金属硫蛋白对阿霉素心脏毒性的保护作用及其对ONOO^-生成的抑制

目的研究金属硫蛋白(MT)对阿霉素(DOX)所致心脏毒性损伤的保护作用及其对过氧亚硝酸阴离子(ONOO-)生成的抑制。方法MT野生型小鼠(MT / )及MT敲除小鼠(MT-/-)随机分成4组,即对照组,DOX处理组,锌处理组,锌预处理 DOX组。动物连续两天皮下给予ZnSO4(300μmol/kg)或生理盐水,第3天单次腹腔注射DOX(15mg/kg)或生理盐水。给药后第4天进行血浆肌酸激酶(CK)活力和心肌型肌钙蛋白(cTnT)含量测定,心脏病理组织学检查,以及心脏组织中3-硝基酪氨酸(3-NT)的免疫组织化学分析。结果DOX给药引起MT / 和MT-/-小鼠心肌组织出现严重的毒性损伤,表现为血浆CK活性和cTnT含量升高,心肌组织HE染色异常;锌预处理诱导了MT / 小鼠MT的高表达,从而抑制了DOX诱发的心脏毒性作用;而MT-/-小鼠因MT基因的缺失,虽也经锌诱导,但无法有效保护心脏免于遭受DOX的心脏毒性作用。进一步的研究发现,DOX明显引起心脏组织ONOO-生成增加,而MT高表达的情况下抑制了DOX引起的上述变化。结论锌诱导的MT对DOX引起的心脏毒性具有保护作用,这种保护作用可能与抑制DOX引起的ONOO-生成增加有关。     

锌诱导金属硫蛋白表达对多柔比星心脏毒性的保护作用及其机制(英文)

目的:研究Zn诱导金属硫蛋白(metallothionein,MT)表达对多柔比星(doxorubicin,DOX)心脏毒性的保护作用及其机制。方法:雄性C57／BL6J小鼠随机分成4组(n=6),即对照组(control)、给药组(DOX)、预处理组(Zn)、预处理给药组(Zn+DOX)。动物单次腹腔注射DOX(20 mg·kg-1)或等剂量的生理盐水(NS),此前24 h及48 h分别给予ZnSO4(300μmol·kg-1,sc)或等剂量的NS预处理。DOX给药后d 4,测定血浆肌酸激酶(CK)及乳酸脱氢酶(LDH)活性;光学显微镜检查心脏组织形态学改变;测定心脏组织匀浆中MT、丙二醛(MDA)和还原型谷胱甘肽(GSH)含量以及谷胱甘肽过氧化物酶(GSHpx)、超氧化物歧化酶(SOD)、过氧化氢酶((CAT)活性并测定组织过氧化氢(H2O2)浓度。结果:与对照组相比,Zn能显著诱导心脏MT的过表达,而对CK、LDH、MDA、GSHpx、SOD、CAT、GSH、H2O2以及组织形态学无明显影响;给药组病理学检查可见心肌纤维浊肿、肌浆溶解、胞核淡染或固缩,CK、LDH及MDA升高,组织GSHpx、SOD活性及GSH含量显著下降,CAT活性及H2O2浓度升高;Zn预处理能显著抑制DOX诱导的心脏毒性效应,心脏毒性损伤明显减轻。提示Zn预处理诱导心脏MT过表达后,MT可作为体内有效的抗氧化物拮抗DOX心脏毒性。结论:Zn诱导MT表达对DOX心脏毒性具有明显的保护作用,其机制可能与MT体内清除自由基功能有关。     

