纳米雄黄制备及诱导U937肿瘤细胞凋亡机制研究
|
摘要
砷剂在治疗血液肿瘤方面已取得了令人瞩目的成绩,尤其是近年来对急性早幼粒细胞白血病(APL)的治疗已得到世界的公认,目前用于治疗APL的砷化合物主要是雄黄和As_2O_3。本课题组近年来开发的复方黄黛片对急性早幼粒细胞白血病的完全缓解率达98.6%。其中君药雄黄为硫化物类矿物雄黄族雄黄,主要成分为四硫化四砷,难溶于水,在胃肠道仅极少部分被吸收。随着纳米技术在中医药学中的应用,已有研究证明纳米技术可以改变雄黄的理化性质、增加其水溶性,从而达到减毒增效的用药目的。为了进一步完善纳米级雄黄的制备工艺,提高其生物利用度,本文对纳米雄黄粉体(nanoparticle realgar powders,NRP)的制备工艺、分析方法及其诱导细胞凋亡的机制进行了较为系统的研究。
主要对纳米雄黄粉体的制备工艺进行了优化,建立了纳米雄黄粉体的粒度分析研究方法,并对纳米雄黄粉体在小鼠体内的药动学进行了初步研究。同时本文也深入研究了PI3-K/Akt和SIRT1/p53途径在纳米雄黄粉体诱导U937细胞凋亡过程中所发挥的作用。
在对纳米级雄黄制备工艺进行优化研究的实验中,我们利用温度可控惰性气体高能球磨机来制备纳米级雄黄粉体,采用正交设计实验方法,对球料比(4:1～16:1)、球磨转速(23～38Hz)、球磨时间(4～16h)、球磨介质去离子水量(10～150mL)、球磨温度(-20～10℃)等球磨参数进行五因素四水平的正交实验设计。实验结果表明,制备纳米级雄黄的最佳工艺参数为球料比16:1、球磨转速38Hz、球磨温度-20℃、球磨时间12 h、去离子水量取50 mL。
采用扫描电镜和原子力显微镜对纳米雄黄表观形貌进行直接观察测定,用激光光散射法对纳米雄黄的粒度分布范围进行分析测定。经扫描电镜、原子力显微镜和激光散射颗粒度测定仪的测量,结果表明经上述优化工艺制备的纳米雄黄制剂粒径在100 nm以下的达90%,其中较大颗粒是由粒径在5～30 nm左右的细小晶粒和其周围的非晶体聚集而成。实验结果表明,扫描电镜法、原子力显微镜法和激光光散射法快速、简便、准确,可用于纳米雄黄的粒度检测。
小鼠体内药动学研究结果:纳米雄黄中砷在小鼠体内的药动学行为符合开放性血管外给药—室模型—级速率过程;纳米雄黄与传统水飞雄黄的药代动力学参数经统计学分析均有显著差异(P<0.05);与传统水飞雄黄相比,纳米雄黄中砷达峰时间早、峰浓度高、AUC大,在体内吸收快,消除慢,药物在体内维持时间长。
体外活性实验证明:纳米雄黄可明显诱导肿瘤细胞NB_4、HL-60、K562及U937产生凋亡,对U937作用尤为明显,本文对PI3-K/Akt和SIRT1/p53途径在纳米雄黄粉体诱导U937细胞凋亡过程中所发挥的作用进行了深入讨论。将20,40,60,80或100μg/mL的NRP作用于淋巴瘤U937细胞12,24,36或48小时,通过MTT法检测到NRP诱导U937细胞的死亡成一定时间和浓度依赖性。荧光显微镜下细胞呈明显的凋亡形态学特征,细胞膜出泡、细胞核浓缩且有颗粒状的凋亡小体出现。采用乳酸脱氢酶活力(LDH)实验,测定凋亡和坏死细胞的比例,20～80μg/mLNRP作用U937细胞24h,凋亡的细胞显著增加,而坏死的细胞没有显著的变化且仍低于10.8%,当NRP的浓度增加至120μg/mL时,凋亡细胞比率开始明显下降,坏死细胞比率开始明显增加,结果表明NRP诱导U937细胞的死亡过程是一个介于细胞凋亡与细胞坏死之间的平衡过程。我们采用流式细胞术和Western blot方法相结合,检测了PI3-K/Akt途径对NRP诱导U937细胞凋亡的影响,实验结果表明PI3-K/Akt途径对细胞凋亡具有保护作用,而NRP通过抑制PI3-K/Akt途径的活化从而促进了U937细胞的凋亡。我们采用MTT法和Western blot方法进一步考察了SIRT1和p53在NRP诱导U937细胞凋亡过程中所发挥的作用,结果表明NRP活化了p53,而SIRT1的抑制剂sirtinol进一步增强了p53的活化。且Western blot结果显示,PI3-K的抑制剂wortmannin对SIRT1的表达有明显的抑制作用,从而增强了p53的活化作用。以上结果说明,在NRP诱导U937细胞死亡过程中,PI3-K/Akt信号通路与SIRT1/p53信号通路密切相关。NRP抑制了PI3-K/Akt途径的激活,从而抑制了SIRT1蛋白表达,使p53进一步激活,并引发了U937细胞通过caspase途径进行的凋亡。
The arsenical agents(As) such as realgar and AS_2O_3 show an obvious effect on hematological oncology,especially Acute Promyelocytic Leukemia(APL).The previous research of our work found the alleviation rate of the compound realgar natural indigo tablets on APL could be 98.6%.The main component of this tablet is a kind of mineral medicine-realgar,which is indissoluble and hard for absorption. There were references that the physi-chemical properties,efficiency and toxicity of realgar could be changed by nano-technology.For the purpose of promoting the bio-availability,and decreasing the toxicity of it,the preparation of nanoparticle realgar powders(NRP) by nano-technology,and the phamacokinetics in mice, together with the further mechanism of human histocytic lymphoma U937 cell apoptosis were studied.
NRP were milled with a plenary mill which was full of nitrogen.And the factors, such as the mass ratio of steel balls to realgar(4:1-16:1),the velocity of revolution (23-3 8Hz),the time of ball milling(4-16h),the temperature time(-20~10℃) and the volume of H_2O(10-150mL) were checked and analysed under the arrangement of orthogonal design of experiment.The result showed tharthe optimum parameters in the preparation of NRP were as follows:the mass ratio of mill balls to realgar was 16:1,the velocity of revolution was 38Hz,the temperature was -20℃,and the ball milling time was 12h adding 50 mL H_2O as surfactant.
NRP were dectected by scanning electron microscopy(SEM),atomic force microscopy(AFM),and laser scattering particle size distribution analyzer(PSD).The result exhibited that the size of about 90%of realgar particles were under 100 nm,and the bigger particles were the polymers of small grains at 5-30 nm and amorphous bodies around them.These methods of AFM,PSD and SEM showed the rapid,simple and accurate characters for the detection size distribution and apparent state.
The data obtained from a single oral administration of NRP revealed that the elimination model of As was in accordance with first order kinetics and one compartment model.The pharmacokinetics parameters of NRP were obviously different from these of traditional realgar,the absorption phase of which increased while elimination phase decreased.
The previous study showed that NRP could induce NB_4,HL-60,K562,U937 cell apoptosis.We herein research on the mechanism by which nanoparticle realgar powders(NRP) induce human histocytic lymphoma U937 cell apoptosis.The U937 cells were treated with 20,40,60,80 or 100μg/mL NRP for 12,24,36 or 48 h, respectively,and the cell death ratio was detected by MTT assay.The result showed that the NRP inhibited the cell growth in a concentration- and time- dependent manner. We also observed the morphologic changes by acridine orange(AO) staining.U937 cells treated with NRP showed membrane blebbing,condensed nuclear and granular apoptotic bodies under the fluorescence microscopy.The apoptotic and necrotic ratio was measured by LDH activity-based assay.The results indicated that when the cells were cultured with 20-80μg/mL NRP for 24 h,the majority of U937 cells underwent apoptosis and increased in a concentration-dependent manner,and the ratio of necrotic cells were still below 10.8%.However,incubation of U937 cells with 120μg/mL NRP made the necrotic ratio augmented markedly,showing that NRP induced U937 cell death through mediating the balance between apoptosis and necrosis.In order to investigate the effects of PI3-K/Akt signal pathway on the NRP-induced U937 cell death,flow cytometric analysis and western blot analysis were carried out.The results showed that NRP inhibited the activation of the PI3-K/Akt signal pathway,and consequently promoted the cell death.Furthermore, the western blot analysis in combination with MTT assay was applied to examine the roles of SIRT1 and p53 in the NRP-induced U937 cell death,and the results indicated that NRP activated p53,and the SIRT1 inhibitor sirtinol further promoted the activation of p53.In the experiment of western blot analysis,the PI3-K inhibitor wortmannin decreased the expression of SIRT1,and then,made the p53 activated further.Based on all the results,PI3-K/Akt signal pathway was intimately associated with SIRT1/ p53 signal pathway in NRP-induced U937 cell apoptosis.In NRP-treated cells,PI3-K/Akt pathway was restrained,which further inhibited the expression of SIRT1,and played a positive role for p53 activation.Consequently,all these contributed to the NRP-induced U937 cell apoptosis by means of caspase pathway.
主要对纳米雄黄粉体的制备工艺进行了优化,建立了纳米雄黄粉体的粒度分析研究方法,并对纳米雄黄粉体在小鼠体内的药动学进行了初步研究。同时本文也深入研究了PI3-K/Akt和SIRT1/p53途径在纳米雄黄粉体诱导U937细胞凋亡过程中所发挥的作用。
在对纳米级雄黄制备工艺进行优化研究的实验中,我们利用温度可控惰性气体高能球磨机来制备纳米级雄黄粉体,采用正交设计实验方法,对球料比(4:1～16:1)、球磨转速(23～38Hz)、球磨时间(4～16h)、球磨介质去离子水量(10～150mL)、球磨温度(-20～10℃)等球磨参数进行五因素四水平的正交实验设计。实验结果表明,制备纳米级雄黄的最佳工艺参数为球料比16:1、球磨转速38Hz、球磨温度-20℃、球磨时间12 h、去离子水量取50 mL。
采用扫描电镜和原子力显微镜对纳米雄黄表观形貌进行直接观察测定,用激光光散射法对纳米雄黄的粒度分布范围进行分析测定。经扫描电镜、原子力显微镜和激光散射颗粒度测定仪的测量,结果表明经上述优化工艺制备的纳米雄黄制剂粒径在100 nm以下的达90%,其中较大颗粒是由粒径在5～30 nm左右的细小晶粒和其周围的非晶体聚集而成。实验结果表明,扫描电镜法、原子力显微镜法和激光光散射法快速、简便、准确,可用于纳米雄黄的粒度检测。
小鼠体内药动学研究结果:纳米雄黄中砷在小鼠体内的药动学行为符合开放性血管外给药—室模型—级速率过程;纳米雄黄与传统水飞雄黄的药代动力学参数经统计学分析均有显著差异(P<0.05);与传统水飞雄黄相比,纳米雄黄中砷达峰时间早、峰浓度高、AUC大,在体内吸收快,消除慢,药物在体内维持时间长。
体外活性实验证明:纳米雄黄可明显诱导肿瘤细胞NB_4、HL-60、K562及U937产生凋亡,对U937作用尤为明显,本文对PI3-K/Akt和SIRT1/p53途径在纳米雄黄粉体诱导U937细胞凋亡过程中所发挥的作用进行了深入讨论。将20,40,60,80或100μg/mL的NRP作用于淋巴瘤U937细胞12,24,36或48小时,通过MTT法检测到NRP诱导U937细胞的死亡成一定时间和浓度依赖性。荧光显微镜下细胞呈明显的凋亡形态学特征,细胞膜出泡、细胞核浓缩且有颗粒状的凋亡小体出现。采用乳酸脱氢酶活力(LDH)实验,测定凋亡和坏死细胞的比例,20～80μg/mLNRP作用U937细胞24h,凋亡的细胞显著增加,而坏死的细胞没有显著的变化且仍低于10.8%,当NRP的浓度增加至120μg/mL时,凋亡细胞比率开始明显下降,坏死细胞比率开始明显增加,结果表明NRP诱导U937细胞的死亡过程是一个介于细胞凋亡与细胞坏死之间的平衡过程。我们采用流式细胞术和Western blot方法相结合,检测了PI3-K/Akt途径对NRP诱导U937细胞凋亡的影响,实验结果表明PI3-K/Akt途径对细胞凋亡具有保护作用,而NRP通过抑制PI3-K/Akt途径的活化从而促进了U937细胞的凋亡。我们采用MTT法和Western blot方法进一步考察了SIRT1和p53在NRP诱导U937细胞凋亡过程中所发挥的作用,结果表明NRP活化了p53,而SIRT1的抑制剂sirtinol进一步增强了p53的活化。且Western blot结果显示,PI3-K的抑制剂wortmannin对SIRT1的表达有明显的抑制作用,从而增强了p53的活化作用。以上结果说明,在NRP诱导U937细胞死亡过程中,PI3-K/Akt信号通路与SIRT1/p53信号通路密切相关。NRP抑制了PI3-K/Akt途径的激活,从而抑制了SIRT1蛋白表达,使p53进一步激活,并引发了U937细胞通过caspase途径进行的凋亡。
The arsenical agents(As) such as realgar and AS_2O_3 show an obvious effect on hematological oncology,especially Acute Promyelocytic Leukemia(APL).The previous research of our work found the alleviation rate of the compound realgar natural indigo tablets on APL could be 98.6%.The main component of this tablet is a kind of mineral medicine-realgar,which is indissoluble and hard for absorption. There were references that the physi-chemical properties,efficiency and toxicity of realgar could be changed by nano-technology.For the purpose of promoting the bio-availability,and decreasing the toxicity of it,the preparation of nanoparticle realgar powders(NRP) by nano-technology,and the phamacokinetics in mice, together with the further mechanism of human histocytic lymphoma U937 cell apoptosis were studied.
NRP were milled with a plenary mill which was full of nitrogen.And the factors, such as the mass ratio of steel balls to realgar(4:1-16:1),the velocity of revolution (23-3 8Hz),the time of ball milling(4-16h),the temperature time(-20~10℃) and the volume of H_2O(10-150mL) were checked and analysed under the arrangement of orthogonal design of experiment.The result showed tharthe optimum parameters in the preparation of NRP were as follows:the mass ratio of mill balls to realgar was 16:1,the velocity of revolution was 38Hz,the temperature was -20℃,and the ball milling time was 12h adding 50 mL H_2O as surfactant.
NRP were dectected by scanning electron microscopy(SEM),atomic force microscopy(AFM),and laser scattering particle size distribution analyzer(PSD).The result exhibited that the size of about 90%of realgar particles were under 100 nm,and the bigger particles were the polymers of small grains at 5-30 nm and amorphous bodies around them.These methods of AFM,PSD and SEM showed the rapid,simple and accurate characters for the detection size distribution and apparent state.
The data obtained from a single oral administration of NRP revealed that the elimination model of As was in accordance with first order kinetics and one compartment model.The pharmacokinetics parameters of NRP were obviously different from these of traditional realgar,the absorption phase of which increased while elimination phase decreased.
The previous study showed that NRP could induce NB_4,HL-60,K562,U937 cell apoptosis.We herein research on the mechanism by which nanoparticle realgar powders(NRP) induce human histocytic lymphoma U937 cell apoptosis.The U937 cells were treated with 20,40,60,80 or 100μg/mL NRP for 12,24,36 or 48 h, respectively,and the cell death ratio was detected by MTT assay.The result showed that the NRP inhibited the cell growth in a concentration- and time- dependent manner. We also observed the morphologic changes by acridine orange(AO) staining.U937 cells treated with NRP showed membrane blebbing,condensed nuclear and granular apoptotic bodies under the fluorescence microscopy.The apoptotic and necrotic ratio was measured by LDH activity-based assay.The results indicated that when the cells were cultured with 20-80μg/mL NRP for 24 h,the majority of U937 cells underwent apoptosis and increased in a concentration-dependent manner,and the ratio of necrotic cells were still below 10.8%.However,incubation of U937 cells with 120μg/mL NRP made the necrotic ratio augmented markedly,showing that NRP induced U937 cell death through mediating the balance between apoptosis and necrosis.In order to investigate the effects of PI3-K/Akt signal pathway on the NRP-induced U937 cell death,flow cytometric analysis and western blot analysis were carried out.The results showed that NRP inhibited the activation of the PI3-K/Akt signal pathway,and consequently promoted the cell death.Furthermore, the western blot analysis in combination with MTT assay was applied to examine the roles of SIRT1 and p53 in the NRP-induced U937 cell death,and the results indicated that NRP activated p53,and the SIRT1 inhibitor sirtinol further promoted the activation of p53.In the experiment of western blot analysis,the PI3-K inhibitor wortmannin decreased the expression of SIRT1,and then,made the p53 activated further.Based on all the results,PI3-K/Akt signal pathway was intimately associated with SIRT1/ p53 signal pathway in NRP-induced U937 cell apoptosis.In NRP-treated cells,PI3-K/Akt pathway was restrained,which further inhibited the expression of SIRT1,and played a positive role for p53 activation.Consequently,all these contributed to the NRP-induced U937 cell apoptosis by means of caspase pathway.
引文
[1]一ノ濑升,尾崎义治,贺集诚一郎.超微颗粒导论[M].赵修建,张联盟译.武汉:武汉工业大学出版社,1991.
[2]Keahler T.Nanotechnology:basic concepts and definitions[J].Clin Chem,1994,40(9):1797-1799.
[3]李国庆,卢广文,林意群.纳米技术及其在生物工程和医药学上的应用[J].医疗设备,2002,(3):8-11.
[4]张玉华,潘云涛,马峥.从文献计量看世界纳米研究的发展状况[J].世界科技研究与发展,2002,(3):49-54.
[5]杨祥良.基于纳米技术的中药基础问题研究[J].华中理工大学学报,2000,28(12):104-105.
[6]徐辉碧主编.纳米医药[M].第1版.北京:清华大学出版社,2004.2.
[7]王晓波,袭荣刚,李忠亮,等.纳米级雄黄粉体的制备[J].解放军药学学报,2002,18(3):129-134.
[8]Liversidge GG,Cundy KC.Particle size reduction for improvement of oral bioavailability of hydrophobic drugs:I.Absolute oral bioavailability of nano-crystalline danazol in beagle dogs[J].Int J Pharm,1995,125(1):91-97.
[9]Kayser O,Olbrich C,Yardley V,et al.Formulation of amphotericin B as nano-suspension for oral administration[J].Int J Pharm,2003,254(1):73-75
[10]Clark MA,Jepson MA,Hirst BH.Exploring M cells for drug and vaccine delivery[J].Adv Drug Dliv Rev,2001,50(1-2):81-106.
[11]Krause KP,Kayser O,Mader K,et al.Heavy metal contamination of nano-suspensions produced by high-pressure homogenisation[J].Int J Pharm,2000,196(2):169-172.
[12]Zhu Maoquan,Liu Song,Gu Hongzhan,et al.Study on Sol id Dispersion of Tanshinone[J].Journal of East China University of Science and Technology,2001,27(2):191-194.
[13]Ribrioux S,Kleymann G,WinfriedH,et al.Use of Nano-gold andFluorescent labeled Antibody Fv Fragments in Immun ocytochemistry[J].J Histochem Cytochem,1996,44(3):207-213.
[14]张小宁,张郁,姬海红,等.微射流法制备莪术油纳米脂质体的研究[J].中国药学杂志,2004,39(5):356-358.
[15]张小宁.中药纳米新技术——微射流纳米药物制剂的生产[J].流程工业,2002,6:36-67.
[16]HE Lei,WANG Guiling,ZHANG Qiang.Studies on Hypersensitivity and Pharmacokinetics of Paclitaxel Microemulsion.Acta Pharmaceutica Sinica,2003,38(3):227-230.
[17]王勇,胡坪,刘清飞,等.Chinese Traditional Patent Medicine January.2007,Vol.29 No.1 112-117
[18]Vila A,Sanchez A,Tobio M,et al.Design of biodegradable particles for protein delivery[J].J Control Release,2002,78:15-24.
[19]Yong Zhang,Nathan Kohler,Miqin Zhang.Surface modification of super paramagnetic magnetite nano-particles and their intracellular up take[J].B iom aterials,2002,23:1553-1561.
[20]Caroline Lemarehand,Ruxandra Oref,Patrick Couvreur.Poly-saccharide decorated nanoparticles [J].Eur J Pharm B iopharm,2004,58:327-341.
[21]AngelaM.De Campos,Alejandro Sanchez,Ruxandra Gref,et al.The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa[J].Eur J Pharm Sci,2003,20:73-81.
[22]Hirofumi Takcuchi,Hiromitsu Yamamoto,Yoshiaki Kawashima.Mucoadhesive nanoparticulate systems for pep tide drug delivery[J].Adv Drug Deliver Rev,2001,47:39-54.
[23]Cassidy O E,Rowley G,Fletcher I W,et al.Surface modification and electrostatic charge of polystyrene particles[J].Int J Pharm,1999,182:199-211.
[24]Moghimi SM,Gray T.A single dose of intravenously injected poloxamine-coated longcirculating particles triggers macrophage clearance of subsequent doses in rats[J].Clin Sci,1997,93(4):371-379.
[25]Kreuter J,Nano-particles.In:Kreuter J.(Ed.).Colloidal Drug Delivery Systems[J].New York:Marcel Dekker,1994,219-342.
[26]Xu H B,Yang X L,Xie C S,et al.Nano-technology apply in Chinese tradi-tional medicine investigation[J].J China Pharm Univ,2001,32(3):161-162.
[27]Langer R.Biomaterials in drug delivery and tissue engineering:One laboratory,sexperience [J].Acc Chem Res,2000,(33):94-101.
[28]靳琦,胡定邦,王子炎.论中药现代化研究的基本思路[J].中国医药学报,2000;15(2):57.
[29]MEI Zhinan.Experimental research on triptolide solid lipid nano-particle for decreasing liver toxicity of triptolide.Chinese Traditional and Herbal Drugs,2003,(9):817.Chinese.
[30]张卫东,刑建国.维感颗粒中挥发油β2环糊精包合物制备及稳定性研究[J].中成药,2005,27(5):515-517.
[31]纪明慧,刘红,何猛雄等.益智挥发油β2环糊精包合物的稳定性考察[J].中药材,2005,28(10):952-953.
[32]黎洪珊,赵京玲,魏树礼.环孢菌素A聚乳酸纳米粒胶体的制备和大鼠的口服吸收[J].中国药学杂志,1999,34(8):532-536.
[33]顾琳慧.日本开发纳米技术抗癌药投药方法[J].中国肿瘤,2001,10(8):479.
[34]Wei H,Li Y G.Nano-technolgoy apply on biomedicine engineering research actuality an development current[J].Foreign Med Sci:Sect Biomed Engirt,1999,22(6):340.
[35]丁玉玲,马淑贤,卢秀容,等.人参皂甙脂质体(GSL)的研制[J].中国药学杂志,1995,30(7):414-417.
[36]张晓辉,张贵君.纳米中药的研究前景[J].中医药信息,2003,20(1):25-26.
[37]高斐,王东凯,陈修毅.中药口服固体缓释制剂的研究进展[J].中草药,2005,36(7):1110-1113.
[34]Deng YJ,Xu F,Jin YG,et al.Preparation stability and immuno enhancement of APS lipisomes[J].Chin Phar Sci.1996,5(2):93-99.
[39]Storm P B,Moriarity J L,Tyler B,et al.Polymer delivery of camptothecin against 9L gliosarcoma:release,distribution,and efficacy[J].J Neurooncol,2002,56(3):209-217.
[40]王学清,张涛,贺颖,药学学报[J].2004,39(1):68-71.
[41]吴华,袁志芳,张小丽.中国医院药学杂志[J].2005,25(10):933-935.
[42]Chen J,Wu Z H.Medication transfer through blood and brain barrier by nanotech-nology[J].Foreign Med Sci:Pharmacy,2002,19(6):333-336.
[43]陈大兵,杨天智,吕万良,等.紫杉醇长循环固态脂质纳米粒的制备和体内外研究[J].药学学报,2002,37(1):54-58.
[44]陈永法,龚明涛,张钧寿,等.紫杉醇冻干纳米乳在大鼠体内的药动学[J].中国天然药物,2005,3(6):370-372.
[45]杨惠森,张拴,宁显唯.纳米技术在生物医药研究中的应用[J].陕西中医学院学报,2003,26(3):67-70.
[46]杨红武,毛衍平,邱应海,等.缬草β-环糊精包合物的工艺及稳定性研究[J].中国医院药学杂志,1998,18(12):544-547.
[47]邓嵘,陈济民,姚崇舜.莪术油明胶微球肝动脉栓塞[J].药学学报,2000;35(7):539.
[48]谢崇文,李旺生,凌艳等.β-环糊精在中药制剂中的应用及研究进展[J].中国中医药信息杂志,2001;8(3):36.
[49]丁寅,袁红宇,郭立玮等.负载士的宁纳米微粒研究[J].南京中医药大学学报(自然科学版),2002;18(3):156.
[50]孙铭,朱争艳,于美丽,等。去甲斑蝥素纳米控释制剂抗肿瘤的实验研究[J].肿瘤学杂志,2001,(6):321-325.
[51]徐辉碧,杨祥良,黄开勋.雄黄抑制小鼠肉瘤S180的尺寸效应的初步研究[J].武汉大学学报(自然科学版).Mar.2000,288-289.
[52]YANG ZH,ZHU MX,GONG YF,et ah Protection of nanometer-particulate Seoil the unbalanced immune functions and oxidative damage in mice induced by D-galactose[J].Studies of Trace Elements and Health,1999,16(1):4.
[53]WANG ZY,ZHANG DS,GU N,et ah Prepration and evaluation of arsenic trioxide nanoparticles for the treatment of human liver cancer cells SMMC-7721 in vitro[J].Journal of Southeast University,2005,21(1):58.
[54]Nobs L,Buchegger F,Gurny R,et ah Surface modification of poly(lactic acid)nano-particles by covalent attachment of thiolgroups bymeans of three methods[J].Int J Pharm,2003,250(2):327.
[55]De Jawghere F,Allemann E,Feijen J,et al.Freezedrying and lyopreservation of diblock and trilock[J].Pharm Dev Technol,2000,5(4):473.
[56]李泳雪,王春龙,李杰.纳米技术在现代中药制剂中的应用[J].中草药,2002,33(8):673-675.
[57]Wen J,Kim GJA,Leong KW.Poly(D,L-lactide-co-ethyl ethylene phosphate) as new drug carriers[J].J Control Release,2003,92(1-2):39.
[58]Yasugi K,Nakamura T,Nagasaki Y,et al.Sugar-installed polymer micelles:Synthesis and micellization of poly(ethylene glycol)-poly(D,L-lactide) block copolymers having sugar groups at the PEG chainend[J].Macromolecules,1999,32(4):8024.
[59]Müller RH,Jacobs C.Buparvaquone mucoadhensive nano-suspension:preparation,optimization and long-term stability[J].Int.J Pharm.,2002,237(1-2):151-161.
[60]Rao GC,Kumar MS,Mathivanan N,et al.Nano-suspensions as the most promising approach in nano-particulate drug delivery systems[J].Pharmazie,2004,59(1):5-9.
[61]Patravale VB,Date AA,Kulkarni RM.Nano-suspensions:a promising drug delivery strategy [J].J Pharm Pharmcol,2004,56(7):827-840.
[62]Maeda H.The enhanced permeability and retention(EPR)effect in tumor vasculature:the key role of tumor-seleclibe macromo lecular drug targating[J].Adv Enzyme Regul,2001,41:189.
[63]Wang Hui,Zeng Meiqin.Determination of particle size distribution of nano-meter sized powder by small angle X-ray scattering method[J].Powder Metallurgy Tech-nology,2004,22(1):7-11.
[64]YUAN Yuyan,BAI Huaping,LI Fengsheng.Principle of laser scattering and its applica-tion in ultrafine particle size analysis[J].ORDNANCE MATERIAL SCIENCE AND ENGINEERING,2001,24(5):59-62.
[65]De Smet,JGAE etc.Measurement of particl size and shape by forward light scattering.World Congr[J].PartTechnol,1998,3:458-467.
[66]Puckhaber M,R(O|¨)thele S.Laser diffraction millennium link for particle size analysis[J].Powder Handling &Processing,1999,11(1):91-95.
[67]Barth G,Howard,Flippen B,etal.Particle size analysis[J].Anal Chem,1995,67:257-272.
[68]Binnig G,Rohrer H,Gerber C,etal.Surface studies by scanning tunneling microscopy[J].Phys Rev Lett,1982,49:57-61.
[69]Binnig G,Quate CF,Gerber C.Related Articles,Links Atomic force microscope[J].Phys Rev Lett.1986 Mar 3;56(9):930-933.
[70]谭毅,王贵学,蔡绍皙.原子力显微镜在细胞生物学研究中的应用[J].生物医学工程学杂志,2004,21(1):160-163.
[71]Santos Nuno C,Castanho Miguel ARB.An overview of the biophysical Appli-cations of atomic force microscopy[J].Biophysical Chemistry,2004,107:133-149.
[72]吴爱国,魏刚,李壮.原子力显微镜技术对生物样品的研究[J].分析化学研究报告,2004,32(11):1421-1425.
[73]BERNE BJ,PECORA R.Dynamic light scattering,with applications to chemistry,biology and physics[M].New York:Wiley-Interscience,1976.
[74]DEREK B,CHARLOTTE W,STAFFAN W.Characterisation of colloidal silica particles with respect to size and shape by means of viscosity and dynamic light scattering measurement[J].Colloidsand Surfaces,1996,118:89-95.
[75]Berg Rasmussen F,Molenbroek A M,Clausen BS,etal.Research note Particle Size Distribution of an Ni/ SiO_2 Catalyst Determined by ASAXS[C].Journal of Catalysis,2000,205-208.
[76]HE Xiaoxiang,WANG Xingqing.DISCUSSION OF MEASUREMENT METHODS OF NANO-PARTICL E SIZE[J].Powder Metall Urgy Industry.2006,16(6):31-36.
[1].彭黎明,王曾礼.细胞凋亡的基础与临床.北京:人民卫生出版社,2000,1-285.
[2].姜泊.细胞凋亡的基础与临床.北京:人民卫生出版社,1999,1-25.
[3].郑德先.细胞凋亡的研究进展.中华病理学杂志,1996,25(1):50-53.
[4].张志文.细胞程序性死亡与细胞凋亡.生理科学进展,1996,27:297-302.
[5].冯建芳,章静波.程序性细胞死亡及细胞凋亡.生理科学进展 1995;26:373-378.
[6].彭远英,彭正松,喻可芳.凋亡细胞的超微结构变化.细胞生物学杂志 2003;25:280-283.
[7].刘丽芳,吴人亮,吴翠环.细胞胀亡(oncogenisis):一种不同于凋亡(apoptosis)的死亡方式.国外医学分子生物学分册 2002;24:285-288.
[8].苏长青,龚西渝.细胞凋亡的形态特点及生物学意义.临床与实验病理学杂志,1996,12(4):346-348.
[9].Majno G,Joris I.Apoptosis,oncosis,and necrosis,an overview of cell death.Am J Pathol,1995,146(1):3-15.
[10].彭黎明.吞噬细胞对凋亡细胞的识别与吞噬.中华病理学杂志,1999,28:304-306.
[11].Nagata S.Apoptotic DNA fragmentation.Exp Cel lRes,2000,10:12-18.
[12].Wolf BB,Green DR.Suicidal tendencies:apoptotic cell death by caspase family proteins.J Biol Chem.1999;274:20049-20052.
[13].Reed JC.Mechanisms of apoptosis.American J Patho.l 2000;157:1415-1430.
[14].Paul Dent and Steven Grant.Pharmacologic interruption of the mitogen-activated extracellular-regulated kinase/mitogen-activated protein kinase signal transduction pathwaypotential role in promoting cytotoxic drug action.Clin Cancer Res.2001;7:775-783.
[15].Haupt S,Berger M,Goldberg Z,et al.Apoptosis -the p53 network.J Cell Sci.2003;116:4077-4085.
[16].Villa P,Kaufmann SH,Earnshaw WC.Caspase and caspase inhibitors.Trend Biochem Sci,1997,22:388-393.
[17].Stennicke HR,Salvesen S.Properties of the caspases.Biochimica et Biophysica Acta,1998,1387:17-31.
[18].Salvesen GS,Dixit VM.Caspase:intracellular signaling by proteolysis.Cell,1997,91:443-446.
[19].Takahashi A,Earnshaw WC.ICE-related proteases in apoptosis.Curr Opin Gene Dev,1996,6:50-55.
[20].Enari M,Sakahira H,Yokoyama H,et al.A caspase-activated Dnase that degrades DNA during apoptosis and inhibitor ICAD.Nature,1998,391:43-50.
[21].Miyashita T and Reed JC.Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.Cell.1995;80:293-299.
[22].Karpinich NO,Tafani M,Rothman RJ,et al.The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c.J Biol Chem.2002;277:16547-16552.
[23].Lukianova NI,Kulik GL,Chehun VF.Role of the p53 and bc1-2 genes in apoptosis and drug resistance of tumors.Vopr Onko.2000;46:121-128.
[24].Schuler M,Bossy-Wetzel E,Goldstein JC,et al.p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release.J Biol Chem.2000;275:7337-7342.
[25].Bouvard V,Zaitchouk T,Vacher M,et al.Tissue and cell-specific expression of the p53-target genes:bax,fas,mdm2 and waf1/p21,before and following ionising irradiation in mice.Oncogene.2000;19:649-660.
[26].Huang G,Ma WY,Maxiner A,et al.p38 Kinase Mediates UV-induced Phosphorylation of p53 Protein at Serine 389.JBiol Chem.1999;274:12229-12235.
[27].Persons DL,Yazlovitskaya EM and Pelling JC.Effect of Extracellular Signal-regulated Kinase on p53 accumulation in response to Cisplatin.J Biol Chem.2000;275:35778-35785.
[28].Banin S,Moyal L,Shieh S,et al.Enhanced phosphorylation of p53 by ATM in response to DNA damage.Science 1998,281:1674-1677.
[29].Chipuk JE,Kuwana T,Bouchier-Hayes L,et al.Direct Activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis.Science 2004,303:1010-1014.
[30].Xiang H,Kinoshita Y,Knudson CM,et al.Bax involvement in p53-mediated neuronal cell death.J Neurosci.1998;18:1363-1373.
[31].Keller D,Zeng X,Li X,et al.The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53.Biochem Biophys Res Commun.1999;261:464-471.
[32].Ashkenazi A.Death receptors:signaling and modulation.Science,1998,281:1305-1308.
[33].Baker S.Modulation of life and death by the TNF receptor superfamily.Oncogene,1998,17:3261-3270.
[34].Li H.Cleavage of BID by Caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.Cell,1998,94:491-501.
[35].Nagata S.Apoptosis by death factor.Cell,1997,88:355-365.
[36].Orlinick JR.,Vaishnaw AK.Elkon KB.Structure and function of Fas/Fas ligand.Int Rev Immunol,1999,18:293-308.
[37].Kroemer G The proto-oncogene Bc1-2 and its role in regulating apoptosis.Nat Med,1997,3:614-619.
[38].Hengartner MO,Horvitz HR.C.elegant cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogenebcl-2.Cell,1994,76:665-676.
[39].Green DR,Reed JC.Mitochondria and apoptosis.Science,1998,281:1309-1311.
[40].Grooss A,McDonnell JM,Korsmeyer SJ.Bcl-2 family members and the mitochondria in apoptosis.Genes Dev,1999,13:1899-1911.
[41].Joza N.Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.Nature,2001,410(6828):549-554.
[42].Harris MH,Thompson CB.The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability.Cell Death Differ,2000,7(12):1182-1191.
[43].Shi Y.A structural view of mitochondria-mediated apoptosis.Nat Struct Biol,2001,8(5):394-401.
[44].Downward J.Targeting RAS signaling pathways in cancer therapy.Nature Rev Cancer,2003,3:11-22.
[45].Sawyers CL.Opportunities and challenges in the development of kinase inhibitor therapy for cancer.Genes Dev,2003,17:2998-3010.
[46].Vivanco I,Sawyers CL.The phosphatidylinositol 3-Kinase AKT pathway in human cancer.Nature Rev Cancer,2002,2:489-501.
[47].McCormick F.Survival pathways meet their end.Nature,2004,428:267-269.
[48].Peng HB,Libby P,liao JK et al.Induction and stabilization of IkB by nitric oxide mediates inhibition of NF-kB.J Biol Chem.1995;270:14214-14219.
[49].Hirano F,Tanaka H,Miura T,et al.Inbibitiong of NF-kappaB-dependent transcription of human immunodeficiency virus 1 promoter by a phosphodiester compound of vitamin C and Vitamine E,EPC-K1.Immunopharma.1998;39:31-38.
[50].Besson A,Yong VW.Involvement of p21Waf1/Cip1 in protein kinase C alpha-induced cell cycle progression.Mol Cell Biol,2000,20:4580-4590.
[51].Rocha AB,Mans DRA,Regner A,et al.Targeting protein kinase C:new therapeutic opportunities against high-grade malignat gliomas? Oncologist,2002,7:17-33.
[52].Marais R,Light Y,Mason C,et al.Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C.Science,1998,280:109-112.
[53].Vrana JA,Grant S.Synergistic induction of apoptosis in human leukemia cells(U937)exposed to bryostatin-1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade.Blood,2001,97:2105-2114.
[54].Zhuang S,Hirai S,Mizuno K,et al.Involvement of protein kinase C in the activation of extracellular signal-regulated kinase 1/2 by UVC irradiation.Biochem Biophys Res Commun,1997,240:273-278.
[55].Auvinen M.Cell transformation,invasion,and angiogenesis:a regulatory role for ornithine decarboxylase and polyamines? J Natl Cancer Inst,1997,89:533-537.
[56].Barrett CM,Lewis FL,Roaten JB,et al.Novel extranuclear-target anthracyclines override the antiapoptotic functions of Bc1-2 and target protein kinase C pathways to induce apoptosis.Mol Cancer Ther,2002,1:469-481.
[57].Haldar S,Jena N,Croce CM.Inactivation of Bc1-2 by phosphorylation.Proc Natl Acad Sci USA,1995,92:4352-4356.
[58].Kitamura Y,Miyamura A,Takata K,Inden M,Tsuchiya D,Nakamura K,et al.Possible involvement of both endoplasmic reticulum-and mitochondria-dependent pathways in thapsigargin-induced apoptosis in human neuroblastoma SH-SY5Y cells.J Pharmacol Sci,2003,92:228-236.
[59].Ganeshaguru K,Wickeremasinghe RG,Jones DT,et al.Action of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro.Haematologia,2002,87:167-176.
[60].Huang G,Ma WY,Maxiner A,Sun Y and Dong Z.p38 Kinase Mediates UV-induced Phosphorylation of p53 Protein at Serine 389.J Biol Chem,1999,274:12229-12235.
[61].Keller D,Zeng X,Li X,et al.The p38 MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53.Biochem Biophys Res Commun,1999,261:464-471.
[62].Persons DL,Yazlovitskaya EM and Pelling JC.Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin.J Biol Chem,2000,275:35778-35785.
[63].Petrache I,Choi ME,Otterbein LE,et al.Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells.Am J Physiol,1999,277:L589-L595.
[64].Yu C,Wang S,Dent P and Grant S.Sequence-dependent potentiation of paclitaxel-mediated apoptosis in human leukemia cells by inhibitors of the mitogen-activated protein kinase kinase/mitogen-activated protein kinase pathway.Mol Pharmacol,2001,60:143-154.
[65].Suzuki K,Hino M,Kutsuna H,Hato F,Sakamoto C and Takahashi T.Selective activation of p38 mitogen-activated protein kinase cascade in human neutrophils stimulated by IL-1beta.J Immunol,2001,167:5940-5947.
[66].Yang SE,Hsieh MT,Tsai TH and Hsu SL.Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells.Br J Pharmacol,2003,138:193-201.
[1]宋海明,张宝述,孙红娟.行星式球磨机在加工蛭石粉体中的应用研究.矿山机械.2007;35(4):14-16.
[2]张小林,谭崇洋,林峰.油性铝银浆的制备工艺及改进对策.广东化工.2007;34(11):57-59.
[3]沈辉,宗友强,李福平,等.行星磨粉碎氧化锆的工艺及应用.稀有金属.2003,27(1):210-213.
[4]蒋建平,周小华.一种新型超细粉磨设备AC型循环式湿法行星磨简介.江苏陶瓷.1994,(4):6-11.
[5]潘年松,邹俊,张学愈,等.莪术超微颗粒制备的正交实验研究.中国现代应用药学杂志.2007;24(4):297-299.
[6]曲源,李青山,朱润芝.高能纳米球磨机的应用研究.应用链接.2007;4(5):66-68.
[7]谭立新,蔡一湘.超细粉体粒度分析的分散条件比较.中国粉体技术,2000,6(1):23-25.
[8]杨瑛,杨永华,蔡光先.100种中药粉末的粒度测定.时珍国医国药.2006;17(12):2401-2402.
[9]邹文博,许明哲,王晨,等.激光散射法测定乳糖的粒度.药物分析杂志.2007;27(9):1420-1423.
[10]彭峰,谢志勇,王红娟.原子力显微镜对几种纳米材料的结构表征研究.显微与测量.2005;2(1):48-51.
[11]Fotiadis D,Muller DJ,Tsiotis G,Hasier L,Tittmann P,Mini T,Jeno P,Gross H,Engel A.Surface alialysis of the photo-system I complex by electron and atomic force microscope.Mol Biol.1998;283:83-94.
[12]陈英飞,章海军,张冬仙.原子力显微镜在纳米粗糙度测量中的应用.光学仪器.2003;35(4):25-29.
[13]祖元刚,张宇亮,刘志国,等.原子力显微镜在植物学研究中的应用.植物学通报.2006;23(6):708-717.
[14]任利,李伟,聂爱国,等.当归超微粉和普通粉的显微特征观察.河南中医学院学报.2005;20(6):27-28.
[15]牛超群,于淼,张秋颖,等.药用矿物蒙脱石的电子显微镜分析.中国药学杂志.2005;40(16):1220-1222.
[16]戴宏,马克力,陈尔纲.烟草碎粒粒度的扫描电镜研究.电子显微学报.2002;21(5):572-573.
[17]陆华,等.真空科学与技术.1993:6.
[18]干蜀毅.常规扫描电子显微镜的特点和发展.分析仪器.2000;(1):51-53.
[19]陈耀文,林月娟,张海丹,等.扫描电子显微镜与原子力显微镜技术之比较.中国体视学与图像分析.2006;11(4):53-58.
[20]HUNDER G,JAVDANI J,ELSENHANS B,et al.Use of r-spectrometry for simultaneous determination of ~(210)Pb、~(73)As、~(109)Cd、~(203)Hg and ~(59)Fe distribution and excretion in rats at low does[J].Toxicology,2000,150(1-3):69-82.
[1]Zhang CL,Wu LJ,Zuo HJ,Tashiro SI,Onodera S,and Ikejima T.Cytochrome c release from oridonin-treated apoptosis A375-S2 cells is dependent on p53 and extracellular signal-regulated kinase activation.J Pharmacol Sci 2004;96:155-63.
[2]Vaziri H,Dessain SK,Ng EE,Imai SI,Frye RA,Pandita TK,Guarente L,Weinberg RA.Hsir2(SIRT1) functions as an NAD-dependent p53 deacetylase.Cell 2001;107:149-59.
[3]Vercammen D,Beyaet R,Denecker G,Goossens V,Van Loo G,Declercq W,Grooten J,Fiers W,Vandenabeele P.J Exp Med 1998;187:1477-85.
[4]Trtoman LC,Alimonti A,Scaglioni PP,Koutcher JA,Cordon-Cardo C,Pandolfi PP.Identification of a tumor suppressor network opposing nuclear Akt function.Nature 2006;441:523-7.
[5]Zhang CL,Wu LJ,Tashiro SI,Onodera S,Ikejima T.Oridonin induces a caspase-independent but mitochondria-and MAPK.dependent cell death in the murine fibrosarcoma cell line L929.Biol Pharm Bull 2004;27:1527-31.
[6]Hans O.Kalkman.The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia.Pharmacol Therapeut 2006;110:117-34.
[7]Liu Y Q,You S,Tashiro SI,Onodera S,Ikejima T.Activation of phosphoinositide 3-kinase,protein kinase C,and extracellular signal-regulated kinase is required for oridonin-enhanced phagocytosis of apoptotic bodies in human macrophage-like U937 cells.J Pharmacol Sci 2005;98:361-71.
[8]Wang XW,Zhan Q,Coursen JD,Khan MA,Kontny HU,Yu LJ,Hollander MC,O'Connor PM,Fornace AJ,Harris CC.GADD45 induction of a G2/M cell cycle checkpoint.Proc Natl Acad Sci USA 1999;96:3706-11.
[9]Ford J,Jiang M,and Milner J.Cancer-specific functions of SERT1 enable human epithelial cancer cell growth and survival.Cancer Res 2005;65:10457-63.
[10]Wang C,Wang MW,Tashiro SI,Onodera S,Ikejima T.Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2cell death.J Pharmacol Sci 2005;7:494-500.
[11]Brunet A,Datta SR,Greenberg ME,Transcription-dependent and -independent control of neuronal survival by the PI3-K-Akt signaling pathway.Curr Opin Neurobiol 2001;11: 297-305.
[12]Fang L,Li G,Liu G,Lee SW,Aaronson SA.p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3-K/Akt signaling cascades.Embo J 2001;20:1931-9.
[13]Shaw RJ,Cantley LC.Ras,PI3-K and mTOR signalling controls tumour cell growth.Nature 2006;1038:424-30.
[14]Cui Q,Tashiro SI,Onodera S,Ikejima T.Augmentation of oridonin-induced apoptosis observed with reduced autophagy.J Pharmacol Sci 2006;101:230-9.
[15]Rodriguez MS,Desterro JM,Lain S,Lane DP,Hay RT.Multiple C-terminal lysine residuestarget p53 for ubiquitinproteasomemediated degradation.Mol Cell Biol 2000;20:8458-67.
[16]Mayo LD,Dixon JE,Durden DL,Tonks NK,Donner DB.PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy.J Biol Chem 2002;277:5484-9.
[17]Mayo LD,Donner DB.The PTEN,Mdm2,p53 tumor suppressoroncoprotein network.Trends Biochem Sci 2002;27:462-7.
[18]Ogawara Y,Kishishita S,Obata T,Isazawa Y,Suzuki T,Tanaka K,et al.Akt enhances Mdm2-mediated ubiquitination and degradation of p53.J Biol Chem 2002;277:21843-50.
[19]Cui Q,Tashiro SI,Onodera S,Ikejima T.Augmentation of oridonin-induced apoptosis observed with reduced autophagy.J Pharmacol Sci 2006;101:230-9.
[2]Keahler T.Nanotechnology:basic concepts and definitions[J].Clin Chem,1994,40(9):1797-1799.
[3]李国庆,卢广文,林意群.纳米技术及其在生物工程和医药学上的应用[J].医疗设备,2002,(3):8-11.
[4]张玉华,潘云涛,马峥.从文献计量看世界纳米研究的发展状况[J].世界科技研究与发展,2002,(3):49-54.
[5]杨祥良.基于纳米技术的中药基础问题研究[J].华中理工大学学报,2000,28(12):104-105.
[6]徐辉碧主编.纳米医药[M].第1版.北京:清华大学出版社,2004.2.
[7]王晓波,袭荣刚,李忠亮,等.纳米级雄黄粉体的制备[J].解放军药学学报,2002,18(3):129-134.
[8]Liversidge GG,Cundy KC.Particle size reduction for improvement of oral bioavailability of hydrophobic drugs:I.Absolute oral bioavailability of nano-crystalline danazol in beagle dogs[J].Int J Pharm,1995,125(1):91-97.
[9]Kayser O,Olbrich C,Yardley V,et al.Formulation of amphotericin B as nano-suspension for oral administration[J].Int J Pharm,2003,254(1):73-75
[10]Clark MA,Jepson MA,Hirst BH.Exploring M cells for drug and vaccine delivery[J].Adv Drug Dliv Rev,2001,50(1-2):81-106.
[11]Krause KP,Kayser O,Mader K,et al.Heavy metal contamination of nano-suspensions produced by high-pressure homogenisation[J].Int J Pharm,2000,196(2):169-172.
[12]Zhu Maoquan,Liu Song,Gu Hongzhan,et al.Study on Sol id Dispersion of Tanshinone[J].Journal of East China University of Science and Technology,2001,27(2):191-194.
[13]Ribrioux S,Kleymann G,WinfriedH,et al.Use of Nano-gold andFluorescent labeled Antibody Fv Fragments in Immun ocytochemistry[J].J Histochem Cytochem,1996,44(3):207-213.
[14]张小宁,张郁,姬海红,等.微射流法制备莪术油纳米脂质体的研究[J].中国药学杂志,2004,39(5):356-358.
[15]张小宁.中药纳米新技术——微射流纳米药物制剂的生产[J].流程工业,2002,6:36-67.
[16]HE Lei,WANG Guiling,ZHANG Qiang.Studies on Hypersensitivity and Pharmacokinetics of Paclitaxel Microemulsion.Acta Pharmaceutica Sinica,2003,38(3):227-230.
[17]王勇,胡坪,刘清飞,等.Chinese Traditional Patent Medicine January.2007,Vol.29 No.1 112-117
[18]Vila A,Sanchez A,Tobio M,et al.Design of biodegradable particles for protein delivery[J].J Control Release,2002,78:15-24.
[19]Yong Zhang,Nathan Kohler,Miqin Zhang.Surface modification of super paramagnetic magnetite nano-particles and their intracellular up take[J].B iom aterials,2002,23:1553-1561.
[20]Caroline Lemarehand,Ruxandra Oref,Patrick Couvreur.Poly-saccharide decorated nanoparticles [J].Eur J Pharm B iopharm,2004,58:327-341.
[21]AngelaM.De Campos,Alejandro Sanchez,Ruxandra Gref,et al.The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa[J].Eur J Pharm Sci,2003,20:73-81.
[22]Hirofumi Takcuchi,Hiromitsu Yamamoto,Yoshiaki Kawashima.Mucoadhesive nanoparticulate systems for pep tide drug delivery[J].Adv Drug Deliver Rev,2001,47:39-54.
[23]Cassidy O E,Rowley G,Fletcher I W,et al.Surface modification and electrostatic charge of polystyrene particles[J].Int J Pharm,1999,182:199-211.
[24]Moghimi SM,Gray T.A single dose of intravenously injected poloxamine-coated longcirculating particles triggers macrophage clearance of subsequent doses in rats[J].Clin Sci,1997,93(4):371-379.
[25]Kreuter J,Nano-particles.In:Kreuter J.(Ed.).Colloidal Drug Delivery Systems[J].New York:Marcel Dekker,1994,219-342.
[26]Xu H B,Yang X L,Xie C S,et al.Nano-technology apply in Chinese tradi-tional medicine investigation[J].J China Pharm Univ,2001,32(3):161-162.
[27]Langer R.Biomaterials in drug delivery and tissue engineering:One laboratory,sexperience [J].Acc Chem Res,2000,(33):94-101.
[28]靳琦,胡定邦,王子炎.论中药现代化研究的基本思路[J].中国医药学报,2000;15(2):57.
[29]MEI Zhinan.Experimental research on triptolide solid lipid nano-particle for decreasing liver toxicity of triptolide.Chinese Traditional and Herbal Drugs,2003,(9):817.Chinese.
[30]张卫东,刑建国.维感颗粒中挥发油β2环糊精包合物制备及稳定性研究[J].中成药,2005,27(5):515-517.
[31]纪明慧,刘红,何猛雄等.益智挥发油β2环糊精包合物的稳定性考察[J].中药材,2005,28(10):952-953.
[32]黎洪珊,赵京玲,魏树礼.环孢菌素A聚乳酸纳米粒胶体的制备和大鼠的口服吸收[J].中国药学杂志,1999,34(8):532-536.
[33]顾琳慧.日本开发纳米技术抗癌药投药方法[J].中国肿瘤,2001,10(8):479.
[34]Wei H,Li Y G.Nano-technolgoy apply on biomedicine engineering research actuality an development current[J].Foreign Med Sci:Sect Biomed Engirt,1999,22(6):340.
[35]丁玉玲,马淑贤,卢秀容,等.人参皂甙脂质体(GSL)的研制[J].中国药学杂志,1995,30(7):414-417.
[36]张晓辉,张贵君.纳米中药的研究前景[J].中医药信息,2003,20(1):25-26.
[37]高斐,王东凯,陈修毅.中药口服固体缓释制剂的研究进展[J].中草药,2005,36(7):1110-1113.
[34]Deng YJ,Xu F,Jin YG,et al.Preparation stability and immuno enhancement of APS lipisomes[J].Chin Phar Sci.1996,5(2):93-99.
[39]Storm P B,Moriarity J L,Tyler B,et al.Polymer delivery of camptothecin against 9L gliosarcoma:release,distribution,and efficacy[J].J Neurooncol,2002,56(3):209-217.
[40]王学清,张涛,贺颖,药学学报[J].2004,39(1):68-71.
[41]吴华,袁志芳,张小丽.中国医院药学杂志[J].2005,25(10):933-935.
[42]Chen J,Wu Z H.Medication transfer through blood and brain barrier by nanotech-nology[J].Foreign Med Sci:Pharmacy,2002,19(6):333-336.
[43]陈大兵,杨天智,吕万良,等.紫杉醇长循环固态脂质纳米粒的制备和体内外研究[J].药学学报,2002,37(1):54-58.
[44]陈永法,龚明涛,张钧寿,等.紫杉醇冻干纳米乳在大鼠体内的药动学[J].中国天然药物,2005,3(6):370-372.
[45]杨惠森,张拴,宁显唯.纳米技术在生物医药研究中的应用[J].陕西中医学院学报,2003,26(3):67-70.
[46]杨红武,毛衍平,邱应海,等.缬草β-环糊精包合物的工艺及稳定性研究[J].中国医院药学杂志,1998,18(12):544-547.
[47]邓嵘,陈济民,姚崇舜.莪术油明胶微球肝动脉栓塞[J].药学学报,2000;35(7):539.
[48]谢崇文,李旺生,凌艳等.β-环糊精在中药制剂中的应用及研究进展[J].中国中医药信息杂志,2001;8(3):36.
[49]丁寅,袁红宇,郭立玮等.负载士的宁纳米微粒研究[J].南京中医药大学学报(自然科学版),2002;18(3):156.
[50]孙铭,朱争艳,于美丽,等。去甲斑蝥素纳米控释制剂抗肿瘤的实验研究[J].肿瘤学杂志,2001,(6):321-325.
[51]徐辉碧,杨祥良,黄开勋.雄黄抑制小鼠肉瘤S180的尺寸效应的初步研究[J].武汉大学学报(自然科学版).Mar.2000,288-289.
[52]YANG ZH,ZHU MX,GONG YF,et ah Protection of nanometer-particulate Seoil the unbalanced immune functions and oxidative damage in mice induced by D-galactose[J].Studies of Trace Elements and Health,1999,16(1):4.
[53]WANG ZY,ZHANG DS,GU N,et ah Prepration and evaluation of arsenic trioxide nanoparticles for the treatment of human liver cancer cells SMMC-7721 in vitro[J].Journal of Southeast University,2005,21(1):58.
[54]Nobs L,Buchegger F,Gurny R,et ah Surface modification of poly(lactic acid)nano-particles by covalent attachment of thiolgroups bymeans of three methods[J].Int J Pharm,2003,250(2):327.
[55]De Jawghere F,Allemann E,Feijen J,et al.Freezedrying and lyopreservation of diblock and trilock[J].Pharm Dev Technol,2000,5(4):473.
[56]李泳雪,王春龙,李杰.纳米技术在现代中药制剂中的应用[J].中草药,2002,33(8):673-675.
[57]Wen J,Kim GJA,Leong KW.Poly(D,L-lactide-co-ethyl ethylene phosphate) as new drug carriers[J].J Control Release,2003,92(1-2):39.
[58]Yasugi K,Nakamura T,Nagasaki Y,et al.Sugar-installed polymer micelles:Synthesis and micellization of poly(ethylene glycol)-poly(D,L-lactide) block copolymers having sugar groups at the PEG chainend[J].Macromolecules,1999,32(4):8024.
[59]Müller RH,Jacobs C.Buparvaquone mucoadhensive nano-suspension:preparation,optimization and long-term stability[J].Int.J Pharm.,2002,237(1-2):151-161.
[60]Rao GC,Kumar MS,Mathivanan N,et al.Nano-suspensions as the most promising approach in nano-particulate drug delivery systems[J].Pharmazie,2004,59(1):5-9.
[61]Patravale VB,Date AA,Kulkarni RM.Nano-suspensions:a promising drug delivery strategy [J].J Pharm Pharmcol,2004,56(7):827-840.
[62]Maeda H.The enhanced permeability and retention(EPR)effect in tumor vasculature:the key role of tumor-seleclibe macromo lecular drug targating[J].Adv Enzyme Regul,2001,41:189.
[63]Wang Hui,Zeng Meiqin.Determination of particle size distribution of nano-meter sized powder by small angle X-ray scattering method[J].Powder Metallurgy Tech-nology,2004,22(1):7-11.
[64]YUAN Yuyan,BAI Huaping,LI Fengsheng.Principle of laser scattering and its applica-tion in ultrafine particle size analysis[J].ORDNANCE MATERIAL SCIENCE AND ENGINEERING,2001,24(5):59-62.
[65]De Smet,JGAE etc.Measurement of particl size and shape by forward light scattering.World Congr[J].PartTechnol,1998,3:458-467.
[66]Puckhaber M,R(O|¨)thele S.Laser diffraction millennium link for particle size analysis[J].Powder Handling &Processing,1999,11(1):91-95.
[67]Barth G,Howard,Flippen B,etal.Particle size analysis[J].Anal Chem,1995,67:257-272.
[68]Binnig G,Rohrer H,Gerber C,etal.Surface studies by scanning tunneling microscopy[J].Phys Rev Lett,1982,49:57-61.
[69]Binnig G,Quate CF,Gerber C.Related Articles,Links Atomic force microscope[J].Phys Rev Lett.1986 Mar 3;56(9):930-933.
[70]谭毅,王贵学,蔡绍皙.原子力显微镜在细胞生物学研究中的应用[J].生物医学工程学杂志,2004,21(1):160-163.
[71]Santos Nuno C,Castanho Miguel ARB.An overview of the biophysical Appli-cations of atomic force microscopy[J].Biophysical Chemistry,2004,107:133-149.
[72]吴爱国,魏刚,李壮.原子力显微镜技术对生物样品的研究[J].分析化学研究报告,2004,32(11):1421-1425.
[73]BERNE BJ,PECORA R.Dynamic light scattering,with applications to chemistry,biology and physics[M].New York:Wiley-Interscience,1976.
[74]DEREK B,CHARLOTTE W,STAFFAN W.Characterisation of colloidal silica particles with respect to size and shape by means of viscosity and dynamic light scattering measurement[J].Colloidsand Surfaces,1996,118:89-95.
[75]Berg Rasmussen F,Molenbroek A M,Clausen BS,etal.Research note Particle Size Distribution of an Ni/ SiO_2 Catalyst Determined by ASAXS[C].Journal of Catalysis,2000,205-208.
[76]HE Xiaoxiang,WANG Xingqing.DISCUSSION OF MEASUREMENT METHODS OF NANO-PARTICL E SIZE[J].Powder Metall Urgy Industry.2006,16(6):31-36.
[1].彭黎明,王曾礼.细胞凋亡的基础与临床.北京:人民卫生出版社,2000,1-285.
[2].姜泊.细胞凋亡的基础与临床.北京:人民卫生出版社,1999,1-25.
[3].郑德先.细胞凋亡的研究进展.中华病理学杂志,1996,25(1):50-53.
[4].张志文.细胞程序性死亡与细胞凋亡.生理科学进展,1996,27:297-302.
[5].冯建芳,章静波.程序性细胞死亡及细胞凋亡.生理科学进展 1995;26:373-378.
[6].彭远英,彭正松,喻可芳.凋亡细胞的超微结构变化.细胞生物学杂志 2003;25:280-283.
[7].刘丽芳,吴人亮,吴翠环.细胞胀亡(oncogenisis):一种不同于凋亡(apoptosis)的死亡方式.国外医学分子生物学分册 2002;24:285-288.
[8].苏长青,龚西渝.细胞凋亡的形态特点及生物学意义.临床与实验病理学杂志,1996,12(4):346-348.
[9].Majno G,Joris I.Apoptosis,oncosis,and necrosis,an overview of cell death.Am J Pathol,1995,146(1):3-15.
[10].彭黎明.吞噬细胞对凋亡细胞的识别与吞噬.中华病理学杂志,1999,28:304-306.
[11].Nagata S.Apoptotic DNA fragmentation.Exp Cel lRes,2000,10:12-18.
[12].Wolf BB,Green DR.Suicidal tendencies:apoptotic cell death by caspase family proteins.J Biol Chem.1999;274:20049-20052.
[13].Reed JC.Mechanisms of apoptosis.American J Patho.l 2000;157:1415-1430.
[14].Paul Dent and Steven Grant.Pharmacologic interruption of the mitogen-activated extracellular-regulated kinase/mitogen-activated protein kinase signal transduction pathwaypotential role in promoting cytotoxic drug action.Clin Cancer Res.2001;7:775-783.
[15].Haupt S,Berger M,Goldberg Z,et al.Apoptosis -the p53 network.J Cell Sci.2003;116:4077-4085.
[16].Villa P,Kaufmann SH,Earnshaw WC.Caspase and caspase inhibitors.Trend Biochem Sci,1997,22:388-393.
[17].Stennicke HR,Salvesen S.Properties of the caspases.Biochimica et Biophysica Acta,1998,1387:17-31.
[18].Salvesen GS,Dixit VM.Caspase:intracellular signaling by proteolysis.Cell,1997,91:443-446.
[19].Takahashi A,Earnshaw WC.ICE-related proteases in apoptosis.Curr Opin Gene Dev,1996,6:50-55.
[20].Enari M,Sakahira H,Yokoyama H,et al.A caspase-activated Dnase that degrades DNA during apoptosis and inhibitor ICAD.Nature,1998,391:43-50.
[21].Miyashita T and Reed JC.Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.Cell.1995;80:293-299.
[22].Karpinich NO,Tafani M,Rothman RJ,et al.The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c.J Biol Chem.2002;277:16547-16552.
[23].Lukianova NI,Kulik GL,Chehun VF.Role of the p53 and bc1-2 genes in apoptosis and drug resistance of tumors.Vopr Onko.2000;46:121-128.
[24].Schuler M,Bossy-Wetzel E,Goldstein JC,et al.p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release.J Biol Chem.2000;275:7337-7342.
[25].Bouvard V,Zaitchouk T,Vacher M,et al.Tissue and cell-specific expression of the p53-target genes:bax,fas,mdm2 and waf1/p21,before and following ionising irradiation in mice.Oncogene.2000;19:649-660.
[26].Huang G,Ma WY,Maxiner A,et al.p38 Kinase Mediates UV-induced Phosphorylation of p53 Protein at Serine 389.JBiol Chem.1999;274:12229-12235.
[27].Persons DL,Yazlovitskaya EM and Pelling JC.Effect of Extracellular Signal-regulated Kinase on p53 accumulation in response to Cisplatin.J Biol Chem.2000;275:35778-35785.
[28].Banin S,Moyal L,Shieh S,et al.Enhanced phosphorylation of p53 by ATM in response to DNA damage.Science 1998,281:1674-1677.
[29].Chipuk JE,Kuwana T,Bouchier-Hayes L,et al.Direct Activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis.Science 2004,303:1010-1014.
[30].Xiang H,Kinoshita Y,Knudson CM,et al.Bax involvement in p53-mediated neuronal cell death.J Neurosci.1998;18:1363-1373.
[31].Keller D,Zeng X,Li X,et al.The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53.Biochem Biophys Res Commun.1999;261:464-471.
[32].Ashkenazi A.Death receptors:signaling and modulation.Science,1998,281:1305-1308.
[33].Baker S.Modulation of life and death by the TNF receptor superfamily.Oncogene,1998,17:3261-3270.
[34].Li H.Cleavage of BID by Caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.Cell,1998,94:491-501.
[35].Nagata S.Apoptosis by death factor.Cell,1997,88:355-365.
[36].Orlinick JR.,Vaishnaw AK.Elkon KB.Structure and function of Fas/Fas ligand.Int Rev Immunol,1999,18:293-308.
[37].Kroemer G The proto-oncogene Bc1-2 and its role in regulating apoptosis.Nat Med,1997,3:614-619.
[38].Hengartner MO,Horvitz HR.C.elegant cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogenebcl-2.Cell,1994,76:665-676.
[39].Green DR,Reed JC.Mitochondria and apoptosis.Science,1998,281:1309-1311.
[40].Grooss A,McDonnell JM,Korsmeyer SJ.Bcl-2 family members and the mitochondria in apoptosis.Genes Dev,1999,13:1899-1911.
[41].Joza N.Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.Nature,2001,410(6828):549-554.
[42].Harris MH,Thompson CB.The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability.Cell Death Differ,2000,7(12):1182-1191.
[43].Shi Y.A structural view of mitochondria-mediated apoptosis.Nat Struct Biol,2001,8(5):394-401.
[44].Downward J.Targeting RAS signaling pathways in cancer therapy.Nature Rev Cancer,2003,3:11-22.
[45].Sawyers CL.Opportunities and challenges in the development of kinase inhibitor therapy for cancer.Genes Dev,2003,17:2998-3010.
[46].Vivanco I,Sawyers CL.The phosphatidylinositol 3-Kinase AKT pathway in human cancer.Nature Rev Cancer,2002,2:489-501.
[47].McCormick F.Survival pathways meet their end.Nature,2004,428:267-269.
[48].Peng HB,Libby P,liao JK et al.Induction and stabilization of IkB by nitric oxide mediates inhibition of NF-kB.J Biol Chem.1995;270:14214-14219.
[49].Hirano F,Tanaka H,Miura T,et al.Inbibitiong of NF-kappaB-dependent transcription of human immunodeficiency virus 1 promoter by a phosphodiester compound of vitamin C and Vitamine E,EPC-K1.Immunopharma.1998;39:31-38.
[50].Besson A,Yong VW.Involvement of p21Waf1/Cip1 in protein kinase C alpha-induced cell cycle progression.Mol Cell Biol,2000,20:4580-4590.
[51].Rocha AB,Mans DRA,Regner A,et al.Targeting protein kinase C:new therapeutic opportunities against high-grade malignat gliomas? Oncologist,2002,7:17-33.
[52].Marais R,Light Y,Mason C,et al.Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C.Science,1998,280:109-112.
