Journal of Pineal Research最新文献

Hepatocyte lipotoxicity is central to the aetiology of nonalcoholic fatty liver disease (NAFLD), a leading cause of liver failure and transplantation worldwide. Long-lasting toxic pollutants have increasingly been considered as environmental risk factors of NAFLD. These include cadmium (Cd), a metal that synergizes with other cellular toxicants and metabolic stimuli to induce fat build-up and lipotoxicity. Recent studies demonstrated that melatonin (MLT) holds great potential as repairing agent in this form of hepatocyte lipotoxicity. In this study, the molecular hints of this MLT effect were investigated by lipidomics analysis in undifferentiated HepaRG cells, a human pre-hepatocyte cell line, exposed to Cd toxicity either alone or combined with prototypical free fatty acids (FFA), namely the saturated species palmitic acid and the monounsaturated oleic acid (OA and PA, respectively), to simulate the cellular lipotoxicity conditions of fatty liver disease. Cd exposure synergized with FFAs to induce cellular steatosis, and PA produced higher levels of lipotoxicity compared to OA by leading to increased levels of H₂O₂ production and apoptotic death. These effects were associated with changes of the cellular lipidome, which approximate those of NAFLD liver, with differentially expressed lipids in different classes that included triacylglycerols (TG), di- and mono-acylglycerols, phospholipids (PL), sphingolipids, acylcarnitines and FA; characteristic differences were observed in all these classes comparing the combinations of Cd exposure with PA or OA treatments. MLT significantly reduced the effects of either individual or combinatorial treatments of Cd and FFAs on lipotoxicity hallmarks, also repairing most of the alterations of the cellular lipidome, including those of the chain length and number of double bonds of acyl residues esterified to TG and PL classes. These findings and their bioinformatics interpretation suggest a role for the earliest acyl elongase and desaturase steps of FA metabolism in this repairing effect of MLT; biochemistry studies validated such interpretation identifying a specific role for SCD1 activity. This lipidomics study shed light on the cytoprotective mechanism of MLT in Cd and FFA-induced hepatocyte lipotoxicity, highlighting a repairing effect of this molecule on the cellular lipidome, which may hold therapeutic potential in fatty liver diseases.

Human genetic variants of the orphan G protein-coupled receptor GPR50 are suggested risk factors for neuropsychiatric disorders. However, the function of GPR50 in the central nervous system (CNS) and its link to CNS disorders remain poorly defined. Here, we generated GPR50 knockout (GPR50-KO) mice and show that the absence of GPR50 increases neurite outgrowth, cell motility and migration of isolated neural progenitor cells (NPCs) and hypothalamic radial glial cells (tanycytes). These observations were phenocopied in NPCs and tanycytes from wild-type mice treated with neutralizing antibodies the against the prototypical neurite growth inhibitor Nogo-A. Treatment of NPCs and tanycytes from GPR50-KO cells with neutralizing antibodies had no further, additive, effect. Inhibition of neurite growth by GPR50 occurs through activation of the G_12/13 protein-RhoA pathway in a manner similar to, but independent of Nogo-A and its receptors. Collectively, we show that GPR50 acts as an inhibitor of neurite growth and cell migration in the brain by activating the G_12/13 protein-RhoA pathway.

In the production environment of chickens, exposure to unpredictable light patterns is a common painless stressor, widely used to influence growth rate and egg production efficiency. The pineal gland, a key regulator of circadian rhythms through melatonin secretion, responds to environmental light cues, and its function is modulated by epigenetic mechanisms. In this study, we investigated how the pineal gland methylome and transcriptome (including micro-RNAs) interact to respond to a rearing exposure to unpredictable illumination patterns, with a particular focus on sex differences. We conducted an integrative multi-omic analysis—including methylomic (MeDIP-seq), transcriptomic (RNA-seq), and miRNA expression profiling—on the pineal gland of Hy-Line White chickens (n = 34, 18 females, 16 males) exposed to either a standard 12:12 light–dark cycle (control) or a randomized, unpredictable light schedule from Days 3 to 24 post-hatch. Our findings reveal that unpredictable light exposure alters the pineal gland methylome and transcriptome in a sex-specific manner. However, while transcriptomic differences between sexes increased due to the stress, methylomic differences decreased, particularly on the Z chromosome. These changes were driven by females (the heterogametic sex in birds), which became more male-like in their pineal methylome after exposure to the illumination stress, leading to reduced epigenetic sexual dimorphism while maintaining differences at the gene expression level. Further, we implemented a fixed sex effect model as a biological proof of concept, identifying a network of 12 key core genes interacting with 102 other genes, all linked to circadian regulation and stress adaptation. This network of genes comprises a core regulatory framework for circadian response. Additionally, tissue-specific expression analysis and cell-type specific expression analysis revealed enrichment in brain regions critical for circadian function, including neuronal populations involved in circadian regulation and the hypothalamic–pituitary–thyroid axis. Together, these findings provide strong evidence of sex-specific epigenetic transcriptomic responses of the pineal gland upon illumination stress and offer valuable insights into the interplay of different omic levels in relation to circadian response.

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.