Journal of Pineal Research最新文献

The cAMP response element-binding protein (CREB) and Period1 (Per1) have been implicated in depression, but their interactive mechanisms remain unclear. This study investigated the integrative role of CREB and Per1 in depression and explores a potential strategy for rapid antidepressant treatment. Using a chronic unpredictable stress (CUS) model, we conducted behavioral assessments including the sucrose preference test, forced swimming test, elevated plus maze, and open field test. Gene expression was manipulated via stereotaxic surgery and RNA interference (RNAi), while protein levels and viral injection sites were verified through Western blot analysis and immunofluorescence. Additionally, we generated Per1 CRE knockout rats using CRISPR/Cas9, with genotypes confirmed by Sanger sequencing. CUS significantly reduced phosphorylated CREB (pCREB) and PER1 levels in the CA1 region. Both Per1 knockdown in CA1 and CRE sequence knockout induced depression-like behaviors, whereas Per2 knockdown in CA1 produced mania-like behaviors. Notably, CRE knockout in the Per1 promoter increased pCREB binding to the Per2 promoter, upregulating PER2 expression in the CA1 and resulting in depression-like phenotypes that are partially lithium-responsive. Treatment with the adenosine A₁ receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) elevated pCREB and PER1 levels in the CA1 and elicited rapid antidepressant effects. These effects were present in heterozygotes but absent in homozygotes with a mutated Per1 CRE sequence. These results revealed the pivotal role of the pCREB-CRE-Per1 pathway in CUS-induced depression and its mediation of rapid antidepressant-like effects via adenosine A₁ receptor activation. Moreover, the CRE sequence in the Per1 promoter may be a critical molecular link to the pathophysiology of bipolar depression.

The treatment of prostate cancer (PCa) remains challenging, and while melatonin (MEL) has demonstrated therapeutic potential, its precise mechanisms require further elucidation. Through integrated in vitro, in vivo, and bioinformatics analyses, this study demonstrated that MEL functioned as a novel ferroptosis inducer in PCa by disrupting androgen receptor (AR) liquid-liquid phase separation (LLPS). We found that MEL effectively inhibited PCa proliferation, migration, and invasion in vitro while suppressing tumor growth safely in mice models. Mechanistically, MEL impaired AR LLPS dynamics, reducing AR-driven transcription of minichromosome maintenance protein 5 (MCM5). MCM5 was a clinically relevant biomarker associated with aggressive PCa and poor survival. Crucially, downregulated MCM5 attenuated its physical interaction with NRF2, leading to uncontrolled activation of the NRF2/HMOX1 pathway, GPX4 suppression, and accumulation of ferroptosis hallmarks. These findings defined an AR/MCM5/NRF2 axis regulating ferroptosis susceptibility, establishing MEL as the first-reported ferroptosis inducer that expands the mechanistic foundation and therapeutic potential of MEL-based PCa treatment strategies.

Systemic lupus erythematosus (SLE) is an autoimmune disorder featuring abnormal B cell differentiation and excessive autoantibody production, leading to multiorgan damage. Despite advances in understanding SLE pathogenesis, the molecular mechanisms driving aberrant B cell differentiation remain elusive. Melatonin, a neuroendocrine hormone with immunomodulatory properties, has been shown to regulate immune responses, but its role in B cell differentiation and SLE is poorly understood. This study investigates the role of melatonin and its receptors in B cell differentiation and SLE pathogenesis. We observed reduced serum melatonin levels and decreased expression of melatonin receptors in B cells from SLE patients and MRL/Lpr mice. Activation of melatonin receptors inhibited the protein kinase A (PKA) signaling pathway and reduced phosphorylation of cyclic-AMP response binding protein (CREB), leading to epigenetic downregulation of PRDM1 and IRF4, key transcription factors for plasmablast and plasma cell differentiation. Consequently, melatonin receptor activation suppressed abnormal B cell differentiation into antibody-secreting cells. Our findings highlight melatonin and its receptor signaling as potential therapeutic targets for SLE and other autoimmune diseases mediated by aberrant antibody-secreting cell activity. This study provides novel insights into the protective role of melatonin in SLE and offers a promising avenue for developing targeted therapies.

