梅花鹿鹿茸总蛋白对顺铂诱导肾损伤小鼠的保护作用及其机制

目的研究梅花鹿鹿茸总蛋白(SVPr)对小鼠肾毒性的保护作用及其机制。方法 40只ICR小鼠随机分为5组,即正常对照组(ig蒸馏水)、模型组(ig蒸馏水7 d,第7天ip给予顺铂25 mg·kg~(-1)造模,随后ig蒸馏水3 d)及SVPr 5,10和20 mg·kg~(-1)给药组(ig给予SVPr 7 d,末次给药2 h后ip给予顺铂25 mg·kg~(-1),随后ig给予SVPr治疗3 d)。用试剂盒方法测定小鼠肾功能指标尿素氮(BUN)和血肌酐(SCr),氧化应激反应指标超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽(GSH)和丙二醛(MDA)及炎症因子肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)水平,Western蛋白印迹法测定胱天蛋白酶3、促凋亡蛋白(Bax)和抗凋亡蛋白(Bcl-2)表达,HE染色观察肾组织病理变化。结果 SVPr 5,10和20 mg·kg~(-1)可显著降低SCr,BUN,MDA,TNF-α和IL-6的水平及活化的胱天蛋白酶3和Bax表达(P<0.05,P<0.01),增加SOD,CAT和GSH的活性及Bcl-2的表达(P<0.05,P<0.01);改善肾组织病理变化。结论 SVPr改善顺铂诱导的小鼠肾毒性,其机制与抑制氧化应激、炎症反应及细胞凋亡有关。     

卡维地洛对顺铂致大鼠急性肾衰竭的预防作用

目的观察卡维地洛对顺铂致大鼠急性肾衰竭的影响,并初步探讨其作用机制。方法Wistar大鼠给予卡维地洛5,15和30mg.kg-1,ig,每日1次,连续6d,于d3单次ip顺铂10mg.kg-1。于d6测定血清尿素氮(BUN)和肌酐(SCr)含量,尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)活性,肾组织丙二醛(MDA)含量、超氧化物歧化酶(SOD)及谷胱甘肽过氧化物酶(GSH-Px)活性;苏木素-伊红染色观察肾脏病理改变。结果顺铂组大鼠血清BUN和SCr含量升高,尿NAG活性升高,肾组织MDA水平增加,SOD和GSH-Px水平降低,肾脏病理改变明显。预先给予卡维地洛5和15mg.kg-1可明显逆转上述改变,但加大剂量至30mg.kg-1时效应反而降低。结论在一定剂量范围内,卡维地洛可能通过减少活性氧产生,增加抗氧化酶活性而减轻顺铂所致急性肾衰竭。     

顺铂对不同性别小鼠肝肾毒性的比较研究

目的观察顺铂诱导不同性别小鼠所致急性肝肾损伤差异,并进一步探讨不同性别小鼠肝肾脏中谷胱甘肽(GSH)含量差异。方法选择ICR雌性和雄性小鼠,分别一次性腹腔注射0、10、20和40 mg/kg的顺铂,通过体重的变化确定小鼠的中毒情况,通过检测血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的活性来观察顺铂诱导的急性肝损伤差异,通过检测血清尿素氮(BUN)的含量来确定顺铂诱导的急性肾损伤差异,采用比色法检测雌雄小鼠肝肾中GSH的含量。结果顺铂能够引起不同性别的小鼠体重下降(P0.01),血清ALT和AST水平明显上升(P0.001,P0.01),但是没有性别差异;顺铂诱导BUN明显升高(P0.05,P0.001),且具有性别差异(P0.05,P0.01,P0.001)。顺铂(10和20 mg/kg)引起雄性肝脏中GSH含量明显升高(P0.01,P0.001),而在40 mg/k降低,与阴性对照组没有明显区别。顺铂(40 mg/kg)引起雌性肝脏GSH含量明显升高(P0.001)。顺铂引起雌雄小鼠肾脏GSH含量明显升高(P0.05,P0.01,P0.001),且不同性别的差异也有统计学意义(P0.05)。结论顺铂能够诱导明显的急性肝肾损伤。其中诱导的肝损伤在雌雄小鼠体内并无差异,而顺铂引起的肾损伤在雄性小鼠体内比雌性小鼠更严重。在毒性剂量下,GSH含量在小鼠肝脏没有性别差异,而肾脏具有性别差异,其中在雌性小鼠中GSH含量明显高于雄性。     

