褪黑素、维生素E对阿霉素所致大鼠心肌损伤的影响
摘要
背景:在恶性肿瘤化疗过程中,抗肿瘤药物存在着严重的不良反应一直是个限制性问题。阿霉素(adriamycin,ADM)属蒽环类抗生素,是治疗多种实体瘤的常用药,但其累积剂量有关的严重心脏毒性,大大限制了ADM大剂量长期应用。阿霉素的诱变性和心脏毒性部分于其能引起氧自由基的形成,然而心脏不能有效的转运自由基,在心肌线粒体上有一位于线粒体内膜的不同于其他组织细胞的独特的酶,此酶使阿霉素还原为半醌,引起严重的氧化应激相关。因此,找到有效的抗氧化剂减轻阿霉素对心肌的损伤,为临床防治阿霉素心肌疾病提供新的可能性。
目的:研究褪黑素(MLT)、VitE对阿霉素(ADM)诱导的心肌损伤大鼠进行干预实验,观察它们对大鼠阿霉素心肌损伤的保护作用,并初步探讨其作用机制。为防治心肌疾病提供新的思路,为今后进一步开发研究提供理论依据。
方法:采用成年SD大鼠40只,随机分为空白对照组、ADM组、MLT+ADM组、VitE+ADM组、MLT+VitE+ADM组,每组各8只。实验30天后Masson氏三色染色法进行左室胶原特异染色及半定量分析,计算胶原容积分数(CVF),并作HE染色,光镜下病理形态学观察,测定心肌超氧化物酶(SOD)活性及丙二醛(MDA)含量,测定Bcl-2/Bax蛋白的表达。
结果:病理损伤分级经Ridit分析可见ADM组、VitE+ADM组、MLT+ADM组、MLT+VitE+ADM组心肌损伤程度依次减轻。与正常对照组大鼠比较,阿霉素组大鼠心肌MDA含量显著升高,而SOD活性显著降低,心肌细胞Bax/Bcl-2基因的蛋白阳性表达增高,心肌损伤。给予MLT、VitE治疗可明显降低心肌组织中MDA含量,并显著增强SOD活性,抑制心肌细胞Bcl-2/Bax基因的蛋白阳性表达心肌损伤减轻。Masson染色显示ADM组左室胶原明显增多,心肌间质明显纤维化。ADM组胶原容积分数(CVF)较空白组明显增加(P<0.01);而VitE+ADM组较ADM组心肌纤维化程度减轻,CVF较ADM组降低(P<0.01),MLT+ADM组较VitE+ADM组CVF明显降低(P<0.01),MLT+VitE+ADM组较MLT+ADM组CVF明显降低(P<0.01)。两种抗氧化剂相比,MLT在大鼠心肌组织的抗氧化能力强于VitE,二者联用则抗氧化能力强于二者单独应用。
结论:MLT和VitE均可通过增强阿霉素诱导的心肌损伤大鼠的抗氧化能力和抑制氧化应激反应。在心肌损伤的发生、发展中具有一定的保护作用,并且MLT的抗氧化能力强于VitE,联用MLT和VitE则抗氧化能力表现更明显,其机制可能与褪黑素能从多个环节防止自由基损伤并且具有协同作用有关。
Background: In chemotherapy for malignant process,the adverse reactions of anti-cancer drugs limit the application of anti-cancer drugs.Adriamycin(ADM) is an anthracycline antibiotic, a commonly used drug of the cancer treatment drugs, but the cumulative dose-related cardiac toxicity is a major constraint on the long-term application of high-dose ADM.ADM induced cardiac toxicity most because of it caused the formation of oxygen free radicals, but the heart can not effectively trans-shipment oxygen free radicals ,in myocardial mitochondria there is a unique enzyme, the enzyme so that ADM reduced to semiquinone, cause severe oxidative stress.Therefore, to find an effective anti-oxidants reduce the adriamycin on myocardial injury,it provide a new possibilitie for clinical prevention and treatment on adriamycin induced myocardial injury.
Objective:To study effects of melatonin on adriamycin induced myocardial injury in rats.
Methods:Forty adult SD rats were randomized into five groups(n=8):control group, ADM group, MLT+ADM group, VitE+ADM group, MLT+VitE+ADM groups.After 30 days,left ventricular collagen volume fraction,the activity of myocardial superoxide dismutase,the concentration of malondialdehyde, the Bax/Bcl-2 of protein expression were assayed. The pathomorphology changes cardiomyocytes were detected optical microscope.
