芒果甙在保护柔红霉素致大鼠心肌细胞毒性中铁代谢的改变其机制的研究
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摘要
目的探讨铁代谢在芒果甙保护柔红霉素致大鼠心肌毒性细胞中的改变,并对其作用机制进行初步研究。
方法以柔红霉素单用或联合应用不同浓度芒果甙为处理因素作用于大鼠心肌细胞24小时、48小时及72小时,应用qRT-PCR法检测各组心肌细胞铁调节蛋白1(IRP1)、铁调节蛋白2(IRP2)mRNA表达情况；应用RT-PCR法检测铁蛋白(Fn) mRNA表达情况；同时采用免疫细胞化学染色法检测转铁蛋白(Tf)及转铁蛋白受体(TfR)表达情况。
结果
1、25-200μ mol/L芒果甙模型组在干预24小时后铁调节蛋白1、铁调节蛋白2表达水平较柔红霉素组降低,干预48小时后,二者表达较柔红霉素组升高(P<0.05),干预72小时后,各浓度芒果甙模型组铁调节蛋白1表达较柔红霉素组下降,而铁调节蛋白2表达较柔红霉素组逐渐升高；
2、干预24小时、72小时25-200μ mol/L芒果甙模型组铁蛋白表达较柔红霉素组随浓度升高逐渐降低,干预48小时后则较柔红霉素组均升高(P<0.05);
3、柔红霉素组24、48小时的转铁蛋白、转铁蛋白受体表达均明显高于空白对照组；25-200μ mol/L芒果甙模型组24小时两者表达亦明显高于空白对照组,48小时则显著下降,低于柔红霉素组；72小时柔红霉素组的转铁蛋白受体表达明显低于空白对照组,而25-200μ mol/L芒果甙模型组表达较柔红霉素组逐渐升高(P 结论芒果甙能改变柔红霉素心肌毒性细胞的铁代谢水平,由此可推测,铁代谢可能是芒果甙保护柔红霉素致大鼠心肌细胞毒性的机制之一。
Objective To study the changes of iron metabolism in the mangiferin protection of daunorubicin induced rat myocardial toxicity cell, and investigate its preliminary mechanism.
Methods With4μmol/L daunorubicin alone or combined application of25-200μmol/L concentrations of mangiferin for processing factors acting on rat myocardial cells of24h,48h and72h, application of qRT-PCR assay for the detection of myocardial cells in each group of iron regulatory protein1(IRP1), iron regulatory protein2(IRP2) mRNA expression, application of RT-PCR method for the detection of ferritin (Fn) mRNA expression, while the use of immunocytochemical staining method for the detection of transferrin (Tf) and transferrin receptor (TfR) expression.
Results
1、The25-200μmol/L concentrations of mangiferin model groups intervented in24h both decreased the expression levels compared with the negative control group, while in the intervention of48h,72h, compared with the daunorubicin group elevated expression (P<0.05)
2、The intervention of24h、72h,25-200μmol/L concentrations of mangiferin model group compared with the daunorubicin group expression gradually decreased, but all higher than the daunorubicin group in48h(P<0.05).
3、With the daunorubicin group and the25-200μmol/L concentrations of mangiferin model groups in24h, the transferrin expression of transferrin receptor were significantly higher than those in blank control group. Transferrin receptor expression of the daunorubicin group in72h was significantly lower than those in blank control group, but the expression25-200μmol/L concentrations of mangiferin model group compared with daunorubicin group rose (P<0.05)
Conclusion Mangiferin can change the iron metabolism level of daunorubicin myocardial toxicity cells. Which can be assumed, iron metabolism may be one of the mechanisms for mangiferin protection of rat myocardial cells induced by daunorubicin toxicity.
