Melatonin is released by the pineal gland and exerts numerous physiological effects via specific G protein-coupled receptors named MT1 and MT2 receptors. It is well known that melatonin acts as a key regulator of circadian rhythm through the activation of these receptors on the central nervous system. However, the expression and function of melatonin receptors in the lower urinary tract remain unclear. This study aimed to investigate the expression and function of melatonin receptors in female urethra. mRNA expression analysis exhibited high expression of MT1 and MT2 receptor mRNA in human and rat female urethra. A study of isolated female rat urethral tissue strips using melatonin receptor agonists and an antagonist strongly revealed that stimulation of melatonin MT1 receptor induced urethral smooth muscle contraction. Further investigation of the mechanism underlying this melatonin MT1 receptor-related urethral contraction demonstrated that stimulation of MT1 receptors in urethra activates intracellular Ca2+ mobilization via Gq protein-dependent pathways, resulting in smooth muscle contraction. In vivo studies also revealed that melatonin receptor agonists induced an increase in urethral perfusion pressure in female rats. This is the first study to clearly demonstrate the expression and function of melatonin receptors in the urethra. These findings suggested that activation of MT1 receptors could be a potential pharmacological target for modulation of urethral function.

Melatonin is an endogenous chemical predominantly synthesized in the pineal gland, widely recognized for its hormonal roles, such as regulating sleep and circadian rhythms. Through mechanisms such as anti-oxidative reduction, anti-inflammatory, and immunomodulation, it is suggested that melatonin exhibits biochemical properties in in vitro conditions. Beyond these functions, melatonin has garnered attention for its pharmacological benefits, particularly as a therapeutic agent that is exogenously administered as a supplement in various diseases ranging from insomnia to immunological and gastrointestinal disorders. However, emerging studies highlight potential toxicological concerns associated with exogenous melatonin use, especially in specific populations. This review provided a comprehensive exploration of melatonin's dual role as a therapeutic and potentially toxic agent. It summarized what is currently known about its pharmacological, toxicological, and biochemical characteristics as well as toxicity mechanisms, and safety concerns in susceptible groups. By highlighting new knowledge gaps about melatonin's clinical uses, the study opens the door for further studies to maximize its therapeutic benefits while maintaining its safety.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among reproductive women, characterized by hyperandrogenism, oligo-ovulation and polycystic ovarian morphology. Incorporating complementary medicine alongside traditional lifestyle therapies for PCOS may offer additional benefits for affected women. Melatonin (MT), a hormone secreted by the pineal gland, has emerged as a potential treatment for regulating ovarian function in PCOS. However, the specific effects and underlying mechanisms of MT on PCOS need to be elucidated.

This review consolidates evidence from randomized controlled trials, original research articles, systematic reviews, and meta-analyses regarding MT supplementation in PCOS, with a particular focus on its interaction with the Hippo pathway, to provide a comprehensive overview of current knowledge.

Current evidence suggests that MT plays a role in modulating PCOS through various mechanisms and is associated with the Hippo pathway. However, several uncertainties and key limitations in the existing literature must be addressed before these treatments can be integrated into standard clinical practice.

Not applicable.

Aluminum oxide nanoparticles (Al2O3 NPs) are widely utilized in vaccine manufacturing and other medical preparations. Melatonin has numerous effects as an antioxidant and anti-apoptotic. The purpose of this study was to examine the beneficial impact of melatonin on Al2O3 NPs toxicity in the spinal cord. Forty male rats were divided into four groups: Group I, the negative controls (received standard diet and distilled water); Group II, Al2O3 NPs (received 30 mg/kg bw Al2O3 NPs); Group III, melatonin and Al2O3 NPs (received 30 mg/kg bw Al2O3 NPs + 10 mg/kg bw melatonin); Group IV, melatonin (received 10 mg/kg bw melatonin). All treatments were administered daily for 28 days by gastric gavage. After that, all rats were sacrificed, then, the samples from different spinal cords were subjected to histopathological, biochemical, and immunohistochemical analyses. Al2O3 NPs markedly elevated malondialdehyde and 8-hydroxydeoxyguanosine while inhibiting superoxide dismutase and catalase. Al2O3 NPs also induced histological alterations in both gray and white matter manifested by neuronal degeneration, vacuolation, axonal degeneration, ballooning, and fusion of myelin sheaths. Furthermore, immunohistochemical results displayed a strong positive expression of caspase-3. Conversely, melatonin significantly mitigated the effects of Al2O3 NPs by increasing the activities of antioxidant enzymes and inhibiting malondialdehyde and 8-hydroxydeoxyguanosine. Moreover, melatonin alleviated most histological alterations induced by Al2O3 NPs and reduced caspase-3 immunoreactivity. Collectively, melatonin could protect the spinal cord and mitigate Al2O3 NPs-induced neurotoxicity.

This study aims to assess the efficacy of melatonin in mitigating the adverse effects of hypobaric hypoxia on the cardiovascular system of neonatal lambs (30 days old). Two groups were considered for this purpose: (i) Melatonin-treated group (N = 5) and (ii) Control group (N = 6) without treatment. All subjects were exposed to hypobaric hypoxia during gestation and perinatal periods, with melatonin administered after birth. The study focused on the carotid artery, a known predictor of cardiovascular risk. Biomechanical tests, morphometric, and histological measurements were conducted, and a numerical model was developed based on the biomechanical data. Key findings showed remodeling effects: Firstly, a realignment of collagen fibers towards a longitudinal direction was observed with melatonin treatment, similar to non-hypoxic arteries. Second, changes in residual stress and ex-vivo luminal radius were noted, aiming to reduce wall stress and increase vascular resistance. These changes indicate an antihypertensive response, reducing the effects of increased blood pressure and flow due to hypobaric hypoxia. This study demonstrates that biomechanical and histomorphometric methodologies effectively assess the beneficial effects of melatonin treatment under hypobaric hypoxia exposure.

