白藜芦醇对阿霉素诱导心脏毒性保护作用的研究进展

阿霉素是多种血液恶性肿瘤和实体瘤的主要治疗药物。然而,其临床应用受剂量相关性心脏毒性的限制。阿霉素诱导心脏毒性的机制可能涉及多种信号通路,包括自由基产生、钙超载、线粒体功能障碍、细胞凋亡和自噬。已有研究表明白藜芦醇与阿霉素联合用药可以预防心脏毒性,并且对肿瘤细胞发挥协同治疗效应。主要对白藜芦醇的心脏毒性保护作用进行综述,阐明白藜芦醇在阿霉素诱导心脏毒性中保护作用的机制。     

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats

Context: Doxorubicin (Dox) is one of the most active chemotherapeutic agents used to treat various types of cancers. Its clinical utility is compromised due to fatal cardiac toxicity characterized by an irreversible cardiomyopathy.

Objective: This study evaluates the cardioprotective potential of naringin (NR) against Dox-induced acute cardiac toxicity in rats.

Materials and methods: Male Wistar rats were randomly divided into five groups. NR (50 and 100?mg/kg) was administered intraperitoneally (i.p.) daily from 0 to 14?d. Doxorubicin (15?mg/kg, i.p.) was given as a single dose on the 10th day. On the 14th day, all animals were sacrificed and oxidative stress parameters that include malondialdehyde (MDA), glutathione (GSH) level, superoxide dismutase (SOD), catalase (CAT) activities, and all mitochondrial complexes (I-IV) activities were evaluated along with histopathological studies of the heart.

Results: Doxorubicin-induced cardiotoxicity was confirmed by increased (p?<?0.05) MDA, decreased (p?<?0.05) GSH levels, SOD, and CAT activities, mitochondrial complexes (I–IV) activities in the heart tissue. NR (100?mg/kg) showed cardioprotection as evident from significant decreased MDA (p?<?0.001) level, raised (p?<?0.001) GSH level, SOD and CAT activities and increased mitochondrial complexes I (p?<?0.01), II (p?<?0.001), III (p?<?0.001), and IV (p?<?0.05) activities. Further, Dox-induced cardiotoxicity was confirmed by histopathological studies. These obtained results indicated the protective role of NR against Dox-induced cardiac toxicity in rats.

Conclusion: NR can be used in combination with Dox due to its high cardioprotective effect against Dox-induced cardiomyopathy.     

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.     

Protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity

Adriamycin is a potent antitumor drug that is known to cause severe cardiotoxicity. This study examined the protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity. Calceolarioside significantly inhibited the adriamycin induced cell death and caspase-3 activation, which may be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Calceolarioside increased the expression of the antioxidant molecules and decreased the level of intracellular reactive oxygen species. Catalase, glutathione, N-acetylcysteine, Mannitol and Mn-TBAP (manganese (III) tetrakis-(4-benzoic acid) porphyrin) significantly inhibited the H9c2 cell death induced by adriamycin. Calceolarioside significantly inhibited H9c2 cell death, and was more effective than that observed with the other antioxidants, including probucol, ascorbic acid, and alpha-tocopherol. Overall, these results suggest that calceolarioside can inhibit adriamycin-induced apoptosis in H9c2 cardiomyocyte by inhibiting the generation of reactive oxygen species. Calceolarioside may be a potential candidate agent that inhibits cardiomyocyte-toxicity in adriamycin-exposed patients.     

The protective effect of prostacyclin on adriamycin-induced apoptosis in rat renal tubular cells

