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Biomedical subjects

N Shimojo

Publications and source records attributed to N Shimojo.

At least 19 recordsLinked to original sources
PubMed2001

Impairment of spermatogenesis in rats by methylmercury: involvement of stage- and cell- specific germ cell apoptosis.

Methylmercury has been shown to affect the male reproductive organs. However, the specific mode of impairment of spermatogenesis during methylmercury exposure remains unknown. In this study, we characterized the induction of germ cell apoptosis and reproductive toxicity in Wistar male rats that had been exposed to methylmercuric chloride (MMC). Subcutaneous injection of MMC at a dose of 10 mg/kg per day for 8 days resulted in a 28% testicular weight loss at 14 days after the first injection. In addition, the ventral and dorso-lateral prostatic lobes showed a 65 and 52% decrease, respectively, at 14 days, although no effects were observed in the epididymis. Sperm production also was suppressed by the administration of MMC. After exposure to MMC, fragmentation of testicular DNA was found to be increased at 3 days after the first injection, with a 20-fold increase over control levels at 14 days. In situ detection of apoptosis by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) staining revealed that spermatocytes and spermatids at stages VII-VIII and IX-XI, respectively, steps which are considered to be highly sensitive to testosterone, were the major cell types affected. Consequently, a marked cell loss in elongated spermatids at stages XII-XIV and I was observed at 14 days. In addition, plasma testosterone levels were reduced at 6 days after exposure to MMC, and remained at approximately 20% of control levels during the 14-day observation period. Our results suggest that methylmercury impairs spermatogenesis by germ cell deletion via cell- and stage- specific apoptosis.

Animals↗
PubMed2001

Catecholamines and opioid peptides increase in plasma in humans during possession trances.

Naturally induced possession trances have been observed in healthy people of many societies. The neurophysiological basis of this phenomenon remains unknown, however, because of the difficulty in accessing subjects in trances due to their sacred context. In the present study, we measured the plasma levels of several neuroactive substances from subjects exhibiting or lacking possession trance characteristics during Balinese dedicatory dramas under natural conditions. The trance group exhibited significant increases in plasma concentrations of noradrenaline, dopamine and beta-endorphin, compared with controls who performed the same actions as the trance group. The present finding suggests that catecholamines and opioid peptides are involved in possession trances.

Adult↗
PubMed2001

Exposure to ozone aggravates nasal allergy-like symptoms in guinea pigs.

The ability of O3 exposure to aggravate ovalbumin (OVA)-induced nasal allergy-like symptoms was studied in guinea pigs. Guinea pigs were exposed to filtered air or to 0.4 ppm O3 for 5 weeks. During the exposure, 1% OVA or saline was administered into the nasal cavities once a week. Sneezes and nasal secretions were measured for a 20-min period following OVA administration. The number of eosinophils infiltrating both nasal epithelium and subepithelium and titers of specific anti-OVA-IgG were measured 24 h after the last administration. Ozone increased OVA-induced sneezing and nasal secretion, as well as induced nasal hyper-responsiveness to physical stimuli. The number of eosinophils infiltrating the nasal subepithelium was increased by O3, and the titer of anti-OVA-IgG tended to increase in the O3-exposed animals. Thus, exposure to O3 aggravated nasal allergy-like symptoms by inducing nasal hyper-responsiveness, the infiltration of eosinophils, and by tending to increase the production of anti-OVA-IgG.

Administration, Intranasal↗
PubMed2001

Ozone exposure enhances expression of cell-surface molecules associated with antigen-presenting activity on bronchoalveolar lavage cells in rats.

