Search Results (116)

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

Recently, it has been proposed that plant melatonin receptors belong to the superfamily of G protein-coupled receptors (GPCRs). However, a detailed description of the phylogeny, protein structure, and binding properties of melatonin, which is still lacking, can help determine the signaling and function of this compound. Melatonin receptor homologs (PMTRs) were identified in 90 Viridiplantae sensu lato proteomes using profile Hidden Markov Models (HMM), which yielded 174 receptors across 87 species. Phylogenetic analysis revealed an expansion of PMTR sequences in angiosperms, which were grouped into three clades. Docking studies uncovered a conserved internal melatonin-binding site in PMTRs, which was analogous to the site in human MT1 receptors. Binding affinity simulations indicated this internal site exhibits stronger melatonin binding compared to a previously reported superficial pocket. Ligand–receptor interaction analysis and alanine scanning highlighted a major role of hydrophobic interactions, with hydrogen bonds contributing predominantly at the internal site, while non-interacting charged residues stabilize the binding pocket. Tunnel and ligand transport simulations suggested melatonin moves favorably through the internal cavity to access the binding site. Also, we presented for the first time details of these pockets in a non-model species, Capsicum chinense. Taken together, the structural analyses presented here illustrate opportunities and theoretical evidence for performing structure–function studies via mutations in specific residues within the proposed new melatonin-binding site in PMTRs, shedding light on their role in plant melatonin signaling. Full article

A significant proportion of children with Autism spectrum disorder (ASD) experience sleep issues, such as insomnia and other disorders, as assessed by the Sleep Disturbance Scale for Children. Our study investigated the link between six single nucleotide polymorphisms (SNPs) in the melatonin receptor genes MT1 and MT2 and ASD susceptibility, clinical severity and associated sleep problems. A total of 139 ASD children, 82 siblings, and 53 unrelated healthy controls, all of Sardinian ancestry, were studied; among them, 38 children with co-occurring sleep issues were assessed for the outcomes of a rehabilitative program, including behavioral therapy and sleep hygiene. The MT2 rs10830963 G allele is more prevalent in ASD children and their siblings compared to the healthy controls, while rs2119882 (MT1) and rs1562444 (MT2) are associated with DIMS, DA, and SHY. ASD Children carrying the rs2119882 T allele have higher scores for DIMS and DA compared to C allele carriers, and those carrying rs1562444 A allele have higher scores for SHY than G allele carriers. After rehabilitative treatment, homozygous TT carriers of rs2119882 showed less improvement in DIMS symptoms compared to CT and CC carriers. A similar result was observed for AA carriers of SNP rs1562444 about SHY. We may suggest that the MT1 and MT2 variants may serve as useful predictive genetic markers for the severity of sleep disorders in children with ASD, potentially informing the design of more targeted rehabilitative treatments. Full article

Background: Glaucoma is a leading cause of irreversible visual loss worldwide, characterized by progressive retinal ganglion cell (RGC) degeneration and optic nerve damage. Current therapies mainly focus on lowering intraocular pressure (IOP), yet fail to address pressure-independent neurodegenerative mechanisms. Melatonin, an endogenously produced indoleamine, has gained attention for its potential in modulating both IOP and neurodegeneration through diverse cellular pathways. This review evaluates the therapeutic relevance of melatonin in glaucoma by examining its mechanistic actions and emerging delivery approaches. Methods: A comprehensive literature search was conducted via PubMed and Medline to identify studies published between 2000 and 2025 on melatonin’s roles in glaucoma. Included articles discussed its effects on IOP regulation, RGC survival, oxidative stress, mitochondrial integrity, and inflammation. Results: Evidence supports melatonin’s involvement in IOP reduction via MT receptor activation and its synergism with adrenergic and enzymatic regulators. Moreover, it protects RGCs by mitigating oxidative stress, preventing mitochondrial dysfunction, and inhibiting apoptotic and inflammatory cascades. Recent advances in ocular drug delivery systems enhance its bioavailability and therapeutic potential. Conclusions: Melatonin represents a multi-target candidate for glaucoma treatment. Further clinical studies are necessary to establish optimal dosing strategies, delivery methods, and long-term safety in patients. Full article

