Crosstalk Between Aging, Circadian Rhythm, and Melatonin.

Circadian rhythms (CRs) are 24-hour periodic oscillations governed by an endogenous circadian pacemaker located in the suprachiasmatic nucleus (SCN), which organizes the physiology and behavior of organisms. Circadian rhythm disruption (CRD) is also indicative of the aging process. In mammals, melatonin is primarily synthesized in the pineal gland and participates in a variety of multifaceted intracellular signaling networks and has been shown to synchronize CRs. Endogenous melatonin synthesis and its release tend to decrease progressively with advancing age. Older individuals experience frequent CR disruption, which hastens the process of aging. A profound understanding of the relationship between CRs and aging has the potential to improve existing treatments and facilitate development of novel chronotherapies that target age-related disorders. This review article aims to examine the circadian regulatory mechanisms in which melatonin plays a key role in signaling. We describe the basic architecture of the molecular circadian clock and its functional decline with age in detail. Furthermore, we discuss the role of melatonin in regulation of the circadian pacemaker and redox homeostasis during aging. Moreover, we also discuss the protective effect of exogenous melatonin supplementation in age-dependent CR disruption, which sheds light on this pleiotropic molecule and how it can be used as an effective chronotherapeutic medicine.

Exogenous Melatonin Enhances the Low Phosphorus Tolerance of Barley Roots of Different Genotypes.

Melatonin (N-acetyl-5-methoxytryptamine) plays an important role in plant growth and development, and in the response to various abiotic stresses. However, its role in the responses of barley to low phosphorus (LP) stress remains largely unknown. In the present study, we investigated the root phenotypes and metabolic patterns of LP-tolerant (GN121) and LP-sensitive (GN42) barley genotypes under normal P, LP, and LP with exogenous melatonin (30 µM) conditions. We found that melatonin improved barley tolerance to LP mainly by increasing root length. Untargeted metabolomic analysis showed that metabolites such as carboxylic acids and derivatives, fatty acyls, organooxygen compounds, benzene and substituted derivatives were involved in the LP stress response of barley roots, while melatonin mainly regulated indoles and derivatives, organooxygen compounds, and glycerophospholipids to alleviate LP stress. Interestingly, exogenous melatonin showed different metabolic patterns in different genotypes of barley in response to LP stress. In GN42, exogenous melatonin mainly promotes hormone-mediated root growth and increases antioxidant capacity to cope with LP damage, while in GN121, it mainly promotes the P remobilization to supplement phosphate in roots. Our study revealed the protective mechanisms of exogenous MT in alleviating LP stress of different genotypes of barley, which can be used in the production of phosphorus-deficient crops.

Role of Melatonin in Bovine Reproductive Biotechnology.

Melatonin has profound antioxidant activity and numerous functions in humans as well as in livestock and poultry. Additionally, melatonin plays an important role in regulating the biological rhythms of animals. Combining melatonin with scientific breeding management has considerable potential for optimizing animal physiological functions, but this idea still faces significant challenges. In this review, we summarized the beneficial effects of melatonin supplementation on physiology and reproductive processes in cattle, including granulosa cells, oocytes, circadian rhythm, stress, inflammation, testicular function, spermatogenesis, and semen cryopreservation. There is much emerging evidence that melatonin can profoundly affect cattle. In the future, we hope that melatonin can not only be applied to cattle, but can also be used to safely and effectively improve the efficiency of animal husbandry.

Emerging roles of brain tanycytes in regulating blood-hypothalamus barrier plasticity and energy homeostasis.

Seasonal changes in food intake and adiposity in many animal species are triggered by changes in the photoperiod. These latter changes are faithfully transduced into a biochemical signal by melatonin secreted by the pineal gland. Seasonal variations, encoded by melatonin, are integrated by third ventricular tanycytes of the mediobasal hypothalamus through the detection of the thyroid-stimulating hormone (TSH) released from the pars tuberalis. The mediobasal hypothalamus is a critical brain region that maintains energy homeostasis by acting as an interface between the neural networks of the central nervous system and the periphery to control metabolic functions, including ingestive behavior, energy homeostasis, and reproduction. Among the cells involved in the regulation of energy balance and the blood-hypothalamus barrier (BHB) plasticity are tanycytes. Increasing evidence suggests that anterior pituitary hormones, specifically TSH, traditionally considered to have unitary functions in targeting single endocrine sites, display actions on multiple somatic tissues and central neurons. Notably, modulation of tanycytic TSH receptors seems critical for BHB plasticity in relation to energy homeostasis, but this needs to be proven.

