Melatonin is traditionally classified as a melanogenesis inhibitor. However, in some tissues it has been recently found to stimulate melanogenesis, paradoxically, with a parallel decrease of tyrosinase activity. This study explores this paradox by examining melatonin's potential role in pigment formation. Pigments were synthesized from DL-DOPA and melatonin via autooxidation or enzymatic reaction with tyrosinase. The resulting biopolymers were characterized using dry-mass determination, Electron Paramagnetic Resonance (EPR) spectroscopy, potentiometric titration, Dynamic Light Scattering (DLS), and spectrophotometry. The biological effect of melatonin supplementation on the mitochondrial activity of primary melanocyte cell culture (HEMn-DP) after solar-simulated illumination was assessed using the MTT assay. The presence of melatonin during autooxidation increased the overall melanin free radical signal as determined using EPR, however did not impact the signal during enzymatic synthesis. More so, enzymatic oxidation of melatonin alone yielded a detectable pigment (Melat-Mel) with about 4.4% efficiency. EPR spectra of melatonin-derived polymers and copolymers in the presence of zinc (II) ions and after thermal treatment demonstrated behavior typical to melanin pigments. UV-Vis spectrometry showed a change in the absorption profile for copolymer (DOPA/Melat-Mel) with higher UV and lower VIS absorbance compared with homopolymer (DOPA-Mel). DLS measurements confirmed the formation of supramolecular aggregation for all the examined variants. Potentiometric titration showed that copolymer with melatonin exhibits the highest buffering capacity among examined pigments. Loading of HEMn-DP cells with melatonin yielded a dose-dependent reduction of mitochondrial activity following solar-simulated light treatment with no dark toxicity observed. The study provides a chemical model that may help explain part of the "melatonin paradox" in pigmentation, while emphasizing that direct confirmation of melatonin-containing pigment formation in cells remains to be established.
Moderate nitrogen (N) reduction can lower production costs in upland rice but may constrain photosynthesis, N assimilation, and yield formation. Melatonin has the potential to regulate photosynthesis and nutrient metabolism; however, whether it improves the effectiveness of reduced N application by altering functional leaf N allocation remains unclear. A 2-year field experiment was conducted in 2024 and 2025 with four N application rates (0, 120, 160, and 200 kg N ha-1) and foliar applications of either water or 100 μmol L-1 melatonin. Photosynthetic performance, functional leaf N allocation, N metabolism, and grain yield were evaluated. An additional inhibition experiment using p-chlorophenylalanine (p-CPA) was also conducted. The beneficial effects of melatonin were observed mainly at N application rates of 120 and 160 kg N ha-1. In 2024 and 2025, grain yield under N2M1 was 7.27% and 8.19% higher, respectively, than under N2M0 and did not differ significantly from that under the conventional N treatment without melatonin (N3M0). Melatonin increased the net photosynthetic rate, maximum Rubisco carboxylation rate (Vcmax), and maximum electron transport rate (Jmax). At 160 kg N ha-1, the model-estimated proportion of N allocated to photosynthetic functions at the full heading stage increased from 73.55% to 86.79%, whereas the proportion of storage N decreased from 16.66% to 2.86%. Photosynthetic N-use efficiency (PNUE = Pn/leaf N content per unit area) increased by 11.10%, accompanied by improvements in nitrate reductase (NR) and glutamine synthetase (GS) activities and N fertilizer-use efficiency. The p-CPA treatment reduced endogenous melatonin content, photosynthetic performance, and N metabolism, whereas exogenous melatonin supplementation partially restored these responses. In conclusion, the effects of exogenous melatonin on upland rice were strongly dependent on N supply. At 160 kg N ha-1, melatonin produced marked compensatory effects on photosynthetic performance and grain yield. These responses were associated with improved photosynthetic capacity, model-estimated functional N allocation, and N assimilation, indicating that combining melatonin application with a 20% reduction in N fertilizer has potential for maintaining upland rice yield.
