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Biomedical subjects

S Adachi

Publications and source records attributed to S Adachi.

At least 73 records · Page 4Linked to original sources
PubMed2000

Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria.

Adenine deoxynucleosides induce apoptosis in quiescent lymphocytes and are thus useful drugs for the treatment of indolent lymphoproliferative diseases. To explain why deoxyadenosine and its analogs are toxic to a cell that is not undergoing replicative DNA synthesis, several mechanisms have been proposed, including the direct binding of dATP to the pro-apoptotic factor Apaf-1 and the activation of the caspase-9 and -3 pathways. In this study it is shown, by means of several assays on whole cells and isolated mitochondria, that 2-chloro-2'-deoxyadenosine (2CdA) and 2-choloro-2'-ara-fluorodeoxyadenosine (CaFdA) disrupt the integrity of mitochondria from primary chronic lymphocytic leukemia (B-CLL) cells. The nucleoside-induced damage leads to the release of the pro-apoptotic mitochondrial proteins cytochrome c and apoptosis-inducing factor. The other adenine deoxynucleosides tested displayed comparable DNA-damaging potency but did not affect mitochondrial function. Interference with mitochondrial integrity, thus, may be a factor in the potent cytotoxic effects of 2CdA and CaFdA toward nondividing lymphocytes.

Adenine Nucleotides↗
PubMed2000

Absence of residual quasiparticle conductivity in the underdoped cuprate YBa2Cu4O8.

We report measurements of the in-plane thermal conductivity kappa of the stoichiometric underdoped cuprate YBa2Cu4O8 (Y124) below 1 K. kappa(T) is shown to follow a simple phononic T3 dependence at the lowest temperature T for both current directions, with a negligible linear quasiparticle contribution. This observation is in marked contrast with behavior reported in optimally doped cuprates, and implies that extended zero-energy (or low-energy) quasiparticles are absent in Y124.

Journal Article↗
PubMed2000

Sensory mechanism of oxygen sensor FixL from Rhizobium meliloti: crystallographic, mutagenesis and resonance Raman spectroscopic studies.

FixL of Rhizobium meliloti (RmFixL) is a sensor histidine kinase of the two-component system, which regulates the expression of the genes related to nitrogen fixation in the root nodule in response to the O(2) levels. The crystal structure of the sensor domain of FixL (RmFixLH), which contains a heme (Fe-porphyrin) as a sensing site, was determined at 1.4 A resolution. Based on the structural and spectroscopic analyses, we propose the O(2) sensing mechanism that differs from the case proposed in BjFixLH as follows; conformational changes in the F/G loop, which are induced by steric repulsion between the bent-bound O(2) and the Ile209 side-chain, would be transmitted to the histidine kinase domain. Interaction between the iron-bound O(2) and Ile209 was also observed in the resonance Raman spectra of RmFixLH as evidenced by the fact that the Fe-O(2) and Fe-CN stretching frequencies were shifted from 575 to 570 cm(-1) (Fe-O(2)), and 504 to 499 cm(-1), respectively, as the result of the replacement of Ile209 with an Ala residue. In the I209A mutant of RmFixL, the O(2) sensing activity was destroyed, thus confirming our proposed mechanism.

Bacterial Proteins↗
PubMed2000

Microbial production of 2-chloro-alpha-methylbenzyl alcohol and its adsorptive recovery.

An adsorptive process was combined with yeast-mediated production of chiral 2-chloro-alpha-methylbenzyl alcohol (o-Cl-1-PA) for effective product recovery and reuse of the reaction medium. Low temperature was suitable for long-term reactor operation, and continuous production using a shallow-bed reactor was achieved for at least 22 days while maintaining a high conversion. The appropriate size of the adsorption column for product recovery from the reactor effluent was estimated through measurement of breakthrough curves of o-Cl-1-PA in a packed bed of the resin at various adsorbate concentrations and feed flow rates. Using the adsorption column, 98% of the product and the residual substrate were recovered from the reactor effluent, and the effluent from the adsorption column was successfully reused as the reaction medium after microfiltration to save the medium consumption.

Journal Article↗
PubMed2000

Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine.

