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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：阿霉素（DXR）是一种有效的化学治疗剂。DOX诱导的心肌病（DICM），DXR的一个主要限制，是治疗选择有限的并发症。我们以前报道过，红参（蒸干人参的根种植超过六年；RGin）对DICM的治疗有益。然而,RGin的作用机制尚不清楚.在这项研究中,我们研究了RGin治疗DICM疗效的作用机制.
方法：将四周龄的DBA/2小鼠分为：媒介物，DXR,RGin,和DXR+RGin(n=10/组)。用DXR（4mg/kg，一周一次,累积20mg/kg，i.p.）或RGin（0.5g/kg，一周三次,i.p.）。为了评估疗效，测量生存率和左心室射血分数（LVEF）作为心功能的量度，和心肌细胞进行Masson三色染色。为了研究作用机制，进行蛋白质印迹以评估核因子红细胞2相关因子2（Nrf2）的表达，血红素加氧酶1，转铁蛋白受体（TfR），和其他相关蛋白质。使用EasyR软件分析数据。使用单向方差分析进行组间比较，并使用事后Tukey检验进行分析。使用Kaplan-Meier方法估计生存率，并使用对数秩检验进行比较。在所有分析中P<0.05被认为是统计学上显著的。
结果：RGin治疗可延长生存期并防止LVEF降低。在DXR组中，Nrf2未被激活,细胞死亡加速。此外，TfR水平有所上升,提示铁代谢异常.然而,DXR+RGin组显示Nrf2通路的激活和心肌细胞死亡的抑制。此外，TfR表达没有增加，表明铁代谢没有异常。因此,RGin在DICM中的作用机制涉及通过激活Nrf2途径增加抗氧化活性和抑制细胞死亡。
结论：RGin是治疗DICM的有用候选药物。其功效由Nrf2通路的激活支持，增强抗氧化活性并抑制细胞死亡。
方法：将四周龄的DBA/2小鼠分为：媒介物，DXR,RGin,和DXR+RGin(n=10/组)。用DXR（4mg/kg，一周一次,累积20mg/kg，i.p.）或RGin（0.5g/kg，一周三次,i.p.）。为了评估疗效，测量生存率和左心室射血分数（LVEF）作为心功能的量度，和心肌细胞进行Masson三色染色。为了研究作用机制，进行蛋白质印迹以评估核因子红细胞2相关因子2（Nrf2）的表达，血红素加氧酶1，转铁蛋白受体（TfR），和其他相关蛋白质。使用EasyR软件分析数据。使用单向方差分析进行组间比较，并使用事后Tukey检验进行分析。使用Kaplan-Meier方法估计生存率，并使用对数秩检验进行比较。在所有分析中P<0.05被认为是统计学上显著的。
结果：RGin治疗可延长生存期并防止LVEF降低。在DXR组中，Nrf2未被激活,细胞死亡加速。此外，TfR水平有所上升,提示铁代谢异常.然而,DXR+RGin组显示Nrf2通路的激活和心肌细胞死亡的抑制。此外，TfR表达没有增加，表明铁代谢没有异常。因此,RGin在DICM中的作用机制涉及通过激活Nrf2途径增加抗氧化活性和抑制细胞死亡。
结论：RGin是治疗DICM的有用候选药物。其功效由Nrf2通路的激活支持，增强抗氧化活性并抑制细胞死亡。
