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Biomedical subjects

T Ikeda

Publications and source records attributed to T Ikeda.

At least 73 records · Page 4Linked to original sources
PubMed2001

Normalization of elevated hepatic 8-hydroxy-2'-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet.

Accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA, which may result from the continuous reactive oxygen species (ROS) generation associated with chronic inflammation, has been reported in various human preneoplastic lesions and in cancerous tissues. However, no direct causative relationship between the 8-OHdG formation and carcinogenesis has been thus far demonstrated in humans. Directly proving the causality requires showing that depletion of 8-OHdG levels in tissue by interfering with ROS generation results in a reduction in cancer. Chronic hepatitis C virus (HCV) infection is associated with a high risk of hepatocellular carcinoma (HCC). Several studies on patients with chronic HCV have shown that hepatic iron overload is attributable to liver injury and that iron depletion improved serum aminotransferase levels. Excess iron is known to generate ROS within cells, which causes mutagenic lesions, such as 8-OHdG. In this study, therefore, we have evaluated whether therapeutic iron reduction (phlebotomy and low iron diet) with a long-term follow-up (6 years) would decrease the hepatic 8-OHdG levels and the risk of HCC development in patients with chronic HCV. Patients (34) enrolled were those who had undergone standard IFN therapy but had no sustained response. Quantitative immunohistochemistry using the KS-400 image analyzing system and electrochemical detection was used for 8-OHdG detection. With this treatment, elevated hepatic 8-OHdG levels in patients with chronic hepatitis C (8.3 +/- 4.6/10(5) dG) significantly decreased to almost normal levels (2.2 +/- 0.9/10(5) dG; P < 0.001) with concomitant improvement of hepatitis severity, including fibrosis, whereas HCV titers were unaffected. None of these patients developed HCC. Thus, long-term iron reduction therapy in patients with chronic hepatitis C may potentially lower the risk of progression to HCC.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Novel mutation in exon 18 of the cartilage oligomeric matrix protein gene causes a severe pseudoachondroplasia.

Pseudoachondroplasia (PSACH) is a common skeletal dysplasia characterized by disproportionate short stature, early-onset osteoarthrosis, and dysplasia of the spine, epiphysis, and metaphysis. Multiple epiphyseal dysplasia (MED) is a similar but less severe disorder characterized by dysplasia of the epiphysis. Both disorders are caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. COMP mutations cluster in a region of the gene that encodes calmodulin-like repeats (CLRs) and correlate closely with disease severity. Typically, mutations in exon 13 that composes the seventh CLR produce severe PSACH phenotypes, whereas mutations found elsewhere in the gene produce mild PSACH or MED phenotypes. We have identified a PSACH patient carrying a novel mutation in exon 18 of COMP that composes the C-terminal globular domain. This mutation produced a severe PSACH phenotype with marked short stature and deformities of the spine and extremities. Our results extend the range of disease-causing mutations within the COMP gene and demonstrate the importance of the additional domain of COMP protein in its in vivo function.

Achondroplasia↗
PubMed2001

Structure of a quinohemoprotein amine dehydrogenase with an uncommon redox cofactor and highly unusual crosslinking.

The crystal structure of the heterotrimeric quinohemoprotein amine dehydrogenase from Paracoccus denitrificans has been determined at 2.05-A resolution. Within an 82-residue subunit is contained an unusual redox cofactor, cysteine tryptophylquinone (CTQ), consisting of an orthoquinone-modified tryptophan side chain covalently linked to a nearby cysteine side chain. The subunit is surrounded on three sides by a 489-residue, four-domain subunit that includes a diheme cytochrome c. Both subunits sit on the surface of a third subunit, a 337-residue seven-bladed beta-propeller that forms part of the enzyme active site. The small catalytic subunit is internally crosslinked by three highly unusual covalent cysteine to aspartic or glutamic acid thioether linkages in addition to the cofactor crossbridge. The catalytic function of the enzyme as well as the biosynthesis of the unusual catalytic subunit is discussed.

