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Biomedical subjects

N Asano

Publications and source records attributed to N Asano.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of GM-CSF gene polymorphisms (3606T/C and 3928C/T) in Japanese patients with atopic dermatitis.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is thought to play an important role in the pathogenesis of atopic dermatitis. To examine whether GM-CSF single nucleotide polymorphisms (SNPs) are associated with susceptibility to atopic dermatitis, we investigated the genotype and allele frequencies of the SNPs 3606T/C and 3928C/T of the GM-CSF gene in 181 Japanese patients with atopic dermatitis and 100 controls, using a PCR restriction fragment length polymorphism method. A strong linkage disequilibrium existed between the polymorphisms 3606 and 3928, suggesting two common GM-CSF haplotypes, 3606*T-3928*C and 3606*C-3928*T. However, there was no significant difference in genotype or allele frequencies between patients with atopic dermatitis and controls for either of the two polymorphisms, thus GM-CSF SNPs do not appear to be associated with susceptibility to atopic dermatitis in Japanese patients. A large-scale study is necessary to confirm these findings.

Adolescent↗
PubMed2005

Significance of chemokine receptor expression in aggressive NK cell leukemia.

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.

Adult↗
PubMed2005

The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population.

BACKGROUND: Helicobacter pylori infection is associated with variable clinical outcomes, including gastroduodenal diseases, and genetic factors may be relevant in this process. AIMS: We investigated the effects of an interleukin 8 (IL-8) gene polymorphism on the risk of gastroduodenal diseases, the degree of H pylori induced gastritis, and IL-8 gene transcription. SUBJECTS: The study was performed in 244 healthy control subjects and 690 H pylori positive patients with non-cardia gastric cancer, gastric ulcer, duodenal ulcer, or gastritis. METHODS: We identified the IL-8 -251 A/T polymorphism by direct sequence analysis, and measured the gastritis score and serum pepsinogen (PG). The transcriptional promoter activity of the IL-8 gene was assessed by luciferase assay. RESULTS: IL-8 -251A was associated with a higher risk of gastric cancer and gastric ulcer. Patients carrying IL-8 -251A showed an increased risk of gastric cancer (odds ratios (OR) 2.01 (95% confidence interval (CI) 1.38-2.92)) and gastric ulcer (OR 2.07 (95% CI 1.37-3.12)). Compared with patients younger than 49 years, atrophy and metaplasia scores in the antrum were significantly higher and the PG I/II ratio significantly lower in -251A carriers than in T/T carriers. In the in vitro assay, IL-8 -251A showed enhanced promoter activity in response to IL-1beta or tumour necrosis factor alpha. CONCLUSIONS: The IL-8 -251A allele may be associated with progression of gastric atrophy in patients with H pylori infection, and may increase the risk of gastric cancer and gastric ulcer in Japanese people.

Adolescent↗
PubMed2004

Hepatic glycogen breakdown is implicated in the maintenance of plasma mannose concentration.

D-mannose is an essential monosaccharide constituent of glycoproteins and glycolipids. However, it is unknown how plasma mannose is supplied. The aim of this study was to explore the source of plasma mannose. Oral administration of glucose resulted in a significant decrease of plasma mannose concentration after 20 min in fasted normal rats. However, in fasted type 2 diabetes model rats, plasma mannose concentrations that were higher compared with normal rats did not change after the administration of glucose. When insulin was administered intravenously to fed rats, it took longer for plasma mannose concentrations to decrease significantly in diabetic rats than in normal rats (20 and 5 min, respectively). Intravenous administration of epinephrine to fed normal rats increased the plasma mannose concentration, but this effect was negated by fasting or by administration of a glycogen phosphorylase inhibitor. Epinephrine increased mannose output from the perfused liver of fed rats, but this effect was negated in the presence of a glucose-6-phosphatase inhibitor. Epinephrine also increased the hepatic levels of hexose 6-phosphates, including mannose 6-phosphate. When either lactate alone or lactate plus alanine were administered as gluconeogenic substrates to fasted rats, the concentration of plasma mannose did not increase. When lactate was used to perfuse the liver of fasted rats, a decrease, rather than an increase, in mannose output was observed. These findings indicate that hepatic glycogen is a source of plasma mannose.