硫酸锌诱导金属硫蛋白对阿霉素致心脏氧自由基产生的影响

目的:研究硫酸锌诱导金属硫蛋白(MT)对阿霉素(DOX)致氧自由基产生的影响。方法:雄性野生型小鼠(MT+/+)及敲除MT基因的转基因小鼠(MT-/-)随机分成4组,即对照组、DOX组、锌预处理组、锌预处理+DOX组。动物单次腹腔注射DOX(15 mg.kg-1)或生理盐水(NS),此前24 h及48 h分别给予锌(ZnSO4,20 mg.kg-1,s.c.)或NS预处理。给药4 d后测定心脏组织超氧阴离子(O2.-)水平及还原型谷胱甘肽(GSH)含量,Westernblot检测内皮型一氧化氮合酶(eNOS)的表达情况。结果:DOX能显著增加MT+/+小鼠及MT-/-小鼠心脏组织中O2.-的生成,耗竭GSH,上调eNOS的表达水平,而且MT-/-小鼠变化更为明显。Zn预处理能显著降低DOX致MT+/+小鼠O2.-生成增加以及GSH耗竭,抑制DOX诱导的eNOS表达增强,但在MT-/-小鼠中无此效应。结论:MT可抑制DOX致氧自由基产生增加及GSH耗竭,此效应可能与eNOS表达改变有关。     

金属硫蛋白在细菌脂多糖引发肝脏损伤中的作用

目的探讨金属硫蛋白(Metallothionein,MT)对细菌脂多糖(Lipopolysaccharide,LPS)引起的肝脏损伤的影响及其可能机制。方法利用MT基因敲除(MT-/-)小鼠及与之对应的野生型(MT / )小鼠腹腔注射LPS(10 mg/kg)造成急性肝损伤模型,通过测定不同时间点血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)活力,肝脏丙二醛(MDA)含量,以及肝脏组织病理学检查结果,判断LPS对两种小鼠肝脏损伤程度的差异。结果LPS可以使两种小鼠血清酶ALT、AST活力均呈时间依赖性升高,肝脏内脂质过氧化产物增加。组织病理学检查显示,肝脏出现肝细胞浊肿,空泡变性,液化坏死,星状细胞增生。MT / 小鼠血清ALT,AST升高趋势较MT-/-小鼠更为显著。炎症反应早期MT-/-小鼠肝组织内炎性细胞浸润程度轻于MT / 小鼠,随炎症反应时间延长,MT-/-小鼠较MT / 小鼠肝组织损伤程度呈加重趋势。LPS致MT-/-小鼠肝脏脂质过氧化程度较MT / 小鼠更为严重。结论MT对LPS引起的肝脏损伤具有一定的保护作用,其可能机制与MT增强机体清除LPS能力以及对LPS致炎过程中生成的ROS的清除作用有关。     

豨莶草醇提物对多柔比星致小鼠慢性心肌损伤的保护作用

目的:探讨豨莶草(HS)醇提物对多柔比星(DOX)致小鼠慢性心肌损伤的影响。方法:将48只小鼠随机分为3组,即空白对照(Con)组小鼠每天ig 1次蒸馏水(2 mL/100 g),并每周ip 1次生理盐水,持续8周;DOX组小鼠每天ig 1次蒸馏水(2 mL/100g),并每周ip 1次DOX(3 mg/kg),持续8周;DOX+HS醇提物组小鼠每天ig 1次HS(340 mg/kg),并每周ip 1次DOX(3 mg/kg),持续8周。给药结束后,测定小鼠体质量、心脏系数、心功能变化以及血清生化指标[丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、肌酸磷酸激酶(CK)、肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)及总胆固醇(TC)]水平。结果:与Con组比较,DOX组小鼠体质量减轻(P<0.01);心脏系数升高(P<0.05);心率减慢、R波增高(P<0.05或P<0.01);血清中生化指标均有所升高,其中AST差异有统计学意义(P<0.01)。与DOX组比较,DOX+HS醇提物组小鼠心脏系数降低(P<0.01);心率增加(P<0.01);血清中生化指标均有所降低,其中CK、LDH、TC差异有统计学意义(P<0.01)。结论:HS醇提物对DOX致小鼠慢性心肌损伤有一定的保护作用。     