Laboratory and animal studies indicate that melatonin exerts a negative impact on breast cancer progression and metastasis. These actions are both receptor-dependent and -independent. Of the two transmembrane melatonin receptors identified in humans, breast cancer expresses only MT1. The aim of this study was to investigate the expression of MT1 in hormone-receptor-positive, HER2-negative invasive ductal breast carcinoma in postmenopausal women and its possible correlations with clinicopathological parameters and survival. A total of 118 patients with luminal A/B primary breast cancer with or without axillary metastases were identified. The MT1 receptor expression was immunohistochemically assessed as a percentage of stained cells and a weighted index (WI) (percentage multiplied by staining intensity). Most tumor samples (84.7%) and metastasized lymph nodes (96%) stained positive for MT1, with varying intensity. No statistically significant correlations were found between the MT1 expression or the WI in the primary tumor and the patient and tumor characteristics, or the MT1 and WI in the metastasized lymph nodes. The survival analysis did not reveal a significant effect of MT1 expression or the WI on the risk of recurrence or survival. Full article

Prenatal constant light exposure (CLE) impaired the anxiety response and circadian rhythms of testicular enzymes in adult male rat offspring, while melatonin corrected these deficiencies. However, the mechanism by which CLE induces these long-term behavioral consequences and the impact of melatonin system have not been examined. The aim of the present study was to investigate the effects of prenatal CLE and melatonin treatment on anxiety- and depression-like behaviors, and the melatonin system in male and female adult rat offspring. Six groups of male and female rat offspring (P60) exposed to either light/dark (LD) or CL regimes, and treated with vehicle or melatonin (10 mg/kg, s.c.) were evaluated for anxiety by open field (OF), elevated plus maze (EPM), and light/dark (LD) tests, and depressive-like response by splash test and sucrose preference test. Plasma adrenocorticotropic hormone (ACTH), corticosterone (CORT) and melatonin expression, and hippocampal MT1A and MT1b receptor expression were assessed by ELISA. Prenatal CLE induced behavioral deficits and elevated plasma CORT levels, while melatonin levels, their circadian rhythmicity, and hippocampal MT receptor expression were not altered in male and female offspring in the CLE regime. However, prenatal melatonin treatment corrected behavioral deficits in a sex-specific manner by up-regulating hippocampal MT receptors, even without altering systemic melatonin levels or normalizing CORT in either sex. The results of this study suggest critical insights into how prenatal environmental factors and therapeutic interventions shape physiological and behavioral outcomes. Full article

Rhododendron simsii (R. simsii), a significant ornamental plant species, is adversely affected by the severe soil heavy metal pollution resulting from rapid industrialization, particularly in terms of its growth environment. Cadmium (Cd), a representative heavy metal pollutant, poses a significant threat to plant growth and photosynthetic physiology. Despite the importance of understanding Cd stress resistance in rhododendrons, research in this area is limited. This study focused on the role of exogenous melatonin (MT) in mitigating Cd-induced stress, emphasizing its impact on photosynthetic physiology. Gas exchange parameters, prompt and delayed fluorescence (DF), 820 nm modulated reflectance (Mr₈₂₀), and antioxidant enzyme activity, were measured. The findings revealed that under Cd stress, MT-free treatment imposed a more severe limitation on both stomatal and non-stomatal processes in R. simsii leaves, significantly reducing the net photosynthetic rate. In contrast, exogenous MT improved photosynthetic efficiency by increasing the maximum photochemical efficiency of photosystem II, the quantum yield of electron transport, and the photosynthetic performance index. DF and Mr₈₂₀ analysis demonstrated that MT provided robust protection to both the donor and receptor sides of photosystems I and II. Furthermore, MT significantly decreased malondialdehyde (MDA) content, a marker of oxidative stress, and enhanced the activity of antioxidant enzymes, including superoxide dismutase (SOD) and guaiacol peroxidase (POD). In conclusion, exogenous MT plays a critical role in alleviating Cd-induced stress by enhancing antioxidant defense mechanisms and safeguarding the photosynthetic apparatus, thereby improving the Cd tolerance of R. simsii. Full article

Camels (Camelus dromedarius) are seasonal short-day breeders, regulated by photoperiod and melatonin secretion. However, no studies have explored melatonin levels in camel seminal plasma or their relationship with testosterone, age, or climatic factors, nor is it known whether melatonin receptors exist in camel spermatozoa to respond to seminal melatonin. This study aimed to analyze melatonin levels in camel seminal plasma and its specific receptors in spermatozoa. Semen samples were obtained from November to March (breeding season). Testosterone and melatonin levels were measured in seminal plasma by ELISA. Melatonin receptors were localized in spermatozoa using immunofluorescence, and their presence was confirmed by Western Blot. Melatonin levels were higher from November to January and decreased in February and March. No correlation between testosterone and melatonin levels was found, but both hormones were negatively correlated with daylength (p = 0.0089 and p = 0.0688, respectively). Testosterone, but not melatonin, levels were affected by age. Two melatonin receptors (MT1, MT2) were detected on camel spermatozoa, with several immunotypes labeled mainly in the tail and post-acrosome region, but also in the acrosome and neck. Western Blot analysis confirmed the presence of these receptors, showing a 39 kDa band for MT1 and a 36 kDa band for MT2. Understanding melatonin’s effects on sperm could help ejaculates’ processing procedures, semen handling, and infertility issues in camels. Full article

