环孢素A对小鼠早期胚胎体外发育的影响
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摘要
目前体外受精一胚胎移植(In vitro fertilization and embryo transfer, IVF-ET)的胚胎种植率低。胚胎植入是IVF-ET技术临床妊娠的关键,而着床前的胚胎发育一定程度上决定了胚胎的植入潜能。为改善妊娠结局,生殖医学临床在不断改进超促排卵方案以求获得高质量卵子的同时,胚胎实验室也在不断探索胚胎体外发育的合适条件及有利因素。
环孢素A(Cyclosporin A, CsA)是一种免疫抑制剂,广泛用于器官移植后免疫排斥反应和免疫性疾病的防治。研究显示,合适剂量的CsA不仅能诱导母胎界面及外周的免疫耐受,还能促进人早孕期绒毛滋养细胞增殖、抑制滋养细胞凋亡,增强其运动、迁移和侵袭能力从而对妊娠起到双重调节作用。绒毛细胞滋养细胞来源于胚胎滋养叶细胞,除滋养细胞外CsA尚对多种细胞的生长具有调节作用,故推测CsA可能在植入前的胚胎发育中发挥作用。
目的
本研究通过观查不同时期添加CsA和添加不同浓度CsA的培养基中2细胞胚胎体外培养的发育情况,探讨CsA对植入前胚胎发育的影响及起始阶段和有利于早期胚胎发育的最佳剂量。旨在探索体外受精-胚胎移植(In vitro fertilization and embryo transfer, IVF-ET)中改善胚胎质量,提高胚胎种植潜能的有效途径。
方法
1.4周龄ICR雌鼠实验前超促排卵,自然交配。实验当天解剖小鼠,收集2细胞胚胎。所获胚胎同等级别均分为几个实验组,卵裂液(cleavage medium, CM)和囊胚液(blastocyst medium, BM)序贯培养,每天观察胚胎发育至囊胚孵出。
2.观察从不同时期添加1μmol/LCsA对小鼠胚胎体外发育的影响。胚胎共分三组培养,2细胞期加入CsA组、桑椹胚期加入CsA组和未加CsA组(对照组)。观察各期胚胎发育情况。
3.观察不同浓度CsA对小鼠胚胎体外发育的影响。胚胎共分四组培养,培养基分别添加10、1、0.1、0μmol/LCsA。观察各组囊胚形成及孵出情况。
4.扩张期囊胚总细胞计数。采用Hoechst 33258荧光染色,荧光显微镜下计数。
5.统计方法：采用SPSS13.0统计学软件对实验数据进行统计学分析。定性资料采用卡方检验；定量资料采用方差分析。a=0.05为检验水准,P<0.05为差异有显著性。
结果
1.从不同时期添加1μmol/L的CsA对早期胚胎发育的影响
2细胞期加入CsA,桑葚胚加入CsA和未加入CsA组(对照组),三组胚胎4-8细胞胚胎形成率分别为71.9%、62.5%和63.6%；桑葚胚形成率分别为70.8%、62.5%和62.5%；囊胚形成率分别为62.9%、58%和53.4%；囊胚孵出率分别为37.5%、25.5%和21.3%,差异均无显著性(P>0.05)。
2.不同浓度CsA对早期胚胎发育的影响
10、1、0.1、0μmol/LCsA组,总囊胚形成率分别为82.1%、73.6%、70.7%和71.3%,差异无统计学意义(P>0.05)；扩张期囊胚形成率分为65.5%、50.6%、47.7%和48.2%,除10μmol/LCsA组与其它三组比较差异有显著性外(P<0.05),其余各组比较均无显著性；囊胚孵出率分别为44.9%、42.2%、34.4%和38.7%,差异无显著性(P>0.05)。囊胚孵出率(Y)和CsA的浓度(X)存在相关性,相关方程Y=0.05251gX+0.405(r=0.9629)。
3.不同浓度的CsA对小鼠囊胚总细胞数的影响
添加有10、1、0.1、0μmol/LCsA组,扩张囊胚总细胞数(x±s)分别为79±4.5、78+4.2、74.6±4.3和77.2+5.3,除1组和3组比较差异有显著性外(P<0.05),其余各组比较均无显著性(P>0.05)。
结论
一定剂量的CsA从2细胞期就起到促进胚胎发育的作用,CsA在1-10μmol/L范围内呈剂量依赖性促进小鼠胚胎体外发育的囊胚形成和孵出率。
At present, embryo implantation rate is low in in vitro fertilization and embryo transfer (IVF-ET). Clinic pregnancy's crucial factor is embryo implantation of wich capacity is decided by the preimplantaion embryo development in some degree. To improve pregnancy outcome, the clinic was improving the controlled ovarian hyper stimulation (COH) protocals, while embryo lab was exploring appropriate conditions and favorable factors for embryo development in vitro.
