[Tracheal smooth muscle dilation effect by anticholinergic agent in chronic pulmonary emphysema].
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Aged↗
Biomedical subjects
N Ito
Publications and source records attributed to N Ito.
Crystal structure at 1.92 A resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin.
The crystal structure of the RNA-binding domain of the small nuclear ribonucleoprotein U1A bound to a 21-nucleotide RNA hairpin has been determined at 1.92 A resolution. The ten-nucleotide RNA loop binds to the surface of the beta-sheet as an open structure, and the AUUGCAC sequence of the loop interacts extensively with the conserved RNP1 and RNP2 motifs and the C-terminal extension of the RNP domain. These interactions include stacking of RNA bases with aromatic side chains of proteins and many direct and water-mediated hydrogen bonds. The structure reveals the stereochemical basis for sequence-specific RNA recognition by the RNP domain.
Amino Acid Sequence↗
Phenotypic alteration of hepatocellular foci in rats treated with clofibrate and phenobarbital.
In male F344 rats pretreated with diethylnitrosamine (DEN), subsequent administration of clofibrate increased the proportion of eosinophilic foci, to become the most abundant type, and reduced numbers of basophilic, clear and vacuolated foci, the total not being changed. A similar shift towards eosinophilia was also observed in phenobarbital-treated animals, but in this case clear increases in total number and area were apparent. Expression of the glutathione S-transferase placental form (GST-P) in foci was much lowered by clofibrate treatment, while the proportion of positive foci was very high in both phenobarbital and control groups. A marked contrast was found with eosinophilic foci, with 74% positive after phenobarbital as compared to only 15% for clofibrate. Thus, the decrease in GST-P positive foci by clofibrate was mainly due to increased negativity in the most abundant eosinophilic type foci. In a long-term feeding study without DEN initiation, similar negativity of foci was observed and, furthermore, only minimal effects of clofibrate on foci development was revealed in both young and old animals.
Animals↗
Duration dependent induction of invasive prostatic carcinomas with pharmacological dose of testosterone propionate in rats pretreated with 3,2'-dimethyl-4-aminobiphenyl and development of androgen-independent carcinomas after castration.
Male F344 rats were first treated with 3,2'-dimethyl-4-aminobiphenyl for 20 weeks in the presence of testicular androgens and then administered of a pharmacological dose of testosterone propionate (TP) for various periods (maximum 40 weeks). This resulted in development of invasive carcinomas in the dorso-lateral prostate as well as the seminal vesicles whose incidences were TP duration-dependent. However, in situ carcinomas of the ventral prostate were not affected by the TP treatment and atypical hyperplasias were clearly decreased. When animals were subjected to orchiectomy after 20-weeks-treatment with the TP, invasive adenocarcinomas were still subsequently noted in the dorso-lateral prostate and seminal vesicles, demonstrating a certain androgen-independence. The data indicate that, in spite of the necessity of high dose of TP for induction of invasive prostate carcinomas in the present experimental model, a proportion of the resulting tumors are hormone-independent.
Aminobiphenyl Compounds↗
Inhibition of mammary gland carcinogenesis by green tea catechins and other naturally occurring antioxidants in female Sprague-Dawley rats pretreated with 7,12-dimethylbenz[alpha]anthracene.
Effects of the naturally occurring antioxidants on mammary gland carcinogenesis were examined in female Sprague-Dawley rats pretreated with 7,12-dimethylbenz[alpha]anthracene (DMBA). Groups of 15-16 7-week-old rats received a 50 mg/kg body weight intra-gastric dose of DMBA, and starting one week thereafter placed on diet containing 0.4% catechol, 1.0% gamma-oryzanol, 2.0% phytic acid, 1.0% green tea catechins (GTC), 1.0% tannic acid or basal diet alone for 35 weeks. Although the final incidences and multiplicities of mammary tumors were not significantly different between DMBA-treated groups, the numbers of survivors in the antioxidant-treated groups at the end of the experiment at week 36 were significantly higher than in the basal diet group. In particular, the survival rate of the GTC group at 93.8% strongly contrasted with that of only 33.3% for rats on the basal diet. At the end of week 18, when all the animals were still alive, the average size of palpable mammary tumors was significantly smaller in the catechol, phytic acid and catechins groups. These results indicate that antioxidants, and GTC in particular, inhibit rat mammary gland carcinogenesis after DMBA initiation.
