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Aim: Morphine is one of the important opioids used in chronic and acute pain management. However, it has many side effects, including the development of addiction, which seriously limits its use. Melatonin shows its physiological effects through melatonin receptor 1 (MT1), melatonin receptor 2 (MT2) and heterodimer receptors (MT1/MT2). No study has examined the presence of MT1/MT2 mRNA in the hypothalamus and hippocampus and its relationship with the addiction process. The aim of this study was to investigate the gene expression levels of MT1, MT2 and MT1/MT2 in rat hippocampus and hypothalamus during morphine addiction and morphine withdrawal. Materials and Methods: A total of 36 male Wistar rats were divided into 3 groups (n=12). Control (C) group received saline subcutaneously for 6 days. Morphine (M) and morphine+naloxone (M+N) groups received 10 mg/kg/day morphine subcutaneously for 6 days. On the seventh day, saline was injected intraperitoneally into C and M groups and 1 mg/kg naloxone was injected intraperitoneally into M+N group. 30 minutes later, hippocampus and hypothalamus tissues of rats were dissected. Melatonin receptor genes expression level were analysed by quantitative qPCR. Results: Both MT1 and MT1/MT2 gene expression levels in the hypothalamus were higher in the M+N group than in the C group (p<0.05). There was no difference between the expression levels of MT2 receptors in the hypothalamus (p>0.05). There was no difference in MT1, MT2 and MT1/MT2 gene expression in the hippocampus (p>0.05). Conclusion: This is the first study to show the presence of MT1/MT2 in the hypothalamus and hippocampus, and it is possible that MT1 and MT1/MT2 receptors, especially in the hypothalamus, play a role in the addiction process. [ABSTRACT FROM AUTHOR]

Treatment with melatonin is routinely prescribed for its potent antioxidant and cognitive‐promoting effects, nevertheless, it has yet to find neuromodulatory effects in normal and disease conditions. Therefore, to investigate its neuromodulatory mechanisms, melatonin was systemically administered over 10 consecutive days to both intracortical normal saline‐ and amyloid‐β 1‐42 (Aβ) peptide‐injected rats. At the behavioral level, treatment with melatonin was associated with reduced efficacy in restoring Aβ‐induced deficit in passive‐avoidance memory. Whole‐cell patch‐clamp recordings from CA1 pyramidal neurons revealed that melatonin treatment reduced spontaneous and evoked intrinsic excitability in control rats while exerting a reduction of spontaneous, but not evoked activity, in the Aβ‐injected group. Interestingly, treatment with melatonin enhances after‐hyperpolarization in control, but not Aβ‐injected rats. In contrast, our voltage‐clamp study showed that Ih current is significantly enhanced by Aβ injection, and this effect is further strengthened by treatment with melatonin in Aβ‐injected rats. Finally, we discovered that the transcription of melatonin receptors 1 (MT1) and 2 (MT2) is significantly upregulated in the hippocampi of Aβ‐injected rats. Collectively, our study demonstrates that systemic treatment with melatonin has differential neuromodulation on CA1 neuronal excitability, at least in part, via differential effects on after‐hyperpolarization and Ih currents due to Aβ‐induced neurotoxicity. Summary: The molecular and cellular underpinnings of AD pathology are accompanied by developing aberrant neuronal excitability. These neuronal properties are also a part of melatonin effectors by which melatonin exerts its cognitive‐promoting and anti‐seizure effects. In this paper, we answer the question of how melatonin may influence neuronal excitability in healthy and AD‐like conditions. Answering this query is important considering the fact that melatonin effectiveness is altered with the development of AD. This may be due to, as we demonstrate, the deregulation of melatonin receptors in the hippocampus of AD rats. These findings are significant because shed further light on the cellular mechanisms of melatonin and help us to understand AD pathophysiology. [ABSTRACT FROM AUTHOR]

Seizures and epilepsies pose significant challenges in pediatric populations, necessitating precise classification and effective management. The International League Against Epilepsy updated its classification system in 2017 to standardize epilepsy care. This study investigated melatonin, a neurohormone known for its role in circadian rhythm regulation, and its potential to enhance the diagnosis, management, and quality of life of pediatric epilepsy patients. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted to explore the relationship between melatonin and pediatric epilepsies. PubMed searches were performed using specific search terms, with eligibility criteria including studies on melatonin's pathophysiological, biochemical, and therapeutic effects in pediatric epilepsy. Studies involving patients aged 0-18 years were published between 2003 and 2023. Four-teen studies with 898 pediatric patients were included. Melatonin was administered as an adjunct to antiepileptic therapy with the aim of alleviating disorders associated with epileptic encephalopathies or assisting electroencephalogram procedures. Findings were varied: Some studies indicated a reduction in seizure frequency with melatonin, while others provided inconclusive results. Improvements in sleep disorders related to epilepsy were noted with melatonin supplementation, which indirectly enhanced the overall quality of life. Melatonin has potential as an adjunctive therapy for pediatric epilepsy, with positive effects on seizure frequency and sleep quality. However, methodological limitations in some studies and inconclusive data underscore the need for further research to determine the efficacy of melatonin in pediatric epilepsy management. The diverse potential of melatonin in treating neurological disorders highlights the importance of continued, comprehensive research into its therapeutic application. [ABSTRACT FROM AUTHOR]

Introduction. Melatonin and serotonin can influence certain aging processes in the ovaries. The main melatonin receptors are represented by types MT1 and MT2. The goal of investigation. Here, we evaluated the expression of genes and synthesis of MT1 and MT2 receptors, as well as serotonin synthesis in the ovaries during ontogenesis. Methods. We analyzed histological material obtained from the ovaries of infants, women of younger and older reproductive age, premenopausal, menopausal, and postmenopausal women. For the analysis of MT1 and MT2 receptors and serotonin expression and synthesis, RT-PCR and immunohistochemistry were used. Results. We found that the synthesis of serotonin, as well as MT1 and MT2 receptors in the ovaries significantly decrease in ontogenesis. The sharpest drop in these molecules was observed in samples obtained from one-year-old infants, as well as from pubescent girls and menopausal women. A statistically significant 2.3–7.6-fold decrease in the expression of MTNR1A and MTNR1B genes in the ovaries was also observed in one-year-old infants, in adolescents, and in middle-aged women. Conclusions. These data are crucial to understanding the fundamental mechanisms of aging of the female reproductive system and the search for molecules predicting its aging. [ABSTRACT FROM AUTHOR]

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Seizures and epilepsies pose significant challenges in pediatric populations, necessitating precise classification and effective management. The International League Against Epilepsy updated its classification system in 2017 to standardize epilepsy care. This study investigated melatonin, a neurohormone known for its role in circadian rhythm regulation, and its potential to enhance the diagnosis, management, and quality of life of pediatric epilepsy patients. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted to explore the relationship between melatonin and pediatric epilepsies. PubMed searches were performed using specific search terms, with eligibility criteria including studies on melatonin’s pathophysiological, biochemical, and therapeutic effects in pediatric epilepsy. Studies involving patients aged 0-18 years were published between 2003 and 2023. Four-teen studies with 898 pediatric patients were included. Melatonin was administered as an adjunct to antiepileptic therapy with the aim of alleviating disorders associated with epileptic encephalopathies or assisting electroencephalogram procedures. Findings were varied: Some studies indicated a reduction in seizure frequency with melatonin, while others provided inconclusive results. Improvements in sleep disorders related to epilepsy were noted with melatonin supplementation, which indirectly enhanced the overall quality of life. Melatonin has potential as an adjunctive therapy for pediatric epilepsy, with positive effects on seizure frequency and sleep quality. However, methodological limitations in some studies and inconclusive data underscore the need for further research to determine the efficacy of melatonin in pediatric epilepsy management. The diverse potential of melatonin in treating neurological disorders highlights the importance of continued, comprehensive research into its therapeutic application.

