This study presents a bibliometric analysis of the publications on melatonin research from the Scopus database during the period 2015-2019. Based on the keywords used, which are related to melatonin in the article title, the study retrieved 4411 documents for further analysis using various tools. We used Microsoft Excel to conduct the frequency analysis, VOSviewer for data visualization, and Harzing's Publish or Perish for citation metrics and analysis. This study reports the results using standard bibliometric indicators such as the growth of publications, authorship patterns, collaboration, and prolific authors, country contribution, most active institutions, preferred journals, and top-cited articles. Based on our findings, there is a continuous growth of publications on melatonin research for 5 years since 2015. China was the largest contributor to melatonin research, followed by the United States. The Journal of Pineal Research published the most number of publications related to melatonin research. Our findings suggest that the role of melatonin in plant and food sciences, as well as in cancer, may in later years take over the clusters that earlier dominated melatonin research.
Melatonin is a phylogenetically well-preserved molecule with diverse physiological functions. In addition to its well-known regulatory control of the sleep/wake cycle, as well as circadian rhythms generally, melatonin is involved in immunomodulation, hematopoiesis, and antioxidative processes. Recent human and animal studies have now shown that melatonin also has important oncostatic properties. Both at physiological and pharmacological doses melatonin exerts growth inhibitory effects on breast cancer cell lines. In hepatomas, through its activation of MT1 and MT2 receptors, melatonin inhibits linoleic acid uptake, thereby preventing the formation of the mitogenic metabolite 1,3-hydroxyoctadecadienoic acid. In animal model studies, melatonin has been shown to have preventative action against nitrosodiethylamine (NDEA)-induced liver cancer. Melatonin also inhibits the growth of prostate tumors via activation of MT1 receptors thereby inducing translocation of the androgen receptor to the cytoplasm and inhibition of the effect of endogenous androgens. There is abundant evidence indicating that melatonin is involved in preventing tumor initiation, promotion, and progression. The anticarcinogenic effect of melatonin on neoplastic cells relies on its antioxidant, immunostimulating, and apoptotic properties. Melatonin's oncostatic actions include the direct augmentation of natural killer (NK) cell activity, which increases immunosurveillance, as well as the stimulation of cytokine production, for example, of interleukin (IL)-2, IL-6, IL-12, and interferon (IFN)-gamma. In addition to its direct oncostatic action, melatonin protects hematopoietic precursors from the toxic effect of anticancer chemotherapeutic drugs. Melatonin secretion is impaired in patients suffering from breast cancer, endometrial cancer, or colorectal cancer. The increased incidence of breast cancer and colorectal cancer seen in nurses and other night shift workers suggests a possible link between diminished secretion of melatonin and increased exposure to light during nighttime. The physiological surge of melatonin at night is thus considered a "natural restraint" on tumor initiation, promotion, and progression.
Dome matrix was designed with gastric and intestinal targeting capacities using melatonin and caffeine as model drugs, and alginate, chitosan and cellulose as composite materials. The melatonin, caffeine and intermediate hydroxypropylmethylcelluose-based dispersible modules were prepared through compaction. Caffeine piled module was capped at both ends with melatonin void modules via intermediate dispersible modules into Dome matrix. Dispersion of intermediate module detached melatonin module from Dome matrix and had it floated in stomach providing a more complete melatonin release due to favorable pH-pKa relationship of dissolution medium and drug. With reference to the caffeine module, the detachment of melatonin module facilitated its gastrointestinal transit as a reduced size matrix, with majority of caffeine delivered in colon. The dual site-targeted and -release Dome matrix is applicable as reference oral carrier for pharmaceutical, nutraceutical, functional food and veterinary medicine where a complex formulation and performancein vivoare required.
Lung cancer is the second most common cancer and the most lethal cancer worldwide. Melatonin, an indoleamine produced in the pineal gland, shows anticancer effects on a variety of cancers, especially lung cancer. Herein, we clarify the pathophysiology of lung cancer, the association of circadian rhythm with lung, and the relationship between shift work and the incidence of lung cancer. Special focus is placed on the role of melatonin receptors in lung cancer, the relationship between inflammation and lung cancer, control of cell proliferation, apoptosis, autophagy, and immunomodulation in lung cancer by melatonin. A review of the drug synergy of melatonin with other anticancer drugs suggests its usefulness in combination therapy. In summary, the information compiled may serve as a comprehensive reference for the various mechanisms of action of melatonin against lung cancer, as a guide for the design of future experimental research and for advancing melatonin as a therapeutic agent for lung cancer.
