Melatonin Metabolism Research Articles

Are Melatonin and its Agonist the Natural Solution for Prevention of Delirium in Critically Ill Patients? A Review of Current Studies

Background: Delirium is a neuropsychiatric syndrome, which is a common complication at the intensive care unit (ICU). Delirium is a risk factor for increased duration of mechanical ventilation and increased time of stay at the ICU and death. Melatonin is a hormone produced and secreted by the pineal gland, that regulates circadian rhythm. The aim of this investigation was to demonstrate the effect of melatonin in controlling and improving delirium. Methods: Available data from Pubmed, Scopus, Medline, EMBASE, the Cochrane central register of controlled trials, and Cochrane database systematic reviews were reviewed. Results: Pathogenic pathways of delirium are unclear, yet many risk factors have been identified, including patient’s history, acute illness, environment, administered drugs, and neuronal pathway. Several studies have suggested that delirium could be caused by decreased tryptophan as a precursor to the neurotransmitters, including serotonin and melatonin. On the other hand, a few studies have described that abnormal melatonin metabolism could be one of the mechanisms of delirium. Conclusion: Exogenous melatonin could improve circadian rhythm and prevent delirium, therefore melatonin supplementation could be used for improvement or control of delirium at the ICU.

Plasma melatonin levels in hip fracture patients with and without delirium: A confirmation study

BackgroundMelatonin plays a major role in maintaining circadian rhythm. Changes in melatonin metabolism might lead to circadian rhythm disturbances which are often observed in delirious patients. AimTo assess if high morning plasma melatonin concentrations were associated with delirium. MethodsConsecutive hip fracture patients aged ≥65 years were included. Delirium was assessed daily with the Confusion Assessment MethodBlood samples were collected at 11.00am on weekdays during first week of hospitalization. Melatonin was analyzed by liquid chromatography-tandem mass spectrometry. ResultsWe analyzed 389 samples of 144 participants [mean age 84.0, 70 experienced delirium]. A Generalized Estimating Equations (GEE) model with outcome melatonin level in highest tertile ( >3.36 pg/ml) and covariates delirium group (i.e. never, before, during, post delirium), cognitive impairment, age, sex and anesthesia type, was constructed. Highest melatonin levels were associated with postoperative samples (Odds Ratio(OR) 2.11 compared to preoperative samples; 95% Confidence Interval(CI) 1.17–3.82, p=0.01) and higher age (OR 1.05 per year; CI 1.01–1.11, p=0.03), but not with delirium group(p=0.35). ConclusionUndergoing surgery and aging in general may induce changes in melatonin metabolism. Future research should focus on daily multiple melatonin measurements to determine whether melatonin supplementation might be beneficial for delirium treatment or prevention.

Melatonin, mitochondria, and the skin

The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin-mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.

Impact of temperature on sea bass, Dicentrarchus labrax, retina: Fatty acid composition, expression of rhodopsin and enzymes of lipid and melatonin metabolism

