Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

氧化反应对糖尿病大鼠造影剂肾病发生的影响

目的 :探讨氧化反应对糖尿病大鼠造影剂肾病发生的影响。方法 :建立SD大鼠糖尿病动物模型 ,8w后分 3组 :正常对照组 (SD组 )、糖尿病对照组 (DM组 )和糖尿病 +造影剂组 (CM组 )。其中CM组大鼠经尾静脉一次性注入 76%泛影葡胺 ( 10ml/kg体重 ,3gI(iodine) /10ml) ,DM组注射等量生理盐水。 3d后收集血标本检测血肌酐、血尿素氮 ;取肾脏组织 ,测定肾组织丙二醛 (MDA)与超氧化物歧化酶 (SOD)的含量。结果 :与正常对照组相比 ,糖尿病组 (DM组 )的MDA含量与SOD活性均明显升高 (P <0 .0 5 ) ;糖尿病大鼠注射造影剂 (CM组 ) 3d后MDA含量明显增加 ,SOD活性明显降低 ,与DM组差异有显著性 (P <0 .0 5 )。结论 :糖尿病大鼠造影剂肾病发生时 ,肾脏组织产生过氧化物增多、清除能力下降 ,提示氧化反应对糖尿病造影剂肾病的发生起一定作用     

活血软坚方对大鼠膜性肾小球肾炎肾小管间质损害影响的实验研究

目的：观察活血软坚方对大鼠膜性肾小球肾炎（MN）肾小管间质损害的影响，并探讨活血软坚中药对MN伴发小管间质损伤的作用机制。方法：用阳离子化牛血清白蛋白复制大鼠MN模型，将实验动物随机分为正常组、模型组、雷公藤组、治疗组，观察24h尿蛋白、血浆白蛋白、胆固醇、三酰甘油、血肌酐、尿素氮等生化指标，并对肾组织进行光镜、电镜、免疫荧光观察；采用RT—PCR的方法检测ColⅠmRNA和ColⅢmRNA的表达。结果：本方能明显降低蛋白尿及血清胆固醇、三酰甘油、血肌酐、尿素氮，升高血清白蛋白，减少免疫复合物沉积，改善肾小球及肾小管的病理损伤。结论：活血软坚方能减轻尿蛋白对肾小管的损伤，减少细胞外基质在肾间质的积聚，减轻肾脏病理损伤，从而达到保护肾功能的作用。     

A mathematical analysis of kinetic characteristics of oxidative phosphorylation in the animal brain under hypoxic conditions

The kinetic dependence of the rate of oxidative phosphorylation (ADP/t) on the concentration of exogenous ADP has been mathematically analyzed in the brain mitochondria. This relationship has been approximated by a mathematic model under various vital conditions. We propose an analytical approach to calculating the characteristics of oxidative phosphorylation and predicting the kinetics of oxidative ATP synthesis in brain mitochondria of animals subjected to hypoxia.     

放射性~(125)I粒子组织间植入对家兔尿道损伤的实验研究

目的:研究不同剂量的放射性125I粒子对家兔尿道的放射性损伤。方法:麻醉下将放射性125I粒子植入雄性家兔尿道旁1.0cm处。125I粒子的放射性粒子活度分别为14.8MBq(A组)、29.6MBq(B组)和44.4MBq(C组),对照组(D组)仅尿道旁种植相当于粒子大小无放射性的无菌铅管1粒。植入后4周,摄尿道片,观察粒子位置等情况;原手术切口切开,取放射粒子周围2.0cm范围内的家兔尿道组织作肉眼、光学显微镜和电子显微镜观察,进行放射性损伤的评价。结果:术后4周,肉眼及光学显微镜观察,实验组与对照组粒子周围的尿道粘膜、粘膜下及肌层所见基本一致;C组少部分电镜视野中观察到尿道上皮胞质出现较多空泡变性、空化、嵴稀疏等超微结构的损伤。光镜下尿道入射性损伤评分,A、B、C、D组分别为(2.20±0.18)、(2.23±0.15)、(2.27±0.10)、(2.10±0.17)分,A、B、C组与D组相比,差异无显著性(P>0.05)。对线粒体作FlaMeng半定量分析,A、B、C、D各组评分分别为(1.23±0.13)、(1.34±0.25)、(1.41±0.30)、(1.12±0.13)分,A、B、C各组与D组(对照组)相比,差异无显著性(P>0.05)。结论:放射性125I粒子对尿道放射性损伤随粒子的放射性活度的增加而逐渐加重,呈明显的放射性活度效应关系;正常剂量的放射性粒子对尿道的损伤是很轻微的,是安全可行的。     

