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Inflammation

Inflammation

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The Angiotensin II Receptor Neprilysin Inhibitor LCZ696 Inhibits the NLRP3 Inflammasome By Reducing Mitochondrial Dysfunction in Macrophages and Alleviates Dextran Sulfate Sodium-induced Colitis in a Mouse Model.

Published:1 April 2024 DOI: 10.1007/s10753-023-01939-7 PMID: 38319541
Hsiao-Wen Chiu,?Chun-Hsien Wu,?Wen-Yu Lin,?Wei-Ting Wong,?Wei-Che Tsai,?Hsien-Ta Hsu,?Chen-Lung Ho,?Shu-Meng Cheng,?Cheng-Chung Cheng,?Shih-Ping Yang,?Lan-Hui Li,?Kuo-Feng Hua

Abstract

The intracellular sensor protein complex known as the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in regulating inflammatory diseases by overseeing the production of interleukin (IL)-1β and IL-18. Targeting its abnormal activation with drugs holds significant promise for inflammation treatment. This study highlights LCZ696, an angiotensin receptor-neprilysin inhibitor, as an effective suppressor of NLRP3 inflammasome activation in macrophages stimulated by ATP, nigericin, and monosodium urate. LCZ696 also reduces caspase-11 and GSDMD activation, lactate dehydrogenase release, propidium iodide uptake, and the extracellular release of NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in ATP-activated macrophages, suggesting a potential mitigation of pyroptosis. Mechanistically, LCZ696 lowers mitochondrial reactive oxygen species and preserves mitochondrial integrity. Importantly, it does not significantly impact NLRP3, proIL-1β, inducible nitric oxide synthase, cyclooxygenase-2 expression, or NF-κB activation in lipopolysaccharide-activated macrophages. LCZ696 partially inhibits the NLRP3 inflammasome through the induction of autophagy. In an in vivo context, LCZ696 alleviates NLRP3-associated colitis in a mouse model by reducing colonic expression of IL-1β and tumor necrosis factor-α. Collectively, these findings suggest that LCZ696 holds significant promise as a therapeutic agent for ameliorating NLRP3 inflammasome activation in various inflammatory diseases, extending beyond its established use in hypertension and heart failure treatment.

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MCC950 210826-40-7 C20H24N2O5S 137 suppliers $44.00-$1500.00
MCC950 210826-40-7 C20H24N2O5S 137 suppliers $44.00-$1500.00
MCC950 210826-40-7 C20H24N2O5S 137 suppliers $44.00-$1500.00
MCC950 210826-40-7 C20H24N2O5S 137 suppliers $44.00-$1500.00
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