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Research Progress of RNA Quadruplex. RNA Quadruplex 的研究进展。
Pub Date : 2011-05-16 DOI: 10.1089/oli.2010.0272
Xiaohui Ji, Hongxia Sun, Huaxi Zhou, Junfeng Xiang, Yalin Tang, Changqi Zhao

RNA/DNA sequences rich in guanine (G) can form a 4-strand structure, G-quadruplex, which has been extensively researched and observed in mammalian, fungi, and plants, with in vivo existence in eukaryotic cells. Compared with DNA quadruplex, the potential existence of RNA quadruplex appears to be generally rare; however, it is believed by some researchers to be more inevitable in vivo and speculated to play an important role where it exists. Recently, researches concerning the function of G-quadruplexes in RNAs commence, making much progress. However, there is no available review particularly focusing on RNA quadruplex till now as we know. Therefore, we decide to give a review to comprehensively summarize research progress on it. This review highlights the diverse topologies for RNA quadruplex structure and its effect factors; outlines the current knowledge of RNA quadruplex's physiological functions in biological systems, especially in gene expression; and presents the prospects of RNA quadruplex.

富含鸟嘌呤(G)的 RNA/DNA 序列可形成一种四链结构--G-四联体,这种结构已在哺乳动物、真菌和植物中被广泛研究和观察到,并在真核细胞中存在。与 DNA 四链结构相比,RNA 四链结构的潜在存在似乎一般比较罕见,但一些研究人员认为它在体内更不可避免,并推测它在存在的地方会发挥重要作用。最近,有关 RNA 中 G-四重链功能的研究已经开始,并取得了很大进展。然而,据我们所知,到目前为止还没有专门针对 RNA 四链体的综述。因此,我们决定撰写一篇综述,全面总结这方面的研究进展。这篇综述重点介绍了 RNA 四链体结构的多种拓扑结构及其效应因子;概述了目前对 RNA 四链体在生物系统中的生理功能,尤其是在基因表达中的生理功能的认识;并展望了 RNA 四链体的发展前景。
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引用次数: 0
Polyethylenimine/oligonucleotide polyplexes investigated by fluorescence resonance energy transfer and fluorescence anisotropy. 荧光共振能量转移和荧光各向异性研究聚乙烯亚胺/寡核苷酸多聚物。
Pub Date : 2011-03-01 Epub Date: 2011-03-21 DOI: 10.1089/oli.2010.0271
Young Tag Ko, Ulrich Bickel, Juyang Huang

To advance knowledge on polyplex structure and composition, fluorescence resonance energy transfer (FRET) and anisotropy measurements were applied to polyplexes of rhodamine-labeled polyethylenimine (PEI) and fluorescein-labeled double-stranded oligodeoxynucleotide (ODN). About 25 kDa PEI was compared with low-molecular-weight PEI of 2.7 kDa. FRET reached maxima at amine to phosphate (N/P) ratios of 2 and 3 for 2.7 kDa and 25 kDa PEI, respectively, with similar average distances between donor and acceptor dye molecules in polyplexes. Anisotropy measurements allowed estimating the bound fractions of PEI and ODN. At N/P = 6, all ODN was bound, but only 58% of PEI 25 kDa and 45% of PEI 2.7 kDa. In conclusion, the higher molecular weight of PEI may conformationally restrict the availability of amino groups for charge interaction with phosphate groups in ODN. Moreover, significant fractions of both types of PEI remain free in solution at N/P ratios frequently used for transfection. FRET and anisotropy measurements provide effective tools for probing polyplex compositions and designing optimized delivery systems.

