多壁碳纳米管的表面化学修饰调控细胞自噬的研究
|
摘要
由于具有独特的理化性质,纳米材料在航空航天、能源、建材、涂料、催化、环境保护、电子器件、生物医药以及消费品等领域有着广泛的应用。与纳米材料相关的产品正加速走进人们的日常生活。纳米材料的广泛应用加大了其与人体接触并进入人体的几率,因此研究纳米材料的生物学效应,即其对基本生命过程的影响,从而更好地评价其生物安全性就显得十分必要和紧迫。
自噬,意为自体吞噬,是利用溶酶体机制降解细胞内物质成分的过程的统称。其广泛存在于从低等的酵母菌到高等的哺乳动物细胞等所有真核细胞中,是与泛素-蛋白酶体机制并列的另一种降解途径。通常情况下,细胞保持低水平的基础的自噬活性来应对代谢压力、衰老或破损的细胞器、错误折叠或聚集的蛋白来维持细胞内环境的稳定。在如饥饿、能量缺乏等代谢胁迫的情况下,自噬会被上调,短期内为细胞提供必要的营养和能量,应对生存压力。而如果细胞长时间处于较高的自噬水平,就会引起自噬性细胞死亡。另外,越来越多的研究表明自噬过程的缺失或者紊乱与包括癌症、神经退行、II型糖尿病、粥样动脉硬化等很多疾病的发生和发展都有密不可分的复杂关系。鉴于细胞自噬的复杂性,适当的对自噬进行调控,趋利避害,最大限度地利用它进行疾病的治疗在近年来得到研究人员越来越多的关注。
纳米材料作为一种新型的自噬诱导剂,其对自噬的影响越来越得到人们的关注。由于自噬本身在生物系统中作用的复杂性,纳米材料与细胞自噬的关系也相应得存在着两面性。一方面,许多纳米材料可以诱导自噬,这就对原有的小分子自噬诱导剂形成了有益的补充；另一方面,纳米材料可能会干扰溶酶体功能造成自噬过程的阻滞,从而带来细胞毒性,为纳米材料的应用带来不必要的副作用。因此通过适当的手段对纳米材料进行修饰,从而可控地调节自噬的程度就显得十分必要。
我们对包含MWCNT-COOH在内的共81种具有不同表面修饰的MWCNT库的细胞自噬诱发能力进行了评估,结果发现不同表面修饰分化了MWCNT的自噬诱发能力。通过量化自噬小体的个数,将81种不同表面修饰的MWCNT的自噬诱发能力分成了4类。包含羧基在内的7种多壁碳纳米管具有极强的自噬诱导能力,而也有7种碳管因为适当地修饰而丧失了自噬诱导能力,其他碳管的自噬诱导能力则介于上述两个级别之间,分别具有较弱或较强的自噬诱导级别。因此,表面修饰成功地分化了诱导自噬的能力,并且这种能力不局限于单一细胞性。我们还使用计算化学的手段Pharmacophore Query对碳管表面分子结构与自噬诱导能力之间进行了构效关系的分析,结果发现胺基和羰基这两种氢键受体及其相对位置是诱导自噬的关键基团。在具有最强自噬诱导能力的三种碳管都含有这两种基团,且它们都处于相同的平面内,而在丧失自噬诱导能力的三种碳管中,上述两种基团都发生了一定程度的位移,这可能是由于大的吸电子芳香环的引入造成的。这些发现为今后有目的地设计碳管表面配体,对自噬进行可控的调控提供了一定的理论基础。
在分子层面研究小分子或纳米材料诱发自噬的机制是当前自噬研究领域的前沿。我们使用免疫印迹的方法对强自噬诱导级别的碳管进行自噬通路mTOR的检测后发现,7种最强自噬诱导级别的碳管诱发自噬的通路也发生了分化。我们选取mTOR依赖的MWCNT-COOH和另一种与其自噬级别接近的mTOR非依赖的MWCNT41进行更深入的机制研究。电镜是判断自噬发生的金标准,TEM观察到两种碳管处理后的细胞中都有自噬小体的生成,且部分自噬小体内还包裹有碳管,针对LC3B的免疫印迹实验也表明,两种碳管以剂量依赖的方式诱导HEK293细胞产生自噬。随后我们排除了两种碳管表面配体解离从而诱发自噬的可能。通过Annexin V/7-AAD双染实验及caspase3的免疫印迹实验排除了两种碳管诱导凋亡的可能性。采用具有荧光信号的FITC-BSA分子标记的碳管处理细胞,发现两种碳管在多个时间点具有相似的细胞摄入量。使用Fluo-3AM钙离子荧光探针检测碳管处理后的细胞发现,两种碳管在低浓度(25μg/mL)和高浓度(100μg/mL)时均没有引起细胞内游离钙离子浓度的改变,从而排除通路不同是由于二者对胞内游离钙离子浓度影响的不同带来的。透射电镜观察到两种碳管在细胞内具有相似的亚细胞定位,排除细胞定位不同造成的影响。自噬相关基因PCR阵列实验显示,两种碳管在对IGF-1和IFNA2的表达上发生了显著的不同。结合现有对自噬的认识及课题组前期在碳管的细胞生物学机制等方面的探索,我们推测两种碳管由于表面修饰的不同结合在不同的细胞表面受体上,从而引起了不同的下游自噬通路。MWCNT-COOH通过IGF1R/mTOR/p70S6K通路引起自噬,而MWCNT41则通过IFNA2R干扰了IFNA2的表达,从而引起自噬。
我们的研究对调控纳米材料的自噬进行了新的尝试并取得了一定的成果并且为今后合理地对纳米材料进行修饰提供了一定的理论基础。另一方面,我们发现表面不同修饰的纳米材料可以分化其自噬诱导途径,并且对潜在的机制进行了较为深入的探索,从而加深了现有关于纳米材料与自噬诱导关系的认识。
Materials in the nanometer range often possess unique physical, optical, electronic, and biological properties compared with larger particles. The unique and advanced properties of nanomaterials have led to a rapid increase in their application. These applications include aerospace and airplanes, energy, architecture, chemicals and coatings, catalysts, environmental protection, computer memory, biomedicine and consumer products. This will increase the possibility for the NMs to enter human body. So it is necessary and urgent to evaluate the biosafety issue of NMs in human body.
Autophagy, meaning self-eating, is an evolutionarily conserved catabolic process of the cells to degrade its cellular materials through the lysosome machinery. It exists in all the eukaryotic cells including yeast and mammalian cells, and is the other degradation machinery in addition to the ubiquitin-proteasome machinery. In normal circumstances, autophagy is kept to a basal level to deal with the metabolic stress, damaged organelles as well as the mis-folded or aggregated proteins in order to maintain the cell homeostasis. In time of starvation or energy deficiency, autophagy will be tuned to a higher level to provide cells with necessary nutrients or energy to survive the stress conditions. However, if the stress is constant, cells may die through an autophagy-dependent programmed cell death. Autophagy has been reported to play vital and complex roles in many diseases, including cancer, neurodegeneration, type Ⅱ diabetes, and atherosclerosis. Considering its complexity, proper regulation of autophagy turns out to be a practical strategy for maximum therapeutic outcomes.
There is a growing body of literatures on the autophagy induction by nanomaterials ever since the first witness of autophagosome formation induced by quantum dots. Because of the janus role of autophagy in life, the relationship between nanomaterials and autophagy also has two sides. On one hand, nanomaterials turn out to be a good supplement to the tradational small molecule autophagy inducers. On the other hand, nanomaterials may impair the lysosome function leading to the cytotoxicity associated with the blockade of the autophagy flux. So modifying nanomaterials to tune their autophagy inducing level is very necessary and promising.
To develop safe nanomaterials and nanomedicinal agents that regulate cell autophagy, we explored the possibility of controlling autophagy induction by systematically modifying the surface chemistry of MWCNTs. By analyzing autophagosome formation and autophagy-associated biomarkers, we have classified the autophagy inducing ability of MWCNTs into four categories. Seven MWCNT variants including MWCNT-COOH have the highest autophagy induction ability. While another seven MWCNTs variants lost this ability. The other67MWCNT variants belong to two categories with low and medium autophagy inducing ability. These findings demonstrate that pharmaceutical autophagy modulators and biocompatible nanomaterials can be developed through surface modifications. Our computational efforts have identified surface ligands (pharmacophores) that may switch autophagy on and off, providing a powerful method for the rational design of autophagy modulators and biocompatible nanoparticles.
Studies on the molecular machinery of autophagy induction is the leading edge in the field of autophagy research. We checked the mTOR signaling activation by the seven MWCNTs variants with the highest level by western blot and found that they also deviated the autophagy induction signaling. We then chose mTOR dependent MWCNT-COOH and mTOR independent MWCNT41, which had comparable autophagy inducing ability, to further investigate their autophagy induction mechanisms. TEM showed that both MWCNT variants induced autophagosome formation in cells and western blot against LC3B indicated that their induction of autophagy is dose dependent. We then ruled out the possibility that autophagy was induced by the ligands dissociated from the nanotubes by western blot. Annexin V/7-AAD assay and western blot against cleaved caspase3indicated that both MWCNT variants did not induce apoptosis. Furthermore, cells incubated with fluorescent FITC-BSA tagged MWCNTs exhibited similar cellular uptake amount at various time points through flow cytometry analysis. And both MWCNT variants did not alter the intracellular calcium concentration at both low and high concentrations. TEM analysis found that both MWCNT variants had similar subcellular localizations. After ruling out the above major possibilites that may cause different signalings, we conducted an autophagy specific PCR array expreriment and revealed that the two MWCNT variants altered the mRNA expression of IGF1and IFNA2to different levels. Combining the our previous studies on MWCNTs and the current knowledge on autophagy, we deduced that the differences on the autophagy induction signaling was caused by different cell receptor binding preferences after modification. MWCNT-COOH induced autophagy through IGFlR/mTOR/p70S6K pathway, while MWCNT41induced autophagy by altering the expression of IFNA2through binding to IFNA2R.
Differences in surface chemistry allow MWCNTs to trigger autophagy through different signaling pathways, demonstrating the flexibility and specificity of autophagy modulation by nanoparticles as a result of well-defined interactions with specific molecular signaling pathways.