Administration, Oral↗
PubMed2004

The expression and prognostic significance of bone morphogenetic protein-2 in patients with malignant fibrous histiocytoma.

We investigated the rates of expression of bone morphogenetic protein-2 (BMP-2) in 29 adult patients with high-grade malignant fibrous histiocytoma of soft tissue, using the BMP-2-specific monoclonal antibody, AbH3b2/17, and found that they ranged from 1.9% to 78.9%. The survival at five years of the groups expressing high (> or = 30%) and low (< 30%) levels of BMP-2 was 85.7% and 36.3%, respectively. Multivariable analysis showed that only BMP-2 had prognostic significance for continuous disease-free survival and for overall survival (p < 0.05). Our findings indicate that over-expression of BMP-2 in malignant fibrous histiocytoma of soft tissue is the most reliable prognostic indicator of the parameters assessed.

Adult↗
PubMed2003

Dermatofibrosarcoma protuberans with COL1A1 (exon 18) -PDGFB (exon 2) fusion transcript.

BACKGROUND: Fusion of the collagen type I alpha 1 (COL1A1) gene with the platelet-derived growth factor B-chain (PDGFB) gene has been described in dermatofibrosarcoma protuberans (DFSP). Various exons of the COL1A1 gene have been shown to be involved in the fusion with exon 2 of the PDGFB gene. Objectives We examined the breakpoint of the COL1A1 gene using the tumour specimen from the patient with DFSP. METHODS: Reverse transcriptase-polymerase chain reaction (PCR) was performed using cultured DFSP tumour cells. Nucleotide sequence analysis was carried out using the PCR product to identify the breakpoint. RESULTS: The COL1A1-PDGFB fusion transcript was detected from the tumour specimen. Sequence analysis revealed that exon 18 of the COL1A1 gene was fused with exon 2 of the PDGFB gene. CONCLUSIONS: This study identified a novel COL1A1 breakpoint, namely, exon 18 of the COL1A1 gene.

Adult↗
PubMed2003

Restoration of antibacterial activity of beta-lactams by epigallocatechin gallate against beta-lactamase-producing species depending on location of beta-lactamase.

The combined effects of (-)-epigallocatechin gallate (EGCg) and beta-lactams were investigated against various beta-lactamase-producing clinical isolates, including 21 Staphylococcus aureus, 6 Escherichia coli, 3 Klebsiella pneumoniae and 8 Serratia marcescens strains. Penicillin in combination with EGCg at 12.5 microg mL(-1) showed the most potent synergy against 100% penicillinase-producing S. aureus. However, cefotaxime or imipenem in combination with higher concentration of EGCg (100 microg mL(-1)) only showed slight synergy against 2 of 17 Gram-negative rods. Similar to the effect on the penicillinase from S. aureus, however, EGCg also directly inhibited the extracted beta-lactamases from the Gram-negative rods, thereby protecting beta-lactams from inactivation. The different effects of the combinations on different beta-lactamase-producing species were confirmed to be related to the cellular locations of beta-lactamases. In contrast to a 32.7% extracellular fraction of total beta-lactamase activity in a penicillinase-producing S. aureus, the fractions were 0.6%, 0.6% and 1.2% in a TEM-derived extended-spectrum beta-lactamase-producing E. coli, an inhibitor-resistant beta-lactamase-producing K. pneumoniae and an IMP-producing S. marcescens, respectively. In conclusion, the combination of penicillin with EGCg showed potent synergy against penicillinase-producing S. aureus in-vitro. The combinations of beta-lactams and EGCg against beta-lactamase-producing Gram-negative rods do indicate a limitation owing to the cellular location of beta-lactamases.

Anti-Bacterial Agents↗
PubMed2001

Automated multiple development thin layer chromatography for calystegines and their biosynthetic precursors.

Automated multiple development thin layer chromatography (AMD-TLC) was used for separation of calystegines, a class of nortropane alkaloids, and of precursors of their biosynthesis. The calystegines differ in the number of hydroxyl groups at the nortropane ring system and in the substitution pattern. A combination of TLC methods allows the separation of the individual calystegines and separation of possible precursors of the biosynthesis. Solvent combination, development time, the number of development steps, the drying time between each run and the preconditioning parameters of the silica gel TLC plates were optimised. Limits of detection were evaluated for several detection reagents.

