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Biomedical subjects

H Fukui

Publications and source records attributed to H Fukui.

At least 73 records · Page 4Linked to original sources
PubMed2000

Enhanced urinary excretion of cysteinyl leukotrienes in patients with acute alcohol intoxication.

BACKGROUND & AIMS: Leukotrienes are proinflammatory mediators. Ethanol inhibits the catabolism of both cysteinyl leukotrienes (leukotriene E(4) [LTE(4)] and N-acetyl-LTE(4)) and leukotriene B(4) (LTB(4)) in hepatocytes. We examined the metabolic derangement of leukotriene inactivation by ethanol in humans in vivo. METHODS: LTE(4), N-acetyl-LTE(4), LTB(4), and 20-hydroxy-LTB(4) were quantified in urine samples from 16 patients with acute alcohol intoxication (mean blood ethanol, 75 mmol/L). In 9 healthy volunteers, urinary LTE(4) was determined before and after ethanol consumption (mean blood ethanol, 14 mmol/L). RESULTS: The excretion of LTE(4) during alcohol intoxication was 286 compared with 36 nmol/mol creatinine in healthy subjects (P < 0.01); the corresponding values for N-acetyl-LTE(4) were 101 and 11 nmol/mol creatinine, respectively (P < 0.001). This excretion of cysteinyl leukotrienes decreased when the blood ethanol concentration returned to normal. LTB(4) and 20-hydroxy-LTB(4) were detectable only in patients with excessive blood ethanol concentrations (mean, 95 mmol/L). In healthy volunteers, LTE(4) excretion increased 3-5 hours after ethanol consumption (mean peak concentration of 1.5 nmol/L compared with 0.5 nmol/L for basal values; P < 0.005). CONCLUSIONS: Ethanol at high concentration induces increased leukotriene excretion into urine. These changes are consistent with inhibition of leukotriene catabolism and inactivation induced by ethanol, as well as with a higher leukotriene formation caused by ethanol-induced endotoxemia.

Acute Disease↗
PubMed2000

Mixed endothelin receptor antagonist, SB209670, decreases portal pressure in biliary cirrhotic rats in vivo by reducing portal venous system resistance.

BACKGROUND/AIMS: This study aimed to evaluate the hemodynamic effects of endothelin-1 or mixed endothelin receptor antagonist, SB209670 in cirrhotic rats, and to elucidate the role of endothelin in cirrhotic portal hypertension. METHODS: Secondary biliary cirrhosis was induced by bile duct ligation. Hemodynamics were studied using the radioactive microsphere technique. RESULTS: Plasma and hepatic endothelin levels in cirrhotic rats were significantly higher than those in normal rats (plasma, 9.0+/-1.3 vs. 2.6+/-0.5 pg/ml, p<0.001; liver, 74.8+/-13.3 vs. 12.6+/-2.5 pg/g wet tissue, p<0.001). Intraportal administration of endothelin-1 (3 nmol/kg) progressively raised portal pressure without an initial transient reduction, which was observed in systemic arterial pressure, in both cirrhotic and normal rats. SB209670 (5.4 micromol/kg) reduced portal pressure in cirrhotic rats (-19+/-5%, p<0.01) without modifying systemic arterial pressure and renal blood flow, but not in normal rats. This reduction was associated with reduced portal venous system resistance (vehicle, 2.5+/-0.2 vs. SB209670, 1.7+/-0.1 mmHg x min x 100 g bw/ml, p<0.01), but not with change in portal venous inflow and collateral blood flow. CONCLUSIONS: Mixed endothelin antagonist, SB209670, decreased portal pressure by reducing portal venous system resistance without modifying systemic arterial pressure and renal blood flow in cirrhotic rats. This result, together with the findings that plasma and hepatic endothelin levels were elevated in cirrhotic rats and that exogenous endothelin-1 increased portal pressure, provides further support for a role of endothelin in portal hypertension and suggests a potential use of mixed endothelin antagonist in the pharmacological treatment of portal hypertension.

Animals↗
PubMed2000

Enhancement of hepatocarcinogenesis initiated with diethylnitrosamine or N-nitrosobis(2-hydroxypropyl)amine by a choline-deficient, L-amino acid-defined diet administered prior to the carcinogen exposure in rats.

