Davidsonmelgaard0149

The underlying mechanisms of microRNAs (miRNAs) in regulating nanoplastic toxicity are still largely unclear in organisms. In nanopolystyrene (NPS) exposed Caenorhabditis elegans, the expression of mir-76 (a neuronal miRNA) was significantly decreased, and the mir-76 mutant was resistant to the toxicity of NPS. The aim of this study was to determine the molecular basis of mir-76 in controlling NPS toxicity in nematodes. The mir-76 mutation increased expression of glb-10 encoding a globin protein in NPS (1 μg/L) exposed nematodes. Exposure to NPS (1-100 μg/L) increased the glb-10 expression, and the glb-10(RNAi) worm was susceptible to NPS toxicity in inducing reactive oxygen species (ROS) production and in decreasing locomotion behavior. Using ROS production and locomotion behavior as endpoints, mutation of glb-10 inhibited resistance of mir-76 mutant to NPS toxicity, and neuronal overexpression of mir-76 inhibited the resistance to NPS toxicity in nematodes overexpressing neuronal glb-10 containing 3' untranslated region (3'UTR). Thus, GLB-10 functioned as a target of mir-76 in the neurons to regulate the NPS toxicity. Moreover, a signaling cascade of HRG-7-HRG-5 required for the control of heme homeostasis was identified to function downstream of neuronal GLB-10 to regulate the NPS toxicity. In this signaling cascade, the neuronal HRG-7 regulated the NPS toxicity by antagonizing function of intestinal HRG-5. Furthermore, in the intestine, HRG-5 controlled NPS toxicity by inhibiting functions of hypoxia-inducible transcriptional factor HIF-1 and transcriptional factor ELT-2. Our results highlight the crucial function of heme homeostasis related signaling in regulating the NPS toxicity in organisms.Perinatal exposure to polybrominated diphenyl ethers (PBDEs) may be a potential risk factor for autism spectrum disorders (ASD). BDE-47 is one of the most common PBDEs and poses serious health hazards on the central nervous system (CNS). However, effects of perinatal exposure to BDE-47 on social behaviors and the potential mechanisms are largely unexplored. Thus, we aimed to investigate whether BDE-47 exposure during gestation and lactation led to autistic-like behaviors in offspring rats in the present study. Valproic acid (VPA), which is widely used to establish animal model of ASD, was also adopted to induce autistic-like behaviors. A battery of tests was conducted to evaluate social and repetitive behaviors in offspring rats. We found that perinatal exposure to BDE-47 caused mild autistic-like behaviors in offspring, which were similar but less severe to those observed in pups maternally exposed to VPA. Moreover, perinatal exposure to BDE-47 aggravated the autistic-like behaviors in pups maternally exposed to VPA. Abnormal dendritic development is known to be deeply associated with autistic-like behaviors. Golgi-Cox staining was used to observe the morphological characteristics of dendrites in the prefrontal cortex of pups. We found perinatal exposure to BDE-47 reduced dendritic length and complexity of branching pattern, and spine density in the offspring prefrontal cortex, which may contribute to autistic-like behaviors observed in the present study. Perinatal exposure to BDE-47 also exacerbated the impairments of dendritic development in pups maternally exposed to VPA. Besides, our study also provided the evidence that the inhibition of BDNF-CREB signaling, a key regulator of dendritic development, may be involved in the dendritic impairments induced by perinatal exposure to BDE-47 and/or VPA, and the consequent autistic-like behaviors.Microplastics (MPs) considered as a new persistent environmental pollutant could enter into the circulatory system and result in decrease of sperm quantity and quality in mice. However, the effects of Polystyrene MPs (PS MPs) on the ovary and its mechanism in rats remained unclear. In this present study, thirty-two healthy female Wistar rats were exposed to different concentrations of 0.5 µm PS MPs dispersed in deionized water for 90 days. Using hematoxylin-eosin (HE) staining, the number of growing follicles was decreased compared to the control group. In addition, the activity of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) were decreased while the expression level of malondialdehyde (MDA) was increased in ovary tissue. Confirmed by immunohistochemistry, the integrated optical density of NLRP3 and Cleaved-Caspase-1 had been elevated by 13.9 and 14 in granulosa cells in the 1.5 mg/kg/d group. Furthermore, compared to the control group, the level of AMH had been decreased by 23.3 pg/ml while IL-1β and IL-18 had been increased by 32 and 18.5 pg/ml in the 1.5 mg/kg/d group using the enzyme-linked immune sorbent assay (ELISA). Besides, the apoptosis of granulosa cells was elevated measured by terminal deoxyribonucleotide transferase-mediated nick end labeling (TUNEL) staining and flow cytometry. Moreover, western blot assays showed that the expressions of NLRP3/Caspase-1 signaling pathway related factors and Cleaved-Caspase-3 were increased. These results demonstrated that PS MPs could induce pyroptosis and apoptosis of ovarian granulosa cells via the NLRP3/Caspase-1 signaling pathway maybe triggered by oxidative stress. The present study suggested that exposure to microplastics had adverse effects on ovary and could be a potential risk factor for female infertility, which provided new insights into the toxicity of MPs on female reproduction.A structure-activity relationship (SAR) study in terms of G-quadruplex binding ability and antiproliferative activity of six fluorescent perylenemonoimide (PMIs) derivatives is reported. Saracatinib Src inhibitor A positive charge seems to be the key to target G4. This study also reveals the importance of the element substitution in the potential biological activity of PMIs, being the polyethylene glycol (PEG) chains in the peri position responsible for their antiproliferative activity. Among them, the cationic PMI6 with two PEG chains is the most promising compound since its fluorescence is enhanced in the presence of G-quadruplex structures. Moreover, PMI6 binds to the human telomeric G-quadruplex hTelo with high affinity and displays a high antiproliferative potential towards HeLa (cervical adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian adenocarcinoma) cells. Its fate can be followed inside cells thanks to its fluorescent properties the compound is found to accumulate in the mitochondria.