自噬,意为自体吞噬,是利用溶酶体机制降解细胞内物质成分的过程的统称。其广泛存在于从低等的酵母菌到高等的哺乳动物细胞等所有真核细胞中,是与泛素-蛋白酶体机制并列的另一种降解途径。通常情况下,细胞保持低水平的基础的自噬活性来应对代谢压力、衰老或破损的细胞器、错误折叠或聚集的蛋白来维持细胞内环境的稳定。在如饥饿、能量缺乏等代谢胁迫的情况下,自噬会被上调,短期内为细胞提供必要的营养和能量,应对生存压力。而如果细胞长时间处于较高的自噬水平,就会引起自噬性细胞死亡。另外,越来越多的研究表明自噬过程的缺失或者紊乱与包括癌症、神经退行、II型糖尿病、粥样动脉硬化等很多疾病的发生和发展都有密不可分的复杂关系。鉴于细胞自噬的复杂性,适当的对自噬进行调控,趋利避害,最大限度地利用它进行疾病的治疗在近年来得到研究人员越来越多的关注。
纳米材料作为一种新型的自噬诱导剂,其对自噬的影响越来越得到人们的关注。由于自噬本身在生物系统中作用的复杂性,纳米材料与细胞自噬的关系也相应得存在着两面性。一方面,许多纳米材料可以诱导自噬,这就对原有的小分子自噬诱导剂形成了有益的补充；另一方面,纳米材料可能会干扰溶酶体功能造成自噬过程的阻滞,从而带来细胞毒性,为纳米材料的应用带来不必要的副作用。因此通过适当的手段对纳米材料进行修饰,从而可控地调节自噬的程度就显得十分必要。
我们对包含MWCNT-COOH在内的共81种具有不同表面修饰的MWCNT库的细胞自噬诱发能力进行了评估,结果发现不同表面修饰分化了MWCNT的自噬诱发能力。通过量化自噬小体的个数,将81种不同表面修饰的MWCNT的自噬诱发能力分成了4类。包含羧基在内的7种多壁碳纳米管具有极强的自噬诱导能力,而也有7种碳管因为适当地修饰而丧失了自噬诱导能力,其他碳管的自噬诱导能力则介于上述两个级别之间,分别具有较弱或较强的自噬诱导级别。因此,表面修饰成功地分化了诱导自噬的能力,并且这种能力不局限于单一细胞性。我们还使用计算化学的手段Pharmacophore Query对碳管表面分子结构与自噬诱导能力之间进行了构效关系的分析,结果发现胺基和羰基这两种氢键受体及其相对位置是诱导自噬的关键基团。在具有最强自噬诱导能力的三种碳管都含有这两种基团,且它们都处于相同的平面内,而在丧失自噬诱导能力的三种碳管中,上述两种基团都发生了一定程度的位移,这可能是由于大的吸电子芳香环的引入造成的。这些发现为今后有目的地设计碳管表面配体,对自噬进行可控的调控提供了一定的理论基础。
在分子层面研究小分子或纳米材料诱发自噬的机制是当前自噬研究领域的前沿。我们使用免疫印迹的方法对强自噬诱导级别的碳管进行自噬通路mTOR的检测后发现,7种最强自噬诱导级别的碳管诱发自噬的通路也发生了分化。我们选取mTOR依赖的MWCNT-COOH和另一种与其自噬级别接近的mTOR非依赖的MWCNT41进行更深入的机制研究。电镜是判断自噬发生的金标准,TEM观察到两种碳管处理后的细胞中都有自噬小体的生成,且部分自噬小体内还包裹有碳管,针对LC3B的免疫印迹实验也表明,两种碳管以剂量依赖的方式诱导HEK293细胞产生自噬。随后我们排除了两种碳管表面配体解离从而诱发自噬的可能。通过Annexin V/7-AAD双染实验及caspase3的免疫印迹实验排除了两种碳管诱导凋亡的可能性。采用具有荧光信号的FITC-BSA分子标记的碳管处理细胞,发现两种碳管在多个时间点具有相似的细胞摄入量。使用Fluo-3AM钙离子荧光探针检测碳管处理后的细胞发现,两种碳管在低浓度(25μg/mL)和高浓度(100μg/mL)时均没有引起细胞内游离钙离子浓度的改变,从而排除通路不同是由于二者对胞内游离钙离子浓度影响的不同带来的。透射电镜观察到两种碳管在细胞内具有相似的亚细胞定位,排除细胞定位不同造成的影响。自噬相关基因PCR阵列实验显示,两种碳管在对IGF-1和IFNA2的表达上发生了显著的不同。结合现有对自噬的认识及课题组前期在碳管的细胞生物学机制等方面的探索,我们推测两种碳管由于表面修饰的不同结合在不同的细胞表面受体上,从而引起了不同的下游自噬通路。MWCNT-COOH通过IGF1R/mTOR/p70S6K通路引起自噬,而MWCNT41则通过IFNA2R干扰了IFNA2的表达,从而引起自噬。
我们的研究对调控纳米材料的自噬进行了新的尝试并取得了一定的成果并且为今后合理地对纳米材料进行修饰提供了一定的理论基础。另一方面,我们发现表面不同修饰的纳米材料可以分化其自噬诱导途径,并且对潜在的机制进行了较为深入的探索,从而加深了现有关于纳米材料与自噬诱导关系的认识。
Materials in the nanometer range often possess unique physical, optical, electronic, and biological properties compared with larger particles. The unique and advanced properties of nanomaterials have led to a rapid increase in their application. These applications include aerospace and airplanes, energy, architecture, chemicals and coatings, catalysts, environmental protection, computer memory, biomedicine and consumer products. This will increase the possibility for the NMs to enter human body. So it is necessary and urgent to evaluate the biosafety issue of NMs in human body.
Autophagy, meaning self-eating, is an evolutionarily conserved catabolic process of the cells to degrade its cellular materials through the lysosome machinery. It exists in all the eukaryotic cells including yeast and mammalian cells, and is the other degradation machinery in addition to the ubiquitin-proteasome machinery. In normal circumstances, autophagy is kept to a basal level to deal with the metabolic stress, damaged organelles as well as the mis-folded or aggregated proteins in order to maintain the cell homeostasis. In time of starvation or energy deficiency, autophagy will be tuned to a higher level to provide cells with necessary nutrients or energy to survive the stress conditions. However, if the stress is constant, cells may die through an autophagy-dependent programmed cell death. Autophagy has been reported to play vital and complex roles in many diseases, including cancer, neurodegeneration, type Ⅱ diabetes, and atherosclerosis. Considering its complexity, proper regulation of autophagy turns out to be a practical strategy for maximum therapeutic outcomes.
There is a growing body of literatures on the autophagy induction by nanomaterials ever since the first witness of autophagosome formation induced by quantum dots. Because of the janus role of autophagy in life, the relationship between nanomaterials and autophagy also has two sides. On one hand, nanomaterials turn out to be a good supplement to the tradational small molecule autophagy inducers. On the other hand, nanomaterials may impair the lysosome function leading to the cytotoxicity associated with the blockade of the autophagy flux. So modifying nanomaterials to tune their autophagy inducing level is very necessary and promising.
To develop safe nanomaterials and nanomedicinal agents that regulate cell autophagy, we explored the possibility of controlling autophagy induction by systematically modifying the surface chemistry of MWCNTs. By analyzing autophagosome formation and autophagy-associated biomarkers, we have classified the autophagy inducing ability of MWCNTs into four categories. Seven MWCNT variants including MWCNT-COOH have the highest autophagy induction ability. While another seven MWCNTs variants lost this ability. The other67MWCNT variants belong to two categories with low and medium autophagy inducing ability. These findings demonstrate that pharmaceutical autophagy modulators and biocompatible nanomaterials can be developed through surface modifications. Our computational efforts have identified surface ligands (pharmacophores) that may switch autophagy on and off, providing a powerful method for the rational design of autophagy modulators and biocompatible nanoparticles.
Studies on the molecular machinery of autophagy induction is the leading edge in the field of autophagy research. We checked the mTOR signaling activation by the seven MWCNTs variants with the highest level by western blot and found that they also deviated the autophagy induction signaling. We then chose mTOR dependent MWCNT-COOH and mTOR independent MWCNT41, which had comparable autophagy inducing ability, to further investigate their autophagy induction mechanisms. TEM showed that both MWCNT variants induced autophagosome formation in cells and western blot against LC3B indicated that their induction of autophagy is dose dependent. We then ruled out the possibility that autophagy was induced by the ligands dissociated from the nanotubes by western blot. Annexin V/7-AAD assay and western blot against cleaved caspase3indicated that both MWCNT variants did not induce apoptosis. Furthermore, cells incubated with fluorescent FITC-BSA tagged MWCNTs exhibited similar cellular uptake amount at various time points through flow cytometry analysis. And both MWCNT variants did not alter the intracellular calcium concentration at both low and high concentrations. TEM analysis found that both MWCNT variants had similar subcellular localizations. After ruling out the above major possibilites that may cause different signalings, we conducted an autophagy specific PCR array expreriment and revealed that the two MWCNT variants altered the mRNA expression of IGF1and IFNA2to different levels. Combining the our previous studies on MWCNTs and the current knowledge on autophagy, we deduced that the differences on the autophagy induction signaling was caused by different cell receptor binding preferences after modification. MWCNT-COOH induced autophagy through IGFlR/mTOR/p70S6K pathway, while MWCNT41induced autophagy by altering the expression of IFNA2through binding to IFNA2R.
Differences in surface chemistry allow MWCNTs to trigger autophagy through different signaling pathways, demonstrating the flexibility and specificity of autophagy modulation by nanoparticles as a result of well-defined interactions with specific molecular signaling pathways.
引文
[1]European Commission:Recommendation on the definition of nanomaterial.2011.
[2]Future Markets:The World Market for Nanotechnology and Nanomaterials in Consumer Products; 2010.
[3]Hussain, S.; Al-Nsour, F.; Rice, A. B.; Marshburn, J.; Yingling, B.; Ji, Z.; Zink, J. I.; Walker, N. J.; Garantziotis, S., Cerium dioxide nanoparticles induce apoptosis and autophagy in human peripheral blood monocytes. ACS Nano 2012,6,5820-5829.
[4]秦正红；乐卫东,自噬——生物学与疾病.北京：科学出版社：2011.
[5]Feynman, R. P., There's plenty of room at the bottom. Engineering and Science 1960,23,22-36.
[6]Ouyang, M.; Huang, J.-L.; Lieber, C.M., Fundamental electronic properties and applications of single-walled carbon nanotubes. Acc. Chem. Res 2002,35, 1018-1025.
[7]Forro, L.; Schnonenberger, C.; Dresselhouse, M.; Dresselhouse, G.; Avouris, P., Carbon nanotubes synthesis, structure, properties and applications. Springer, New York:2001.
[8]Zhou, O.; Shimoda, H.; Gao, B.; Oh, S.; Fleming, L.; Yue, G., Materials science of carbon nanotubes:fabrication, integration, and properties of macroscopic structures of carbon nanotubes. Acc. Chem. Res.2002,35,1045-1053.
[9]Niyogi, S.; Hamon, M.; Hu, H.; Zhao, B.; Bhowmik, P.; Sen, R.; Itkis, M.; Haddon, R., Chemistry of single-walled carbon nanotubes. Acc. Chem. Res.2002,35, 1105-1113.
[10]Sun, Y.-P.; Fu, K.; Lin, Y; Huang, W., Functionalized carbon nanotubes: properties and applications. Acc. Chem. Res.2002,35,1096-1104.
[11]Tasis, D.; Tagmatarchis, N.; Bianco, A.; Prato, M., Chemistry of carbon nanotubes. Chem. Rev.2006,106,1105-1136.
[12]O'Connell, M. J.; Bachilo, S. M.; Huffman, C. B.; Moore, V. C.; Strano, M. S.; Haroz, E. H.; Rialon, K. L.; Boul, P. J.; Noon, W. H.; Kittrell, C.; et al., Band Gap Fluorescence from Individual Single-Walled Carbon Nanotubes. Science 2002,297, 593-596.
[13]Fernando, K. S.; Lin, Y.; Wang, W.; Kumar, S.; Zhou, B.; Xie, S.-Y.; Cureton, L. T.; Sun, Y.-P., Diminished band-gap transitions of single-walled carbon nanotubes in complexation with aromatic molecules. J. Am. Chem. Soc.2004,126,10234-10235.
[14]Liu, H. L.; Zhang, Y. L.; Yang, N.; Zhang, Y. X.; Liu, X. Q.; Li, C. G.; Zhao, Y.; Wang, Y. G.; Zhang, G. G.; Yang, P.; et al, A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt-TSC2-mTOR signaling. Cell Death and Dis 2011,2, e159.
[15]Lu, F.; Gu, L.; Meziani, M. J.; Wang, X.; Luo, P. G.; Veca, L. M.; Cao, L.; Sun, Y. P., Advances in bioapplications of carbon nanotubes. Adv. Mater.2009,21,139-152.
[16]Georgakilas, V.; Kordatos, K.; Prato, M.; Guldi, D. M.; Holzinger, M.; Hirsch, A., Organic Functionalization of Carbon Nanotubes. J. Am. Chem. Soc.2002,124, 760-761.
