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Biomedical subjects

Takashi Ishikawa

Publications and source records attributed to Takashi Ishikawa.

At least 19 recordsLinked to original sources
PubMed2007

Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms.

Ethanol is almost totally broken down by oxidative metabolism in vivo. Ethanol per se is considered to be neither carcinogenic, mutagenic nor genotoxic. However, during the metabolic conversion of ethanol to acetaldehyde and acetate, the organism is exposed to both ethanol and acetaldehyde and therefore ethanol is suspected to be co-carcinogenic. The genetic polymorphisms of alcohol dehydrogenase-2 (ADH1B) and acetaldehyde dehydrogenase-2 (ALDH2) influence the metabolism of alcohol. The ADH1B*1/*1 genotype encodes the low-activity form of ADH1B, and ALDH2*1/*2 and ALDH2*2/*2 genotype encode inactive ALDH2. The aim of this study was to test the hypothesis that polymorphisms of the ADH1B and ALDH2 genes are significantly associated with genotoxicity induced by alcohol drinking, measured using the cytokinesis-block micronucleus (CBMN) assay, an established biomarker of genome instability, in peripheral blood lymphocytes of 286 healthy Japanese men. There was a significant trend for the mean micronuclei (MN) frequency in habitual or moderate drinkers without a smoking habit to increase as the numbers of the *1 allele in ADH1B increased (P=0.039 or P=0.029) and the *2 allele in ALDH2 increased (P=0.019 or P=0.037). A logistic regression analysis showed that the number of subjects with MN frequency levels more than median value of MN (3.0) was significantly higher in the subjects with the ADH1B*1 allele as adjusted estimates (OR 2.08, 95% C.I. 1.24-3.48), when the OR for the subjects with the ADH1B*2/*2 genotype was defined as 1.00. The number of subjects with MN frequency levels more than median value of MN was also significantly higher in the subjects with the ALDH2*2 allele as adjusted estimates (OR 1.79, 95% C.I. 1.04-3.11), when the OR for the subjects with the ALDH2*1/*1 genotype was defined as 1.00. The results of this study have identified important novel associations between ADH1B/ALDH2 polymorphisms and genotoxicity in alcohol drinkers.

Adult↗
PubMed2006

Structure of the E. coli signal recognition particle bound to a translating ribosome.

The prokaryotic signal recognition particle (SRP) targets membrane proteins into the inner membrane. It binds translating ribosomes and screens the emerging nascent chain for a hydrophobic signal sequence, such as the transmembrane helix of inner membrane proteins. If such a sequence emerges, the SRP binds tightly, allowing the SRP receptor to lock on. This assembly delivers the ribosome-nascent chain complex to the protein translocation machinery in the membrane. Using cryo-electron microscopy and single-particle reconstruction, we obtained a 16 A structure of the Escherichia coli SRP in complex with a translating E. coli ribosome containing a nascent chain with a transmembrane helix anchor. We also obtained structural information on the SRP bound to an empty E. coli ribosome. The latter might share characteristics with a scanning SRP complex, whereas the former represents the next step: the targeting complex ready for receptor binding. High-resolution structures of the bacterial ribosome and of the bacterial SRP components are available, and their fitting explains our electron microscopic density. The structures reveal the regions that are involved in complex formation, provide insight into the conformation of the SRP on the ribosome and indicate the conformational changes that accompany high-affinity SRP binding to ribosome nascent chain complexes upon recognition of the signal sequence.

Base Sequence↗
PubMed2006

Interactive effect of histamine and prostaglandin D2 on nasal allergic symptoms in rats.

This study was undertaken to investigate the interactive effect of histamine and prostaglandin D(2) in nasal allergic symptoms in rats. The intranasal application of histamine at doses lower than 10 mumol/site caused no sneezing or nasal rubbing. In addition, prostaglandin D(2) also showed no significant increase in these responses, even at a dose of 10 nmol/site. On the other hand, the simultaneous instillation of histamine and prostaglandin D(2) resulted in a 1000 times more potent effect in inducing nasal symptoms than the administration of histamine alone. Thus, prostaglandin D(2) enhanced the actions of histamine in inducing sneezing and nasal rubbing in a dose-dependent manner, and significant effects were observed at doses higher than 1 nmol/site. The responses induced by the simultaneous application of histamine and prostaglandin D(2) were inhibited by chlorpheniramine, cyproheptadine, BW A868C and ramatroban. Chlorpheniramine and cyproheptadine showed the dose-related inhibition of nasal symptoms induced by the combined administration of histamine (10 nmol) and prostaglandin D(2) (10 nmol), but the effect of cyproheptadine was relatively weak compared with chlorpheniramine. Moreover, BW A868C and ramatroban also showed the inhibition of nasal symptoms induced by the simultaneous administration of histamine and prostaglandin D(2) in a dose-dependent manner. BW A868C was more potent in inhibiting the nasal symptoms than ramatroban. These results clearly indicate that prostaglandin D(2) showed a synergistic effect on sneezing and nasal rubbing induced by histamine in rats, and its effect occurred through both prostaglandin D(2) and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) receptors.

