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Plant-derived melatonin from food: a gift of nature
Abstract
In recent years, people have become increasingly interested in bioactive ingredients from plants, especially antioxidant molecules such as melatonin, which are beneficial to human health. The purpose of this article is to provide new information on plant-derived foods with a high content of melatonin. We comprehensively summarize the content of melatonin in plant-derived foods and discuss the factors that influence melatonin levels to provide new ideas on enhancement. Additionally, we describe the biosynthetic pathway of melatonin and identify its major functions. Medicinal herbs are often rich in melatonin while many vegetables and fruits exhibit somewhat lower levels with wide variations among species. The genetic traits of plants, the phenological stage of the cultivar, the photoperiod, the level of stress to which the plants are exposed at the time of harvest, exposure to agrochemicals and determination methods are the main factors affecting the melatonin content. To date, standardization of uniform sampling times and the use of suitable pretreatments as well as determination methods have not been achieved. The results of the studies reviewed highlight the potentially important role of plant melatonin in influencing the progression of human diseases. Based on the health promotional aspects of melatonin, consuming foods containing higher concentrations of tryptophan and melatonin is suggested.
... Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine derived from tryptophan and produced by several organisms such as animals [1][2][3][4][5][6][7], bacteria [8][9][10][11], fungi [7,12] and plants [7,10,13]. In mammals, it was discovered in 1958 in the pineal gland where it is synthesized [14]. ...
... Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine derived from tryptophan and produced by several organisms such as animals [1][2][3][4][5][6][7], bacteria [8][9][10][11], fungi [7,12] and plants [7,10,13]. In mammals, it was discovered in 1958 in the pineal gland where it is synthesized [14]. ...
... Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine derived from tryptophan and produced by several organisms such as animals [1][2][3][4][5][6][7], bacteria [8][9][10][11], fungi [7,12] and plants [7,10,13]. In mammals, it was discovered in 1958 in the pineal gland where it is synthesized [14]. ...
Melatonin is a multifunctional and ubiquitous molecule. In animals, melatonin is a hormone that is involved in a wide range of physiological activities and is also an excellent antioxidant. In plants, it has been considered a master regulator of multiple physiological processes as well as of hormonal homeostasis. Likewise, it is known for its role as a protective biomolecule and activator of tolerance and resistance against biotic and abiotic stress in plants. Since infections by pathogens such as bacteria, fungi and viruses in crops result in large economic losses, interest has been aroused in determining whether melatonin plays a relevant role in plant defense systems against pathogens in general, and against viruses in particular. Currently, several strategies have been applied to combat infection by pathogens, one of them is the use of eco-friendly chemical compounds that induce systemic resistance. Few studies have addressed the use of melatonin as a biocontrol agent for plant diseases caused by viruses. Exogenous melatonin treatments have been used to reduce the incidence of several virus diseases, reducing symptoms, virus titer, and even eradicating the proliferation of viruses such as Tobacco Mosaic Virus, Apple Stem Grooving Virus, Rice Stripe Virus and Alfalfa Mosaic Virus in tomato, apple, rice and eggplant, respectively. The possibilities of using melatonin as a possible natural virus biocontrol agent are discussed.
... The melatonin content in beer is variable and depends on the fermentation conditions, the quality of the cereals used, the alcohol strength of the beer, and the processing system used. 7 For example, craft beers have higher levels of melatonin (333 ± 7 pg / mL) than commercial ones (113 ± 4,13 pg / mL) at equal alcohol levels. 5 There are also differences between different types of commercial beer depending on the alcohol contentthat is, total melatonin, from 58 ± 1,44 pg / mL for dealcoholized beers to 169 ± 2,4 pg / mL for beers with higher measured alcohol values. ...
... 17 An adequate diet to cover the body's energy demands includes the consumption of proteins preferably from fish, fibers of fruit and vegetables, natural largely unrefined sugars, and low fat foods. 18 Melatonin is a normal food component found in yeast and plant material, including edible plant products and medical herbs, 7,12 which can influence the level of melatonin in the circulation and promote healthy benefits by virtue of its cytoprotective, 14 anti-inflammatory, 19 antioxidant 9,20 or anti-apoptotic properties. 14 The effects of melatonin are dose dependent and are related to the time and manner of administration. ...
... Common foods and beverages such as olive oil, coffee, wine, and even beer are rich sources of melatonin. 1,7,[22][23][24][25][26] It is also found in many common fruits and vegetables, including tomatoes, grape skins, tart cherries, walnuts, and other fermented food products, with concentrations markedly higher than those found in vertebrate tissues. [27][28][29] Most foods and drinks consumed by humans contain melatonin, and their intake probably increases circulating melatonin levels and the total antioxidant status of human serum. ...
Beer is a fermented beverage with a low alcohol content originating from cereal fermentation (barley or wheat). It forms part of the diet for many people. It contains melatonin (N‐acetyl‐5‐methoxytryptamine). Melatonin is a molecule with a wide range of antioxidant, oncostatic, immunomodulatory, and cytoprotective properties. The aim of this work was to review the data supporting the idea that a moderate consumption of beer, because of its melatonin content, is particularly useful in healthy diets and in other physiological situations (such as pregnancy, menopause, and old age). Data source: a) The MEDLINE /PubMed search was conducted from 1975 to April 2022, and b) Our own experience and published studies on melatonin, the immune system, and beer. We provide a review of research on the mechanisms of melatonin generation in beer, its concentrations, and its possible effects on health. The melatonin contained in beer, as part of a healthy diet and in some special physiological situations, could act as a protective factor and improve the quality of life of those who drink it in moderation. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
... Melatonin (N-acetyl-5-methoxytryptamine) is a bioactive indoleamine synthesized from the amino acid tryptophan via serotonin (5hydroxytryptamine) as its precursors (Arnao & Hernández-Ruiz, 2018). Melatonin and serotonin have been identified as neurotransmitters that modulate numerous physiological processes in the human body such as mood-related behaviors and circadian rhythms; they are also antioxidant hormones with beneficial effects on human health (Cheng et al., 2021;Erland & Saxena, 2017). Melatonin is mainly produced from the pineal gland and released in a circadian pattern with highest levels at nighttime as 329.5 pg/mL in toddlers and 29.2 pg/mL in the elderly (Waldhauser et al., 1988). ...
... Legume seeds are also a potent source of melatonin and tryptophan. Concentration of melatonin in legume seeds ranges from picograms to nanograms per gram depending on various factors such as type, genetic traits of legumes and the analytical method used (Cheng et al., 2021). Aguilera et al. (2015) have reported melatonin content in mung bean at 14.3 pg/g of dry matter (DM), as measured by ELISA, with high levels found in soybean at 56.49 ng/g DM detected by high-performance liquid chromatography using a fluorescence detector (HPLC-FD) (Sangsopha, Johns, Johns, & Moongngarm, 2020). ...
Melatonin is a bioactive indolamine possessing multifunctional properties in humans and plants. Germination conditions under salinity stress were optimized to maximize melatonin, serotonin, tryptophan and total phenolic content (TPC) levels of Vigna angularis to develop melatonin-rich instant beverage from legume sprouts. The effect of stress conditions on these compounds was also evaluated in soybean and chickpea. Optimum germination conditions of V. angularis were investigated using response surface methodology (RSM) under NaCl stress at 9.5–115.5 mmol/L and 14.1–81.9 h. V. angularis germinated under normal conditions (without NaCl) served as the control. Optimum germination conditions obtained were 68 mmol/L NaCl and germination time 72 h, resulting in increase of melatonin, serotonin and TPC in V. angularis sprouts of 47, 37 and 12%, respectively compared with normal condition. These conditions were successfully applied to germinate soybean and chickpea, while improving melatonin and bioactive compounds levels. The three legume sprouts showed high feasibility to formulate melatonin-rich instant beverages with acceptable sensory quality. These findings provide useful information as an alternative approach to enhance the level of health-beneficial compounds in legume sprouts, with potential use as natural sources of melatonin for functional food product development.
... However, some studies suggested that the melatonin in these plants has low bioavailability meaning that the body may not absorb it as efficiently. However, the presence of other beneficial compounds in plants may enhance its overall effectiveness (Aguilera et al. 2016;Cheng et al. 2021). ...
Gastric cancer (GC) is the third leading reason of death in men and the fourth in women. Studies have documented an inhibitory function of melatonin on the proliferation, progression and invasion of GC cells. MicroRNAs (miRNAs) are small, non-coding RNAs that play an important function in regulation of biological processes and gene expression of the cells. Some studies reported that melatonin can suppress the progression of GC by regulating the exosomal miRNAs. Thus, melatonin represents a promising potential therapeutic agent for subjects with GC. Herein, we evaluate the existing data of both in vivo and in vitro studies to clarify the molecular processes involved in the therapeutic effects of melatonin in GC. The data emphasize the critical function of melatonin in several signaling ways by which it may inhibit cancer cell proliferation, decrease chemo-resistance, induce apoptosis as well as limit invasion, angiogenesis, and metastasis. This review provides a resource that identifies some of the mechanisms by which melatonin controls GC enlargement. In light of the findings, melatonin should be considered a novel and testable therapeutic mediator for GC treatment.
... Plant-derived natural products have always been a paramount source of novel drugs and pesticides [1][2][3][4][5][6][7][8]. For example, the plant-derived drugs paclitaxel (Taxol) and artemisinin are widely used in antitumor and antimalarial treatment, respectively, and continue to occupy a crucial position among other drugs used for these medical conditions [9][10][11][12][13][14]. ...
Simple Summary
Based on the important findings of our research group about the chemical constituents of Eupatorium adenophorum, the present review shares an update about the research progress on the chemical constituents of Eupatorium and their biological activities in the last 10 years. For the first time, it also reviews some studies investigating the chemical constituents of the plant. Considering the multiple properties of this genus, the next step should be to strengthen the study of the action mechanism underlying the active components of this genus. Hopefully, this review can provide new insights for prompting future research on Eupatorium applications and drug development.
Abstract
The genus Eupatorium belongs to the Asteraceae (Compositae) family and has multiple properties, such as invasiveness and toxicity, and is used in folk medicine. The last review on the chemical constituents of this genus and their biological activities was published in 2015. The present review provides an overview of 192 natural products discovered from 2015 to the present. These products include 63 sesquiterpenoids, 53 benzofuran derivatives, 39 thymol derivatives, 15 fatty acids, 7 diterpenoids, 5 monoterpenoids, 4 acetophenones, and 6 other compounds. We also characterized their respective chemical structures and cytotoxic, antifungal, insecticidal, antibacterial, anti-inflammatory, and antinociceptive activities.
... The phytomelatonin content in plants is highly variable, depends on the species, and is affected by genetic factors and external environment. Generally, it occurs at very low endogenous levels, being higher in leaves and roots, and lower in fruits, seeds, and flowers [22,23]. With respect to phylogenetic classification, there is no clear predominance of some family plants over others, in terms of their phytomelatonin endogenous content. ...
The presence of melatonin in plants, called phytomelatonin, has gained great interest in recent years. The determination of phytomelatonin levels in plant extracts for both physiological and plant foodstuff studies requires sophisticated techniques due to the low endogenous levels of this indolic compound with hormonal nature. This chapter presents the most common and advanced techniques in the determination of phytomelatonin, with special emphasis on the techniques of extraction, cleaning, separation, detection, identification, and quantification. Multiple examples and recommendations are presented for a clear overview of the pros and cons of phytomelatonin determinations in plant tissues, seeds, and fruits, mainly.
... Auxin and MT have biosynthetic and structural resemblances, indicating a signalling pathways association. The research on MT has emphasised auxin and MT's physiological effects since its identification in plants (Cheng et al. 2021). MT stimulates plant development in a similar manner to auxin, in commercially significant crops such as wheat, maize, barley, rice, tomato, cucumber, soybean and pepper, together with Arabidopsis thaliana (Nawaz et al. 2021). ...