为了进一步了解多聚物的结构和组成,采用荧光共振能量转移(FRET)和各向异性测量方法对罗丹明标记的聚乙烯亚胺(PEI)和荧光素标记的双链寡脱氧核苷酸(ODN)的多聚物进行了研究。约25 kDa的PEI与2.7 kDa的低分子量PEI比较。对于2.7 kDa和25 kDa的PEI,在胺与磷酸盐(N/P)比分别为2和3时,FRET达到最大值,在多聚物中供体和受体染料分子之间的平均距离相似。各向异性测量允许估计PEI和ODN的结合分数。在N/P = 6时,所有ODN都被结合,但只有58%的PEI 25 kDa和45%的PEI 2.7 kDa被结合。综上所述,PEI较高的分子量可能在构象上限制了ODN中氨基与磷酸基电荷相互作用的可用性。此外,两种PEI的很大一部分在通常用于转染的N/P比率的溶液中保持游离。FRET和各向异性测量提供了有效的工具,探测多路组合和设计优化的输送系统。
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引用次数: 11
Decoy-DNA against special AT-rich sequence binding protein 1 inhibits the growth and invasive ability of human breast cancer. 针对特殊AT-rich序列结合蛋白1的诱饵dna抑制人乳腺癌的生长和侵袭能力。
Pub Date : 2011-03-01 DOI: 10.1089/oli.2010.0277
Asako Yamayoshi, Mariko Yasuhara, Sanjeev Galande, Akio Kobori, Akira Murakami

"Triple-negative" (TN) breast cancers, which are characterized by estrogen receptor (-), progesterone receptor (-), and human epidermal growth factor receptor 2 (-), are typically associated with poor prognosis because of their aggressive tumor phenotypes. In recent years, the number of patients with breast cancers has remarkably increased, but there are only few available drugs for treatment of TN breast cancers. The development of novel drugs targeting TN breast cancer is urgently required. In the present study, we focused on the function of special AT-rich sequence binding protein 1 (SATB1) as a target molecule for the treatment of TN breast cancers. By recruiting chromatin remodeling enzymes and transcriptional factors, SATB1 regulates the expression of >1,000 genes related to cell growth and translocation. We synthesized a decoy DNA against SATB1, including the recognition sequence of SATB1. We examined the inhibitory effects of the decoy DNAs on cellular proliferation of a TN metastatic breast cancer cell line (MDA-MB-231). SATB1-decoy DNA inhibited the proliferation of MDA-MB-231 cells. Especially, it was significant that SATB1-decoy DNA drastically reduced the invasive and metastatic capacity of MBA-MB-231 cells. Further, in the case of MCF7 cells (SATB1-negative breast cancer cell line), SATB1-decoy DNA did not exhibit any inhibitory effect. These data suggest that SATB1-decoy DNA may be an effective candidate for use as a molecular-targeting drug for treatment of TN breast cancer.

“三阴性”(TN)乳腺癌的特征是雌激素受体(-)、孕激素受体(-)和人表皮生长因子受体2(-),由于其侵袭性的肿瘤表型,通常与预后不良相关。近年来,乳腺癌患者数量显著增加,但可用于治疗TN型乳腺癌的药物却很少。迫切需要开发针对TN型乳腺癌的新型药物。在本研究中,我们重点研究了特殊AT-rich sequence binding protein 1 (SATB1)作为靶分子在TN乳腺癌治疗中的作用。通过募集染色质重塑酶和转录因子,SATB1调控了超过1000个与细胞生长和易位相关的基因的表达。我们合成了一个针对SATB1的诱饵DNA,包括SATB1的识别序列。我们研究了诱饵dna对TN转移性乳腺癌细胞系(MDA-MB-231)细胞增殖的抑制作用。satb1诱饵DNA抑制MDA-MB-231细胞的增殖。特别值得注意的是,satb1诱饵DNA显著降低了MBA-MB-231细胞的侵袭和转移能力。此外,在MCF7细胞(satb1阴性乳腺癌细胞系)中,satb1诱饵DNA没有表现出任何抑制作用。这些数据表明,satb1诱饵DNA可能是一种有效的候选分子靶向药物,可用于治疗TN乳腺癌。
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引用次数: 18
PEI-g-PEG-RGD/small interference RNA polyplex-mediated silencing of vascular endothelial growth factor receptor and its potential as an anti-angiogenic tumor therapeutic strategy. PEI-g-PEG-RGD/小干扰RNA多聚体介导的血管内皮生长因子受体沉默及其作为抗血管生成肿瘤治疗策略的潜力。
Pub Date : 2011-03-01 Epub Date: 2011-03-04 DOI: 10.1089/oli.2011.0278
Jihoon Kim, Sung Wan Kim, Won Jong Kim

