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Biomedical subjects

Takayoshi Suzuki

Publications and source records attributed to Takayoshi Suzuki.

At least 19 recordsLinked to original sources
PubMed2007

Granulocyte colony-stimulating factor promotes the translocation of protein kinase Ciota in neutrophilic differentiation cells.

Previously, we suggested that the phosphatidylinositol 3-kinase (PI3K)-p70 S6 kinase (p70 S6K) pathway plays an important role in granulocyte colony-stimulating factor (G-CSF)-dependent enhancement of the neutrophilic differentiation and proliferation of HL-60 cells. While atypical protein kinase C (PKC) has been reported to be a regulator of p70 S6K, abundant expression of PKCiota was observed in myeloid and lymphoid cells. Therefore, we analyzed the participation of PKCiota in G-CSF-dependent proliferation. The maximum stimulation of PKCiota was observed from 15 to 30 min after the addition of G-CSF. From 5 to 15 min into this lag time, PKCiota was found to translocate from the nucleus to the membrane. At 30 min it re-translocated to the cytosol. This dynamic translocation of PKCiota was also observed in G-CSF-stimulated myeloperoxidase-positive cells differentiated from cord blood cells. Small interfering RNA for PKCiota inhibited G-CSF-induced proliferation and the promotion of neutrophilic differentiation of HL-60 cells. These data indicate that the G-CSF-induced dynamic translocation and activation processes of PKCiota are important to neutrophilic proliferation.

Cell Differentiation↗
PubMed2006

Preparation and characterization of mixed-ligand cobalt(III) complexes containing (3-aminopropyl)dimethylphosphine (pdmp). Conformation of the six-membered pdmp chelate ring.

Several new cobalt(III) complexes containing (3-aminopropyl)dimethylphosphine (pdmp) have been prepared, and their molecular structures have been determined. A dichloro complex of trans(Cl,Cl)-cis(P,P)-[CoCl(2)(pdmp)(2)]PF(6) (1) was prepared from trans-[CoCl(2)(py)(4)]Cl.6H(2)O and pdmp. X-Ray crystallography confirmed the (C(2))-chair(2) conformation of two six-membered pdmp chelate rings in 1, while the analogous 1,3-bis(dimethylphosphino)propane (dmpp) complex trans-[CoCl(2)(dmpp)(2)]ClO(4) (3) exhibited the (D(2d))-twist(2) conformation. Substitution reactions of 1 for ethane-1,2-diamine (en), pentane-2,4-dionate (acac), and N,N-dimethyldithiocarbamate (dtc) gave the mixed-ligand tris(chelate)-type complexes of [Co(en)(2)(pdmp)]Cl(2)(PF(6)) (5), [Co(acac)(pdmp)(2)](PF(6))(2) (7), and [Co(dtc)(3-n)(pdmp)(n)](PF(6))(n) [n = 1 (9) or 2 (10)], respectively. The conformer of the complex cation in 5 was assigned as lel.ob.chair by X-ray analysis. In the case of the acac complex 7, both trans(P,N) (7a) and trans(N,N) (7b) isomers were isolated, and the complex cations were characterized as syn-chair(2) and anti-chair(2) conformers, respectively, with respect to the six-membered pdmp chelate rings. These conformers coincide with the most stable ones anticipated by the DFT optimum geometry calculations. In the crystal structure of trans(P,N)-[Co(dtc)(pdmp)(2)](BPh(4))(2) (10') one of the pdmp chelate rings adopted a skew-boat (twist) conformation, which reduced the intramolecular steric ring-ring interaction effectively. The DFT optimized geometries for several isomers and/or conformers of [CoCl(2)(pdmp)(2)](+) were compared.

Chelating Agents↗
PubMed2006

Hydroxyl radical scavenging by edaravone derivatives: Efficient scavenging by 3-methyl-1-(pyridin-2-yl)-5-pyrazolone with an intramolecular base.

We synthesized various 3-methyl-1-phenyl-5-pyrazolone (edaravone) derivatives and evaluated their oxidation potential and hydroxyl radical scavenging activity. It was found 3-methyl-1-(pyridin-2-yl)-5-pyrazolone had a much higher ability to scavenge the radical than did edaravone itself. Its efficient radical scavenging activity was assumed to be due to the increase of its anion form, an active form, by a hydrogen-bonded intramolecular base.

