Journal of Pineal Research

Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro‐oxidant enzymes. In addition to these well‐described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber–Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria‐targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment‐resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age‐related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high‐safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet‐to‐be identified basic action(s) of this ancient molecule.

Abstract: Melatonin, the chief hormone of the pineal gland in vertebrates, is widely distributed in the animal kingdom. Among many functions, melatonin synchronizes circadian and circannual rhythms, stimulates immune function, may increase life span, inhibits growth of cancer cells in vitro and cancer progression and promotion in vivo, and was recently shown to be a potent hydroxyl radical scavenger and antioxidant. Hydroxyl radicals are highly toxic by‐products of oxygen metabolism that damage cellular DNA and other macromolecules. Herein we report that melatonin, in varying concentrations, is also found in a variety of plants. Melatonin concentrations, measured in nine different plants by radioimmunoassay, ranged from 0 to 862 pg melatonin/mg protein. The presence of melatonin was verified by gas chromatography/mass spectrometry. Our findings suggest that the consumption of plant materials that contain high levels of melatonin could alter blood melatonin levels of the indole as well as provide protection of macromolecules against oxidative damage.

The number of studies on melatonin in plants has increased significantly in recent years. This molecule, with a large set of functions in animals, has also shown great potential in plant physiology. This review outlines the main functions of melatonin in the physiology of higher plants. Its role as antistress agent against abiotic stressors, such as drought, salinity, low and high ambient temperatures, UV radiation and toxic chemicals, is analyzed. The latest data on their role in plant–pathogen interactions are also discussed. Both abiotic and biotic stresses produce a significant increase in endogenous melatonin levels, indicating its possible role as effector in these situations. The existence of endogenous circadian rhythms in melatonin levels has been demonstrated in some species, and the data, although limited, suggest a central role of this molecule in the day/night cycles in plants. Finally, another aspect that has led to a large volume of research is the involvement of melatonin in aspects of plant development regulation. Although its role as a plant hormone is still far of from being fully established, its involvement in processes such as growth, rhizogenesis, and photosynthesis seems evident. The multiple changes in gene expression caused by melatonin point to its role as a multiregulatory molecule capable of coordinating many aspects of plant development. This last aspect, together with its role as an alleviating‐stressor agent, suggests that melatonin is an excellent prospect for crop improvement.

Abstract:  A comprehensive investigation was carried out to determine the changes that occurred in water‐stressed cucumber (Cucumis sativus L.) in response to melatonin treatment. We examined the potential roles of melatonin during seed germination and root generation and measured its effect on reactive oxygen species (ROS) levels, antioxidant enzyme activities, and photosynthesis. Melatonin alleviated polyethylene glycol induced inhibition of seed germination, with 100 μm melatonin‐treated seeds showing the greatest germination rate. Melatonin stimulated root generation and vitality and increased the root:shoot ratio; therefore, melatonin may have an effect on strengthening cucumber roots. Melatonin treatment significantly reduced chlorophyll degradation. Seedlings treated with 100 μm melatonin clearly showed a higher photosynthetic rate, thus reversing the effect of water stress. Furthermore, the ultrastructure of chloroplasts in water‐stressed cucumber leaves was maintained after melatonin treatment. The antioxidant levels and activities of the ROS scavenging enzymes, i.e., superoxide dismutase, peroxidase, and catalase, were also increased by melatonin. These results suggest that the adverse effects of water stress can be minimized by the application of melatonin.

Although previous studies have found that melatonin can promote seed germination, the mechanisms involved in perceiving and signaling melatonin remain poorly understood. In this study, it was found that melatonin was synthesized during cucumber seed germination with a peak in melatonin levels occurring 14 hr into germination. This is indicative of a correlation between melatonin synthesis and seed germination. Meanwhile, seeds pretreated with exogenous melatonin (1 μm) showed enhanced germination rates under 150 mm NaCl stress compared to water‐pretreated seeds under salinity stress. There are two apparent mechanisms by which melatonin alleviated salinity‐induced inhibition of seed germination. Exogenous melatonin decreased oxidative damage induced by NaCl stress by enhancing gene expression of antioxidants. Under NaCl stress, compared to untreated control, the activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) were significantly increased by approximately 1.3–5.0‐fold, with a concomitant 1.4–2.0‐fold increase of CsCu‐ZnSOD, CsFe‐ZnSOD, CsCAT, and CsPOD in melatonin‐pretreated seeds. Melatonin also alleviated salinity stress by affecting abscisic acid (ABA) and gibberellin acid (GA) biosynthesis and catabolism during seed germination. Compared to NaCl treatment, melatonin significantly up‐regulated ABA catabolism genes (e.g., CsCYP707A1 and CsCYP707A2, 3.5 and 105‐fold higher than NaCl treatment at 16 hr, respectively) and down‐regulated ABA biosynthesis genes (e.g., CsNECD2, 0.29‐fold of CK2 at 16 hr), resulting in a rapid decrease of ABA content during the early stage of germination. At the same time, melatonin positively up‐regulated GA biosynthesis genes (e.g., GA20ox and GA3ox, 2.3 and 3.9‐fold higher than NaCl treatment at 0 and 12 hr, respectively), contributing to a significant increase of GA (especially GA₄) content. In this study, we provide new evidence suggesting that melatonin alleviates the inhibitory effects of NaCl stress on germination mainly by regulating the biosynthesis and catabolism of ABA and GA₄.

Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. In recent years, a considerable amount of experimental evidence has accumulated showing a relationship between the nervous, endocrine, and immune systems. The molecular basis of the communication between these systems is the use of a common chemical language. In this framework, currently melatonin is considered one of the members of the neuroendocrine–immunological network. A number of in vivo and in vitro studies have documented that melatonin plays a fundamental role in neuroimmunomodulation. Based on the information published, it is clear that the majority of the present data in the literature relate to lymphocytes; thus, they have been rather thoroughly investigated, and several reviews have been published related to the mechanisms of action and the effects of melatonin on lymphocytes. However, few studies concerning the effects of melatonin on cells belonging to the innate immunity have been reported. Innate immunity provides the early line of defense against microbes and consists of both cellular and biochemical mechanisms. In this review, we have focused on the role of melatonin in the innate immunity. More specifically, we summarize the effects and action mechanisms of melatonin in the different cells that belong to or participate in the innate immunity, such as monocytes–macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, and natural killer cells.

Abstract:  Melatonin (N‐acetyl‐5‐methoxytryptamine) 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.

Melatonin, an antioxidant in both animals and plants, has been reported to have beneficial effects on the aging process. It was also suggested to play a role in extending longevity and enhancing abiotic stress resistance in plant. In this study, we demonstrate that melatonin acts as a potent agent to delay leaf senescence and cell death in rice. Treatments with melatonin significantly reduced chlorophyll degradation, suppressed the transcripts of senescence‐associated genes, delayed the leaf senescence, and enhanced salt stress tolerance. Genome‐wide expression profiling by RNA sequencing reveals that melatonin is a potent free radical scavenger, and its exogenous application results in enhanced antioxidant protection. Leaf cell death in noe1, a mutant with over‐produced H₂O₂, can be relieved by exogenous application of melatonin. These data demonstrate that melatonin delays the leaf senescence and cell death and also enhances abiotic stress tolerance via directly or indirectly counteracting the cellular accumulation of H₂O₂.

Abstract:  Melatonin exhibits an array of biological activities, including antioxidant and anti‐inflammatory actions. Diabetic neuropathy is one of the complications of diabetes with a prevalence rate of 50–60%. We have previously reported the protective effect of melatonin in experimental diabetic neuropathy. In this study, we investigated the role of nuclear factor‐kappa B (NF‐κB) and nuclear erythroid 2‐related factor 2 (Nrf2) in melatonin‐mediated protection against streptozotocin‐induced diabetic neuropathy. Melatonin at doses of 3 and 10 mg/kg was administered daily in seventh and eighth week after diabetes induction. Motor nerve conduction velocity and nerve blood flow were improved in melatonin‐treated animals. Melatonin also reduced the elevated expression of NF‐κB, IκB‐α, and phosphorylated IκB‐α. Further, melatonin treatment also reduced the elevated levels of proinflammatory cytokines (TNF‐α and IL‐6), iNOS and COX‐2 in sciatic nerves of animals. The capacity of melatonin to modulate Nrf2 pathway was associated with increased heme oxygenase‐1 (HO‐1) expression, which strengthens antioxidant defense. This fact was also established by decreased DNA fragmentation (because inhibition of excessive oxidant‐induced DNA damage) in the sciatic nerve of melatonin‐treated animals. The results of this study suggest that melatonin modulates neuroinflammation by decreasing NF‐κB activation cascade and oxidative stress by increasing Nrf2 expression, which might be responsible at least in part, for its neuroprotective effect in diabetic neuropathy.

Abstract:  One of the targets of modern plant physiology is to identify tools for improving seed germination and plant growth under unfavorable environmental conditions. Seeds of Brassica oleracea rubrum were pretreated with melatonin at concentrations: 1, 10, and 100 μm using a hydropriming method. Air‐dried seeds of each experimental variants that were nonpretreated (control), hydroprimed (H) or hydroprimed with melatonin (HM1, HM10, and HM100) were germinated in darkness for 3 days at 25°C. Young seedlings were then transferred to the light and grown for an additional 5 days. Both germination and growth tests were performed in water and in CuSO₄ water solutions in concentrations of 0.5 and 1 mm. H, HM1 and HM10 improved seed germination both in water and in the presence of Cu²⁺. One or 10 μm melatonin eliminated the inhibitory effect of the 0.5 mm metal concentration on the fresh weight of seedlings. HM100 had a negative effect; thus seed germination was lower and seedlings had poor establishment. The toxic effect of Cu²⁺ manifested by membrane peroxidation and DNA endoreplication blocking in the seedlings grown from nontreated (control) and H seeds was not observed in the seedlings grown from HM1 and HM10 seeds; in contrast, HM100 enhanced the toxic effect of Cu²⁺.