To evaluate the effects of melatonin on chondrogenic and osteogenic differentiation, chondro-osteogenic transdifferentiation, and inflammatory responses in equine mesenchymal stem cells (eMSCs) in vitro. This in vitro experimental study was conducted from October 2023 through June 2024. The eMSCs were cultured under chondrogenic, osteogenic, and chondro-osteogenic transdifferentiation conditions with or without melatonin and exposed to proinflammatory cytokines (IL-1β and tumor necrosis factor-α [TNF-α]). Expression of chondrogenic and osteogenic markers was measured by quantitative reverse-transcription PCR. Concentrations of IL-1β, TNF-α, IL-6, and IL-8 in culture supernatants were quantified by multiplex immunoassay. In chondrogenic cultures, melatonin was associated with increased collagen type II (COLII) and sex-determining region Y-box transcription factor 9 (SOX9) expression and was associated with higher COLII-to-collagen type I (COLI) and SOX9-to-runt-related transcription factor 2 (RUNX2) ratios, consistent with preservation of chondrogenic phenotype. During chondro-osteogenic transdifferentiation, melatonin increased RUNX2 and ALP expression and decreased COLII:COLI and SOX9:RUNX2 ratios, suggesting promotion of an early osteogenic or hypertrophic shift. In contrast, in osteogenic cultures, melatonin decreased RUNX2, ALP, and COLI expression, indicating context-dependent effects on osteogenic differentiation. Across culture conditions, melatonin significantly reduced IL-1β, TNF-α, IL-6, and IL-8 concentrations in culture supernatants. Melatonin differentially modulated lineage behavior in eMSCs, preserving chondrogenic characteristics in some settings, promoting early osteogenic transition during transdifferentiation, and suppressing proinflammatory mediator production. These findings support further investigation of melatonin as a potential adjunct for modulating proinflammatory responses during equine cartilage repair and other inflammatory musculoskeletal disorders.
Melatonin is the most widely used sleep aid in children, yet no large study has examined its association with objective sleep architecture measured by polysomnography (PSG). To assess whether outpatient melatonin use is associated with differences in PSG-derived sleep architecture in a pediatric sleep clinic population. This cross-sectional, propensity score-matched study used the Nationwide Children's Hospital Sleep DataBank, a deidentified dataset of PSG recordings and linked electronic health record data from children evaluated at a single academic pediatric sleep laboratory between 2017 and 2019. Children with at least 1 technically adequate PSG and complete electronic health record data were included; children older than 18 years were excluded. Data were analyzed from January to March 2026. Outpatient melatonin prescription documented in the medication list. The prespecified primary outcome was percentage of rapid eye movement (REM) sleep. Fourteen additional PSG parameters (sleep stages, respiratory indices, arousal index, periodic limb movements, oxygen desaturation index) were exploratory. Propensity score matching (1:1 nearest-neighbor, caliper 0.2 SD of the logit propensity score) on age, sex, body mass index percentile, comorbidity burden, obstructive sleep apnea, and epilepsy yielded 342 matched pairs (684 children). Outcomes were compared with 2-sided Wilcoxon signed-rank tests at α = .05; Benjamini-Hochberg false discovery rate (FDR) correction was applied across the 15 outcomes. The analytic cohort constituted 3392 children (mean [SD] age, 8.0 [5.0] years; 1924 male [56.7%]), including 346 melatonin users and 3046 nonusers. The matched cohort constituted 684 children (342 users and 342 nonusers). After matching, all 6 covariates achieved standardized mean differences below 0.10. Melatonin users had a lower median percentage of REM sleep than matched nonusers (16.7% [IQR, 11.6%-22.0%] vs 19.0% [IQR, 14.6%-23.2%]; Hedges g = -0.22 [95% CI, -0.32 to -0.11]; FDR-corrected P = .003). Total sleep time, sleep efficiency, non-REM sleep stages, respiratory indices, arousal index, periodic limb movements, and oxygen desaturation index did not differ (FDR-corrected P > .05 for all 14 exploratory outcomes). The REM association was robust to 1:k matching (each melatonin user matched to 2 or 3 nonusers) and to averaging across repeated PSG nights. After adjusting for 3 psychiatric diagnoses (attention-deficit/hyperactivity disorder, anxiety, depression), REM reduction was preserved with attenuated magnitude (16.6% [IQR, 11.6%-22.0%] vs 18.4% [IQR, 13.4%-22.8%]; Hedges g = -0.17 [95% CI, -0.27 to -0.06]; P = .01). In this cross-sectional study of 684 propensity score-matched children, outpatient melatonin use was associated with a small reduction in REM sleep percentage and was not associated with differences in total sleep time, non-REM sleep stages, respiratory parameters, arousal architecture, or periodic limb movements. The REM association was attenuated when psychiatric diagnoses were added to the propensity model. Residual confounding cannot be excluded, and prospective studies with documented dose, timing, and adherence are needed to clarify the directionality of this association.
