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• W4377029149 abstract "<b>Abstract ID 26880</b> <b>Poster Board 357</b> <b>Introduction:</b> Recently, cancer survivors were shown to have a higher risk of severe infections that require hospitalization. Doxorubicin (DOX) is a widely used chemotherapeutic agent in the treatment of cancer patients. DOX has been shown to induce senescence phenotype in endothelial cells (ECs) characterized by endothelial dysfunction and secretion of pro-inflammatory cytokines termed senescence-associated secretory phenotype (SASP). Lipopolysaccharide (LPS), a bacterial component that stimulates inflammation, has been demonstrated to augment the inflammatory SASP phenotype in endothelial models of replicative senescence and irradiation-induced senescence. However, the effect of LPS in DOX-induced endothelial senescence has not been established. Therefore, in the current work, we determined the effect of LPS stimulation in DOX-induced senescent ECs in vitro. Then, we identified the effects of metformin, an anti-diabetic drug that has senomorphic properties, on LPS-induced hyperinflammation. <b>Methods:</b> Human umbilical vein endothelial cells (HUVECs) were either treated with DOX for 24 hours followed by 72 hour-incubation without DOX to establish senescence (Sen-HUVECs) or left untreated as non-senescent proliferating cells (NS-HUVECs). The effect of LPS was determined by stimulating both Sen-HUVECs and NS-HUVECs with LPS (30 ng/ml) for an additional 24 hours. The effects of metformin on LPS stimulation were assessed in both types of cells. Culture media were collected to measure SASP factors using ELISA. Protein expression of the senescence marker, p21, was measured to confirm the induction of senescence. To delineate the molecular mechanisms, the changes in NF-κB, a major signaling pathway involved in inflammation, were determined using western blotting. <b>Results:</b> DOX-induced senescence phenotype was demonstrated by upregulation of p21. A significant hyperstimulation response to LPS was observed in Sen-HUVECs compared to NS-HUVECs, demonstrated by higher secretion of SASP markers in the media including IL-6, CXCL2, and MMP3. The protein expression of ICAM-1, a marker of endothelial dysfunction, was also upregulated in Sen-HUVECs. Pretreatment with metformin blunted LPS-induced upregulation of SASP markers and normalized the expression of ICAM-1. Metformin effects were mediated by the downregulation of LPS-induced activation of NF-κB. <b>Conclusions:</b> Our current work shows that DOX-induced senescent endothelial cells show hyperinflammatory response to LPS. The senomorphic drug, metformin, can be a promising strategy to ameliorate infection-induced hyperinflammation in DOX-treated cancer survivors.<b></b> Research was supported by the National Heart, Lung, and Blood Institute, grant R01HL151740. I.Y.A is supported by the Doctoral Dissertation Fellowship (DDF) offered by the University of Minnesota and the Bighley Graduate Fellowship from the College of Pharmacy." @default.
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• W4377029149 date "2023-05-18" @default.
• W4377029149 modified "2023-09-29" @default.
• W4377029149 title "Metformin Protects Against Liposaccharide (LPS)-induced Hyperinflammation in Doxorubicin-induced Senescent Endothelial Cells" @default.
• W4377029149 doi "https://doi.org/10.1124/jpet.122.268800" @default.
• W4377029149 hasPublicationYear "2023" @default.
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