Amino Acid Sequence↗
PubMed2001

Thoracoscopic surgery for pneumothorax in older patients.

BACKGROUND: Secondary pneumothorax is more common in older pneumothorax patients. Therefore, we set out to investigate the usefulness of thoracoscopic surgery in this group. METHODS: A total of 59 operations were performed on patients aged > or = 50 years, with the goal of excising only the lesions responsible for air leaks by using the minimum degree of dissection. If the patients were found to have numerous bullae, the lesions responsible were identified by pleurography. The duration of chest tube drainage, hospital stay, and recurrence were assessed. RESULTS: The air leaks stopped and all patients were discharged without drains. Postoperative drainage time was 3.8 +/- 3.0 days. Postoperative hospital stay was 10.8 +/- 9.2 days. Six patients died of other diseases, but there was only one recurrence of pneumothorax. CONCLUSION: We consider video-assisted thoracic surgery (VATS), with the goal of excising only the lesions responsible for air leaks, to be particularly efficacious in older pneumothorax patients.

Aged↗
PubMed2001

Ru(3)(CO)(12)-catalyzed coupling reaction of sp(3) C-H bonds adjacent to a nitrogen atom in alkylamines with alkenes.

Catalytic reactions which involve the cleavage of an sp(3) C-H bond adjacent to a nitrogen atom in N-2-pyridynyl alkylamines are described. The use of Ru(3)(CO)(12) as the catalyst results in the addition of the sp(3) C-H bond across the alkene bond to give the coupling products. A variety of alkenes, including terminal, internal, and cyclic alkenes, can be used for the coupling reaction. The presence of directing groups, such as pyridine, pyrimidine, and an oxazoline ring, on the nitrogen of the amine is critical for a successful reaction. This result indicates the importance of the coordination of the nitrogen atom to the ruthenium catalyst. In addition, the nature of the substituents on the pyridine ring has a significant effect on the efficiency of the reaction. Thus, the substitution of an electron-withdrawing group on the pyridine ring as well as a substitution adjacent to the sp(2) nitrogen in the pyridine ring dramatically retards the reaction. Cyclic amines are more reactive than acyclic ones. The choice of solvent is also very important. Of the solvents examined, 2-propanol is the solvent of choice.

Journal Article↗
PubMed2001

Synthesis and metal-ion binding properties of monoazathiacrown ethers.

Synthetic procedures for monoazathiacrown ethers were explored, and monoazatrithia-12-crown-4, monoazatetrathia-15-crown-5, and monoazapentathia-18-crown-6 were obtained in moderate yields by the reaction of bis(2-chloroethyl)amine with the appropriate dithiols in the presence of lithium hydroxide in THF. To evaluate metal-ion binding properties of the monoazathiacrown ethers by solvent extraction, lipophilic dodecyl and dodecanoyl groups were incorporated onto the monoazathiacrown ethers. The solvent extraction experiments suggested that monoazathiacrown ethers have Ag(+) and Hg(2+) selectivities and that the relative selectivity between Ag(+) and Hg(2+) depends on their nitrogen atom properties and numbers of sulfur atoms reflecting the respective affinities of nitrogen and sulfur atoms to Hg(2+) and Ag(+). An interesting ability to bind Mg(2+) was observed in the case of N-dodecyl monoazatrithia-12-crown-4.

Journal Article↗
PubMed2001

Characterization of the metal-substituted dipeptidyl peptidase III (rat liver).

Dipeptidyl peptidase III (DPP III) (EC 3.4.14.4), which has a HELLGH-E (residues 450-455, 508) motif as the zinc binding site, is classified as a zinc metallopeptidase. The zinc dissociation constants of the wild type, Leu(453)-deleted, and E508D mutant of DPP III at pH 7.4 were 4.5 (+/-0.7) x 10(-13), 5.8 (+/-0.7) x 10(-12), and 3.2 (+/-0.9) x 10(-10) M, respectively. The recoveries of the enzyme activities by the addition of various metal ions to apo-DPP III were also measured, and Co(2+), Ni(2+), and Cu(2+) ions completely recovered the enzyme activities as did Zn(2+). The dissociation constants of Co(2+), Ni(2+), and Cu(2+) ions for apo-DPP III at pH 7.4 were 8.2 (+/-0.9) x 10(-13), 2.7 (+/-0.3) x 10(-12), and 1.1 (+/-0.1) x 10(-14) M, respectively. The shape of the absorption spectrum of Co(2+)-DPP III was very similar to that of Co(2+)-carboxypeptidase A or Co(2+)-thermolysin, in which the Co(2+) is bound to two histidyl nitrogens, a water molecule, and a glutamate residue. The absorption spectrum of Cu(2+)-DPP III is also very similar to that of Cu(2+)-thermolysin. The EPR spectrum and the EPR parameters of Cu(2+)-DPP III were very similar to those of Cu(2+)-thermolysin but slightly different from those of Cu(2+)-carboxypeptidase A. The five lines of the superfine structure in the perpendicular region of the EPR spectrum in Cu(2+)-DPP III suggest that nitrogen atoms should coordinate to the cupric ion in Cu(2+)-DPP III. All of these data suggest that the donor set and the coordination geometry of the metal ions in DPP III, which has the HExxxH motif as the metal binding site, are very similar to those of the metal ions in thermolysin, which has the HExxH motif.

Animals↗
PubMed2001

Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis.

Hepatocyte growth factor (HGF) has been proposed as an endogenous cardioprotective agent against oxidative stress. The mechanism of HGF action in the heart, however, has not yet been elucidated. The present study demonstrates that HGF protects adult cardiac myocytes against oxidative stress-induced apoptosis. HGF, at the concentrations which can be detected in the plasma of humans subsequent to myocardial infarction, effectively attenuated death of isolated adult rat cardiac myocytes and cultured HL-1 cardiac muscle cells induced by apoptosis-inducing oxidative stress stimuli such as daunorubicin, serum deprivation, and hydrogen peroxide. We identified expression of c-Met HGF receptor in adult cardiac myocytes, which can be rapidly tyrosine phosphorylated in response to HGF treatment. HGF also activated MEK, p44/42 MAPK, and p90RSK. To determine if MEK-MAPK pathway may be involved in the mechanism of HGF-mediated cardiac myocyte protection, effects of a specific MEK inhibitor, PD98059, were studied. Pretreatment of cells with PD98059 partially blocked HGF signaling for protection against hydrogen peroxide-induced cell death. Thus, HGF protects cardiac myocytes against oxidative stress, in part, via activating MEK-MAPK pathway.

Animals↗
PubMed2001

Association of maspin expression with the malignancy grade and tumor vascularization in breast cancer tissues.

Maspin belongs to a tumor suppressing protein which is usually expressed highly in myoepithelial cells, and is significantly downregulated in breast cancer cells. We focused on identifying the correlation between maspin expression and the clinicopathological features of human breast cancer tissues using immunohistochemistry. There was a significant correlation in that maspin-positive tumor specimens showed a low pathological grade of malignancy, such as a lower infiltration of the tumor into the surrounding tissue and a downregulation of c-erbB2 expression. Moreover, maspin-positive cases showed a significant decrease in tumor vessels positively stained with anti-factor VIII-related antigen antibody. These results suggest that maspin production in myoepithelial cells could downregulate the malignant phenotype of breast cancer.

Biomarkers, Tumor↗
PubMed2001

MK-801 reduces non-noxious stimulus-evoked Fos-like immunoreactivity in the spinal cord of rats with chronic constriction nerve injury.

