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The light/dark cycle is the main external cue to synchronize the human biological clock. Modern lifestyles typically lead to less daylight exposure and blunted 24 h-amplitude. We evaluated the association of outdoor daylight exposure (frequency, duration, regularity and shift) with chronotype estimated by sleep phase, regularity of routines, sleep, well-being (WHO-5), and depressive symptoms (PHQ-9), in a sample of 1,095 participants (81.8% female; 87.9% aged 18-49) surveyed online between July and November 2020. We analyzed direct and indirect associations in daylight-mood relationship with chronotype-estimate, routine regularity, and sleep as mediators. Outdoor daylight exposure was associated with WHO-5/PHQ-9 scores in mediation models, with higher total effects when the exposure was every day (β = 4.13 ± 0.53/ β = -3.81 ± 0.67), for more than 4 hours (β = 3.77 ± 0.91/ β = -3.83 ± 1.31) and during the morning (β = 3.41 ± 0.53/ β = -3.74 ± 0.70) in reference to lack of exposure. Chronotype-estimate, routine regularity score, and sleep problems acted as mediators, while social jetlag and sleep duration did not play an important role in this association. This study advanced the understanding of the complex interplay between light exposure, mental health, and individual characteristics of sleep and other routine regularities, and showed the benefits of optimizing daylight exposure to improve mental health.

Aim: The pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A ( MTNR1A )., Methods: Eight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated., Results: The group of individuals with a renal function decline ≥ 5 mL min -1 1.73 m -2 year -1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20-2.82; p = 0.0046). No other significant associations were found., Conclusions: This is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Daher, Santos-Bezerra, Cavaleiro, Pelaes, Admoni, Perez, Machado, Amaral, Cipolla-Neto and Correa-Giannella.)

Melatonin is an indolamine secreted to circulation by the pineal gland according to a circadian rhythm. Melatonin levels are higher during nighttime, and the principal function of this hormone is to organize the temporal night and day distribution of physiological adaptive processes. Besides hormonal pineal production, melatonin is synthesized in various organs and tissues like the ovaries or the placenta for local utilization. In addition to its function as a circadian messenger, melatonin is also associated with many physiological functions. For example, melatonin has antioxidant properties and is involved in the regulation of energy and bone metabolism, and reproduction. Melatonin impacts several stages of reproduction and the action across the hypothalamus-pituitary-gonadal axis is well described. However, it is not well understood how those actions impact the female reproductive hormones secretion nor the consequent physiological outcomes. Thus, the first part of this chapter describes the regulation of female reproductive hormone synthesis by melatonin. Moreover, melatonin and female reproductive hormones have coincident physiological functions. Life stages like pregnancy or menopause are characterized by alterations in the reproductive hormones secretion that may be associated with certain physiological stages. Therefore, the second part discusses whether melatonin fluctuations could have an overlapping role with reproductive hormones in contributing to clinical outcomes associated with pregnancy and menopause., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Herein, we evaluated pinealectomy-induced melatonin absence to determine its effects on craniofacial and dental development in the offspring., Design: Female Wistar rats in three groups, i.e., intact pregnant rats, pinealectomized pregnant rats (PINX), and pinealectomized pregnant rats subjected to oral melatonin replacement therapy, were crossed 30 days after surgery. The heads of 7-day-old pups were harvested for cephalometric and histological analyses, and maxillae and incisors were collected for mRNA expression analysis., Results: The PINX pups exhibited a reduction in neurocranial and facial parameters such as a decrease in alveolar bone area, incisor size and proliferation, and an increase in odontoblasts and the dentin layer. Based on incisor mRNA expression analysis, we found that Dmp1 expression was upregulated, whereas Col1a1 expression was downregulated. Maxillary mRNA expression revealed that Rankl expression was upregulated, whereas that of Opn and Osx was downregulated., Conclusion: Our results demonstrated that the absence of maternal melatonin during early life could affect dental and maxillary development in offspring, as well as delay odontogenesis and osteogenesis in maxillary tissues., Clinical Relevance: Our findings suggest that disruptions or a lack of melatonin during pregnancy may cause changes in craniofacial and