Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway
Xiaoxue DongLiqi ShuJinyu ZhangYang XuXuejun ChengXingsen ZhaoWenzheng QuQiang ZhuYikai ShouGuoping PengBinggui SunWen YiQiang ShuXuekun Li
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Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.NITRIC oxide (NO) plays an important role in host defense as well as cell injury within the CNS. In contrast to rodent species, human astrocytes are the major glial source of NO. Although interleukin (IL)-1 stimulates astrocyte inducible NO synthase (iNOS) expression, the mechanism is poorly defined. In the present study using primary human fetal astrocyte cultures, we found that IL-1β stimulated activation of nuclear factor kappa B (NF-κB) within 2 h, iNOS mRNA expression at 8 h, and maximal NO production by 5 days post-treatment. This IL-1-induced activation of astrocyte iNOS was suppressed by pyrrolidine dithiocarbamate, an inhibitor of NF-κB activation, suggesting involvement of a NFκB mechanism.
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Inflammation is an important biological process for eliciting immune responses against physiological and pathological stimuli. Inflammation must be efficiently regulated to ensure homeostasis in the body. Nuclear factor-kappa B (NF-κB) signaling is crucial for inflammatory and immune responses. Aberrant activation of NF-κB signaling leads to development of numerous human diseases. In this study, we investigated the function of chromosome 7 open reading frame 41 (C7ORF41) in NF-κB signaling during inflammation. C7ORF41 was upregulated in cells stimulated with tumor necrosis factor-alpha or lipopolysaccharide. Moreover, overexpression of C7ORF41 inhibited the activation of NF-κB and decreased the expression of its downstream target genes. Notably, small hairpin RNA-mediated depletion of C7ORF41 increased the levels of downstream genes and enabled the activation of NF-κB. In conclusion, C7ORF41 negatively regulated inflammation via NF-κB signaling and p65 phosphorylation in vitro. These findings may help to diagnose and prognosticate inflammatory conditions and may help develop new strategies for the management of inflammation-related diseases.
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Nuclear factor of kappa B (NF-κB) is a kind of widespread nuclear transcription regulatory proteins, and it regulates the expression of multiple genes, including inflammation, immunity, cell proliferation, differentiation and apoptosis.The activation of NF-κB signaling pathway is closely related to the genesis and development of COPD.Inhibiting the activating of NF-κB signaling pathways become the new target for treatment of COPD.Now it has been found that a variety of drugs can inhibit the activating of NF-κB signaling pathways by intervening in different sites of NF-κB signaling pathway, which can be used in the treatment of COPD.This paper reviews the NF-κB and the activation and inhibition of its signal pathway, the pathogenesis of NF-κB signal pathway in COPD, and the treatment of various drugs in COPD by blocking NF-κB signaling pathways.
Key words:
Nuclear factor of kappa B; Signal pathway; Chronic obstructive pulmonary disease
Pathogenesis
IκB kinase
Signal pathway
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IκBα
Proinflammatory cytokine
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The inducible transcription factor NF-κB plays a central role in the regulation of many immune and inflammatory responses. Advances in our knowledge of the signaling mechanisms that control the activation of NF-κB and recent insights into the nature of the IκB-kinase represent significant steps forward in understanding this important signaling pathway.
IκB kinase
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Kappa
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Homeostasis
Proinflammatory cytokine
IκB kinase
Pathogenesis
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RELB
Knockout mouse
Pathogenesis
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Objective To observe the effects of oxidized DHA and unoxidized DHA on NF-κB signal transduction pathway, and compare its downstream genes, including MMP-2,COX-2 and CyclinD1 expression. Simultaneously, to explore the mechanism of chemo-sensitivity enhancement induced by DHA. Methods Human gastric cell line MGC-803 cells were cultured in vitro with different treatment. Group A was served as control group. The cells in group B, C and D were exposed to 5-FU; Oxidized DHA +5-FU, and unoxidized DHA + 5-FU, respectively. A Luciferase report gene assay was used to detect the NF-κB activation status in these 4 groups. Meanwhile, the mRNA expression of MMP-2, COX-2 and CyclinD1 were detected. Results NF-κB signal transduction pathway was significantly activated in Group B, as compared with that in Group A. In contract, NF-kB signal pathway was found to be inhibited in group C, as cultured with oxidized DHA and 5-FU, with the simultaneously downregulated its downstream genes. Yet, the unoxidized DHA activated the NF-Kb signal pathway and induced chemoresistance. Conclusions Oxidized DHA can enhance the chemo-sensitivity through the inhibition of NF-κB transduction pathway, and might be served as a potential target of chemo-sensitizer.
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