HIF-1与肿瘤多药耐药关系的研究进展

缺氧是许多肿瘤的特性,缺氧诱导因子1(HIF- 1)在多种肿瘤中广泛存在,可调控一系列靶基因的转录,对于肿瘤多药耐药(MDR)的形成有着多方面的作用。     

人乳腺癌细胞化疗敏感性与相关基因表达的关系

目的探讨人乳腺癌细胞化疗敏感性与多药耐药相关基因和凋亡调控基因表达的关系。方法MTT法检测5株人乳腺癌细胞株Bcap37、MCF-7、T47D、MDA-MB-231和MDA-MB-435对阿霉素(ADM)、顺铂(DDP)、丝裂霉素(MMC)、5-氟尿嘧啶(5-Fu)、卡氮芥(BCNU)的敏感性。流式细胞术检测多药耐药基因P-糖蛋白(P-GP)、谷胱甘肽-S-转移酶-π(GST-π)、肺耐药蛋白(LRP)、多药耐药相关蛋白(MRP)和甲基鸟嘌呤甲基转移酶(MGMT)等耐药相关基因和凋亡调控基因FAS、BCL-2、P53和P16的表达。结果不同人乳腺癌细胞株对同一药物敏感性差异较大。相关分析表明,细胞株对5-Fu的敏感性与P16表达呈正相关(P<0.01),对其余药物的敏感性与所检基因的表达水平无关。结论人乳腺癌细胞株对5-Fu的敏感性与P16表达有关。     

表遗传修饰对多药耐药基因1调控的研究进展

多药耐药基因1(multidrug resistance gene 1，MDR1)的耐药机制与药物的泵出有关。过去的十年里，在有关耐药基因的调控方面已经做了大量的研究。MDR1基因表达受许多因素的影响。最近研究证实，表遗传修饰在调控MDR1基因表达中起重要作用。表遗传通过对DNA的甲基化和组蛋白脱乙酰化的修饰来调节MDR1基因的表达。应用化学物质可以逆转MDR1基因依赖性多药耐药，提高化疗敏感性，这将为癌症治疗提供新策略。     

MiRNA调控肿瘤细胞中P-gP表达的研究进展

微小RNA（miRNA）是一类高度保守的非编码单链RNA分子,与靶基因mRNA3’端非编码区结合,抑制mRNA的翻译,促进靶基因降解。而这种调控机制与很多肿瘤细胞中P型糖蛋白（P,glycoprotein,p-gp）的表达有着密切的联系。p-gp是与耐药相关的跨膜蛋白,过表达可导致肿瘤细胞产生多药耐药（multidrugresistance,MDR）。就miRNA的生物学特性、p-gP的功能进行综述,关系。肿瘤MDR是临床化学治疗失败的主要原因,本文并重点介绍其调控肿瘤细胞中P-gP表达和MDR的     

MicroRNA靶位点单核苷酸多态性与肿瘤及其药物敏感性的研究进展

MicroRNA(miRNA)是一类内源性非编码小RNA。MiRNA通过与蛋白编码基因mRNA的3’非编码区互补配对,影响mRNA的稳定和抑制蛋白质的合成,从而发挥转录后调控作用。研究表明miRNA靶位点单核苷酸多态性可能会通过影响miRNA对靶基因的负调控,参与肿瘤的发生、发展及其耐药。     

结肠癌化疗耐药相关miRNA表达谱的初步研究

目的:应用基因芯片技术筛选结肠癌耐药相关微小RNAs (miRNAs),探究miRNAs对化疗耐药的调控机制。方法:采用基因芯片技术分析结肠癌细胞系HCT8及其耐长春新碱细胞系HCT8/v中miRNAs的表达差异,对部分差异表达的miRNAs应用RT-qPCR进行验证,对表达差异显著的miRNAs进行靶基因预测,利用Gene Ontology (GO)和京都基因与基因组百科全书(KEGG)数据库对预测到的靶基因进行生物信息学分析。结果:筛选出342个差异表达miRNAs,其中190个表达上调,152个表达下调。RT-qPCR验证结果示miR-125-5p、miR-181c-5p和miR-153-3的表达情况和芯片检测结果一致;miR-130a-3p和miR-149-3p的表达与芯片检测结果不一致。GO分析结果显示,耐药相关基因主要富集的旁路是RNA聚合酶II调控区序列特异性DNA结合旁路,主要通过正向调节发挥作用,位置主要是在细胞内有界细胞器上。KEGG分析结果显示,耐药相关基因最为富集的是轴突导向通路、胰岛素信号通路及磷脂酶D信号通路。结论:miRNAs与结肠癌化疗耐药密切相关。对这些miRNAs的研究能使我们对结肠癌的化疗耐药机制有更深入的理解,并为逆转化疗耐药提供新的思路。     

多药耐药基因1 C3435T基因多态性对环孢素A药物动力学影响的Meta分析

背景：多药耐药基因1 C3435T基因多态性影响着P-糖蛋白的功能和表达,从而影响环孢素A血药浓度,产生个体差异。目前多药耐药基因1 C3435T基因多态性对环孢素A药物动力学影响的研究结果不一。 目的：基于国内外报道的国内相关研究,系统评价多药耐药基因1 C3435T基因多态性与环孢素A药物动力学的关系。 方法：计算机检索Cochrane图书馆、Medline、Plumbed、CNKI、万方等数据库,并辅以文献追溯的方法,收集国内外公开发表的国内相关病例对照、队列研究。检索年限均为从建库至2011-12-31。按纳入、排除标准筛选文献并评价纳入研究的质量后,采用RevMan 5.1软件进行Meta分析。 结果与结论：共纳入9篇文献,合计893例患者。Meta分析结果表明,多药耐药基因1 3435CC的环孢素A剂量调整谷浓度显著低于CT基因型(P=0.007)和TT基因型(P=0.000 6);亚组分析显示,肾移植后患者多药耐药基因1 3435CC的环孢素A剂量调整谷浓度显著低于CT基因型 (P < 0.000 01)及TT基因型(P=0.000 3);血液系统疾病患者多药耐药基因1 3435CC的环孢素A剂量调整谷浓度显著低于TT基因型(P=0.004)。多药耐药基因1 3435CC的环孢素A剂量调整峰浓度显著低于TT基因型(P=0.005)。提示多药耐药基因1 C3435T基因多态性对环孢素A血药浓度有影响,CC基因型患者血药浓度低于TT基因型。还需要大样本、前瞻性研究来探讨多药耐药基因1 C3435T基因多态性与环孢素A药物动力学的关系。     

难治性癫痫与多药耐药基因

难治性癫痫的耐药机制尚不十分清楚。多药耐药基因(MDR)是首个被发现与难治性癫痫相关的基因,其表达产物P-糖蛋白(Pgp)在难治性癫痫脑组织中表达增强,颞叶癫痫耐药机制则可能与MDR-1a mRNA及MDR-1b mRNA的高表达相关,特异性Pgp抑制剂能显著提高部分抗癫痫药物在难治性癫痫中的作用。对它们的深入研究可能会为难治性癫痫的治疗提供新途径及为新的抗癫痫药物的研究提供靶点。     

复发的急性白血病患者的多药耐药相关蛋白基因表达增强

鉴于多药耐药(MRD)基因的产物P-糖蛋白在临床耐药中起作用的观点难以得到直接证实;而近来又发现另一基因产物—多药耐药相关蛋白(MRP)的过度表达与某些细胞系的多药耐药产生有关,作者进一步采用定量逆转录聚合酶链反应(RT-PCR)技术对62例初诊或复发的急性白血病患者的MRP和MRD基因从mRNA表达水平进行了检测。     

多重耐药分子生物学进展

多重耐药是因质粒和染色体介导的耐药因素所致细菌对多类抗菌药物耐药。质粒介导的多重耐药通常是不同的单耐药基因装入转座子或者由重组,转位等机制构成的复制子,多由不同基因独立调节机制不同的耐药;而染色体介导的多药耐药似乎是在一个调节位点控制下的多基因协作表型。 目前细菌的多药耐药机制研究主要集中在其外胰蛋白的改变导致的孔道变化或/和主动排出机制所致对多种结构无关药物的耐药。一度曾认为外膜低透性是细菌多药耐药的主要机制,但随着主动排出系统的发现及研究,现在倾向于这种机制似乎更加重要。细菌的主动排出系统可分为四类:(1)MF类(major facilitator);(2)RND(resistance-nodulation-division)类;(3)Smr(staphylococal multidrug resistance)类;(4)ABC(ATP-binding cassette)类,前三类以质子泵作动力,第四类以ATP酶Na~+ -K~+泵作动力。     