Teleost fish are ectothermic vertebrates. Their metabolism, physiology and behavior rely on the external temperature. This study, on the retina of the sea bass Dicentrarchus labrax, reports on the impact of temperature on the fatty acid composition and mRNA abundance of key enzymes of lipid metabolism: fatty acid desaturase-2 (FADS2), fatty acid elongase-5 (ELOVL5), sterol regulatory element-binding protein-1 (SREBP-1), triglyceride lipase and phospholipase A2 (PLA2). We also report on the effects on the photopigment molecule rhodopsin and on enzymes of the melatonin synthesis pathway, namely arylalkylamine N-acetyltransferases 1a and 1b and acetylserotonin methyltransferase. Juvenile fish were placed for 30 days at 18, 23 or 28 °C. At 23 °C, the fatty acid composition of D. labrax retina showed, as generally reported for the retina of other fish species, particularly high amounts of docosahexaenoic (DHA), palmitic and oleic acids. The fatty acids composition was not significantly (P > 0.05) altered between 23 and 28 °C, but did increase at 18 °C compared to 23 and 28 °C. At 18 °C there were noticeable increases in total DHA, ecosapentaenoic, arachidonic, oleic, linoleic, palmitoleic and stearic acids. A negative correlation was found in the abundance of neutral (NL) vs. polar (PL) lipids: 18 °C induced an increase in NL and a decrease in PL, while 28 °C induced higher PL with decreased NL. In NL the changes affected mainly triglycerides. FADS2 and ELOVL5 mRNA abundance decreased from 18° to 28 °C while SREBP-1 and triglyceride lipase mRNA remained stable. Conversely PLA2 mRNA was more abundant at 23 than at 18 and 28 °C. Temperature increased and decreased rhodopsin mRNA abundance, at 28 °C and 18 °C respectively, while there was no effect on mRNA from the melatonin synthesis enzymes. In conclusion the data indicate a temperature induced redistribution of fatty acids among the lipid classes that might affect the physical properties of the plasma membranes as well as functions associated with photoreception or generation of intracellular second messengers. In addition, the results suggest that temperature targets only the proteins and activities of retinal melatonin production. This study opens new lines of investigation related to the role temperature and fatty acids play in fish visual perception. They are relevant in the context of the global warming of seas affecting both the wild and the aquaculture species.

Metabolism of melatonin in the skin: Why is it important?

Melatonin is produced in almost all living taxa and is probably 2-3billion years old. Its pleiotropic activities are related to its local concentration that is secondary to its local synthesis, delivery from distant sites and metabolic or non-enzymatic consumption. This consumption generates metabolites through indolic, kynuric and cytochrome P450 (CYP) mediated hydroxylations and O-demethylation or non-enzymatic processes, with potentially diverse phenotypic effects. While melatonin acts through receptor-dependent and receptor-independent mechanisms, receptors for melatonin metabolites remain to be identified, while their receptor-independent activities are well documented. The human skin with its main cellular components including malignant cells can both produce and rapidly metabolize melatonin in cell-type and context-dependent fashion. The predominant metabolism in human skin occurs through indolic, CYP-mediated and kynuric pathways with main metabolites represented by 6-hydroxymelatonin, N1 -acetyl-N2 -formyl-5-methoxykynuramine (AFMK), N1 -acetyl-5-methoxykynuramine (AMK), 5-methoxytryptamine, 5-methoxytryptophol and 2-hydroxymelatonin. AFMK, 6-hydroxymelatonin, 2-hydroxymelatonin and probably 4-hydroxymelatonin can potentially be produced in epidermis through UVB-induced non-enzymatic melatonin transformation. The skin metabolites are also the same as those produced in lower organisms and plants indicating phylogenetic conservation across diverse species and adaptation by skin of the primordial defense mechanism. As melatonin and its metabolites counteract or buffer environmental stresses to maintain its homeostasis through broad-spectrum activities, both melatoninergic and degradative pathways must be precisely regulated, because the nature of phenotypic regulations will depend on local concentration of melatonin and its metabolites. These can be receptor-mediated or represent non-receptor regulatory mechanisms.

Potential role of CYP1B1 in the development and treatment of metabolic diseases.

Cytochrome P450 1B1 (CYP1B1), a member of CYP superfamily, is expressed in liver and extrahepatic tissues carries out the metabolism of numerous xenobiotics, including metabolic activation of polycyclic aromatic hydrocarbons. Surprisingly, CYP1B1 was also shown to be important in regulating endogenous metabolic pathways, including the metabolism of steroid hormones, fatty acids, melatonin, and vitamins. CYP1B1 and nuclear receptors including peroxisome proliferator-activated receptors (PPARs), estrogen receptor (ER), and retinoic acid receptors (RAR) contribute to the maintenance of the homeostasis of these endogenous compounds. Many natural flavonoids and synthetic stilbenes show inhibitory activity toward CYP1B1 expression and function, notably isorhamnetin and 2,4,3',5'-tetramethoxystilbene. Accumulating evidence indicates that modulation of CYP1B1 can decrease adipogenesis and tumorigenesis, and prevent obesity, hypertension, atherosclerosis, and cancer. Therefore, it may be feasible to consider CYP1B1 as a therapeutic target for the treatment of metabolic diseases.

