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Antisense oligonucleotide

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https://www.readbyqxmd.com/read/28719898/role-of-mir-155-signal-pathway-in-regulating-podocyte-injury-induced-by-tgf-%C3%AE-1
#1
Xu Lin, Xintng Zhen, Haiting Huang, Haohao Wu, Yanwu You, Pengwei Guo, Xiangjun Gu, Fafen Yang
BACKGROUND/AIMS: Transforming growth factor beta 1 (TGF-β1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of miR-155 on podocyte injury induced by TGF-β1 and to determine further molecular mediators involved in the effects of miR-155. METHODS: Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-β1 treatment; TGF-β1 with miR-155 knockdown [using antisense oligonucleotides against miR-155 (ASO-miR-155)] and TGF-β1 with negative control antisense oligonucleotides (ASO-NC)...
July 18, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28716988/blood-pressure-lowering-and-safety-improvements-with-liver-angiotensinogen-inhibition-in-models-of-hypertension-and-kidney-injury
#2
Adam E Mullick, Steve T Yeh, Mark J Graham, Jeffery A Engelhardt, Thazha P Prakash, Rosanne M Crooke
Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade...
July 17, 2017: Hypertension
https://www.readbyqxmd.com/read/28707763/in-vivo-knockdown-of-antisense-noncoding-mitochondrial-rnas-by-a-lentiviral-encoded-shrna-inhibits-melanoma-tumor-growth-and-lung-colonization
#3
Manuel Varas-Godoy, Alvaro Lladser, Nicole Farfan, Claudio Villota, Jaime Villegas, Julio C Tapia, Luis O Burzio, Veronica A Burzio, Pablo D T Valenzuela
The family of non-coding mitochondrial RNAs (ncmtRNA) are differentially expressed according to proliferative status. Normal proliferating cells express sense (SncmtRNA) and antisense ncmtRNAs (ASncmtRNAs), whereas tumor cells express SncmtRNA and downregulate ASncmtRNAs. Knockdown of ASncmtRNAs with oligonucleotides induces apoptotic cell death of tumor cells, leaving normal cells unaffected, suggesting a potential application for developing a novel cancer therapy. In this study, we knocked down the ASncmtRNAs in melanoma cell lines with a lentiviral-encoded shRNA approach...
July 14, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28703575/a-novel-family-of-small-molecules-that-enhance-the-intracellular-delivery-and-pharmacological-effectiveness-of-antisense-and-splice-switching-oligonucleotides
#4
Ling Wang, Yamuna Ariyarathna, Xin Ming, Bing Yang, Lindsey I James, Silvia M Kreda, Melissa Porter, William Janzen, Rudolph L Juliano
The pharmacological effectiveness of oligonucleotides has been hampered by their tendency to remain entrapped in endosomes, thus limiting their access to cytosolic or nuclear targets. We have previously reported a group of small molecules that enhance the effects of oligonucleotides by causing their release from endosomes. Here, we describe a second novel family of oligonucleotide enhancing compounds (OECs) that is chemically distinct from the compounds reported previously. We demonstrate that these molecules substantially augment the actions of splice switching oligonucleotides (SSOs) and antisense oligonucleotides (ASOs) in cell culture...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28696185/in-vitro-evaluation-of-antisense-oligonucleotide-functionalized-core-shell-nanoparticles-loaded-with-%C3%AE-tocopherol-succinate
#5
Ebru Kilicay, Zeynep Karahaliloglu, Pınar Alpaslan, Baki Hazer, Emir Baki Denkbas
Antisense oligonucleotide (ASO)-conjugated-α-tocopherol succinate (TCS)-loaded-poly(lactic acid)-g-poly(ethylene glycol) nanoparticles (ASO-TCS-PLA-PEG NPs), with the ratio of polymer/TCS of 10:2.5, 10:5, 10:7 (w/w) were prepared for targeting cancer therapy. The amphiphilic PLA, amino terminated PEG graft copolymers were synthesized by ring opening polymerization reaction. Nanoparticles were produced by using double emulsion (w/o/w) solvent evaporation method. ASO-TCS-PLA-PEG NPs demonstrated satisfactory encapsulation and loading efficiency and size distribution...
July 11, 2017: Journal of Biomaterials Science. Polymer Edition
https://www.readbyqxmd.com/read/28674733/micrornas-modulate-core-clock-gene-expression-in-pancreatic-islets-during-early-postnatal-life-in-rats
#6
Cécile Jacovetti, Adriana Rodriguez-Trejo, Claudiane Guay, Jonathan Sobel, Sonia Gattesco, Volodymyr Petrenko, Camille Saini, Charna Dibner, Romano Regazzi
AIMS/HYPOTHESIS: Evidence continues to emerge detailing a fine-tuning of the regulation of metabolic processes and energy homeostasis by cell-autonomous circadian clocks. Pancreatic beta cell functional maturation occurs after birth and implies transcriptional changes triggered by a shift in the nutritional supply that occurs at weaning, enabling the adaptation of insulin secretion. So far, the developmental timing and exact mechanisms involved in the initiation of the circadian clock in the growing pancreatic islets have never been addressed...