化疗药物性静脉炎及渗漏损伤的动物实验模型研究概况

化疗药物性静脉炎及渗漏损伤的动物实验模型是研究体内化疗药物性静脉炎及渗漏损伤的发病机制和评价各种治疗方法的重要条件。化疗药物性静脉炎及渗漏损伤的实验研究进展缓慢,其主要原因是缺乏理想的动物模型。依文献报道,化疗药物性静脉炎模型主要以大白兔耳缘静脉注射长春瑞滨等化疗药物为多见,化疗药物渗漏损伤模型主要以大鼠及大白兔背部皮下注射盐酸阿霉素等化疗药物为多见。文章就近年来常用的一些化疗药物性静脉炎及渗漏损伤的动物模型综述如下。     

单细胞凝胶电泳技术在生殖细胞DNA损伤检测中的应用

单细胞凝胶电泳技术(SCGE)是一种快速检测单个细胞DNA损伤的实验技术,在生殖细胞DNA损伤的检测中广泛应用。本综述系统介绍了SCGE在睾丸生精细胞、支持细胞、间质细胞、卵巢细胞以及卵母细胞等生殖细胞DNA损伤检测中的应用现状,并对SCGE在生殖毒性检测中的发展提出了展望。     

Increase in levels of total free fatty acids in rat brain regions following 3-nitropropionic acid administration

Acute exposure to a neurotoxin, 3-nitropropionic acid (3-NPA), in rats results in an increase in total free fatty acid (FFA) concentration in selective brain regions. We investigated the effect of 3-NPA administration on the cerebral concentrations of FFA used as a marker of oxidative stress. Rats (n=3/group) were dosed subcutaneously (s.c.) either with a vehicle (phosphate buffer) or 3-NPA in phosphate buffer at 30 mg/kg body weight. Animals were sacrificed after 1, 2, 3, and 6 h of injection. Brains were then dissected into frontal cortex (FC), caudate nucleus (CN), and hippocampus (HIP). The concentration of total FFA increased from 130 to 300% within 1–2 h after 3-NPA injection in all brain regions when compared with the baseline level obtained from the control rats and taken as 100%. In CN, FFA returned to the baseline level within 3 h of treatment. However, in FC and HIP the concentration of FFA remained significantly elevated above the baseline until 6 h. The released FFA provide a substrate for free radicals formation. The results of this study suggest a role of oxidative stress in the mechanism of 3-NPA toxicity.     

In vitro effect of zinc on oxidative changes in human semen

Summary The in vitro effect of zinc on superoxide anion (O₂^?) generation and on experimentally induced lipid peroxidation (LPO) in spermatozoa of infertile men was investigated. Washed spermatozoa pre-incubated for 30 min at 37°C in the presence of 1 or 3 mmol l^-1 zinc, released less superoxide anions (P<0.03 and P<0.02, respectively; n=9) than the untreated spermatozoa. Similar results were obtained using activated polymorphonuclear leukocytes (1 times 10⁶ cells ml^-1) in the presence of 1 or 3 mmol l^-1 Zn (P<0.001 and P<0.0002, respectively; n=9). The in vitro evidence of the inhibitory effect of zinc on O₂^? generation by human spermatozoa and leukocytes indicates that zinc may act in vivo as a scavenger of excessive O₂^? production by defective spermatozoa and/or leukocytes in semen after ejaculation. A significant stimulatory effect of Zn (3 mmol l^-1) on iron-induced lipid peroxidation, measured by the formation of thiobarbituric acid reactive substances (TBARS), was detected in the spermatozoa of 16 normo- and 17 asthenozoospermic males (P<0.0001 and P<0.001, respectively). In 11 samples with sperm concentration 20.3±2.1 times 10⁶ ml^-1, exhibiting initial TBARS concentration two times higher than in normo-and asthenozoospermic samples (40.5±2.4 vs. 17.1±1.1 and 28.5±4.1 nmoles TBARS 10^-8 spermatozoa), no effect of zinc on the LPO rate was found. The observed inhibitory effect of zinc on superoxide anion regardless of the initial O₂^? level and stimulatory effect of zinc depending on the initial LPO rate in human spermatozoa suggests that this metal ion participates in the oxidative changes occurring after ejaculation and thus may modulate the properties of germ cells.