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Polycystic ovary syndrome (PCOS) is an endocrine disorder seen in women of reproductive age and has been gradually increasing over the years. The mechanism of the syndrome has still not been clearly understood. In this study, the possible effects of exogenously administrated melatonin on melatonin (MT1) receptor, Growth Differentiation Factor-9 (GDF9), and Bone Morphogenetic Protein-15 (BMP15) in experimental PCOS were investigated. Thirty-two 6-8-week-old Sprague-Dawley rats were randomly divided into four groups (n = 8 in each) as Sham control (Group 1), Melatonin (Group 2), PCOS (Group 3), and PCOS + Melatonin (Group 4) groups. At the end of the 21st day, the experiment was terminated, the ovary tissues were taken, and Hematoxylin-Eosin staining, MT1, GDF9, BMP15 immunohistochemical labeling, western blot, and quantitative real-time polymerase chain reaction (qPCR) analyses were performed. Serum Luteinizing Hormone (LH)/Follicle Stimulating Hormone (FSH) levels and colpo-cytological examinations were also carried out. The results revealed that melatonin administration increased the expression levels of the MT1 receptor, GDF9, and BMP15 in PCOS at protein and mRNA levels. It was determined that melatonin administration reduced the microscopic symptoms of PCOS. Melatonin was found to be effective via the MT1 receptor in the pathogenesis of PCOS, and it suppressed the transport pathways of GDF9 to granulosa cells in antral follicles., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Exogenous melatonin inhibited the senescence of preosteoblast cells in type 1 diabetic (T1D) mice and those cultured in high glucose (HG) by multiple regulations. Exogenous melatonin had a protective effect on diabetic osteoporosis, which may depend on the inhibition of senescence., Introduction: Senescence is thought to play an important role in the pathophysiological mechanisms underlying diabetic bone loss. Increasing evidence has shown that melatonin exerts anti-senescence effects. In this study, we investigated whether melatonin can inhibit senescence and prevent diabetic bone loss., Methods: C57BL/6 mice received a single intraperitoneal injection of 160 mg/kg streptozotocin, followed by the oral administration of melatonin or vehicle for 2 months. Then, tissues were harvested and subsequently examined. MC3T3-E1 cells were cultured under HG conditions for 7 days and then treated with melatonin or not for 24 h. Sirt1-specific siRNAs and MT1- or MT2-specific shRNA plasmids were transfected into MC3T3-E1 cells for mechanistic study., Results: The total protein extracted from mouse femurs revealed that melatonin prevented senescence in T1D mice. The micro-CT results indicated that melatonin prevented bone loss in T1D mice. Cellular experiments indicated that melatonin administration prevented HG-induced senescence, whereas knockdown of the melatonin receptors MT1 or MT2 abolished these effects. Sirt1 expression was upregulated by melatonin administration but significantly reduced after MT1 or MT2 was knocked down. Knockdown of Sirt1 blocked the anti-senescence effects of melatonin. Additionally, melatonin promoted the expression of CDK2, CDK4, and CyclinD1, while knockdown of MT1 or MT2 abolished these effects. Furthermore, melatonin increased the expression of the polycomb repressive complex (PRC), but knockdown of MT1 or MT2 abolished these effects. Furthermore, melatonin increased the protein levels of Sirt1, PRC1/2 complex-, and cell cycle-related proteins., Conclusion: This work shows that melatonin protects against T1D-induced bone loss, probably by inhibiting senescence. Targeting senescence in the investigation of diabetic osteoporosis may lead to novel discoveries., (© 2021. The Author(s).)