山楂酸对顺铂所致大鼠肾毒性的保护作用

目的探讨山楂酸对顺铂急性肾毒性的保护作用及作用机制。方法 40只SD雄性大鼠随机分为对照组(予等剂量生理盐水)、顺铂组(顺铂5 mg·kg^(-1))、山楂酸组(山楂酸40 mg·kg(-1))、山楂酸组(山楂酸40 mg·kg^(-1))、顺铂(5 mg·kg(-1))、顺铂(5 mg·kg^(-1))+低剂量山楂酸(10 mg·kg(-1))+低剂量山楂酸(10 mg·kg^(-1))组、顺铂(5 mg·kg(-1))组、顺铂(5 mg·kg^(-1))+高剂量山楂酸(40 mg·kg(-1))+高剂量山楂酸(40 mg·kg^(-1))组,每组8只。顺铂给药方式为腹腔注射,山楂酸给药方式为经口灌胃,干预组腹腔注射顺铂前1 h经口灌胃给予山楂酸。均每日一次,连续两周。给药两周后,检测尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、血清肌酐(Scr)和尿素氮(BUN)、肾组织丙二醛(MDA)和谷胱甘肽(GSH)含量。结果与对照组相比,顺铂组大鼠血清BUN和Scr、尿NAG酶、肾脏组织MDA含量显著升高,肾组织GSH含量显著下降(均P<0.01)。采用山楂酸干预后,大鼠血清BUN和Scr、尿NAG酶、肾脏组织MDA含量较顺铂组显著下降,GSH含量明显上升(P<0.05或P<0.01)。结论山楂酸对顺铂所致大鼠肾毒性有保护作用,其机制可能与抗氧化有关。     

姜黄素对顺铂所致大鼠肾毒性的防护作用

目的研究姜黄素(CMN)对顺铂(CDDP)所致肾损害的防护作用,并探讨其可能机制。方法将42只大鼠按体重随机分6组,分别为对照组、CMN组、CDDP组、CMN(204、0和80 mg/kg) CDDP组。CMN连续给予大鼠灌胃3 d,第2天灌胃后1 h腹腔注射CDDP(5.5 mg/kg)。CDDP处理后,分别在第1、3和5天采血,测定血清尿素氮(BUN)和肌酐(CRE)。第5天采血后处死动物,测定肾脏系数、肾皮质匀浆丙二醛(MDA)、谷胱甘肽(GSH)含量和谷胱甘肽过氧化物酶(GSH-Px)活力以及肾组织铂(Pt)含量等。同时利用体外实验观察对抗增殖作用的影响。结果CMN预处理可减轻CDDP引起的肾脏系数升高及BUN、CRE水平升高;能抑制CDDP引起的MDA形成增高;并能提升CDDP引起的GSH含量和GSH-Px活力下降。CMN低剂量的上述作用明显(P<0.05或P<0.01)。CMN防护组与CDDP组的人卵巢癌细胞系和膀胱癌细胞系的半数抑制浓度差异无显著性。结论CMN经口给予能防护CDDP所致的肾损害,其机制可能与其抗氧化作用和清除自由基活性有密切关系。较高剂量CMN未见防护CDDP所致肾毒性的作用,其原因可能与其助氧化作用有关。CMN对CDDP抗肿瘤细胞增殖作用无明显影响。     