Chrononutrition emerges as a novel approach to promote circadian alignment and metabolic health by means of time-of-the-day dietary intake. However, the relationship between maternal circadian rhythm and temporal dietary intake during pregnancy remains understudied. This study aimed to determine the change in melatonin levels in pregnant women across gestation and its association with temporal energy and macronutrient intake. This was a prospective cohort involving 70 healthy primigravidas. During the second and third trimesters, pregnant women provided salivary samples collected at 9:00, 15:00, 21:00, and 3:00 h over a 24 h day for melatonin assay. Data on chrononutrition characteristics were collected using a 3-day food record. Parameters derived from melatonin measurements including mean, amplitude, maximal level, area under the curve with respect to increase (AUCI), and area under the curve with respect to ground (AUCG) were computed. A rhythmic melatonin secretion over the day that remained stable across trimesters was observed among the pregnant women. There was no significant elevation in salivary melatonin levels as pregnancy advanced. In the second trimester, higher energy intake during 12:00-15:59 h and 19:00-06:59 h predicted a steeper melatonin AUCI (β=-0.32, p = 0.034) and higher AUCG (β = 0.26, p = 0.042), respectively. Macronutrient intake within 12:00-15:59 h was negatively associated with mean melatonin (Fat: β=-0.28, p = 0.041) and AUCG (Carbohydrate: β=-0.37, p = 0.003; Protein: β=-0.27, p = 0.036; Fat: β=-0.32, p = 0.014). As pregnant women progressed from the second to the third trimester, a flatter AUCI was associated with a reduced carbohydrate intake during 12:00-15:59 h (β=-0.40, p = 0.026). No significant association was detected during the third trimester. Our findings show that higher energy and macronutrient intakes particularly during 12:00-15:59 h and 19:00-06:59 h are associated with the disparities in maternal melatonin levels. Findings suggest the potential of time-based dietary approaches to entrain circadian rhythm in pregnant women.
The progressive loss of structure and functions of neurons, including neuronal death, is one of the main factors leading to poor quality of life. Promotion of functional recovery of neuron after injury is a great challenge in neuroregenerative studies. Melatonin, a hormone is secreted by pineal gland and has antioxidative, anti-inflammatory, and anti-apoptotic properties. Besides that, melatonin has high cell permeability and is able to cross the blood-brain barrier. Apart from that, there are no reported side effects associated with long-term usage of melatonin at both physiological and pharmacological doses. Thus, in this review article, we summarize the pharmacological effects of melatonin as neuroprotectant in central nervous system injury, ischemic-reperfusion injury, optic nerve injury, peripheral nerve injury, neurotmesis, axonotmesis, scar formation, cell degeneration, and apoptosis in rodent models.
A complex pathogenesis involving several physiological systems is theorized to underline the development of depressive disorders. Depression is accompanied by circadian regulation disruption and interaction with the functioning of both central and peripheral oscillators. Many aspects of melatonin function unite these systems. The use of drugs for circadian rhythm disorders could inspire a potential treatment strategy for depression. Melatonin plays an essential role in the regulation of circadian rhythms. It exerts effect by activating two types of melatonin receptors, type 1A (MT1) and 1B (MT2). These are G-protein-coupled receptors, predominantly located in the central nervous system. MT1/MT2 agonists could be a useful treatment approach according to all three prevalent theories of the pathogenesis of depression involving either monoamines, synaptic remodeling, or immune/inflammatory events. MT1/MT2 receptors can be a potential target for novel antidepressants with impact on concentrations of neurotrophins or neurotransmitters, and reducing levels of pro-inflammatory cytokines. There is an interesting cross-talk mediated via the physical association of melatonin and serotonin receptors into functional heteromers. The antidepressive and neurogenetic effects of MT1/MT2 agonists can also be caused by the inhibition of the acid sphingomyelinase, leading to reduced ceramide, or increasing monoamine oxidase A levels in the hippocampus. Compounds targeting MT1 and MT2 receptors could have potential for new anti-depressants that may improve the quality of therapeutic interventions in treating depression and relieving symptoms. In particular, a combined effect on MT1 and/or MT2 receptors and neurotransmitter systems may be useful, since the normalization of the circadian rhythm through the melatonergic system will probably contribute to improved treatment. In this review, we discuss melatonergic receptors as a potential additional target for novel drugs for depression.