[Research progress in control strategies of biological clock disorder].

Circadian clock is an internal mechanism evolved to adapt to cyclic environmental changes, especially diurnal changes. Keeping the internal clock in synchronization with the external clock is essential for health. Mismatch of the clocks due to phase shift or disruption of molecular clocks may lead to circadian disorders, including abnormal sleep-wake cycles, as well as disrupted rhythms in hormone secretion, blood pressure, heart rate, body temperature, etc. Long-term circadian disorders are risk factors for various common critical diseases such as metabolic diseases, cardiovascular diseases, and tumor. To prevent or treat the circadian disorders, scientists have conducted extensive research on the function of circadian clocks and their roles in the development of diseases, and screened hundreds of thousands of compounds to find candidates to regulate circadian rhythms. In addition, melatonin, light therapy, exercise therapy, timing and composition of food also play a certain role in relieving associated symptoms. Here, we summarized the progress of both drug- and non-drug-based approaches to prevent and treat circadian clock disorders.

Research progress in control strategies of biological clock disorder / 生理学报

Circadian clock is an internal mechanism evolved to adapt to cyclic environmental changes, especially diurnal changes. Keeping the internal clock in synchronization with the external clock is essential for health. Mismatch of the clocks due to phase shift or disruption of molecular clocks may lead to circadian disorders, including abnormal sleep-wake cycles, as well as disrupted rhythms in hormone secretion, blood pressure, heart rate, body temperature, etc. Long-term circadian disorders are risk factors for various common critical diseases such as metabolic diseases, cardiovascular diseases, and tumor. To prevent or treat the circadian disorders, scientists have conducted extensive research on the function of circadian clocks and their roles in the development of diseases, and screened hundreds of thousands of compounds to find candidates to regulate circadian rhythms. In addition, melatonin, light therapy, exercise therapy, timing and composition of food also play a certain role in relieving associated symptoms. Here, we summarized the progress of both drug- and non-drug-based approaches to prevent and treat circadian clock disorders.

The Pathogenetic Role of Melatonin in Migraine and Its Theoretic Implications for Pharmacotherapy: A Brief Overview of the Research.

Migraine is a chronic disease of global concern, regardless of socio-economic and cultural background. It most often and intensely affects young adults, especially women. Numerous mechanisms of a migraine attack have been identified (disturbances in the reaction of vessels, functions of neurotransmitters, cortical neurons, ion channels, receptors, the process of neurogenic inflammation), and many of its symptoms can be explained by activation of the hypothalamus and disturbances in its communication with other brain regions (including the brainstem). Numerous neuropeptides and neurochemical systems also play a role in migraine. One of them is melatonin, a hormone that allows the body to adapt to cyclically changing environmental and food conditions. In this article, we present the pathophysiological basis of melatonin release from the pineal gland and other tissues (including the intestines) under the influence of various stimuli (including light and food), and its role in stimulating the brain structures responsible for triggering a migraine attack. We analyze publications concerning research on the role of melatonin in various headaches, in various stages of migraine, and in various phases of the menstrual cycle in women with migraine, and its impact on the occurrence and severity of migraine attacks. Melatonin as an internally secreted substance, but also present naturally in many foods. It is possible to supplement melatonin in the form of pharmaceutical preparations, and it seems, to be a good complementary therapy (due to the lack of significant side effects and pharmacological interactions) in the treatment of migraine, especially: in women of childbearing age, in people taking multiple medications for other diseases, as well as those sensitive to pharmacotherapy.

The Role of Melatonin in Chronic Kidney Disease and Its Associated Risk Factors: A New Tool in Our Arsenal?