9,10-Dimethyl-1,2-benzanthracene↗
Dietary carcinogens and mammary carcinogenesis. Induction of rat mammary carcinomas by administration of heterocyclic amines in cooked foods.
Grilled or fried meat and fish contain various mutagenic heterocyclic amines, and structures of at least 19 compounds have already been determined. Among these, 10 have been examined for long term carcinogenicity, all proving to be positive. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), for example, preferentially induced mammary adenocarcinomas in 47% of Fischer 344 female rats when supplemented into the diet at a concentration of 400 parts per million (ppm) for 52 weeks. Moreover, 100 ppm of PhIP for 104 weeks yielded the same incidence. PhIP in the diet for 48 weeks also induced mammary cancer in Sprague-Dawley female rats with incidences of 72 and 25% at 200 ppm and 100 ppm. 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline in the diet at 300 ppm also induced a 25% incidence of mammary adenocarcinomas within 40 weeks. Analysis of PhIP-induced rat mammary carcinomas for ras mutations by polymerase chain reaction-single-strand conformation polymorphism and direct sequencing revealed Ha-ras activation in 3 of 17 carcinomas; all were G-->A transitions at the second letter of codon 12 replacing glycine by glutamic acid. A p53 gene mutation was also found in 1 of 10 carcinomas examined; a G-->T transversion was detected at the third letter of codon 130, with a substitution of asparagine for lysine. PhIP is the most abundant mutagenic and carcinogenic heterocyclic amine in grilled meat, and, therefore, a role for this compound in human carcinogenesis is strongly implied.
Adenocarcinoma↗
Crystal structure of a free radical enzyme, galactose oxidase.
The crystal structure of the copper-containing enzyme, galactose oxidase, has been solved by multiple isomorphous replacement and refined to a resolution of 1.7 A. The X-ray structure reveals a unique polypeptide fold. The protein can be divided into three domains, all of which consist almost entirely of beta-strands. The structure of the second domain is particularly striking, 28 beta-strands arranged in a pseudo 7-fold symmetry. The copper site is on the surface of the protein and extremely rich in aromatic side-chains. The copper ion has two histidines, two tyrosines, and one external ligand in distorted square pyramidal coordination. The presence of pyrroloquinoline quinone as a covalently bound cofactor in GOase has been excluded. Instead, an unexpected covalent linkage between Tyr272 and Cys228 has been observed, whose functional role may relate to the presence of a tyrosine free radical at Tyr272. The tyrosine free radical could be stabilized by delocalization to Cys228 and stacking interactions with Trp290. A structural model for substrate binding is proposed that offers an explanation for the substrate specificity of the enzyme and many of the spectroscopic and enzymological data. Although the model lacks direct confirmation at present, it should provide a stimulus for further spectroscopic and crystallographic studies.
Amino Acid Sequence↗
Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases.
