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https://www.readbyqxmd.com/read/28641400/cytosolic-delivery-of-sirna-by-ultra-high-affinity-dsrna-binding-proteins
#1
Nicole J Yang, Monique J Kauke, Fangdi Sun, Lucy F Yang, Katie F Maass, Michael W Traxlmayr, Yao Yu, Yingda Xu, Robert S Langer, Daniel G Anderson, K Dane Wittrup
Protein-based methods of siRNA delivery are capable of uniquely specific targeting, but are limited by technical challenges such as low potency or poor biophysical properties. Here, we engineered a series of ultra-high affinity siRNA binders based on the viral protein p19 and developed them into siRNA carriers targeted to the epidermal growth factor receptor (EGFR). Combined in trans with a previously described endosome-disrupting agent composed of the pore-forming protein Perfringolysin O (PFO), potent silencing was achieved in vitro with no detectable cytotoxicity...
June 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28641278/astragaloside-iv-alleviates-heat-induced-inflammation-by-inhibiting-endoplasmic-reticulum-stress-and-autophagy
#2
Zhiwei Dong, Jian Zhou, Ying Zhang, Yajie Chen, Zichen Yang, Guangtao Huang, Yu Chen, Zhiqiang Yuan, Yizhi Peng, Tongtong Cao
BACKGROUND: Thermal injury is the main cause of pulmonary disease in stroke after burn and can be life threatening. Heat-induced inflammation is an important factor that triggers a series of induces pathological changes. However, this mechanism underlying heat-induced inflammation in thermal inhalation injury remains unclear. Studies have revealed that astragaloside-IV (AS-IV), a natural compound extracted from Astragalus membranaceus, has protective effects in inflammatory diseases. Here, we investigated whether the protective effects of AS-IV occur because of the suppression of heat-induced endoplasmic reticulum (ER) stress and excessive autophagy Methods: AS-IV was administered to Wistar rats after thermal inhalation injury and 16HBE140-cells were treated with AS-IV...
June 23, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28640996/a-polyoxometalate-based-radiosensitization-platform-for-treating-hypoxic-tumor-by-attenuating-radio-resistance-and-enhancing-radiation-response
#3
Yuan Yong, Chunfang Zhang, Zhanjun Gu, Jiangfeng Du, Zhao Guo, Xinghua Dong, Jiani Xie, Guangjin Zhang, Xiangfeng Liu, Yuliang Zhao
Radioresistance is one of the undesirable impediments in hypoxia tumor, which sharply diminishes therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with admirable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxia tumor. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW10@CS nanosphere) as a radiosensitization system for simultanous extrinsic and intrinsic radiosensitization, by generating overabundance cytotoxic reactive oxygen species (ROS) using high energy X-ray stimulation and mediating the hypoxia-inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1α expression and suppress the broken double-stranded DNA self-healing...
June 22, 2017: ACS Nano
https://www.readbyqxmd.com/read/28640887/epidermal-growth-factor-promotes-cyclin-g2-degradation-via-calpain-mediated-proteolysis-in-gynaecological-cancer-cells
#4
Stefanie Bernaudo, Shahin Khazai, Eilyad Honarparvar, Alina Kopteva, Chun Peng
Cyclin G2 (CCNG2) is an atypical cyclin that functions to inhibit cell cycle progression and is often dysregulated in human cancers. We have previously shown that cyclin G2 is highly unstable and can be degraded through the ubiquitin/proteasome pathway. Furthermore, cyclin G2 contains a PEST domain, which has been suggested to act as a signal for degradation by multiple proteases. In this study, we determined if calpains, a family of calcium-dependent proteases, are also involved in cyclin G2 degradation. The addition of calpain inhibitors or silencing of calpain expression by siRNAs strongly enhanced cyclin G2 levels...
