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Biomedical subjects

E Nakashima

Publications and source records attributed to E Nakashima.

At least 73 records · Page 4Linked to original sources
PubMed1996

A candidate for cancer gene therapy: MIP-1 alpha gene transfer to an adenocarcinoma cell line reduced tumorigenicity and induced protective immunity in immunocompetent mice.

PURPOSE: To evaluate the possibility of cancer gene therapy by the gene delivery of chemokine, the effects of human macrophage inflammatory protein 1 alpha (hu-MIP-1 alpha), murine-macrophage inflammatory protein 1 alpha (mu-MIP-1 alpha), and human-interleukin 8 (hu-IL-8) on tumor progression and immunization were studied. METHODS: Cachexia-inducing and highly tumorigenic adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid, hu-MIP-1 alpha, mu-MIP-1 alpha, or hu-IL-8 expression vector. The production of hu-MIP-1 alpha reached > 1.5 ng/ml in vitro when transfectant cells were cultured at a cell density of 2 x 10(5) cells in 7 ml for 3 days. Immunocompetent BALB/c mice were inoculated into the footpad with the tumor cells, and then primary tumor growth, morphological analyses, and tumor immunogenicity were studied. RESULTS: The secretion of hu-MIP-1 alpha, mu-MIP-1 alpha, and hu-IL-8 did not affect the growth rate in vitro. Reduced tumorigenicities in vivo were observed in transfected cells with hu-MIP-1 alpha and mu-MIP-1 alpha. Morphologic observation of the site of inoculation of cells transfected with hu-MIP-1 alpha showed infiltration of macrophages and neutrophils on the 5th day after the inoculation. Mice that had rejected cells transfected with hu-MIP-1 alpha gene were immune to a subsequent challenge with the parental cells. CONCLUSIONS: The rejection of the cells depends on cytolysis and generates potent and long lasting antitumor immunity. These data suggest that tumor cells transfected with the MIP-1 alpha gene might be useful as an effective therapy for the treatment of certain tumors.

Adenocarcinoma↗
PubMed1996

Contribution of lysosomes to the subcellular distribution of basic drugs in the rat liver.

PURPOSE: We examined the subcellular distribution of the basic drugs, chlorpromazine (CPZ), imipramine (IMP) and biperiden (BP), in rat liver, and evaluated the contribution of lysosome (Lys) to their intracellular distribution in comparison with that of mitochondria (Mit). METHODS: In an in vivo distribution, the concentrations of CPZ, IMP and BP in the liver subcellular fractions were determined. In an in vitro study, uptake of [3H]IMP into Lys and Mit fractions was determined in the presence or absence of several agents. RESULTS: The distribution of these drugs 10 min after administration was quite similar. However, the relative specific contents (the drug concentration per protein of each fraction divided by that of the total homogenate) in Lys were 7.3, 9.6 and 4.2, respectively for CPZ, IMP and BP, whereas those in the other organella were only 0.4 approximately 1.7. In an in vitro uptake study, the dose response of IMP uptake into Lys was biphasic, while that into Mit fractions was monophasic. The binding of IMP to the high affinity sites of Lys was pH dependent and disappeared in 50 mM NH4Cl or 50 microM CPZ, both of which increased the intralysosomal pH, the low affinity sites were not affected by these drugs. CONCLUSIONS: The results indicated that Lys has the highest affinity for the basic drugs in the liver and that its contribution to their subcellular distribution depends on the intralysosomal pH, which is also affected by these drugs. The importance of these effects may become significant in combination therapy using various basic drugs.

Animals↗
PubMed1996

Kinetic evidence for facilitated peritoneal transport of benzoic acid in rats.

To evaluate the dose dependency in apparent peritoneal permeability (Pd) of benzoic acid as a model compound for a monocarboxylic acid transport system, a kinetic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied. We compared the Pd value of benzoic acid to that of phenobarbital which is a more lipophilic drug than benzoic acid. The concentration-time courses of phenobarbital in both peritoneal cavity and serum after the intraperitoneal administration with various doses were parallel according to dose, whereas those of benzoic acid varied in a dose-dependent manner. Using the values of unbound fraction (Fu), the value of Pd for unbound drugs was estimated. The Pd values of benzoic acid at 20 micrograms mL-1 was three times the value determined at 1000 micrograms mL-1. We suggest that certain facilitated transport systems constitute the mechanism of enhanced peritoneal membrane permeability of benzoic acid.

