Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, with endothelial dysfunction and glycocalyx disruption playing central roles in vascular failure. Despite growing recognition of the glycocalyx as a therapeutic target, its temporal dynamics and potential pharmacological modulation remain poorly understood. We performed a translational study combining longitudinal clinical observations in septic patients with mechanistic investigations in a murine cecal ligation and puncture (CLP) model. Plasma from patients was collected at intensive care unit admission and after clinical recovery to assess inflammatory mediators, coagulation parameters, and glycocalyx-related biomarkers. In parallel, the CLP model evaluated systemic and tissue-specific glycocalyx alterations and the effects of injectable melatonin. Acute sepsis induced marked alterations in multiple glycocalyx-related biomarkers in patients, with several changes persisting despite normalization of organ dysfunction and standard inflammatory indices, indicating ongoing endothelial injury and repair. In the CLP model, sepsis reproduced these alterations, while melatonin treatment significantly attenuated systemic cytokine responses and partially restored circulating and tissue glycocalyx components in an organ- and gene-specific manner. These results highlight persistent, dynamic glycocalyx disruption as a key driver of sepsis pathology and support pharmacological stabilization of the glycocalyx as a promising therapeutic strategy. Melatonin emerges as a potential endothelial-protective agent capable of promoting vascular recovery and homeostasis, providing translational insight for interventions targeting microvascular integrity in sepsis.
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 mu M 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-3 beta)/beta-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-3 beta/beta-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).