方法以柔红霉素单用或联合应用不同浓度芒果甙为处理因素作用于大鼠心肌细胞24小时、48小时及72小时,应用qRT-PCR法检测各组心肌细胞铁调节蛋白1(IRP1)、铁调节蛋白2(IRP2)mRNA表达情况；应用RT-PCR法检测铁蛋白(Fn) mRNA表达情况；同时采用免疫细胞化学染色法检测转铁蛋白(Tf)及转铁蛋白受体(TfR)表达情况。
结果
1、25-200μ mol/L芒果甙模型组在干预24小时后铁调节蛋白1、铁调节蛋白2表达水平较柔红霉素组降低,干预48小时后,二者表达较柔红霉素组升高(P<0.05),干预72小时后,各浓度芒果甙模型组铁调节蛋白1表达较柔红霉素组下降,而铁调节蛋白2表达较柔红霉素组逐渐升高；
2、干预24小时、72小时25-200μ mol/L芒果甙模型组铁蛋白表达较柔红霉素组随浓度升高逐渐降低,干预48小时后则较柔红霉素组均升高(P<0.05);
3、柔红霉素组24、48小时的转铁蛋白、转铁蛋白受体表达均明显高于空白对照组；25-200μ mol/L芒果甙模型组24小时两者表达亦明显高于空白对照组,48小时则显著下降,低于柔红霉素组；72小时柔红霉素组的转铁蛋白受体表达明显低于空白对照组,而25-200μ mol/L芒果甙模型组表达较柔红霉素组逐渐升高(P
Objective To study the changes of iron metabolism in the mangiferin protection of daunorubicin induced rat myocardial toxicity cell, and investigate its preliminary mechanism.
Methods With4μmol/L daunorubicin alone or combined application of25-200μmol/L concentrations of mangiferin for processing factors acting on rat myocardial cells of24h,48h and72h, application of qRT-PCR assay for the detection of myocardial cells in each group of iron regulatory protein1(IRP1), iron regulatory protein2(IRP2) mRNA expression, application of RT-PCR method for the detection of ferritin (Fn) mRNA expression, while the use of immunocytochemical staining method for the detection of transferrin (Tf) and transferrin receptor (TfR) expression.
Results
1、The25-200μmol/L concentrations of mangiferin model groups intervented in24h both decreased the expression levels compared with the negative control group, while in the intervention of48h,72h, compared with the daunorubicin group elevated expression (P<0.05)
2、The intervention of24h、72h,25-200μmol/L concentrations of mangiferin model group compared with the daunorubicin group expression gradually decreased, but all higher than the daunorubicin group in48h(P<0.05).
3、With the daunorubicin group and the25-200μmol/L concentrations of mangiferin model groups in24h, the transferrin expression of transferrin receptor were significantly higher than those in blank control group. Transferrin receptor expression of the daunorubicin group in72h was significantly lower than those in blank control group, but the expression25-200μmol/L concentrations of mangiferin model group compared with daunorubicin group rose (P<0.05)
Conclusion Mangiferin can change the iron metabolism level of daunorubicin myocardial toxicity cells. Which can be assumed, iron metabolism may be one of the mechanisms for mangiferin protection of rat myocardial cells induced by daunorubicin toxicity.
引文
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[2]Kaiserova H, Simunek T, van der Vijgh WJ, etc. Flavonoids as protectors against doxorubicin cardiotoxicity:Role of iron chelation, antioxidant activity and inhibition of carbonyl reductase. Biochim Biophys Acta,2007,1772 (9):1065-1074.
[3]Halliwell B, Gutteridge JMC. Oxygen free radicals and iron in relation to biology and medicine:some problems and concepts. Archives of biochemistry and biophysics,1986,246:501-514.
[4]Myers CE, Gianni L, Simone CB, etc. Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry,1982,21 (8):1707-1712.
[5]Wain SM, Whaley FS, Gerber MC, etc. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol,1997,15:1318-1332.
[6]彭志刚,罗军,夏凌辉等.芒果甙诱导慢性髓系白血病K562细胞凋亡中国实验血液学杂志,2004,12(5)：590-594.
