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C Ito

Publications and source records attributed to C Ito.

At least 37 records · Page 2Linked to original sources

Involvement of erythropoietin-induced cytosolic free calcium mobilization in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells.

BACKGROUND/OBJECTIVE: Human recombinant erythropoietin (rHuEPO) induces cytosolic free calcium ([Ca2+]i) mobilization, an activation of mitogen-activated protein (MAP) kinase and DNA synthesis in several tissues. We explored the mechanism of rHuEPO-induced [Ca2+]i mobilization and its role in the activation of MAP kinase and DNA synthesis in vascular smooth muscle cells (VSMC). METHODS: [Ca2+]i concentrations were measured by fura-2. MAP kinase activation was analyzed using an immunocomplex kinase assay and Western blotting. DNA synthesis was measured as an incorporation of 5-bromo-2'-deoxyuridine. RESULTS: Although addition of rHuEPO significantly increased [Ca2+]i, either in the presence or absence of extracellular Ca2+, the peak level and sustained elevation of [Ca2+]i were significantly reduced in the absence of extracellular Ca2+. Pretreatment with genistein completely blocked the elevation of [Ca2+]i in both conditions. Calphostin C and staurosporine did not completely block the elevation of [Ca2+]i. Staurosporine reduced its peak level in a dose-dependent manner, whereas calphostin C reduced its peak level at concentrations over 1 nmol/l in the presence of extracellular Ca2+. Similar results to those with staurosporine were observed with nifedipine. In the absence of extracellular Ca2+, their dose-dependent effects disappeared even though rHuEPO increased [Ca2+]i. rHuEPO activated MAP kinase and DNA synthesis, both of which were significantly suppressed by the chelation of intracellular Ca2+. CONCLUSION: These findings suggest that rHuEPO increases [Ca2+]i by both Ca2+ influx and Ca2+ release from intracellular stores. Tyrosine phosphorylation is critical in the regulation of [Ca2+]i, but protein kinase C activation is important only in the regulation of Ca2+ influx. Dihydropyridine-sensitive L-type Ca2+ channels seem to be involved in rHuEPO-induced Ca2+ influx. In addition, increase of [Ca2+]i by rHuEPO stimulates MAP kinase activation and DNA synthesis in VSMC.

Animals↗

Modulation of endothelin-1-induced cytosolic free calcium mobilization and mitogen-activated protein kinase activation by erythropoietin in vascular smooth muscle cells.

BACKGROUND: It has been reported that human recombinant erythropoietin (rHuEPO) modulates the sensitivity of the cardiovascular system to vasoconstrictors. We investigated whether rHuEPO has modulative effects on the endothelin-1 (ET-1)-induced elevation of cytosolic free calcium concentration ([Ca2+]i) and mitogen-activated protein (MAP) kinase activation in vascular smooth muscle cells (VSMC). METHODS: [Ca2+]i was measured by fura-2/AM, and MAP kinase activation was analyzed by Western blotting. RESULTS: Exposure of VSMC to rHuEPO prior to stimulation with ET-1 enhanced both basal and ET-1-induced elevation of [Ca2+]i in a dose-dependent manner in the presence of extracellular Ca2+. The synergistic effect was also retained in the absence of extracellular Ca2+ after exposure to rHuEPO. However, the effect was diminished in the presence of extracellular Ca2+ combined with the intracellular Ca2+ release inhibitor TMB-8, PKC inhibitor, or PKC depletion. Exposure to rHuEPO also had a synergistic effect on the activation of MAP kinase induced by ET-1; however, this effect was diminished in the presence of the Ca2+ chelator BAPTA-AM. CONCLUSION: The results suggest that rHuEPO has synergistic effects on ET-1-induced [Ca2+]i mobilization, particularly on intracellular Ca2+ release, and MAP kinase activation in VSMC.

Animals↗

Effects of 5-HT(4) receptor agonist prokinetic agents on the action potential parameters of isolated rabbit myocardium.