[17]Zhou, H.; Mu, Q.; Gao, N.; Liu, A.; Xing, Y.; Gao, S.; Zhang, Q.; Qu, G.; Chen, Y.; Liu, G.; et al., A Nano-Combinatorial Library Strategy for the Discovery of Nanotubes with Reduced Protein-Binding, Cytotoxicity, and Immune Response. Nano Lett.2008,8,859-865.
[18]Gao, N.; Zhang, Q.; Mu, Q.; Bai, Y.; Li, L.; Zhou, H.; Butch, E. R.; Powell, T. B.; Snyder, S. E.; Jiang, G.; et al, Steering Carbon Nanotubes to Scavenger Receptor Recognition by Nanotube Surface Chemistry Modification Partially Alleviates NFκB Activation and Reduces Its Immunotoxicity. ACS Nano 2011,5,4581-4591.
[19]Lin, Y.; Taylor, S.; Li, H.; Fernando, K. S.; Qu, L.; Wang, W.; Gu, L.; Zhou, B.; Sun, Y.-P., Advances toward bioapplications of carbon nanotubes. J. Mater. Chem. 2004,14,527-541.
[20]Yun, Y.; Dong, Z.; Shanov, V.; Heineman, W. R.; Halsall, H. B.; Bhattacharya, A. Conforti, L.; Narayan, R. K.; Ball, W. S.; Schulz, M. J., Nanotube electrodes and biosensors. Nano Today 2007,2,30-37.
[21]Katz, E.; Willner, I., Biomolecule-functionalized carbon nanotubes: applications in nanobioelectronics. ChemPhysChem 2004,5,1084-1104.
[22]Balasubramanian, K.; Burghard, M., Biosensors based on carbon nanotubes. Anal. Bioanal. Chem.2006,385,452-468.
[23]Kim, S. N.; Rusling, J. F.; Papadimitrakopoulos, F., Carbon nanotubes for electronic and electrochemical detection of biomolecules. Adv. Mater.2007,19, 3214-3228.
[24]Besteman, K.; Lee, J.-O.; Wiertz, F. G.; Heering, H. A.; Dekker, C., Enzyme-coated carbon nanotubes as single-molecule biosensors. Nano Lett.2003,3, 727-730.
[25]Wong Shi Kam, N.; Dai, H., Single walled carbon nanotubes for transport and delivery of biological cargos. physica status solidi (b) 2006,243,3561-3566.
[26]Lacerda, L.; Raffa, S.; Prato, M.; Bianco, A.; Kostarelos, K., Cell-penetrating CNTs for delivery of therapeutics. Nano Today 2007,2,38-43.
[27]Prato, M.; Kostarelos, K.; Bianco, A., Functionalized Carbon Nanotubes in Drug Design and Discovery. Acc. Chem. Res.2007,41,60-68.
[28]Pastorin, G.; Wu, W.; Wieckowski, S.; Briand, J.-P.; Kostarelos, K.; Prato, M.; Bianco, A., Double functionalisation of carbon nanotubes for multimodal drug delivery. Chem. Commun.2006,1182-1184.
[29]Ali-Boucetta, H.; Al-Jamal, K. T.; McCarthy, D.; Prato, M.; Bianco, A.; Kostarelos, K., Multiwalled carbon nanotube-doxorubicin supramolecular complexes for cancer therapeutics. Chem. Commun.2008,459-461.
[30]Liu, Z.; Sun, X.; Nakayama-Ratchford, N.; Dai, H., Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano 2007,1, 50-56.
[31]Liu, Z.; Winters, M.; Holodniy, M.; Dai, H., siRNA Delivery into Human T Cells and Primary Cells with Carbon-Nanotube Transporters. Angewandte Chemie International Edition 2007,46,2023-2027.
[32]Zhang, Z.; Yang, X.; Zhang, Y.; Zeng, B.; Wang, S.; Zhu, T.; Roden, R. B.; Chen, Y.; Yang, R., Delivery of telomerase reverse transcriptase small interfering RNA in complex with positively charged single-walled carbon nanotubes suppresses tumor growth. Clin. Cancer Res.2006,12,4933-4939.
[33]Torchilin, V. P., Multifunctional nanocarriers. Adv. Drug Delivery Rev.2012.
[34]Yang, S. T.; Fernando, K.; Liu, J. H.; Wang, J.; Sun, H. F.; Liu, Y.; Chen, M.; Huang, Y.; Wang, X.; Wang, H., Covalently PEGylated carbon nanotubes with stealth character in vivo. Small 2008,4,940-944.
[35]Liu, Z.; Davis, C.; Cai, W.; He, L.; Chen, X.; Dai, H., Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc. Natl. Acad. Sci. U. S. A.2008,105,1410-1415.
[36]Riggs, J. E.; Guo, Z.; Carroll, D. L.; Sun, Y.-P., Strong luminescence of solubilized carbon nanotubes. J. Am. Chem. Soc.2000,122,5879-5880.
[37]Welsher, K.; Liu, Z.; Daranciang, D.; Dai, H., Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. Nano Lett.2008,8,586-590.
[38]Cherukuri, P.; Bachilo, S. M.; Litovsky, S. H.; Weisman, R. B., Near-Infrared Fluorescence Microscopy of Single-Walled Carbon Nanotubes in Phagocytic Cells. J. Am. Chem. Soc.2004,126,15638-15639.
[39]Leeuw, T. K.; Reith, R. M.; Simonette, R. A.; Harden, M. E.; Cherukuri, P.; Tsyboulski, D. A.; Beckingham, K. M.; Weisman, R. B., Single-Walled Carbon Nanotubes in the Intact Organism:Near-IR Imaging and Biocompatibility Studies in Drosophila. Nano Lett.2007,7,2650-2654.
[40]Feazell, R. P.; Nakayama-Ratchford, N.; Dai, H.; Lippard, S. J., Soluble single-walled carbon nanotubes as longboat delivery systems for platinum (IV) anticancer drug design. J. Am. Chem. Soc.2007,129,8438-8439.
[41]Porter, A. E.; Gass, M.; Muller, K.; Skepper, J. N.; Midgley, P. A.; Welland, M., Direct imaging of single-walled carbon nanotubes in cells. Nat Nano 2007,2, 713-717.
[42]Casals, E.; Pfaller, T.; Duschl, A.; Oostingh, G. J.; Puntes, V., Time evolution of the nanoparticle protein corona. ACS Nano 2010,4,3623-3632.
[43]Lundqvist, M.; Stigler, J.; Elia, G.; Lynch, I.; Cedervall, T.; Dawson, K. A., Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl. Acad. Sci. U. S. A.2008,105, 14265-14270.
[44]Salvador-Morales, C.; Flahaut, E.; Sim, E.; Sloan, J.; H Green, M. L.; Sim, R. B., Complement activation and protein adsorption by carbon nanotubes. Mol. Immunol. 2006,43,193-201.
[45]Kim, H. R.; Andrieux, K.; Delomenie, C.; Chacun, H.; Appel, M.; Desmaele, D.; Taran, F.; Georgin, D.; Couvreur, P.; Taverna, M., Analysis of plasma protein adsorption onto PEGylated nanoparticles by complementary methods:2-DE, CE and Protein Lab-on-chip(?) system. Electrophoresis 2007,28,2252-2261.
[46]Ge, C.; Du, J.; Zhao, L.; Wang, L.; Liu, Y.; Li, D.; Yang, Y.; Zhou, R.; Zhao, Y.; Chai, Z., Binding of blood proteins to carbon nanotubes reduces cytotoxicity. Proc. Natl. Acad. Sci. U. S. A.2011,108,16968-16973.
[47]Nel, A.; Xia, T.; Madler, L.; Li, N., Toxic potential of materials at the nanolevel. Science 2006,311,622-627.
[48]Tsukahara, T.; Haniu, H., Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells. Mol. Cell. Biochem.2011,352, 57-63.
[49]Pacurari, M.; Yin, X. J.; Zhao, J.; Ding, M.; Leonard, S. S.; Schwegler-Berry, D.; Ducatman, B. S.; Sbarra, D.; Hoover, M. D.; Castranova, V., Raw singlerwall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-κB, and Akt in normal and malignant human mesothelial cells. Environ. Health Perspect.2008,116, 1211.
[50]Srivastava, R. K.; Pant, A. B.; Kashyap, M. P.; Kumar, V.; Lohani, M.; Jonas, L.; Rahman, Q., Multi-walled carbon nanotubes induce oxidative stress and apoptosis in human lung cancer cell line-A549. Nanotoxicology 2011,5,195-207.
[51]Poland, C. A.; Duffin, R.; Kinloch, I.; Maynard, A.; Wallace, W. A.; Seaton, A.; Stone, V.; Brown, S.; MacNee, W.; Donaldson, K., Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat. Nanotechnol.2008,3,423-428.
[52]Zhu, L.; Chang, D. W.; Dai, L.; Hong, Y, DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano Lett.2007,7,3592-3597.
[53]Cheng, W.-W.; Lin, Z.-Q.; Wei, B.-F.; Zeng, Q.; Han, B.; Wei, C.-X.; Fan, X.-J.; Hu, C.-L.; Liu, L.-H.; Huang, J.-H., Single-walled carbon nanotube induction of rat aortic endothelial cell apoptosis:reactive oxygen species are involved in the mitochondrial pathway. Int. J. Biochem. Cell. B.2011,43,564-572.
[54]Wang, L.; Luanpitpong, S.; Castranova, V.; Tse, W.; Lu, Y.; Pongrakhananon, V.; Rojanasakul, Y., Carbon nanotubes induce malignant transformation and tumorigenesis of human lung epithelial cells. Nano Lett.2011,11,2796-2803.
[55]Mizushima, N.; Levine, B.; Cuervo, A.; Klionsky, D., Autophagy fights disease through cellular self-digestion. Nature 2008,451,1069-1075.
[56]Deter, R. L.; Baudhuin, P.; Duve, C. d., Participation of Lysosomes in Cellular Autophagy Induced in Rat Liver by Glucagon. J. Cell Biol.1967,35, C11-C16.
[57]Klionsky, D. J., Autophagy:from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol.2007,8,931-937.
[58]Mizushima, N., Autophagy:process and function. Genes Dev.2007,21, 2861-2873.
[59]Hailey, D.; Rambold, A.; Satpute-Krishnan, P.; Mitra, K.; Sougrat, R.; Kim, P.; Lippincott-Schwartz, J., Mitochondria Supply Membranes for Autophagosome Biogenesis during Starvation. Cell 2010,141,656-667.
[60]Mizushima, N.; Yoshimori, T.; Levine, B., Methods in mammalian autophagy research. Cell 2010,140,313-326.
[61]Takeshige, K.; Baba, M.; Tsuboi, S.; Noda, T.; Ohsumi, Y., Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol.1992,119,301-311.
[62]Baba, M.; Takeshige, K.; Baba, N.; Ohsumi, Y., Ultrastructural analysis of the autophagic process in yeast:detection of autophagosomes and their characterization. J. Cell Biol.1994,124,903-913.
[63]Baba, M.; Osumi, M.; Ohsumi, Y, Analysis of the membrane structures involved in autophagy in yeast by freeze-replica method. Cell Struct. Funct.1995,20,465-471.
[64]Tian, Y.; Li, Z.; Hu, W.; Ren, H.; Tian, E.; Zhao, Y.; Lu, Q.; Huang, X.; Yang, P.; Li, X., C. elegans Screen Identifies Autophagy Genes Specific to Multicellular Organisms. Cell 2010,141,1042-1055.
[65]Kim, J.; Kundu, M.; Viollet, B.; Guan, K.-L., AMPK and mTOR regulate autophagy through direct phosphorylation of Uikl.Nat. Cell Biol.2011,13,132-141.
[66]Nakatogawa, H.; Suzuki, K.; Kamada, Y.; Ohsumi, Y, Dynamics and diversity in autophagy mechanisms:lessons from yeast. Nat. Rev. Mol. Cell Biol.2009,10, 458-467.
[67]Lockshin, R.; Zakeri, Z., Programmed cell death and apoptosis:origins of the theory. Nat. Rev. Mol. Cell Biol.2001,2,545-550.
[68]Yuan, J.; Horvitz, H. R., A first insight into the molecular mechanisms of apoptosis. Cell 2004,116, S53-S56.
[69]Nicholson, D.; Ali, A.; Thornberry, N.; Vaillancourt, J.; Ding, C.; Gallant, M.; Gareau, Y.; Griffin, P.; Labelle, M.; Lazebnik, Y, Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995,376,37-43.
[70]Schwartz, L.; Smith, S.; Jones, M.; Osborne, B., Do all programmed cell deaths occur via apoptosis? Proc. Natl. Acad. Sci. U. S. A.1993,90,980-984.
[71]Kuma, A.; Hatano, M.; Matsui, M.; Yamamoto, A.; Nakaya, H.; Yoshimori, T.; Ohsumi, Y.; Tokuhisa, T.; Mizushima, N., The role of autophagy during the early neonatal starvation period. Nature 2004,432,1032-1036.
[72]Gozuacik, D.; Kimchi, A., Autophagy and Cell Death. In Curr. Top. Dev. Biol, Gerald, P. S., Ed. Academic Press:2007; Vol. Volume 78, pp 217-245.
[73]Levine, B., Cell biology:Autophagy and cancer. Nature 2007,446,745-747.
[74]Kroemer, G.; Levine, B., Autophagic cell death:the story of a misnomer. Nat. Rev. Mol. Cell Biol.2008,9,1004-1010.
[75]Shintani, T.; Klionsky, D. J., Autophagy in Health and Disease:A Double-Edged Sword. Science 2004,306,990-995.
[76]Marx, J., Autophagy:is it cancer's friend or foe? Science 2006,312,1160-1161.
[77]White, E.; DiPaola, R. S., The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res.2009,15,5308-5316.
[78]Mathew, R.; Karantza-Wadsworth, V.; White, E., Role of autophagy in cancer. Nat. Rev. Cancer 2007,7,961-967.
[79]Qu, X.; Yu, J.; Bhagat, G.; Furuya, N.; Hibshoosh, H.; Troxel, A.; Rosen, J.; Eskelinen, E.-L.; Mizushima, N.; Ohsumi, Y.; et al, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. The Journal of Clinical Investigation 2003,112,1809-1820.
[80]Yue, Z.; Jin, S.; Yang, C.; Levine, A. J.; Heintz, N., Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U. S. A.2003,100,15077-15082.
[81]Cadwell, K.; Liu, J. Y.; Brown, S. L.; Miyoshi, H.; Loh, J.; Lennerz, J. K.; Kishi, C.; Kc, W.; Carrero, J. A.; Hunt, S., A key role for autophagy and the autophagy gene Atg1611 in mouse and human intestinal Paneth cells. Nature 2008,456,259-263.
[82]White, E.; Karp, C.; Strohecker, A. M.; Guo, Y.; Mathew, R., Role of autophagy in suppression of inflammation and cancer. Curr. Opin. Cell Biol.2010,22,212-217.
[83]Mathew, R.; Karp, C. M.; Beaudoin, B.; Vuong, N.; Chen, G.; Chen, H.-Y.; Bray, K.; Reddy, A.; Bhanot, G.; Gelinas, C., Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009,137,1062-1075.
[84]Aita, V. M.; Liang, X. H.; Murty, V.; Pincus, D. L.; Yu, W.; Cayanis, E.; Kalachikov, S.; Gilliam, T. C.; Levine, B., Cloning and Genomic Organization of Beclin 1, a Candidate Tumor Suppressor Gene on Chromosome 17q21. Genomics 1999,59,59-65.
[85]Liang, X. H.; Jackson, S.; Seaman, M.; Brown, K.; Kempkes, B.; Hibshoosh, H.; Levine, B., Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999,402,672-676.
[86]Jin, S.; DiPaola, R. S.; Mathew, R.; White, E., Metabolic catastrophe as a means to cancer cell death. J. Cell Sci.2007,120,379-383.
[87]Jin, S.; White, E., Role of autophagy in cancer:management of metabolic stress. Autophagy 2007,3,28-31.
[88]Degenhardt, K.; Mathew, R.; Beaudoin, B.; Bray, K.; Anderson, D.; Chen, G.; Mukherjee, C.; Shi, Y.; Gelinas, C.; Fan, Y, Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006,10,51-64.
[89]Karantza-Wadsworth, V.; Patel, S.; Kravchuk, O.; Chen, G.; Mathew, R.; Jin, S.; White, E., Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev.2007,21,1621-1635.
[90]Mathew, R.; Kongara, S.; Beaudoin, B.; Karp, C. M.; Bray, K.; Degenhardt, K.; Chen, G.; Jin, S.; White, E., Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev.2007,21,1367-1381.
[91]Igney, F. H.; Krammer, P. H., Death and anti-death:tumour resistance to apoptosis. Nat. Rev. Cancer 2002,2,277-288.
[92]Scarlatti, F.; Bauvy, C.; Ventruti, A.; Sala, G.; Cluzeaud, F.; Vandewalle, A.; Ghidoni, R.; Codogno, P., Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J. Biol. Chem.2004,279, 18384-18391.
[93]Bursch, W.; Ellinger, A.; Kienzl, H.; Torok, L.; Pandey, S.; Sikorska, M.; Walker, R.; Hermann, R. S., Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 1996,17,1595-1607.
[94]Kessel, D.; Reiners, J. J.; Hazeldine, S. T.; Polin, L.; Horwitz, J. P., The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80. Mol. Cancer Ther. 2007,6,370-379.
[95]Melendez, A.; Talloczy, Z.; Seaman, M.; Eskelinen, E.-L.; Hall, D. H.; Levine, B., Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003,301,1387-1391.
[96]Colman, R. J.; Anderson, R. M.; Johnson, S. C.; Kastman, E. K.; Kosmatka, K. J.; Beasley, T. M.; Allison, D. B.; Cruzen, C.; Simmons, H. A.; Kemnitz, J. W., Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009,325, 201-204.
[97]Fontana, L.; Partridge, L.; Longo, V. D., Extending healthy life span-from yeast to humans. Science 2010,328,321-326.
[98]Masoro, E. J., Overview of caloric restriction and ageing. Mech. Ageing Dev. 2005,126,913-922.
[99]Levine, B.; Kroemer, G., Autophagy in the pathogenesis of disease. Cell 2008, 132,27-42.
[100]Alvers, A. L.; Fishwick, L. K.; Wood, M. S.; Hu, D.; Chung, H. S.; Dunn Jr, W. A.; Aris, J. P., Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell 2009,8,353-369.
[101]Dwivedi, M.; Song, H.-O.; Ahnn, J., Autophagy genes mediate the effect of calcineurin on life span in C. elegans. Autophagy 2009,5,604-607.
[102]Jia, K.; Levine, B., Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 2007,3,597-599.
[103]Harrison, D. E.; Strong, R.; Sharp, Z. D.; Nelson, J. F.; Astle, C. M.; Flurkey, K.; Nadon, N. L.; Wilkinson, J. E.; Frenkel, K.; Carter, C. S., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009,460,392-395.
[104]Anisimov, V. N.; Zabezhinski, M. A.; Popovich, I. G.; Piskunova, T. S.; Semenchenko, A. V.; Tyndyk, M. L.; Yurova, M. N.; Antoch, M. P.; Blagosklonny, M. V., Rapamycin extends maximal lifespan in cancer-prone mice. The American journal of pathology 2010,176,2092-2097.
[105]Wu, J. J.; Quijano, C.; Chen, E.; Liu, H.; Cao, L.; Fergusson, M. M.; Rovira, I. I.; Gutkind, S.; Daniels, M. P.; Komatsu, M., Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Milano) 2009,1,425.
[106]Twig, G.; Elorza, A.; Molina, A. J.; Mohamed, H.; Wikstrom, J. D.; Walzer, G.; Stiles, L.; Haigh, S. E.; Katz, S.; Las, G., Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. The EMBO journal 2008,27, 433-446.
[107]Chen, C.; Liu, Y.; Liu, Y.; Zheng, P., mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Science signaling 2009,2, ra75.
[108]Mattson, M. P.; Wan, R., Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. The Journal of nutritional biochemistry 2005,16,129-137.
[109]Ravikumar, B.; Duden, R.; Rubinsztein, D. C., Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet.2002,11,1107-1117.
[110]Iwata, A.; Christianson, J. C.; Bucci, M.; Ellerby, L. M.; Nukina, N.; Forno, L. S.; Kopito, R. R., Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc. Natl. Acad. Sci. U. S. A.2005,102, 13135-13140.
[111]Ravikumar, B.; Vacher, C.; Berger, Z.; Davies, J. E.; Luo, S.; Oroz, L. G.; Scaravilli, F.; Easton, D. F.; Duden, R.; O'Kane, C. J., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet.2004,36,585-595.
[112]Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R., Mutation in the a-synuclein gene identified in families with Parkinson's disease. Science 1997,276,2045-2047.
[113]Goedert, M.; Spillantini, M.; Jakes, R.; Rutherford, D.; Crowther, R., Multiple isoforms of human microtubule-associated protein tau:sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989,3,519-526.
[114]DiFiglia, M.; Sapp, E.; Chase, K. O.; Davies, S. W.; Bates, G. P.; Vonsattel, J.; Aronin, N., Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997,277,1990-1993.
[115]Komatsu, M.; Waguri, S.; Chiba, T.; Murata, S.; Iwata, J.-i.; Tanida, I.; Ueno, T.; Koike, M.; Uchiyama, Y.; Kominami, E., Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006,441,880-884.
[116]Hara, T.; Nakamura, K.; Matsui, M.; Yamamoto, A.; Nakahara, Y.; Suzuki-Migishima, R.; Yokoyama, M.; Mishima, K.; Saito, I.; Okano, H., Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006,441,885-889.
[117]Komatsu, M.; Wang, Q. J.; Holstein, G. R.; Friedrich, V. L.; Iwata, J.-i.; Kominami, E.; Chait, B. T.; Tanaka, K.; Yue, Z., Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. U. S. A.2007,104,14489-14494.
[118]Pattingre, S.; Tassa, A.; Qu, X.; Garuti, R.; Liang, X. H.; Mizushima, N.; Packer, M.; Schneider, M. D.; Levine, B., Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005,122,927-939.
[119]Wong, E. S.; Tan, J. M.; Soong, W.-E.; Hussein, K.; Nukina, N.; Dawson, V. L.; Dawson, T. M.; Cuervo, A. M.; Lim, K.-L., Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum. Mol. Genet.2008,17,2570-2582.
[120]Lee, J.-H.; Yu, W. H.; Kumar, A.; Lee, S.; Mohan, P. S.; Peterhoff, C. M.; Wolfe, D. M.; Martinez-Vicente, M.; Massey, A. C.; Sovak, G., Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010,141,1146-1158.
[121]Wong, E.; Cuervo, A. M., Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci.2010,13,805-811.
[122]Zhang, L.; Yu, J.; Pan, H.; Hu, P.; Hao, Y.; Cai, W.; Zhu, H.; Yu, A. D.; Xie, X.; Ma, D.; et al., Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc. Natl. Acad. Sci. U. S. A.2007,104,19023-19028.
[123]Klionsky, D. J.; Emr, S. D., Autophagy as a regulated pathway of cellular degradation. Science 2000,290,1717-1721. [124] Cantley, L. C., The phosphoinositide 3-kinase pathway. Science 2002,296, 1655-1657.
[125]Datta, S. R.; Dudek, H.; Tao, X.; Masters, S.; Fu, H.; Gotoh, Y.; Greenberg, M. E., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997,91,231-241.
