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王玉强
发布时间:2014-05-28

王玉强教授简介

药物研究的第一步是发现有生物活性的化合物,然后是研究这些化合物的作用机理和药理活性。王玉强实验室目前主要从事治疗神经退行性疾病如脑中风、老年痴呆和帕金森、心血管疾病药物如心肌缺血等疾病药物的设计、化学合成、药理活性与作用机理的研究及创新药物的研究与开发。

    王玉强教授从事DNA-minor groove binding 药物CC-1065衍生物的研究多年, 他的实验室合成了100多个CC-1065衍生物, 其中的YW-053是目前已知抗癌活性最强的少数化合物之一,其体外抗癌活性比临床应用的抗癌药物阿霉素强一百万倍 (J. Amer. Chem. Soc. 117, 8917, 1995)

    王玉强教授在美国首次GMP合成治疗老年痴呆药物 memantine,作为核心成员,其团队在美国将memantine 成功开发。Memantine 2003年先后在欧美上市,2011年在日本上市,2013年在中国上市。Memantine 2013年的销售额18亿美元, 属于重磅炸弹级药物。

王玉强实验室近年开展了对中药有效成份分子结构进行系统的化学修饰的工作。在中药穿心莲、川芎及丹参有效成份的结构修饰方面已卓有成效,发现了比天然产物疗效更高,毒性更低的新化合物。其中具有独特作用机理和良好治疗效果的治疗缺血性脑中风新药已完成临床前研究。

王玉强教授1981年毕业于山东师范大学化学系, 获学士学位;1987年获美国 University  of Texas Health Science Center at Houston and M. D. Anderson Cancer Center博士学位。 随后进入美国耶鲁大学 (Yale) 医学院做博士后研究。九十年代初进入美国加州硅谷的生物医药公司从事药物的研究与开发,2005年回国任暨南大学教授,药学院院长,现任暨南大学新药研究所所长,博士生导师2010年获广州经济技术开发区科技领军人才称号

 

代表性论文

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17. Wang, Y.; Ye, W.; Li, L.; Tian, Z.; Jiang, W.; Wang, H.; Wright, S. C.; Larrick, J. W. CC-1065 analogues bearing different DNA-binding subunits: synthesis, antitumor activity and preliminary toxicity study. J. Med. Chem. 46, 634, 2003.

18. Wang, Y.; Yuan, H.; Wang, H.; Wright, S. C.; Larrick, J. W. Synthesis and preliminary cytotoxicity study of glucuronide derivatives of CC-1065 analogues. Bioorg. Med. Chem. 11, 1569, 2003.

19. Wang, X.; Wang, Y.; Zheng, C. Isolation and purification of honokiol and magnolol from Cortex Magnoliae Officinalis by high-speed counter-current chromatography. J. Chromatography A., 1036, 171, 2004.

20. Wang, X.; Wang, Y.; Yuan, J.; Sun, Q.; Liu, J.; Zheng, C. An efficient new method for extraction, separation and purification of psoralen and isopsoralen from Fructus Psoraleae by supercritical fluid extraction and high-speed counter-current chromatography. J. Chromatography A, 1055, 135, 2004.

21. Wang, Y.; Li, L.; Jiang, W.; Larrick, J. W. Synthesis and evaluation of a DHA and 10-hydroxcamptothecin conjugate. Bioorg. Med. Chem. 13, 5592–5599, 2005.

22. Wang, Y.; Li, L.; Jiang, W.; Yang, Z.; Zhang, Z. Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate. Bioorg. Med. Chem. Lett. 16 2974–29772006.

23. Wang, Y.; Li, L.; Tian, Z.; Jiang, W.; Larrick, J. W. Synthesis and antitumor activity of CBI-bearing ester and carbamate prodrugs of CC-1065 analogue. Bioorg. Med. Chem. 14, 7854–7861, 2006.

24. Wang, Y.; Eu, J.; Washburn, M.; Gong, T.; Chen, H. S. V.; Larrick, J. W.; Lipton, S. A.; Stamler, J, S.; Went, G. T.; Porter, S. The Pharmacology of Aminoadamantane nitrates. Curr. Alzheimer Res. 3, 201204, 2006.

