Controlled studies have demonstrated that light supplementation benefits circadian entrainment, sleep and mood. Translating these findings into effective, real-world usage of light supplementation is, however, challenging because naturalistic and supplemental light exposure are shaped by personal habits and environmental light conditions. Bridging this translation gap is especially critical for older adults, given the reduced ocular light sensitivity associated with natural ageing, which exacerbates low daytime indoor light exposure in urban housing. We therefore set out to investigate the determinants of self-directed light supplementation in this population, and what the real-world feasibility and efficacy of daytime light supplementation is. We recruited 202 participants (63-92 years; 139 females) to our interventional, prospective, randomised study in three major EU cities at different latitudes (Amsterdam, Bologna, Tartu). Participants underwent a 2-week baseline assessment of light exposure, rest-activity patterns and sleep through wearables and daily diaries. Participants were then randomised to either 12 weeks of self-implemented indoor light supplementation using a lamp placed in their most frequently used room (> 8000 melanopic EDI, N = 98) or a no-intervention group. A subsequent 2-week reassessment showed that greater naturalistic light exposure was associated with increased daytime activity, consolidated wakefulness, better subjective sleep quality, and reduced metabolic disorder incidence. Individuals with lower naturalistic light exposure self-initiated earlier and longer indoor light supplementation across seasons, in which supplementation onset before 10:00 was associated with greater daytime activity and lower rest-activity fragmentation. These results confirm that this simple, non-pharmacological, and low-cost intervention has broad potential to support healthy ageing in urban settings.
The present study investigates the impact of two missense SNPs in the human melanopsin gene OPN4 -I394T (rs1079610) and P10L (rs2675703)- on non-image-forming (NIF) physiological and behavioural outputs in healthy young adults under real-world conditions. Twenty-five healthy university students were genotyped and analysed under a C-allele dominant model for I394T and a T-allele dominant model for P10L. Over 8 days, participants underwent ambulatory monitoring of wrist skin temperature (WT), sleep, activity and light exposure, together with salivary melatonin assessment under five home-based lighting/time conditions and pupillary light reflex testing. I394T-C carriers exhibited a phase delay in habitual sleep and WT rhythms, reduced WT amplitude, greater internal desynchronization, and lower nocturnal melatonin concentrations under dim light compared to the TT group. Although behavioural and peripheral rhythms were delayed, circadian phase (DLMO) remained preserved, resulting in an increased phase angle of entrainment. On free days, they also showed greater melatonin suppression despite similar light exposure. In contrast, the P10L-T allele was not associated with significant differences in ambulatory, hormonal, or pupillary outcomes. Overall, the I394T variant, but not P10L, significantly associates with NIF physiology in young adults, likely by affecting the coupling between environmental light and downstream circadian outputs, independently of circadian phase. These findings also suggest that I394T-C carriers exhibit features of the circadian phenotype commonly observed in older cohorts, including reduced rhythm robustness and lower melatonin levels, and support a role for this variant in interindividual differences in light sensitivity and circadian function.
Melatonin (MT), a potent bioactive molecule, regulates plant development and stress resistance. However, in complex field environments, how MT seed coating recruits soil microbes via root development modulation and exudate release to boost yield remains unclear. In this 2-year field study, five seed coating treatments with or without MT were used to investigate how MT-associated seed coating coordinates soybean growth with root architecture remodeling, exudate profile changes, rhizosphere microenvironment succession, and plant-microbe associations. Results indicated that MT seed coating treatment significantly increased IAA and GA content in roots by 66.3% and 38.2% compared to CK treatment, while inhibiting ABA content. This hormonal synergistic effect markedly enhanced root vitality by 18.4%, synchronously increased total root length and surface area by 54.5% and 62.6%, induced a significant increase in root tip number, and increased malic acid and citric acid contents in root exudates by 37.2% and 29.8% compared to CK. As a result, soybean yield increased by 10.8% under MT treatment. Rhizosphere analyses showed that MT-containing treatments were associated with higher nitrogen-related enzyme activities and improved inorganic nitrogen availability. Microbiome analyses indicated that stochastic processes remained dominant in bacterial community assembly, but MT reduced the relative contribution of stochasticity and promoted relatively stronger deterministic filtering. Correlation analyses showed that Sphingomonas- and Lysobacter-affiliated taxa were positively associated with growth-promoting hormones, tryptophan, root traits, and nitrogen-turnover indicators. Functional prediction suggested that MT-associated bacterial communities had enhanced potential for amino acid metabolism, membrane transport, and energy metabolism. These findings suggest that MT seed coating may promote soybean growth through coordinated changes in root hormonal balance, root architecture, exudate profiles, rhizosphere nitrogen availability, and microbial community structure.
