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[en] Purpose: To assess the effects of noscapine, a tubulin-binding drug, in combination with radiation in a murine glioma model. Methods and Materials: The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation, or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation, tumors were resected and immunostained to measure proliferation rate, apoptosis, and angiogenic activity. Results: Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, and 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, and a decrease in tumor vessel density compared with tumors treated with radiation alone. Conclusion: Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation, resulting in a significant tumor growth delay. An antiangiogenic mechanism contributed to the effect. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug
[en] Two new DNA probes bearing a fluorescent deoxyguanosine unit labeled with 2-ethynylfluorene (G"F"L )or 2-ethynylfluorenone (G"F"O) were synthesized and examined for their efficiency as quencher-free linear beacon probes. Oligodeoxynucleotides (ODNs) containing a G"F"L or G"F"O unit exhibit low thermal selectivity and few distinctive fluorescence changes upon duplex formation due to the syn conformation about the glycosidic bond. An exciplex emission was observed when the G"F"L unit of ODNs bearing adenine flanking bases was positioned opposite to the adenine nucleobases.
[en] We describe a simple and inexpensive single-nucleotide polymorphism (SNP) typing method, using DNA photoligation with 5-carboxyvinyl-2'-deoxyuridine and two fluorophores. This SNP-typing method facilitates qualitative determination of genes from indica and japonica rice, and showed a high degree of single nucleotide specificity up to 10 000. This method can be used in the SNP typing of actual genomic DNA samples from food crops.
[en] 5-Iodo-2'-deoxyuridine (IUdR) is a thymidine (TdR) analog in which the 5-methyl group of TdR is replaced by iodine. Since the 5-methyl group and the iodine atom have similar van der Waal's radii this substitution gives a compound that behaves remarkably like TdR. Within in cell, both TdR and IUdR are phosphorylated in a stepwise fashion and incorporated into DNA. However, unlike direct iodination, mercuration proceeds with equal facility on both U and C base. In addition, whereas extensive uracil hydrate formation occurs in the iodination reaction no hydration of he 5-6 double bound occurs during mercuration. Since mercurated nucleotides can be rapidly converted to iodonucleotides in high yields, iodination via mercuri intermediates may offer some advantage in the preparation of iodinated nucleotide and polynucleotides. The reaction through 5-mercurated derivatives did minimize single-strand breakage under mild condition and high radiolabeling yield of iodine on the c-5 ring position was obtained and covalently bound mercury atoms did not alter the polynucleotide structure or the interaction of the polynucleotides with proteins and enzymes. Accordingly, iodine labled dUTP in the process of PCR using Taq DNA polymerase could be competitively activated with dTTP maintaining stability
[en] Highlights: •Methylcobalamin activated the Erk1/2 signaling pathway in C2C12 cells. •Methylcobalamin promoted the proliferation and migration in C2C12 cells. •C2C12 cell apoptosis during differentiation was inhibited by methylcobalamin. -- Abstract: Methylcobalamin (MeCbl) is a vitamin B12 analog that has some positive effects on peripheral nervous disorders. Although some previous studies revealed the effects of MeCbl on neurons, its effect on the muscle, which is the final target of motoneuron axons, remains to be elucidated. This study aimed to determine the effect of MeCbl on the muscle. We found that MeCbl promoted the proliferation and migration of C2C12 myoblasts in vitro and that these effects are mediated by the Erk1/2 signaling pathway without affecting the activity of the Akt signaling pathway. We also demonstrated that MeCbl inhibits C2C12 cell apoptosis during differentiation. Our results suggest that MeCbl has beneficial effects on the muscle in vitro. MeCbl administration may provide a novel therapeutic approach for muscle injury or degenerating muscle after denervation
[en] Several different radiolabeled probes have been developed to image Herpes Simplex Virus Type-1 thyrimidine kinase gene (HSV1-TK) expression. The nucleoside prodrugs under investigation for HSV1-TK imaging generally fall into two main chemical and radioisotope categories: the pyrimidine nucleosides, primarily radioiodinated, and the purin nucleosides, primarily radiofluorinated, and their respective analogues. In non-invasive imaging of the HSV1-TK system, many nucleoside derivatives have been recommended as HSV1-TK substrates. Most of these nucleoside derivatives have been developed as prodrugs for tumor proliferation imaging or as anti-viral drugs. For example, 5-fluorouracil (5-FU) and IUdR have been used as tumor agents and acyclovir (ACV), ganciclovir (GCV) and (E)-5-(2-bromovinyl)-2'- deoxyuridine (BVDU) as an anti-viral agents for virus infection several 5-substituted uracil nucleoside derivatives have been identified to have high sensitivity and selective accumulation in HSV1-TK expressing cells. Of those, IVDU was shown to be rapidly accumulated in HSV1- TK expressing cells in vitro. Imaging of the HSV1-TK reporter gene along with various reporter probes is of current interest. In contrast to the mammalian kinase, which phosphorylates thymidine preferentially, HSV1-TK is less discriminative and phosphorylates a wide range of nucleoside analogues such as acycloguanosines and 2'-fluoro-2'-deoxyuridine derivatives that are not phosphorylated efficiently by the native enzyme. More specifically, 5-substituted 2'-fluoro-2'-deoxyarabinofuranosyluracil nucleosides are efficiently phosphorylated by HSV- TK. This property, together with the presence of fluorine in the 2'-arabino-position, endows the 2'-fluoro-2'-deoxyuridines with antiviral activity against HSV