Objective: To investigate whether melatonin (MT) secretion in different parts of the gastrointestinal tract (GIT) exhibits seasonal variations and its correlation with immune regulation. Methods: Sixty Sprague-Dawley rats were divided into control and model groups, and the pineal gland was removed in the model group. Stomach, jejunum, ileum, and colon tissues were obtained during the spring equinox, summer solstice, beginning of autumn, autumn equinox, and winter solstice. The levels of MT, MT receptors (MR), arylalkylamine N-acetyltransferase (AANAT), hydroxyindole-O-methyltransferase (HIOMT), interleukin-2 (IL-2), and interleukin-10 (IL-10) in the GIT were measured using enzyme-linked immunosorbent assay. Results: Except for the stomach, the jejunum, ileum, and the colon showed seasonal tendencies in MT secretion. In the control group, MT secretion in the jejunum and ileum was the highest in the long summer, and colonic MT secretion was the highest in winter. In the model group, MT levels in the colon were highest in the summer. The seasonal rhythms of the MR, AANAT, HIOMT, IL-2, and IL-10 in the colon were roughly similar to those of MT, and changed accordingly after pinealectomy. Conclusions: Gastrointestinal MT secretion is related to seasonal changes, and MT secretion in each intestinal segment is influenced by different seasons. The biological effects of MT in the gut are inextricably linked to the mediation of MR, and a hormone-receptor linkage exists between MT and MR. The effect of seasonal changes on the gastrointestinal immune system may be mediated through the regulation of seasonal secretion of MT.

Abstract Increasing evidence has shown that many environmental and toxic factors can cause testicular damage, leading to testicular ferroptosis and subsequent male reproductive disorders. Melatonin is a major hormone and plays an vital role in regulating male reproduction. However, there is a lack of research on whether Mel can alleviate testicular cell ferroptosis and its specific mechanism. In this study, the results indicated that Mel could enhance the viability of swine testis cells undergoing ferroptosis, reduce LDH enzyme release, increase mitochondrial membrane potential, and affect the expression of ferroptosis biomarkers. Furthermore, we found that melatonin depended on melatonin receptor 1B to exert these functions. Detection of MMP and ferroptosis biomarker protein expression confirmed that MT2 acted through the downstream Akt signaling pathway. Moreover, inhibition of the Akt signaling pathway can eliminate the protective effect of melatonin on ferroptosis, inhibit AMPK phosphorylation, reduce the expression of mitochondrial gated channel (VDAC2/3), and affect mitochondrial DNA transcription and ATP content. These results suggest that melatonin exerts a beneficial effect on mitochondrial function to mitigate ferroptosis through the MT2/Akt signaling pathway in ST cells.

This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron‐like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal‐brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re‐entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT‐intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin‐proficient strains are suited to investigate the circadian and melatoninergic systems. [ABSTRACT FROM AUTHOR]

Increasing evidence has shown that many environmental and toxic factors can cause testicular damage, leading to testicular ferroptosis and subsequent male reproductive disorders. Melatonin is a major hormone and plays an vital role in regulating male reproduction. However, there is a lack of research on whether Mel can alleviate testicular cell ferroptosis and its specific mechanism. In this study, the results indicated that Mel could enhance the viability of swine testis cells undergoing ferroptosis, reduce LDH enzyme release, increase mitochondrial membrane potential, and affect the expression of ferroptosis biomarkers. Furthermore, we found that melatonin depended on melatonin receptor 1B to exert these functions. Detection of MMP and ferroptosis biomarker protein expression confirmed that MT2 acted through the downstream Akt signaling pathway. Moreover, inhibition of the Akt signaling pathway can eliminate the protective effect of melatonin on ferroptosis, inhibit AMPK phosphorylation, reduce the expression of mitochondrial gated channel (VDAC2/3), and affect mitochondrial DNA transcription and ATP content. These results suggest that melatonin exerts a beneficial effect on mitochondrial function to mitigate ferroptosis through the MT2/Akt signaling pathway in ST cells. [ABSTRACT FROM AUTHOR]

Adipose-derived mesenchymal stem cells (ASCs) are adult multipotent stem cells, able to differentiate toward neural elements other than cells of mesodermal lineage. The aim of this research was to test ASC neural differentiation using melatonin combined with conditioned media (CM) from glial cells. Isolated from the lipoaspirate of healthy donors, ASCs were expanded in a basal growth medium before undergoing neural differentiation procedures. For this purpose, CM obtained from olfactory ensheathing cells and from Schwann cells were used. In some samples, 1 µM of melatonin was added. After 1 and 7 days of culture, cells were studied using immunocytochemistry and flow cytometry to evaluate neural marker expression (Nestin, MAP2, Synapsin I, GFAP) under different conditions. The results confirmed that a successful neural differentiation was achieved by glial CM, whereas the addition of melatonin alone did not induce appreciable changes. When melatonin was combined with CM, ASC neural differentiation was enhanced, as demonstrated by a further improvement of neuronal marker expression, whereas glial differentiation was attenuated. A dynamic modulation was also observed, testing the expression of melatonin receptors. In conclusion, our data suggest that melatonin's neurogenic differentiation ability can be usefully exploited to obtain neuronal-like differentiated ASCs for potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Melatonin (5‐methoxy‐N‐acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best‐characterized. They are members of the G protein‐coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell‐context‐depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state‐of‐the‐art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round‐up this review. [ABSTRACT FROM AUTHOR]

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 mLmin-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. [ABSTRACT FROM AUTHOR]