25. Wang, Y., Yang, Z.; Wright, S. C.; Larrick, J. W. Synthesis and preliminary antitumor activity of distamycin nitrogen mustards. Lett. Drug Design and Discov. 4, 37–39, 2007.

26. Suo, X. B.; Zhang, H.; Wang, Y. HPLC determination of andrographolide in rat whole blood: study on the pharmacokinetics of andrographolide incorporated in liposomes and tablets.
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27. Suo, X. B.; Deng, Y. J.; Zhang, H.; Wang, Y. Degradation kinetics of water-insoluble lauroyl-indapamide in aqueous solutions: prediction of the stabilities of the drug in liposomes. Arch Pharm Res. 30, 876883, 2007.

28. Wang, Y.; Jiang, J.; Jiang, X.; Cai, S.; Han, H.; Li, L.; Tian, T.; Jiang, W.; Zhang, Z.; Xiao, Y.; Wei Wright, S. C.; Larrick, J. W. Synthesis and antitumor activity evaluations of albumin-binding prodrugs of CC-1065 analogue. Bioorg. Med. Chem. 16, 65526559, 2008.

29. Sun, Y.; Jiang, J.; Zhang, Z.; Yu, P.; Wang, L.; Xu, C.; Liu, W.; Wang, Y. Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke. Bioorg. Med. Chem. 16, 88688874, 2008.

30. Chen, W-M.; Cheng, C.; Li, B-Z.; Ho, T-L.; Cai, Z-S.; Wang, Y.; Sun, P-H. Pyridine-4-thiol and amphoteric analogs: novel Pprotection of aryl bromides in strong alkali. Helvetica Chimica Acta.  91, 20622068, 2008.

31. Guo, J-L.; Li, B-Z.; Chen, W-M.; Sun, P-H.; Wang, Y. Synthesis of substituted 1H-pyrrol-2(5H)-ones and 2(5H)-furanones as inhibitors of P. aeruginosa biofilm. Lett. Drug Design and Discov. 6, 107–113, 2009.

32. Jiang, X.;  Yu, P.; Jiang, J.;  Zhang, Z.; Wang, Z.; Yang, Z.; Tian, Z.; Wright, S. C.; Larrick, J. W.; Wang, Y. Synthesis and evaluation of antibacterial activities of andrographolide analogues. Eur. J. Med. Chem. 44, 2936–2943, 2009.

33. Chen, J-X.; Xue, H-J.; Ye, W-C.; Fang, B-H., Liu, Y-H., Yuan, S-H., Yu, P.; Wang, Y. Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro. Biol. Pharm. Bull. 32, 1385–1391, 2009.

34. Zhang, Z.; Jiang, J.; Pei, Y.; Zeng, X.; Wang, Z.; Larrick, J. W.; Wang, Y. Hypoglycemic and beta cell protective andrographolide analogue for diabetes treatment. J. Translational Med. 7:62, 2009.

35. Xu, J.; Huang, S.; Luo, H.;  Li, G.; Bao, J.; Cai, S.; Wang, Y. QSAR studies on andrographolide derivatives as α-glucosidase inhibitors. Int. J. Mol. Sci. 11, 880895, 2010.

36. Wang, Z.; Yu, P.; Zhang, G.; Xu, L.; Wang, D.; Wang, L.; Zeng, X.; Wang, Y. Design, synthesis and antibacterial activity of novel andrographolide derivatives. Bioorg. Med. Chem. 18, 4269–4274, 2010.

37. Sun, H.; Xu, L.; Yu, P.; Jiang, J.; Zhang, G.; Wang, Y. Synthesis and preliminary evaluation of neuroprotection of celastrol analogues in PC12 cells. Bioorg. Med. Chem. Lett. 20, 3844–3847, 2010.

38. Zhang, Z.; Li, S.; Jiang, J.; Yu, P.; Liang, J.; Wang, Y. Preventive effects of Flos puerariae lobatae water extract and its active ingredient puerarin in acute and chronic alcohol treated rat and mice model. Chinese Med. 5:36, 2010.