BACKGROUND: The increasing incidence of chronic kidney disease (CKD), as a consequence of the high prevalence of arterial hypertension and type 2 diabetes mellitus (T2DM), warrants the need for developing effective treatment approaches. In this regard, the pineal gland-derived hormone melatonin may represent an appealing treatment approach of CKD and its associated risk factors. SUMMARY: Targeting the adverse pathophysiology surrounding CKD and its associated risk factors has been the concept of pharmacologic treatment developed for its management. This review article aimed to present the role of melatonin in this direction, by providing an overview of melatonin's physiology followed by its effect as a therapeutic agent in arterial hypertension and T2DM. KEY MESSAGES: Melatonin, the primary darkness hormone, possesses pleiotropic mechanisms of action which may have important implications in various pathologic states since its receptors are situated across various organ systems. As a treatment tool in arterial hypertension, melatonin may be efficacious in reducing both daytime and nocturnal blood pressure by influencing endothelial function, oxidative stress, the autonomic nervous system, and the renin-angiotensin system. Melatonin may also increase insulin sensitivity and ß-cell function. However, late meal intake may be detrimental in glucose regulation, as consumption close to melatonin peak concentrations may induce hyperglycemia and insulin resistance. This finding may explain the inconsistent glycose regulation achieved with melatonin in clinical trials and meta-analyses. Additionally, the presence of genetic variants to melatonin receptor 2 may predispose to T2DM development. Finally, we present the available preclinical evidence supporting melatonin's efficacy in ameliorating CKD's pathophysiology since melatonin supplementation has not been adequately explored in patients with CKD. The combined use of stem cells with melatonin is an appealing therapeutic approach which ought to be assessed further.

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.

The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

Plant-derived melatonin from food: a gift of nature.

In recent years, people have become increasingly interested in bioactive ingredients from plants, especially antioxidant molecules such as melatonin, which are beneficial to human health. The purpose of this article is to provide new information on plant-derived foods with a high content of melatonin. We comprehensively summarize the content of melatonin in plant-derived foods and discuss the factors that influence melatonin levels to provide new ideas on enhancement. Additionally, we describe the biosynthetic pathway of melatonin and identify its major functions. Medicinal herbs are often rich in melatonin while many vegetables and fruits exhibit somewhat lower levels with wide variations among species. The genetic traits of plants, the phenological stage of the cultivar, the photoperiod, the level of stress to which the plants are exposed at the time of harvest, exposure to agrochemicals and determination methods are the main factors affecting the melatonin content. To date, standardization of uniform sampling times and the use of suitable pretreatments as well as determination methods have not been achieved. The results of the studies reviewed highlight the potentially important role of plant melatonin in influencing the progression of human diseases. Based on the health promotional aspects of melatonin, consuming foods containing higher concentrations of tryptophan and melatonin is suggested.

Insight into the roles of melatonin in bone tissue and bone­related diseases (Review).

Bone­related diseases comprise a large group of common diseases, including fractures, osteoporosis and osteoarthritis (OA), which affect a large number of individuals, particularly the elderly. The progressive destruction and loss of alveolar bone caused by periodontitis is a specific type of bone loss, which has a high incidence and markedly reduces the quality of life of patients. With the existing methods of prevention and treatment, the incidence and mortality of bone­related diseases are still gradually increasing, creating a significant financial burden to societies worldwide. To prevent the occurrence of bone­related diseases, delay their progression or reverse the injuries they cause, new alternative or complementary treatments need to be developed. Melatonin exerts numerous physiological effects, including inducing anti­inflammatory and antioxidative functions, resetting circadian rhythms and promoting wound healing and tissue regeneration. Melatonin also participates in the health management of bone and cartilage. In the present review, the potential roles of melatonin in the pathogenesis and progression of bone injury, osteoporosis, OA and periodontitis are summarized. Furthermore, the high efficiency and diversity of the physiological regulatory effects of melatonin are highlighted and the potential benefits of the use of melatonin for the clinical prevention and treatment of bone­related diseases are discussed.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

The role of melatonin in Multiple Sclerosis.