Simple Summary: Day length is a critical environmental factor for gonadal development in animals. However, related studies on male pigs are limited. The present study investigated the effects of different day lengths on behavior changes, growth parameters, testicular size, testosterone secretion, steroidogenesis proteins, and melatonin receptors in Meishan male pigs. The results indicated that a long day length (LDL, 14 h light/10 h dark, 14L/10D) could increase the lying time, decrease the exploring time, and increase the body height, chest circumference, testicular length, testicular weight, crude protein digestibility, and fecal testosterone and cortisol contents compared to a short day length (SDL, 10L/14D) in Meishan male pigs, accompanied by the changes in sex hormone synthesis proteins and melatonin receptor 1b (MT2), but with no change in melatonin receptor 1a (MT1). This suggests that the effect of day length on growth and gonadal development in male pigs may be conducted via MT2 and influence steroid synthesis and secretion in the testis, and proper day length should be provided in male pig breeding. Day length is a critical environmental factor for regulating animal growth and development. This study aimed to investigate the effects of different day lengths on the developmental changes of growth parameters, testicular sizes, testosterone secretion in Meishan male pigs, and steroidogenesis proteins and melatonin receptors. Fourteen Meishan male pigs (10 weeks (wks) of age) with the same parity, paired in litter and body weight (BW), were evenly allocated into a short-day-length group (SDL, 10 light/14 dark) and long-day-length group (LDL, 14 light/10 dark). After 12 wks of the experiment, the LDL-treated boars had more lying time and less exploring time. The LDL treatment led to significant increases in body height, chest circumference, testicular length, testicular weight, crude protein digestibility, and fecal testosterone at the 10th and 12th wks of the experiment, and cortisol at the 10th wk, compared to the SDL treatment, with no differences in the final BW, testicular width, and epididymis weight. Furthermore, the LDL treatment significantly increased the protein levels of melatonin receptor 1b (MT2), aromatase (CYP19), and steroidogenic factor 1 (SF1) in the testis, with no differences in the protein levels of melatonin receptor 1a (MT1), steroidogenic acute regulatory (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD), and cholesterol side-chain cleavage enzyme (P450scc). The present study suggests that day length has an effect on the growth and gonadal development in male pigs maybe via MT2 and influences steroid synthesis and secretion in the testis. Therefore, proper day length should be considered in male pig breeding. [ABSTRACT FROM AUTHOR]

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2‐[125I]iodomelatonin, showed slow dissociation with different half‐lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure–activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2‐[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2‐iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype‐selective ligand UCM1014. We found that equilibrium conditions for 2‐[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype‐selective compounds were not significantly affected by the length of incubation, suggesting that structure–activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2‐iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2‐selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor–ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow‐binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure–activity relationships and with interactions taken at the receptor binding site. [ABSTRACT FROM AUTHOR]

Evidence suggests that the neuroprotective effects of melatonin involve both receptor‐dependent and ‐independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post‐KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression‐like behaviors following KA‐induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 μg/μL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA‐induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA‐induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA‐induced hippocampal neuronal loss, memory impairment, and depression‐like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon‐mediated activation of melatonin receptors provides neuroprotection against KA‐induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes. [ABSTRACT FROM AUTHOR]

The population of T lymphocytes producing IL‐17 (Th17) plays a dual role during pregnancy and its activity is tightly controlled during this period. One of the factors involved in this process may be the pineal hormone melatonin, which can effectively regulate this T cell population. Here we have shown that exogenous melatonin in pharmacological concentrations is able to enhance the differentiation of Th17 cells of pregnant women in vitro. The stimulatory effects of melatonin were limited to in the first trimester of pregnancy and were apparently mediated by both membrane and nuclear melatonin receptors. Since exogenous melatonin is currently considered as a promising drug in solving various problems associated with reproduction, it is necessary to take into account its immunoregulatory effects. [ABSTRACT FROM AUTHOR]

AimThe 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).MethodsEight 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.ResultsThe 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.ConclusionsThis 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.

Heat shock proteins (Hsps) responses against stress conditions. Melatonin completes its stress relieving activities via its MT1 and MT2 receptors. The present study delineates the expression pattern of Hsp70/Hsc70 and MT1/MT2 receptor proteins along with the AANAT gene expression in the splenic tissue of mice subjected to hyperthermic stress in a temperature dependent and time dependent manner. In vivo thermal stress resulted increase in expression of Hsp70, Hsc70 and MT2 receptors proteins in both temperature dependent and time dependent manner. Optimum heat exposure at 430C and maximized Hsps expression was observed after 5 hours of heat exposure. Heat stress caused increase in AA-NAT gene expression of the splenic tissue resulted in the synthesis of melatonin which might act as signal molecule for upregulating the activity and rise of the stress responsive genes and proteins like: Hsp70/Hsc70, whereas simultaneous increase of MT2 expression shows its possible involvement in such mechanism.

The hormone melatonin is involved in regulation of functioning of almost all organs and systems of the organism. In the immune system, T lymphocytes are an important target of melatonin: they express specific melatonin receptors with different affinities – membrane MT1 and MT2 and nuclear RORa, as well as intracellular molecules that nonspecifically bind melatonin at high concentrations. Moreover, many in vitro studies reveal their own production of melatonin by T lymphocytes in response to polyclonal activation and its involvement as autocrine or paracrine factor in the induction of IL-2 and IL-2 receptor (IL-2R) synthesis by T cells, with melatonin receptors involvement in implementation of these effects. Since IL-2/IL-2R-dependent signal is a key event in T lymphocytes proliferative response induction, intrinsic melatonin seems to be directly involved at least in the clonal expansion of these cells. In this work, we investigated the contribution of T cells’ melatonin to regulation of the next stage of T lymphocyte activation, namely, the differentiation of T helper populations Th17 and Treg. It was shown that blockade of both membrane and nuclear melatonin receptors did not cause statistically significant changes in Th17 differentiation, although the trend was fixed for a decrease. Simultaneously, CD4+FoxP3+Т cells level decreased under the nonselective blockade of membrane hormone receptors, and Treg-associated cytokine TGF-b concentration in activated cultures supernatants decreased both in case of MT1/MT2 nonselective blockade and MT2 selective blockade. The data indicate that melatonin produced by T lymphocytes in culture can contribute to the control of naive CD4+T cell differentiation into Treg in vitro, and the hormone effects are mediated by membrane melatonin receptors. The presence of a large number targets with different affinities for melatonin in T lymphocytes determines the key role of the hormone concentration in its effects on these cells. And when interpreting data on melatonin-dependent regulation of Treg, it is important to take into account the hormone’s own production by lymphocytes, since T cells’ melatonin can mask the exogenous hormone effects or interfere with its action due to competitive binding to hormone receptors.

Background: Melatonin is an indoleamine hormone secreted by the pineal gland at night and has an essential role in regulating human circadian rhythms (the internal 24-h clock) and sleep-wake patterns. However, it has recently gained considerable attention for its demonstrated ability in disease management. This review discusses the major biological activities of melatonin, its metabolites as nutritional supplements, and its bioavailability in food sources. Methods: The information acquisition process involved conducting a comprehensive search across academic databases including PubMed, Scopus, Wiley, Embase, and Springer using relevant keywords. Only the most recent, peer-reviewed articles published in the English language were considered for inclusion. Results: The molecular mechanisms by which melatonin induces its therapeutic effects have been the subject of various studies. Conclusion: While melatonin was initially understood to only regulate circadian rhythms, recent studies indicate that it has a far-reaching effect on various organs and physiological systems, such as immunity, cardiovascular function, antioxidant defense, and lipid hemostasis. As a potent antioxidant, anti-cancer, anti-inflammatory, and immunoregulatory agent, multiple therapeutic applications have been proposed for melatonin.

