血脑脊液屏障转运体研究方法的进展

doi:10.3969/j.issn.2095-1396.2016.03.007

摘要/Abstract

摘要： 血脑屏障（Blood—brain barrier，BBB）已被公认为是一个横亘在脑和血液之间的具有动态及高度组织化特性的界面，其主要目的是防止溶质自由通行和通过孤立它的外围来保护中枢神经系统，其功能异常会先于或者加速一些神经系统疾病的恶化。BBB转运体的研究为解析BBB的功能、探索神经系统相关疾病的发病机制及促进脑部为靶向药物研发提供理论依据。文章主要对BBB转运体的分类和功能、BBB模型及转运体研究方法进行了概述，为中枢神经系统药物的新药设计、提高药物靶向性和药物相互作用等研究提供借鉴。

关键词: 血脑屏障, 转运体, 血脑屏障模型, 研究方法

Abstract: Blood—brain barrier (BBB) has been acknowledged as junction with dynamic and highly organized feature between brain and blood. It plays an important role in preventing free passage of solutes and protecting the central nervous system (CNS) by isolating it from the periphery. The abnormal function of it may speed up the deterioration of several neurological diseases. Its function abnormality precedes or accelerates the deterioration of some nervous system diseases. The study of transporters of blood brain barrier is intended to provide a theoretical evidence for analyzing the function of BBB, exploring the pathogenesis of nervous system disease and promoting the development of brain targeted drug. In this article, the blood brain barrier transporter classification and function, blood brain barrier model and transporter research methods are summarized to provide references for drug development, improving target activity and drug interaction.

Key words: blood&, mdash, brain barrier, transporter, blood&, mdash, brain barrier model, research methods

陈建，侯宏卫，刘勇，王安，胡清源. 血脑脊液屏障转运体研究方法的进展[J]. 神经药理学报, 2016, 6(3): 44-55.

CHEN Jian,HOU Hong-wei，LIU Yong，WANG An，HU Qing-yuan. Advances in Research Methods of Blood—Brain Barrier Transporters[J]. Acta Neuropharmacologica, 2016, 6(3): 44-55.

参考文献

[1] Brian T Hawkins, Thomas P Davis. The blood-brain barrier/neurovascular unit in health and disease [J]. Pharmacological Reviews, 2005, 57(2): 173-185.

[2] 许兵, 张俞, 杜久林. 血脑屏障的研究进展 [J]. 生理学报, 2016, 68(3): 306-322.

[3] Brian Wai Chow, Gu Cheng-hua. The molecular constituents of the blood–brain barrier [J]. Trends Neurosciences, 2015, 38(10): 598-608.

[4] 董小平, 喻斌, 金路, 等. 血脑屏障细胞组成研究进展 [J]. 中国实验方剂学杂志, 2012, 18(8): 281-284.

[5] 张海威, 张力. 血脑脊液屏障上 P-糖蛋白的研究进展 [J]. Acta Neuropharmacologica, 2016, 6(2):53-64.

[6] N Joan Abbott, Lars Rönnbäck, Elisabeth Hansson. Astrocyte–endothelial interactions at the blood–brain barrier [J]. Nature Reviews Neuroscience, 2006, 7(1): 41-53.

[7] Andrew D Wong, Ye Mao, Amanda F Levy, et al. The blood-brain barrier: an engineering perspective [J]. Frontiers Neuroengineering, 2013, 6:7.

[8] David S Miller. Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier [J]. Trends in Pharmacological Sciences, 2010, 31(6): 246-254.

[9] 李聃, 盛莉, 李燕. 药物转运体的研究方法 [J]. 药学学报, 2014, 49(7): 963-970.

[10] Eric J Murphy. The blood–brain barrier and protein‐mediated fatty acid uptake: role of the blood–brain barrier as a metabolic barrier [J]. J Neurochemistry, 2017, 141(3): 324-329.