Each year millions of travelers undertake long distance flights over one or more continents. These multiple time zone flights produce a constellation of symptoms known as jet lag. Familiar to almost every intercontinental traveler is the experience of fatigue upon arrival in a new time zone, but almost as problematic are a number of other jet lag symptoms. These include reduced alertness, nighttime insomnia, loss of appetite, depressed mood, poor psychomotor coordination and reduced cognitive skills, all symptoms which are closely affected by both the length and direction of travel. The most important jet lag symptoms are due to disruptions to the body's sleep/wake cycle. Clinical and pathophysiological studies also indicate that jet lag can exacerbate existing affective disorders. It has been suggested that dysregulation of melatonin secretion and occurrence of circadian rhythm disturbances may be the common links which underlie jet lag and affective disorders. Largely because of its regulatory effects on the circadian system, melatonin has proven to be highly effective for treating the range of symptoms that accompany transmeridian air travel. Additionally, it has been found to be of value in treating mood disorders like seasonal affective disorder. Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock. Melatonin resets disturbed circadian rhythms and promotes sleep in jet lag and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and shift-work disorder. Although post-flight melatonin administration works efficiently in transmeridian flights across less than 7-8 times zones, in the case longer distances, melatonin should be given by 2-3 days in advance to the flight. To deal with the unwanted side effects which usually accompany this pre-departure treatment (acute soporific and sedative effects in times that may not be wanted), the suppression of circadian rhythmicity by covering symmetrically the phase delay and the phase advance portions of the phase response curve for light, together with the administration of melatonin at local bedtime to resynchronize the circadian oscillator, have been proposed. The current view that sleep loss is a major cause of jet lag has focused interest on two recently developed pharmacological agents. Ramelteon and agomelatine are melatonin receptor agonists which, compared to melatonin itself, have a longer half-life and greater affinity for melatonin receptors and consequently are thought to hold promise for treating a variety of circadian disruptions.
BACKGROUND: The relationship between the activity of the epiphysis and gonads in rats of different sex and age in different seasons of the year was determined by studying the levels of melatonin and testosterone in the blood plasma. Determination of the levels of melatonin and testosterone in the serum of rats was carried out by enzyme-linked immunosorbent assay. To assess the relationship between the levels of melatonin and testosterone the correlation coefficient was calculated. Based on the study of the levels of melatonin and testosterone in serum the circannual relationship between the activity of the pineal gland and gonads in males of reproductive age has been determined. In females, the relationship between the levels of melatonin and testosterone without the circannual dependence has been determined. The strongest correlation between melatonin and testosterone is present in males at the age of 9 months in autumn, and it corresponds to the human age of 29-30 years.
This report documents an incidental finding during a study investigating the effects of melatonin supplementation on the development of blood pressure in SHR. Administration of 10 mg/kg/day of melatonin in drinking water during pregnancy to Wistar-Kyoto (WKY) dams caused a loss of more than 50% of the pups by the age of three weeks and 95% by the age of 6 weeks. There was no maternal morbidity or mortality in the two strains or death of any of the SHR pups. No obvious physical defects were present but mean body weight was lower in the surviving WKY rats when compared to that of melatonin supplemented SHR or non-supplemented WKY pups. The reason for the high mortality in WKY pups is uncertain and appears to be strain if not batch specific. There is a need for caution in its use, particularly during pregnancy, and clearly necessitates more detailed studies.
Pineal melatonin biosynthesis is regulated by the circadian clock located in the suprachiasmatic nucleus of the hypothalamus. Melatonin has been found to modulate the learning and memory process in human as well as in animals. Endogenous melatonin modulates the process of newly acquired information into long-term memory, while melatonin treatment has been found to reduce memory deficits in elderly people and in various animal models. However, the mechanisms mediating the enhancing effect of melatonin on memory remain elusive. This review intends to explore the possible mechanisms by looking at previous data on the effects of melatonin treatment on memory performance in rodents.