氯化钆保护细菌脂多糖引发肝脏损伤及其可能机制

目的探讨氯化钆(Gadolinium Chloride,GdCl3)在细菌脂多糖(Lipopolysaccharide,LPS)引起的肝脏损伤中的作用及其机制。方法将MT基因敲除小鼠(MT-/-)及与之对应的野生型小鼠(MT / )各分为4组:生理盐水对照组、LPS染毒组、GdCl3组、GdCl3预处理 LPS染毒组。动物腹腔注射LPS(10mg/kg)或生理盐水(NS),此前24h给予GdCl3(10mg/kg,i.v.)或NS预处理。注射LPS后24h测定血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)活力以及一氧化氮(NO)含量,镉饱和法测定肝脏金属硫蛋白(MT)含量,进行肝组织病理学检查,判定不同处理对MT-/-小鼠及MT / 小鼠肝脏的影响的差异。结果注射LPS后,MT-/-小鼠及MT / 小鼠血ALT,AST活力,血NO含量均较对照组升高,2种小鼠肝组织均出现大量炎性细胞浸润、肝细胞浊肿、空泡变性、灶性液化坏死、星状细胞增生。LPS致MT-/-小鼠肝组织损伤程度较MT / 小鼠更为严重。氯化钆、LPS均可以诱导MT / 小鼠肝脏MT生成。GdCl3预处理可以降低LPS对MT-/-小鼠及MT / 小鼠血ALT,AST活力,血NO含量的影响,可以减轻LPS对2种小鼠肝组织病理学损伤。结论GdCl3预处理可以有效减轻LPS对MT-/-小鼠及MT / 小鼠引起的肝脏损伤,其可能机制与其对肝脏Kupffer细胞抑制作用有关。     

氯化钆保护细菌脂多糖引发肝脏损伤及其可能机制研究

目的探讨氯化钆(Gadolinium chloride,Gd Cl3)在细菌脂多糖(Lipopolysaccharide,LPS)引起肝脏损伤的影响及其机制。方法将MT基因敲除小鼠(MT-/-)及与之对应的野生型小鼠(MT+/+)各分为4组:生理盐水对照组、LPS染毒组、Gd Cl3组和Gd Cl3预处理+LPS染毒组。动物腹腔注射LPS(10 mg/kg,腹腔注射)或生理盐水(NS,腹腔注射),此前24 h给予Gd Cl3(10 mg/kg,尾静肪注射)或NS预处理。注射LPS后24 h测定血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)活力以及一氧化氮(NO)含量,镉饱和法测定肝脏金属硫蛋白(MT)含量,进行肝组织病理学检查,判定不同处理对MT-/-小鼠及MT+/+小鼠肝脏影响的差异。结果注射LPS后,MT-/-小鼠及MT+/+小鼠血ALT、AST活力,血NO含量均较对照组升高,两种小鼠肝组织均出现大量炎性细胞浸润、肝细胞浊肿、空泡变性、灶性液化坏死、星状细胞增生。组织病理学检查结果显示MT-/-小鼠肝组织损伤程度较MT+/+小鼠更为严重。氯化钆、LPS均可以诱导MT+/+小鼠肝脏MT生成。Gd Cl3预处理可以同时降低LPS对MT-/-小鼠及MT+/+小鼠血ALT,AST活力,血NO含量的影响,可以减轻LPS对两种小鼠肝组织病理学损伤。结论 Gd Cl3预处理可以有效减轻由LPS引起的肝脏损伤,MT通过其对Kuffer细胞的抑制作用保护LPS引起的肝脏损伤。     