[126]Backer, J., The regulation and function of Class III PI3Ks:novel roles for Vps34. Biochem. J 2008,410,1-17.
[127]Fleming, A.; Noda, T.; Yoshimori, T.; Rubinsztein, D. C., Chemical modulators of autophagy as biological probes and potential therapeutics. Nat. Chem. Biol.2011,7, 9-17.
[128]Meley, D.; Bauvy, C.; Houben-Weerts, J. H.; Dubbelhuis, P. F.; Helmond, M. T.; Codogno, P.; Meijer, A. J., AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem.2006,281,34870-34879.
[129]Meijer, A. J.; Codogno, P., AMP-activated protein kinase and autophagy. Autophagy 2007,3,238-240.
[130]Williams, R. S.; Cheng, L.; Mudge, A. W.; Harwood, A. J., A common mechanism of action for three mood-stabilizing drugs. Nature 2002,417,292-295.
[131]Sarkar, S.; Floto, R. A.; Berger, Z.; Imarisio, S.; Cordenier, A.; Pasco, M.; Cook, L. J.; Rubinsztein, D. C., Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol.2005,170,1101-1111.
[132]Hallcher, L.; Sherman, W. R., The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J. Biol. Chem.1980,255, 10896-10901.
[133]Inhorn, R. C.; Majerus, P., Properties of inositol polyphosphate 1-phosphatase.J. Biol. Chem.1988,263,14559-14565.
[134]Shaltiel, G.; Shamir, A.; Shapiro, J.; Ding, D.; Dalton, E.; Bialer, M.; Harwood, A. J.; Belmaker, R. H.; Greenberg, M. L.; Agam, G., Valproate decreases inositol biosynthesis. Biol. Psychiatry 2004,56,868-874.
[135]Williams, A.; Sarkar, S.; Cuddon, P.; Ttofi, E. K.; Saiki, S.; Siddiqi, F. H.; Jahreiss, L.; Fleming, A.; Pask, D.; Goldsmith, P., Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol.2008,4, 295-305.
[136]Garcia-Arencibia, M.; Hochfeld, W. E.; Toh, P. P.; Rubinsztein, D. C. In Autophagy, a guardian against neurodegeneration, Semin. Cell Dev. Biol., Elsevier: 2010; pp 691-698.
[137]Sczekan, S. R.; Strumwasser, F., Antipsychotic drugs block IP3-dependent Ca2+-release from rat brain microsomes. Biol. Psychiatry 1996,40,497-502.
[138]Chen, Y.; Yang, L.; Feng, C.; Wen, L.-P., Nano neodymium oxide induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCI-H460 cells. Biochem. Biophys. Res. Commun.2005,337,52-60.
[139]Yu, L.; Lu, Y.; Man, N.; Yu, S.-H.; Wen, L.-P., Rare Earth Oxide Nanocrystals Induce Autophagy in HeLa Cells. Small 2009,5,2784-2787.
[140]Man, N.; Yu, S.-H., Rare earth oxide nanocrystals as a new class of autophagy inducers. Autophagy 2010,6,310-311.
[141]Seleverstov, O.; Zabirnyk, O.; Zscharnack, M.; Bulavina, L.; Nowicki, M.; Heinrich, J.-M.; Yezhelyev, M.; Emmrich, F.; O'Regan, R.; Bader, A., Quantum Dots for Human Mesenchymal Stem Cells Labeling. A Size-Dependent Autophagy Activation. Nano Lett.2006,6,2826-2832.
[142]Zabirnyk, O.; Yezhelyev, M.; Seleverstov, O., Nanoparticles as a novel class of autophagy activators. Autophagy 2007,3,278-281.
[143]Zhang, Q.; Yang, W.; Man, N.; Zheng, F.; Shen, Y.; Sun, K.; Li, Y.; Wen, L.-P., Autophagy-mediated chemosensitization in cancer cells by fullerene C60 nanocrystal. Autophagy 2009,5,1107-1117.
[144]Li, X.; Chen, N.; Su, Y.; He, Y.; Yin, M.; Wei, M.; Wang, L.; Huang, W.; Fan, C.; Huang, Q., Autophagy-Sensitized Cytotoxicity of Quantum Dots in PC 12 Cells. Advanced Healthcare Materials 2013.
[145]Sun, T.; Yan, Y.; Zhao, Y.; Guo, F.; Jiang, C., Copper oxide nanoparticles induce autophagic cell death in a549 cells. PLoS ONE 2012,7, e43442.
[146]Li, C.; Liu, H.; Sun, Y.; Wang, H.; Guo, F.; Rao, S.; Deng, J.; Zhang, Y.; Miao, Y.; Guo, C., PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway. Journal of molecular cell biology 2009,1,37-45.
[147]Ma, X.; Wu, Y.; Jin, S.; Tian, Y.; Zhang, X.; Zhao, Y.; Yu, L.; Liang, X.-J., Gold Nanoparticles Induce Autophagosome Accumulation through Size-Dependent Nanoparticle Uptake and Lysosome Impairment. ACS Nano 2011,5,8629-8639.
[148]Stern, S.; Adiseshaiah, P.; Crist, R., Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Particle and Fibre Toxicology 2012,9, 20.
[149]Zhang, Y.; Zheng, F.; Yang, T.; Zhou, W.; Liu, Y.; Man, N.; Zhang, L.; Jin, N.; Dou, Q.; Zhang, Y.; et al., Tuning the autophagy-inducing activity of lanthanide-based nanocrystals through specific surface-coating peptides. Nat. Mater.2012,11,817-826.
[150]Vellai, T., Autophagy genes and ageing. Cell. Death. Differ.2008,16,94-102.
[151]Mizushima, N.; Hara, T., Intracellular Quality Control by Autophagy:How Does Autophagy Prevent Neurodegeneration? Autophagy 2006,2,302-304.
[152]Ost, A.; Svensson, K.; Ruishalme, I.; Brannmark, C.; Franck, N.; Krook, H.; Sandstrom, P.; Kjolhede, P.; Stralfors, P., Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol. Med.2010,16, 235.
[153]Liao, X.; Sluimer, Judith C.; Wang, Y.; Subramanian, M.; Brown, K.; Pattison, J. S.; Robbins, J.; Martinez, J.; Tabas, I., Macrophage Autophagy Plays a Protective Role in Advanced Atherosclerosis. Cell Metab.2012,15,545-553.
[154]Lynch-Day, M. A.; Mao, K.; Wang, K.; Zhao, M.; Klionsky, D. J., The Role of Autophagy in Parkinson's Disease. Cold Spring Harbor Perspectives in Medicine 2012,2.
[155]Liu, Z.; Cai, W.; He, L.; Nakayama, N.; Chen, K.; Sun, X.; Chen, X.; Dai, H., In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotechnol.2007,2,47-52.
[156]Sarkar, S.; Perlstein, E. O.; Imarisio, S.; Pineau, S.; Cordenier, A.; Maglathlin, R. L.; Webster, J. A.; Lewis, T. A.; O'Kane, C. J.; Schreiber, S. L.; et al, Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat. Chem. Biol.2007,3,331-338.
[157]Klionsky, D. J.; Abdalla, F. C.; Abeliovich, H.; Abraham, R. T.; Acevedo-Arozena, A.; Adeli, K.; Agholme, L.; Agnello, M.; Agostinis, P.; Aguirre-Ghiso, J. A.; et al, Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. Autophagy 2012,8,445-544.
[158]Lu, Y.; Zhang, L.; Li, J.; Su, Y.-D.; Liu, Y.; Xu, Y.-J.; Dong, L.; Gao, H.-L.; Lin, J.; Man, N.; et al, MnO Nanocrystals:A Platform for Integration of MRI and Genuine Autophagy Induction for Chemotherapy. Adv. Funct. Mater.2013,23, 1534-1546.
[159]Liu, E. Y.; Ryan, K. M., Autophagy and cancer-issues we need to digest. J. Cell Sci.2012,125,2349-2358.
[160]Kostarelos, K.; Lacerda, L.; Pastorin, G.; Wu, W.; WieckowskiSebastien; Luangsivilay, J.; Godefroy, S.; Pantarotto, D.; Briand, J.-P.; Muller, S.; et al, Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell type. Nat Nano 2007,2,108-113.
[161]H(?)yer-Hansen, M.; Jaattela, M., Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell. Death. Differ.2007,14, 1576-1582.
[162]Wang, L.; Dong, Z.; Huang, B.; Zhao, B.; Wang, H.; Zhao, J.; Kung, H.; Zhang, S.; Miao, J., Distinct patterns of autophagy evoked by two benzoxazine derivatives in vascular endothelial cells. Autophagy 2010,6,1115-1124.
[163]Yang, R.-B.; Mark, M. R.; Gray, A.; Huang, A.; Xie, M. H.; Zhang, M.; Goddard, A.; Wood, W. I.; Gurney, A. L.; Godowski, P. J., Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 1998,395,284-288.
[164]Kapadia, S.; Lee, J.; Torre-Amione, G.; Birdsall, H. H.; Ma, T. S.; Mann, D. L., Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. The Journal of Clinical Investigation 1995,96, 1042-1052.
[165]U.S. Food and Drug Administration:Guidance for Industry:Pyrogen and Endotoxins Testing:Questions and Answers.2012.
[166]Levine, B.; Mizushima, N.; Virgin, H. W., Autophagy in immunity and inflammation. Nature 2011,469,323-335.
[167]Lee, H. K.; Lund, J. M.; Ramanathan, B.; Mizushima, N.; Iwasaki, A., Autophagy-Dependent Viral Recognition by Plasmacytoid Dendritic Cells. Science 2007,315,1398-1401.
[168]Miyazaki, Y.; Hiraoka, S.; Tsutsui, S.; Kitamura, S.; Shinomura, Y; Matsuzawa, Y, Epidermal growth factor receptor mediates stress-induced expression of its ligands in rat gastric epithelial cells. Gastroenterology 2001,120,108-116.
[2]Future Markets:The World Market for Nanotechnology and Nanomaterials in Consumer Products; 2010.
[3]Hussain, S.; Al-Nsour, F.; Rice, A. B.; Marshburn, J.; Yingling, B.; Ji, Z.; Zink, J. I.; Walker, N. J.; Garantziotis, S., Cerium dioxide nanoparticles induce apoptosis and autophagy in human peripheral blood monocytes. ACS Nano 2012,6,5820-5829.
[4]秦正红；乐卫东,自噬——生物学与疾病.北京：科学出版社：2011.
[5]Feynman, R. P., There's plenty of room at the bottom. Engineering and Science 1960,23,22-36.
[6]Ouyang, M.; Huang, J.-L.; Lieber, C.M., Fundamental electronic properties and applications of single-walled carbon nanotubes. Acc. Chem. Res 2002,35, 1018-1025.
[7]Forro, L.; Schnonenberger, C.; Dresselhouse, M.; Dresselhouse, G.; Avouris, P., Carbon nanotubes synthesis, structure, properties and applications. Springer, New York:2001.
[8]Zhou, O.; Shimoda, H.; Gao, B.; Oh, S.; Fleming, L.; Yue, G., Materials science of carbon nanotubes:fabrication, integration, and properties of macroscopic structures of carbon nanotubes. Acc. Chem. Res.2002,35,1045-1053.
[9]Niyogi, S.; Hamon, M.; Hu, H.; Zhao, B.; Bhowmik, P.; Sen, R.; Itkis, M.; Haddon, R., Chemistry of single-walled carbon nanotubes. Acc. Chem. Res.2002,35, 1105-1113.
[10]Sun, Y.-P.; Fu, K.; Lin, Y; Huang, W., Functionalized carbon nanotubes: properties and applications. Acc. Chem. Res.2002,35,1096-1104.