N-乙酰半胱氨酸和亚硒酸钠对镉亚慢性毒性的影响

目的探讨N-乙酰半胱氨酸(N-acetyl cysteine,NAC)和亚硒酸钠(Na2SeO3)对亚慢性染镉大鼠肝肾毒性的影响及其机制。方法32只Wistart大鼠随机分为4组,每组8只,第1组为对照组,第2组为单位染镉组,第3、4组为干预组。大鼠连续6周皮下注射7μmol/kg氯化镉,然后干预组分别腹腔注射1 mmol/kg NAC和10μmol/kg Na2SeO3,共2周;测定大鼠尿N-乙酰-β-苷酶(NAG)、碱性磷酸酶活力(ALP)和肝、肾皮质谷胱甘肽(GSH)、丙二醛(MDA)含量及谷胱甘肽过氧化物酶(GSH-Px)活力。结果亚慢性染镉使大鼠肝、肾皮质和尿镉含量显著升高,尿ALP、NAG和蛋白含量显著升高,肝、肾皮质GSH含量显著升高,GSH-Px活力显著降低。与单纯染镉组比较,NAC处理组尿镉、NAG和蛋白含量显著下降,肝、肾皮质GSH显著降低;Na2SeO3处理组尿镉、ALP及肝、肾皮质GSH含量显著下降,GSH-Px活力显著升高。结论NAC和Na2SeO3对镉致肾损伤的恢复具有促进作用,其机制可能与NAC或Na2SeO3改变体内GSH含量和GSH-Px活力有关。     

维生素E 对顺铂所致的小鼠肾毒性的影响及其机制研究

目的观察维生素E对抗癌药物顺铂致小鼠肾毒性的影响及其可能机制。方法采用10mg.kg-1顺铂腹腔注射诱导小鼠肾脏损伤,48小时后分别予维生素E250mg.kg-1和500mg.kg-1口服灌胃,顺铂诱导72小时后通过检测小鼠血清尿素氮和肌酐水平评价肾功能的变化,检测肾组织中丙二醛(malonaldehyde,MDA)含量,过氧化物歧化酶(super oxide dismutase,SOD)、过氧化氢酶(catalase,CAT)、还原型谷胱甘肽(reduce glutathione,GSH)和谷胱甘肽过氧化物酶(glutathion peroxidase,GPX)活性的变化,以评价小鼠肾组织氧化应激水平。结果与正常小鼠相比,10mg.kg-1顺铂诱导的小鼠血清尿素氮、肌酐水平和肾组织MDA水平均显著升高(P<0.01),而肾组织SOD、CAT、GSH、GPX的活性均显著降低(P<0.01);与10mg.kg-1顺铂诱导的小鼠相比,250mg.kg-1和500mg.kg-1维生素E灌胃的小鼠血清尿素氮、肌酐水平和肾组织MDA水平均显著降低(P<0.01),250mg.kg-1维生素E灌胃的小鼠肾组织GPX的活性显著升高(P<0.01),500mg.kg-1维生素E灌胃的小鼠肾组织CAT和GPX的活性均显著升高(P<0.01),而三组之间肾组织SOD活性的差异无统计学意义(P>0.05)。结论高剂量的维生素E可以有效改善顺铂诱导的小鼠肾功能,可能与其降低肾组织的氧化应激有关。     

双环醇对大鼠肾脏缺血-再灌注损伤的保护作用

目的观察双环醇对缺血-再灌注诱发肾损伤的保护作用.方法在大鼠肾动脉缺血-再灌注模型上观察双环醇对肾缺血-再灌注引起的血清丙二醛(MDA)、尿素氮(BUN),肾脏还原型谷胱甘肽(GSH)、谷胱甘肽巯基转移酶(GST)及肾线粒体膜流动性改变的影响.结果双环醇ig 50及200 mg*kg-1可剂量依赖性保护缺血-再灌注引起的血清MDA及BUN升高、肾GSH含量降低,同时可诱导GST活性,缓解由于缺血-再灌注损伤引起的线粒体膜流动性降低.结论双环醇对肾缺血-再灌注损伤有保护作用.     