2017: PloS One
https://www.readbyqxmd.com/read/28640810/lassim-a-network-inference-toolbox-for-genome-wide-mechanistic-modeling
#5
Rasmus Magnusson, Guido Pio Mariotti, Mattias Köpsén, William Lövfors, Danuta R Gawel, Rebecka Jörnsten, Jörg Linde, Torbjörn Nordling, Elin Nyman, Sylvie Schulze, Colm E Nestor, Huan Zhang, Gunnar Cedersund, Mikael Benson, Andreas Tjärnberg, Mika Gustafsson
Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets...
June 22, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28640690/a-new-layer-of-rrna-regulation-by-small-interference-rnas-and-the-nuclear-rnai-pathway
#6
Xufei Zhou, Xiangyang Chen, Yun Wang, Xuezhu Feng, Shouhong Guang
Ribosome biogenesis drives cell growth and proliferation, but mechanisms that modulate this process remain poorly understood. For a long time, small ribosomal RNA sequences have been widely treated as non-specific degradation products and neglected as garbage sequences. Recently, we identified a new class of antisense ribosomal siRNAs (risiRNAs) that downregulate pre-rRNA through the nuclear RNAi pathway in C. elegans. risiRNAs exhibit sequence characteristics similar to 22G RNA while complement to 18S and 26S rRNA...
June 22, 2017: RNA Biology
https://www.readbyqxmd.com/read/28637297/a-role-for-progesterone-regulated-sfrp4-expression-in-uterine-leiomyomas
#7
Meaghan A Delaney, Ying-Wooi Wan, Gyoung-Eun Kim, Chad J Creighton, Margaret G Taylor, Ramya Masand, Andrew Park, Cecilia Valdes, William Gibbons, Zhandong Liu, Matthew L Anderson
Context: Despite progesterone's key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood. Objective: The aim of this study was to identify novel gene products mediating progesterone's effects in uterine leiomyomas. Design: Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro...
June 14, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28637023/cationic-liquid-crystalline-nanoparticles-for-the-delivery-of-synthetic-rnai-based-therapeutics
#8
Emanuela Gentile, Taro Oba, Jing Lin, Ruping Shao, Feng Meng, Xiaobo Cao, Heather Y Lin, Majidi Mourad, Apar Pataer, Veerabhadran Baladandayuthapani, Dong Cai, Jack A Roth, Lin Ji
RNA interference (RNAi)-based therapeutics have been used to silence the expression of targeted pathological genes. Small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitor have performed this function. However, short half-life, poor cellular uptake, and nonspecific distribution of small RNAs call for the development of novel delivery systems to facilitate the use of RNAi. We developed a novel cationic liquid crystalline nanoparticle (CLCN) to efficiently deliver synthetic siRNAs and miRNAs. CLCNs were prepared by using high-speed homogenization and assembled with synthetic siRNA or miRNA molecules in nuclease-free water to create CLCN/siRNA or miRNA complexes...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28637007/c-fos-dependent-mir-22-targets-mdc1-and-regulates-dna-repair-in-terminally-differentiated-cells
#9
Jung-Hee Lee, Seon-Joo Park, Seok Won Kim, Gurusamy Hariharasudhan, Sung-Mi Jung, Semo Jun, Jeongsik Yong, Ho Jin You
Terminally differentiated cells have a reduced capacity to repair double-stranded breaks (DSB) in DNA, however, the underlying molecular mechanism remains unclear. Here, we show that miR-22 is upregulated during postmitotic differentiation of human breast MCF-7 cells, hematopoietic HL60 and K562 cells. Increased expression of miR-22 in differentiated cells was associated with decreased expression of MDC1, a protein that plays a key role in the response to DSBs. This downregulation of MDC1 was accompanied by reduced DSB repair, impaired recruitment of the protein to the site of DNA damage following IR...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636969/human-virus-derived-small-rnas-can-confer-antiviral-immunity-in-mammals
#10
Yang Qiu, Yanpeng Xu, Yao Zhang, Hui Zhou, Yong-Qiang Deng, Xiao-Feng Li, Meng Miao, Qiang Zhang, Bo Zhong, Yuanyang Hu, Fu-Chun Zhang, Ligang Wu, Cheng-Feng Qin, Xi Zhou
RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates; however, whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner and loaded into AGO, and they were fully active in degrading cognate viral RNAs...
