes. MDA levels were significantly increased due to acute ethanol intoxication. GPx activity was higher in the three experimental groups than the control levels. The activity of CAT was increased significantly in the melatonin plus ethanol-treated group but the other groups appeared not to be influenced by acute ethanol treatment. Cu--Zn SOD activity remained unaltered. These results suggest that antioxidants may be a protective agent for the testicular injury caused by ethanol consumption.