The aim of this investigation was to measure the natural nocturnal plasma melatonin concentration in gestating and fresh ewes. Studies in humans showed that maternal melatonin had a significant increase as pregnancy progressed and then decreased after birth. Two studies conducted in sheep so far, considering the entire gestation, have led to conflicting results. The breed of 16 pregnant ewes selected for the research was the Tsigai. Blood samples were taken into EDTA vacutainers predetermined times a night at different stages of their gestation. The RIA method was used to determine the melatonin concentrations. For estimation of its variations during gestation, population genetic statistics was applied. It was found that the average plasma melatonin concentration of 134 pg mL-1 is characteristic for the investigated period, and that it rises between the autumnal equinox and the winter solstice. Secondly, it was revealed that the average melatonin concentration adjusted for midnight is 162.4 pg mL-1, and its moderate variation is characteristic for the night. The investigation showed that there is no connection between the plasma melatonin concentration of the ewes and their gestational age in the Tsigai breed in Middle Europe. Our result is consistent with the results of single studies in sheep and donkey, in contrast to human observations. With regard to the nocturnal plasma melatonin, the concentration is reduced at the same level (30 pg mL-1) in ewes and lambs during the early postpartum period without nightly fluctuation. The expelled placenta, the constant vigilance between the mother and her lamb, and the opposition between melatonin and prolactin may provide a plausible explanation for this.

This review presents recent findings on the effect of melatonin on ram spermatozoa. This hormone regulates seasonal reproduction in the ovine species through the hypothalamic-pituitary-gonadal axis, but it also exerts direct effects on spermatogenesis, seminal quality and fertility. In the testis, melatonin stimulates blood flow to this organ, but it also appears to be involved in the differentiation of spermatogonial stem cells and the secretion of testosterone through the MT1 and MT2 receptors. In the epididymis, this hormone modulates sperm maturation and the secretory activity of epidydimal epithelial cells. In addition, the antioxidant activity of melatonin may protect spermatozoa from oxidative damage during their formation in the testis and their maturation in the epididymis. After ejaculation, the melatonin present in seminal plasma may also protect sperm from oxidative damage and premature capacitation and may improve seminal quality. Finally, once the sperm begins its transit through the female genital tract, melatonin may modulate sperm capacitation. Thus, melatonin could have a bimodal activity in ram sperm capacitation, so high concentrations, such as those in seminal plasma, have a decapacitating effect. In contrast, low concentrations, such as those present in the female reproductive tract, may promote it, likely through interaction with MT2 receptors. In addition, melatonin could also be involved in chemotaxis and fertilisation, although further studies are needed to elucidate the specific role of melatonin in these processes. Finally, the effect of latitude and melatonin receptor gene polymorphisms in ram reproduction is also discussed.

Photoperiod is the main environmental signal that affects animal behavior and reproduction. Light stimulus is traduced by a neural pathway that modulates pineal gland melatonin release, which synchronizes physiologic functions with day duration, highly influencing seasonal reproduction. The plains vizcacha (Lagostomus maximus) is a Hystricomorph rodent with seasonal reproduction that inhabits the Neotropic in South America. The aim of this work was to elucidate the effect of light/darkness exposition on the reproductive hypothalamic-pituitary-ovarian (HPO) axis in the female plains vizcacha. During 15 days, animals were subjected to different light/darkness regimens (Control group, CTL: 12:12 h dark:light; Darkness group, DARK: continuous darkness; Light group, LIGHT: continuous light). The melatoninergic system and reproductive hormones were evaluated. Plasma melatonin levels significantly decreased in DARK whereas both melatonin receptors (MT1 and MT2) expression significantly increased in the hypothalamus and decreased in the pituitary gland, and only MT1 expression increased in the ovaries. Continuous light did not induce significant variations in melatonin levels related to CTL, however, MTs expression changed at pituitary and ovary levels. Strikingly, both light/darkness regimens increased reproductive hormone expression. While darkness induced hypothalamic gonadotropin-releasing hormone (GnRH) expression and estradiol (E2) secretion, light increased LH and progesterone (P4) secretion. In conclusion, light availability may impact the reproductive axis of plains vizcacha inducing hormonal changes, with an organ-specific response, and sustaining HPO axis activity, thus ensuring reproduction. Environmental light and darkness, their availability and exposure length, could synchronize the reproductive axis in seasonal breeding species like the plains vizcacha. New & Noteworthy: Hypothalamic, pituitary, and ovarian variations were induced by continuous light or darkness in the plains vizcacha. Plasma melatonin decreased by continuous darkness-inducing hypothalamic, pituitary, and ovarian melatonin receptors variations. Fifteen days of continuous darkness induced GnRH, LH, and estradiol secretion, while 15 days of continuous light induced LH and P4 secretion. Environmental light/darkness would synchronize the reproductive axis in seasonal breeding species like the plains vizcacha.