In this study, we investigated the effects of ozone (O3) exposure on expression of cell-surface molecules associated with antigen presentation and on accessory activity of bronchoalveolar lavage cells (BAL cells). Rats were exposed to 1 ppm O3 for 3 days. Expression of cell-surface molecules was measured by flow cytometry. Accessory activity of BAL cells was assessed by the allogeneic mixed lymphocyte reaction (MLR) and specific antigen-presenting activity. O3 exposure increased the expression of Ia, B7.1, B7.2, and CD11b/c on BAL cells. Morphological and immunological studies showed the Ia-positive cells to have monocyte-like features. Peripheral blood monocytes expressed Ia, B7.1, B7.2, and CD11b/c. The Ia expression on the monocytes was further increased by treatment of them with BAL fluid from O3-exposed rats (O3-BALF). Resident alveolar macrophages, however, did not express Ia antigen, and the Ia expression was not increased by O3-BALF. Neutrophils, which also infiltrated in response to O3 exposure, did not express Ia, B7.1, and B7.2. Therefore, infiltrating monocytes may have caused the increased expression of Ia and B7 molecules on BAL cells exposed to O3. The accessory activity of BAL cells in terms of MLR and specific antigen-presenting activity was also enhanced by O3 exposure. The present study suggests that monocytes infiltrating in response to O3 exposure caused enhancements of the expression of Ia and costimulatory molecules on and the accessory activity of BAL cells.

Administration, Inhalation↗
PubMed2001

Phenanthraquinone inhibits eNOS activity and suppresses vasorelaxation.

Diesel exhaust particles cause an impairment of endothelium-dependent vasorelaxation and are associated with cardiopulmonary-related diseases and mortality, but the mechanistic details are poorly understood. Since we reported previously that phenanthraquinone, an environmental chemical contained in diesel exhaust particles, suppresses neuronal nitric oxide synthase (nNOS) activity by shunting electrons away from the normal catalytic pathway, it was hypothesized that phenanthraquinone inhibits endothelial NOS (eNOS) activity and affects vascular tone. Therefore, the effects of phenanthraquinone on eNOS activity, endothelium-dependent relaxation, and blood pressure were examined in the present study. Phenanthraquinone inhibited NO formation evaluated by citrulline formed by total membrane fraction of bovine aortic endothelial cells with an IC(50) value of 0.6 microM. A kinetic study revealed that phenanthraquinone is a competitive inhibitor with respect to NADPH and a noncompetitive inhibitor with respect to L-arginine. Endothelium-dependent relaxation of rat aortic rings by ACh was significantly inhibited by phenanthraquinone (5 microM), whereas the endothelium-independent relaxation by nitroglycerin was not. Furthermore, an intraperitoneal injection of phenanthraquinone (0.36 mmol/kg) to rats resulted in an elevation of blood pressure (1.4-fold, P < 0.01); under this condition, plasma levels of stable NO metabolites, nitrite/nitrate, in phenanthraquinone-treated rats was reduced to 68% of control levels. The present findings suggest that phenanthraquinone has a potent inhibitory action on eNOS activity via a similar mechanism reported for nNOS, thereby causing the suppression of NO-mediated vasorelaxation and elevation of blood pressure.

Air Pollutants↗
PubMed2000

Zeta-crystallin catalyzes the reductive activation of 2,4,6-trinitrotoluene to generate reactive oxygen species: a proposed mechanism for the induction of cataracts.

Exposure to 2,4,6-trinitrotoluene (TNT) has been shown to cause induction of cataract in which oxidative stress plays a critical role. From bovine lens we purified to homogeneity and identified an enzyme that catalyzes the reduction of TNT, resulting in the production of reactive oxygen species. The final preparation of TNT reductase showed a single band with a subunit molecular weight of 38 kDa on SDS-PAGE. Sequence data from peptides obtained by digestion with lysylendopeptidase Achromobacter protease I (API) revealed that TNT reductase is identical to zeta-crystallin. Superoxide anions were formed during reduction of TNT by zeta-crystallin, though negligible enzyme activity or protein content for superoxide dismutase, a superoxide scavenging enzyme, was found in the lens. Thus, the present results suggest that the induction of cataracts by TNT may be associated with increased oxidative stress, as a result of reductive activation of TNT generating superoxide anions, there being minimal antioxidant enzyme activity for defense against reactive oxygen species exogenously produced in the lens.