BACKGROUND: Many kinds of human malignant tissue, including hepatocellular carcinoma (HCC), were reported to overexpress transforming growth factor-beta 1 (TGF-beta 1) gene. However, little work has been done on the circulating TGF-beta 1 in patients with malignant tumors. METHODS: Plasma TGF-beta 1 levels in patients with HCC (n = 26) were compared with those in patients with chronic hepatitis (CH) (n = 12) and cirrhosis (n = 11) and in normal subjects (n = 20) using an enzyme-linked immunosorbent assay system after acid/ethanol extraction. RESULTS: The patients with HCC had significantly higher plasma TGF-beta 1 levels (19.3 +/- 19.5 ng/ml; mean +/- standard deviation [SD]) than those in normal subjects (1.4 +/- 0.8 ng/ml) and in patients with CH (3.0 +/- 3.1 ng/ml) and cirrhosis (3.7 +/- 2.1 ng/ml) (P < 0.01). Plasma TGF-beta 1 concentrations in the patients with cirrhosis were also significantly higher than those in the normal subjects (P < 0.05). The extracted plasma TGF-beta 1 from the patients with HCC had biologic activity according to a growth inhibitory assay using mink lung epithelial cells. No significant correlation was found between the plasma TGF-beta 1 levels in the patients with HCC and serum alpha-fetoprotein levels. After successful treatment for HCC, the amount of plasma TGF-beta 1 significantly decreased from 22.6 plus or minus 16.7 ng/ml (mean +/- SD) to 10.2 plus or minus 6.5 ng/ml (P < 0.05). CONCLUSIONS: We demonstrated higher levels of plasma TGF-beta 1 in the patients with HCC than those in patients with chronic hepatitis and cirrhosis. Plasma TGF-beta 1 might be a candidate for a novel tumor marker for hepatocellular carcinoma.
Biomarkers, Tumor↗
Role of endogenous interferon-beta in lipopolysaccharide-triggered activation of the inducible nitric-oxide synthase gene in a mouse macrophage cell line, J774.
The role of endogenous tumor necrosis factor alpha (TNF-alpha) and interferon-beta (IFN-beta) in lipopolysaccharide (LPS)-induced activation of the inducible nitric-oxide synthase (i-NOS) gene was investigated. By Northern analysis or reverse-transcription polymerase chain reaction, the mouse macrophage cell line (J774) was found to respond to LPS treatment by increased expression of mRNAs specific for TNF-alpha, IFN-beta, and i-NOS with the kinetics unique for each gene. Bioassay of the culture supernatants showed that TNF-alpha and IFN-beta secreted by J774 cells increased from an undetectable level to about 300 and 340 units/ml, respectively, 3-6 h after LPS stimulation. Nitrite concentration was found to increase from 0 to 7.8 and 28.5 microM by 12 and 24 h, respectively, in the culture supernatant of LPS-treated J774 cells. The presence of a neutralizing dose of antibodies against IFN-beta, but not against TNF-alpha, during treatment with either 10 ng or 1 microgram of LPS/ml significantly, but not completely decreased the level of i-NOS-specific mRNA expression and NO production. The incubation of J774 cells with mouse natural IFN-beta itself (up to the level of 1,200 units/ml) did not induce i-NOS-specific mRNA and therefore did not stimulate J774 cells to produce NO. However, natural IFN-beta synergistically augmented the expression of i-NOS mRNA and the production of NO by J774 cells triggered by suboptimal concentrations of LPS (1 to 5 ng/ml). These data thus suggest that endogenous IFN-beta, but not TNF-alpha, produced by LPS-stimulated J774 cells specifically contributes, probably in an auto/paracrine fashion, to the activation of the i-NOS gene expression by LPS.
Amino Acid Oxidoreductases↗
Effects of testosterone, dihydrotestosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis.
Post-initiation effects of testosterone propionate (TP), alpha-dihydrotestosterone (DHT) and ethinyl estradiol (EE) on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-prostate carcinogenesis in F344 rats have been investigated by administration of each hormone individually or either androgen in combination with EE. DMAB plus TP resulted in induction of invasive adenocarcinomas in the lateral and anterior prostate and seminal vesicles, as shown in a previous study, whereas DHT did not exhibit any positive modulation potential. Administration of EE together with TP produced increased carcinoma incidence in the lateral and anterior prostate, from 17 and 28% to 70% and 80%, respectively. Dorsal prostate tumors, all of the non-invasive in situ type, were also evident in 30% of animals receiving both TP and EE. Rats treated with DHT plus EE, however, did not develop tumors. Our experiment thus provides evidence that estrogen may play an important role in prostate carcinogenesis.