Postmenopausal osteoporosis (PMOP) is linked to iron accumulation. Melatonin has iron-chelating and antioxidant properties, but its mechanism against osteoclastogenesis remains unclear. This study investigated whether melatonin suppresses osteoclast formation by targeting the iron/ROS-CREB-PGC-1β-mediated mitochondrial biogenesis pathway. In vitro, bone marrow-derived macrophages (BMMs) were treated with RANKL and melatonin (10-1000 nM). Melatonin concentration-dependently inhibited osteoclast differentiation, reduced intracellular ferrous and total iron levels, decreased ROS and oxidative stress markers, and suppressed mitochondrial biogenesis. Mechanistically, melatonin indirectly suppressed PGC‑1β expression via inhibition of CREB phosphorylation, without affecting PGC‑1α expression. The CREB activator forskolin reversed melatonin's effects, whereas the CREB inhibitor 666-15 mimicked them. In vivo, ovariectomized (OVX) mice received weekly injections of iron dextran to model moderate iron overload, with or without oral melatonin. Melatonin ameliorated iron‑induced bone loss, improved bone microarchitecture and biomechanical properties, reduced tissue iron stores and bone ROS levels, and suppressed osteoclast mitochondrial biogenesis and the CREB/PGC-1β pathway; these effects were counteracted by forskolin. In conclusion, melatonin prevents osteoclastogenesis and counters bone loss due to iron accumulation in estrogen‑deficient conditions by chelating iron, scavenging ROS, and blocking the iron/ROS‑activated CREB/PGC‑1β axis, thereby suppressing mitochondrial biogenesis. This study offers a mechanistic explanation for using melatonin as a possible treatment for PMOP, particularly when accompanied by iron overload.
Iron (Fe) is indispensable for plant growth and development. Notably, melatonin (MT) serves as a key regulator to improve plant tolerance under nutrient stress conditions. Currently, the exact mechanism regulating MT's involvement in the rice Fe-deficiency response remains to be elucidated. This study reveals that Fe-deficiency stress triggers a rapid increase in endogenous MT levels in rice roots and induces the expression of MT synthesis-related genes, underscoring the involvement of MT in the rice Fe-starvation response. Exogenously applied MT rescues the root growth inhibition triggered by Fe deficiency and efficiently mitigates leaf chlorosis in rice. Mechanistically, MT decreases Fe retention in the root cell wall and its hemicellulose fraction, thereby promoting the remobilization of stored Fe and increasing soluble Fe content. Additionally, MT selectively reshapes the transport networks by robustly upregulating genes associated with Strategy II Fe acquisition and internal Fe transport-including Ferric Reductase Defective 3-like 1 (OsFRDL1), Iron-related transcription factor 3 (OsIRO3), Nicotianamine Aminotransferase 1 (OsNAAT1), OsNAS1, OsNAS2, Yellow Stripe-Like 2 (OsYSL2), and OsYSL15-to accelerate root-to-shoot Fe translocation. Notably, this enhanced internal Fe recycling partially improves the plant's Fe nutritional status, which is consistent with a systemic negative feedback response that partially attenuates the core Strategy I ferrous iron transporters (OsIRT1/2) along with root-surface ferric reductase (FCR) activity and proton secretion. Moreover, nitric oxide (NO) acts as a pivotal downstream mediator in MT-induced mitigation of the rice Fe-starvation response. In conclusion, MT alleviates Fe deficiency in rice by promoting the remobilization of hemicellulose-bound Fe and enhancing root-to-shoot Fe translocation in an NO-dependent manner. These processes are accompanied by partial attenuation of root-surface FCR activity, proton secretion, and OsIRT1/2 expression, revealing a coordinated adjustment between internal Fe reutilization and external Fe-acquisition responses.
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.
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.
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.