June 20, 2017: Immunity
https://www.readbyqxmd.com/read/28636940/hectd3-mediates-an-hsp90-dependent-degradation-pathway-for-protein-kinase-clients
#11
Zhaobo Li, Lihong Zhou, Chrisostomos Prodromou, Velibor Savic, Laurence H Pearl
Inhibition of the ATPase cycle of the HSP90 chaperone promotes ubiquitylation and proteasomal degradation of its client proteins, which include many oncogenic protein kinases. This provides the rationale for HSP90 inhibitors as cancer therapeutics. However, the mechanism by which HSP90 ATPase inhibition triggers ubiquitylation is not understood, and the E3 ubiquitin ligases involved are largely unknown. Using a siRNA screen, we have identified components of two independent degradation pathways for the HSP90 client kinase CRAF...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28636937/the-conserved-rna-binding-cyclophilin-rct1-regulates-small-rna-biogenesis-and-splicing-independent-of-heterochromatin-assembly
#12
An-Yun Chang, Stephane E Castel, Evan Ernst, Hyun Soo Kim, Robert A Martienssen
RNAi factors and their catalytic activities are essential for heterochromatin assembly in S. pombe. This has led to the idea that siRNAs can promote H3K9 methylation by recruiting the cryptic loci regulator complex (CLRC), also known as recombination in K complex (RIKC), to the nucleation site. The conserved RNA-binding protein Rct1 (AtCyp59/SIG-7) interacts with splicing factors and RNA polymerase II. Here we show that Rct1 promotes processing of pericentromeric transcripts into siRNAs via the RNA recognition motif...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28636657/novel-sirna-formulation-to-effectively-knockdown-mutant-p53-in-osteosarcoma
#13
Anup K Kundu, Swathi V Iyer, Sruti Chandra, Amit S Adhikari, Tomoo Iwakuma, Tarun K Mandal
OBJECTIVES: The tumor suppressor p53 plays a crucial role in the development of osteosarcoma. The primary objective of this study is to develop and optimize lipid based nanoparticle formulations that can carry siRNA and effectively silence mutant p53 in 318-1, a murine osteosarcoma cell line. METHODS: The nanoparticles were composed of a mixture of two lipids (cholesterol and DOTAP) and either PLGA or PLGA-PEG and prepared by using an EmulsiFlex-B3 high pressure homogenizer...
2017: PloS One
https://www.readbyqxmd.com/read/28636549/p53-independent-p21-induction-by-melk-inhibition
#14
Tatsuo Matsuda, Taigo Kato, Kazuma Kiyotani, Yunus Emre Tarhan, Vassiliki Saloura, Suyoun Chung, Koji Ueda, Yusuke Nakamura, Jae-Hyun Park
MELK play critical roles in human carcinogenesis through activation of cell proliferation, inhibition of apoptosis and maintenance of stemness. Therefore, MELK is a promising therapeutic target for a wide range of cancers. Although p21 is a well-known p53-downstream gene, we found that treatment with a potent MELK inhibitor, OTS167, could induce p21 protein expression in cancer cell lines harboring loss-of-function TP53 mutations. We also confirmed that MELK knockdown by siRNA induced the p21 expression in p53-deficient cancer cell lines and caused the cell cycle arrest at G1 phase...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636545/reversal-effect-of-jagged1-signaling-inhibition-on-ccl4-induced-hepatic-fibrosis-in-rats
#15
Guiju Tang, Zhihong Weng, Jun Song, Yixiong Chen
The role of the Notch ligand Jagged1 in hepatic fibrosis remains to be elucidated. In the current study, we investigated the role of Jagged1 in the activation of hepatic stellate cells (HSCs) and development of hepatic fibrosis in rats. In vitro, Jagged1 in HSCs was downregulated and upregulated by Jagged1 siRNA and pcDNA3.1 Jagged1, respectively. The levels of epithelial-mesenchymal transition (EMT) markers and HSC activation markers were assessed using western blot analysis. The proliferation and migration capacity of HSCs were assessed using 5-ethynyl-2'-deoxyuridine (EdU) incorporation and Transwell migration assays...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636389/tumor-microenvironment-responsive-multistaged-nanoplatform-for-systemic-rnai-and-cancer-therapy
#16
Xiaoding Xu, Phei Er Saw, Wei Tao, Yujing Li, Xiaoyuan Ji, Mikyung Yu, Morteza Mahmoudi, Jonathan Rasmussen, Dana Ayyash, Yuxiao Zhou, Omid C Farokhzad, Jinjun Shi
While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core...
