Circulating extracellular vesicle content reveals <i>de novo</i> DNA methyltransferase expression as a molecular method to predict septic shock

Dakhlallah, Duaa; Wisler, Jon; Gencheva, Marieta; Brown, Candice M.; Leatherman, Erin R.; Singh, Kiran; Brundage, Kathy; Karsies, Todd; Dakhlallah, Ahmad; Witwer, Kenneth W.; Sen, Chandan K.; Eubank, Timothy D.; Marsh, Clay B.

doi:10.1080/20013078.2019.1669881

Cited by 44 publications

(49 citation statements)

References 70 publications

(84 reference statements)

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“…There is an extensive system of proteins in the cells involved in writing the methylation pattern on DNA via de-novo methylation (DNMT3A and DNMT3B) and copying methylation patterns during DNA replication via methylation maintenance (DNMT1) (17). Reportedly, circulating extracellular vesicle DNMTs are highly correlated with sepsis severity and may serve as a predicting factor (34). As observed during the current study, DNMT1 was upregulated in CLP mice, which substantiated the findings of a previous study on LPS endotoxic shock models (35).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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-κB 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-κB 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Therefore, DNA methylation acts as a switch for transcriptional activation or repression of genes that are essential for development and proper cellular functioning. Till date, DNMT1, DNMT3A, DNMT3B, DNMT2 and DNMT3L are known mammalian DNMTs [ [421] , [422] , [423] , [424] ]. Whereas activation induced cytidine deaminase (AICDA) and thymine DNA glycosylase (TDG) are examples of enzymes that demethylate DNA and protect unmethylated regions of mammalian genomes from de novo methylation [ 425 , 426 ].…”

Section: Sevs In Cancer Liquid Biopsymentioning

confidence: 99%

Small extracellular vesicles in cancer

Abhange

Makler

Wen

et al. 2021

Bioactive Materials

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Extracellular vesicles (EV) are lipid-bilayer enclosed vesicles in submicron size that are released from cells. A variety of molecules, including proteins, DNA fragments, RNAs, lipids, and metabolites can be selectively encapsulated into EVs and delivered to nearby and distant recipient cells. In tumors, through such intercellular communication, EVs can regulate initiation, growth, metastasis and invasion of tumors. Recent studies have found that EVs exhibit specific expression patterns which mimic the parental cell, providing a fingerprint for early cancer diagnosis and prognosis as well as monitoring responses to treatment. Accordingly, various EV isolation and detection technologies have been developed for research and diagnostic purposes. Moreover, natural and engineered EVs have also been used as drug delivery nanocarriers, cancer vaccines, cell surface modulators, therapeutic agents and therapeutic targets. Overall, EVs are under intense investigation as they hold promise for pathophysiological and translational discoveries. This comprehensive review examines the latest EV research trends over the last five years, encompassing their roles in cancer pathophysiology, diagnostics and therapeutics. This review aims to examine the full spectrum of tumor-EV studies and provide a comprehensive foundation to enhance the field. The topics which are discussed and scrutinized in this review encompass isolation techniques and how these issues need to be overcome for EV-based diagnostics, EVs and their roles in cancer biology, biomarkers for diagnosis and monitoring, EVs as vaccines, therapeutic targets, and EVs as drug delivery systems. We will also examine the challenges involved in EV research and promote a framework for catalyzing scientific discovery and innovation for tumor-EV-focused research.

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“…showed that circulating EVs had significantly higher loads of DNA methyltransferase (DNMT) mRNA, which regulates gene expression. [ 96 ] Specifically, more severely ill patients showed increases in the ratio of de novo methylating factors DNMT3A and DNMT3B to the maintenance methylating factor DNMT1 encapsulated within these circulating EVs. [ 96 ] Research has also shown sepsis‐induced differential expression of other EV‐associated molecules, including miRNAs.…”

Section: Endogenous Roles Of Evs In Sepsismentioning

confidence: 99%

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

Kronstadt

Pottash

Levy

et al. 2021

Advanced Therapeutics

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Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.

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Circulating extracellular vesicle content reveals de novo DNA methyltransferase expression as a molecular method to predict septic shock

Cited by 44 publications

References 70 publications

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

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

Small extracellular vesicles in cancer

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

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