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Dna decoy

Julien Mamet, Scott Harris, Michael Klukinov, David C Yeomans, Renee R Donahue, Brad K Taylor, Kelly Eddinger, Tony Yaksh, Donald C Manning
Background AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord...
January 2017: Molecular Pain
Aveline Filliol, Claire Piquet-Pellorce, Céline Raguénès-Nicol, Sarah Dion, Muhammad Farooq, Catherine Lucas-Clerc, Peter Vandenabeele, Mathieu J M Bertrand, Jacques Le Seyec, Michel Samson
BACKGROUND & AIMS: The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of pathogen associated molecular patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the receptor interacting protein kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis...
January 11, 2017: Journal of Hepatology
Christopher T Esapa, Sian E Piret, M Andrew Nesbit, Nellie Y Loh, Gethin Thomas, Peter I Croucher, Matthew A Brown, Steve D M Brown, Roger D Cox, Rajesh V Thakker
Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry...
2016: PloS One
Thomas Thibault, Jeril Degrouard, Patrick Baril, Chantal Pichon, Patrick Midoux, Jean-Marc Malinge
Double-stranded DNA minicircles of less than 1000 bp in length have great interest in both fundamental research and therapeutic applications. Although minicircles have shown promising activity in gene therapy thanks to their good biostability and better intracellular trafficking, minicircles down to 250 bp in size have not yet been investigated from the test tube to the cell for lack of an efficient production method. Herein, we report a novel versatile plasmid-free method for the production of DNA minicircles comprising fewer than 250 bp...
March 17, 2017: Nucleic Acids Research
Mihalis S Kariolis, Yu Rebecca Miao, Anh Diep, Shannon E Nash, Monica M Olcina, Dadi Jiang, Douglas S Jones, Shiven Kapur, Irimpan I Mathews, Albert C Koong, Erinn B Rankin, Jennifer R Cochran, Amato J Giaccia
The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6...
January 3, 2017: Journal of Clinical Investigation
Min-Jung Park, Seung Hoon Lee, Su-Jin Moon, Jung-Ah Lee, Eun-Jung Lee, Eun-Kyung Kim, Jin-Sil Park, Jennifer Lee, Jun-Ki Min, Seok Jung Kim, Sung-Hwan Park, Mi-La Cho
Mesenchymal stem cells (MSCs) are attractive agents for cellular therapy in rheumatoid arthritis (RA). The receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for endogenous inflammatory ligands. Soluble RAGE (sRAGE) is a truncated form of RAGE that functions as a decoy and acts as an anti-inflammatory molecule. The aim of this study was to determine whether sRAGE has therapeutic effects and the mechanisms active in sRAGE-overexpressing MSCs (sRAGE-MSCs) in an experimental model of RA...
November 2, 2016: Scientific Reports
Aravind Chandrasekaran, Justin Chan, Carmay Lim, Lee-Wei Yang
Structure-encoded conformational dynamics are crucial for biomolecular functions. However, there is insufficient evidence to support the notion that dynamics play a role in guiding protein-nucleic acid interactions. Here, we show that protein-DNA docking orientation is a function of protein intrinsic dynamics, but the binding site itself does not display unique patterns in the examined spectrum of motions. This revelation is made possible by a novel technique that locates "dynamics interfaces" in proteins across which protein parts are anticorrelated in their slowest dynamics...
November 8, 2016: Journal of Chemical Theory and Computation
Zhipeng Wang, Davit A Potoyan, Peter G Wolynes
Eukaryotic transcription factors in the NF-κB family are central components of an extensive genetic network that activates cellular responses to inflammation and to a host of other external stressors. This network consists of feedback loops that involve the inhibitor IκBα, numerous downstream functional targets, and still more numerous binding sites that do not appear to be directly functional. Under steady stimulation, the regulatory network of NF-κB becomes oscillatory, and temporal patterns of NF-κB pulses appear to govern the patterns of downstream gene expression needed for immune response...