Abstract Background The purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers. Methods A case–control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions. Results Rotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40–1.55); AP = 0.60, (95% CI, 0.07–1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23–1.91); AP = 0.77, (95% CI, 0.36–1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011). Conclusions Rotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.

Day length is a critical environmental factor for regulating animal growth and development. This study aimed to investigate the effects of different day lengths on the developmental changes of growth parameters, testicular sizes, testosterone secretion in Meishan male pigs, and steroidogenesis proteins and melatonin receptors. Fourteen Meishan male pigs (10 weeks (wks) of age) with the same parity, paired in litter and body weight (BW), were evenly allocated into a short-day-length group (SDL, 10 light/14 dark) and long-day-length group (LDL, 14 light/10 dark). After 12 wks of the experiment, the LDL-treated boars had more lying time and less exploring time. The LDL treatment led to significant increases in body height, chest circumference, testicular length, testicular weight, crude protein digestibility, and fecal testosterone at the 10th and 12th wks of the experiment, and cortisol at the 10th wk, compared to the SDL treatment, with no differences in the final BW, testicular width, and epididymis weight. Furthermore, the LDL treatment significantly increased the protein levels of melatonin receptor 1b (MT2), aromatase (CYP19), and steroidogenic factor 1 (SF1) in the testis, with no differences in the protein levels of melatonin receptor 1a (MT1), steroidogenic acute regulatory (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD), and cholesterol side-chain cleavage enzyme (P450scc). The present study suggests that day length has an effect on the growth and gonadal development in male pigs maybe via MT2 and influences steroid synthesis and secretion in the testis. Therefore, proper day length should be considered in male pig breeding.

Heat shock proteins (Hsps) responses against stress conditions. Melatonin completes its stress relieving activities via its MT1 and MT2 receptors. The present study delineates the expression pattern of Hsp70/Hsc70 and MT1/MT2 receptor proteins along with the AANAT gene expression in the splenic tissue of mice subjected to hyperthermic stress in a temperature dependent and time dependent manner. In vivo thermal stress resulted increase in expression of Hsp70, Hsc70 and MT2 receptors proteins in both temperature dependent and time dependent manner. Optimum heat exposure at 430C and maximized Hsps expression was observed after 5 hours of heat exposure. Heat stress caused increase in AA-NAT gene expression of the splenic tissue resulted in the synthesis of melatonin which might act as signal molecule for upregulating the activity and rise of the stress responsive genes and proteins like: Hsp70/Hsc70, whereas simultaneous increase of MT2 expression shows its possible involvement in such mechanism. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers. Methods: A case–control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions. Results: Rotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40–1.55); AP = 0.60, (95% CI, 0.07–1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23–1.91); AP = 0.77, (95% CI, 0.36–1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011). Conclusions: Rotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: Hyperoxia-induced apoptosis in alveolar epithelial type II cells (AECIIs) plays a critical role in the development of bronchopulmonary dysplasia (BPD). Melatonin has been shown to improve BPD. However, the protective effect of melatonin on hyperoxia-induced apoptosis in AECIIs and the precise mechanisms involved remain unclear. Methods: Human alveolar epithelial type II A549 cells were treated with hyperoxia as an in vitro model to investigate the antiapoptotic mechanism of melatonin. CCK-8 assays were performed to investigate the viability of A549 cells. Hoechst 33,258 staining was carried out to quantify apoptosis in A549 cells. The protein expression levels of E26 oncogene homolog 1 (ETS1), Bcl-2, Bax, Bim, Wnt, β-catenin, AKT and phosphorylated AKT were measured by western blotting. LY294002, SC79 and the downregulation of ETS1, melatonin receptor 1 (MT1) and MT2 with specific siRNAs were used to investigate the role of the PI3K/AKT pathway, ETS1, MT1 and MT2 in hyperoxia-induced apoptosis in A549 cells. Results: Melatonin prevented hyperoxia-induced apoptosis in A549 cells, and the upregulation of E26 oncogene homolog 1 (ETS1) contributed to the antiapoptotic effect of melatonin. Melatonin activated the PI3K/AKT axis, which led to ETS1 upregulation and inhibited apoptosis in hyperoxia-exposed A549 cells. Furthermore, melatonin-induced activation of the PI3K/AKT axis, upregulation of ETS1 and inhibition of apoptosis were reversed by melatonin receptor 2 (MT2) siRNA in hyperoxia-exposed A549 cells. Conclusion: Melatonin prevents hyperoxia-induced apoptosis by activating the MT2/PI3K/AKT/ETS1 axis in alveolar epithelial cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Reproductive activity in mares shows a seasonal pattern that is associated with an increasing photoperiod with a pronounced incidence of ovulations during spring and summer. The photoperiodic control of reproductive activity is mediated by melatonin, secreted by the pineal gland, which plays an inhibitory role in ovulatory activity via the hypothalamic-pituitary axis. Considering that there is little information on the direct effect of melatonin on the development of equine ovarian follicles, we studied the seasonal variations in mRNA expression of gonadotropin receptors (Fshr and Lhr), melatonin receptors (Mt1 and Mt2), melatonin-synthetizing enzymes (Asmt and Aanat) and melatonin concentration in developing follicles (small—<20 mm, medium—20 to 35 mm and large—>35 mm) from five mares raised in natural photoperiods. There was an increased mRNA expression of gonadotropin receptors and melatonin-related genes and an increase of melatonin levels in developing follicles during the spring/summer seasons. The total number of large follicles (potential ovulatory follicles) was significantly higher during the spring/summer seasons. Our results demonstrate that melatonin upregulates the mRNA expression of melatonin receptors and melatonin-forming enzymes in mare developing follicles during reproductive seasons. This study investigated the seasonal variations in mRNA expression of FSH (Fshr), LH (Lhr) receptors, melatonin (Mt1 and Mt2) receptors, melatonin-synthetizing enzymes (Asmt and Aanat) and melatonin concentration in developing follicles from mares raised in natural photoperiods. For one year, ultrasonographic follicular aspiration procedures were performed monthly, and small (<20 mm), medium (20 to 35 mm) and large (>35 mm) follicles were recovered from five mares. One day before monthly sample collections, an exploratory ultrasonography conducted to record the number and the size of all follicles larger than 15 mm. The total number of large follicles were higher during the spring/summer (8.2 ± 1.9) than during autumn/winter (3.0 ± 0.5). Compared to autumn/winter seasons, there was an increase of Fshr and Aanat mRNA expressions in small, medium and large follicles, an increase of Lhr and Asmt mRNA expressions in medium and large follicles and an increase of Mt1 and Mt2 mRNA expressions in small and large follicles during spring/summer. The melatonin levels in follicular fluid were also higher during the spring/summer seasons. The present data show that melatonin locally upregulates the mRNA expression of Mt1 and Mt2 receptors and melatonin-forming enzymes in mare developing follicles during reproductive seasons. [ABSTRACT FROM AUTHOR]