39. Xu, J.; Lu, Y.; Luo, H.; Huang, S.; Bao, J.; Cai, S.; Wang Y. Homology modeling of α-glucosidase and its interactions with andrograpolide derivatives. Lett. Drug Design and Discov. 8, 440451, 2011.

40. Chen, H.; Li, S.; Wu, J.; Jiang, J.; Wang, Y. Pharmacokinetic study of a novel stroke therapeutic, 2-[[(1,1-dimethylethyl)oxidoimino]methyl]-3,5,6-trimethylpyrazine, by a simple HPLC-UV method in rats. Eur. J. Drug. Metab. Ph. 36, 95–101, 2011.

41. Zeng, X.; Liu, X.; Liang, H.; Bian J.; Pei, G.; Dai, H.; Polyak, S. W.; Song, F.; Ma, L.; Wang, Y.; Zhang, Z. Synergistic effect of AL-1 and various antibiotics on the formation of biofilms and production ofexopolysaccharide and pyocyanin by Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 55, 3015–3017, 2011.

42. Cui, Q.; Zhang, G.; Yu, P.; Wang, Y. Synthesis and preliminary evaluation of anti-HIV agent AZT prodrug. Yao Xue Xue Bao. 46, 1015–1018, 2011.

43. Lu, X.; Wan, S.; Jiang, J.;  Jiang, X.; Yang, W.; Yu, P.; Xu, L.; Zhang, Z.; Zhang, G.; , Zaijun Z.; Shan, L.; Wang, Y. Synthesis and biological evaluations of novel apocynin analogues. Eur. J. Med. Chem. 46, 26912698. 2011.

44. Cui, Q.; Zhang, G.; Yu, P.; Wang, Y. Synthesis and preliminary evaluation of anti-HIV agent AZT prodrug.  Acta Pharmaceutica Sinica, 46, 1015–1018, 2011.

45. Yao, H.; Li, S.; Yu, P.; Tang, X.; Jiang, J.; Wang, Y. Reaction characteristics of andrographolide and its analogue AL-1with GSH as a simple chemical simulation of NF-κB Inhibition. Molecules 17, 728–739, 2011.

46. Sun, Y.; Yu.; Zhang, G.; Wang, L.; Zhong, H.; Zhai, Z.; Wang, L.; Wang, Y. Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models. J. Neurosci. Res. 90, 1662–1669, 2012. 

47. Sun, Y.; Zhang, G.; Zhang, Z.; Yu, P.; Zhong, H.; Du, J.; Wang, Y. Novel multi-functional nitrones for treatment of ischemic stroke. Bioorg. Med. Chem. 20, 3939–3945, 2012.

48. Yu, P.; Xia, L.; Zhao, J.; Zhang, G.; Zhang, Z,; Lang, M.; Wang, Y. Synthesis and preliminary anticancer evaluation of 10-hydroxycamptothecin analogs. Biol. Pharm. Bull. 35, 1295–1299, 2012.

49. Ma, Li.; Liu, X.; Liang, H.; Che, Y.; Dai, H.; Yu, K.; Liu, M.; Ma, L.; Yang, C-H.; Song, F.; Wang, Y.; Zhang, L. Molecular targets of 14-alpha-lipoyl andrographolide on quorum sensing in Pseudomonas aeruginosa.  Antimicrob. Agents Chemother. 56, 6088–6094, 2012.

50. Cui, G.; Hung, M.; Shan, L.; Lei, S.; Choi, I.; Zhang, Z.; Hoi, M. P.; Yu, P.; Wang, Y.; Lee, S. M. A novel danshensu derivative confers cardioprotection via PI3K/Akt and Nrf2 pathways. Intl. J. Cardio. 168, 1349–1359, 2013.

51. Zhu, Y.; Yu, G.;  Zhang, Y.; Xu, Z.; Wang, Y.; Yan, G.;, He, Q. A novel andrographolide derivative AL-1 exerts its cytotoxicity on K562 cells through a ROS-dependent mechanism. Proteomics, 13,169178, 2013.

52. Cui, Q.; Shan, L.; Zhu, H.;  Yu, P.; Wang, Y. Synthesis and preliminary evaluation of Danshensu derivatives modified at hydroxyl group. J. Intl. Pharm. Res. 40, 795–800, 2013.