September 2016: Journal of the Royal Society, Interface
Amanda L Edwards, Dimphna H Meijer, Rachel M Guerra, Remco J Molenaar, John A Alberta, Federico Bernal, Gregory H Bird, Charles D Stiles, Loren D Walensky
Basic helix-loop-helix (bHLH) transcription factors play critical roles in organism development and disease by regulating cell proliferation and differentiation. Transcriptional activity, whether by bHLH homo- or heterodimerization, is dependent on protein-protein and protein-DNA interactions mediated by α-helices. Thus, α-helical decoys have been proposed as potential targeted therapies for pathologic bHLH transcription. Here, we developed a library of stabilized α-helices of OLIG2 (SAH-OLIG2) to test the capacity of hydrocarbon-stapled peptides to disrupt OLIG2 homodimerization, which drives the development and chemoresistance of glioblastoma multiforme, one of the deadliest forms of human brain cancer...
November 18, 2016: ACS Chemical Biology
Sonya VanPatten, Shan Sun, Mingzhu He, Kai Fan Cheng, Ahmad Altiti, Angelos Papatheodorou, Czeslawa Kowal, Venkatesh Jeganathan, James M Crawford, Ona Bloom, Bruce T Volpe, Christian Grant, Nathalie Meurice, Thomas R Coleman, Betty Diamond, Yousef Al-Abed
Systemic lupus erythematosus is an autoimmune disease that can affect numerous tissues and is characterized by the production of nuclear antigen-directed autoantibodies (e.g., anti-dsDNA). Using a combination of virtual and ELISA-based screens, we made the intriguing discovery that several HIV-protease inhibitors can function as decoy antigens to specifically inhibit the binding of anti-dsDNA antibodies to target antigens such as dsDNA and pentapeptide DWEYS. Computational modeling revealed that HIV-protease inhibitors comprised structural features present in DWEYS and predicted that analogues containing more flexible backbones would possess preferred binding characteristics...
October 13, 2016: Journal of Medicinal Chemistry
Yang-Ye Hu, Yuan Wang, Shuang Liang, Xue-Li Yu, Lei Zhang, Lin-Yin Feng, Yi Feng
Over-activated microglia during stroke has been documented to aggravate brain damage. Our previous studies showed that senkyunolide I (SEI) exerted anti-inflammatory effects against endotoxin insult in vitro and ameliorative effects on cerebral ischemia/reperfusion (I/R) injury in vivo. Using oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic stroke, we here investigated the anti-inflammatory effect of SEI on microglial cells and explored the underlying mechanisms. OGD for 3h followed by reoxygenation for 12h significantly enhanced the release of pro-inflammatory cytokines and expressions of inflammation-related enzymes in BV-2 cells, which was inhibited by pretreatment with SEI...
August 11, 2016: Brain Research
A D Ranzi, G O Introíni, J C Prolla, R Brackmann, N C Bassani, A C Pasqualotto, C G Bica
OBJECTIVE: The purpose of the present, prospective, cohort study was to monitor urine cytology samples from recipients of renal transplants to search for the occurrence of decoy cells and degenerated inclusion-bearing cells with an aim to correlate the existence of these cells with molecular detection of polyomavirus BK (BKV) DNA in urine. MATERIAL AND METHODS: This study included patients who underwent renal transplantation. Patients had their urine tested quarterly, during the first year post-transplantation, for the presence of decoy cells and degenerated cells, as well as by quantitative determination of BKV load in the urine and plasma...
April 2017: Cytopathology: Official Journal of the British Society for Clinical Cytology
Catherine A Kemme, Dan Nguyen, Abhijnan Chattopadhyay, Junji Iwahara
Eukaryotic genomic DNA contains numerous high-affinity sites for transcription factors. Only a small fraction of these sites directly regulates target genes. Other high-affinity sites can serve as naturally present decoys that sequester transcription factors. Such natural decoys in genomic DNA may provide novel regulatory mechanisms for transcription factors.
August 7, 2016: Transcription
Jingqiu Li, Haihua Tian, Jie Yang, Zhaohui Gong
The revolutionary findings in nonprotein-coding part of human genome analysis have revealed a large number of RNA transcripts longer than 200 nucleotides that lack coding protein function, termed long noncoding RNAs (lncRNAs). Recently, accumulating shreds of evidence suggest that lncRNAs are widely distributed in human genome and deeply involved in cellular activities such as cell growth, proliferation, and apoptosis. Generally, lncRNAs regulate cell behaviors by targeting cell cycle-associated cyclins, cyclin-dependent kinases (CDKs), and/or CDK inhibitors...