[11]Tasis, D.; Tagmatarchis, N.; Bianco, A.; Prato, M., Chemistry of carbon nanotubes. Chem. Rev.2006,106,1105-1136.
[12]O'Connell, M. J.; Bachilo, S. M.; Huffman, C. B.; Moore, V. C.; Strano, M. S.; Haroz, E. H.; Rialon, K. L.; Boul, P. J.; Noon, W. H.; Kittrell, C.; et al., Band Gap Fluorescence from Individual Single-Walled Carbon Nanotubes. Science 2002,297, 593-596.
[13]Fernando, K. S.; Lin, Y.; Wang, W.; Kumar, S.; Zhou, B.; Xie, S.-Y.; Cureton, L. T.; Sun, Y.-P., Diminished band-gap transitions of single-walled carbon nanotubes in complexation with aromatic molecules. J. Am. Chem. Soc.2004,126,10234-10235.
[14]Liu, H. L.; Zhang, Y. L.; Yang, N.; Zhang, Y. X.; Liu, X. Q.; Li, C. G.; Zhao, Y.; Wang, Y. G.; Zhang, G. G.; Yang, P.; et al, A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt-TSC2-mTOR signaling. Cell Death and Dis 2011,2, e159.
[15]Lu, F.; Gu, L.; Meziani, M. J.; Wang, X.; Luo, P. G.; Veca, L. M.; Cao, L.; Sun, Y. P., Advances in bioapplications of carbon nanotubes. Adv. Mater.2009,21,139-152.
[16]Georgakilas, V.; Kordatos, K.; Prato, M.; Guldi, D. M.; Holzinger, M.; Hirsch, A., Organic Functionalization of Carbon Nanotubes. J. Am. Chem. Soc.2002,124, 760-761.
[17]Zhou, H.; Mu, Q.; Gao, N.; Liu, A.; Xing, Y.; Gao, S.; Zhang, Q.; Qu, G.; Chen, Y.; Liu, G.; et al., A Nano-Combinatorial Library Strategy for the Discovery of Nanotubes with Reduced Protein-Binding, Cytotoxicity, and Immune Response. Nano Lett.2008,8,859-865.
[18]Gao, N.; Zhang, Q.; Mu, Q.; Bai, Y.; Li, L.; Zhou, H.; Butch, E. R.; Powell, T. B.; Snyder, S. E.; Jiang, G.; et al, Steering Carbon Nanotubes to Scavenger Receptor Recognition by Nanotube Surface Chemistry Modification Partially Alleviates NFκB Activation and Reduces Its Immunotoxicity. ACS Nano 2011,5,4581-4591.
[19]Lin, Y.; Taylor, S.; Li, H.; Fernando, K. S.; Qu, L.; Wang, W.; Gu, L.; Zhou, B.; Sun, Y.-P., Advances toward bioapplications of carbon nanotubes. J. Mater. Chem. 2004,14,527-541.
[20]Yun, Y.; Dong, Z.; Shanov, V.; Heineman, W. R.; Halsall, H. B.; Bhattacharya, A. Conforti, L.; Narayan, R. K.; Ball, W. S.; Schulz, M. J., Nanotube electrodes and biosensors. Nano Today 2007,2,30-37.
[21]Katz, E.; Willner, I., Biomolecule-functionalized carbon nanotubes: applications in nanobioelectronics. ChemPhysChem 2004,5,1084-1104.
[22]Balasubramanian, K.; Burghard, M., Biosensors based on carbon nanotubes. Anal. Bioanal. Chem.2006,385,452-468.
[23]Kim, S. N.; Rusling, J. F.; Papadimitrakopoulos, F., Carbon nanotubes for electronic and electrochemical detection of biomolecules. Adv. Mater.2007,19, 3214-3228.
[24]Besteman, K.; Lee, J.-O.; Wiertz, F. G.; Heering, H. A.; Dekker, C., Enzyme-coated carbon nanotubes as single-molecule biosensors. Nano Lett.2003,3, 727-730.
[25]Wong Shi Kam, N.; Dai, H., Single walled carbon nanotubes for transport and delivery of biological cargos. physica status solidi (b) 2006,243,3561-3566.
[26]Lacerda, L.; Raffa, S.; Prato, M.; Bianco, A.; Kostarelos, K., Cell-penetrating CNTs for delivery of therapeutics. Nano Today 2007,2,38-43.
[27]Prato, M.; Kostarelos, K.; Bianco, A., Functionalized Carbon Nanotubes in Drug Design and Discovery. Acc. Chem. Res.2007,41,60-68.
[28]Pastorin, G.; Wu, W.; Wieckowski, S.; Briand, J.-P.; Kostarelos, K.; Prato, M.; Bianco, A., Double functionalisation of carbon nanotubes for multimodal drug delivery. Chem. Commun.2006,1182-1184.
[29]Ali-Boucetta, H.; Al-Jamal, K. T.; McCarthy, D.; Prato, M.; Bianco, A.; Kostarelos, K., Multiwalled carbon nanotube-doxorubicin supramolecular complexes for cancer therapeutics. Chem. Commun.2008,459-461.
[30]Liu, Z.; Sun, X.; Nakayama-Ratchford, N.; Dai, H., Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano 2007,1, 50-56.
[31]Liu, Z.; Winters, M.; Holodniy, M.; Dai, H., siRNA Delivery into Human T Cells and Primary Cells with Carbon-Nanotube Transporters. Angewandte Chemie International Edition 2007,46,2023-2027.
[32]Zhang, Z.; Yang, X.; Zhang, Y.; Zeng, B.; Wang, S.; Zhu, T.; Roden, R. B.; Chen, Y.; Yang, R., Delivery of telomerase reverse transcriptase small interfering RNA in complex with positively charged single-walled carbon nanotubes suppresses tumor growth. Clin. Cancer Res.2006,12,4933-4939.
[33]Torchilin, V. P., Multifunctional nanocarriers. Adv. Drug Delivery Rev.2012.
[34]Yang, S. T.; Fernando, K.; Liu, J. H.; Wang, J.; Sun, H. F.; Liu, Y.; Chen, M.; Huang, Y.; Wang, X.; Wang, H., Covalently PEGylated carbon nanotubes with stealth character in vivo. Small 2008,4,940-944.
[35]Liu, Z.; Davis, C.; Cai, W.; He, L.; Chen, X.; Dai, H., Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc. Natl. Acad. Sci. U. S. A.2008,105,1410-1415.
[36]Riggs, J. E.; Guo, Z.; Carroll, D. L.; Sun, Y.-P., Strong luminescence of solubilized carbon nanotubes. J. Am. Chem. Soc.2000,122,5879-5880.
[37]Welsher, K.; Liu, Z.; Daranciang, D.; Dai, H., Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. Nano Lett.2008,8,586-590.
[38]Cherukuri, P.; Bachilo, S. M.; Litovsky, S. H.; Weisman, R. B., Near-Infrared Fluorescence Microscopy of Single-Walled Carbon Nanotubes in Phagocytic Cells. J. Am. Chem. Soc.2004,126,15638-15639.
[39]Leeuw, T. K.; Reith, R. M.; Simonette, R. A.; Harden, M. E.; Cherukuri, P.; Tsyboulski, D. A.; Beckingham, K. M.; Weisman, R. B., Single-Walled Carbon Nanotubes in the Intact Organism:Near-IR Imaging and Biocompatibility Studies in Drosophila. Nano Lett.2007,7,2650-2654.
[40]Feazell, R. P.; Nakayama-Ratchford, N.; Dai, H.; Lippard, S. J., Soluble single-walled carbon nanotubes as longboat delivery systems for platinum (IV) anticancer drug design. J. Am. Chem. Soc.2007,129,8438-8439.
[41]Porter, A. E.; Gass, M.; Muller, K.; Skepper, J. N.; Midgley, P. A.; Welland, M., Direct imaging of single-walled carbon nanotubes in cells. Nat Nano 2007,2, 713-717.
[42]Casals, E.; Pfaller, T.; Duschl, A.; Oostingh, G. J.; Puntes, V., Time evolution of the nanoparticle protein corona. ACS Nano 2010,4,3623-3632.
[43]Lundqvist, M.; Stigler, J.; Elia, G.; Lynch, I.; Cedervall, T.; Dawson, K. A., Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl. Acad. Sci. U. S. A.2008,105, 14265-14270.
[44]Salvador-Morales, C.; Flahaut, E.; Sim, E.; Sloan, J.; H Green, M. L.; Sim, R. B., Complement activation and protein adsorption by carbon nanotubes. Mol. Immunol. 2006,43,193-201.
[45]Kim, H. R.; Andrieux, K.; Delomenie, C.; Chacun, H.; Appel, M.; Desmaele, D.; Taran, F.; Georgin, D.; Couvreur, P.; Taverna, M., Analysis of plasma protein adsorption onto PEGylated nanoparticles by complementary methods:2-DE, CE and Protein Lab-on-chip(?) system. Electrophoresis 2007,28,2252-2261.
[46]Ge, C.; Du, J.; Zhao, L.; Wang, L.; Liu, Y.; Li, D.; Yang, Y.; Zhou, R.; Zhao, Y.; Chai, Z., Binding of blood proteins to carbon nanotubes reduces cytotoxicity. Proc. Natl. Acad. Sci. U. S. A.2011,108,16968-16973.
[47]Nel, A.; Xia, T.; Madler, L.; Li, N., Toxic potential of materials at the nanolevel. Science 2006,311,622-627.
[48]Tsukahara, T.; Haniu, H., Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells. Mol. Cell. Biochem.2011,352, 57-63.
[49]Pacurari, M.; Yin, X. J.; Zhao, J.; Ding, M.; Leonard, S. S.; Schwegler-Berry, D.; Ducatman, B. S.; Sbarra, D.; Hoover, M. D.; Castranova, V., Raw singlerwall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-κB, and Akt in normal and malignant human mesothelial cells. Environ. Health Perspect.2008,116, 1211.
[50]Srivastava, R. K.; Pant, A. B.; Kashyap, M. P.; Kumar, V.; Lohani, M.; Jonas, L.; Rahman, Q., Multi-walled carbon nanotubes induce oxidative stress and apoptosis in human lung cancer cell line-A549. Nanotoxicology 2011,5,195-207.
[51]Poland, C. A.; Duffin, R.; Kinloch, I.; Maynard, A.; Wallace, W. A.; Seaton, A.; Stone, V.; Brown, S.; MacNee, W.; Donaldson, K., Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat. Nanotechnol.2008,3,423-428.
[52]Zhu, L.; Chang, D. W.; Dai, L.; Hong, Y, DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano Lett.2007,7,3592-3597.
[53]Cheng, W.-W.; Lin, Z.-Q.; Wei, B.-F.; Zeng, Q.; Han, B.; Wei, C.-X.; Fan, X.-J.; Hu, C.-L.; Liu, L.-H.; Huang, J.-H., Single-walled carbon nanotube induction of rat aortic endothelial cell apoptosis:reactive oxygen species are involved in the mitochondrial pathway. Int. J. Biochem. Cell. B.2011,43,564-572.
[54]Wang, L.; Luanpitpong, S.; Castranova, V.; Tse, W.; Lu, Y.; Pongrakhananon, V.; Rojanasakul, Y., Carbon nanotubes induce malignant transformation and tumorigenesis of human lung epithelial cells. Nano Lett.2011,11,2796-2803.
[55]Mizushima, N.; Levine, B.; Cuervo, A.; Klionsky, D., Autophagy fights disease through cellular self-digestion. Nature 2008,451,1069-1075.
[56]Deter, R. L.; Baudhuin, P.; Duve, C. d., Participation of Lysosomes in Cellular Autophagy Induced in Rat Liver by Glucagon. J. Cell Biol.1967,35, C11-C16.
[57]Klionsky, D. J., Autophagy:from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol.2007,8,931-937.
