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Biomedical subjects

N Ito

Publications and source records attributed to N Ito.

At least 235 records · Page 13Linked to original sources
PubMed1995

Chemoprevention by dehydroepiandrosterone and indomethacin in a rat multiorgan carcinogenesis model.

The chemopreventive efficacy of dehydroepiandrosterone (DHEA) and indomethacin (IM) alone or in combination was investigated in a rat multiorgan carcinogenesis model. These two chemicals were selected as chemopreventive agents with different functions. Animals were sequentially given five carcinogens with different organ target sites in the first 4-week initiation period. One week after its completion, the rats received 0.3% DHEA in the diet, 20 ppm IM in the drinking water, or 0.3% DHEA + 20 ppm IM until experimental week 28. DHEA enhanced hepatocarcinogenesis, but concurrent treatment with IM suppressed tumor development as compared to the DHEA group. DHEA inhibited tumor development in the thyroid, with a similar tendency observed for the small intestine. In addition, treatment with this hormone decreased occurrences of preneoplasias in the urinary bladder and seminal vesicles. Treatment with IM clearly suppressed development of preneoplasias or neoplasias in the lung and small and large intestines. In the urinary bladder, treatment with IM tended to decrease preneoplastic lesion development. Analysis of multiplicity of total tumors of any category revealed comparable values for DHEA and control groups, while the IM group showed a significant reduction. IM in combination with DHEA caused suppression as compared to DHEA alone. In a separate 8-week experiment, DHEA or IM were administered for 4 weeks after prior carcinogen application, and biochemical responses in the target organs were investigated. DHEA increased glucose-6-phosphate dehydrogenase levels in the liver but caused a decrease in the small intestine. In addition, DHEA decreased serum T4 but not T3. IM decreased prostaglandin E2 content in the small intestine. In conclusion, although DHEA or IM exert significant chemopreventive effects in multiorgans with the exception of the DHEA-treated liver case, treatment in combination did not result in amplification of their beneficial influence. Our results suggest the possible application of IM for chemoprevention in high-risk individuals, but the question of effects of DHEA in the liver must be answered before this hormone can be considered for use in humans.

Animals↗
PubMed1995

Increasing development of pepsinogen-altered pyloric glands and adenocarcinoma in glandular stomach of analbuminemic rats.

The susceptibility of pepsinogen-altered pyloric glands (PAPG) and neoplastic glandular stomach lesions induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and catechol or sodium cholate in Nagase analbuminemic rats (NAR) was compared to Sprague-Dawley rats (SD). Male NAR and SD rats were given a single dose of 80 mg/kg body weight of MNNG by gastric intubation and, 2 weeks later, fed basal diet containing 0.8% catechol or 0.3% sodium cholate for 18 weeks. The animals were killed at the end of week 20 or after maintenance on basal diet at week 60. The number of pepsinogen-altered pyloric glands at week 20 was significantly (P < 0.001) higher in NAR fed either catechol or sodium cholate compared with SD rats. At week 60, adenomatous hyperplasias and adenocarcinomas were observed in 7 (88%; P < 0.01) and 3 (38%; P < 0.01) of 8 NAR fed catechol and in 4 (22%) and 0 of 18 SD rats, respectively. The results show that the frequency of PAPG in NAR and SD rats is related to the susceptibility to glandular stomach carcinoma. PAPG is a useful endpoint lesion for evaluation of gastric carcinogenicity in a 20-week carcinogenicity test, and NAR are sensitive for glandular stomach carcinogenesis.

Adenocarcinoma↗
PubMed1995

Structure of deoxyhaemoglobin of the antarctic fish Pagothenia bernacchii with an analysis of the structural basis of the root effect by comparison of the liganded and unliganded haemoglobin structures.

