Journal of Pineal Research最新文献

Melatonin has been shown to travel freely through biological membranes. The consequences of this demonstration have been largely underestimated these past years. In particular, the behavior of melatonin during the preparation of samples from organs (ex vivo), from cells (in cellulo), or subcellular compartment(s) has been experimentally ignored. Melatonin is not retained in samples but can diffuse immediately outside those samples. Similarly, melatonin cannot be “trapped” in membrane-based organelles like mitochondria, nucleus, ER/Golgi, or lipid droplets of any sort. Consequently, existing data should be carefully reinterpreted, and future experiments should take the fact of melatonin diffusion into account, in particular when trying to provide convincing experimental evidence for local production of melatonin in cells and organelles outside of the pineal gland and the retina.

Anthropogenic activities have increased cadmium (Cd) accumulation in agricultural soils, severely affecting crop productivity. This study investigated the role of melatonin (Mlt) and a Pseudomonas consortium (PGPR) in modulating secondary metabolism in Brassica juncea L. seedlings under Cd stress. Combined Mlt–PGPR treatment significantly reduced Cd accumulation and regulated the expression of genes involved in Cd transport and detoxification. Enhanced levels of osmolytes and organic acids were observed, along with upregulation of genes associated with osmoprotection and metal chelation. Antioxidant defense was experimentally assessed through enzymatic and non-enzymatic analyses, confirming improved redox homeostasis. FTIR spectroscopy supported treatment-induced biochemical alterations. Transcriptomic profiling revealed activation of melatonin biosynthesis genes and secondary metabolism-related pathways. A structural model of BjCand2, a putative melatonin receptor, and docking analysis suggested its involvement in signaling regulation. Overall, Mlt–PGPR application mitigates Cd toxicity through coordinated receptor-mediated signaling and metabolic reprogramming.

Melatonin, a signaling molecule secreted by the pineal gland, is closely associated with physiological activities, such as animal growth, development, and reproduction. Multiple studies have indicated that melatonin acts on the adenohypophysis to promote the synthesis and secretion of growth hormone (GH), but the specific mechanism of melatonin remains unclear. We have previously reported that melatonin levels in bovine serum are closely correlated with GH levels. In the present study, transcriptome sequencing was performed on primary bovine adenohypophyseal cells treated with melatonin, which identified FOXO1 as a key transcription factor that is responsive to melatonin and regulates GH synthesis and secretion. Cellular experiments revealed that melatonin binds to the MTNR1A in bovine adenohypophyseal cells, activates the cAMP/PKA signaling pathway, and promotes the expression of FOXO1 protein. Dual-luciferase reporter assays verified the binding of FOXO1 to the GH1 promoter. Treatment with Luzindole, 4P-PDOT, 2′,5′-Dideoxyadenosine or H-89 elucidated the molecular mechanism through which melatonin promotes GH synthesis and secretion in adenohypophyseal cells through the cAMP/PKA/CREB/FOXO1 pathway. The present study provides critical evidence for the direct action of melatonin on adenohypophyseal cells and its targeted regulatory sites, and it offers new insights into the conserved and species-specific modes of action of melatonin across different species, providing data and theoretical support for the application of melatonin in promoting animal growth and development.

