Melatonin has demonstrated antitumor activity in various cancer models, but its effects may depend on the therapeutic dose and cellular environment. We found that melatonin at millimolar concentrations significantly downregulated transglutaminase 2 (TGM2), histone serotonylation (H3K4me3Q5ser), and YTHDF1/m[6]A (N6-methyladenosine) in a colorectal cancer model. Cross-interference between TGM2 and YTHDF1 supports a link between these regulatory processes, while molecular docking, pharmacological interventions, and co-immunoprecipitation experiments suggest the existence of a signaling pathway involving melatonin and the HTR2B receptor. A combined analysis of CHIP-seq and meRIP-seq identified salt-induced kinase 1 (SIK1) as a potential downstream target, and SIK1 interference affected the proliferation and migration of colorectal cancer. Collectively, these findings support a working model in which melatonin-induced tumor suppression is associated with coordinated changes in TGM2/H3K4me3Q5ser and YTHDF1-associated m[6]A regulation, with SIK1 emerging as a potential convergent downstream effector.

Although zinc (Zn) deficiency severely inhibits rice growth, it remains unclear how melatonin (MT) promotes adaptation under conditions of insufficient Zn supply. To address this issue, rice seedlings were treated with MT, the NO donor sodium nitroprusside (SNP), or the NO scavenger c-PTIO, alone or in combination, under Zn-deficient conditions. Zn starvation rapidly promoted endogenous MT accumulation in rice roots, together with a 90.2%-179.5% rise in the transcript levels of MT biosynthetic genes. Exposure to Zn deprivation reduced root/shoot length and root/shoot biomass, by 46.2%/31.3% and 27.5%/39.6%, respectively. Among the tested concentrations, 10 μM MT produced the strongest protective effect, increasing root length, shoot height, root biomass, and shoot biomass by 59.9%, 34.2%, 21.7%, and 51.8%, respectively, relative to plants that were merely deficient in Zn. In Zn-deficient plants, MT raised Zn concentration in root and shoot both by 16.2% and xylem sap Zn concentration by 15.6%. MT also increased root cell-wall Zn content, pectin abundance, and pectin-associated Zn by 20.0%, 39.3%, and 31.9%, respectively. At the expression level, MT moderated the induction of OsZIP4, OsZIP5, OsZIP8, OsZIP9, OsZIP10, and OsHMA3 by Zn deficiency and further repressed OsZIP1, implying feedback regulation of the Zn-homeostasis network instead of direct activation of Zn-transporter transcription. Root NO content rose by 29.8% after MT treatment, and SNP elicited increases in root and shoot Zn concentrations comparable to those associated with MT. Overall, the data suggest that an NO-associated response contributes to MT-mediated Zn-deficiency tolerance by restoring Zn homeostasis, promoting apoplastic Zn remobilization and root-to-shoot transport, and limiting oxidative damage.

Preterm white matter injury (PWMI) is a serious neurologic condition that threatens neonatal survival and severely impairs the cognitive and motor development of affected children. Melatonin (Mel), a neuroendocrine hormone with anti-inflammatory and antioxidant properties, has shown neuroprotective potential in neonatal brain injury, although the mechanisms underlying its effects in PWMI remain incompletely understood. In this study, we established a neonatal rat model of PWMI and combined multimodal magnetic resonance imaging (MRI) with histological analyses to investigate the effects of Mel on oligodendrocyte precursor cells (OPCs) proliferation, differentiation, and subsequent white matter development. We discovered that Mel administration increased cerebral oxygenation and blood flow, thereby altering the cerebral metabolic microenvironment and mitigating white matter damage caused by hypoxic-ischemic injury. Moreover, Mel promoted the proliferation of OPCs and exerted neuroprotective effects by activating the protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK-3β)/β-catenin signaling pathway. In addition, Mel treatment facilitated neural fiber formation in distant white matter regions of PWMI models, ultimately alleviating cognitive and motor impairments in affected rats. Collectively, these findings suggest that Mel facilitates oligodendrogenesis and white matter repair after PWMI, at least in part through modulation of the AKT/GSK-3β/β-catenin pathway. Multimodal MRI can provide a useful noninvasive approach for monitoring treatment-related changes in white matter injury and development, supporting further investigation of Mel as a potential therapeutic strategy for PWMI.

