阿霉素致大鼠心脏氧化损伤及其机制的研究

目的观察不同剂量阿霉素（ADR）给药后不同时间对大鼠心脏的作用，探讨ADR心脏毒性损伤的可能作用机制。方法60只大鼠随机分为对照组和3个给药组。给药组分别单次腹腔注射5、10和20ms／kg的ADR溶液；对照组给予生理盐水。给药后第1、2和4天每组分别处死5只动物，取心室制备组织匀浆，用硫代巴比妥酸法（TBA）测定丙二醛（MDA）含量，二硫代双硝基苯甲酸法（DTNB）测定总巯基（TSH）和非蛋白巯基（NPSH）含量，Griess试剂法测定一氧化氮（NO）含量。结果随着剂量的增加，给药后第1天心脏组织中NPSH、TSH含量增加；给药后第2天TSH、NO含量增加；给药后第4天MDA、NO含量增加，NPSH含量降低；与对照组比较，20ms／kg组差异有显著性（P〈0．05，P〈0．01）。结论阿霉素致心脏损伤的机制可能与心脏组织中NPSH的耗竭及NO产生过多有关。     

大蒜多糖对阿霉素所致小鼠心脏毒性的拮抗作用

目的　研究大蒜多糖 (GP)对中毒性心肌炎的拮抗作用并探讨其机制。方法　建立小鼠阿霉素 (ADR)中毒性心肌炎模型,测定血清、心肌多项生化指标,并观察心肌结构变化。结果　ADR(3mg·kg-1ip, qod×7)可致小鼠血清肌酸激酶(CK)、乳酸脱氢酶(LDH)、谷草转氨酶(GOT)和诱导型一氧化氮合酶(iNOS)活力升高(P<0 01),同时心肌超氧化物歧化酶(SOD)活力下降而丙二醛 (MDA)含量升高 (P<0 01),线粒体水肿明显。GP( 0 75 ~3 0g·kg-1 ig, qd×15)能逆转ADR所致的上述改变,表现为剂量相关性降低血清CK、LDH、GOT和iNOS活力,增加心肌SOD活力和降低MDA含量,尤其以GP大剂量组作用明显 (P<0 05或P<0 01)。光镜和电镜结果也证实了GP的保护作用。结论　GP能拮抗阿霉素所致的小鼠中毒性心肌炎,其作用机制与增强心肌SOD活力和抗心肌脂质过氧化有关。     

β—胡萝卜素对阿霉素所致的大鼠心脏毒性的作用

目的：研究β－胡萝卜素减轻阿霉素所致的大鼠心脏毒性的作用及其机制，方法：应用光学显微镜技术观察心肌组织的病理变化，心肌ＭＤＡ值用巴比妥酸法测定，ＳＯＤ活性用邻苯二酚法测定，ＧＳＨ－Ｐｘ活性用ＤＴＮＢ法测定，运用顺磁共振（ＥＳＲ）技术测定半醌自由基，结果：β－胡萝卜素素１０或３０ｍｇ．ｋｇ＾－１可明显减轻阿霉素引起的大鼠心肌损害，保护ＳＯＤ，ＧＳＨ－Ｐｘ活性，对抗阿霉素引起的心肌ＭＤＡ水平升高，体外     

富硒麦芽对阿霉素致小鼠心脏毒性的保护作用

目的：探讨含硒制剂诱导金属硫蛋白在对抗阿霉素心脏毒性中的作用,比较无机硒制剂亚硒酸钠与有机硒制剂富硒麦芽。方法：不同时间给小鼠喂予硒制剂后取血分离血清,按常规查ＧＯＴ和ＣＫ活性,按ＤＴＮＢ法测ＧＳＨ－Ｐｘ活性;取心、肝、肾组织按Ｈｇ－Ｃｈｅｌｅｘ法测金属硫蛋白（）含量并做心脏病理学检查。结果：两种含硒制剂均能减轻阿霉素引起的体重下降,ＧＯＴ与ＣＫ酶升高及心脏病理损害,其中富硒麦芽的效果略优于亚硒酸     

黄芪注射液治疗阿霉素致乳腺癌心肌损害的临床观察

目的:观察黄芪注射液对阿霉素所致乳腺癌患者相关性心脏毒性损伤的干预治疗作用。方法:将80例III期乳腺癌患者随机分为治疗组(黄芪加化疗)和对照组(单纯化疗)。两组均给予CAF方案化疗6周期,比较两组化疗前后动态心电图(H0lter)、心脏超声、心肌酶谱的变化情况。结果:化疗后治疗组动态心电图异常发生率为39.2%,明显低于对照组的94.3%,两组间比较,心肌酶谱有统计学意义(P<0.05),心脏超声左心室舒张末内径(LVDd)、舒张早期与晚期充盈速度比值(E/A)、左室射血分数(LVEF)等各项指标的改变差异均有统计学意义(P<0.05)。结论:黄芪是预防和减轻阿霉素引起的急性心脏毒性的有效药物。     

