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J BIOL CHEM:药物所等发现抗癫痫药物VPA可用于治疗自身免疫病

2012-07-03 上海药物研究所 上海药物研究所

近10多年来,开发老药的新治疗作用,并在此基础上进一步开发出新药,成为了药物研究的重要发展趋势之―。6月25日,Journal of Biological Chemistry在线发表了同济大学生命科学与技术学院、中科院上海药物研究所及华山医院合作研究的有关老药新用的又一新成果。 多发性硬化(Multiple sclerosis,MS)是一种与神经系统相关的自身免疫性疾病,是仅次于创伤的中青年人致

近10多年来,开发老药的新治疗作用,并在此基础上进一步开发出新药,成为了药物研究的重要发展趋势之―。6月25日,Journal of Biological Chemistry在线发表了同济大学生命科学与技术学院、中科院上海药物研究所及华山医院合作研究的有关老药新用的又一新成果。

多发性硬化(Multiple sclerosis,MS)是一种与神经系统相关的自身免疫性疾病,是仅次于创伤的中青年人致残原因,目前尚缺乏有效的治疗药物,有着“死不了的癌症”之称。Valproic acid(VPA)具有抗惊厥及稳定情绪的作用,临床上主要用于治疗癫痫、双相情感障碍及重度抑郁症。VPA的主要分子靶点是组蛋白去乙酰化酶(HDAC),通过对HDAC的抑制,VPA可以调控细胞的增殖、凋亡及分化,因此近年来发现VPA也可用于癌症等与细胞增殖异常相关的疾病治疗。

利用MS的动物模型EAE小鼠,博士生吕婕、副教授杜昌升等研究了VPA的药效,发现VPA的治疗可以使EAE小鼠发病时间推迟,发病症状减轻,发病率降低,并且中枢神经系统的炎症细胞浸润显著减少。T细胞平衡失调是导致MS/EAE的主要原因。研究发现,VPA可以在体内外抑制T细胞的过度增殖及分化,并诱导活化的T细胞凋亡,从而恢复T细胞的动态平衡,减轻EAE病情。而其促凋亡机制是通过上调caspase蛋白来实现的。目前临床用于MS治疗的口服药物非常缺乏,而VPA具有良好的口服生物利用度,其在自身免疫病治疗中的应用值得期待。本研究同时也提出了HDAC可成为自身免疫病治疗的靶点。

本研究工作是在谢欣研究员指导下完成。谢欣研究员是中科院上海药物研究所课题组长,国家新药筛选中心副主任,同济大学生命科学与技术学院兼职教授,博士生导师。主要从事基于GPCR的新药发现及机制研究,以及小分子化合物调控干细胞命运的研究。研究组在不久前报道了靶向半胱氨酸白三烯受体的抗哮喘药物可用于治疗MS (Journal of Immunology. 2011;187(5):2336-45)。本研究工作中的MS病人样品由华山医院的吴志英教授团队采集提供。

本研究工作得到自然科学基金委、科技部以及上海市科委项目的支持。

doi:10.1074/jbc.M112.356584

PMC:
PMID:

The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis

Jie Lv1, Changsheng Du1, Wei Wei1, Zhiying Wu2, Guixian Zhao2, Zhenxin Li2 and Xin Xie3,*

1 School of Life Sciences and Technology,Tongji University,China;

2 Fudan University,China;

3 Shanghai Institute of Materia Medica,CAS,China

Abstract

Maintaining a constant number and ratio of immune cells is one critical aspect of the tight regulation of immune homeostasis. Breakdown of this balance will lead to autoimmune diseases such as Multiple Sclerosis (MS). The antiepileptic drug valproic acid (VPA) was reported to regulate the growth, survival and differentiation of many cells. However, its function in T cells homeostasis and MS treatment remain unknown. In this study, VPA was found to reduce spinal cord inflammation, demyelination, and disease scores in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Further study indicated that VPA induced apoptosis in activated T cells and maintained the immune homeostasis. This effect was found to be mainly mediated by the caspase-8/caspase-3 pathway. Interestingly, this phenomenon was also confirmed in human T cells. Considering the long history of clinical use and our new findings,we believe VPA might be a safe and effective therapy for autoimmune diseases,such as multiple sclerosis.

 

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    2014-07-26 chen111111

    用丙戊酸治疗多发性硬化,具体能改善什么临床症状呢?

    0

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    2012-09-05 sunylz
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当整个世界在人体水平上对肥胖宣战的时候,密歇根州大学的科学家在微观层面已经取得了令人惊奇发现,这也许可以帮助人类取得这场斗争的胜利。 他们的工作有助于解释为什么肥胖发生时,贮脂细胞会变得更胖,燃烧脂肪的速度会变慢。如果他们的研究结果可以从小鼠推广到人类,这将为抗击肥胖提供一个新的药物靶点。相关研究论文在线发表于6月25日的Journal of Clinical Investigation杂志。

Int J Oncol:川芎嗪靶向COX-2抑制肿瘤转移

环氧化酶(cyclooxygenase,COX)是参与花生四烯酸的环氧酶代谢途径中的限速酶,可催化花生四烯酸转化为前列腺素(prostaglandins,PGs)。近年来研究显示,COX-2在一些肿瘤中存在过度表达现象,提示COX-2可能与肿瘤的发生发展密切相关。 环氧合酶(COX)-2在肺癌中起着重要作用,是肺癌侵袭和转移的关键因素。传统中药川芎有效成分川芎嗪(TMP),历来用于治疗神经、血管

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