Melatonin (MEL) is an endogenous hormone that regulates circadian rhythm, immune function and oxidative stress responses. Norepinephrine (NE), an endogenous catecholamine, increases blood pressure through the sympathetic nervous system and is commonly administered intraoperatively or in the clinically ill patient for hemodynamic support. Although endogenous NE is known to stimulate MEL synthesis, the effects of exogenous intravenous NE on plasma MEL concentration, particularly under general anaesthesia (GA), remain poorly characterised. This study examined the influence of intravenous NE on plasma MEL concentrations in healthy volunteers, both awake and under general anaesthesia. A secondary analysis was conducted using data from a prospective, single-centre, cross-over study involving volunteers who received stepwise NE infusions while awake and under total intravenous general anaesthesia. Arterial blood samples were collected to determine plasma MEL and NE concentrations. Linear mixed-effects modelling was used to assess the relationship between NE and MEL concentrations. A total of 36 healthy volunteers were enroled, yielding 417 MEL-NE samples. Intravenous NE administration was significantly associated with higher plasma MEL concentration, corresponding to an estimated 26% increase in MEL per 1 standard-deviation increase in NE concentration (Estimate = 0.230, p < 0.001). MEL concentrations were approximately 43% higher in the awake phase compared to GA (Estimate = 0.356, p < 0.001). GA did not significantly modify the NE-MEL association (Estimate = -0.02877, p = 0.528). Substantial positive correlation was observed between baseline MEL concentrations and the magnitude of the response to NE administration (r = 0.74). In conclusion, intravenous NE increases plasma MEL concentrations in both awake and anaesthetised individuals. Substantial interindividual variation in MEL response suggests underlying physiological differences. Future studies should explore the long-term effects of NE administration on MEL concentrations. Trial Registration: The study is registered in the Dutch Trial Register (NL9312).

Melatonin (MT) is a secondary metabolite that plays a role in environmental stress response in plants. However, the physiological and molecular mechanisms by which MT alleviates excessive copper (Cu) toxicity in rice (Oryza sativa) remain unknown. Herein, exogenous MT application increased root and shoot biomass and inhibited the expression of Cu uptake-associated genes, thereby reducing the Cu uptake capacity of the root and Cu concentration in vivo and effectively enhancing Cu stress tolerance compared with Cu treatment. Transcriptome analysis revealed the essential transcription factor CARBON STARVED ANTHER (OsCSA) as responsive to Cu stress. Compared with the wild type, OsCSA overexpression lines exhibited significantly enhanced Cu tolerance, which was manifested by increased MT content, up-regulated expression of the reactive oxygen species (ROS) scavenging genes CATALASE C and ASCORBATE PEROXIDASE, elevated activities of catalase, superoxide dismutase, and ascorbate peroxidase, and decreased hydrogen peroxide and malondialdehyde content. OsCSA-knockout plants showed the opposite results, and exogenous MT rescued its excessive Cu-sensitive phenotype. Further experiments established that OsCSA directly binds to the GTTA/TAAC element of CAFFEIC ACID O-METHYLTRANSFERASE 12 (OsCOMT12) promoter, up-regulating its expression. Under Cu stress, significant increases in Cu concentration and ROS accumulation were also observed in loss-of-function oscomt12 mutants, consistent with the results observed in OsCSA-knockout lines. Additionally, knockout of OsCOMT12 in the OsCSA-overexpression background abolished the positive effect of OsCSA on Cu stress tolerance. These findings establish the OsCSA-OsCOMT12 regulatory module as a new mechanism for MT-mediated Cu stress response in rice, providing a target for genetic improvement of Cu-tolerant crops.

H. Zhou, D. Li, P. Zhu, Q. Ma, S. Toan, J. Wang, S. Hu, Y. Chen, and Y. Zhang, "Inhibitory Effect of Melatonin on Necroptosis via Repressing the Ripk3-PGAM5-CypD-mPTP Pathway Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury," Journal of Pineal Research 65, no. 3 (2018): e12503, https://doi.org/10.1111/jpi.12503. The above article, published online on 28 May 2018, in Wiley Online Library (https://onlinelibrary.wiley.com/) has been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley and Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate duplications of image panels of Figures 2A, 4A and 7A between this and other articles that were published either around the same time or later by different author groups, depicting different experimental conditions. Further review identified additional issues, including undisclosed splicing in Figure 1J, 4B and 5I, as well as image section insertions in Figure 4A and E. As a result, the editors have lost confidence in the integrity of the data and consider the conclusions of the manuscript to be substantially compromised. The authors and their institution were informed of these concerns and the retraction decision, but remained unresponsive.

Cadmium (Cd) contamination, a major constraint on plant growth, causes a serious threat to ecological safety. Populus tomentosa is a promising woody species for Cd phytoremediation, but the mechanism of Cd phytoremediation by melatonin (MT) in this species remains unclear. To elucidate how MT confers Cd tolerance in P. tomentosa, four treatments (control, MT: 100 μmol·L[-1] melatonin, Cd: 100 μmol·L[-1] CdCl2, and MT + Cd, CM: 100 μmol·L[-1] CdCl2 + 100 μmol·L[-1] melatonin) on seedlings were conducted, and integrated analyses of physiological traits, noninvasive micro-test (NMT) data, transcriptomes, and metabolomes were further performed. Cd stress significantly inhibited seedling growth, reduced chlorophyll content, promoted excessive Cd accumulation, and triggered a burst of reactive oxygen species (ROS). Exogenous MT application reversed Cd-induced growth suppression by promoting root Cd[2+] efflux while reducing Cd influx, decreasing Cd deposition in leaves, and activating superoxide dismutase and peroxidase to scavenge ROS under Cd treatment. Transcriptomic and metabolomic profiling suggested that metabolic pathways, including hormone signaling, glutathione metabolism, and phenylpropanoid biosynthesis, might be participated in the MT-mediated Cd response. Furthermore, three transcription factors, ERF098, bHLH041, and MYB308, were also identified as candidate regulators of MT-mediated Cd detoxification. Heterologous expression in yeast revealed that MYB308 not only enhanced Cd tolerance but also reduced Cd accumulation under Cd stress. These findings elucidate the multilayered regulatory network underlying MT-enhanced Cd tolerance in P. tomentosa, and provide genetic resources for breeding Cd-resistant tree varieties and theoretical guidance for remediating Cd-contaminated soils.