Melatonin is a naturally occurring biologically active amine produced by plants, animals and microbes. This review explores the biosynthesis of melatonin in plants, with a particular focus on its diverse roles in Arabidopsis thaliana, a model species. Melatonin affects abiotic and biotic stress resistance in A. thaliana. Exogenous and endogenous melatonin is addressed in association with various conditions, including cold stress, high light stress, intense heat and infection with Botrytis cinerea or Pseudomonas, as well as in seed germination and lateral root formation. Furthermore, melatonin confers stress resistance in Arabidopsis by initiating the antioxidant system, remedying photosynthesis suppression, regulating transcription factors involved with stress resistance (CBF, DREB, ZAT, CAMTA, WRKY33, MYC2, TGA) and other stress-related hormones (abscisic acid, auxin, ethylene, jasmonic acid and salicylic acid). This article additionally addresses other precursors, metabolic components, expression of genes (COR, CBF, SNAT, ASMT, PIN, PR1, PDF1.2 and HSFA) and proteins (JAZ, NPR1) associated with melatonin and reducing both biological and environmental stressors. Furthermore, the future perspective of melatonin rich agri-crops is explored to enhance plant tolerance to abiotic and biotic stresses, maximise crop productivity and enhance nutritional worth, which may help improve food security.
... Phytomelatonin has been detected in all photosynthetic species (plants, algae, and some bacteria) analyzed so far. In algae and plants, endogenous levels of phytomelatonin are very low, between picograms and nanograms per gram of tissue [110,130]. On the other hand, phytomelatonin-rich extracts can have several advantages in addition to being natural, such as the presence of biologically healthy compounds, such as antioxidants, vitamins, etc. However, obtaining phytomelatonin-rich extracts in sufficient concentrations to meet the expectations of the natural supplement industry has not been an easy task due to contrary factors, such as low and variable content in phytomelatonin. ...
Melatonin dietary supplements are widely consumed worldwide, with developed countries as the largest consumers, with an estimated annual growth rate of approximately 10% until 2027, mainly in developing countries. The wide use of melatonin against sleep disorders and particular problems, such as jet lag, has been added to other applications, such as anti-aging, anti-stress, immune system activation, anticancer, and others, which have triggered its use, normally without a prescription. The chemical industry currently covers 100% of the needs of the melatonin market. Motivated by sectors with more natural consumption habits, a few years ago, the possibility of obtaining melatonin from plants, called phytomelatonin, arose. More recently, the pharmaceutical industry has developed genetically modified microorganisms whose ability to produce biological melatonin in bioreactors has been enhanced. This paper reviews the aspects of the chemical and biological synthesis of melatonin for human consumption, mainly as dietary supplements. The pros and cons of obtaining melatonin from microorganisms and phytomelatonin from plants and algae are analyzed, as well as the advantages of natural melatonin, avoiding unwanted chemical by-products from the chemical synthesis of melatonin. Finally, the economic and quality aspects of these new products, some of which are already marketed, are analyzed.
... Melatonin is an indole molecule widely found in plants and animals; as an endogenous metabolite of living organisms, it can be degraded by the organisms themselves and is nontoxic, safe, and residue-free to humans [1]. One notable difference in melatonin synthesis in animals and plants concerns the availability of the synthetic precursor tryptophan. ...
Melatonin plays key roles in improving fruit quality and yield by regulating various aspects of plant growth. However, the effects of how melatonin regulates primary and secondary metabolites during fruit growth and development are poorly understood. In this study, the surfaces of tomato fruit were sprayed with different concentrations of melatonin (0, 50, and 100 µmol·L−1) on the 20th day after anthesis; we used high-performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry (LC/MS) to determine the changes in primary and secondary metabolite contents during fruit development and measured the activity of sucrose metabolizing enzymes during fruit development. Our results showed that 100 µmol·L−1 melatonin significantly promoted the accumulation of soluble sugar in tomato fruit by increasing the activities of sucrose synthase (SS), sucrose phosphate synthase (SPS), and acid convertase (AI). The application of 100 µmol·L−1 melatonin also increased the contents of ten amino acids in tomato fruit as well as decreased the contents of organic acids. In addition, 100 µmol·L−1 melatonin application also increased the accumulation of some secondary metabolites, such as six phenolic acids, three flavonoids, and volatile substances (including alcohols, aldehydes, and ketones). In conclusion, melatonin application improves the internal nutritional and flavor quality of tomato fruit by regulating the accumulation of primary and secondary metabolites during tomato fruit ripening. In the future, we need to further understand the molecular mechanism of melatonin in tomato fruit to lay a solid foundation for quality improvement breeding.
... Internal and external factors may affect the melatonin content, mainly including genetic traits, phenological period of the cultivar, the photoperiod, planting environment and agrochemicals [9]. In order to explore the dominant germplasm of melatonin, the melatonin content of 842 sesame accessions collected from natural populations was determined. ...
In recent years, people have become increasingly interested in bioactive molecules in plants that are beneficial to human health, and melatonin (N-acetyl-5-methoxytryptamine) has attracted research attention due to its excellent performance. In this study, the content of melatonin in oilseeds was investigated. From the results, it was found that sesame is an important natural food source of melatonin intake. Furthermore, the variation in melatonin content was explored in a natural sesame population, and its contents varied from 0.04 to 298.62 ng g−1. Through a genome-wide association study (GWAS), a candidate gene SiWRKY67 was screened that regulates melatonin content in sesame. The sesame hairy root transformation system was developed and used to verify this gene, and it was found that the overexpression of SiWRKY67 could positively promote the melatonin content in the hairy roots. Our results provide not only a foundation for understanding the genetic structure of melatonin content in sesame seeds but also a reference for the marker-assisted breeding of sesame varieties with high melatonin content.
... Compared to other nuts, walnuts are richer in melatonin (Verde et al., 2022). The available studies have mainly focused on pathological experiments or nutritional value evaluation of melatonin in walnuts (Bonomini et al., 2018;Cheng et al., 2021;Kamoun et al., 2021;Steffen et al., 2021). However, systematic reports on the mechanism of melatonin synthesis and inheritance in walnut are still lacking. ...
Melatonin widely mediates multiple developmental dynamics in plants as a vital growth stimulator, stress protector, and developmental regulator. N-acetylserotonin methyltransferase (ASMT) is the key enzyme that catalyzes the final step of melatonin biosynthesis in plants and plays an essential role in the plant melatonin regulatory network. Studies of ASMT have contributed to understanding the mechanism of melatonin biosynthesis in plants. However, AMST gene is currently uncharacterized in most plants. In this study, we characterized the JrASMT gene family using bioinformatics in a melatonin-rich plant, walnut. Phylogenetic, gene structure, conserved motifs, promoter elements, interacting proteins and miRNA analyses were also performed. The expansion and differentiation of the ASMT family occurred before the onset of the plant terrestrialization. ASMT genes were more differentiated in dicotyledonous plants. Forty-six ASMT genes were distributed in clusters on 10 chromosomes of walnut. Four JrASMT genes had homologous relationships both within walnut and between species. Cis-regulatory elements showed that JrASMT was mainly induced by light and hormones, and targeted cleavage of miRNA172 and miR399 may be an important pathway to suppress JrASMT expression. Transcriptome data showed that 13 JrASMT were differentially expressed at different periods of walnut bud development. WGCNA showed that JrASMT1/10/13/23 were coexpressed with genes regulating cell fate and epigenetic modifications during early physiological differentiation of walnut female flower buds. JrASMT12/28/37/40 were highly expressed during morphological differentiation of flower buds, associated with altered stress capacity of walnut flower buds, and predicted to be involved in the regulatory network of abscisic acid, salicylic acid, and cytokinin in walnut. The qRT-PCR validated the results of differential expression analysis and further provided three JrASMT genes with different expression profiles in walnut flower bud development. Our study explored the evolutionary relationships of the plant ASMT gene family and the functional characteristics of walnut JrASMT. It provides a valuable perspective for further understanding the complex melatonin mechanisms in plant developmental regulation.
... In recent years, it has been proposed that obtaining phytomelatonin (discovered its presence in 1995) from plants (Pérez-Llamas et al., 2020;Arnao and Hernández-Ruiz, 2018) could be a natural alternative in the making of melatonin supplements since, in some cases, by-products of certain toxicity have been detected in synthetic melatonin preparations (Mayeno and Gleich, 1994;Naylor et al., 1999;Williamson et al., 1998). Phytomelatonin is present in all the plants studied, generally at low concentrations, being its most relevant content in aromatic and medicinal plants (Arnao, 2014;Arnao and Hernández-Ruiz, 2015;Cheng et al., 2021). ...
The use of medicinal plants as an alternative phytotherapeutic remedy against mild illnesses and dysfunctions is increasingly embraced by people. Among these dysfunctions, episodes of nervousness and anxiety due to lack of sleep and insomnia are becoming more and more frequent among the population. To remedy these problems, several plants with sedative activity are recommended. In particular, valerian root (Valeriana officinalis L.) is the most recommended and studied with a significant difference. This study presented a quantification of the phytomelatonin contents in valerian root and several related and recommended herb supplements against nervousness, anxiety, and insomnia. The results showed the presence of phytomelatonin in all the samples analyzed. The high phytomelatonin contents in valerian root and its supplements indicated that, in addition to the known constituents of valerian root such as valerenic acid, phytomelatonin also contributed to the phytotherapeutic activity of this plant since the relaxing and sleep-inducing activity of melatonin is well documented. The recommended daily doses of valerian are analyzed according to their phytomelatonin content, and recommendations are given on the possible synergistic action of the components of valerian as a relaxant and sleep inducer in patients with these dysfunctions. It is also recommended to document the phytomelatonin contents in phytotherapeutic preparations.
... This same year another communication appeared (Kolar et al., 1995), in which a Czech research group identified the presence of melatonin in Chenopodium rubrum by LC-MS/MS (see Kolar et al., 1997), with which I personally had a curious experience (Box 1). Subsequent studies have quantified phytomelatonin in many plants and it is now accepted that it is present in all plants, although many gaps remain in our knowledge, especially regarding non-vascular plants (Zohar et al., 2011;Arnao, 2014;Cheng et al., 2021). ...
Phytomelatonin, a multifunctional molecule presents in plants studied to date, has an important role in plants as a modulatory agent (biostimulator), which improves their tolerance response to both biotic and abiotic stress. In the primary metabolism of plants, melatonin improves the photosynthesis rate and efficiency, as well related actions such as stomatal conductance, intercellular CO2 and Rubisco activity; it has also been seen to downregulate some senescence transcription factors. Melatonin upregulates many enzyme transcripts related to carbohydrates (including sucrose and starch), amino acids and lipid metabolism, optimizing N, P and S uptake. With respect to the plant secondary metabolism, a clear increase in polyphenol, glucosinolate, terpenoid and alkaloid levels has been described in numerous melatonin-treated plants. Generally, the most important genes of these secondary biosynthesis pathways were upregulated by melatonin. The great regulatory capacity of melatonin is a result of its control of the redox and plant hormone networks. Melatonin acts as a plant master regulator, up/down-regulating different plant hormone levels and signalling, and is a key piece in redox homeostasis; besides having a capacity to counteract and tolerate diverse critical situations such as pathogen infections or abiotic stresses. Possible future applications of melatonin for crop improvement and postharvest product preservation are proposed.
... Moreover, the presence of melatonin in plant was confirmed in Chenopodium rubrum via chromatography/tandem mass spectrometry and radio-immuno-assays [71]. Melatonin has multi-functional actions that improve cellular and organ health in various plant species and it is a powerful antioxidant in both animals and plants [72]. ...
