Multiplatform-Integrated Identification of Melatonin Targets for a Triad of Psychosocial-Sleep/Circadian-Cardiometabolic Disorders.

Several psychosocial, sleep/circadian, and cardiometabolic disorders have intricately interconnected pathologies involving melatonin disruption. Therefore, we hypothesize that melatonin could be a therapeutic target for treating potential comorbid diseases associated with this triad of psychosocial-sleep/circadian-cardiometabolic disorders. We investigated melatonin's target prediction and tractability for this triad of disorders. The melatonin's target prediction for the proposed psychosocial-sleep/circadian-cardiometabolic disorder triad was investigated using databases from Europe PMC, ChEMBL, Open Targets Genetics, Phenodigm, and PheWAS. The association scores for melatonin receptors MT1 and MT2 with this disorder triad were explored for evidence of target-disease predictions. The potential of melatonin as a tractable target in managing the disorder triad was investigated using supervised machine learning to identify melatonin activities in cardiovascular, neuronal, and metabolic assays at the cell, tissue, and organism levels in a curated ChEMBL database. Target-disease visualization was done by graphs created using "igraph" library-based scripts and displayed using the Gephi ForceAtlas algorithm. The combined Europe PMC (data type: text mining), ChEMBL (data type: drugs), Open Targets Genetics Portal (data type: genetic associations), PhenoDigm (data type: animal models), and PheWAS (data type: genetic associations) databases yielded types and varying levels of evidence for melatonin-disease triad correlations. Of the investigated databases, 235 association scores of melatonin receptors with the targeted diseases were greater than 0.2; to classify the evidence per disease class: 37% listed psychosocial disorders, 9% sleep/circadian disorders, and 54% cardiometabolic disorders. Using supervised machine learning, 546 cardiovascular, neuronal, or metabolic experimental assays with predicted or measured melatonin activity scores were identified in the ChEMBL curated database. Of 248 registered trials, 144 phase I to IV trials for melatonin or agonists have been completed, of which 33.3% were for psychosocial disorders, 59.7% were for sleep/circadian disorders, and 6.9% were for cardiometabolic disorders. Melatonin's druggability was evidenced by evaluating target prediction and tractability for the triad of psychosocial-sleep/circadian-cardiometabolic disorders. While melatonin research and development in sleep/circadian and psychosocial disorders is more advanced, as evidenced by melatonin association scores, substantial evidence on melatonin discovery in cardiovascular and metabolic disorders supports continued R&D in cardiometabolic disorders, as evidenced by melatonin activity scores. A multiplatform analysis provided an integrative assessment of the target-disease investigations that may justify further translational research.

The role of sleep in telogen effluvium and trichodynia: A commentary in the context of the current pandemic.

Telogen effluvium (TE), a common hair disease, is supposed to be related to stress, which could be secondary to poor sleep. We call attention to the current COVID-19 pandemic, that is leading to an increase in the prevalence of sleep disturbances, and as a consequence, higher states of stress and anxiety, which are possible triggers for TE. In parallel, trichodynia is a sensorial symptom that is commonly related with hair diseases, including TE. We argue that substance P, a neuropeptide that has participation in the neuroinflammation and in the sleep regulation, may play a possible role in this scalp paresthesia. We suggest that there may be an association between this substrate and sleep, which can aggravate trichodynia and TE. Further studies on this subject could provide more evidence on these relationships, and help to improve the patients' quality of life and management of the condition.

Exposure to the cannabinoid agonist WIN 55, 212-2 in adolescent rats causes sleep alterations that persist until adulthood.

Cannabis and, to a lesser extent, synthetic cannabinoids are used during adolescence, a period in which multiple brain areas are still undergoing development. Among such areas is the hypothalamus, which is implicated in the control of sleep-wake cycle. In the present report, we show that exposing adolescent rats to the cannabinoid receptor agonist WIN 55, 212-2 (0.1, 0.3 or 1.0 mg/kg, i.p) for 14 days during adolescence (i.e., from post-natal day 30-44) resulted in significant sleep disturbances when the animals became adult (post-natal day 80). These included decreased wakefulness and enhanced rapid eye movement sleep. Furthermore, we found that labeling for NeuN, a marker of postmitotic neurons, was significantly increased the dorsomedial hypothalamic nucleus of rats treated with WIN 55, 212-2. The results suggest that excessive cannabinoid receptor activation during adolescence can persistently influence sleep patterns and neuronal activity later in life.

Influence of Dietary Sources of Melatonin on Sleep Quality: A Review.