Study questionAre melatonin receptors (melatonin receptor 1A (MR1A) and melatonin receptor 1B (MR1B)) expressed in human endometrium and endometriotic tissue, and does melatonin affect endometrial cell proliferation?Summary answerMelatonin receptors are expressed in human eutopic endometrium, endometriomas and peritoneal lesions, although to different extents, and melatonin treatment attenuated estradiol-induced endometrial epithelial cell proliferation in culture.What is known alreadyMelatonin decreased endometriotic lesion volume in a rat model of endometriosis. Melatonin treatment reduced pain scores in and analgesic use by women with endometriosis.Study design, size, durationBasic science study using human endometrial tissue and an endometrial epithelial cell line.Participants/materials, setting, methodsMeasurement of melatonin receptor expression (mRNA and protein) in women with surgically confirmed endometriosis (endometrioma (n = 20) or peritoneal lesion (n = 11) alone) and women without surgical evidence of endometriosis (control, n = 15). Collection of endometrial and endometriotic tissue samples, gynecologic history and demographic information. Quantification of estradiol (1.0 nM) and melatonin (0.1 nM-1.0 μM) ± estradiol-induced endometrial epithelial cell proliferation in cultures of endometrial epithelial cells (CRL-1671) following 24 and 48 hours of culture.Main results and the role of chanceMR1A and MR1B were localized by immunohistochemistry in glandular epithelial cells of endometrial biopsies from women with and without endometriosis. Both receptors were expressed in eutopic and ectopic endometrial tissue. mRNA expression of MR1A and MR1B was significantly greater in peritoneal lesions than in either endometriomas or eutopic endometrium. However, protein expression of MR1A was decreased in peritoneal lesions compared to control eutopic endometrium, whereas MR1B expression did not differ between the groups. Melatonin (0.1 nM-1.0 μM) treatment inhibited estradiol (1.0 nM)-induced endometrial epithelial cell proliferation at 48 hours but not 24 hours of culture.Limitations, reasons for cautionBeneficial effects of melatonin seen in culture have yet to be comprehensively evaluated in women with endometriosis.Wider implications of the findingsOur data suggest that melatonin may be useful as an adjunct to current endometriosis treatments.Study funding/competing interest(s)This study was supported by the Canadian Institutes of Health Research (grant MOP142230 to W.G.F.). A.A.M. is supported by a resident research grant through the Physicians Services Incorporated Foundation. The authors have no conflicts of interest.

Glaucoma, a major ocular neuropathy originating from a progressive degeneration of retinal ganglion cells, is often associated with increased intraocular pressure (IOP). Daily IOP fluctuations are physiologically influenced by the antioxidant and signaling activities of melatonin. This endogenous modulator has limited employment in treating altered IOP disorders due to its low stability and bioavailability. The search for low-toxic compounds as potential melatonin agonists with higher stability and bioavailability than melatonin itself could start only from knowing the molecular basis of melatonergic activity. Thus, using a computational approach, we studied the melatonin binding toward its natural macromolecular targets, namely melatonin receptors 1 (MT1) and 2 (MT2), both involved in IOP signaling regulation. Besides, agomelatine, a melatonin-derivative agonist and, at the same time, an atypical antidepressant, was also included in the study due to its powerful IOP-lowering effects. For both ligands, we evaluated both stability and ligand positioning inside the orthosteric site of MTs, mapping the main molecular interactions responsible for receptor activation. Affinity values in terms of free binding energy (ΔGbind) were calculated for the selected poses of the chosen compounds after stabilization through a dynamic molecular docking protocol. The results were compared with experimental in vivo effects, showing a higher potency and more durable effect for agomelatine with respect to melatonin, which could be ascribed both to its higher affinity for hMT2 and to its additional activity as an antagonist for the serotonin receptor 5-HT2c, in agreement with the in silico results. [ABSTRACT FROM AUTHOR]

A comparative analysis of vascular stiffness indices and the results of blood test was carried out in 85 healthy donors aged 19-64 years, carriers of polymorphic variants of type 1 and type 2 melatonin receptor genes. The associations of polymorphic markers of type 1 MTNR1A (rs34532313) and type 2 MTNR1B (rs10830963) melatonin receptor genes with parameters of vascular stiffness and blood parameters in healthy patients were studied. Genotyping was performed using allele-specific PCR. In all patients, 24-h BP monitoring with assessment of arterial stiffness was performed. Allele C homozygotes of MTNR1A differed significantly from carriers of the major T allele by elevated triglyceride, LDL, and fibrinogen levels. The major allele C of the rs10830963 polymorphic variant of the MTNR1B gene is associated with elevated LDL and triglycerides, as well as with individual differences in the elastic properties of the vascular wall in the examined subjects. [ABSTRACT FROM AUTHOR]

Sleep is a restorative period that plays a crucial role in the physiological functioning of the body, including that of the immune system, memory processing, and cognition. Sleep disturbances can be caused by various physical, mental, and social problems. Recently, there has been growing interest in sleep. Maydis stigma (MS, corn silk) is a female maize flower that is traditionally used as a medicinal plant to treat many diseases, including hypertension, edema, and diabetes. It is also used as a functional food in tea and other supplements. β-Sitosterol (BS) is a phytosterol and a natural micronutrient in higher plants, and it has a similar structure to cholesterol. It is a major component of MS and has anti-inflammatory, antidepressive, and sedative effects. However, the potential effects of MS on sleep regulation remain unclear. Here, we investigated the effects of MS on sleep in mice. The effects of MS on sleep induction were determined using pentobarbital-induced sleep and caffeine-induced sleep disruption mouse models. MS extracts decreased sleep latency and increased sleep duration in both the pentobarbital-induced sleep induction and caffeine-induced sleep disruption models compared to the positive control, valerian root extract. The butanol fraction of MS extracts decreased sleep latency time and increased sleep duration. In addition, β-sitosterol enhances sleep latency and sleep duration. Both MS extract and β-sitosterol increased alpha activity in the EEG analysis. We measured the mRNA expression of melatonin receptors 1 and 2 (MT1/2) using qRT-PCR. The mRNA expression of melatonin receptors 1 and 2 was increased by MS extract and β-sitosterol treatment in rat primary cultured neurons and the brain. In addition, MS extract increased the expression of clock genes including per1/2, cry1/2, and Bmal1 in the brain. MS extract and β-sitosterol increased the phosphorylation of ERK1/2 and αCaMKII. Our results demonstrate for the first time that MS has a sleep-promoting effect via melatonin receptor expression, which may provide new scientific evidence for its use as a potential therapeutic agent for the treatment and prevention of sleep disturbance. [ABSTRACT FROM AUTHOR]

It has widely been thought that in the process of nerve regeneration Schwann cells populate the injury site with myelinating, non–myelinating, phagocytic, repair, and mesenchyme–like phenotypes. It is now clear that the Schwann cells modify their shape and basal lamina as to accommodate re–growing axons, at the same time clear myelin debris generated upon injury, and regulate expression of extracellular matrix proteins at and around the lesion site. Such a remarkable plasticity may follow an intrinsic functional rhythm or a systemic circadian clock matching the demands of accurate timing and precision of signalling cascades in the regenerating nervous system. Schwann cells react to changes in the external circadian clock clues and to the Zeitgeber hormone melatonin by altering their plasticity. This raises the question of whether melatonin regulates Schwann cell activity during neurorepair and if circadian control and rhythmicity of Schwann cell functions are vital aspects of neuroregeneration. Here, we have focused on different schools of thought and emerging concepts of melatonin–mediated signalling in Schwann cells underlying peripheral nerve regeneration and discuss circadian rhythmicity as a possible component of neurorepair.