Effects of pre-administration of a choline-deficient, L-amino acid-defined (CDAA) diet on hepatocarcinogenesis initiated with diethylnitrosamine (DEN) or N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats were investigated. A pre-administrating period was set as 1 week, because CDAA diet induces liver injuries by this time-point. In a time-course study, male Fischer 344 rats, 6 weeks old, received a 1-week pre-administration of choline-supplemented, L-amino acid-defined (CSAA) or CDAA diet, DEN at a dose of 100 mg/kg body weight by a single intraperitoneal injection, then CSAA or CDAA diet for up to 8 weeks, and were sacrificed 4, 6 and 8 weeks after DEN. CDAA diet administered only after DEN significantly increased the numbers of glutathione S-transferase placental form (GST-P)-positive lesions 4, 6 and 8 weeks after DEN and their sizes 6 and 8 weeks after DEN. CDAA diet administered both before and after DEN similarly increased the numbers and sizes of GST-P-positive lesions, but with a significantly greater degree than obtained by the diet administered only after DEN. In a dose response study, rats received vechicle or DEN, at a dose of 0.001, 0.01, 0.1, 1, 10, 20, 50, 100 or 200 mg/kg body weight, 1 week after the commencement of CSAA or CDAA diet, and sacrificed 8 weeks after vehicle or DEN. The significant increases of the numbers of GST-P-positive lesions were obtained after 50-200 mg/kg body weight of DEN under the CSAA diet administration, whereas those were detected after 10-200 mg/kg under CDAA diet administration. Sizes became significantly larger with only 200 mg/kg body weight of DEN in the CSAA case but with 50-200 mg/kg in the CDAA case. Male Wistar rats received a 1-week pre-administration of CSAA or CDAA diet, vehicle or BHP, at a dose of 600 or 1200 mg/kg body weight, by a single intraperitoneal injection, then CSAA or CDAA diet for 8 weeks, and were then sacrificed. The numbers of GST-P-positive lesions demonstrated significant increment with 1200 mg/kg body weight of BHP by CDAA diet administered only after BHP and, to a significantly greater degree, by the diet administered both before and after BHP. While CDAA diet administered only after BHP did not alter the sizes of GST-P-positive lesions, the diet administered both before and after 600 and 1200 mg/kg body weight of BHP significantly increased the sizes of the lesions. These results indicate that the pre- plus post-administration of CDAA diet enhances hepatocarcinogenesis initiated with DEN or BHP, more than the post-administration only, thus providing a sensitive model to detect weak liver carcinogenic potency of environmental chemicals.

Amino Acids↗
PubMed2000

Electrochemotherapy for colorectal cancer with commonly used chemotherapeutic agents in a mouse model.

We examined here the usefulness of electrochemotherapy against colorectal cancer (CRC) using a mouse model. Electropermeabilization profoundly increased the sensitivity of murine CRC, Colon 26, and MC38 cells to bleomycin (BLM) but not to 5-fluorouracil (5-FU) or to cisplatin (CDDP) in vitro. In vivo experiments revealed that electrochemotherapy with 5-FU, CDDP, or BLM was much more effective against CRC compared with the treatment of the drug alone. Electrochemotherapy with BLM or CDDP exhibited profound antitumor effects on subcutaneously established CRC in mice, and complete tumor regression was observed in five and four of eight animals, respectively. Electrochemotherapy with 5-FU also had an impact on CRC development, and complete cure was observed in one of eight animals. Subsequent analyses revealed that electropermeabilization significantly increased intratumoral amounts of BLM and CDDP but not 5-FU. These results indicate that electrochemotherapy may be a promising treatment modality against CRC.

Animals↗
PubMed2000

Particle-mediated gene transfer into murine livers using a newly developed gene gun.

Although particle-mediated gene transfer using gene gun technology has been applied for gene transfer into epidermis, applications of this technology to visceral tissues have not been well investigated. Although all helium gas-driven gene gun instruments have used macrocarriers to discharge DNA-coated microprojectiles so far, we used a newly developed gene gun instrument, in which a hammering bullet is used to discharge microprojectiles. With the gene gun, gold particles coated with lacZ expression plasmid were discharged to murine livers. LacZ expression was induced much more profoundly in the liver by particle-mediated gene transfer than by simple plasmid injection and electroporation-mediated gene transfer. LacZ expression was broadly and randomly distributed throughout the bombarded livers, indicating that particle-mediated gene transfer can induce transgene expression even at relatively distant areas from the surface of the bombarded tissue. Furthermore, although transgene expression was at its peak on day 2 after the bombardment, it was still detectable even on day 28. These results indicate that particle-mediated gene transfer with a newly developed gene gun may provide a new approach to gene therapy for human diseases.

Animals↗
PubMed2000

Analysis of K-ras codon 12 mutations and p53 overexpression in colorectal nodule-aggregating tumors.

BACKGROUND AND AIMS: Morphologically, colorectal nodule-aggregating tumors are quite different from polypoid-type colorectal tumors that develop via the adenoma-carcinoma sequence. Although polypoid-type colorectal tumors are well known to have a high incidence of K-ras gene mutation and p53 overexpression, colorectal nodule-aggregating tumors have not been examined in terms of genetic changes and clinicopathological features. In the present study, therefore, we analysed the clinicopathological features, genetic changes in K-ras codon 12, and p53 overexpression in colorectal nodule-aggregating tumors. METHODS: A total of 18 colorectal nodule-aggregating tumors were surgically resected and then analysed clinicopathologically. Immunohistochemistry and polymerase chain reaction-single stranded conformational polymorphism were performed to analyse p53 abnormalities in the tumors. K-ras codon 12 mutations were screened out by the polymerase chain reaction-restriction fragment length polymorphism method and analysed by fluorescence direct sequencing. RESULTS: p53 overexpression was observed in six lesions (33%). p53-overexpressing cells were observed in parts of carcinoma or adenoma showing high-grade atypia. Four of the 10 (40%) samples had a p53 gene mutation. Nine of the 18 (50%) samples had a K-ras codon 12 point mutation. In eight cases (89%), the mutations of the K-ras codon 12 were of the same type: GGT (glycine) to GTT (valine). CONCLUSIONS: The colorectal nodule-aggregating tumor has distinctive characteristics showing a morphological phenotype of the superficial-type tumors and genotype of the polypoid tumors in terms of K-ras gene mutation and p53 overexpression.

Adenoma↗
PubMed2000

Incidence of P53 and K-ras alterations in ovarian mucinous and serous tumors.

Clarification of the pathogenic relationships existing among ovarian cystadenomas, tumors of low malignant potential (LMP) and various adenocarcinoma types, a series of 29 mucinous and 19 serous ovarian tumors including adenomas, LMP tumors and adenocarcinomas were examined. P53 protein was detected by the streptavidin-biotin method and point mutation of K-ras codon 12 was detected by polymerase chain reaction-restriction fragment length polymorphism analysis. P53 overexpression was observed more frequently in serous adenocarcinomas (5/8, 63%) than in mucinous adenocarcinomas (2/9, 22%) and was correlated with the malignant potential of serous tumors. Furthermore, the proportion of P53-positive cells was significantly higher in serous adenocarcinomas than in mucinous adenocarcinomas. P53 overexpression may therefore be closely related to the early events of carcinogenesis in serous tumors. Although mutation of the K-ras oncogene appears to be an important event in the early tumorigenesis of mucinous tumors, mutation of the K-ras oncogene in serous tumors may be dependent on morphology. Different complex pathways of oncogene and/or tumor suppressor gene abnormalities may be involved in the development of mucinous and serous adenocarcinomas.

Cell Transformation, Neoplastic↗
PubMed2000

Neutrophil chemoattractant 2 beta regulates expression of the Reg gene in injured gastric mucosa in rats.

BACKGROUND & AIMS: Regenerating (Reg) protein has a trophic effect on gastric mucosal cells. We have shown that Reg gene expression is increased in enterochromaffin-like (ECL) cells during the healing of damaged gastric mucosa around mucosal erosion. This study was designed to explore the stimulants of Reg expression during the healing of gastric mucosal damage. METHODS: Time course changes of the expression of genes for various proinflammatory cytokines and Reg were investigated after induction of gastric mucosal lesions in rats. The direct effect of proinflammatory cytokines on Reg gene expression and Reg protein production were investigated in vitro using counterflow elutriation-enriched rat ECL cells. CXC receptor 2 (CXCR-2) expression was investigated in ECL cells by reverse-transcription polymerase chain reaction. Reg gene expression was also investigated in rats treated by the neutralizing antibody of cytokine-induced neutrophil chemoattractant (CINC-2 beta). RESULTS: During healing, the gene expression of several proinflammatory cytokines and Reg was markedly augmented. Among the proinflammatory cytokines, CINC-2 beta is the only cytokine in which augmented expression preceded the increase of Reg gene expression. In rats treated with CINC-2 beta neutralizing antibody, the augmentation of Reg gene expression was significantly inhibited. When ECL cells were incubated with these proinflammatory cytokines, CINC-2 beta dose-dependently increased Reg messenger RNA and Reg protein in ECL cells. CXCR-2 was identified in isolated ECL cells. CONCLUSIONS: CINC-2 beta, expressed in damaged gastric mucosa, stimulates the production of Reg protein in ECL cells via CXCR-2 and may be involved in the accelerated healing of injured gastric mucosa.

