P2X7 receptor antagonist A-438079 alleviates oxidative stress of lung in LPS-induced septic rats

Özkanlar, Seçkin; Ulaş, Nergis; Kaynar, Özgür; Satıcı, Emine

doi:10.1007/s11302-023-09936-z

Cited by 4 publications

(2 citation statements)

References 58 publications

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“…A438079 has previously been shown effective in several models of inflammatory disease ( 56 – 62 ). However, despite potent effect, it has been noted that clinical translation may be a challenge owing to its short half-life of 40 minutes ( 63 ) to ~1 hour ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Inflammasome modulation with P2X7 inhibitor A438079-loaded dressings for diabetic wound healing

Yaron,

Bakkaloglu,

Grigaitis

et al. 2024

Front. Immunol.

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The inflammasome is a multiprotein complex critical for the innate immune response to injury. Inflammasome activation initiates healthy wound healing, but comorbidities with poor healing, including diabetes, exhibit pathologic, sustained activation with delayed resolution that prevents healing progression. In prior work, we reported the allosteric P2X7 antagonist A438079 inhibits extracellular ATP-evoked NLRP3 signaling by preventing ion flux, mitochondrial reactive oxygen species generation, NLRP3 assembly, mature IL-1β release, and pyroptosis. However, the short half-life in vivo limits clinical translation of this promising molecule. Here, we develop a controlled release scaffold to deliver A438079 as an inflammasome-modulating wound dressing for applications in poorly healing wounds. We fabricated and characterized tunable thickness, long-lasting silk fibroin dressings and evaluated A438079 loading and release kinetics. We characterized A438079-loaded silk dressings in vitro by measuring IL-1β release and inflammasome assembly by perinuclear ASC speck formation. We further evaluated the performance of A438079-loaded silk dressings in a full-thickness model of wound healing in genetically diabetic mice and observed acceleration of wound closure by 10 days post-wounding with reduced levels of IL-1β at the wound edge. This work provides a proof-of-principle for translating pharmacologic inhibition of ATP-induced inflammation in diabetic wounds and represents a novel approach to therapeutically targeting a dysregulated mechanism in diabetic wound impairment.

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Section: Discussionmentioning

confidence: 99%

Inflammasome modulation with P2X7 inhibitor A438079-loaded dressings for diabetic wound healing

Yaron,

Bakkaloglu,

Grigaitis

et al. 2024

Front. Immunol.

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“…It has been proved that A438079 (P2X7R antagonist) suppresses cellular inflammation and reduces oxidative stress with its anti-inflammatory effect in liver tissues. [9,21] High cytokine levels are related to cell toxicity, [22] and inflammation. [23] The treatment can reduce oxidative stress by downregulating pro-inflammatory cytokines and by restoring the antioxidant status.…”

Section: Discussionmentioning

confidence: 99%

Blockade of P2X7 receptor‐mediated purinergic signaling with A438079 protects against LPS‐induced liver injury in rats

Kara

Özkanlar

2023

J Biochem & Molecular Tox

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The study aimed to investigate the hepatoprotective effects of purinergic receptor (P2X7R) antagonism by A438079 in liver damage. An experimental model of inflammation was performed by intraperitoneal (i.p.) lipopolysaccharide (LPS) administration in the rat. The groups were Control, A438079, dimethyl sulfoxide (DMSO), LPS, LPS + DMSO, and LPS + A438079. Following LPS (8 mg/kg) injection, A438079 (15 mg/kg) and DMSO (0.1 mL) were administrated (i.p) in the study groups. The blood and the liver tissues were removed for histological, biochemical, and western blot analyses. In the biochemical analysis, serum aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, the tissue glutathione (GSH) level, and superoxide dismutase (SOD) activity dramatically decreased and malondialdehyde (MDA) level increased in the LPS and LPS + DMSO groups compared to the LPS + A438079 group. In the histological analysis, severe sinusoidal dilatation, necrotic hepatocytes, and inflammatory cell infiltration were observed in the LPS and LPS + DMSO groups while these effects were lessened in the LPS + A438079 group. The relative protein expression levels of P2X7R, Nf‐kB‐p65, IL‐6, and Caspase‐3 were significantly higher in the LPS and the LPS + DMSO groups than in the LPS + A438079 group. On the other hand, these protein expressions were considerably lower in the Control, A438079, and DMSO groups compared to the LPS + A438079 group. In addition, Bcl‐2 protein expression was significantly lower in the LPS and the LPS + DMSO groups and higher in the LPS + A438079 group compared to the other groups. The protective effect of A438079 against LPS‐induced hepatic inflammation may be related to P2X7R antagonism, inflammatory mediators, and apoptotic cell death.

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The impact of the P2X7 receptor on the tumor immune microenvironment and its effects on tumor progression

Zou,

Li,

Chai

et al. 2024

Biochemical and Biophysical Research Communications

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P2X7 receptor antagonist A-438079 alleviates oxidative stress of lung in LPS-induced septic rats

Cited by 4 publications

References 58 publications

Inflammasome modulation with P2X7 inhibitor A438079-loaded dressings for diabetic wound healing

Inflammasome modulation with P2X7 inhibitor A438079-loaded dressings for diabetic wound healing

Blockade of P2X7 receptor‐mediated purinergic signaling with A438079 protects against LPS‐induced liver injury in rats

The impact of the P2X7 receptor on the tumor immune microenvironment and its effects on tumor progression

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