We have determined the structure of deoxyhaemoglobin from the antarctic fish Pagothenia bernacchii at pH 6.2 to a resolution of 2.2 A with X-ray data from a twinned crystal deconvoluted so as to approximate data from a single crystal. The R-factor between the (twinned) model and the observed data is 16% for reflections used in refinement and 22% for reflections not used in refinement. The T (deoxy) structure was compared with the R (liganded) structure at pH 8.0 in an attempt to understand the structural basis of the greater affinity for hydrogen ions of T, relative to R, that comprises the Root effect. Up to half of the effect can be attributed to interaction of the residues Asp95 (G1)alpha and Asp101 (G3)beta: in R the residues are far apart and their carboxyl groups are unprotonated, but the shift at the alpha 1 beta 2 interface that accompanies the R to T transition brings them so close that they appear to share a proton between them. The proximity of Asp99 (G1)beta may contribute to the required raising of the pKa values of the other two Asp residues. These and neighbouring residues are sufficiently conserved in the haemoglobins of trout (component IV), carp and bluefin tuna, all of which exhibit the Root effect, for the same mechanism to apply. However, the environment is equally conserved in haemoglobins of Trematomus newnesi (major component) and trout (component I), which do not exhibit the Root effect, so that the structural factors controlling the Asp-Asp interaction remain unclear. No other residue appears to undergo an R to T change in the immediate neighbourhoods that could account for any significant portion of the Root effect, so at least half of the effect must result either from long-range electrostatic interactions or from a large number of local interactions.

Animals↗
PubMed1995

Modulating effects of ellagic acid, vanillin and quercetin in a rat medium term multi-organ carcinogenesis model.

Effects of dietary supplementation with the antioxidants ellagic acid, quercetin and vanillin were examined using a medium term multi-organ carcinogenesis model in rats. Groups of 10-15 male F344 rats were given i.p. injections of diethylnitrosamine (DEN, 100 mg/kg body wt.) and N-methylnitrosourea (MNU, 20 mg/kg body wt), s.c. injections of 1,2-dimethylhydrazine (DMH, 40 mg/kg body wt.), together with 0.05% N-butyl-N-(4- hydroxybutyl)nitrosamine (BBN) and 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN), both in the drinking water, for a total multiple initiation period of 4 weeks (DMBDD) treatment). Ellagic acid, quercetin or vanillin, each at a dose of 1% each in the diet were administered from 1 day before and throughout the carcinogen exposure period, or after completion of the initiation regimen. All surviving animals were sacrificed at the end of week 36, and major organs were examined histopathologically. In the small intestine, significant reductions in the incidence and number of tumors (adenomas and carcinomas) were observed in the groups administered ellagic acid during (8%, 0.08 +/- 0.29) or after (8%, 0.08 +/- 0.29) DMBDD treatment, and those receiving quercetin after DMBDD treatment (0%) compared to the control value (57%, 1.07 +/- 1.21). Although the incidences were not statistically significant, slightly decreased numbers of small intestinal tumors were found in the groups receiving vanillin during (0.33 +/- 0.72), or after (0.40 +/- 0.83) DMBDD treatment. The incidence of large intestinal carcinomas in the group treated with vanillin during DMBDD treatment was significantly higher (73%) than the control value (21%). These results indicated that while ellagic acid and quercetin exerted potent chemopreventive action in both the initiation and promotion stages in the present experimental system, their beneficial effects were restricted to the small intestine. Since small intestinal carcinomas are very infrequent in humans, the advantages of these phenolic compounds for human application as chemopreventors should not be overestimated.

1,2-Dimethylhydrazine↗
PubMed1995

Crystallization of RNA-protein complexes. I. Methods for the large-scale preparation of RNA suitable for crystallographic studies.

In vitro transcription using bacteriophage RNA polymerases and linearised plasmid or oligodeoxynucleotide templates has been used extensively to produce RNA for biochemical studies. This method is, however, not ideal for generating RNA for crystallisation because efficient synthesis requires the RNA to have a purine rich sequence at the 5' terminus, also the subsequent RNA is heterogenous in length. We have developed two methods for the large scale production of homogeneous RNA of virtually any sequence for crystallization. In the first method RNA is transcribed together with two flanking intramolecularly-, (cis-), acting ribozymes which excise the desired RNA sequence from the primary transcript, eliminating the promoter sequence and heterogeneous 3' end generated by run-off transcription. We use a combination of two hammerhead ribozymes or a hammerhead and a hairpin ribozyme. The RNA-enzyme activity generates few sequence restrictions at the 3' terminus and none at the 5' terminus, a considerable improvement on current methodologies. In the second method the BsmAI restriction endonuclease is used to linearize plasmid template DNA thereby allowing the generation of RNA with any 3' end. In combination with a 5' cis-acting hammerhead ribozyme any sequence of RNA may be generated by in vitro transcription. This has proven to be extremely useful for the synthesis of short RNAs.