Administration, Intranasal↗
PubMed2006

Effects of some antiepileptics on septal-kindled seizures in rats.

PURPOSE: The present study was performed to understand the characteristics of septal kindling in rats, especially the efficacies of antiepileptic drugs in comparison with amygdala kindling. METHODS: Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus, and electrodes were implanted into the right frontal cortex, the hippocampus, the lateral septal and the amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. Bipolar stimulation was applied to the lateral septal or the amygdala every day until a generalized seizure was obtained. Carbamazepine (CBZ), zonisamide (ZNS) and clobazam (CLB) were orally administered to fully kindled rats. RESULT: A considerable number of stimulations was required to establish septal-kindled seizures. In addition, wet dog shakes were observed during the septal kindling procedure, different from amygdala kindling. The oral administration of CBZ, ZNS and CLB caused a dose-dependent inhibition both of seizure stage and after-discharge (AD) duration of septal-kindled seizures. CBZ and ZNS caused a more potent inhibition of septal-kindled seizures than amygdala kindled seizures, whereas CLB inhibited both septal and amygdala kindled seizures to almost the same extent. CONCLUSION: Septal kindling was confirmed to possess some characteristics, which were evidently different from that of amygdala kindling. In addition, it was demonstrated that septal kindling was also available as a model for the evaluation of antiepileptic drugs.

Amygdala↗
PubMed2006

Mechanism of imipramine-induced seizures in amygdala-kindled rats.

The present study was undertaken to get insight in the possible mechanisms of imipramine-induced seizures in amygdala-kindled rats. The intraperitoneal (i.p.) injection of imipramine produced potent behavioral and electroencephalogram (EEG) seizures in amygdala-kindled rats. Histidine (1500 mg/kg, i.p.) and histamine (10 and 20 microg, i.c.v.) significantly attenuated the seizures induced by imipramine (50 mg/kg, i.p.) in kindled rats. In addition, the inhibition of imipramine-induced seizures by histamine (20 microg, i.c.v.) was antagonized by an H1 antagonist, pyrilamine. An H3 antagonist, thioperamide (50 microg, i.c.v.), also significantly attenuated the imipramine-induced seizures in kindled rats. The i.p. injection of alpha-methyl-p-tyrosine at a dose of 250 mg/kg significantly diminished the seizures induced by imipramine. However, p-chlorophenylalanine and physostigmine did not affect the imipramine-induced seizures to any extent. These data give strong hints that the H1 receptor antagonistic properties and the brain noradrenaline activating effects of imipramine are centrally involved in imipramine-induced seizures, and central serotonergic and cholinergic neurotransmissions are not involved in the seizures induced by imipramine in amygdala-kindled rats.

Amygdala↗
PubMed2006

Predicting 5-fluorouracil chemosensitivity of liver metastases from colorectal cancer using primary tumor specimens: three-gene expression model predicts clinical response.

We identified genes related to 5-fluorouracil (5-FU) sensitivity in colorectal cancer and utilized these genes for predicting the 5-FU sensitivity of liver metastases. Eighty-one candidate genes involved in 5-FU resistance in gastric and colon cancer cell lines were previously identified using a cDNA microarray. In this study, the mRNA expression levels of these 81 selected genes and the genes of 5-FU-related enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT), were measured using real-time quantitative RT-PCR assays of surgically resected materials from primary colorectal tumors in 22 patients. Clinical responses were estimated by evaluating the effects of 5-FU-based hepatic artery injection (HAI) chemotherapy for synchronous liver metastases. Four genes (TNFRSF1B, SLC35F5, NAG-1 and OPRT) had significantly different expression profiles in 5-FU-nonresponding and responding tumors (p < 0.05). A "Response Index" system using three genes (TNFRSF1B, SLC35F5 and OPRT) was then developed using a discriminate analysis; the results were well correlated with the individual chemosensitivities. Among the 11 cases with positive scores in our response index, 9 achieved a reduction in their liver metastases after 5-FU-based chemotherapy, whereas only 1 of the 11 cases with negative scores responded well to chemotherapy. Our "Response Index" system, consisting of TNFRSF1B, SLC35F5 and OPRT, has great potential for predicting the efficacy of 5-FU-based chemotherapy against liver metastases from colorectal cancer.

