Abstract
Sepsis is caused by organ dysfunction initiated by an unrestrained host immune response to infection. The emergence of antibiotic-resistant bacteria has rapidly increased in the last decades and has stimulated a firm research platform to combat infections caused by antibiotic-resistant bacteria that cannot be eradicated with conventional antibiotics. Strategies like epigenetic regulators such as lysine demethylase (Kdm) has received attention as a new target. Thus, we sought to investigate the epigenetic mechanisms in sepsis pathophysiology with the aim of discovering new concepts for treatment. A transcriptome analysis of dendritic cells during their inflammatory state identified Kdm as a critical molecule in sepsis regulation. Next, 8-hydroxyquinoline-5-carboxylic acid (IOX1) ability to control endotoxemia induced by Lipopolysaccharide and bacterial sepsis was demonstrated. IOX1 has been shown to regulate endotoxemia and sepsis caused by Escherichia coli and carbapenem-resistant Acinetobacter baumannii and has also contributed to the suppression of multidrug-resistant bacterial growth through the inhibition of DNA Gyrase. These findings show that IOX1 could be a component agent against bacterial sepsis by functioning as a broad-spectrum antibiotic with dual effects.
Highlights
Sepsis is caused by organ dysfunction initiated by an unrestrained host immune response to infection
IOX1 significantly reduced the secretion of tumor necrosis factor-α (TNF)-α, interleukin 1β (IL-1β), interleukin 6 (IL-6), IL-12p70 and interleukin 10 (IL-10) induced by LPS (Fig. 1C)
The expression of surface molecules, such as CD80, CD86, MHC-I and MHC-II, induced by LPS was significantly reduced (Fig. 1D). These results indicate that IOX1 can effectively regulate the immune activity of bone marrow dendritic cells (DCs) induced by LPS
Summary
Sepsis is caused by organ dysfunction initiated by an unrestrained host immune response to infection. IOX1 has been shown to regulate endotoxemia and sepsis caused by Escherichia coli and carbapenem-resistant Acinetobacter baumannii and has contributed to the suppression of multidrug-resistant bacterial growth through the inhibition of DNA Gyrase. These findings show that IOX1 could be a component agent against bacterial sepsis by functioning as a broad-spectrum antibiotic with dual effects. It has been reported that 8-hydroxyquinoline-5-carboxylic acid (IOX1) does not require a prodrug form during application and has a broad spectrum of cell permeability, suggesting that it could be an effective Kdm inhibitor[18,19] Suggests that it might be used as a therapeutic intervention for diseases such as anemia, inflammation and cancer. We tested IOX1 in the treatment of sepsis, and we propose it as a new promising broad-spectrum therapeutic agent for sepsis
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