组蛋白去乙酰化酶抑制剂与肾脏疾病

组蛋白去乙酰化是组蛋白表观遗传学修饰的重要的方式之一。组蛋白去乙酰化酶(HDACs)作为调控基因的关键蛋白,其功能异常早已被证实与肿瘤、神经退行性病变、肾脏病等发生和发展关系密切,进而推动HDAC抑制剂(HDACi)的研发及临床应用。本文综述HDACs在肾脏病发生发展中的作用及HDACi在肾脏病治疗中的应用前景。     

组蛋白去乙酰化抑制剂在前列腺癌临床治疗中的研究进展

组蛋白乙酰化和去乙酰化程度的失衡,可影响基因转录的正常进行,引起前列腺癌中抑癌基因的失活与原癌基因的激活,从而促进前列腺癌的发生.针对此现象,研究人员发现许多去乙酰化抑制剂可通过抑制组蛋白去乙酰化酶(HDAC)活性而促进前列腺癌细胞的生长阻滞、分化及凋亡等,达到治疗目的,本文主要总结和回顾组蛋白乙酰化抑制剂在前列腺癌临...     

组蛋白去乙酰化酶抑制剂通过Snail诱导肝卵圆细胞上皮-间质转化

目的 探讨组蛋白去乙酰化酶抑制剂(HDACi)诱导肝卵圆细胞(WB-F344)上皮-间质转化(EMT)和促使其迁移能力增强的机制.方法 流式细胞术检测肝卵圆细胞的干细胞标志物.应用组蛋白去乙酰化酶抑制剂(SAHA、TSA、NaBu)处理肝卵圆细胞,诱导EMT,观察其形态学变化;划痕试验观察肝卵圆细胞迁移能力的变化.Western blot、荧光定量PCR检测肝卵圆细胞上皮和间质Marker变化及EMT关键转录因子Snail的变化,激光共聚焦检测Snail入核情况.siRNA干扰Snail后,Western blot检测EMT Marker的变化,并观察其形态变化.结果 流式细胞术检测显示在培养过程中肝卵圆细胞干细胞性能未发生改变.HDACi可以诱导WB-F344细胞的EMT,包括形态改变、上皮细胞标志物E-cadherin下调和间质细胞标志物Vimentin上调.HDACi可以促进EMT的关键转录因子Snail的蛋白水平和mRNA水平的增加,以及促进其核转录.siRNA干扰Snail可以抑制HDACi诱导肝卵圆细胞EMT过程.划痕试验显示HDACi可以提高肝卵圆细胞的迁移能力.结论 组蛋白去乙酰化酶抑制剂通过促进snail表达和入核来诱导肝卵圆细胞EMT,提高其迁移能力.     

组蛋白去乙酰化酶抑制剂对胆囊癌细胞系和肝外胆管癌细胞系HDAC1表达的影响

目的 观察组蛋白去乙酰化酶抑制剂-曲古抑菌素(TSA)在体外和体内对胆囊癌细胞和肝外胆管癌细胞HDAC1表达的影响.方法 用TSA作用于胆囊癌细胞系(Mz-ChA-1)和肝外胆管癌细胞系(QBC939、KMBC、OZ),然后用逆转录-聚合酶链反应(RT-PCR)检测HDAC1之mR-NA的表达变化,用Western blot检测其蛋白的表达变化.将这些细胞接种在裸鼠皮下建立胆囊癌和肝外胆管癌裸鼠种植瘤模型,用免疫组织化学方法 观察TSA在体内对裸鼠种植瘤组织中HDAC1蛋白表达的影响.结果 TSA可以减弱胆囊癌细胞系(Mz-ChA-1)和肝外胆管癌细胞系(QBC939、KMBC、OZ)HDAC1 mRNA和蛋白的表达;TSA作用前后的胆囊癌细胞系(Mz-ChA-1)和肝外胆管癌细胞系(KMBC)裸鼠成瘤组织中的各种蛋白的表达均无变化.结论 TSA在体外可以抑制胆囊癌和肝外胆管癌HDAC1的表达;TSA抑制HDAC1表达的作用可能受到体内环境的影响而消失.     