二苯乙烯苷对多柔比星致小鼠心脏损伤的保护作用研究

目的:研究中药何首乌主要有效成分二苯乙烯苷(THSG)对多柔比星(DOX)致小鼠心脏损伤的保护作用及其机制。方法:取小鼠随机分为正常对照组、模型组和THSG高、中、低剂量组(150、100、50mg·kg-1·d-1),每组20只,THSG各剂量组灌胃给予相应药物2d,第3天除正常对照组外其余各组单剂量腹腔注射DOX15mg·kg-1建立心脏损伤模型,建模同时THSG各剂量组继续灌胃给药5d,然后处死小鼠。观察各组小鼠体重、心脏指数、存活率和心肌病理形态变化,考察小鼠血清中乳酸脱氢酶(LDH)、肌酸激酶(CK)水平及心脏组织中丙二醛(MDA)、还原型谷胱甘肽(GSH)含量。结果:与正常对照组比较,模型组小鼠体重明显减轻(P<0.01),心脏指数和存活率均略减小,LDH、CK、MDA水平均明显升高(P<0.01),GSH含量明显降低(P<0.01),可见明显的心肌纤维断裂甚至消失,心肌间质水肿并伴有局灶性心内膜下出血。与模型组比较,THSG高、中、低剂量组小鼠体重、心脏指数和存活率均无明显差异,LDH、CK、MDA水平均明显降低(P<0.05或P<0.01),GSH含量明显增加(P<0.05或P<0.01),心肌组织病理形态学变化明显好转。结论:THSG对DOX致小鼠心脏损伤具有保护作用,其机制可能与抗氧化损伤有关。     

金属硫蛋白对NMDA诱导小鼠大脑皮层神经细胞损伤的保护作用

目的金属硫蛋白(metallothionein,MT)是一类低分子量富含半胱氨酸,能与铜和锌等金属相结合的金属结合蛋白,它参与金属离子Cu2 、Zn2 稳态的维持,调节锌金属蛋白的生物合成和活性,抗自由基损伤和参与调节谷氨酸能等神经元的活动。NMDA受体广泛分布于中枢神经系统,对神经元信号的传递和基因表达的调控起着重要作用,而且还影响大脑的认知功能和脑细胞的生长发育。过度激动NMDA受体是许多神经系统疾病的病因,可使大脑产生包括神经元坏死和细胞凋亡的神经损害。本实验采用原代培养MT基因敲除小鼠和野生型小鼠的皮层神经细胞,研究MT对于NMDA诱导的神经细胞损伤的保护作用。方法取新生24h内的MT-Ⅰ和Ⅱ基因敲除小鼠(MT-/-)和C57BL/6野生型小鼠(MT / )的大脑皮层进行神经细胞原代培养,检测生长不同时间(第1、4、7和10d)的MT / 和MT-/-组皮层神经细胞的生长状况(MTT法),绘制两者的生长曲线。于细胞培养第10d向培养基中加入不同浓度NMDA(0、25、50、100、200和400μmol/L),作用24h,观察损伤后的细胞形态变化,测定存活率(MTT法)、乳酸脱氢酶(LDH)漏出率,通过MT / 和MT-/-2组的比较研究MT对神经细胞的保护作用。结果显示MT / 组皮层神经细胞在生长不同天数的MTT值均高于MT-/-组,说明MT的缺失导致2组细胞在基础的生长状况上存在差异。给予NMDA引起神经毒性损伤后,MT / 组皮层神经细胞的存活率要高于MT-/-组,且都随着NMDA剂量的增大而降低,在100、200μmol/L浓度时差异有统计学意义。同时MT / 组神经细胞LDH漏出率要低于MT-/-组,说明MT可降低NMDA所致细胞LDH漏出的增加。结论MT对于NMDA所致神经细胞损伤有保护作用。     

金属硫蛋白-Ⅰ/Ⅱ对丙烯酰胺诱导星形胶质细胞损伤的保护作用

目的探索金属硫蛋白Ⅰ/Ⅱ(MetallothioneinⅠ/Ⅱ,MTⅠ/Ⅱ)对丙烯酰胺诱导星形胶质细胞损伤的保护作用。方法采用新生C57野生型(MT+/+)和MT敲除型(MT-/-)小鼠进行大脑皮层星形胶质细胞原代培养,并采用免疫细胞化学法鉴定细胞纯度。MT+/+和MT-/-两种细胞分别给予0.01、0.1和1 mmol/L丙烯酰胺处理,于不同时间点检测其细胞存活率,乳酸脱氢酶(LDH)漏出率和细胞凋亡率。结果细胞培养至15 d,两种细胞在形态学上无明显差异,细胞纯度达到90%以上。丙烯酰胺低剂量组(0.01 mmol/L)作用24 h后,MT-/-细胞存活率明显低于MT+/+,高剂量组(1 mmol/L)作用时间短于24 h,可见MT+/+细胞的存活率明显高于MT-/-,随着作用时间延长后,未见明显差异。丙烯酰胺作用24 h后,LDH漏出率和细胞凋亡率均随剂量依赖性增加,且丙烯酰胺中低剂量组(0.01和0.1 mmol/L)MT-/-细胞LDH漏出率和凋亡率明显高于MT+/+细胞。结论 MTⅠ/ⅡI对丙烯酰胺引起的星形胶质细胞损伤具有一定的保护作用。     

Metallothionein protects against doxorubicin-induced cardiomyopathy through inhibition of superoxide generation and related nitrosative impairment

Metallothionein (MT) has been shown to be an effective protector against DOX-induced cardiomyopathy, however the involved precise mechanisms are still unknown. The present study was undertaken to clarify whether the inhibition of superoxide generation and related nitrosative damage were involved in the metallothionein attenuation of DOX-induced cardiac injury. MT-I/II null (MT-/-) mice and corresponding wild-type mice (MT+/+) were pretreated with either saline or zinc (300 micromol/kg, s.c., once a day for 2 days) prior to a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. DOX caused remarkable cardiac damage in both MT+/+ and MT-/- mice as demonstrated by biochemical and histopathological alterations. Zinc pretreatment significantly increased the cardiac MT levels and therefore inhibited the cardiac toxic effects of DOX only in MT+/+ mice, but not in MT-/- mice. Furthermore, elevated formation of superoxide and peroxynitrite were obviously observed after DOX treatment, while these elevation were prevented by MT induction by zinc in MT+/+ mice, but not in MT-/- mice. These findings suggest that metallothionein induction by zinc exhibits protective effects on the cardiac toxicology of DOX, which might be mediated through the prevention of superoxide generation and related nitrosative impairment.     

Alleviation of the acute doxorubicin-induced cardiotoxicity by Lycium barbarum polysaccharides through the suppression of oxidative stress

The present study aims to investigate whether Lycium barbarum polysaccharides (LBP) could protect against acute doxorubicin (DOX)-induced cardiotoxicity. Rats received daily treatment of either distilled water (4 ml/kg) or LBP (200 mg/kg) for 10 days and then followed by an intravenous injection at day 7 of either saline (10 ml/kg) or DOX (10 mg/kg). DOX induced significantly myocardial damage in rats, which were characterized as conduction abnormalities, decreased heart-to-body weight ratio, increased serum CK, and myofibrillar disarrangement. DOX treatment also increased MDA and decreased SOD and GSH-Px activity in cardiac tissues. Pretreatment with LBP significantly reduced DOX-induced oxidative injury in cardiac tissue, suggesting by the fact that LBP significantly attenuated DOX-induced cardiac myofibrillar disarrangement and LBP was effective in decreasing the levels of serum CK and thus improving conduction abnormalities caused by DOX. LBP treatment significantly increased SOD and GSH-Px activity and decreased the MDA level of heart tissues damaged by DOX exposure in rats. Furthermore, the cytotoxic study showed that LBP protect against cytotoxicity of DOX in cardiac myoblasts H9c2 but dose not attenuate the anti-tumor activity of DOX. In summary, our evidence indicates that LBP elicited a typical protective effect on DOX-induced acute cardiotoxicity via suppressing oxidative stress.     

Effects of water-soluble antioxidant from spinach, NAO, on doxorubicin-induced heart injury.

Doxorubicin (DOX) produces clinically restorative responses in numerous human cancers, but its cardiotoxicity has limited its usefulness. Because reactive oxygen species may affect DOX-induced antitumor activity and cardiotoxicity, we evaluated the prophylactic effect of spinach natural antioxidant (NAO) on DOX-induced cardiotoxicity and oxidative stress in female Balb/c mice using histological, electron microscopical and biochemical parameters. Mice were treated with NAO for 7 days prior to and/or for 6 days after DOX administration. Pretreatment with NAO (cumulative dose: 130 mg/kg) did not hinder the effectiveness of DOX. Light and electron microscopy of DOX-treated heart revealed myocardial degeneration. When administered combined before and after DOX, NAO conferred the most significant cardiac protection. The effects of NAO on the lipid peroxidation product, malondialdehyde, and on H2O2/ hydroperoxides were examined on day 6 following DOX administration; levels of both were elevated in DOX-treated mice, compared to control. Pretreatment with NAO prevented these changes. Pretreatment with NAO before DOX administration decreased catalase and increased superoxide dismutase activities compared to the DOX group. Our results suggest usage of NAO in combination with DOX as a prophylactic strategy to protect heart muscle from DOX-induced cellular damage.     

Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats

Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100 mg/kg/day for 10 consecutive days) and DOX (15 mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats’ hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN’s antioxidant activity.     

Global gene expression profiles of MT knockout and wild-type mice in the condition of doxorubicin-induced cardiomyopathy

Increasing evidence from in vivo and in vitro studies has indicated that MT exerts protective effects against DOX-induced cardiotoxicity; however the underlying precise mechanisms still remain an enigma. Therefore, the present study was designed using MT knockout mice in concert with genomic approaches to explore the possible molecular and cellular mechanisms in terms of the genetic network changes. MT-I/II null (MT?/?) mice and corresponding wild-type mice (MT+/+) were administrated with a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. Global gene expression profiles of cardiac mRNA from two genotype mice revealed that 381 characteristically MT-responsive genes were identified between MT+/+ mice and MT?/? mice in response to DOX, including fos, ucp3, car3, atf3, map3k6, etc. Functional analysis implied MAPK signaling pathway, p53 signaling pathway, Jak-STAT signaling pathway, PPAR signaling pathway, Wnt signaling pathway, etc. might be involved to mediate the protection of DOX cardiomyopathy by MT. Results from the present study not only validated the previously reported possible mechanisms of MT protection against DOX toxicity, but also provided new clues into the molecular mechanisms involved in this process.     

Intraperitoneal glycerol induces oxidative stress in rat kidney

1. Glycerol has been used for the treatment of intracranial hypertension, cerebral oedema and glaucoma. Experimentally, intramuscular administration of hypertonic glycerol solution is used to produce acute renal failure. In this model, glycerol causes rhabdomyolysis and myoglobinuria, resulting in the development of renal injury. The pathogenesis is thought to involve vascular congestion, the formation of casts and oxidative stress. However, the effect of glycerol itself independent of rhabdomyolysis has not been investigated. Therefore, the aim of the present study was to investigate the effects of i.p. glycerol on some biochemical and oxidative stress parameters in the kidney of young rats. 2. Rats received 10 mL/kg, i.p., hypertonic glycerol solution (50% v/v) or saline (NaCl 0.85 g%) followed by 24 h water deprivation. Twenty-four hours after the administration of glycerol, rats were killed. Creatinine levels and the activity of creatine kinase (CK) and lactate dehydrogenase (LDH) were determined in the plasma. In addition, CK, pyruvate kinase and LDH activity and oxidative stress parameters (free radical formation, lipid peroxidation and protein carbonylation) were measured in renal tissue. 3. Glycerol did not alter plasma CK activity and increased plasma creatinine levels, suggesting renal insufficiency and the absence of rhabdomyolysis. Renal CK and pyruvate kinase activity was decreased, suggesting diminution of energy homeostasis in the kidney. Plasma and renal LDH activity was decreased, whereas the formation of free radicals, lipid peroxidation and protein carbonylation were increased, suggesting oxidative stress. 4. These results are similar to those described after the intramuscular administration of glycerol. Therefore, it is possible that glycerol may provoke renal lesions by mechanisms other than those induced by rhabdomyolysis.     