[58]Mizushima, N., Autophagy:process and function. Genes Dev.2007,21, 2861-2873.
[59]Hailey, D.; Rambold, A.; Satpute-Krishnan, P.; Mitra, K.; Sougrat, R.; Kim, P.; Lippincott-Schwartz, J., Mitochondria Supply Membranes for Autophagosome Biogenesis during Starvation. Cell 2010,141,656-667.
[60]Mizushima, N.; Yoshimori, T.; Levine, B., Methods in mammalian autophagy research. Cell 2010,140,313-326.
[61]Takeshige, K.; Baba, M.; Tsuboi, S.; Noda, T.; Ohsumi, Y., Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol.1992,119,301-311.
[62]Baba, M.; Takeshige, K.; Baba, N.; Ohsumi, Y., Ultrastructural analysis of the autophagic process in yeast:detection of autophagosomes and their characterization. J. Cell Biol.1994,124,903-913.
[63]Baba, M.; Osumi, M.; Ohsumi, Y, Analysis of the membrane structures involved in autophagy in yeast by freeze-replica method. Cell Struct. Funct.1995,20,465-471.
[64]Tian, Y.; Li, Z.; Hu, W.; Ren, H.; Tian, E.; Zhao, Y.; Lu, Q.; Huang, X.; Yang, P.; Li, X., C. elegans Screen Identifies Autophagy Genes Specific to Multicellular Organisms. Cell 2010,141,1042-1055.
[65]Kim, J.; Kundu, M.; Viollet, B.; Guan, K.-L., AMPK and mTOR regulate autophagy through direct phosphorylation of Uikl.Nat. Cell Biol.2011,13,132-141.
[66]Nakatogawa, H.; Suzuki, K.; Kamada, Y.; Ohsumi, Y, Dynamics and diversity in autophagy mechanisms:lessons from yeast. Nat. Rev. Mol. Cell Biol.2009,10, 458-467.
[67]Lockshin, R.; Zakeri, Z., Programmed cell death and apoptosis:origins of the theory. Nat. Rev. Mol. Cell Biol.2001,2,545-550.
[68]Yuan, J.; Horvitz, H. R., A first insight into the molecular mechanisms of apoptosis. Cell 2004,116, S53-S56.
[69]Nicholson, D.; Ali, A.; Thornberry, N.; Vaillancourt, J.; Ding, C.; Gallant, M.; Gareau, Y.; Griffin, P.; Labelle, M.; Lazebnik, Y, Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995,376,37-43.
[70]Schwartz, L.; Smith, S.; Jones, M.; Osborne, B., Do all programmed cell deaths occur via apoptosis? Proc. Natl. Acad. Sci. U. S. A.1993,90,980-984.
[71]Kuma, A.; Hatano, M.; Matsui, M.; Yamamoto, A.; Nakaya, H.; Yoshimori, T.; Ohsumi, Y.; Tokuhisa, T.; Mizushima, N., The role of autophagy during the early neonatal starvation period. Nature 2004,432,1032-1036.
[72]Gozuacik, D.; Kimchi, A., Autophagy and Cell Death. In Curr. Top. Dev. Biol, Gerald, P. S., Ed. Academic Press:2007; Vol. Volume 78, pp 217-245.
[73]Levine, B., Cell biology:Autophagy and cancer. Nature 2007,446,745-747.
[74]Kroemer, G.; Levine, B., Autophagic cell death:the story of a misnomer. Nat. Rev. Mol. Cell Biol.2008,9,1004-1010.
[75]Shintani, T.; Klionsky, D. J., Autophagy in Health and Disease:A Double-Edged Sword. Science 2004,306,990-995.
[76]Marx, J., Autophagy:is it cancer's friend or foe? Science 2006,312,1160-1161.
[77]White, E.; DiPaola, R. S., The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res.2009,15,5308-5316.
[78]Mathew, R.; Karantza-Wadsworth, V.; White, E., Role of autophagy in cancer. Nat. Rev. Cancer 2007,7,961-967.
[79]Qu, X.; Yu, J.; Bhagat, G.; Furuya, N.; Hibshoosh, H.; Troxel, A.; Rosen, J.; Eskelinen, E.-L.; Mizushima, N.; Ohsumi, Y.; et al, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. The Journal of Clinical Investigation 2003,112,1809-1820.
[80]Yue, Z.; Jin, S.; Yang, C.; Levine, A. J.; Heintz, N., Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U. S. A.2003,100,15077-15082.
[81]Cadwell, K.; Liu, J. Y.; Brown, S. L.; Miyoshi, H.; Loh, J.; Lennerz, J. K.; Kishi, C.; Kc, W.; Carrero, J. A.; Hunt, S., A key role for autophagy and the autophagy gene Atg1611 in mouse and human intestinal Paneth cells. Nature 2008,456,259-263.
[82]White, E.; Karp, C.; Strohecker, A. M.; Guo, Y.; Mathew, R., Role of autophagy in suppression of inflammation and cancer. Curr. Opin. Cell Biol.2010,22,212-217.
[83]Mathew, R.; Karp, C. M.; Beaudoin, B.; Vuong, N.; Chen, G.; Chen, H.-Y.; Bray, K.; Reddy, A.; Bhanot, G.; Gelinas, C., Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009,137,1062-1075.
[84]Aita, V. M.; Liang, X. H.; Murty, V.; Pincus, D. L.; Yu, W.; Cayanis, E.; Kalachikov, S.; Gilliam, T. C.; Levine, B., Cloning and Genomic Organization of Beclin 1, a Candidate Tumor Suppressor Gene on Chromosome 17q21. Genomics 1999,59,59-65.
[85]Liang, X. H.; Jackson, S.; Seaman, M.; Brown, K.; Kempkes, B.; Hibshoosh, H.; Levine, B., Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999,402,672-676.
[86]Jin, S.; DiPaola, R. S.; Mathew, R.; White, E., Metabolic catastrophe as a means to cancer cell death. J. Cell Sci.2007,120,379-383.
[87]Jin, S.; White, E., Role of autophagy in cancer:management of metabolic stress. Autophagy 2007,3,28-31.
[88]Degenhardt, K.; Mathew, R.; Beaudoin, B.; Bray, K.; Anderson, D.; Chen, G.; Mukherjee, C.; Shi, Y.; Gelinas, C.; Fan, Y, Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006,10,51-64.
[89]Karantza-Wadsworth, V.; Patel, S.; Kravchuk, O.; Chen, G.; Mathew, R.; Jin, S.; White, E., Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev.2007,21,1621-1635.
[90]Mathew, R.; Kongara, S.; Beaudoin, B.; Karp, C. M.; Bray, K.; Degenhardt, K.; Chen, G.; Jin, S.; White, E., Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev.2007,21,1367-1381.
[91]Igney, F. H.; Krammer, P. H., Death and anti-death:tumour resistance to apoptosis. Nat. Rev. Cancer 2002,2,277-288.
[92]Scarlatti, F.; Bauvy, C.; Ventruti, A.; Sala, G.; Cluzeaud, F.; Vandewalle, A.; Ghidoni, R.; Codogno, P., Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J. Biol. Chem.2004,279, 18384-18391.
[93]Bursch, W.; Ellinger, A.; Kienzl, H.; Torok, L.; Pandey, S.; Sikorska, M.; Walker, R.; Hermann, R. S., Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 1996,17,1595-1607.
[94]Kessel, D.; Reiners, J. J.; Hazeldine, S. T.; Polin, L.; Horwitz, J. P., The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80. Mol. Cancer Ther. 2007,6,370-379.
[95]Melendez, A.; Talloczy, Z.; Seaman, M.; Eskelinen, E.-L.; Hall, D. H.; Levine, B., Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003,301,1387-1391.
[96]Colman, R. J.; Anderson, R. M.; Johnson, S. C.; Kastman, E. K.; Kosmatka, K. J.; Beasley, T. M.; Allison, D. B.; Cruzen, C.; Simmons, H. A.; Kemnitz, J. W., Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009,325, 201-204.
[97]Fontana, L.; Partridge, L.; Longo, V. D., Extending healthy life span-from yeast to humans. Science 2010,328,321-326.
[98]Masoro, E. J., Overview of caloric restriction and ageing. Mech. Ageing Dev. 2005,126,913-922.
[99]Levine, B.; Kroemer, G., Autophagy in the pathogenesis of disease. Cell 2008, 132,27-42.
[100]Alvers, A. L.; Fishwick, L. K.; Wood, M. S.; Hu, D.; Chung, H. S.; Dunn Jr, W. A.; Aris, J. P., Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell 2009,8,353-369.
[101]Dwivedi, M.; Song, H.-O.; Ahnn, J., Autophagy genes mediate the effect of calcineurin on life span in C. elegans. Autophagy 2009,5,604-607.
[102]Jia, K.; Levine, B., Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 2007,3,597-599.
[103]Harrison, D. E.; Strong, R.; Sharp, Z. D.; Nelson, J. F.; Astle, C. M.; Flurkey, K.; Nadon, N. L.; Wilkinson, J. E.; Frenkel, K.; Carter, C. S., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009,460,392-395.
[104]Anisimov, V. N.; Zabezhinski, M. A.; Popovich, I. G.; Piskunova, T. S.; Semenchenko, A. V.; Tyndyk, M. L.; Yurova, M. N.; Antoch, M. P.; Blagosklonny, M. V., Rapamycin extends maximal lifespan in cancer-prone mice. The American journal of pathology 2010,176,2092-2097.
[105]Wu, J. J.; Quijano, C.; Chen, E.; Liu, H.; Cao, L.; Fergusson, M. M.; Rovira, I. I.; Gutkind, S.; Daniels, M. P.; Komatsu, M., Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Milano) 2009,1,425.
[106]Twig, G.; Elorza, A.; Molina, A. J.; Mohamed, H.; Wikstrom, J. D.; Walzer, G.; Stiles, L.; Haigh, S. E.; Katz, S.; Las, G., Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. The EMBO journal 2008,27, 433-446.
[107]Chen, C.; Liu, Y.; Liu, Y.; Zheng, P., mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Science signaling 2009,2, ra75.
[108]Mattson, M. P.; Wan, R., Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. The Journal of nutritional biochemistry 2005,16,129-137.
[109]Ravikumar, B.; Duden, R.; Rubinsztein, D. C., Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet.2002,11,1107-1117.
[110]Iwata, A.; Christianson, J. C.; Bucci, M.; Ellerby, L. M.; Nukina, N.; Forno, L. S.; Kopito, R. R., Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc. Natl. Acad. Sci. U. S. A.2005,102, 13135-13140.
[111]Ravikumar, B.; Vacher, C.; Berger, Z.; Davies, J. E.; Luo, S.; Oroz, L. G.; Scaravilli, F.; Easton, D. F.; Duden, R.; O'Kane, C. J., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet.2004,36,585-595.
[112]Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R., Mutation in the a-synuclein gene identified in families with Parkinson's disease. Science 1997,276,2045-2047.
[113]Goedert, M.; Spillantini, M.; Jakes, R.; Rutherford, D.; Crowther, R., Multiple isoforms of human microtubule-associated protein tau:sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989,3,519-526.
[114]DiFiglia, M.; Sapp, E.; Chase, K. O.; Davies, S. W.; Bates, G. P.; Vonsattel, J.; Aronin, N., Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997,277,1990-1993.
[115]Komatsu, M.; Waguri, S.; Chiba, T.; Murata, S.; Iwata, J.-i.; Tanida, I.; Ueno, T.; Koike, M.; Uchiyama, Y.; Kominami, E., Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006,441,880-884.
[116]Hara, T.; Nakamura, K.; Matsui, M.; Yamamoto, A.; Nakahara, Y.; Suzuki-Migishima, R.; Yokoyama, M.; Mishima, K.; Saito, I.; Okano, H., Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006,441,885-889.