Mutational analysis of the yeast multidrug resistance ABC transporter Pdr5p with altered drug specificity

Multidrug resistance ABC transporter Pdr5p of Saccharomyces cerevisiae is particularly important due to its ability to export a wide range of unrelated substrates. To clarify its function, we generated Pdr5p mutants by random mutagenesis and screened for mutants with altered drug specificity in vivo by using 5 drug compounds. Nine point mutations that caused significant changes in drug specificity distributed throughout the length of Pdr5p, namely, in the extracellular, transmembrane or cytoplasmic regions of the transporter. We then investigated their effects upon drug resistance, using 36 chemically related or distinct substrates. From this study, overall geometry of the Pdr5p was suggested to contribute in acquiring the enormous range of drug specificity. Based on their ability to inhibit the growth of the mutant strains, the 36 tested drugs were classified into: drugs to which the mutants responded differently (Group 1), drugs to which all the mutants showed sensitivity (Group 2), and drugs to which all the mutants exhibited resistance (Group 3). The ability of the compounds to be partitioned to the plasma membrane seemed an important factor for recognition by Pdr5p.     

microRNA调控结核分枝杆菌感染巨噬细胞凋亡的研究进展

细胞凋亡对于机体抑制或清除胞内结核分枝杆菌( Mycobacterium tuberculosis, Mtb)尤为重要, Mtb感染巨噬细胞后,往往会诱导机体启动一系列机制调控巨噬细胞凋亡。在 Mtb感染的巨噬细胞内存在差异表达的microRNAs (miRNAs),miRNA可直接结合凋...     

Gel microstructure regulates proliferation and differentiation of MC3T3-E1 cells encapsulated in alginate beads

For cell transplantation into damaged tissues, viable cells must be delivered to the defect site in a suitable carrier. However, the hypoxic and nutrient-limited environment in the carrier can induce massive cell death. The aims of this study were to increase the viability and regulate the behavior of osteoprogenitor cells encapsulated in alginate hydrogels through control of the gel microstructure. Cell survivability in alginate beads was improved through the use of α-MEM as the solvent for alginic acid sodium salt, and by CaCl(2) solutions, which supplied additional nutrients for the cells compared to water or buffer. The mesh size and shear modulus of the hydrogel were hypothesized to regulate proliferation and differentiation of osteoprogenitor cells. MC3T3-E1 cells demonstrated enhanced osteoblast differentiation when encapsulated in high-density alginate with smaller mesh size and more rigid mechanical properties, as confirmed by increased alkaline phosphatase activity and osteocalcin secretion. However, MC3T3-E1 cells encapsulated in low-density alginate beads with a larger mesh size and more compliant mechanical properties exhibited increased proliferation. These results demonstrate that the microstructure of alginate hydrogels can regulate the behavior of osteoprogenitor cells, thus suggesting that the tuning the properties of the gel may be a useful approach for enhancing new bone formation.     

Long non-coding RNAs in retinoblastoma

Retinoblastoma represents 3% of all childhood cancers and is the most common intraocular malignant tumor with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have reported new insights into the mechanism of retinoblastoma development, the involvement of regulatory non-coding RNAs remains unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous non-protein-coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidence has shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration, and invasion. Several lncRNAs, including BANCR, AFAP1-AS1, NEAT1, XIST, ANRIL, PlncRNA-1, HOTAIR, PANDAR, DANCR, and THOR, promote the progression and metastasis of retinoblastoma. However, some lncRNAs, such as MEG3, MT1JP, and H19, play a tumor suppressive role. Our review summarizes the functional role of lncRNAs in retinoblastoma and their potential clinical applications for diagnosis, prognosis, and treatment.