Glutamate plays a crucial role in cognitive impairments after ischemic stroke. There is a scarcity of information about how glutamate-induced activation of cAMP-response element binding (CREB) signaling pathway regulates both the negative and positive regulators of synaptic plasticity. Recent studies have demonstrated the involvement of prominent epigenetic repressors, such as MeCP2 and DNMTs, in stroke. Neuroprotective effects of oxytocin against ischemia have been previously reported, while the underlying mechanism is still elusive. In this research, the possible role of CREB-mediated DNA hypermethylation and the potential mechanism of oxytocin in a rat model of permanent middle cerebral artery occlusion (pMCAO) were assessed. Adult male Sprague-Dawley rats were pretreated with intraperitoneal injection of oxytocin at the onset of pMCAO. The effects of oxytocin on spines and the expression levels of synaptic genes were determined. The regulatory effects of oxytocin on glutamate level, N-methyl- D -aspartate receptors (NMDARs), its downstream CREB pathway, and global or gene-specific DNA methylation status were evaluated by immunofluorescence, co-immunoprecipitation, and chromatin immunoprecipitation, respectively. We found that CREB could act as a common transcription factor for MeCP2 and DNMT3B after ischemic stroke. Oxytocin dose-dependently deactivated NR2B-related CaM-CREB pathway and inhibited DNA hypermethylation at the CpG islands of Ngf gene in pMCAO-operated rats. Moreover, oxytocin prevented pMCAO-induced reduction in the number of spines and neural cells. DNA hypermethylation in Ngf gene contributed to the cognitive deficits post-stroke. The neuroprotective effects of oxytocin against ischemia could be attributed to inhibiting glutamate release, providing additional evidence on the mechanism of oxytocin against ischemic stroke.
Nasopharyngeal carcinoma (NPC) is one of the common head and neck cancers in Southern China and Southeast Asia. Although current studies have adequately characterized the tumor microenvironment (TME) of NPC, little attention has been paid to how cell-cell interactions within the TME promote tumorigenesis. In this study, it is found that C1q + tumor-associated macrophages (TAMs) are significantly enriched in NPC tumors. Moreover, both enriched C1q + TAMs and elevated C1q expression are associated with the progression and poor prognosis in NPC patients. In vitro and in vivo studies demonstrate that C1q directly boosts the malignancy and stemness of tumor cells. Mechanistically, C1q activates the Phosphatidylinositol-3-kinase (PI3K)/AKT pathway through interacting with GPR17, a member of the G protein-coupled receptor family, thereby inducing DNA hypermethylation of tumor cells to promote tumor development. It is further proved that DNA hypermethylated NPC cells induced by C1q elicited the immunosuppressive phenotype of TAMs. Targeted blockade of C1q with a neutralizing antibody restricts NPC progression in the humanized mouse model. It is assumed that the differentiation of C1q + TAMs possibly acquired both M1 and M2 polarization conditions. These findings provide new insights into the cellular communication in the TME of NPC and may have important applications for the development of new targeted therapies.
Cong Yuan,Lihong Wang,Long Zhu,Benhui Ran,Xue Xue,Zaizhao Wang
Ubiquitous BPA exposure resulted in DNA methylation errors and oxidative stress . Numerous studies have demonstrated that oxidative stress can lead to changes in DNA methylation levels and supplementation with antioxidants, including N-acetylcysteine (NAC), was able to restore these changes. Our previous study supposed that BPA-induced de novo synthesis of glutathione (GSH) promoted DNA methylation process in Gobiocypris rarus testes . To validate this conjecture and explore the protective effects of NAC on BPA toxicity, the present study was carried out. Adult male G. rarus was treated with 225 μg L −1 BPA and/or NAC for 7 days. The sperm motility and DNA integrity of G. rarus were determined. Meanwhile, the levels of 5-methylcytosine (5mC), GSH, hydrogen peroxide (H 2 O 2 ), DNA methyltransferase proteins (DNMTs), γ-glutamyl cysteine synthetase (GCS), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), homocysteine (HCY), nicotinamide adenine dinucleotide phosphate (NADPH) and cysteine in the testes were detected. Furthermore, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured. Results indicated that NAC addition resulted in increase of cysteine contents and partially inhibited the BPA-induced DNA hypermethylation of G. rarus testes. In addition, the changes in DNA methylation levels in the testes after BPA and/or NAC treatment might be controlled by DNA methylation process that mediated by DNMTs. Moreover, BPA exposure caused oxidative stress in the testes and the elimination of H 2 O 2 might be mainly accomplished by CAT while it changed to mainly through GPx after NAC supplement. Finally, the positive response of testicular antioxidant enzyme system and the antioxidant activity of NAC itself protected sperm motility and DNA integrity from oxidative damage in each group.
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