Matched MeSH terms: Melatonin/pharmacology*; Melatonin/therapeutic use
Workplace architectural lighting conditions that are biologically dim during the day are causing healthy individuals to experience light-induced health and performance-related problems. Dynamic lighting was reported beneficial in supporting individuals' psychological behavior and physiological responses during work period in Europe. It has yet to be investigated in workplaces with minimal/no natural daylight contribution in tropical Malaysia. Hence, an exploratory experimental study was initiated in an experimental windowless open-plan workplace in Universiti Putra Malaysia, Serdang. The aim was to identify dynamic lighting configurations that were more supportive of a morning boosting effect than the control constant lighting, to support dayshift individuals' psychophysiological wellbeing indicators during the peak morning work period. The immediate impact of a 2-hour morning exposure to overhead white LED (6500 K) with different horizontal illuminance levels and oscillations (lighting patterns) were investigated on physiological indicator limited to urinary 6-sulfatoxymelatonin, and psychological indicators for alertness, mood, visual comfort, cognitive and visual task performance. Not all of the investigated dynamic lighting configurations were supportive of a morning boost. Only configurations 500increased to750 and 500increased to1000 lx therapeutically supported most of the indicators. Both these configurations suppressed urinary 6-sulfatoxymelatonin, and improved alertness, cognitive performance, positive affect, and visual comfort better than 'visit 1: 500constant500' lx (control). The increasing oscillation was observed more beneficial for the morning boost in tropical Malaysia, which is in reverse to that specified in the human rhythmic dynamic lighting protocol developed by researchers from the Netherlands for application during winter. The findings from this study present the feasibility of dynamic architectural lighting acting as an environmental therapeutic solution in supporting the individuals' psychophysiological wellbeing indicators in windowless open-plan workplace in tropical Malaysia. Further investigations on the two prospective configurations are recommended to determine the better supportive one for the morning boosting effect in Malaysia.
Ambient light and temperature affect reproductive function by regulating kisspeptin and gonadotrophin-releasing hormone (GnRH) in vertebrates. Melatonin and melatonin receptors, as well as the two-pore domain K+ channel-related K+ (TREK) channels, are affected by light and/or temperature; therefore, these molecules could modulate kisspeptin and GnRH against ambient light and temperature. In this study, we investigated the effect of light and temperature, which affect melatonin levels in gene expression levels of TREK channels, kisspeptin, and GnRH. We first investigated the effects of different light and temperature conditions on brain melatonin concentrations by ELISA. Fish were exposed to either constant darkness, constant light, high temperature (35°C), or low temperature (20°C) for 72 h. Brain melatonin levels were significantly high under constant darkness and high temperature. We further investigated the effects of high brain melatonin levels by constant darkness and high temperature on gene expression levels of melatonin receptors (mt1, mt2, and mel1c), TREK channels (trek1b, trek2a, and trek2b), gnrh3, and kiss2 in the adult zebrafish brain by real-time polymerase chain reaction. Fish were exposed to constant darkness or elevated temperatures (35°C) for 72 h. trek2a, kiss2, and gnrh3 levels were increased under constant darkness. High temperature decreased gene expression levels of mt1, mt2, mel1c, and gnrh3 in the preoptic area, whereas other genes remained unchanged. Melatonin receptors, TREK channels, gnrh3, and kiss2 responded differently under high melatonin conditions. The melatonin receptors and the TREK channels could play roles in the regulation of reproduction by environmental cues, especially ambient light and temperature.
Malaria remains a global health problem affecting more than 515 million people all over the world including Malaysia. It is on the rise, even within unknown regions that previous to this were free of malaria. Although malaria eradication programs carried out by vector control programs are still effective, anti-malarial drugs are also used extensively for curtailing this disease. But resistance to the use of anti-malarial drugs is also increasing on a daily basis. With an increased understanding of mechanisms that cause growth, differentiation and development of malarial parasites in rodents and humans, new avenues of therapeutic approaches for controlling the growth, synchronization and development of malarial parasites are essential. Within this context, the recent discoveries related to IP3 interconnected signalling pathways, the release of Ca2+ from intracellular stores of Plasmodium, ubiquitin protease systems as a signalling pathway, and melatonin influencing the growth and differentiation of malarial parasites by its effects on these signalling pathways have opened new therapeutic avenues for arresting the growth and differentiation of malarial parasites. Indeed, the use of melatonin antagonist, luzindole, has inhibited the melatonin's effect on these signalling pathways and thereby has effectively reduced the growth and differentiation of malarial parasites. As Plasmodium has effective sensors which detect the nocturnal plasma melatonin concentrations, suppression of plasma melatonin levels with the use of bright light during the night or by anti-melatonergic drugs and by using anti-kinase drugs will help in eradicating malaria on a global level. A number of patients have been admitted with regards to the control and management of malarial growth. Patents related to the discovery of serpentine receptors on Plasmodium, essential for modulating intra parasitic melatonin levels, procedures for effective delivery of bright light to suppress plasma melatonin levels and thereby arresting the growth and elimination of malarial parasites from the blood of the host are all cited in the paper. The purpose of the paper is to highlight the importance of melatonin acting as a cue for Plasmodium faciparum growth and to discuss the ways of curbing the effects of melatonin on Plasmodium growth and for arresting its life cycle, as a method of eliminating the parasite from the host.
