Self-Cascade Redox Modulator Trilogically Renovates Intestinal Microenvironment for Mitigating Endotoxemia.

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Immunology

Background:

• Endotoxemia is a severe condition leading to multi-organ failure, often unresponsive to current single-target treatments.
• Bacterial endotoxins trigger life-threatening inflammatory responses and organ damage.
• There is a critical need for advanced therapeutic strategies to manage endotoxemia effectively.

Purpose of the Study:

• To investigate the potential of alanine fullerene redox modulator (AFRM) as a multi-target therapeutic agent for endotoxemia.
• To elucidate the mechanisms by which AFRM modulates the intestinal microenvironment to mitigate endotoxemia.
• To evaluate the efficacy of AFRM in repairing epithelial barrier integrity and suppressing inflammation.

Main Methods:

• AFRM was synthesized and characterized for its redox regulatory properties, including superoxide dismutase (SOD)-like and peroxidase (POD)-like enzyme activities, and hydroxyl radical (•OH) scavenging.
• Proteomics was employed to analyze AFRM's effects on macrophage signaling pathways (LPS/TLR4/NF-κB, MAPK/ERK) and pyroptosis-related proteins (GSDMD).
• The impact of AFRM on intestinal epithelial barrier integrity, extracellular matrix, and tight junction proteins was assessed in an endotoxemia mouse model.

Main Results:

• AFRM demonstrated broad-spectrum redox modulation, acting as an enzyme mimetic and radical scavenger.
• AFRM suppressed inflammatory macrophage activation by regulating redox homeostasis and down-regulating key signaling pathways.
• AFRM inhibited macrophage pyroptosis by preventing gasdermin D (GSDMD) activation and restored epithelial barrier function by modulating extracellular redox balance.

Conclusions:

• AFRM effectively remodels the intestinal microenvironment, offering a multi-target therapeutic strategy for endotoxemia.
• AFRM synergistically mitigates endotoxemia by suppressing inflammation, inhibiting pyroptosis, and repairing epithelial barrier integrity.
• Fullerene-based self-cascade redox modulators represent a promising therapeutic avenue for managing endotoxemia.