To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR = 1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.
Climate change increasingly exposes crops to overlapping abiotic and biotic stresses, creating a need for regulatory strategies that improve stress tolerance without imposing unnecessary fitness costs under favorable conditions. Melatonin has been widely associated with plant responses to drought, salinity, temperature extremes, oxidative stress, and pathogen challenge, where it contributes to redox balance, hormone crosstalk, and stress-responsive gene regulation. However, the benefits of melatonin appear to depend strongly on when, where, and to what extent it is produced. In this review, we examine melatonin biosynthesis and function from a promoter-centered perspective, focusing on how stress-associated signals may regulate the core biosynthetic genes TDC, T5H, SNAT, and ASMT/COMT across tissues and stress contexts. Because direct functional validation of specific promoter architectures in plant melatonin biosynthesis genes remains limited, this review presents the promoter-centered model as a hypothesis-generating framework rather than a fully established regulatory mechanism. Here, we argue that the melatonin-mediated stress tolerance depends primarily on regulated, context-dependent pathway activation rather than constitutive pathway enhancement. We therefore discuss how current knowledge of stress signaling, cis-regulatory organization, and genome editing can be used to frame future efforts in promoter engineering of melatonin biosynthesis genes. Throughout, we distinguish established findings from forward-looking hypotheses and highlight key experimental questions that must be addressed before these concepts can be translated into crop improvement.
Melatonin exhibits anti-inflammatory, antioxidant, and osteogenic properties that may enhance outcomes of nonsurgical periodontal therapy (NSPT). Previous reviews were limited by small sample sizes, heterogeneous methodology, and incomplete quantitative synthesis. To evaluate the clinical efficacy of melatonin as an adjunct to NSPT compared with NSPT alone in patients with periodontitis. A systematic search of seven databases (through April 2025) identified randomized controlled trials comparing NSPT with and without adjunctive melatonin. Primary outcomes were clinical attachment level (CAL) gain and probing pocket depth (PPD) reduction at 1, 2, 3, and 6 months. Secondary outcomes included bleeding on probing (BoP) at 1, 3 and 6 months, gingival index (GI) at 1, 2, 3 and 6 months, plaque index (PI) at 1, 3 and 6 months, and glycated hemoglobin (HbA1c) at 2 months only. Random-effects meta-analyses were performed using the Hartung-Knapp-Sidik-Jonkman (HKSJ) method with REML estimation of between-study variance. Prediction intervals were calculated. Sensitivity, subgroup, and influence analyses were conducted. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE guidelines. Eighteen RCTs (828 patients) were included, with 16 contributing to quantitative synthesis. Adjunctive melatonin significantly improved CAL at 2 months (MD -1.48 mm; 95% CI: -2.11 to -0.85), 3 months (MD -0.41 mm; 95% CI: -0.69 to -0.13), and 6 months (MD -0.68 mm; 95% CI: -1.31 to -0.04), while CAL gain at 1 month was not significant (MD: -0.02 mm; 95% CI: -0.90 to 0.85). PPD reduction at 1 month favored the control group (MD 0.19 mm; 95% CI: 0.04 to 0.34), while PPD reduction was significant favoring adjunctive melatonin at 2 months (MD -1.80 mm; 95% CI: -2.49 to -1.12) and 3 months (MD -0.29 mm; 95% CI: -0.53 to -0.05) but was not statistically significant at 6 months. BoP reduction was not significant across all follow-up timepoints. GI reduction was significant at 2 months (MD: -0.71; 95% CI: -1.02 to -0.38), while PI reduction at 6 months was significant (MD: -0.69; 95% CI: -0.77 to -0.64). HbA1c decreased significantly