Harbingers of Hope: Scientists and the Pursuit of World Peace.

The ongoing wars in many regions-such as the conflict between Israel and Hamas-as well as the effects of war on communities, social services, and mental health are covered in this special editorial. This article emphasizes the need for international efforts to promote peace, offer humanitarian aid, and address the mental health challenges faced by individuals and communities affected by war and violence.

Possible Application of Melatonin in Long COVID.

Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, "long COVID". Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or "brain fog"), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration ("brain fog") and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.

Melatonin's Benefits and Risks as a Therapy for Sleep Disturbances in the Elderly: Current Insights.

Aging is accompanied by circadian changes, including disruptive alterations in the sleep/wake cycle, as well as the beginning of low-degree inflammation ("inflammaging"), a scenario that leads to several chronic illnesses, including cancer, and metabolic, cardiovascular, and neurological dysfunctions. As a result, any effective approach to healthy aging must consider both the correction of circadian disturbance and the control of low-grade inflammation. One of the most important prerequisites for healthy aging is the preservation of robust circadian rhythmicity (particularly of the sleep/wake cycle). Sleep disturbance disrupts various activities in the central nervous system, including waste molecule elimination. Melatonin is a chemical with extraordinary phylogenetic conservation found in all known aerobic creatures whose alteration plays an important role in sleep changes with aging. Every day, the late afternoon/nocturnal surge in pineal melatonin helps to synchronize both the central circadian pacemaker found in the hypothalamic suprachiasmatic nuclei (SCN) and a plethora of peripheral cellular circadian clocks. Melatonin is an example of an endogenous chronobiotic substance that can influence the timing and amplitude of circadian rhythms. Moreover, melatonin is also an excellent anti-inflammatory agent, buffering free radicals, down-regulating proinflammatory cytokines, and reducing insulin resistance, among other things. We present both scientific and clinical evidence that melatonin is a safe drug for treating sleep disturbances in the elderly.

Corrigendum: Potential genetic overlap between insomnia and sleep symptoms in major depressive disorder: A polygenic risk score analysis.

[This corrects the article DOI: 10.3389/fpsyt.2021.734077.].

Melatonin use during pregnancy and lactation: A scoping review of human studies

Objective: The prevalence of sleep disorders during the perinatal period is high and large health administrative database surveys have shown that the use of exogenous melatonin in pregnant populations is quite common, about 4%. Much of the concern about using melatonin during pregnancy and breastfeeding stems from animal research. Thus, the objective of this article is to provide a critical review of human studies related to exogenous melatonin use during pregnancy and breastfeeding. Methods: The electronic databases Ovid, MEDLINE, Embase, and the Cochrane Library were searched using terms and keywords related to melatonin, pregnancy, and breastfeeding. Results: Fifteen studies were included in this review. Eight focused on melatonin use during pregnancy and seven focused on melatonin use during breastfeeding. There was a variety of study designs, including case reports, cohort studies, and clinical trials. There is a lack of randomized, controlled trials examining the efficacy and safety of melatonin as a treatment for sleep disorders during pregnancy or breastfeeding and, notably, insomnia was not the primary outcome measure in any of the studies included in this review. Clinical trials that used exogenous melatonin during pregnancy and breastfeeding for other clinical conditions have not suggested major safety concerns or adverse events. Conclusion: Contrary to what animal studies have suggested, evidence from clinical studies to date suggests that melatonin use during pregnancy and breastfeeding is probably safe in humans. This review further emphasizes the need for clinical studies on sleep disorders, including exogenous melatonin, during pregnancy and lactation.

Dysregulated light/dark cycle impairs sleep and delays the recovery of patients in intensive care units: A call for action for COVID-19 treatment.

