A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K+-dependent pH regulation

Shun Chin Yang, Yi Hsuan Wang, Yung Fong Tsai, Ya Wen Chang, Tian Shung Wu, Chiu Ming Ho, Tsong Long Hwang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations

Abstract

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 Ca2+ 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 Ca2+ 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.

Original languageEnglish
Pages (from-to)7127-7143
Number of pages17
JournalFASEB Journal
Volume34
Issue number5
DOIs
StatePublished - 01 05 2020

Bibliographical note

Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology

Keywords

  • Mannich bases of heterocyclic chalcone
  • alkalization
  • degranulation
  • neutrophil
  • respiratory burst

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