Simple Summary: Animal reproduction is closely related to economic benefits and food safety in domestic animals, as well as human fertility. There are many factors that affect the reproductive ability of animals, among which studies have confirmed that melatonin can affect animal reproduction. Melatonin receptors play important roles in mediating melatonin signaling, and they are expected to become a drug target for the improvement of animal reproduction capacity and treatment of reproductive diseases. In this review, we briefly summarize melatonin receptors MT1- and MT2-mediated signal transduction, as well as their role in reproductive regulation, including their effects on gametogenesis, gamete quality, reproductive rhythm, endocrine function, and embryonic development. We also briefly summarize the developments in pharmacological research regarding melatonin receptors as drug targets, which can provide a future perspective for the development of drugs and therapeutic methods based on melatonin receptors or their mediated signaling pathways. Melatonin, a hormone produced by the mammalian pineal gland, influences various physiological activities, many of which are related to animal reproduction, including neuroendocrine function, rhythm regulation, seasonal behavior, gonadogenesis, gamete development and maturation, sexual maturation, and thermoregulation. Melatonin exerts beneficial actions mainly via binding with G-protein-coupled receptors (GPCR), termed MT1 and MT2. Melatonin receptors are crucial for mediating animal reproduction. This paper reviews the characteristics of melatonin receptors including MT1 and MT2, as well as their roles in mediating signal transduction and biological effects, with a focus on their function in animal reproduction. In addition, we briefly summarize the developments in pharmacological research regarding melatonin receptors as drug targets. It is expected that this review will provide a reference for further exploration and unveiling of melatonin receptor function in reproductive regulation. [ABSTRACT FROM AUTHOR]

The photoperiodic system is concealed in the highly complex black-box, comprising four functional subunits: 1) a photo/thermo-sensitive input unit, 2) a photoperiodic clock based on a circadian system, 3) a condenser unit counting the number of inductive signals, and 4) a neuroendocrine switch that triggers a phenotypic shift. This review aims to summarize the research history and current reach of our understanding on this subject to connect it with the molecular mechanism of the circadian clock rapidly being unveiled. The review also focuses on the mode of intersubunit information transduction. It will scan the recent advancement in research on each functional subunit, but special attention will be given to the circadian clock–endocrine conjunct and the role of melatonin signaling in the regulation of insect photoperiodism. Prothoracicotropic hormone (PTTH) probably plays the most crucial role in the regulation of pupal diapause, which is the simplest model system of diapause regulation by hormones investigated so far, particularly in the Chinese oak silkmoth (Antheraea pernyi). A search for the trigger to release the PTTH found some candidates, that is, indoleamines. Indolamine metabolism is controlled by arylalkylamine N -acetyltransferase (aaNAT). Indolamine dynamics and aaNAT enzymatic activity changed according to photoperiods. aaNAT activity and melatonin content in the brain showed not only a photoperiodic response but also a circadian fluctuation. aaNAT had multiple E-boxes, suggesting that it is a clock-controlled gene (ccg), which implies that cycle (cyc, or brain–muscle Arnt-like 1 = Bmal1)/Clock (Clk) heterodimer binds to E-box and stimulates the transcription of aaNAT , which causes the synthesis of melatonin. RNAi against transcription modulators, cyc, or Clk downregulated aaNAT transcription, while RNAi against repressor of cyc/Clk, per upregulated aaNAT transcription. Immunohistochemical localization showed that the circadian neurons carry epitopes of melatonin-producing elements such as aaNAT, the precursor serotonin, HIOMT, and melatonin as well as clock gene products such as cyc-ir, Per-ir, and dbt-ir, while PTTH-producing neurons juxtaposed against the clock neurons showed hMT2-ir in A. pernyi brain. Melatonin probably binds to the putative melatonin receptor (MT) that stimulates Ca2+ influx, which in turn activates PKC. This induces Rab 8 phosphorylation and exocytosis of PTTH, leading to termination of diapause. All the PTTH-expressing neurons have PKC-ir, and Rab8-ir. When diapause is induced and maintained under short days, serotonin binding to 5HTR1B suppresses PTTH release in a yet unknown way. RNAi against this receptor knocked out photoperiodism; short day response is blocked and diapause was terminated even under the short day condition. The result showed that a relatively simple system controls both induction and termination in pupal diapause of A. pernyi : the circadian system regulates the transcription of aaNAT as a binary switch, the enzyme produces a melatonin rhythm that gates PTTH release, and 5HTR1B and MT are probably also under photoperiodic regulation. Finally, we listed the remaining riddles which need to be resolved, to fully understand this highly complex system in future studies. [ABSTRACT FROM AUTHOR]

Although acute melatonin treatment effectively reduces cardiac ischemia/reperfusion (I/R) injury in lean rats by modulating melatonin receptor 2 (MT2), there is no information regarding the temporal effects of melatonin administration during cardiac I/R injury in prediabetic obese rats. Prediabetic obese rats induced by chronic consumption of a high-fat diet (HFD) were used. The rats underwent a cardiac I/R surgical procedure (30-min of ischemia, followed by 120-min of reperfusion) and were randomly assigned to receive either vehicle or melatonin treatment. In the melatonin group, rats were divided into 3 different subgroups: (1) pretreatment, (2) treatment during ischemic period, (3) treatment at the reperfusion onset. In the pretreatment subgroup either a nonspecific MT blocker (Luzindole) or specific MT2 blocker (4-PPDOT) was also given to the rats prior to melatonin treatment. Pretreatment with melatonin (10 mg/kg) effectively reduced cardiac I/R injury by reducing infarct size, arrhythmia, and LV dysfunction. Reduction in impaired mitochondrial function, mitochondrial dynamic balance, oxidative stress, defective autophagy, and apoptosis were observed in rats pretreated with melatonin. Unfortunately, the cardioprotective benefits were not observed when 10-mg/kg of melatonin was acutely administered to the rats after cardiac ischemia. Thus, we increased the dose of melatonin to 20 mg/kg, and it was administered to the rats during ischemia or at the onset of reperfusion. The results showed that 20-mg/kg of melatonin effectively reduced cardiac I/R injury to a similar extent to the 10-mg/kg pretreatment regimen. The MT2 blocker inhibited the protective effects of melatonin. Acute melatonin treatment during cardiac I/R injury exerted protective effects in prediabetic obese rats. However, a higher dose of melatonin is required when given after the onset of cardiac ischemia. These effects of melatonin were mainly mediated through activation of MT2. [ABSTRACT FROM AUTHOR]