Exposure to an adequate light-dark cycle is important for the speedy recovery of hospitalized and institutionalized patients. Light exposure, including natural light, offers several health benefits to both patients and nursing staff. This includes physical (e.g., decreased confusion and disorientation) and mental health benefits (e.g., prevention of depression) and a reduction in the hospital stay. Improved alertness and performance can also be noted among hospital staff. In this commentary, we discuss disrupting factors that include light during the nighttime along with noise and physical procedures on the patient and others. We then address some of the important steps that can be undertaken to restore a more normal environment for patients in the intensive care unit, which can be particularly important for COVID-19 patients.

Timing is everything: Circadian rhythms and their role in the control of sleep.

Sleep and the circadian clock are intertwined and have persisted throughout history. The suprachiasmatic nucleus (SCN) orchestrates sleep by controlling circadian (Process C) and homeostatic (Process S) activities. As a "hand" on the endogenous circadian clock, melatonin is critical for sleep regulation. Light serves as a cue for sleep/wake control by activating retino-recipient cells in the SCN and subsequently suppressing melatonin. Clock genes are the molecular timekeepers that keep the 24 h cycle in place. Two main sleep and behavioural disorder diagnostic manuals have now officially recognised the importance of these processes for human health and well-being. The body's ability to respond to daily demands with the least amount of effort is maximised by carefully timing and integrating all components of sleep and waking. In the brain, the organization of timing is essential for optimal brain physiology.

Mitochondria's role in sleep: Novel insights from sleep deprivation and restriction studies.

OBJECTIVES/METHODS: The biology underlying sleep is not yet fully elucidated, but it is known to be complex and largely influenced by circadian rhythms. Compelling evidence supports of a link among circadian rhythms, sleep and metabolism, which suggests a role for mitochondria. These organelles play a significant role in energy metabolism via oxidative phosphorylation (OXPHOS) and several mitochondrial enzymes display circadian oscillations. However, the interplay between mitochondria and sleep is not as well-known. This review summarises human and animal studies that have examined the role of mitochondria in sleep. Literature searches were conducted using PubMed and Google Scholar. RESULTS: Using various models of sleep deprivation, animal studies support the involvement of mitochondria in sleep via differential gene and protein expression patterns, OXPHOS enzyme activity, and morphology changes. Human studies are more limited but also show differences in OXPHOS enzyme activity and protein levels among individuals who have undergone sleep deprivation or suffer from different forms of insomnia. CONCLUSIONS: Taken altogether, both types of study provide evidence for mitochondria's involvement in the sleep-wake cycle. We briefly discuss the potential clinical implications of these studies.

Coadministration of Melatonin and Insulin Improves Diabetes-Induced Impairment of Rat Kidney Function.

INTRODUCTION: The present study was designed to evaluate the therapeutic efficacy of melatonin and insulin coadministration in diabetes-induced renal injury in rats. RESEARCH DESIGN AND METHODS: Diabetes was achieved by giving streptozotocin (15 mg/kg) for 6 consecutive days. The diabetic condition was confirmed by assessing the blood glucose level; animals having blood glucose levels above 250 mg were considered as diabetic. Following the confirmation, animals were randomly divided into different experimental groups, viz group I served as the control (CON), group II diabetic (D), group III D+melatonin (MEL), group IV D+insulin (INS), group V D+MEL+INS, group VI D+glibenclamide (GB), group VII CON+MEL, group VIII CON+INS, and group IX CON+GB. Following the completion of the experimental period, animals were sacrificed, blood was collected via a retro-orbital puncture, and kidneys were harvested. Diabetic rats exhibited a significant increment in blood glucose and biochemical indexes of renal injury (tubular disruption, swollen glomeruli with loss of glomerular spaces, and distortion of the endothelial lining) including augmented levels of serum creatinine, urea, uric acid, Na+, and K+, and inhibition/suppression of the activity of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and GSH-S-transferase in the renal cortex. RESULTS: By examining thiobarbiturate reactive substances, reduced GSH, superoxide dismutase activity, and catalase activity in the renal cortex of control and diabetic rats, it was documented that treatment with melatonin or insulin alone or in combination showed a significant ad integrum recovery of GSH-dependent antioxidative enzymatic activities. Melatonin and insulin coadministration caused greater reductions in circulating tumor necrosis factor-α, tumor growth factor-ß1, interleukin (IL)-1ß, and IL-6 levels in diabetic rats, whereas IL-10 levels increased, as compared to each treatment alone. Diabetic rats showed a significant increase in the expression of both MT1 and MT2 melatonin receptor genes. Melatonin or insulin treatment alone or in combination resulted in significant restoration of the relative expression of both melatonin receptors in the renal cortex. CONCLUSION: The coadministration of exogenous melatonin and insulin abolished many of the deleterious effects of type 1 diabetes on rat renal function.