人参茎叶总皂苷对顺铂致小鼠肾损伤的保护作用及机制

目的观察人参茎叶总皂苷(GSLS)对顺铂(CDDP)诱导肾损伤小鼠的保护作用,并探讨其可能机制。方法 32只雄性ICR小鼠随机分为正常对照组、CDDP模型组(一次性ip给予CDDP 20 mg·kg~(-1)诱导小鼠肾损伤)、CDDP+GSLS 150和300 mg·kg~(-1)给药组。给药组连续给予GSLS 7 d,末次给药1 h后,一次性ip给予CDDP 20 mg·kg~(-1)诱导小鼠肾损伤,继续给予GSLS 150和300 mg·kg~(-1)3 d,分别采用脲酶法和肌氨酸氧化酶法检测小鼠血尿素氮(BUN)和肌酐(CRE)水平,评价肾功能的变化;分别采用可见光法和微量酶标法检测肾组织中过氧化氢酶(CAT)和还原型谷胱甘肽(GSH)水平,评价小鼠肾组织中氧化应激的水平;采用生物素双抗体夹心酶联免疫吸附法检测肿瘤坏死因子α(TNF-α)和白细胞介素1β(IL-1β),评价肾组织中炎症水平;HE和PAS染色法观察肾组织病理变化;TUNEL和Hoechst33258染色法观察细胞凋亡。结果与正常对照组比较,CDDP组小鼠体质量显著下降(P<0.05),肾指数和血清中CRE,BUN,TNF-α和IL-1β水平显著升高(P<0.05,P<0.01),其中CRE和BUN分别升高了1倍和3倍,肾组织CAT和GSH显著下降(P<0.05);CDDP组肾组织中出现肾小球肿胀、肾小管扩张、肾小球上皮细胞坏死,管腔内出现透明管型,细胞核固缩或消失,肾间质水肿和炎症细胞浸润,大量糖原沉积,此外还有大量的TUNEL阳性细胞和Hoechst33258阳性细胞表达;与CDDP组比较,GSLS各治疗组小鼠血清中CRE和BUN水平明显降低(P<0.05,P<0.01),肾组织糖原沉积减少,肾小管上皮细胞凋亡减少(P<0.05);CDDP+GSLS 300 mg·kg~(-1)组TNF-α和IL-1β显著降低(P<0.05),CAT和GSH显著升高(P<0.05),肾组织坏死程度减轻(P<0.05)。结论GSLS对CDDP诱导的小鼠肾损伤具有保护作用,其机制可能与改善氧化应激、减少炎症反应及抗细胞凋亡有关。     

MaFGF对急性染顺铂小鼠肾损害的保护作用研究

目的探讨改构型酸性成纤维细胞生长因子(MaFGF)对急性染顺铂(DDP)小鼠肾损害的保护作用及其机制。方法腹腔注射(ip)DDP 10 mg/kg,建立小鼠肾损伤模型,然后每日ipMa FGF 10或20μg/kg,连续7 d。采用全自动分析仪测定肌酐(Scr)、尿素氮(BUN)含量,试剂盒测定丙二醛(MDA)、一氧化氮(NO)含量和超氧化物岐化酶(SOD)、谷胱肽过氧化物酶(GSH-Px)活性,观察肾脏病理学变化。结果 Ma FGF可明显降低血清Scr、BUN及肾皮质MDA、NO含量(P<0.05),引起SOD、GSH-Px活性明显升高(P<0.05),使受损的肾结构明显改善。结论 Ma FGF对顺铂致肾功能损伤有保护作用,其机制可能与抗顺铂的脂质过氧化反应有关。     

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug–drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.     

阿西维辛或谷胱甘肽降低顺铂引起的肾脏毒性和顺铂-DNA加合物在鼠肾脏中的水平(英文)

目的　为了了解阿西维辛 (acivicin)和GSH预防肾脏毒性的机制 ,研究了顺铂 DNA加合物在大鼠肾脏中的水平。方法　顺铂 (6mg·kg- 1)从尾静脉注入大鼠 ,5d后处死。其他两组动物在给顺铂前2 .5h ,给予阿西维辛或者GSH。测量顺铂 DNA加合物在肾脏中的浓度、血中尿素氮 (BUN)和丝氨酸肌酸的浓度。结果　在给顺铂前 2 .5h ,给 10mg·kg- 1阿西维辛完全阻断了顺铂引起的肾脏毒性。具体表现是血氮和肌酸浓度降低 ,DNA加合物减少了17.1% (P <0 .0 5 )。在给顺铂前 ,给 5 0 0mg·kg- 1GSH ,肾脏毒性和顺铂 DNA加合物水平均显著性减低 (P <0 .0 5 )。另外 ,在DNA加合物和血氮之间存在着一个弱正相关关系。结论　DNA加合物在顺铂引起的肾脏毒性中引了一些作用。但是DNA加合物和血氮之间的弱相关关系提示DNA加合物与肾脏毒性只有较弱的联系 ,在顺铂引起的肾脏毒性中不是主要因素     

Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats.

