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Fluoro RNA

Hiroshi Sawayama, Yoko Ogata, Takatsugu Ishimoto, Kosuke Mima, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Glucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors support the feasibility of GLUT1 inhibition as a treatment for various cancers. The anti-proliferative effects of GLUT1-specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro- and anti-proliferative signaling and effector molecules was examined by western blotting and qRT-PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy...
March 12, 2019: Cancer Science
Chao Li, Shuo Huang, Jun Guo, Cheng Wang, Zhichao Huang, Ruimin Huang, Liang Liu, Sheng Liang, Hui Wang
PURPOSE: This study aims to explore whether 4-(2S,4R)-[18 F]fluoroglutamine (4-[18 F]FGln) positron emission tomography (PET) imaging is helpful in identifying and monitoring MYCN-amplified neuroblastoma by enhanced glutamine metabolism. PROCEDURES: Cell uptake studies and dynamic small-animal PET studies of 4-[18 F]FGln and 2-deoxy-2-[18 F]fluoro-D-glucose ([18 F]FDG) were conducted in human MYCN-amplified (IMR-32 and SK-N-BE (2) cells) and non-MYCN-amplified (SH-SY5Y cell) neuroblastoma cells and animal models...
March 8, 2019: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Dong You, Hong You
OBJECTIVE: This study was performed to investigate effect of long non-coding RNA (lncRNA) MEG3 on nerve growth and neurological impairment in a rat model after cerebral ischemia-reperfusion injury (IRI) through the Wnt/β-catenin signaling pathway. METHODS: Rat models of middle cerebral artery occlusion (MCAO) were established to stimulate an environment of cerebral IRI. The modeled rats were subjected to negative control (NC), MEG3, si-MEG3, classical Wnt pathway inhibitor DKK1 or classical Wnt pathway activator LiCl to validate the effect of MEG3 on neurological impairment and nerve growth...
March 2019: Biomedicine & Pharmacotherapy
Seema Mengshetti Bagmare, Longhu Zhou, Ozkan Sari, Coralie De Schutter, Hongwang Zhang, Jong Hyun Cho, Sijia Tao, Leda Bassit, Kiran Verma, Robert Domaoal, Maryam Ehteshami, Yong Jiang, Reuben Ovadia, Mahesh Kasthuri, Olivia Ollinger Russell, Tamara McBrayer, Tony Whitaker, Judy Pattassery, Maria Luz Pascual, Lothar Uher, Biing Y Lin, Sam Lee, Franck Amblard, Steven J Coats, Raymond Felix Schinazi
HCV nucleoside inhibitors display pan-genotypic activity, a high barrier to selection of resistant virus and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-D-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM...
January 17, 2019: Journal of Medicinal Chemistry
Wenchao Liu, Ran Li, Jian Yin, Shenquan Guo, Yunchang Chen, Haiyan Fan, Gancheng Li, Zhenjun Li, Xifeng Li, Xin Zhang, Xuying He, Chuanzhi Duan
BACKGROUND: Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potential mechanism mediated by Notch1 signaling pathway inhibition...
January 15, 2019: Journal of Neuroinflammation
Lianhua Zhao, John H Zhang, Prativa Sherchan, Paul R Krafft, Wei Zhao, Sa Wang, Shengpan Chen, Zaiyu Guo, Jiping Tang
Targeting neuronal apoptosis after intracerebral hemorrhage (ICH) may be an important therapeutic strategy for ICH patients. Emerging evidence indicates that C1q/TNF-Related Protein 9 (CTRP9), a newly discovered adiponectin receptor agonist, exerts neuroprotection in cerebrovascular disease. The aim of this study was to investigate the anti-apoptotic role of CTRP9 after experimental ICH and to explore the underlying molecular mechanisms. ICH was induced in mice via intrastriatal injection of bacterial collagenase...
January 14, 2019: Cell Transplantation
D S Novopashina, A S Nazarov, M A Vorobjeva, M S Kuprushkin, A S Davydova, A A Lomzov, D V Pyshnyi, S Altman, A G Venyaminova
The ability of a series of novel modified external guide sequences (EGS oligonucleotides) to induce the hydrolysis of target RNA with bacterial ribonuclease P has been studied; the most efficient modification variants have been selected. We have found patterns of the oligonucleotide sugar-phosphate backbone modi-fications that enhance oligonucleotide stability in the biological environment and do not violate the ability to interact with the enzyme and induce the RNA hydrolysis. It has been shown that analogues of EGS oligonucleotides selectively modified at 2'-position (2'-O-methyl and 2'-fluoro) or at internucleotide phosphates (phosphoryl guanidines) can be used for the addressed cleavage of a model RNA target by bacterial RNase P...
