Journal of Pineal Research最新文献

Evidence exists for the daily rhythmicity of bone metabolism that may be influenced by melatonin production, reproductive hormones, the light/dark cycle, or all three, but the ability to determine their independent contributions is confounded by the synchrony of the sleep/wake and dark/light cycles with the endogenous circadian system in sighted individuals. Blind participants, who often have no circadian light perception and may exhibit desynchrony between their sleep/wake cycle and circadian system, provide an opportunity to study the independent contribution of melatonin and light on bone metabolism in a field-based setting. In this exploratory study, 35 pre-, peri-, and postmenopausal blind women (N = 13, 8, and 14, respectively) both with (N = 17) and without (N = 18) visual light perception (LP and NPL, respectively) who were either normally entrained (N = 19) or abnormally entrained or non-entrained (N = 16) to the 24-h day were randomly selected from a cohort of 130 visually impaired women. Levels of 6-sulfatoxymelatonin (aMT6s; ng/h) and the bone resorption marker amino-terminal cross-linked telopeptide of collagen I (NTx; BCE nM/h) were assayed from serial urine samples collected over 48 h and fit by a cosinor model to determine the presence of significant 24-h rhythms. Most blind women (N = 32/35, 91%) had a significant 24-h aMT6s rhythm (mean ± SD, 03:44 ± 4:27 hh:mm), but fewer women had a significant 24-h NTx rhythm (N = 20/35, 57%; 21:01 ± 5:50 hh:mm). There was no significant difference in the proportion of women with significant NTx rhythms by visual light perception status (LP: N = 10/17, 59% vs. NPL, N = 10/18, 56%), entrainment status (Entrained: N = 11/19, 58% vs. Abnormal or Not entrained: N = 9/16, 56%) or reproductive status (Premenopausal: N = 7/13, 54% vs. Perimenopausal: 5/8, 63% vs. Postmenopausal: 8/14, 57%). There was no correlation between the peak timings of aMT6s and NTx among the 17 participants with significant rhythms in both metabolites (r = 0.07, p = 0.80). NTx area under the curve was significantly higher among perimenopausal women with LP (p = 0.04). Our results do not support a direct influence of light, melatonin, or reproductive status on NTx rhythms, but the apparent increase of NTx in the perimenopausal period warrants further investigation.

Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease, and the most common neurodegenerative disease that causes movement dysfunction. Without innovations in prevention and treatment, the incidence and prevalence of Parkinson's disease is projected to increase by > 30% by 2030, making the development of new treatments an urgent priority. We previously investigated the association between melatonin receptor agonists and Parkinson's disease using the US Food and Drug Administration's Adverse Event Reporting System (FAERS). The results showed that ramelteon may reduce the incidence of Parkinson's disease. However, since the US FAERS relies on spontaneous reports, which are susceptible to reporting bias, further validation using real-world data is required. This study investigated the association between ramelteon use and risk of developing Parkinson's disease using the DeSC database, a Japanese claims database reported to be representative of the general Japanese population. The association was evaluated using sequence symmetry analysis, with the adjusted sequence ratio (ASR) serving as the evaluation index. Our DeSC database analysis showed a negative association between ramelteon use and Parkinson's disease (ASR: 0.959, 95% confidence interval: 0.955–0.964). Our results support previous reports suggesting that ramelteon may help suppress the onset of Parkinson's disease. However, even though this study used real-world data, these results should be interpreted with caution, as a sequence symmetry analysis cannot be adjusted for covariates. Therefore, additional pharmacoepidemiological studies are needed to further verify the potential risk of Parkinson's disease associated with ramelteon use.

The association between modern lifestyle factors and dry eye disease (DED) pathogenesis has garnered increasing scientific attention. Emerging evidence implicates circadian disruption—a prevalent consequence of contemporary living patterns—as a significant yet not fully clarified pathogenic factor in DED development. To address this knowledge gap, we developed a circadian disruption mouse model using chronic jet lag exposure. Mice subjected to chronic jet lag exhibited conjunctival clock gene dysregulation and upregulated pro-inflammatory mediators, such as TNF-α, IL-6, and IL-17. Transcriptomic profiling demonstrated marked activation of IL-17-mediated inflammatory pathways within the conjunctival tissue. Therapeutic IL-17 neutralization substantially attenuated ocular surface inflammation, improved corneal epithelial integrity, and decreased apoptotic cell density in circadian disruption-induced dry eye mouse model. Moreover, REV-ERBα agonism potently suppressed IL-17 transcription, whereas BMAL1 deficiency exacerbated IL-17-driven inflammatory responses through REV-ERBα downregulation. Chronic jet lag additionally induced ocular surface microbiota dysbiosis, characterized by Firmicutes overproliferation. Melatonin administration effectively suppressed conjunctival IL-17 expression through BMAL1-REV-ERBα pathway activation while reducing the relative abundance of Firmicutes to restore ocular surface microbiota balance. Our study reveals that circadian disruption induces ocular surface inflammation through the BMAL1-REV-ERBα-IL-17 signaling axis and exacerbates dysbiosis of the ocular surface microbiota. Melatonin mitigates these pathological alterations via dual-directional modulation of circadian-immune signaling crosstalk and restoration of microbiota balance. Importantly, this study establishes melatonin as a multifaceted therapeutic agent for combating lifestyle-associated DED, while elucidating the underlying mechanisms governing circadian rhythm-microbiome axis dynamics in ocular surface pathogenesis.