Differential expression and interaction of melatonin and thyroid hormone receptors with estrogen receptor α improve ovarian functions in letrozole-induced rat polycystic ovary syndrome.

AIMS: The objective of the present study was to investigate the effect of melatonin and L-thyroxine (T4) on the expression of various receptors, and some metabolic, reproductive, and gonadotropic hormones in letrozole-induced polycystic ovary syndrome (PCOS) in rats. MATERIAL AND METHODS: Assessment of gravimetric, hormonal profile and thyroid histology and relative expression of melatonin receptors (MT1, MT2) and estrogen receptor α (Erα) in thyroid and ovary, and type II iodothyronine deiodinase (Dio2) and thyroid hormone receptor α (TRα) in the ovary were performed using standard protocols. KEY FINDINGS: A significant increase in thyroid follicles numbers was noted in the hyperthyroid rat. T4 treatment to PCOS showed the expected increment in the circulating level of triiodothyronine (T3) and T4. Melatonin and T4 treatment of PCOS rats resulted in a significant decrease in the circulating level of T3 and T4. Hyperthyroid rats showed a decrement in plasma melatonin levels. However, T4 treatment to PCOS rats showed increased circulating melatonin levels, and a decrease in the circulating level of gonadotropins (LH and FSH), and testosterone. Melatonin treatment to PCOS-hyperthyroid rats resulted in the normal expression of ovarian and thyroid MT1 and ERα, receptors, which had been altered in PCOS and hyperthyroid rats, without any significant change in the MT2 receptor. SIGNIFICANCE: The present findings suggest a fine interplay and cross-talk via melatonin and its two receptors with ERα, TRα, and Dio2in thyroid and ovarian tissue during PCOS and hyperthyroidism pathogenicity.

Melatonin use during pregnancy and lactation: A scoping review of human studies.

OBJECTIVE: The prevalence of sleep disorders during the perinatal period is high and large health administrative database surveys have shown that the use of exogenous melatonin in pregnant populations is quite common, about 4%. Much of the concern about using melatonin during pregnancy and breastfeeding stems from animal research. Thus, the objective of this article is to provide a critical review of human studies related to exogenous melatonin use during pregnancy and breastfeeding. METHODS: The electronic databases Ovid, MEDLINE, Embase, and the Cochrane Library were searched using terms and keywords related to melatonin, pregnancy, and breastfeeding. RESULTS: Fifteen studies were included in this review. Eight focused on melatonin use during pregnancy and seven focused on melatonin use during breastfeeding. There was a variety of study designs, including case reports, cohort studies, and clinical trials. There is a lack of randomized, controlled trials examining the efficacy and safety of melatonin as a treatment for sleep disorders during pregnancy or breastfeeding and, notably, insomnia was not the primary outcome measure in any of the studies included in this review. Clinical trials that used exogenous melatonin during pregnancy and breastfeeding for other clinical conditions have not suggested major safety concerns or adverse events. CONCLUSION: Contrary to what animal studies have suggested, evidence from clinical studies to date suggests that melatonin use during pregnancy and breastfeeding is probably safe in humans. This review further emphasizes the need for clinical studies on sleep disorders, including exogenous melatonin, during pregnancy and lactation.