Feasibility of melatonin for prevention of delirium in critically ill patients: a protocol for a multicentre, randomised, placebo-controlled study

IntroductionDelirium is highly prevalent in the intensive care unit (ICU) and is associated with adverse clinical outcomes. At this time, there is no drug that effectively prevents delirium in critically...

Interactions of Tryptophan and Its Catabolites With Melatonin and the Alpha 7 Nicotinic Receptor in Central Nervous System and Psychiatric Disorders: Role of the Aryl Hydrocarbon Receptor and Direct Mitochondria Regulation.

Recent work indicates an intimate interaction of the tryptophan catabolite (TRYCAT) pathways with the melatonergic pathways, primarily via TRYCAT pathway induction taking tryptophan away from the production of serotonin, which is a necessary precursor for the melatonergic pathways. The alpha 7 nicotinic receptor may be significantly modulated by this interaction, given its inactivation by the TRYCAT, kynurenic acid, and its induction by melatonin. Similarly, the aryl hydrocarbon receptor is activated by both kynurenic acid and kynurenine, leading to CYP1A2 and melatonin metabolism, whereas melatonin may act to inhibit the aryl hydrocarbon receptor. These 2 receptors and pathways may therefore be intimately linked, with relevance to a host of intracellular processes of clinical relevance. In this article, these interactions are reviewed. Interestingly, mitochondria may be a site for direct interactions of these pathways and receptors, suggesting that their differential induction may not only be modulating neuronal, glia, and immune cell processes and activity but also be directly acting to regulate mitochondrial functioning. This is likely to have significant consequences as to how an array of diverse central nervous system and psychiatric conditions are conceptualized and treated.

Inhibition of melatonin metabolism in humans induced by chemical components from herbs and effective prediction of this risk using a computational model.

Herbs which are widely used as food and medicine, are involved in many physiopathological processes. Melatonin is a human hormone, synthesized and secreted by the pineal gland, with a range of biological functions. Here, we have evaluated the potential influences of components extracted from common herbs on melatonin metabolism in humans. An in vivo pharmacokinetic study involving 12 healthy subjects, in vitro incubations with human liver microsomes (HLMs) and recombinant human cytochrome P (CYP) isoenzymes and an in silico quantitative structure-activity relationship (QSAR) model analysis using comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to explore these interactions. After systematic screening of 66 common herbs, Angelica dahurica exhibited the most potent inhibition of melatonin metabolism in vitro. The in vivo pharmacokinetic study indicated inhibition of melatonin metabolism, with approximately 12- and 4-fold increases in the AUC and Cmax of melatonin in human subjects. Coumarins from A. dahurica, including imperatorin, isoimperatorin, phellopterin, 5-methoxypsoralen and 8-methoxypsoralen, markedly inhibited melatonin metabolism with Ki values of 14.5nM, 38.8nM, 6.34nM, 5.34nM and 18nM respectively, through inhibition of CYP 1A2, 1A1 and 1B1 in HLMs. A QSAR model was established and satisfactorily predicted the potential risk of coumarins for inhibition of melatonin metabolism in vivo. Coumarins from A. dahurica inhibited melatonin metabolism in vivo and in vitro. Our findings provide vital guidance for the clinical use of melatonin.

RNA-seq Analysis of Overexpressing Ovine AANAT Gene of Melatonin Biosynthesis in Switchgrass.