Aged↗
PubMed2006

Vesicles from docosahexaenoic acid.

In dilute aqueous solution and at room temperature, cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) self-assembles into vesicles (self-closed bilayers), if the molar ratio of the neutral form of DHA to anionic DHA is kept between 1:1 and 1:3 (corresponding to a bulk pH between 8.5 and 9.2 for a system with 10 mM DHA). By using polycarbonate membrane extrusion, stable unilamellar DHA vesicles with an average diameter of 80 nm can be prepared at pH 8.8. Cryo-transmission electron microscopy indicates that the width of the DHA bilayers in the vesicles is clearly below twice the length of an extended DHA molecule, indicating a high conformational flexibility of DHA within the vesicle bilayer. These DHA bilayers have a similar thickness like bilayers of vesicles prepared at pH 8.5 from oleic acid (cis-9-octadecenoic acid). Using calcein as fluorescent reference compound, it is shown that water-soluble molecules can be encapsulated inside DHA vesicles which may make them interesting for medical or food applications.

Colloids↗
PubMed2006

A polymorphism of the methionine synthase reductase gene increases chromosomal damage in peripheral lymphocytes in smokers.

The cytogenetic effects of cigarette smoke has been evaluated as one of many potential confounders in a large number of biomonitoring studies of occupationally or environmentally exposed populations and control subjects. Despite the well-known presence of carcinogens in the cigarette smoke, the results in the scientific literature linking smoking habits to micronuclei (MN) frequency, one of the cytogenetic markers, are rather controversial. Here, we investigated the relationships among MN frequency, smoking habits and five folate metabolic enzyme gene polymorphisms (MTHFR C677T and A1298C, MTR A2756G, MTRR A66G and TYMS 3'UTR) in 132 healthy Japanese men who were non-habitual drinkers. In never- and former-smokers, no statistically significant differences in the mean MN frequencies were observed according to the five folate metabolic enzyme gene polymorphisms. In current-smokers, however, subjects with the AA genotype for MTRR had a significantly higher mean MN frequency than the AG genotypes for MTRR (p<0.05). Furthermore, among subjects with the AA genotype for MTRR, current-smokers were found to have a significantly higher mean MN frequency than never- and former-smokers (p<0.05). To further characterize this association, we stratified the smoking status into five groups: non-smokers (never-smokers and former-smokers), 1-10 cigarettes/day, 11-20 cigarettes/day, 21-30 cigarettes/day and >or=31 cigarettes/day. There was an overall trend for the mean MN frequency in subjects with the MTRR AA genotype to increase as the number of cigarettes smoked per day increased (p<0.01, Jonckheere-Terpstra test). The results of our preliminary study suggest that the MTRR AA genotype acts to increase the MN frequency resulting from cigarette smoking. Therefore, studies on human genotoxicity based on cytogenetic markers of MN should take into account both the MTRR polymorphism and the potential confounding effect of smoking, although these preliminary findings need to be validated in larger populations because of the relatively small sample size.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2006

Reclassification of Arthrobacter duodecadis Lochhead 1958 as Tetrasphaera duodecadis comb. nov. and emended description of the genus Tetrasphaera.

Phylogenetic analysis based on 16S rRNA gene sequences and chemotaxonomic features of Arthrobacter duodecadis Lochhead 1958 indicated that the bacterium belonged within the genus Tetrasphaera. A. duodecadis IAM 14868(T) could be distinguished from other species by the presence of 3-hydroxy meso-diaminopimelic acid in the peptidoglycan and a series of 10-methyl fatty acids. In addition, DNA-DNA relatedness studies indicated that the strain belonged to a genomic species that could be readily distinguished from its nearest neighbours, the type strains of Tetrasphaera elongata, Tetrasphaera japonica and Tetrasphaera australiensis. These features support our proposal to reclassify A. duodecadis in the genus Tetrasphaera, as Tetrasphaera duodecadis comb. nov. The type strain is IAM 14868(T) (=NBRC 12959(T) = ATCC 13347(T) = NCIMB 9222(T)). An emended description of the genus Tetrasphaera is given.

Actinomycetales↗
PubMed2006

Epileptogenic activity of methicillin-resistant Staphylococcus aureus (MRSA) antibiotics in rats.