Melatonin is a hormone of the epiphysis and a regulator of circadian rhythms of living organisms, which affects a number of important physiological processes. Melatonin synthesis has also been found in other organs, in particular in various structural systems of the eyeball. A number of studies demonstrate that melatonin plays an important role in a variety of biochemical and physiological processes that ensure functioning of visual analyzer. This review provides information on the synthesis of melatonin, its secretion and metabolism, considers key information about melatonin receptors (MT1, MT2 and MT3), their localization in various eye’s structures, and their affinity to melatonin. Over the last years, researchers’ attention has been drawn to the therapeutic properties of melatonin, relevant for treatment of age-related diseases. The aggressive effects of solar radiation and environmental toxicants expose the organ of vision to oxidative attacks. A large amount of evidence has been accumulated of the participation of oxidative stress in the development of many eye diseases, resulting in an imbalance between the generation of reactive oxygen species and the expression of antioxidant enzymes. Melatonin, which has antioxidant and anti-inflammatory properties and regulates mitochondrial functions, can be a powerful tool to counter age-related changes. Globally, the number of people of all ages with visual impairment is estimated at 285 million. Cataract and age-related macular degeneration (AMD) are the leading causes of vision loss around the world. AMD and cataracts often coexist in patients, so there is a concern that age-related cataract surgery increases the risk of morbidity and progression of AMD. The pathogenesis of both cataracts and AMD is still unclear, although a number of theories have been put forward, including oxidative stress, age-related changes, inflammatory processes, etc. Analysis of modern domestic and foreign literature shows good perspectives of using melatonin as preventive and therapeutic agent in the treatment of ophthalmic diseases of various origins.

Introduction: Previous studies reported the beneficial effects of pretreatment with melatonin on the heart during cardiac ischemia/reperfusion (I/R) injury. However, the effects of melatonin given after cardiac ischemia, as well as its comparative temporal effects are unknown. These include pretreatment, during ischemia, and at the onset of reperfusion. Also, the association between melatonin receptors and cardiac arrhythmias, mitochondrial function and dynamics, autophagy, and mitophagy during cardiac I/R have not been investigated. Objectives: We tested two major hypotheses in this study. Firstly, the temporal effect of melatonin administration exerts different cardioprotective efficacy during cardiac I/R. Secondly, melatonin provides cardioprotective effects via MT2 activation, leading to improvement in cardiac mitochondrial function and dynamics, reduced excessive mitophagy and autophagy, and decreased cardiac arrhythmias, resulting in improved LV function. Methods: Male rats were subjected to cardiac I/R, and divided into 4 intervention groups: vehicle, pretreatment with melatonin, melatonin given during ischemia, and melatonin given at the onset of reperfusion. In addition, either a non-specific melatonin receptor (MT) blocker or specific MT2 blocker was given to rats. Results: Treatment with melatonin at all time points alleviated cardiac I/R injury to a similar extent, quantified by reduction in infarct size, arrhythmia score, LV dysfunction, cardiac mitochondrial dysfunction, imbalance of mitochondrial dynamics, excessive mitophagy, and a decreased Bax/Bcl2 ratio. In H9C2 cells, melatonin increased %cell viability by reducing mitochondrial dynamic imbalance and a decrease in Bax protein expression. The cardioprotective effects of melatonin were dependent on MT2 activation. Conclusion: Melatonin given before or after ischemia exerted equal levels of cardioprotection on the heart with I/R injury, and its beneficial effects on cardiac arrhythmias, cardiac mitochondrial function and dynamics were dependent upon the activation of MT2.

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT 1 /MT 2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress. • Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. • Ramelteon markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. • Activation of melatonin receptors balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. • Ramelteon protects RSDS-elicited behavioral changes through the MT 1 receptor in the hippocampus. [ABSTRACT FROM AUTHOR]

This study investigated the seasonal variations in mRNA expression of FSH (Fshr), LH (Lhr) receptors, melatonin (Mt1 and Mt2) receptors, melatonin-synthetizing enzymes (Asmt and Aanat) and melatonin concentration in developing follicles from mares raised in natural photoperiods. For one year, ultrasonographic follicular aspiration procedures were performed monthly, and small (35 mm) follicles were recovered from five mares. One day before monthly sample collections, an exploratory ultrasonography conducted to record the number and the size of all follicles larger than 15 mm. The total number of large follicles were higher during the spring/summer (8.2 ± 1.9) than during autumn/winter (3.0 ± 0.5). Compared to autumn/winter seasons, there was an increase of Fshr and Aanat mRNA expressions in small, medium and large follicles, an increase of Lhr and Asmt mRNA expressions in medium and large follicles and an increase of Mt1 and Mt2 mRNA expressions in small and large follicles during spring/summer. The melatonin levels in follicular fluid were also higher during the spring/summer seasons. The present data show that melatonin locally upregulates the mRNA expression of Mt1 and Mt2 receptors and melatonin-forming enzymes in mare developing follicles during reproductive seasons.

Preclinical and clinical evidence supports melatonin and its analogues as potential treatment for diseases involving cognitive deficit such as Alzheimer's disease. In this work, we evaluated by in silico studies a set of boron-containing melatonin analogues on MT1 and MT2 receptors. Then, we synthesized a compound (borolatonin) identified as potent agonist. After chemical characterization, its evaluation in a rat model with cognitive deficit showed that it induced ameliorative effects such as those induced by equimolar administration of melatonin in behavioral tests and in neuronal immunohistochemistry assays. Our results suggest the observed effects are by means of action on the melatonin system. Further studies are required to clarify the mechanism(s) of action, as the beneficial effects on disturbed memory by gonadectomy in male rats are attractive. [ABSTRACT FROM AUTHOR]

In most fish, reproduction is seasonal or periodic under the suitable conditions. In turbot (Scophthalmus maximus) farms, one of the most economically important marine flatfish species, changes in daylength could cause changes in the spawning time. In this study, to characterize the regulation of reproductive physiology following light signals, three melatonin receptors (Mtnr) investigated in turbot were named smMtnr1, smMtnr2, and smMtnr1c. Distinct expression profiles demonstrated that Mtnr mRNAs were concentrated in the brain (as detected in the hypothalamus (Hy) and mesencephalon (Me)), gonad and eye. The most abundant Mtnr1 and Mtnr2 mRNA expression levels were detected in the central nervous system at the beginning of the breeding season, suggesting that Mtnr1 and Mtnr2 may play vital roles in the regulation of turbot gonadal development. In addition, the melatonin profiles gradually increased and reached to the highest level at the spawning stage, indicating that melatonin is a potent hormone in the regulation of fish oocyte growth and maturation. The results of this study suggested that melatonin is the primary factor that transduces the light signal and regulates the physiological functions of turbot seasonal reproduction. Moreover, the results of this study may establish a foundation for further research seeking to identify fish melatonin receptors involved in the gonadal development and gamete maturation. [ABSTRACT FROM AUTHOR]

