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Rainer M. Bohle – One of the best experts on this subject based on the ideXlab platform.

  • 3Deazaadenosine Prevents Smooth Muscle Cell Proliferation and Neointima Formation by Interfering With Ras Signaling
    Circulation research, 2009
    Co-Authors: Daniel Sedding, Werner Haberbosch, Gerhard Walker, Ludger Fink, Harald Tillmanns, Monique Tröbs, Fabian Reich, Wigbert S. Rau, Klaus T. Preissner, Rainer M. Bohle
    Abstract:

    3Deazaadenosine (c3Ado) is a potent inhibitor of S -adenosylhomocysteine hydrolase, which regulates cellular methyltransferase activity. In the present study, we sought to determine the effect of c3Ado on vascular smooth muscle cell (VSMC) function and neointima formation in vivo. c3Ado dose-dependently prevented the proliferation and migration of human coronary VSMCs in vitro. This was accompanied by an increased expression of the cyclin-dependent kinase inhibitors p21 WAF1/Cip1 , p27 Kip1 , a decreased expression of G 1 /S phase cyclins, and a lack of retinoblastoma protein hyperphosphorylation. In accordance with these findings, fluorescence-activated cell-sorting analysis of propidium iodide–stained cells indicated a cell cycle arrest in the G 0 /G 1 phase. Importantly, c3Ado did not affect the number of viable (trypan blue exclusion) or apoptotic cells (TUNEL). Mechanistically, c3Ado prevented FCS-induced Ras carboxyl methylation and membrane translocation and activity by inhibiting isoprenylcysteine carboxyl methyltransferase and reduced FCS-induced extracellular signal-regulated kinase (ERK)1/2 and Akt phosphorylation in a dose-dependent manner. Conversely, rescuing signal transduction by overexpression of a constitutive active Ras mutant abrogated c3Ado’s effect on proliferation. For in vivo studies, the femoral artery of C57BL/6 mice was dilated and mice were fed a diet containing 150 μg of c3Ado per day. c3Ado prevented dilation-induced Ras activation, as well as ERK1/2 and Akt phosphorylation in vivo. At day 21, VSMC proliferation (proliferating-cell nuclear antigen [PCNA]-positive cells), as well as the neointima/media ratio (0.7±0.2 versus 1.6±0.4; P S -adenosylhomocysteine hydrolase by c3Ado may represent a save and effective novel approach to prevent vascular proliferative disease.

  • 3 Deazaadenosine inhibits vasa vasorum neovascularization in aortas of apoe ldl double knockout mice
    Atherosclerosis, 2009
    Co-Authors: A C Langheinrich, Daniel Sedding, Werner Haberbosch, Marian Kampschulte, Regina Moritz, Jochen Wilhelm, Erik L Ritman, Rainer M. Bohle
    Abstract:

    Abstract Background Atherosclerosis and inflammation/angiogenesis are strongly associated including growth of vasa vasorum (VV) and plaque neovascularization, but a causative role for neovascularization has still not been established. Hence, we investigated the effect of 3Deazaadenosine (c 3 Ado), an anti-inflammatory and anti-proliferative drug, on plaque progression and VV neovascularization in apoE −/− /LDL −/− double knockout mice. Methods The arterial trees from apoE −/− /LDL −/− mice with, or without c 3 Ado at the age of 16 weeks ( n =10), 18 weeks ( n =8) and 20 weeks ( n =7) were infused in situ with Microfil, and the aortas harvested and scanned with micro-CT (12μm cubic voxel). We characterized plaque volume and VV luminal volume along the descending aorta using Analyze 6.0 software. Cellular effects of c 3 Ado on human endothelial and vascular smooth muscle cells were investigated in cell cultures and on nylon cDNA expression arrays. Results Lesions spatially connected to VV increased from 16 to 20 weeks significantly ( p 3 Ado ( p p 3 Ado. Moreover, c 3 Ado dose-dependently prevented the proliferation and migration of human coronary artery endothelial cells in vitro. Conclusion The smaller lesion volume in animals treated with c 3 Ado was closely associated with a reduced VV neovascularization, suggesting a direct relationship between lesion growth and VV development.