We investigated the role of N-methyl-D-aspartate (NMDA) receptors on non-noxious stimulus-induced pain by examining the effect of MK-801, a non-competitive NMDA receptor antagonist, on Fos-like immunoreactivity (FLI) in the spinal dorsal horn by non-noxious stimulation to rats with chronic constriction injury (CCI) of the sciatic nerve. In CCI rats that did not receive the non-noxious stimulus, FLI was significantly increased in laminae V/VI of the dorsal horn at the 7th and 14th days after surgery relative to sham rats. When CCI rats received non-noxious stimuli, rubbing the plantar of the hind paw, FLI in laminae I/II at the 14th day was significantly increased relative to CCI rats that did not receive the stimulation. In sham rats, the same stimulus significantly decreased FLI in laminae III/IV and V/VI at the 7th and 14th day. When MK-801 was administered intraperitoneally prior to non-noxious stimulation in CCI rats at the 14th day after surgery, the stimulus-induced FLI in laminae I/II in CCI rats was significantly reduced. This study indicates that NMDA receptor is involved in upregulating FLI in response to non-noxious stimulation of CCI rats.

Animals↗
PubMed2001

Ca(2+) stabilizes the semiquinone radical of pyrroloquinoline quinone.

Spectroelectrochemical studies were performed on the interaction between Ca(2+) and pyrroloquinoline quinone (PQQ) in soluble glucose dehydrogenase (sGDH) and in the free state by applying a mediated continuous-flow column electrolytic spectroelectrochemical technique. The enzyme forms used were holo-sGDH (the holo-form of sGDH from Acinetobacter calcoaceticus) and an incompletely reconstituted form of this, holo-X, in which the PQQ-activating Ca(2+) is lacking. The spectroelectrochemical and ESR data clearly demonstrated the generation of the semiquinone radical of PQQ in holo-sGDH and in the free state in the presence of Ca(2+). In contrast, in the absence of Ca(2+) no semiquinone was observed, either for PQQ in the free state (at pH 7.0) or in the enzyme (holo-X). Incorporation of Ca(2+) into the active site of holo-X, yielding holo-sGDH, caused not only stabilization of the semiquinone form of PQQ but also a negative shift (of 26.5 mV) of the two-electron redox potential, indicating that the effect of Ca(2+) is stronger on the oxidized than on the reduced PQQ. Combining these data with the observations on the kinetic and chemical mechanisms, it was concluded that the strong stimulating effect of Ca(2+) on the activity of sGDH can be attributed to facilitation of certain kinetic steps, and not to improvement of the thermodynamics of substrate oxidation. The consequences of this conclusion are discussed for the oxidative as well as for the reductive part of the reaction of sGDH.

Acinetobacter calcoaceticus↗
PubMed2001

Role of inorganic polyphosphate in promoting ribosomal protein degradation by the Lon protease in E. coli.

Inorganic polyphosphate (polyP), a polymer of hundreds of phosphate (Pi) residues, accumulates in Escherichia coli in response to stresses, including amino acid starvation. Here we show that the adenosine 5'-triphosphate-dependent protease Lon formed a complex with polyP and degraded most of the ribosomal proteins, including S2, L9, and L13. Purified S2 also bound to polyP and formed a complex with Lon in the presence of polyP. Thus, polyP may promote ribosomal protein degradation by the Lon protease, thereby supplying the amino acids needed to respond to starvation.

ATP-Dependent Proteases↗
PubMed2001

Identification of human liver diacetyl reductases by nano-liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry.

Several forms of diacetyl-reducing enzyme were found to exist in the human liver cytosol. Three (DAR-2, DAR-5, and DAR-7) of them were purified as a single band on SDS-PAGE by a combination of a few kinds of column chromatographies. The in-gel tryptic digests of the purified enzymes were analyzed by nano-liquid chromatography (LC)/Fourier transform ion cyclotron resonance mass spectrometry (FT ICR MS), which provided peptide masses at a ppm-level accuracy. The enzymes, DAR-2, DAR-5, and DAR-7, were identified as alcohol dehydrogenase beta subunit (ADH2), carbonyl reductase (CBR1), and aldehyde reductase (AKR1A1), respectively, by peptide mass fingerprinting. In addition, an alternating-scan acquisition of nano-LC/FT ICR mass spectra, i.e., switching of normal acquisition conditions and in-source fragmentation conditions scan by scan, provided sets of parent and fragment ion masses of many of the tryptic peptides in a single LC/MS run. The peptide sequence-tag information at the ppm-level accuracy was used to further confirm the protein identities. It was demonstrated that nano-LC/FT ICR MS can be used for rigorous protein identification at a subpicomole level as an alternative technique to nano-LC/MS/MS.

