oligodeoxynucleotides
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4'-Alkoxy-oligothymidylates were prepared as model compounds to study the influence of a C4'-alkoxy group on hybridisation. The phosphodiester homooligomers (15 units long) containing either a 4'-methoxy or 4'-(2-methoxyethoxy) group were found to display increased hybridisation with both dA(15) and rA(15) complementary counterparts compared to the natural oligothymidylate. In addition, we found their hybridisation behaviour to be similar to that of the regioisomeric 2'-O-methyl-oligothymidylate. The formed complexes (duplexes and triplexes) were studied using UV spectroscopy and polyacrylamide gel electrophoresis (PAGE). Structural background of the hybridization behaviour was examined using NMR and MDS. The favourable hybridisation properties of the 4'-alkoxyoligothymidylates indicated that 4'-alkoxy modified nucleotides are promising compounds for the assembly of chimeric oligonucleotides with tunable properties.
- MeSH
- exprese genu genetika MeSH
- financování organizované MeSH
- hipokampus chemie patofyziologie MeSH
- laboratorní zvířata MeSH
- modely u zvířat MeSH
- oligodeoxyribonukleotidy genetika MeSH
- potkani Wistar MeSH
- receptory N-methyl-D-aspartátu metabolismus nedostatek MeSH
- schizofrenie enzymologie etiologie patofyziologie MeSH
- statistika jako téma metody MeSH
- úleková reakce fyziologie MeSH
- Publikační typ
- srovnávací studie MeSH
Výsledky současných experimentálních studií ukazují na funkční změny N-methyl-D-aspartátových receptoru v některých oblastech mozku pacientů trpících schizofrenií. Příčinou může být změněná exprese hlavních receptorových podjednotek nebo jejich zrychlená internalizace. Zatímco snížená exprese receptorové NRl podjednotky u myší způsobila změnu prepulzní inhibice akustické úlekové reakce, u potkanů jsme podobnou změnu neprokázali. V naší práci jsme u potkanů ovlivňovali expresi NRl proteinu v hipokampu pomocí antisense oligodeoxynukleotidů pro NMDA-NRl, a to samostatně nebo v kombinaci s NR2A či NR2B a sledovali zmíněný parametr chování.
Results of recent experimental studies have shown that fun- ctions of N-methyl-D-aspartate receptors are changed in some schizophrenic brain regions. The cause might be the changed expression of essential subunits or their accelerated internalization. While the decreased expression of NR1 subunit in mouse caused change in prepulse inhibition of acoustic startle, in rats we have not proved a deficit in the prepulse inhibition. In our work using antisense oligodeoxynucleotide for NMDA-NR1 separately or in combination with NR2A or NR2B, we affected expression of NR1 protein in the rat hip- pocampus and evaluated the mentioned parameter of behaviour.
- Klíčová slova
- animální model, NMDA receptor, aODN-NR1/NR2, PPI,
- MeSH
- schizofrenie MeSH
- Publikační typ
- abstrakty MeSH
Dendrimers are artificial polymeric macromolecules which are widely considered to be a promising tool for future gene therapy applications. They have been used as efficient delivery vehicles for antisense oligonucleotides targeting the interior of cells. We demonstrate that dendriplexes formed from anti-HIV oligodeoxynucleotides ANTI-TAR, GEM91, and SREV in complex with generation 4 maltose (PPI-Mal G4) and maltotriose (PPI-Mal-III G4) modified poly(propylene imine) dendrimers are able to self-assemble into highly organized 1D and 3D nanostructures. The resulting nanostructures were characterized by fluorescence methods, laser Doppler electrophoresis, dynamic light scattering (DLS), atomic force microscopy (AFM) and molecular modeling. The results show that ANTI-TAR and GEM 91 dendriplexes self-assemble into fibrils with length scales up to several hundreds of nm. SREV, on the contrary, forms quadrilateral- like 3D nanostructures. A good correlation between the various experimental methods and molecular modeling indicates the formation of those nanostructures in solution. Space symmetry of the oligonucleotides and the resulting dendriplex monomeric units are probably the most important factors which influence the way of self-assembling.
- MeSH
- antisense oligonukleotidy aplikace a dávkování chemie MeSH
- dendrimery chemie MeSH
- fluorescenční polarizace MeSH
- HIV infekce farmakoterapie MeSH
- látky proti HIV aplikace a dávkování chemie MeSH
- lidé MeSH
- maltosa chemie MeSH
- molekulární modely MeSH
- nanostruktury chemie MeSH
- polypropyleny chemie MeSH
- radiační rozptyl MeSH
- světlo MeSH
- thionukleotidy chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Unmethylated oligodeoxynucleotides containing guanine-cytidine dimers (CpG ODN) have been described as potent inducers of selected antitumour immune responses and the immunotherapeutic efficacy of CpG ODN has been examined either alone or as a vaccine adjuvant. We hypothesized that CpG ODN therapy could be an effective tool for immunotherapy of not only conventional MHC class I(+) tumours but also of those tumours that have lost MHC class I expression during their progression. To address this hypothesis, we employed the animal model resembling MHC class I-proficient and -deficient human papilloma virus (HPV) 16-associated tumours. A cell line transformed with HPV16 E6 and E7 oncogenes, TC-1, as a prototype of MHC class I-positive line, and its MHC class I-deficient sublines TC-1/A9 and TC-1/P3C10 were injected into syngeneic C57BL/6 mice and the growing tumours were subjected to immunotherapy with CpG ODN 1826. The therapy started either 1 day after the challenge with the tumour cells or later, when the tumours had reached a palpable size. In both settings, CpG ODN 1826 significantly reduced the growth of MHC class I-proficient and -deficient tumours. Furthermore, we demonstrated that CpG ODN 1585, whose mechanism of action preferably involves indirect activation of the natural killer cells, induced regression of the MHC class I-deficient tumours TC1/A9 but not of the MHC class I-proficient tumours TC-1. This study infers that synthetic CpG ODN have a potential for the therapy of both MHC class I-proficient and -deficient tumours and thus could be also used against tumours that tend to down-regulate their MHC class I expression.
- MeSH
- CpG ostrůvky MeSH
- down regulace MeSH
- financování organizované MeSH
- geny MHC třídy I MeSH
- imunoterapie metody MeSH
- infekce papilomavirem MeSH
- lidský papilomavirus 16 MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádory terapie virologie MeSH
- oligonukleotidy MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
Oligodeoxynucleotides containing guanine-cytidine dimers (CpG ODN) are potent inducers of anti-tumour immune responses. In this study, we analyzed the capacity of CpG ODN to inhibit the growth of both MHC class I-positive and -deficient tumours after debulking the tumour mass by chemotherapy or surgery. We employed an animal model resembling human papillomavirus (HPV) 16-associated tumours. Tumour cell lines with distinct cell surface expression of the MHC class I molecules were injected into syngeneic C57BL/6 mice, and the growing tumours were either subjected to cytoreductive chemotherapy with ifosfamide derivative, CBM-4A, or surgically removed. Subsequent treatment with synthetic CpG ODN significantly blocked the growth of the recurrent tumours. Our results indicate that the therapy with CpG ODN can be effective for the treatment of minimal residual tumour disease of the tumours that have escaped from the immune surveillance by downmodulating the MHC class I expression.
- MeSH
- CpG ostrůvky MeSH
- financování organizované MeSH
- geny MHC třídy I MeSH
- lidé MeSH
- lidský papilomavirus 16 metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory genetika terapie virologie MeSH
- oligonukleotidy chemie terapeutické užití MeSH
- recidiva MeSH
- reziduální nádor farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
