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Biomedical subjects

A Fujimori

Publications and source records attributed to A Fujimori.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genetic analysis of the DNA-dependent protein kinase reveals an inhibitory role of Ku in late S-G2 phase DNA double-strand break repair.

Two major complementary double-strand break (DSB) repair pathways exist in vertebrates, homologous recombination (HR), which involves Rad54, and non-homologous end-joining, which requires the DNA-dependent protein kinase (DNA-PK). DNA-PK comprises a catalytic subunit (DNA-PKcs) and a DNA-binding Ku70 and Ku80 heterodimer. To define the activities of individual DNA-PK components in DSB repair, we targeted the DNA-PKcs gene in chicken DT40 cells. DNA-PKcs deficiency caused a DSB repair defect that was, unexpectedly, suppressed by KU70 disruption. We have shown previously that genetic ablation of Ku70 confers RAD54-dependent radioresistance on S-G(2) phase cells, when sister chromatids are available for HR repair. To test whether direct interference by Ku70 with HR might explain the Ku70(-/-)/DNA-PKcs(-/-/-) radioresistance, we monitored HR activities directly in Ku- and DNA-PKcs-deficient cells. The frequency of intrachromosomal HR induced by the I-SceI restriction enzyme was increased in the absence of Ku but not of DNA-PKcs. Significantly, abrogation of HR activity by targeting RAD54 in Ku70(-/-) or DNA-PKcs(-/-/-) cells caused extreme radiosensitivity, suggesting that the relative radioresistance seen with loss of Ku70 was because of HR-dependent repair pathways. Our findings suggest that Ku can interfere with HR-mediated DSB repair, perhaps competing with HR for DSB recognition.

Animals↗
PubMed2001

Evidence for ubiquitous strong electron-phonon coupling in high-temperature superconductors.

Coupling between electrons and phonons (lattice vibrations) drives the formation of the electron pairs responsible for conventional superconductivity. The lack of direct evidence for electron-phonon coupling in the electron dynamics of the high-transition-temperature superconductors has driven an intensive search for an alternative mechanism. A coupling of an electron with a phonon would result in an abrupt change of its velocity and scattering rate near the phonon energy. Here we use angle-resolved photoemission spectroscopy to probe electron dynamics-velocity and scattering rate-for three different families of copper oxide superconductors. We see in all of these materials an abrupt change of electron velocity at 50-80 meV, which we cannot explain by any known process other than to invoke coupling with the phonons associated with the movement of the oxygen atoms. This suggests that electron-phonon coupling strongly influences the electron dynamics in the high-temperature superconductors, and must therefore be included in any microscopic theory of superconductivity.

Journal Article↗
PubMed2001

Dual nature of the electronic structure of (La(2--x--y)Nd(y)Sr(x))CuO(4) and La(1.85)Sr(0.15)CuO(4).

High resolution angle-resolved photoemission measurements have been carried out on (La(1.4--x)-Nd(0.6)Sr(x))CuO(4), a model system with static one-dimensional (1D) charge ordering (stripe), and (La(1.85)-Sr(0.15))CuO(4), a high temperature superconductor (T(c) = 40 K) with possible dynamic stripes. In addition to the straight segments near ( pi,0) and ( 0,pi) antinodal regions, we have identified the existence of spectral weight along the [1,1] nodal direction in the electronic structure of both systems. This observation of nodal state, together with the straight segments near antinodal regions, reveals the dual nature of the electronic structure of stripes due to the competition of order and disorder.

Journal Article↗
PubMed2001

XAS and MCD studies in Eu0.6Sr0.4MnO3.

Eu(1-x)Sr(x)MnO3 system is one of the perovskite manganites that exhibit the giant magneto resistance effect and the transition from the insulator phase to the metal. Eu(0.6)Sr(0.4)MnO3 behaves as a ferromagnetic semiconductor and has an Insulator-Metal (IM) transition induced by external magnetic field, which could be found only in this system among the perovskite manganites group. The mechanism of the transition was investigated by X-ray Magnetic Circular Dichroism (XMCD) at the Mn L2,3-edges of and the Eu M4,5-edges in Eu(0.6)Sr(0.4)MnO3.