dental development, at least in animal experiments; however, in humans, these feedings are still poorly understood, and thus careful evaluations of melatonin levels in humans need to be investigated in craniofacial alterations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pineal microdialysis is characterized by the real-time monitoring of melatonin, neurotransmitters, metabolites, and other compounds released by the pineal gland throughout 24 h. It is a technique with great advantages that allows in vivo study of the ongoing pineal gland metabolism. In this chapter, we describe the entire process of pineal microdialysis that includes probe manufacturing, surgical procedure for its implantation, and the sample collection process., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The pinealectomy technique consists of the surgical removal of the superficial pineal gland. This procedure allows the ablation of circulating indoles produced by this gland. Withdrawal of systemic melatonin, a pineal hormone, affects animal circadian rhythms and induces several physiological changes that are the subject of many investigations. In this chapter, we describe the pinealectomy protocol adapted to rats. We describe the animal placement on the stereotaxic fixation system, and the procedure for the pineal gland removal and animal recovery from surgery., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Pineal gland secretes the hormone melatonin at night with a circadian rhythm. The synthesis and secretion of melatonin are stimulated at night by norepinephrine released by sympathetic postganglionic neurons projecting from the superior cervical ganglia. Norepinephrine simultaneously activates α- and β-adrenoceptors, triggering melatonin synthesis.To study the regulation of melatonin production and secretion, it is very convenient to use an ex vivo preparation. Thus, it is possible to keep intact pineal glands in culture and to study the actions of agonists, antagonists, modulators, toxic agents, etc., in melatonin synthesis. Artificial melatonin synthesis stimulation in vitro is usually achieved by using a β-adrenergic agonist alone or in association with an α-adrenergic agonist. In this chapter, the methodology of cultured pineal glands will be described. Several papers were published by our group using this methodology, approaching the role played in melatonin synthesis control by angiotensin II and IV, insulin, glutamate, voltage-gated calcium channels, anhydroecgonine methyl ester (AEME, crack-cocaine product), monosodium glutamate (MSG), signaling pathways like NFkB, pathophysiological conditions like diabetes, etc., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Melatonin is synthesized and secreted by the pineal gland in mammals. Its synthesis is triggered at night by norepinephrine released in the interstices of the gland. This nocturnal production is dependent on the transcription, translation, and/or activation of the enzymes arylalkylamine-N-acetyltransferase (AANAT), acetylserotonin O-methyltransferase (ASMT), and tryptophan hydroxylase (TPH). In this chapter, the methodology for the analysis of AANAT, ASMT, and TPH activities by radiometric assays will be presented. Several papers were published by our group utilizing these methodologies, evaluating the enzymes modulation by voltage-gated calcium channels, angiotensin II, insulin, anhydroecgonine methyl ester (AEME, crack-cocaine product), ethanol, monosodium glutamate (MSG), signaling pathways such as NFkB, and pathophysiological conditions such as diabetes., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Melatonin has been shown to increase brown adipose tissue (BAT) mass, which can lead to important metabolic effects, such as bodyweight reduction and glycemic improvement. However, BAT mass can only be measured invasively and. The gold standard for non-invasive measurement of BAT activity is positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose ( 18 F-FDG PET). There is no study, to our knowledge, that has evaluated if melatonin influences BAT activity, measured by this imaging technique in animals., Methods: Three experimental groups of Wistar rats (control, pinealectomy, and pinealectomy replaced with melatonin) had an 18 F-FDG PET performed at room temperature and after acute cold exposure. The ratio of increased BAT activity after cold exposure/room temperature was called "acute thermogenic capacity" (ATC) We also measured UCP-1 mRNA expression to correlate with the 18 F-FDG PET results., Results: Pinealectomy led to reduced acute thermogenic capacity, compared with the other groups, as well as reduced UCP1 mRNA expression., Conclusion: Melatonin deficiency impairs BAT response when exposed to acute cold exposure. These results can lead to future studies of the influence of melatonin on BAT, in animals and humans, without needing an invasive evaluation of BAT., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: In a previous