Sleep is an essential biological phenomenon, being a physiological and behavioral process necessary for quality of life. Melatonin is a circadian hormone produced at night by the pineal gland, regulated by the light/dark cycle, under the control of the suprachiasmatic nucleus. Melatonin is an indoleamine, synthesized from the essential amino acid tryptophan via serotonin. Melatonin is also found in plants, where it helps fight oxidative stress. To present a systematic review on the ability of food sources of melatonin to promote healthy sleep. A literature search was performed on the PubMed, Scopus, and ScienceDirect databases, including only randomized, placebo-controlled trials published in English between 2005 and 2019. The methodological quality of the trials was assessed by the Jadad scale. Of the 25 eligible articles, eight met the inclusion criteria. They addressed the intake of milk or cherry juice in children, adults, and elderly subjects and evaluated sleep quality by questionnaires, sleep diary, actigraphy, or polysomnography. The analysis of the studies presented limitations, including lack of homogeneity of treatment dosage and duration. Nonetheless, the results indicated that the consumption of milk and sour cherries, sources of melatonin, may improve sleep quality in humans. These results pointed out to the potential suitability of food sources of melatonin as adjuvants in the prevention and treatment of sleep disorders. Further studies are necessary to better ascertain the aspects relevant to their use.

Chronic sleep restriction in the rotenone Parkinson's disease model in rats reveals peripheral early-phase biomarkers.

Parkinson's disease (PD) is a chronic disorder that presents a range of premotor signs, such as sleep disturbances and cognitive decline, which are key non-motor features of the disease. Increasing evidence of a possible association between sleep disruption and the neurodegenerative process suggests that sleep impairment could produce a detectable metabolic signature on the disease. In order to integrate neurocognitive and metabolic parameters, we performed untargeted and targeted metabolic profiling of the rotenone PD model in a chronic sleep restriction (SR) (6 h/day for 21 days) condition. We found that SR combined with PD altered several behavioural (reversal of locomotor activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters (branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to mitochondrial impairment). If combined, our results bring a plethora of parameters that represents reliable early-phase PD biomarkers which can easily be measured and could be translated to human studies.

Day/night melatonin content in cerebral palsy.

Changes in the sleep-wake cycle are frequent and may impair quality of life in individuals with cerebral palsy (CP). To investigate if a lack of a day/night variation of melatonin content could be related with sleep disorders (SD), the SD were evaluated with a Sleep Questionnaire and the melatonin content using ELISA in 33 individuals with CP and 24 controls. The indicative of SD were present in 47% of CP group, and the most frequent was the indicative of sleep breathing disorder. The CP group showed higher diurnal and lower nocturnal melatonin content than controls. Individuals with CP that had indicative of SD showed lower nocturnal content of melatonin than those without SD. These results showed that the lack of the day/night variation of melatonin was related to SD in individuals with CP.

Biological rhythms, metabolic syndrome and current depressive episode in a community sample.

The purpose of this study was to assess the disruption in biological rhythms and metabolic syndrome (MetS) in individuals with depressive episode. This was a cross-sectional, population-based study with a representative sample of 905 young adults. Current depressive episode were confirmed by a psychologist using the Mini International Neuropsychiatric Interview (MINI)-Plus. Self-reported biological rhythms were assessed using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). MetS was defined using modified NCEP/ATPIII criteria. Significant main effects of current depressive episode (p<0.001, η(2)=0.163) and MetS (p=0.001, η(2)=0.011) were observed on total BRIAN score. There was a significant interaction between depression and MetS in total biological rhythm scores (p=0.002, η(2)=0.011) as well as sleep (p=0.001, η(2)=0.016) and social domains (p<0.001, η(2)=0.014). In the depressive group, subjects with MetS had a higher disruption in total BRIAN scores (p=0.010), sleep domain (p=0.004), social domain (p=0.005) and in the eating pattern domain approached the level of significance (p=0.098), when compared to subjects with no MetS. The results of the present study showed that self-reported disruptions in biological rhythms are associated with key components of the MetS in community adults with MDD. The understanding of the complex interactions between biological rhythms, MetS and depression are important in the development of preventive and therapeutic strategies.

Translational research and symptom management in oncology nursing.

In recent years, translational research (TR) has become a new approach for bridging basic research and clinical practice. This article examines studies in which the authors used TR to learn more about the underlying causes of selected symptoms, and to discuss these results in the context of cancer nursing and symptom management. A literature review was undertaken, plus critical analysis of the authors. TR conducted by cancer nursing scholars has been relatively limited in the past, but is becoming more common as nurses complete additional academic work in the basic sciences and develop research teams with colleagues of those areas of knowledge. The goal in these studies is to show how a set of variables explains differential interventional effects. The availability of TR provides new evidence for the management of symptoms experienced by individuals with cancer, which could lead to improvements in the care of cancer patients across the world.