53. Yan, G.; Zhou, H.; Wang, Y.; Zhong, Y.; Tan, Z.; Wang, Y.; He, Q. Protective effects of andrographolide analogue AL-1 on ROS-induced RIN-m β cell death by inducing ROS generation. PLoS One, 8(6):e63656, 2013.

54. Talantovaa, M.; Sanz-Blascoa, S.; Zhang. X.; Xia, P.; Waseem Akhtara, M.; Okamotoa, S.; Dziewczapolskib, G.; Nakamuraa, T.; Gang, C.; Pratta, A. E.; Kanga, Y-J.; Tua, S.; Molokanovaa, E.; McKerchera, S. R.; Hiresd, A. A.; Sasone, H.; Stoufferf, D. G.; Buczynskif, M. W.; Solomong, J.; Michaelc, S.; Powersg, E. T.; Kellyg, J. W.; Robertsj, A.; Tonga, G.; Fang-Newmeyera, T.; Parkera, J.; Hollanda, E. A.; Zhang, D.; Nakanishia, N.; Chen, H-S, V.; Woloskere, H.; Wang, Y.; Parsonsf, L. H.;  Ambasudhana,R.;   Masliahc, E.; Heinemannb, S. F.; Piña-Crespoa, J. C.; Lipton, S. A. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. PNAS, 110, E2518–2527, 2013.

55. Xu, D.; Duan, H.; Du, J.; Zhang, Z.; Cui, W.; Wang, L.; Sun, Y.; Lang, M.; Hoi, P. M.; Han, Y.; Wang, Y.; Lee, S. M. The novel tetramethylpyrazine bis-nitrone (TN-2) protects against MPTP/MPP+-induced neurotoxicity via inhibition of mitochondrial-dependent apoptosis. J. Neuroimmun. Pharmacol. 9, 245–258, 2014.

56. Xu, D.; Zhang, K.; Zhang, Z.; Sun, Y.; Guo, B.; Wang, Y.; Hoi, P. M.; Han, Y.; Lee, S. M. A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-κB and the PKCα/PI3-K/Akt pathways. Neurochem. Int. 2014 Sep 10;78C:76-85. doi: 10.1016.

57. Guo, B.; Xu, D.; Duan, H.; Du, J.; Zhang, Z.; Lee, S. M.; Wang, Y. Therapeutic effects of multifunctional tetramethylpyrazine nitrone on models of Parkinson’s disease in vitro and in vivo. Biol. Pharm. Bull.  37, 274285, 2014. 

58. Cui, W.; Zhang, Z.; Hu, S.; Mak, S.; Xu, D.; Choi, C.; Wang, Y.; Tsim, K.; Lee, M.; Rong, J.; Han, Y. Sunitinib produces neuroprotective effect via inhibiting nitric oxide overproduction. CNS Neurosci. Ther.  20, 244–252, 2014.

59. Sun, Y.; Liao, K.; Li, S.; Zhang, Z.; Yu, P.; Wang, Y. Pharmacokinetic analysis of bis-nitrone tetramethylpyrazine (TN-2) in rats and its protein binding in vitro. Lett. Drug Design and Discov. 11, 770–777, 2014.

60. Wu, H.; Li, W.; Sun, Y.; Xu, L.; Yu, P.; Wang, Y.; Zhang, Z. Determination of AL-1 in rat plasma and tissues by high-performance liquid chromatography and tts application in AL-1 pharmacokinetic study. J. Pharm. Biomed. Sci., 4, 573580, 2014.

61. Lang, M.; Yan, R.; Wang, Y.; Yu, P. A selective O- and N-acylation protocol for carbamyl chloride. Chin. J. Org. Chem. 2014 (advance online).

62. Cui, Q.; Chen, Y.; Zhang, M.; Shan, L.; Sun, Y.; Yu, P.; Zhang, G.; Wang, D.; Zhao, Z.; Xu, Q.; Xu, B.; Wang, Y. Design, synthesis and preliminary cardioprotective effect evaluation of Danshensu derivatives. Chem. Biol. & Drug Des. 84, 282–291, 2014.