Melatonin, renowned for regulating sleep-wake cycles, also exhibits notable anti-aging properties for the skin. Synthesized in the pineal gland and various tissues including the skin, melatonin's efficacy arises from its capacity to combat oxidative stress and shield the skin from ultraviolet (UV)-induced damage. Moreover, it curbs melanin production, thereby potentially ameliorating hyperpigmentation. The presence of melatonin receptors in diverse skin cell types and its documented ability to enhance skin tone, hydration, and texture upon topical administration underscores its promise as an anti-aging agent. Melatonin's protective effects likely emanate from its multifaceted characteristics, encompassing antioxidant, anti-inflammatory, and immunomodulatory functions, as well as its influence on collagen synthesis and mitochondrial activity. Chronic inflammation and oxidative stress initiate a detrimental feedback loop. Reactive oxygen species (ROS), notorious for damaging cellular structures, provoke immune responses by oxidizing vital molecules and activating signaling proteins. This triggers heightened expression of inflammatory genes, perpetuating the cycle. Such dysregulation significantly compromises the body's resilience against infections and other health adversities. This study embarks on an exploration of the fundamental signaling pathways implicated in skin aging. Furthermore, it delves into the therapeutic potential of melatonin and its anti-aging attributes within the realm of skin health.

Hair follicles, unique skin appendages, undergo cyclic phases (anagen, catagen, telogen) governed by melatonin and associated molecular pathways. Melatonin, synthesized in the pineal gland, skin, and gut, orchestrates these cycles through antioxidant activity and signaling cascades (e.g., Wnt, BMP). This review examines melatonin's biosynthesis across tissues, its regulation of cashmere growth patterns, and its interplay with non-coding RNAs and the gut-skin axis. Recent advances highlight melatonin's dual role in enhancing antioxidant capacity (via Keap1-Nrf2) and modulating gene expression (e.g., Wnt10b, CTNNB1) to promote hair follicle proliferation. By integrating multi-omics insights, we construct a molecular network of melatonin's regulatory mechanisms, offering strategies to improve cashmere yield and quality while advancing therapies for human alopecia.

Microglia, the brain's resident macrophages, are key mediators of neuroinflammation, responding to immune pathogens and toxins. They play a crucial role in clearing cellular debris, regulating synaptic plasticity, and phagocytosing amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Recent studies indicate that microglia not only exhibit intrinsic circadian rhythms but are also regulated by circadian clock genes, influencing specific functions such as phagocytosis and the modulation of neuroinflammation. Disruption of the circadian rhythm is closely associated with AD pathology. In this review, we will provide an overview of how circadian rhythms regulate microglia-mediated neuroinflammation in the progression of AD, focusing on the pathway from the central nervous system (CNS) and the peripheral immune system. We also discuss potential therapeutic targets, including hormone modulation, lifestyle interventions, and anti-inflammatory therapies, aimed at maintaining brain health in AD. This will shed light on the involvement of circadian rhythm in AD and explore new avenues for AD treatment.

Myocardial ischemia/reperfusion (MIR) injury, a primary cause of mortality in acute myocardial infarction, exhibits diurnal variation associated with disruptions in diurnal rhythm. Melatonin (MLT), a potent antioxidant known for its cardioprotective properties, also demonstrates diurnal rhythmicity. This study aimed to investigate the time-dependent cardioprotective effects of MLT in MIR and to clarify the role of the circadian gene Per2 in mediating these effects. Using in vivo (mice) and in vitro (H9c2 cardiomyocytes) models of MIR, we administered MLT at two distinct diurnal time points: ZT1 and ZT13. We evaluated infarct size, cardiac function, apoptosis, and the expression levels of Per2 and other circadian genes. Pretreatment with MLT at ZT13 significantly reduced infarct size and enhanced cardiac function compared to ZT1 administration. This time-dependent cardioprotective effect correlated with the diurnal expression pattern of Per2, which was notably augmented by dark phase administration of MLT without phase alteration. Crucially, Per2 knockdown in both models abrogated the cardioprotective effects of MLT. Our findings underscore that MLT confers superior cardioprotection against MIR injury when administered at dark phase, aligning with the circadian variation of Per2 expression. These effects reveal the therapeutic potential of targeting the MLT-Per2 axis in chronotherapy to mitigate MIR injury.

Melatonin released from the pineal gland plays an important role in maintaining the light/dark cycle. Melatonin exerts its effects on various organs through receptor and nonreceptor pathways. Recently, the role of melatonin in various metabolic disorders has been investigated. This review focuses on the molecular pathways associated with melatonin and its role in metabolic disorders. In humans, melatonin acts through two G protein-coupled receptors (MT1 and MT2). Melatonin modulates insulin release, such as elevated insulin levels in the evening compared to morning hours, exerts cardioprotective effects through the cGMP pathway and nitric oxide production in endothelial cells, and controls oxidative stress and apoptosis in myocardial tissue. Melatonin through MT2 receptors increases lipolysis and thermogenesis, which have a positive effect on weight reduction in obese individuals. Currently, most drugs that target melatonin receptors are primarily used to treat neurological disorders. A detailed investigation to explore the role of melatonin and its signalling pathway in peripheral organs is essential to develop therapeutic molecules for managing metabolic disorders.

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.