study developed by our group, we identified a phase inversion in 6-sulfatoxymelatonin - melatonin metabolite in urine - daily profile in Fabry's disease patients. Since melatonin is an endogenous marker, it could also be accompanied by behavioral changes in sleep-wake cycle, which impairs the overall patient's life quality., Objective: In this study, we evaluated sleep-wake cycle in Fabry disease patients. We hypothesized that patients would have increased daytime naps, given our previous results for urinary 6-sulfatoxymelatonin., Patients/methods: This was a cross-sectional and case-control study, performed between October 2016 and May 2017. Volunteers recorded activity and rest rhythm by actigraphy and answered Pittsburgh Sleep Quality Index (PSQI). From actigraphy data, we calculated sleep parameters: sleep latency, wake after sleep onset, sleep (WASO) efficiency, awakenings index (PSQI), and the amount and duration of daytime naps. We included 16 Fabry disease patients with biochemical and molecular diagnosis and 10 control individuals matched by age and gender., Results: We did not observe significant differences for any of the parameters analyzed (p > 0.05). However, evaluating the magnitude of the effect, we found that patients dozed, on average, about 42 min longer (d = 0.9 - large effect size) than control group., Conclusions: This is a preliminary study, a proof-of-concept, and our results indicate that changes in melatonin secretion phase may have behavioral consequences in sleep-wake cycle, with longer duration of daytime naps., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Melatonin, a pineal hormone synthesized at night, is critical for the synchronization of circadian and seasonal rhythms, being a key regulator of energy metabolism in many animal species. Although studies in humans are lacking, several reports, mainly on hibernating animals, demonstrated that melatonin supplementation and a short photoperiod increase brown adipose tissue (BAT) mass. The present proof-of-concept study is the first, to our knowledge, to evaluate BAT in patients with melatonin deficiency (radiotherapy or surgical removal of pineal gland) before and after daily melatonin (3 mg) replacement for 3 months. All four studied patients presented increased BAT volume and activity measured by positron emission tomography-MRI. We also found an improvement in total cholesterol and triglyceride blood levels without significant effects on body weight, liver fat, and HDL and LDL levels. Albeit not statistically significant, fasting insulin levels and HOMA of insulin resistance decreased in all four patients. The present results show that oral melatonin replacement increases BAT volume and activity and improves blood lipid levels in patients with melatonin deficiency, suggesting that melatonin is a possible BAT activator. Future studies are warranted because hypomelatoninemia is usually present in aging and appears as a result of light-at-night exposure and/or the use of β-blocker drugs., (© 2019 by the American Diabetes Association.)

Brown adipose tissue (BAT) influences energy balance through nonshivering thermogenesis, and its metabolism daily and seasonal variations are regulated by melatonin through partially known mechanisms. We evaluated the role of melatonin in BAT molecular machinery of male Control, pinealectomized (PINX), and melatonin-treated pinealectomized (PINX/Mel) adult rats. BAT was collected either every 3 hours over 24 hours or after cold or high-fat diet (HFD) acute exposure. HFD PINX animals presented decreased Dio2 expression, while HFD PINX/Mel animals showed increased Dio2, Ucp1, and Cidea expression. Cold-exposed PINX rats showed decreased Dio2 and Lhs expression, and melatonin treatment augmented Adrβ3, Dio2, Ucp1, and Cidea expression. Daily profiles analyses showed altered Dio2, Lhs, Ucp1, Pgc1α, and Cidea gene and UCP1 protein expression in PINX animals, leading to altered rhythmicity under sub-thermoneutral conditions, which was partially restored by melatonin treatment. The same was observed for mitochondrial complexes I, II, and IV protein expression and enzyme activity. Melatonin absence seems to impair BAT responses to metabolic challenges, and melatonin replacement reverses this effect, with additional increase in the expression of crucial genes, suggesting that melatonin plays an important role in several key points of the thermogenic activation pathway, influencing both the rhythmic profile of the tissue and its ability to respond to metabolic challenges, which is crucial for the organism homeostasis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A local renin-angiotensin system (RAS) has been postulated in the pineal gland. In addition to angiotensin II (Ang II), other active metabolites have been described. In this study, we aimed to investigate a role for Ang IV in melatonin synthesis and the presence of its proposed (IRAP)/AT 4 receptor (insulin-regulated aminopeptidase) in