9,10-Dimethyl-1,2-benzanthracene↗
Strong promoting effect of Opisthorchis viverrini infection on dimethylnitrosamine-initiated hamster liver.
Continuous administration of dimethylnitrosamine (DMN) to Syrian hamsters infected with the liver fluke, Opisthorchis viverrini (OV) results in a 100% incidence of cholangiocellular carcinomas. In a two-stage experiment, however, dosing with liver flukes caused only a few lesions to develop (Flavel, D.J. and Lucus, S.B. (1983) Carcinogenesis, 4, 927]. To clarify this anomaly, Syrian hamsters were initiated with 20 mg/kg DMN injected i.p. 19 days prior to 80 OV metacercaria infection. At 45 weeks, the animals receiving both DMN and the parasite demonstrated a 44% incidence of cholangiocarcinomas, a 93% incidence of cholangiofibrosis, a 35% incidence of mucous cystadenomas and a 98% incidence of hepatocellular nodules with an average number of 9.1 +/- 4.1 per animal. Animals receiving DMN alone developed 85% hepatocellular nodules with an average number of only 3.0 +/- 2.7 and no bile duct lesions. In the parasite alone group, only cholangiofibrosis was detected in a few animals and no lesions were encountered in untreated controls. These results thus demonstrate that the post-initiation influence of Opisthorchiasis is indeed effective in promoting the development of both cholangiolar and hepatocellular lesions initiated by DMN.
Animals↗
Properties of protein kinase C isoforms (beta II, epsilon, and zeta) in a macrophage cell line (J774) and their roles in LPS-induced nitric oxide production.
Northern analysis of poly(A)+ RNA extracted from J774 cells (a mouse macrophage cell line) showed that this cell line constitutively expresses mRNAs specific for protein kinase C (PKC)-beta I, -beta II, -epsilon and -zeta, but not those for PKC-alpha, -gamma or -delta. Western analysis of the total cell lysate showed that J774 cells express PKC-beta II, -epsilon and -zeta isoenzymes, but failed to show the expression of PKC-beta I. The exposure of J774 cells to > 10 nM PMA led to a loss of immunoreactive PKC-beta II in 4 h. The down-regulation of immunoreactive PKC-epsilon required more than 8 h of the exposure to > 100 nM PMA. Immunoreactive PKC-zeta was most resistant to PMA treatment and was not significantly reduced after the exposure to 300 to 600 nM PMA for 24 h. PMA-mediated, persistent down-regulation of PKC-beta II is probably a result of the inhibition of PKC-beta II biosynthesis at the posttranscriptional level, because PMA-exposed cells were found to gradually increase the expression of PKC-beta II specific mRNA. PMA-pretreated cells responded to a low dose (10 ng/ml), but not to a high dose (1 microgram/ml), of LPS by significantly lower expression of mRNA specific for the inducible nitric oxide synthase (i-NOS) gene and production of nitric oxide (NO) than the control cells did. Thus, PKC could be a part of the signal transduction apparatus involved in LPS-induced inducible nitric oxide synthase gene activation.
Amino Acid Oxidoreductases↗
Lack of promoting activity of 7-methoxy-2-nitro-naphtho-[2,1-b]furan (R7000) in a medium-term rat liver bioassay.
Among the nitro-naphthofurans, 7-methoxy-2-nitro-naphtho[2,1-b]furan (R7000) has proved to be a very potent mutagen that causes sarcomas at the subcutaneous injection site and carcinomas in the forestomach after p.o. administration. In the present study, possible promoting activity for diethylnitrosamine (200 mg/kg, i.p.)-initiated liver carcinogenesis was assessed in rats. R7000 dissolved in 5% ethanol solution at doses of 10 or 50 mg/l given as the drinking water for 6 weeks did not enhance development of pre-neoplastic glutathione S-transferase placental form positive foci. Thus, it was concluded that R7000 may not be carcinogenic for the rat liver under the present experimental conditions.