  • 3Deazaadenosine inhibits vasa vasorum neovascularization in aortas of ApoE(-/-)/LDL(-/-) double knockout mice.
    Atherosclerosis, 2008
    Co-Authors: Alexander C. Langheinrich, Daniel Sedding, Werner Haberbosch, Marian Kampschulte, Regina Moritz, Jochen Wilhelm, Erik L Ritman, Rainer M. Bohle
    Abstract:

    Atherosclerosis and inflammation/angiogenesis are strongly associated including growth of vasa vasorum (VV) and plaque neovascularization, but a causative role for neovascularization has still not been established. Hence, we investigated the effect of 3Deazaadenosine (c(3)Ado), an anti-inflammatory and anti-proliferative drug, on plaque progression and VV neovascularization in apoE(-/-)/LDL(-/-) double knockout mice. The arterial trees from apoE(-/-)/LDL(-/-) mice with, or without c(3)Ado at the age of 16 weeks (n=10), 18 weeks (n=8) and 20 weeks (n=7) were infused in situ with Microfil, and the aortas harvested and scanned with micro-CT (12mum cubic voxel). We characterized plaque volume and VV luminal volume along the descending aorta using Analyze 6.0 software. Cellular effects of c(3)Ado on human endothelial and vascular smooth muscle cells were investigated in cell cultures and on nylon cDNA expression arrays. Lesions spatially connected to VV increased from 16 to 20 weeks significantly (p<0.001). The volume of atherosclerotic lesions was significantly reduced in animals treated with c(3)Ado (p<0.01). This was accompanied by a significant decrease of vasa vasorum neovascularization along the descending aorta (p<0.01). Using nylon cDNA expression arrays, we identified the regulation of anti-proliferative, anti-inflammatory genes in human smooth muscle cells which might be involved in the anti-angiogenic effects of c(3)Ado. Moreover, c(3)Ado dose-dependently prevented the proliferation and migration of human coronary artery endothelial cells in vitro. The smaller lesion volume in animals treated with c(3)Ado was closely associated with a reduced VV neovascularization, suggesting a direct relationship between lesion growth and VV development.

Noriaki Minakawa – One of the best experts on this subject based on the ideXlab platform.

  • Groove modification of siRNA duplexes to elucidate siRNA–protein interactions using 7-bromo-7-Deazaadenosine and 3-bromo-3Deazaadenosine as chemical probes
    Organic & biomolecular chemistry, 2016
    Co-Authors: Noriko Saito-tarashima, Akira Matsuda, Hirotaka Kira, Tomoya Wada, Kazuya Miki, Shiho Ide, Naoshi Yamazaki, Noriaki Minakawa
    Abstract:

    Elucidation of dynamic interactions between RNA and proteins is essential for understanding the biological processes regulated by RNA, such as RNA interference (RNAi). In this study, the logical chemical probes, comprising 7-bromo-7-Deazaadenosine (Br7C7A) and 3-bromo-3Deazaadenosine (Br3C3A), to investigate small interfering RNA (siRNA)-RNAi related protein interactions, were developed. The bromo substituents of Br7C7A and Br3C3A are expected to be located in the major and the minor grooves, respectively, and to act as a steric hindrance in each groove when these chemical probes are incorporated into siRNAs. A comprehensive investigation using siRNAs containing these chemical probes revealed that (i) Br3C3A(s) at the 5′-end of the passenger strand enhanced their RNAi activity, and (ii) the direction of RISC assembly is determined by the interaction between Argonaute2, which is the main component of RISC, and siRNA in the minor groove near the 5′-end of the passenger strand. Utilization of these chemical probes enables the investigation of the dynamic interactions between RNA and proteins.

  • groove modification of sirna duplexes to elucidate sirna protein interactions using 7 bromo 7 Deazaadenosine and 3 bromo 3 Deazaadenosine as chemical probes
    Organic and Biomolecular Chemistry, 2016
    Co-Authors: Noriko Saitotarashima, Akira Matsuda, Hirotaka Kira, Tomoya Wada, Kazuya Miki, Shiho Ide, Naoshi Yamazaki, Noriaki Minakawa
    Abstract:

