心脏毒性
丹皮酚
细胞凋亡
阿霉素
纤维化
斑马鱼
药理学
体内
癌症研究
心脏纤维化
医学
化学
细胞生物学
生物
毒性
内科学
化疗
病理
生物化学
基因
生物技术
替代医学
作者
Syeda Thabassum Akhtar Iqbal,Pichiah Balasubramanian Tirupathi Pichiah,R. Sudhakaran,Sankarganesh Arunachalam
标识
DOI:10.1021/acs.chemrestox.9b00093
摘要
Adriamycin is a commonly prescribed chemotherapeutic drug for a wide range of cancers. Adriamycin causes cardiotoxicity as an adverse effect that limits its clinical application in cancer treatment. Several mechanisms have been proposed to explain the toxicity it causes in heart cells. Disruption of inherent cardiac repair mechanism is the least understood mechanism of Adriamycin-induced cardiotoxicity. Adriamycin induces pathological remodeling in cardiac cells by promoting apoptosis, hypertrophy, and fibrosis. We found that Adriamycin inhibited Notch1 in a time- and dose-dependent manner in H9c2 cells. We used Paeonol, a Notch1 activator, and analyzed the markers of apoptosis, hypertrophy, and fibrosis in H9c2 cells in vitro and in adult zebrafish heart in vivo as model systems to study Adriamycin-induced cardiotoxicity. Paeonol activated Notch1 signaling and expression of its downstream target genes effectively in the Adriamycin-treated condition in vitro and in vivo. Also we detected that Notch activation using Paeonol protected the cells from apoptosis, collagen deposition, and hypertrophy response using functional assays. We conclude that Adriamycin induced cardiotoxicity by promoting the pathological cardiac remodeling through inhibition of Notch1 signaling and that the Notch1 reactivation by Paeonol protected the cells and reversed the cardiotoxicity.
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