This narrative review explores the link between breast cancer and night shift work in nurses, focusing on genetic and epigenetic factors. Breast cancer disproportionately affects women globally, and night shift work is increasingly recognized as a potential risk factor. Nurses who work consecutive overnight shifts face elevated risks due to disruptions in their circadian rhythms. Studies suggest that working six or more successive night shifts, particularly over five years or more, may increase breast cancer risk. This review hypothesizes that disruptions in the sleep-wake cycle, such as changes in melatonin production and telomere length, could contribute to breast cancer susceptibility. Currently, there is limited genetic evidence to support this hypothesis. However, it is plausible that genetic and epigenetic alterations, including changes in genes like ER and HER2, may heighten the risk for night shift nurses. These alterations may involve variations in telomere length, DNA methylation, and disruptions in critical breast cancer-related genes. We highlight various genetic and epigenetic changes that may influence this increased susceptibility. Further research is needed to explore the underlying mechanisms and contributing factors in this association.

Persons with multiple sclerosis (PwMS) suffer from sleep disturbances, fatigue and pain, which can be due, at least in part, to decreased levels of endogenous melatonin. These alterations could exacerbate postural instability, gait disorders and fall risk. Acute effects of exogenous melatonin on physical disorders have been studied in PwMS but its long-term effects on these parameters have not been explored yet in this population. This study aimed to determine the impact of chronic melatonin intake on dynamic postural stability, walking performance and fall risk in PwMS.

This randomized placebo-controlled study included 27 PwMS who were assigned to either melatonin group (MG, n=15) or placebo group (PG, n=12) (3 mg/night for 12 weeks). Dynamic postural balance (force platform), walking performance (locometer) and fall risk (Four Square Step Test) were evaluated pre (T0)- and post (T1)-intervention. Sleep quality (Pittsburgh Sleep Quality Index (PSQI)), fatigue perception (Fatigue Severity Scale (FSS)), neuropathic pain (Neuropathic Pain Questionnaire 4 (DN4)) and quality of life (International Multiple Sclerosis (MS) Quality of Life Questionnaire) were also assessed at T0 and T1.

The center of pressure mean velocity decreased in MG compared with PG in the frontal plane (22.98 %, p=0.028). Stride length and walking speed increased in MG comparatively with PG (18.09 %, p=0.036; 9.65 %, p=0.025, respectively). The PSQI (55.89 %, p<0.001), FSS (32.38 %, p=0.003) and DN4 (32.41 %, p=0.035) scores decreased in MG compared with PG.

12-week melatonin supplementation can be recommended for managing MS-related gait disorders and dynamic postural imbalance. This therapy may also be prescribed for PwMS due to its anti-fatigue and analgesic effects as well as its benefits on sleep quality.

This study was prospectively recorded in the Pan African Clinical Trial Registry database (PACTR202007465309582) (https://pactr.samrc.ac.za/.).

Melatonin plays a crucial role in various behavioral and physiological aspects of animals, including regulating their circadian rhythms. This review provides a comprehensive evaluation of the multifaceted effects of melatonin on animal behavior, such as temperament, stress, and aggression regulation. The focus is on the complex interactions between melatonin and the hormonal and neurotransmitter systems, highlighting how melatonin interacts with cortisol, serotonin, and dopamine to influence behavior. Additionally, it investigates the effects of melatonin on the hypothalamic-pituitary-gonada (HPG) axis and stress responses, emphasizing its potential to improve stress management and social interactions, thereby enhancing animal welfare. The review also examines the seasonal variations of melatonin and its impact on aggression and reproductive activities related to photoperiods, as well as its effects on learning and memory to suggest improvements in animal training methods and practices. Furthermore, it discusses the influence of melatonin on appetite and physical activity regulation, implying its involvement in metabolic processes. In conclusion, further research is needed to elucidate the complex mechanisms underlying the extensive influence of melatonin on animal behavior. Through this review, the aim is to integrate the overall knowledge about melatonin and animal behavioral temperament and to propose new research areas for animal management based on behavioral and hormonal regulation.

Obstructive sleep apnea syndrome (OSAS) significantly affects the sleep-wake circadian rhythm through intermittent hypoxia and chronic sleep fragmentation. OSAS patients often experience excessive daytime sleepiness, frequent awakenings, and sleep fragmentation, leading to a disrupted circadian rhythm and altered sleep-wake cycle. These disruptions may exacerbate OSAS symptoms and contribute to neurodegenerative processes, particularly through the modulation of clock gene expression such as CLOCK, BMAL1, and PER. Emerging evidence connects OSAS to cognitive impairment and suggests that these changes may contribute to the development of neurodegenerative disorders such as Alzheimer disease, suggesting that OSAS could be a reversible risk factor for these conditions. Biomarkers, including melatonin and orexin, play crucial roles in understanding these mechanisms. In OSAS patients, melatonin, a marker of circadian rhythmicity, often shows altered secretion patterns that are not fully corrected by continuous positive airway pressure therapy. Orexin, which regulates the sleep-wake cycle, exhibits increased cerebrospinal fluid levels in OSAS patients, possibly due to compensatory mechanisms against sleep impairment and daytime sleepiness. These biomarkers highlight the intricate relationship between circadian rhythm disruptions and neurodegenerative risks in OSAS, emphasizing the need for further research and potential therapeutic strategies to mitigate these effects and improve patient outcomes.

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), primarily constituted of α-synuclein (α-Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α-Syn. However, the exact clearance mechanism and related molecular targets remain elusive.

BV2 cells, primary microglia from wild-type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α-Syn was induced using pre-formed fibrils (PFF) α-Syn. Co-immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real-time PCR were used to elucidate the mechanisms of molecular regulation.

In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α-Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α-Syn in neurons induced by pre-formed fibrils (PFF) α-Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway.

Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.

