Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 14, Issue -, Pages 4901-4913Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S269223
Keywords
HGFs; pyroptosis; NLRP3; ED-71; Nrf2/HO-1
Categories
Funding
- National Nature Science Foundation of China [81771108, 81970964]
- Shandong Key Research and Development Project [2018GSF118134]
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Purpose: Periodontitis is a major chronic oral disease that is accelerated by activation of the NLRP3 inflammasome and the resulting pyroptosis. According to recent studies, active vitamin D and its analogs have been reported to have great anti-inflammatory effects. However, the anti-inflammatory mechanism of a newly found vitamin D analog, eldecalcitol (ED-71), is still unclear. This study investigates whether ED-71 could protect human gingival fibroblasts (HGFs) from LPS-induced pyroptosis and, if so, determine its underlying mechanism. Methods: After HGFs were treated with LPS alone or with LPS and ED-71, their viability was measured by CCK8 assay. The degrees of inflammation and pyroptosis were measured via LDH assay, H2O2 assay, fluorescent staining, flow cytometry, and Western blots. Intracellular ROS, Hoechst 33,342, and PI stains were assessed with a fluorescence microscope. ROS inhibitor NAC, NLRP3 inhibitor MCC950, and Nrf2 inhibitor ML385 were added to further clarify the mechanism. Results: LPS induced cytotoxicity in HGFs, as shown by CCK8 assay. LPS also increased intracellular ROS, H2O2 levels, release of LDH, and expression of the pyroptosis-related proteins NLRP3, caspase-1, and IL-1 beta. NAC and MCC950 reduced LPS-induced NLRP3, caspase-1, and IL-1 beta. Pretreatment with ED-71 effectively inhibited the LPS-induced pyroptosis and was associated with activation of the Nrf2/HO-1 signaling pathway. This beneficial effect of ED-71 was suppressed by ML385. Conclusion: This study demonstrates the therapeutic effect of ED-71 on LPS-induced NLRP3 inflammasome-dependent pyroptosis in HGFs and further reveals that ED-71 can inhibit pyroptosis by activating the Nrf2/HO-1 pathway. Our results thus suggest that ED-71 is a potential candidate for the treatment of periodontitis.
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