Journal of Pineal Research最新文献

Periodontal ligament stem cells (PDLSCs) bring new hope to patients with poor periodontium recovery and impaired regeneration. However, the complex inflammatory microenvironment continually inhibits stem cell function and hinders stem cell therapy effectiveness. Melatonin is a naturally occurring neurohormone that participates in the regulation of a large spectrum of biological functions. We investigated the effect of melatonin on periodontium regeneration both in vitro and in vivo. The results showed that melatonin promoted periodontitis recovery and enhanced the osteogenesis of inflamed PDLSCs (Inf-PDLSCs) depending on concentrations. Further mechanistic exploration indicated that autophagy activation played a significant role in enhancing the osteogenic differentiation of Inf-PDLSCs after melatonin treatment. Additionally, melatonin-induced upregulation of TEME110 participated in the initiation of autophagy activation and enhancement of osteogenesis in Inf-PDLSCs. Collectively, the results of our study provide evidence that melatonin-mediated osteogenesis of Inf-PDLSCs is important for periodontal tissue regeneration. Moreover, melatonin as a therapeutic drug for periodontitis treatment deserves further investigation.

Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production. Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial-triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine N-acetyltransferase knockout (AANAT-KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT-KO deficiency elevated BAK and BAX levels in AANAT-KO neurons. Further, we found that exogenous melatonin treatment of AANAT-KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.

Myocardial ischemia/reperfusion (MIR) injury, a primary cause of mortality in acute myocardial infarction, exhibits diurnal variation associated with disruptions in diurnal rhythm. Melatonin (MLT), a potent antioxidant known for its cardioprotective properties, also demonstrates diurnal rhythmicity. This study aimed to investigate the time-dependent cardioprotective effects of MLT in MIR and to clarify the role of the circadian gene Per2 in mediating these effects. Using in vivo (mice) and in vitro (H9c2 cardiomyocytes) models of MIR, we administered MLT at two distinct diurnal time points: ZT1 and ZT13. We evaluated infarct size, cardiac function, apoptosis, and the expression levels of Per2 and other circadian genes. Pretreatment with MLT at ZT13 significantly reduced infarct size and enhanced cardiac function compared to ZT1 administration. This time-dependent cardioprotective effect correlated with the diurnal expression pattern of Per2, which was notably augmented by dark phase administration of MLT without phase alteration. Crucially, Per2 knockdown in both models abrogated the cardioprotective effects of MLT. Our findings underscore that MLT confers superior cardioprotection against MIR injury when administered at dark phase, aligning with the circadian variation of Per2 expression. These effects reveal the therapeutic potential of targeting the MLT-Per2 axis in chronotherapy to mitigate MIR injury.

Cadmium (Cd) pollution significantly hampers cleaner production of peanut (Arachis hypogaea L.). Therefore, exploring of tolerance mechanisms to Cd stress and breeding of low-Cd peanut cultivars are urgently needed and require intense efforts. Herein, multi-omics and physiological studies reveal that multiple biological processes, including melatonin (MT) biosynthesis, are involved in the Cd tolerance in peanut plants. Exogenous MT was applied to peanut plants under Cd stress, which decreased Cd accumulation in roots, shoots and seeds for 40%–60%, and promoted the antioxidant capacity. Integrated investigation reveals that MT-mediated Cd tolerance is mainly attributed to the enhanced metabolism of linolenic acid, glutathione (GSH), and phenylpropanoid (lignin), and development of casparian strip in root cell wall. Defense genes, such as non-race-specific disease resistance gene 1/harpininduced gene 1 (NDR1/HIN1)-like in peanut (AhNHL), were also significantly upregulated by MT under Cd stress. Overexpression of the AhNHL gene in tobacco reduced Cd accumulation for 37%–46%, and alleviated photosynthesis-inhibition induced by Cd stress. Transcriptomic analysis suggested that AhNHL confers the Cd tolerance mainly through promoting phenylpropanoid biosynthesis and GSH metabolism. Additionally, exogenous GSH effectively alleviated the Cd stress through improving Cd sequestration and antioxidant capacity in peanut plants, while apply of the GSH biosynthesis inhibitor (buthionine sulfoximine) exacerbated the Cd phytotoxicity. Transcriptomic analysis reveals that exogenous GSH improves Cd tolerance through affecting the expression of genes involved in transcription regulation, and metal ion binding and transport. Our findings provide novel insights into molecular mechanisms underlying Cd tolerance in plants, which would facilitate breeding of low-Cd peanut cultivars.

Growing evidence demonstrates that meditation practice supports cognitive functions, including attention and interoceptive processing, and is associated with structural changes across cortical networks, including prefrontal regions and the insula. However, the extent of subcortical morphometric changes linked to meditation practice is less appreciated. A noteworthy candidate is the pineal gland, a key producer of melatonin, which regulates circadian rhythms that augment sleep-wake patterns and may also provide neuroprotective benefits to offset cognitive decline. Increased melatonin levels, as well as increased fMRI BOLD signal in the pineal gland, have been observed in meditators versus controls. However, it is not known if long-term meditators exhibit structural changes in the pineal gland linked to the lifetime duration of practice. In the current study, we performed voxel-based morphometry (VBM) analysis to investigate: (1) whether long-term meditators (LTMs) (n = 14) exhibited greater pineal gland MRI-derived signal intensity compared to a control group (n = 969), (2) a potential association between the estimated lifetime hours of meditation (ELHOM) and pineal gland signal intensity, and (3) whether LTMs show greater grey matter (GM) maintenance (BrainPAD) that is associated with pineal gland signal intensity. The results revealed greater pineal gland signal intensity and lower BrainPAD scores (younger brain age) in LTMs compared to controls. Exploratory analysis revealed a positive association between ELHOM and greater signal intensity in the pineal gland but not with GM maintenance as measured by BrainPAD score. However, greater pineal signal intensity and lower BrainPAD scores were correlated in LTMs. The potential mechanisms by which meditation influences pineal gland function, hormonal metabolism, and GM maintenance are discussed – in particular, melatonin's roles in sleep, immune response, inflammation modulation, and stem cell and neural regeneration.

Circadian clocks in the body drive daily cycles in physiology and behavior. A master clock in the brain maintains synchrony with the environmental day–night cycle and uses internal signals to keep clocks in other tissues aligned. Work in cell cultures uncovered cyclic changes in tissue oxygenation that may serve to reset and synchronize circadian clocks. Here we show in healthy humans, following a randomized controlled single-blind counterbalanced crossover study design, that one-time exposure to moderate ambient hypoxia (FiO₂ ~15%, normobaric) for ~6.5 h during the early night advances the dim-light onset of melatonin secretion by 9 min (95% CI: 1–16 min). Exposure to moderate hypoxia may thus be strong enough to entrain circadian clocks to a 24-h cycle in the absence of other entraining cues. Together, the results provide direct evidence for an interaction between the body's hypoxia-sensing pathway and circadian clocks. The finding offers a mechanism through which behaviors that change tissue oxygenation (e.g., exercise and fasting/eating) can affect circadian timing and through which hypoxia-related diseases (e.g., obstructive sleep apnea and chronic obstructive pulmonary disease) can result in circadian misalignment and associated pathologies.

Trial Registration: Registration number: DRKS00023387; German Clinical Trials Register: http://www.drks.de