Melatonin (MT) plays a critical role in regulating rice responses to heavy metal stress. However, the mechanism by which MT alleviates copper (Cu) toxicity in rice remains insufficiently understood. In this study, excessive Cu increased endogenous MT level in rice roots, accompanied by enhanced gene expression involved in MT biosynthesis, suggesting its role in Cu stress responses. Exogenous MT reduced Cu accumulation and restored root growth in rice under Cu stress, thereby mitigating Cu-induced phytotoxicity. Mechanistically, MT increased the root pectin content and its Cu retention, thereby reducing Cu influx into the cytoplasm. Additionally, exogenous MT upregulated the expression of Heavy Metal ATPase 4 (OsHMA4) involved in vacuolar sequestration, as well as Cu efflux transporter genes OsHMA6 and OsHMA9. Conversely, it downregulated the plasma membrane Cu uptake-associated genes Copper Transporter (OsCOPT1, OsCOPT2, and OsCOPT3), the vacuolar Cu exporter OsCOPT7, and the xylem loading transporter gene OsHMA5, thereby alleviating Cu toxicity in rice. Furthermore, MT elevated nitric oxide (NO) levels in root tips, and application of the exogenous NO scavenger, 2-(4-carboxyphenyl)−4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), attenuated the mitigative effect of MT on excess Cu-stressed rice. In summary, MT alleviates Cu toxicity by reducing Cu binding to root cell walls, thereby limiting Cu uptake and translocation from roots to shoots. This process may depend on NO accumulation and provides new insights into the molecular mechanisms underlying MT-induced Cu tolerance in rice.

Soil contamination by microplastics (MPs) and heavy metals has become a global ecological and environmental issue and poses considerable threats to crop production and human health. In plants, melatonin (MT) functions as a powerful biostimulant, orchestrating vital physiological processes and enhancing stress tolerance. In this study, through controlled pot experiments, how exogenous MT (0.1 mmol L⁻¹) modulates maize responses to low-density polyethylene (LDPE) MPs, cadmium (Cd), and their combination was investigated. Simultaneous exposure to LDPE MPs and Cd exacerbated oxidative damage, inhibited chlorophyll biosynthesis, suppressed photosynthetic capacity, and reduced biomass in maize plants, alongside increasing shoot and root Cd²⁺ levels. Conversely, exogenous MT application reduced the malondialdehyde content by 12.5% under combined stress conditions, indicating a substantial reduction in oxidative damage. Additionally, MT inhibited the absorption and accumulation of Cd²⁺, increased the chlorophyll content, enhanced the photosynthetic efficiency, improved the plant height and stem diameter, thereby increasing maize plant biomass by 5.6%. MT also increased the activity of reactive oxygen species scavenging antioxidant enzymes and promoted the biosynthesis of non-enzymatic antioxidants such as proline and soluble sugars. Metabolomic analysis revealed that exogenous MT treatment significantly affected the levels of 210 metabolites. Notably, key metabolic pathways, including purine metabolism, phenylpropanoid biosynthesis, and tryptophan metabolism, were upregulated, indicating their pivotal role in the stress response mechanism of plants. These results reveal that exogenous MT effectively alleviates the synergistic phytotoxicity of PE MPs and Cd in maize plants, underscoring its promise as a practical strategy for enhancing crop resilience in contaminated environments.

Aging is associated with increased susceptibility to bacterial infections, particularly multidrug-resistant (MDR) strains, which often result in antibiotic treatment failure and high mortality rates in the elderly. However, effective preventive and therapeutic strategies remain limited. Herein, we showed that aged mice exhibited higher susceptibility to colistin-resistant Salmonella enterica serotype Typhimurium and methicillin-resistant Staphylococcus aureus compared to young mice. Notably, pre-supplementation with melatonin, a hormone markedly reduced in the aging gut, effectively restricted MDR bacterial infections in aged mice by enhancing microbial colonization resistance. Mechanistically, melatonin-induced alterations in the gut microbiota, particularly the enrichment of butyrate-producing bacteria including Faecalibaculum, Muribaculaceae, and Ruminococcus, played a pivotal role in enhancing resistance to pathogenic bacteria. Elevated gut butyrate levels following melatonin pre-supplementation not only preserved intestinal barrier integrity and mitigated inflammaging, but also directly inhibited pathogenic bacterial growth by disrupting intracellular pH homeostasis, leading to proton motive force dissipation and metabolic disturbances. These findings underscore melatonin and its metabolite, butyrate, as promising candidates for the prevention of MDR bacterial infections in the aging population.