at 2 months in diabetic patients (MD -1.33%; 95% CI: -1.48 to -1.18). Prediction intervals for CAL and PPD crossed the null at all timepoints, suggesting that true effects may vary substantially and could be negligible in some clinical settings. Subgroup analyses did not demonstrate statistically significant effect modification by administration route or disease severity. Melatonin as an adjunct to NSPT may provide short-term improvements in CAL, PPD, and glycemic control. However, substantial heterogeneity and wide prediction intervals limit confidence in consistent clinical benefit across populations. Further high-quality, adequately powered RCTs with standardized protocols and longer follow-up are required to clarify long-term clinical benefits.
Melatonin is present in breast milk with a diurnal pattern, potentially supporting early circadian rhythm development. This systematic review and meta-analysis aimed to evaluate the effects of exogenous melatonin supplementation, compared with no treatment or placebo, on milk yield, milk composition, somatic cell count, colostrum composition, and neonatal growth outcomes in lactating ruminant livestock. A systematic search of PubMed, Scopus, Web of Science, and Google Scholar was conducted up to March 15, 2026. All continuous outcomes were pooled as standardized mean differences (SMD) to account for variability in measurement scales across studies. We identified 25 eligible studies in lactating animals. Melatonin supplementation did not significantly alter milk yield across species (SMD = 0.49). Significant improvements were observed in milk fat (SMD = 0.77) and protein content (SMD = 0.39), particularly in cows. Melatonin also significantly reduced somatic cell count (SMD = -1.98). Other components such as lactose, total solids, and solid not fats showed no significant change. Neonatal outcomes, including birth weight, weight at weaning, and daily gain, showed no significant improvement. Colostrum analysis showed a small increase in lactose content but no consistent effects on fat, protein, or IgG. However, most pooled analyses demonstrated substantial heterogeneity (I2 frequently > 90%). Exogenous melatonin shows potential for improving milk quality and mammary health in ruminant dairy animals, but its impact on milk yield and neonatal development remains unclear. These preclinical findings are hypothesis‑generating, and carefully designed clinical studies would be required before considering melatonin use in lactating women.
Sheep seasonal reproduction is regulated by photoperiod via melatonin. Indoleamine 2,3-dioxygenase 2 (IDO2), an enzyme involved in tryptophan metabolism through the kynurenine pathway and belonging to the IDO family, may contribute to melatonin homeostasis, but its role in reproductive seasonality remains unclear. In this study, genome-wide selection analyses combining Z(FST) and XP-EHH between seasonal and non-seasonal sheep identified a selection signature encompassing the IDO2 region and revealed g.-809T>C as a functional candidate variant within this region. Experiments employing electrophoretic mobility shift assay (EMSA) and luciferase assays revealed that this site lies within the CLOCK transcription factor binding domain. The -809C variant reduced promoter activity compared to -809T (p < 0.05). Sheep with the CC genotype had higher plasma melatonin levels than TC/TT counterparts (p < 0.05). These findings suggest that the g.-809C allele decreases IDO2 transcription by reducing CLOCK binding affinity, thereby potentially affecting IDO2-associated tryptophan/melatonin metabolism and increasing melatonin levels, which may contribute to photoperiodic responses in sheep. This IDO2 variation provides new insights into the genetic regulation of melatonin-mediated reproductive seasonality and represents a potential marker for genetic improvement of reproductive seasonal traits in sheep.