Alkaloids↗
PubMed2001

Evaluation of the rodent micronucleus assay by a 28-day treatment protocol: Summary of the 13th Collaborative Study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Environmental Mutagen Society of Japan (JEMS)-Mammalian Mutagenicity Study Group (MMS).

To examine whether micronucleus tests can be incorporated into general toxicology assays, we performed micronucleus tests applying the treatment protocols typically used in such assays. In this 13th Collaborative Study of the CSGMT, both rats and mice were tested, although rats were used in the majority of the studies. Fifteen mutagens were tested in rats, mainly by oral (p.o.) administration. Micronucleus induction was evaluated 2, 3, and 4 days, and 1, 2, 3, and 28 days after the beginning of the treatment in the peripheral blood, and at 28 days in the bone marrow. Of the 15 chemicals that induced micronuclei in rats in short-term assays, two chemicals (1,2-dimethylhydrazine.2HCl and mitomycin C) were negative in all our experiments, possibly because of insufficient dose levels. The remaining 13 were positive within the estimated dose range of a general toxicology assay, suggesting the possibility of integrating the micronucleus assay into general toxicology assays. Three patterns were observed in micronucleus induction during the period of repeated treatment: (1) gradual increases in micronucleus frequency with sequential doses, (2) a peak at 3-5 days followed by gradual decreases in micronucleus frequency with sequential doses, and (3) a rapid increase in micronucleus frequency followed by a plateau. We evaluated factors that might have been involved in those patterns, such as the spleen function, target organ exposure, extramedullary hematopoiesis, hypothermia, and hypoxia. Another factor we considered was dosage. Because the dosages employed in a general toxicity assay are usually lower than those used in short-term micronucleus assays, this discrepancy was considered the greatest potential problem for integrating the micronucleus assay into general toxicology assays. Our results indicate that the integration of the micronucleus assay into a 28-day toxicological assay is feasible. To serve this purpose, blood samples collected 4 days after the beginning of treatment and blood and bone marrow samples collected at autopsy should be examined. Furthermore, although it is recognized that mice may be suitable for performing independent micronucleus assays, we propose that rats can provide biologically important and relevant information regarding potential chemical mutagens that can be evaluated under conditions used in the conduct of general toxicology studies.

Animals↗
PubMed2001

Polyhydroxylated alkaloids -- natural occurrence and therapeutic applications.

Over one hundred polyhydroxylated alkaloids have been isolated from plants and micro-organisms. These alkaloids can be potent and highly selective glycosidase inhibitors and are arousing great interest as tools to study cellular recognition and as potential therapeutic agents. However, only three of the natural products so far have been widely studied for therapeutic potential due largely to the limited commercial availability of the other compounds.

Alkaloids↗
PubMed2001

Dihydroxynortropane alkaloids from calystegine-producing plants.

Three dihydroxynortropanes, 2alpha,7beta-dihydroxynortropane, 2alpha,3beta-dihydroxynortropane, and 3alpha,7beta-dihydroxynortropane, were isolated from calystegine-producing plants in the families Convolvulaceae and Solanaceae. 2alpha,7beta-Dihydroxynortropane was isolated from six species in the Convolvulaceae whereas only Calystegia soldanella contained it and 2alpha,3beta-dihydroxynortropane. Although neither of these were detectable in three species tested in the Solanaceae, 3alpha,7beta-dihydroxynortropane was, however, isolated from Duboisia leichhardtii.

Alkaloids↗
PubMed2001

Iminosugars: potential inhibitors of liver glycogen phosphorylase.