Antipyrine↗
PubMed2006

Cis-bis[(3-aminopropyl)dimethylphosphine-kappa2N,P]palladium(II) dichloride methanol solvate.

In the title compound, cis-[Pd(C5H14NP)2]Cl2.CH4O, the coordination geometry around the PdII center is distorted square planar, with a cis-P2N2 configuration of the two chelating (3-aminopropyl)dimethylphosphine (pdmp) ligands. The six-membered pdmp chelate rings adopt chair conformations, and pairing of the chairs designates the complex cation as a (Cs)-chair2 conformer. The distances between the PdII center and the Cl- anions are greater than 4.5 A, indicating no obvious interaction.

Journal Article↗
PubMed2006

8-Hydroxydeoxyguanosine levels in human leukocyte and urine according to exposure to organophosphorus pesticides and paraoxonase 1 genotype.

OBJECTIVE: In order to investigate a role of paraoxonase 1 (PON1) polymorphism in organophosphorus (OP)-induced 8-hydroxydeoxyguanosine (8-OHdG) levels, urinary metabolites of OP, PON1 genotypes, and 8-OHdG levels in leukocyte and urine were measured in OP indoor insecticide sprayers and controls in summer and winter. METHODS: The study population contained 18 male sprayers and age-matched 18 male controls. Sprayers were primarily exposed to OP insecticides (mainly fenitrothion, dichlorvos, chlorpyrifos, and diazinon), and partially to pyrethroids (mainly permethrin) and carbamates (mainly propoxur). Urinary metabolites of OP were measured by gas chromatography-mass spectrometry. 8-OHdG levels in leukocyte and urine were measured by ELISA kit. PON1 genotype was identified using allele-specific fluorogenic TaqMan probes. RESULTS: The mean concentrations of urinary dimethyl phosphate (DMP) and total dialkyl phosphates (DAP) in summer and those of 8-OHdG in summer and winter were significantly higher in OP sprayers than controls. This resulted in a significant positive correlation between 8-OHdG levels and urinary DMP or DAP, suggesting a correlation between OP metabolites and production of oxidative stress. Of PON1 genotypes, incidences of Q/Q, Q/R, and R/R types were 17, 39, and 44% in OP sprayers and controls, respectively. Although PON1 polymorphism did not contribute to the leukocyte and urinary 8-OHdG levels, the urinary OP metabolite concentrations in summer showed a significant decrease as the number Q allele decreased. CONCLUSION: These results indicate that an increase in OP metabolites is associated with a high level of oxidative stress in OP sprayers, although the contribution of the PON1 polymorphism to the metabolism of OP is still unclear.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2006

Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate.

To find novel histone deacetylase 6 (HDAC6)-selective inhibitors and clarify the structural requirements for HDAC6-selective inhibition, we prepared thiolate analogues designed based on the structure of an HDAC6-selective substrate and evaluated the histone/alpha-tubulin acetylation selectivity by Western blot analysis. Aliphatic compounds 17b-20b selectively caused alpha-tubulin acetylation over histone H4 acetylation. In enzyme assays using HDAC1, HDAC4, and HDAC6, compounds 17a-19a exhibited HDAC6-selective inhibition over HDAC1 and HDAC4.

Acetylation↗
PubMed2006

Novel configurational structures of sodium tetrakis(3-heptafluorobutylryl-(+)-camphorato) Ln(III) complexes with a trapped Na+ by Na+...FC interactions in the solid state and in solution.

For newly prepared sodium tetrakis(3-heptafluorobutylryl-(+)-camphorato) Ln(III) complexes, the X-ray crystal analysis revealed an unprecedented pseudo-achiral dodecahedron (DD-8 (D(2d))), whereas in CHCl3 solution, the exciton CD and 19F NMR spectra showed a novel chiral Delta-SAPR-8 (C4) configuration which is stereospecifically formed by a trapped Na+ ion with Na+...FC (fluorocarbon) interactions.

Camphor↗
PubMed2006

Flow cytometric analysis of micronuclei in peripheral blood reticulocytes: I. Intra- and interlaboratory comparison with microscopic scoring.