The influence of sleep restriction on expression of apoptosis regulatory proteins p53, Bcl-2 and Bax following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide.

PURPOSE: The aim of this study was to evaluate whether sleep restriction (SR) could affect the mechanisms and pathways' essentials for cancer cells in tongue cancer induced by 4-nitroquinoline 1-oxide in Wistar rats. METHODS: The animals were distributed into 4 groups of 5 animals each treated with 50 ppm 4 NQO solution through their drinking water for 4 and 12 weeks. The animals were submitted to sleep restriction for 21 days using the modified multiple platform method, which consisted of placing 5 rats in a cage (41 × 34 × 16 cm) containing 10 circular platforms (3.5 cm in diameter) with water 1 cm below the upper surface. The investigations were conducted using immunohistochemistry of p53, Bax and Bcl-2 proteins related to apoptosis and its pathways. RESULTS: Although no histopathologic abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure in all groups, in 12 weeks were observed pre-neoplastic lesions. Data analysis revealed statistically significant differences (P < 0.05) in 4 weeks group for p53, and for bcl-2. Following 12 weeks of 4NQO administration, we found significant differences between SR and control groups in p53, bax, and bcl-2 immunoexpression. CONCLUSION: Our results reveal that sleep restriction exerted alterations in proteins associated with proliferation and apoptosis in carcinogenesis.

Are sleep disturbances preclinical markers of Parkinson's disease?

Parkinson's disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfunction, pain, sleep disorders and cognitive impairment. Amongst these alterations, sleep disturbances play an important role in the pathology, but presence of disturbed sleep is not currently considered in diagnosis. However, sleeping problems may precede by many years the classic motor abnormalities of PD and should be clinically evaluated as a potential marker before disease onset. The first disturbance reported with this potential was the disorder REM sleep behaviour and currently several other disturbances have gained importance as potential markers, such as excessive daytime sleepiness, restless legs syndrome and new evidence also points to changes in circadian rhythms. Here we present a brief review of the major evidence indicating that sleep disturbances precede the motor symptoms in PD and neurodegeneration occurs in regions that could underlie these phenomena in order to provide support for the conclusion that disturbances of sleep should be considered as valuable preclinical markers for PD.

Fibromyalgia and sleep in animal models: a current overview and future directions.

Sleep disorders are highly prevalent in patients with fibromyalgia (FM). Many of the daytime symptoms, such as chronic pain and fatigue, may be related to the non-restorative sleep patterns associated with the disease. Pain influences the sleep process and sleep disturbances decrease the pain threshold in a reciprocal framework. Thus, understanding the link between sleep and FM has become an important research topic in basic science. Therefore, in the current review we connect these topics and provide some insights into the cyclic relationship between sleep and pain, which has been addressed mainly in animal models. Additionally, we highlight the urgent need for sleep studies in FM animal models, which might improve the knowledge base and accelerate advances in this field.

The association of testosterone, sleep, and sexual function in men and women.

Testosterone has been the focus of several investigations and review studies in males, but few have addressed its effects on sleep and sexual function, despite evidence of its androgenic effects on circadian activity in both sexes. Studies have been conducted to understand how sleeping increases (and how waking decreases) testosterone levels and how this rhythm can be related to sexual function. This review addresses the inter-relationships among testosterone, sexual function and sleep, including sleep-disordered breathing in both sexes, specifically its effects related to sleep deprivation. In addition, hormonal changes in testosterone that occur in the gonadal and adrenal axis with obstructive sleep apnea and other conditions of chronic sleep deprivation, and which consequently affect sexual life, have also been explored. Nevertheless, hormone-associated sleep disruptions occur across a lifetime, particularly in women. The association between endogenous testosterone and sex, sleep and sleep disturbances is discussed, including the results of clinical trials as well as animal model studies. Evidence of possible pathophysiological mechanisms underlying this relationship is also described. Unraveling the associations of sex steroid hormone concentrations with sleep and sexual function may have clinical implications, as sleep loss reduces testosterone levels in males, and low sex steroid hormone concentrations have been associated with sexual dysfunction.

Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis.

Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones.

Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis

Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones.