Sevoflurane (Sev) is one of the most widely used pediatric anesthetics. The major concern of neonatal repeated application of Sev is its potential long-term impairment of cognition and learning/memory, for which there still lacks effective treatment. At the cellular level, Sev exerts toxic effects in multiple aspects, making it difficult for effective interference. Melatonin is a pineal hormone regulated by and feedbacks to biological rhythm at physiological condition. Recent studies have revealed significant neuroprotective effects of exogenous melatonin or its agonists under various pathological conditions. Whether melatonin could prevent the long-term toxicity of Sev remains elusive. Here, we report that neonatal repeated Sev exposure up-regulated MT1 receptor in hippocampal neurons and oligodendrocytes. Pretreatment with melatonin significantly alleviated Sev-induced synaptic deficiency, dysmyelination, and long-term learning impairment. Both MT1-shRNA and MT1 knockout effectively blocked the protective effects of melatonin on synaptic development, myelination, and behavior performance. Interestingly, long-lasting suppression of Wnt signaling, instead of cAMP/PKA signaling, was observed in hippocampal neurons and oligodendrocytes after neonatal Sev exposure. Pharmacologically activating Wnt signaling rescued both the long-term synaptic deficits and dysmyelination induced by Sev. Further analysis showed that MT1 receptor co-expressed well with β-catenin and Axin2 and bound to β-catenin by its C-terminal. Melatonin pretreatment effectively rescued Sev-induced Wnt suppression. Wnt signaling inhibitor XAV939 significantly compromised the protective effects of melatonin. Taken together, our data demonstrated a beneficial effect of melatonin pretreatment on the long-term synaptic impairment and dysmyelination induced by neonatal Sev exposure, and a novel MT1 receptor-mediated interaction between melatonin and canonical Wnt signaling, indicating that melatonin may be clinically applied for improving the safety of pediatric Sev anesthesia., (© 2021 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

Osteoporosis and neurodegenerative diseases are common diseases in the aging population. Studies demonstrate the complex communication among skeletal, muscular, and nervous systems and point to the emerging roles of neuromuscular systems in bone homeostasis. The discovery that the nervous system directly regulates bone remodeling implies that osteoporosis is a neuroskeletal disease. Melatonin, a hormone secreted from the pineal gland, is a melatonin receptor 1A (MT1) and 1B (MT2) agonist and influences the function of diverse systems. Melatonin is a pharmaceutical ingredient in numerous medicines, over-the-counter medicines, nutraceuticals, and dietary supplements, which benefit disease prevention and treatment, including osteoporosis and neurodegenerative diseases. This review aims to summarize the recent advances in preventing senile, postmenopausal, and neurodegenerative osteoporosis with melatonin and provide new insights into how neuromuscular systems influence bone homeostasis. More preclinical and clinical studies in neuroskeletal biology will eventually improve the lives of people fighting osteoporosis., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm. Here we aim to study the specific role of each melatonin receptor (MT 1 and MT 2 ) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors. MT 1 -/- , MT 2 -/- and WT (C57BL/6) mice were used.  Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice. MT 2 -/- mice showed anhedonia and lower CBT compared to WT and MT 1 -/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT 2 -/- mice. Further, MT 2 -/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia. Our findings show a primary role for MT 2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function., Competing Interests: Declaration of Competing Interest All the authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

The aim of this study was to characterize the MTNR1A locus in Sarda sheep breed, in order to identify potential single nucleotide polymorphisms (SNPs) associated with reproductive resumption. The reproductive performance of 200 lactating ewes, aged 3-5 years, with body condition score (BCS) 2.5-4.0, at least at their third lambing were monitored for two consecutive years. In both year the enrolled ewes were exposed for 100 days to 10 adult, fertile rams. Mating, pregnancy and lambing for each ewe were recorded in order to evaluate differences in reproductive performance according to the analysed genotypes. From individual blood samples, DNA was extracted to amplify and to sequence promotor, the coding region, a part