[11] 周宓, 王志强. 跨血脑屏障药物转运的研究进展 [J]. 生命科学研究, 2009, 13(4): 370-376.

[12] Vasilis Vasiliou, Konstandinos Vasiliou, Daniel W Nebert. Human ATP-binding cassette (ABC) transporter family [J]. Human Genomics, 2009, 3(3): 281.

[13] Wolfgang Löscher, Heidrun Potschka. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family [J]. NeuroRx, 2005, 2(1): 86-98.

[14] Karobi Moitra, Michael Dean. Evolution of ABC transporters by gene duplication and their role in human disease [J]. Biological Chemistry, 2011, 392(1-2): 29-37.

[15] Young Hee Choi, Ai-Ming Yu. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development [J]. Current Pharmaceutical Design, 2014, 20(5): 793-807.

[16] Ms Hartz A, Bjorn Bauer. ABC transporters in the CNS-an inventory [J]. Current Pharmaceutical Biotechnology, 2011, 12(4): 656-673.

[17] Batista Da Silva Junior J, Marinho Dezani T, Bersani Dezani A, et al. Evaluating potential P-gp substrates: main aspects to choose the adequate permeability model for assessing gastrointestinal drug absorption [J]. Mini Reviews in Medicinal Chemistry, 2015, 15(10): 858-871.

[18] Bai Zhao-shi, Gao Mei-qi, Zhang Hui-juan, et al. BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe [J]. Cancer Letters, 2017, 402(28): 81-92.

[19] Zhu Tong, Corrie Howieson, Tomasz Wojtkowski, et al. The effect of verapamil, a P‐glycoprotein inhibitor, on the pharmacokinetics of peficitinib, an orally administered, once‐daily JAK inhibitor [J]. Clinical Pharmacology in Drug Development, 2017, DOI: 10.1002/cpdd.344.

[20] Daniela Cihalova, Martina Ceckova, Radim Kucera, et al. Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro [J]. Biochemical Pharmacology, 2015, 98(3): 465-472.

[21] Trevor J Mathias, Karthika Natarajan, Suneet Shukla, et al. The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations [J]. Investigational New Drugs, 2015, 33(2): 300-309.

[22] Branka Radic-Sarikas, Melinda Halasz, Kilian V M Huber, et al. Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter [J]. Scientific Reports, 2017, 7(1): 3091.

[23] Bryan H Norman, Joseph M Gruber, Sean P Hollinshead, et al. Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1) [J]. Bioorganic & Medicinal Chemistry Letters, 2002, 12(6): 883-886.

[24] Zhang Yun-kai, Wang Yi-jun, Pranav Gupta, et al. Multidrug resistance proteins (MRPs) and cancer therapy [J]. J AAPS, 2015, 17(4): 802-812.

[25] Chen S E, Zhang Z Y, Zhang J J. Meloxicam increases intracellular accumulation of doxorubicin via downregulation of multidrug resistance-associated protein 1 (MRP1) in A549 cells [J]. Genet Mol Res, 2015, 14(4): 14548-14560.

[26] Mao Qing-cheng, Jashvant D Unadkat. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport—an update [J]. J AAPS, 2015, 17(1): 65-82.

[27] Liao Ming-xiang, Chuang Bei-ching, Zhu Qing, et al. Preclinical absorption, distribution, metabolism, excretion, and pharmacokinetics of a novel selective inhibitor of breast cancer resistance protein (BCRP) [J]. Xenobiotica, 2017, DOI: 10.1080/00498254.2017.1328147.

[28] Nisha Vijay, Marilyn E Morris. Role of monocarboxylate transporters in drug delivery to the brain [J]. Current pharmaceutical design, 2014, 20(10): 1487-1498.

[29] Valquiria Bueno, Isabelle Binet, Ulrich Steger, et al. The specific monocarboxylate transporter (MCT1) inhibitor, AR-C117977, a novel immunosuppressant, prolongs allograft survival in the mouse [J]. Transplantation, 2007, 84(9): 1204-1207.

[30] Indranil Bhattacharya, Kathleen Boje. GHB (γ-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier [J]. J Pharmacology Experimental Therapeutics, 2004, 311(1): 92-98.

[31] König J. Uptake transporters of the human OATP family [M]. Drug Transporters. Springer. 2011: 1-28.

[32] Sachiyo Funakoshi, Teruo Murakami, Ryoko Yumoto, et al. Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and β‐methyldigoxin in rats [J]. J Pharmaceutical Sciences, 2005, 94(6): 1196-1203.

[33] Qiang Fu, Beom-jin Lee, Wonjae Lee, et al. Pharmacokinetic drug interaction between fexofenadine and fluvastatin mediated by organic anion-transporting polypeptides in rats [J]. European J Pharmaceutical Sciences, 2009, 37(3): 413-417.

[34] Katrin Wlcek, Fabienne Koller, Peter Ferenci, et al. Hepatocellular organic anion–transporting polypeptides (OATPs) and multidrug resistance–associated protein 2 (MRP2) are inhibited by silibinin [J]. Drug Metabolism and Disposition, 2013, 41(8): 1522-1528.

[35] Takashi Okura, Sayaka Kato, Yusuke Takano, et al. Functional characterization of rat plasma membrane monoamine transporter in the blood–brain and blood–cerebrospinal fluid barriers [J]. J Pharmaceutical Sciences, 2011, 100(9): 3924-3938.

[36] Duan Hai-chuan, Hu Tao, Robert S Foti, et al. Potent and selective inhibition of plasma membrane monoamine transporter by HIV protease inhibitors [J]. Drug Metabolism Disposition, 2015, 43(11): 1773-1780.

[37] Sanjay K Nigam, Kevin T Bush, Gleb Martovetsky, et al. The organic anion transporter (OAT) family: a systems biology perspective [J]. Physiological Reviews, 2015, 95(1): 83-123.

[38] Sumio Ohtsuki, Tetsuya Terasaki. Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development [J]. Pharmaceutical Research, 2007, 24(9): 1745-1758.

[39] Sumio Ohtsuki. New aspects of the blood–brain barrier transporters; its physiological roles in the central nervous system [J]. Biological and Pharmaceutical Bulletin, 2004, 27(10): 1489-1496.

[40] Fanuel T Hagos, Monica J Daood, Jacob A Ocque, et al. Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine [J]. Xenobiotica, 2017, 47(4): 346-353.

[41] Amy G Aslamkhan, Deborah M Thompson, Jennifer L Perry, et al. The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3 [J]. J American Physiology-Regulatory, Integrative and Comparative Physiology, 2006, 291(6): R1773-R1780.

[42] Thomas Couroussé, Sophie Gautron. Role of organic cation transporters (OCTs) in the brain [J]. Pharmacology & Therapeutics, 2015, 146: 94-103.

[43] Abdullah Mayati, Arnaud Bruyere, Amelie Moreau, et al. Protein kinase c-independent inhibition of organic cation transporter 1 activity by the bisindolylmaleimide ro 31-8220 [J]. PLoS one, 2015, 10(12): e0144667.

[44] Sekhar G N, Georgian A R, Sanderson L, et al. Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB) [J]. PLoS one, 2017, 12(3): e0173474.

[45] Toshiki Kurosawa, Kei Higuchi, Takashi Okura, et al. Involvement of proton-coupled organic cation antiporter in varenicline transport at blood-brain barrier of rats and in human brain capillary endothelial cells [J]. J Pharmaceutical Sciences, 2017, doi: 10.1016/j.xphs.2017.04.032.

[46] N Joan Abbott, Adjanie A K Patabendige, Diana E M Dolman, et al. Structure and function of the blood–brain barrier [J]. Neurobiology Disease, 2010, 37(1): 13-25.

[47] Zoran Redzic. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences [J]. Fluids Barriers CNS, 2011, 8(1): 3.