The reciprocal interaction between sleep and type 2 diabetes mellitus: facts and perspectives

Type 2 diabetes mellitus is a systemic disease characterized by intolerance to glucose and peripheral resistance to insulin. This endocrine disease affects fundamental mechanisms of the central nervous system and jeopardizes the balance of vital functions such as the cardiovascular and circadian rhythm. The increased prevalence of metabolic disorders in our society is aggravated by endemic voluntary postponement of bedtime and by the current sedentary lifestyle, leading to epidemic proportions of obese people. Diabetes and chronic loss of sleep share the fact that both affect millions and one is detrimental to the other. Indeed, sleep deficits have marked modulatory effects on glucose metabolism and insulin sensitivity and foster metabolic syndrome that culminates in sleep disorders like restless syndrome and sleep apnea, which in turn lead to poor sleep quality. We examine the hypothesis that these two worldwide emerging disorders are due to two interlinked cycles. In our paradigm, we establish an intimate relationship between diabetes and sleep disturbances and postulate possible mechanisms that provide support for this conjecture. In addition, we propose some perspectives about the development of the reciprocal interaction between predictor components of metabolic syndrome and sleep disturbances that lead to poor sleep quality. The ability to predict the development and identify or associate a given mode of sleep disturbance to diabetes would be a valuable asset in the assessment of both. Furthermore, major advances in care coupled with healthy lifestyles can ensure a higher quality of life for people with diabetes.

The reciprocal interaction between sleep and type 2 diabetes mellitus: facts and perspectives.

Type 2 diabetes mellitus is a systemic disease characterized by intolerance to glucose and peripheral resistance to insulin. This endocrine disease affects fundamental mechanisms of the central nervous system and jeopardizes the balance of vital functions such as the cardiovascular and circadian rhythm. The increased prevalence of metabolic disorders in our society is aggravated by endemic voluntary postponement of bedtime and by the current sedentary lifestyle, leading to epidemic proportions of obese people. Diabetes and chronic loss of sleep share the fact that both affect millions and one is detrimental to the other. Indeed, sleep deficits have marked modulatory effects on glucose metabolism and insulin sensitivity and foster metabolic syndrome that culminates in sleep disorders like restless syndrome and sleep apnea, which in turn lead to poor sleep quality. We examine the hypothesis that these two worldwide emerging disorders are due to two interlinked cycles. In our paradigm, we establish an intimate relationship between diabetes and sleep disturbances and postulate possible mechanisms that provide support for this conjecture. In addition, we propose some perspectives about the development of the reciprocal interaction between predictor components of metabolic syndrome and sleep disturbances that lead to poor sleep quality. The ability to predict the development and identify or associate a given mode of sleep disturbance to diabetes would be a valuable asset in the assessment of both. Furthermore, major advances in care coupled with healthy lifestyles can ensure a higher quality of life for people with diabetes.

Indomethacin reverts sleep disorders produced by ozone exposure in rats.

Ozone (O(3)) exposure causes pulmonary biochemical changes both in humans and experimental animals, inducing the release of inflammatory mediators such as cytokines and eicosanoids. Some of these reaction products have been characterized as endogenous sleep-promoting substances and have been implicated in the development of sleepiness in patients with inflammatory disease. Furthermore, sleep alterations are known to occur in O(3)-exposed humans and experimental animals. In order to test the probable involvement of such inflammatory mediators in O(3)-induced sleep disorders, we blocked prostaglandin synthesis administrating the cyclooxygenase inhibitor indomethacin (IM) and compared conventional electrographic sleep parameters in rats under four different experimental conditions: treatment with IM alone, O(3)-exposure, pre-treatment with IM plus O(3) exposure, and control conditions. We found that O(3) exposure increased slow wave sleep (SWS) and decreased rapid eye movement sleep (REMs) significantly, while IM pre-treatment reduced these O(3)-induced sleep disorders. IM treatment alone did not affect sleep. These findings strongly support a role for inflammatory mediators in O(3) exposure-induced neurological alterations.

Striatal dopaminergic stimulation produces c-Fos expression in the PPT and an increase in wakefulness.

Striatal activation can modify activity in cortical areas related to specific striatal functions possibly through a process of disinhibition within the basal ganglia. Anatomical studies have shown substantial GABAergic innervation from these nuclei to the pedunculopontine tegmental nucleus (PPT). Thus, dopaminergic stimulation of the striatum could produce PPT disinhibition and result in non-specific cortical activation. To test this hypothesis, d-amphetamine was infused both into the striatum of freely moving rats for motor and electrocorticographic recordings, and into the striatum of animals under deep anesthesia for c-Fos immunohistochemistry. The results show that intrastriatal amphetamine increases wakefulness independent of motor activity, and it increases c-Fos expression in the PPT and adjacent areas. They also suggest that the striatum participates in non-specific cortical activation probably as a result of its relationship with the PPT.