    Elucidation of dynamic interactions between RNA and proteins is essential for understanding the biological processes regulated by RNA, such as RNA interference (RNAi). In this study, the logical chemical probes, comprising 7-bromo-7-Deazaadenosine (Br7C7A) and 3-bromo-3Deazaadenosine (Br3C3A), to investigate small interfering RNA (siRNA)–RNAi related protein interactions, were developed. The bromo substituents of Br7C7A and Br3C3A are expected to be located in the major and the minor grooves, respectively, and to act as a steric hindrance in each groove when these chemical probes are incorporated into siRNAs. A comprehensive investigation using siRNAs containing these chemical probes revealed that (i) Br3C3A(s) at the 5′-end of the passenger strand enhanced their RNAi activity, and (ii) the direction of RISC assembly is determined by the interaction between Argonaute2, which is the main component of RISC, and siRNA in the minor groove near the 5′-end of the passenger strand. Utilization of these chemical probes enables the investigation of the dynamic interactions between RNA and proteins.

  • Identification of A-minor tertiary interactions within a bacterial group I intron active site by 3Deazaadenosine interference mapping.
    Biochemistry, 2002
    Co-Authors: Juliane K. Soukup, Noriaki Minakawa, And Akira Matsuda, Scott A. Strobel
    Abstract:

    The A-minor motifs appear to be the most ubiquitous helix packing elements within RNA tertiary structures. These motifs have been identified throughout the ribosome and almost every other tertiary-folded RNA for which structural information is available. These motifs utilize the packing of the donor adenosine’s N1, N3, and/or 2′-OH against the 2′-OHs and minor groove edge of the acceptor base pair. The ability to identify biochemically which adenosines form A-minor motifs and which base pairs they contact is an important experimental objective. Toward this goal, we report the synthesis and transcriptional incorporation of 5′-O-(1-thio)-3Deazaadenosine triphosphate and its use in Nucleotide Analogue Interference Mapping (NAIM) and Nucleotide Analogue Interference Suppression (NAIS). This analogue makes it possible for the first time to explore the functional importance of the N3 imino group of adenosine in RNA polymers. Interference analysis of the group I self-splicing introns from Tetrahymena and Azoarcus indicates that A-minor motifs are integral to the helix packing interactions that define the 5′-splice site of the intron. Specifically, Azoarcus A58 in the J4/5 region contacts the G.U wobble pair at the cleavage site in the P1 helix, and Azoarcus A167 in the J8/7 region contacts the C13-G37 base pair in the P2 helix. Both of these structural features are conserved between the eukaryotic and bacterial introns. These results suggest that nucleotide analogue interference patterns can identify and distinguish A-minor interactions in RNA tertiary structure, particularly the most prevalent type I and type II varieties. Furthermore, clustering of 3Deazaadenosine interferences is suggestive of A patches, in which a series of consecutive A-minor motifs mediate helix packing. Biochemical identification of these interactions may provide valuable constraints for RNA structure prediction.

K Müller – One of the best experts on this subject based on the ideXlab platform.

  • Failure to obtain drug-resistant variants of influenza virus after treatment with inhibiting doses of 3Deazaadenosine and H 7
    Archives of Virology, 1991
    Co-Authors: C Scholtissek, K Müller
    Abstract:

    3Deazaadenosine and H 7 specifically inhibit influenza virus replication under conditions at which they have no effect on other tested RNA viruses. This effect can be significantly potentiated by concomitant application of both compounds. Even under the most stringent conditions we failed to obtain any drug resistant variants. A possible explanation for this failure is that these compounds presumably do not act on a viral component like amantadine which was used as a control, but they interfere with cellular enzymes (factors) absolutely essential for influenza virus replication but more or less dispensable for the survival of the cell.

  • Failure to obtain drug-resistant variants of influenza virus after treatment with inhibiting doses of 3Deazaadenosine and H7.
    Archives of virology, 1991
    Co-Authors: C Scholtissek, K Müller
    Abstract:

    3Deazaadenosine and H7 specifically inhibit influenza virus replication under conditions at which they have no effect on other tested RNA viruses. This effect can be significantly potentiated by concomitant application of both compounds. Even under the most stringent conditions we failed to obtain any drug resistant variants. A possible explanation for this failure is that these compounds presumably do not act on a viral component like amantadine which was used as a control, but they interfere with cellular enzymes (factors) absolutely essential for influenza virus replication but more or less dispensable for the survival of the cell.