[53].Vrana JA,Grant S.Synergistic induction of apoptosis in human leukemia cells(U937)exposed to bryostatin-1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade.Blood,2001,97:2105-2114.
[54].Zhuang S,Hirai S,Mizuno K,et al.Involvement of protein kinase C in the activation of extracellular signal-regulated kinase 1/2 by UVC irradiation.Biochem Biophys Res Commun,1997,240:273-278.
[55].Auvinen M.Cell transformation,invasion,and angiogenesis:a regulatory role for ornithine decarboxylase and polyamines? J Natl Cancer Inst,1997,89:533-537.
[56].Barrett CM,Lewis FL,Roaten JB,et al.Novel extranuclear-target anthracyclines override the antiapoptotic functions of Bc1-2 and target protein kinase C pathways to induce apoptosis.Mol Cancer Ther,2002,1:469-481.
[57].Haldar S,Jena N,Croce CM.Inactivation of Bc1-2 by phosphorylation.Proc Natl Acad Sci USA,1995,92:4352-4356.
[58].Kitamura Y,Miyamura A,Takata K,Inden M,Tsuchiya D,Nakamura K,et al.Possible involvement of both endoplasmic reticulum-and mitochondria-dependent pathways in thapsigargin-induced apoptosis in human neuroblastoma SH-SY5Y cells.J Pharmacol Sci,2003,92:228-236.
[59].Ganeshaguru K,Wickeremasinghe RG,Jones DT,et al.Action of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro.Haematologia,2002,87:167-176.
[60].Huang G,Ma WY,Maxiner A,Sun Y and Dong Z.p38 Kinase Mediates UV-induced Phosphorylation of p53 Protein at Serine 389.J Biol Chem,1999,274:12229-12235.
[61].Keller D,Zeng X,Li X,et al.The p38 MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53.Biochem Biophys Res Commun,1999,261:464-471.
[62].Persons DL,Yazlovitskaya EM and Pelling JC.Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin.J Biol Chem,2000,275:35778-35785.
[63].Petrache I,Choi ME,Otterbein LE,et al.Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells.Am J Physiol,1999,277:L589-L595.
[64].Yu C,Wang S,Dent P and Grant S.Sequence-dependent potentiation of paclitaxel-mediated apoptosis in human leukemia cells by inhibitors of the mitogen-activated protein kinase kinase/mitogen-activated protein kinase pathway.Mol Pharmacol,2001,60:143-154.
[65].Suzuki K,Hino M,Kutsuna H,Hato F,Sakamoto C and Takahashi T.Selective activation of p38 mitogen-activated protein kinase cascade in human neutrophils stimulated by IL-1beta.J Immunol,2001,167:5940-5947.
[66].Yang SE,Hsieh MT,Tsai TH and Hsu SL.Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells.Br J Pharmacol,2003,138:193-201.
[1]宋海明,张宝述,孙红娟.行星式球磨机在加工蛭石粉体中的应用研究.矿山机械.2007;35(4):14-16.
[2]张小林,谭崇洋,林峰.油性铝银浆的制备工艺及改进对策.广东化工.2007;34(11):57-59.
[3]沈辉,宗友强,李福平,等.行星磨粉碎氧化锆的工艺及应用.稀有金属.2003,27(1):210-213.
[4]蒋建平,周小华.一种新型超细粉磨设备AC型循环式湿法行星磨简介.江苏陶瓷.1994,(4):6-11.
[5]潘年松,邹俊,张学愈,等.莪术超微颗粒制备的正交实验研究.中国现代应用药学杂志.2007;24(4):297-299.
[6]曲源,李青山,朱润芝.高能纳米球磨机的应用研究.应用链接.2007;4(5):66-68.
[7]谭立新,蔡一湘.超细粉体粒度分析的分散条件比较.中国粉体技术,2000,6(1):23-25.
[8]杨瑛,杨永华,蔡光先.100种中药粉末的粒度测定.时珍国医国药.2006;17(12):2401-2402.
[9]邹文博,许明哲,王晨,等.激光散射法测定乳糖的粒度.药物分析杂志.2007;27(9):1420-1423.
[10]彭峰,谢志勇,王红娟.原子力显微镜对几种纳米材料的结构表征研究.显微与测量.2005;2(1):48-51.
[11]Fotiadis D,Muller DJ,Tsiotis G,Hasier L,Tittmann P,Mini T,Jeno P,Gross H,Engel A.Surface alialysis of the photo-system I complex by electron and atomic force microscope.Mol Biol.1998;283:83-94.
[12]陈英飞,章海军,张冬仙.原子力显微镜在纳米粗糙度测量中的应用.光学仪器.2003;35(4):25-29.
[13]祖元刚,张宇亮,刘志国,等.原子力显微镜在植物学研究中的应用.植物学通报.2006;23(6):708-717.
[14]任利,李伟,聂爱国,等.当归超微粉和普通粉的显微特征观察.河南中医学院学报.2005;20(6):27-28.
[15]牛超群,于淼,张秋颖,等.药用矿物蒙脱石的电子显微镜分析.中国药学杂志.2005;40(16):1220-1222.
[16]戴宏,马克力,陈尔纲.烟草碎粒粒度的扫描电镜研究.电子显微学报.2002;21(5):572-573.
[17]陆华,等.真空科学与技术.1993:6.
[18]干蜀毅.常规扫描电子显微镜的特点和发展.分析仪器.2000;(1):51-53.
[19]陈耀文,林月娟,张海丹,等.扫描电子显微镜与原子力显微镜技术之比较.中国体视学与图像分析.2006;11(4):53-58.
[20]HUNDER G,JAVDANI J,ELSENHANS B,et al.Use of r-spectrometry for simultaneous determination of ~(210)Pb、~(73)As、~(109)Cd、~(203)Hg and ~(59)Fe distribution and excretion in rats at low does[J].Toxicology,2000,150(1-3):69-82.
[1]Zhang CL,Wu LJ,Zuo HJ,Tashiro SI,Onodera S,and Ikejima T.Cytochrome c release from oridonin-treated apoptosis A375-S2 cells is dependent on p53 and extracellular signal-regulated kinase activation.J Pharmacol Sci 2004;96:155-63.
[2]Vaziri H,Dessain SK,Ng EE,Imai SI,Frye RA,Pandita TK,Guarente L,Weinberg RA.Hsir2(SIRT1) functions as an NAD-dependent p53 deacetylase.Cell 2001;107:149-59.
[3]Vercammen D,Beyaet R,Denecker G,Goossens V,Van Loo G,Declercq W,Grooten J,Fiers W,Vandenabeele P.J Exp Med 1998;187:1477-85.
[4]Trtoman LC,Alimonti A,Scaglioni PP,Koutcher JA,Cordon-Cardo C,Pandolfi PP.Identification of a tumor suppressor network opposing nuclear Akt function.Nature 2006;441:523-7.
[5]Zhang CL,Wu LJ,Tashiro SI,Onodera S,Ikejima T.Oridonin induces a caspase-independent but mitochondria-and MAPK.dependent cell death in the murine fibrosarcoma cell line L929.Biol Pharm Bull 2004;27:1527-31.
[6]Hans O.Kalkman.The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia.Pharmacol Therapeut 2006;110:117-34.
[7]Liu Y Q,You S,Tashiro SI,Onodera S,Ikejima T.Activation of phosphoinositide 3-kinase,protein kinase C,and extracellular signal-regulated kinase is required for oridonin-enhanced phagocytosis of apoptotic bodies in human macrophage-like U937 cells.J Pharmacol Sci 2005;98:361-71.
[8]Wang XW,Zhan Q,Coursen JD,Khan MA,Kontny HU,Yu LJ,Hollander MC,O'Connor PM,Fornace AJ,Harris CC.GADD45 induction of a G2/M cell cycle checkpoint.Proc Natl Acad Sci USA 1999;96:3706-11.
[9]Ford J,Jiang M,and Milner J.Cancer-specific functions of SERT1 enable human epithelial cancer cell growth and survival.Cancer Res 2005;65:10457-63.
[10]Wang C,Wang MW,Tashiro SI,Onodera S,Ikejima T.Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2cell death.J Pharmacol Sci 2005;7:494-500.
[11]Brunet A,Datta SR,Greenberg ME,Transcription-dependent and -independent control of neuronal survival by the PI3-K-Akt signaling pathway.Curr Opin Neurobiol 2001;11: 297-305.
[12]Fang L,Li G,Liu G,Lee SW,Aaronson SA.p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3-K/Akt signaling cascades.Embo J 2001;20:1931-9.
[13]Shaw RJ,Cantley LC.Ras,PI3-K and mTOR signalling controls tumour cell growth.Nature 2006;1038:424-30.
[14]Cui Q,Tashiro SI,Onodera S,Ikejima T.Augmentation of oridonin-induced apoptosis observed with reduced autophagy.J Pharmacol Sci 2006;101:230-9.
[15]Rodriguez MS,Desterro JM,Lain S,Lane DP,Hay RT.Multiple C-terminal lysine residuestarget p53 for ubiquitinproteasomemediated degradation.Mol Cell Biol 2000;20:8458-67.
[16]Mayo LD,Dixon JE,Durden DL,Tonks NK,Donner DB.PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy.J Biol Chem 2002;277:5484-9.
[17]Mayo LD,Donner DB.The PTEN,Mdm2,p53 tumor suppressoroncoprotein network.Trends Biochem Sci 2002;27:462-7.
[18]Ogawara Y,Kishishita S,Obata T,Isazawa Y,Suzuki T,Tanaka K,et al.Akt enhances Mdm2-mediated ubiquitination and degradation of p53.J Biol Chem 2002;277:21843-50.
[19]Cui Q,Tashiro SI,Onodera S,Ikejima T.Augmentation of oridonin-induced apoptosis observed with reduced autophagy.J Pharmacol Sci 2006;101:230-9.