Journal of Pineal Research最新文献

Atrazine (ATR) is a widespread environmental herbicide that seriously affects agricultural work and human safety. Melatonin (MLT) as an endogenous neuroendocrine hormone is widely found in animals and plants, which have antioxidant and anti-inflammatory effects. Pink1/Parkin-mediated mitophagy keeps normal physiological processes by degrading damaged mitochondria in cells. Therefore, we investigated the potential role and mechanism of MLT in ATR-induced toxic injury of the spleen. The results showed that MLT alleviated ATR-induced unclear boundary between the white pulp and the red pulp of the spleen. It is also shown that ATR resulted in swollen mitochondria, partial extinction of mitochondrial membranes and cristae, and increased mitophagy under the action of MLT. ATR-induced reactive oxygen species (ROS) activates the Pink1/Parkin pathway, which guides mitophagy development and then causes the activation of TLR4/NF-κB inflammatory pathway. Meanwhile, these damages further exacerbated the production of NLRP3 inflammasomes, leading to spleen necrosis. Interestingly, these changes were improved after MLT treatment. Collectively, we found that MLT alleviates ATR-induced immune impairment in splenic macrophages via regulating Parkin-TLR4-NLRP3 axis which elucidates the effect of melatonin on the spleen and provides a novel perspective on melatonin in splenic inflammatory injury treatment.

Melatonin (MLT) has been reported to attenuate Concanavalin A (Con A)-induced acute liver injury via the inhibition of immune cells. Whereas the response of hepatocyte to Con A-caused inflammatory storm and the mechanism of MLT on hepatocyte remain not fully understood. Our RNA-seq and bioinformatic analyses suggested that OPA1 and fatty acid β-oxidation might be critical. It was found that MLT ameliorated Con A-induced acute liver injury, promoted mitochondrial fusion, fatty acid β-oxidation, modulated metabolic reprogramming and inhibited apoptosis. The overexpression and knockdown of OPA1 by adenovirus proved that these processes were governed by OPA1. With the overexpression plasmid, agonist, inhibitor and SiRNA, we found that MLT promoted OPA1 upregulation to enhance fatty acid β-oxidation, which inhibited apoptosis. The MLT and OPA1-promoted fatty acid β-oxidation enhanced ATP production rather than reduced lipid accumulation. AMPK/FOXO1 was required for MLT and OPA1-mediated fatty acid β-oxidation and apoptosis. NOTCH1 was also necessary for this apoptotic process. The results were verified in immune deficiency mice and AML12 cells induced by Con A-stimulated monocyte supernatant. MLT might control the transcription of OPA1 through MEF2A. TOMM70 was critical for MLT translocation and OPA1 upregulation. In conclusion, the present study demonstrated that MLT attenuated Con A-induced acute liver injury via the OPA1-controlled fatty acid β-oxidation to inhibit apoptosis in hepatocyte.

The determination of melatonin levels in saliva represents one of the key methods for assessing the timing of the central circadian clock in humans, both in research and clinical settings. Melatonin levels in saliva are typically determined in a laboratory setting by RIA or enzyme-linked immunosorbent assay and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presented a serious challenge to the routine, safe assessment of melatonin in saliva samples. However, SARS-CoV-2 present in biological fluids can be inactivated by exposure to temperatures of at least 55–60°C for 30 min and the aim of this study was to assess the validity of applying a pretreatment heating step to saliva samples being prepared for melatonin determination using the Novolytix Radioimmunoassay (RK-DSM2). 40 archived saliva samples collected under a Dim Light Melatonin Onset sampling protocol were thawed and aliquoted into three identical groups—Controls (no pretreatment), 56°C pre-assay heat-treatment (30 min), and 70°C pre-assay heat-treatment (30 min). Melatonin concentrations in samples that were heated to 56°C for 30 min before assaying showed close agreement with the untreated controls, with the Pearson's correlation coefficient between the two sets of samples of 0.99 (p < 0.0001) and the slope of the Deming regression analysis close to 1.0 (Y = 1.04X + 0.168). When saliva samples were pretreated to 70°C for 30 min before assaying, the subsequent melatonin determinations were still strongly correlated with the untreated controls (Pearsons correlation coefficient = 0.97 (p < 0.0001), however melatonin concentrations were consistently overestimated when compared to the untreated controls with Deming regression slope of Y = 1.26X + 0.241. These results indicate that a 56°C pretreatment step is suitable for inclusion in standard operating protocols for melatonin determinations using the Novolytix RIA, as a way of effectively minimizing the potential for accidental pathogen exposure while handling saliva samples.

Cadmium (Cd) is a widespread environmental contaminant with high toxicity to human health. Melatonin has been shown to improve Cd-induced liver damage. However, its mechanism has not yet been elucidated. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver damage and fibrosis. A combination of 16S rRNA gene sequencing and mass spectrometry-based metabolomics was adopted to investigate changes in the gut microbiome and its metabolites on the regulation of melatonin in Cd-induced liver injury and fibrosis of mice. Further, nonabsorbable antibiotics, a fecal microbiota transplantation (FMT) program and intestine-specific farnesoid X receptor (FXR) knockout mice were employed to explore the mechanism of melatonin (MT) on liver injury and fibrosis in Cd treated mice. MT significantly improved hepatic inflammation, bile duct hyperplasia, liver damage, and liver fibrosis, with a notable decrease in liver bile acid levels in Cd-exposed mice. MT treatment remodeled the gut microbiota, improved gut barrier function, and reduced the production of gut-derived lipopolysaccharide (LPS). MT significantly decreased the intestinal tauro-β-muricholic acid levels, which are known as FXR antagonists. Notably, MT prominently activated the intestinal FXR signaling, subsequently inhibiting liver bile acid synthesis and decreasing hepatic inflammation in Cd-exposed mice. However, MT could not ameliorate Cd-induced liver damage and fibrosis in Abx-treated mice. Conversely, MT still exerted a protective effect on Cd-induced liver damage and fibrosis in FMT mice. Interestingly, MT failed to reverse liver damage and fibrosis in Cd-exposed intestinal epithelial cell-specific FXR gene knockout mice, indicating that intestinal FXR signaling mediated the protective effect of MT treatment. MT improves Cd-induced liver damage and fibrosis through reshaping the intestinal flora, activating the intestinal FXR-mediated suppression of liver bile acid synthesis and reducing LPS leakage in mice.

Cocaine abuse has been strongly linked to blood−brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT₁ receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications.