羅衛(wèi)民+劉越峰+羅湘玉+等
羅衛(wèi)民1 劉越峰2 羅湘玉1 張 軍1
1.湖北醫(yī)藥學(xué)院附屬十堰市太和醫(yī)院心胸外科,湖北十堰 442000;
2.湖北醫(yī)藥學(xué)院附屬十堰市人民醫(yī)院眼科,湖北十堰 442000
[摘要] 目的 觀察金櫻子(Rosa Laevigata Michx,RLM)對阿霉素(Doxorubicin,DOX)誘導(dǎo)心肌損傷的保護作用。 方法 Wistar大鼠隨機分為空白對照組(8只)、DOX模型組(15只)、RLM和DOX聯(lián)合用藥組(每個劑量組30只)??瞻讓φ战M僅給予等體積生理鹽水,DOX模型組大鼠用DOX腹腔注射,使其累計劑量達15 mg/kg。聯(lián)合用藥組在DOX組基礎(chǔ)上每千克體重分別用1,2和5 g RLM灌胃。處理結(jié)束后,測量血清中天冬氨酸轉(zhuǎn)氨酶(aspartate transaminase,AST)、肌酸激酶(creatine kinase,CK-MB)、乳酸脫氫酶(lactate dehydrogenase,LDH)、總膽固醇(total cholesterol,TC)的含量,同時采用比色法測量還原型谷胱甘肽(glutathione,GSH)、丙二醛(myocardial lipid peroxide,MDA)、腫瘤壞死因子α(tumour necrosis factor-alpha,TNF-α)及caspase-3的含量。 結(jié)果 DOX能顯著增高大鼠血清中AST,LDH,CK-MB和TC水平,5 g/L RLM處理能將血清中AST降至(6.73±0.18)U/L,LDH降至(251.34±33.08)U/L,CK-MB降至(53.62±4.45)U/L,TC降至(67.82±9.47)mg/dL,與DOX模型組比較,差異有統(tǒng)計學(xué)意義(P < 0.05)。DOX也降低還原型GSH水平,能增加MDA,TNF-α及caspase-3的含量。而給予RLM處理后,每毫克組織中GSH水平增加至(1.06±0.11)mg/g,MDA降至(0.82±0.14)nmol/mg,TNF-α降至(3.49±0.05)pg/mg,caspase-3 OD值降至(0.83±0.02),與DOX模型組比較,差異有統(tǒng)計學(xué)意義(P < 0.05)。 結(jié)論 RLM通過其抗氧化、抗炎癥及抗凋亡機制發(fā)揮對DOX誘導(dǎo)的心肌毒性的保護作用。
[關(guān)鍵詞] 金櫻子;阿霉素;氧化應(yīng)激
[中圖分類號] R965 [文獻標識碼] A [文章編號] 1673-7210(2014)03(a)-0015-04
Antioxidant and antiapoptosis effect of Rosa Laevigata Michx. on Doxorubicin-induced cardiac injury rats
LUO Weimin1 LIU Yuefeng2 LUO Xiangyu1 ZHANG Jun1
1.Department of Cardiothoracic Surgery, the Taihe Hospital of Shiyan Affiliated to Hubei University of Medicine, Hubei Province, Shiyan 442000, China; 2.Department of Ophthalmology, the People's Hospital of Shiyan Affiliated to Hubei University of Medicine, Hubei Province, Shiyan 442000, China
[Abstract] Objective To evaluate the cardioprotective effects of Rosa Laevigata Michx. (RLM) on DOX-induced heart injury in rats. Methods Wistar rats were randomized divided into control group, Doxorubicin model group and RLM groups. Rats in control group (n=8) were injected by normal saline injection, while the Doxorubicin model group were administrated by intraperitoneal injection (n=15) in a cumulative dose of 15 mg/kg for two weeks. For the RLM groups, 1, 2, 5 g/kg of ALM were given after DOX injection (n=30 in each dose group). Activities and levels of aspartate transaminase (AST), creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) in serum were detected. The level of reduced glutathione (GSH), malondialdehyde (MDA), tumour necrosis factor-alpha (TNF-α) and caspase-3 levels in cardiac tissue were detected by a colorimetric method. Results DOX significant increased the AST, CK-MB, LDH, and TC level in serum. 5 g/L RLM treatment could decrease AST to (6.73±0.18) U/L, LDH to (251.34±33.08) U/L, CK-MB to (53.62±4.45) U/L, TC to (67.82±9.47) mg/dL, there were statistical significances as compared with those in DOX modec group (P < 0.05). DOX could also decrease the reduced GSH, and accumulation of MDA, TNF-α and caspase-3. After treatment with RLM, the content of GSH in each milligram of protein increased to (1.06±0.11) mg/g, MDA decreased to (0.82±0.14) nmol/mg, TNF-α decreased to (3.49±0.05) pg/mg, and decreased the OD value of caspase-3 OD to (0.83±0.02). There were statistical significances as compared with those in DOX group (P < 0.05). Conclusion RLM mediates their protective effect against DOX-induced cardiac injury through antioxidant, anti-inflammatory and antiapoptotic mechanisms.
[Key words] Rosa Laevigata Michx.; Doxorubicin; Oxidative stress
[基金項目] 湖北省十堰市科學(xué)技術(shù)研究與開發(fā)計劃(指導(dǎo))項目(Ⅱ)(編號2009S48)。
[作者簡介] 羅衛(wèi)民(1978.3-),男,湖北十堰人,碩士;研究方向:心肌保護。
通訊作者
阿霉素(Doxorubicin,DOX) 是一種廣泛應(yīng)用于腫瘤治療的蒽環(huán)類抗生素。盡管其對包括白血病在內(nèi)的多種惡性腫瘤具有抑制作用,但其蓄積性不可逆性心肌病以及充血性心衰限制了其使用[1]。DOX導(dǎo)致的毒性心肌病原因很多,其中活性氧(reactive oxygen species,ROS)介導(dǎo)的心肌細胞凋亡是其重要機制之一[2]。因此,在DOX治療的同時預(yù)防性使用抗氧化藥物干預(yù),有望降低其副作用[3]。近年來,某些藥用植物在心血管疾病的預(yù)防過程中具有一定的預(yù)防作用[4],金櫻子為薔薇科金櫻子(Rosa Laevigata Michx.,RLM)的果實,研究發(fā)現(xiàn)它具有強大的抗氧化和清除自由基能力[5-6]。本研究旨在觀察RLM對DOX誘發(fā)的心臟毒性的保護作用。
1 材料與方法
1.1 主要實驗試劑
DOX購自意大利Pharmacia公司(批號:8NB002-A),血清天冬氨酸轉(zhuǎn)氨酶(aspartate transaminase,AST)檢測試劑盒購自Quimica Clinica Aplicada。血清總膽固醇(total cholesterol,TC)、乳酸脫氫酶(lactate dehydrogenase,LDH)和肌酸激酶(creatine kinase,CK-MB)試劑盒為Stanbio產(chǎn)品。還原型谷胱甘肽(glutathione,GSH)及丙二醛(myocardial lipid peroxide,MDA)檢測試劑盒購自南京建成生物技術(shù)研究所。心肌腫瘤壞死因子α(tumour necrosis factor-alpha,TNF-α)ELISA試劑盒和caspase-3的比色測定試劑盒購自Quantikine。分析純試劑主要購自Sigma-Aldrich公司。
金櫻子購于十堰市中草藥材公司,經(jīng)去籽后用煎藥機進行熬煎。金櫻子的鑒定由湖北醫(yī)藥學(xué)院肖勝全教授完成,其提取液濃度為2.0 g/mL。
1.2 實驗分組
成年雄性Wistar大鼠由湖北醫(yī)藥學(xué)院實驗動物部提供,體重(250±5)g,在SPF環(huán)境下給予標準實驗室的水和食物飼養(yǎng)2周。大鼠隨機分成5組:空白對照組(8只),大鼠接受等體積的生理鹽水作為陰性對照;DOX模型組(15只),大鼠連續(xù)兩周每間隔48 h注射DOX(2.5 mg/kg,ip)共6次,使其累積劑量達15 mg/kg。RLM高、中、低劑量組(每組各30只):在DOX模型組的基礎(chǔ)上,大鼠每日給予RLM(1、2、5 g/kg)灌胃,DOX停止后,持續(xù)RLM灌胃4周。
1.3 血清及心肌組織的獲取
大鼠處理結(jié)束后,獲取血液標本,8000×g離心10 min獲取血清用于測定TC、AST、LDH和CK-MB。隨后解剖大鼠,分離心臟,生理鹽水漂洗2次。將心臟組織剪切,制備成20%的勻漿后,二喹啉甲酸法測定其總蛋白濃度及AST、LDH、CK-MB活性、TC水平(mg/dL)。
1.4 心肌MDA測定
心臟勻漿與等體積2.3%的KCl混合,600×g,4℃離心15 min,獲取上清用于測定MDA。其原理基于脂質(zhì)過氧化產(chǎn)物與硫代巴比妥酸發(fā)生過氧化反應(yīng),生成粉紅色的有色絡(luò)合物,從而用分光光度計以四甲氧基丙烷為標準品,532 nm和520 nm波長處測量其OD值。結(jié)果用nmol/mg表示。
1.5 心肌GSH測定
將等體積的心臟勻漿和預(yù)冷7.5%5-磺酸基水楊酸緩沖液以沉淀蛋白。隨后4℃,600×g離心10 min,獲取上清用于測量還原型GSH。其原理基于還原型GSH能與5,5-二硫代雙(2-硝基苯甲酸)反應(yīng),產(chǎn)物在421 nm波長處能形成最大吸收峰。含量用mg/g組織表示。
1.6 TNF-α和caspase-3測定
50 mg心肌組織加入0.8 mL pH 7.4的裂解緩沖液中制成勻漿,10 000×g,4℃離心15 min。獲取上清用于TNF-α和caspase-3測定。其中TNF-α根據(jù)試劑盒提供的步驟進行,采用固相夾心ELISA法,四甲基聯(lián)苯胺(TMB)法顯色并于450 nm波長處測量其吸光度,用pg/mg蛋白表示。采用間接法測定caspase-3活性,基于caspase-3切除底物分子DEVD-pNA中的發(fā)光基團pNA,隨后在405 nm處用測量其吸光度,用OD值表示,從而間接反應(yīng)其活性。
1.7 統(tǒng)計學(xué)方法
應(yīng)用SPSS 17.0軟件進行統(tǒng)計學(xué)分析,計量資料數(shù)據(jù)以均數(shù)±標準差(x±s)表示,并采用單因素方差分析數(shù)據(jù),行t檢驗,以P < 0.05為差異有統(tǒng)計學(xué)意義。
2 結(jié)果
2.1 各組大鼠血生化指標情況
心臟功能和血脂參數(shù)顯示,DOX注射后,血清AST、LDH、CK-MB、TC水平顯著增高。而同時給予RLM干預(yù)后,這些參數(shù)隨著RLM濃度的增高而不斷改善,見表1。
表1 不同濃度金櫻子處理對阿霉素心肌損傷大鼠
血生化指標的影響(x±s)
注:與空白對照組比較,*P < 0.05,**P < 0.01;與DOX模型組比較,#P < 0.05;AST:血清天冬氨酸轉(zhuǎn)氨酶;LDH:乳酸脫氫酶;TC:血清總膽固醇;CK-MB:肌酸激酶;RLM:金櫻子;DOX:阿霉素
2.2 不同濃度RLM對心肌DOX處理后MDA含量的影響
與空白對照組相比,DOX處理組能誘導(dǎo)心肌MDA明顯增加(P < 0.01),給予不同濃度RLM處理后,心肌MDA含量隨之降低,其中DOX+5 g/kg RLM處理后,MDA含量降低最多[(0.82±0.14) nmol/mg]。見圖1。
1.空白對照組;2.DOX模型組;3.DOX+1 g/kg RLM;4.DOX+3 g/kg RLM;5.DOX+5 g/kg RLM;與空白對照組比較,#P < 0.01;與DOX模型組比較,*P < 0.05;RLM:金櫻子;DOX:阿霉素
圖1 RLM對血清丙二醛含量的影響
2.3 不同濃度RLM對DOX心肌毒性大鼠GSH含量的影響
與空白對照組相比,DOX組大鼠血清總GSH含量顯著降低(P < 0.01)。而同時給予不同濃度RLM處理后,GSH含量隨之升高。5 g/kg RLM處理大鼠后,GSH含量[(1.06±0.11) pg/g]接近對照組水平(圖2)。
1.空白對照組;2.DOX模型組;3.DOX+1 g/kg RLM;4.DOX+3 g/kg RLM;5.DOX+5 g/kg RLM;與空白對照組比較,#P < 0.01;與DOX模型組比較,*P < 0.05;RLM:金櫻子;DOX:阿霉素
圖2 RLM對血清還原型谷胱甘肽含量的影響
2.4 RLM干預(yù)對大鼠血清TNF-α含量的影響
空白對照組大鼠血清中TNF-α含量較低,DOX處理后TNF-α顯著增高(P < 0.01)。RLM干預(yù)能以劑量依賴性方式降低血清中TNF-α的含量,其中DOX+5 g/kg RLM處理后,TNF-α含量降低最多[(3.49±0.05) pg/mg],見圖3。
2.5 RLM抑制caspase-3活性
DOX處理后,caspase-3活性增加了近50%。同時經(jīng)1~5 g/kg RLM處理后,caspase-3活性逐漸降至正常水平,其中DOX+5 g/kg RLM處理后,caspase-3活性降低最多(0.83±0.02)。見圖4。
1. 空白對照組;2.DOX模型組;3.DOX+1 g/kg RLM;4.DOX+3 g/kg RLM;5.DOX+5 g/kg RLM;與空白對照組比較,#P < 0.01;與DOX模型組比較,*P < 0.05;RLM:金櫻子;DOX:阿霉素
圖4 RLM對caspase-3活性的影響
3 討論
DOX是一種抗腫瘤抗生素,可抑制RNA和DNA的合成,對RNA的抑制作用最強,抗瘤譜較廣,對多種腫瘤均有作用,屬周期非特異性藥物,對各種生長周期的腫瘤細胞都有殺滅作用。主要適用于急性白血病,對急性淋巴細胞白血病及粒細胞白血病均有效,一般作為第二線藥物,即在首選藥物耐藥時可考慮應(yīng)用此藥。惡性淋巴瘤,可作為交替使用的首選藥物。DOX和其他奎寧蒽環(huán)類藥物一樣,主要的毒性反應(yīng)有:白細胞和血小板減少,60%~80%的患者可發(fā)生;100%的患者有不同程度的毛發(fā)脫落,停藥后可以恢復(fù)生長;心臟毒性,表現(xiàn)為心律失常,ST-T改變,多出現(xiàn)在停藥后的1~6個月[7]。本研究通過DOX建立心肌毒性模型發(fā)現(xiàn),血清AST、LDH和CK-MB顯著增加,這可能是由于DOX損傷心肌細胞膜后,AST、LDH和CK-MB漏出所致。