富硒麦芽对阿霉素致小鼠心脏毒性的保护作用

目的:探讨含硒制剂诱导金属硫蛋白在对抗阿霉素心脏毒性中的作用,比较无机硒制剂亚硒酸钠与有机硒制剂富硒麦芽。方法:不同时间给小鼠喂予硒制剂后取血分离血清,按常规查GOT和CK活性,按DTNB法测GSH-Px活性;取心、肝、肾组织按Hg Chelex法测金属硫蛋白(MT)含量并做心脏病理学检查。结果:两种含硒制剂均能减轻阿霉素引起的体重下降、GOT与CK酶升高及心脏病理损害,其中富硒麦芽的效果略优于亚硒酸钠。两者还能增加GSH-Px酶活性,诱导心脏中MT合成增加,连续使用硒制剂的整体效果优于先或后使用该制剂。结论:除升高GSH-Px外,硒制剂诱导合成MT很可能是减轻阿霉素心脏毒性的保护机制之一。两种硒制剂比较使用富硒麦芽较亚硒酸钠更为安全,且不降低原已证实的亚硒酸钠对心肌的保护作用。     

羟丁酸钠对离体大鼠缺血再灌注损伤心肌的影响

目的比较不同剂量羟丁酸钠对离体大鼠缺血再灌注损伤心肌脂质过氧化作用的影响。方法将24只成年Wistar大鼠随机分为4组(n=6):心肌缺血再灌注组(I/R组),1 mmol/L羟丁酸钠组(RL组),2.5 mmol/L羟丁酸钠组(RM组),10 mmol/L羟丁酸钠组(RH组)。采用Langendorff离体心脏缺血再灌注模型,四组均以K-H液平衡灌注10 min,再以K-H液及1、2.5、10 mmol/L羟丁酸钠的K-H液分别灌注10 min,然后全心停止灌注25 min,再分别继续灌注30 min。测定冠脉流出液总乳酸脱氢酶(LDH)活性;灌注末,用2.5%戊二醛固定左室心肌组织,观察心肌超微结构;留取心尖部心肌组织以检测8-异前列腺素、超氧化物歧化酶(SOD)活性。结果与IR组比较,RL组8-异前列腺素含量、SOD及LDH活性差异均无统计学意义(P>0.05),超微结构也未见损伤减轻;RM组8-异前列腺素含量、SOD活性差异均无统计学意义(P>0.05),LDH活性差异有统计学意义(P<0.05),超微结构可见损伤减轻;RH组8-异前列腺素含量、LDH活性升高(P<0.05),SOD活性差异均无统计学意义(P>0.05),超微结构可见损伤加重。结论羟丁酸钠(1、2.5 mmol/L)不能降低心肌缺血再灌注损伤大鼠的8-异前列腺素含量,抑制脂质过氧化反应;但是2.5 mmol/L羟丁酸钠能减轻大鼠心肌缺血再灌注损伤;10 mmol/L羟丁酸钠则加重了脂质过氧化反应和心肌缺血再灌注损伤。     

蛇床子素对阿霉素心脏毒性的影响

目的 研究蛇床子素对阿霉素引起的心脏毒性的影响,并探讨其作用机制.方法 用给SD大鼠ip阿霉素(ADR)的方法复制ADR心脏毒性模型.采用颈总动脉插管的方法,用十六导生理记录仪测定大鼠的血流动力学各项指标,酶促反应定磷比色法测定心肌肌浆网(SR)Ca2+-ATP酶的活性.结果 蛇床子素对ADR引起的心脏毒性大鼠的血流动力学有明显改善作用,能显著升高心肌SRCa2+-ATP酶的活性.结论 蛇床子素对ADR引起的心脏毒性有保护作用,其作用机制可能与激活SR膜Ca2+-ATP酶、促进Ca2+储备、降低胞浆中Ca2+浓度、阻止Ca2+超载有关.     

