Journal of Pineal Research最新文献

Light and temperature change constantly under natural conditions and play vital roles in coordinating plant morphogenesis. However, how these two signals are integrated with endogenous signals to fine-tune plant morphology requires further investigation. Given that phytomelatonin is a multifunctional regulator connecting environmental signals and plant development, here we propose that phytomelatonin is involved in the integration of light and temperature signals. When co-treated with darkness and warm ambient temperature, the light–temperature signal showed synergistic upregulation of phytomelatonin synthesis and thus hypocotyl growth. Phytomelatonin synthesis gene SEROTONIN N-ACETYLTRANSFERASE (SNAT) was induced under constant darkness or warm temperature, reaching its peak level under the combined treatment. The snat mutant, with reduced phytomelatonin content and hypocotyl length, was less sensitive to darkness and warm temperature, whereas 35S::SNAT-GFP had more phytomelatonin and longer hypocotyls than the wild type, indicating that SNAT is needed for light–temperature morphogenesis. Furthermore, SNAT expression and phytomelatonin content were reduced in cop1 but increased in hy5. HY5 inhibits SNAT expression by binding to its promoter. The hy5 snat seedlings had less phytomelatonin and shorter hypocotyls than the hy5 seedlings, along with the SNAT mutation in 35S::COP1 snat seedlings reversed the phenotype of 35S::COP1, further verifying that SNAT acts downstream of COP1-HY5 module. Moreover, RNA-Seq revealed that phytomelatonin is associated with light–temperature signal in controlling hypocotyl elongation-related genes. Taken together, our results showed that the light–temperature signal regulates SNAT-mediated phytomelatonin synthesis through COP1-HY5 module to coordinate plant morphogenesis.

Thalassemia patients often exhibit low bone mineral density (BMD). The iron overload associated with thalassemia elevates oxidative stress levels, leading to reduced BMD. Melatonin improves BMD in postmenopausal osteopenia, however, its effect on BMD in thalassemia patients with iron overload has not been investigated. A randomized controlled study was conducted at Hematology Clinic, Faculty of Medicine, Chiang Mai University. Thalassemia patients with osteopenia and iron overloaded condition, as indicated by BMD Z-score <−2 at l-spine, femoral neck, or total hip, and serum ferritin level > 500 μg/L were recruited in this study. Patients were randomized to receive either melatonin 20 mg/day or placebo at bedtime for 12 months. BMD was re-evaluated 12 months after interventions. Bone turnover markers (BTM), malondialdehyde (MDA as an oxidative stress marker), and pain scores were assessed at baseline, 6, and 12 months. The outcomes, including BMD, BTM, MDA, and pain scores, were evaluated in all patients. Forty-one thalassemia patients (18 males) were enrolled in the study and randomly assigned to either the melatonin group (n = 21) or the placebo group (n = 20). Characteristics of patients were not differences between groups. Mean age was 30.8 ± 6.2 years old. Thirty-three patients (80.4%) were transfusion-dependent patients. At 12 months, mean BMD at l-spine in melatonin group was not significantly different from placebo group (p = 0.069). However, l-spine BMD at 12 months in the melatonin group was significantly greater than baseline (p = 0.029). Serum levels of P1NP and MDA were significantly reduced at 6 months compared to baseline following melatonin treatment. The melatonin group experienced a notable decrease in back pain scores after 12 months compared to the initial measurements. 20 mg daily melatonin supplementation for 12 months alleviated l-spine BMD loss in iron-overloaded thalassemia with low BMD. Melatonin also significantly reduced circulating oxidative stress and mitigated back pain in these patients.