Potential Genetic Overlap Between Insomnia and Sleep Symptoms in Major Depressive Disorder: A Polygenic Risk Score Analysis.

Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of insomnia, and other sleep traits in over 1 million individuals was recently published and provides many promising hits for genetics of insomnia in a population-based sample. Methods: Using data from the largest available GWAS of insomnia and other sleep traits, we sought to test if sleep variable PRS scores derived from population-based studies predicted sleep variables in samples of depressed cases [Psychiatric Genomics Consortium - Major Depressive Disorder subjects (PGC MDD)]. A leave-one-out analysis was performed to determine the effects that each individual study had on our results. Results: The only significant finding was for insomnia, where p-value threshold, p = 0.05 was associated with insomnia in our PGC MDD sample (R 2 = 1.75-3, p = 0.006). Conclusion: Our results reveal that <1% of variance is explained by the variants that cover the two significant p-value thresholds, which is in line with the fact that depression and insomnia are both polygenic disorders. To the best of our knowledge, this is the first study to investigate genetic overlap between the general population and a depression sample for insomnia, which has important treatment implications, such as leading to novel drug targets in future research efforts.

Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status.

This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-protein-coupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.

Chronotherapy.

The objective of chronotherapy is to optimize medical treatments taking into account the body's circadian rhythms. Chronotherapy is referred to and practiced in two different ways: (1) to alter the sleep-wake rhythms of patients to improve the sequels of several pathologies; (2) to take into account the circadian rhythms of patients to improve therapeutics. Even minor dysfunction of the biological clock can greatly affect sleep/wake physiology causing excessive diurnal somnolence, increase in sleep onset latency, phase delays or advances in sleep onset, frequent night awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep, or increased periodic leg movements. Chronotherapy aims to restore the proper circadian pattern of the sleep-wake cycle, through adequate sleep hygiene, timed light exposure, and the use of chronobiotic medications, such as melatonin, that affect the output phase of circadian rhythms, thus controlling the clock. Concerning the second use of chronotherapy, therapeutic outcomes as diverse as the survival after open-heart surgery or the efficacy and tolerance to chemotherapy vary according to the time of day. However, humans are heterogeneous concerning the timing of their internal clocks. Not only different chronotypes exist but also the endogenous human circadian period (τ) is not a stable trait as it depends on many internal and external factors. If any scheduled therapeutic intervention is going to be optimized, a tool is needed for simple diagnostic and objectively measurement of an individual's internal time at any given time. Methodologic advances like the use of single-sample gene expression and metabolomics are discussed.

Melatonin's neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders.

Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin's prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin's potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin's ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.

Autism Spectrum Disorder patients may be susceptible to COVID-19 disease due to deficiency in melatonin.

Patients with Autism Spectrum Disorder (ASD) may be particularly prone to develop COVID-19. An unusual extended course of COVID-19 disease illness has been reported in one ASD patient and a group of patients have COVID-19 disease in a neurodevelopmental facility. It has been widely reported that many of those with ASD have substantial sleep disorders with low levels of melatonin and various genetic alterations related to melatonin production have been found. Several lines of evidence point to a substantial role of melatonin in the body's innate defense system including acting as a scavenger, an antioxidant and modulating the immune system. We therefore hypothesize that melatonin deficiency may predispose those ASD patients who have low melatonin output to COVID-19 disease. Potential implications for treatment are discussed.

Can Melatonin Be a Potential "Silver Bullet" in Treating COVID-19 Patients?