Animals↗
Heparin-binding EGF-like growth factor is a potent mitogen for rat hepatocytes.
We examined the hepatotrophic activity of heparin-binding EGF-like growth factor (HB-EGF), a recently identified potent mitogen for vascular smooth muscle cells and fibroblasts. HB-EGF stimulated DNA synthesis of rat hepatocytes in primary culture in a dose-dependent manner up to 30 ng/ml. The maximal stimulation by HB-EGF represented more than 80% of that induced by HGF. In normal rat liver, the transcript of HB-EGF gene was detected in the non-parenchymal cells and very low level in the hepatocytes. In the regenerating liver on the 3rd day after 70% hepatectomy, the HB-EGF mRNA increased in the non-parenchymal cells, suggesting that HB-EGF may contribute to liver regeneration through a paracrine mechanism.
Animals↗
Induction and promotion of forestomach tumors by sodium nitrite in combination with ascorbic acid or sodium ascorbate in rats with or without N-methyl-N'-nitro-N-nitrosoguanidine pre-treatment.
In experiment I, short-term effects of combined treatment with anti-oxidants, sodium ascorbate (NaAsA) and sodium nitrite (NaNO2) on forestomach cell proliferation were examined in F344 male rats. Groups of 5 animals aged 6 weeks were treated for 4 weeks with 0.8% catechol, 0.8% hydroquinone, 1% tert-butyl-hydroquinone (TBHQ), 2% gallic acid or 2% pyrogallor alone or in combination with 0.3% NaNO2 in the drinking water and/or 1% NaAsA in the diet. The thicknesses of forestomach mucosa in rats treated with anti-oxidants and NaNO2 in combination were greater than those with antioxidant alone and additional NaAsA treatment further enhanced the thickening of mucosa. It was noteworthy that values for mucosae of animals treated with NaNO2 and NaAsA without anti-oxidant were similar to those for anti-oxidants. In experiment 2, effects of combined treatment with NaAsA or ascorbic acid (AsA) and NaNO2 on carcinogenesis were examined in F344 male rats with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) pre-treatment. Groups of 20 or 15 rats, respectively, aged 6 weeks, were given a single intra-gastric administration of 150 mg/kg body weight of MNNG in DMSO:water = 1:1 or the vehicle alone by stomach tube. Starting 1 week later, they received supplements of 1% NaAsA or 1% AsA in the diet and 0.3% NaNO2 in drinking water in combination, each of the individual chemicals alone, or basal diet until the end of week 52. In MNNG-treated animals, incidences of forestomach papillomas and carcinomas were significantly enhanced in the NaNO2 alone group (84 and 47%, respectively) as compared with the basal diet group (30 and 10%), with further significant increase in carcinomas occurring with additional NaAsA (79%, p < 0.05) or AsA (85%, p < 0.05) treatment. In animals without MNNG, all animals in the NaNO2 group demonstrated mild hyperplasia, additional administration of NaAsA or AsA remarkably enhancing the grade of hyperplasia, and resulting in 53% and 20% incidences, respectively, of papillomas. Thus NaNO2 was demonstrated to exert promoter action for forestomach carcinogenesis, with NaAsA and AsA acting as co-promoters. The results strongly indicate that combined treatment with NaAsA or AsA and NaNO2 may induce forestomach carcinomas in the long term.
Animals↗
Carcinogenicity of 4-methoxyphenol and 4-methylcatechol in F344 rats.