Results:By Ridit analysis pathological injury scale can be seen by ADM group, VitE+ADM group, MLT+ADM group, MLT+VitE+ADM group in turn reduce the extent of myocardial injury. Compared with the control group of rats,the concentration of MDA in ADM group rats were significantly higher, the activity of SOD were significant lower, myocardial cells’Bax gene protein expression were higher and Bcl-2 gene protein expression were lower. To MLT, VitE treatment can significantly reduce the myocardial tissue’concentration of MDA, and significantly enhance the activity of SOD,the expression of bcl-2 increased significantly while the expression of bax decreased significantly.Masson staining showed increased left ventricular collagen, myocardial interstitial fibrosis obvious in ADM group. ADM group collagen volume fraction (CVF) was higher than the control group(P<0.01); and VitE+ADM group CVF lower than the ADM group (P<0.01), MLT+ADM group CVF lower than VitE+ADM group(P<0.01), MLT+VitE+ADM group CVF lower than MLT+ADM group(P<0.01). Compared the two kinds of antioxidants, MLT in the rat myocardium of the antioxidant capacity is higher than VitE, the combined effect of antioxidant capacity is more than the two separate applications.
Conclusion:MLT and VitE can enhance myocardial antioxidant capacity and protection myocardial,and the antioxidant capacity of MLT is higher than VitE, the combined effect of antioxidant capacity is significantly,the mechanisms are possibly due to MLT can prevent free radical damage from various sectors and have synergies.
目的:研究褪黑素(MLT)、VitE对阿霉素(ADM)诱导的心肌损伤大鼠进行干预实验,观察它们对大鼠阿霉素心肌损伤的保护作用,并初步探讨其作用机制。为防治心肌疾病提供新的思路,为今后进一步开发研究提供理论依据。
方法:采用成年SD大鼠40只,随机分为空白对照组、ADM组、MLT+ADM组、VitE+ADM组、MLT+VitE+ADM组,每组各8只。实验30天后Masson氏三色染色法进行左室胶原特异染色及半定量分析,计算胶原容积分数(CVF),并作HE染色,光镜下病理形态学观察,测定心肌超氧化物酶(SOD)活性及丙二醛(MDA)含量,测定Bcl-2/Bax蛋白的表达。
结果:病理损伤分级经Ridit分析可见ADM组、VitE+ADM组、MLT+ADM组、MLT+VitE+ADM组心肌损伤程度依次减轻。与正常对照组大鼠比较,阿霉素组大鼠心肌MDA含量显著升高,而SOD活性显著降低,心肌细胞Bax/Bcl-2基因的蛋白阳性表达增高,心肌损伤。给予MLT、VitE治疗可明显降低心肌组织中MDA含量,并显著增强SOD活性,抑制心肌细胞Bcl-2/Bax基因的蛋白阳性表达心肌损伤减轻。Masson染色显示ADM组左室胶原明显增多,心肌间质明显纤维化。ADM组胶原容积分数(CVF)较空白组明显增加(P<0.01);而VitE+ADM组较ADM组心肌纤维化程度减轻,CVF较ADM组降低(P<0.01),MLT+ADM组较VitE+ADM组CVF明显降低(P<0.01),MLT+VitE+ADM组较MLT+ADM组CVF明显降低(P<0.01)。两种抗氧化剂相比,MLT在大鼠心肌组织的抗氧化能力强于VitE,二者联用则抗氧化能力强于二者单独应用。
结论:MLT和VitE均可通过增强阿霉素诱导的心肌损伤大鼠的抗氧化能力和抑制氧化应激反应。在心肌损伤的发生、发展中具有一定的保护作用,并且MLT的抗氧化能力强于VitE,联用MLT和VitE则抗氧化能力表现更明显,其机制可能与褪黑素能从多个环节防止自由基损伤并且具有协同作用有关。
Background: In chemotherapy for malignant process,the adverse reactions of anti-cancer drugs limit the application of anti-cancer drugs.Adriamycin(ADM) is an anthracycline antibiotic, a commonly used drug of the cancer treatment drugs, but the cumulative dose-related cardiac toxicity is a major constraint on the long-term application of high-dose ADM.ADM induced cardiac toxicity most because of it caused the formation of oxygen free radicals, but the heart can not effectively trans-shipment oxygen free radicals ,in myocardial mitochondria there is a unique enzyme, the enzyme so that ADM reduced to semiquinone, cause severe oxidative stress.Therefore, to find an effective anti-oxidants reduce the adriamycin on myocardial injury,it provide a new possibilitie for clinical prevention and treatment on adriamycin induced myocardial injury.