[117]Komatsu, M.; Wang, Q. J.; Holstein, G. R.; Friedrich, V. L.; Iwata, J.-i.; Kominami, E.; Chait, B. T.; Tanaka, K.; Yue, Z., Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. U. S. A.2007,104,14489-14494.
[118]Pattingre, S.; Tassa, A.; Qu, X.; Garuti, R.; Liang, X. H.; Mizushima, N.; Packer, M.; Schneider, M. D.; Levine, B., Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005,122,927-939.
[119]Wong, E. S.; Tan, J. M.; Soong, W.-E.; Hussein, K.; Nukina, N.; Dawson, V. L.; Dawson, T. M.; Cuervo, A. M.; Lim, K.-L., Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum. Mol. Genet.2008,17,2570-2582.
[120]Lee, J.-H.; Yu, W. H.; Kumar, A.; Lee, S.; Mohan, P. S.; Peterhoff, C. M.; Wolfe, D. M.; Martinez-Vicente, M.; Massey, A. C.; Sovak, G., Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010,141,1146-1158.
[121]Wong, E.; Cuervo, A. M., Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci.2010,13,805-811.
[122]Zhang, L.; Yu, J.; Pan, H.; Hu, P.; Hao, Y.; Cai, W.; Zhu, H.; Yu, A. D.; Xie, X.; Ma, D.; et al., Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc. Natl. Acad. Sci. U. S. A.2007,104,19023-19028.
[123]Klionsky, D. J.; Emr, S. D., Autophagy as a regulated pathway of cellular degradation. Science 2000,290,1717-1721. [124] Cantley, L. C., The phosphoinositide 3-kinase pathway. Science 2002,296, 1655-1657.
[125]Datta, S. R.; Dudek, H.; Tao, X.; Masters, S.; Fu, H.; Gotoh, Y.; Greenberg, M. E., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997,91,231-241.
[126]Backer, J., The regulation and function of Class III PI3Ks:novel roles for Vps34. Biochem. J 2008,410,1-17.
[127]Fleming, A.; Noda, T.; Yoshimori, T.; Rubinsztein, D. C., Chemical modulators of autophagy as biological probes and potential therapeutics. Nat. Chem. Biol.2011,7, 9-17.
[128]Meley, D.; Bauvy, C.; Houben-Weerts, J. H.; Dubbelhuis, P. F.; Helmond, M. T.; Codogno, P.; Meijer, A. J., AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem.2006,281,34870-34879.
[129]Meijer, A. J.; Codogno, P., AMP-activated protein kinase and autophagy. Autophagy 2007,3,238-240.
[130]Williams, R. S.; Cheng, L.; Mudge, A. W.; Harwood, A. J., A common mechanism of action for three mood-stabilizing drugs. Nature 2002,417,292-295.
[131]Sarkar, S.; Floto, R. A.; Berger, Z.; Imarisio, S.; Cordenier, A.; Pasco, M.; Cook, L. J.; Rubinsztein, D. C., Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol.2005,170,1101-1111.
[132]Hallcher, L.; Sherman, W. R., The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J. Biol. Chem.1980,255, 10896-10901.
[133]Inhorn, R. C.; Majerus, P., Properties of inositol polyphosphate 1-phosphatase.J. Biol. Chem.1988,263,14559-14565.
[134]Shaltiel, G.; Shamir, A.; Shapiro, J.; Ding, D.; Dalton, E.; Bialer, M.; Harwood, A. J.; Belmaker, R. H.; Greenberg, M. L.; Agam, G., Valproate decreases inositol biosynthesis. Biol. Psychiatry 2004,56,868-874.
[135]Williams, A.; Sarkar, S.; Cuddon, P.; Ttofi, E. K.; Saiki, S.; Siddiqi, F. H.; Jahreiss, L.; Fleming, A.; Pask, D.; Goldsmith, P., Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol.2008,4, 295-305.
[136]Garcia-Arencibia, M.; Hochfeld, W. E.; Toh, P. P.; Rubinsztein, D. C. In Autophagy, a guardian against neurodegeneration, Semin. Cell Dev. Biol., Elsevier: 2010; pp 691-698.
[137]Sczekan, S. R.; Strumwasser, F., Antipsychotic drugs block IP3-dependent Ca2+-release from rat brain microsomes. Biol. Psychiatry 1996,40,497-502.
[138]Chen, Y.; Yang, L.; Feng, C.; Wen, L.-P., Nano neodymium oxide induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCI-H460 cells. Biochem. Biophys. Res. Commun.2005,337,52-60.
[139]Yu, L.; Lu, Y.; Man, N.; Yu, S.-H.; Wen, L.-P., Rare Earth Oxide Nanocrystals Induce Autophagy in HeLa Cells. Small 2009,5,2784-2787.
[140]Man, N.; Yu, S.-H., Rare earth oxide nanocrystals as a new class of autophagy inducers. Autophagy 2010,6,310-311.
[141]Seleverstov, O.; Zabirnyk, O.; Zscharnack, M.; Bulavina, L.; Nowicki, M.; Heinrich, J.-M.; Yezhelyev, M.; Emmrich, F.; O'Regan, R.; Bader, A., Quantum Dots for Human Mesenchymal Stem Cells Labeling. A Size-Dependent Autophagy Activation. Nano Lett.2006,6,2826-2832.
[142]Zabirnyk, O.; Yezhelyev, M.; Seleverstov, O., Nanoparticles as a novel class of autophagy activators. Autophagy 2007,3,278-281.
[143]Zhang, Q.; Yang, W.; Man, N.; Zheng, F.; Shen, Y.; Sun, K.; Li, Y.; Wen, L.-P., Autophagy-mediated chemosensitization in cancer cells by fullerene C60 nanocrystal. Autophagy 2009,5,1107-1117.
[144]Li, X.; Chen, N.; Su, Y.; He, Y.; Yin, M.; Wei, M.; Wang, L.; Huang, W.; Fan, C.; Huang, Q., Autophagy-Sensitized Cytotoxicity of Quantum Dots in PC 12 Cells. Advanced Healthcare Materials 2013.
[145]Sun, T.; Yan, Y.; Zhao, Y.; Guo, F.; Jiang, C., Copper oxide nanoparticles induce autophagic cell death in a549 cells. PLoS ONE 2012,7, e43442.
[146]Li, C.; Liu, H.; Sun, Y.; Wang, H.; Guo, F.; Rao, S.; Deng, J.; Zhang, Y.; Miao, Y.; Guo, C., PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway. Journal of molecular cell biology 2009,1,37-45.
[147]Ma, X.; Wu, Y.; Jin, S.; Tian, Y.; Zhang, X.; Zhao, Y.; Yu, L.; Liang, X.-J., Gold Nanoparticles Induce Autophagosome Accumulation through Size-Dependent Nanoparticle Uptake and Lysosome Impairment. ACS Nano 2011,5,8629-8639.
[148]Stern, S.; Adiseshaiah, P.; Crist, R., Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Particle and Fibre Toxicology 2012,9, 20.
[149]Zhang, Y.; Zheng, F.; Yang, T.; Zhou, W.; Liu, Y.; Man, N.; Zhang, L.; Jin, N.; Dou, Q.; Zhang, Y.; et al., Tuning the autophagy-inducing activity of lanthanide-based nanocrystals through specific surface-coating peptides. Nat. Mater.2012,11,817-826.
[150]Vellai, T., Autophagy genes and ageing. Cell. Death. Differ.2008,16,94-102.
[151]Mizushima, N.; Hara, T., Intracellular Quality Control by Autophagy:How Does Autophagy Prevent Neurodegeneration? Autophagy 2006,2,302-304.
[152]Ost, A.; Svensson, K.; Ruishalme, I.; Brannmark, C.; Franck, N.; Krook, H.; Sandstrom, P.; Kjolhede, P.; Stralfors, P., Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol. Med.2010,16, 235.
[153]Liao, X.; Sluimer, Judith C.; Wang, Y.; Subramanian, M.; Brown, K.; Pattison, J. S.; Robbins, J.; Martinez, J.; Tabas, I., Macrophage Autophagy Plays a Protective Role in Advanced Atherosclerosis. Cell Metab.2012,15,545-553.
[154]Lynch-Day, M. A.; Mao, K.; Wang, K.; Zhao, M.; Klionsky, D. J., The Role of Autophagy in Parkinson's Disease. Cold Spring Harbor Perspectives in Medicine 2012,2.
[155]Liu, Z.; Cai, W.; He, L.; Nakayama, N.; Chen, K.; Sun, X.; Chen, X.; Dai, H., In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotechnol.2007,2,47-52.
[156]Sarkar, S.; Perlstein, E. O.; Imarisio, S.; Pineau, S.; Cordenier, A.; Maglathlin, R. L.; Webster, J. A.; Lewis, T. A.; O'Kane, C. J.; Schreiber, S. L.; et al, Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat. Chem. Biol.2007,3,331-338.
[157]Klionsky, D. J.; Abdalla, F. C.; Abeliovich, H.; Abraham, R. T.; Acevedo-Arozena, A.; Adeli, K.; Agholme, L.; Agnello, M.; Agostinis, P.; Aguirre-Ghiso, J. A.; et al, Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. Autophagy 2012,8,445-544.
[158]Lu, Y.; Zhang, L.; Li, J.; Su, Y.-D.; Liu, Y.; Xu, Y.-J.; Dong, L.; Gao, H.-L.; Lin, J.; Man, N.; et al, MnO Nanocrystals:A Platform for Integration of MRI and Genuine Autophagy Induction for Chemotherapy. Adv. Funct. Mater.2013,23, 1534-1546.
[159]Liu, E. Y.; Ryan, K. M., Autophagy and cancer-issues we need to digest. J. Cell Sci.2012,125,2349-2358.
[160]Kostarelos, K.; Lacerda, L.; Pastorin, G.; Wu, W.; WieckowskiSebastien; Luangsivilay, J.; Godefroy, S.; Pantarotto, D.; Briand, J.-P.; Muller, S.; et al, Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell type. Nat Nano 2007,2,108-113.
[161]H(?)yer-Hansen, M.; Jaattela, M., Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell. Death. Differ.2007,14, 1576-1582.
[162]Wang, L.; Dong, Z.; Huang, B.; Zhao, B.; Wang, H.; Zhao, J.; Kung, H.; Zhang, S.; Miao, J., Distinct patterns of autophagy evoked by two benzoxazine derivatives in vascular endothelial cells. Autophagy 2010,6,1115-1124.
[163]Yang, R.-B.; Mark, M. R.; Gray, A.; Huang, A.; Xie, M. H.; Zhang, M.; Goddard, A.; Wood, W. I.; Gurney, A. L.; Godowski, P. J., Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 1998,395,284-288.
[164]Kapadia, S.; Lee, J.; Torre-Amione, G.; Birdsall, H. H.; Ma, T. S.; Mann, D. L., Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. The Journal of Clinical Investigation 1995,96, 1042-1052.
[165]U.S. Food and Drug Administration:Guidance for Industry:Pyrogen and Endotoxins Testing:Questions and Answers.2012.
[166]Levine, B.; Mizushima, N.; Virgin, H. W., Autophagy in immunity and inflammation. Nature 2011,469,323-335.
[167]Lee, H. K.; Lund, J. M.; Ramanathan, B.; Mizushima, N.; Iwasaki, A., Autophagy-Dependent Viral Recognition by Plasmacytoid Dendritic Cells. Science 2007,315,1398-1401.
[168]Miyazaki, Y.; Hiraoka, S.; Tsutsui, S.; Kitamura, S.; Shinomura, Y; Matsuzawa, Y, Epidermal growth factor receptor mediates stress-induced expression of its ligands in rat gastric epithelial cells. Gastroenterology 2001,120,108-116.