September 2016: DNA and Cell Biology
Xin Liu, Guo Fu, Zhenyu Ji, Xiabing Huang, Cong Ding, Hui Jiang, Xiaolong Wang, Mingxuan Du, Ting Wang, Qiaozhen Kang
Asthma is a chronic inflammatory airway disease. It was prevalently perceived that Th2 cells played the crucial role in asthma pathogenesis, which has been identified as the important target for anti-asthma therapy. The soluble IL-4 receptor (sIL-4R), which is the decoy receptor for Th2 cytokine IL-4, has been reported to be effective in treating asthma in phase I/II clinical trail. To develop more efficacious anti-asthma agent, we attempt to test whether the Helicobacter pylori neutrophil-activating protein (HP-NAP), a novel TLR2 agonist, would enhance the efficacy of sIL-4R in anti-asthma therapy...
August 2016: Inflammation
Jing Hu, Daniah Al-Waili, Aishlin Hassan, Guo-Chang Fan, Mei Xin, Jiukuan Hao
The present study generated a novel DNA complex to specifically target endothelial NF-κB to inhibit cerebral vascular inflammation. This DNA complex (GS24-NFκB) contains a DNA decoy which inhibits NF-κB activity, and a DNA aptamer (GS-24), a ligand of transferrin receptor (TfR), which allows for targeted delivery of the DNA decoy into cells. The results indicate that GS24-NFκB was successfully delivered into a murine brain-derived endothelial cell line, bEND5, and inhibited inflammatory responses induced by tumor necrosis factor α (TNF-α) or oxygen-glucose deprivation/re-oxygenation (OGD/R) via down-regulation of the nuclear NF-κB subunit, p65, as well as its downstream inflammatory cytokines, inter-cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1)...
August 4, 2016: Neuroscience
N H Abd Ellah, L Taylor, N Ayres, M M Elmahdy, G N Fetih, H N Jones, E A Ibrahim, G M Pauletti
Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethylmethacrylate) diblock copolymer (pHPMA-b-pDMAEMA)...
2016: Cancer Gene Therapy
Kannan Sridharan, Nithya Jaideep Gogtay
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are simple linear polymers that have been the subject of considerable research in the last two decades and have now moved into the realm of being stand-alone therapeutic agents. Much of this has stemmed from the appreciation that they carry out myriad functions that go beyond mere storage of genetic information and protein synthesis. Therapy with nucleic acids either uses unmodified DNA or RNA or closely related compounds. From both a development and regulatory perspective, they fall somewhere between small molecules and biologics...
September 2016: British Journal of Clinical Pharmacology
Nicholas B Struntz, Daniel A Harki
Catch and release DNA decoys (CRDDs) are a new class of non-natural DNA probes that capture and dissociate from DNA-binding proteins using a light trigger. Photolytic cleavage of non-natural nucleobases in the CRDD yields abasic sites and truncation products that lower the affinity of the CRDD for its protein target. Herein, we demonstrate the ability of the first-generation CRDD to bind and release NF-κB proteins. This platform technology should be applicable to other DNA-binding proteins by modification of the target sequence...
June 17, 2016: ACS Chemical Biology
Taseem A Mokhdomi, Shoiab Bukhari, Naveed Anjum Chikan, Asif Amin, Asrar H Wafai, Sajad H Wani, Nisar A Chowdri, Raies A Qadri
Vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in diverse pathologies, including cancers. Although VEGFR-1 is considered as functionally impaired kinase, its decoy characteristics make it an important regulator of VEGFR-mediated signaling, particularly in tumor angiogenesis. VEGFR-1 conveys signaling via its tyrosine kinase (TK) domain whose activation is regulated by phosphorylation of specific tyrosine residues. Thus dysregulation of VEGFR-1 signaling, as reported in most of the cancers, might be a consequence of altered phosphorylation that could be attributed to genotypic variations in its TK domain...
August 2016: European Journal of Human Genetics: EJHG
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