Journal Article↗
PubMed2001

Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.

Administration, Oral↗
PubMed2001

Synthesis and structure-activity relationships in a series of ethenesulfonamide derivatives, a novel class of endothelin receptor antagonists.

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.

Animals↗
PubMed2001

Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

Animals↗
PubMed2001

Comparison of the angiotensin II type 1-receptor antagonist YM358 and the angiotensin-converting enzyme inhibitor enalapril in rats with cardiac volume overload.

We evaluated the effects of chronic oral administration of an angiotensin II type 1 (AT1)-receptor antagonist YM358 and an angiotensin converting enzyme inhibitor enalapril on hemodynamics and cardiac hypertrophy in rats with volume overload-induced heart failure. We assessed changes of cardiac hemodynamics and cardiac hypertrophy at 2 and 4 weeks after administration of YM358 (3, 30 mg/kg per day) or enalapril (30 mg/kg per day) in abdominal aortocaval shunt rats. YM358 (30 mg/kg) attenuated increases of left ventricle (LV)/body weight (BW), left atrium (LA)/BW, right ventricle (RV)/BW and heart/BW ratios, but did not affect cardiac hemodynamics in shunt rats. Enalapril also reduced the increased LV/BW and heart/BW ratios together with significant reductions of systolic blood pressure, left ventricular systolic pressure and the first derivative of left ventricular pressure. These data suggest that the effects on attenuation of the development of cardiac hypertrophy are not different for YM358 and enalapril, although the effects on cardiac hemodynamics are different for the same dosages. The attenuating action of YM358 on cardiac hypertrophy was independent of the action on hemodynamics and indicated the direct action of the AT1 receptor on the heart.

Angiotensin Receptor Antagonists↗
PubMed2001

DNA repair studies: experimental evidence in support of chicken DT40 cell line as a unique model.

DT40 is a chicken B lymphocyte cell line that exhibits a high ratio of targeted and random integration of transfected DNA constructs. Using the DT40 cell line makes it comparatively easy to disrupt multiple genes in a single cell and to generate conditional targeted mutants including tet-controlled cre-lox-mediated and temperature-sensitive mutants. The DT40 mutants show a strong phenotypic resemblance to murine mutants with respect to genes involved in DNA recombination and repair. Because of these characteristics, DT40 is an attractive model for the analysis of DNA recombination and repair studies in vertebrates despite obvious concerns associated with the use of a transformed cell line that may have certain cell-line-specific characteristics. We present experimental evidence to demonstrate the usefulness of the DT40 cell line as a unique model to study DNA damaging events and their associated repair pathways.

Animals↗
PubMed2000

Angle-resolved photoemission study of insulating and metallic Cu-O chains in PrBa2Cu3O7 and PrBa2Cu4O8

We compare the angle-resolved photoemission spectra of the hole-doped Cu-O chains in PrBa2Cu3O7 (Pr123) and in PrBa2Cu4O8 (Pr124). While, in Pr123, a dispersive feature from the chain takes a band maximum at k(b) (momentum along the chain) approximately pi/4 and loses its spectral weight around the Fermi level, it reaches the Fermi level at k(b) approximately pi/4 in Pr124. Although the chains in Pr123 and Pr124 are approximately 1/4 filled, they show contrasting behaviors: While the chains in Pr123 have an instability to charge ordering, those in Pr124 avoid it and show an interesting spectral feature of a metallic coupled-chain system.

Journal Article↗
PubMed2000

Signal joint formation is also impaired in DNA-dependent protein kinase catalytic subunit knockout cells.

