Parthenolide alleviates doxorubicin-induced cardiotoxicity via regulation of Cyp1a1 and Nppa and suppression of NLRP3 inflammasome

IF 3.9 3区医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE

Journal of Traditional and Complementary Medicine Pub Date : 2025-11-01 Epub Date: 2024-10-28 DOI:10.1016/j.jtcme.2024.10.004

Yuanying Yang , Shanshan Wei , Sa Liu , Suifen Xie , Wei Xiao , Jian Liu , Ning Xie , Wenqun Li , Bikui Zhang

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Abstract

Background and aim

Doxorubicin (Dox) has limited clinical use due to its multiple adverse reactions, typically severe cardiotoxicity. Parthenolide (PTL) is the main active ingredient extracted from the buds of Tanacetum balsamita and exhibits diverse pharmacological properties. However, the cardioprotective effects and underlying mechanisms of PTL against Dox-induced cardiotoxicity (DIC) need to be fully investigated. Herein, this study was designed to explore the protective mechanism of PTL against DIC.

Experimental procedure

A stable cardiotoxicity model was established in H9c2 cells (1 μM for 24 h) and C57BL/6 J mice (15 mg/kg). RNA sequencing was used to identify key genes mediating the protection of PTL against DIC. The key genes and mechanism of PTL against DIC were comprehensively examined by transcriptomic technologies and experimental validation.

Results and conclusion

A combination administration of PTL effectively inhibited Dox-induced cytotoxicity as well as cardiomyocyte apoptosis in H9c2 cells. PTL also exerts a protective effect on Dox-induced cardiac injury by improving myocardial function, histological morphological changes, and myocardial apoptosis in Dox-treated mice. Subsequently, we utilized the transcriptomic approach and validated the results by RT-qPCR, confirming that Cyp1a1 and Nppa were the key genes in PTL against DIC. PTL could also protect from DIC via the suppression of the NLRP3 inflammasome activation and subsequent secretion of IL-1β and Caspase1. Our study confirmed that PTL treatment attenuated DIC in mice and H9c2 cells via regulation of Nppa and Cyp1a1 and the suppression of the NLRP3 inflammasome activation and subsequent secretion of pro-inflammatory cytokines.

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Parthenolide通过调节Cyp1a1和Nppa以及抑制NLRP3炎性体减轻阿霉素诱导的心脏毒性

背景和目的多柔比星（Dox）由于其多重不良反应，特别是严重的心脏毒性，临床应用有限。Parthenolide （PTL）是从香醋草（Tanacetum balsamita）芽中提取的主要活性成分，具有多种药理特性。然而，PTL对dox诱导的心脏毒性（DIC）的心脏保护作用和潜在机制需要充分研究。本研究旨在探讨PTL对DIC的保护机制。实验方法H9c2细胞（1 μM）和C57BL/6 J小鼠（15 mg/kg）分别建立稳定的心脏毒性模型。利用RNA测序技术鉴定PTL对DIC保护的关键基因。通过转录组学技术和实验验证，全面研究了PTL抗DIC的关键基因和机制。结果与结论PTL联合用药可有效抑制dox诱导的H9c2细胞毒性及心肌细胞凋亡。PTL还通过改善dox处理小鼠心肌功能、组织学形态学改变和心肌凋亡，对dox诱导的心脏损伤具有保护作用。随后，我们利用转录组学方法并通过RT-qPCR验证结果，证实Cyp1a1和Nppa是PTL抗DIC的关键基因。PTL还可以通过抑制NLRP3炎性小体的激活和随后IL-1β和Caspase1的分泌来保护DIC。我们的研究证实，PTL通过调节Nppa和Cyp1a1以及抑制NLRP3炎性小体的激活和随后的促炎细胞因子的分泌来减轻小鼠和H9c2细胞的DIC。

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来源期刊

Journal of Traditional and Complementary Medicine Medicine-Complementary and Alternative Medicine

CiteScore

9.30

自引率

6.70%

发文量

审稿时长

66 days

期刊介绍： eJTCM is committed to publish research providing the biological and clinical grounds for using Traditional and Complementary Medical treatments as well as studies that demonstrate the pathophysiological and molecular/biochemical bases supporting the effectiveness of such treatments. Review articles are by invitation only. eJTCM is receiving an increasing amount of submission, and we need to adopt more stringent criteria to select the articles that can be considered for peer review. Note that eJTCM is striving to increase the quality and medical relevance of the publications.