Journal of Pineal Research最新文献

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/m⁶A (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 m⁶A 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 (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.

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 Cd²⁺ 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