Journal of Pineal Research最新文献

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.

Citrus canker, caused by Xanthomonas citri subsp citri (Xcc), represents a severe threat to the citrus industry. The conventional control measures for citrus canker primarily rely on chemical bactericide. However, overuse of bactericide will cause environmental and food security concerns. To address this problem, efforts are being made to develop environmentally friendly bio-bactericide alternatives. In this study, we identified a caffeic acid O-methyltransferase gene, AbCOMT1, from Atalantia buxifolia, a Citrus-related species exhibiting high resistance to citrus canker. AbCOMT1 encodes a key enzyme involved in melatonin biosynthesis, and its overexpression in sweet orange significantly enhances resistance to citrus canker. We found elevated melatonin levels in the AbCOMT1 overexpressing sweet orange lines and demonstrated that the AbCOMT1 overexpression not only directly inhibited Xcc proliferation but also activated citrus immune responses. To further improve the inhibitory efficacy of melatonin, we tested several melatonin derivatives, achieving a tenfold increase in inhibitory activity. Notably, the melatonin derivative MT-3 exhibited outstanding efficacy in controlling citrus canker under field conditions. Our results revealed AbCOMT1 as a promising resistance gene and identified the highly efficient melatonin derivatives for citrus canker disease control.

The purpose of this investigational study was to assess the cardiovascular effects of melatonin replacement therapy in pinealectomized patients. This was a prospective open-label, single-arm proof-of-concept study The study comprised 11 patients aged 16.7 ± 1.7 years, who had undergone pinealectomy, experienced no tumor recurrence, and exhibited undetectable salivary melatonin levels. A 6-month melatonin regimen (0.3 mg daily) was administered. Ambulatory blood pressure monitoring was conducted at baseline, 3-month, and 6-month intervals. First of all, no hypertension was observed in pinealectomized patients. Over the course of the study, diastolic blood pressure progressively decreased, reaching statistical significance at 6 months. Pulse pressure exhibited a gradual increase, reaching statistical significance after 6 months. Short-term blood pressure variability increased significantly for both systolic and diastolic pressures. Morning systolic and diastolic blood pressure levels were significantly decreased by melatonin replacement therapy. Melatonin had no effect on the average heart rate or its variability. Melatonin-deficient pinealectomized patients were normotensive. Melatonin replacement in these patients led to reduced diastolic pressure, increased pulse pressure, and enhanced short-term blood pressure variability. These results are consistent with improved cardiovascular health. Furthermore, melatonin's temporal specificity suggests that it might enhance nighttime recovery, heightening reactivity during wakefulness. While melatonin is used as a dietary supplement for similar effects, caution is advised, and further research is needed to optimize its use in various health and disease contexts. Further, considering the study's limitations, more extensive research would strengthen these findings.