本研究還發(fā)現(xiàn),DOX還可以導(dǎo)致TC含量增高,這可能是由于DOX導(dǎo)致腎病綜合征所致[8]。RLM屬薔薇科薔薇屬常綠蔓性灌木野生果樹,其果實中總糖含量達24%,其中多糖含量約為金櫻子果實的8.73%。研究顯示,RLM的抗氧化能力與丁基羥基甲苯相當,并能顯著清除超氧陰離子自由基、抑制羥自由基對細胞膜的破壞而引起的溶血和脂質(zhì)過氧化產(chǎn)物的形成,從而具有顯著的抗氧化作用[9]。此外,RLM金櫻子能減輕糖尿病腎病大鼠的氧化損傷,減少過氧化質(zhì),升高抗氧化酶活性,機制可能與干預(yù)氧化應(yīng)激、抑制核因子-κB、TNF-α表達有關(guān)。本研究顯示通過RLM灌胃后,大鼠的血清指標得到了顯著的改善[10-13]。同時,本研究還觀察了RLM對氧化應(yīng)激的影響。結(jié)果發(fā)現(xiàn),DOX能顯著增加心肌中MDA含量,同時顯著降低GSH水平。這可能是DOX導(dǎo)致氧化應(yīng)激,大量氧自由基的產(chǎn)生導(dǎo)致GSH減少。脂質(zhì)過氧化導(dǎo)致心肌細胞損傷后引起AST、LDH和CK-MB漏出至循環(huán)系統(tǒng)是由于心臟損傷[14]??诜LM能明顯降低脂蛋白過氧化物酶而提高GSH,這表明這些藥物能清除自由基和減少細胞損傷。另一方面,氧化應(yīng)激可激活p38絲裂原激活的蛋白激酶和核因子-κB,從導(dǎo)致TNF-α大量合成,反過來加重氧化應(yīng)激狀態(tài)而使線粒體膜通透性發(fā)生改變,隨后導(dǎo)致自由基和細胞色素C從線粒體中釋放到細胞質(zhì),激活caspase-3而引起凋亡發(fā)生[15-17]。RLM可能通過抑制組織中的應(yīng)激反應(yīng)而降低心肌中TNF-α和caspase-3含量。
總之,本研究證實RLM對DOX導(dǎo)致的心肌損傷有保護作用,其機制可能與抗氧化、抗炎和抗凋亡有關(guān)。在下一步研究中,筆者將對其分子機制進行進一步探討。
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[10] Zhou Y,Liao Q,Luo Y,et al. Renal protective effect of Rosa laevigata Michx. by the inhibition of oxidative stress in streptozotocin-induced diabetic rats [J].Mol Med Rep,2012,5(6):1548-1554.
[11] 趙海山,趙成建,張歡,等.甘脯酰阿霉素對斑馬魚胚胎的毒性評估[J].中國藥房,2012,23(41):3882-3884.
[12] 劉煥龍,康寧,李軍霞,等.戊地昔布聯(lián)合阿霉素對人乳腺癌細胞增殖的抑制作用及其機制研究[J].中國藥房,2012,23(29):2705-2707.
[13] 張祥林,鄭石磊,董福仁,等.鹽酸多西環(huán)素聯(lián)合碘油對兔VX2肝瘤凋亡、增殖及肝功能的影響研究[J].中國藥房,2012,23(33):3092-3094.
[14] Firdous AP,Kuttan R. Chemo protective activity of carotenoid meso-zeaxanthin against Doxorubicin-induced cardio toxicity [J]. J Exp Ther Oncol,2012,10(2):101-106.
[15] Alkreathy HM,Damanhouri ZA,Ahmed N,et al. Mechanisms of cardioprotective effect of aged garlic extract against Doxorubicin-induced cardiotoxicity[J]. Integr Cancer Ther,2012,11(4):364-370.
[16] 阿迪拉·阿扎提,趙龍,張玲,等.心肌細胞/膠原復(fù)合體移植心梗大鼠梗死周邊區(qū)的電偶聯(lián)網(wǎng)絡(luò)變化[J].中國實驗動物學(xué)報,2013,21(1):75-79.
