Yoshikawa Naoki, Hirata Naoto, Kurone Yuichiro, Shimoeda Sadahiko
Department of Pharmaceutical Health Care and Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
Cardiooncology. 2024 Jun 22;10(1):39. doi: 10.1186/s40959-024-00242-0.
Doxorubicin (DXR) is an effective chemotherapeutic agent. DOX-induced cardiomyopathy (DICM), a major limitation of DXR, is a complication with limited treatment options. We previously reported that Red Ginseng (steamed and dried the root of Panax Ginseng cultivated for over six years; RGin) is beneficial for the treatment of DICM. However, the mechanism underlying the action of RGin remains unclear. In this study, we investigated the mechanism of action underlying the efficacy of RGin in the treatment of DICM.
Four-week-old DBA/2 mice were divided into: vehicle, DXR, RGin, and DXR + RGin (n = 10/group). Mice were treated with DXR (4 mg/kg, once a week, accumulated 20 mg/kg, i.p.) or RGin (0.5 g/kg, three times a week, i.p.). To evaluate efficacy, the survival rate and left ventricular ejection fraction (LVEF) were measured as a measure of cardiac function, and cardiomyocytes were subjected to Masson trichrome staining. To investigate the mechanism of action, western blotting was performed to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, transferrin receptor (TfR), and other related proteins. Data were analyzed using the Easy R software. Between-group comparisons were performed using one-way analysis of variance and analyzed using a post-hoc Tukey test. Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. P < 0.05 was considered statistically significant in all analyses.
RGin treatment prolongs survival and protects against reduced LVEF. In the DXR group, Nrf2 was not activated and cell death was accelerated. Furthermore, there was an increase in the TfR levels, suggesting abnormal iron metabolism. However, the DXR + RGin group showed activation of the Nrf2 pathway and suppression of myocardial cell death. Furthermore, there was no increase in TfR expression, suggesting that there were no abnormalities in iron metabolism. Therefore, the mechanism of action of RGin in DICM involves an increase in antioxidant activity and inhibition of cell death through activation of the Nrf2 pathway.
RGin is a useful therapeutic candidate for DICM. Its efficacy is supported by the activation of the Nrf2 pathway, which enhances antioxidant activity and inhibits cell death.
阿霉素（DXR）是一种有效的化疗药物。阿霉素诱导的心肌病（DICM）是DXR的一个主要局限性，是一种治疗选择有限的并发症。我们之前报道过红参（六年以上人工栽培的人参根蒸制干燥而成；RGin）对DICM的治疗有益。然而，RGin作用的潜在机制仍不清楚。在本研究中，我们调查了RGin治疗DICM疗效的作用机制。
将四周龄的DBA/2小鼠分为：溶剂对照组、DXR组、RGin组和DXR+RGin组（每组n = 10）。小鼠接受DXR（4mg/kg，每周一次，累积剂量20mg/kg，腹腔注射）或RGin（0.5g/kg，每周三次，腹腔注射）治疗。为评估疗效，测量存活率和左心室射血分数（LVEF）作为心脏功能的指标，并对心肌细胞进行Masson三色染色。为研究作用机制，进行蛋白质免疫印迹法以评估核因子红细胞2相关因子2（Nrf2）、血红素加氧酶1、转铁蛋白受体（TfR）及其他相关蛋白的表达。使用Easy R软件分析数据。组间比较采用单因素方差分析，并使用事后Tukey检验进行分析。存活率采用Kaplan-Meier法估计，并使用对数秩检验进行比较。在所有分析中，P < 0.05被认为具有统计学意义。
RGin治疗可延长生存期并防止LVEF降低。在DXR组中，Nrf2未被激活且细胞死亡加速。此外，TfR水平升高，提示铁代谢异常。然而，DXR+RGin组显示Nrf2通路激活且心肌细胞死亡受到抑制。此外，TfR表达未增加，提示铁代谢无异常。因此，RGin在DICM中的作用机制包括通过激活Nrf2通路增加抗氧化活性和抑制细胞死亡。
RGin是DICM的一种有用的治疗候选药物。其疗效得到Nrf2通路激活的支持，该通路增强抗氧化活性并抑制细胞死亡。