Metabolic engineering in plant can be describe as a tool using molecular biological technologies which promotes enzymatic reactions that can enhance the biosynthesis of existing compounds such as glycine betaine (GB) in plant species that are able to accumulate GB, or produce news compounds like GB in non-accumulators plants. Moreover we can include to these definition, the mediation in the degradation of diverse compounds in plant organism. For decades, one of the most popular ideas in metabolic engineering literature is the idea that the improvement of gly betaine or melatonin accumulation in plant under environmental stress can be the main window to ameliorate stress tolerance in diverse plant species. A challenging problem in this domain is the integration of different molecular technologies like transgenesis, enzyme kinetics, promoter analysis, biochemistry and genetics, protein sorting, cloning or comparative physiology to reach that objective. A large number of approaches have been developed over the last few decades in metabolic engineering to overcome this problem. Therefore, we examine some previous work and propose some understanding about the use of metabolic engineering in plant stress tolerance. Moreover, this chapter will focus on melatonin (Hormone) and gly betaine (Osmolyte) biosynthesis pathways in engineering stress resistance.
... This same year another communication appeared (Kolar et al., 1995), in which a Czech research group identified the presence of melatonin in Chenopodium rubrum by LC-MS/MS (see Kolar et al., 1997), with which I personally had a curious experience (Box 1). Subsequent studies have quantified phytomelatonin in many plants and it is now accepted that it is present in all plants, although many gaps remain in our knowledge, especially regarding non-vascular plants (Zohar et al., 2011;Arnao, 2014;Cheng et al., 2021). ...
Reactive oxygen and nitrogen species (ROS and RNS) have received increasing interest on the part of researchers over the years. These chemical species of a radical nature are characterized by their dual cellular action: on the one hand they are highly reactive chemical species that can alter the structure of macromolecules, thereby generating dysfunctions, and on the other hand, they are used by the cell as messengers. Under stress conditions, both ROS and RNS act as indicators in various physiological processes such as germination, growth and development, photosynthesis and yield, senescence, and others. For its part, melatonin (N-acetyl-5-methoxytryptamine) is the a hormone synthesized in the pineal gland of animals with numerous cellular and physiological roles. Since its discovery in plants in 1995, it has been widely studied, and numerous functions have been attributed to it in vascular plants. In addition to its recognized role as a universal antioxidant, other relevant functions in plants include its protective role in stress situations (biotic and abiotic), its rhizogenic- and vegetative growth effects, and its protective role in leaf senescence and in the photosynthetic and stomatic apparatus. Also studied have been its action as an osmoregulator agent and metabolic corrector in different stresses, its effects on climacteric and non-climacteric fruits, its effects on seed germination, among others. One of the most outstanding aspects is the implication of melatonin as a multi-signal molecule in plants. The role of melatonin as a gene expression regulator in many physiological situations is studied in this chapter. Its relationship with central elements of the plant redox network such as ROS and RNS, and the regulation of important elements is discussed. The relationship of melatonin with plant hormones such as gibberellins, auxin, abscisic acid, cytokinins, ethylene, brassinosteroids, salicylic- and jasmonic acids and polyamines is also discussed.
... Melatonin is a potent antioxidant, and its presence in numerous plants and foods has been described as beneficial to human health [1]. Melatonin is also a hormone synthesized in multiple organs such as the pineal gland, which functions during the night period and regulates the circadian rhythm [2,3]. ...
Melatonin improves metabolic alterations associated with obesity and its diabetes (diabesity). We intend to determine whether this improvement is exerted by changing Zn and/or Cu tissue levels in liver, muscle, pancreas, and brain, and in internal (perirenal, perigonadal, and omentum) and subcutaneous lumbar white adipose tissues (IWAT and SWAT, respectively). Male Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight/day) or vehicle for 6 weeks. Zn and Cu concentrations were not significantly influenced by diabesity in the analyzed tissues (p > 0.05), with the exception of Zn in liver. In skeletal muscle Zn and Cu, and in perirenal WAT, only Zn levels increased significantly with melatonin supplementation in ZDF rats (p < 0.05). This cytoplasmic Zn enhancement would be probably associated with the upregulation of several Zn influx membrane transporters (Zips) and could explain the amelioration in the glycaemia and insulinaemia by upregulating the Akt and downregulating the inhibitor PTP1B, in obese and diabetic conditions. Enhanced Zn and Cu levels in muscle cells could be related to the reported antioxidant melatonin activity exerted by increasing the Zn, Cu-SOD, and extracellular Cu-SOD activity. In conclusion, melatonin, by increasing the muscle levels of Zn and Cu, joined with our previously reported findings improves glycaemia, insulinaemia, and oxidative stress in this diabesity animal model.
... This same year another communication appeared (Kolar et al., 1995), in which a Czech research group identified the presence of melatonin in Chenopodium rubrum by LC-MS/MS (see Kolar et al., 1997), with which I personally had a curious experience (Box 1). Subsequent studies have quantified phytomelatonin in many plants and it is now accepted that it is present in all plants, although many gaps remain in our knowledge, especially regarding non-vascular plants (Zohar et al., 2011;Arnao, 2014;Cheng et al., 2021). ...
This work demonstrates that how chromium affects the energy metabolism in experimental rats and how pre-treatment with melatonin protects against such changes with the associated mechanisms involved.
Catechol-O-methyltransferase (COMT) plays a central role in the metabolic inactivation of endogenous neurotransmitters and xenobiotic drugs and hormones having catecholic structures. Its inhibitors are used in clinical practice to treat Parkinson's disease. In this study, a fluorescence-based visualization inhibitor screening method was developed to assess the inhibition activity on COMT both in vitro and in living cells. Following the screening of 94 natural products, Pu-erh tea extract exhibited the most potent inhibitory effect on COMT with an IC50 value of 0.34 μg mL-1. In vivo experiments revealed that Pu-erh tea extract substantially hindered COMT-mediated levodopa metabolism in rats, resulting in a significant increase in levodopa levels and a notable decrease in 3-O-methyldopa in plasma. Subsequently, the chemical components of Pu-erh tea were analyzed using UHPLC-Q-Exactive Orbitrap HRMS, identifying 24 major components. Among them, epigallocatechin gallate, gallocatechin gallate, epicatechin gallate, and catechin gallate exhibited potent inhibition of COMT activity with IC50 values from 93.7 nM to 125.8 nM and were the main bioactive constituents in Pu-erh tea responsible for its COMT inhibition effect. Inhibition kinetics analyses and docking simulations revealed that these compounds competitively inhibit COMT-mediated O-methylation at the catechol site. Overall, this study not only explained how Pu-erh tea catechins inhibit COMT, suggesting Pu-erh tea as a potential dietary intervention for Parkinson's disease, but also introduced a new strategy for discovering COMT inhibitors more effectively.
Seed germination (SG) is the first stage in a plant's life and has an immense importance in sustaining crop production. Abiotic stresses reduce SG by increasing the deterioration of seed quality, and reducing germination potential, and seed vigor. Thus, to achieve a sustainable level of crop yield, it is important to improve SG under abiotic stress conditions. Melatonin (MEL) is an important biomolecule that interplays in developmental processes and regulates many adaptive responses in plants, especially under abiotic stresses. Thus, this review specifically summarizes and discusses the mechanistic basis of MEL‐mediated SG under abiotic stresses. MEL regulates SG by regulating some stress‐specific responses and some common responses. For instance, MEL induced stress specific responses include the regulation of ionic homeostasis, and hydrolysis of storage proteins under salinity stress, regulation of C‐repeat binding factors signaling under cold stress, starch metabolism under high temperature and heavy metal stress, and activation of aquaporins and accumulation of osmolytes under drought stress. On other hand, MEL mediated regulation of gibberellins biosynthesis and abscisic acid catabolism, redox homeostasis, and Ca ²⁺ signaling are amongst the common responses. Nonetheless factors such as endogenous MEL contents, plant species, and growth conditions also influence above‐mentioned responses. In conclusion, MEL regulates SG under abiotic stress conditions by interacting with different physiological mechanisms.
Human hormone melatonin (N-acetyl-5-metoxy tryptamine), is a tryptophan metabolite synthesized in pineal gland. Melatonin is shown to control and a modulate circadian rhythms, seasonal reproduction, sleep regulation, retinal physiology. Besides its physiological role, the role of melatonin as a strong antioxidant that can subdue inflammatory pathways and scavenge free radicals has been proven in a numerous studies. Antioxidative ability of melatonin is based on its role as a scavenger of reactive oxygen species including hydroxyl radical, superoxide ion, peroxy radicals, singlet oxygen, nitric oxide, peroxynitrate and its metabolites. Antioxidative mechanism can proceed through several mechanistic pathways including hydrogen atom transfer, electron transfer and formation of radical adducts. Only much later melatonin has been detected in a different plant species. High concentrations of melatonin have been found in a different medicinal plant. Amounts of melatonin in these plant tissues amounted to several micrograms per gram of tissue (amounts more than those found in blood).
Daytime melatonin concentrations are related to light intensity to which the plants are exposed. Meanwhile, it has been shown in various plants that contain large amounts of melatonin to respond to intense light, especially UV, by increasing of methoxyl indole. This suggests a photoprotective role, which it already is presumably because of the numerous photoreactions to which melatonin is subject and ability melatonin to neutralize singlet oxygen and free radicals caused by UV rays. Recent research shows that melatonin concentrations differ not only between plants species but also among varieties of the same species, and to a considerable extent about the degree of growth, location, specific plant organ, as well as the time and season of harvest. At the current level of understanding, the presence of melatonin in plants is, in most cases, accepted although there are still many unanswered questions. Thus, we performed systematic review of a literature according to PRISMA protocol to analyze the origin, content in various plant species, detection and therapeutic potentials of phytomelatonin.
