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A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K + ‐dependent pH regulation
Author(s) -
Yang ShunChin,
Wang YiHsuan,
Tsai YungFong,
Chang YaWen,
Wu TianShung,
Ho ChiuMing,
Hwang TsongLong
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201903123r
Subject(s) - chalcone , chemistry , intracellular , neutrophil extracellular traps , innate immune system , respiratory burst , inflammation , elastase , reactive oxygen species , extracellular , biochemistry , microbiology and biotechnology , nadph oxidase , immunology , enzyme , biology , receptor , stereochemistry
Human neutrophils have a vital role in host defense and inflammatory responses in innate immune systems. Growing evidence shows that the overproduction of reactive oxygen species and granular proteolytic enzymes from activated neutrophils is linked to the pathogenesis of acute inflammatory diseases. However, adequate therapeutic targets are still lacking to regulate neutrophil functions. Herein, we report that MVBR‐28, synthesized from the Mannich bases of heterocyclic chalcone, has anti‐neutrophilic inflammatory effects through regulation of intracellular pH. MVBR‐28 modulates neutrophil functions by attenuating respiratory burst, degranulation, and migration. Conversely, MVBR‐28 has no antioxidant effects and fails to alter elastase activity in cell‐free systems. The anti‐inflammatory effects of MVBR‐28 are not seen through cAMP pathways. Significantly, MVBR‐28 potently inhibits extracellular Ca 2+ influx in N ‐formyl‐methionyl‐leucyl‐phenylalanine (fMLF)‐ and thapsigargin‐activated human neutrophils. Notably, MVBR‐28 attenuates fMLF‐induced intracellular alkalization in a K + ‐dependent manner, which is upstream of Ca 2+ pathways. Collectively, these findings provide new insight into Mannich bases of heterocyclic chalcone regarding the regulation of neutrophil functions and the potential for the development of MVBR‐28 as a lead compound for treating neutrophilic inflammatory diseases.