Objective:To study effects of melatonin on adriamycin induced myocardial injury in rats.
Methods:Forty adult SD rats were randomized into five groups(n=8):control group, ADM group, MLT+ADM group, VitE+ADM group, MLT+VitE+ADM groups.After 30 days,left ventricular collagen volume fraction,the activity of myocardial superoxide dismutase,the concentration of malondialdehyde, the Bax/Bcl-2 of protein expression were assayed. The pathomorphology changes cardiomyocytes were detected optical microscope.
Results:By Ridit analysis pathological injury scale can be seen by ADM group, VitE+ADM group, MLT+ADM group, MLT+VitE+ADM group in turn reduce the extent of myocardial injury. Compared with the control group of rats,the concentration of MDA in ADM group rats were significantly higher, the activity of SOD were significant lower, myocardial cells’Bax gene protein expression were higher and Bcl-2 gene protein expression were lower. To MLT, VitE treatment can significantly reduce the myocardial tissue’concentration of MDA, and significantly enhance the activity of SOD,the expression of bcl-2 increased significantly while the expression of bax decreased significantly.Masson staining showed increased left ventricular collagen, myocardial interstitial fibrosis obvious in ADM group. ADM group collagen volume fraction (CVF) was higher than the control group(P<0.01); and VitE+ADM group CVF lower than the ADM group (P<0.01), MLT+ADM group CVF lower than VitE+ADM group(P<0.01), MLT+VitE+ADM group CVF lower than MLT+ADM group(P<0.01). Compared the two kinds of antioxidants, MLT in the rat myocardium of the antioxidant capacity is higher than VitE, the combined effect of antioxidant capacity is more than the two separate applications.
Conclusion:MLT and VitE can enhance myocardial antioxidant capacity and protection myocardial,and the antioxidant capacity of MLT is higher than VitE, the combined effect of antioxidant capacity is significantly,the mechanisms are possibly due to MLT can prevent free radical damage from various sectors and have synergies.
引文
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6 Tomás-Zapico C,Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes[J].J Pineal Res, 2005,39:99-104.
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9 Silva SO,Rodrigues MR,Carvalho SR,et al.Oxidation of melatonin and its catabolies,N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-5-methoxy- kynuramine,by activated leukocytes[J].J Pineal Res, 2004,37(3):171-175.
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11 Wang H,Wei W,Zhang S Y,et al.Melatonin-selenium nanoparticles inhibit oxidativestress and protect against hepatic injury induced by Bacillus Calmette-Guerin/lipopolysaccharide in mice[J].J Pineal Res,2005,39(2):156-163.
12罗明奎,蔡昌启,雷玉洁,王开发.等级资料Ridit分析及正确使用[J].中国卫生统计,2003,20(4):252-254.
13 Wallace KB.Doxorubicin induced cardiac mitochondrionopathy[J].Pharmacol Toxicol,2003,93:105-115.
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15 Morishima I,Matsui H,Mukawa H,et al.Melatonin,a pineal hormone with anti- oxidant property, protects against adriamycin cardiomyopathy in rats[J]. Life Sci, 1998,63(7):511-521.
16 Tao ZW,Li YJ,Deng HW.Attenuation of myocardial injury due to oxygen free radicals (OFR) by pretreatment with OFR or calcitonin gene-related peptide[J]. Zhongguo Yao Li Xue Bao,1997,18(4):312-316.
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28 Ozdemir D,Uysal N,Tugyan K,et al.The efect of melatonin on endotoxemia-induced intestinal apoptosis and oxidative stress in infant rats[J].Intensive Care Med, 2007,33(3):511-516.
1 Hardeland R.Antioxidative protection by melatonin:multiplicity of mechanisms from radical detoxification to radical avoidance[J].Endocrine, 2005,27:119-130.