Germination and seedling development are regarded as important steps in the successful growth of a new plant. It is a method of reproductive adaptation in terrestrial plants that help to spread their progeny, which can then survive in a dormant state until favorable environmental conditions for further growth of the next generation. Many hormones participate in the whole process. The presence of melatonin in plants is now confirmed. Melatonin (N-acetyl-5-methoxytryptamine) is a signaling molecule with many functions, universally reported in different plant parts and known to play an important role in several physiological mechanisms during unfavourable conditions. Many studies have suggested that melatonin participates in many physiological processes like detoxification of free radicals, signaling molecules, chlorophyll preservation, photosynthesis enhancement, increased root development, and environmental protection. However, as of now, there is no known specific role for melatonin in embryo and seed development. However, few papers address its role in seed germination. The current chapter’s recent advancements in the role of melatonin research in embryos are discussed.KeywordsMelatoninSeed developmentMelatonin and seed germinationN-acetyl-5-methoxytryptamineIndoleaminesMetabolic regulatorPlant growth regulatorsAntioxidantsPhoto regulation
Salinity is one of the major abiotic factors limiting plant growth and agricultural productivity. Salt stress disrupts the ion compartmentalization and leaf water status, resulting in an ionic imbalance and impairing mineral uptake and ion homeostasis. Plants cope with ion toxicity through various mechanisms, including ionic balance which is one of the important stress responses against salt stress. Notably, melatonin holds a crucial function in plant’s responses to salinity stress through its ample potential in regulating the signaling related to stress-mediated pathways in various plants. In this context, the role of melatonin in promoting ion homeostasis under salinity stress by mediating various physiological and molecular mechanisms has been described in detail. As a master regulator in plants, melatonin can improve plant defense response to salt stress conditions by directly regulating ROS and RNS or indirectly regulating Ca2+ levels and K+/Na+ homeostasis. Exogenously applied melatonin regulates calcium signaling-related genes such as PLC2, HIPP02, CML10, CML45, and Na+/H+ antiporter-related genes (SOS1, SOS2, and SOS3); besides increasing Ca2+-ATPase activity for ATP synthesis, which improves plant development under stresses. Moreover, it has a significant contribution to K+ signaling by increasing RBOHF-dependent ROS signaling that improves the K+ level under salt stress, indicating that melatonin may improve plant stress response through regulating NADPH function in the K+ transporters pathway and K+ transporter genes such as AKT1, GORK, SOS1, HAK1, HAK5, and HAK21. In conclusion, melatonin enhances K+/Na+ and Ca2+/Na+ levels by increasing the influx and distribution of K+ and Ca2+ with decreasing Na+ levels under salt stress conditions to maintain ion hemostasis, thus plant stress tolerance. The comprehensive knowledge of the versatile role of melatonin in anti-stress regulation will help decipher its mode of action and signaling cascade in plants that aid in understanding the roles of melatonin-mediated ion homeostasis under salinity stress conditions. KeywordsMelatoninIon homeostasisSignalingNitric oxideCalciumPotassiumSalt stress
The efficiency of aggregation-induced electrochemiluminescence (AIECL) in tetraphenylethene (TPE) derivatives were significantly enhanced by combining the regulation of molecular structure and solvent. Firstly, the linear increase of the benzene ring resulted in enhanced molecular aggregation and promoted the electrochemical reaction of the anode, due to increased molecular conjugation and higher lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO). The ECL efficiency of 4,4,4,4-(Ethene-1,1,2,2-tetrayl) tetrakis (([1,1,4,1-terphenyl]-4-carbaldehyde)) (T3) nanoparticles (NPs) with more benzene rings were 5558 times that of 4,4,4,4-(ethene-1,1,2,2-tetrayl) tetrabenzaldehyde (T1) NPs, and its relative ECL efficiency of T3 NPs reached 55.58% compared to the [Ru (bpy)3]2+/tripropylamine (TPrA) system. Furthermore, solvents with different polarities played a crucial role in modulating the degree of molecular aggregation, which also effectively facilitated the AIE process and reduced the aggregation-caused quenching (ACQ) effect caused by excessively dense aggregation. This aspect had often been overlooked in previous AIECL studies. T3 NPs demonstrated optimal ECL performance at fw = 70% (fw was the H2O content in tetrahydrofuran (THF)/H2O), and its ECL efficiency was 232 times greater than fw = 100% and 1853 times greater than fw = 0%. Additionally, it was found that melatonin (MT), one of the hormones widely used to treat insomnia, exhibited antioxidant and free radical scavenging properties, which exerted a significant quenching effect on the ECL of the T3 NPs/TPrA system. Consequently, a sensitive sensing platform was developed for MT with a low detection limit of 8.78 × 10-10 mol L-1, which promoted the application of AIECL in efficient ultra-sensitive biosensing.
Food allergy affects more than 500 million people in the world, and its prevalence is increasing at an alarming rate causing serious public health concerns; however, prevention and treatment methods are still under investigation and are relatively scarce so far. Insights on pathophysiology reveal a complex interplay of the immune cells (e.g., DCs, T cells, and B cells) resulting in allergy or tolerance. Studies have shown that melatonin metabolisms are altered in patients with allergic diseases, suggesting that melatonin might impact allergic diseases. Notably, melatonin can orchestrate the differentiation and function of immune cells. Additionally, the disease severities of many allergic diseases and the function of the immune system exhibit circadian rhythmicity. Therefore, melatonin, a rhythm regulator, may also act indirectly on the immune system through the circadian clock to regulate food allergies. Herein, we reviewed the impacts of melatonin on food allergy and its underlying regulatory mechanisms, providing a theoretical reference for melatonin as effective means of prevention and treatment for food allergy in the future.
Background:
Triptolide (TP) is an important active compound from Tripterygium wilfordii Hook F (TwHF), however, it is greatly limited in clinical practice due to its severe toxicity, especially testicular injury. Melatonin is an endogenous hormone and has beneficial effects on the reproductive system. However, whether triptolide-induced testicular injury can be alleviated by melatonin and the underlying mechanism are not clear.
Purpose:
In this study, we aimed to explore whether triptolide-induced testicular Sertoli cells toxicity can be mitigated by melatonin and the underlying mechanisms involved.
Methods:
Cell apoptosis was assessed by flow cytometry, western blot, immunofluorescence and immunohistochemistry. Fluorescent probe Mito-Tracker Red CMXRos was used to observe the mitochondria morphology. Mitochondrial membrane potential and Ca2+ levels were used to investigate mitochondrial function by confocal microscope and flow cytometry. The expression levels of SIRT1/Nrf2 pathway were detected by western blot, immunofluorescence and immunohistochemistry. Small interfering RNA of NRF2 and SIRT1 inhibitor EX527 was used to confirm the role of SIRT1/NRF2 pathway in the mitigation of triptolide-induced Sertoli cell damage by melatonin. Co-Immunoprecipitation assay was used to determine the interaction between SIRT1 and NRF2.
Results:
Triptolide-induced dysfunction of testicular Sertoli cells was significantly improved by melatonin treatment. Specifically, triptolide-induced oxidative stress damage and changes of mitochondrial morphology, mitochondrial membrane potential, and BTB integrity were alleviated by melatonin. Mechanistically, triptolide inhibited SIRT1 and then reduced the activation of NRF2 pathway via regulating the interaction between SIRT1 and NRF2, thereby downregulating the downstream antioxidant genes, which was reversed by melatonin. Nevertheless, knockdown of NRF2 or inhibition of SIRT1 abolished the protective effect of melatonin.
Conclusion:
Triptolide-induced testicular Sertoli cell damage could be alleviated by melatonin via regulating the crosstalk between SIRT1 and NRF2, which is helpful for developing a new strategy to alleviate triptolide-induced toxicity.
Cardiovascular disease (CVD) is a global health concern due to its high mortality. Heavy metals are the potential risk factor for CVD. Among other heavy metals, chromium (Cr) is considered a serious threat to human health due to its high oxidative capacity. In the current study, male Wistar rats were treated with Cr to induce cardiac tissue injuries, meanwhile, melatonin was given to test whether this treatment can protect against Cr-induced cardiac damage. The results showed that Cr markedly altered the heart weight, biomarkers of oxidative stress, activities of antioxidant and pro-oxidant enzymes, as well as tissue morphology. On contrary, melatonin treatment significantly suppressed all these alterations via its antioxidant activity. In addition, melatonin also significantly reduced tissue Cr concentration probably through its metal-chelating activity. The current study has demonstrated that melatonin is a promising antioxidant to protect the heart from Cr-induced oxidative damage, confirming that melatonin can be a future therapeutic agent for Cr-mediated toxicity in the heart or other organs.
Chromium (Cr), a hazardous heavy metal, is toxic to human health and the environment. Severe detrimental effects of Cr on different physiological systems involve oxidative stress. In the current study, sodium dichromate di-hydrate was subcutaneously injected to male Wistar rats at a dose of 5 mg/kg b.w. and experimented up to 14 days to induce alterations in hepatic and renal tissues. Another group of rats was pre-treated with melatonin at three different doses (5, 10, and 20 mg/kg b.w.; orally) and 20 mg/kg b.w. dose was evidenced to provide maximal protection against Cr-induced alterations. The study demonstrated that melatonin efficiently preserved body weight, organ weight, intracellular antioxidant enzymes, and tissue morphology. Furthermore, melatonin was also found to protect organ damage markers, oxidative stress-biomarkers, activities of pro-oxidant enzymes, levels of reactive oxygen species (ROS), nitric oxide (NO), and collagen content through its antioxidative mechanisms. Moreover, melatonin effectively decreased tissue Cr content through its metal-chelating activity. Hence, the present study has established melatonin as a promising antioxidant for conserving the liver and kidney tissues from Cr-induced oxidative damage thereby strengthening the notion that this small indoleamine can act as a future therapeutic against Cr-induced oxidative stress-mediated tissue damage.
Soil salinization severely inhibits plant growth and has become one of the major limiting factors for global agricultural production. Melatonin (N-acetyl-5-methoxytryptamine) plays an important role in regulating plant growth and development and in responding to abiotic stresses. Tryptamine-5-hydroxylase (T5H) is an enzyme essential for the biosynthesis of melatonin in plants. Previous studies have identified the gene MnT5H for melatonin synthesis in mulberry (Morus notabilis), but the role of this gene in response to salinity stress in mulberry is remain unclear. In this study, we ectopically overexpressed MnT5H2 in tobacco (Nicotiana tabacum L.) and treated it with NaCl solutions. Compared to wild-type (WT), melatonin content was significantly increased in the overexpression-MnT5H2 tobacco. Under salt stress, the expression of NtCAT, NtSOD, and NtERD10C and activity of catalase (CAT), peroxidase (POD), and the content of proline (Pro) in the transgenic lines were significantly higher than that in WT. The Malondialdehyde (MDA) content in transgenic tobacco was significantly lower than that of WT. Furthermore, transgenic tobacco seedlings exhibited faster growth in media with NaCl. This study reveals the changes of melatonin and related substance content in MnT5H2-overexpressing tobacco ultimately lead to improve the salt tolerance of transgenic tobacco, and also provides a new target gene for breeding plant resistance to salt.
The goals of this work were to screen physiological and biochemical indexes to assess a set of V. vinifera germplasm resources, to compare evaluation methods for cold hardiness, and to establish a comprehensive method that can be used for more accurate screening for cold hardiness in V. vinifera. Four single methods were used to evaluate the cold hardiness of 20 germplasms resources and 18 physiological and biochemical indexes related to cold hardiness were determined. The LT50 values determined by electrical conductivity (EL), 2,3,5-triphenyltetrazolium chloride staining (TTC), differential thermal analysis (DTA), and recovery growth (RG) methods showed extremely significant positive correlation. Bound water content (BW), proline content (Pro), total soluble sugar content (TSS), malondialdehyde content (MDA), catalase content (CAT), and ascorbic acid content (ASA) exhibited significant correlation with LT50 values measured by different evaluation methods. The comprehensive cold hardiness index calculated by principal component analysis (PCA) combined with subordinate function (SF) was negatively correlated with LT50 values measured by different evaluation methods. Meili and Ecolly exhibited the highest cold hardiness, indicating their potential for use as parents for cold hardiness breeding. EL, DTA, TTC, and RG methods successfully distinguished cold hardiness among different V. vinifera germplasm lines. Measurements of BW, Pro, TSS, MDA, CAT, and ASA in dormant shoots also can be used as main physiological and biochemical indexes related to cold hardiness of V. vinifera. Comprehensive evaluation by PCA combined with SF can accurately screen cold hardiness in V. vinifera. This study provides a reference and accurate identification method for the selection of cold hardiness parents and the evaluation of cold hardiness of germplasm of V. vinifera.
The role of melatonin in obesity control is extensively accepted, but its mechanism of action is still unclear. Previously we demonstrated that chronic oral melatonin acts as a brown-fat inducer, driving subcutaneous white adipose tissue (sWAT) into a brown-fat-like function (beige) in obese diabetic rats. However, immunofluorescence characterization of beige depots in sWAT and whether melatonin is a beige-fat inducer by de novo differentiation and/or transdifferentiation of white adipocytes are still undefined. Lean (ZL) and diabetic fatty (ZDF) Zücker rats were subdivided into two groups, control (C) and oral melatonin-supplemented (M, 10 mg kg-1 day-1) for 6 weeks. Mesenchymal stem cells (MSCs) were isolated from both rat inguinal fat and human lipoaspirates followed by adipogenesis assays with or without melatonin (50 nM for 12 h in a 24 h period, 12 h+/12 h-) mimicking the light/dark cycle. Immunofluorescence and western-blot assays showed the partial transdifferentiation of white adipocytes in both ZL and ZDF rats, with increasing thermogenic and beige markers, UCP1 and CITED1 and decreasing white adipocyte marker ASC-1 expression. In addition, melatonin increased UCP1, CITED1, and PGC1-α expression in differentiated adipocytes in both rats and humans. These results demonstrate that melatonin increases brown fat in obese diabetic rats by both adipocyte transdifferentiation and de novo differentiation. Furthermore, it promotes beige MSC adipogenesis in humans. This may contribute to the control of body weight attributed to melatonin and its metabolic benefits in human diabesity.