Accumulating evidence suggests that reticulocytes (RETs) in the peripheral blood of rats may represent a suitable cell population for use in the micronucleus assay, despite the ability of the rat spleen to selectively remove micronucleated erythrocytes from the peripheral circulation. To evaluate the analytical performance of a previously described flow cytometric method (Torous et al., 2003, Toxicol. Sci. 74, 309-314) that may allow this assay to be conducted using peripheral blood in lieu of bone marrow sampling, we compared the sensitivity and performance characteristics of the flow cytometric technique with two established microscopy-based scoring methods. Peripheral blood samples from single Sprague-Dawley rats treated for 6 days with either vehicle or cyclophosphamide were prepared in replicate for scoring by the three methods at different laboratories. These blood-based measurements were compared to those derived from bone marrow specimens from the same animals, stained with acridine orange, and scored by microscopy. Through the analysis of replicate specimens, inter- and intralaboratory variability were evaluated for each method. Scoring reproducibility over time was also evaluated. These data support the premise that rat RETs harvested from peripheral blood are a suitable cell population to assess genotoxicant-induced micronucleus formation. The interlaboratory comparison provides evidence of the general robustness of the micronucleus endpoint using different analytical approaches. Furthermore, data presented herein demonstrate a clear advantage of flow cytometry-based scoring over microscopy-significantly lower inter- and intralaboratory variation and higher statistical sensitivity.

Animals↗
PubMed2006

Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109.

Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp),1,2 we extended the structure-activity relationship (SAR) study to analogues bearing a substituted biphenyl group and succeeded in a significant advancement of activity. Starting from compound 1, optimization of the A, B, and C rings afforded potent inhibitors with low nanomolar potency against genotype 1b NS5B. The compounds, which have a substituent with a carbonyl function at the 4-position of the B-ring, efficiently blocked subgenomic viral RNA replication in the replicon cell assay at low submicromolar concentrations. Among the new compounds, compound 10n (JTK-109) exhibited favorable pharmacokinetic profiles, high selectivity for NS5B, and good safety profiles, suggesting the potential for a clinical candidate in the treatment of hepatitis C.

Animals↗
PubMed2006

Identification of novel PPARalpha ligands by the structural modification of a PPARgamma ligand.

To develop novel PPARalpha ligands, we designed and synthesized several 3-{3-[2-(nonylpyridin-2-ylamino)ethoxy]phenyl}propanoic acid derivatives. Compound 10, the meta isomer of a PPARgamma agonist 1, has been identified as a PPARalpha ligand. The introduction of methyl and ethyl groups at the C-2 position of the propanoic acid of 10 further improved the PPARalpha-binding potency.

Ligands↗
PubMed2006

Benzimidazole inhibitors of hepatitis C virus NS5B polymerase: identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole.

A series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase (RdRp). A SAR study was performed and led to identify the 2-[(4-diarylmethoxy)phenyl]-benzimidazoles as potent inhibitors. They inhibit subgenomic HCV RNA replication in the replicon cells at low micromolar concentrations (EC(50) as low as 1.1microM). They are selective against DNA polymerases (IC(50)>10microM) and exhibit low cytotoxicity.

Benzimidazoles↗
PubMed2006

Syntheses, structural determinations of [Ru(ROCS2)2(PPh3)2](+/0) pairs, and kinetic analyses of thermal reactions involving transient trans-[Ru(iPrOCS2)2(PPh3)2] species (ROCS2(-) = ethyl- or isopropyldithiocarbonate and PPh3 = triphenylphosphine).