[7]吴泽广,彭志刚,杨杰等.芒果甙对柔红霉素致大鼠心肌细胞过氧化损伤的保护作用.中药药理与临床,2011;(27)2：37-40.
[8]Kwok JC, Richardson DR. Unexpected anthracyclinemediated alterations in iron-regulatory protein-RNAbinding activity:the iron and copper complexes of anthracyclines decrease RNA-binding activity. Mol Pharmacol,2002,62,888-900.
[9]徐丽华,刘春雷,常玉梅等.双标准曲线相对定量PCR试验原理与方法.生物技术通报.2011,1：71-75.
[10]袁晓军,何珂骏,房定珠等.全反式维甲酸诱导K562细胞铁代谢变化的研究.临床儿科杂志.2010,28(6)：501-507.
[11]张勇.蒽环类药物心脏毒性的治疗进展.当代医学,2009,162：6-7.
[12]吕俊,丁念,朱家蔷等.蒽环类药物心脏毒性及其预防的研究进展.中国医院药学杂志.2008,15：1302-1303.
[13]Greiner MA, Lipshultz SE:Epidcnniology of Anthracycline Cardiotoxieity in Children and Adults [J]. Semin Oncol,1998,25 (4): 72-85.
[14]Gianni L, Herman EH, Lipshultz SE, etc. Anthracycline cardiotoxicity:from bench to bedside. J Clin Oncol,2008,26, 3777-3784.
[15]Doroshow JH:Effect of anthracyline antibiotics on oxygen redical formation in rat heart. Cancer Res,19983,43,460-472
[16]Luo X, Everovsky Y, Cole D,etc. Doxorubicin-induced acute changes in cytotoxic aldehydes, antioxidant status and cardiac function in the rat. Biochim Biophys Acta,1997,1360,45-52.
[17]Haillwell B, Gutteridge JMC, Free radicals in biology and medicine, Oxford University Press, Oxford, New York,2007.
[18]Myers CE, Gianni L, Simone CB, etc. Oxidative destruction of erythrocyte ghost menbranes catalyzed by the doxorubicin-iron complex. Biochemistry,1982,21,1707-1712.
[19]Paglia DE, Radclife RW. Anthracyline cardiotoxicity in a black rhinoceros(Diceros bi-cornis):Evidence for impared antioxidant ca-pacity compounded by iron overload [J]. Vepathol,2001,37(1): 86-88.
[20]Keizer HG, Pinedo HM, Schuurhuis GJ, et,al. Doxorubicin (adriamycin):a critical review of free redical-dependent mechanisms of cytotoxicity. Pharmacol Ther,1990,47,219-231.
[21]Mladenka P, Simunek T, Hubl M, etc. The role of reactive oxygen and nitrogen species in cellular iron metabolism. Free Radic Res, 2006,40,263-272.
[22]Tomas CE, Aust SD. Release of iron from ferrtin by cardiotoxic anthracycline antibiotics. Arch Biochem Biophys,1986,248,684-689.
[23]Hershko C,Link G, Tzahor M, etc. Anthraxyxline toxicity is poteintiated by iron and inhibited by deferoxamine:studies in rat heart cells in culture. J Lab Clin Med,993,122,245-251.
[24]Voest EE, Van Acker SA, van der Vijgh WJ,etc. Comparison of different iron chelators as protective agents against acute doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol,1994, 26,1179-1185.
[25]Zanninelli G, Glickstein H, Breuer W, etc. Chelation and mobilization of cellular iron by different classes of chelators. Mol Pharmacol,1997,51,842-852.
[26]Barnabe N, Zastre JA, Venkataram S, etc. Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Free Radic Biol Med,2002,33,266-275.
[27]Xu LJ, Jin L, Pan H, etc. Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin. Acta Pharmacol Sin, 2006,27,1333-1339.
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