November 2018: Molekuliarnaia Biologiia
Jasmin Aldag, Tina Persson, Roland K Hartmann
Lipopolysaccaride binding protein (LBP), a glycosylated acute phase protein, plays an important role in the pathophysiology of sepsis. LBP binds with high affinity to the lipid part of bacterial lipopolysaccaride (LPS). Inhibition of the LPS-LBP interaction or blockage of LBP-mediated transfer of LPS monomers to CD14 may be therapeutical strategies to prevent septic shock. LBP is also of interest as a biomarker to identify septic patients at high risk for death, as LBP levels are elevated during early stages of severe sepsis...
December 5, 2018: International Journal of Molecular Sciences
I Olaposi Omotuyi, Oyekanmi Nash, David Safronetz, A Ayodeji Ojo, H Tomisin Ogunwa, S Niyi Delakun
Lassa virus infection is clinically characterized by multi-organ failure in humans. Without an FDA-approved vaccine, ribavirin is the frontline drug for treatment but with attendant toxicities. 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is an emerging alternative drug with proven anti-Lassa virus activity in experimental model. One of the mechanisms of action is its incorporation into nascent single strand RNA (ssRNA) which forms complex with Lassa nucleoprotein (LASV-NP). Here, using Molecular Dynamics simulation, the structural and electrostatics changes associated with LASV-NP- ssRNA complex has been studied when none, one or four of its bases has been substituted with T-705...
December 10, 2018: Chemical Biology & Drug Design
Daniel O'Reilly, Zachary J Kartje, Eman A Ageely, Elise Malek-Adamian, Maryam Habibian, Annabelle Schofield, Christopher L Barkau, Kushal J Rohilla, Lauren B DeRossett, Austin T Weigle, Masad J Damha, Keith T Gagnon
CRISPR (clustered regularly interspaced short palindromic repeat) endonucleases are at the forefront of biotechnology, synthetic biology and gene editing. Methods for controlling enzyme properties promise to improve existing applications and enable new technologies. CRISPR enzymes rely on RNA cofactors to guide catalysis. Therefore, chemical modification of the guide RNA can be used to characterize structure-activity relationships within CRISPR ribonucleoprotein (RNP) enzymes and identify compatible chemistries for controlling activity...
December 4, 2018: Nucleic Acids Research
Agota Aučynaitė, Rasa Rutkienė, Daiva Tauraitė, Rolandas Meškys, Jaunius Urbonavičius
Ribose methylation is among the most ubiquitous modifications found in RNA. 2'- O -methyluridine is found in rRNA, snRNA, snoRNA and tRNA of Archaea , Bacteria , and Eukaryota . Moreover, 2'- O -methylribonucleosides are promising starting materials for the production of nucleic acid-based drugs. Despite the countless possibilities of practical use for the metabolic enzymes associated with methylated nucleosides, there are very few reports regarding the metabolic fate and enzymes involved in the metabolism of 2'- O -alkyl nucleosides...
November 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
C I Edvard Smith, Rula Zain
Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, spliceswitching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNAdecoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. DNAtargeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines...
October 4, 2018: Annual Review of Pharmacology and Toxicology
Beatrice Paradiso, Michele Simonato, Gaetano Thiene, Anna Lavezzi
Formalin-fixed, paraffinembedded (FFPE) human brain tissues are very often stored in formalin for long time. Formalin fixation reduces immunostaining, and the DNA/RNA extraction from FFPE brain tissue becomes suboptimal. At present, there are different protocols of fixation and several procedures and kits to extract DNA/RNA from paraffin embedding tissue, but a gold standard protocol remains distant. In this study, we analyzed four types of fixation systems and compared histo and immuno-staining. Based on our results, we propose a modified method of combined fixation in formalin and formic acid for the autoptic adult brain to obtain easy, fast, safe and efficient immunolabelling of long-stored FFPE tissue...