The first synthesis of the single isomers (3R,4R,5R); (3S,4S,5S): (3R,4R,5S) and (3S,4S,5R) of 5-hydroxymethyl-piperidine-3,4-diol from Arecolin is reported, including the synthesis of a series of N-substituted derivatives of the (3R,4R,5R)-isomer (Isofagomine). The inhibitory effect of these isomers as well as of a series of N-substituted derivatives of the (3R,4R,5R)-isomer and selected hydroxypiperidine analogues on liver glycogen phosphorylase (GP) showed that the (3R,4R,5R) configuration was essential for obtaining an inhibitory effect at submicromolar concentration. The results also showed that all three hydroxy groups should be present and could not be substituted, nor were extra OH groups allowed if sub-micromolar inhibition should be obtained. Some inhibitory effect was retained for N-substituted derivatives of Isofagomine; however, N-substitution always resulted in a loss of activity compared to the parent compound, IC50 values ranging from 1 to 100 microM were obtained for simple alkyl, arylalkyl and benzoylmethyl substituents. Furthermore, we found that it was not enough to assure inhibitory effect to have the (R,R,R) configuration. Fagomine, the (2R,3R,4R)-2-hydroxymethylpiperidine-3,4-diol analogue, showed an IC50 value of 200 microM compared to 0.7 microM for Isofagomine. In addition, Isofagomine was able to prevent basal and glucagon stimulated glycogen degradation in cultured hepatocytes with IC50 values of 2-3 microM.

Animals↗
PubMed2001

alpha- and beta-homogalactonojirimycins (alpha- and beta-homogalactostatins): synthesis and further biological evaluation.

The homoiminosugars alpha- and beta-homogalactonojirimycins were prepared from a common intermediate, tetra-O-benzyl-D-galacto-heptenitol 6, by way of highly stereoselective reaction sequences involving, as the key steps, an internal amidomercuration (alpha-epimer) and a double reductive amination (beta-epimer). alpha-Homogalactonojirimycin retains a large part of the potent activity of the parent galactonojirimycin and 1-deoxygalactonojirimycin as an inhibitor of alpha-galactosidases. However, by contrast with the parent iminosugars, it does not inhibit beta-galactosidases, with the exception of the Jack beans enzyme. beta-Homogalactonojirimycin is a weak alpha-galactosidase inhibitor and is completely devoid of activity towards beta-galactosidases. Thus, a marked selectivity toward one family of enzymes has been achieved by the addition of an alpha-CH(2)OH group in the structure of the parent iminosugars.

Amination↗
PubMed2001

Polyhydroxylated alkaloids isolated from mulberry trees (Morusalba L.) and silkworms (Bombyx mori L.).

New polyhydroxylated alkaloids, (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine-N-propionamide from the root bark of Morus alba L., and 4-O-alpha-D-galactopyranosyl-calystegine B(2) and 3 beta,6 beta-dihydroxynortropane from the fruits, were isolated by column chromatography using a variety of ion-exchange resins. Fifteen other polyhydroxylated alkaloids were also isolated. 1-Deoxynojirimycin, a potent alpha-glucosidase inhibitor, was concentrated 2.7-fold by silkworms feeding on mulberry leaves. Some alkaloids contained in mulberry leaves were potent inhibitors of mammalian digestive glycosidases but not inhibitors of silkworm midgut glycosidases, suggesting that the silkworm has enzymes specially adapted to enable it to feed on mulberry leaves. The possibility of preventing the onset of diabetes and obesity using natural dietary supplements containing 1-deoxynojirimycin and other alpha-glucosidase inhibitors in high concentration is of great potential interest.

Alkaloids↗
PubMed2001

Issues of intervention aimed at preventing prospective surplus of physicians in Japan.

OBJECTIVES: In Japan, regulatory intervention aimed at preventing a prospective surplus of physicians is an important medical issue. The study committees organized by the Ministry of Health and Welfare (MHW) in 1986, 1993 and 1998, concluded that the number of physicians would exceed demand for their services in the future. As a result, the government planned to reduce the number of medical students. However, MHW has not been successful in the intervention so far, as shown by the fact that their initial plan for a 10% reduction in the number of students enrolled in medical school has not been attained. In this paper, we examine why the MHW policy failed. METHODS: We reviewed those forecasts performed by past MHW study committees and examined whether the government policy of controlling physician training was appropriate. Additionally, we did a preliminary projection of specialty-specific demand for physician services as a reference for future physician manpower policies in Japan. RESULTS: We found that both conflicts among various interest groups and a lack of precise projections of physician services hampered the proper formation and implementation of a physician manpower policy in Japan. CONCLUSIONS: It might be necessary to examine the appropriateness of the MHW policy in reducing the overall number of students enrolled in medical schools. As a first step in formulating and implementing a physician manpower policy, we should begin to consolidate the necessary data to conduct precise and proper projections of future physician demand.