L-Carnitine facilitates the transport of fatty acids into the mitochondrial matrix where they are used for energy production. Recent studies have shown that L-carnitine is capable of protecting the heart against ischemia/reperfusion injury and has beneficial effects against Alzheimer's disease and AIDS. The mechanism of action, however, is not yet understood. In the present study, we found that in Jurkat cells, L-carnitine inhibited apoptosis induced by Fas ligation. In addition, 5 mM carnitine potently inhibited the activity of recombinant caspases 3, 7 and 8, whereas its long-chain fatty acid derivative palmitoylcarnitine stimulated the activity of all the caspases. Palmitoylcarnitine reversed the inhibition mediated by carnitine. Levels of carnitine and palmitoyl-CoA decreased significantly during Fas-mediated apoptosis, while palmitoylcarnitine formation increased. These alterations may be due to inactivation of beta-oxidation or to an increase in the activity of the enzyme that converts carnitine to palmitoylcarnitine, carnitine palmitoyltransferase I (CPT I). In support of the latter possibility, fibroblasts deficient in CPT I activity were relatively resistant to staurosporine-induced apoptosis. These observations suggest that caspase activity may be regulated in part by the balance of carnitine and palmitoylcarnitine.

Acylation↗
PubMed2000

Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein.

Wnt signaling has an important role in both embryonic development and tumorigenesis. beta-Catenin, a key component of the Wnt signaling pathway, interacts with the TCF/LEF family of transcription factors and activates transcription of Wnt target genes. Here, we identify a novel beta-catenin-interacting protein, ICAT, that was found to inhibit the interaction of beta-catenin with TCF-4 and represses beta-catenin-TCF-4-mediated transactivation. Furthermore, ICAT inhibited Xenopus axis formation by interfering with Wnt signaling. These results suggest that ICAT negatively regulates Wnt signaling via inhibition of the interaction between beta-catenin and TCF and is integral in development and cell proliferation.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Successive expression and activation of NFAT family members during thymocyte differentiation.

Differentiation of immature CD4(+)CD8(+) thymocytes to mature CD4(+) or CD8(+) T cells is induced by positive selection and appears to involve calcineurin-dependent activation of NFAT, a family of transcription factors. NFATx is predominantly expressed in CD4(+)CD8(+) thymocytes, whereas NFATp and NFATc are expressed at much lower levels in the thymus than in mature T cells. However, how or when each NFAT member is involved in the differentiation pathway is unclear. Using an in vitro model system where isolated CD4(+)CD8(+) thymocytes can survive and differentiate into semi-mature CD4-lineage T cells, we suggest that low calcineurin activity sustained for approximately 20 h is required for cell survival and differentiation. Accordingly, the DNA binding activity of NFAT slowly increased during the stimulation of 20 h to induce the differentiation. NFATx significantly contributed to the early rise, but the late increase was mostly due to NFATc activation. Meanwhile, the expression of NFATx mRNA decreased and that of NFATc mRNA increased. The DNA-binding activity of NFATp was detectable but low throughout the stimulation. NFATp became dominantly active after the semi-mature T cells differentiated into mature and activated CD4 T cells. These findings suggest that NFATx and NFATc successively play roles in T cell development.

Animals↗
PubMed2000

Rational design, synthesis and structure-activity relationships of antitumor (E)-2-benzylidene-1-tetralones and (E)-2-benzylidene-1-indanones.

Novel substituted 6,7-dimethoxy-1-tetralones and 5,6-dimethoxy-1-indanones have been synthesized and evaluated for their cytotoxicity. Compounds with 3'-lipophilic, 3',5'-dilipophilic, or 3',5'-dilipophilic-4'-hydrophilic substituents on (E)-2-benzylidene moiety showed highly cytotoxic effects. The unique structure of 42 possibly matches the pharmacophore features for these cytotoxic compounds.

Antineoplastic Agents↗
PubMed2000

Proton delivery in NO reduction by fungal nitric-oxide reductase. Cryogenic crystallography, spectroscopy, and kinetics of ferric-NO complexes of wild-type and mutant enzymes.

Fungal nitric-oxide reductase (NOR) is a heme enzyme that catalyzes the reduction of NO to N(2)O through its ferric-NO complex, the first intermediate of the catalysis. Crystal structures of the ferric-NO forms of wild type (WT) fungal NOR, and of the Ser(286) --> Val and Ser(286) --> Thr mutant enzymes were determined to 1.7-A resolution at cryogenic temperature (100 K). This shows a slightly tilted and bent NO binding to the heme iron, in sharp contrast to the highly bent NO coordination found in ferrous hemoproteins. In the WT structure, a specific hydrogen-bonding network that connects the active site to the solvent was identified, H(2)O(Wat(74))-Ser(286)-H(2)O(Wat(33))-Asp(393)-solvent. Wat(74) is located 3.10 A from the iron-bound NO. Replacement of Ser(286) with Val or Thr scarcely alters the NO coordination structure but expels the water molecules, Wat(74) from the active site. The Asp(393) mutation does not influence the position of Wat(74), but disrupts the hydrogen-bonding network at Wat(33), as evidenced by enzymatic, kinetic, and spectroscopic (resonance Raman and IR) results. The structural changes observed upon the Ser(286) or the Asp(393) mutation are consistent with the dramatic loss of the enzymatic activity for the NO reduction of fungal NOR. We have conclusively identified the water molecule, Wat(74), adjacent to the iron-bound NO as a proton donor to the Fe-NO moiety. In addition, we find the hydrogen-bonding network, H(2)O(Wat(74))-Ser(286)-H(2)O(Wat(33))-Asp(393), as a proton delivery pathway in the NO reduction reaction by fungal NOR.