Animals↗
PubMed1996

Effects of beraprost sodium and insulin on the electroretinogram, nerve conduction, and nerve blood flow in rats with streptozotocin-induced diabetes.

The effect of a prostacyclin analog, beraprost sodium, on the electroretinogram, motor nerve conduction velocity, and nerve blood flow was determined in rats with streptozotocin-induced diabetes and was compared with the effect of insulin. Beraprost sodium (0.01 mg x kg-1 x day-1 for 8 weeks) significantly shortened the peak latency of the electroretinogram b-wave, increased tail nerve conduction velocity, and increased sciatic nerve blood flow in diabetic rats (P < 0.0003, 0.0001, and 0.0001 vs. untreated diabetic rats, respectively). This was accompanied by a significant increase in the 6-keto-prostaglandin F1alpha content of the thoracic aorta and a marked increase in the cAMP content of the sciatic nerve. Beraprost sodium had no effect on the sorbitol and fructose contents of the sciatic nerve and retina, but insulin (8-10 U/day) significantly reduced both parameters. These findings suggest that beraprost sodium may be useful for prevention of vascular and neural dysfunction in the retina and peripheral nerve.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Effect of propionyl-L-carnitine on motor nerve conduction, autonomic cardiac function, and nerve blood flow in rats with streptozotocin-induced diabetes: comparison with an aldose reductase inhibitor.

The effects of propionyl-L-carnitine (PCAL) on caudal motor nerve conduction velocity, the coefficient of variation of the R-R interval on the electrocardiogram, and sciatic nerve blood flow were compared with those of [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate, an aldose reductase inhibitor, in rats with streptozotocin-induced diabetes. Diabetic control rats showed significantly delayed nerve conduction (P < .05), decreased R-R variability (P < .05) and reduced sciatic nerve blood flow (P < .05). Oral administration of PCAL (0.5 g/kg/day) and [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (0.05% in the diet: 60 mg/kg/day) for 8 weeks significantly improved both nerve conduction (P < .05) and R-R variability (P < .05) in diabetic rats, along with the normalization of sciatic nerve blood flow. PCAL treatment increased the nerve tissue levels of carnitine and myo-inositol and reduced the serum triglyceride level in diabetic rats. Our results suggests that PCAL could have therapeutic potential for the treatment of diabetic neuropathy.

Aldehyde Reductase↗
PubMed1995

Polyol pathway, 2,3-diphosphoglycerate in erythrocytes and diabetic neuropathy in rats.

The relationship between the 2,3-diphosphoglycerate concentration in red blood cells as a biological indicator of tissue hypoxia and diabetic neuropathy, and the effect of a potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2'5'-dioxospiro [chroman-4,4'-imidazolidine]-2-carboxamide (SNK-860), on both were investigated in streptozotocin-induced diabetic rats. Diabetic rats demonstrated significantly delayed motor nerve conduction velocity and reduced sciatic nerve blood flow. Altered biochemical features in the sciatic nerves, including a marked accumulation of sorbitol and fructose, myo-inositol depletion and decreased Na+/K(+)-ATPase activity were also detected in diabetic rats. These defects were accompanied by a decrease in the red blood cell 2,3-diphosphoglycerate concentration. Treatment with SNK-860 partially or completely ameliorated these abnormalities. These observations suggest that a decrease in the red blood cell 2,3-diphosphoglycerate concentration is one of the factors contributing to tissue hypoxia, which results in diabetic neuropathy, and that this decrease is mediated through an aldose reductase inhibitor-sensitive pathway.

2,3-Diphosphoglycerate↗
PubMed1995

Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice.