Climate change has caused severe drought, affecting global crop production. Broomcorn millet is a drought-tolerant crop preferred for water-saving agriculture because of its short life cycle and high water use efficiency. This study evaluated the drought tolerance of 300 broomcorn millet varieties from 21 sources under well-watered, semi-arid conditions (Yulin, Shaanxi, China) and unwatered, arid conditions (Dunhuang, Gansu, China). Two broomcorn millet varieties with contrasting drought tolerance attributes, DT 43 (drought-tolerant) and DS 190 (drought-sensitive), were selected for comparative physiological and transcriptional assessment under the two drought stress conditions (polyethylene glycol 6000 [PEG-6000] and soil drought) and corresponding melatonin treatments. The two forms of drought stress decreased photosynthetic capacity and triggered transcriptome reprogramming in both broomcorn millet cultivars. However, PEG induced a more ‘severe’ and ‘rapid’ drought stress than the ‘milder’ and ‘slower’ soil moisture drought stress. Moreover, PEG stress caused severe growth arrest and photosynthesis inhibition, especially for DS190. About 61.38% and 48.78% differentially expressed genes (DEGs) were up-regulated in DT 43 under PEG and soil drought stresses, respectively. Moreover, 74.31% and 54.59% DEGs were up-regulated in DS 190 under PEG and soil drought stresses, respectively. Most DEGs in DT 43 were significantly enriched in hormone signal transduction, mitogen-activated protein kinase (MAPK) signaling, and carbon metabolism pathways. However, most DEGs in DS 190 were enriched in plant photosynthesis, chlorophyll metabolism, and nitrogen metabolism pathways. Moreover, melatonin enhanced the drought resistance of the two genotypes, increasing photosynthetic and antioxidant enzyme activity and thus mitigating transcription response. Therefore, these unique mechanisms of enhancing drought resistance can improve bioenergy crops, especially for the cultivation of drought-tolerant varieties.
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by a progressive loss of visual function that primarily affect photoreceptors, resulting in the complete disorganization and remodeling of the retina. Progression of the disease is enhanced by increased oxidative stress in the retina, aqueous humor, plasma, and liver of RP animal models and patients. Melatonin has beneficial effects against age-related macular degeneration, glaucoma, and diabetic retinopathy, in which oxidative stress plays a key role. In the present study, we used the P23HxLE rat as an animal model of RP. Melatonin treatment (10 mg/kg b.w. daily in drinking water for 6 months) improved the parameters of visual function and decreased the rate of desynchronization of the circadian rhythm, both in P23HxLE and wild-type rats. Melatonin reduced oxidative stress and increased antioxidant defenses in P23HxLE animals. In wild-type animals, melatonin did not modify any of the oxidative stress markers analyzed and reduced the levels of total antioxidant defenses. Treatment with melatonin improved visual function, circadian synchronization, and hepatic oxidative stress in P23HxLE rats, an RP model, and had beneficial effects against age-related visual damage in wild-type rats.
Osteoporosis and neurodegenerative diseases are common diseases in the aging population. Studies demonstrate the complex communication among skeletal, muscular, and nervous systems and point to the emerging roles of neuromuscular systems in bone homeostasis. The discovery that the nervous system directly regulates bone remodeling implies that osteoporosis is a neuroskeletal disease. Melatonin, a hormone secreted from the pineal gland, is a melatonin receptor 1A (MT1) and 1B (MT2) agonist and influences the function of diverse systems. Melatonin is a pharmaceutical ingredient in numerous medicines, over-the-counter medicines, nutraceuticals, and dietary supplements, which benefit disease prevention and treatment, including osteoporosis and neurodegenerative diseases. This review aims to summarize the recent advances in preventing senile, postmenopausal, and neurodegenerative osteoporosis with melatonin and provide new insights into how neuromuscular systems influence bone homeostasis. More preclinical and clinical studies in neuroskeletal biology will eventually improve the lives of people fighting osteoporosis.
Coronaviruses (CoVs) are RNA viruses that cause infections of the respiratory, gastrointestinal, and central nervous systems, among others. The pathological symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include excessive inflammation, elevated oxidative stress, and an exaggerated immune response, ultimately leading to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often, death. Melatonin is a multifunctional and highly significant biomolecule that has anti-inflammatory, anti-oxidative, anti-apoptotic, and neuroprotective actions with no serious undesired side effects, even when administered in high doses. In this review, we present a brief account of the origin of coronaviruses, their characteristic features, infections, transmission, and the causes of coronavirus disease 2019 (COVID-19). We discuss their structure, genome organization, and mechanisms of cellular entry, as well as the pathogenicity of severe acute respiratory syndrome (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. Furthermore, we provide an account of the typical characteristic features of melatonin, such as its antioxidant, anti-inflammatory, immunomodulatory, and ameliorative effects on various virus-induced infections. Additionally, we identify the rationale for using melatonin as both a prospective adjuvant with vaccine therapy, and as an antiviral immune stimulator. Finally, we provide a perspective on the use of melatonin as a treatment against COVID-19.
The recent pandemic of COVID-19 has already infected millions of individuals and has resulted in the death of hundreds of thousands worldwide. Based on clinical features, pathology, and the pathogenesis of respiratory disorders induced by this and other highly homogenous coronaviruses, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response contribute to COVID-19 pathology; these are caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This leads to a cytokine storm and subsequent progression triggering acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and often death. We and others have reported melatonin to be an anti-inflammatory and anti-oxidative molecule with a high safety profile. It is effective in critical care patients by reducing their vascular permeability and anxiety, inducing sedation, and improving their quality of sleep. As melatonin shows no harmful adverse effects in humans, it is imperative to introduce this indoleamine into clinical trials where it might be beneficial for better clinical outcomes as an adjuvant treatment of COVID-19-infected patients. Herein, we strongly encourage health care professionals to test the potential of melatonin for targeting the COVID-19 pandemic. This is urgent, since there is no reliable treatment for this devastating disease.
Reactive oxygen species have a crucial role in the pathogenesis of perinatal diseases. Exposure to inflammation, infections, or high oxygen concentrations is frequent in preterm infants, who have high free iron levels that enhance toxic radical generation and diminish antioxidant defense. The peculiar susceptibility of newborns to oxidative stress supports the prophylactic use of melatonin in preventing or decreasing oxidative stress-mediated diseases. Melatonin, an effective direct free-radical scavenger, easily diffuses through biological membranes and exerts pleiotropic activity everywhere. Multiple investigations have assessed the effectiveness of melatonin to reduce the “oxygen radical diseases of newborn” including perinatal brain injury, sepsis, chronic lung disease (CLD), and necrotizing enterocolitis (NEC). Further studies are still awaited to test melatonin activity during perinatal period.
Plant melatonin research is a rapidly developing field. A variety of isoforms of melatonin's biosynthetic enzymes are present in different plants. Due to the different origins, they exhibit independent responses to the variable environmental stimuli. The locations for melatonin biosynthesis in plants are chloroplasts and mitochondria. These organelles have inherited the melatonin biosynthetic capacities from their bacterial ancestors. Under ideal conditions, chloroplasts are the main sites of melatonin biosynthesis. If chloroplast pathway is blocked for any reason, the mitochondrial pathway will be activated for melatonin biosynthesis to maintain its production. Melatonin metabolism in plants is a less studied field. its metabolism is quite different from that of animals even though they share similar metabolites. Several new enzymes for melatonin metabolism in plants have been cloned and these enzymes are absent in the animals. It seems that the 2-hydroxymelatonin is a major metabolite of melatonin in plants and its level is roughly 400-fold higher than that of melatonin. In the current article, from evolutionary point of view, we update the information on plant melatonin biosynthesis and metabolism. This review will hopefully help the reader to understand the complexity of these processes and to promote the research enthusiasm in these fields.
The high mortality of deadly virus infectious diseases including SARS, MERS, COVID-19, and avian flu is often caused by the uncontrolled innate immune response and destructive inflammation. The majority of viral diseases are self-limiting under the help of the activated adaptive immune system. This activity is cell proliferation dependent and thus, it requires several weeks to develop. Patients are vulnerable and mortality usually occurs during this window period. To control the innate immune response and reduce the inflammation during this period will increase the tolerance of patients and lowers the mortality in the deadly virus infection. Melatonin is a molecule that displays respective properties, since it downregulates the overreaction of the innate immune response and overshooting inflammation, but also promotes the adaptive immune activity. Many studies have reported the beneficial effects of melatonin on deadly virus infections in different animal models and its therapeutic efficacy in septic shock patients. Furthermore, melatonin has a great safety margin without serious adverse effects. We suggest the use of melatonin as an adjunctive or even regular therapy for deadly viral diseases, especially if no efficient direct anti-viral treatment is available.
Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome-related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1–4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a novel coronavirus (2019-nCoV) which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started from 12 December 2019, has caused 2,050 laboratory-confirmed infections with 56 fatal cases by 26 January 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The 2019-nCoV virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.
Prevention of neurodegenerative diseases is presently a major goal for our Society and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. Melatonin combines both chronobiotic and cytoprotective properties. As a chronobiotic, melatonin can modify phase and amplitude of biological rhythms. As a cytoprotective molecule, melatonin reverses the low degree inflammatory damage seen in neurodegenerative disorders and aging. Low levels of melatonin in blood characterizes advancing age. In experimental models of Alzheimer's disease (AD) and Parkinson's disease (PD) the neurodegeneration observed is prevented by melatonin. Melatonin also increased removal of toxic proteins by the brain glymphatic system. A limited number of clinical trials endorse melatonin's potentiality in AD and PD, particularly at an early stage of disease. Calculations derived from animal studies indicate cytoprotective melatonin doses in the 40–100 mg/day range. Hence, controlled studies employing melatonin doses in this range are urgently needed. The off-label use of melatonin is discussed.
Melatonin is an ancient molecule that can be traced back to the origin of life. Melatonin's initial function was likely that as a free radical scavenger. Melatonin presumably evolved in bacteria; it has been measured in both α-proteobacteria and in photosynthetic cyanobacteria. In early evolution, bacteria were phagocytosed by primitive eukaryotes for their nutrient value. According to the endosymbiotic theory, the ingested bacteria eventually developed a symbiotic association with their host eukaryotes. The ingested α-proteobacteria evolved into mitochondria while cyanobacteria became chloroplasts and both organelles retained their ability to produce melatonin. Since these organelles have persisted to the present day, all species that ever existed or currently exist may have or may continue to synthesize melatonin in their mitochondria (animals and plants) and chloroplasts (plants) where it functions as an antioxidant. Melatonin's other functions, including its multiple receptors, developed later in evolution. In present day animals, via receptor-mediated means, melatonin functions in the regulation of sleep, modulation of circadian rhythms, enhancement of immunity, as a multifunctional oncostatic agent, etc., while retaining its ability to reduce oxidative stress by processes that are, in part, receptor-independent. In plants, melatonin continues to function in reducing oxidative stress as well as in promoting seed germination and growth, improving stress resistance, stimulating the immune system and modulating circadian rhythms; a single melatonin receptor has been identified in land plants where it controls stomatal closure on leaves. The melatonin synthetic pathway varies somewhat between plants and animals. The amino acid, tryptophan, is the necessary precursor of melatonin in all taxa. In animals, tryptophan is initially hydroxylated to 5-hydroxytryptophan which is then decarboxylated with the formation of serotonin. Serotonin is either acetylated to N-acetylserotonin or it is methylated to form 5-methoxytryptamine; these products are either methylated or acetylated, respectively, to produce melatonin. In plants, tryptophan is first decarboxylated to tryptamine which is then hydroxylated to form serotonin.
