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Circulating extracellular vesicle content reveals de novo DNA methyltransferase expression as a molecular method to predict septic shock
Journal of Extracellular Vesicles ( IF 16.0 ) Pub Date : 2019-09-28 , DOI: 10.1080/20013078.2019.1669881
Duaa A. Dakhlallah 1, 2 , Jon Wisler 3 , Marieta Gencheva 1 , Candice M. Brown 1, 2, 4 , Erin R. Leatherman 5 , Kanhaiya Singh 3 , Kathy Brundage 1 , Todd Karsies 6 , Ahmad Dakhlallah 1 , Kenneth W. Witwer 7 , Chandan K. Sen 3 , Timothy D. Eubank 1, 2 , Clay B. Marsh 8
Affiliation  

Extracellular vesicles (EVs) are mRNA-containing cell fragments shed into circulation during pathophysiological events. DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) regulate gene expression by modifying DNA methylation and altering transcription. Sepsis is a systemic insult resulting in vascular dysfunction, which can lead to shock and death. We analysed plasma from ICU patients for circulating EV numbers, defined as particles isolated from 1 mL plasma at 21,000xg, and DNMTs mRNA content as prognostic markers of septic shock. Compared to plasma from critically ill patients with or without sepsis, plasma from septic shock patients contained more EVs per mL, expressed as total DNMTs mRNAs over 5 days, and more individual DNMT mRNAs at each day. A comparison of EV-DNMT1 (maintenance methylation) with EV-DNMT3A+DNMT3B (de novo methylation) expression correlated highly with severity, and EVs from septic shock patients carried more total DNMT mRNAs and more DNMT3A+DNMT3B mRNAs than control or sepsis EVs. Total plasma EVs also correlated with sepsis severity. EV-DNMT mRNAs load, when coupled with total plasma EV number, may be a novel method to diagnose septic shock upon ICU admittance and offer opportunities to more precisely intervene with standard therapy or other targeted interventions to regulate EV release and/or specific DNMT activity.



中文翻译:

循环的细胞外囊泡含量揭示了从头DNA甲基转移酶的表达,作为预测败血性休克的分子方法

细胞外囊泡(EVs)是在病理生理事件期间掉入循环中的含mRNA细胞片段。DNA甲基转移酶(DNMT1,DNMT3A和DNMT3B)通过修饰DNA甲基化和改变转录来调节基因表达。败血症是导致血管功能障碍的全身性损伤,可导致休克和死亡。我们分析了ICU患者血浆中的循环EV值,定义为从1mL血浆中以21,000x g分离的颗粒,以及DNMTs mRNA含量作为败血性休克的预后标志物。与来自脓毒症或无败血症的危重患者的血浆相比,败血性休克患者的血浆每毫升包含更多的EV,以5天总DNMT mRNA表示,每天更多。EV- DNMT1的比较EV- DNMT3A + DNMT3B从头甲基化)表达(维持甲基化)与严重程度高度相关,败血性休克患者的EV携带的总DNMT mRNA数量更多,而DNMT3A + DNMT3B的mRNA含量高于对照或败血症EV。血浆总电动汽车也与败血症的严重程度相关。EV-DNMT mRNA负荷与总血浆EV数结合可能是诊断ICU入院后败血症性休克的新方法,并提供机会更精确地干预标准疗法或其他靶向干预措施,以调节EV释放和/或特定DNMT活性。

更新日期:2019-09-28
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