Controlled-potential electrochemical oxidation of cis-[Ru(ROCS2)2(PPh3)2] (R = Et, iPr) yielded corresponding Ru(III) complexes, and the crystal structures of cis-[Ru(ROCS2)2(PPh3)2] and trans-[Ru(ROCS2)2(PPh3)2](PF6) were determined. Both pairs of complexes exhibited almost identical coordination structures. The Ru-P distances in trans-[Ru(III)(ROCS2)2(PPh3)2](PF6) [2.436(3)-2.443(3) A] were significantly longer than those in cis-[Ru(II)(ROCS2)2(PPh3)2] [2.306(1)-2.315(2) A]: the smaller ionic radius of Ru(III) than that of Ru(II) stabilizes the trans conformation for the Ru(III) complex due to the steric requirement of bulky phosphine ligands while mutual trans influence by the phosphine ligands induces significant elongation of the Ru(III)-P bonds. Cyclic voltammograms of the cis-[Ru(ROCS2)2(PPh3)2] and trans-[Ru(ROCS2)2(PPh3)2]+ complexes in dichloromethane solution exhibited typical dual redox signals corresponding to the cis-[Ru(ROCS2)2(PPh3)2](+/0) (ca. +0.15 and +0.10 V vs ferrocenium/ferrocene couple for R = Et and iPr, respectively) and to trans-[Ru(ROCS2)2(PPh3)2](+/0) (-0.05 and -0.15 V vs ferrocenium/ferrocene for R = Et and iPr, respectively) couples. Analyses on the basis of the Nicholson and Shain's method revealed that the thermal disappearance rate of transient trans-[Ru(ROCS2)2(PPh3)2] was dependent on the concentration of PPh3 in the bulk: the rate constant for the intramolecular isomerization reaction of trans-[Ru(iPrOCS2)2(PPh3)2] was determined as 0.338 +/- 0.004 s(-1) at 298.3 K (deltaH* = 41.8 +/- 1.5 kJ mol(-1) and deltaS* = -114 +/- 7 J mol(-1) K(-1)), while the dissociation rate constant of coordinated PPh3 from the trans-[Ru(iPrOCS2)2(PPh3)2] species was estimated as 0.113 +/- 0.008 s(-1) at 298.3 K (deltaH* = 97.6 +/- 0.8 kJ mol(-1) and deltaS* = 64 +/- 3 J mol(-1) K(-1)), by monitoring the EC reaction (electrode reaction followed by chemical processes) at different concentrations of PPh3 in the bulk. It was found that the trans to cis isomerization reaction takes place via the partial dissociation of iPrOCS2(-) from Ru(II), contrary to the previous claim that it takes place by the twist mechanism.

Journal Article↗
PubMed2006

Simultaneous determination of urinary dialkylphosphate metabolites of organophosphorus pesticides using gas chromatography-mass spectrometry.

In this study, we developed a safe and sensitive method for the simultaneous determination of urinary dialkylphosphates (DAPs), metabolites of organophosphorus insecticides (OPs), including dimethylphosphate (DMP), diethylphosphate (DEP), dimethylthiophosphate (DMTP), and diethylthiophosphate (DETP), using a pentafluorobenzylbromide (PFBBr) derivatization and gas chromatography-mass spectrometry (GC-MS). Several parameters were investigated: pH on evaporation, reaction temperature and time for the derivatization, the use of an antioxidant for preventing oxidation, and a clean-up step. The pH was set at 6, adjusted with K2CO3, and the reaction temperature and time of derivatization were 80 degrees C and 30 min, respectively. Sodium disulfite was chosen as an antioxidant. The clean-up step was performed with a Florisil/PSE mini-column to remove the unreacted PFBBr and sample matrix. This established procedure markedly shortened the sample preparation time to only about 3 h, and completely inhibited the unwanted oxidization of dialkylthiophosphates. The limits of determination (LOD) were approximately 0.3 microg/L for DMP, and 0.1 microg/L for DEP, DMTP, and DETP in 5 mL of human urine. Within-series and between-day imprecision for the present method using pooled urine spiked with DAPs was less than 20.6% in the calibration range of 1-300 microg/L, and the mean recovery was 56.7-60.5% for DMP, 78.5-82.7% for DEP, 88.3-103.9% for DMTP, and 84.2-92.4% for DETP. This method detected geometric mean values of the urinary DAPs in Japanese with and without occupational exposure to OPs, 16.6 or 27.4 for DMP, 1.0 or 0.7 for DEP, 1.3 or 2.3 for DMTP, and 1.0 or 1.1 microg/L for DETP, respectively. The present method, which does not require special equipment except for GC-MS, is quick, safe, and sensitive enough to be adopted in routine biological monitoring of non-occupational as well as occupational exposure to OPs.