Wampee (Clausena lansium) is a tropical and southern subtropical fruit tree whose productivity is limited by low-temperature stress (LTS). This study investigated the physiochemical and molecular mechanisms by which melatonin (MLT) enhances chilling tolerance in wampee. MLT treatment improved membrane stability and reduced oxidative damage by enhancing antioxidant capacity and osmotic adjustment. Metabolomic and transcriptomic analyses revealed that differentially expressed genes and metabolites were primarily associated with flavonoid biosynthesis and starch and sucrose metabolism pathways. Eleven key candidate genes were identified, including sucrose synthase, granule-bound starch synthase, trehalose-6-phosphate synthase, chalcone-flavonone isomerase, flavonoid 3',5'-hydroxylase, and UDP-glycosyltransferase. MLT treatment also increased soluble carbohydrate levels, such as sucrose and fructose, and enhanced sucrose phosphate synthase activity. Transcription factors ClbHLH2 and ClNAC1 enhanced wampee's cold tolerance by activating the sucrose-biosynthetic genes ClSUS2 and ClSPS1, respectively. These findings provide insights into the molecular and physiological mechanisms underlying wampee adaptation to LTS and highlight MLT as a potential tool to improve wampee's cold tolerance.
Melatonin have been proposed as a potential alternative in enhancing drought tolerance. However, the mechanisms underlying remain poorly understood. This study tested the hypothesis that melatonin improves drought tolerance by regulating polyamine metabolism. Hydroponically grown foxtail millet (Setaria italica L.) seedlings were subjected to drought stress induced by polyethylene glycol (PEG-6000, 10%), with or without melatonin application. The results showed that exogenous melatonin improved drought tolerance by improving water uptake, increasing root hydraulic conductivity (Lpr) and whole-plant hydraulic conductance (Kplant) by 37% and 33%, respectively. Melatonin also significantly increased the activities of key enzymes involved in polyamine biosynthesis, specifically arginine decarboxylase (ADC), ornithine decarboxylase (ODC), and S-adenosyl-l-methionine decarboxylase (SAMDC), while concurrently decreasing the activities of polyamine degrading enzymes, namely polyamine oxidase (PAO) and diamine oxidase (DAO). Additionally, melatonin elevated the levels of putrescine (Put), spermidine (Spd), and spermine (Spm) in both roots and leaves. Transcriptome analysis further indicated that melatonin upregulated genes related to polyamine biosynthesis. To further verify the role of polyamines in melatonin-induced drought tolerance, seedlings were treated with exogenous Spd or a polyamine biosynthesis inhibitor (dicyclohexylammonium sulfate, DCHA) under combined drought and melatonin conditions. Exogenous Spd produced effects similar to those of melatonin under drought stress, while DCHA abolished the melatonin-induced drought tolerance and reduced its beneficial effects on root water absorption. These findings demonstrate that polyamines are involved in melatonin-induced drought tolerance in foxtail millet, supporting the positive role of melatonin in modulating drought tolerance.
Hearing impairment is attributed to factors such as age, genetic predisposition, and environmental influences, among which environmental factors are considered modifiable. Among various environmental factors, the role of poor lifestyle habits is particularly critical, yet the specific mechanisms by which they contribute to hearing damage remain unclear. This study reveals that dysregulated hormone levels due to disrupted light exposure may significantly increase susceptibility to sensorineural hearing loss. In mice, circadian rhythm disruption was found to reduce melatonin and elevate serotonin levels in the inner ear, thereby increasing vulnerability to cisplatin-induced ototoxicity. In both in vivo and in vitro cisplatin-treatment models, we showed that combined treatment with melatonin protected hearing, reduced inner ear cell death, and preserved synaptic connections, whereas serotonin co-administration exacerbated the damage. Using small molecule-protein interaction prediction, we identified NOS3 as a potential target of both melatonin and serotonin, through which they appear to regulate the NO signaling pathway and influence hair cell ferroptosis. Finally, exogenous supplementation of NOS3 in cochlear tissues effectively mitigated cisplatin-induced hair cell damage, even under conditions of circadian rhythm disruption. These findings indicate that the melatonin/serotonin balance modulates susceptibility to sensorineural hearing loss via the NOS3-NO signaling pathway.