Cyclosporine A (CsA) is immune depressant which is widely used to suppress immunological rejection in organ transplantation and treat immunological disease's. Researches reveal that appropriate dosage of CsA induce the maternal-fetal immunity tolerance and enhance proliferation, movement, migration, invasion and inhibit apoptosis in trophoblasts. So CsA regulates early pregnancy from two aspects above. Placental trophoblast cell originat from trophectoderm cell. CsA can promote cell proliferation of many other kinds besides trophoblast cells, So we infer CsA can play a role in preimplantation embryo development.
Objectives
In this research,2-cell embryos development in vitro were observed when they were cultured in medium with CsA at different stage and medium with different consentration CsA respectively to discuss the effect and outset stage of CsA on early embryo development and the optimum dosage which is favorable for embryo development. The aim is to explore an effective way which can improve profound implantation capacity and promote implamtation rate of embryos.
Methods
1.2-cell embryos were obtained dissectively from ICR female mice (4 weeks after birth) after controlled ovulation hyperstimulation (COH) and mated naturally. Embryos obtained were divided into several groups and cultured subsequently in cleavage medium (CM) and blastocyst medium (BM). Embryo development were observed every day until hatching.
2. To test the effect of 1μmol/L of CsA on embryos of different stage. The embryos were divided into 3 groups:CsA was added in medium from 2-cell stage, morula stage and medium without CsA. Embryos development at every stage were observed.
3. To observe the effect of different concentration of CsA on early embryo development, the embryos were divided into 4 groups:2-cell embryos were cultured in medium with 10μmol/L,1μmol/L,0.1μmol/L and 0μmol/L (control) respectively. Blastocyst formation and hatching were observed.
4. Total cell number of was counted in expanded blastocysts. Using Hoechst 33258 fluorescent dying. under fluorescence microscope.
5. Statistical analysis was done by SPSS13.0 software package. Qualitative data were testes by x2, whereas quantitative data were tested by analysis of variance.
Results
1. Effect of 1μmol/L of CsA on embryos of different stage
Groups added CsA from 2-cell stage, morula stage and without CsA,4-8cell embryo formation rates were 71.9%,62.5% vs 63.6% respectively; morula formation rates were 70.8%,62.5% vs 62.5% respectively; blastocyst formation rates were 62.9%,58% vs 53.4% respectively; blastocyst hatching rates were 37.5%,25.5% vs 21.3% respectively, all differences were not significant(P>0.05).
2. The effect of different concentration of CsA on preimplantation embryos
Groups added with 10、1、0.1、0μmol/L CsA, the total blastocyts formation rates were 82.1%,73.6%,70.7%, and71.3% respectively, difference was not significant (P>0.05). the expanded blastocyst formation were 65.5%,50.6%,47.7% and 48.2% respectively, there was no significant difference except for comparison between G1 and other three groups (P<0.05). the blastocyts hatching rates were 44.9%,42.2%, 34.4% and 38.7% respectively, difference was not significant(P>0.05). the linear regression formation between concentrations of CsA(X) and hatching rates(Y) was Y=0.05251gX+0.405 (r=0.9629).
3. Effect of different concentration of CsA on total number of blastocyst cell.
The total number of blastocyst cell(x±s) in G1, G2, G3, and G4 were 79±4.5, 78±4.2,74.6±4.3, and 77.2±5.3 respectively, significant difference only existed between G1 and G3 (P<0.05).