Environmental factors are crucial causes of polycystic ovary syndrome (PCOS). There is growing evidence of an association between circadian rhythm disturbance and PCOS, but the underlying molecular mechanisms This study aimed to explore the molecular mechanism of PCOS induced by circadian rhythm disturbance and evaluate the therapeutic potential of melatonin. A rat model of circadian rhythm disturbance was established via 24-h continuous light exposure. Rats were randomly divided into the Control group (normal circadian rhythm), Model group (continuous light exposure), and Model + Melatonin treatment group (continuous light exposure + melatonin). Reproductive endocrine indicators, ovarian histomorphology, and ovarian granulosa cell (GC) function were assessed. Additionally, circadian rhythms of serum hormones, autophagy-related markers (LC3), and hypothalamic clock genes were detected at six zeitgeber time (ZT) points. Autophagy and apoptosis levels in GCs, as well as the activation of MAPK and PI3K/Akt/mTOR pathways, were also detected. Continuous light exposure induced PCOS-like phenotypes in rats, characterized by disrupted estrous cycles, cystic ovarian changes, and loss of circadian rhythms in serum hormones, autophagy marker LC3, and hypothalamic clock genes. Moreover, continuous light exposure reduced GC viability, increased GC autophagy and apoptosis, activated the MAPK pathway, and inhibited the PI3K/Akt/mTOR pathway in GCs. Melatonin treatment significantly ameliorated these PCOS-like phenotypes. Our study showed circadian rhythm disturbance induced PCOS via MAPKs and PI3K/Akt/mTOR signaling pathways and increased autophagy level in rat ovarian GCs. Melatonin had a therapeutic effect on PCOS by reversing these signaling pathway abnormalities and reducing autophagy and apoptosis levels in GCs.
This experimental rat study aims to investigate the preventive role of melatonin in potential neurodegenerative changes associated with periodontitis in the hippocampus and cerebral cortex. Twenty-four Sprague Dawley rats were divided into three groups: Control (n = 8), Ep (n = 8), Ep + Mel (n = 8). Systemic melatonin (10 mg/kg/day) was administered to the Ep + Mel group for 35 days of periodontitis induction, starting from the application of bilateral lower first molar ligation. Following sacrification of all groups, periodontal bone loss was analyzed in Micro-CT sections (sagittal and coronal). Cerebral cortex and hippocampus tissues and serum samples were analyzed histopathologically, immunohistochemically, and biochemically. Micro-CT results showed that the experimental periodontitis model was successful. When Ep + Mel and Ep were compared, a significant difference was observed in terms of histopathological damage, Caspase-3, GFAP, and Iba-1 immunopositivity (p < 0.05). Systemic melatonin administration was found to significantly reduce tissue and serum levels of IL-1β, IL-1β/IL-10, and Aβ1-42 (p < 0.05). Additionally, serum TNF-α and tissue TOS and OSI levels were significantly reduced in the melatonin group (p < 0.05). Tissue TAS and serum IL-10 showed no significant change (p > 0.05). This study demonstrated that systemic melatonin may limit periodontal tissue destruction and periodontitis-associated neuroinflammatory, neurooxidative, and neuroapoptotic changes in the cerebral cortex and hippocampus.