Tumor angiogenesis appears to be achieved by the expression of vascular endothelial growth factor (VEGF) within solid tumors that stimulate host vascular endothelial cell mitogenesis and possibly chemotaxis. VEGF's angiogenic actions are mediated through its high-affinity binding to 2 endothelium-specific receptor tyrosine kinase, Flt-1 (VEGFR1), and Flk-1/KDR (VEGFR2). RNA interference-mediated knockdown of protein expression at the messenger RNA level provides a new therapeutic strategy to overcome various diseases. To achieve high efficacy in RNA interference-mediated therapy, it is critical to develop an efficient delivering system to deliver small interference RNA (siRNA) into tissues or cells site-specifically. We previously reported an angiogenic endothelial cell-targeted polymeric gene carrier, PEI-g-PEG-RGD. This targeted carrier was developed by the conjugation of the ανβ3/ανβ5 integrin-binding RGD peptide (ACDCRGDCFC) to the cationic polymer, branched polyethylenimine, with a hydrophilic polyethylene glycol (PEG) spacer. In this study, we used PEI-g-PEG-RGD to deliver siRNA against VEGFR1 into tumor site. The physicochemical properties of PEI-g-PEG-RGD/siRNA complexes was evaluated. Further, tumor growth profile was also investigated after systemic administration of PEI-g-PEG-RGD/siRNA complexes.

肿瘤血管生成似乎是通过实体瘤内血管内皮生长因子(VEGF)的表达来实现的,VEGF刺激宿主血管内皮细胞有丝分裂和可能的趋化性。VEGF的血管生成作用是通过其与2内皮特异性受体酪氨酸激酶Flt-1 (VEGFR1)和Flk-1/KDR (VEGFR2)的高亲和力结合介导的。RNA干扰介导的信使RNA水平的蛋白表达下调为克服各种疾病提供了一种新的治疗策略。为了实现RNA干扰介导治疗的高效率,开发一种高效的递送系统将小干扰RNA (siRNA)特异性地递送到组织或细胞中至关重要。我们之前报道了一种血管生成内皮细胞靶向聚合基因载体PEI-g-PEG-RGD。该靶向载体是通过ανβ3/ανβ5整合素结合RGD肽(ACDCRGDCFC)与阳离子聚合物支化聚乙烯亚胺结合,并以亲水性聚乙二醇(PEG)间隔物偶联而成。在本研究中,我们使用PEI-g-PEG-RGD将靶向VEGFR1的siRNA递送到肿瘤部位。对PEI-g-PEG-RGD/siRNA复合物的理化性质进行了评价。此外,还研究了全身给药PEI-g-PEG-RGD/siRNA复合物后的肿瘤生长情况。
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引用次数: 30
Oligo/polynucleotide-based gene modification: strategies and therapeutic potential. 基于寡核苷酸/多核苷酸的基因修饰:策略和治疗潜力。
Pub Date : 2011-03-01 Epub Date: 2011-03-21 DOI: 10.1089/oli.2010.0273
R Geoffrey Sargent, Soya Kim, Dieter C Gruenert

Oligonucleotide- and polynucleotide-based gene modification strategies were developed as an alternative to transgene-based and classical gene targeting-based gene therapy approaches for treatment of genetic disorders. Unlike the transgene-based strategies, oligo/polynucleotide gene targeting approaches maintain gene integrity and the relationship between the protein coding and gene-specific regulatory sequences. Oligo/polynucleotide-based gene modification also has several advantages over classical vector-based homologous recombination approaches. These include essentially complete homology to the target sequence and the potential to rapidly engineer patient-specific oligo/polynucleotide gene modification reagents. Several oligo/polynucleotide-based approaches have been shown to successfully mediate sequence-specific modification of genomic DNA in mammalian cells. The strategies involve the use of polynucleotide small DNA fragments, triplex-forming oligonucleotides, and single-stranded oligodeoxynucleotides to mediate homologous exchange. The primary focus of this review will be on the mechanistic aspects of the small fragment homologous replacement, triplex-forming oligonucleotide-mediated, and single-stranded oligodeoxynucleotide-mediated gene modification strategies as it relates to their therapeutic potential.