Spontaneous parturition in both humans and sows occurs predominantly at night. Melatonin is thought to facilitate nocturnal parturition in humans by synergistically enhancing myometrial contractions with oxytocin, but the precise underlying mechanisms remain unclear. In this study, in vivo analyses showed that melatonin levels in both serum and myometrium were significantly increased in laboring sows, accompanied by increased melatonin synthesized in the myometrium. Moreover, exogenous melatonin administration to pregnant sows potentially shifted parturition time. Functional studies demonstrated that melatonin supplementation significantly enhanced spontaneous myometrial contractility and sensitivity to oxytocin. Mechanistic investigations revealed that transcription factors NRF2 and MAFF were involved in the signaling pathway of melatonin, enhancing myometrial contractility. Silencing NRF2 or MAFF in melatonin-treated myometrial cells reduced the expression of contraction-associated proteins (CAPs) and attenuated collagen gel contraction. Dual-luciferase reporter assays indicated that NRF2 and MAFF directly targeted the promoters of key contraction-associated genes, including PTGS2 and OXTR. Additionally, molecular analysis revealed that melatonin enhanced myometrial contraction by binding to the MT2 receptor. Furthermore, our results showed that PKC participated in melatonin-induced myometrial contraction by regulating NRF2 and MAFF expression. Collectively, our data reveal, for the first time, that the MT2-PKC-NRF2/MAFF axis mediates melatonin-enhanced myometrial contraction in sows. These findings advance our understanding of parturition initiation in mammals and may provide a novel theoretical basis for developing therapeutic strategies for preterm or delayed/prolonged labor.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by significant challenges in social interactions and repetitive behaviors. Its prevalence is high, with males affected at a rate four times higher than females. Among various comorbidities associated with ASD, sleep disorders and abnormal melatonin levels have emerged as critical areas of concern. Melatonin, a potent endogenous hormone, plays essential roles as a circadian regulator, anti-inflammatory, and antioxidant agent through the release of pro- and anti-inflammatory cytokines and stimulation of endogenous antioxidant enzymes. This study sets out to examine the effects of melatonin administration during gestation and lactation on ASD-related behaviors, focusing on sex-specific differences in a well-established ASD model. Pregnant rats received an intraperitoneal injection of valproic acid (VPA) or saline at gestational day 12.5 (E12.5) and were treated with melatonin or vehicle from E13 until weaning. Our results indicated that chronic melatonin supplementation effectively reversed behavioral, circadian, and morphological abnormalities in male offspring. In females, melatonin prevented the inflammatory responses induced by VPA. Furthermore, chronic melatonin treatment restored the altered profile of serum melatonin observed in VPA animals and also restored the circadian expression of enzymes critical for its synthesis. These findings highlight sex-specific alterations prevalent in this model and strongly suggest that melatonin represents a promising therapeutic approach for mitigating ASD-related behaviors in the VPA model, warranting further investigation to assess its clinical relevance.

Chronic manganese (Mn) exposure induces severe neurotoxicity, characterized by impaired neurogenesis and disrupted metabolic homeostasis. Although melatonin (MT) possesses established neuroprotective properties, its clinical utility is hindered by poor bioavailability and limited brain delivery. Here, we developed a brain-targeted, rabies virus glycoprotein (RVG)-modified liposomal delivery system encapsulating melatonin (MT@RVG-Lip) to enhance therapeutic efficacy. Multi-omics analyses including brain and intestinal transcriptomics, serum metabolomics, and gut metagenomics were conducted to elucidate the underlying mechanisms. MT@RVG-Lip significantly improved motor deficits and enhanced neurogenesis while reducing neuroinflammation in Mn-exposed mice. Compared with regular MT and CaNa₂-EDTA, MT@RVG-Lip more effectively alleviated Mn-disrupted gene expression in neurogenesis regions, particularly genes involved in amino acid metabolism. Additionally, MT@RVG-Lip demonstrated a regulatory effect on serum amino acid profiles and intestinal transporter gene expression. Gut microbiota analysis further revealed that MT@RVG-Lip partially reversed Mn-associated dysbiosis and promoted the improvement of key amino acid-related microbiota-mediated metabolic pathways. The RVG-modified liposomal formulation conferred sustained release and improved brain-targeting capability, prolonging MT bioavailability and enhancing therapeutic outcomes. These findings provide a new mechanistic framework for MT-based interventions in neurodegenerative diseases and highlight the therapeutic potential of multifunctional delivery strategies.

N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) is a ubiquitous tire-derived transformation product with emerging reproductive toxicity; however, its impact on mammalian oocytes and the potential protective role of melatonin (MT) remain unclear. Here, we evaluate 6PPD-Q–induced impairment of mouse oocyte competence and assess the protective efficacy of MT. 6PPD-Q exposure significantly decreases polar body extrusion, fertilization, and 2-cell embryo formation, whereas MT co-treatment markedly restores these developmental outcomes. Mechanistically, MT alleviates 6PPD-Q–induced meiotic spindle defects and cortical F-actin disorganization, reduces DNA damage, and suppresses early apoptotic signaling. Smart-seq. 2 transcriptomic profiling further reveals that 6PPD-Q triggers extensive transcriptional reprogramming, with prominent disruption of mitochondrial metabolism, oxidative phosphorylation, and organelle homeostasis, whereas MT mitigates these pathway perturbations. Consistently, functional assays demonstrate that MT reduces excessive cellular and mitochondrial reactive oxygen species, restores mitochondrial membrane potential and adenosine triphosphate levels, and mitigates global organellar disorganization. Collectively, these findings identify MT as a cytoprotective modulator of 6PPD-Q–induced oocyte dysfunction by preserving mitochondrial and endomembrane homeostasis, thereby supporting oocyte maturation and fertilization.