July 4, 2017: Diabetologia
https://www.readbyqxmd.com/read/28673859/a-novel-penetratin-modified-complex-for-noninvasive-intraocular-delivery-of-antisense-oligonucleotides
#7
Lingyu Tai, Chang Liu, Kuan Jiang, Xishan Chen, Linglin Feng, Weisan Pan, Gang Wei, Weiyue Lu
Inhibition of gene expression by nucleic acids is a promising strategy in the treatment of ocular diseases. However, intraocular delivery of nucleic acids to the posterior ocular tissues remains a great challenge due to the presence of various biological barriers. To circumvent this problem, we established a novel penetratin (P) modified poly(amidoamine) dendrimer (D)/hyaluronic acid (H) complex to deliver antisense oligonucleotides (ASOs, O). Complexes (D/O, HD/O and PHD/O) were easily prepared and modification layers (hyaluronic acid and penetratin) were respectively absorbed on the surface via electrostatic interaction...
June 30, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28670289/non-coding-rna-contribution-to-thoracic-and-abdominal-aortic-aneurysm-disease-development-and-progression
#8
REVIEW
Yuhuang Li, Lars Maegdefessel
Multiple research groups have started to uncover the complex genetic and epigenetic machinery necessary to maintain cardiovascular homeostasis. In particular, the key contribution of non-coding RNAs (ncRNAs) in regulating gene expression has recently received great attention. Aneurysms in varying locations of the aorta are defined as permanent dilations, predisposing to the fatal consequence of rupture. The characteristic pathology of an aneurysm is characterized by progressive vessel wall dilation, promoted by dying vascular smooth muscle cells and limited proliferation, as well as impaired synthesis and degradation of extracellular matrix components, which at least partially is the result of transmural inflammation and its disruptive effect on vessel wall homeostasis...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28667529/unbiased-race-based-massive-parallel-surveys-of-human-iga-antibody-repertoires
#9
Hanane El Bannoudi, Céline Anquetil, Marc J Braunstein, Sergei L Kosakovsky Pond, Gregg J Silverman
For investigations of human B-cell receptor (BCR) repertoires, we have developed a protocol for large-scale surveys of human antibody heavy chain (VH) rearrangements. Here we study IgA repertoires, as more IgA antibodies are synthesized in the human body on a daily level than all other isotypes combined. In fact, IgA is secreted at all mucosal surfaces, and it is also secreted in the perspiration that coats our cutaneous surfaces. In these studies we can characterize the IgA clonal diversity of B-cell populations obtained from any donor...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28666875/in-vitro-and-in-vivo-inhibition-of-proangiogenic-retinal-phenotype-by-an-antisense-oligonucleotide-downregulating-upar-expression
#10
Matteo Lulli, Maurizio Cammalleri, Irene Granucci, Ewa Witort, Federico Di Gesualdo, Antonella Lupia, Rosa Loffredo, Giovanni Casini, Massimo Dal Monte, Sergio Capaccioli
Neoangiogenesis is the main pathogenic event involved in a variety of retinal diseases. It has been recently demonstrated that inhibiting the urokinase-type plasminogen activator receptor (uPAR) results in reduced angiogenesis in a mouse model of oxygen-induced retinopathy (OIR), establishing uPAR as a therapeutic target in proliferative retinopathies. Here, we evaluated, in cultured human retinal endothelial cells (HRECs) and in OIR mice, the potential of a specific antisense oligodeoxyribonucleotide (ASO) in blocking the synthesis of uPAR and in providing antiangiogenic effects...
June 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28663102/rnase-h1-dependent-antisense-oligonucleotides-are-robustly-active-in-directing-rna-cleavage-in-both-the-cytoplasm-and-the-nucleus
#11
Xue-Hai Liang, Hong Sun, Joshua G Nichols, Stanley T Crooke
RNase H1-dependent antisense oligonucleotides (ASOs) are active in reducing levels of both cytoplasmic mRNAs and nuclear retained RNAs. Although ASO activity in the nucleus has been well demonstrated, the cytoplasmic activity of ASOs is less clear. Using kinetic and subcellular fractionation studies, we evaluated ASO activity in the cytoplasm. Upon transfection, ASOs targeting exonic regions rapidly reduced cytoplasmically enriched mRNAs, whereas an intron-targeting ASO that only degrades the nuclear pre-mRNA reduced mRNA levels at a slower rate, similar to normal mRNA decay...
