Journal of Pineal Research最新文献

In mammals, seasonal opportunities and challenges are anticipated through programmed changes in physiology and behavior. Appropriate anticipatory timing depends on synchronization to the external solar year, achieved through the use of day length (photoperiod) as a synchronizing signal. In mammals, nocturnal production of melatonin by the pineal gland is the key hormonal mediator of photoperiodic change, exerting its effects via the hypothalamopituitary axis. In this review/perspective, we consider the key developments during the history of research into the seasonal synchronizer effect of melatonin, highlighting the role that the pars tuberalis–tanycyte module plays in this process. We go on to consider downstream pathways, which include discrete hypothalamic neuronal populations. Neurons that express the neuropeptides kisspeptin and (Arg)(Phe)–related peptide-3 (RFRP-3) govern seasonal reproductive function while neurons that express somatostatin may be involved in seasonal metabolic adaptations. Finally, we identify several outstanding questions, which need to be addressed to provide a much thorough understanding of the deep impact of melatonin upon seasonal synchronization.

Parkinson's disease affects millions of people worldwide, and without significant progress in disease prevention and treatment, its incidence and prevalence could increase by more than 30% by 2030. Researchers have focused on targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease. This study investigated the association between melatonin receptor agonists and Parkinson's disease, using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS). The target drugs were melatonin receptor agonists including ramelteon, tasimelteon, and agomelatine. Parkinson's disease cases were defined according to the Medical Dictionary for Regulatory Activities (MedDRA) 25.0; Standardized MedDRA Query (SMQ) using both the “narrow” and “broad” preferred terms (PTs) associated with Parkinson's disease. The association between melatonin receptor agonists (ramelteon, tasimelteon, and agomelatine) and Parkinson's disease was evaluated by the reporting odds ratio. Upon analyzing the data from all patients registered in the FAERS, ramelteon (ROR: 0.66, 95% confidence interval [95% CI]: 0.51–0.84) and tasimelteon (ROR: 0.49, 95% CI: 0.38–0.62) showed negative correlations with Parkinson's disease. Conversely, only agomelatine was positively correlated with Parkinson's disease (ROR: 2.63, 95% CI: 2.04–3.40). These results suggest that among the melatonin receptor agonists, ramelteon and tasimelteon are negatively correlated with Parkinson's disease. In contrast, agomelatine was shown to be positively correlated with Parkinson's disease. These results should be used in research to develop drugs for the treatment of Parkinson's disease, fully considering the limitations of the spontaneous reporting system.

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ-amino-butyric acid, arginine-vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary-derived adenylate cyclase-activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin-releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β-adrenergic receptors in SCN and a mouse SCN-derived immortalized cell line by immunohistochemical, immuno-cytochemical, and pharmacological techniques. We then characterized the effects of β-adrenergic agonists and antagonists on cAMP-regulated element (CRE) signaling. Moreover, we investigated the interaction of β-adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β-blockers applied as anti-hypertensive drugs.

This study explores the 24-h rhythmic cycle of protein O-GlcNAcylation within the brain and highlights its crucial role in regulating the circadian cycle and neuronal function based on zebrafish as an animal model. In our experiments, disruption of the circadian rhythm, achieved through inversion of the light-dark cycle or daytime melatonin treatment, not only impaired the rhythmic changes of O-GlcNAcylation along with altering expression patterns of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in zebrafish brain but also significantly impeded learning and memory function. In particular, circadian disruption affected rhythmic expression of protein O-GlcNAcylation and OGT in the nuclear fraction. Notably, the circadian cycle induces rhythmic alterations in O-GlcNAcylation of H2B histone protein that correspond to changes in H3 trimethylation. Disruption of the cycle interfered with these periodic histone code alterations. Pharmacological inhibition of OGT with OSMI-1 disrupted the wake-sleep patterns of zebrafish without affecting expression of circadian rhythm-regulating genes. OSMI-1 inhibited the expression of c-fos, bdnf, and calm1, key genes associated with brain function and synaptic plasticity, and decreased the binding of O-GlcNAcylated H2B and OGT to promoter regions of these genes. The collective findings support the potential involvement of circadian cycling of the O-GlcNAc histone code in regulating synaptic plasticity and brain function. Overall, data from this study provide evidence that protein O-GlcNAcylation serves as a pivotal posttranslational mechanism integrating circadian signals and neuronal function to regulate rhythmic physiology.

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models through the CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes’ significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNA^Lys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of Kars^R504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and high mortality rates. Therefore, it is necessary to identify new targets and therapeutic strategies to improve the prognosis of patients with PDAC. Integrative therapies are increasingly being used to boost the efficacy of the known anticancer therapeutic approaches. Hence, this study aimed to evaluate the effects of a novel combination of different potential anticancer molecules, melatonin (MLT), cannabidiol (CBD), and oxygen–ozone (O₂/O₃) to treat PDAC using in vitro and in vivo models of human PDAC. The effect of this combination was investigated in combination with gemcitabine (GEM), the most common chemotherapeutic drug used for PDAC treatment. The combination of MLT + CBD + O₂/O₃ was more effective than the individual treatments in inhibiting PDAC cell viability and proliferation, inducing cell death, and modulating the RAS pathway protein levels. Moreover, different combinations of treatments reduced tumor mass in the PDAC mouse model, thus promoting the effect of GEM. In conclusion, a mixture of MLT + CBD + O₂/O₃ could serve as a potential adjuvant therapeutic strategy for PDAC.