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Antisense protein

Osmond J D'Cruz, Sanjive Qazi, Larn Hwang, Kevin Ng, Vuong Trieu
Background: Overexpression of the cytokine - transforming growth factor-beta 2 (TGF-β2) - has been implicated in the malignant progression of pancreatic cancer (PAC). OT-101 (trabedersen) is an antisense oligodeoxynucleotide designed to target the human TGF-β2 mRNA. In a Phase I/II study, OT-101 treatment with subsequent chemotherapy was characterized by outstanding overall survival (OS) in patients with PAC. Objective: This study sought to identify 1) co-regulated sets of cyto-/chemokines; 2) potential mechanisms that link TGF-β receptor type 2 receptor inhibition that may result in the induction of a cytokine storm; and 3) predictive biomarkers for OS outcome in OT-101-treated patients with PAC...
2018: OncoTargets and Therapy
Bo Wei, Qiao Lin, Ya-Ge Ji, Yi-Can Zhao, Li-Na Ding, Wen-Juan Zhou, Li-Hua Zhang, Chuan-Yu Gao, Wen Zhao
BACKGROUND AND PURPOSE: Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin (LUT), a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanism, especially the role of LUT on the antioxidant enzymes (e.g. peroxiredoxin family, PRXs), remains elusive. EXPERIMENTAL APPROACH: The current study was designed to evaluate the impact of LUT on MI/R injury in vivo and in vitro, as well as the underlying mechanism with a focus on PRXs signaling...
May 21, 2018: British Journal of Pharmacology
Christina Maria Steger, Nikolaos Bonaros, Ralf Joachim Rieker, Johannes Bonatti, Thomas Schachner
Gene therapy for avoiding intimal hyperplasia of vein grafts after coronary artery bypass grafting is still discussed controversially. A promising application of gene therapy in vein grafts is the use of antisense oligonucleotides to block the expression of genes encoding cell cycle regulatory proteins in vascular smooth muscle cells. C-myc, either directly or by regulating the expression of other proteins, controls cell proliferation, apoptosis and cell survival, tissue remodeling, angiogenesis, cell metabolism, production of inflammatory and anti-inflammatory cytokines, and also participates in cell transformation...
May 15, 2018: Experimental and Molecular Pathology
Vance L Trudeau
Genetic manipulation of teleost endocrine systems started with transgenic overexpression of pituitary growth hormone. Such strategies enhance growth and reduce fertility, but the fish still breed. Genome editing using transcription activator-like effector nuclease in zebrafish and medaka has established the role of follicle stimulating hormone for gonadal development and luteinizing hormone for ovulation. Attempts to genetically manipulate the hypophysiotropic neuropeptidergic systems have been less successful...
2018: Frontiers in Neuroscience
Cyrinne Achour, Francesca Aguilo
High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
Joshua Lee, Yusuke Echigoya, William Duddy, Takashi Saito, Yoshitsugu Aoki, Shin'ichi Takeda, Toshifumi Yokota
Antisense-mediated exon skipping has made significant progress as a therapeutic platform in recent years, especially in the case of Duchenne muscular dystrophy (DMD). Despite FDA approval of eteplirsen-the first-ever antisense drug clinically marketed for DMD-exon skipping therapy still faces the significant hurdles of limited applicability and unknown truncated protein function. In-frame exon skipping of dystrophin exons 45-55 represents a significant approach to treating DMD, as a large proportion of patients harbor mutations within this "hotspot" region...
2018: PloS One
Lucía Echevarría, Philippine Aupy, Aurélie Goyenvalle
Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle wasting that has currently no cure. Exon-skipping strategy represents one of the most promising therapeutic approaches that aims to restore expression of a shorter but functional dystrophin protein. The antisense field has remarkably progress over the last years with recent accelerated approval of the first ASO-based therapy for DMD, Exondys 51, though the therapeutic benefit remains to be proven in patients. Despite clinical advances, the poor effective delivery to target all muscle remains the main hurdle for antisense drug therapy...