[48] Matthias A Hediger, Benjamin Clémençon, Robert E Burrier, et al. The ABCs of membrane transporters in health and disease (SLC series): introduction [J]. Molecular Aspects Medicine, 2013, 34(2): 95-107.

[49] William A Banks. Physiology and pathology of the blood-brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders [J]. J Neurovirology, 1999, 5(6): 538-555.

[50] Pardridge W. The blood-brain barrier. Permeability, substrate transport and drug and gene targeting [J]. Cerebral Blood Flow Metabolism, 2002, 2:119-139.

[51] Reinhard Gabathuler. Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases [J]. Neurobiology Disease, 2010, 37(1): 48-57.

[52] Angela R Jones, Eric V Shusta. Blood–brain barrier transport of therapeutics via receptor-mediation [J]. Pharmaceutical Res, 2007, 24(9): 1759-1771.

[53] William M Pardridge. Drug transport across the blood–brain barrier [J]. J Cerebral Blood Flow & Metabolism, 2012, 32(11): 1959-1972.

[54] De Vivo Darryl C, Rosario R Trifiletti, Ronald I Jacobson, et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay [J]. J New England Medicine, 1991, 325(10): 703-709.

[55] Berislav V Zlokovic. The blood-brain barrier in health and chronic neurodegenerative disorders [J]. Neuron, 2008, 57(2): 178-201.

[56] Joo F, Karnushina I. A procedure for the isolation of capillaries from rat brain [J]. Cytobios, 1973, 8(29): 41.

[57] Ferenc Joó. The blood-brain barrier in vitro: ten years of research on microvessels isolated from the brain [J]. Neurochemistry Int, 1985, 7(1): 1-25.

[58] Ferenc Joó. The cerebral microvessels in culture, an update [J]. J Neurochemistry, 1992, 58(1): 1-17.

[59] Rajesh N Kalaria, Stephen A Gravina, James W Schmidley, et al. The glucose transporter of the human brain and blood‐brain barrier [J]. Annals Neurology, 1988, 24(6): 757-764.

[60] Bradley E Enerson, Lester R Drewes. The rat blood—brain barrier transcriptome [J]. J Cerebral Blood Flow & Metabolism, 2006, 26(7): 959-973.

[61] Yasuo Uchida, Sumio Ohtsuki, Yuki Katsukura, et al. Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors [J]. J Neurochemistry, 2011, 117(2): 333-345.

[62] Richard Daneman, Zhou Lu, Dritan Agalliu, et al. The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells [J]. PLoS One, 2010, 5(10): e13741.

[63] Pertti Panula, Joo F, Rechardt L. Evidence for the presence of viable endothelial cells in cultures derived from dissociated rat brain [J]. Cellular Molecular Life Sciences, 1978, 34(1): 95-97.

[64] Szilvia Veszelka, Andrea E Tóth, Frizsina R Walter, et al. Docosahexaenoic acid reduces amyloid-β induced toxicity in cells of the neurovascular unit [J]. J Alzheimer's Disease, 2013, 36(3): 487-501.

[65] Dietmar Zenker, David Begley, Hansjurgen Bratzke, et al. Human blood‐derived macrophages enhance barrier function of cultured primary bovine and human brain capillary endothelial cells [J]. J Physiology, 2003, 551(3): 1023-1032.

[66] Caroline Coisne, Lucie Dehouck, Christelle Faveeuw, et al. Mouse syngenic in vitro blood-brain barrier model: a new tool to examine inflammatory events in cerebral endothelium [J]. Laboratory Investigation, 2005, 85(6): 734.

[67] Maxime Culot, Stefan Lundquist, Dorothee Vanuxeem, et al. An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening [J]. Toxicology in Vitro, 2008, 22(3): 799-811.

[68] Adjanie Patabendige, Robert A Skinner, Louise Morgan, et al. A detailed method for preparation of a functional and flexible blood–brain barrier model using porcine brain endothelial cells [J]. Brain Res, 2013, 1521:16-30.