基于寡核苷酸和多核苷酸的基因修饰策略被开发为替代基于转基因和经典的基于基因靶向的基因治疗方法,用于治疗遗传性疾病。与基于转基因的策略不同,寡核苷酸/多核苷酸基因靶向方法保持了基因的完整性以及蛋白质编码与基因特异性调控序列之间的关系。与传统的基于载体的同源重组方法相比,基于寡核苷酸/多核苷酸的基因修饰也有几个优点。这些包括与目标序列的基本完全同源性以及快速设计患者特异性寡核苷酸/多核苷酸基因修饰试剂的潜力。一些基于寡核苷酸/多核苷酸的方法已经被证明可以成功地介导哺乳动物细胞基因组DNA的序列特异性修饰。这些策略包括使用多核苷酸小DNA片段、三聚体形成的寡核苷酸和单链寡脱氧核苷酸来介导同源交换。本综述的主要重点将放在小片段同源替代、三聚体形成的寡核苷酸介导和单链寡脱氧核苷酸介导的基因修饰策略的机制方面,因为它与它们的治疗潜力有关。
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引用次数: 21
Antisense oligonucleotides targeting abhydrolase domain containing 2 block human hepatitis B virus propagation. 以含2的脱氢酶结构域为靶点的反义寡核苷酸可阻断乙型肝炎病毒的传播。
Pub Date : 2011-03-01 Epub Date: 2011-04-05 DOI: 10.1089/oli.2011.0280
Xiaoran Ding, Jing Yang, Shengqi Wang

Hepatitis B virus (HBV) infection is a major health concern worldwide and only a minority of treated patients develop a sustained protective response following a short course of therapy, and most patients require prolonged treatment to suppress viral replication. However, several recent reports showed that inhibition of certain host cell proteins prevented viral infection, specifically the human abhydrolase domain containing 2 (ABHD2) has been confirmed by our previous study to be upregulated in HepG2.2.15 cells but downregulated by lamivudine. These observations suggested that ABHD2 was important for HBV propagation and could be a target of novel anti-HBV drugs. To assess the importance of ABHD2 to the HBV infection process, antisense oligonucleotides (ASODNs) were used to downregulate ABHD2 expression in HepG2.2.15 cells. From 5 ASODNS candidates tested, AB3 significantly downregulated ABHD2 mRNA and protein expression levels. Further, AB3 significantly reduced HBV DNA, hepatitis B surface antigen, and hepatitis B "e" antigen protein expression levels in cell medium without affecting cell viability. These results suggest that downregulation of ABHD2 using ASODNs blocked HBV replication and expression without affecting host cell physiology. Further, data demonstrated an essential role of ABHD2 in HBV propagation, suggesting it can serve as a novel target for anti-HBV drug development.

乙型肝炎病毒(HBV)感染是世界范围内的一个主要健康问题,只有少数接受治疗的患者在短期治疗后产生持续的保护性反应,大多数患者需要长期治疗以抑制病毒复制。然而,最近的一些报道表明,抑制某些宿主细胞蛋白可以防止病毒感染,特别是我们之前的研究证实,人类ABHD2结构域在HepG2.2.15细胞中上调,而拉米夫定则下调。这些观察结果表明,ABHD2对HBV的传播很重要,可能成为新型抗HBV药物的靶点。为了评估ABHD2在HBV感染过程中的重要性,我们使用反义寡核苷酸(ASODNs)下调HepG2.2.15细胞中ABHD2的表达。在5个ASODNS候选物中,AB3显著下调ABHD2 mRNA和蛋白的表达水平。此外,AB3显著降低HBV DNA、乙型肝炎表面抗原和乙型肝炎“e”抗原蛋白在细胞培养基中的表达水平,而不影响细胞活力。这些结果表明,使用ASODNs下调ABHD2可阻断HBV的复制和表达,而不影响宿主细胞生理。此外,数据显示ABHD2在HBV传播中发挥重要作用,表明它可以作为抗HBV药物开发的新靶点。
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引用次数: 18
A sol-gel-based microfluidics system enhances the efficiency of RNA aptamer selection. 基于溶胶-凝胶的微流体系统提高了RNA适体选择的效率。
Pub Date : 2011-03-01 Epub Date: 2011-03-17 DOI: 10.1089/oli.2010.0263
Ji-Young Ahn, Minjoung Jo, Pooja Dua, Dong-Ki Lee, Soyoun Kim