The effort to elucidate the mechanism of V(D)J recombination has given rise to a dispute as to whether DNA-dependent protein kinase catalytic subunit (DNA-PKcs) contributes to signal joint formation (sjf). Observations reported to date are confusing. Analyses using DNA-PKcs-deficient cells could not conclude the requirement of DNA-PKcs for sjf, because sjf can be formed by end-joining activities which are diverse among cells other than those participating in V(D)J recombination. Here, we observed V(D)J recombination in DNA-PKcs knockout cells and showed that both signal and coding joint formation were clearly impaired in the cells. Subsequently, to directly demonstrate the requirement of DNA-PKcs for sjf, we introduced full-length cDNA of DNA-PKcs into the knockout cells. Furthermore, several mutant DNA-PKcs cDNA constructs designed from mutant cell lines (irs-20, V3, murine scid, and SX9) were also introduced into the cells to obtain further evidence indicating the involvement of DNA-PKcs in sjf. We found as a result that the full-length cDNA complemented the aberrant sjf and that the mutant cDNAs constructs also partially complemented it. Lastly, we looked at whether the kinase activity of DNA-PKcs is necessary for sjf and, as a result, demonstrated a close relationship between them. Our observations clearly indicate that the DNA-PKcs controls not only coding joint formation but also the sjf in V(D)J recombination through its kinase activity.

Animals↗
PubMed2000

Suppression of heat-induced HSP-70 by simultaneous exposure to 50 mT magnetic field.

Effect of extremely low frequency magnetic field (ELFMF) at 50 mT and 60 Hz on heat-induced expression of heat shock protein 70 (hsp-70) was examined in HL60RG cells. No increase in hsp-70 production was observed in the cells after exposure to 50 mT ELFMF alone. Simultaneous exposure to 50 mT ELFMF in combination with mild heat at 42 and 40 degrees C suppressed heat-induced hsp-70 expression. The suppression of hsp-70 occurred when cells were simultaneously exposed to both for longer periods of more than 5 h. However, the suppression of hsp-70 was not observed at a magnetic density of 5 and 0.5 mT. This result suggests that exposure to 50 mT ELFMF may act on a protection against the concomitant mild heat stress in HL60RG cells.

Blotting, Western↗
PubMed2000

Identification of four highly conserved regions in DNA-PKcs.

The gene for the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is responsible for severe combined immune deficiency (SCID) and its products associate with Ku70/Ku86 autoantigens, c-Abl, and other factors to exert its roles. Investigations to date suggest that DNA-PKcs comprises several regions which specifically interact with these known and other as yet unidentified factors. Nevertheless, the relationship between the structure and function of the DNA-PKcs molecule is poorly understood. Here we report cloning of the entire DNA-PKcs cDNA from chicken and Xenopus laevis. Comparative study of the DNA-PKcs polypeptides from four different vertebrates revealed at least three novel conserved regions in addition to the carboxyl-terminal region containing the phosphatidylinositol-3 kinase domain. We also demonstrated that the four vertebrates share the common genomic organization between a licensing factor, MCM4, and DNA-PKcs, both of which locate in a head-to-head manner within a few kilobase intervals. These data provide useful clues for the further genetic study of this huge multifunctional enzyme.

Amino Acid Sequence↗
PubMed2000

Effects of YM358, an angiotensin II type 1 (AT1) receptor antagonist, and enalapril on blood pressure and vasoconstriction in two renal hypertension models.

The effects of the angiotensin II type 1 receptor antagonist YM358 on blood pressure were compared to those of the angiotensin converting enzyme inhibitor enalapril in one-kidney, one-clip renal hypertensive rats (1K1C RHR), two-kidney, one-clip renal hypertensive rats (2K1C RHR) and normotensive rats (NTR). Additionally, the local drug actions in peripheral tissues were investigated using isolated mesenteric arteries from these rats. In 2K1C RHR, YM358 and enalapril produced a long-lasting hypotensive effect in a dose-dependent manner. In 1K1C RHR, YM358 (30 mg/kg) also produced an antihypertensive effect, whereas enalapril (30 mg/kg) had no effect. Administration of YM358, but not enalapril, to 1K1C RHR, 2K1C RHR and NTR did not affect heart rate. In isolated mesenteric arteries from 1K1C RHR and 2K1C RHR, angiotensin II (Ang II), angiotensin I (Ang I) and tetradecapeptide (TDP), a physiologically active renin substrate, produced concentration-dependent vasoconstriction. YM358 (10(-7) M) inhibited the vasoconstricting responses to Ang II, Ang I and TDP in isolated mesenteric arteries. In contrast, enalaprilat (10(-7) M), an active metabolite of enalapril, did not completely inhibit the response to Ang I and TDP. These results indicate that YM358 has higher efficacy than enalapril for the treatment of hypertension.