63. Xu, L.; Li, Y.; Wan, S.; Wang, Y.; Yu, P. Apocynin nitrone protects rats from LPS-mediated acute lung injury via inhibition of NADPH oxidase. Intl. Immunopharmacol. 20, 377–382, 2014.

64. Du, E.; Liang, Z.; Xu, L.; Sun, S.; Zhang, G.; Yu, P.; Wang, Y. Synthesis and preliminary biologic activity evaluation of nitric oxide-releasing andrographolide analogues. Chem Pharma Bull. 62, 519–523, 2014.

65. Zhang, Z.; Lai, D.; Wang, L.; Pei, Y.; Zhu, L.; Guo, B.; Xu, L.; Sun, Y.; Xu, L.; Zhou, L.; Sun, Y.; Lee, S-M.; Wang, Y. Neuroprotective effects of the andrographolide analogue AL-1 in the MPP+/MPTP-induced Parkinson’s disease model in vitro and in mice. Pharmacol. Biochem. Be. 122, 191–202, 2014.

66. Lang, M.; Yao, H.; Fu, P.; Wang, Y.; Yu, P. An unexpected replacing a methyl carbon with an amino group in the tetramethylpyrazine system. Res. Chem. Intermed2014 (advance online).

67. Li, Z.; Fu, P.; Wang, Y.; Yu, P. Li, Z.; Fu, P.; Wang, Y. Yu, P. Synthesis of 3-(5H-Pyrazolyl)-cyclobutanone Derivatives. Asia J. Chem. 2014 (advance online).

68. Zhou, X.; Zhu, L.; Wang, L.; Guo, B.; Sun, Y.; Zhang, Z.; Wang, Y.  Protective effect of edaravone in primary cerebellar granule neurons against iodoacetic acid-induced cell injury. Free Radical Res. 2014 (advance online).

69. Zhao, Y.; Szeto, S. S. W.; Kong, R. P. W.; Law, C. H.; Li, G.; Quan, Q.; Zhang, Z.; Wang, Y.; Chu, I. K. Online two-dimensional porous graphitic carbon/reversed phase liquid chromatography platform applied to shotgun proteomics and glycoproteomics. Anal. Chem. 2014 Dec 16;86(24):12172-9. doi: 10.1021 (advance online).

70. Sun, Y.; Tan, Z.; Liang, Z.; Wang, L.; Shan, L.; Yu, P.; Wang, Y. Synthesis and relationship of stability and biological activity of new DSS and TMP conjugates. MedChemComm. 2014 6(4). DOI: 10.1039(advance online). 

71. Law, C. H.; Szeto, S. S. W.; Kong, R. P. W.; Zhang, Z.; Wang, Y.; Quan, Q.; Lee, S. M. Y. Chu, I. K. A versatile reversed phase-strong cation exchange-reversed phase (RP-SCX-RP) multidimentional liquid chromatography platfprm for qualitative and quantitative shotgun proteomics. Analyst. 2015 Feb 21;140(4):1237-52. doi: 10.1039 (advance online).

72. Zhang, Z.; Li, G.; Szeto, S. S.; Chong, C.; Quan, Q.; C.; Cui, W.; Guo, B.; Wang, Y.; Han, Y.; Siu, M.; Lee, S. M.; Chu, I. K. Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson's disease. Free Radic. Biol. Med. 2015 Jul;84:331-43. doi: 10.1016 (advance online).

73. Li, Y.; Yan, H.; Zhang, Z.; Zhang, G.; Sun, Y.; Yu, P.; Wang, Y.; Xu, L. Andrographolide derivative AL-1 improves insulin resistance through down-regulation of NF-κB signaling pathway. Br. J. Pharmacol. 2015 Jun;172(12):3151-8. doi: 10.1111 (advance online).

74. Cui, G.; Shan, L.; Guo, L.; Chu, I. K.; Li, G.; Quan, Q.; Zhao, Y.; Chong, C.; Zhang, Z.; Yu, P.; Hoi, P. M.; Wang, Y.; Lee, S. M. Y. Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy. Sci. Report, 2015 Jun 3;5:10353. doi: 10.1038 (advance online).