Animals↗
PubMed2000

Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.

Actins↗
PubMed2000

Magnetic resonance angiography for monitoring prophylactic endoscopic treatment of high risk esophageal varices.

BACKGROUND AND STUDY AIMS: Endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL) are used worldwide as the treatment for esophageal varices. We evaluated portal hemodynamics using magnetic resonance angiography (MRA) in these two forms of treatment. PATIENTS AND METHODS: The study was carried out in 50 cirrhotic patients. MRA was performed to identify the hepatofugal supply vein selectively for esophageal varices. Those who showed a positive MR angiogram for the supply vein were randomly allocated to one of two groups, using the sealed envelope method, and underwent either EIS or EVL. On the other hand, those with a negative angiogram received only EVL. EIS was done to embolize esophageal varices as well as their feeders by intravariceal injection of sclerosant under fluoroscopic guidance. RESULTS: A positive MR angiogram of the hepatofugal left gastric vein as the supply vein was observed in 41 patients. Nine patients showed negative MRA results. Among those with positive angiograms, the rate of eradication of the left gastric vein was higher in the EIS-treated group than in the EVL treated group (50% vs. 8.6%). After either treatment, the recurrence-free rate for high risk esophageal varices was higher in patients with complete eradication of the left gastric vein than in those without (88% vs. 35%). In patients with negative angiogram results, who only underwent EVL, high risk esophageal varices did not reappear over a long period. CONCLUSION: MRA is useful for evaluating portal hemodynamics. With the aim of avoiding recurrence of esophageal varices, EIS was suitable for patients who had a hepatofugal supply vein for the varices because recurrence could be prevented by embolization of the supply vein. EVL may be expected to be efficacious in patients where no image of a hepatofugal supply vein is found on MRA.

Adult↗
PubMed2000

Shape-memory alloy loop snare for endoscopic photodynamic therapy of early gastric cancer.

BACKGROUND AND STUDY AIMS: Photodynamic therapy (PDT) has proved effective in the treatment of gastric cancer, but there is room for improvement. To achieve the technical goal of carrying out endoscopic PDT, endoscopists need to determine the precise area for laser irradiation at adequate dosages. This report describes the use of a shapememory alloy (SMA) loop snare as a useful tool in endoscopic PDT. PATIENTS AND METHODS: Eleven patients with biopsy-proved early gastric cancer were treated with endoscopic PDT after intravenous injection of Photofrin II (2 mg/kg b.w.). Five patients underwent PDT using the SMA loop snare, and six underwent PDT without the use of the device. Cancer lesions smaller than 2 cm in diameter were irradiated with an excimer-dye laser (4 mJ, 80 Hz, 630 nm) for 20 min. RESULTS: All five patients (100%) treated with PDT using the SMA loop snare, and four of the six patients (67%) treated with PDT without use of the SMA loop snare, showed complete remission. CONCLUSIONS: The SMA loop snare routinely forms a circle 2 cm in diameter, covering an area of 3.14 cm2, and makes it possible to mark and calculate the precise area of cancerous lesions for irradiation at appropriate dosages. The findings of this study suggest that the SMA loop snare is an effective tool for PDT in early gastric cancer.

Aged↗
PubMed2000

Retrovirus-mediated in vivo gene therapy using the herpes simplex virus thymidine kinase gene against carcinomatous peritonitis.

BACKGROUND: Carcinomatous peritonitis is characterized by massive malignant ascites, while peritoneally disseminated carcinomatosis is characterized by a large number of metastatic solid tumors in the peritoneal cavity. Although both are fatal end-stage manifestations of malignancies derived from the digestive system, the former is usually more serious than the latter due to massive malignant ascites. Although the effectiveness of gene therapy against peritoneally disseminated carcinomatosis has been shown in animal experiments, its effectiveness against carcinomatous peritonitis remains to be examined. METHODS: A carcinomatous peritonitis model was made by inoculating murine hepatocellular carcinoma cells, MH134, into the peritoneal cavity of syngeneic C3H/He mice, resulting in production of massive malignant ascites without development of intraperitoneal solid tumors. Model animals were injected intraperitoneally with retroviruses carrying the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment. RESULTS: Retrovirus-mediated in vivo gene therapy with the HSV-tk/GCV system was shown to have a significant impact on survival of animals with carcinomatous peritonitis not only at an early stage, but also at an advanced stage. Furthermore, repeated injections of HSV-tk-carrying retroviruses significantly prolonged the survival of animals with carcinomatous peritonitis compared with a single injection protocol. When intraperitoneal administration of recombinant interleukin-2 (IL-2) was added to the HSV-tk/GCV system, levels of IL-1beta and IL-2 in malignant ascites were significantly increased, resulting in significantly reduced ascite volume and prolonged survival. CONCLUSIONS: Our results indicate the feasibility of retrovirus-mediated in vivo gene therapy with the HSV-tk/GCV system plus IL-2 treatment against carcinomatous peritonitis.