Bacteriophage T7↗
PubMed1995

Crystallisation of RNA-protein complexes. II. The application of protein engineering for crystallisation of the U1A protein-RNA complex.

The hairpin is one of the most commonly found structural motifs of RNA and is often a binding site for proteins. Crystallisation of U1A spliceosomal protein bound to a RNA hairpin, its natural binding site on U1snRNA, is described. RNA oligonucleotides were synthesised either chemically or by in vitro transcription using T7 RNA polymerase and purified to homogeneity by gel electrophoresis. Crystallisation trials with the wild-type protein sequence and RNA hairpins containing various stem sequences and overhanging nucleotides only resulted in a cubic crystal form which diffracted to 7-8 A resolution. A new crystal form was grown by using a protein variant containing mutations of two surface residues. The N-terminal sequence of the protein was also varied to reduce heterogeneity which was detected by protein mass spectrometry. A further crystallisation search using the double mutant protein and varying the RNA hairpins resulted in crystals diffracting to beyond 1.7 A. The methods and strategy described in this paper may be applicable to crystallisation of other RNA-protein complexes.

Amino Acid Sequence↗
PubMed1995

Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma.

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in tumor progression by promoting angiogenesis or suppressing immune system. We reported previously that transforming growth factor-beta 1 (TGF-beta 1) is overproduced by human hepatocellular carcinoma (HCC) tissues and that plasma TGF-beta 1 levels are elevated in patients with HCC. In the present study, we investigated the relationship between plasma TGF-beta 1 levels and tumor vascularity as assessed by conventional celiac angiography in 17 patients with HCC. The plasma TGF-beta 1 level did not correlate with tumor size or underlying liver disease. However, we found that plasma TGF-beta 1 levels correlated positively with the tumor vascularity. These results suggest that excessive TGF-beta 1 production may contribute to tumor angiogenesis in HCC.

Aged↗
PubMed1995

Ki-ras mutations with frequent normal allele loss versus absence of p53 mutations in rat prostate and seminal vesicle carcinomas induced with 3,2'-dimethyl-4-aminobiphenyl.

We have developed a prostate carcinogenesis model in Fischer 344 rats using 3,2'-dimethyl-4-aminobiphenyl (DMAB) as a carcinogen to examine various potential modifying factors. In this study, mutational changes in the ras and p53 genes were assessed in DMAB-induced rat prostate and seminal vesicle carcinomas by single-strand conformation polymorphism analysis and subsequent direct DNA sequencing. Eight of 22 prostate adenocarcinomas (three of nine (33.3%) from the ventral lobe and five of 13 (38.5%) from the dorsolateral lobe, including three transplantable tumors) and one of 11 seminal vesicle adenocarcinomas (9.1%) demonstrated point mutations in the Ki-ras gene. One prostate malignant fibrohistiocytoma examined was negative. Among the positive cases, five (three ventral prostate carcinomas and two transplantable tumors) also showed loss of the normal allele. In contrast, other than one mutation in the p53 gene in the malignant fibrohistiocytoma, there were no mutations in the Ha-ras or p53 genes. These results indicate that mutational activation of the Ki-ras gene, but not of the Ha-ras or p53 genes may play a mechanistic role in prostate and seminal vesicle carcinogenesis by DMAB and that a loss of the normal allele of the Ki-ras gene may also be involved in the process.

Adenocarcinoma↗
PubMed1995

Lack of promoting activity of four pesticides on induction of preneoplastic liver cell foci in rats.