Iron is the dominant metal in the brain and is distributed widely. However, it can lead to various neuropathological and neurobehavioral abnormalities as well as oxidative stress. On the other hand, melatonin, a pineal hormone, is known for its neuroprotective properties, as well as its ability to act as a natural chelator against oxidative stress. It has also been used as an antidepressant and anxiolytic. The study investigated the potential of melatonin and EDTA treatment to prevent anxiety, depressive behavior, and memory impairment in male rats induced by chronic iron administration, and its connection to oxidative stress regulation in the hippocampus and prefrontal cortex. The rats were divided into six groups and intraperitoneally injected for 8 weeks with NaCl solution (control), iron sulfate (1 mg/kg), melatonin (4 mg/kg), EDTA (4 mg/kg), 1 mg/kg of iron + 4 mg/kg of melatonin, or 1 mg/kg of iron + 4 mg/kg of EDTA. In this study, we performed a neurobehavioral assessment and biochemical determinations of oxidative stress levels in the hippocampus and prefrontal cortex of each animal. The results indicate that chronic exposure to iron sulfate induced anxiety-like depressive behavior, and cognitive impairment also increased the levels of lipid peroxidation and nitric oxide, and reduced the activity of catalase in the hippocampus and prefrontal cortex in male Wistar rats, suggesting the induction of oxidative stress. In contrast, these alterations were reversed by melatonin better than EDTA. The results of this study show that melatonin protects against the neurobehavioral changes caused by iron, which may be associated with decreasing oxidative stress in the hippocampus and prefrontal cortex.

Circadian rhythms are self-sustaining oscillations within biological systems that play key roles in a diverse multitude of physiological processes. The circadian clock mechanisms in brain and peripheral tissues can oscillate independently or be synchronized/disrupted by external stimuli. Dental enamel is a type of mineralized tissue that forms the exterior surface of the tooth crown. Incremental Retzius lines are readily observable microstructures of mature tooth enamel that indicate the regulation of amelogenesis by circadian rhythms. Teeth enamel is formed by enamel-forming cells known as ameloblasts, which are regulated and orchestrated by the circadian clock during amelogenesis. This review will first examine the key roles of the circadian clock in regulating ameloblasts and amelogenesis. Several physiological processes are involved, including gene expression, cell morphology, metabolic changes, matrix deposition, ion transportation, and mineralization. Next, the potential detrimental effects of circadian rhythm disruption on enamel formation are discussed. Circadian rhythm disruption can directly lead to Enamel Hypoplasia, which might also be a potential causative mechanism of amelogenesis imperfecta. Finally, future research trajectory in this field is extrapolated. It is hoped that this review will inspire more intensive research efforts and provide relevant cues in formulating novel therapeutic strategies for preventing tooth enamel developmental abnormalities.

This paper provides a summary of the role of nitric oxide (NO) and hormones in the development of chronic stress, anxiety, depression, and post-traumatic stress disorder (PTSD). These mental health conditions are prevalent globally and involve complex molecular interactions. Although there is a significant amount of research and therapeutic options available, the underlying mechanisms of these disorders are still not fully understood. The primary pathophysiologic processes involved in chronic stress, anxiety, depression, and PTSD include dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the intracellular influence of neuronal nitric oxide synthase (nNOS) on transcription factors, an inflammatory response with the formation of nitrergic oxidative species, and reduced serotonergic transmission in the dorsal raphe nucleus. Despite the extensive literature on this topic, there is a great need for further research to clarify the complexities inherent in these pathways, with the primary aim of improving psychiatric care.

Asthma is a common chronic inflammatory disease affecting more than 260 million people worldwide. Nocturnal exacerbations of asthma symptoms significantly affect sleep quality and contribute to the most serious asthma exacerbations, which can lead to respiratory failure or death. Although β2-adrenoceptor agonists are the standard of care for asthma, their bronchodilatory effect for nocturnal asthma is limited, and medications that specifically target symptoms of nocturnal asthma are lacking.

Melatonin, which is secreted by the pineal gland, plays a crucial role in regulating circadian rhythms. Peak serum melatonin concentrations, which are inversely correlated with diurnal changes in pulmonary function, are higher in patients with nocturnal asthma than in healthy individuals. Melatonin potentiates bronchoconstriction through the melatonin MT2 receptor expressed in the smooth muscles of the airway and attenuates the bronchodilatory effects of β2-adrenoceptor agonists, thereby exacerbating asthma symptoms. Melatonin inhibits mucus secretion and airway inflammation, potentially ameliorating asthma symptoms.

Melatonin may exacerbate or ameliorate various pathophysiological conditions associated with asthma. As a potential therapeutic agent for asthma, the balance between its detrimental effects on airway smooth muscles and its beneficial effects on mucus production and inflammation remains unclear. Further studies are needed to elucidate whether melatonin worsens or improves asthma symptoms.

Most animals have large amounts of the special substance melatonin, which is controlled by the light/dark cycle in the suprachiasmatic nucleus. According to what is now understood, the gastrointestinal tract (GIT) and other areas of the body are sites of melatonin production. According to recent studies, the GIT and adjacent organs depend critically on a massive amount of melatonin. Not unexpectedly, melatonin's many biological properties, such as its antioxidant, anti-inflammatory, pro-apoptotic, anti-proliferative, anti-metastasis, and antiangiogenic properties, have drawn the attention of researchers more and more. Because melatonin is an antioxidant, it produces a lot of secretions in the GIT's mucus and saliva, which shields cells from damage and promotes the development of certain GIT-related disorders. Melatonin's ability to alter cellular behavior in the GIT and other associated organs, such as the liver and pancreas, is another way that it functions. This behavior alters the secretory and metabolic activities of these cells. In this review, we attempted to shed fresh light on the many roles that melatonin plays in the various regions of the gastrointestinal tract by focusing on its activities for the first time.