[17] 仇普斌,劉超,李偉,等.誘導(dǎo)人臍帶間充質(zhì)干細胞向心肌細胞分化及對小鼠心肌梗死的治療作用[J].中國實驗動物學(xué)報,2012,20(5):9-14.
(收稿日期:2013-10-24 本文編輯:衛(wèi) 軻)
[3] Basu S,Ganguly A,Chakraborty P,et al. Targeting the mitochondrial pathway to induce apoptosis/necrosis through ROS by a newly developed Schiff's base to overcome MDR in cancer [J]. Biochimie,2012,94(1):166-183.
[4] Uma MB,Shrivastava S,Kuncha M,et al. Ethanolic extract of Boswellia ovalifoliolata bark and leaf attenuates Doxorubicin-induced cardiotoxicity in mice [J]. Environ Toxicol Pharmacol,2013,36(3):840-849.
[5] Jia Y,Ji L,Zhang S,et al. Total flavonoids from Rosa Laevigata Michx fruit attenuates hydrogen peroxide induced injury in human umbilical vein endothelial cells [J]. Food Chem Toxicol,2012,50(9):3133-3141.
[6] 趙云濤, 國興明,李付振. 金櫻子多糖的抗氧化作用[J].云南中醫(yī)中藥雜志,2003,24(4):35-37.
[7] Fu Z,Guo J,Jing L,et al. Enhanced toxicity and ROS generation by Doxorubicin in primary cultures of cardiomyocytes from neonatal metallothionein-I/II null mice [J]. Toxicol in Vitro,2010,24(6):1584-1591.
[8] Ai S,Zheng J,Lin Q,et al. Proteomic analysis indicates altered expression of plasma proteins in a rat nephropathy model [J]. Clin Exp Nephrol,2013,17(1):24-31.
[9] Zhang S,Zheng L,Dong D,et al. Effects of flavonoids from Rosa laevigata Michx fruit against high-fat diet-induced non-alcoholic fatty liver disease in rats[J]. Food Chem,2013,141(3):2108-2116.
[10] Zhou Y,Liao Q,Luo Y,et al. Renal protective effect of Rosa laevigata Michx. by the inhibition of oxidative stress in streptozotocin-induced diabetic rats [J].Mol Med Rep,2012,5(6):1548-1554.
[11] 趙海山,趙成建,張歡,等.甘脯酰阿霉素對斑馬魚胚胎的毒性評估[J].中國藥房,2012,23(41):3882-3884.
[12] 劉煥龍,康寧,李軍霞,等.戊地昔布聯(lián)合阿霉素對人乳腺癌細胞增殖的抑制作用及其機制研究[J].中國藥房,2012,23(29):2705-2707.
[13] 張祥林,鄭石磊,董福仁,等.鹽酸多西環(huán)素聯(lián)合碘油對兔VX2肝瘤凋亡、增殖及肝功能的影響研究[J].中國藥房,2012,23(33):3092-3094.
[14] Firdous AP,Kuttan R. Chemo protective activity of carotenoid meso-zeaxanthin against Doxorubicin-induced cardio toxicity [J]. J Exp Ther Oncol,2012,10(2):101-106.
[15] Alkreathy HM,Damanhouri ZA,Ahmed N,et al. Mechanisms of cardioprotective effect of aged garlic extract against Doxorubicin-induced cardiotoxicity[J]. Integr Cancer Ther,2012,11(4):364-370.
[16] 阿迪拉·阿扎提,趙龍,張玲,等.心肌細胞/膠原復(fù)合體移植心梗大鼠梗死周邊區(qū)的電偶聯(lián)網(wǎng)絡(luò)變化[J].中國實驗動物學(xué)報,2013,21(1):75-79.
[17] 仇普斌,劉超,李偉,等.誘導(dǎo)人臍帶間充質(zhì)干細胞向心肌細胞分化及對小鼠心肌梗死的治療作用[J].中國實驗動物學(xué)報,2012,20(5):9-14.