Four pesticides were examined for hepatopromoting activity using a medium-term bioassay based upon induction of glutathione S-transferase placental form (GST-P) positive foci in the rat liver. Male F344 rats were initially injected with diethylnitrosamine (DEN; 200 mg/kg body weight) intraperitoneally and 2 weeks later were treated with O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN; 75 and 150 ppm), diazinon (500 and 1,000 ppm), phenthoate (500 and 1,000 ppm), or iprobenfos (500 and 1,000 ppm) in the diet for 6 weeks and then killed, all rats being subjected to partial hepatectomy at week 3. All of the pesticides gave negative results, the numbers and areas of GST-P positive foci not exceeding the control values for animals given DEN alone. Indeed, a significant reduction of foci development was seen for EPN (75 ppm). These findings provide experimental evidence that the presently examined four pesticides do not have hepatocarcinogenic potential in rats.

Animals↗
PubMed1995

Histochemical differences of the lectin affinities of backbone polylactosamine structures carrying the ABO blood group antigens in papillary carcinoma and other types of thyroid neoplasm.

Endo-beta-galactosidase from Escherichia freundii cleaves linear polylactosamine structure as follows: R-GlcNAc-beta 1-3Gal-beta 1-4GlcNAc-beta 1-R' + H2O-->R-GlcNAc-beta 1-3Gal + GlcNAc-beta 1-R'. Staining with Griffonia simplicifolia agglutinin II (GSA-II) following enzyme digestion reveals the distribution of R-GlcNac-beta 1-3Gal-beta 1-4GlcNAc-beta 1-R' structures in tissue sections. In this study, the procedure was applied to formalin-fixed, paraffin-embedded tissue sections from 26 cases of papillary carcinomas including 2 follicular variants, 8 follicular carcinomas, 7 adenomas, 1 anaplastic carcinoma and 1 medullary carcinoma in order to investigate whether different types of polyactosamine-containing structure are produced in these thyroid neoplasms. Simultaneously, the susceptibility of the ABH antigens expressed in these neoplastic cells to endo-beta-galactosidase digestion was examined. Most of the papillary carcinoma cells from all the individuals examined were strongly stained by GSA-II following enzyme digestion. Without enzyme digestion, little or no reactivity with GSA-II was observed. Among other types of neoplasms, only one case of follicular carcinoma exhibited reactivity with GSA-II following enzyme digestion. ABH antigens were expressed in 22 cases of papillary carcinomas, 2 adenomas, 5 follicular carcinomas and 1 anaplastic carcinoma, and their expression was dependent on the ABO blood group of the patients. Endo-beta-galactosidase digestion resulted in the elimination of these antigens not only in papillary carcinomas but also in other neoplasms.(ABSTRACT TRUNCATED AT 250 WORDS)

ABO Blood-Group System↗
PubMed1995

Dexamethasone inhibits nitric oxide-mediated cytotoxicity via effects on both macrophages and target cells.

In order to evaluate the mode of action of dexamethasone (DEX) on macrophage-mediated cytotoxicity and to understand its association with nitric oxide (NO) production, the effect of DEX on macrophage- and spermine NONOate-mediated cytotoxicity was studied. DEX caused 100% inhibition of cytotoxicity by LPS- and IFN gamma-activated macrophages whereas it caused only partial inhibition of NO production. Inhibition of macrophage-mediated cytotoxicity by DEX was not reversed by supplementation of rTNF alpha. The partial inhibition of NO production by DEX was due to partial inhibition of iNOS mRNA expression. Incubation of macrophages with DEX for up to 24 h prior to activation did not cause further inhibition of NO production. DEX failed to inhibit NO production if added 6 h after addition of LPS and IFN gamma. Addition of P815 cells after the onset of NO production resulted in partial restoration of cytotoxicity in DEX-treated macrophages. Incubation of P815 cells with spermine NONOate, a synthetic NO donor, resulted in P815 cell lysis, which was dose-dependent, had a lag phase of 3 h and was blocked by hemoglobin. DEX also inhibited spermine NONOate-mediated tumor cell lysis, indicating that DEX may have a protective effect on tumor targets. These results indicate that DEX inhibits macrophage-mediated cytotoxicity by decreasing NO production and by inhibiting the cytotoxic effects of NO on the target cells.

Animals↗
PubMed1995

Effect of ingestion of 20 pesticides in combination at acceptable daily intake levels on rat liver carcinogenesis.