Conclusion
The tendency of early embryo development in vitro reveals that appropriate dosage's CsA improves embryo development from 2-cell stage. In the range between 1μmol/L and lOμmol/L, the CsA may dose-dependently promote blastocyst formation and hatching.
环孢素A(Cyclosporin A, CsA)是一种免疫抑制剂,广泛用于器官移植后免疫排斥反应和免疫性疾病的防治。研究显示,合适剂量的CsA不仅能诱导母胎界面及外周的免疫耐受,还能促进人早孕期绒毛滋养细胞增殖、抑制滋养细胞凋亡,增强其运动、迁移和侵袭能力从而对妊娠起到双重调节作用。绒毛细胞滋养细胞来源于胚胎滋养叶细胞,除滋养细胞外CsA尚对多种细胞的生长具有调节作用,故推测CsA可能在植入前的胚胎发育中发挥作用。
目的
本研究通过观查不同时期添加CsA和添加不同浓度CsA的培养基中2细胞胚胎体外培养的发育情况,探讨CsA对植入前胚胎发育的影响及起始阶段和有利于早期胚胎发育的最佳剂量。旨在探索体外受精-胚胎移植(In vitro fertilization and embryo transfer, IVF-ET)中改善胚胎质量,提高胚胎种植潜能的有效途径。
方法
1.4周龄ICR雌鼠实验前超促排卵,自然交配。实验当天解剖小鼠,收集2细胞胚胎。所获胚胎同等级别均分为几个实验组,卵裂液(cleavage medium, CM)和囊胚液(blastocyst medium, BM)序贯培养,每天观察胚胎发育至囊胚孵出。
2.观察从不同时期添加1μmol/LCsA对小鼠胚胎体外发育的影响。胚胎共分三组培养,2细胞期加入CsA组、桑椹胚期加入CsA组和未加CsA组(对照组)。观察各期胚胎发育情况。
3.观察不同浓度CsA对小鼠胚胎体外发育的影响。胚胎共分四组培养,培养基分别添加10、1、0.1、0μmol/LCsA。观察各组囊胚形成及孵出情况。
4.扩张期囊胚总细胞计数。采用Hoechst 33258荧光染色,荧光显微镜下计数。
5.统计方法：采用SPSS13.0统计学软件对实验数据进行统计学分析。定性资料采用卡方检验；定量资料采用方差分析。a=0.05为检验水准,P<0.05为差异有显著性。
结果
1.从不同时期添加1μmol/L的CsA对早期胚胎发育的影响
2细胞期加入CsA,桑葚胚加入CsA和未加入CsA组(对照组),三组胚胎4-8细胞胚胎形成率分别为71.9%、62.5%和63.6%；桑葚胚形成率分别为70.8%、62.5%和62.5%；囊胚形成率分别为62.9%、58%和53.4%；囊胚孵出率分别为37.5%、25.5%和21.3%,差异均无显著性(P>0.05)。
2.不同浓度CsA对早期胚胎发育的影响
10、1、0.1、0μmol/LCsA组,总囊胚形成率分别为82.1%、73.6%、70.7%和71.3%,差异无统计学意义(P>0.05)；扩张期囊胚形成率分为65.5%、50.6%、47.7%和48.2%,除10μmol/LCsA组与其它三组比较差异有显著性外(P<0.05),其余各组比较均无显著性；囊胚孵出率分别为44.9%、42.2%、34.4%和38.7%,差异无显著性(P>0.05)。囊胚孵出率(Y)和CsA的浓度(X)存在相关性,相关方程Y=0.05251gX+0.405(r=0.9629)。
3.不同浓度的CsA对小鼠囊胚总细胞数的影响
添加有10、1、0.1、0μmol/LCsA组,扩张囊胚总细胞数(x±s)分别为79±4.5、78+4.2、74.6±4.3和77.2+5.3,除1组和3组比较差异有显著性外(P<0.05),其余各组比较均无显著性(P>0.05)。
结论
一定剂量的CsA从2细胞期就起到促进胚胎发育的作用,CsA在1-10μmol/L范围内呈剂量依赖性促进小鼠胚胎体外发育的囊胚形成和孵出率。
At present, embryo implantation rate is low in in vitro fertilization and embryo transfer (IVF-ET). Clinic pregnancy's crucial factor is embryo implantation of wich capacity is decided by the preimplantaion embryo development in some degree. To improve pregnancy outcome, the clinic was improving the controlled ovarian hyper stimulation (COH) protocals, while embryo lab was exploring appropriate conditions and favorable factors for embryo development in vitro.