the pineal gland. The effect of Ang IV on melatonin synthesis was investigated in vitro using isolated pinealocytes. IRAP protein expression and activity were evaluated by Western blot and fluorimetry using Leu-4Me-β-naphthylamide as a substrate. Melatonin was analyzed by HPLC, calcium content by confocal microscopy and cAMP by immunoassay. Ang IV significantly augmented the NE-induced melatonin synthesis to a similar degree as that achieved by Ang II. This Ang IV effect in pinealocytes appears to be mediated by an increase in the intracellular calcium content but not by cAMP. The (IRAP)/AT 4 expression and activity were identified in the pineal gland, which were significantly higher in membrane fractions than in soluble fractions. Ang IV significantly reduced IRAP activity in the pineal membrane fractions. The main findings of the present study are as follows: (1) Ang IV potentiates NE-stimulated melatonin production in pinealocytes, (2) the (IRAP)/AT 4 receptor is present in the rat pineal gland, and (3) Ang IV inhibits IRAP activity and increases pinealocytes [Ca 2+ ] i . We conclude that Ang IV is an important component of RAS and modulates melatonin synthesis in the rat pineal gland., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Maternal melatonin provides photoperiodic information to the fetus and thus influences the regulation and timing of the offspring's internal rhythms and preparation for extra-uterine development. There is clinical evidence that melatonin deprivation of both mother and fetus during pregnancy, and of the neonate during lactation, results in negative long-term health outcomes. As a consequence, we hypothesized that the absence of maternal pineal melatonin might determine abnormal brain programming in the offspring, which would lead to long-lasting implications for behavior and brain function. To test our hypothesis, we investigated in rats the effects of maternal melatonin deprivation during gestation and lactation (MMD) to the offspring and the effects of its therapeutic replacement. The parameters evaluated were: (1) somatic, physical growth and neurobehavioral development of pups of both sexes; (2) hippocampal-dependent spatial learning and memory of the male offspring; (3) adult hippocampal neurogenesis of the male offspring. Our findings show that MMD significantly delayed male offspring's onset of fur development, pinna detachment, eyes opening, eruption of superior incisor teeth, testis descent and the time of maturation of palmar grasp, righting reflex, free-fall righting and walking. Conversely, female offspring neurodevelopment was not affected. Later on, male offspring show that MMD was able to disrupt both spatial reference and working memory in the Morris Water Maze paradigm and these deficits correlate with changes in the number of proliferative cells in the hippocampus. Importantly, all the observed impairments were reversed by maternal melatonin replacement therapy. In summary, we demonstrate that MMD delays the appearance of physical features, neurodevelopment and cognition in the male offspring, and points to putative public health implications for night shift working mothers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Smith-Magenis syndrome (SMS) causes sleep disturbance that is related to an abnormal melatonin profile. It is not clear how the genomic disorder leads to a disturbed synchronization of the sleep/wake rhythm in SMS patients. To evaluate the integrity of the intrinsically photosensitive retinal ganglion cell (ipRGC)/melanopsin system, the transducers of the light-inhibitory effect on pineal melatonin synthesis, we recorded pupillary light responses (PLR) in SMS patients., Methods: Subjects were SMS patients (n = 5), with molecular diagnosis and melatonin levels measured for 24 hours and healthy controls (n = 4). Visual stimuli were 1-second red light flashes (640 nm; insignificant direct ipRGC activation), followed by a 470-nm blue light, near the melanopsin peak absorption region (direct ipRGC activation). Blue flashes produce a sustained pupillary constriction (ipRGC driven) followed by baseline return, while red flashes produce faster recovery., Results: Pupillary light responses to 640-nm red flash were normal in SMS patients. In response to 470-nm blue flash, SMS patients had altered sustained responses shown by faster recovery to baseline. SMS patients showed impairment in the expected melatonin production suppression during the day, confirming previous reports., Conclusions: SMS patients show dysfunction in the sustained component of the PLR to blue light. It could explain their well-known abnormal melatonin profile and elevated circulating melatonin levels during the day. Synchronization of daily melatonin profile and its photoinhibition are dependent on the activation of melanopsin. This retinal dysfunction might be related to a deficit in melanopsin-based photoreception, but a deficit in rod function is also possible.