Melatonin is a pineal hormone that modulates the circadian system and exerts soporific and phase-shifting effects. It is also involved in many other physiological processes, such as those implicated in cardiovascular, endocrine, immune, and metabolic functions. However, the role of melatonin in glucose metabolism remains contradictory, and its action on human adipose tissue (AT) explants has not been demonstrated. We aimed to assess whether melatonin (a pharmacological dose) influences insulin sensitivity in human AT. This will help better understand melatonin administration's effect on glucose metabolism. Abdominal AT (subcutaneous and visceral) biopsies were obtained from 19 participants with severe obesity (age: 42.84 ± 12.48 years; body mass index: 43.14 ± 8.26 kg/m2) who underwent a laparoscopic gastric bypass. AT biopsies were exposed to four different treatments: control (C), insulin alone (I) (10 nM), melatonin alone (M) (5000 pg/mL), and insulin plus melatonin combined (I + M). All four conditions were repeated in both subcutaneous and visceral AT, and all were performed in the morning at 8 a.m. (n = 19) and the evening at 8 p.m. (in a subsample of n = 12). We used western blot analysis to determine insulin signaling (using the pAKT/tAKT ratio). Furthermore, RNAseq analyses were performed to better understand the metabolic pathways involved in the effect of melatonin on insulin signaling. As expected, insulin treatment (I) increased the pAKT/tAKT ratio compared with control (p < .0001). Furthermore, the addition of melatonin (I + M) resulted in a decrease in insulin signaling as compared with insulin alone (I); this effect was significant only during the evening time (not in the morning time). Further, RNAseq analyses in visceral AT during the evening condition (at 8 p.m.) showed that melatonin resulted in a prompt transcriptome response (around 1 h after melatonin addition), particularly by downregulating the insulin signaling pathway. Our results show that melatonin reduces insulin sensitivity in human AT during the evening. These results may partly explain the previous studies showing a decrease in glucose tolerance after oral melatonin administration in the evening or when eating late when endogenous melatonin is present.

Circadian rhythm (CR) disturbance is intricately associated with Parkinson's disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive.

A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function.

Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption.

CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.

Circadian clocks are evolved endogenous biological systems that communicate with environmental cues to optimize physiological processes, such as the sleep-wake cycle, which is nearly related to quality of life. Sleep disorders can be treated using pharmacological strategies targeting melatonin, orexin, or core clock genes. Exercise has been widely explored as a behavioral treatment because it challenges homeostasis in the human body and affects the regulation of core clock genes. Exercise intervention at the appropriate time of the day can induce a phase shift in internal clocks. Although exercise is a strong external time cue for resetting the circadian clock, exercise therapy for sleep disorders remains poorly understood.

This review focused on exercise as a potential treatment for sleep disorders by tuning the internal circadian clock. We used scientific paper depositories, including Google Scholar, PubMed, and the Cochrane Library, to identify previous studies that investigated the effects of exercise on circadian clocks and sleep disorders.

The exercise-induced adjustment of the circadian clock phase depended on exercise timing and individual chronotypes. Adjustment of circadian clocks through scheduled morning exercises can be appropriately prescribed for individuals with delayed sleep phase disorders. Individuals with advanced sleep phase disorders can synchronize their internal clocks with their living environment by performing evening exercises. Exercise-induced physiological responses are affected by age, sex, and current fitness conditions.

Personalized approaches are necessary when implementing exercise interventions for sleep disorders.

Our previous research has shown that melatonin (MLT) can reduce cryopreserved ovarian damage in mice. Yet, the molecular mechanism of MLT protection is still unclear. Some studies have shown that melatonin receptor 1 (MT1) is very important for animal reproductive system. To evaluate whether MLT exerts its protective effect on cryopreserved mice ovarian tissue via MT1, we added antagonist of MT1/MT2 (Luzindor) or antagonist of MT2 (4P-PDOT) to the freezing solution, followed by cryopreservation and thawing of ovarian tissue. The levels of total superoxide dismutase (T-SOD), catalase (CAT), nitric oxide (NO) and malondialdehyde (MDA) were detected. Besides, by using RT-PCR and Western blotting, the expression of Bcl-2, Bax and Nrf2/HO-1 signalling pathway-related proteins was detected. These findings demonstrated that compared with the melatonin group, the addition of Luzindor increased apoptosis, NO and MDA activities, decreased CAT and T-SOD activities and inhibited Nrf2/HO-1 signalling pathway. In conclusion, melatonin can play a protective role in cryopreserved ovarian tissue of mice through MT1 receptor.