Adriamycin-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. Adriamycin-induced apoptosis of renal tubular cells has been reported in adriamycin-treated rats. In addition, prostacyclin (PGI(2)) is known to have various protective effects on many kinds of cells. To investigate the protective effect of PGI(2) on cells undergoing adriamycin-induced apoptosis, this study selectively augmented PGI(2) production via adenovirus-mediated transfer of genes for cyclooxygenase-1 (COX-1) and prostacyclin synthase (PGIS) (two key enzymes of PGI(2) synthesis) to renal tubular cells. This PGI(2) overexpression protected rat renal tubular cells from adriamycin-induced apoptosis. Ad-COX-1/PGIS transfection was found to reduce the adriamycin-stimulated activities of caspase-3 and caspase-9, inhibit adriamycin-induced release of cytochrome c, elevate the expression of Bcl-x(L), and suppress the activation and translocation of nuclear factor-kappaB (NF-kappaB) in adriamycin-treated renal tubular cells. Our results reveal that selective augmentation of PGI(2) production can protect rat renal tubular cells from adriamycin-induced apoptosis via the NF-kappaB signaling pathway. This implies the therapeutic potential of combined COX-1 and PGIS gene transfer in gene therapy for chronic renal diseases.     

丙泊酚对内毒素性大鼠急性肺损伤的保护作用

目的探讨丙泊酚对内毒素(LPS)性大鼠急性肺损伤(ALI)的影响。方法 60只SD大鼠随机均分5组:A组为ALI模型;B1、B2、B3组静脉注射LPS5mg/kg后,再分别输注丙泊酚5、10、15mg.kg-1.h-1;C组为假手术对照。放血处死大鼠,右肺HE染色,左肺测定湿干重比;分离外周血中性粒细胞(PMN),流式细胞仪检测PMN凋亡。结果与C组比较,A组肺部损伤严重,肺泡损伤比值(IQA)显著增加、PMN的凋亡率显著降低(P<0.05);与A组比较,丙泊酚处理组肺损伤程度减轻,IQA降低,凋亡显著增加,且呈剂量依赖性(P<0.05)。结论丙泊酚减轻LPS诱导的大鼠ALI,这可能与促进PMN的凋亡有关。     

The protective effect of C-phycocyanin on paraquat-induced acute lung injury in rats

To investigate the potential protective effect of C-phycocyanin (PC) on paraquat (PQ)-induced acute lung injury, rats were divided into control, PQ-treated and PQ + PC-treated groups. Rats in PQ-treated group were orally administered with 50 mg/kg PQ, and rats in PQ + PC-treated group were intraperitoneally injected with 50 mg/kg PC after administration of PQ. At 8, 24, 48 and 72 h after treatments, GSH-Px and SOD activities, MDA levels in plasma and BALF, HYP, NF-κB, IκB-α and TNF-α contents in lung tissues were measured. The pathological changes in lung were observed. After treatment with PC, the levels of MDA and the relative contents of NF-κB and TNF-α were significantly decreased, the activities of GSH-Px and SOD and the relative contents of IκB-α were significantly increased. The degree of rat lung damage was obviously reduced in PQ + PC-treated group. The results suggested that PC treatment significantly attenuated PQ-induced acute lung injury.     

A possible protective role for reduced glutathione in aflatoxin B1 toxicity: effect of pretreatment of rats with phenobarbital and 3-methylcholanthrene on aflatoxin toxicity.

To determine if brain-acetylcholinesterase (AChE) inhibition in a marine teleost Lagodon rhomboides (pinfish) by an organophosphate pesticide (naled) is specific enough to diagnose anticholinesterase poisoning, brain-AChE inhibition by sublethal exposure in seawater was compared to brain-AChE inhibition caused by lethal exposure. A sublethl exposure did not inhibit brain-AChE as much as lethal exposure in periods of 24, 48, and 72 hr. Consistent levels of inhibition (84–89% inhibition) occurred when 40–60% of an exposed population of pinfish was killed. This correlation of brain-AChE inhibition with exposure and death in a fish population shows that brain-AChE measurements are of value in diagnosing anticholinesterase poisoning in a marine fish.     