The purpose of this 1-year study was to assess the effect of osteogenic loading combined with melatonin on musculoskeletal health and well-being in a population with osteopenia. Participants were randomized into one of four groups and received mock loading plus plant fiber as placebo (ML/Placebo), mock loading plus 5 mg melatonin (ML/Melatonin), osteogenic loading plus placebo (OL/Placebo), and osteogenic loading plus 5 mg melatonin (OL/Melatonin). The loading protocol was designed to deliver multiples of body weight (MOB; 1-2 MOB for mock loading and 1.5–4.2 MOB for osteogenic loading) to the upper body (targeting the arm, chest, and shoulders), core (targeting the spine and core stability), lower body (targeting the legs and hip) and postural (targeting the spine and posture). Following these interventions, musculoskeletal health was measured by DXA and functional testing using timed-up-and-go (TUG) and sit-to-stand (STS) assessments. Markers of bone health (e.g., P1NP, CTX, CRP, cortisol, and melatonin) were assessed in urine collected during the night (10 pm–6 am). Mental health assessments were conducted using PSS, CES-D, STAI and QualiOst. Time-dependent increases in the amount of force exerted (in lbs) were observed in the OL groups for all musculoskeletal systems targeted, compared to those participants receiving ML. Over 12mos, compared to baseline, participants in the OL/Melatonin group had statistically significant increases in lumbar spine T-scores (mean difference [MD] = 0.13, standard deviation [SD] = 0.05, p = 0.015) and BMD (MD = 0.013, SD = 0.006, p = 0.021). No other statistically significant effects were noted for T-scores, BMD, or FRAX scores. Additionally, no significant differences were observed when T-scores were compared between groups. Functional assessments at 12mos revealed increases in TUG times (MD = −1.7, SD = 0.3, p = 0.002) from baseline and deterioration for STS (MD = 2.8, SD = 0.59, p = 0.004) from month 03 for ML/placebo group, which did not occur for the other interventions. Correlation analysis revealed negative associations between TUG performance and CTX levels starting at 3mos in the OL/Melatonin group (r = −0.960, p = 0.04). The change in STS repetitions over a 12-month period (12mo–0mo) was negatively associated with the P1NP:CTX ratio (r = −0.978, p = 0.02) and positively associated with melatonin levels in the OL/Melatonin group (r = 0.958, p = 0.04). No changes in nocturnal output of CRP or cortisol and subject-reported outcomes were observed for any of the interventions within and between groups. The results from this study reveal that osteogenic loading combined with melatonin may be an alternative therapeutic intervention for those with osteopenia.

Postmenopausal women have a significantly increased risk of cardiovascular disease and osteoporosis due to the lack of estrogen protection. To explore the effects of melatonin on clock genes and glucose and lipid metabolic disorders of postmenopausal women, the models of ovariectomized (OVX) mice under different dietary conditions were generated and given melatonin gavage for 8 weeks. Biochemical indexes of serum and the morphology and histology of livers of the mice were checked. Transcriptome analysis, qPCR and Western blot were used to detect the expressional levels of genes related to clock and glucose and lipid metabolism in the livers of mice. The intestinal microbiota of the ovariectomized mice under different dietary conditions was further analyzed with 16S rDNA sequences. Melatonin significantly reduced the high concentrations of TC and LDL-C in the serum and lipid accumulation in the livers of the ovariectomized mice, and downregulated the protein expression associated with cholesterol and fatty acid biosynthesis, including HMGCR, FDPS, IDI1, MVK, LSS, FASN, and ACC. Melatonin could also improve the insulin resistance of the ovariectomized mice, upregulate the protein expression levels of p-IRS1, p-AKT, and p-mTOR, and reduce the protein expression level of p-Glycogen Synthase under high-fat diet (HFD) conditions. In addition, melatonin restored the clock genes expression disturbances caused by ovarian removal or high-fat diets, and upregulated the expression of the core circadian clock genes Clock and Bmal1. Melatonin also effectively increased the abundance of beneficial bacteria, improved the structure of microflora, and reduced the harmful bacteria of the ovariectomized mice fed with HFD. These results suggest that melatonin could affect liver clock genes expression and gut microbiota in ovariectomized mice, and improve glucose and lipid metabolic disorders under different dietary conditions.