RNA and DNA aptamers that bind to target molecules with high specificity and affinity have been a focus of diagnostics and therapeutic research. These aptamers are obtained by SELEX often requiring many rounds of selection and amplification. Recently, we have shown the efficient binding and elution of RNA aptamers against target proteins using a microfluidic chip that incorporates 5 sol-gel binding droplets within which specific target proteins are imbedded. Here, we demonstrate that our microfluidic chip in a SELEX experiment greatly improved selection efficiency of RNA aptamers to TATA-binding protein, reducing the number of selection cycles needed to produce high affinity aptamers by about 80%. Many aptamers were identical or homologous to those isolated previously by conventional filter-binding SELEX. The microfluidic chip SELEX is readily scalable using a sol-gel microarray-based target multiplexing. Additionally, we show that sol-gel embedded protein arrays can be used as a high-throughput assay for quantifying binding affinities of aptamers.

RNA和DNA适体以高特异性和亲和力结合靶分子,已成为诊断和治疗研究的热点。这些适体是通过SELEX获得的,通常需要多轮选择和扩增。最近,我们已经展示了利用微流控芯片有效结合和洗脱RNA适体对靶蛋白的作用,微流控芯片包含了5个溶胶-凝胶结合液滴,其中嵌入了特定的靶蛋白。在SELEX实验中,我们证明了我们的微流控芯片极大地提高了RNA适配体对tata结合蛋白的选择效率,将产生高亲和力适配体所需的选择周期减少了约80%。许多适体与以前通过常规过滤结合SELEX分离的适体相同或同源。微流控芯片SELEX很容易扩展使用溶胶-凝胶微阵列为基础的目标复用。此外,我们表明,溶胶-凝胶嵌入的蛋白质阵列可以作为一种高通量分析,用于量化适配体的结合亲和力。
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引用次数: 30
Development of single-stranded DNA aptamers for specific Bisphenol a detection. 用于双酚a特异性检测的单链DNA适体的研制。
Pub Date : 2011-03-01 Epub Date: 2011-03-17 DOI: 10.1089/oli.2010.0267
Minjoung Jo, Ji-Young Ahn, Joohyung Lee, Seram Lee, Sun Woo Hong, Jae-Wook Yoo, Jeehye Kang, Pooja Dua, Dong-Ki Lee, Seunghun Hong, Soyoun Kim

The development of reagents with high affinity and specificity to small molecules is crucial for the high-throughput detection of chemical compounds, such as toxicants or pollutants. Aptamers are short and single-stranded (ss) oligonucleotides able to recognize target molecules with high affinity. Here, we report the selection of ssDNA aptamers that bind to Bisphenol A (BPA), an environmental hormone. Using SELEX process, we isolated high affinity aptamers to BPA from a 10(15) random library of 60 mer ssDNAs. The selected aptamers bound specifically to BPA, but not to structurally similar molecules, such as Bisphenol B with one methyl group difference, or 4,4'-Bisphenol with 2 methyl groups difference. Using these aptamers, we developed an aptamer-based sol-gel biochip and detected BPA dissolved in water. This novel BPA aptamer-based detection can be further applied to the universal and high-specificity detection of small molecules.