阿霉素对心脏的毒性作用

阿霉素(ADM)属于蒽环类抗生素,用它治疗一系列实体瘤(乳腺癌、肺癌、卵巢癌、膀胱癌、甲状腺癌、软组织肉瘤、原发性肝癌等),也用于治疗某些血组织增生病(急性白血病、淋巴肉芽肿瘤)。ADM毒性表现为抑制造血功能(白细胞与淋巴细胞减少),以及脱发、恶心、呕吐、口腔炎,但这些副作用具有可逆性,一旦停药后症状即可消失。但是ADM正如蒽环类中其它抗肿瘤抗生素一样也具有心脏毒性作用,有时引起心肌病和郁血性心功能不全。ADM因治疗许多恶性肿瘤被广泛地应用,所以及早诊断、预防和治疗这类抗生素所引起的心肌中毒是一个迫切问题。文献报道在阿霉素心肌毒性的一些风险因子中,主要风险因子是体内ADM总蓄积     

L-精氨酸对阿霉素致大鼠心肌损伤的影响

目的：从分子水平上研究L-精氨酸（L—arginine，L—Arg）对阿霉素（ADM）致大鼠心肌损伤的影响，探讨一氧化氮（nitric oxide，NO）含量增加与超氧化物歧化酶（superoxide dismutase，SoD）、谷胱甘肽过氧化物酶（glutathione peroxidase，GPx）活性降低的机制。方法：32只SD大鼠随机分成4组（n=8）：对照组、L-Arg组、ADM组、ADM＋L—Arg组。采用生化方法测定相关分子的含量和酶的活性，采用逆转录聚合酶链反应方法分析相关基因的表达。结果：与ADM组比较，ADM＋L．A职组心肌NO、丙二醛含量明显增加及血清肌酸激酶同功酶MB的活性明显升高（P〈0．01），铜锌超氧化物歧化酶（Cu—ZnSOD）mRNA、锰超氧化物歧化酶（MnSOD）mRNA、谷胱甘肽过氧化物酶（GPx）mRNA的表达水平及其酶活性明显降低（P〈0．01）。结论：L—A职加重心肌损伤，机制可能是L—Arg增加ADM处理的大鼠心肌的NO含量，NO抑制Cu—ZnSOD mRNA、MnSOD mRNA、GPx mRNA表达增加，加重Cu—ZnSOD、Mn SoD和GPx活性的降低，致使活性氧增加而损伤心肌。     

Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats

Adriamycin is a potent anticancer agent, its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study aimed to investigate the possible protective role of the natural antioxidant silymarin on ADR-induced heart and kidney toxicity. Studies were performed on four groups of rats. 1--control group, 2--silymarin group (50 mg/kg), 3--adriamycin group (10 mg/kg), 4--adriamycin+silymarin group. On the third day after ADR injection, plasma was separated for determination of LDH, CPK, cholesterol and total lipids. 30 days after ADR injection, plasma was separated for determination of creatinine and urea levels. Frozen heart specimens (72 h) and frozen kidney specimens (30days) were used for estimation of lipid peroxides and GSH contents. Histopathological examinations of heart and kidney sections were also done. Pretreatment of ADR-treated rats with silymarin resulted in a significant decrease in the plasma CPK, LDH, creatinine and urea. On the other hand silymarin pretreatment did not change ADR-induced hyperlipidemia. Silymarin pretreatment significantly decreased the myocardial MDA contents. In addition, silymarin pretreatment normalized renal tissue contents of MDA and GSH. Histopathological examination of heart and kidney sections revealed that ADR caused only mild myocardial injury in silymarin pretreated rats. Also, silymarin pretreatment inhibited ADR-induced renal tubular damage in rats. These results have suggested that, silymarin ameliorated ADR-induced cardiotoxicity and protected against ADR-induced nephrotoxicity in male albino rats. The mechanisms of silymarin induced protection against ADR-induced toxicities were proved to be due to inhibition of lipid peroxidation and protection against GSH depletion.     

灵芝孢子粉对大鼠心肌缺血脂质过氧化损伤的影响

目的观察灵芝孢子粉对心肌缺血大鼠的干预作用及抗氧化损伤的药物疗效。方法将30只Wistar大鼠随机分为对照组、模型组及灵芝孢子粉治疗组,雌雄各半。对照组：常规饲养,不做其他处置。模型组：同对照组常规饲养3周后,行左冠状动脉前降支结扎建立心肌缺血模型后继续饲养1周。治疗组：灵芝孢子粉按2．5g／kg灌胃给药3周,再行左冠状动脉前降支结扎建立心肌缺血模型后,继续给药1周。动物处死取材后,观察心肌梗死面积,血清MDA含量及SOD活性变化。结果灵芝孢子粉治疗组明显缩小心肌梗死区面积,降低血清MDA含量,提高血清SOD活性。结论灵芝孢子粉对大鼠实验性心肌缺血具有保护性作用,其机制可能通过降低脂质过氧化损伤有关。     