75. Li, S.; Shan, L.; Zhang, Z.; Li, W.; Liao, K.; Li, S.; Yu, P.; Wang, Y. Pharmacokinetic and metabolism studies of ADTM, a novel Danshensu derivative confers cardioprotection by HPLC-UV and LC-MS/MS.  J. Chromatogr. Sci. 2015 Jul;53(6):872-8. doi: 10.1093 (advance online).

76. Chen, H.; Xu, D.; Tan, G.; Cai, W.; Zhang, G.; Cui, W.; Wang, J.; Long, C.; Sun, Y.; Yu, P.; Tsim, K.; Zhang, Z.; Han, Y.; Wang, Y. A Potent multifunctional neuroprotective derivative of tetramethylpyrazine.  J. Mol. Neurosci., 2015 Aug;56(4):977-87. doi: 10.1007 (advance online).

77. Lee, R.; Shan, L.; Zhang, Z.; Wang, Y.; Yang, C.; Kwan, Y-W.; Lee, S. M.; Hoi, M. P.; Chan, S-W.; Cheung, A. C.; Cheung, K-H. Relaxation effect of a novel danshensu/tetramethylpyrazine derivative on rat mesenteric arteries. Eur. J. Pharmacol. 2015 Aug 15;761:153-60. doi: 10.1016 (advance online).

78. Wang, L.; Zhang, X.; Chan, J.; Shan, L.; Cui, Q.; Wang, Y.; Li, J.; Chen, H.; Zhang, Q.; Yu, P.; Han, Y.; Wang, Y.; Lee, S-M. A novel danshensu derivative prevents cardiac dysfunction and improves the chemotherapeutic efficacy of doxorubicin in breast cancer cells" J. Cell. Biochem. 2015 Jun 8. doi: 10.1002 (advance online).

79. Quan, Q.; Szeto, S. S. W.; Zhang, Z.; Wang, Y.; Chu, I. K. Fully Automated Multidimensional Reversed-Phase Liquid Chromatography with Tandem Anion/Cation Exchange Columns for Simultaneous Global Endogenous Tyrosine Nitration Detection, Integral Membrane Protein Characterization, and Quantitative Proteomics Mapping in Cerebral Infarcts. Anal. Chem. 2015 ((advance online).

80. Hu, S.; Cui, W.;  Zhang, Z.; Mak, S.; Xu, D.; Li, G.; Hu, Y.; Wang, Y.; Lee, M.; Tsim, K.W.; Han, Y. Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β. J. Mol. Neurosci., 2015 Sept 7. DOI 10.1007/s12031-015-0638-y (advance online).

81. Takahashi, H.; Xia, P.; Cui, J.; Talantova, BodhinathanK.; Li, W.; Holland, E.; Tong, G.; Pina-Crespo, J.; Zhang, D.; Nakanishi, N.; Larrick, J. W.; McKercher, S.; Nakamura, T.; Wang, Y.; Lipton, S.A. Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease. Sci. Report. 2015 (advance online).

82. Yan, H.; Li, Y.; Yang, Y.; Zhang, Z.; Zhang, G.; Sun, Y.; Yu, P.; Wang, Y.; Xu, L. Protective effects of andrographolide derivative AL-1 on high glucose-induced oxidative stress in RIN-m cells. Curr. Pharm. Des. 2015 Sep 21. 2015 (advance online).

83. Zhu, L.; Sun, Y.; Zhang, G.; Zhang, Z.; Wang, Y. Radical-scavenging and anti-oxidative activities of TBN in cell-free system and murine H9c2 cardiomyoblast cells. Free Radical Res. 2015 (advance online).

84. Zhou, X.; Zhu, L.; Wang, L.; Guo, B.; Zhang, G.; Sun, Y.; Zhang, Z.; Lee, M-Y.; Yu, P.; Wang, Y.
Protective effect of edaravone in primary cerebellar granule neurons against iodoacetic acid-induced cell injury,
Oxidat. Med. Cell. Longev. http://dx.doi.org/10.1155/2015/606981, 2015.

 

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