[69] P Marc D Watson, Judy C Paterson, George Thom, et al. Modelling the endothelial blood-CNS barriers: a method for the production of robust in vitro models of the rat blood-brain barrier and blood-spinal cord barrier [J]. BMC Neuroscience, 2013, 14(1): 59.

[70] Nikolett Sándor, Fruzsina R Walter, Alexandra Bocsik, et al. Low dose cranial irradiation-induced cerebrovascular damage is reversible in mice [J]. PLoS One, 2014, 9(11): e112397.

[71] Barbara Deracinois, Sophie Duban-Deweer, Gwenael Pottiez, et al. TNAP and EHD1 are over-expressed in bovine brain capillary endothelial cells after the re-induction of blood-brain barrier properties [J]. PLoS One, 2012, 7(10): e48428.

[72] Shinsuke Nakagawa, Maria A Deli, Hiroko Kawaguchi, et al. A new blood–brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes [J]. Neurochemistry Int, 2009, 54(3): 253-263.

[73] Maria A Deli, Csongor S Abrahám, Yasufumi Kataoka, et al. Permeability studies on in vitro blood–brain barrier models: physiology, pathology, and pharmacology [J]. Cellular and Molecular Neurobiology, 2005, 25(1): 59-127.

[74] Barbara Deracinois, Gwenael Pottiez, Philippe Chafey, et al. Glial‐cell‐mediated re‐induction of the blood‐brain barrier phenotype in brain capillary endothelial cells: A differential gel electrophoresis study [J]. Proteomics, 2013, 13(7): 1185-1199.

[75] 姜波, 刘伟, 金晓玲, 等. 药物跨血脑屏障转运的实验模型研究进展 [J]. 国际药学研究杂志, 2016, 43(4): 652-657.

[76] Garberg P, Ball M, Borg N, et al. In vitro models for the blood–brain barrier [J]. Toxicology in Vitro, 2005, 19(3): 299-334.

[77] Eva Hellinger, Szilvia Veszelka, Andrea E Tóth, et al. Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood–brain barrier penetration models [J]. J European Pharmaceutics and Biopharmaceutics, 2012, 82(2): 340-351.

[78] N Joan Abbott, Lars Rönnbäck, Elisabeth Hansson. Astrocyte-endothelial interactions at the blood-brain barrier [J]. Nature Reviews Neuroscience, 2006, 7(1): 41.

[79] Yoshinobu Takakura, Andrew M Trammel, Sandra L Kuentzel, et al. Hexose uptake in primary cultures of bovine brain microvessel endothelial cells. II. Effects of conditioned media from astroglial and glioma cells [J]. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1991, 1070(1): 11-19.

[80] Pifferi F, Jouin M, Alessandri J, et al. n-3 Fatty acids modulate brain glucose transport in endothelial cells of the blood–brain barrier [J]. Prostaglandins, Leukotrienes and Essential Fatty Acids, 2007, 77(5): 279-286.

[81] Fabien Pifferi, Melanie Jouin, Jean-Marc Alessandri, et al. n-3 long-chain fatty acids and regulation of glucose transport in two models of rat brain endothelial cells [J]. Neurochemistry Int, 2010, 56(5): 703-710.

[82] Yadollah Omidi, Jaleh Barar, Somaieh Ahmadian, et al. Characterization and astrocytic modulation of system L transporters in brain microvasculature endothelial cells [J]. Cell Biochemistry Function, 2008, 26(3): 381-391.

[83] Regina A, Roux F, Revest P. Glucose transport in immortalized rat brain capillary endothelial cells in vitro: transport activity and GLUT1 expression [J]. Biochimica et Biophysica Acta (BBA)-General Subjects, 1997, 1335(1): 135-143.

[84] Anthony Régina, Stephanie Morchoisne, Nancy D Borson, et al. Factor (s) released by glucose-deprived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells [J]. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2001, 1540(3): 233-242.