Two clones, one cachexigenic (clone 20) and the other noncachexigenic (clone 5), from a murine colon adenocarcinoma, colon 26 cells, were used to analyze the involvement of immune reactions as well as the cytokine network in cachexia. Clone 20 induced cachexia in nude and SCID mice as well as in normal BALB/c mice, suggesting that lymphocytes played little, if any, role in the process. Both clones failed to express mRNA of interleukin (IL) 1 alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha in vitro with or without the coculture of NIH3T3 cells or spleen cells. However, IL-6 mRNA was selectively detected at the tumor site of clone 20 but not at that of clone 5-bearing mice. In contrast, tumor necrosis factor alpha mRNA was detected at tumor sites and in spleens of only clone 5-bearing mice, suggesting a potential role of IL-6, but not tumor necrosis factor alpha, in inducing cachexia. Anti-IL-6 antibody partially reversed the weight loss induced by clone 20, whereas the continuous infusion of IL-6 failed to cause weight loss, despite being associated with an elevation of a serum acute phase protein. These results suggest that IL-6 is necessary but not sufficient for the induction of cachexia. Both clones expressed IL-6 mRNA in the presence of IL-1 in vitro, and mice bearing either clone expressed IL-1 beta mRNA at the tumor site. Moreover, IL-1 receptor antagonist (IL-1Ra) mRNA was detected at the tumor site of clone 5-bearing mice but not at that of clone 20-bearing mice, suggesting that IL-1Ra might block IL-1 activity to reduce IL-6 production in clone 5-bearing mice. However, the transfection of clone 20 with IL-1Ra cDNA failed to abolish its capacity to produce IL-6 and to cause cachexia. Collectively, additional factor(s) besides IL-1Ra and IL-1 beta may control IL-6 and some other cachexigenic factor production, thereby causing cachexia in this model.

Adenocarcinoma↗
PubMed1995

Reversal of drug sensitivity in MDR subline of P388 leukemia by gene-targeted antisense oligonucleotide.

We attempted to reverse multidrug resistance (MDR) by treatment with 25-mer antisense phosphorothioate oligonucleotide. The phosphorothioate analogs, the sequences of which are sense or antisense to the initiation codon of mouse mdr1 mRNA, were tested against murine leukemic P388/S and adriamycin-resistant P388/ADR cell lines. A weak inhibitory effect on the growth of P388/S and P388/ADR cells was observed at a sense and antisense oligonucleotide concentration of 30 microM. Using the monoclonal antibody to P-glycoprotein and a flow cytometry technique, we showed that the level of expression of P-glycoprotein in P388/ADR cells treated with antisense oligonucleotide was lower than when treated with sense oligonucleotide. The antisense oligonucleotide potentiated the growth-inhibitory effect of vinblastine on P388/ADR cells, whereas sense oligonucleotide did not. This was accompanied by an increase in vinblastine retention in the cells. The reversal of the resistance by antisense oligonucleotide was increased by the combination with 1 microM verapamil. These results suggest that the antisense oligonucleotide and low dose verapamil may be useful in circumventing the resistance to anticancer drugs of MDR tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Interference by gliclazide in the glucose oxidase/peroxidase method for glucose assay.

Gliclazide interferes with the glucose determination using the glucose oxidase/peroxidase (EC 1.1.3.4/1.11.1.7) (GOD-PERID) method utilizing 2,2-azino-di-(3-ethyl-benzothiazoline-6-sulphonic acid) (ABTS) as the oxygen acceptor chromogen. There was an essentially linear relationship between the concentrations of gliclazide and decreasing glucose readings. One mu mol/1 of gliclazide in samples leads to an apparent loss of about 2.5 mu mol/l of glucose. However, gliclazide did not interfere with the glucose determination using the hexokinase/glucose-6-phosphate dehydrogenase method. This interference in the GOD-PERID method for glucose assay can occur in the in vitro experimental samples and cause underestimation of the glucose values. It is suggested that careful attention should be paid to the limited applicability of the GOD-PERID method for glucose assay.

Animals↗
PubMed1995

Human MCAF gene transfer enhances the metastatic capacity of a mouse cachectic adenocarcinoma cell line in vivo.

PURPOSE: To evaluate the effect of monocyte chemotactic and activating factor (MCAF/MCP-1/JE) on tumor progression and metastasis. METHODS: Cachexia-inducing adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid or MCAF expression vector. Spontaneous lung metastases were determined in mouse. RESULTS: The production of MCAF reached 0.4 ng/ml in vitro when transfectant cells were cultured at a cell density of 5 x 10(4) cells/ml for 3 days. Transfection of MCAF expression vector did not affect the growth rate in vitro. Also, after MCAF-transfection, the size of tumors after intra-footpad inoculation was similar to that of the parental cells. When the primary tumors were resected on the 10th day after inoculation, the incidence of spontaneous lung metastasis was less than 20% in both cells. The number of endothelial cells in the primary tumor rapidly increased from the 10th to the 14th day after inoculation, as revealed by immunohistochemical staining. In accordance with enhanced angiogenesis, the incidence rates of spontaneous metastasis increased when the primary tumors were resected on the 14th day after inoculation. Moreover, the spontaneous lung metastases were augmented in the animals injected with MCAF-transfectants compared to those injected with parental cells with a concomitant increase of angiogenesis. CONCLUSIONS: These results suggest that MCAF may augment the metastastic potential by modulating tumor associated angiogenesis.