[en] We have shown that the hydrogel of a compound which does not contain directly positive charge or an amino group can still be transcribed into a silica structure, as long as the acidic proton for the polymerization process can interact with the gelator molecules. Preliminary results using other gelators that do not contain positive charges or amino groups either, indicate that this phenomenon is of a general nature. As a consequence, the transcription of a much broader range of TEOS can now be taken into consideration. Being able to transcribe such entities will undoubtedly lead to a greater variety of inorganic materials with interesting new shapes and properties. We show the rare example for the hydrogel assembly based on 2'-deoxyuridine that can be successfully transcribed into the silica structure by sol-gel polymerization of TEOS although it does not possess either directly positive charge or efficient H-bonding amine group. The amide-type NH group of is quite difficult to act as a direct driving force to sol-gel transcription, because the amide-type NH group forms the intermolecular hydrogen-bonding interaction between gelator and the protonation of acidic proton at amide-type NH group is more difficult than that of free amine. We have found that acidic proton can protonate at the molecular aggregates in the gel fibers, thus providing the driving force necessary for the transcription process
[en] Hydrodynamic-based procedure is a simple and effective gene delivery method to lead a high gene expression in liver tissue. Non-invasive imaging reporter gene system has been used widely with herpes simplex virus type 1 thymidine kinase (HSV1-tk) and its various substrates. In the present study, we investigated to image the expression of HSV1-tk gene with 5-(2-iodovinyl)-2'-deoxyuridine (IVDU) in mouse liver by the hydrodynamicbased procedure. HSV1-tk or enhanced green fluorescence protein (EGFP) encoded plasmid DNA was transferred into the mouse liver by hydrodynamic injection. At 24 h post-injection, RT-PCR, biodistribution, fluorescence imaging, nuclear imaging and digital wholebody autoradiography (DWBA) were performed to confirm transferred gene expression. In RT-PCR assay using mRNA from the mouse liver, specific bands of HSV1-tk and EGFP gene were observed in HSV1-tk and EGFP expressing plasmid injected mouse, respectively. Higher uptake of radiolabeled IVDU was exhibited in liver of HSV1-tk gene transferred mouse by biodistribution study. In fluorescence imaging, the liver showed specific fluorescence signal in EGFP gene transferred mouse. Gamma-camera image and DWBA results showed that radiolabeled IVDU was accumulated in the liver of HSV1-tk gene transferred mouse. In this study, hydrodynamic-based procedure was effective in liver-specific gene delivery and it could be quantified with molecular imaging methods. Therefore, co-expression of HSV1-tk reporter gene and target gene by hydrodynamic-based procedure is expected to be a useful method for the evaluation of the target gene expression level with radiolabeled IVDU
[en] We found that DNA polymerase I from Chlamydiophila pneumoniae AR39 (CpDNApolI) presents DNA-dependent DNA polymerase activity, but has no detectable 3' exonuclease activity. CpDNApolI-dependent DNA synthesis was performed using DNA templates carrying different lesions. DNAs containing 2'-deoxyuridine (dU), 2'-deoxyinosine (dI) or 2'-deoxy-8-oxo-guanosine (8-oxo-dG) served as templates as effectively as unmodified DNAs for CpDNApolI. Furthermore, the CpDNApolI could bypass natural apurinic/apyrimidinic sites (AP sites), deoxyribose (dR), and synthetic AP site tetrahydrofuran (THF). CpDNApolI could incorporate any dNMPs opposite both of dR and THF with the preference to dAMP-residue. CpDNApolI preferentially extended primer with 3'-dAMP opposite dR during DNA synthesis, however all four primers with various 3'-end nucleosides (dA, dT, dC, and dG) opposite THF could be extended by CpDNApolI. Efficiently bypassing of AP sites by CpDNApolI was hypothetically attributed to lack of 3' exonuclease activity
[en] Bromodeoxyuridine (BUdR), a potential radiosensitizing drug, was given by intravenous infusion at 650-1000 mg/m2/day for up to 12 days. In vivo incorporation into human bone marrow was assayed by differential chromatid staining as well as by comparison of in vitro radiation survival curves of granulocyte-macrophage progenitor cells scored at both day 7 and day 14. Although a difference was found in the radiation survival of control (untreated) day-7 progenitor cells (Do 1.39 Gy) and day-14 progenitor cells (Do = 0.89 Gy), a similar degree of in vitro radiosensitization was found for BUdR-treated bone marrow progenitor cells scored at day 7 and day 14. The culture technique provided a bioassay for the in vivo action of BUdR. BUdR treatment produced transient moderate myelosuppression that probably resulted from BUdR incorporation into normal marrow cells