The carcinogenic potentials of 4-methoxyphenol (4-MP) and 4-methylcatechol (4-MC), phenolic compounds which are structurally similar to the known forestomach carcinogen BHA and the glandular stomach carcinogen catechol respectively, and cause considerably enhanced cell proliferation and cytotoxicities in rat forestomach and/or glandular stomach epithelium, were examined in male and female F344 rats. Groups of 30 male and female animals were administered diets containing 2% 4-MP or 2% 4-MC for 104 weeks. Histopathological findings in the 4-MP case included atypical hyperplasias (male, 67%, female, 37%), papillomas (50%, 23%) and squamous-cell carcinomas (77%, 20%) in the forestomach. 4-MC induced forestomach papillomas (70%, 93%) and squamous-cell carcinomas (53%, 37%), also glandular stomach submucosal hyperplasias (90%, 93%), adenomas (100%, 100%) and adenocarcinomas (57%, 47%), with ulceration or erosion. The degree of differentiation of the squamous-cell carcinomas induced by 4-MP was less than with 4-MC. The present study demonstrated unequivocal forestomach carcinogenicity for 4-MP and forestomach and glandular stomach carcinogenicity for 4-MC, with cytotoxicity and cell proliferation both appearing as important factors for these non-genotoxic carcinogens.
Animals↗
Endothelin-1 as an aggravating factor of disseminated intravascular coagulation associated with malignant neoplasms.
BACKGROUND: Vascular endothelial damage may play an important role in the pathophysiology of disseminated intravascular coagulation (DIC), a frequent complication of malignant neoplasms. It may mediate a variety of triggering events to initiate DIC and platelet aggregation, which in turn leads to additional endothelial destruction. If so, endothelin-1 (ET-1), the most potent vasoconstrictor of naturally occurring pressor substances known, may leak from injured endothelial cells and aggravate the disease process. METHODS: The study included 36 patients with various malignant neoplasms in whom DIC developed. The authors measured plasma levels of ET-1 and big ET-1, a precursor peptide of ET-1, in these patients and compared them with other laboratory abnormalities during the course of DIC. RESULTS: Plasma ET-1 and big ET-1 levels were elevated in most patients with DIC. When compared with the results of other diagnostic tests, elevated plasma big ET-1 was the most frequently found abnormality associated with DIC. Elevation of plasma ET-1 and big ET-1 levels was closely related to the initiation and progression of DIC and provided a higher degree of sensitivity and specificity than did other indicators in assessing patients with cancer and DIC. CONCLUSIONS: Vascular endothelial damage with the resultant increases in plasma ET-1 and big ET-1 levels is universally associated with DIC caused by malignancy. Excessive secretion or leakage of ET-1 and big ET-1 from injured endothelial cells may cause vasospasm and aggravate the DIC process by facilitating the formation of intravascular microthrombi, ultimately leading to ischemic end-organ dysfunction. Plasma ET-1 and big ET-1 are sensitive and specific markers for vascular endothelial injury in DIC.
Adult↗
Infrequent mutation of Ha-ras and p53 in rat mammary carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the heterocyclic amines, a group of potent carcinogens contained in cooked meat and fish. Female F344 rats fed a diet containing 100 or 400 ppm PhIP developed mammary carcinomas within 104 or 52 wk, respectively, at the rate of 47% for each group; these carcinomas were examined for mutations in three members of the ras gene family and in the p53 gene. Single-strand conformation polymorphism (SSCP) analysis and direct sequencing demonstrated a G-->A transition at the second position of Ha-ras codon 12, with the resultant substitution of glutamic acid for glycine, in two of 10 carcinomas induced by 100 ppm PhIP and in one of seven induced by the 400 ppm dose. No mutations in Ki-ras or N-ras were detected. cDNA polymerase chain reaction-SSCP analysis and direct sequencing demonstrated a G-->T transversion at the third position of p53 codon 130, with the resultant substitution of asparagine for lysine, in one of the 10 carcinomas induced by 100 ppm of PhIP for which freshly frozen samples were available. PhIP-induced rat mammary carcinogenesis can be regarded as a unique system in that rat mammary carcinomas are negative for ras and p53 mutations.
Animals↗