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• W4313705955 endingPage "114228" @default.
• W4313705955 startingPage "114228" @default.
• W4313705955 abstract "Canagliflozin (CANA) shows anti-inflammatory and anti-oxidative effects on endothelial cells (ECs). In diabetes mellitus (DM), excessive reactive oxygen species (ROS) generation, increased intracellular calcium (Ca2+) and enhanced extracellular signal regulated kinase (ERK) 1/2 phosphorylation are crucial precursors for inflammasome activation. We hypothesized that: (1) CANA prevents the TNF-α triggered ROS generation in ECs from diabetic donors and in turn suppresses the inflammasome activation; and (2) the anti-inflammatory effect of CANA is mediated via intracellular Ca2+ and ERK1/2.Human coronary artery endothelial cells from donors with DM (D-HCAECs) were pre-incubated with either CANA or vehicle for 2 h before exposure to 50 ng/ml TNF-α for 2-48 h. NAC was applied to scavenge ROS, BAPTA-AM to chelate intracellular Ca2+, and PD 98059 to inhibit the activation of ERK1/2. Live cell imaging was performed at 6 h to measure ROS and intracellular Ca2+. At 48 h, ELISA and infra-red western blot were applied to detect IL-1β, NLRP3, pro-caspase-1 and ASC.10 µM CANA significantly reduced TNF-α related ROS generation, IL-1β production and NLRP3 expression (P all <0.05), but NAC did not alter the inflammasome activation (P > 0.05). CANA and BAPTA both prevented intracellular Ca2+ increase in cells exposed to TNF-α (P both <0.05). Moreover, BAPTA and PD 98059 significantly reduced the TNF-α triggered IL-1β production as well as NLRP3 and pro-caspase-1 expression (P all <0.05).CANA suppresses inflammasome activation by inhibition of (1) intracellular Ca2+ and (2) ERK1/2 phosphorylation, but not by ROS reduction." @default.
• W4313705955 created "2023-01-08" @default.
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• W4313705955 date "2023-03-01" @default.
• W4313705955 modified "2023-10-01" @default.
• W4313705955 title "Canagliflozin inhibits inflammasome activation in diabetic endothelial cells – Revealing a novel calcium-dependent anti-inflammatory effect of canagliflozin on human diabetic endothelial cells" @default.
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• W4313705955 doi "https://doi.org/10.1016/j.biopha.2023.114228" @default.
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