7 results on '"Ura, K."'
Search Results
2. Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.
- Author
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Hamanaka T, Nishizawa K, Sakasegawa Y, Oguma A, Teruya K, Kurahashi H, Hara H, Sakaguchi S, and Doh-Ura K
- Subjects
- Animals, Cell Line, Melanins administration & dosage, Mice, Neurons metabolism, Prion Diseases drug therapy, Protein Binding, Protein Interaction Mapping, Survival Analysis, Melanins metabolism, Prion Diseases prevention & control, Prions metabolism
- Abstract
Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear. IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
- Full Text
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3. Efficacy and mechanism of a glycoside compound inhibiting abnormal prion protein formation in prion-infected cells: implications of interferon and phosphodiesterase 4D-interacting protein.
- Author
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Nishizawa K, Oguma A, Kawata M, Sakasegawa Y, Teruya K, and Doh-ura K
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins genetics, Cell Line, Cytoskeletal Proteins, Down-Regulation drug effects, Mice, PrPSc Proteins antagonists & inhibitors, PrPSc Proteins genetics, Prion Diseases drug therapy, Prion Diseases genetics, Signal Transduction drug effects, Carrier Proteins metabolism, Glycosides pharmacology, Interferons metabolism, PrPSc Proteins metabolism, Prion Diseases metabolism
- Abstract
Unlabelled: A new type of antiprion compound, Gly-9, was found to inhibit abnormal prion protein formation in prion-infected neuroblastoma cells, in a prion strain-independent manner, when the cells were treated for more than 1 day. It reduced the intracellular prion protein level and significantly modified mRNA expression levels of genes of two types: interferon-stimulated genes were downregulated after more than 2 days of treatment, and the phosphodiesterase 4D-interacting protein gene, a gene involved in microtubule growth, was upregulated after more than 1 day of treatment. A supplement of interferon given to the cells partly restored the abnormal prion protein level but did not alter the normal prion protein level. This interferon action was independent of the Janus activated kinase-signal transducer and activator of transcription signaling pathway. Therefore, the changes in interferon-stimulated genes might be a secondary effect of Gly-9 treatment. However, gene knockdown of phosphodiesterase 4D-interacting protein restored or increased both the abnormal prion protein level and the normal prion protein level, without transcriptional alteration of the prion protein gene. It also altered the localization of abnormal prion protein accumulation in the cells, indicating that phosphodiesterase 4D-interacting protein might affect prion protein levels by altering the trafficking of prion protein-containing structures. Interferon and phosphodiesterase 4D-interacting protein had no direct mutual link, demonstrating that they regulate abnormal prion protein levels independently. Although the in vivo efficacy of Gly-9 was limited, the findings for Gly-9 provide insights into the regulation of abnormal prion protein in cells and suggest new targets for antiprion compounds., Importance: This report describes our study of the efficacy and potential mechanism underlying the antiprion action of a new antiprion compound with a glycoside structure in prion-infected cells, as well as the efficacy of the compound in prion-infected animals. The study revealed involvements of two factors in the compound's mechanism of action: interferon and a microtubule nucleation activator, phosphodiesterase 4D-interacting protein. In particular, phosphodiesterase 4D-interacting protein was suggested to be important in regulating the trafficking or fusion of prion protein-containing vesicles or structures in cells. The findings of the study are expected to be useful not only for the elucidation of cellular regulatory mechanisms of prion protein but also for the implication of new targets for therapeutic development.
- Published
- 2014
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4. Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner.
- Author
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Kawasaki Y, Kawagoe K, Chen CJ, Teruya K, Sakasegawa Y, and Doh-ura K
- Subjects
- Administration, Oral, Animals, Brain pathology, Brain Chemistry, Cell Line, Flow Cytometry, Heterocyclic Compounds pharmacokinetics, Immunoblotting, Mice, Prions analysis, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacology, Prion Diseases drug therapy, Prion Diseases prevention & control, Prions drug effects
- Abstract
The establishment of effective therapeutic interventions for prion diseases is necessary. We report on a newly developed amyloidophilic compound that displays therapeutic efficacy when administered orally. This compound inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion strain-dependent manner: effectively for RML prion and marginally for 22L prion and Fukuoka-1 prion. When the highest dose (0.2% [wt/wt] in feed) was given orally to cerebrally RML prion-inoculated mice from inoculation until the terminal stage of disease, it extended the incubation periods by 2.3 times compared to the control. The compound exerted therapeutic efficacy in a prion strain-dependent manner such as that observed in the cell culture study: most effective for RML prion, less effective for 22L prion or Fukuoka-1 prion, and marginally effective for 263K prion. Its effectiveness depended on an earlier start of administration. The glycoform pattern of the abnormal prion protein in the treated mice was modified and showed predominance of the diglycosylated form, which resembled that of 263K prion, suggesting that diglycosylated forms of abnormal prion protein might be least sensitive or resistant to the compound. The mechanism of the prion strain-dependent effectiveness needs to be elucidated and managed. Nevertheless, the identification of an orally available amyloidophilic chemical encourages the pursuit of chemotherapy for prion diseases.