Up-regulation of transforming growth factor-beta 1 in the spleen of aniline-treated rats

Aniline exposure produces selective toxicity to the spleen, leading to a variety of sarcomas in rats following chronic exposure. Fibrosis appears to be an important preneoplastic lesion of the spleen. However, early molecular events leading to splenic fibrosis are not known. Earlier studies have shown that aniline exposure in rats leads to excessive deposition of iron and increased lipid peroxidation in the spleen, which may produce changes in the expression of fibrogenic cytokines, such as transforming growth factor-beta 1 (TGF-beta 1), leading to splenic fibrosis. Therefore, this study was designed to establish whether aniline exposure leads to induction/overexpression of TGF-beta 1 and association of such induction with lipid peroxidation (oxidative stress) in the spleen. To achieve this, male Sprague-Dawley rats were given 1 mmol/kg/day aniline hydrochloride in water by gavage for 7 days, while controls received water only. Aniline treatment resulted in significant increases in spleen weight (97%), spleen-to-body weight ratios (104%), and splenocyte population (25%). Malondialdehyde-protein adducts, quantitated by a competitive ELISA, showed a 56% increase in the spleen of aniline-treated rats. TGF-beta 1, measured in the supernatants of cultured splenocytes by an ELISA specific for TGF-beta 1, showed a significant increase (60%) in the total TGF-beta 1 from aniline-treated rats. These increases were further confirmed by Western blot analysis, which showed approximately 2.5-fold increase in cell-associated TGF-beta 1 protein expression in aniline-treated rats. Furthermore, determination of TGF-beta 1 mRNA expression showed a 4-fold increase in the spleens of aniline-treated rats. These results suggest an association between formation of MDA-protein adducts and overexpression of TGF-beta 1 as a result of aniline insult, which together could promote splenic injury and fibrogenesis.     

Antioxidative and hepatoprotective effects of magnolol on acetaminophen-induced liver damage in rats

Acute liver failure (ALF), an often fatal condition characterized by massive hepatocyte necrosis, is frequently caused by drug poisoning, particularly with acetaminophen (N-acetyl-p-aminophenol/APAP). Hepatocyte necrosis is consecutive to glutathione (GSH) depletion and mitochondrial damage caused by reactive oxygen species (ROS) overproduction. Magnolol, one major phenolic constituent of Magnolia officinalis, have been known to exhibit potent antioxidative activity. In this study, the anti-hepatotoxic activity of magnolol on APAP-induced toxicity in the Sprague-Dawley rat liver was examined. After evaluating the changes of several biochemical parameters in serum, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were elevated by APAP (500 mg/kg) intraperitoneal administration (8 and 24 h) and reduced by treatment with magnolol (0.5 h after APAP administration; 0.01, 0.1, and 1 μg/kg). Histological changes around the hepatic central vein, lipid peroxidation (thiobarbituric acid-reactive substance/TBARS), and GSH depletion in liver tissue induced by APAP were also recovered by magnolol treatment. The data show that oxidative stress followed by lipid peroxidation may play a very important role in the pathogenesis of APAP-induced hepatic injury; treatment with lipid-soluble antioxidant, magnolol, exerts anti-hepatotoxic activity. Our study points out the potential interest of magnolol in the treatment of toxic ALF. Yen-Yi Ho and Ming-Tsung Lai contributed equally to this work.     

Synergistic effects of ferritin and propolis in modulation of beryllium induced toxicogenic alterations

Synergistic therapeutic potential of ferritin (5mg/kg, i.p.) and propolis (honeybee hive product; 200mg/kg, p.o.) was analyzed to encounter the beryllium induced biochemical and ultra morphological alterations. Female albino rats were exposed to beryllium nitrate (1mg/kg, i.p.) daily for 28 days followed by treatment of above mentioned therapeutic agents either individually or in combination for five consecutive days. Exposure to beryllium increased its concentration in serum, liver and kidney and significantly altered the activities of CYP2E1 and CYP1A2 enzymes, microsomal lipid peroxidation and microsomal proteins. Activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, protein, creatinine and urea in serum as well as hemoglobin and blood glucose level; activity of acid phosphatase, alkaline phosphatase, adenosine triphosphatase, glucose-6-phosphatase and succinic dehydrogenase, total triglycerides, total cholesterol, total protein contents, glycogen contents, lipid peroxidation and glutathione level in liver and kidney were significantly altered after beryllium administration. Beryllium exposure severely altered ultramorphology of liver and kidney that proved its toxic consequences at cellular level. Ferritin in combination with propolis dramatically reversed the alterations of these variables towards control in a synergistic manner concluding its beneficial effects over monotherapy in attenuating beryllium induced systemic toxicity.     

