ECDD-S16 targets vacuolar ATPase: A potential inhibitor compound for pyroptosis-induced inflammation
Issued Date
2023-01-01
Resource Type
eISSN
19326203
Scopus ID
2-s2.0-85178023048
Pubmed ID
38011122
Journal Title
PloS one
Volume
18
Issue
11
Rights Holder(s)
SCOPUS
Bibliographic Citation
PloS one Vol.18 No.11 (2023) , e0292340
Suggested Citation
Ekchariyawat P., Saengfak R., Sanongkiet S., Charoenwongpaiboon T., Khongpraphan S., Mala S., Luangjindarat C., Munyoo B., Chabang N., Charoensutthivarakul S., Borwornpinyo S., Tuchinda P., Ponpuak M., Pudla M., Utaisincharoen P. ECDD-S16 targets vacuolar ATPase: A potential inhibitor compound for pyroptosis-induced inflammation. PloS one Vol.18 No.11 (2023) , e0292340. doi:10.1371/journal.pone.0292340 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/91369
Title
ECDD-S16 targets vacuolar ATPase: A potential inhibitor compound for pyroptosis-induced inflammation
Author's Affiliation
Other Contributor(s)
Abstract
BACKGROUND: Cleistanthin A (CA), extracted from Phyllanthus taxodiifolius Beille, was previously reported as a potential V-ATPase inhibitor relevant to cancer cell survival. In the present study, ECDD-S16, a derivative of cleistanthin A, was investigated and found to interfere with pyroptosis induction via V-ATPase inhibition. OBJECTIVE: This study examined the ability of ECDD-S16 to inhibit endolysosome acidification leading to the attenuation of pyroptosis in Raw264.7 macrophages activated by both surface and endosomal TLR ligands. METHODS: To elucidate the activity of ECDD-S16 on pyroptosis-induced inflammation, Raw264.7 cells were pretreated with the compound before stimulation with surface and endosomal TLR ligands. The release of lactate dehydrogenase (LDH) was determined by LDH assay. Additionally, the production of cytokines and the expression of pyroptosis markers were examined by ELISA and immunoblotting. Moreover, molecular docking was performed to demonstrate the binding of ECDD-S16 to the vacuolar (V-)ATPase. RESULTS: This study showed that ECDD-S16 could inhibit pyroptosis in Raw264.7 cells activated with surface and endosomal TLR ligands. The attenuation of pyroptosis by ECDD-S16 was due to the impairment of endosome acidification, which also led to decreased Reactive Oxygen Species (ROS) production. Furthermore, molecular docking also showed the possibility of inhibiting endosome acidification by the binding of ECDD-S16 to the vacuolar (V-)ATPase in the region of V0. CONCLUSION: Our findings indicate the potential of ECDD-S16 for inhibiting pyroptosis and prove that vacuolar H+ ATPase is essential for pyroptosis induced by TLR ligands.