Cardio protective effect of glucose-insulin infusion on acute digoxin toxicity in rat

We recently observed a case of digoxin and insulin self-poisoning without cardiac repercussion. We raised the hypothesis that insulin may have a cardio-protective effect in case of digoxin toxicity. We have therefore evaluated the effect of glucose-insulin infusion on mortality and ECG abnormalities during acute digoxin toxicity in rats. Before and after a hyperinsulinemia-euglycemia clamp, rats in glucose-insulin-digoxin (GID) group (n=10) received an intravenous infusion of 12ml/h or 2,5ml/h digoxin (0.25mg/ml) respectively until death occured. Animals receiving digoxin or saline solution intravenously served as control (n=10). ECG recording was performed in all animals over the entire period. Serum insulin and digoxin concentrations were measured by ELISA method after digoxin administration. When digoxin was administered after the clamp, all animals in GID group were alive, whereas 80% of animals in the digoxin group were dead (p<0.001) after 30min. The administration of Digoxin provoked rapid death of rats in the digoxin group in 15+/-12min whereas in GID group the survival period was significantly increased to 38+/-3min (p<0.001). Twenty minutes after digoxin administration, P waves disappeared for 78% of animals in digoxin group while they were present in all rats of GID group (p<0.001). Animal death occurred after a digoxin infusion volume of 7.7+/-0.6ml and 3.0+/-2.4ml in GID and digoxin group respectively (p<0.001). Five minutes after digoxin administration, potassium plasmatic level increased significantly in digoxin group as compared to GID group: 7.1+/-2mmol/l versus 4.4+/-0.4mmol/l (p<0.001). When digoxin was infused before the clamp, 40% of animals in GID group were alive after 180min and the other 60% died after 137+/-40min whereas death of rats in the digoxin group occurred within 80+/-10min (p<0.001). The death of animals was preceded by the P waves disappearing. Thirty minutes after digoxin administration, the potassium plasmatic level increased significantly in the digoxin group as compared to the GID group: 6.9+/-0.5mmol/l versus 4.9+/-0.3mmol/l (p<0.001). At the time of death, both volume of digoxin infusion and serum digoxin concentration were increased in GID group as compared to digoxin group: 5.7+/-1.6ml versus 3.3+/-0.4ml (p<0.001) and 10.7+/-8.3mg/l versus 8.5+/-4.6mg/l. CONCLUSION: Glucose-insulin infusion delayed the abnormalities in cardiac conduction and improved rat survival after acute digoxin toxicity. These results suggest a cardioprotective effect of insulin in case of acute digoxin toxicity.     

Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats

Context: Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species.

Objective: This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats.

Materials and methods: Male Sprague–Dawely rats were divided into four groups. Group I was control. Group II received Pro (70?mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15?mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity.

Results: Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes.

Discussion and conclusion: These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.     

Hyperhydrating effect of acute administration of angiotensin II in rats.

Water intake, urine output, and fluid exchange (water intake less urine output) were measured in rats at hourly intervals for 7 hours and at 24 hours following acute administration of angiotensin II (AII, 200 micrograms/kg SC). AII induced the expected abrupt increase in water intake and a more gradual increase in urine output. The change in fluid exchange (fluid exchange of the AII-treated group less fluid exchange of controls) became positive within the first hour after treatment with AII, decreased linearly with time, and reached 0 at approximately 10 to 12 hours after treatment with AII. When AII was administered intracerebroventricularly (50 ng), similar results were observed. In this case, the change in fluid exchange (delta F) reached 0 in about 6 hours. Imposition of a water load (1% of body weight, IP) on the group receiving AII SC failed to affect the time required for delta F to reach 0 if the water load was disregarded. However, inclusion of the load as a part of intake extended the time the rats remained in positive fluid balance beyond that of the nonloaded, AII-treated control group. In the case of the larger water load (3% of body weight, IP), delta F returned to that of controls in about 4 to 5 hours if the water load was disregarded. However, inclusion of the load as part of intake extended the period of hyperhydration well beyond that of both the nonloaded, AII-treated group and the AII-treated group given the 1% load.(ABSTRACT TRUNCATED AT 250 WORDS)     

The comparative acute toxicity of two cardiac glycosides in adult and newborn rats

In comparison with adult rats, the cardiac glycosides (digitoxin and proscillaridin) have been shown by LD50 determinations to be 200–1000 times more toxic to 7-day-old rats. This was not due to major differences in the rate of intestinal absorption. Reversal of toxicity with respect to sex was observed in adult rats, males being more sensitive to proscillaridin and females more sensitive to digitoxin.     