Endoplasmic reticulum (ER) stress is a crucial factor in the progression of obesity-related type 2 diabetes (diabesity), contributing to skeletal muscle (SKM) dysfunction, calcium imbalance, metabolic inflexibility, and muscle atrophy. The ER and mitochondria together regulate intracellular calcium levels, and melatonin, a natural compound with antioxidant properties, may alleviate these challenges. Our previous research showed that melatonin raises intracellular calcium and preserves muscle structure by enhancing mitochondrial function in obese diabetic rats. This study further explores melatonin’s potential to reduce ER stress in the vastus lateralis (VL) muscle by modulating the unfolded protein response (UPR) and restoring calcium levels disrupted by diabesity. Five-week-old Zücker diabetic fatty (ZDF) rats and lean littermates of both sexes were divided into control and melatonin-treated groups (10 mg/kg/day for 12 weeks). Flame atomic absorption spectrometry results showed that melatonin restored VL intraorganellar calcium homeostasis, increasing calcium levels in mitochondria and reducing them in the ER by raising the activity and expression of calcium transporters in both sexes of ZDF rats. Melatonin also decreased ER stress markers (GRP78, ATF6, IRE1α, and PERK) and reduced pro-apoptosis markers (Bax, Bak, P-JNK, cleaved caspase 3 and 9) while increasing Bcl2 levels and melatonin receptor 2 (MT2) expression. These findings suggest that melatonin may protect against muscle atrophy in obese and diabetic conditions by mitigating ER stress and calcium imbalance, highlighting its therapeutic potential. Full article

Circadian rhythms are important for maintaining homeostasis, from regulating physiological activities (e.g., sleep–wake cycle and cognitive performance) to cellular processes (e.g., cell cycle and DNA damage repair). Melatonin is a key regulator of circadian rhythms and exerts control by binding to melatonin receptor 1 (MT1), decreasing neuronal firing in the suprachiasmatic nucleus (SCN). Previous work studying effects of melatonin on circadian rhythms utilized in vivo models. Since MT1 is also expressed outside of the brain, it is important to study impacts of melatonin on circadian gene oscillations in vitro. We evaluated the effects of melatonin and an MT1 inverse agonist, UCSF7447, in U2OS circadian reporter cell lines, which facilitate detailed assessments of oscillatory changes. We report that cellular circadian rhythms are responsive to treatment with MT1-targeting molecules; their activities are not dependent upon the SCN. Corroborating in vivo data, both melatonin and UCSF7447 lengthened the periods of BMAL1 and PER2, and while melatonin delayed circadian phases, UCSF7447 advanced them. Compounds were also dosed at two different times, however this did not yield changes. Our findings indicate the importance of utilizing in vitro models and that the direct effects of melatonin likely go beyond the SCN and should be explored further. Full article

Background: Morphine analgesic tolerance (MAT) limits the clinical application of morphine in the management of chronic pain. IIK7 is a melatonin type 2 (MT2) receptor agonist known to have antioxidant properties. Oxidative stress is recognized as a critical factor in MAT. This study sought to assess the impact of IIK7 on the progression of MAT and its potential to reverse pre-existing MAT. Methods: Wistar rats underwent partial sciatic nerve transection (PSNT) surgery to induce neuropathic pain (NP). Seven days post nerve transection, we implanted an intrathecal (i.t.) catheter and linked it to an osmotic pump. Rats were randomly divided into the following groups: sham-operated/vehicle, PSNT/vehicle, PSNT/IIK7 50 ng/h, PSNT/MOR 15 g/h, and PSNT/MOR 15 g + IIK7 50 ng/h. We implanted two i.t. catheters for drug administration and the evaluation of the efficacy of IIK7 in reversing pre-established MAT. We linked one to an osmotic pump for MOR or saline continuous i.t. infusion. On the 7th day, the osmotic pump was disconnected, and 50 μg of IIK7 or the vehicle was administered through the second catheter. After 3 h, 15 μg of MOR or saline was administered, and the animal behavior tests were performed. We measured the levels of mRNA for Nrf2 and HO-1, pro-inflammatory cytokines (PICs), and the microglial and astrocyte activation in the spinal cord. Results: The co-administration of IIK7 with MOR delayed MAT development in PSNT rats by restoring Nrf2 and HO-1 while also inhibiting the microglial-cell and astrocyte activation, alongside the suppression of PICs. Additionally, a single injection of high-dose 50 μg IIK7 was efficient in restoring MOR’s antinociception in MOR-tolerant rats. Conclusions: Our results indicate that the co-infusion of ultra-low-dose IIK7 can delay MAT development and a high dose can reverse pre-existing MAT. Full article

