The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversely affect the GABAergic synaptic transmission, the aim of this study was to investigate whether and how neonatal inflammation affects GABAergic synaptic transmission resulting in cognitive impairment. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3-5. It was found that blocking GABAergic synaptic transmission reversed the deficit in hippocampus-dependent memory or the induction failure of long-term potentiation in the dorsal CA1 in adult LPS mice. An increase of mIPSCs amplitude was further detected in adult LPS mice indicative of postsynaptic potentiation of GABAergic transmission. Additionally, neonatal LPS resulted in the increased expression and function of K+-Cl--cotransporter 2 (KCC2) and the decreased expression of transforming growth factor-beta 1 (TGF-β1) in the dorsal CA1 during adulthood. The local TGF-β1 overexpression improved KCC2 expression and function, synaptic plasticity and memory of adult LPS mice. Adult LPS mice show hypermethylation of TGFb1 promoter and negatively correlate with reduced TGF-β1 transcripts. 5-Aza-deoxycytidine restored the changes in TGFb1 promoter methylation and TGF-β1 expression. Altogether, the results suggest that hypermethylation-induced reduction of TGF-β1 leads to enhanced GABAergic synaptic inhibition through increased KCC2 expression, which is a underlying mechanism of neonatal inflammation-induced hippocampus-dependent memory impairment in adult mice.
Abstract In response to the difficulty of accurately diagnosing weak internal faults in transformers using traditional diagnostic methods, this paper proposes a transformer mechanical fault diagnosis approach relying on a combination of variational mode decomposition (VMD) and grey wolf optimization algorithm optimized multiple kernel extreme learning machine (GWO-MKELM). Firstly, VMD obtains the modal components of different orders of the raw vibration signal and uses multi-scale fuzzy entropy (MFE) to compute the entropy value of the optimal modal component. Secondly, to thoroughly apply the diagnostic ability of KELM, a mixed kernel function is constructed using the Gaussian radial kernel function and polynomial kernel function, and a GWO-MKELM diagnostic model is established. Finally, the experimental data proves the effectiveness and superiority of the suggested diagnostic model. This method could supply direction for the formulation of transformer condition maintenance policies.
Abstract Background: Early growth response family members (EGRs), EGR1-4, have increasingly attracted attention in multiple cancers. However, the exact expression patterns and prognostic values of EGRs in the progress of breast cancer (BRCA) remain largely unknown. Methods: The mRNA expression and prognostic characteristics of EGRs were examined by the Cancer Genome Atlas (TCGA), Oncomine and Kaplan-Meier plotter. Enrichment analyses were conducted based on protein-protein interaction (PPI) network. The Tumor Immune Estimation Resource (TIMER) database and MethSurv were further explored. The protein expression level of EGR1 and cell migration were measured by Western blotting, immunohistochemistry, wound-healing assay and Boyden chamber assay in BRCA. Results: The transcriptional levels of EGR1/2/3 displayed significantly low expression in BRCA compared to that in normal tissues, while EGR4 was shown adverse expression pattern. Survival analysis revealed up-regulated EGR1-4 were remarkably associated with favorable relapse-free survival (RFS). A close correlation with specific tumor-infiltrating immune cells (TIICs) and several CpG sites of EGRs were exhibited. Immunohistochemistry assays showed that the protein expression of EGR1 was remarkably downregulated in BRCA compared to that in paracancerous tissues. Cell migration of MCF10A cells was increased after the silence of EGR1 by siRNA transfection. Conclusions: This study provides a novel insight to the role of EGR1 in the prognostic value and cell migration of BRCA.
Tumor microenvironment interacts with gastric cancer (GC) cells and affects tumor development.The communication between GC cells and fibroblasts has not been clearly studied and understood.MiR-10b-5p was found highly expressed in tissue and serum samples of patients with advanced stages (stage III+IV) than that in early stage patients (stage I+II).The expression determination of serum exosomal microRNA was also shown with high expression of miR-10b-5p in GC patients with advanced stages.Dual-luciferase activity assays indicated that miR-10b-5p targeted PTEN in GC cells and KLF11 in fibroblasts.The silence of miR-10b-5p up-regulated the expression of PTEN and repressed PI3K/Akt/mTORC1 signaling in GC cells.Clonogenic assay and MTT assay demonstrated that miR-10b-5p inhibitor could significantly reduce the colony formation and cell viability of GC cells.And the incubation of exosomal miR-10b-5p could increase the proliferation of GC cells.Immunohistochemistry staining revealed that high expression of α-SMA was detected in GC tissues with advanced stages.The overexpression of miR-10b-5p down-regulated KLF11 expression and elevated TGFβR1 expression in fibroblasts.In addition, miR-10b-5p inhibitor blocked the secretion of TGFβ1 in GC cells and the directional migration of fibroblasts.Therefore, up-regulated exosomal miR-10b-5p is involved in the interaction of GC cells and fibroblasts in tumor microenvironment via participating in the regulation of TGFβ signaling pathway.
Abstract Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1 + ) and GFAP-positive (GFAP + ) cells in hippocampi, which indicated TRPV4-induced microglial cell and astrocyte activation. The protein levels of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome components NLRP3, apoptosis-related spotted protein (ASC) and cysteinyl aspartate-specific protease-1 (caspase-1) were increased in GSK1016790A-injected mice, which indicated NLRP3 inflammasome activation. GSK1016790A also increased proinflammatory cytokine IL-1β, TNF-α and IL-6 protein levels, which were blocked by caspase-1 inhibitor Ac-YVAD-cmk. GSK1016790A-induced neuronal death was attenuated by Ac-YVAD-cmk. Icv. injection of TRPV4-specific antagonist HC-067047 markedly increased the number of surviving cells 3 d post status epilepticus in pilocarpine model of temporal lobe epilepsy in mice (pilocarpine-induced status epilepticus, PISE). HC-067047 also markedly blocked the increase in Iba-1 and GFAP protein levels, as well as Iba-1 + and GFAP + cells 3 d post-PISE. Finally, the increased protein levels of NLRP3, ASC and caspase-1 as well as IL-1β, TNF-α and IL-6 were markedly blocked by HC-067047. We conclude that TRPV4-induced neuronal death is mediated at least partially by enhancing the neuroinflammatory response, and this action is involved in neuronal injury following status epilepticus.
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