益母草提取物对阿霉素心肌损伤的防护作用

目的：研究益母草提取物对阿霉素所致的心肌受损细胞的保护作用。方法：以MTT法将H9C2心肌细胞置于（36.5±0.5）℃,95%空气加5%二氧化碳混合气体中培养。实验组心肌细胞培养液中加益母草提取液和阿霉素;对照组加阿霉素;对照空白组两者都不加。结果：实验组细胞存活率为63.4%,对照组细胞存活率为48.5%,组间差异有统计学意义（P<0.05）。结论：益母草提取物对阿霉素所致的心肌受损细胞具有保护作用。     

柚皮苷激活Maxi K对糖尿病心脏的保护作用

目的探讨柚皮苷(naringin, NA)通过激活大电导钙激活钾离子通道(the large conductance Ca;activated K;channels, Maxi K)对糖尿病心肌病的保护作用。方法高脂饲料喂养SD大鼠,随后腹腔注射链脲佐菌素(streptozotocin, STZ)建立糖尿病大鼠模型。造模后随机分为模型组(DCM),柚皮苷治疗组(NA),柚皮苷+Maxi K特异性抑制剂治疗组(NA+PAX),每组8只大鼠。治疗组大鼠连续给药12周,定期检测血糖。结束后观察大鼠心功能、形态及纤维化改变;并检测心脏Maxi K的α及β亚基变化。结果超声显示NA可部分恢复大鼠心功能,而特异性阻断Maxi K后,NA对心脏的保护作用明显下降;纤维化分析显示NA治疗后可降低大鼠胶原蛋白及纤连蛋白表达,该作用可被PAX部分逆转;而Western blot结果显示Maxi Kα及β亚基在DCM组表达下降,NA治疗后无明显改变。结论柚皮苷通过促进细胞膜表面Maxi K通道开放而非增加其表达产生对糖尿病大鼠的心脏保护作用。     

山莨菪碱对横纹肌溶解致急性肾损伤大鼠保护作用的研究#br#

目的　观察山莨菪碱对横纹肌溶解引发急性肾小管上皮细胞溶酶体相关膜蛋白2（LAMP2）和组织蛋白酶B（Cathepsin B）表达的影响并探讨其机制。方法　63只雄性SD大鼠随机均分为对照组、模型组和给药组。模型组和给药组采用甘油肌注法建立横纹肌溶解致急性肾损伤大鼠模型,给药组建模前腹腔注射山莨菪碱（1 mg/kg）。甘油肌注后不同时点,HE染色观察肾组织病理学变化;检测肾功能指标［尿素氮（BUN）、肌酐（Scr）、肌酸激酶（CK）］、血清肌红蛋白（Mb）水平及肾组织中超氧化物歧化酶（SOD）、丙二醛（MDA）含量。甘油肌注诱导急性肾损伤24 h时,采用免疫组化法和Western blot法检测肾组织中LAMP2、Cathepsin B、Megalin蛋白的表达。结果　HE染色示模型组大鼠发生明显肾脏损伤,山莨菪碱给药后肾脏损伤情况明显改善。模型组在甘油肌注24 h和48 h的Scr、12 h和24 h的BUN、6 h的CK、24 h的Mb均高于对照组,而给药组上述各时点的指标水平均低于模型组（P＜0.05）。给药组甘油肌注6 h和12 h的MDA含量低于模型组,而SOD活性高于模型组（P＜0.05）。甘油肌注24 h时,免疫组化和Western blot结果显示,模型组LAMP2、Cathepsin B、Megalin蛋白表达水平高于对照组,而给药组LAMP2、Cathepsin B、Megalin蛋白表达水平均低于模型组（P＜0.05）。结论　山莨菪碱可能通过减少Mb的生成,下调肾组织内LAMP2和Cathepsin B的表达以及抑制氧化应激反应发挥其肾脏保护作用。     

The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats.