[85] Keita Shimomura, Takashi Okura, Sayaka Kato, et al. Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood–brain barrier model [J]. Fluids and Barriers of the CNS, 2013, 10(1): 8.

[86] P M Abdul Muneer, Saleena Alikunju, Adam M Szlachetka, et al. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction [J]. Molecular Neurodegeneration, 2011, 6(1): 23.

[87] Hans Christian Helms, Rasmus Madelung, Helle Sonderby Waagepetersen, et al. In vitro evidence for the brain glutamate efflux hypothesis: Brain endothelial cells cocultured with astrocytes display a polarized brain‐to‐blood transport of glutamate [J]. Glia, 2012, 60(6): 882-893.

[88] Yadollah Omidi, Lee Campbell, Jaleh Barar, et al. Evaluation of the immortalised mouse brain capillary endothelial cell line, b. End3, as an in vitro blood–brain barrier model for drug uptake and transport studies [J]. Brain Res, 2003, 990(1): 95-112.

[89] Yoshiharu Mitsunaga, Hitomi Takanaga, Hirotami Matsuo, et al. Effect of bioflavonoids on vincristine transport across blood–brain barrier [J]. J European Pharmacology, 2000, 395(3): 193-201.

[90] Kuresh Youdim, Alex Avdeef, N Joan Abbott. In vitro trans-monolayer permeability calculations: often forgotten assumptions [J]. Drug Discovery, 2003, 8(21): 997-1003.

[91] Hans Christian Helms, Maria Hersom, Louise Borella Kuhlmann, et al. An electrically tight in vitro blood–brain barrier model displays net brain-to-blood efflux of substrates for the ABC transporters, P-gp, Bcrp and Mrp-1 [J]. J AAPS, 2014, 16(5): 1046-1055.

[92] Julie Cattelotte, Pascal André, Melissa Ouellet, et al. In situ mouse carotid perfusion model: glucose and cholesterol transport in the eye and brain [J]. J Cerebral Blood Flow & Metabolism, 2008, 28(8): 1449-1459.

[93] Nicolas Tournier, Wadad Saba, Salvatore Cisternino, et al. Effects of selected OATP and/or ABC transporter inhibitors on the brain and whole-body distribution of glyburide [J]. J AAPS, 2013, 15(4): 1082-1090.

[94] Kentaro Yano, Shinobu Takimoto, Toshimitsu Motegi, et al. Role of P-glycoprotein in regulating cilnidipine distribution to intact and ischemic brain [J]. Drug Metabolism Pharmacokinetics, 2014, 29(3): 254-258.

[95] Ge Shu-fan, Gao Song, Yin Tai-jun, et al. Determination of pharmacokinetics of chrysin and its conjugates in wild-type FVB and Bcrp1 knockout mice using a validated LC-MS/MS method [J]. J Agricultural Food Chemistry, 2015, 63(11): 2902-2910.

[96] Yoshiki Matsuda, Yoshihiro Konno, Takashi Hashimoto, et al. In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein–cannulated rats [J]. Drug Metabolism Disposition, 2013, 41(8): 1514-1521.

[97] So Yeun Kim, Eun-Sook Choi, Hyo-Jung Lee, et al. Transthyretin as a new transporter of nanoparticles for receptor-mediated transcytosis in rat brain microvessels [J]. Colloids and Surfaces B: Biointerfaces, 2015, 136:989-996.

[98] Zhang Xue-de, Li Wei, Hou Yan-li, et al. Comparative membrane proteomic analysis between lung adenocarcinoma and normal tissue by iTRAQ labeling mass spectrometry [J]. J American Translational Res, 2014, 6(3): 267.

[99] Matthew D Harwood, Achour B, Russell M R, et al. Application of an LC–MS/MS method for the simultaneous quantification of human intestinal transporter proteins absolute abundance using a QconCAT technique [J]. J Pharmaceutical Biomedical Analysis, 2015, 110:27-33.