脂肪乳预处理对大鼠静脉注射布比卡因与罗哌卡因致心脏毒性的影响

目的：研究脂肪乳对布比卡因、罗哌卡因导致的大鼠心脏毒性的影响,并初步探讨其机制。方法：SD成年雄性大鼠72只,体重200～280g,随机分为5组,空白对照组（A组,n=8）、布比卡因对照组（B组）、布比卡因＋脂肪乳组（C组）、罗哌卡因对照组（D组）、罗哌卡因＋脂肪乳组（E组）,B、C、D、E每组再分为致死组（1组）和取材组（2组）（每组n=8）。A组经大鼠静脉泵入0.9%氯化钠溶液3ml/（kg·min）,6min后开胸取心,B、C、D、E组大鼠经静脉泵入0.9%氯化钠溶液或脂肪乳3ml/（kg·min）,共5min,再以2mg/（kg·min）速度泵入相应的局麻药,取材组泵入局麻药1min开胸取心肌,致死组泵入局麻药致心跳停搏。持续监测平均动脉压和心率,记录大鼠出现心律失常、心跳停止的时间及各对应时相局麻药的累积剂量,A组及取材组测心肌ATP含量。结果：C1组出现心律失常和心跳停止的时间比B1组明显延迟、布比卡因用量大于B1组,差异均有统计学意义（P〈0.001）,而D1组与E1组之间差异无统计学意义。各组心肌ATP酶含量比较,A组〉D2组〉C2组〉B2组,任意两组比较差异均有统计学意义（P〈0.001）,而D2、E2组之间差异无统计学意义。结论：脂肪乳能够减轻布比卡因的心脏毒性,其机制可能与增加心肌ATP含量有关,但脂肪乳对罗哌卡因的心脏毒性无明显作用。     

褪黑素对阿霉素所致心脏毒性的保护作用的实验研究

目的 体内研究抗氧化剂褪黑素对阿霉素所致心肌毒性的保护作用.方法 制备乳腺癌大鼠模型,随机分为空白组（Blank组）、溶酶组（Diss组）、阿霉素组（ADM组）、褪黑素组（MLT组）和褪黑素联合阿霉素组（M＋A组）5组.分别检测心肌组织中脂质过氧化物（LPO）,超氧化物歧化酶（SOD）谷胱甘肽过氧化物酶（GSH-Px）浓度,处死各组部分小鼠,取心肌组织分别于光镜和电镜下观察,每组剩余小鼠比较1个月后生存率.结果 共制备乳腺癌大鼠130例,成功116例;Blank组、Diss组和MLT组心肌中LPO、SOD和GSH-Px含量无显著差别,ADM组LPO含量明显增高,SOD和GSH-Px显著低于空白组,而M＋A组较ADM组LPO明显降低,差异有统计学意义（P＜0.05）,SOD、GSH-Px显著增高,差异有统计学意义（P＜0.05）;光镜和电镜下可见：Blank组、Diss组和MLT组大鼠的心肌组织均未发现异常,ADM组可见程度不一的心肌损伤,M＋A组心肌损伤则明显减轻;1月生存率以MLT组和M＋A组最好,2组比较差异有统计学意义（P＜0.05）,ADM组与Diss组和Blank组间未见差异.结论 褪黑素对阿霉素的抗乳腺癌作用具有一定增敏作用,与阿霉素同时应用可能通过降低对心肌的氧化损伤而减轻其造成的心肌损伤.     

硒对氯化汞免疫毒性的影响及其机理

采用免疫毒理学和生化毒理学方法，研究了亚硒酸钠对氯化汞免疫毒性的影响及作用机理。结果表明：氯化汞染毒的ＩＣＲ小鼠血中碳廓清率、ＳＲＢＣ致敏小鼠的ＤＴＨ反应、ＤＮＣＢ所致的ＤＣＨ反应、血清溶血素形成和免疫器官脏体比均明显低于对照组，预先投以亚硒酸钠后，再给同剂量的氯化汞的小鼠上述各指标都有不同程度提高。免疫器官脂质过氧化作用，汞组与对照组比较：脂质过氧化物含量明显升高，而谷胱甘肽过氧化物酶活性明显降低；硒汞组与汞组比较：脂质过氧化物含量明显降低，而谷胱甘肽过氧化物酶活性明显升高。上述结果提示：亚硒酸钠对氯化汞所致的免疫毒性和免疫器官的脂质过氧化损伤具有保护作用