It is widely known that there is an increase in the inflammatory responses and oxidative stress in temporal lobe epilepsy (TLE). Further, the seizures follow a circadian rhythmicity. Retinoic acid receptor-related orphan receptor alpha (RORα) is related to anti-inflammatory and antioxidant enzyme expression and is part of the machinery of the biological clock and circadian rhythms. However, the participation of RORα in this neurological disorder has not been studied. The aim of this study was to evaluate the RORα mRNA and protein content profiles in the hippocampus of rats submitted to a pilocarpine-induced epilepsy model at different time points throughout the 24-h light-dark cycle analyzing the influence of the circadian rhythm in the expression pattern during the acute, silent, and chronic phases of the experimental model. Real-time PCR and immunohistochemistry results showed that RORα mRNA and protein expressions were globally reduced in both acute and silent phases of the pilocarpine model. However, 60days after the pilocarpine-induced status epilepticus (chronic phase), the mRNA expression was similar to the control except for the time point 3h after the lights were turned off, and no differences were found in immunohistochemistry. Our results indicate that the status epilepticus induced by pilocarpine is able to change the expression and daily variation of RORα in the rat hippocampal area during the acute and silent phases. These findings enhance our understanding of the circadian pattern present in seizures as well as facilitate strategies for the treatment of seizures., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Melatonin, the main hormone produced by the pineal gland, is secreted in a circadian manner (24-hr period), and its oscillation influences several circadian biological rhythms, such as the regulation of clock genes expression (chronobiotic effect) and the modulation of several endocrine functions in peripheral tissues. Assuming that the circadian synchronization of clock genes can play a role in the regulation of energy metabolism and it is influenced by melatonin, our study was designed to assess possible alterations as a consequence of melatonin absence on the circadian expression of clock genes in the epididymal adipose tissue of male Wistar rats and the possible metabolic repercussions to this tissue. Our data show that pinealectomy indeed has impacts on molecular events: it abolishes the daily pattern of the expression of Clock, Per2, and Cry1 clock genes and Pparγ expression, significantly increases the amplitude of daily expression of Rev-erbα, and affects the pattern of and impairs adipokine production, leading to a decrease in leptin levels. However, regarding some metabolic aspects of adipocyte functions, such as its ability to synthesize triacylglycerols from glucose along 24 hr, was not compromised by pinealectomy, although the daily profile of the lipogenic enzymes expression (ATP-citrate lyase, malic enzyme, fatty acid synthase, and glucose-6-phosphate dehydrogenase) was abolished in pinealectomized animals., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: The circadian rhythm in mammalian pineal melatonin secretion is modulated by norepinephrine (NE) released at night. NE interaction with β1-adrenoceptors activates PKA that phosphorylates the transcription factor CREB, leading to the transcription and translation of the arylalkylamine-N-acetyltransferase (AANAT) enzyme. Several studies have reported the interplay between CREB and the nuclear factor-κB (NF-κB) and a circadian rhythm for this transcription factor was recently described in the rat pineal gland. In this work we studied a direct effect of NE on NF-κB activation and the role played by this factor on melatonin synthesis and Aanat transcription and activity., Main Methods: Cultured rat pineal glands were incubated in the presence of two different NF-κB inhibitors, pyrrolidine-dithiocarbamate or sodium salicylate, and stimulated with NE. Melatonin content was quantified by HPLC with electrochemical detection. AANAT activity was measured by a radiometric assay and the expression of Aanat mRNA was analyzed by real-time PCR. Gel shift assay was performed to study the NF-κB activation in cultured rat pineal glands stimulated by NE., Key Findings: Our results showed that the p50/p50 homodimer of NF-κB is activated by NE and that it has a role in melatonin synthesis, acting on Aanat transcription and activity., Significance: Here we present evidence that NF-κB is an important transcription factor that acts, directly or indirectly, on Aanat transcription and activity leading to a modulation of melatonin synthesis. NE plays a role in the translocation of NF-κB p50/p50 homodimer to the nucleus of pinealocytes, thus probably influencing the nocturnal pineal melatonin synthesis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The pineal gland, through