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Biomedical subjects

Makoto Nomura

Publications and source records attributed to Makoto Nomura.

12 recordsLinked to original sources
PubMed2006

Effects of three Chinese herbal medicines on plasma and liver lipids in mice fed a high-fat diet.

Chinese herbal medicines, Inchinko-to, Bofu-tsusho-san and Dai-saiko-to, containing 3, 18 and 8 components, respectively, have since long been used as an anti-inflammatory, antipyretic, choleretic and diuretic agent for liver disorders and jaundice, as an anti-obesity agent, a hypocholesterolemic agent for liver disorders and a therapeutic and/or preventive agent for cholesterol gallstone disease with hypertriglycerid-emia in China and Japan, respectively. In the present study, we investigated the effects of these three herbal medicines in young male mice fed a high-fat diet. Plasma levels of lipids and the numbers of the fatty droplets in the liver cytoplasm were markedly lowered by the diets supplemented with three herbal medicines. The liver weights and the body growth were reduced by the diet supplemented with Dai-saiko-to, which slightly affected the concentrations of total protein, albumin, creatinine or calcium, and the activity of lactate dehydrogenase. Thus, Dai-saiko-to, besides Bofu-tsusho-san, seems effective in the activities of anti-obesity, anti-hyperlipidemia and anti-hyperlipids in liver cytoplasm, when used carefully.

Animals↗
PubMed2006

NMR spectroscopic study of a DNA duplex with mercury-mediated T-T base pairs.

Recently, we reported that T-T mismatches can specifically recognize Hg(II) (T-Hg(II)-T pair formation). In order to understand the properties of the T-Hg(II)-T pair, we recorded NMR spectra for a DNA duplex, d(CGCGTTGTCC).d(GGACTTCGCG), with two successive T-T mismatches (Hg (II)-binding sites). We assigned 1H resonances for mercury-free and di-mercurated duplexes, and performed titration experiments with Hg(II) by using 1D 1H NMR spectra. Because of the above mentioned assignments, we could confirm the existence of mono-mercurated species, because individual components gave independent NMR signals in the titration spectra.

Base Composition↗
PubMed2006

Studies of DNA recognition mechanism of transcription factor IRF-4.

Transcription factor IFN regulatory factor-4 (IRF-4) prefers a DNA sequence including CCGAAA, though the consensus DNA-binding sequence of the IRF family proteins is NNGAAA, and the crystal structure of PU.1/IRF-4/DNA (GTGAAA) ternary complex indicates the NN region of DNA does not interact with IRF-4 directly. This suggests that there is an indirect DNA recognition mechanism in IRF-4. In order to account for the sequence preference of IRF-4, we focused on structural properties of DNA duplexes recognized by IRF-4. Here, we performed solution NMR studies on DNA duplexes containing GGGAAA and CCGAAA sequences, and assigned most of proton resonances of DNA 17 mer with GGGAAA. (1)H-(1)H NOESY spectra indicated B-form like structure for GGGAAA. We also assigned imino proton resonances of DNA 17 mer with CCGAAA. For the imino proton region, the (1)H-(1)H NOESY spectra of these two DNA duplexes were similar.

Base Sequence↗
PubMed2006

Relationship of serum advanced glycation end products with deterioration of periodontitis in type 2 diabetes patients.

BACKGROUND: A close relationship between diabetes and chronic periodontitis has been demonstrated. We previously found that Porphyromonas gingivalis with the type II fimA gene is an infectious factor closely associated with the deterioration seen in diabetic periodontitis patients. In the present study, we examined whether other biomarkers are related to the development and deterioration of periodontitis often seen in type 2 diabetic individuals. METHODS: A total of 97 type 2 diabetes patients with and without periodontitis were recruited, and their periodontal and diabetic conditions were analyzed. The ratio (%) of teeth with an attachment loss >5 mm among all teeth in each subject was used as an index of periodontal deterioration. Peripheral blood was tested for levels of glycated hemoglobin (HbA1c), advanced glycation end products (AGEs), C-reactive protein (CRP), and cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL]-1beta). Subgingival plaque samples were also examined for the occurrences of Actinobacillus actinomycetemcomitans, Tannerella forsythensis, Treponema denticola, and Prevotella intermedia. RESULTS: Serum AGEs were significantly associated with deterioration of periodontitis, whereas no other serum biochemical marker or bacterial occurrence showed a clear relationship with that condition. CONCLUSION: AGEs may be factors associated with diabetic periodontitis and may be useful as biomarkers that reflect such deterioration.

Adult↗
PubMed2005

Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats.

DNA trinucleotide repeats, particularly CXG, are common within the human genome. However, expansion of trinucleotide repeats is associated with a number of disorders, including Huntington disease, spinobulbar muscular atrophy and spinocerebellar ataxia. In these cases, the repeat length is known to correlate with decreased age of onset and disease severity. Repeat expansion of (CAG)n, (CTG)n and (CGG)n trinucleotides may be related to the increased stability of alternative DNA hairpin structures consisting of CXG-CXG triads with X-X mismatches. Small-molecule ligands that selectively bound to CAG repeats could provide an important probe for determining repeat length and an important tool for investigating the in vivo repeat extension mechanism. Here we report that napthyridine-azaquinolone (NA, 1) is a ligand for CAG repeats and can be used as a diagnostic tool for determining repeat length. We show by NMR spectroscopy that binding of NA to CAG repeats induces the extrusion of a cytidine nucleotide from the DNA helix.