Case-Control Studies↗
PubMed2006

Tetracycline, metronidazole and amoxicillin-metronidazole combinations in proton pump inhibitor-based triple therapies are equally effective as alternative therapies against Helicobacter pylori infection.

BACKGROUND: A proton pump inhibitor (PPI)-based triple therapy with clarithromycin (CAM) and amoxicillin (AMPC) is now a standard regimen for Helicobacter pylori (HP) eradication in Japan. However, the CAM-resistant rate has increased recently and alternative therapies are sorely needed. Therefore the aim of the present study was to evaluate the effectiveness and safety of the PPI-tetracycline (TC)-metronidazole (MNZ) regimen (the PTM regimen) as an alternative therapy in comparison with the PPI-AMPC-MNZ (PAM) regimen. METHODS: Sixty-four HP-positive patients visiting the HP-eradication clinic in Tokai University Hospital from July 1998 to March 2003 were treated with either PTM or PAM as alternative therapies. The HP eradication was assessed by urea breath test (UBT), HP stool antigen test, or HP culture method more than 2 months after completion of the treatments. The drug resistances against CAM, AMPC, TC, and MNZ were assessed by the agar dilution method. RESULTS: Fifty-six patients (26 PTM and 30 PAM) completed medication and evaluation of the eradication. The eradication rates of PTM were 82.8% (24/29) and 92.3% (24/26), while those of PAM were 74.3% (26/35) and 89.7% (26/29) by intention-to-treat and per-protocol analysis, respectively. The differences between the regimens were not statistically significant. There were no severe adverse effects observed in either of the regimens. The drug-resistance analyses showed 15 CAM- and one MNZ-resistant cases but no TC or AMPC resistance in the available 25 samples. CONCLUSION: The PTM and PAM regimens were equally effective and safe as alternative HP eradication therapies. And PTM would be particularly useful in penicillin allergy cases.

Amoxicillin↗
PubMed2006

Epigenetic control using natural products and synthetic molecules.

The term "epigenetics" is defined as "heritable changes in gene expression that occur without changes in DNA sequence". Recently, it has been revealed that DNA methylation and histone modifications such as acetylation, methylation and phosphorylation are epigenetic mechanisms according to this definition. In other words, these posttranslational modifications are important factors in determining when and where a gene will be expressed. To date, several enzymes that catalyze DNA or histone modifications have been identified, such as DNA methyltransferases and histone deacetylases. Inhibitors and activators of enzymes controlling epigenetic modifications are considered useful not only as tools for the elucidation of cellular and biological phenomena, but also as therapeutic agents, since disruption of the balance of epigenetic networks is known to cause some disease states such as cancer. In this review, we present natural products and synthetic molecules that inhibit or activate enzymes catalyzing DNA methylation or histone modifications, and discuss the potential of epigenetic therapy.

Acetylation↗
PubMed2006

Rational design of non-hydroxamate histone deacetylase inhibitors.

While most inhibitors of histone deacetylases (HDACs) are hydroxamic acid derivatives, several non-hydroxamates have recently been developed as inhibitors and attracted quite a deal of attention. In this review, we present the rational design, inhibitory effect and antiproliferative activity of non-hydroxamate HDAC inhibitors.

Catalysis↗
PubMed2005

Structure and reactivity of a pyridine-1-imido-2-thiolato complex of iridium(III), CpIr(1-N-2-Spy), generated by photolysis of the (azido)(pyridine-2-thiolato) complex, CpIr(2-Spy)(N3).

Photolysis of the (azido)(pyridine-2-thiolato)iridium(III) complex CpIr(2-Spy)(N3) (1) gave a pyridine-1-imido-2-thiolato complex, CpIr(1-N-2-Spy) (2), in which one of the nitrogen atoms of the azide ligand has been inserted into the Ir-N(py) bond (Cp = eta5-C5Me5). Complex 2 reacted quantitatively with methyl iodide to give the N-methylated product, [CpIr(1-NMe-2-Spy)]I (3). X-ray crystallography revealed that both 2 and 3 have similar two-legged piano stool structures with planar 1-N-2-Spy2- or 1-NMe-2-Spy- ligands, which form iridacyclopentadienyl-like rings by moderate S(ppi)/N(ppi) to Ir(dpi) pi donation.

Journal Article↗