Diabetes mellitus (DM) promotes cardiac arrhythmias, whereas melatonin confers antiarrhythmic effects. Cellular targets modified by DM and melatonin largely overlap, which warrants testing melatonin as an antiarrhythmic agent in DM. Herein, we evaluated electrophysiological and antiarrhythmic properties of melatonin in the experimental DM model. Experiments were performed in 41 control and 71 diabetic rats. 34 diabetic animals were treated with melatonin (orally, 10 mg/kg daily) for 1 month, and 37 diabetic animals received a placebo. Electrophysiological studies included electrocardiography, in vivo epicardial mapping with induction of ischemia-reperfusion, and patch-clamp studies in ventricular cardiomyocytes. Collagen deposition was assessed in postmortem histological studies. RT-PCR and Western blotting methods were used to estimate Gja1 gene expression and Cx43 protein level, respectively. Melatonin treatment in diabetic animals did not influence the level of glycaemia, but mitigated the progression of myocardial fibrosis. Melatonin treatment prevented the DM-related decrease in conduction velocity, increase in duration and dispersion of repolarization, as well as corresponding changes in their electrocardiographic correlates (QRS, QT, and Tpeak-Tend intervals, respectively). Melatonin also prevented the development of reperfusion ventricular tachycardia/fibrillation. The patch-clamp studies showed that melatonin treatment significantly reduced calcium current, prevented DM-related action potential duration prolongation, but did not modify DM-related increase in sodium current. RT-PCR studies demonstrated that melatonin treatment prevented the DM-related upregulation of Gja1 gene expression and increase in Cx43 level. Melatonin treatment of diabetic rats conferred antiarrhythmic effects associated with electrophysiological changes reflected in ECG parameters, which warrants further testing of melatonin in a clinical context.
Sleep disturbance perturbs circadian and immune homeostasis and is increasingly associated with female reproductive dysfunction, yet the underlying cellular mechanisms remain unclear. Here, we identify granulosa cell pyroptosis as a central mechanism linking sleep disturbance to ovarian reserve decline. Mendelian randomization analyses support an association between frequent sleep disorders and ovarian dysfunction, consistent with clinical evidence of reduced ovarian reserve in women with poor sleep quality. Mechanistically, sleep disturbance induces a pro-inflammatory ovarian microenvironment characterized by oxidative stress, activation of the NLRP3 inflammasome, and pyroptotic death of granulosa cells, accompanied by ultrastructural damage. Melatonin, a key circadian regulator and a potent antioxidant, suppresses NLRP3-mediated pyroptosis, alleviates oxidative stress, and preserves granulosa cell integrity. In a randomized clinical setting, melatonin supplementation partially restores ovarian reserve markers and improves reproductive outcomes. These findings define an inflammation-driven pyroptotic pathway underlying sleep disturbance-induced ovarian dysfunction and establish melatonin as a mechanistic modulator of ovarian inflammasome activation, supporting circadian-targeted strategies for preserving female reproductive health.
The circadian rhythm system plays an essential role in maintaining skeletal homeostasis, yet the precise impact of circadian rhythm abnormalities on bone mineral density (BMD) remains poorly understood. In this study, we systematically investigated the effects of rhythm disruption on bone metabolism by establishing murine models exposed to winter-simulated extended darkness (8-h light:16-h dark) and severe non-24-h light-dark cycles (8L:8D, 6L:6D, and 4L:4D). Our structural and histological analyses revealed that abnormal circadian rhythms profoundly uncouple bone remodeling, leading to a precipitous decline in trabecular bone mass. Crucially, we demonstrated that enhanced osteoclast activity due to the extended period of darkness in winter increases the risk of fractures, and this skeletal deterioration is further exacerbated under increasingly fragmented non-24-h rhythms. Mechanistically, circadian misalignment induced a severe downregulation of the Sirt3-SOD2 signaling pathway in bone tissue, which released physiological constraints on RANKL expression and subsequently drove rampant osteoclastogenesis. Pharmacological intervention with the endogenous circadian synchronizer melatonin partially mitigated this rhythm-disrupted bone loss by restoring Sirt3 expression and predominantly enhancing osteoblast anabolism; however, its capacity to directly suppress rhythm-induced osteoclast hyperactivation was limited. Furthermore, co-treatment with the Sirt3 inhibitor 3-TYP abolished the osteoprotective effects of melatonin by concurrently impairing osteoblast function. Collectively, these findings identify circadian rhythm disruption as a critical intrinsic driver of BMD decline. This chronobiological perspective elucidates that photoperiod-induced circadian disruptions may act as a risk factor for diminished bone density by driving osteoclastogenesis, warranting further translational research in humans.
