Journal of traditional and complementary medicine · 2024
Parthenolide alleviates doxorubicin-induced cardiotoxicity via regulation of Cyp1a1 and Nppa and suppression of NLRP3 inflammasome.
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Yang Yuanying, Wei Shanshan, Liu Sa, Xie Suifen, Xiao Wei, Liu Jian, Xie Ning, Li Wenqun, Zhang Bikui
Аннотация
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.
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.