组蛋白去乙酰化酶抑制剂蛋白去乙酰化酶抑制剂对原发性肝癌细胞增殖的影响

目的 观察组蛋白去乙酰化酶(HDAC)抑制剂蛋白去乙酰化酶抑制剂(TSA)对原发性肝癌细胞增殖的影响.方法 噻唑蓝(MTT)法检测不同浓度(30、150、1000μg/L)TSA对原发性肝癌细胞生长的影响.结果 TSA浓度为30μg/L时,实验组与对照组细胞的吸光度值差异无统计学意义(P>0.05),说明TSA(30μg/L)对细胞的增殖基本无影响;当TSA浓度达到1000μg/L时,实验组细胞大量崩解、坯死,对细胞产生了严重的毒性作用;当TSA浓度为150μg/L时,实验组细胞无崩解、坏死现象,其36h和48h细胞的吸光度值低于对照组,差异有统计学意义(P<0.05).结论 HDAC抑制剂TSA对体外培养的原发性肝癌细胞的增殖生长具有抑制作用,并且这种抑制作用呈现一定剂量依赖性和时间依赖性.     

HDAC抑制剂SAHA对人肝癌细胞分化诱导作用的研究

目的 探讨组蛋白去乙酰化酶(histone deacetylases,HDAC)抑制剂SAHA(suberoylanilide hydroxamic acid)对人肝癌SMMC-7721细胞的分化诱导作用.方法 倒置显微镜观察SAHA对SMMC-7721细胞形态的影响;MTT比色法测定SAHA对SMMC-7721细胞增殖的抑制情况;免疫细胞化学检测SAHA对SMMC-7721细胞中甲胎蛋白(AFP)和增殖细胞核抗原(PCNA)表达的影响;流式细胞术(FCM)分析细胞周期;RT-PCR方法榆测处理前后SMMC-7721细胞p21WAF1基因mRNA的表达变化.结果 实验组细胞增殖速度显著减慢,与正常细胞形念变化相似;MTT比色法测定结果显示不同浓度SAHA对SMMC-7721细胞的增殖均有抑制作用,并有明显的剂量依赖和时间依赖关系;免疫细胞化学检测显示SAHA能显著降低PCNA和AFP在SMMC-7721细胞中的表达;流式细胞仪检测结果显示,SMMC-7721细胞经SAHA处理后,G0/G1期细胞明显增加,S期细胞则明显减少,细胞被阻滞于G0/G1期;RT-PCR检测结果表明,实验组细胞中p21WAF1 mRNA的表达明显增加.结论 SAHA对人肝癌细胞具有显著的诱导分化作用,诱导肝癌细胞分化的机理可能与抑制HDAC的活性,上调p21 WAF1 mRNA表达,及阻滞肝癌细胞G0/G1期有关.     

组蛋白去乙酰化酶抑制剂在肾细胞癌治疗中的研究进展

组蛋白去乙酰化酶(HDACs)参与肿瘤的发生与发展,并被证实与肾细胞癌(RCC)密切相关。当前,以HDACs为靶点的组蛋白去乙酰化酶抑制剂(HDACIs)已成为一种新型药物应用于RCC的治疗,临床前实验表明HDACIs与多种药物联合作用具有强大的抗RCC效应,多项Ⅰ/Ⅱ期临床实验也初步证明了联合用药方案治疗RCC的有效性及安全性。本文对HDACIs在RCC治疗的研究进展进行综述。     

组蛋白去乙酰化酶抑制剂通过树突细胞发挥免疫调节作用研究

组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACI）主要通过抑制组蛋白去乙酰化酶的活性使组蛋白乙酰化程度升高,引起染色质重组,DNA转录活化或抑制,细胞周期停滞,细胞分化及细胞凋亡等一系列生物学效应。根据化学结构的不同,HDACI可以分为6类：（1）短链脂肪酸类,如4．丁酸苯酯和丙戊酸;     