Global heavy metal (HM) stresses pose serious threats to environmental plants and animals. Melatonin has shown potent effects on improving plant stress resistance and phytoremediation upon HM stress, however, the systematic discussion of these extensive mechanisms and the gaps to practical applications remain elusive. This review aims to systemically provide the mechanistic understanding and environmental implication of melatonin integrative effects on alleviating HM toxicity. On the one hand, melatonin modulates HM homeostasis, induces HM detoxification, keeps photosynthesis and nutrient balance, and activates antioxidant defense systems to improve plant defense resistance to HM. On the other hand, melatonin triggers multiple transcriptional gene networks and extensive phytohormone crosstalks in plant defense responses. Notably, melatonin and melatonin-producing microbes exhibit potential applications in keeping plant growth and improving phytoremediation under HM conditions, indicating their effects on plant-microbiome-soil synergistic feedbacks. Finally, the current challenges and future perspectives of melatonin integrative mechanisms and applications are elucidated, highlighting that basic scientific questions and combined technologies should be further integrated to promote its practical applications. In summary, this review clarifies the multifaceted mechanisms of melatonin-integrated plant responses and potential remediation applications for environmental HMs, providing relative broad-spectrum and long-term strategies.
Triple-negative breast cancer (TNBC) is a distinct molecular subtype of breast cancer, characterized by high mortality and metastasis. Indoleamine 2,3-dioxygenase (IDO) is a highly expressed enzyme in cancer cells that contributes to immunosuppression. The IDO inhibition has been widely used in cancer immunotherapy. In this study, we evaluated the efficacy of indoximod, an IDO inhibitor, in combination with melatonin on TNBC tumor progression and metastasis in vitro and in vivo. Indoximod reduced the viability of 4T1 cells by inducing apoptosis and G2/M cell cycle arrest. Moreover, the combination of melatonin and TNF-α increased indoximod-mediated cell death. In vivo, coadministration of indoximod and melatonin resulted in enhanced antiproliferative and antimetastatic activities in the TNBC model. Tumor generation-induced neutrophil counts, TNF-α, IL-1β, and IL-10 levels were significantly reduced in mice receiving indoximod and melatonin in combination. Importantly, the accumulation of myeloid-derived suppressor cells (MDSCs), a key driver of tumor progression and metastasis, decreased in the primary tumor, metastatic liver, and lung of mice treated with indoximod and melatonin combination. Our findings revealed that melatonin enhances the immunotherapeutic efficacy of indoximod in TNBC.
Disuse osteoporosis, a consequence of prolonged mechanical unloading, is characterized by bone loss and elevated fracture susceptibility. Although melatonin exhibits bone‑anabolic properties, its mechanistic role in the context of mechanical unloading remains elusive. Our findings demonstrate that melatonin promotes osteogenic differentiation and suppresses osteoblast apoptosis, collectively mitigating unloading‑induced osteoporotic bone loss in hindlimb unloading (HLU) mice. Moreover, unloading suppressed YTHDF3 expression in osteoblasts and bone tissue, which was effectively rescued by melatonin administration. Functionally, YTHDF3 potentiated osteoblast differentiation and matrix mineralization while inhibiting apoptotic cell death. At the molecular level, YTHDF3 directly recognized m6A‑modified Dapk2 transcripts and promoted their decay. DAPK2 was characterized as a negative regulator that impedes osteoblast differentiation and survival. Genetic analyses established that melatonin‑driven suppression of DAPK2 and functional recovery of osteoblasts are contingent upon YTHDF3. In summary, we delineate a melatonin/YTHDF3/DAPK2 protective axis that safeguards against unloading‑induced bone deterioration via post‑transcriptional regulation of Dapk2, thereby unveiling new mechanistic perspectives and therapeutic opportunities for disuse osteoporosis.
