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Biomedical subjects

Yasuhiro Igarashi

Publications and source records attributed to Yasuhiro Igarashi.

At least 19 recordsLinked to original sources
PubMed2006

Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12.

Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic beta cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located approximately 1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation. This region contains an E box and binding sites for hepatocyte nuclear factor (HNF)-1alpha. Mutation introduced in each binding site markedly reduced activin A responsiveness. It has been reported that HNF-1alpha synergizes with basic helix-loop-helix (bHLH) proteins in activating the PAX4 promoter, and we demonstrated that activin A strongly enhanced the functional activity of E47/E12 without the increase in its binding ability. In addition, suppression of E47/E12 expression in AR42J-B13 cells using siRNA oligonucleotides results in the significant decrease in the intrinsic activin A-induced PAX4 expression. Our results suggest that activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter.

Activins↗
PubMed2005

Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients.

Insulin resistance is associated with the circulating free fatty acid (FFA) level and intracellular lipid content in muscle and liver. We investigated the effect of 2-wk diet and exercise therapy on total adiposity, circulating FFA, intracellular lipid content in muscle and liver, and peripheral insulin sensitivity. Type 2 diabetic patients were divided into a diet group (n = 7) and a diet plus exercise group (n = 7). We performed a hyperinsulinemic-euglycemic clamp study before and after treatment. Intramyocellular lipid (IMCL) in the tibialis anterior muscle and intrahepatic lipid (IHL) were evaluated by (1)H-magnetic resonance spectroscopy. Fasting FFA were not altered, and total body fat showed a slight, but significant, decrease in both groups after treatment. IMCL was decreased by 19%, and the glucose infusion rate was increased by 57% in the diet plus exercise group, whereas neither IMCL nor glucose infusion rate was significantly altered in the diet group. However, IHL showed a significant decrease in both groups. In summary, we found that 2 wk of diet and exercise decreased IMCL and increased muscle insulin-mediated glucose uptake, whereas diet with or without exercise decreased IHL. These effects were evident despite a small decrease in body fat and were observed independently of fasting FFA levels.

Blood Glucose↗
PubMed2005

Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata.

A new pyrrolizidine alkaloid, cremastrine (1), was isolated from the bulbs of Cremastra appendiculata. Its configuration was determined by spectroscopic and chemical analyses. Compound 1 inhibited the binding of tritium-labeled N-methylscopolamine to the muscarinic M3 receptor with a K(i) value of 126 nM.

Japan↗
PubMed2005

Nocardimicins A, B, C, D, E, and F, siderophores with muscarinic M3 receptor inhibiting activity from Nocardia sp. TP-A0674.

In the screening for muscarinic M3 receptor binding inhibitors from microbial secondary metabolites, the extract of Nocardia sp. TP-A0674 was found to be highly active. Bioassay-guided fractionation of it led to the isolation of six new siderophores, nocardimicins A (1), B (2), C (3), D (4), E (5), and F (6), as active principles. Their chemical structures were determined by spectroscopic and degradation analysis. Of these congeners, nocardimicin B (2) inhibited the binding of tritium-labeled N-methylscopolamine to the muscarinic M3 receptor most potently with a Ki value of 0.13 microM. Compound 2 showed more selective activity to M3 and M4 receptors than other subtypes.

Humans↗
PubMed2005

Anicemycin, a new inhibitor of anchorage-independent growth of tumor cells from Streptomyces sp. TP-A0648.

The anchorage-independence of cells is closely related to their tumorigenicity. In the screening of inhibitors of anchorage-independent growth of tumor cells, anicemycin was isolated from the fermentation broth of an actinomycete strain TP-A0648. The producing strain was isolated from a leaf of Aucuba japonica collected in Toyama, Japan and identified as Streptomyces sp. based on the taxonomic data. The structure of anicemycin was elucidated as a new analog of spicamycin by NMR and MS analysis. Anicemycin inhibited the anchorage-independent growth of the human ovary cancer SKOV-3 cells with an IC50 of 0.015 microM about three times more potently than their anchorage-dependent growth.

Antibiotics, Antineoplastic↗
PubMed2005

Absolute configuration of TPU-0043, a pentaene macrolide from Streptomyces sp.