Climacteric and non-climacteric fruits are differentiated by the ripening process, in particular by the involvement of ethylene, high respiration rates and the nature of the process, being autocatalytic or not, respectively. Here, we focus on the biosynthesis, metabolism and function of three compounds (auxin, salicylic acid and melatonin) sharing not only a common precursor (chorismate), but also regulatory functions in plants, and therefore in fruits. Aside from describing their biosynthesis in plants, with a particular emphasis on common precursors and points of metabolic diversion, we will discuss recent advances on their role in fruit ripening and the regulation of bioactive compounds accumulation, both in climacteric and non-climacteric fruits.
Neurodegenerative diseases are typified by neuronal loss associated with progressive dysfunction and clinical presentation. Neurodegenerative diseases are characterized by the intra‐ and extracellular conglomeration of misfolded proteins that occur because of abnormal protein dynamics and genetic manipulations; these trigger processes of cell death in these disorders. The disrupted signaling mechanisms involved are oxidative stress–mediated mitochondrial and calcium signaling deregulation, alterations in immune and inflammatory signaling, disruption of autophagic integrity, proteostasis dysfunction, and anomalies in the insulin, Notch, and Wnt/β‐catenin signaling pathways. Herein, we accentuate some of the contemporary translational approaches made in characterizing the underlying mechanisms of neurodegeneration. Melatonin‐induced cognitive enhancement and inhibition of oxidative signaling substantiates the efficacy of melatonin in combating neurodegenerative processes. Our review considers in detail the possible roles of melatonin in understanding the synergistic pathogenic mechanisms between aggregated proteins and in regulating, modulating, and preventing the altered signaling mechanisms discovered in cellular and animal models along with clinical evaluations pertaining to neurodegeneration. Furthermore, this review showcases the therapeutic potential of melatonin in preventing and treating neurodegenerative diseases with optimum prognosis.
Cancers of the reproductive organs have a strong association with mitochondrial defects, and a deeper understanding of the role of this organelle in preneoplastic–neoplastic changes is important to determine the appropriate therapeutic intervention. Mitochondria are involved in events during cancer development, including metabolic and oxidative status, acquisition of metastatic potential, resistance to chemotherapy, apoptosis, and others. Because of their origin from melatonin-producing bacteria, mitochondria are speculated to produce melatonin and its derivatives at high levels; in addition, exogenously administered melatonin accumulates in the mitochondria against a concentration gradient. Melatonin is transported into tumor cell by GLUT/SLC2A and/or by the PEPT1/2 transporters, and plays beneficial roles in mitochondrial homeostasis, such as influencing oxidative phosphorylation and electron flux, ATP synthesis, bioenergetics, calcium influx, and mitochondrial permeability transition pore. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on the main functions of melatonin on mitochondrial processes, and reviews from a mechanistic standpoint, how mitochondrial crosstalk evolved in ovarian, endometrial, cervical, breast, and prostate cancers relative to melatonin’s known actions. We put emphasis on signaling pathways whereby melatonin interferes within cancer-cell mitochondria after its administration. Depending on subtype and intratumor metabolic heterogeneity, melatonin seems to be helpful in promoting apoptosis, anti-proliferation, pro-oxidation, metabolic shifting, inhibiting neovasculogenesis and controlling inflammation, and restoration of chemosensitivity. This results in attenuation of development, progression, and metastatic potential of reproductive cancers, in addition to lowering the risk of recurrence and improving the life quality of patients.
Breast cancer is the most common neoplastic disorder diagnosed in women. The main goal of this study was to explore the effect of melatonin against breast cancer metastasis and compared this with the actions of taxol (a well‐known chemotherapeutic drug), and the impact of their combination against breast cancer metastasis. Melatonin showed no cytotoxic effect while taxol showed antiproliferative and cytotoxic effects on MCF‐7 and MDA‐MB‐231 cells. Furthermore, melatonin inhibited the generation of reactive oxygen species. Melatonin and taxol clearly decreased cell migration and invasion at low doses, especially those matching the normal physiological concentration at night. Melatonin and taxol markedly reduced DJ‐1 and ID‐1 and increased KLF17 messenger RNA and protein expression levels. The present results also showed that melatonin and taxol induced GSK3‐β nuclear and Snail cytosolic localization. These changes were accompanied by a concurrent rise in E‐cadherin expression. The above data show that normal levels of melatonin may help in preventing breast cancer metastasis through inhibiting DJ‐1/KLF17/ID‐1 signaling pathway. The combination of melatonin and taxol is a potent candidate against breast cancer metastasis, better than using melatonin or taxol as a single drug.
Dysregulation of neuronal Ca2+ and oxidative stress plays an important role in the activation of cysteine proteases including calpains and caspases that contribute to neuronal death. In neurodegenerative diseases, traumatic brain injury, stroke, and neuropathic pain calpain activities are markedly increased. Melatonin is a beneficial supplement in the treatment of central nervous system (CNS) disorders. Melatonin is a potent antioxidant and works as a free-radical scavenger to regulate a large number of molecular pathways, including oxidative stress, inflammation, apoptosis, and cell death under different pathological conditions. However, limited studies have evaluated the inhibitory effect of melatonin on calpains. This review summarizes the current knowledge related to the effects of melatonin on calpains in some of the common CNS disorders.
Purpose
Changes in the circadian rhythm may contribute to the development of cancer and are correlated with the high risk of breast cancer (BC) in night workers. Melatonin is a hormone synthesized by the pineal gland at night in the absence of light. Levels of melatonin and the metabolite of oxidative metabolism AFMK (acetyl-N-formyl-5-methoxykynurenamine), are suggested as potential biomarkers of BC risk. The aims of this study were to evaluate levels of melatonin and AFMK in women recently diagnosed with BC, women under adjuvant chemotherapy, and night-shift nurses, and compare them with healthy women to evaluate the relation of these compounds with BC risk.
Methods
Blood samples were collected from 47 women with BC, 9 healthy women, 10 healthy night shift nurses, and 6 patients under adjuvant chemotherapy. Compound levels were measured by mass spectrometry.
Results and conclusions
Our results showed that women with BC had lower levels of melatonin compared to control group women, and even lower in night-shift nurses and in patients under adjuvant chemotherapy. There was no significant difference of AFMK levels between the groups. In addition to this, high levels of melatonin and AFMK were related to patients with metastasis, and high levels of AFMK were related to the presence of lymph node-positive, tumor > 20 mm and patients who sleep with light at night. Our results showed a reduction of melatonin levels in BC patients, suggesting a relation with the disease, and in addition, point to the importance of melatonin supplementation in women that work at night to reduce the BC risk.
Phytomelatonin (plant melatonin) is chemically related to the amino acid tryptophan and has many diverse properties. Phytomelatonin is an interesting compound due to its outstanding actions at the cellular and physiological level, especially its protective effect in plants exposed to diverse stress situations, while its vegetable origin offers many opportunities because it is a natural compound. We present an overview of its origin, its action in plants in general (particularly in plant species with high levels of phytomelatonin), and its possibilities for use as a nutraceutical with particular attention paid to the beneficial effects that it may have in human health. The differences between synthetic melatonin and phytomelatonin, according to its origin and purity, are presented. Finally, the current market for phytomelatonin and its limits and potentials are discussed.
This study was aimed to evaluate the effects of germination process on melatonin, total phenols, total flavonoids and antioxidant activities of broad beans (Vicia faba L.), lupine seeds (Lupinus albus), chickpea seeds (Cicer arietinum L.), lentil seeds (Lens culimaris), fenugreek seeds (Trigonella foenum-graecum L.) and common beans (Phaseolus vulgaris) fractions (cotyledons, radicles and seed hulls). Radicle length of germinated legumes and sensory properties of legumes after 6 days of germination were also evaluated. Fenugreek and chickpea seeds had higher melatonin (54.22 and 24.42 ng/g), total phenols (5.79 and 5.68 mg gallic acid /g) and total flavonoids (8.86 and 8.43 mg quercetin /g), respectively than other legumes however, common beans showed the lowest values. Broad beans and lentil seeds had the highest antioxidant activities while lupine seeds showed the lowest value among all other legumes. The mean values of melatonin for cotyledons, radicles and seed hulls were increased by 386.26, 261.98 and 183.22%, respectively compared with the third day of germination. The increases in melatonin content of legume fractions were parallel to the increases in radicle lengths, total phenols, total flavonoids and antioxidant activities throughout the germination time. Overall acceptability of legumes had rating scores ranged between like moderately and like very much except for chickpea which had rating score described as like slightly.
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 anti-radical 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. This article is protected by copyright. All rights reserved.
Melatonin is a phylogenetically ancient molecule. It is ubiquitously present in almost all organisms from primitive photosynthetic bacteria to humans. Its original primary function is presumable to be that of an antioxidant with other functions of this molecule having been acquired during evolution. The synthetic pathway of melatonin in vertebrates has been extensively studied. It is common knowledge that serotonin is acetylated to form N-acetylserotonin by aralkylamine N-acetyltransferase (AANAT) or arylamine N-acetyltransferase (SNAT or NAT) and N-acetylserotonin is, subsequently, methylated to melatonin by N-acetylserotonin O-methyltransferase (ASMT; also known as hydroxyindole-O-methyltransferase, (HIOMT). This is referred to as a classic melatonin synthetic pathway. Based on new evidence, we feel that this classic melatonin pathway is not generally the prevailing route of melatonin production. An alternate pathway is known to exist, in which serotonin is first O-methylated to 5-methoxytryptamine (5-MT) and, thereafter, 5-MT is N-acetylated to melatonin. Here, we hypothesize that the alternate melatonin synthetic pathway may be more important in certain organisms and under certain conditions. Evidence strongly supports that this alternate pathway prevails in some plants, bacteria and, perhaps, yeast, and may also occur in animals. This article is protected by copyright. All rights reserved.
Melatonin is an endogenous antioxidant hormone, reduced along ageing and low levels are associated with some chronic diseases. Germination of legumes increases the plant levels of melatonin, making sprouts a suitable food source of this hormone. However, information on its bioavailability after consumption is lacking. We aimed to evaluate in rats the effect of kidney bean sprouts intake on plasma levels of melatonin and metabolically related compounds (serotonin, 6-sulfatoxymelatonin), total phenolic compounds and total antioxidant capacity. In addition, we compared plasma bioavailability derived from kidney bean sprouts versus synthetic melatonin intake. Kidney beans were germinated for 6 days and an extract prepared in water. Male young Sprague Dawley rats were used; blood and urine samples were obtained before and after 90 min of administration of kidney bean sprout extract via a gavage. Plasmatic melatonin levels increased after sprout ingestion (16%, p < 0.05). This increment correlated with urinary of 6-sulfatoxymelatonin content, the principal biomarker of plasmatic melatonin levels (p < 0.01). Nevertheless, phenolic compounds and antioxidant capacity levels did not exhibited any significant variation. The comparison of the bioavailability between the melatonin contained in the kidney bean sprouts and in a synthetic solution evidenced a slight higher levels of plasmatic melatonin (17%) in rats fed with the solution of synthetic melatonin. We conclude that kidney bean sprouts could be a good source of dietary melatonin and other bioactive compounds known to have health benefits.
The aim of this experimental animal model study is to investigate the effects of caffeic acid phenethyl ester (CAPE) and melatonin on the maturation of newly-formed regenerated bone in distraction osteogenesis.
