Paeonol Reverses Adriamycin Induced Cardiac Pathological Remodeling through Notch1 Signaling Reactivation in H9c2 Cells and Adult Zebrafish Heart.

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.

Squalene is a potential endocrine modulator in rat: A proof-of-principle study with 3-methylcholanthrene-induced toxicity.

Oestrus urine was proved as a potential endocrine modulator in alleviating the toxicity induced by 3-methylcholanthrene (3-MC) in male rats. We, in this study, aimed to prove the attributing potential of toxicity alleviation to squalene, an oestrus-specific pheromone in rats. A single dose of 3-methylcholanthrene (25 mg/kg BW, i.p.) was administered to male Wistar rats with concurrent exposure to squalene sprayed in bedding material (Group III). Group II rats did receive 3-MC treatment but did not expose to squalene. Group I rats were intact control neither administered 3-MC nor sprayed with squalene. In consequence of 3-MC toxicity, liver and testes weights were increased and the components of blood cells (RBC and WBC count, Hb level) and testosterone concentration were significantly reduced in Group II rats. Moreover, sperm count was reduced and antioxidants (testes and epididymis) were significantly altered. Exposure to squalene in Group III rats comparatively normalised all the variable components towards baseline and reorganised the histological architecture of reproductive tissues that were exacerbated with 3-MC toxicity. This study ultimately proved squalene as a potent molecule in alleviating the toxicity induced by 3-methylcholanthrene.