Melatonin is synthesised from tryptophan by the sequential action of enzymes that are highly expressed in the pineal gland. Homeobox gene-encoded transcription factors typically control organ development; however, a set of homeobox genes is strongly expressed in the adult pineal gland. Previous in vitro experiments revealed that knockdown of homeobox genes in rat pinealocyte cultures reduced expression of melatonin-synthesising enzymes. Until now, it was not possible to determine the impact of homeobox genes on melatonin synthesis in vivo, which is needed to evaluate physiological functions. Using the cone-rod homeobox (Crx) gene as an example, we therefore developed an experimental pipeline to deliver short-hairpin RNA, via adeno-associated viral vectors, into the pineal gland of adult rats. This approach enabled us to selectively reduce Crx expression in the mature pineal gland, which we confirmed at both the transcript and protein levels. We employed a common approach in pharmacology to correlate Crx knockdown with the expression level of the tagged fluorescent reporter, which provided a quantitative basis to define data exclusion/inclusion criteria. Our efforts confirmed that knockdown of Crx in vivo reduced the expression of two melatonin-synthesising enzymes, namely tryptophan hydroxylase 1 and acetylserotonin O-methyltransferase, consistent with in vitro data. Furthermore, knockdown of pineal Crx significantly reduced nighttime plasma melatonin levels. Our work demonstrates a method through which knockdown of target genes in the rat pineal gland can be achieved without the need for transgenic models.
Benzene exposure is a major risk factor for hematologic malignancies, including acute myeloid leukemia (AML), through mechanisms involving genotoxicity, oxidative stress, and dysregulation of hematopoietic signaling pathways. This study investigated the protective effects of melatonin, vitamin C, and their combination against benzene-induced pre-leukemic alterations in rats, with emphasis on bone marrow genotoxicity, oxidative stress, and activin A/follistatin expression. Forty male Wistar rats were allocated into five groups (n=8): control, benzene, benzene + melatonin, benzene + vitamin C, and benzene + combined treatment. Genotoxicity was assessed using bone marrow micronucleus assays, while oxidative stress biomarkers, serum activin A/follistatin levels, and bone marrow gene expression were evaluated using biochemical assays, ELISA, and qPCR, respectively. Benzene exposure significantly increased micronucleus frequency, reduced %PCE and PCE/NCE ratio, elevated %NCE, and suppressed activin A and follistatin expression. Melatonin or vitamin C alone partially attenuated these abnormalities, whereas combined treatment demonstrated the strongest protective effects, including marked improvement of genotoxicity indices, restoration of catalase activity, and significant upregulation of activin A and follistatin gene expression. Combined melatonin and vitamin C supplementation attenuated benzene-associated pre-leukemic alterations, particularly genotoxic and oxidative stress-related abnormalities. Combined melatonin and vitamin C supplementation attenuated benzene-associated pre-leukemic alterations in rats, particularly genotoxic and oxidative stress-related abnormalities. These protective effects were accompanied by modulation of activin A/follistatin expression patterns, suggesting a potential association between restoration of this signaling axis and improved bone marrow homeostasis. However, further mechanistic studies are required to determine whether activin A/follistatin signaling directly contributes to the observed protective effects.
Melatonin exerts pleiotropic physiological functions and diverse disease associations, but its genetic architecture remains largely uncharacterized. Using low-coverage whole-genome sequencing (lcWGS) in 3,605 Han Chinese adults, we identified four independent loci (P < 1 × 10⁻⁷) associated with circulating melatonin (pg/mL)-located within or near LINC01807, PTPRD, EDIL3/NBPF22P, and LMO1/STK33. Conditional analyses indicated that the STAARpipeline single-variant and sliding-window signals were largely driven by these genome-wide association study (GWAS) lead variants, whereas a gene-centric noncoding aggregation signal in the ZSWIM9 promoter region remained independent. These genes showed tissue-specific expression in neural, vascular, and adrenal tissues (GTEx ). The heritability of serum melatonin was estimated at 21.72% (SE = 11.2%, P = 0.029) using GCTA-GREML, with the four independent significant loci collectively explaining 3.40%. Genetic risk score and one-sample Mendelian randomization analyses suggested a protective effect of higher serum melatonin levels on hypertension risk (OR = 0.45, P = 0.015), as well as on systolic (β = - 4.14, P = 0.014) and diastolic blood pressure (β = - 3.10, P = 0.007). Summary-data-based Mendelian Randomization and colocalization analyses suggested that LMO1 and PTPRD may influence hypertension through tissue-specific expression and DNA methylation. These findings reveal novel genetic contributors to melatonin regulation and establish their putative causal relationship with hypertension.