June 21, 2017: Nano Letters
https://www.readbyqxmd.com/read/28636190/uchl1-promotes-invasion-of-breast-cancer-cells-through-activating-akt-signaling-pathway
#17
Yanhong Luo, Jianfeng He, Chunlin Yang, Matthew Orange, Xingcong Ren, Nick Blair, Tao Tan, Jin-Ming Yang, Hua Zhu
As a de-ubiquitin enzyme, ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to be overexpressed in several human cancers. However, the function of UCH-L1 in invasion of breast cancers is still unclear. Here we report that the expression of UCH-L1 is significantly higher in cancer cells with higher invasive ability. While ectopic UCH-L1 expression failed to alter cell proliferation in MCF-7 cells, it caused a significant upregulation of cellular invasion. Furthermore, siRNA mediated knockdown of UCH-L1 led to suppression of invasion in UCH-L1 overexpressing MCF-7 cells...
June 21, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28636115/sirna-mediated-down-regulation-of-clic4-gene-inhibits-cell-proliferation-and-accelerates-cell-apoptosis-of-mouse-liver-cancer-hca-f-and-hca-p-cells
#18
Qiu-Yun Yu, Xin-Feng Zhou, Qing Xia, Jia Shen, Jia Yan, Jiu-Ting Zhu, Xiang Li, Ming Shu
This study explored the effects involved in silencing CLIC4 on apoptosis and proliferation of mouse liver cancer Hca-F and Hca-P cells. A CLIC4-target small interfering RNA (siRNA) was designed to compound into two individual complementary oligonucleotide chains. A process of annealing and connection to a pSilencer vector was followed by transfection with Hca-F and Hca-P cells. Quantitative real-time polymerase chain reaction and western blotting techniques were used to determine CLIC4 mRNA and protein expressions...
June 21, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28634844/thrombospondin-1-production-regulates-the-inflammatory-cytokine-secretion-in-thp-1-cells-through-nf-%C3%AE%C2%BAb-signaling-pathway
#19
Tian Xing, Yao Wang, Wen-Jie Ding, Yuan-Ling Li, Xiao-Dong Hu, Cong Wang, Ao Ding, Ji-Long Shen
Thrombospondin-1 (TSP-1) is upregulated in several inflammatory diseases. Recent data have shown that macrophages from TSP-1-deficient mice have a reduced inflammatory phenotype, suggesting that TSP-1 plays a part in macrophage activation. DNA microarray approach revealed that Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) may induce the enhanced TSP-1 expression in human monocytes, suggesting a role of TSP-1-mediated pathogenesis in periodontitis. Until recently, the function of TSP-1 has been a matter of debate...
June 20, 2017: Inflammation
https://www.readbyqxmd.com/read/28634229/akt-activation-by-ca2-calmodulin-dependent-protein-kinase-kinase-2-camkk2-in-ovarian-cancer-cells
#20
Angela M Gocher, Gissou Azabdaftari, Lindsey M Euscher, Shuhang Dai, Loukia G Karacosta, Thomas F Franke, Arthur M Edelman
Hyperactivation of Akt is associated with oncogenic changes in the growth, survival and chemoresistance of cancer cells. The PI3K/Phosphoinositide-dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr308. We observed that Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (beta) (CaMKK2) is highly expressed in high-grade serous ovarian cancer and investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, Caov-3)...
June 20, 2017: Journal of Biological Chemistry
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