组蛋白去乙酰化酶抑制剂对人骨肉瘤细胞抑制增殖和诱导分化的研究

[目的]观察组蛋白去乙酰化酶抑制剂曲古抑菌素A(TSA)对人骨肉瘤MG-63细胞增殖和分化的影响.[方法]不同浓度的TSA作用MG-63细胞,采用噻唑蓝(MTT)法、倒置相差显微镜观察药物对细胞生长的影响并绘制细胞生长曲线;软琼脂集落形成实验观察细胞生长和侵袭能力的变化;流式细胞仪测定细胞周期变化.[结果]TSA可明显抑制MG-63细胞增殖,并呈现剂量和时间的依赖性;细胞形态呈明显的良性分化;瘤细胞的软琼脂集落形成率明显降低;TSA能够延缓细胞周期G1-S进程,阻滞细胞于G1期,停留在G2/M期.[结论]TSA对MG-63细胞有明显的抑制增殖和诱导分化作用.     

组蛋白去乙酰化酶抑制剂在器官移植中的研究进展

真核生物细胞核内组蛋白在被乙酰化修饰后可引起结构的改变,影响与DNA的结合,组蛋白去乙酰化酶抑制剂通过抑制组蛋白去乙酰化酶而发挥生物学作用,具有较强的免疫抑制作用,参与了免疫应答的许多过程及免疫功能的调节。本文从组蛋白去乙酰化酶抑制剂的分类、作用机制及对免疫细胞、免疫分子及在器官移植方面的应用等方面做一综述。     

Histone deacetylase inhibitors as potential therapeutic approaches for chordoma: An immunohistochemical and functional analysis

Chordomas are rare malignancies of the axial skeleton. Therapy is mainly restricted to surgery. This study investigates histone deacetylase (HDAC) inhibitors as potential therapeutics for chordomas. Immunohistochemistry (IHC) was performed using the HDAC 1–6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 male, 17 female). Pan‐HDAC‐inhibitors Vorinostat (SAHA), Panobinostat (LBH‐589), and Belinostat (PXD101) were tested for their efficacy in the chordoma cell line MUG‐Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG‐Chor1, UCh‐1), cleaved caspase‐3, and PARP cleavage. p‐Values below 0.05 were considered significant. IHC was negative for HDAC1, positive for HDAC2 in most (n = 36; 72%), and for HDACs 3–6 in all specimens available (n = 43; 86%). HDAC6 expression was strongest. SAHA and LBH‐589, but not PXD101 caused a significant increase of G2/M phase cells and of cleaved caspase‐3 (p = 0.0003, and p = 0.0014 after 72 h, respectively), and a peak of caspase 3/7 activity. PARP cleavage confirmed apoptosis. The presented chordoma series expressed HDACs 2–6 with strongest expression of HDAC6. SAHA and LBH‐589 significantly increased apoptosis and changed cell cycle distribution in vitro. HDAC‐inhibitors should be further evaluated as therapeutic options for chordoma. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1999–2005, 2013     

Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors

Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor‐specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T‐cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17‐producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL‐10, and TGF‐b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN‐g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation.     

HDAC inhibitors in kidney development and disease

The discovery that histone deacetylase inhibitors (HDACis) can attenuate acute kidney injury (AKI)-mediated damage and reduce fibrosis in kidney disease models has opened the possibility of utilizing HDACis as therapeutics for renal injury. Studies to date have made it abundantly clear that HDACi treatment results in a plethora of molecular changes, which are not always linked to histone acetylation, and that there is an essential need to understand the specific target(s) of any HDACi of interest. New lines of investigation are beginning to delve more deeply into target identification of specific HDACis and to address the relative toxicity of different HDACi classes. This review will focus on the utilization of HDACis during kidney organogenesis, injury, and disease, as well as on the development of these compounds as therapeutics.