The present study was undertaken to clarify the epileptogenic activity induced by intracerebroventricular injection (i.c.v.) of antibiotics effective in methicillin-resistant Staphylococcus aureus (MRSA) in chronically electrode implanted rats. Teicoplanin (10-100 microg, i.c.v.) caused dose-related electroencephalographic (EEG) seizure characterized by an uninterrupted high voltage and wave complex. At the same time, the rats showed forelimb clonus, head nodding, jumping and severe convulsion. At a high dose (100 microg, i.c.v.), the drug caused a severe twisting immediately after the intracerebroventricular injection (i.c.v.) followed by jumping and violent convulsion with a continuous rhythmic spike and wave complex in EEG. On the other hand, vancomycin (30-1000 microg, i.c.v.) caused no or almost no epileptogenic activity in terms of behavior and in EEG. However, at a high dose (1000 microg, i.c.v.), the drug caused an occasional spike from the hippocampus without showing any behavioral changes in the rats. Fosfomycin (30-1000 microg, i.c.v.), cefazolin (10-100 microg, i.c.v.) and penicillin G (30-300 microg, i.c.v.), used as reference drugs, caused dose-dependent epileptogenic activity in both EEG. From these findings, it was found that teicoplanin caused a potent epileptogenic activity, different to vancomycin. Therefore, it can be concluded that vancomycin may be safety on epileptogenic activity used for the clinical purpose of infections caused by MRSA.

Animals↗
PubMed2006

Matrilysin (MMP-7) degrades VE-cadherin and accelerates accumulation of beta-catenin in the nucleus of human umbilical vein endothelial cells.

Matrilysin, MMP-7, is an important target for anti-metastasis therapy of colorectal cancer because it is a strong proteolytic factor secreted from the cancer cell itself and it induces tumor angiogenesis. In a previous report, we showed that matrilysin accelerated human umbilical vein endothelial cell (HUVEC) proliferation in low serum conditioned medium. In the present study, we show that matrilysin stimulation decreased VE-cadherin expression, induced accumulation of beta-catenin in the nucleus of the HUVEC, and up-regulated matrilysin mRNA expression. These results compel a hypothesis that matrilysin cleaves VE-cadherin and releases beta-catenin from the VE-cadherin/catenin complex; the free beta-catenin can activate T-cell factor (Tcf) DNA binding protein, which accelerates cell proliferation and matrilysin expression.

Antigens, CD↗
PubMed2006

[Advances in breast cancer chemotherapy].

Progress in chemotherapy for breast cancer was reviewed in the management of primary and metastatic diseases. In the metastatic setting, a survival advantage from combinations of drugs has not been proved over single agents given in sequence. Currently, active agents include anthracyclines, taxanes, vinorelbine, and fluoropyrimidines. Prospective randomized trials demonstrated that adjuvant systemic chemotherapy reduced annual odds of recurrence and death with combination therapy, regardless of age, stage, nodel status and hormone receptor status. One of the recent important questions in the adjuvant setting is the role of taxanes. Although many adjuvant taxane studies are still on going, 4 cycles of anthracycline-containing regimen sequenced with 4 cycles of a taxane appear to be the most beneficial treatment for advanced disease. Controversies and future directions are the high cost of treatment and the prediction of response to each drug for individual patients.

Anthracyclines↗
PubMed2005

Protein identification from product ion spectra of peptides validated by correlation between measured and predicted elution times in liquid chromatography/mass spectrometry.

Reversed-phase liquid chromatography (LC) directly coupled with electrospray-tandem mass spectrometry (MS/MS) is a successful choice to obtain a large number of product ion spectra from a complex peptide mixture. We describe a search validation program, ScoreRidge, developed for analysis of LC-MS/MS data. The program validates peptide assignments to product ion spectra resulting from usual probability-based searches against primary structure databases. The validation is based only on correlation between the measured LC elution time of each peptide and the deduced elution time from the amino acid sequence assigned to product ion spectra obtained from the MS/MS analysis of the peptide. Sufficient numbers of probable assignments gave a highly correlative curve. Any peptide assignments within a certain tolerance from the correlation curve were accepted for the following arrangement step to list identified proteins. Using this data validation program, host protein candidates responsible for interaction with human hepatitis B virus core protein were identified from a partially purified protein mixture. The present simple and practical program complements protein identification from usual product ion search algorithms and reduces manual interpretation of the search result data. It will lead to more explicit protein identification from complex peptide mixtures such as whole proteome digests from tissue samples.

Chromatography, Liquid↗
PubMed2005

Interobserver variation in the histopathological assessment of nonalcoholic steatohepatitis.