Diabetic cardiomyopathy (DCM) is one of the most severe cardiovascular complications of diabetes mellitus (DM), yet effective treatment strategies remain lacking. Cellular senescence is a principal risk factor for multiple cardiovascular diseases, contributing significantly to cardiac dysfunction and disease progression. Melatonin, an endogenous hormone primarily secreted by the pineal gland, exerts cardioprotective effects against DCM. However, the underlying molecular mechanism remains incompletely understood, particularly whether melatonin ameliorates DCM by suppressing cardiomyocyte senescence. In this study, a streptozotocin (STZ)‑induced diabetic mouse model in vivo and an in vitro model of high‑glucose (HG)‑treated primary neonatal rat cardiomyocytes (NRCMs) were established. Melatonin ameliorated cardiac dysfunction in diabetic mice and alleviated the senescence phenotype in cardiomyocytes. Suppressing oxidative stress with the ROS scavenger N-acetylcysteine (NAC) effectively attenuated cardiomyocyte senescence, confirming the causal role of oxidative stress in senescence progression under HG conditions. Mechanistically, melatonin effectively upregulated the expression of melatonin receptor 1B (MT2), thereby activating the SIRT1/Nrf2 signaling pathway and promoting Nrf2 nuclear translocation. Notably, genetic ablation of Nrf2 in diabetic mice, as well as pharmacological inhibition of MT2, SIRT1, or Nrf2 in NRCMs, substantially abolished the protective effects of melatonin. Collectively, melatonin alleviates DCM by attenuating oxidative stress-induced cellular senescence through activation of the MT2/SIRT1/Nrf2 signaling pathway. These findings uncover a novel mechanism underlying the cardioprotective action of melatonin against DCM.

Sunitinib resistance contributes to poor outcomes in advanced renal cell carcinoma (RCC). This study investigated the anti-metastatic effects and underlying mechanisms of melatonin in sunitinib-resistant (SR)-RCC. Melatonin significantly inhibited the migration and invasion of A498-SR and Caki-1-SR cells. SR-RCC cells exhibited elevated CTSD expression, impaired endoplasmic reticulum (ER) stress signaling with reduced GRP78 and IRE1α, and enhanced p38 MAPK activation, all of which were reversed by melatonin. Silencing p38 MAPK further potentiated the inhibitory effects of melatonin on cell migration and invasion. Mechanistically, CTSD expression was regulated through both GRP78/p38 MAPK-mediated ER stress. In vivo, melatonin markedly reduced lung metastasis of Caki-1-SR cells without causing significant toxicity to major organs. Collectively, these findings demonstrate that melatonin inhibited the metastatic potential of SR-RCC by decreasing CTSD expression, restoring ER stress response, and decreasing p38 MAPK expression, supporting its potential as an anti-metastatic therapeutic agent for SR-RCC.

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 immune response to bacterial infection demonstrates circadian rhythmicity, with heightened antibacterial immunity often observed during the daytime. This circadian-gated immune response is believed to have evolved to synchronize peak antibacterial immunity with the increased threat of infection when active. Using a larval zebrafish infection model, we have previously shown that light has a positive effect on antibacterial immunity, with enhanced survival and neutrophil recruitment observed when infections are delivered during the light phase. However, the specific contribution of the light-detecting pineal gland and its principal hormone, melatonin, to this circadian immune response has not been investigated. Here, we examined whether the pineal gland modulates the host response to bacterial infection in a time-of-day-dependent manner by targeted ablation of the pineal gland. To generate pineal gland-deficient larvae we created the transgenic zebrafish line Tg(exorh:YFP-NTR2.0) that restricts expression of the highly efficient nitroreductase variant NTR2.0 to pinealocytes, enabling metronidazole-mediated pinealectomy. We also analyzed larvae lacking the brain-specific homeobox (bsx) gene, that encodes a transcription factor essential for pineal gland development. Both approaches resulted in complete loss of the pineal gland, confirmed by live imaging, the absence of arylalkylamine N-acetyltransferase 2 (aanat2) expression and diminished melatonin production. Pineal gland-deficient larvae exhibited normal survival and neutrophil recruitment when infected during the light phase, indicating that daytime immune defenses can be maintained independently of the pineal gland. In contrast, infection of pineal gland-deficient larvae during the dark phase led to significantly reduced survival, which correlated with impaired neutrophil recruitment to the infection site. These findings demonstrate that the pineal gland plays an important role in supporting nighttime antibacterial immunity in larval zebrafish.

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.

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.

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.

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.