Circadian rhythm disruption is a risk factor for metabolic and age-associated diseases. The liver is a key target of such desynchronosis. The effect of chronic continuous light exposure and the corrective effect of melatonin on the liver status were investigated in rats. Desynchronosis mediated by melatonin deficiency was shown to induce the formation of a pro-senescent and metabolically dysfunctional liver phenotype. Melatonin administration significantly reduced the severity of the identified disorders and prevented statistically significant deviations in most of the parameters under study. The results, together with previous data on ultrastructural damage to hepatocytes and a negative impact of desynchronosis on lifespan, indicate that chronic continuous light exposure is a significant pro-gerontological factor and that melatonin is an effective agent for correcting the associated disturbances of liver homeostasis.
This study aimed to evaluate the effect of melatonin on sleep Quality, anxiety, and depression in the patients with primary breast cancer undergoing adjuvant chemotherapy in a double-blind, placebo-controlled trial. Forty patients with stage I-III breast cancer were allocated randomly to the intervention and control groups. The intervention group received 6 mg/day/6 months. At baseline, middle and end of chemotherapy, patients were evaluated using Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Hospital Anxiety, and Depression Scale (HADS) questionnaires, respectively. Melatonin administration resulted in significant improvements in sleep latency (1.50 ± 1.04,1.28 ± 1.02,1.00 ± 1.08, P = 0.001), sleep efficiency (1.11 ± 1.08, 0.83 ± 1.15, 0.56 ± 0.92, P = 0.003), and total Pittsburgh Sleep Quality Index scores (8.39 ± 4.63, 7.56 ± 4.41, 6.50 ± 3.71, P = 0.003) when compared to the placebo group throughout the three phases of chemotherapy. Importantly, no statistically significant differences were noted during the Adriamycin phase of chemotherapy. In contrast, during the Taxol phase, the melatonin showed a statistically significant improvement in anxiety levels (7.33 ± 4.01 to 5.67 ± 0.88, P = 0.077) and overall PSQI scores (8.39 ± 4.62 to 9.13 ± 4.96, P = 0.015). These results indicate that melatonin may be a promising therapeutic option for addressing sleep disturbances in breast cancer patients.
Sleep deprivation is a common concern for cancer patients. It has proven difficult to determine severity of sleep disturbances in a cancer group. Patients may fail to mention insomnia because they assume it is a common and temporary reaction to a cancer diagnosis or treatment, a condition that is frequently overlooked in cancer management. This prospective, double-blind, randomized comparative trial evaluated the efficacy and safety of oral melatonin (3 mg/day) versus oral olanzapine (5 mg/day) in 60 advanced cancer patients with insomnia over four weeks. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale (AIS) at baseline, 2nd wk, and 4th wk. Both groups demonstrated significant, time-dependent improvement in sleep parameters (p < 0.001). Melatonin showed statistically significant superiority over olanzapine in PSQI scores at week four and overall AIS scores across all time points; however, melatonin exhibited a more favorable adverse effect profile, while olanzapine was associated with somnolence, akathisia, and weight gain. Both agents are effective for cancer-related insomnia symptoms, with melatonin offering a superior tolerability advantage in the palliative setting. Larger placebo-controlled trials with objective sleep measures are warranted to confirm these findings.