An antifungal pentaene macrolide TPU-0043 was isolated from Streptomyces sp. TP-A0625. The absolute configuration of TPU-0043 was determined to be 2R-(n-butyl)-16-methyl-3S,5S,7S,9R,11R,13R,15S,26S, 27R-nonahydroxyoctacosa-16,18,20,22,24-pentaenoic acid, 27-lactone, by X-ray crystallography of its 13-p-bromobenzenesulfonyl derivative.

Antifungal Agents↗
PubMed2005

Nocardimicins G, H and I, siderophores with muscarinic M3 receptor binding inhibitory activity from Nocardia nova JCM 6044.

In the screening for muscarinic M3 receptor binding inhibitors from microbial secondary metabolites, the extract of Nocardia nova JCM 6044 was found to be highly active. Bioassay-guided isolation led to the identification of three siderophores, nocardimicins G (1), H (2) and I (3). Their chemical structures were determined by spectroscopic analysis using NMR and MS. 1 and 2 inhibited the binding of tritium-labeled N-methylscopolamine to the muscarinic M3 receptor with Ki values of 0.44 microM and 0.37 microM, respectively, whereas 3 showed no inhibition at 10 microM. 1 and 2 also showed weak binding inhibitory activity to the M5 receptor but not to the M1, M2 and M4 receptors at 10 microM.

Hydroxamic Acids↗
PubMed2005

Cloning and characterization of the goadsporin biosynthetic gene cluster from Streptomyces sp. TP-A0584.

The biosynthetic gene cluster of goadsporin, a polypeptide antibiotic containing thiazole and oxazole rings, was cloned from Streptomyces sp. TP-A0584. The cluster contains a structural gene, godA, and nine god (goadsporin) genes involved in post-translational modification, immunity and transcriptional regulation. Although the gene organization is similar to typical bacteriocin biosynthetic gene clusters, each goadsporin biosynthetic gene shows low homology to these genes. Goadsporin biosynthesis is initiated by the translation of godA, and the subsequent cyclization, dehydration and acetylation are probably catalysed by godD, godE, godF, godG and godH gene products. godI shows high similarity to the 54 kDa subunit of the signal recognition particle and plays an important role in goadsporin immunity. Furthermore, four goadsporin analogues were produced by site-directed mutagenesis of godA, suggesting that this biosynthesis machinery is used for the heterocyclization of peptides.

Cloning, Molecular↗
PubMed2005

Cytochrome P450 homolog is responsible for C-N bond formation between aglycone and deoxysugar in the staurosporine biosynthesis of Streptomyces sp. TP-A0274.

The staurosporine biosynthetic gene cluster in Streptomyces sp. TP-A0274 consists of 15 sta genes. In the cluster, it was predicted that staN, which shows high similarity to cytochrome P450 is involved in C-N bond formation between the nitrogen at N-12 of aglycone and the carbon at C-5' of deoxysugar. The staN disruptant produced holyrine A instead of staurosporine. The structure of holyrine A is aglycone linking to 2,3,6-trideoxy-3-aminoaldohexose between N-13 and C-1' of deoxysugar. Holyrine A was converted to staurosporine by the staD disruptant. These results indicate that StaN, cytochrome P450 is responsible for C-N bond formation. This is the first example of C-N bond formation catalyzed by cytochrome P450. In addition, holyrine A was confirmed to be an intermediate of staurosporine biosynthesis, which suggests that the N- and O-methylation at C-3' and C-4' takes place after the formation of the C-N bond between C-5' and N-12 in the biosynthetic pathway.

Amines↗
PubMed2005

Pradimicin resistance of yeast is caused by a mutation of the putative N-glycosylation sites of osmosensor protein Sln1.

Pradimicin, a mannose-binding antifungal antibiotic, induces apoptosis-like cell death in Saccharomyces cerevisiae. Previously we found that the substitution of the 74th amino acid from glycine to cysteine in Ypd1 yields a mutant resistant to pradimicin. In this study, the involvement of a membrane-spanning osomosensor, Sln1, which is located upstream of Ypd1, was investigated. A mutant, sln1 DeltaNG, that lacks the putative N-glycosylation sites in the extracellular domain became resistant to pradimicin. On the other hand, the null mutants of Ssk1, Pbs2, and Hog1, which are located downstream of the Sln1 cascade, were sensitive to pradimicin as well as the wild-type strain. In conclusion, pradimicin exerts its fungicidal action with the involvement of Sln1, but the downstream branch, Ssk1 and the HOG pathway, is not involved.