Preterm birth is associated with increased oxidative stress and brain dysmaturation, contributing to adverse neurodevelopmental outcomes. Preterm infants are physiologically unable to produce melatonin during early postnatal life, potentially increasing their vulnerability to oxidative injury. We planned and conducted a prospective, multicentre, randomized, double-blind, placebo-controlled study to investigate whether 15 days of early oral melatonin (ME) supplementation after birth increases ME levels and reduces oxidative stress in preterm newborns at the end of administration period. The level of malondialdehyde (MDA), a lipid peroxidation product, was considered an early biological marker of the efficacy of ME treatment. The results of the first phase of the study are already available to view on Journal of Pineal Research. Here, we presented the results of the second phase of the trial, in which we investigated whether early oral ME supplementation supports clinical outcomes and brain maturation at term-equivalent age (TEA) in 54 infants with a gestational age of ≤ 29 weeks + 6 days, who received either oral ME or a placebo (PL) for 15 days after birth. No significant differences were observed between groups in the incidence of major neonatal comorbidities in particular patent ductus arteriosus (PDA), sepsis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). Cranial ultrasound findings and clinical assessments using General Movements (GMs), the Neonatal Neurobehavioral Scale (NNNS), and the NAVEG scale showed comparable results. On the other hand, magnetic resonance imaging (MRI) revealed a significantly higher total brain maturity score in ME-treated infants compared with the PL group (46 vs. 43; p = 0.011), with in particular more advanced white matter and subplate compartment maturation. Quantitative MRI analysis demonstrated significantly higher T1-weighted/T2-weighted signal ratio values in major white matter tracts, including the pyramidal tract, consistent with enhanced myelination. Additionally, we observed a positive trend in the association between reduced serum MDA levels-reflecting lower lipid peroxidation-at the end of ME administration and higher T1-weighted/T2-weighted ratio values in the pyramidal bundles in subjects at TEA. These findings suggest that early oral melatonin supplementation supports cerebral white matter maturation in preterm infants, potentially through antioxidant mechanisms. Melatonin may represent a promising adjunctive strategy to mitigate oxidative stress-related brain dysmaturation in this vulnerable population, warranting further investigation in larger trials. Trial Registration: ClinicalTrials.gov Registration Number: NCT04235673; Web link to study on registry: https://clinicaltrials.gov/study/NCT04235673.
Sleep regularity may represent a modifiable risk factor affecting osteoporosis susceptibility, but epidemiological evidence remains scarce. This research sought to analyze the link between sleep regularity parameters and incident osteoporosis, its interaction with genetic risk, and the potential for improved sleep regularity to mitigate risk in individuals with different genetic predispositions within a population-based cohort. A longitudinal analysis was conducted using data from the UK Biobank, which included 87,231 participants without osteoporosis at the time of accelerometer data collection in 2013-2015, with follow-up until June 30, 2023. Sleep regularity parameters were determined by calculating the within-person standard deviation (SD) of 7-day accelerometer-tracked sleep parameters (including sleep duration, onset time, wake-up time, and midpoint). We investigated the association between these four sleep regularity parameters and osteoporosis risk, and assessed the potential reduction of osteoporosis occurrence by enhancing sleep regularity. Additionally, subgroup and sensitivity analyses were executed. Across a median follow-up period of 8.6 years, 2035 new osteoporosis cases were recorded. Participants in the top quartile of SD for sleep duration, onset time, and midpoint had higher osteoporosis risk compared to those in the bottom quartile (fully adjusted HRs ranged from 1.17 to 1.21). Sleep duration SD showed the highest population attributable fraction (PAF). Moreover, a statistically significant additive gene-sleep interaction was identified. When considering both sleep regularity and osteoporosis polygenic risk score (PRS), the group with the highest risk nearly doubled their osteoporosis risk compared to the group with the lowest risk (fully adjusted HRs ranged from 2.22 to 2.24). Importantly, improving sleep regularity mitigated the PRS effect on osteoporosis, with the greatest absolute risk reduction observed in individuals with intermediate PRS-1.6 to 1.7 times that of those with high PRS. Irregular sleep patterns were associated with an increased risk of developing osteoporosis, with exploratory analyses suggesting potential variation across levels of genetic susceptibility. These findings underscore the potential importance of maintaining stable sleep patterns for bone health and suggest that sleep regularity may represent a modifiable behavioral factor for osteoporosis prevention, warranting further investigation.