Amino Acid Sequence↗
PubMed2000

Improved method for simultaneous determination of L-arginine and its mono- and dimethylated metabolites in biological samples by high-performance liquid chromatography.

An improved method has been developed for the determination of L-arginine and its methylated metabolites, N(G)-monomethyl-L-arginine (L-NMMA), N(G),N(G)-dimethyl-L-arginine (asymmetric DMA, ADMA) and N(G),N(G)'-dimethyl-L-arginine (symmetric DMA, SDMA) in biological samples. Extraction of these compounds with a strong cation-exchange resin AG50W-X8 with L-homoarginine (2-amino-6-guanidinohexanoic acid) as an internal standard gave a recovery of more than 70% except for SDMA from plasma samples. After extracted samples were converted to fluorescent derivatives with o-phthalaldehyde (OPA) in an alkaline medium, the following high-performance liquid chromatographic separation with a ODS column (wide-pore size, 300 A) was successfully performed with an isocratic mobile phase system. The method permits quantitative determination of L-arginine and its methylated metabolites at concentrations as low as 4 microM and 0.18 microM, respectively. Using this method, the levels of L-arginine, L-NMMA, ADMA and SDMA in human plasma, urine and rat tissue were determined.

Adult↗
PubMed2000

Decreased serum concentrations of nitric oxide metabolites among Chinese in an endemic area of chronic arsenic poisoning in inner Mongolia.

Prolonged exposure to arsenic results in peripheral and cardiovascular manifestations, as does impaired production of endothelial nitric oxide (NO). In vitro studies have indicated that endothelial cells undergo damage by arsenic. However, no information has been available on the relationship between NO synthesis and chronic arsenic poisoning in humans. The present study was designed to reveal this question. The subjects were 33 habitants who continued to drink well water containing high concentrations of inorganic arsenic (mean value = 0.41 microg/ml) for about 18 years in Inner Mongolia, China, and 10 other people who lived in this area but exposed to minimal concentrations of arsenic (mean value = 0.02 microg/ml) were employed as controls. Mean blood concentration of total arsenic was six times higher in exposed subjects than controls; 42.1 vs. 7.3 ng/ml, p <.001. Mean serum concentration of nitrite/nitrate, stable metabolites of endogenous NO, was lower in arsenic-exposed subjects than in controls: 24.7 vs. 51.6 microM, p<.001. In total samples, an inverse correlation with serum nitrite/nitrate levels was strong for blood inorganic arsenic (r = -0.52, p <.001) and less strong for its metabolites, monomethyl arsenic (r = -0.45, p<.005) and dimethyl arsenic (r = -0.37, p<.05). Furthermore, serum nitrite/nitrate concentration was significantly correlated with nonprotein sulfhydryl level in whole blood (r = 0.58, p<.001). In an in vitro study, we demonstrated that inorganic arsenite or arsenate suppresses the activity of endothelial NO synthase in human umbilical vein endothelial cells. These results suggest that long-term exposure to arsenic by drinking well water possibly reduces NO production in endothelial cells, resulting in a decrease in reduced nitrite/nitrate concentrations. Peripheral vascular disorders caused by arsenic may be attributable in part to impairment of NO production in vivo.

Adolescent↗
PubMed2000

Involvement of granzyme B expression in the enhancement of natural killer activity by beta-endorphin.

Beta-Endorphin has been reported to enhance natural killer (NK) activity in vitro. However, few studies have examined the precise regulation of the cytolytic stage of NK cells. We therefore investigated the regulation by beta-endorphin of cytotoxicity-associated molecules such as granzyme B, perforin, and Fas ligand (FasL) in human CD16(+) NK cells. On semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, the granzyme B mRNA level apparently increased in CD16(+) NK cells from high responding subjects having ratios >1.5 for the LU(30) ratio. An increase in intracellular granzyme B molecules was also detected in CD16(+) NK cells by flow cytometry. On the other hand, perforin and FasL appeared not to be involved in regulation by beta-endorphin. These findings suggest that up-regulation of granzyme B expression may be involved in the enhancement of NK activity by beta-endorphin.

Adult↗
PubMed2000

Intense exercise causes decrease in expression of both endothelial NO synthase and tissue NOx level in hearts.

Cardiac myocytes produce nitric oxide (NO). We studied the effects of intense exercise on the expression of NO synthase (NOS) and the tissue level of nitrite (NO(2)(-))/nitrate (NO(3)(-)) (i.e., NOx), which are stable end products of NO in the heart. Rats ran on a treadmill for 45 min. Immediately after this exercise, the heart was quickly removed. Control rats remained at rest during the same 45-min period. The mRNA level of endothelial NOS (eNOS) in the heart was markedly lower in the exercised rats than in the control rats. Western blot analysis confirmed downregulation of eNOS protein in the heart after exercise. Tissue NOx level in the heart was significantly lower in the exercised rats than in the control rats. The present study revealed for the first time that production of NO in the heart is decreased by intense exercise. Because NO attenuates positive inotropic and chronotropic responses to beta(1)-adrenergic stimulation in the heart, the decrease in cardiac production of NO by intense exercise may contribute to the acceleration of increase in myocardial contractility and heart rate during intense exercise.

Animals↗
PubMed2000

A novel mouse model of Graves' disease: implications for a role of aberrant MHC class II expression in its pathogenesis.

Mice immunized with fibroblasts expressing an MHC class II molecule and human thyrotropin receptor (TSHR), but not either alone, develop major features characteristic of Graves' disease (GD), such as thyroid-stimulating autoantibodies directed against TSHR, increased serum thyroid hormone levels, and enlarged thyroid glands. The results indicate the need for the simultaneous expression of a class II molecule and the TSHR on the surface of the fibroblasts to develop stimulating anti-TSHR antibodies and full-blown GD in our model. A T cell line established from a mouse with hyperthyroidism proliferates in response to fibroblasts expressing a class II molecule and TSHR, but not to the fibroblasts expressing only TSHR, indicating that the class II molecules on the fibroblasts present TSHR-derived peptide(s) to T cells. These results strongly suggest that the acquisition of antigen-presenting ability by thyrocytes can lead to the induction or progression of GD. We identified a T cell epitope of TSHR by the proliferative response of spleen cells from mice immunized with fibroblasts expressing a class II molecule and TSHR to 80 overlapping peptides spanning the extracellular domain of human TSHR. The identification of a major T cell epitope provides an important clue to a novel therapy of GD.

Animals↗
PubMed2000

Graves' disease: a host defense mechanism gone awry.

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.

Animals↗
PubMed1999

A new boronated porphyrin (STA-BX909) for neutron capture therapy: an in vitro survival assay and in vivo tissue uptake study.

A new boronated porphyrin compound (STA-BX909) was developed as a possible agent for boron neutron capture therapy. The boron concentration was measured by an in vivo rat experimental brain tumor model and an in vitro cell culture study. This agent was compared to sodium borocaptate (BSH) which has been used in clinical trials of boron neutron capture therapy. In the 9L rat brain tumor model, STA-BX909 achieved a higher boron tumor/blood ratio 24 h after injection in comparison to BSH. A boron concentration study in cultured glioma cell lines (U-251, U-87, 9L) demonstrated an increased boron concentration as a function of exposure time to STA-BX909, while the boron concentration remained stable with increasing exposure time to BSH. Use of a colony forming assay with thermal neutron irradiation revealed more cytotoxicity with STA-BX909 than BSH when the same concentration of 10B was administered. We concluded that STA-BX909 may be an effective drug for use in boron neutron capture therapy and that it merits further investigation.

Animals↗
PubMed1999

Circadian variation in nasal reactivity in children with allergic rhinitis: correlation with the activity of eosinophils and basophilic cells.

BACKGROUND: In allergic rhinitis, the major symptoms of runny nose, sneezing, and stuffy nose tend to become worse upon waking up in the morning, and yet the mechanisms underlying this phenomenon are poorly understood. We investigated whether the worsening of allergic rhinitis in the morning is associated with changes in the activity of inflammatory cells. METHODS: Nasal reactivity to methacholine was assessed twice in 8 children with allergic rhinitis and 8 healthy control subjects at 6.00 a.m. and 3.00 p.m. The amounts of eosinophil cationic protein (ECP), histamine and tryptase in induced nasal secretions and peripheral blood were also measured. RESULTS: Nasal reactivity to methacholine was higher at 6.00 a.m. not only in patients but also in healthy controls. Serum ECP and plasma histamine levels showed no circadian patterns. On the other hand, significantly higher levels of inflammatory activation products were found in nasal secretions at 6.00 a.m., thus showing a direct association with nasal reactivity. CONCLUSION: These results suggest that the circadian variation in nasal reactivity is associated with changes in the activity of eosinophils and basophilic cells in the nasal mucosa.

Adolescent↗
PubMed1998

Inhibition of nitric oxide formation and superoxide generation during reduction of LY83583 by neuronal nitric oxide synthase.

6-Anilino-5,8-quinolinedione (LY83583) has been widely used as an agent to reduce levels of nitric oxide (NO)-dependent cGMP in tissues. We report here that suppression of NO formation and production of superoxide during enzymatic reduction of LY83583 by neuronal NO synthase appeared to be potentially involved in the pharmacological action caused by LY83583. LY83583 suppressed neuronal NO synthase activity of 20,000 x g rat cerebellar supernatant preparation in a concentration-dependent manner (IC50 value = 12.9 microM). A kinetic study revealed that LY83583 is a competitive inhibitor with respect to NADPH, with a Ki value of 2.57 microM. With purified neuronal NO synthase it was found that LY83583 was a potent inhibitor of NO formation by the enzyme and served as efficient substrate for reduction with a specific activity of 173 nmol of NADPH oxidized per mg of protein per minute. The reductase activity was stimulated about 19.8-fold by addition of CaCl2/calmodulin, indicating that the presence of CaCl2/calmodulin is essential to express maximal activity of LY83583 reduction. Although LY83583 was a good substrate for both NADPH-cytochrome P450 reductase (P450 reductase) and DT-diaphorase, these flavin enzymes-catalyzed reductions of LY83583 were less than the neuronal NO synthase-mediated reduction in the presence of CaCl2/calmodulin. Enzymatic generation of superoxide during reduction of LY83583 by neuronal NO synthase, P450 reductase or DT-diaphorase was confirmed by electron spin resonance (ESR) experiments. Thus the present results indicate that a benzoquinone derivative LY83583 appears to interact with the P450 reductase domain on neuronal NO synthase, resulting in inhibition of NO formation and superoxide generation, which is involved in suppression of intracellular cGMP content.

Aminoquinolines↗
PubMed1998

Serum antioxidant vitamins and risk of lung and stomach cancers in Shenyang, China.

In a hospital-based case control study, we measured serum concentrations of vitamin A, beta-carotene and vitamin E for subjects with cancer (58 cases of lung cancer and 22 cases of stomach cancer) and 63 matched controls in Shenyang, China. Lung cancer patients had significantly (P < 0.01) lower mean serum levels of vitamin A, beta-carotene and vitamin E than controls, while the mean serum level of vitamin E did not differ between stomach cancer patients and the controls. Lower serum levels of vitamin A, vitamin E and beta-carotene were associated with an increased risk of lung cancer. Lower serum levels of vitamin A and beta-carotene were associated with a higher risk of stomach cancer, although the number of cases was small. An increased risk of lung cancer associated with lower serum levels of vitamin A and vitamin E was more evident among heavy smokers than among non-heavy smokers.

Adult↗