Aspartic Acid↗
PubMed2000

Involvement of mi-transcription factor in expression of alpha-melanocyte-stimulating hormone receptor in cultured mast cells of mice.

The microphthalmia (mi) locus encodes a member of the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein family of transcription factors (MITF). We have reported that expression of several genes was impaired in cultured mast cells (CMCs) of mi/mi mice due to a defective transactivation ability of mutant MITF (mi-MITF). We also found that mi/mi CMCs did not express a receptor (MC1R) for alpha-melanocyte-stimulating hormone. The overexpression of the wild-type (+/+) MITF but not mi-MITF normalized the expression of the MC1R in mi/mi CMCs, indicating the involvement of +-MITF in the MC1R gene expression. Next, we analyzed the promoter region of the MC1R gene by the transient cotransfection assay. The luciferase construct under the control of the MC1R promoter and the cDNA-encoding +-MITF or mi-MITF were cotransfected into NIH/3T3 fibroblasts. The cotransfection of +-MITF but not mi-MITF increased the luciferase activity. There were five CANNTG motifs recognized by bHLH-Zip-type transcription factors in the cloned promoter region. We found +-MITF bound two of five CANNTG motifs, and both motifs were essential for the transactivation of the MC1R gene by +-MITF. These results indicated that +-MITF directly transactivated the MC1R gene through these two motifs.

Animals↗
PubMed2000

Early oxidative DNA damages and late development of lung cancer in diesel exhaust-exposed rats.

To demonstrate DNA damages in the early stage of diesel exhaust exposure, an inhalation study of 1 through 12 months was conducted. The lung burden of diesel soot increased with increase in exposure duration. Histologically, hyperplastic foci of alveolar epithelia were found at 6-month exposure and became prominent at the 12th month, with slight nuclear atypia and positive p53 staining. The level of 8-OH-hydroxyguanosine (8-OH-dG) in the exposed rat lungs showed an increase from 1 month of exposure, followed by a gradual increase, reaching almost a plateau level at the 9th month. An in vitro experiment demonstrated significant 8-OH-dG formation when diesel particles and H(2)O(2) were added to the DNA solution. The level of bulky aromatic DNA adducts peaked at the 1st month of exposure, followed by a decrease. By the end of the observation period of 30 months, lung tumors developed even in the 6-month exposure group, and the earliest lung tumors were found only in rats that survived longer than 18 months. In conclusion, persisting oxidative stress on DNA induced in the early phase of diesel exhaust exposure, together with inflammation, seems to play an important role in carcinogenesis at advance ages after a long latent period.

Animals↗
PubMed2000

Molecular cloning and characterization of Japanese eel ovarian P450c17 (CYP17) cDNA.

As a first step in investigating the mechanism underlying the steroidogenic shift from the production of ovarian androgens (vitellogenic stage) to that of 17alpha-hydroxylated progestins (maturational stage) in Japanese eel during induced oogenesis, a cDNA encoding Japanese eel (Anguilla japonica) ovarian P450c17 (CYP17: steroid 17alpha-hydroxylase/C(17-20) lyase) was cloned and sequenced. This cDNA contained the complete coding region representing 510 amino acid residues, which showed high sequence homology to those of rainbow trout (74%) and mammals (45-55%). The protein encoded by this cDNA possessed high enzymatic activities of 17alpha-hydroxylase and C(17-20) lyase, thus quickly converting pregnenolone and progesterone to their respective delta(4) and delta(5) C19 products. P450c17 produced a single transcript of 2.4 kb in length, as assessed by Northern blot. Transcript levels of this enzyme significantly increased throughout artificially induced ovarian development. Considering this together with the previous data showing that C(17-20) lyase activity decreased from the vitellogenic to the maturational stage, whereas 17alpha-hydroxylase activity increased, the present data suggest that changes in C(17-20) lyase activity (the production of androgens) do not depend on transcriptional changes of the P450c17 gene.