melatonin, seems to be of fundamental importance in determining the metabolic adaptations of adipose and muscle tissues to physical training. Evidence shows that pinealectomized animals fail to develop adaptive metabolic changes in response to aerobic exercise and therefore do not exhibit the same performance as control-trained animals. The known prominent reduction in melatonin synthesis in aging animals led us to investigate the metabolic adaptations to physical training in aged animals with and without daily melatonin replacement. Male Wistar rats were assigned to four groups: sedentary control (SC), trained control (TC), sedentary treated with melatonin (SM), and trained treated with melatonin (TM). Melatonin supplementation lasted 16 wk, and the animals were subjected to exercise during the last 8 wk of the experiment. After euthanasia, samples of liver, muscle, and adipose tissues were collected for analysis. Trained animals treated with melatonin presented better results in the following parameters: glucose tolerance, physical capacity, citrate synthase activity, hepatic and muscular glycogen content, body weight, protein expression of phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and protein kinase activated by adenosine monophosphate (AMPK) in the liver, as well as the protein expression of the glucose transporter type 4 (GLUT4) and AMPK in the muscle. In conclusion, these results demonstrate that melatonin supplementation in aging animals is of great importance for the required metabolic adaptations induced by aerobic exercise. Adequate levels of circulating melatonin are, therefore, necessary to improve energetic metabolism efficiency, reducing body weight and increasing insulin sensitivity., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In aged rats, insulin signaling pathway (ISP) is impaired in tissues that play a pivotal role in glucose homeostasis, such as liver, skeletal muscle, and adipose tissue. Moreover, the aging process is also associated with obesity and reduction in melatonin synthesis from the pineal gland and other organs. The aim of the present work was to evaluate, in male old obese Wistar rats, the effect of melatonin supplementation in the ISP, analyzing the total protein amount and the phosphorylated status (immunoprecipitation and immunoblotting) of the insulin cascade components in the rat hypothalamus, liver, skeletal muscle, and periepididymal adipose tissue. Melatonin was administered in the drinking water for 8- and 12 wk during the night period. Food and water intake and fasting blood glucose remained unchanged. The insulin sensitivity presented a 2.1-fold increase both after 8- and 12 wk of melatonin supplementation. Animals supplemented with melatonin for 12 wk also presented a reduction in body mass. The acute insulin-induced phosphorylation of the analyzed ISP proteins increased 1.3- and 2.3-fold after 8- and 12 wk of melatonin supplementation. The total protein content of the insulin receptor (IR) and the IR substrates (IRS-1, 2) remained unchanged in all investigated tissues, except for the 2-fold increase in the total amount of IRS-1 in the periepididymal adipose tissue. Therefore, the known age-related melatonin synthesis reduction may also be involved in the development of insulin resistance and the adequate supplementation could be an important alternative for the prevention of insulin signaling impairment in aged organisms., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The glutamatergic modulation of melatonin synthesis is well known, along with the importance of astrocytes in mediating glutamatergic signaling in the central nervous system. Pinealocytes and astrocytes are the main cell types in the pineal gland. The objective of this work was to investigate the interactions between astrocytes and pinealocytes as a part of the glutamate inhibitory effect on melatonin synthesis. Rat pinealocytes isolated or in coculture with astrocytes were incubated with glutamate in the presence of norepinephrine, and the melatonin content, was quantified. The expression of glutamate receptors, the intracellular calcium content and the NF- κ B activation were analyzed in astrocytes and pinealocytes. TNF- α 's possible mediation of the effect of glutamate was also investigated. The results showed that glutamate's inhibitory effect on melatonin synthesis involves interactions between astrocytes and pinealocytes, possibly through the release of TNF- α . Moreover, the activation of the astrocytic NF- κ B seems to be a necessary step. In astrocytes and pinealocytes, AMPA, NMDA, and group I metabotropic glutamate receptors were observed, as well as the intracellular calcium elevation. In conclusion, there is evidence that the modulation of melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through the activation of the astrocytic NF- κ B transcription factor and possibly by subsequent TNF- α release.

