Journal of Pineal Research最新文献

This study examined whether melatonin could decrease CD4 + T cell apoptosis and reduce mortality rates in sepsis-induced mice. Fifty-one male C57BL/6 mice were randomly classified into three groups: Sham, cecal ligation and puncture (CLP), and CLP plus melatonin (CLP + MLT). Mice in the CLP + MLT group were intraperitoneally administered melatonin at 30 mg/kg 10 min before and 30 min after CLP and then once daily for 6 days. Lymphocyte counts, cytokine levels, and apoptosis rates in CD4+ and CD8 + T cells in the spleen and peripheral blood were examined using automatic blood cell analysis, enzyme-linked immunosorbent assay, or flow cytometry. The results demonstrated that melatonin improved the survival of mice following CLP, decreased the levels of IFN-γ, IL-1β, and IL-2 in the serum, and significantly upregulated lymphocyte counts. In addition, melatonin increased the percentage of CD4 + T cells and inhibited the apoptosis of these cells in the spleen and peripheral blood of mice following CLP. Melatonin protected against sepsis-induced organ damage. Melatonin inhibited CD4 + T cell apoptosis in vitro, possibly via the Bcl-2/BAX but not through the PD-1 pathway. Our results suggest that melatonin could mitigate Pro-inflammatory responses, attenuate organ injury, and suppress CD4 + T cell apoptosis via the Bcl-2/BAX pathway, thereby improving survival rates in a mouse model of sepsis. Targeted therapy to protect CD4 + T cells against apoptosis could represent a new approach for sepsis treatment in the future.

Abdominal sepsis and the resultant lung injury lead to high mortality rates, with macrophage metabolic dysfunction and subsequent immune dysregulation being key contributing factors. The clarification of the therapeutic value of direct peritoneal resuscitation (DPR) combined with melatonin in regulating macrophage metabolic reprogramming is crucial for the development of potential treatment strategies. Lipopolysaccharide exposure led to a decrease in mitochondrial membrane potential (MMP) of macrophage, morphological changes in mitochondria, and a substantial accumulation of reactive oxygen species (ROS) within the cells. Melatonin protects the stability of the mitochondrial electron transport chain (ETC) by enhancing the synthesis of Uqcrc1, thereby restoring macrophage function. Silencing Uqcrc1 effectively blocked this protective effect. In the rat sepsis model, DPR combined with melatonin enhanced the survival of alveolar macrophages (AMs) and reduced lung tissue damage. Importantly, in the DPR combined with melatonin treated group, the macrophage metabolic reprogramming was evident through enhanced oxidative phosphorylation and increased adenosine triphosphate (ATP) synthesis, both of which contributed to improved immune function and reduced inflammation. It is found that melatonin promotes the synthesis of Uqcrc1, stabilizing the ETC in macrophages. The combination of DPR and melatonin alleviated sepsis-induced lung injury in rats by modulating macrophage metabolic reprogramming.

Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionarily conserved molecule with diverse physiological functions across prokaryotes, plants, and animals, including circadian rhythms regulation in animals and developmental modulation in plants. Although the biosynthetic pathways of melatonin have been well elucidated in mammals and plants, the enzymatic mechanisms underlying microbial melatonin synthesis remain largely unexplored. Saccharomyces cerevisiae, a genetically tractable eukaryotic model, provides a valuable system for elucidating fungal melatonin biosynthesis. In this study, we identified the GNA1 gene as a potential serotonin N-acetyltransferase candidate in S. cerevisiae through genome-wide comparative analysis. The GNA1 protein was heterologously expressed in Escherichia coli BL21(DE3), purified, and subjected to detailed enzymatic characterization. In vitro assays revealed that GNA1 exhibits acetyltransferase activity toward both serotonin and 5-methoxytryptamine (5-MT), with maximal catalytic efficiency observed at 30°C and pH 8.5. Substrate specificity and kinetic analyses demonstrated a pronounced preference for 5-MT, supporting a biosynthetic route in which serotonin undergoes O-methylation before acetylation by GNA1 to yield melatonin. This study provides the first biochemical evidence linking GNA1 to melatonin biosynthetic pathway in yeast and offers new insights into microbial melatonin biosynthesis, highlighting its potential evolutionary and metabolic significance.

The glymphatic system is a critical waste clearance system in the brain, playing an essential role in maintaining homeostasis within the central nervous system. Aquaporin 4 (AQP4), an indispensable component of the glymphatic system, is vital for ensuring the proper function of this system. Melatonin has been proven to be protective in treating hypoxic-ischemic encephalopathy (HIE). The aim of this study was to examine if alterations occur in the glymphatic system function in the brain of HIE model rats, and to determine whether melatonin can enhance the function of the glymphatic system by regulating AQP4, along with elucidating the mechanisms underlying melatonin's effects on AQP4. 10-day-old rat pups were subjected to hypoxic-ischemic (HI) injury; melatonin and roscovitine (an inhibitor of cyclin-dependent kinase 5) were injected intraperitoneally at 10 min following HI induction. At 24 h post-HI, intracisternal tracer infusion, neurobehavioral tests, immunofluorescence staining, western blot analysis, Evans blue (EB) permeability assay, brain water content test, ELISA detection, and co-immunoprecipitation tests were performed. At 28 days post-HI, neurobehavioral tests, intracisternal EB infusion, Nissl staining, and cerebral blood flow (CBF) evaluations were performed. The results showed that melatonin improved neurological function, restored glymphatic function, maintained blood–brain barrier integrity, alleviated brain edema, increased CBF, and reduced brain atrophy; both melatonin and roscovitine inhibited cyclin-dependent kinase 5 (CDK5) activity, enhanced the interaction between AQP4 and alpha-syntrophin (α-Syn), and maintained AQP4 polarity. In conclusion, the current study suggests that melatonin may enhance the interaction between AQP4 and α-Syn by inhibiting CDK5 activity after HI to maintain glymphatic function.

Melatonin is a known pleiotropic antioxidant and signaling molecule, found in both plants and animals. Although melatonin was found to translocate via the human glucose transporter 1 (GLUT1), any mechanism of transporter-mediated uptake of melatonin has remained unknown in plants. In the present manuscript, we found an orthologue of GLUT1 in tobacco and established its role as a functional phytomelatonin transporter (MelT) using fluorescence tracking, via melatonin-conjugated quantum dot nanoparticles. Overexpression of NtMelT in the model plant Nicotiana benthamiana showed increased uptake of the conjugated nanofluorophores to a maximum of 5.4-fold in roots and 2.1-fold in leaves, while application of N-ethylmaleimide (inhibitor of glucose transporter) suppressed their translocation. This ensured the specificity of NtMelT for transporting melatonin. Due to increased uptake and distribution, the transgenic lines maintained a maximum of 4.6-fold more endogenous melatonin. The transgenics were tolerant against arsenic, copper, lead, nickel, and fluoride toxicity. Increased activity of the enzymatic antioxidants detoxified excess reactive oxygen species and alleviated the associated physiological injuries. Translocation of melatonin significantly reduced bioaccumulation of the toxic pollutants and ensured normal flowering and seed setting in the transgenic plants. Overall, the present research provides a solution for safe rice cultivation under polluted environment.