Dataset Information

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-?B Pathway.

ABSTRACT: Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transferase inhibitor, Decitabine, may mitigate inflammation and improve survival by inhibiting the NF-?B signaling pathway. To test the hypothesis, mice challenged with caecal ligation and puncture (CLP) were subcutaneously injected with Decitabine solution (0.5, 1, and 1.5 mg/kg) 2 h following operation. Our results indicated that Decitabine reduces DNA methyltransferases (DNMTs), attenuates NF-?B activation, downregulates inflammatory cytokine levels, and inhibits the progression of sepsis. Thus, DNA methylation may be indispensable for sepsis and serve as a predicting factor. The use of Decitabine could represent a novel strategy in the treatment of sepsis.

SUBMITTER: Cao L

PROVIDER: S-EPMC7343767 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway.

Cao Luxi L Zhu Tingting T Lang Xiabing X Jia Sha S Yang Yi Y Zhu Chaohong C Wang Yucheng Y Feng Shi S Wang Cuili C Zhang Ping P Chen Jianghua J Jiang Hong H

Frontiers in immunology 20200702

Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transfer ...[more]

PMID: 32714333

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Project description:Sepsis‑associated encephalopathy (SAE) is a common and severe complication of sepsis. The cognitive dysfunction that ensues during SAE has been reported to be caused by impairments of the hippocampus. Microglia serves a key role in neuroinflammation during SAE through migration. Forkhead box C1 (Foxc1) is a member of the forkhead transcription factor family that has been found to regulate in cell migration. However, the role of Foxc1 in neuroinflammation during SAE remains unknown. In the present study, the mechanistic role of Foxc1 on microglial migration, neuroinflammation and neuronal apoptosis during the occurrence of cognitive dysfunction in SAE was investigated. A microglia‑mediated inflammation model was induced by LPS in BV‑2 microglial cells in vitro, whilst a SAE‑related cognitive impairment model was established in mice using cecal ligation and perforation (CLP) surgery. Cognitive function in mice was evaluated using the Morris Water Maze (MWM) trial. Lipopolysaccharide (LPS) treatment was found to trigger BV‑2 cell migration, inflammation and neuronal apoptosis. In addition, CLP surgery induced cognitive injury, which was indicated by longer latencies and shorter dwell times in the goal quadrant compared with those in the Sham group in the MWM trial. LPS treatment or CLP induction decreased the expression of Foxc1 and inhibitor of NF‑κB (IκΒα) whilst increasing that of p65, IL‑1β and TNF‑α. After Foxc1 was overexpressed, the cognitive dysfunction of mice that underwent CLP surgery was improved, with the expression of IκBα also increased, microglial cell migration, the expression of p65, IL‑1β and TNF‑α and neuronal apoptosis were all decreased in vivo and in vitro, which were in turn reversed by the inhibition of IκBα in vitro. Overall, these results suggest that the overexpression of Foxc1 inhibited microglial migration whilst suppressing the inflammatory response and neuronal apoptosis by regulating the IκBα/NF‑κB pathway, thereby improving cognitive dysfunction during SAE.

Dataset Information

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-?B Pathway.

Publications

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway.

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