Cyclosporine A (CsA) is immune depressant which is widely used to suppress immunological rejection in organ transplantation and treat immunological disease's. Researches reveal that appropriate dosage of CsA induce the maternal-fetal immunity tolerance and enhance proliferation, movement, migration, invasion and inhibit apoptosis in trophoblasts. So CsA regulates early pregnancy from two aspects above. Placental trophoblast cell originat from trophectoderm cell. CsA can promote cell proliferation of many other kinds besides trophoblast cells, So we infer CsA can play a role in preimplantation embryo development.
Objectives
In this research,2-cell embryos development in vitro were observed when they were cultured in medium with CsA at different stage and medium with different consentration CsA respectively to discuss the effect and outset stage of CsA on early embryo development and the optimum dosage which is favorable for embryo development. The aim is to explore an effective way which can improve profound implantation capacity and promote implamtation rate of embryos.
Methods
1.2-cell embryos were obtained dissectively from ICR female mice (4 weeks after birth) after controlled ovulation hyperstimulation (COH) and mated naturally. Embryos obtained were divided into several groups and cultured subsequently in cleavage medium (CM) and blastocyst medium (BM). Embryo development were observed every day until hatching.
2. To test the effect of 1μmol/L of CsA on embryos of different stage. The embryos were divided into 3 groups:CsA was added in medium from 2-cell stage, morula stage and medium without CsA. Embryos development at every stage were observed.
3. To observe the effect of different concentration of CsA on early embryo development, the embryos were divided into 4 groups:2-cell embryos were cultured in medium with 10μmol/L,1μmol/L,0.1μmol/L and 0μmol/L (control) respectively. Blastocyst formation and hatching were observed.
4. Total cell number of was counted in expanded blastocysts. Using Hoechst 33258 fluorescent dying. under fluorescence microscope.
5. Statistical analysis was done by SPSS13.0 software package. Qualitative data were testes by x2, whereas quantitative data were tested by analysis of variance.
Results
1. Effect of 1μmol/L of CsA on embryos of different stage
Groups added CsA from 2-cell stage, morula stage and without CsA,4-8cell embryo formation rates were 71.9%,62.5% vs 63.6% respectively; morula formation rates were 70.8%,62.5% vs 62.5% respectively; blastocyst formation rates were 62.9%,58% vs 53.4% respectively; blastocyst hatching rates were 37.5%,25.5% vs 21.3% respectively, all differences were not significant(P>0.05).
2. The effect of different concentration of CsA on preimplantation embryos
Groups added with 10、1、0.1、0μmol/L CsA, the total blastocyts formation rates were 82.1%,73.6%,70.7%, and71.3% respectively, difference was not significant (P>0.05). the expanded blastocyst formation were 65.5%,50.6%,47.7% and 48.2% respectively, there was no significant difference except for comparison between G1 and other three groups (P<0.05). the blastocyts hatching rates were 44.9%,42.2%, 34.4% and 38.7% respectively, difference was not significant(P>0.05). the linear regression formation between concentrations of CsA(X) and hatching rates(Y) was Y=0.05251gX+0.405 (r=0.9629).
3. Effect of different concentration of CsA on total number of blastocyst cell.
The total number of blastocyst cell(x±s) in G1, G2, G3, and G4 were 79±4.5, 78±4.2,74.6±4.3, and 77.2±5.3 respectively, significant difference only existed between G1 and G3 (P<0.05).
Conclusion
The tendency of early embryo development in vitro reveals that appropriate dosage's CsA improves embryo development from 2-cell stage. In the range between 1μmol/L and lOμmol/L, the CsA may dose-dependently promote blastocyst formation and hatching.
引文
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[40]Hongbo W, Yan W, Stephen M, et al. Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression in human preimplantation embryos[J]. Fertility and Sterility, 2003,80(2):736-742
[41]zhou WH, Du MR, Dong L, et al. Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway[J]. Hum Reprod,2007,22(10): 2743-2750
[1]onocyte/macrophage associated cytokines/chemokines in sensitized cardiac graft recipients[J]. Transplantation,2001,71(8):1179-1183
[2]Tajima K, Amakawa R, Ito T, et al. Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets[J]. Immunology,2003,108(3):321-328
[3]杨晓勇,张小东,高居忠.不同免疫抑制剂对树突细胞抗原递呈功能影响的比较研究[J].中华细胞与干细胞移植,2009,1(1)：58-65
[4]Chen T, Guo J, Yang M, et al. Cyclosporin A inpairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxyrenase-2 expression[J]. Blood,2004, 103(2):413-421
[5]Mallard. F, Brissot. E, Chevallier. P, Impact Of Cyclosporine A (CsA) Concentration On The Incidence Of Severe Acute Graft-Versus-Host Disease (GVHD) After Allogeneic Stem Cell Transplantation (allo-SCT)[J]. Biology of Blood and Marrow Transplantation 2009,15(2):116-117
[6]Du MR, Zhou WH, Dong L, et al. Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated API and Ca2+/calcineurin/NFAT signaling pathways[J]. Biol Reprod,2008,78(6):1102-1110
[7]Radwan Oczko M, Boratynska M, Klinger M, et al. Risk factors of gingival overgrowth ih kidney transplant recipients treated with cycloaporine A[J]. Ann Transplant,2003,8 (4):57
[8]王文瑜,闫福华,姚丽艳等.环孢素A与牙龈卟啉菌内毒素对牙龈成纤维细胞增殖及TGF-β1分泌影响的研究[J].口腔医学,2010,30(1)：12-14
[9]Hojo M, Morimoto T, MaluccioM, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism[J]. Nature,1999,397:530
[10]范卫新,Mecklenburg L,朱文元,等.环孢素对毛囊细胞凋亡和部分生长因子mRNA表达的影响[J].临床皮肤科杂志,2003,32(8)：435-438
[11]宋丽华,肖洲生,潘玮等.环孢素A对成骨细胞分化的影响[J].中华器官移植杂志,2003,24(4)：236-238
[12]于颖彦,李琦,朱正纲等.环孢素A抑制胃癌细胞株生长及其机制探讨[J].中华消化杂志,2005,25(2)：105-106
[13]杨龙,杨军珂,杨新春等.环孢素A对抑制外周血内皮祖细胞增殖活性的作用[J].中华 器官移植杂志,2008,29(10)：1042-1049
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[15]杜美蓉,李大金.环孢素A的药效学研究[J].中国要学杂志,2005,40(1)：1-3
[16]Norihiko O, Wang LX, Mi WY, et al. nhibition of mitochondrial remodeling by cyclosporine A preserves myocardial performance in a neonatal rabbit model of cardioplegic arrest[J].Thoracic and Cardiovascular Surgery,2008,135(3):585-593
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[2]林戈,卢光琇.配子质量对早期胚胎发育的影响.生殖与避孕[J],2000,20(5)：263-267
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[5]Susanna X, Tiziana M, Daniela T, et al. Embryo quality and implantation rate in two different culture media:ISM1 versus Universal IVF Medium[J]. Fertility and Sterility,2010,93(6): 1859-1863
[6]田莉,吴丹,沈浣长.短效GnRH激动剂在控制性超排卵长方案中应用效果比较[J].中国妇产科临床杂志,2009,10(6)：413-453
[7]赵红岩,孙莹璞,苏迎春等.短效达必佳两种将调节方案在控制性超排卵中的效果比较[J].生殖与避孕,2010,93(97)：2216-2221
[8]Hojo M, Morimoto T, MaluccioM, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism[J]. Nature,1999,397:530
[9]范卫新,Mecklenburg L,朱文元等.环孢素对毛囊细胞凋亡和部分生长因子mRNA表达的影响[J].临床皮肤科杂志,2003,32(8)：435-438
[10]宋丽华,肖洲生,潘玮等.环孢素A对成骨细胞分化的影响[J].中华器官移植杂志,2003,24(4)：236-238
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[12]于颖彦,李琦,朱正纲等.环孢素A抑制胃癌细胞株生长及其机制探讨[J].中华消化杂志,2005,25(2)：105-106
[13]杨龙,杨军珂,杨新春等.环孢素A对抑制外周血内皮祖细胞增殖活性的作用[J].中华器官移植杂志,2008,29(10)：1042-1049
[14]Sivaraman P. Management of pregnancy in transplant recipients [J].Transplantation Proceedings,2004,36:1999-2000.
[15]闫凤亭,李大金,孙晓溪等.环孢霉素A对小鼠妊娠失败模型妊娠预后的影响[J].中国免疫学杂志,2002,18(12)：711-713
[16]董琳,朱晓勇,杜美蓉等.环孢素A对小鼠自然流产模型外周CD4+CD25+T细胞及妊娠结局的影响[J].现代免疫学,2006,(2)：113-115
[17]周雯慧,杜美蓉,杜丽等.环孢素A对人蜕膜免疫细胞分泌IL-10与IFN-γ的调控作用 [J].现代免疫学,2006,26(4)：314-331
[18]宋华东.人胚胎植入过程中细胞因子谱的变化及米非司酮、环孢素A对其的影响[D].[硕士学位论文].广东：第一军医大学,2007
[19]Zhou WH, Dong L, Du MR, et al. Cyclosporin A improves murine pregnancy outcome in abortion-prone matings:involvement of CD80/86 and CD28/CTLA-4[J]. Reproduction, 2008,135(3):385-395
[20]闫凤亭,李大金,孙晓溪等.环孢素A对正常早孕期滋养细胞体外生长的调节作用[J].中华妇产科杂志,2002,37(2)：74-76
[21]Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct3/4 defines differentiation, dedifferentiation or self-renewal of ES cells [J]. Nat Genet,2000,24:372-376
[22]Niwa H, Toyooka Y, Shimosato D, et al. Interaction between Oct3/4 and Cdx2 Determines Trophectoderm Differentiation[J]. Cell,2001,123(5):917-929
[23]Watson AJ, WesthusinM E, De Sousa PA, et al. Gene expression regulation blastocyst formation [J]. Theriogenol,1999,51:117-133
[24]'Sullivan CM, Rancourt SL, LiuSY, et al. A novel murine tryptase involved in blastocyst hatching and outgrowth[J]. Reproduction,2001,122:61-71
[25]Du MR, Zhou WH, Dong L, et al. Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated API and Ca2+/calcineurin/NFAT signaling pathways[J]. Biol Reprod,2008,78(6):1102-1110
[26]Chiu WT, Shen SC, Chow JM, et al. Contribution of reactive oxygen species to migration/invasion of human glioblastoma cells U87 via ERK-dependent COX-2/PGE2 activation[J]. Neurobiology of Disease,2010,37(1):118-129
[27]杜美蓉,李大金.环孢素A的药效学研究[J].中国药学杂志,2005,40(1)：1-3
[28]Norihiko O, Wang LX, Mi WY, et al. nhibition of mitochondrial remodeling by cyclosporine A preserves myocardial performance in a neonatal rabbit model of cardioplegic arrest[J].Thoracic and Cardiovascular Surgery,2008,135(3):585-593
[29]Mbye LH, Singh IN, Sullivan PG, et al. Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog[J]. Exp Neurol,2008,209(1):243-253
[30]Jung JY, Jeong YJ, Jeong TS, et al. Inhibition of apoptotic signals in overgrowth of human gingival fibroblasts by cyclosporin A treatment[J]. Arch Oral Biol,2008,53(11):1042-1049
[31]黄睿,庄广伦.线粒体与卵子发育潜能[J].国外医学生殖健康分册,2004,23(1)：18-20
[32]Mohamed A, Bedaiwy MD, Tommaso Falcone MD, et al. Differential growth of human embryos in vitro:Role of reactive oxygen species[J]. Fertility and Sterility,2004,8(3):593-600
[33]James WC, Michael H. Toxic effects of oxygen on human embryo developmen t[J]. Hum Repro,2000,15(12):199-206
[34]Menezo Y, Barak Y. Comparison between day-2 embryos obtained either from ICSI or resulting from short insemination IVF:influence of maternal age[J]. Human Reprod,2000, 15(8):1776-1780
[35]Nasr-Esfahani MH, Aitken J R, Johnson MH. Hydrogen peroside levels in mouse oocytes and early cleavage stage embryos developed in vitro or in vivo[J]. Development,1990,109: 501-507
[36]Hung TH, Chen SF, Liou JD, et al. Bax, Bak and Mitochondrial Oxidants are Involved in Hypoxia-reoxygenation-induced Apoptosis in Human Placenta[J]. Placenta.2008,29(7): 565-583
[37]Matsuura K, Hayashi N, Takiue C, et al. Blastocyst quality scoring based on morphologic grading correlates with cell number[J]. Fertil Steril,2010
[38]Richter K S, Harris D C, Daneshmand S T, et al. Quantitative grading of a human blastocyst: optimal inner cell mass size andshape[J]. Fertil Steril,2001,76(6):1157-1167.