Rapid eye movement sleep deprivation (REM-SD) is associated with increased oxidative stress, characterized by disruption of the oxidant-antioxidant balance and accumulation of reactive oxygen species (ROS). Melatonin may act as a potential modulator of REM-SD-associated oxidative alterations through its circadian regulatory effects, direct ROS scavenging activity, and support of endogenous antioxidant defense mechanisms. This study aimed to evaluate the effects of melatonin treatment administered during the six-day REM-SD period or during the recovery period following REM-SD on oxidative stress-related parameters in 8-12-week-old male Sprague-Dawley rats (n = 84). REM-SD was induced using the modified multiple platform method (MMPM). Biochemical markers reflecting oxidative balance, including total antioxidant status (TAS), total oxidant status (TOS), the lipid peroxidation product malondialdehyde (MDA), non-enzymatic antioxidant glutathione (GSH), and enzymatic antioxidants, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels, were assessed using the enzyme-linked immunosorbent assay (ELISA). The findings demonstrated that REM-SD predominantly affected enzymatic antioxidant defense-related parameters. Melatonin modulated these responses, mainly by increasing enzymatic antioxidant levels and reducing lipid peroxidation. However, no significant change was observed in TOS, whereas the effect on TAS was limited and time-dependent. During the recovery period, several oxidative stress markers partially normalized, indicating a possible reactivation of endogenous antioxidant defenses. In conclusion, six-day MMPM-induced REM-SD appears to alter oxidative stress-related parameters, while melatonin may help attenuate some of these alterations by modulating antioxidant defense mechanisms. These effects varied according to the timing of administration and the specific parameter examined.
Melatonin is a key endocrine output of the circadian system, but its low endogenous abundance and dynamic fluctuation make accurate detection in biological samples challenging. Here, we report a highly sensitive needle-type organic electrochemical transistor (OECT) biosensor for melatonin detection based on an Au nanocoral-gated acupuncture needle. A hierarchically nanoporous coral-like Au structure was fabricated on the needle surface via a dynamic hydrogen bubble templating strategy, generating a high-surface-area and highly electroactive gate for immobilization of a thiolated melatonin aptamer. By integrating this recognition-enhancing nanostructured gate with the intrinsic signal amplification capability of the OECT, the platform efficiently converts interfacial molecular recognition into amplified electrical outputs. The optimized biosensor achieved a detection limit of 160 fM, showed good selectivity against structurally related interferents, and maintained reliable performance in serum-containing media. In rat plasma, the biosensor showed satisfactory agreement with ELISA and accurately tracked the circadian secretion profile of melatonin. Moreover, the needle-type configuration enabled skin-interfaced measurements and interstitial-fluid detection without causing obvious extensive tissue damage under short-term insertion conditions. The platform further resolved circadian phase shifts induced by light-dark reversal, demonstrating its ability to study physiologically meaningful endocrine dynamics. These results highlight this OECT platform as a promising strategy for low-abundance melatonin analysis, minimally invasive biosensing, and circadian rhythm analysis.
The risk allele (G) of MTNR1B rs10830963 has been associated with impaired glucose tolerance, increased fasting glucose and type 2 diabetes (T2D). Late evening eating, when endogenous melatonin levels are elevated, is associated with impaired glucose control in MTNR1B risk carriers. Endogenous melatonin levels remain elevated into the morning so may influence glucose response to breakfast. To investigate the interaction of MTNR1B genotype and type of breakfast on postprandial glucose response in a real-world setting. Following an overnight fast, participants consumed either a standard carbohydrate-rich or protein-enriched porridge breakfast. Post-prandial glucose levels were recorded for two hours using a continuous glucose monitor (CGM). One week later, participants repeated the protocol consuming the alternate breakfast. A two-way mixed ANOVA determined the effect of breakfast and genotype on post-prandial glucose levels. Fifty-four adults completed the study. Fasting glucose was significantly higher (p = 0.008) in GG (5.53 ± 0.43 mmol/L) compared to CC or CG participants (5.02 ± 0.42 and 5.19 ± 0.52 mmol/L). Post-prandial iAUC was significantly greater following the carbohydrate-rich breakfast compared to the protein-enriched breakfast (p < 0.001). Following the carbohydrate-rich breakfast iAUC was significantly greater in GG participants compared to CC (p = 0.026) and CG participants (p = 0.029). There was no significant difference between genotype groups following the protein-enriched breakfast (p > 0.05). The study findings demonstrate, in a relatively young and healthy population, MTNR1B genotype significantly affects markers associated with T2D risk. Personalised genotype-based advice to adjust timing and composition of meals consumed when endogenous melatonin levels are increased may reduce subsequent T2D risk.