In mammals, the melatonin (Mel) concentration in the gastrointestinal tract is 400 times greater than in the pineal gland. However, the origin of Mel in the gastrointestinal tract and its role in reproductive regulation remains unclear. Therefore, we analyzed three potential Mel sources (feed, microorganisms, and the rumen wall) for their contribution to high Mel levels in the rumen and their biological effects. The feed contained high Mel concentrations, and Mel in rumen fluid and blood peaked two hours after feeding. Rumen microbial analysis showed a strong positive correlation between Mel and specific microbes, including Megasphaera, Butyrivibrio, Acetobacter, and Olsenella. In vitro experiments indicated that rumen microorganisms synthesized Mel from tryptophan. The rumen wall also contains key enzymes, AANAT and HIOMT, which catalyze Mel synthesis and membrane receptors MT1 and MT2 that mediate the function of Mel, suggesting that the rumen wall synthesizes Mel. Mel peaked in both rumen fluid and blood two hours after feeding. Feeding also altered blood levels of Mel, Gonadotropin-releasing hormone (GnRH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), progesterone (P4), and Estradiol (E2), with a correlation between Mel and fluctuations in GnRH, LH, P4, and E2 levels. Our findings suggest that feed is the primary source of high Mel levels in the rumen and impacts reproductive hormone fluctuations. This study elucidates the origin of high rumen Mel concentrations and reveals that food intake affects the natural secretion of various hormones, offering a new perspective on food sources for regulating reproductive physiology. Full article

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. Full article

Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary tumor microenvironment, there is a cell subpopulation called cancer stem cells (CSCs), which are capable of forming spheres in vitro and resisting anti-tumor treatments, partly explaining the recurrence of some tumors. Previously, it has been described that spheres derived from canine mammary carcinoma cells CF41.Mg and REM 134 exhibit stemness characteristics. Melatonin has shown anti-tumor effects on mammary tumor cells; however, its effects have been poorly evaluated in canine mammary CSCs. This study aimed to analyze the effect of melatonin on the chemoresistance exhibited by stem-like neoplastic cells derived from canine mammary carcinoma to cytotoxic drugs such as doxorubicin and mitoxantrone. CF41.Mg and REM 134 cells were cultured in high-glucose DMEM supplemented with fetal bovine serum and L-glutamine. The spheres were cultured in ultra-low attachment plates in DMEM/F12 medium without fetal bovine serum and with different growth factors. The CD44⁺/CD24^−/low phenotype was analyzed by flow cytometry. The viability of sphere-derived cells (MTS reduction) was studied in the presence of melatonin (0.1 or 1 mM), doxorubicin, mitoxantrone, and luzindole. In addition, the gene (RT-qPCR) of the multidrug resistance bombs MDR1 and ABCG2 were analyzed in the presence of melatonin. Both cell types expressed the MT1 gene, which encodes the melatonin receptor MT1. Melatonin 1 mM does not modify the CD44⁺/CD24^−/low phenotype; however, the hormone reduced viability (p < 0.0001) only in CF41.Mg spheres, without inducing an additive effect when co-incubated with cytotoxic drugs. These effects were independent of the binding of the hormone to its receptor MT1, since, by pharmacologically inhibiting them, the effect of melatonin was not blocked. In CF41.Mg spheres, the relative gene expression of ABCG2 and MDR1 was decreased in response to the hormone (p < 0.001). These results indicate that melatonin negatively modulates the cell survival of spheres derived from CF41.Mg cells, in a way that is independent of its MT1 receptor. These effects did not counteract the resistance to doxorubicin and mitoxantrone, even though the hormone negatively regulates the gene expression of MDR1 and ABCG2. Full article

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. Full article