GSKJ4 Protects Mice Against Early Sepsis via Reducing Proinflammatory Factors and Up-Regulating MiR-146a

Pan, Yuchen; Wang, Jiali; Yuan, Xue; Zhao, Jiaojiao; Li, Dan; Zhang, Shaolong; Li, Kuanyu; Hou, Yayi; Fan, Hong

doi:10.3389/fimmu.2018.02272

Cited by 33 publications

(35 citation statements)

References 35 publications

(38 reference statements)

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“…The underlying regulatory mechanisms by which the promoter rs653765 G→A SNP confers sepsis progression have not yet been elucidated. As a cis -acting element, the promoter is the center for orchestrating gene transcription due to harboring numerous TF binding sites (38–40). Genetic variations in the promoter regions have been demonstrated to modify the transcriptional activity of target genes by altering the binding affinity of TFs and further influence the biological function of target genes (41–43).…”

Section: Discussionmentioning

confidence: 99%

A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression

Chen

Wang

Zhang

et al. 2019

mBio

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Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. In vitro results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the ADAM10 gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention in vivo decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model. IMPORTANCE Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases.

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Section: Discussionmentioning

confidence: 99%

A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression

Chen

Wang

Zhang

et al. 2019

mBio

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“…Also, in vitro inhibition of the epigenetically active bromodomain and extraterminal domain (BET) proteins suppressed inflammation induced by the fungal pathogens Candida albicans and Aspergillus fumigatus [144]. Moreover, the pharmacological inhibition of the histone Lys demethylase JMJD3 protected mice against early septic death and reduced pro-inflammatory cytokine production via up-regulation of miR-146a [145]. Similarly, histone demethylase KDM3C demonstrated an anti-inflammatory effect by suppressing NF-κB signaling against oral bacterial infection in mice [146].…”

Section: Infectionsmentioning

confidence: 99%

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

et al. 2020

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Aim and objective Emerging translational evidence suggests that epigenetic alterations (DNA methylation, miRNA expression, and histone modifications) occur after external stimuli and may contribute to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. This review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. Additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction, n-3 PUFA, Mediterranean diet, vitamin D, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed. Methods Original and review articles encompassing epigenetics and inflammation were screened from major databases (including PubMed, Medline, Science Direct, Scopus, etc.) and analyzed for the writing of the review paper. Conclusion Although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.

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“…Based on the bioinformatics analysis and the dual-luciferase reporter gene assay in the present study, miR-27b could target Jumonji D3 (JMJD3), a histone lysine demethylase, regulates transcription and actives the expression of genes via demethylating H3K27me3 [ 22 – 24 ]. More importantly, JMJD3 has been reported to play a critical role in the epigenetic regulation during sepsis [ 25 , 26 ]. Furthermore, an interaction between JMJD3 and the activation of nuclear factor-κB (NF-κB) has been highlighted [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

Sun

Chen

et al. 2021

Stem Cell Res Ther

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Background Exosomal microRNAs (miRs) derived from mesenchymal stem cells (MSCs) have been shown to play roles in the pathophysiological processes of sepsis. Moreover, miR-27b is highly enriched in MSC-derived exosomes. Herein, we aimed to investigate the potential role and downstream molecular mechanism of exosomal miR-27b in sepsis. Methods Inflammation was induced in bone marrow-derived macrophages (BMDMs) by lipopolysaccharide (LPS), and mice were made septic by cecal ligation and puncture (CLP). The expression pattern of miR-27b in MSC-derived exosomes was characterized using RT-qPCR, and its downstream gene was predicted by in silico analysis. The binding affinity between miR-27b, Jumonji D3 (JMJD3), or nuclear factor κB (NF-κB) was characterized to identify the underlying mechanism. We induced miR-27b overexpression or downregulation, along with silencing of JMJD3 or NF-κB to examine their effects on sepsis. The production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 was detected by ELISA. Results miR-27b was highly expressed in MSC-derived exosomes. Mechanistic investigations showed that miR-27b targeted JMJD3. miR-27b decreased expression of pro-inflammatory genes by inhibiting the recruitment of JMJD3 and NF-κB at gene promoter region. Through this, MSC-derived exosomal miR-27b diminished production of pro-inflammatory cytokines in LPS-treated BMDMs and septic mice, which could be rescued by upregulation of JMJD3 and NF-κB. Besides, in vitro findings were reproduced by in vivo findings. Conclusion These data demonstrated that exosomal miR-27b derived from MSCs inhibited the development of sepsis by downregulating JMJD3 and inactivating the NF-κB signaling pathway.

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GSKJ4 Protects Mice Against Early Sepsis via Reducing Proinflammatory Factors and Up-Regulating MiR-146a

Cited by 33 publications

References 35 publications

A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression

A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

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