Angiotensin I↗
PubMed2000

[Three cases in which CR was obtained in residual metastatic lesions by intrahepatic arterial infusion after resection of hepatic metastases from colorectal carcinoma].

We report three cases in which CR was maintained after infusion (WHF) was performed for residual metastatic lesions following resection of hepatic metastases from colorectal cancer. (Case 1) A 55-year-old female with sigmoidal cancer and hepatic metastases, H2 (4 lesions). Right lobectomy and partial resection of the left lobe were performed. On the third month following surgery, CT showed two lesions in the lateral segment of the left lobe, and WHF was then begun. One month after the start of infusion, the lesions calcified and following that, disappeared. Infusion was performed for 12 months and the total amount of 5-FU was 52.8 g. Eight years and nine months following surgery, the patient is currently alive and without recurrence. (Case 2) A 65-year-old male with rectal cancer and hepatic metastases, H3 (6 lesions). Four lesions were removed by hepatic resection; however, 2 deep lesions in S4 and S5 were left unresected. WHF was begun one month following surgery, following which the lesions were undetectable by either CT or US. Infusion was performed for 18 months and the total amount of 5-FU was 81 g. Two years and ten months after surgery an isolated lung metastasis was discovered in the right lung and a thoracoscopic partial resection was performed. Eight years and four months following the original surgery and five years and four months following the lung operation the patient is alive and without recurrence. (Case 3) A 55-year-old male with rectal cancer and subsequently discovered hepatic metastases, H3 (5 lesions). Resection of the lateral segment and a partial resection of the right lobe were performed; however, one deep lesion in S7 was left unresected. WHF was begun on the 10th day following surgery. At about eight months there was a change in shape and shrinkage of the lesion. Infusion was performed for 11 months and the total amount of 5-FU was 48 g. Ten months following surgery, CT showed a new lesion in S7 and a partial resection was performed. Intraoperative US confirmed the disappearance of the previous residual lesion in S7. One year and one month following the original surgery, the patient is alive and without recurrence. From these results, it is suggested that with postoperative WHF it is possible to obtain a complete cure in cases of colorectal cancer with hepatic metastases without the resection of all lesions. (*WHF: 5-FU 1,000 mg/m2/5 hrs/week).

Aged↗
PubMed1999

Enhanced phosphorylation of p53 serine 18 following DNA damage in DNA-dependent protein kinase catalytic subunit-deficient cells.

DNA-dependent protein kinase (DNA-PK) controls signal transduction following DNA damage. However, the molecular mechanism of the signal transduction has been elusive. A number of candidates for substrates of DNA-PK have been reported on the basis of the in vitro assay system. In particular, the Ser-15 amino acid residue in p53 was one of the first such in vitro substrates to be described, and it has drawn considerable attention due to its biological significance. Moreover, p53 Ser-15 is a site that has been shown to be phosphorylated in response to DNA damage. In addition, crucial evidence indicating that DNA-PK controls the transactivation of p53 following DNA damage was reported quite recently. To clarify these important issues, we conducted the experiments with dna-pkcs null mutant cells, including gene knockout cells. As a result, we detected enhanced phosphorylation of p53 Ser-18, which corresponds to Ser-15 of human p53, and significant expression of p21 and mdm2 following ionizing radiation. Furthermore, we identified a missense point mutation in the p53 DNA-binding motif region in SCGR11 cells, which were established from severe combined immunodeficient (SCID) mice and used for previous study on the role of DNA-PK in p53 transactivation. Our observation clearly indicates that DNA-PK catalytic subunit does not phosphorylate p53 Ser-18 in vivo or control the transactivation of p53 in response to DNA damage, and these results further emphasize the different pathways in which ataxia telangiectasia-mutated (ATM) and DNA-PK operate following radiation damage.

Animals↗