- Published
- 2007
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5. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models.
- Author
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Doh-ura K, Ishikawa K, Murakami-Kubo I, Sasaki K, Mohri S, Race R, and Iwaki T
- Subjects
- Animals, Brain pathology, Disease Models, Animal, Mice, Pentosan Sulfuric Polyester administration & dosage, Pentosan Sulfuric Polyester toxicity, Prion Diseases metabolism, Prion Diseases pathology, Prions metabolism, Pentosan Sulfuric Polyester therapeutic use, Prion Diseases drug therapy
- Abstract
The therapeutic efficacy of direct drug infusion into the brain, the target organ of transmissible spongiform encephalopathies, was assessed in transgenic mice intracerebrally infected with 263K scrapie agent. Pentosan polysulfate (PPS) gave the most dramatic prolongation of the incubation period, and amphotericin B had intermediate effects, but antimalarial drugs such as quinacrine gave no significant prolongation. Treatment with the highest dose of PPS at an early or late stage of the infection prolonged the incubation time by 2.4 or 1.7 times that of the control mice, respectively. PPS infusion decreased not only abnormal prion protein deposition but also neurodegenerative changes and infectivity. These alterations were observed within the brain hemisphere fitted with an intraventricular infusion cannula but not within the contralateral hemisphere, even at the terminal disease stage long after the infusion had ended. Therapeutic effects of PPS were also demonstrated in mice infected with either RML agent or Fukuoka-1 agent. However, at doses higher than that providing the maximal effects, intraventricular PPS infusion caused adverse effects such as hematoma formation in the experimental animals. These findings indicate that intraventricular PPS infusion might be useful for the treatment of transmissible spongiform encephalopathies in humans, providing that the therapeutic dosage is carefully evaluated.
- Published
- 2004
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6. Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies.
- Author
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Murakami-Kubo I, Doh-Ura K, Ishikawa K, Kawatake S, Sasaki K, Kira J, Ohta S, and Iwaki T
- Subjects
- Animals, Brain metabolism, Humans, Immunohistochemistry, Injections, Intraventricular, Mice, Mice, Transgenic, Neuroblastoma, PrPSc Proteins metabolism, Quinacrine pharmacology, Quinine analogs & derivatives, Quinine pharmacology, Quinolines pharmacology, Structure-Activity Relationship, Surface Plasmon Resonance, Tumor Cells, Cultured, PrPSc Proteins drug effects, Prion Diseases drug therapy, Quinolines chemistry, Quinolines therapeutic use
- Abstract
We previously reported that quinacrine inhibited the formation of an abnormal prion protein (PrPres), a key molecule in the pathogenesis of transmissible spongiform encephalopathy, or prion disease, in scrapie-infected neuroblastoma cells. To elucidate the structural aspects of its inhibiting action, various chemicals with a quinoline ring were screened in the present study. Assays of the scrapie-infected neuroblastoma cells revealed that chemicals with a side chain containing a quinuclidine ring at the 4 position of a quinoline ring (represented by quinine) inhibited the PrPres formation at a 50% inhibitory dose ranging from 10(-1) to 10(1) micro M. On the other hand, chemicals with a side chain at the 2 position of a quinoline ring (represented by 2,2'-biquinoline) more effectively inhibited the PrPres formation at a 50% inhibitory dose ranging from 10(-3) to 10(-1) micro M. A metabolic labeling study revealed that the action of quinine or biquinoline was not due to any alteration in the biosynthesis or turnover of normal prion protein, whereas surface plasmon resonance analysis showed a strong binding affinity of biquinoline with a recombinant prion protein. In vivo studies revealed that 4-week intraventricular infusion of quinine or biquinoline was effective in prolonging the incubation period in experimental mouse models of intracerebral infection. The findings suggest that quinoline derivatives with a nitrogen-containing side chain have the potential of both inhibiting PrPres formation in vitro and prolonging the incubation period of infected animals. These chemicals are new candidates for therapeutic drugs for use in the treatment of transmissible spongiform encephalopathies.
- Published
- 2004
- Full Text
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7. Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation.
- Author
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Doh-Ura K, Iwaki T, and Caughey B
- Subjects
- Animals, Inhibitory Concentration 50, Leucine pharmacology, Lysosomes drug effects, Lysosomes metabolism, Neuroblastoma, Tumor Cells, Cultured, Cysteine Proteinase Inhibitors pharmacology, Leucine analogs & derivatives, PrPSc Proteins drug effects, PrPSc Proteins metabolism, Quinacrine pharmacology
- Abstract
We report that lysosomotropic agents and cysteine protease inhibitors inhibited protease-resistant prion protein accumulation in scrapie-infected neuroblastoma cells. The inhibition occurred without either apparent effects on normal prion protein biosynthesis or turnover or direct interactions with prion protein molecules. The findings introduce two new classes of inhibitors of the formation of protease-resistant prion protein.
- Published
- 2000
- Full Text
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