The effect of oral erdosteine on tissue malondialdehyde (MDA) and nitric oxide (NO) levels, and catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities are investigated in the cisplatin model of acute renal failure in rats. A single dose of cisplatin caused kidney damage manifested by kidney histology as well as increases in plasma creatinine and blood urea nitrogen (BUN) levels. Treatment with free radical scavenger erdosteine attenuated increases in plasma creatinine and BUN, and tissue MDA and NO levels, and provided a histologically-proven protection against cisplatin-induced acute renal failure. Erdosteine also reduced depletion in the tissue CAT, GSH-Px, and SOD activities. These results show that erdosteine may be a promising drug for protection against cisplatin-induced nephrotoxicity. However, further studies with different doses of erdosteine are warranted for clarifying the issue.     

Protective effect of Cyclea peltata Lam on cisplatin-induced nephrotoxicity and oxidative damage

The aim of the present investigation was to evaluate the protective effect of a 70% methanolic leaf extract of Cyclea peltata Lam on cisplatin-induced renal toxicity. The concentration of creatinine, urea, sodium, and potassium in serum and levels of malonyldyaldehyde (MDA), glutathione (GSH), as well as gluathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities were determined in kidney tissue. The marked cisplatin-induced renal damage, characterized by a significant increase in creatinine and urea levels, decreased in extract-treated group, whereas sodium and potassium levels did not change significantly. C. peltata Lam extract significantly changed the increased MDA level and decreased GSH levels found in rats treated with cisplatin alone. The reduced activities of GSH-Px, SOD, and CAT in groups treated with cisplatin alone were significantly increased by the extract. The protective effect was greater in the post-treated than in the pre-treated group of animals. The results indicate that the post-treatment of C. peltata Lam extract might effectively ameliorate the oxidative stress parameters observed in cisplatin induced renal toxicity and could be used as a natural antioxidant against cisplatin-induced oxidative stress.     

Proteasome inhibitors prevent cisplatin-induced mitochondrial release of apoptosis-inducing factor and markedly ameliorate cisplatin nephrotoxicity

We demonstrate the effect of proteasome inhibitors in mitochondrial release of apoptosis-inducing factor (AIF) in cisplatin-exposed renal tubular epithelial cells (LLC-PK₁ cells) and in a model of cisplatin nephrotoxicity. Immunofluorescence and subcellular fractionation studies revealed cisplatin-induced translocation of AIF from the mitochondria to nucleus. Mcl-1, a pro-survival member of the Bcl-2 family, is rapidly eliminated on exposure of renal cells to cisplatin. Proteasome inhibitors PS-341 and MG-132 blocked cisplatin-induced Mcl-1 depletion and markedly prevented mitochondrial release of AIF. PS-341 and MG132 also blocked cisplatin-induced activation of executioner caspases and apoptosis. These studies suggest that proteasome inhibitors prevent cisplatin-induced caspase-dependent and -independent pathways. Overexpression of Mcl-1 was effective in blocking cisplatin-induced cytochrome c and AIF release from the mitochondria. Downregulation of Mcl-1 by small interfering RNA promoted Bax activation and cytochrome c and AIF release, suggesting that cisplatin-induced Mcl-1 depletion and associated Bax activation are involved in the release of AIF. Expression of AIF protein in the mouse was highest in the kidney compared to the heart, brain, intestine, liver, lung, muscle, and spleen. In an in vivo model of cisplatin nephrotoxicity, proteasome inhibitor MG-132 prevented mitochondrial release of AIF and markedly attenuated acute kidney injury as assessed by renal function and histology. These studies provide evidence for the first time that the proteasome inhibitors prevent cisplatin-induced mitochondrial release of AIF, provide cellular protection, and markedly ameliorate cisplatin-induced acute kidney injury. Thus, AIF is an important therapeutic target in cisplatin nephrotoxicity and cisplatin-induced depletion of Mcl-1 is an important pathway involved in AIF release.     

Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity

Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5 mg/kg) caused marked renal damage, characterized by a significant (P < 0.05) increase in serum creatinine, blood urea nitrogen (BUN) and relative weight of kidney with higher kidney MDA (malondialdehyde), tROS (total reactive oxygen species), caspase 3, GSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (P < 0.05) attenuated the increase in lipid peroxidation, caspase-3 and ROS generation and enhanced the levels of reduced glutathione, tissue nitrite level and activities of SOD, CAT, GSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.     

Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.     

Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats

Cisplatin is one of the most active cytotoxic agents in the treatment of cancer but its clinical use is associated with nephrotoxicity. Several studies suggest that supplementation with antioxidant can influence cisplatin induced nephrotoxicity. In the present study, we investigated the effect of selenium with high dose vitamin E administration on lipid peroxidation (MDA) and scavenging enzyme activity in kidneys, liver and lens of cisplatin-induced toxicity in rats. Forty female Wistar rats were used. They were randomly divided into five groups. The first and second groups were used as control and cisplatin (6 mg/kg BW) intraperitoneally administrated groups. Groups III, IV and V received intraperitoneally five doses of selenium (1.5 mg/kg BW) and a high dose of vitamin E (1000 mg/kg BW) combination before, simultaneously and after with cisplatin, respectively. Glutathione peroxidase (GSH-Px), vitamin E and beta-carotene levels in the kidney, lens and liver, vitamin A and reduced glutathione (GSH) levels in the kidney were significantly (P<0.05 to <0.001) lower in the cisplatin group than in the control whereas there was a significant increase in kidney, liver and lens MDA levels in rats treated with cisplatin. The decreased antioxidant enzymes and vitamins and increased MDA levels in the kidney, lens and liver of animals administered with cisplatin were significantly (P<0.05 to <0.001) improved with selenium and a high dose vitamin E injection. In conclusion, this data demonstrates that there is an increase in lipid peroxidation in the kidney, liver and lens of animals administered with cisplatin whereas there is a decrease in antioxidant vitamins and enzymes. However, intraperitoneally injected selenium combined with a high dose of vitamin E seem to produce a significant improvement on antioxidants concentrations in rats treated before, simultaneously and after with cisplatin. The selenium with high dose vitamin E injection may play a role in preventing cisplatin-induced nephropathy and cataract formation in cancer patient.     

The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice

Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p<0.05) and weight (p<0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with cisplatin.     

1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats

BackgroundCisplatin (a platinum-compound) is a anti-neoplastic drug used in the treatment of various cancers but eventually results in severe adverse effects namely nephrotoxicity or renal disorder through generation of reactive oxygen species (ROS). This biochemical measurements and histopathology analysis investigated a possible protective effect of 1,2-diazole with regards to cisplatin-induced nephrotoxicity in experimental animals.MethodsAnimals were divided into four groups of six mice each. Group A: normal control, vehicle (1 % (w/v) gum acacia in phosphate buffer saline (PBS)). Group B: cisplatin group, vehicle + cisplatin (7.5 mg/kg). Group C: 1,2-diazole (10 mg/kg) + cisplatin and Group D: silymarin (50 mg/kg) + cisplatin. Each vehicle/drug treatment was given daily via intraperitoneal (ip) injection for 10 consecutive days starting from day 1. On group B, C and D cisplatin was given in single dose only on day 5 one hour post drug administration. Animals were allowed till 10^th day and on day 11 all four groups animals were anesthetized. Blood samples were collected and serum was isolated for biochemical measurements. The rats were then euthanized by cervical dislocation and their kidney was recovered and then prepared for biochemical measurements and histopathology analyses.ResultsPretreatment with 1,2-diazole prevented nephrotoxicity induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress by significantly increasing the enzymatic and non enzymatic antioxidant enzymes such as glutathione peroxidase (GPx), glutathione (GSH) and diminishing the lipid peroxidation (LPO). The pretreatment with 1,2-diazole does not affect superoxide dismutase (SOD), catalase (CAT), serum urea and creatinine level during nephrotoxicity when compared to cisplatin-induced group. Moreover, the 1,2-diazole animals shown significant decrease in urine volume and kidney weight when compared with cisplatin-induced group. Histopathological findings reveals the protective efficacy of 1,2-diazole that restores histopathological changes against nephrotoxicity.ConclusionThese analysis will provide a critical evidence that 1,2-diazole could provide a new protective strategy against cisplatin-induced nephrotoxicity.