Animals↗
PubMed2000

Assessment of efficiency and safety of adenovirus mediated gene transfer into normal and damaged murine livers.

BACKGROUND: When recombinant adenoviruses are infused directly into the circulation, transgene expression is almost completely restricted to the liver. AIMS: Efficiency and safety of adenovirus mediated gene transfer into damaged livers were examined in mice with liver cirrhosis or fulminant hepatitis. METHODS: Liver cirrhosis and fulminant hepatitis were induced by intraperitoneal administration of thioacetamide and D-galactosamine followed by lipopolysaccharide, respectively. Mice were infused with adenoviruses carrying the Escherichia coli beta-galactosidase gene, lacZ gene, into the tail vein. Transduction efficiency of the lacZ gene was estimated histochemically by X-gal staining and quantitatively using a chemiluminescent assay. Activation of adenovirus specific T cells and development of neutralising antibodies against adenovirus were also examined. RESULTS: Histochemical evaluation revealed that approximately 40%, 80%, and 40% of cells in normal, cirrhotic, and fulminant hepatitis livers, respectively, were stained blue using X-gal staining. Quantitative analyses revealed that levels of lacZ expression in cirrhotic livers were approximately 2.5-fold and sixfold greater than those in normal and fulminant hepatitis livers, respectively. Although transgene expression in fulminant hepatitis livers was significantly lower than that in normal livers, marked levels of transgene expression were achieved even in fulminant hepatitis livers. Significant adverse effects of adenoviruses were not observed in damaged livers. There were no significant differences in cellular or humoral immune responses to adenoviruses among animals with normal, cirrhotic, and fulminant hepatitis livers. CONCLUSIONS: Our results suggest that gene therapy with adenoviruses may be used efficiently and safely, even in patients with severe liver disease.

Adenoviridae↗
PubMed2000

Effect of endothelin-1 (1-31) on human mesangial cell proliferation.

It was previously found that human chymase cleaves big endothelins (ETs) at the Tyr31-Gly32 bond and produces 31-amino acid ETs (1-31). In the present study, human plasma concentrations of ET-1 (1-31) and ET-1 were examined and the effect of synthetic ET-1 (1-31) on the proliferation of cultured human mesangial cells (HMCs) was investigated. The proliferative effect of ET-1 (1-31) was evaluated from the [3H]-thymidine uptake. The activity of extracellular signal-regulated kinase (ERK) and DNA binding activity of activator protein-1 were determined by using an in-gel kinase assay and gel mobility shift assay, respectively. Immunoreactive ET-1 (1-31) was detectable in plasma, but the level was slightly lower than that of ET-1. ET-1 (1-31) increased [3H]-thymidine incorporation in HMCs to a degree similar to that induced by ET-1. ET-1 (1-31) also activated ERK1/2. Inhibition of protein kinase C and ERK kinase caused a reduction of ET-1 (1-31)-induced ERK1/2 activation. The ERK1/2 activation was followed by an increase in transcription factor activator protein-1 DNA binding activity. These findings suggest that ET-1 (1-31) is a bioactive peptide in humans and ET-1 (1-31) itself stimulates HMC proliferation.

Adult↗
PubMed2000

NMR determination of the absolute configuration of an alpha-exo-methylene-gamma-lactone.

Both the enantiomers of the axially chiral reagent, 2'-methoxy-1,1'-binaphthalene-2-carbohydroximoyl chloride (MBCC), were used to convert igalan, an alpha-exo-methylene-gamma-lactone, to yield 4,5-dihydroisoxazoles. The absolute configuration of igalan was determined to be (3aR,5R,6R,7aR)-6-ethenylhexahydro-6-methyl-3-methylen e-5-(1-methylethenyl)-2(3H)-benzofuranone (IUPAC name) on the basis of NOE correlations in these derivatives. The absolute configurations of other alpha-exo-methylene-gamma-lactones can be determined by the same method.

Lactones↗