开发对小分子具有高亲和力和特异性的试剂对于高通量检测化合物(如毒物或污染物)至关重要。适配体是短的单链寡核苷酸,能够识别具有高亲和力的靶分子。在这里,我们报道了结合双酚A (BPA)的ssDNA适配体的选择,双酚A是一种环境激素。使用SELEX工艺,我们从60个单核苷酸随机文库中分离出高亲和力的双酚a适配体。所选择的适体与BPA特异性结合,而不是与结构相似的分子结合,例如具有一个甲基差异的双酚B,或具有两个甲基差异的4,4'-双酚。利用这些适配体,我们开发了一种基于适配体的溶胶-凝胶生物芯片,并检测了溶解在水中的BPA。这种基于双酚a适配体的检测方法可以进一步应用于小分子的通用和高特异性检测。
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引用次数: 167
Cell-specific aptamer-mediated targeted drug delivery. 细胞特异性适配体介导的靶向药物递送。
Pub Date : 2011-02-01 Epub Date: 2010-12-23 DOI: 10.1089/oli.2010.0264
Jiehua Zhou, John J Rossi

Nucleic acid aptamers are in vitro-selected small, single-stranded DNA or RNA oligonucleotides that can specifically recognize their target on the basis of their unique 3-dimensional structures. Recent advances in the development of escort aptamers to deliver and enhance the efficacy of other therapeutic agents have drawn enthusiasm in exploiting cell-type-specific aptamers as drug delivery vehicles. This review mainly focuses on the recent developments of aptamer-mediated targeted delivery systems. We also place particular emphasis on aptamers evolved against cell membrane receptors and possibilities for translation to clinical applications.

核酸适体是体外选择的小单链DNA或RNA寡核苷酸,可以根据其独特的三维结构特异性识别其靶标。护卫适体递送和增强其他治疗药物疗效的最新进展,引起了利用细胞类型特异性适体作为药物递送载体的热情。本文主要综述了适体介导的靶向递送系统的最新进展。我们还特别强调了针对细胞膜受体进化的适体和翻译到临床应用的可能性。
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引用次数: 154
T-oligos inhibit growth and induce apoptosis in human ovarian cancer cells. t -寡核苷酸抑制人卵巢癌细胞生长并诱导细胞凋亡。
Pub Date : 2011-02-01 Epub Date: 2011-01-31 DOI: 10.1089/oli.2010.0259
Sibaji Sarkar, Douglas V Faller

Ovarian cancer remains a leading cause of death among women worldwide, and current treatment regimens for advanced disease are inadequate. Oligonucleotides with sequence homology to telomeres (called T-oligos) have been shown to mimic DNA damage responses in cells and induce cytotoxic effects in certain tumor cell lines. We studied the effects of 2 distinct 16 mer T-oligos in 4 human ovarian epithelial carcinoma cell lines. A T-oligo with perfect homology to the telomere overhang region demonstrated some cytotoxic activity in half of the cell lines. A G-rich T-oligo derivative showed more potency and broader cytotoxic activity in these lines than the parental T-oligo. Activation of apoptotic pathways in ovarian cancer cells by exposure to the T-oligo was demonstrated by multiple independent assays. T-oligo was shown to have additive, or more than additive, activity in combination with 2 different histone deacetylase drugs currently in clinical testing. T-oligos may therefore provide a new and tumor-targeted approach to ovarian cancers.

卵巢癌仍然是全世界妇女死亡的主要原因,目前对晚期疾病的治疗方案不足。与端粒序列同源的寡核苷酸(称为t寡核苷酸)已被证明在细胞中模拟DNA损伤反应并诱导某些肿瘤细胞系的细胞毒性作用。我们研究了2种不同的16 mer t寡核苷酸在4种人卵巢上皮癌细胞系中的作用。一个与端粒悬垂区完全同源的t寡核苷酸在一半的细胞系中显示出一定的细胞毒活性。富含g的t寡核苷酸衍生物在这些细胞系中表现出比亲本t寡核苷酸更强的效力和更广泛的细胞毒活性。暴露于t寡核苷酸可激活卵巢癌细胞的凋亡通路。T-oligo与目前正在临床试验的两种不同的组蛋白去乙酰化酶药物联合使用时,显示出附加或超过附加的活性。因此,t寡核苷酸可能为卵巢癌提供一种新的肿瘤靶向治疗方法。
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引用次数: 43
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