Melatonin is not only synthesized by the pineal gland but also in many other organs and tissues of the body, particularly by lymphoid organs such as the bone marrow, thymus and lymphocytes. Melatonin participates in various functions of the body, among which its immunomodulatory role has assumed considerable significance in recent years. Melatonin has been shown to be involved in the regulation of both cellular and humoral immunity. Melatonin not only stimulates the production of natural killer cells, monocytes and leukocytes, but also alters the balance of T helper (Th)-1 and Th-2 cells mainly towards Th-1 responses and increases the production of relevant cytokines such as interleukin (IL)-2, IL-6, IL-12 and interferon-gamma. The regulatory function of melatonin on immune mechanisms is seasonally dependent. This fact may in part account for the cyclic pattern of symptom expression shown by certain infectious diseases, which become more pronounced at particular times of the year. Moreover, melatonin-induced seasonal changes in immune function have also been implicated in the pathogenesis of seasonal affective disorder and rheumatoid arthritis. The clinical significance of the seasonally changing immunomodulatory role of melatonin is discussed in this review.
Profound disturbances in sleep architecture occur in major depressive disorders (MDD) and in bipolar affective disorders. Reduction in slow wave sleep, decreased latency of rapid eye movement (REM) sleep and abnormalities in the timing of REM/non-REM sleep cycles have all been documented in patients with MDD. It is thus evident that an understanding of the basic mechanisms of sleep regulation is essential for an analysis of the pathophysiology of depressive disorders. The suprachiasmatic nucleus (SCN), which functions as the body's master circadian clock, plays a major role in the regulation of the sleep/wakefulness rhythm and interacts actively with the homeostatic processes that regulate sleep. The control of melatonin secretion by the SCN, the occurrence of high concentrations of melatonin receptors in the SCN, and the suppression of electrical activity in the SCN by melatonin all underscore the major influence which this neurohormone has in regulating the sleep/wake cycle. The transition from wakefulness to high sleep propensity is associated with the nocturnal rise of endogenous melatonin secretion. Various lines of evidence show that depressed patients exhibit disturbances in both the amplitude and shape of the melatonin secretion rhythm and that melatonin can improve the quality of sleep in these patients. The choice of a suitable antidepressant that improves sleep quality is thus important while treating a depressive disorder. The novel antidepressant agomelatine, which combines the properties of a 5-HT(2C) antagonist and a melatonergic MT(1)/MT(2) receptor agonist, has been found very effective for resetting the disturbed sleep/wake cycle and in improving the clinical status of MDD. Agomelatine has also been found useful in treating sleep problems and improving the clinical status of patients suffering from seasonal affective disorder.
Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K+) channel-related K+ (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α2-adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α2-adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α2-adrenoceptor.
Although melatonin supplementation is known to influence numerous physiological functions, little is however known of its effects on pregnancy outcome. This study investigated the effects of melatonin supplementation on pregnancy outcome in Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats aged 12-13 weeks. Upon confirmation of proestrus, each female rat was housed overnight with a male of the same strain. On the next morning, following confirmation of mating (vaginal smear), WKY female rats were isolated into individual metabolic cages and given 0, 25, 50 or 100 mg/kg per day of melatonin in drinking water from day 1 of pregnancy to day 21 postpartum. SD females were given 0 or 100 mg/kg per day of melatonin. Maternal weight, duration of pregnancy, litter size, birth weight and body weight of pups up to day 42, and pup mortality were recorded. Data were analyzed using ANOVA for repeated measures. Compared to controls, maternal weight gain during pregnancy was significantly lower in melatonin-supplemented dams (P < 0.01). Litter size was significantly smaller in melatonin-supplemented dams (P < 0.01). Mean birth weight of pups was significantly lower only in pups of dams given 100 mg/kg per day of melatonin (P < 0.001). Mean body weight of pups of dams given melatonin was significantly lower than controls (P < 0.01). Pup mortalities were 9.5% and 21.6% in WKY dams given 25 and 100 mg/kg per day of melatonin respectively, and all pup deaths occurred after day 21 of weaning. The results suggest that melatonin supplementation during antenatal and postpartum period appears to adversely affect litter size, pup growth and mortality in WKY and SD rats. The precise mechanism causing the death is not clear.