Pathological assessment is considered as the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). However, there is no agreement of histological features required for the diagnosis of NASH. In the present study, eight experienced hepatopathologists read liver biopsy specimen slides of 21 cases of NASH and suspected NASH independently and were asked to assess histopathological features and render a diagnosis. Interobserver variation among pathologists was evaluated by kappa statistics. Significant, good agreement was present in evaluation of the extent of steatosis and grade of fibrosis. Agreement was moderate concerning the localization of steatosis, localization of fibrosis, and glycogen nuclei. Only slight or poor agreement was seen in evaluation of type of steatosis, ballooning, intralobular necroinflammatory change, portal inflammation, and degree of neutrophilic infiltration. Thus the agreement varied for histological variables. Significant, moderate agreement was seen in the diagnosis of NASH but agreement was poor in the diagnosis of suggestive NASH. The agreement for the diagnosis of NASH was not high as for the individual histological findings that were thought to be the basis of the diagnosis. In conclusion, some histological features in NASH might prove useful for the development of a standardized and reliable pathological diagnosis and scoring system.

Journal Article↗
PubMed2005

A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma.

BACKGROUND & AIMS: Percutaneous radiofrequency ablation is a recently introduced treatment for hepatocellular carcinoma, whereas ethanol injection is now a standard therapy. We compared their long-term outcomes. METHODS: Two hundred thirty-two patients with hepatocellular carcinoma who had 3 or fewer lesions, each 3 cm or less in diameter, and liver function of Child-Pugh class A or B were entered onto a randomized controlled trial. The primary end point was survival, and the secondary end points were overall recurrence and local tumor progression. RESULTS: One hundred eighteen patients were assigned to radiofrequency ablation and 114 to ethanol injection. The number of treatment sessions was smaller (2.1 times vs 6.4 times, respectively, P < .0001) and the length of hospitalization was shorter (10.8 days vs 26.1 days, respectively, P < .0001) in radiofrequency ablation than in ethanol injection. Four-year survival rate was 74% (95% CI: 65%-84%) in radiofrequency ablation and 57% (95% CI: 45%-71%) in ethanol injection. Radiofrequency ablation had a 46% smaller risk of death (adjusted relative risk, 0.54 [95% CI: 0.33-0.89], P = .02), a 43% smaller risk of overall recurrence (adjusted relative risk 0.57 [95% CI: 0.41-0.80], P = .0009), and an 88% smaller risk of local tumor progression (relative risk, 0.12 [95% CI: 0.03-0.55], P = .006) than ethanol injection. The incidence of adverse events was not different between the 2 therapies. CONCLUSIONS: Judging from higher survival but similar adverse events, radiofrequency ablation is superior to ethanol injection for small hepatocellular carcinoma.

Adult↗
PubMed2005

Outbreak of hepatitis C virus infection in an outpatient clinic.

BACKGROUND: From January through September 2001, seven patients were admitted to Fukaya Red Cross Hospital with typical clinical manifestations of acute hepatitis. Six were outpatients of the clinic, which is located near the hospital. An extensive survey of clinic outpatients conducted by the local health department revealed six more new acute hepatitis cases during this period. METHODS: A case control study was carried out to identify potential risk factors for infection. In total, 1946 outpatients with clinic records were scheduled to undergo hepatitis C virus (HCV)-antibody testing. For the HCV-Ab positive patients, HCV-RNA was subtyped and quantified, and sequences of HCV hypervariable region 1 were determined. RESULTS: Ultimately, 12 patients with acute hepatitis and two asymptomatic subjects were found to be a part of this outbreak. HCV isolates were divided into three major groups using phylogenetic tree analysis. Only a past history of visiting the clinic was significantly associated with acute hepatitis. The timing of the parenteral medical procedure at the clinic and the onset of acute hepatitis strongly suggested association of the two events. CONCLUSIONS: Our findings suggest that nosocomial HCV infection can occur in an outpatient clinic, even in countries where post-transfusion hepatitis has been almost entirely eliminated.

Adult↗
PubMed2005

Prediction of chemosensitivity of colorectal cancer to 5-fluorouracil by gene expression profiling with cDNA microarrays.

5-Fluorouracil (5-FU) is the most widely used anticancer agent for gastrointestinal cancers. Because many tumors show primary resistance, it is clinically meaningful to predict tumor sensitivity to the drug before treatment. cDNA microarrays containing 21,168 clones were used to identify genes associated with sensitivity to 5-FU. Gene expression profiling of 3 colorectal cancer cell lines (DLD-1, HT-29 and NUGC-3) and the corresponding 5-FU-resistant sublines (DLD-1/FU, HT-29/FU and NUGC-3/5FU/L) showed 81 genes that were differentially expressed. The gene set thus identified successfully predicted the sensitivities of 5 other colorectal cancer cell lines and could also separate 5-FU resistant clinical samples from sensitive ones.

Antimetabolites, Antineoplastic↗