August 27, 2018: European Journal of Histochemistry: EJH
Maja M Janas, Carole E Harbison, Victoria K Perry, Brenda Carito, Jessica E Sutherland, Akshay K Vaishnaw, Natalie D Keirstead, Garvin Warner
Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2'-O-methyl and 2'-deoxy-2'-fluoro ribose modifications...
August 23, 2018: Toxicologic Pathology
Stefanie Pektor, Lina Hilscher, Kerstin C Walzer, Isabelle Miederer, Nicole Bausbacher, Carmen Loquai, Mathias Schreckenberger, Ugur Sahin, Mustafa Diken, Matthias Miederer
BACKGROUND: [18 F]Fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI...
August 15, 2018: EJNMMI Research
Quentin Vicens, Estefanía Mondragón, Francis E Reyes, Philip Coish, Paul Aristoff, Judd Berman, Harpreet Kaur, Kevin W Kells, Phil Wickens, Jeffery Wilson, Robert C Gadwood, Heinrich J Schostarez, Robert K Suto, Kenneth F Blount, Robert T Batey
The flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative, 5FDQD, that protects mice against diarrhea-causing Clostridium difficile bacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis, and purification of derivatives; (3) in vitro testing for productive binding using two chemical probing methods; (4) in vitro transcription termination assays; and (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates...
September 20, 2018: ACS Chemical Biology
Toshifumi Kano, Yui Katsuragi, Yusuke Maeda, Yoshihito Ueno
Synthesis and properties of double-stranded RNAs (dsRNAs) and small interfering RNAs (siRNAs) containing 4'-C-aminoethyl-2'-deoxy-2'-fluorouridine are described. Thermal denaturation studies showed that incorporation of 4'-C-aminoethyl-2'-fluoro analog improved the thermal stabilities of dsRNAs and siRNAs compared to the corresponding 4'-C-aminoethyl-2'-O-methyl analog. siRNA incorporating eight 4'-aminoethyl-2'-fluoro analogs in the passenger strand showed sufficient RNAi activity at 1 nM concentration, which was similar to that of the unmodified siRNA...
August 15, 2018: Bioorganic & Medicinal Chemistry
Reka Agnes Haraszti, Rachael Miller, Marie-Cecile Didiot, Annabelle Biscans, Julia F Alterman, Matthew R Hassler, Loic Roux, Dimas Echeverria, Ellen Sapp, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Extracellular vesicles are promising delivery vesicles for therapeutic RNAs. Small interfering RNA (siRNA) conjugation to cholesterol enables efficient and reproducible loading of extracellular vesicles with the therapeutic cargo. siRNAs are typically chemically modified to fit an application. However, siRNA chemical modification pattern has not been specifically optimized for extracellular vesicle-mediated delivery. Here we used cholesterol-conjugated, hydrophobically modified asymmetric siRNAs (hsiRNAs) to evaluate the effect of backbone, 5'-phosphate, and linker chemical modifications on productive hsiRNA loading onto extracellular vesicles...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Johanna Huchting, Evelien Vanderlinden, Matthias Winkler, Hiba Nasser, Lieve Naesens, Chris Meier
We here disclose chemical synthesis of ribonucleoside 5'-monophosphate (RMP), -diphosphate (RDP), and -triphosphate (RTP) and cycloSal-, Di PPro-, and Tri PPPro nucleotide prodrugs of the antiviral pseudobase T-1105. Moreover, we include one nucleoside diphosphate prodrug of the chemically less stable T-705. We demonstrate efficient T-1105-RDP and -RTP release from the Di PPro and Tri PPPro compounds by esterase activation. Using crude enzyme extracts, we saw rapid phosphorylation of T-1105-RDP into T-1105-RTP...
July 3, 2018: Journal of Medicinal Chemistry
Xiaolong Wang, Jingnü Xian, Gang Chen, Haibo Peng
Oligonucleotides are widely used as effective tools to regulate gene expression and drugs for targeted gene therapy. Therefore, they are potentially useful for the treatment of viral, tumor and hereditary diseases. Therapeutic oligonucleotides include antisense oligonucleotide, small interference RNA (siRNA), Ribozyme, DNAzyme, anti-gene, CpG, decoy and aptamer. Therapeutic oligonucleotides usually carry certain modifications, such as phosphorothioates, fluoro or locked nucleic acids, to enhance the stability and specificity, and reduce the side-effects, because natural oligonucleotides have poor stability in vivo, low specificity and side effects...
May 25, 2018: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
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