Melatonin is a neurohormone mainly produced by the pineal gland following a circadian rhythm. It is characterized as a pleiotropic factor because it not only regulates the wake-sleep rhythm but also exerts antinociceptive, antidepressant, anxiolytic, and immunomodulating properties. Recent studies suggest that dysregulation of melatonin secretion is associated with the pathogenesis of various autoimmune diseases, such as, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). MS is an autoimmune disorder characterized by an abnormal immune response directed against the myelin sheath in the central nervous system, demyelination, oligodendrocyte death, and axonal degeneration. Recent evidence reveals that melatonin secretion is dysregulated in MS patients, suggesting that melatonin could be a potential target for therapeutic intervention. Here, we summarize the available literature regarding the role of melatonin in immune processes relevant for experimental autoimmune encephalomyelitis (EAE), MS, and the current clinical trials of melatonin supplementation in MS patients.

Biological Rhythms Advance in Depressive Disorder.

Most processes of human body, such as brain function, are regulated by biological rhythms. Disturbance of biological rhythms impairs mood, behavior, cognition, sleep, and social activity and may lead to mental disorders. Disturbed rhythms are widely observable in patients with major depressive disorders (MDD) and make risk of onset, comorbidity, response of antidepressants, recurrence, cognition, social function, and complications of physical health. Therefore, it is crucial to assess and manage focus on biological rhythms for patients with MDD. There are several validated ways of assessing the biological rhythms, including 24 h fluctuations in cortisol or melatonin, sleep monitoring, actigraphy, and self-report scales. Chronotherapy, such as cognitive-behavioral therapy, interpersonal and social rhythm therapy, sleep deprivation, and bright light therapy was widely reported for treatment in patients with MDD. Monoamine antidepressants and lithium are attributed to regulation of biological rhythm. And some rhythm-regulated agents have been shown efficacy of antidepressant. Considering the crucial clinical significance of disturbed biological rhythms in MDD, we describe the mechanisms, clinical features, measurements, and treatments of the biological rhythms in patients with MDD.

Melatonin Action on the Activity of Phagocytes from the Colostrum of Obese Women.

BACKGROUND AND OBJECTIVES: Breastfeeding promotion is an important public health strategy for counter-balancing the negative effects of maternal overweight and obesity. Colostrum contains melatonin, which can attenuate the impacts of excessive maternal weight and boost the infant's immune system. Therefore, the objective of this study was to analyze the effects of melatonin on mononuclear (MN) phagocytes from the colostrum of women with pre-gestational obesity. Materials and Methods: Colostrum samples were collected postpartum from 100 women at a public hospital in São Paulo, Brazil. The donors were divided into two groups: the control group and the high body mass index (BMI) group. Melatonin levels in the colostrum were determined by an ELISA Kit, and the functional activity of MN cells was assessed using the phagocytosis assay by flow cytometry, and reactive oxygen species (ROS), intracellular calcium, and apoptosis were assessed by fluorimetry using a microplate reader. RESULTS: The colostrum of mothers with pre-gestational high BMI exhibited higher melatonin levels (p < 0.05) and lower phagocytosis (p < 0.05) and ROS release (p < 0.05). Superoxide release was similar between the normal and high BMI groups (p > 0.05). Intracellular calcium release and apoptosis were also higher in the high BMI group (p < 0.05). Melatonin levels likely increased the phagocytosis rate and reduced intracellular calcium release and the apoptosis index (p < 0.05). CONCLUSIONS: The results suggest that melatonin is a possible mechanism for maternal-infant protection against obesity and restores the functional activity of colostrum phagocytes in obese mothers.

Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care.

Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.

Effect of melatonin on regulation of apoptosis and steroidogenesis in cultured buffalo granulosa cells.

This study was aimed to address melatonin receptor expression, mRNA level of hypothalamus and hypophysis hormone receptors (GnRHR, FSHR, and LHR), steroidogenesis, cell cycle, apoptosis, and their regulatory factors after addition of melatonin for 24 hr in cultured buffalo granulosa cells (GCs). The results revealed that direct addition of different concentrations of melatonin (100 pM, 1 nM, and 100 nM) resulted in significant upregulation (p < 0.05) of mRNA level of melatonin receptor 1a (MT1) without affecting melatonin receptor 1b (MT2). Melatonin treatment significantly downregulated (p < 0.05) mRNA level of FSH and GnRH receptors, whereas 100 nM dose of melatonin significantly increased mRNA level of LH receptor. Treatment with 100 nM of melatonin significantly decreased the basal progesterone production with significant decrease (p < 0.05) in mRNA levels of StAR and p450ssc, and lower mRNA level of genes (Insig1, Lipe, and Scrab1) that affect cholesterol availability. Melatonin supplementation suppressed apoptosis (100 nM, p < 0.05) and enhanced G2/M phase (1 nM, 100 nM, p < 0.05) of cell cycle progression which was further corroborated by decrease in protein expression of caspase-3, p21, and p27 and increase in bcl2. Our results demonstrate that melatonin regulates gonadotrophin receptors and ovarian steroidogenesis through MT1. Furthermore, the notion of its incorporation in apoptosis and proliferation of buffalo GCs extends its role in buffalo ovaries.