Melatonin, a multifunctional signalling molecule in plants, has been increasingly recognized for its role in improving stress tolerance, regulating hormone signalling, and enhancing crop productivity. Exogenous melatonin application represents a promising strategy to enhance crop productivity under global agricultural challenges. This study aimed to investigate the physiological and molecular mechanisms by which melatonin improves yield in Brassica napus. under optimal conditions. Two-week old plants were treated with 10 μM melatonin for 7 days and phenotype was observed. The plants exhibited significant increases in plant height, leaf number, pods per plant, seeds per pod, and 100-seed weight compared to controls. Transcriptomic analysis revealed 2924 differentially expressed genes (DEGs; 1655 upregulated, 1269 downregulated) from 66 258 genes in response to exogenously applied melatonin. Functional enrichment highlighted profound upregulation of photosynthesis-related pathways, including photosystem I/II components (PsbO, PsaH), electron transport genes (PetE, PetH), and F-type ATPase subunits. Melatonin also reconfigured phytohormone signaling, upregulating auxin (AUX1; BnaA10g27610D), ABA (ABF; BnaA06g04750D), cytokinin (CRF1; BnaA06g34500D, A-ARR; BnaC03g48210D, Bna08g14280D, Bna09g36380D, BnaCnng49490D, BnaA06g16900D, and BnaA06g06240D), and gibberellin-associated genes while downregulating ABA repressors (PYR/PYL; BnaA06g40360D, BnaC07g19450, PP2C; BnaA06g23040D, and BnaA01g37370D). Transcription factor profiling showed activation of growth-promoting families (NAC, TCP, bHLH) and suppression of stress-responsive TFs (MYB, AP2/ERF, WRKY). Validation via RT-qPCR confirmed RNA-seq reliability (R² = 0.96). Our study demonstrated that low-dose melatonin enhances B. napus yield by coordinately boost photosynthetic efficiency, optimizing hormone signaling, and activating growth-promoting transcription factors to prioritize reproductive development.

Acute circadian misalignment, such as that induced by a single episode of jet lag, can leave molecular traces even after behavioral rhythms appear to recover. Here, we applied an integrated multi-omics approach—combining liver transcriptomics and plasma metabolomics—to characterize residual signatures on the 7th day after a single 6-h phase advance in male mice. Our data revealed significant alterations, particularly in the core clock genes Bmal1 and Cry1, and the metabolites l-arginine and SM(d18:1/18:1(11Z)), with notable differences at Zeitgeber Time 0 (ZT0). Additionally, we identified l-Serine as a potential biomarker for circadian misalignment, independent of sampling time. These findings provide new insights into potential biomarkers for detecting acute circadian misalignment.

Major Depressive Disorder (MDD) is closely associated with neuroinflammation, but the underlying mechanisms remain to be fully elucidated. This study investigates the role of NPAS2 in mediating neuroinflammation-induced depressive-like behaviors using NPAS2 knockout (KO) mice and lipopolysaccharide (LPS) treatment. We confirmed that NPAS2 protein expression in the hippocampus was significantly increased in mice exposed to LPS or chronic unpredictable mild stress (CUMS). Moreover, in the hippocampus, NPAS2 in astrocytes is more sensitive to inflammatory stimuli than that in neurons. NPAS2 KO mice demonstrated attenuated astrocyte activation, reduced neuroinflammation associated with the inhibition of NF-κB and JAK2/STAT3 signaling pathways, and resilience to depressive- and anxiety-like behaviors. Mechanistically, the antidepressant effects in NPAS2 KO mice were mediated through the BDNF/TrkB signaling pathway, which is regulated by inflammatory factors and controls synaptic plasticity. This conclusion was supported by the reversal of these effects using the BDNF receptor antagonist k252a. These findings highlight the critical role of astrocytic NPAS2 in mediating neuroinflammation-induced depressive-like behaviors and suggest that targeting NPAS2 may represent a novel therapeutic strategy for MDD.

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.