Exposure of agricultural workers and the general population to pesticides is a major concern, and possible summation or synergistic effects deserves particular attention. In this study, however, combined dietary administration of 19 organophosphorus compounds and one organochlorine pesticide, each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of lesions. The results thus provide direct support for the present safety factor approach to the quantitative hazard evaluation of pesticides.

Administration, Oral↗
PubMed1995

Rat strain differences in catechol carcinogenicity to the stomach.

The carcinogenic potential of catechol was compared in male Wistar, WKY, Lewis and SD strains of rats. Groups of 30 animals were treated with powdered diet containing 0.8% catechol for 104 wk and then examined histopathologically. Induction of glandular stomach adenocarcinomas occurred in 67, 73 and 77% of Wistar, Lewis and SD animals, respectively, but in only 10% of WKY rats. In addition, catechol induced forestomach papillomas in 20% (P < 0.05), and squamous cell carcinomas in 3% of SD rats. The results thus indicate that Wistar, Lewis and SD rats are much more susceptible than WKY rats to induction of glandular stomach adenocarcinomas by 0.8% catechol, and that this phenolic antioxidant also possesses weak carcinogenic activity for the SD rat forestomach.

Adenocarcinoma↗
PubMed1995

Analysis of the potential carcinogenicity of coffee and its related compounds in a medium-term liver bioassay of rats.

The potential carcinogenicity of coffee and related compounds was examined using a medium-term liver bioassay based on the induction of glutathione S-transferase placental form (GST-P)-positive foci in F344 rats. A total of 230 males were initially injected with diethylnitrosamine (200 mg/kg body weight, ip) or saline as controls and 2 wk later were fed on diet or drinking water supplemented as follows for 6 wk: 5% regular instant coffee; 5% decaffeinated instant coffee; freshly brewed coffee, 8 g in 140 ml water; 0.1% caffeine, 0.2% methylglyoxal, 0.2% glyoxal; or 0.3% theophylline in the drinking water (w/v); and 0.4% theobromine in the diet (w/w). All rats were subjected to two-thirds partial hepatectomy at wk 3 and killed at wk 8. The resultant values for GST-P-positive hepatic focus induction were slightly increased with methylglyoxal and decreased with glyoxal and theobromine compared with the corresponding controls. Although the increase in number of foci for methylglyoxal was statistically significant at P < 0.05, the value was within the historical control levels. Regular and decaffeinated instant coffee as well as fresh-brewed coffee, caffeine and theophylline exerted no effects on focus development. Thus, the coffee-related compounds examined demonstrated no obvious enhancing potential, and it is therefore concluded that coffee and its main constituents are not carcinogenic for the rat liver.

Administration, Oral↗
PubMed1995

Lack of carcinogenicity of pesticide mixtures administered in the diet at acceptable daily intake (ADI) dose levels in rats.

Carcinogenic effects of pesticide mixtures were examined with our medium-term carcinogenesis protocols using male F344 rats. In the 8-week liver model, combined dietary administration of 20 pesticides (19 organophosphorus compounds and 1 organochlorine), each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 weeks, mixtures of 40 pesticides (high volume compounds) and 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not enhance carcinogenesis in any organ initiated by 5 different known carcinogens in combination. These results provide support for the safety factor (usually 100) approach presently used for the quantitative hazard evaluation of pesticides.

Animals↗
PubMed1995

Complex partial status epilepticus in childhood.

We report 5 pediatric patients (2 male, 3 female; age range: 4-8 years) with complex partial status epilepticus (CPSE). Four patients had previous illnesses and mild motor or mental retardation. In 2 patients, CPSE was induced by inappropriate management or selection of antiepileptic drugs. Clinical features varied and automatisms were observed in 3 patients. In 1 patient, decreased physical tone with syncope and impaired consciousness with amaurosis were observed. The episodes of CPSE were continuous in 3 patients and recurrent in 2 patients. In 4 patients, ictal electroencephalographic (EEG) findings, including video-EEG analyses of 3 patients, demonstrated persistent focal epileptic features. Intravenous diazepam abolished CPSE in 3 patients with brief periods of definite EEG localizations remaining. In 4 patients, seizure prognoses were favorable after appropriate treatments; in 1 patient, seizures were intractable even after antiepileptic drug administration.

Anticonvulsants↗