Melatonin (5-methoxy-acetyl tryptamine) is a sleep-inducing hormone, and the pineal gland produces it in response to the circadian clock of darkness. In the body, MT1 and MT2 receptors are mostly found, having an orthosteric pocket and ligand binding determinants. Melatonin acts by binding on melatonin receptors, intracellular proteins, and orphan nuclear receptors. It inhibits adenyl cyclase and activates phospholipase C, resulting in gene expression and an intracellular alteration environment. Melatonin signaling pathways are also associated with other intracellular signaling pathways, i. e., cAMP/PKA and MAPK/ERK pathways. Relative expression of different proteins depends on the coupling profile of G protein, accounting pharmacology of the melatonin receptor bias system, and mediates action in a Gi-dependent manner. It shows antioxidant, antitumor, antiproliferative, and neuroprotective activity. Different types of melatonin agonists have been synthesized for the treatment of sleeping disorders. Researchers have developed therapeutics that target melatonin signaling, which could benefit a wide range of medical conditions. This review focuses on melatonin receptors, pharmacology, and signaling cascades; it aims to provide basic mechanical aspects of the receptor's pharmacology, melatonin's functions in cancer and neurodegenerative diseases, and any treatments and drugs designed for these diseases. This will allow a basic comparison between the receptors in question, highlighting any parallels and differences that may exist and providing fundamental knowledge about these receptors to future researchers.

Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.

Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.

The goal of the treatment for Alzheimer's dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.

Melatonin is a ubiquitous molecule found in living organisms, ranging from bacteria to plants and mammals. It possesses various properties, partly due to its robust antioxidant nature and partly owed to its specific interaction with melatonin receptors present in almost all tissues. Melatonin regulates different physiological functions and contributes to the homeostasis of the entire organism. In the human eye, a small amount of melatonin is also present, produced by cells in the anterior segment and the posterior pole, including the retina. In the eye, melatonin may provide antioxidant protection along with regulating physiological functions of ocular tissues, including intraocular pressure (IOP). Therefore, it is conceivable that the exogenous topical administration of sufficiently high amounts of melatonin to the eye could be beneficial in several instances: for the treatment of eye pathologies like glaucoma, due to the IOP-lowering and neuroprotection effects of melatonin; for the prevention of other dysfunctions, such as dry eye and refractive defects (cataract and myopia) mainly due to its antioxidant properties; for diabetic retinopathy due to its metabolic influence and neuroprotective effects; for macular degeneration due to the antioxidant and neuroprotective properties; and for uveitis, mostly owing to anti-inflammatory and immunomodulatory properties. This paper reviews the scientific evidence supporting the use of melatonin in different ocular districts. Moreover, it provides data suggesting that the topical administration of melatonin as eye drops is a real possibility, utilizing nanotechnological formulations that could improve its solubility and permeation through the eye. This way, its distribution and concentration in different ocular tissues may support its pleiotropic therapeutic effects.

Hepatic fibrosis, when left untreated, causes serious health problems that progress to cirrhosis and, in some cases, liver cancer. Activation of hepatic stellate cells may be a key characteristic in the development of hepatic fibrosis. Melatonin, a pineal hormone, exerts anti-fibrotic effects; however, the exact mechanisms remain unclear. In this study, the beneficial effects of melatonin against hepatic fibrosis and the underlying mechanisms were investigated using the human hepatic stellate cell line, LX-2, and in vivo murine animal models. The results showed that melatonin suppressed the expression of transforming growth factor (TGF)-β1-induced fibrosis markers and production of reactive oxygen species in LX-2 cells. Either 4-phenyl-2-propionamidotetralin, a melatonin receptor 2 selective antagonist, or melatonin receptor 2 small interfering RNA abolished the suppressive effects of melatonin, suggesting the involvement of melatonin receptor 2 in melatonin-induced anti-fibrotic and anti-oxidative actions. Melatonin increased the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), a positive circadian clock gene. BMAL1 knockdown reduced the anti-fibrotic and anti-oxidative effects of melatonin, demonstrating the protective effects of melatonin against TGF-β1-induced hepatic stellate cell activation by exhibiting melatonin receptor 2-BMAL1-anti-oxidative effects. In high-fat diet-induced and carbon tetrachloride-induced hepatic fibrosis models, oral melatonin administration decreased the expression of hepatic fibrosis markers and increased the expression of messenger RNA and levels of proteins of BMAL1 and melatonin receptor 2. Thus, melatonin exerted protective effects against hepatic fibrosis through melatonin receptor 2 activation, followed by an upregulation of the BMAL1-anti-oxidative enzyme pathways.

Alterations in circadian sleep patterns constitute a salient manifestation in major depressive disorder. GW117, an emergent antidepressant, functions as an agonist for melatonin 1 and melatonin 2 (MT1/MT2) receptors, in tandem with antagonism of the serotonin (5-HT) 2C receptor. The present investigation is dedicated to elucidating the role and underlying mechanisms by which GW117 ameliorates circadian sleep disruptions. Utilizing an adapted chronic unpredictable mild stress protocol, we induced a depressive-like phenotype and perturbed circadian rhythms in rodent models. Our methodological approach integrated quantitative polymerase chain reaction (qPCR) in real-time, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques to probe alterations in the expression of core circadian genes and homeostatic sleep markers. The impact of GW117 was assessed across various dosages (10, 20, and 40 mg/kg) on these molecular signatures. In a parallel examination, we evaluated the influence of GW117 (administered at 15, 40, and 60 mg/kg) on the sleep patterns of healthy mice. The results showed that GW117 significantly improved sleep-wake circadian rhythms, altered sleep architecture, and shortened sleep latency. Furthermore, GW117 increased the expression of several clock genes in the hypothalamus of chronic unpredictable mild stress model rats and normal mice. It also regulated circadian biomarkers, including melatonin and cortisol. Based on our findings, we propose that the beneficial effects of GW117 on sleep rhythms may be due to the melatonin system-mediated activation of the Wnt/β-catenin signaling pathway.

Endotoxins, products of Gram-negative bacteria, are the primary cause of blood-brain barrier (BBB) damage. In the present study, we aimed to investigate the possible neuroprotection mechanisms of melatonin on BBB damage induced by endotoxemia.