June 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28661486/the-role-of-map2-kinases-and-p38-kinase-in-acute-murine-liver-injury-models
#12
Jun Zhang, Robert W M Min, Khanh Le, Sheng Zhou, Mariam Aghajan, Tin A Than, Sanda Win, Neil Kaplowitz
c-Jun N-terminal kinase (JNK) mediates hepatotoxicity through interaction of its phospho-activated form with a mitochondrial outer membrane protein, Sh3bp5 or Sab, leading to dephosphorylation of intermembrane Src and consequent impaired mitochondrial respiration and enhanced ROS release. ROS production from mitochondria activates MAP3 kinases, such as MLK3 and ASK1, which continue to activate a pathway to sustain JNK activation, and amplifies the toxic effect of acetaminophen (APAP) and TNF/galactosamine (TNF/GalN)...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28660478/drugs-in-development-for-hepatitis-b
#13
REVIEW
Altaf Dawood, Syed Abdul Basit, Mahendran Jayaraj, Robert G Gish
With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions...
June 28, 2017: Drugs
https://www.readbyqxmd.com/read/28655327/advances-in-the-delivery-of-rna-therapeutics-from-concept-to-clinical-reality
#14
REVIEW
James C Kaczmarek, Piotr S Kowalski, Daniel G Anderson
The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation...
June 27, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28646206/crispr-cas9-mediated-genome-editing-via-postnatal-administration-of-aav-vector-cures-haemophilia-b-mice
#15
Tsukasa Ohmori, Yasumitsu Nagao, Hiroaki Mizukami, Asuka Sakata, Shin-Ichi Muramatsu, Keiya Ozawa, Shin-Ichi Tominaga, Yutaka Hanazono, Satoshi Nishimura, Osamu Nureki, Yoichi Sakata
Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28641935/fatty-acid-modified-gapmer-antisense-oligonucleotide-and-serum-albumin-constructs-for-pharmacokinetic-modulation
#16
Michael Lykke Hvam, Yunpeng Cai, Frederik Dagnæs-Hansen, Jesper Sejrup Nielsen, Jesper Wengel, Jørgen Kjems, Kenneth A Howard
Delivery technologies are required for realizing the clinical potential of molecular medicines. This work presents an alternative technology to preformulated delivery systems by harnessing the natural transport properties of serum albumin using endogenous binding of gapmer antisense oligonucleotides (ASOs)/albumin constructs. We show by an electrophoretic mobility assay that fatty acid-modified gapmer and human serum albumin (HSA) can self-assemble into constructs that offer favorable pharmacokinetics. The interaction was dependent on fatty acid type (either palmitic or myristic acid), number, and position within the gapmer ASO sequence, as well as phosphorothioate (PS) backbone modifications...
July 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28641106/antisense-oligonucleotides-translation-from-mouse-models-to-human-neurodegenerative-diseases
#17
REVIEW
Kathleen M Schoch, Timothy M Miller
Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression...
June 21, 2017: Neuron
https://www.readbyqxmd.com/read/28639617/gene-therapy-for-spinomuscular-atrophy-a-biomedical-advance-a-missed-opportunity-for-more-equitable-drug-pricing
#18
T Friedmann
An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease...
June 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28639196/specific-increase-of-protein-levels-by-enhancing-translation-using-antisense-oligonucleotides-targeting-upstream-open-frames
#19
Xue-Hai Liang, Wen Shen, Stanley T Crooke
A number of diseases are caused by low levels of key proteins; therefore, increasing the amount of specific proteins in human bodies is of therapeutic interest. Protein expression is downregulated by some structural or sequence elements present in the 5' UTR of mRNAs, such as upstream open reading frames (uORF). Translation initiation from uORF(s) reduces translation from the downstream primary ORF encoding the main protein product in the same mRNA, leading to a less efficient protein expression. Therefore, it is possible to use antisense oligonucleotides (ASOs) to specifically inhibit translation of the uORF by base-pairing with the uAUG region of the mRNA, redirecting translation machinery to initiate from the primary AUG site...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28637928/the-long-noncoding-rna-wisper-controls-cardiac-fibrosis-and-remodeling
#20
Rudi Micheletti, Isabelle Plaisance, Brian J Abraham, Alexandre Sarre, Ching-Chia Ting, Michael Alexanian, Daniel Maric, Damien Maison, Mohamed Nemir, Richard A Young, Blanche Schroen, Arantxa González, Samir Ounzain, Thierry Pedrazzini
Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer-associated RNA) as a cardiac fibroblast-enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis...
June 21, 2017: Science Translational Medicine
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