Sarcopenia, a condition associated with aging, involves progressive loss of muscle mass, strength, and function, leading to impaired mobility, health, and increased mortality. The underlying mechanisms remain unclear, which limits the development of effective therapeutic interventions. Emerging evidence implicates chronodisruption as a key contributor to sarcopenia, emphasizing the role of Bmal1, a circadian clock gene critical for muscle integrity and mitochondrial function. In a skeletal muscle-specific and inducible Bmal1 knockout model (iMS-Bmal1^−/−), we observed hallmark features of sarcopenia, including disrupted rhythms, impaired muscle function, and mitochondrial dysfunction. Exercise and melatonin treatment reversed these deficits independently of Bmal1. Building on these findings, the present study elucidates several mechanisms underlying these changes and the pathways by which melatonin and exercise exert their beneficial effects. Our findings indicate that iMS-Bmal1^−/− mice exhibit reduced expression of satellite cell and muscle regulatory factors, indicating impaired muscle regeneration. While mitochondrial respiration remained unchanged, notable alterations in mitochondrial dynamics disrupted mitochondria in skeletal muscle. In addition, these mice showed alterations in muscle energy metabolism, compromised antioxidant defense, and inflammatory response. Remarkably, exercise and/or melatonin successfully mitigated these deficits, restoring muscle health in Bmal1-deficient mice. These findings position exercise and melatonin as promising therapeutic candidates for combating sarcopenia and emphasize the need to elucidate the molecular pathways underlying their protective effects.

Sleep deprivation impairs daytime cognitive functioning and is a risk factor for various diseases related to immune dysregulation. N⁶-methyladenosine (m⁶A) is a common epigenetic RNA modification with essential roles in regulating neurogenesis and circadian rhythms. m⁶A dysregulation resulting in immune imbalance has received much attention. In this study, we elucidated the landscape and specific mechanisms of m⁶A regulators in the peripheral blood of patients with sleep deprivation through RNA sequencing and single-cell transcriptomics data sets. We observed that m⁶A regulator upregulation aggravated sleep loss and immune disorders. Women were more sensitive to sleep deprivation. Notably, m⁶A regulator ALKBH5 was downregulated in peripheral blood mononuclear cells (PBMC) of patients with sleep deprivation at the transcriptome level. However, ALKBH5 was cell-type specific upregulated in T cells (TC), B cells (BC), and natural killer (NK) cells, involving the dysregulation of acquired immune mechanisms by aberrant cell–cell communication that mediated ligand–receptor interactions across diverse cell types. Furthermore, the immune dysregulation of sleep loss could be regulated by a potential pathway between ALKBH5 and CD99 in SH-SY5Y and HT22 cells. Sleep deprivation group CD3⁺/CD45⁺ T cells had higher levels of ALKBH5 mRNA than the control group. This study demonstrated that abnormal m⁶A modification patterns caused by m⁶A regulators play a key role in the dysregulation of innate and acquired immunity in sleep deprivation.

Disruption of the circadian clock has been closely linked to the initiation, development, and progression of cancer. This study aims to explore the impact of circadian rhythm disruption (CRD) on triple-negative breast cancer (TNBC). We analyzed bulk and single-cell RNA sequencing data to assess circadian rhythm status in TNBC using multiple bioinformatic tools, alongside metabolomic profiles and tumor microenvironment evaluations to understand the influence of CRD on metabolic reprogramming and immune evasion. The results indicate that TNBC experiences profound CRD. Patients with a higher CRDscore exhibit significantly poorer relapse-free survival compared to those with a lower CRDscore. Cyclic ordering by periodic structure (CYCLOPS) identified significant changes in rhythmic gene expression patterns between TNBC and normal tissues, with TNBC showing a “rush hour” effect, where peak expression times are concentrated within specific time windows. Transcripts with disrupted circadian rhythms in TNBC were found to be involved in key pathways related to cell cycle regulation, metabolism, and immune response. Metabolomic analysis further revealed that TNBCs with high CRDscore are enriched in carbohydrate and amino acid metabolism pathways, notably showing upregulation of tryptophan metabolism. High CRDscore was also linked to an immunosuppressive tumor microenvironment, characterized by reduced immune cell infiltration, exhausted CD8⁺ T cells, and a diminished response to immune checkpoint blockade therapy. These findings suggest that the disrupted molecular clock in TNBC may activate tryptophan metabolism, thereby promoting immune evasion and potentially reducing the effectiveness of immunotherapy.