Adenocarcinoma↗
PubMed1995

Height reduction among prenatally exposed atomic-bomb survivors: a longitudinal study of growth.

Using a random coefficient regression model, sex-specific longitudinal analyses of height were made on 801 (392 male and 409 female) atomic-bomb survivors exposed in utero to detect dose effects on standing height. The data set resulted from repeated measurements of standing height of adolescents (age 10-18 y). The dose effect, if any, was assumed to be linear. Gestational ages at the time of radiation exposure were divided into trimesters. Since an earlier longitudinal data analysis has demonstrated radiation effects on height, the emphasis in this paper is on the interaction between dose and gestational age at exposure and radiation effects on the age of occurrence of the adolescent growth spurt. For males, a cubic polynomial growth-curve model applied to the data was affected significantly by radiation. The dose by trimester interaction effect was not significant. The onset of adolescent growth spurt was estimated at about 13 y at 0 Gy. There was no effect of radiation on the adolescent growth spurt. For females, a quadratic polynomial growth-curve model was fitted to the data. The dose effect was significant, while the dose by trimester interaction was again not significant.

Adolescent↗
PubMed1995

Systematic approach to a dosage regimen for phenytoin based on one-point, steady-state plasma concentration.

A systematic approach to individualizing the phenytoin (PHT) dose from a previous dose (D) and steady-state concentration (Css) pair was established by the combined use of two methods based on recently reported population pharmacokinetic parameters. This system applies the Michaelis-Menten equation to the initial data pair (D1-Css1) and solves for (a) maximum metabolic rate constant (Vmax) assuming the population mean for the Michaelis constant (Km) (method 1), and (b) Km assuming the population mean for Vmax (method 2). The derived estimates of Vmax and Km are then put through a series of filters, which results in the selection of method 1 and/or method 2 or allocation of a third category that needs further evaluation. A simulation study was performed to find a series of filters. The presented approach was applied retrospectively to the patients' data of 35 sets. Accurate predictions of the Css error within 5 micrograms/ml were obtained in 84% of the 25 cases, and in 30% of the 10 cases excluded. This systematic approach gives better prediction performance in mean error, mean absolute error, and root mean square error than a Bayesian feedback method.

Adult↗
PubMed1995

Neonatal cholestasis in two siblings: a variant of Dubin-Johnson syndrome?

OBJECTIVE: Two Japanese brothers with neonatal cholestasis associated with pigment granules in the hepatocytes and hepatosteatosis were evaluated for the possible role of hepatosteatosis in the Dubin-Johnson syndrome. METHODOLOGY AND RESULTS: The morphology of pigment accumulation and the laboratory data in these cases were examined. The elevation of urinary coproporphrin isomer I to more than 90% and the presence cholestasis resembled that in the Dubin-Johnson syndrome, but the hypertriglyceridaemia ( > 1.13 mmol/L as triolein) and the hepatosteatosis differed. Both infants were thought to have familial hypertriglyceridaemia. However, this diagnosis was difficult to confirm in the absence of data on the normal values of apolipoprotein and lipoprotein isomer for infants. CONCLUSIONS: A neonatal variant of the Dubin-Johnson syndrome may account for the unusual findings in these infants.

Cholestasis↗
PubMed1995

Anti-Human T-lymphotropic virus type-I antibodies in atomic-bomb survivors.