Amino Acid Sequence↗
PubMed2000

Adult aortic arch atresia.

Atresia in the aortic arch is a rare and severe congenital cardiovascular anomaly. Without surgical therapy, only a few patients can survive to adulthood. A 29-year-old woman with atresia of the aortic arch (Celoria-Patton Type A) without any intracardiac shunt underwent primary surgical correction involving reconstruction of the aortic arch with prosthetic interposition between the transverse aortic arch and the descending aorta and division of the persistent ductus arteriosus. Her postoperative course was uneventful, and she is now doing well at three years to date after surgical treatment.

Adult↗
PubMed2000

Predicting the prognosis of non-small cell lung cancer patient treated with conservative therapy using contrast-enhanced MR imaging.

The aim of this study was to evaluate the therapeutic effect more accurately and predict the prognosis of treated non-small cell lung cancer by using contrast-enhanced magnetic resonance imaging (CE-MRI). Contrast-enhanced computed tomography (CE-CT) and CE-MRI were examined 90 non-small cell lung cancer patients treated with conservative therapies. Enhancement patterns of CE-MRI were classified into three types: peripheral; mottled; and homogeneous. Reduction ratio of tumor size (RRT) based on the World Health Organization response criteria and a new response rate; reduction ratio of viable tumor size (RRVT) which evaluates not only the reduction of tumor size but also changes in necrosis and/or cavity size, were evaluated. Changes of enhancement pattern were compared and correlated with pathological diagnosis. The RRTs, RRVTs, and interobserver agreements evaluated by all modalities were compared. The RRTs and RRVTs in each subgroup were correlated and compared with prognoses. Change of enhancement pattern depended on therapy had no tendency (p = 0.06). Enhancement pattern had significant correlation with pathological diagnosis (p < 0.0001). Partial response (PR) case of RRVT had significant difference between imaging techniques (p = 0.04). The RRVT of other cases and RRT had no significant difference. Interobserver agreements of RRT and RRVT were almost perfect (n > or = 0.93). Prognosis had better correlation with RRVT than with RRT. Differences of relapse-free survival and survival between patients considered as having no change (NC) by RRT and PR by RRVT (NC-PR) and patients considered as having NC by RRT and RRVT were significant (p = 0.03, p = 0.01). There were no significant differences of relapse-free survival and survival between NC-PR patients and patients considered as having PR by RRT and RRVT. The CE-MRI technique could accurately evaluate the therapeutic effect and predict the prognosis of treated non-small cell lung cancer.

Aged↗
PubMed2000

Idiopathic calcifying pancreatitis in a Japanese pediatric patient.

We recently experienced a rare case of chronic pancreatitis in a 13-year-old Japanese boy. Recently, in hereditary pancreatitis patients, some mutations have been identified in the trypsinogen gene. The purpose of this study was to investigate whether the same mutations could also be found in this patient. Polymerase chain reaction (PCR)-amplified products of his cationic and anionic trypsinogen genes were examined by direct sequence analysis. The gene analysis failed to show any mutation in any exons and their flanking intronic sequences of his trypsinogen genes. These findings indicate that the chronic calcifying pancreatitis in the present patient is "idiopathic", and thus a rare case of juvenile pancreatitis.

Adolescent↗
PubMed2000

IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies.

Serum interleukin-18 (IL-18) levels were measured in women in different trimesters of pregnancy, in labour, puerperium and in various complicated pregnancies. There was a significant elevation of IL-18 levels in pregnant sera from the first trimester until the onset of labour. Once labour began, IL-18 levels increased further and remained until at least the third day of puerperium. The high levels of IL-18 in sera were also observed in various complicated pregnancies, such as premature rupture of membranes (PROM), acute fatty liver of pregnancy and fetal growth restriction. IL-18 is likely to play a role in pregnancy.

Female↗
PubMed2000

Effect of the molar ratio of an energy source to the substrate on yeast-mediated production of 2-chloro-alpha-methylbenzyl alcohol.

Pachysolen tannophilus cells immobilized in Ca-alginate gels were shown to catalyze the asymmetric reduction of acetophenone (AP) and chloroacetophenones (Cl-APs) to their corresponding alcohols. The position of the Cl-group on the aromatic ring of AP greatly affected the reaction rate, and o-Cl-AP was the most readily reduced. For the reduction of o-Cl-AP to 2-chloro-alpha-methylbenzyl alcohol, the effect of the molar ratio of the energy source, glucose, to the substrate was examined in both batch and continuous operations, and a molar ratio much lower than that conventionally used was found to be sufficient for the reduction.

Journal Article↗