Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation
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University of Cincinnati / OhioLINK
2015
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14393016182021-08-03T06:32:47Z Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation Hu, Jing Pharmaceuticals neuroinflammation NF-kappa B decoy GS24 aptamer ICAM-1 VCAM-1 Because transcription factor nuclear factor (NF)- κB plays an important role in vascular inflammation at blood-brain barrier, the present study constructed a novel DNA complex to specifically target endothelial NF-κB for inhibition of cerebral inflammation. This DNA complex (GS24-NFκB) contains two functional domains: a DNA Decoy for inhibiting NF-κB activity and a DNA aptamer (GS-24), a ligand of transferrin receptor (TfR), for targeted delivery of the DNA Decoy into brain endothelial cells. The results indicated that GS24-NFκB was delivered into murine brain-derived endothelial (bEnd5) cells and the delivery was specific and TfR-dependent. The DNA chimera inhibited inflammatory responses in the cells induced by tumor necrosis factor a (TNF-α) or oxygen-glucose deprivation/reoxygenation (OGD/R) via down-regulation of nuclear NF-κB subunit, P65, as well as its downstream inflammatory cytokines, such as inter cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). The anti-inflammatory effect of the GS24-NFκB was shown as significant reduction in monocyte adhesion to the bEnd5 cells induced by TNF-a or OGD/R after GS24-NFκB treatment. Pharmacokinetic study suggested its poor nuclease resistance and rapid clearance from systemic circulation. Organ uptake of GS24-NFκB including brain uptake was much higher compared to the scramble control and high organ uptake was observed in liver and spleen with high expression of TfR. The brain uptake is 0.39%ID/g, which is comparable to the brain uptake of anti-TfR monoclonal antibody, OX26 (0.44%ID/g). Intravenous injection of GS24-NFκB (15mg/kg) was able to significantly reduce the expressions of phospho-P65 and VCAM-1 in brain endothelial cells in mouse lipopolysaccharide (LPS) induced inflammatory model, suggesting effective inhibition of activation and transcriptional activity of NF-κB. However, the disease-modifying effects of GS24-NFκB need to be further investigated in future. In conclusion, our approach using DNA nanotechnology has successfully delivered the therapeutic decoy into brain endothelial cells and induce pharmacological effect. It could be potentially applied for inhibition of inflammation in ischemic stroke and other neuroinflammatory diseases affecting cerebral vasculature. 2015-09-11 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Pharmaceuticals neuroinflammation NF-kappa B decoy GS24 aptamer ICAM-1 VCAM-1 |
| spellingShingle |
Pharmaceuticals neuroinflammation NF-kappa B decoy GS24 aptamer ICAM-1 VCAM-1 Hu, Jing Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation |
| author |
Hu, Jing |
| author_facet |
Hu, Jing |
| author_sort |
Hu, Jing |
| title |
Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation |
| title_short |
Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation |
| title_full |
Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation |
| title_fullStr |
Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation |
| title_full_unstemmed |
Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation |
| title_sort |
targeting transcription factor nf-kappa b by dual functional oligodeoxynucleotide complex for inhibition of neuroinflammation |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2015 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618 |
| work_keys_str_mv |
AT hujing targetingtranscriptionfactornfkappabbydualfunctionaloligodeoxynucleotidecomplexforinhibitionofneuroinflammation |
| _version_ |
1719438863596781568 |