[39]Anil K, Jose R, Beth H, et al. Expression of the αv integrin adhesion molecule during develo pment of preimplantation human embryos[J].'Fertility and Sterility,2001,76(61):153-156
[40]Hongbo W, Yan W, Stephen M, et al. Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression in human preimplantation embryos[J]. Fertility and Sterility, 2003,80(2):736-742
[41]zhou WH, Du MR, Dong L, et al. Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway[J]. Hum Reprod,2007,22(10): 2743-2750
[1]onocyte/macrophage associated cytokines/chemokines in sensitized cardiac graft recipients[J]. Transplantation,2001,71(8):1179-1183
[2]Tajima K, Amakawa R, Ito T, et al. Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets[J]. Immunology,2003,108(3):321-328
[3]杨晓勇,张小东,高居忠.不同免疫抑制剂对树突细胞抗原递呈功能影响的比较研究[J].中华细胞与干细胞移植,2009,1(1)：58-65
[4]Chen T, Guo J, Yang M, et al. Cyclosporin A inpairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxyrenase-2 expression[J]. Blood,2004, 103(2):413-421
[5]Mallard. F, Brissot. E, Chevallier. P, Impact Of Cyclosporine A (CsA) Concentration On The Incidence Of Severe Acute Graft-Versus-Host Disease (GVHD) After Allogeneic Stem Cell Transplantation (allo-SCT)[J]. Biology of Blood and Marrow Transplantation 2009,15(2):116-117
[6]Du MR, Zhou WH, Dong L, et al. Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated API and Ca2+/calcineurin/NFAT signaling pathways[J]. Biol Reprod,2008,78(6):1102-1110
[7]Radwan Oczko M, Boratynska M, Klinger M, et al. Risk factors of gingival overgrowth ih kidney transplant recipients treated with cycloaporine A[J]. Ann Transplant,2003,8 (4):57
[8]王文瑜,闫福华,姚丽艳等.环孢素A与牙龈卟啉菌内毒素对牙龈成纤维细胞增殖及TGF-β1分泌影响的研究[J].口腔医学,2010,30(1)：12-14
[9]Hojo M, Morimoto T, MaluccioM, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism[J]. Nature,1999,397:530
[10]范卫新,Mecklenburg L,朱文元,等.环孢素对毛囊细胞凋亡和部分生长因子mRNA表达的影响[J].临床皮肤科杂志,2003,32(8)：435-438
[11]宋丽华,肖洲生,潘玮等.环孢素A对成骨细胞分化的影响[J].中华器官移植杂志,2003,24(4)：236-238
[12]于颖彦,李琦,朱正纲等.环孢素A抑制胃癌细胞株生长及其机制探讨[J].中华消化杂志,2005,25(2)：105-106
[13]杨龙,杨军珂,杨新春等.环孢素A对抑制外周血内皮祖细胞增殖活性的作用[J].中华 器官移植杂志,2008,29(10)：1042-1049
[14]Chiu WT, Shen SC, Chow JM, et al. Contribution of reactive oxygen species to migration/invasion of human glioblastoma cells U87 via ERK-dependent COX-2/PGE2 activation[J]. Neurobiology of Disease,2010,37(1):118-129
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