Cardioprotective effects of Glycyrrhiza uralensis extract against doxorubicin-induced toxicity

The purpose of the present study was to investigate the cardioprotective effects of Glycyrrhiza uralensis extract (GUE) against doxorubicin (DOX)-induced cardiotoxicity. Imprinting control region (ICR) mice were treated with saline, DOX (20 mg/kg intraperitoneal [ip] for once), GUE (100 mg/kg intragastric [ig] for 8 days), co-treatments with DOX and GUE (100 mg/kg ig for 8 days), and amifostine (100 mg/kg intravenous [iv] for once), respectively. Serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GSH-P(X)) activity, and glutathione (GSH) level in heart tissue were measured. Histopathologic analysis of heart tissue was also performed. Treatment with GUE significantly protected the mice from DOX-induced cardiotoxicity, indicated by decreased levels of serum LDH and CK-MB, improved heart morphology and increased GSH-P(X) activity and GSH level. Additionally, GUE did not compromise the tumor-inhibitory effect of DOX. In conclusion, our studies imply the potentially clinical application of GUE to overcome the cardiotoxicity of doxorubicin.     

Relationship between anti-oxidant activities and doxorubicin-induced lipid peroxidation in P388 tumour cells and heart and liver in mice

1. The present study found that, compared with mouse heart and liver, P388 ascitic tumour had significantly lower superoxide dismutase (SOD) activity and that compared with the mouse liver, the heart had significantly lower SOD and catalase activities, as well as a lower glutathione content. 2. At 7.5 mg/kg, doxorubicin (DOX), a superoxide radical inducer, induced significant lipid peroxidation only in the tumour, whereas 15.0 mg/kg DOX induced lipid peroxidation in both the tumour and heart, but not in the liver. 3. Overall, the results of the present study suggest that the differential anti-oxidant activities in P388 ascitic tumour, heart and liver in mice may explain their differential responses and, hence, susceptibility to DOX-induced lipid peroxidation.     

Naproxen aggravates doxorubicin-induced cardiomyopathy in rats

Background:

The repercussion of the heated dispute on cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) led to the national and international withdrawal of several of the recently introduced coxibs. Further debate and research have highlighted risks of the classical NSAIDs too. There is much controversy about the cardiovascular safety of a nonselective NSAID naproxen (NAP) and its possible cardioprotective effect.

Objectives:

The study was undertaken to determine the cardiovascular effects of NAP on doxorubicin-induced cardiomyopathy in rats.

Materials and Methods:

Male albino rats received a single i.p. injection of normal saline (normal control group) and doxorubicin (DOX) 15 mg/kg (toxic control group). Naproxen was administered alone (50 mg/kg/day, p.o.) and in combination with DOX and DOX + trimetazidine (TMZ) (10 mg/kg/day, p.o.) for 5 days after 24 h of DOX treatment. DOX-induced cardiomyopathy was assessed in terms of increased activities of serum lactate dehydrogenase (LDH), tissue thiobarbituric acid reactive substances (TBARS) and decreased activities of myocardial glutathione, superoxide dismutase and catalase, followed by transmission electron microscopy of the cardiac tissue.

Results:

Doxorubicin significantly increased oxidative stress as evidenced by increased levels of LDH and TBARS and decreased antioxidant enzymes levels. Both biochemical and electron microscopic studies revealed that NAP itself was cardiotoxic and aggravated DOX-induced cardiomyopathy and abolished the protective effect of TMZ in rats.

Conclusions:

This study indicates that NAP has the potential to worsen the situation in patients with cardiovascular disease. Therefore, it should be used cautiously in patients with compromised cardiac function.