Melatonin serves important functions in the promotion of growth and anti-stress regulation by efficient radical scavenging and regulation of antioxidant enzyme activity in various plants. To investigate its regulatory roles and metabolism pathways, the transcriptomic profile of overexpressing the ovine arylalkylamine N-acetyltransferase (oAANAT) gene, encoding the penultimate enzyme in melatonin biosynthesis, was compared with empty vector control using RNA-seq in switchgrass, a model plant of cellulosic ethanol conversion. The 85.22 million high quality reads that were assembled into 135,684 unigenes were generated by Illumina sequencing for transgenic oAANAT switchgrass with an average sequence length of 716 bp. A total of 946 differentially expression genes in transgenic line comparing to control switchgrass, including 737 up-regulated and 209 down-regulated genes, were mainly enriched with two main functional patterns of melatonin identifying by gene ontology analysis: the growth regulator and stress tolerance. Furthermore, KEGG maps indicated that the biosynthetic pathways of secondary metabolite (phenylpropanoids, flavonoids, steroids, stilbenoid, diarylheptanoid, and gingerol) and signaling pathways (MAPK signaling pathway, estrogen signaling pathway) were involved in melatonin metabolism. This study substantially expands the transcriptome information for switchgrass and provides valuable clues for identifying candidate genes involved in melatonin biosynthesis and elucidating the mechanism of melatonin metabolism.

Molecular cloning of melatonin 3-hydroxylase and its production of cyclic 3-hydroxymelatonin in rice (Oryza sativa).

Melatonin is metabolized in animals to cyclic 3-hydroxymelatonin (3-OHM) not by an enzymatic pathway, but by interaction with hydroxyl radicals. The production of 3-OHM in animals suggests the possible presence of 3-OHM in plants. Prior to the identification of 3-OHM in plants, we directly cloned the corresponding gene(s) responsible for 3-OHM synthesis using Escherichia coli library strains expressing genes belonging to the 2-oxoglutarate-dependent dioxygenase (2-ODD) superfamily from rice. Three of 35 E.coli library strains supplemented with 1mmol/L melatonin were found to produce 3-OHM in their extracellular medium, suggestive of three 2-ODD genes involved in 3-OHM production. The purified recombinant 2-ODD 11, 2-ODD 26, and 2-ODD 33 proteins were shown to catalyze the metabolism of melatonin to 3-OHM, with 2-ODD 11 showing the highest melatonin 3-hydroxylase (M3H) catalytic activity. Consistent with the presence of M3H genes, rice leaves supplemented with 5mmol/L melatonin produced 3-OHM [233μg/g fresh weight (FW)], 2-hydroxymelatonin (21μg/g FW), and N1 -acetyl-N2 -formyl-5-methoxykynuramine (5μg/g FW). Three M3H transcripts were induced upon the treatment of rice leaves with cadmium followed by an increase in M3H enzyme activity. Cloning of M3H genes in plants has paved the way for the studies of melatonin in plants in terms of its multiple physiological roles.

Distinct roles of N-acetyl and 5-methoxy groups in the antiproliferative and neuroprotective effects of melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin’s antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin’s antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.

Serotonin and melatonin secretion in postmenopausal women with eating disorders.

Postmenopausal women manifest emotional disorders associated with an increase in appetite. The aim of the study was to assess the serotonin and melatonin secretion and metabolism in postmenopausal women in relation to eating disorders. Sixty postmenopausal women and 30 women without hormonal disturbances were enrolled into the study and divided into three groups: group I (control) - women without menstrual disorders, group II - postmenopausal women without appetite disorders and change in body weight, and group III - postmenopausal women with increased appetite and weight gain. Serum melatonin, serotonin, urinary 6-sulfatoxymelatonin (aMT6s), and 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured. Serum serotonin and melatonin levels in groups II and III were lower compared to group I. Urinary 5-HIAA and aMT6s excretion was lower in overweight women. In group III the correlation between the serum level of serotonin, melatonin, and BMI was negative; a high statistical significance was found between BMI and urinary aMT6s excretion. Melatonin supplementation and use of drugs modulating the serotonin homeostasis together with female hormones have a beneficial effect in complex treatment of disorders of eating in postmenopausal women. (Endokrynol Pol 2016; 67 (3): 299-304).

