Bazedoxifene attenuates intestinal injury in sepsis by suppressing the NF-κB/NLRP3 signaling pathways

  • Eur J Pharmacol. 2023 Mar 24;947:175681. doi: 10.1016/j.ejphar.2023.175681.
Xiao Zhang  1 ,  Wei Ning  1 ,  Ge Gao  2 ,  Yong Zhou  3 ,  Xiang-Bing Duan  2 ,  Xin Li  2 ,  Dai Li  4 ,  Ren Guo  5
Affiliations
  • 1. Phase I Clinical Research Center, Xiangya Hospital, Central South University, Changsha, 410005, China; Laboratory Department, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 2. Laboratory Department, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 3. Department of Physiology, School of Basic Medical Science, Central South University, Changsha, 410078, China.
  • 4. Phase I Clinical Research Center, Xiangya Hospital, Central South University, Changsha, 410005, China. Electronic address: [email protected].
  • 5. Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. Electronic address: [email protected].
PMID: 36965746 DOI: 10.1016/j.ejphar.2023.175681
Abstract

Acute inflammatory injury is the primary cause of sepsis, leading to various organ failures. Bazedoxifene (BAZ) has been proven to have anti-inflammatory effects. However, its effects on sepsis-induced intestinal injury are unclear. Here, we demonstrated the beneficial effects of BAZ on intestinal injury and explored the underlying mechanisms using cecal ligation and perforation (CLP)-mediated sepsis mouse model and in vitro cultured intestinal epithelial MODE-K cells. We found that BAZ elevated the survival rate of septic mice and attenuated CLP-triggered intestinal damage. BAZ inhibited intestinal inflammation and restored the impaired intestinal barriers in CLP mice. The mechanistic study in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-stimulated MODE-K cells showed that BAZ significantly downregulated the expression of NOD-like Receptor protein 3 (NLRP3), interleukin-1β (IL-1β), Caspase-1, and gasdermin D (GSDMD), and markedly reduced the phosphorylation of molecules in the nuclear factor kappa B (NF-κB) pathway. Moreover, BAZ prominently rescued the decreased viability of MODE-K cells and reduced Lactate Dehydrogenase (LDH) release upon LPS/ATP challenge. However, BAZ did not affect the inflammasome assembly, as evidenced by the lack of changes in ASC (Apoptosis speck-like protein containing a CARD) speck formation. Our results suggest that BAZ relieves inflammation and intestinal barrier function disruption by suppressing the NF-κB/NLRP3 signaling pathways. Therefore, BAZ is a potential therapeutic candidate for treating intestinal injury in sepsis.

Keywords
Bazedoxifene; Inflammation; Intestinal injury; NF-κB; NLRP3 inflammasome; Sepsis.
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