Adolescent↗
PubMed2001

Novel alpha-L-fucosidase inhibitors from the bark of Angylocalyx pynaertii (Leguminosae).

The extract of bark of Angylocalyx pynaertii (Leguminosae) was found to potently inhibit mammalian alpha-L-fucosidases. A thorough examination of the extract resulted in the discovery of 15 polyhydroxylated alkaloids, including the known alkaloids from seeds of this plant, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), 1-deoxymannojirimycin (DMJ) and 2,5-imino-1,2,5-trideoxy-D-mannitol (6-deoxy-DMDP). Among them, eight sugar-mimic alkaloids showed the potent inhibitory activity towards bovine epididymis alpha-L-fucosidase and their Ki values are as follows: 6-deoxy-DMDP (83 microM), 2,5-imino-1,2,5-trideoxy-L-glucitol (0.49 microM), 2,5-dideoxy-2,5-imino-D-fucitol (17 microM), 2,5-imino-1,2,5-trideoxy-D-altritol (3.7 microM), DMJ (4.7 microM), N-methyl-DMJ (30 microM), 6-O-alpha-L-rhamnopyranosyl-DMJ (Rha-DMJ, 0.06 microM), and beta-L-homofuconojirimycin (beta-HFJ, 0.0053 microM). We definitively deduced the structural requirements of inhibitors of alpha-L-fucosidase for the piperidine alkaloids (DMJ derivatives). The minimum structural feature of alpha-L-fucosidase inhibitors is the correct configuration of the three hydroxyl groups on the piperidine ring corresponding to C2, C3 and C4 of L-fucose. Furthermore, the addition of a methyl group in the correct configuration to the ring carbon atom corresponding to C5 of L-fucose generates extremely powerful inhibition of alpha-L-fucosidase. The replacement of the methyl group of beta-HFJ by a hydroxymethyl group reduced its inhibitory potential about 80-fold. This suggests that there may be a hydrophobic region in or around the active site. The existence or configuration of a substituent group on the ring carbon atom corresponding to the anomeric position of L-fucose does not appear to be important for the inhibition. Interestingly, Rha-DMJ was a 70-fold more potent inhibitor of alpha-L-fucosidase than DMJ. This implies that the lysosomal alpha-L-fucosidase may have subsites recognizing oligosaccharyl structures in natural substrates.

1-Deoxynojirimycin↗
PubMed2001

LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers.

BACKGROUND & AIMS: One approach to the development of targeted cancer chemotherapy exploits increased uptake of the agent into neoplastic cells. In this scenario, higher concentrations of the agent in cancer cells are responsible for differential killing, whereas the low concentration in normal human cells decreases side effects. The aim of this study was to isolate an organic anion transporter that is weak in normal cells, but abundantly expressed in cancer cells, to deliver the anticancer drugs to the cells. METHODS: A human liver complementary DNA (cDNA) library was screened with liver-specific transporter (LST)-1 cDNA as a probe. Northern blot analyses were performed using the isolated cDNA (termed LST-2). An LST-2-specific antibody was raised, and immunohistochemical analyses including immunoelectron microscopy were performed. Xenopus oocyte expression system was used for functional analysis. We also established a permanent cell line that consistently expresses LST-2 to examine the relationship between methotrexate uptake and sensitivity. RESULTS: The isolated cDNA, LST-2, has 79.7% of overall homology with human LST-1. LST-2 exclusively expressed in the liver under normal conditions and its immunoreactivity was highest at the basolateral membrane of the hepatocytes around the central vein. Although its weak expression in the liver, LST-2 is abundantly expressed in the gastric, colon, and pancreatic cancers. On the other hand, the LST-1 was only detected in a hepatic cell line. LST-2 transports methotrexate in a saturable and dose-dependent manner. Furthermore, introduction of the LST-2 gene into mammalian cells potentiates sensitivity to methotrexate. CONCLUSIONS: LST-2 is one of the prime candidate molecules for determining methotrexate sensitivity and may be a good target to deliver anticancer drugs to the gastrointestinal cancers.

Amino Acid Sequence↗