Similar Effects between Follicular and Luteal Phases on the Urinary Levels of 6‐sulfatoxymelatonin following Endurance Exercise

The major urinary melatonin catabolite is 6‐sulfatoxymelatonin, which has been demonstrated as a good marker of pineal function. Although previous studies have shown exercise‐induced changes in melatonin metabolism, it still remains inconclusive whether prolonged exercise during two different menstrual cycle phases influences urinary 6‐sulfatoxymelatonin secretion. The purpose of the study was to determine the effects of the follicular and luteal phases on the urinary levels of 6‐sulfatoxymelatonin after 2‐h endurance exercise in women. Eleven recreationally active premenopausal women served as the participants (peak oxygen uptake (VO2peak): 46.1±5.0 mL/kg/min [mean±SD]). During the follicular (F: 5~8 days after the onset of the menses) and luteal (L: 22~25 days after the onset of the menses) phases, all participants carried out the same submaximal exercise protocol (2‐h cycling exercise at 60%VO2peak). Carbohydrate‐electrolyte solution was consumed every twenty minutes (2 ml/kg body mass) during each exercise protocol in order to delay fatigue and prevent hypoglycemia and dehydration. Before (Pre) and after (immediately Post) each exercise, spot urine samples were collected for later analysis of the urinary levels of 6‐sulfatoxymelatonin quantified by enzyme‐linked immunosorbent assay. Regarding the urinary levels of 6‐sulfatoxymelatonin (ng/mg creatinine), two‐way (phase × time) analysis of variances demonstrated a significant main effect for time (p<0.05), but not for phase or interaction (Pre=21.1±3.5, Post=33.0±8.5 for F; Pre=16.3±5.4, Post=33.5±9.5 for L). These findings indicate that acute moderate cycling exercise appears to be similar at the urinary levels of 6‐sulfatoxymelatonin during two different menstrual phases.Support or Funding InformationSupported partly by funds from the Grant‐in‐Aid for Scientific Research (C) (Grant No.23500867).

Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain.

Melatonin is used in the therapy of sleep and mood disorders and as a neuroprotective agent. The aim of our study was to demonstrate that melatonin supported (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine. We measured serotonin tissue content in some brain regions (the cortex, hippocampus, nucleus accumbens, striatum, thalamus, hypothalamus, brain stem, medulla oblongata, and cerebellum) (model A), as well as its extracellular concentration in the striatum using an in vivo microdialysis (model B) after melatonin injection (100 mg/kg i.p.) to male Wistar rats. Melatonin increased the tissue concentration of serotonin in the brain structures studied of naïve, sham-operated, or serotonergic neurotoxin (5,7-dihydroxytryptamine)-lesioned rats (model A). Intracerebroventricular quinine (a CYP2D inhibitor) prevented the melatonin-induced increase in serotonin concentration. In the presence of pargyline (a monoaminoxidase inhibitor), the effect of melatonin was not visible in the majority of the brain structures studied but could be seen in all of them in 5,7-dihydroxytryptamine-lesioned animals when serotonin storage and synthesis via a classic tryptophan pathway was diminished. Melatonin alone did not significantly increase extracellular serotonin concentration in the striatum of naïve rats but raised its content in pargyline-pretreated animals (model B). The CYP2D inhibitor propafenone given intrastructurally prevented the melatonin-induced increase in striatal serotonin in those animals. The obtained results indicate that melatonin supports CYP2D-catalyzed serotonin synthesis from 5-methoxytryptamine in the brain in vivo, which closes the serotonin-melatonin-serotonin biochemical cycle. The metabolism of exogenous melatonin to the neurotransmitter serotonin may be regarded as a newly recognized additional component of its pharmacological action.