It is well known that melatonin participates in the regulation of many important physiological functions such as sleep-wakefulness cycle, motor coordination and neural plasticity, and cognition. However, as there are contradictory results regarding the melatonin production diurnal profile under alcohol consumption, the aim of this paper was to study the phenomenology and mechanisms of the putative modifications on the daily profile of melatonin production in rats submitted to chronic alcohol intake. The present results show that rats receiving 10% ethanol in drinking water for 35 days display an altered daily profile of melatonin production, with a phase delay and a reduction in the nocturnal peak. This can be partially explained by a loss of the daily rhythm and the 25% reduction in tryptophan hydroxylase activity and, mainly, by a phase delay in arylalkylamine N-acetyltransferase gene expression and a 70% reduction in its peak activity. Upstream in the melatonin synthesis pathway, the results showed that noradrenergic signaling is impaired as well, with a decrease in β1 and α1 adrenergic receptors' mRNA contents and in vitro sustained loss of noradrenergic-stimulated melatonin production by glands from alcohol-treated rats. Together, these results confirm the alterations in the daily melatonin profile of alcoholic rats and suggest the possible mechanisms for the observed melatonin synthesis modification., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Purpose: Retinal melatonin synthesis occurs in the photoreceptor layer in a circadian manner, controlling several physiologic rhythmic phenomena, besides being the most powerful natural free radical scavenger. The purpose of the present work was to evaluate the diurnal profile of retinal melatonin content and the regulation of its synthesis in the retina of streptozotocin-induced diabetic rats., Methods: Diabetes was induced in male Wistar rats (12 hour-12 hour light/dark cycle) with streptozotocin. Control, diabetic, and insulin-treated diabetic animals were killed every 3 hours throughout the light-dark cycle. Retinal melatonin content was measured by high-performance liquid chromatography, arylalkylamine N-acetyltransferase (AANAT) activity was analyzed by radiometric assay, Bmal1 gene expression was determined by qPCR, and cyclic adenosine monophosphate (cAMP) content was assessed by ELISA., Results: Control animals showed a clear retinal melatonin and AANAT activity daily rhythm, with high levels in the dark. Diabetic rats had both parameters reduced, and the impairment was prevented by immediate insulin treatment. In addition, the Bmal1 expression profile was lost in the diabetic group, and the retinal cAMP level was reduced 6 hours after lights on and 3 hours after lights off., Conclusions: The present work shows a melatonin synthesis reduction in diabetic rats retinas associated with a reduction in AANAT activity that was prevented by insulin treatment. The Bmal1-flattened gene expression and the cAMP reduction seem to be responsible for the AANAT activity decrease in diabetic animals. The melatonin synthesis reduction observed in the pineal gland of diabetic rats is also observed in a local melatonin tissue synthesizer, the retina.

Malignant mesotheliomas of the tunica vaginalis are extremely rare tumors, especially in young patients. We report a case of a 15-year old patient presenting with clinical signs of hydrocele. Preoperative ultrasound scanning revealed two papillary lesions. Initially, before mesothelioma was suspected, the patient was submitted to focal resection of the macroscopic lesions. Following diagnosis by histopathology, the patient was submitted to radical orchiectomy and hemiscrotectomy. The patient presents no signs of local or systemic recurrence at the time of writing. A review of the literature on the subject has been included.

The mammalian pineal gland synthesizes melatonin in a circadian manner, peaking during the dark phase. This synthesis is primarily regulated by sympathetic innervations via noradrenergic fibers, but is also modulated by many peptidergic and hormonal systems. A growing number of studies reveal a complex role for melatonin in influencing various physiological processes, including modulation of insulin secretion and action. In contrast, a role for insulin as a modulator of melatonin synthesis has not been investigated previously. The aim of the current study was to determine whether insulin modulates norepinephrine (NE)-mediated melatonin synthesis. The results demonstrate that insulin (10(- 8)M) potentiated norepinephrine-mediated melatonin synthesis and tryptophan hydroxylase (TPOH) activity in ex vivo incubated pineal glands. When ex vivo incubated pineal glands were synchronized (12h NE-stimulation, followed by 12h incubation in the absence of NE), insulin potentiated NE-mediated melatonin synthesis and arylalkylamine-N-acetyltransferase (AANAT) activity. Insulin did not affect the activity of hydroxyindole-O-methyltranferase (HIOMT), nor the gene expression of tpoh, aanat, or hiomt, under any of the conditions investigated. We conclude that insulin potentiates NE-mediated melatonin synthesis in cultured rat pineal gland, potentially through post-transcriptional events.