The effects of TS-951, a novel gastrointestinal prokinetic agent with 5-HT(4) receptor agonistic action, on the action potential parameters of isolated rabbit Purkinje fiber, ventricular muscle and sinoatrial node, and on the spontaneously beating rates of isolated rabbit right atria were compared with those of cisapride. TS-951 had no effect on the action potential parameters in both rabbit Purkinje fiber and ventricular muscle preparations. However, cisapride significantly prolonged action potential duration (APD) in both preparations. Both TS-951 and cisapride produced a negative chronotropic effect in rabbit right atria; TS-951 and cisapride at 3 x 10(-5) mol/l reduced the beating rate by about 20 and 40%, respectively. In the sinoatrial node preparations, TS-951 (3 x 10(-5) mol/l) as well as cisapride (10(-6) mol/l) prolonged cycle length and APD and reduced the diastolic depolarization rate. These results indicate that TS-951 does not appear to possess electrophysiological features leading to cardiotoxicity such as QT prolongation and, thus, torsades de pointes in common with cisapride.

Action Potentials↗

Pharmacological characterization of a novel 5-HT4 receptor agonist, TS-951, in vitro.

The pharmacological effect of a novel selective 5-HT4 receptor agonist, TS-951 (N-[endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide) was investigated in vitro. TS-951 potently inhibited specific [3H]GR113808 binding both in guinea-pig striatum and in mouse brain. The affinity of TS-951 for the 5-HT4 receptor was higher than those of other agonists, 5-HT, cisapride, mosapride and renzapride. On the longitudinal muscle of the guinea-pig ileum, TS-951 caused a concentration-dependent increase in the amplitude of electrically induced submaximal twitch contractions. On the longitudinal muscle of the guinea-pig distal colon, TS-951 also caused concentration-dependent contractions. TS-951 is a high-affinity, selective and potent 5-HT4 receptor agonist. This compound therefore can be considered as a useful pharmacological tool for investigating 5-HT4 receptor-mediated events.

Animals↗

Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists.

A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.

Amides↗

In vitro absorption and metabolism of nobiletin, a chemopreventive polymethoxyflavonoid in citrus fruits.

The polymethoxyflavonoid (PMF), nobiletin (NOB), specifically occurs in citrus fruits, and is currently believed to be a promising anti-inflammatory and antitumor promoting agent. In the present study, we investigated the in vitro absorption and metabolism of NOB and compared them with those of the polyhydroxyflavonoid (PHF), luteolin (LT). NOB preferentially accumulated in a differentiated Caco-2 cell monolayer, which is a model for small intestinal epithelial cells, while LT did not. Treatment of NOB with a rat liver S-9 mixture led to the formation of 3'-demethyl-NOB, while that of LT did not. We thus suggest that PMFs including NOB have properties distinct from those of general flavonoids for absorption and metabolism in vitro.

Animals↗

[Secondary eosinophilia in a patient with hypereosinophilic syndrome after allogeneic bone marrow transplantation from a sibling donor].

A 23-year-old man first visited a local hospital in 1998 because of exertional dyspnea. Peripheral blood examination revealed mild leukocytosis with 82% eosinophils, and he was treated with prednisolone. As the eosinophilia did not improve, he was referred to Tokai University Hospital in March 1999 for further diagnosis and treatment. The patient was diagnosed as having hypereosinophilic syndrome (HES) because of unexplained hypereosinophilia persisting for more than 6 months, resulting in cardiac dysfunction. His disease was progressive in spite of immunosuppressive therapy, interferon-alpha and cytotoxic chemotherapy. Since he had an HLA-identical brother, allogeneic bone marrow transplantation (BMT) was performed in October 1999. After completion of the immunosuppressive therapy on day 79 after BMT, the number of eosinophils gradually increased again. Although we suspected recurrence of the disease, DNA fingerprinting revealed that the peripheral granulocytes were 100% donor type. An increase of interleukin-5 (IL-5) produced by peripheral lymphocytes and a decrease of the Th1/2 ratio suggested that the eosinophilia was related to GVHD. The eosinophilia was eventually controlled by cyclosporin. We conclude that DNA fingerprinting and examination of the IL-5 level and Th1/2 ratio are useful for differentiating between relapse and GVHD in cases of eosinophilia occurring after BMT for HES.