Adult T-cell leukemia (ATL), induced by human T- lymphotropic virus type-I (HTLV-I), is endemic in Nagasaki, Japan. To investigate the effects of atomic-bomb radiation on development of this specific type of leukemia, 6182 individuals in the Radiation Effects Research Foundation (RERF) Adult Health Study sample in Hiroshima and Nagasaki were examined for positive rate of HTLV-I antibody. Several lymphocyte parameters were also studied for 70 antibody- positive subjects in Nagasaki. The HTLV-I antibody-positive rate was higher in Nagasaki (6.36%) than in Hiroshima (0.79%) and significantly increased with increasing age, but no association was observed with radiation dose. Whether relationship existed between antibody titer levels and radiation dose among antibody-positive subjects was not The frequency of abnormal lymphocytes tended to be higher in antibody-positive subjects than in antibody-negative subjects, and higher in females than in males regardless of radiation dose. The lymphocyte count was lower in antibody-positive subjects than in antibody-negative subjects and lower in female than in male subjects. No evidence was found to suggest that atomic-bomb radiation plays an important role in HTLV-I infection.

Adult↗
PubMed1995

An aldose reductase inhibitor, TAT, reduces ADP-induced platelet hyperaggregation in streptozotocin-induced diabetic rats with neuropathy.

To investigate the relationship between metabolic and vascular factors, especially polyol pathway and platelet aggregation, in the pathogenesis of diabetic neuropathy, the effects of a novel potent aldose reductase inhibitor, TAT ((5-(3-thienyl) tetrazol-1-yl) acetic acid monohydrate) on adenosine diphosphate-induced platelet aggregation, polyol contents in platelets, motor nerve conduction velocity (MNCV), and sciatic nerve blood flow (SNBF) were examined in streptozotocin-induced diabetic rats. Diabetic rats demonstrated hyperaggregation in response to adenosine diphosphate, accompanied by sorbitol and fructose accumulation and myoinositol depletion in platelets. Treatment with TAT improved these abnormalities in diabetic rats. A delayed MNCV and a reduced SNBF in diabetic rats were normalized by the administration of TAT. These observations suggest that increased polyol pathway activity plays an important role in platelet aggregation in the development of diabetic neuropathy and that aldose reductase inhibitor is useful for the treatment of diabetic neuropathy from the viewpoint not only of metabolic factors but also of vascular factors.

Adenosine Diphosphate↗
PubMed1995

Relationship between cataracts and epilation in atomic bomb survivors.

Among 1713 atomic bomb survivors who underwent ophthalmological examinations from 1963-1964, the risk of cataract formation per unit dose of radiation was significantly greater for those who reported hair loss of 67% or more after exposure (the epilation group) than for those who reported less or no hair loss (the no-epilation group) (P < 0.01). Such an epilation effect has also been associated with leukemia mortality and the frequency of chromosome aberrations. Although this might be interpreted as indicating differential sensitivity to radiation between the epilation group and the no-epilation group, it could also be explained by imprecision in dose estimates. We have calculated that a 48% random error in DS86 dose estimates could be in accordance with the dose-response relationship for the prevalence of cataracts in the epilation group or the no-epilation group. Possible mechanisms for variation in radiosensitivity are discussed.

Alopecia↗
PubMed1995

Quantitative relationship between structure and peritoneal membrane transport based on physiological pharmacokinetic concepts for acidic drugs.

To describe quantitatively the peritoneal transport of drugs, the kinetic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied. The apparent peritoneal permeability (Pd) of unbound drugs in rats and the partition coefficient (Papp) in an octanol:water system at pH 7.4 were estimated among acidic drugs. Using the values of unbound fraction (fS), the Pd values of the drugs were estimated from concentration-time profiles in serum and the peritoneal dialysate after intraperitoneal administration of drugs. The intrinsic membrane permeability (Pdm) was calculated based on a physiological pharmacokinetic model. The fS.Pdm values of thiopental and thiamylal (6.5 and 5.4 ml/min) were 2-3 times greater than the effective peritoneal blood flow, indicating that the peritoneal transport of the barbiturates with high lipophilicity was dominantly blood flow-limited. Evidence shows a high degree of correlation between log Pdm and log Papp. By considering the relationships, we estimated the Pdm of quinolonecarboxilic acids. The fS.Pdm values of quinolonecarboxilic acids were < 10% of the peritoneal effective blood flow rate, indicating that the peritoneal transport of quinolonecarboxilic acids was dominantly diffusion-limited because of low lipophilicity. In conclusion, there was a good correlation between log Pdm and log Papp. The prediction of Pdm can be useful to describe the peritoneal pharmacokinetics.

Acids↗