Adult, female Sprague-Dawley rats (n = 42) were separated into four random groups as a control group and three treatment groups. Lipopolysaccharide (7,5 mg/kg/day) was administrated for a single dose to generate a 24-hour sepsis model on rats. Melatonin (10 mg/kg/day) was treated a week before sepsis. Afterward, the dissected brain tissues were examined by histopathological, biochemical, and molecular analyses.

LPS caused weight loss in the groups. As a result, degenerated neurons with cytoplasmic vacuoles and irregular pyknotic nuclei, pale stained necrotic neurons, and vascular congestion were observed in LPS-exposed rats. However, MEL decreased the number of degenerated neurons in treated groups. MEL treatment increased ZO1 and Occludin immunoreactivity while decreasing TLR4 in brain tissues. MEL effect on protein expression was recorded for ZO1 increase and TLR4 decrease in brain tissue compared to LPS groups. MEL also decreased MDA levels in brain tissue.

MEL recovered the degenerative damage of sepsis by contributing to blood-brain barrier integrity, and by decreasing inflammation, thus the neuroprotective effects of MEL might provide an experimental basis for clinical applications.

Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.

Polycystic ovarian syndrome (PCOS) is a genetically complex disorder that involves the interplay of multiple genes and environmental factors. It is characterized by anovulation and irregular menses and is associated with type 2 diabetes. Neuroendocrine pathways and ovarian and adrenal dysfunctions are possibly implicated in the disorder pathogenesis. The melatonin system plays a role in PCOS. Melatonin receptors are expressed on the surface of ovarian granulosa cells, and variations in the melatonin receptor genes have been associated with increased risk of PCOS in both familial and sporadic cases. We have recently reported the association of variants in MTNR1A and MTNR1B genes with familial type 2 diabetes. In this study, we aimed to investigate whether MTNR1A and MTNR1B contribute to PCOS risk in peninsular families. In 212 Italian families phenotyped for PCOS, we amplified by microarray 14 variants in the MTNR1A gene and 6 variants in the MTNR1B gene and tested them for linkage and linkage disequilibrium with PCOS. We detected 4 variants in the MTNR1A gene and 2 variants in the MTNR1B gene significantly linked and/or in linkage disequilibrium with the risk of PCOS (P < 0.05). All variants are novel and have not been reported before with PCOS or any of its related phenotypes, except for 3 variants previously reported by us to confer risk for type 2 diabetes and 1 variant for type 2 diabetes-depression comorbidity. These findings implicate novel melatonin receptor genes' variants in the risk of PCOS with potential functional roles.

Atrazine (ATZ) is a widely used herbicide that has toxic effects on animals. Melatonin (MLT) is a natural hormone with strong antioxidant properties. However, the effect of MLT on the glucose metabolism disorder caused by ATZ is still unclear. Mice were divided into four groups randomly and given 21 days of gavage: blank control group (Con), 5 mg/kg MLT group (MLT), 170 mg/kg ATZ group (ATZ), and 170 mg/kg ATZ and 5 mg/kg MLT group (ATZ + MLT). The results show that ATZ alters mRNA levels of metabolic enzymes related to glycogen synthesis and glycolysis and increased metabolites (glycogen, lactate, and pyruvate). ATZ causes abnormalities in glucose metabolism in mouse liver, interfering with glycemia regulation ability. MLT can regulate the endoplasmic reticulum to respond to disordered glucose metabolism in mice liver. This study suggested that MLT has the power to alleviate the ATZ-induced glycogen overdeposition and glycolytic deficit.

Low levels of 6-sulfatoxymelatonin, the primary urinary metabolite of melatonin, have been linked to cancer and cardiometabolic outcomes in White and female populations.

We examined the association between adulthood adiposity and 6-sulfatoxymelatonin levels in a racially and ethnically diverse population. Our study included 4,078 men in the Multiethnic Cohort with adiposity measurements at enrollment (1993-1996) and biomarkers measured in urines collected in 1995 and 2005. Multivariable linear regression models were used to estimate the percent change in 6-sulfatoxymelatonin levels and 95% confidence intervals (CI). Associations were examined separately by racial/ethnic group.

The prevalence of obesity varied by race and ethnicity, from 10% for Japanese American men to 34% for Native Hawaiian men. Compared with men with normal body mass index (BMI), men who were overweight (-7.8%; 95% CI, -11.9 to -3.5%) and obese (-18.1%; 95% CI, -23.2 to -12.6%) had significantly lower 6-sulfatoxymelatonin levels adjusting for potential confounding factors. Increasing weight gain in adulthood was also associated with lower 6-sulfatoxymelatonin (Ptrend < 0.0001). The inverse associations for BMI and weight change were qualitatively similar across racial and ethnic groups.

Obesity is inversely associated with melatonin in a racially diverse population. This finding is relevant given higher rates of obesity among Black, Native Hawaiian, and Latino men, as well as potential racial and ethnic differences in circadian function.

Melatonin may be a relevant biomarker among obesity-associated malignancies and could shed light on a potential mechanism of cancer disparities.

Evidence suggests that the neuroprotective effects of melatonin involve both receptor-dependent and -independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post-KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression-like behaviors following KA-induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 μg/μL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA-induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA-induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA-induced hippocampal neuronal loss, memory impairment, and depression-like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon-mediated activation of melatonin receptors provides neuroprotection against KA-induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes.