Biomedical subjects
Publications and source records attributed to N Miyata.
This report describes the anti-platelet aggregation activity of 48 pyrazines. Among alkyl- and arylpyrazines tested, 2,3-diphenylpyrazines showed the strongest anti-platelet aggregation activity. Then, various substituents were introduced into the phenyl groups, and the 2,3-bis(p-methoxyphenyl)pyrazine derivatives were consequently found to possess considerably strong inhibitory activity.
The NO-generating abilities of aromatic N-nitroso compounds (nitrosoureas, nitrosamides and nitrosamines), and N-acetyl-S-nitroso-DL-penicillamine at ambient temperature were compared by employing the Griess reaction. 3,3-Dibenzyl-1-(4-tolyl)-1-nitrosourea showed the greatest NO-generating ability among the tested compounds. The NO-generating ability of the aromatic N-nitrosoureas and N-nitrosamides was greater than that of the N-nitrosamines, presumably reflecting differences in electrostatic repulsion between the carbonyl oxygen and nitroso oxygen in these compounds. In addition, a conjugative effect between the aromatic ring carbon and neighboring nitrogen influences the NO-generating ability; the conjugative effect in the case of N-nitrosoureas and N-nitrosamides having an ortho-alkyl substituted aromatic ring, or N-nitrosamines having a bulky N-group, such as tert-butyl, is decreased by an increase in steric hindrance around the nitroso group. The N-NO bond then becomes more stable. The NO-generating ability was related to the reciprocal of the ID50 value for growth inhibition of cultured L-5178 Y cells by the aromatic N-nitroso compounds. On the other hand, NO production from the aliphatic N-nitroso compounds was not observed under our conditions, and these N-nitroso compounds did not show effective cytotoxic activity.
PURPOSE: To characterize immunologically and virologically the infiltrating cells in the aqueous humor of patients with human T-cell leukemia virus type-1 (HTLV-1) uveitis (HU). METHODS: With their informed consent, patients had 0.1 ml of the aqueous humor in the anterior chamber collected with a needle under an operating microscope. An aliquot of the collected sample from patients without steroid therapy was examined by May-Giemsa staining and immunocytochemically. The presence of the HTLV-1-infected cells was investigated by polymerase chain reaction (PCR) using the gag and pol regions of the provirus genome. The population of the infected cells was compared by PCR testing the amplification of the virus genome from 60 cells, or determining the endpoint of successful amplification of the twofold dilution series of the samples, collected from the aqueous humor and peripheral blood mononuclear cells (PBMCs), which were obtained at the same time. Expression of viral and cytokine genes was studied by reverse transcriptase-PCR (RT-PCR). The interleukin-6 (IL-6) level in the aqueous humor of patients with HU and control subjects was measured by a high-sensitivity enzyme-linked immunosorbent assay kit. RESULTS: The number of the infiltrating cells ranged from 475 to 3563 (mean = 2111) per 0.1 ml of aqueous humor, and all the identifiable cells were lymphocytes. Most of them were CD3-positive T cells (mean = 78%), whereas CD4-positive cells constituted less than half (mean = 35.3%). HTLV-1 provirus was detected by PCR in the infiltrating cells of 36 of 38 patients with HU tested, whereas it was detected in 1 of 4 seropositive patients with other entities of uveitis. A higher population of the infected cells in the aqueous humor than in the PBMC was found in seven of nine patients with HU by two independent approaches. Expression of HTLV-1 env or pX genes or both was shown in all 12 patients with HU tested by RT-PCR. IL-6 messenger ribonucleic acid (mRNA) was detected by RT-PCR in 10 of these 12 patients, whereas those of interleukin-1 alpha, interleukin-2, interleukin-4, and tumor-necrosis factor-alpha were not, and that of interferon-gamma was detected in only 1 patient. The IL-6 level was elevated significantly in the aqueous humor of nine patients with HU compared with that of five control subjects (520.2 +/- 841 pg/ml versus 2.77 +/- 1.59 pg/ml, P < 0.01 by Mann-Whitney test). CONCLUSIONS: HU is characterized by lymphocytic infiltration with a predominance of T cells and by the presence and probable accumulation of HTLV-1-infected lymphocytes in the affected eye. Production of viral antigens and IL-6 by the infiltrating cells could be responsible for the development of HU.
We report here five pediatric patients with human T-lymphotropic virus type 1 (HTLV-I) uveitis. The patients were one boy and four girls aged between 3 and 14 years. The transmission route was considered to be breast feeding from their mothers. All patients had unilateral uveitis and the ocular symptoms were similar to those in HTLV-I uveitis in adults. The ocular inflammation responded to therapy with topical or systemic corticosteroids, but recurred in three patients. HTLV-I provirus DNA was detected by polymerase chain reaction (PCR) from infiltrating cells in the anterior chamber in one patient. The percentage of HTLV-I-infected cells in the peripheral blood mononuclear cells was measured by quantitative PCR, and the values were high (2.9 approximately 7.3%) in three cases tested as compared with an asymptomatic carrier. These five cases show that HTLV-I uveitis can be induced in a relatively short period (3 approximately 10 years) after the viral infection, and that HTLV-I uveitis should be considered as one possible etiology of uveitis in children, particularly in a viral endemic area.
A survey was conducted in a highland community of Gifu prefecture on 815 residential elderly persons, over 65 years old, utilizing self-administered questionnaires to study the degree of association between life style factors and health conditions. A total of 718 valid participants (90.6% of the total) were analyzed and cross-examined by applying Breslow's seven health factors, daily behavior factors, physical health consciousness, social mobility factors (13 behavior factors which were determined by the Institute of the Elderly) to determine associations with respondents health conditions. Of the participants, 310 were male and 408 were female with mean ages of 73.8 +/- 6.9 years old and 74.0 +/- 6.9 respectively. The survey results indicated that there were no prominent gender differences over the mobility rate and physical health consciousness among participants. However, it was also found that in the male participants the per person prevalence of past history of illness was higher than in females. In the daily activity analysis, female participants indicated a higher prevalence of difficulty in walking and balance maintenance while ascending and descending stairs. In the general daily activity analysis, male participants had a higher requirement for an aide. In social mobility, male participants recorded a high degree of self-reliance by being physically, socially, and intellectually active and the female participants by fulfilling their social responsibilities. Breslow's seven health indicators were applied and their evaluation points were calculated as 3.9 +/- 1.7 for male participants and 3.5 +/- 1.8 for female participants which showed a significantly higher score for the male participants. The survey also indicated that factors which increase the Breslow score for males, were having a spouse, hobbies, a satisfactory life, a habit of exercising, and non-smoking which in females an appropriate sleeping habit (not less than 7 hours), and working, were the positively related factors.
Nitric oxide (NO), which plays an important role in the vital functions of organisms, is gaseous and labile molecule. Much attention has been paid to the stability and easily handling of NO donors, for careful handling of NO is required during experimental work. We synthesized a series of aromatic N-nitrosoureas and N-nitrosamides which efficiently liberates NO at room temperature. Generation of NO from the aromatic N-nitroso compounds was chemically confirmed by the trapping of NO as a nitrosyl complex of tetraphenylporphyrinatocobalt (II) and spectrophotometrically quantified by means of the Griess reaction using a newly designed test apparatus. 3,3-Dibenzyl-1-(4-tolyl)-1-nitrosourea showed the greatest NO-generating ability among the synthesized N-nitroso compounds. Further, the NO-generating ability was related to the reciprocal of the ID50 value for growth inhibition of cultured L-5178Y cell by the aromatic N-nitroso compounds.
Newly synthesized dinitrobenzo[a]pyrenes and 6-aza analogues of 1- and 3-nitrobenzo[a]pyrenes showed strong mutagenic activity in Salmonella assays (TA98 and TA98NR). Nitroreduction is essential for metabolic activation of nitroarene. The structure activity relationships of mono-, di- and trinitrophenanthrene were studied. Electrochemical ease of nitroreduction and dihedral angles of nitro substituents to aromatic rings is found to be important factor to determine their mutagenic potency. Nitroarene is oxidatively metabolized to form hydroxylated and nitrosubstituted derivatives and the same oxidative products were obtained by the reaction of nitroarene with chemically generated superoxide anion radical, suggesting the participation of superoxide in metabolic oxidation of nitroarene. Catalytic activity of nitroarene as a mediator in the reductive activation of molecular oxygen was also evaluated by using potential step chronocoulometry method. The potential relevence of toxicity caused by redox cycling could be solved by using this method.
[60]Fullerene (C60) was solubilized with poly(vinylpyrrolidone) (PVP) in water, and the aqueous solution was applied to a mouse midbrain cell differentiation system. On incubation of C60 with various concentrations of PVP, cell differentiation and proliferation were potently inhibited, although weaker than the vehicle controls. C60 was clearly distributed into the yolk sac and embryos by intraperitoneal administration to pregnant mice at 50 mg/kg and had a harmful effect on both conceptuses by microscopical evaluation. This in vivo and in vitro action on embryogenesis is a novel and seriously harmful activity of C60.
To determine the mutagenicity of nitrophenanthrenes, three mononitrophenanthrenes (NPhs), 11 dinitrophenanthrenes (diNPhs) and eight trinitrophenanthrenes (tiNPhs) were synthesized, and their mutagenicity was investigated by using Salmonella typhimurium his- strains TA98, TA100, and TA98NR, nitroreductase-deficient, and TA98/1,8-DNP6, O-acetyltransferase-deficient mutants, and strains YG1021 and YG1026, nitroreductase-overproducing mutants of TA98 and TA100, respectively, and strains YG1024 and YG1029, O-acetyltransferase-overproducing mutants of TA98 and TA100, respectively. 1-, 3- and 9-NPhis induced 329, 620 and 438 revertants per nmol in strain TA100, respectively, and 4,839, 11,309 and 16728 revertants per nmol, respectively, in strain YG1029. Mutagenicity of 1,6-, 2,6-, 2,9-, 2,10-, 3,5-, 3,6- and 3,10-diNPh was elevated in strains YG1021, YG1024, YG1026 and YG1029. Among these derivatives, 1,6-, 2,6-, 3,6- and 3,10-diNPhs were more mutagenic in strains YG1024 and YG1029 than YG1021 and YG1026, and they showed a structure-activity relationship between mutagenicity and NO2-substitution. Nitro derivatives substituted at the 3 and 6 positions of their chemical structure strongly mutated both strains YG1024 and YG1029, whereas those substituted at the 9 and 10 positions showed weak mutagenicity. In addition, nitro substituents at positions 4 and 5 were perpendicular while those on positions 2,3,6 and 7 were nearly coplanar to the aromatic ring. Furthermore, 2,6,9-, 3,6,9- and 1,6,9-trinitrophenanthrenes (triNPhs) were mutagenic for strain TA100, and their mutagenicity was more enhanced in YG1024 and YG1029 than in YG1021 and YG1026. Of the eight triNPhs all except 1,5,10-triNP were mutagenic in TA98 and TA100, and their mutagenicity was more enhanced in YG1024 and YG1029 than in YG1021 and YG1026. These results suggest that these compounds are mutagens that are activated by O-acetyltransferase esterification following nitroreductase. The nitrated derivatives substituted at the 2(7) and 3(6) positions of the phenanthrene ring were highly mutagenic. The relationship between chemical structure and the mutagenicity of NPh derivatives is discussed.
1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates. 2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates. 3. Bmax and Kd values of hyperplastic prostates were greater than those of the control. 4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained. 5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland. 6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.
A 56-year-old female with Graves' disease who presented with decreased secretion of gonadotropins is described. She was admitted to hospital because of her being in a state of confusion. One month before admission she had been diagnosed as having Graves' disease and was treated with methimazole since then. Plasma LH and FSH levels were undetectable, and their responses to LH-RH were extremely decreased in spite of undetectable levels of plasma estradiol and estriol. One year after treatment, both basal and stimulated values of LH and FSH reverted to normal as did those of TSH. Reversible suppression of gonadotropins as described herein has never been reported in cases of Graves' disease.
Fullerene C60 dissolved in polyvinylpyrrolidone was mutagenic for Salmonella strains TA102, TA104 and YG3003 in the presence of rat liver microsomes when it was irradiated by visible light. The mutagenicity was elevated in strain YG3003, a repair enzyme-deficient mutant of TA102. The mutation was reduced in the presence of beta-carotene and parabromophenacyl bromide, a scavenger and an inhibitor, respectively, of phospholipase. The results suggest that singlet oxygen was generated by irradiating the C60 by visible light and that the mutagenicity was due to oxidized phospholipids in rat liver microsomes. Of the phospholipids in rat liver microsomes, the linoleate fraction isolated by high performance liquid chromatography was a major component, and played an important role in mutagenicity. Methyl linoleate, which was prepared for gas chromatographic analysis, was readily oxidized to hydroperoxymethyl linoleate, and associated with both 10- and 12-hydroxyl derivatives with a double bond in chemical structure by singlet oxygen: radicals to the hydroxyl function were probably generated. Because of the instability of the hydroxymethyl linoleate radicals, guanine residues generated radicals. The results of ESR spectrum analysis suggested generation of radicals at the guanine base but not thymine, cytosine and adenine bases as estimated with the g value of 2.0150. On the other hand, the singlet oxygen-generating C60 formed 8-hydroxydeoxyguanosine (8-OH-dG) upon treatment with 2' deoxyguanosine and microsomes or linoleate. The formation of 8-OH-dG was highly elevated in the presence of microsomes and linoleate. The level of 8-OH-dG formed with and without the microsome fraction was 47 and 9.6 units, respectively, per 10(4) deoxyguanosine. It was considered that the mechanism is indirect action of singlet oxygen due to lipid peroxidation of linoleate that causes oxidative DNA damage.
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It is well known that urokinase-type plasminogen activator (uPA) activates fibrinolysis of tumor cells and accelerates their metastasis and invasion. Human adenosquamous cell line, AOI cells, were stimulated to produce and accumulate of uPA by radiation. In AOI cells, there was relationship between uPA production and accumulation and the radiation doses. It was suggested that radiation had the possibility to accelerate the metastasis and invasion by increasing the production and accumulation of uPA from cancer cells.
Bilateral injections of the thyrotropin-releasing hormone (TRH) analogue, N alpha-[((S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate (YM-14673, 0.1 microgram and 1 microgram/0.2 microliters), into the nucleus accumbens, the dorsal and ventrolateral striatum produced repetitive jaw movements in a dose-dependent manner. The effects were greatest in the nucleus accumbens and smallest in the ventrolateral striatum. Pattern of the movements differed from that produced by injections of a mixture of SKF 38393 (5 micrograms) and quinpirole (10 micrograms); frequent tongue protrusions were evident in rats treated with the mixture but those were not seen in YM-14673-treated rats. TRH (1 microgram, 10 micrograms and 30 micrograms/0.2 microliters) did not evoke jaw movements from any of the sites. The non-selective dopamine receptor antagonist, cis-(Z)-flupentixol (10 micrograms), significantly reduced the response to administration of YM-14673 (1 microgram) into the nucleus accumbens or dorsal striatum, while the 5-hydroxytryptamine (5-HT)2A receptor antagonist, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride (ICI 169,369, 0.2 micrograms), did not affect the response to YM-14673 (1 microgram). Given intrathecally (0.5 microgram/5 microliters), both YM-14673 and TRH produced wet-dog shakes. Although the mechanisms giving rise to the display of jaw movements after intrastriatal injections of YM-14673 remain unknown, stimulation of the dopamine D1/D2 receptors may at least partly contribute to these effects. Anyhow, these mechanisms differ from that underlying the ability of YM-14673 and TRH to elicit wet-dog shakes, a mechanism that is known to involve serotonergic processes.
Fullerene C60 was solubilized with polyvinylpyrrolidone (PVP) in water, and the aqueous solution was applied to the rat limb bud cell differentiation system. By the incubation with various concentrations of C60 with poly(vinylpyrrolidone), cell differentiation was extremely promoted, up to the levels of a 3.2-fold increase of the controls. Although poly(vinylpyrrolidone) alone inhibited the cell differentiation in proportion to the concentration, the observed promoting action by C60 surpassed the action of poly(vinylpyrrolidone). This specific promoting action on the chondrogenesis is the novel significant activity of C60.
For the detection of tumor-promoting activities of phenolic antioxidants, the inhibitory activities on the intercellular gap-junctional communication were investigated using the V79 metabolic cooperation (MC) assay. Among eight antioxidants, 4,4'-butylidene-bis(3-methyl-6-tert-butyl-phenol), 2,2'-methylene-bis(4-methyl-6-tert-butylphenol) (MBMBP), and styrenated phenol (SP) showed stronger inhibitory activities than lithocholic acid, which is known to be a tumor promotor. However, 4,4'-thio-bis(3-methyl-6-tert-butylphenol), Irganox 1010, and 1330 did not inhibit at any concentrations. When the single-electron oxidation potentials were compared among antioxidants, the electrochemical ease estimated with the first oxidation potential was correlated with the cytotoxic potentials (r = 0.88), but not with the inhibitory activities in an MC assay. The tumor-promoting activity of MBMBP was also investigated using an in vitro, two-stage Balb/c 3T3 transformation assay. MBMBP did not show initiating activity, but significant promoting activity at concentrations of both 1 and 2.5 micrograms/ml were noted. These concentrations were close to the lowest effective inhibitory concentration (1.3 micrograms/ml) of MBMBP in an MC assay. In conclusion, there is a possibility that the phenolic antioxidants that show inhibitory activities in an MC assay contribute to the enhancement of tumor incidence induced by biomaterials.
We investigated the anti-inflammatory effects of 0.1% diclofenac sodium on anterior inflammation after cataract surgery. Fibrin precipitation after surgery in patients without systemic or ocular disease was markedly less when diclofenac sodium ophthalmic solution was used in combination with topical corticosteroids. There was also a reduction in fibrin precipitation in other patients, especially in those with diabetes mellitus, primary angle-closure glaucoma, and exfoliation syndrome. In conclusion, diclofenac sodium was shown to be clinically useful as a topical preparation to suppress inflammation after cataract surgery.