Amino Acid Sequence↗
PubMed2005

Characteristics of Japanese subjects who progress from normal to impaired glucose tolerance. Longitudinal study excluding changes in body weight.

In this retrospective longitudinal study, we focused on the clinical characteristics of Japanese individuals with recent onset impaired glucose tolerance (IGT) who have been followed up for insulin secretory function and 75-gram oral glucose tolerance test (OGTT) for more than 3 years annually before they progressed from normal glucose tolerance (NGT) to IGT. Subjects whose body weight did not show significant change for the period were selected and labeled as either NGT (no change in OGTT over 3 years) or IGT (progressors from NGT to IGT) groups (n = 24, each). We compared the basal biochemical data and response of plasma glucose and serum insulin after OGTT of the two groups. In the IGT progressors, significant increase of plasma glucose at 30 to 120 minutes during OGTT and significant decrease of HDL-cholesterol were observed since 3 years before onset of IGT. In addition to increase of serum glucose and decrease of HDL-cholesterol, serum insulin at 120 minutes during OGTT were significantly and remarkably high at onset and 3 years before onset of IGT. Plasma glucose at 30-120 minutes and serum insulin level at 120 minutes after glucose load are potentially significant predictors of progression from NGT to IGT even in subjects who do not show increase of body weight.

Aged↗
PubMed2004

Reduction of insulin-stimulated glucose uptake by peroxynitrite is concurrent with tyrosine nitration of insulin receptor substrate-1.

Inducible nitric oxide synthetase plays an essential role in insulin resistance induced by a high-fat diet. The reaction of nitric oxide with superoxide leads to the formation of peroxynitrite (ONOO-), which can modify several proteins. In this study, we investigated whether peroxynitrite impairs insulin-signalling pathway. Our experiments showed that 3-(4-morpholinyl)sydnonimine hydrochloride (SIN-1), a constitutive producer of peroxynitrite, dose-dependently inhibited insulin-stimulated glucose uptake. While SIN-1 did not affect the insulin receptor protein level and tyrosine phosphorylation, it reduced the insulin receptor substrate-1 (IRS-1) protein level, and IRS-1 associated phosphatidylinositol-3 kinase (PI-3 kinase) activity. Although SIN-1 did not induce Ser307 phosphorylation of IRS-1, tyrosine nitration of IRS-1 was detected in SIN-1-treated-Rat1 fibroblasts expressing human insulin receptors. Mass spectrometry showed that peroxynitrite induced at least four nitrated tyrosine residues in rat IRS-1, including Tyr939, which is critical for association of IRS-1 with the p85 subunit of PI-3 kinase. Our results suggest that peroxynitrite reduces the IRS-1 protein level and decreases phosphorylation of IRS-1 concurrent with nitration of its tyrosine residues.

3T3-L1 Cells↗
PubMed2004

Directed biosynthesis of fluorinated pseurotin A, synerazol and gliotoxin.

Aspergillus fumigatus TP-F0196 produces pseurotin A, synerazol and gliotoxin. Phenylalanine is a common biosynthetic precursor of these antibiotics. Feeding fluorophenylalanine to the culture induced the production of novel fluorinated analogs. These fluorinated antibiotics were obtained from the culture broth by solvent extraction and purified by chromatographies, and their antimicrobial and antitumor activities were investigated. Among the novel fluorinated analogs, 19- and 20-fluorosynerazols exhibited potent anti-angiogenic activity in the chorioallantoic membrane assay. In addition, 19-fluorosynerazol showed more potent cytocidal activity against several cancer cell lines than synerazol.

Angiogenesis Inhibitors↗
PubMed2004

[Lactate].

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Humans↗
PubMed2003

DNA alkylation properties of yatakemycin.

Yatakemycin represents the newest and now most potent member of a class of naturally occurring antitumor compounds that includes CC-1065 and the duocarmycins, which derive their biological properties from a characteristic DNA alkylation reaction. Herein, the first description of the yatakemycin DNA alkylation properties is detailed, constituting the first such study of a naturally occurring "sandwiched" member of this class. Thus, the event, sequence selectivity, relative rate and efficiency, and reversibility of the DNA alkylation reaction of yatakemycin are described.

Alkylation↗