of intron and of 3' Untranslated region (3' UTR) of the MTNR1A gene. A total number of 29 SNPs were found (named SNP1 to SNP29), five of which caused also amino acid changes. The polymorphic sites found at positions g.17355452C > T (SNP16, rs430181568) and g.17355358C > T (SNP17, rs407388227) were linked (D' = 1 and r 2  = 1) and showed a significant association to DRIL trait (distance in days from ram introduction to lambing). In both years, the ewes carrying C/C genotype in both these polymorphic sites showed the lowest DRIL compared to the other genotypes (P < 0.05). The ewes carrying C/C and T/C genotype exhibited the lambing peak at 170 days, and approximately 60% of the total lambing at 180 days from the ram introduction. Instead, ewes carrying T/T genotype showed the lambing peak around 200 days after ram introduction. Six haplotypes have been identified and the most frequent haplotype was also associated with lower DRIL (P < 0.05). Litter size displayed no statistical significance either among genotypes or among haplotypes. This study provided the major part of the MTNR1A gene in Sarda sheep breed and evidenced that SNP17 is associated with a shorter DRIL. The obtained results underlined the role of this polymorphism in improving reproductive efficiency in Sarda sheep and provides a suitable information for improving genetic selection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The melatonin receptor (MTNR) gene, reported to be associated with insulin sensitivity, diabetes and metabolic syndrome, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to investigate whether an association exists between two single nucleotide polymorphism (SNP) variants (rs2119882 and rs10830963) of the MTNR gene and PCOS in Han Chinese., Study Design: In total, 263 family trios (789 participants) were enrolled in this family-based transmission disequilibrium test (TDT). Genotypes were obtained by sequencing. In total, 135 trios of rs2119882 and 127 trios of rs10830963 were tested., Results: An association was detected between rs2119882 (p=0.0209) and PCOS, suggesting that the MTNR gene may indicate increased susceptibility to PCOS in Chinese. No significant association was found for rs10830963 (transmitted:non-transmitted=76:51, p=0.1573). The association between the MTNR gene variants and clinical characteristics of women with PCOS was investigated. CC genotype carriers had higher levels of clinical and metabolic features than the TC and TT genotypes. A significant difference in transmission of allele C of rs2119882 was found between obese and non-obese women with PCOS (Chi-squared=5.5983, p=0.018)., Conclusion: This study may provide a basis for further studies of the MTNR gene in the aetiology of PCOS., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Kynuramines, metabolites of melatonin and L-tryptophan, are synthesized endogenously by oxygenases or in spontaneous reaction by an interaction with free radicals. We have reported previously that melatonin stimulates expression and phosphorylation of heat shock protein (HSP) 27, as well as production of HSP70 and HSP90αβ in pancreatic carcinoma cells (PANC-1). Based on those results, we hypothesized that above processes could have been involved in the interruption of intrinsic proapoptotic pathway. Herein, we report that incubation of PANC-1 cells with N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) or with L-kynurenine (L-KYN) lead to the overexpression of heat shock protein synthesis and these effects are partially reversed by 5-HT3 or MT1/MT2 receptor antagonists. PANC-1 cells in culture were treated with AFMK or L-KYN, with non selective MT1/MT2 receptor antagonist (luzindole), with 5-HT2 and 5-HT3 receptor antagonists (ketanserin and MDL72222), or combination of these substances. Both AFMK and L-KYN significantly decreased cytoplasmic HSP27 and this effect was presumably due to increased of its phosphorylation and consequent nuclear translocation, confirmed by immunoprecipitation of phosphorylated form of HSP27. These changes were accompanied by marked augmentation of HSP70 and HSP90αβ in the cytosolic fraction. Pretreatment of cell cultures with luzindole or MDL72222 followed by the addition of AFMK or L-KYN reversed the stimulatory effects of these substances on HSP expression in PANC-1 cells, whereas ketanserin failed to influence mentioned above phenomenon. We conclude that activation of HSPs in pancreatic carcinoma cells seems to be dependent on an interaction of AFMK or L-KYN with MT1/MT2 or/and 5-HT3 receptors.

Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT(1)-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers., (Copyright 2010 Elsevier Ltd. All rights reserved.)