DNA↗
PubMed2005

NMR structural analysis of the G.G mismatch DNA complexed with naphthyridine-dimer.

Naphthyridine-dimer (ND) specifically recognizes G.G mismatch DNA (Figure 1). However, its detailed recognition mechanism is not clear. Here a DNA oligomer d(CTAACGGAATG)/d(CATTCGGTTAA) complexed with ND was studied by NMR. The stoichiometry of DNA to ND was determined to be 1:2 at NMR concentration (2.5 mM). Proton resonances were completely assigned including H5' and H5'' using 1H-1H and 1H-13C 2D spectra of the complex. These spectra showed that four naphthyridine rings are staked in the helix and form hydrogen bonds with the four G residues in CGG/CGG region. These results indicate ND can specifically recognize the CGG/CGG sequence.

Base Pair Mismatch↗
PubMed2005

Solution structure of a small-molecular ligand complexed with CAG trinucleotide repeat DNA.

NMR structure of the first identified ligand, naphthyridine-azaquinolone (NA), complexed with the CAG-CAG triad is reported. The determined structure revealed the invasive ligands binding to the A-A mismatch and flanking G-C base pairs, causing the widowed cytosines to flip out from pi-stack. Hydrogen-bond pairs between NA and DNA, naphthyridine-guanine and azaquinolone-adenine, are well stacked in the right-handed DNA helix, showing structural mimicry of Watson-Crick base pairing. This is the first observation that the small molecular ligand induced the base flipping of the nucleotide base in the Watson-Crick base pair.

Base Pairing↗
PubMed2004

Paramagnetic NMR study of Cu(2+)-IDA complex localization on a protein surface and its application to elucidate long distance information.

The paramagnetic metal chelate complex Cu(2+)-iminodiacetic acid (Cu(2+)-IDA) was mixed with ubiquitin, a small globular protein. Quantitative analyses of (1)H and (15)N chemical shift changes and line broadenings induced by the paramagnetic effects indicated that Cu(2+)-IDA was localized to a histidine residue (His68) on the ubiquitin surface. The distances between the backbone amide proton and the Cu(2+) relaxation center were evaluated from the proton transverse relaxation rates enhanced by the paramagnetic effect. These correlated well with the distances calculated from the crystal structure up to 20 A. Here, we show that a Cu(2+)-IDA is the first paramagnetic reagent that specifically localizes to a histidine residue on the protein surface and gives the long-range distance information.

Amides↗
PubMed2004

Solution NMR study of DNA recognition mechanism of IRF4 protein.

Transcription factor IRF-4 prefers the DNA sequence including CCGAAA. The consensus sequence of the IRF family proteins is NNGAAA, and all crystal structures indicate the NN region does not interact with IRF proteins directly. Here the sequence preference of IRF-4 was investigated by NMR and fluorescence antisotropy as an example of the indirect sequence recognition. The 1H-15N HSQC spectra of the IRF-4/DNA complex containing the CCGAAA sequence indicated that the 1:1 complex was formed. The dissociation constants (Kd) for two DNA oligomers containing CCGAAA and GGGAAA were determined by fluorescence antistropy, but their difference was very small.

Anisotropy↗
PubMed2003

Synthesis of the cyclic and acyclic acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine, a potent antitumor nucleoside. Design of prodrugs to be selectively activated in tumor tissues via the bio-reduction-hydrolysis mechanism.

We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1), the 2',3'-O-nitrobenzylidene derivatives 2 and 3 and the 5'-O-(alkoxy)(nitrophenyl)methyl derivatives 6-10 as potential prodrugs of ECyd. These prodrugs can be selectively activated in tumor tissues via a bio-reduction-hydrolysis mechanism owing to the characteristic properties of tumor tissues, such as hypoxia and lower pH. Although the 2',3'-O-(4-nitrobenzylidene) derivatives 2 and 3 were converted bio-reductively into the corresponding 4-aminobenzylidene derivatives by rat S-9 mix, the reduction products, that is, the corresponding amino congeners 4 and 5, proved to be rather stable in an aqueous solution at pH 6.5 used as a pH model for acidic tumor tissues. In contrast, the 5'-O-(alkoxy)(4-nitropheny)methyl derivatives 6-8 were also reduced by rat S-9 mix to the corresponding amino congeners 11-13, which were hydrolyzed to release ECyd more effectively at pH 6.5 than at pH 7.4. Accordingly, the acyclic acetals 6-8 may be efficient prodrugs of ECyd, that are effectively reduced under physiological conditions releasing ECyd in acidic tumor tissues.

Acetals↗