Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 11, 2024

ABSTRACT Background Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish mice, potent Cyp1 inhibitors prevent cardiotoxicity. However, the role chronic cardiomyopathy, well mechanisms underlying cardioprotection associated with inhibition, have not been fully elucidated. Methods The pathway was evaluated using a small molecule inhibitor wild-type (WT) or Cyp1-null mice ( Cyp1a1/1a2 -/- , Cyp1b1 Cyp1a1/1a2/1b1 ). Low-dose administered serial intraperitoneal intravenous injections, respectively. Expression isoforms measured RT-qPCR, myocardial tissue isolated from left ventricle for RNA sequencing. Cardiac function transthoracic echocardiography. Results In WT treatment decrease Cyp1a2 increase expression liver. Co-treatment novel YW-130 protected against cardiac dysfunction compared alone. were mice. Male, female, had increased following sequencing showed upregulation Fundc1 downregulation Ccl21c treated Dox, implicating changes mitophagy chemokine-mediated inflammation possible Cyp1a-mediated cardioprotection. Conclusions Taken together, this study highlights potential therapeutic value Cyp1a inhibition mitigating anthracycline cardiomyopathy.

Language: Английский

FUNDC1 mediated mitochondria-dependent ferroptosis of epithelial cells in model of asthma by FBXL2/ar/GPX4 signaling pathway of SUMO1 at K136

International Reviews of Immunology, Journal Year: 2024, Volume and Issue: 44(2), P. 45 - 57

Published: Sept. 25, 2024

This study aimed to explore the critical role of FUNDC1 on epithelial cells in model asthma. Patients with asthma and normal healthy volunteers were obtained from our hospital. The serum mRNA expression was down-regulated patients Meanwhile, positive correlation IgE anti-HDM protein. lung tissue mice decreased Sh-FUNDC1 enhanced up-regulation reduced IL-4, IL-5, IL-10 IL-13 activity levels vitro asthma.FUNDC1 down-regulation promoted ferroptosis through inhibition mitochondrial damage. induced FBXL2 AR protein interlinked is modified by SUMO1 at K136. FBXL2, ASN-205, GLN-204, ARG-235, GLN-237 form hydrogen bonds FUNDC1's ASP-15, ASP-16, GLU-25, ARG-29, lengths 2.3, 3.1, 2.9, 2.9 Å, respectively. induction effects Overall, prevents airway FBXL2/AR/GPX4 signaling pathway might benefit treatment or other pulmonary disease.

Language: Английский