(收稿日期:2013-10-24 本文編輯:衛(wèi) 軻)
[3] Basu S,Ganguly A,Chakraborty P,et al. Targeting the mitochondrial pathway to induce apoptosis/necrosis through ROS by a newly developed Schiff's base to overcome MDR in cancer [J]. Biochimie,2012,94(1):166-183.
[4] Uma MB,Shrivastava S,Kuncha M,et al. Ethanolic extract of Boswellia ovalifoliolata bark and leaf attenuates Doxorubicin-induced cardiotoxicity in mice [J]. Environ Toxicol Pharmacol,2013,36(3):840-849.
[5] Jia Y,Ji L,Zhang S,et al. Total flavonoids from Rosa Laevigata Michx fruit attenuates hydrogen peroxide induced injury in human umbilical vein endothelial cells [J]. Food Chem Toxicol,2012,50(9):3133-3141.
[6] 趙云濤, 國興明,李付振. 金櫻子多糖的抗氧化作用[J].云南中醫(yī)中藥雜志,2003,24(4):35-37.
[7] Fu Z,Guo J,Jing L,et al. Enhanced toxicity and ROS generation by Doxorubicin in primary cultures of cardiomyocytes from neonatal metallothionein-I/II null mice [J]. Toxicol in Vitro,2010,24(6):1584-1591.
[8] Ai S,Zheng J,Lin Q,et al. Proteomic analysis indicates altered expression of plasma proteins in a rat nephropathy model [J]. Clin Exp Nephrol,2013,17(1):24-31.
[9] Zhang S,Zheng L,Dong D,et al. Effects of flavonoids from Rosa laevigata Michx fruit against high-fat diet-induced non-alcoholic fatty liver disease in rats[J]. Food Chem,2013,141(3):2108-2116.
[10] Zhou Y,Liao Q,Luo Y,et al. Renal protective effect of Rosa laevigata Michx. by the inhibition of oxidative stress in streptozotocin-induced diabetic rats [J].Mol Med Rep,2012,5(6):1548-1554.
[11] 趙海山,趙成建,張歡,等.甘脯酰阿霉素對斑馬魚胚胎的毒性評估[J].中國藥房,2012,23(41):3882-3884.
[12] 劉煥龍,康寧,李軍霞,等.戊地昔布聯(lián)合阿霉素對人乳腺癌細胞增殖的抑制作用及其機制研究[J].中國藥房,2012,23(29):2705-2707.
[13] 張祥林,鄭石磊,董福仁,等.鹽酸多西環(huán)素聯(lián)合碘油對兔VX2肝瘤凋亡、增殖及肝功能的影響研究[J].中國藥房,2012,23(33):3092-3094.
[14] Firdous AP,Kuttan R. Chemo protective activity of carotenoid meso-zeaxanthin against Doxorubicin-induced cardio toxicity [J]. J Exp Ther Oncol,2012,10(2):101-106.
[15] Alkreathy HM,Damanhouri ZA,Ahmed N,et al. Mechanisms of cardioprotective effect of aged garlic extract against Doxorubicin-induced cardiotoxicity[J]. Integr Cancer Ther,2012,11(4):364-370.
[16] 阿迪拉·阿扎提,趙龍,張玲,等.心肌細胞/膠原復(fù)合體移植心梗大鼠梗死周邊區(qū)的電偶聯(lián)網(wǎng)絡(luò)變化[J].中國實驗動物學(xué)報,2013,21(1):75-79.
[17] 仇普斌,劉超,李偉,等.誘導(dǎo)人臍帶間充質(zhì)干細胞向心肌細胞分化及對小鼠心肌梗死的治療作用[J].中國實驗動物學(xué)報,2012,20(5):9-14.
(收稿日期:2013-10-24 本文編輯:衛(wèi) 軻)