The iron chelating activity of deferoxamine (DFO) has been exploited to obtain protection against the peroxidative damage in rat heart which was induced by the administration of an acute dose of doxorubicin (DXR, 25 mg x kg(-1), i.v.). The peroxidative lesions were evaluated both biochemically and histopathologically, 48 h after DXR administration. Abnormal biochemical changes including a marked increase in the levels of serum creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH), as well as elevated serum creatinine, blood urea nitrogen and transaminases (ALT and AST) levels were observed. Myocardial tissue from DXR treated rats showed a marked increase in malondialdehyde (MDA) production and depletion of reduced glutathione (GSH) contents. Similar results were also observed in both kidney and liver tissues. Pretreatment of rats with DFO, given i.p. 30 min prior to DXR injection, substantially reduced the peroxidative damage in the myocardium, hepatic and renal tissues and markedly lowered the serum CK-MB, LDH and the other biochemical variables. The protective effects obtained by DFO administration, however, were not complete and did not reach those of the control group. The significant protection against DXR-induced cardiomyopathy by DFO was evident from the histopathological findings observed by light microscopy. DFO at a dosing level equivalent to 10-fold of that of DXR was useful to obtain protective effects. Higher DFO dosing levels did not, however, show more improvement in the DXR-induced cardiotoxicity and at the same time exhibited hepatoxicity which was confirmed by microscopical examination. These results strongly suggest that DFO protects against acute DXR-induced cardiotoxicity in a dose-dependent manner with recognizing the presence of mild DFO-related biochemical and cytological hepatic toxicity.     

丁酸钠对重症急性胰腺炎大鼠肺损伤的保护作用

目的探讨丁酸钠对大鼠重症急性胰腺炎（SAP）合并肺损伤的治疗作用。方法牛磺胆酸钠逆行胰胆管注射制作SAP动物模型,30只SD大鼠分成对照组、SAP组及丁酸钠（NaB）治疗组,检测胰腺湿/干重比值、胰腺及肺脏病理改变、肺脏细胞凋亡情况。结果 NaB治疗组肺组织湿/干重比值下降;NaB治疗组胰腺及肺组织病理改变明显减轻。NaB治疗组肺组织细胞凋亡指数显著高于SAP组。结论 NaB可以有效诱导SAP大鼠肺组织细胞发生凋亡,减轻肺损伤。     

Evaluation of protective effect of rutin on lead acetate-induced testicular toxicity in Wistar rats

In this study, the effect of rutin (RT) was investigated on lead-induced testis tissue damage in rats. Oral administration of rutin (50?mg/kg) effectively inhibited the levels of marker enzymes and antioxidant enzymes as compared with lead acetate-treated group. Antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and histopathological changes of testes were investigated. Lead acetate decreased the levels of SOD, CAT, GPx, and GST compared with the control group. Light microscopic analyses revealed that lead acetate induced several histopathological changes in testis tissue. In the RT-treated group, there were statistically significantly decreases in antioxidant enzyme activities and pathological changes in the tissue. The results suggest that RT possesses significant potential in reduced lead acetate-induced testicular toxicity.     

磷酸肌酸钠对小鼠阿霉素心肌损伤的保护机制初探

目的:探讨磷酸肌酸钠对小鼠阿霉素心肌损伤的保护作用。方法:雌性BALB/C小鼠60只,建立阿霉素心肌病模型,随机分为磷酸肌酸钠组、阿霉素组、正常对照组。观察小鼠的一般情况,血清中心肌酶TnI、N端前脑钠肽(NT-proB-NP)及心肌组织中超氧化物歧化酶(SOD)、丙二醛(MDA)、ATP酶及乳酸脱氢酶(LDH)的变化,心肌组织HE染色病理变化。结果:与阿霉素组比较,磷酸肌酸钠组LDH、MDA明显降低(P<0.05),SOD和ATP酶活力明显升高(P<0.05);血清NT-proBNP及TnI水平降低(P>0.05)。阿霉素组心肌组织出现明显的水肿、变性。结论:磷酸肌酸钠通过减少氧自由基对阿霉素所致的心肌损伤具有保护作用。