Tissue injury healing is impaired in aging, and this impairment is caused in part by reduced angiogenesis. Melatonin, a neuroendocrine hormone that regulates sleep and circadian rhythm, is also produced in the gastrointestinal tract. The expression of melatonin receptors MT1 and MT2 in gastric endothelial cells and their roles in aging-related impairment of gastric angiogenesis have not been examined. We hypothesized that MT1 and MT2 expression is reduced in gastric endothelial cells of aging rats and that melatonin treatment can upregulate their expression and improve angiogenesis. We examined the expression of MT1 and MT2 in gastric endothelial cells (GECs) isolated from young and aging rats. We also examined the effects of melatonin treatment on angiogenesis, GEC mitochondrial function, expression of vascular endothelial growth factor (VEGF), its signaling receptor (VEGFR-2), and the inhibitor of apoptosis protein, survivin. Young and aging GECs expressed MT1 (in the cytoplasm and mitochondria) and MT2 (in nucleus and mitochondria). In aging GECs, MT1 and MT2 levels, in vitro angiogenesis, and mitochondrial membrane potential were significantly reduced (by 1.5-fold, 1.9-fold, 3.1-fold, and 1.63-fold, respectively) compared with young GECs. Melatonin treatment of aging GECs significantly increased MT1 and MT2 expression compared with the controls, induced nuclear translocation of MT1, and significantly ameliorated the aging-related impairment of angiogenesis and mitochondrial function. Aging GECs have significantly reduced MT1 and MT2 expression, angiogenesis, and mitochondrial membrane potential compared with young GECs. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function. NEW & NOTEWORTHY This study showed reduced expression of melatonin receptors MT1 and MT2, angiogenesis, and mitochondrial function in gastric endothelial cells (GECs) isolated from aging rats. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function. These studies provide new insight into the mechanisms of the aging-related impairment of angiogenesis and delayed tissue injury healing and provide a rationale for melatonin treatment to reverse these abnormalities. [ABSTRACT FROM AUTHOR]

Treatment of complications of peptic ulcer disease is an urgent problem in abdominal surgery due to the high prevalence of bleeding (19-57) and perforations (3-14 cases per 100,000 population).The objective of the study was to assess the possibility of predicting the development of ulcerative disease complications determining the ratio of the level of melatonin receptors (MT1/MT2) in the duodenal mucosa.Methods and materials. 56 patients with different course of peptic ulcer disease were examined. All patients underwent esophagogastroduodenoscopy with biopsy of the bulb duodenum. Biopsies were analyzed on a flow cytometer. The results were statistically processed.Results. The ratio of melatonin receptors MT1/MT2 significantly differed in the group of patients with bleeding and in the group with perforation. During the statistical analysis, it was found that at a value of MT1/MT2≥1,7, it is possible to assume the development of complications in the patient in the form of perforation or bleeding.Conclusion. The method of determining the ratio of melatonin receptors (MT1/MT2) in patients with complicated peptic ulcer disease can be used for prediction the risk of complications.

Aim. To investigate the specific features of the expression of second-type melatonin receptors (MTNR1B) by epithelial cells of the distal esophagus in gastroesophageal reflux disease (GERD), depending on the severity of endoscopic changes in the mucous membrane.Materials and methods. The study included 48 GERD patients, out of whom 37 and 11 people were suffering from non-erosive reflux disease (NERD) and erosive reflux disease (ERD), respectively. The control group consisted of 18 patients without GERD, comparable with the main groups by gender, age and body mass index. In order to determine the expression of MTNR1B, esophagogastroduodenoscopy with the collection of biopsy material from the mucous membrane of the distal esophagus was performed. The quantification of the MTNR1B expression intensity was carried out using the Aperio ImageScope_v9.1.19.1567 software. The level of melatonin metabolite, 6-sulphatehydroxymelatonin (6-SOMT), was determined in daily urine, as well as separately in daytime and nighttime portions.Results. The intensity of MTNR1B expression by esophageal epithelial cells in patients with NERD demonstrated no difference with the control group (0.436 (0.123, 0.668) and 0.437 (0.202, 0.692), respectively; p> 0.05). A significant decrease in the expression of MTNR1B receptors was noted in patients with ERD compared to NERD patients (0.127 (0.059, 0.156) and 0.436 (0.123, 0.668), respectively; p = 0.017) and patients in the control group (0.437 (0.202, 0.692); p = 0.033). The low intensity of MTNR1B expression was associated with more pronounced endoscopic changes in the mucous membrane of the esophagus (r = –0.40; p = 0.0015). A statistically significant relationship was found between the expression intensity of MTNR1B and the level of melatonin in the daytime (r = 0.42; p = 0.018), as well as the night/day index reflecting the daily rhythm of melatonin synthesis (r = –0.43; p = 0.016).Conclusions. The obtained data indicate that a decrease in the intensity of MTNR1B expression by esophageal epithelial cells can be considered as a prognostically unfavourable sign of the GERD course. The low intensity of MTNR1B expression is associated with a more severe (erosive) form of GERD and more pronounced endoscopic changes in the mucous membrane of the esophagus.

Glaucoma, a major ocular neuropathy originating from a progressive degeneration of retinal ganglion cells, is often associated with increased intraocular pressure (IOP). Daily IOP fluctuations are physiologically influenced by the antioxidant and signaling activities of melatonin. This endogenous modulator has limited employment in treating altered IOP disorders due to its low stability and bioavailability. The search for low-toxic compounds as potential melatonin agonists with higher stability and bioavailability than melatonin itself could start only from knowing the molecular basis of melatonergic activity. Thus, using a computational approach, we studied the melatonin binding toward its natural macromolecular targets, namely melatonin receptors 1 (MT1) and 2 (MT2), both involved in IOP signaling regulation. Besides, agomelatine, a melatonin-derivative agonist and, at the same time, an atypical antidepressant, was also included in the study due to its powerful IOP-lowering effects. For both ligands, we evaluated both stability and ligand positioning inside the orthosteric site of MTs, mapping the main molecular interactions responsible for receptor activation. Affinity values in terms of free binding energy (ΔGbind) were calculated for the selected poses of the chosen compounds after stabilization through a dynamic molecular docking protocol. The results were compared with experimental in vivo effects, showing a higher potency and more durable effect for agomelatine with respect to melatonin, which could be ascribed both to its higher affinity for hMT2 and to its additional activity as an antagonist for the serotonin receptor 5-HT2c, in agreement with the in silico results.