Melatonergic Treatment: Focus on Metabolism and Chronobiology

Introduction: Melatonin is produced in various organs, but its preferentially nocturnal synthesis and release by the pineal gland is decisive for its chronobiological actions. The short half-life of circulating melatonin has been reason for developing synthetic melatonergic agonists. With regard to age- and disease-related dysfunction of the melatonergic system, treatment with melatonin or its synthetic analogs may be used for alleviating health problems with a respective etiology. This review addresses limitations arising from drug-specific metabolism and disregarded chronobiological rules. Metabolism: Differences are illustrated by comparing the metabolism of melatonin and two approved synthetic melatonergic agonists, ramelteon and agomelatine. Apart from hydroxylation and dealkylation reactions, melatonin can be converted to methoxylated kynuramines, a route absent in the two synthetic drugs. An unsual property is present in the ramelteon metabolite M-II, which still displays melatonergic activity, but attains 30 to 100 times higher levels than the parent compound. Two double hydroxylated agomelatine metabolites may be involved in sometimes occurring hepatotoxicity. Chronobiology of Melatonergic Drugs: Sleep latency facilitation and readjustment of circadian rhythms require only short actions. Circadian entrainment must consider the phase response curve and requires repetitive well-timed administration. Findings in nocturnally active rodents cannot be generally translated to humans, especially not regarding sleep and, perhaps, not in insulin resistance. Conclusions: Melatonin and synthetic analogs can be suitable for treating sleep-onset difficulties, circadian rhythm sleep disorders and subtypes of depression with an etiology of circadian dysfunction. Applications in the field of metabolic syndrome and insulin resistance have to be seen with caution.

Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A.

Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2′-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm.

Specific features of melatonin metabolism in chronic rhinosinusitis poliposa associated with multimorbid cardiovascular pathology

The problem of chronic rhinosinusitis poliposa (CRP) associated with multimorbid cardiovascular pathology (MCVP) is pressurizing. A complex evaluation of biochemical, cardiovascular, X­ray and endoscopic parameters in patients with CRP and MCVP made it possible to assume the existence of mechanisms of central and peripheral regulation systems abnormalities resulting in “difficult” and clinically “poorly” controlled CRP course.

Managing Sleep Disturbances in Cirrhosis.

Sleep disturbances, particularly daytime sleepiness and insomnia, are common problems reported by patients suffering from liver cirrhosis. Poor sleep negatively impacts patients' quality of life and cognitive functions and increases mortality. Although sleep disturbances can be an early sign of hepatic encephalopathy (HE), many patients without HE still complain of poor quality sleep. The pathophysiology of these disturbances is not fully understood but is believed to be linked to impaired hepatic melatonin metabolism. This paper provides an overview for the clinician of common comorbidities contributing to poor sleep in patients with liver disease, mainly restless leg syndrome and obstructive sleep apnea. It discusses nondrug and pharmacologic treatment options in these patients, such as the use of light therapy and histamine (H1) blockers.

Melatonergic system-based two-gene index is prognostic in human gliomas.

Gliomas, the most common primary brain tumors in adults, are classified into four malignancy grades according to morphological features. Recent studies have shown that melatonin treatment induces cytotoxicity in glioma-initiating cells and reduces the invasion and migration of glioma cell lines, inhibiting the nuclear factor κB (NFκB) oncopathway. Given that C6 rat glioma cells produce melatonin, we investigated the correlation between the capacity of gliomas to synthesize/metabolize melatonin and their overall malignancy. We first characterized the melatonergic system of human gliomas cell lines with different grades of aggressiveness (HOG, T98G, and U87MG) and demonstrated that glioma-synthesized melatonin exerts an autocrine antiproliferative effect. Accordingly, the sensitivity to exogenous melatonin was higher for the most aggressive cell line, U87MG, which synthesized/accumulated less melatonin. Using The Cancer Genome Atlas RNAseq data of 351 glioma patients, we designed a predictive model of the content of melatonin in the tumor microenvironment, the ASMT:CYP1B1 index, combining the gene expression levels of melatonin synthesis and metabolism enzymes. The ASMT:CYP1B1 index negatively correlated with tumor grade, as well as with the expression of pro-proliferation and anti-apoptotic NFκB target genes. More importantly, the index was a grade- and histological type-independent prognostic factor. Even when considering only high-grade glioma patients, a low ASMT:CYP1B1 value, which suggests decreased melatonin and enhanced aggressiveness, was strongly associated with poor survival. Overall, our data reveal the prognostic value of the melatonergic system of gliomas and provide insights into the therapeutic role of melatonin.