May 16, 2018: Human Molecular Genetics
Peng Qin, Ann E Loraine, Sheila McCormick
Background: cis-NATs ( cis-natural antisense transcripts ) are transcribed from opposite strands of adjacent genes and have been shown to regulate gene expression by generating small RNAs from the overlapping region. cis-NATs are important for plant development and resistance to pathogens and stress. Several genome-wide investigations identified a number of cis-NAT pairs, but these investigations predicted cis-NATS using expression data from bulk samples that included lots of cell types. Some cis-NAT pairs identified from those investigations might not be functional, because both transcripts of cis-NAT pairs need to be co-expressed in the same cell...
2018: F1000Research
Sally A Moody
Microinjecting lineage tracers into a single blastomere in the normal, intact embryo identifies the repertoire of cell types derived from it. In order to reveal the full developmental potential of that blastomere or identify the mechanisms by which its fate is determined, one needs to modify its gene expression under controlled experimental conditions. One method by which this is easily accomplished in Xenopus is by microinjecting synthetic mRNAs or antisense oligonucleotides into an identified blastomere to target altered gene expression specifically to its lineage...
May 16, 2018: Cold Spring Harbor Protocols
Umbertina Conti Reed, Edmar Zanoteli
Spinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector...
April 2018: Arquivos de Neuro-psiquiatria
Ming-Rong Cao, Ze-Ping Han, Ji-Ming Liu, Yu-Guang Li, Yu-Bing Lv, Jia-Bin Zhou, Jin-Hua He
Computational analysis and bioinformatics have significantly advanced the ability of researchers to process and analyze biological data. Molecular data from human and model organisms may facilitate drug target validation and identification of biomarkers with increased predictive accuracy. The aim of the present study was to investigate the function of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) using online databases, and to predict their regulatory mechanism. HCC-associated lncRNAs, their downstream transcription factors and microRNAs (miRNAs/miRs), as well as the HCC-associated target genes, were identified using online databases...
May 2018: Oncology Letters
Jinlu Hu, Jiao Zhan, Hui Chen, Chenliu He, Huaixing Cang, Qiang Wang
Pili are found on the surface of many bacteria and play important roles in cell motility, pathogenesis, biofilm formation, and sensing and reacting to environmental changes. Cell motility in the model cyanobacterium Synechocystis sp. PCC 6803 relies on expression of the putative pilA9-pilA10-pilA11-slr2018 operon. In this study, we identified the antisense RNA PilR encoded in the noncoding strand of the prepilin-encoding gene pilA11 . Analysis of overexpressor [PilR(+)] and suppressor [PilR(-)] mutant strains revealed that PilR is a direct negative regulator of PilA11 protein...
2018: Frontiers in Microbiology
Johannes Winkler
Although recent clinical successes of antisense, splice-switching, and siRNA oligonucleotides have established the therapeutic utility of this novel class of medicines, the efficient systemic application for non-liver targets remains elusive. Exploitation of active receptor-mediated targeting followed by efficient and productive cellular uptake is required for enabling the therapy of extrahepatic diseases on the expressional level. Evasion of liver accumulation and organ-specific targeting and also efficient cytosolic delivery after endosomal internalization are currently insufficiently solved issues...
May 7, 2018: Nucleic Acid Therapeutics
Yuchen Nan, Yan-Jin Zhang
Phosphorodiamidate morpholino oligomers (PMO) are short single-stranded DNA analogs that are built upon a backbone of morpholine rings connected by phosphorodiamidate linkages. As uncharged nucleic acid analogs, PMO bind to complementary sequences of target mRNA by Watson-Crick base pairing to block protein translation through steric blockade. PMO interference of viral protein translation operates independently of RNase H. Meanwhile, PMO are resistant to a variety of enzymes present in biologic fluids, a characteristic that makes them highly suitable for in vivo applications...