The therapeutic potential of melatonin as a chronobiotic cytoprotective agent to counteract the consequences of COVID-19 infections has been advocated. Because of its wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound, melatonin could be unique in impairing the consequences of SARS-CoV-2 infection. Moreover, indirect evidence points out to a possible antiviral action of melatonin by interfering with SARS-CoV-2/angiotensin-converting enzyme 2 association. Melatonin is also an effective chronobiotic agent to reverse the circadian disruption of social isolation and to control delirium in severely affected patients. As a cytoprotector, melatonin serves to combat several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease. In view of evidence on the occurrence of neurological sequels in COVID-19-infected patients, another putative application of melatonin emerges based on its neuroprotective properties. Since melatonin is an effective means to control cognitive decay in minimal cognitive impairment, its therapeutic significance for the neurological sequels of SARS-CoV-2 infection should be considered. Finally, yet importantly, exogenous melatonin can be an adjuvant capable of augmenting the efficacy of anti-SARS-CoV-2 vaccines. We discuss in this review the experimental evidence suggesting that melatonin is a potential "silver bullet" in the COVID 19 pandemic.

Elderly as a High-risk Group during COVID-19 Pandemic: Effect of Circadian Misalignment, Sleep Dysregulation and Melatonin Administration.

The association of age with a higher vulnerability to COVID-19 infection is a subject of major importance. Several factors, including higher stress due to social isolation, diminished melatonin levels with age, and higher exposure of individuals to light at the evening, which reduces melatonin levels and disrupts circadian rhythmicity are relevant for maintaining the circadian health in aged individuals. Properly administered, chronotherapy restores the optimal circadian pattern of the sleep-wake cycle in the elderly. It involves adequate sleep hygiene, timed light exposure, and the use of a chronobiotic medication like melatonin, which affects the output phase of circadian rhythms thus controlling the biological clock. Besides, the therapeutic potential of melatonin as an agent to counteract the consequences of COVID-19 infections has been advocated due to its wide-ranging effects as an antioxidant, anti-inflammatory, and as an immunomodulatory agent, as well as to a possible antiviral action. This article discusses how chronotherapy may reverse the detrimental circadian condition of the elderly in the COVID-19 pandemic.

Clarifying the role of sleep in depression: A narrative review.

It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology. Thus, episodes of depression and mania or hypomania can arise as a consequence of the disruption of zeitgebers (time cues). In addition, the habit of sleeping at a time that is out of phase with the body's other biological rhythms is a common finding in depressed patients. In this review, we have covered a vast area, emerging from human and animal studies, which supports the link between sleep and depression. In doing so, this paper covers a broad range of distinct mechanisms that may underlie the link between sleep and depression. This review further highlights the mechanisms that may underlie such link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation), as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of pharmacotherapy, chronotherapy, comorbidity of obstructive sleep apnea and depression), are presented.

Understanding the role of sleep and its disturbances in Autism spectrum disorder.

BACKGROUND: Several studies have established a positive relationship between sleep difficulties and symptomatology in ASD children. The rationale for this review is to describe and discuss the sleep difficulties, which are one of the significant complications associated with autism spectrum disorder (ASD). PURPOSE: Many types of sleep disorders have been reported in ASD individuals, but still lack a comprehensive study and in-depth analysis. Despite the contribution of sleep problems to the overall symptoms of ASD, the symptoms of disturbed sleep experienced by many affected patients have only recently started to receive attention from clinicians and family members. MATERIALS AND METHODS: This narrative overview has been prepared based on searching standard research databases with specific keywords; b. Additional search was made using the bibliographies of the retrieved articles; and c. author's collection of relevant peer-reviewed articles. Once selected, manuscripts are then compared and summarized based on the author's perspective. Results are based on a qualitative rather than a quantitative level. RESULTS: This article highlights the role of sleep in the brain and neural development of children and emphasizes that the intensity of sleep problems is associated with an increased occurrence of ASD symptoms. It also suggests the significance of treating sleep problems in ASD individuals. CONCLUSIONS: The review provides broader perspectives and a better understanding of sleep problems in pathophysiology, mechanism, and management with respect to ASD individuals. Finally, the implications for clinical practice and future agendas have also been discussed.