Integration of Melatonin Related Redox Homeostasis, Aging, and Circadian Rhythm.

Circadian rhythms (CRs) are intrinsic clocks organizing the behavior and physiology of organisms. These clocks are thought to have coevolved with cellular redox regulation. Metabolism, redox homeostasis, circadian clock, and diet offer insights into aging. Mitochondria play a pivotal role in redox homeostasis, CR, and aging. Melatonin is synthesized in mitochondria, is the key regulator of CRs, and shows substantial antioxidative effects. Melatonin levels tend to decrease significantly with advancing age. Recent reports showed that disruptions of CRs may render aging populations even more susceptible to age-related disorders. Recent and high-quality articles investigating CR, redox homeostasis, aging, and their relationship during aging process were included. Putting special emphasis on the possible effects of melatonin on redox homeostasis and mitochondrial dynamics, recent clinical evidence highlighting the importance of circadian mechanisms was utilized. A deeper understanding of the role of altered mitochondrial redox homeostasis in the pathogenesis of age-related disorders and its relationship with CR could offer novel therapeutic interventions. Chronotherapy, a therapeutic approach considering CR of organisms and best therapeutic times, could potentially reduce side effects and improve therapeutic efficiency. Redox homeostasis, energy metabolism, and CR are all intertwined.

Melatonin and their analogs as a potential use in the management of Neuropathic pain.

Melatonin (N-acetyl-5-methoxytryptamine), secreted by the pineal gland is known to perform multiple functions including, antioxidant, anti-hypertensive, anti-cancerous, immunomodulatory, sedative and tranquilizing functions. Melatonin is also known to be involved in the regulation of body mass index, control the gastrointestinal system and play an important role in cardioprotection, thermoregulation, and reproduction. Recently, several studies have reported the efficacy of Melatonin in treating various pain syndromes. The current paper reviews the studies on Melatonin and its analogs, particularly in Neuropathic pain. Here, we first briefly summarized research in preclinical studies showing the possible mechanisms through which Melatonin and its analogs induce analgesia in Neuropathic pain. Second, we reviewed research indicating the role of Melatonin in attenuating analgesic tolerance. Finally, we discussed the recent studies that reported novel Melatonin agonists, which were proven to be effective in treating Neuropathic pain.

Maternal photoperiodic programming enlightens the internal regulation of thyroid-hormone deiodinases in tanycytes.

Seasonal rhythms in physiology are widespread among mammals living in temperate zones. These rhythms rely on the external photoperiodic signal being entrained to the seasons, although they persist under constant conditions, revealing their endogenous origin. Internal long-term timing (circannual cycles) can be revealed in the laboratory as photoperiodic history-dependent responses, comprising the ability to respond differently to similar photoperiodic cues based on prior photoperiodic experience. In juveniles, history-dependence relies on the photoperiod transmitted by the mother to the fetus in utero, a phenomenon known as "maternal photoperiodic programming" (MPP). The response to photoperiod in mammals involves the nocturnal pineal hormone melatonin, which regulates a neuroendocrine network including thyrotrophin in the pars tuberalis and deiodinases in tanycytes, resulting in changes in thyroid hormone in the mediobasal hypothalamus. This review addresses MPP and discusses the latest findings on its impact on the thyrotrophin/deiodinase network. Finally, commonalities between MPP and other instances of endogenous seasonal timing are considered, and a unifying scheme is suggested in which timing arises from a long-term communication between the pars tuberalis and the hypothalamus and resultant spontaneous changes in local thyroid hormone status, independently of the pineal melatonin signal.