Unilateral femoral lengthening(extension) was applied to 39 adult male Wistar albino rats, which were randomly allocated to 3 groups of 13; control, melatonin and CAPE groups. Through a 7-day latent waiting period and 15 days of distraction, melatonin of 25 mg/kg and CAPE of 10 μmol/kg were administered to the respective groups. The animals were sacrificed on Day 82. Radiographic, histological and biomechanical evaluations were made and measurements were taken.
At the end of 82 days, the distraction osteogenesis area was seen to be completely filled with new bone formation in all 3 groups both radiologically and histologically. Biomechanically, the maximum torsional fracture strength (Maximum Torque (N-m)) of the melatonin group was higher compared to that of the control group, although it was not statistically significant (p > 0.05). The maximum torsional momentum of the CAPE group was statistically significantly high (p < 0.05). The degree of rigidity (N-m/deg) of both the melatonin and CAPE groups was higher than that of the control group and the CAPE group was found to be statistically significantly higher than the melatonin group (p < 0.05).
Melatonin and CAPE increase the maturation of new bone in distraction osteogenesis. These effects are probably due to the reducing effect on bone resorption by inhibiting NF-κB and free oxygen radicals.
In recent years melatonin has emerged as a research highlight in plant studies. Melatonin has different functions in many
aspects of plant growth and development. The most frequently mentioned functions of melatonin are related to abiotic stresses
such as drought, radiation, extreme temperature, and chemical stresses. This review mainly focuses on the regulatory effects
of melatonin when plants face harsh environmental conditions. Evidence indicates that environmental stress can increase the
level of endogenous melatonin in plants. Overexpression of the melatonin biosynthetic genes elevates melatonin levels in transgenic
plants. The transgenic plants show enhanced tolerance to abiotic stresses. Exogenously applied melatonin can also improve
the ability of plants to tolerate abiotic stresses. The mechanisms by which melatonin alleviates abiotic stresses are discussed.
Melatonin and melatonin isomers exist and/or coexist in living organisms including yeasts, bacteria and plants. The levels of melatonin isomers are significantly higher than that of melatonin in some plants and in several fermented products such as in wine and bread. Currently, there are no reports documenting the presence of melatonin isomers in vertebrates. From an evolutionary point of view, it is unlikely that melatonin isomers do not exist in vertebrates. On the other hand, large quantities of the microbial flora exist in the gut of the vertebrates. These microorganisms frequently exchange materials with the host. Melatonin isomers, which are produced by these organisms inevitably enter the host's system. The origins of melatonin and its isomers can be traced back to photosynthetic bacteria and other primitive unicellular organisms. Since some of these bacteria are believed to be the precursors of mitochondria and chloroplasts these cellular organelles may be the primary sites of melatonin production in animals or in plants, respectively. Phylogenic analysis based on its rate-limiting synthetic enzyme, serotonin N-acetyltransferase (SNAT), indicates its multiple origins during evolution. Therefore, it is likely that melatonin and its isomer are also present in the domain of archaea, which perhaps require these molecules to protect them against hostile environments including extremely high or low temperature. Evidence indicates that the initial and primary function of melatonin and its isomers was to serve as the first-line of defence against oxidative stress and all other functions were acquired during evolution either by the process of adoption or by the extension of its antioxidative capacity.
Plums are considered a source of phytochemicals with beneficial health effects. The study was aimed at characterizing Japanese plums (Prunus salicina Lindl. cv. Crimson globe) nutritionally and functionally and evaluating the antioxidant effect of a plum-enriched diet in young, middle-aged, and elderly individuals. Participants consumed 200 g of plums twice a day for 5 days. First-void morning urines were collected before treatment (basal values), the immediate day after the last ingestion of plums (assay), and 1 day afterwards (post-assay), and urinary 6-sulfatoxymelatonin (aMT6-s) and total antioxidant capacity were measured. Nutritionally, plums were shown to contain low carbohydrate values. From a functional point of view, serotonin, melatonin, phenolic compounds and anthocyanins were detected. Fruit consumption increased significantly the participants’ urinary aMT6-s and total antioxidant capacity levels in relation to their corresponding basal and post-assay values. Plums may be seen as a source of antioxidants with potential properties for counteracting oxidation.
Skin cancer, particularly melanoma, is a leading cause of death worldwide. The therapeutic methods for this malignancy are not effective, and due to the side effects of these treatments, applying an appropriate alternative or complementary treatment is important. According to available data, melatonin as the main product of the pineal gland has oncostatic and antitumoral properties. Also, melatonin acts as an anti‐inflammatory and reactive oxygen species inducer agent which suppresses the growth of tumors. It also has apoptosis induction characteristics through regulating signaling pathways, including heat shock protein 70, nuclear factor‐erythroid 2 p45‐related factor 2 and others. Thus, adding melatonin to chemo‐ and radiotherapy may have synergistic therapeutic effects and increase the survival time in patients with skin cancer. Few clinical studies have evaluated the efficacy of melatonin in skin cancer. Based on the related mechanisms, this review discusses about how melatonin may improve outcomes in skin cancer patients.
Melatonin is a signal molecule that modulates the biological circadian rhythms of vertebrates. Melatonin deficiency is thought to be associated with several disorders, including insomnia, cancer, and cardiovascular and neurodegenerative diseases. Accumulating evidence has also indicated that melatonin may be involved in the homeostasis of bone metabolism. Age‐related reductions in melatonin are considered to be critical factors in bone loss and osteoporosis with aging. Thus, serum melatonin levels might serve as a biomarker for the early detection and prevention of osteoporosis. Compared to conventional antiosteoporosis medicines, which primarily inhibit bone loss, melatonin both suppresses bone loss and promotes new bone formation. Mechanistically, by activating melatonin receptor 2 (MT2), melatonin upregulates the gene expression of alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), BMP6, osteocalcin and osteoprotegerin to promote osteogenesis while inhibiting the receptor activator of NF‐kB ligand (RANKL) pathway to suppress osteolysis. In view of the distinct actions of melatonin on bone metabolism, we hypothesize that melatonin may be a novel remedy for the prevention and clinical treatment of osteoporosis.
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Due to the broad distribution of extrapineal melatonin in multiple organs and tissues, we analyzed the presence and subcellular distribution of the indoleamine in the heart of rats. Groups of sham-operated and pinealectomized rats were sacrificed at different times along the day, and the melatonin content in myocardial cell membranes, cytosol, nuclei and mitochondria, were measured. Other groups of control animals were treated with different doses of melatonin to monitor its intracellular distribution. The results show that melatonin levels in the cell membrane, cytosol, nucleus, and mitochondria vary along the day, without showing a circadian rhythm. Pinealectomized animals trend to show higher values than sham-operated rats. Exogenous administration of melatonin yields its accumulation in a dose-dependent manner in all subcellular compartments analyzed, with maximal concentrations found in cell membranes at doses of 200 mg/kg bw melatonin. Interestingly, at dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The results confirm previous data in other rat tissues including liver and brain, and support that melatonin is not uniformly distributed in the cell, whereas high doses of melatonin may be required for therapeutic purposes.
There still lacking effective treatment for bladder cancer. This study investigated whether melatonin (Mel) can suppress the growth and invasion of bladder cancer cells. Male C57B/L6 mice were categorized into control group (i.e., subcutaneous injection of HT1197 bladder cancer cell line at the back] and treatment group [subcutaneous HT1197 cells + intra‐peritoneal Mel (100 mg/kg/day) from day 8 to day 21 after tumor cell injection]. In vitro, Mel suppressed cell growth of four bladder cancer cell lines (i.e., T24, RT4, HT1197, HT1376), cell migration in HT1197/HT1376, mitochondrial membrane potential (MMP) in T24 and colony formation in RT4 cells as well as arrested the cell cycle at G0 phase and inhibited the mitotic phase of T24 cells (all p<0.0001). Protein expression of ZNF746 in RT4/T24 cells and protein expression phosphorylated (p)‐AKT/MMP‐2/MMP‐9 in HT1197/HT1376 cells were reduced following Mel treatment (all p<0.001). Transfection of T24 cells with plasmid‐based shRNA (i.e., ZNF746‐silencing) downregulated the protein expression of MMP‐9, cell growth and invasion and attachment to endothelial cells but upregulated the colony formation (all p<0.001). Mel suppressed oxidative stress and MMP but upregulated mitochondria mass in ZNF746‐silenced T24 cells, whereas these parameters exhibited a similar patter to Mel treatment in ZNF746‐silenced T24 cells (all p<0.0001). In vivo study demonstrated that Mel treatment significantly suppressed cellular expressions of MMP‐9/MMP‐2, protein expressions of ZNF746/p‐AKT and tumor size (all p<0.001). Mel treatment suppressed the growth, migration, and invasion of bladder carcinoma cells through down‐regulating ZNF746‐regulated MMP‐9/MMP‐2 signaling.
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Characterization of the melatonin (MLT) biosynthesis pathway in plants is still limited. Additionally, a metabolomic analysis of MLT biosynthesis in plants is still a challenge due to analyte structural and chemical diversity, low analyte abundances, and plant matrix complexities. Herein, a sensitive liquid chromatography mass spectrometry (LC‐MS) method enabling the simultaneous determination of 7 plant MLT biosynthetic metabolites was developed. In the proposed strategy, the targeted metabolites, which included tryptophan (Trp), tryptamine (TAM), 5‐hydroxytryptophan (5HTP), serotonin (5HT), N‐acetylserotonin (NAS), 5‐methoxytryptamine (5MT), and MLT, were purified from plant extracts using a one‐step dispersive solid‐phase extraction (DSPE). The samples were then chemically labelled with dansyl chloride (DNS‐Cl), followed by analysis using LC‐MS. The limit of detection (LOD) values ranged from 0.03 to 1.36 pg/mL and presented a 22–469 fold decrease when compared to the unlabeled metabolites. Due to the high sensitivity of the proposed method, the consumption of plant materials was reduced to 10 mg FW. Ultimately, the established method was utilized to examine the distributions of MLT and its intermediates in rice shoots and roots with or without cadmium (Cd) stress. The results suggested that under normal condition, MLT may also be generated via a Trp/TAM/5HT/5MT/MLT path (Pathway II) in addition to the previously reported Trp/TAM/5HT/NAS/MLT path (Pathway I), although Pathway I was shown to be dominant. During Cd stress, MLT was also shown to be produced through these two pathways, with Pathway II shown to be dominant in rice shoots and roots.
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Pancreatic cancer has a high mortality rate due to the absence of early symptoms and subsequent late diagnosis; additionally, pancreatic cancer has a high resistance to radio‐ and chemotherapy. Multiple inflammatory pathways are involved in the pathophysiology of pancreatic cancer. Melatonin an indoleamine produced in the pineal gland mediated and receptor‐independent action is the pancreas and other where has both receptors. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. Melatonin may be an effective apoptosis inducer in cancer cells through regulation of a large number of molecular pathways including oxidative stress, heat shock proteins, and vascular endothelial growth factor. Limited clinical studies, however, have evaluated the role of melatonin in pancreatic cancer. This review summarizes what is known regarding the effects of melatonin on pancreatic cancer and the mechanisms involved.
Melatonin's therapeutic potential has been highly underestimated because its biological functional roles are diverse and relevant mechanisms are complicated. Among the numerous biological activities of melatonin, its regulatory effects on pluripotent mesenchymal stem cells (MSCs), which are found in bone marrow stem cells (BMSCs) and adipose tissue (AD-MSC), have been recently proposed, which has received increasingly more attention in recent studies. Moreover, receptor-dependent and receptor-independent responses to melatonin are identified to occur in these cells by regulating signaling pathways, which drive the commitment and differentiation of MSCs into osteogenic, chondrogenic, or adipogenic lineages. Therefore, the aim of our current review is to summarize the evidence related to the utility of melatonin as a regulatory agent by focusing on its relationship with the differentiation of MSCs. In particular, we aimed to review its roles in promoting osteogenic and chondrogenic differentiation and the relevant signaling cascades involved. Also, the roles that melatonin and, particularly, its receptors play in these processes are highlighted.
Melatonin is a physiological indoleamine involved in circadian rhythm regulation and it is currently used for secondary sleep disorders supported by empirical evidence. A small amount of evidence and some controversial results have been obtained in some randomized controlled trials (RCT). The objective of this meta-analysis is to determine the efficacy of exogenous melatonin versus placebo in managing secondary sleep disorders. Literature retrieval of eligible RCT was performed in 5 databases (PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and Web of Science). In total, 7 studies of 205 patients were included. Pooled data demonstrate that exogenous melatonin lowers sleep onset latency and increases total sleep time, whereas it has little if any effect on sleep efficiency. Although, the efficacy of melatonin still requires further confirmation, this meta-analysis clearly supports the use of melatonin as a management for patients with secondary sleep disorders.
The consumption of teas and herbal infusions has increased in Europe and the USA in recent years. The goal of this work was to provide new knowledge on the contents of melatonin and other bioactive non-nutrient compounds of nineteen highly consumed herbal infusions. Melatonin was previously assessed in some medicinal plants alcoholic extracts but not described in herbal aqueous infusions as we reported for the first time. Noticeable melatonin contents were found in most of herbal infusions, showing chamomile and green tea the highest values. These studied herbal infusions could be considered as potential dietary sources of this antioxidant compound, and they also exhibited high levels of total phenolic compounds and total flavonoids (lemon balm revealed the highest contents). From results, the total phenolic compounds and total flavonoids were associated with the inhibition of lipase and α-glucosidase, as well as to the in vitro antioxidant capacity measured through five different methods (DPPH, ABTS, FRAP, ORAC, and deoxyribose assays). Thus, the studied teas and herbal infusions could be consided as suitable drinks herein validated for their bioactive compounds that may act as antioxidants and non-protein inhibitors of digestive enzymes, presenting health-promoting properties.
A decade has passed since melatonin was first reported in grapes in 2006. During this time, melatonin has not only been found in the berries of most wine grape (Vitis vinifera L.) cultivars, but also in most grape-related foodstuffs, e.g. wine, grape juice and grape vinegar. In this review, we discuss the melatonin content in grapes and grape-related foodstuffs (especially wine) from previous studies, the physiological function of melatonin in grapes, and the factors contributing to the production of melatonin in grapes and wines. In addition, we identify future research needed to clarify the mechanisms of grape melatonin biosynthesis and regulation, and establish more accurate analysis methods for melatonin in grapes and wines.
Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 μg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P < 0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P < 0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of ...
Epigenetic modifications, including methylation or acetylation as well as posttranscriptional modifications are mechanisms used by eukaryotic cells to increase the genome diversity in terms of differential gene expression and protein diversity. Among these modifying enzymes, sirtuins, a class III histone deacetylase (HDAC) enzymes are of particular importance. Sirtuins regulate the cell cycle, DNA repair, cell survival and apoptosis, thus having important roles in normal and cancer cells. Sirtuins can also regulate metabolic pathways by changing preference for glycolysis under aerobic conditions as well as glutaminolysis. These actions make sirtuins a major target in numerous physiological processes as well as in other contexts such as calorie restriction-induced antiaging, cancer or neurodegenerative disease. Interestingly melatonin, a nighttime-produced indole synthesized by pineal gland and many other organs, have important cytoprotective effects in many tissues including aging, neurodegerative diseases, immunomodulation and cancer. The pleiotropic actions of melatonin in different physiological and pathological conditions indicate that may be basic cellular targetd for the indole. Thus, much research has focused attention on the potential mechanisms of the indole in modulating expression and/or activity of sirtuins. Numerous findings report a rise in activity, especially on SIRT1, in a diversity of cells and animal models after melatonin treatment. This contrasts, however, with data reporting an inhibitory effect of melatonin on this sirtuin in some tumor cells. This review tabulates and discusses the recent findings relating melatonin with sirtuins, particularly SIRT1 and mitochondrial SIRT3, showing the apparent dichotomy with the differential actions documented in normal and in cancer cells. This article is protected by copyright. All rights reserved.
Melatonin is an animal hormone as well as a signaling molecule in plants. It was first identified in plants in 1995, and almost all enzymes responsible for melatonin biosynthesis had already been characterized in these species. Melatonin biosynthesis from tryptophan requires four-step reactions. However, six genes, i.e., TDC, TPH, T5H, SNAT, ASMT, and COMT, have been implicated in the synthesis of melatonin in plants, suggesting the presence of multiple pathways. Two major pathways have been proposed based on the enzyme kinetics: one is the tryptophan/tryptamine/serotonin/N-acetylserotonin/melatonin pathway, which may occur under normal growth conditions; the other is the tryptophan/tryptamine/serotonin/5-methoxytryptamine/melatonin pathway, which may occur when plants produce large amounts of serotonin, e.g., upon senescence. The melatonin biosynthetic capacity associated with conversion of tryptophan to serotonin is much higher than that associated with conversion of serotonin to melatonin, which yields a low level of melatonin synthesis in plants. Many melatonin intermediates are produced in various subcellular compartments, such as the cytoplasm, endoplasmic reticulum, and chloroplasts, which either facilitates or impedes the subsequent enzymatic steps. Depending on the pathways, the final subcellular sites of melatonin synthesis vary at either the cytoplasm or chloroplasts, which may differentially affect the mode of action of melatonin in plants. This article is protected by copyright. All rights reserved.
High levels of melatonin have been reported in various foods but not in mulberry or its wine. This study investigated the dynamic changes of melatonin levels during mulberry fruit development and ethanol fermentation of 2 different colored mulberry cultivars ("Hongguo2ˮ Morus nigra, black and "Baiyuwangˮ Morus alba, white) at 2 fermentation temperatures (16 and 25 °C). Our results showed that the melatonin level increased in the beginning of mulberry development but decreased in the end. The MnTDC gene expression level correlated with melatonin production, which implied that TDC may be the rate-limiting enzyme of the melatonin biosynthetic process in mulberries. During mulberry fermentation, the melatonin concentration increased rapidly in the beginning and then decreased gradually. Low temperature delayed the melatonin production during fermentation. A relatively high level of melatonin was found in "Hongguo2ˮ compared with "Baiyuwangˮ during fruit development and fermentation. The variation of melatonin correlated with the ethanol production rate, suggesting that melatonin may participate in physiological regulation of Saccharomyces cerevisiae during the fermentation stage.
The cloning of the gene encoding melatonin 2-hydroxylase (M2H), which is responsible for the synthesis of 2-hydroxymelatonin, has expanded the study of melatonin metabolism in plants. Kinetic analysis of M2H enzymatic activity demonstrated that the catalytic efficiency of M2H is much higher than those of other melatonin biosynthetic enzymes such as serotonin N-acetyltransferase (SNAT) and N-acetylserotonin O-methyltransferase (ASMT), suggesting that melatonin metabolism is rapid in plants. To test this prediction, we selected 24 plant species belonging to 16 families and quantified the levels of melatonin and 2-hydroxymelatonin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The melatonin levels in most of the species were less than 1 ng/g fresh weight (FW), while those in leaves from radish and feverfew were 3.5 and 3.3 ng/g FW, respectively. In contrast, the average levels of 2-hydroxymelatonin were much higher at 6.2 ng/g FW. The average ratio of 2-hydroxymelatonin to melatonin in plants was approximately 368:1 indicating that the accumulation of 2-hydroxymelatonin predominates over that of melatonin. These data were consistent with previous results on the kinetics of the corresponding enzymes, as well as with in vivo melatonin conversion data. Among several melatonin metabolites in plants, the most abundant metabolite was found to be 2-hydroxymelatonin (99%) followed by 4-hydroxymelatonin (0.05%), but 6-hydroxymelatonin was not detected in rice seedlings. This article is protected by copyright. All rights reserved.
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Melatonin is remarkably functionally-diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immuno-regulating molecule and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary since photosynthesis is associated with the generation of toxic free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple non-sulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Melatonin has been proposed as a potent anti-oxidant and its presence in many plants and foods has been suggested to be beneficial for health. Indeed, the concentrations of melatonin in blood, and the melatonin metabolite 6 sulphatoxymelatonin in urine, have been found to increase significantly after ingestion of melatonin rich foods. In this review the studies have been critically evaluated in light of the reported plant melatonin concentrations and our knowledge of pharmacokinetics of orally administered pure melatonin. In the case of studies involving measurement of plasma melatonin following ingestion of beer or fruits the reported increases in melatonin are not consistent with the amount of melatonin ingested. Similarly the amount of melatonin metabolite excreted following ingestion of melatonin rich foods greatly exceed the amount ingested. It is concluded that studies reporting the appearance of melatonin in blood and its metabolites in urine following ingestion of melatonin rich foods are flawed. While there may be health benefits for certain foods it is difficult to accept that they are due to their low melatonin content.
This book, divided into 5 parts, deals with topics on amino acids in higher plants. Part I (enzymes and metabolism) contains 16 chapters pursuing the theme of amino acid metabolism through the driving actions of the principal enzymes, emphasizing recent advances particularly with reference to localization, biophysical characterization and regulation. Part II (dynamics) includes two chapters designed to explore transport dynamics at the cellular and whole plant levels and the relationship to external factors. Part III (chemical ecology) contains 6 chapters designed to encapsulate the theme of biochemical diversity with reference to the impact of amino acids and related derivatives on metabolic pathways, ecology and the environment. Part IV (plant products: quality and safety) has 3 chapters indicating the potential and actual value of plant products as sources of amino acids for the nutrition of humans and other vertebrates. The primary objective in the final part is to collate the main findings in the foregoing chapters within an integrated overview. Issues such as comparative metabolism, signal transduction and molecular interactions may be considered within a more comprehensive perspective. Similarly, the effects of biotic and environmental pressures on amino acid metabolism and defence mechanisms may be developed into an integrated model of plant responses to a changing environment.
Melatonin is a pleiotropic substance that is widely distributed in all kingdoms. Discovered in animals in 1958, this neurohormone is synthesized in the pineal gland and has multiple physiological actions in mammals, where it is related with some dysfunctions and diseases. In plants, so-called phytomelatonin was discovered in 1975. As in the case of animals, phytomelatonin has diverse physiological roles at different developmental stages of plants. Also, this indolic compound plays a relevant role in plant stress situations. Early problems concerning the detection and quantification of phytomelatonin in plant tissues have been resolved with the widespread use of techniques based on mass spectrometry. Phytomelatonin levels in plant samples vary widely, from picograms to micrograms per gram of tissues. A classification of the plants analyzed to date with regard to their phytomelatonin content is presented. The possible use of phytomelatonin as a nutraceutical for humans has led to two fronts being opened up: the search for plant materials with a high phytomelatonin content, and intervention to obtain phytomelatonin-rich plants, either by modifying their biosynthetic capacity or through selective agricultural techniques. Finally, the possible beneficial effects of the intake of phytomelatonin and other plant indolic compounds in the diet are discussed.
This study reports the effects of two different illumination conditions during germination (12 h light/12 h dark vs 24 h dark) in lentils (Lens culinaris L.) and kidney beans (Phaseolus vulgaris L.) on the content of melatonin and phenolic compounds, as well as the antioxidant activity. Germination led to relative increase in melatonin content and significant antioxidant activity, while the content of phenolic compounds decreased. The highest melatonin content was obtained after 6 days of germination under 24 h dark for both legumes. These germinated legume seeds with improved levels of melatonin might play a protective role against free radicals. Thus, considering the potent antioxidant activity of melatonin, these sprouts can be consumed as