Acetoin Dehydrogenase↗
PubMed2001

A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload.

Ferritin, which is composed of H and L subunits, plays an important role in iron storage and in the control of intracellular iron distribution. Synthesis of both ferritin subunits is controlled by a common cytosolic protein, iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5'-UTR of the H- and L-ferritin mRNAs. In the present study, we have identified a single point mutation (A49U) in the IRE motif of H-ferritin mRNA, in four of seven members of a Japanese family affected by dominantly inherited iron overload. Gel-shift mobility assay and Scatchard-plot analysis revealed that a mutated IRE probe had a higher binding affinity to IRP than did the wild-type probe. When mutated H subunit was overexpressed in COS-1 cells, suppression of H-subunit synthesis and of the increment of radiolabeled iron uptake were observed. These data suggest that the A49U mutation in the IRE of H-subunit is responsible for tissue iron deposition and is a novel cause of hereditary iron overload, most likely related to impairment of the ferroxidase activity generated by H subunit.

Aged↗
PubMed2001

Abdominal ultrasonography reveals the perforation site of duodenal ulcers.

Regardless of whether or not the laparoscopic approach is used, the simple closure using an omental patch is considered to be preferable to other surgical therapies for a duodenal ulcer perforation. We used abdominal ultrasonography (US) to identify the perforation site of the duodenal ulcer. To our knowledge, this is the first report describing how the perforation site of duodenal ulcers can be identified using US. Three patients diagnosed with perforated duodenal ulcers based on abdominal computed tomography and abdominal radiographic findings were scheduled for surgery. Under general anesthesia, US demonstrated free air on the liver and a "fish-eye sign" when the anterior or lateral wall was perforated. We performed a simple closure using an omental patch through a skin incision measuring only 3 cm in diameter above the area showing the fish-eye sign. The postoperative recovery was no different from that seen when a laparoscopic approach is used at our hospital. Even though the laparoscopic procedure is still the surgical modality of choice, the US technique allows for a successful diagnosis without invasive examinations. We believe that most surgeons and/or radiologists should try to detect the fish-eye sign using US as the diagnostic modality of first choice if they suspect a duodenal ulcer perforation. This technique allows us to mark the perforation site accurately before surgery.

Duodenal Ulcer↗
PubMed2001

2-Acylimino-3H-thiazoline derivatives: a novel template for platelet GPIIb/IIIa receptor antagonists.

In the course of our research for the low-molecular weight RGD peptide mimics, we have found that a rigid 2-acylimino-3H-thiazoline structure is suitable for the peptide backbone mimics. Introduction of amidinophenyl and beta-alanine moiety as arginine and aspartic acid side-chain surrogates to this backbone mimic resulted in a highly potent fibrinogen receptor antagonist 2-(4-amidinobenzoylimino)-3,4-dimethyl-N-(2-carboxyethyl)-3H-thiazoline-5-carboxamide (7c), namely PS-028 (Ki = 46.5 +/- 5.8 microM).

Animals↗
PubMed2001

Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma.

We examined the effect of berberine, a major component with anti-fungal properties contained in Coptidis Rhizoma and Phellodendri Cortex, on the lymph node metastasis of murine lung cancer. Oral administration of berberine for 14 days significantly inhibited the spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma (LLC) into the lung parenchyma in a dose-dependent manner, but did not affect the tumor growth at the implantation site of the lung. Combined treatment with berberine and an anti-cancer drug, CPT-11, resulted in a marked inhibition of tumor growth at the implantation site and of lymphatic metastasis, as compared with either treatment alone. Anti-activator protein-1 (anti-AP-1) transcriptional activity of non-cytotoxic concentrations of berberine caused the inhibition of the invasiveness of LLC cells through the repression of expression of urokinase-type plasminogen activator (u-PA).

Animals↗