2018: Frontiers in Microbiology
Lijia Yu, Duanwei Liang, Changmai Chen, XinJing Tang
RNA interference (RNAi) mediated gene silencing holds significant promise in gene therapy. It is very important to manually regulate the activity of small interference RNAs (siRNAs) in the controllable mode. Here, we designed and synthesized a series of caged siRNAs through bioconjugation of cyclo(Arg-Gly-Asp-DPhe-Lys) (cRGD) peptide to the 5' end of siRNA through a photolabile linker. These cRGD modified caged siRNAs allowed for precise light-regulation of gene expression of two exogenous reporter genes (firefly luciferase and green fluorescent protein, GFP) and an endogenous gene (the mitosis motor protein, Eg5) in the integrin αvβ3 positive cells...
May 4, 2018: Biomacromolecules
Rami A Al-Horani, Daniel K Afosah
Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding...
May 4, 2018: Medicinal Research Reviews
Tamjid A Chowdhury, Chris Koceja, Shahram Eisa-Beygi, Benjamin P Kleinstiver, Suresh N Kumar, Chien-Wei Lin, Keguo Li, Shubhangi Prabhudesai, J Keith Joung, Ramani Ramchandran
OBJECTIVE: Tie1 (tyrosine kinase containing immunoglobulin and epidermal growth factor homology 1), an endothelial and hematopoietic cell-specific receptor tyrosine kinase, is an important regulator of angiogenesis and critical for maintaining vascular integrity. The post-transcriptional regulation of tie1 mRNA expression is not understood, but it might partly explain Tie1's differential expression pattern in endothelium. Following up on our previous work that identified natural antisense transcripts from the tie1 locus- tie1 antisense ( tie1AS ), which regulates tie1 mRNA levels in zebrafish-we attempted to identify the mechanism of this regulation...
May 3, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Iliana Michailidou, Aldo Jongejan, Jeroen P Vreijling, Theodosia Georgakopoulou, Marit B de Wissel, Ruud A Wolterman, Patrick Ruizendaal, Ngaisah Klar-Mohamad, Anita E Grootemaat, Daisy I Picavet, Vinod Kumar, Cees van Kooten, Trent M Woodruff, B Paul Morgan, Nicole N van der Wel, Valeria Ramaglia, Kees Fluiter, Frank Baas
The complement system is a key driver of neuroinflammation. Activation of complement by all pathways, results in the formation of the anaphylatoxin C5a and the membrane attack complex (MAC). Both initiate pro-inflammatory responses which can contribute to neurological disease. In this study, we delineate the specific roles of C5a receptor signaling and MAC formation during the progression of experimental autoimmune encephalomyelitis (EAE)-mediated neuroinflammation. MAC inhibition was achieved by subcutaneous administration of an antisense oligonucleotide specifically targeting murine C6 mRNA (5 mg/kg)...
May 3, 2018: Acta Neuropathologica Communications
Alejandro Garanto, Saskia D van der Velde-Visser, Frans P M Cremers, Rob W J Collin
Choroideremia is a progressive genetic eye disorder caused by mutations in the CHM gene that encodes the Rab escort protein-1 (REP-1). One of the many CHM mutations described so far is a deep-intronic variant, c.315-4587T>A, that creates a novel splice acceptor site resulting in the insertion of a 98-bp pseudoexon in the CHM transcript. Antisense oligonucleotides (AONs) are a potential therapeutic tool for correcting splice defects, as they have the properties to bind to the pre-mRNA and redirect the splicing process...
2018: Advances in Experimental Medicine and Biology
Justin M Wolfe, Colin M Fadzen, Zi-Ning Choo, Rebecca L Holden, Monica Yao, Gunnar J Hanson, Bradley L Pentelute
Cell-penetrating peptides (CPPs) can facilitate the intracellular delivery of large therapeutically relevant molecules, including proteins and oligonucleotides. Although hundreds of CPP sequences are described in the literature, predicting efficacious sequences remains difficult. Here, we focus specifically on predicting CPPs for the delivery of phosphorodiamidate morpholino oligonucleotides (PMOs), a compelling type of antisense therapeutic that has recently been FDA approved for the treatment of Duchenne muscular dystrophy...
April 25, 2018: ACS Central Science
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