2 Tomas-Zapico C,Coto-Montes A.A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes[J].J Pineal Res, 2005,39:99-104.
3 Hardeland R,Pandi-Perumal SR,Cardinali DP. Melatonin[J].Int J Biochem Cell Biol,2006,38:313-316.
4 Suzen S, Bozkaya P, Coban T, Nebiogu D.Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: discussion on possible antioxidant mechanisms and comparison with melatonin[J].J Enzyme Inhib Med Chem, 2006,21:405-411.
5 Silva SO,Rodrigues MR,Carvalho SR,et al.Oxidation of melatonin and its catabolies,N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-5-methoxyk- ynuramine,by activated leukocytes[J].J Pineal Res, 2004,37(3):171-175.
6 Tomás-Zapico C, Coto-Montes A.A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes[J].J Pineal Res,2005,39(2):99-104.
7 Tocharus,Jiraporn,Chongthammakun,et al.Melatonin inhibits amphetamine-induced nitric oxide synthase mRNA overexpression in microglial cell lines[J].Neuroscience Letters,2008,439(2):134-137.
8 Ozdemir D,Uysal N,Tugyan K,et al.The efect of melatonin on endotoxemia-induced intestinal apoptosis and oxidative stress in infant rats[J].Intensive Care Med, 2007,33(3):511-516.
9 Wang H,Wei W,Zhang S Y,et al.Melatonin-selenium nanoparticles inhibit oxidative stress and protect against hepatic injury induced by Bacillus Calmette-Guerin/lipopolysaccharide in mice[J].J Pineal Res,2005,39(2):156-163.
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31王延荣,朱大年.褪黑素的降压机制[J].国外医学心血管疾病分册, 2005,32(4):214-216.
2 J.M. Berthiaume,K.B. Wallace.Adriamycin-induced oxidative mitochondrial cardiotoxicity[J].Cell Biol Toxicol 2007,23:15-25.
3 Conklin KA.Coenzyme Q10 for Prevention of Anthracycline-Induced Cardiotoxicity[J].Integr Cancer Ther,2005,4(2):110-113.
4魏涛,唐芬芳,金宗濂.褪黑素的生理功能[J].食品工业技术,2002,23(9):98-102.
5 Hardeland R.Antioxidative protection by melatonin:multiplicity of mechanisms from radical detoxification to radical avoidance[J].Endocrine,2005,27:119-130.
6 Tomás-Zapico C,Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes[J].J Pineal Res, 2005,39:99-104.
7 Hardeland R,Pandi-Perumal SR,Cardinali DP. Melatonin[J].Int J Biochem Cell Biol,2006,38:313-316.
8 Suzen S,Bozkaya P,Coban T,Nebiogu D.Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives:discussion on possible antioxidant mechanisms and comparison with melatonin[J].J Enzyme Inhib Med Chem,2006,21:405- 411.
9 Silva SO,Rodrigues MR,Carvalho SR,et al.Oxidation of melatonin and its catabolies,N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-5-methoxy- kynuramine,by activated leukocytes[J].J Pineal Res, 2004,37(3):171-175.
10 Ozdemir D,Uysal N,Tugyan K,et al.The efect of melatonin on endotoxemia-induced intestinal apoptosis and oxidative stress in infant rats[J].Intensive Care Med,2007,33(3):511-516.
11 Wang H,Wei W,Zhang S Y,et al.Melatonin-selenium nanoparticles inhibit oxidativestress and protect against hepatic injury induced by Bacillus Calmette-Guerin/lipopolysaccharide in mice[J].J Pineal Res,2005,39(2):156-163.
12罗明奎,蔡昌启,雷玉洁,王开发.等级资料Ridit分析及正确使用[J].中国卫生统计,2003,20(4):252-254.
13 Wallace KB.Doxorubicin induced cardiac mitochondrionopathy[J].Pharmacol Toxicol,2003,93:105-115.
14 Konorev EA,Kotamraju S,Zhao H,et al.Paradoxical effects of metalloporphyrins on doxorubicin-induced apoptosis:scavenging of reactive oxygen species versus induction of heme oxygenase-1[J].Free Radic Biol Med,2002,33(7):988-993.
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16 Tao ZW,Li YJ,Deng HW.Attenuation of myocardial injury due to oxygen free radicals (OFR) by pretreatment with OFR or calcitonin gene-related peptide[J]. Zhongguo Yao Li Xue Bao,1997,18(4):312-316.
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