Adult↗

[Susceptibilities of bacteria isolated from patients with lower respiratory infectious diseases to antibiotics (1999)].

From October 1999 to September 2000, we collected the specimen from 430 patients with lower respiratory tract infections in 17 institutions in Japan, and investigated the susceptibilities of isolated bacteria to various antibacterial agents and antibiotics and patients' characteristics. Of 515 strains that were isolated from specimen (mainly from sputum) and assumed to be bacteria causing in inflammation, 506 strains were investigated. The breakdown of the isolated bacteria were: Staphylococcus aureus 78, Streptococcus pneumoniae 101, Haemophilus influenzae 104, Pseudomonas aeruginosa (non-mucoid) 58, P. aeruginosa (mucoid) 11, Moraxella subgenus Branhamella catarrhalis 41, Klebsiella pneumoniae 18, etc. Of 78 S. aureus strains, those with 4 micrograms/ml or above of MIC of oxacillin (methicillin-resistant S. aureus: MRSA) occupied 57.7%. Vancomycin and arbekacin showed the most potent activities against MRSA without detection of ABK-resistant strain (MIC: 64 micrograms/ml) and decrease of VCM-sensitive strains those were found in 1998. The frequency of S. pneumoniae exhibiting low sensitivity to penicillin (penicillin-intermediate S. pneumoniae: PISP + penicillin-resistant S. pneumoniae: PRSP) decreased to 34.7% from 46.0% in 1998. The frequency of PRSP was 3.0%, being the least number after 1991. Carbapenems showed strong activities against S. pneumoniae. Especially, panipenem inhibited the growth of all 101 strains with MIC of 0.063 microgram/ml. Generally, all drugs showed strong activities against H. influenzae with MIC80s of 4 micrograms/ml or below. MICs of ofloxacin ranged between 0.063 microgram/ml and 4 micrograms/ml in 1998, however, those were 0.125 microgram/ml or below in all H. influenzae in 1999 showing the strongest activity. Tobramycin and ciprofloxacin showed strong activities against P. aeruginosa (both mucoid and non-mucoid) with MIC80s of 1 microgram/ml. Number of isolated P. aeruginosa (mucoid) was little as 11, however, the susceptibilities to all drugs were better than P. aeruginosa (non-mucoid). K. pneumoniae showed good susceptibilities to all drugs except for ampicillin with decreasing of low-sensitive strains compared to those detected in 1998. Also, all drugs generally showed strong activities against M. (B.) catarrhalis. MIC80s of all drugs were 2 micrograms/ml or below. The drug which showed the strongest activity was imipenem inhibiting all 41 strains with MIC of 0.063 microgram/ml. On the patients' characteristics, the number of patients aged 80 years or older who had been increased was decreased in 1999 in the distribution by age. The percentage of the elderly patients aged 70 years or older was 47.0%, which occupied almost a half number of the total patients as in the last year. As for the incidence by disease, bacterial pneumonia and chronic bronchitis were the highest. They were noted in 37.9% and 30.5% of the patients, respectively. In 1999, bronchial asthma was frequently observed as compared in recent years. It was noted in about 10% of the patients which is the same % as in bronchiectasis. We examined the number of strains from these patients with infections before and after administration of antibiotics. In patients with bacterial pneumonia, the number of isolated strains was almost the same between those before and after administration. However, in patients with chronic bronchitis, the number of strains remarkably decreased to less than the half of the total after administration of antibiotics in the last year, but it decreased to 2/3 of the total in 1999. On the administration of antibiotics and isolated bacteria by the day of administration, the bacteria which were isolated more before administration were H. influenzae in 28.4%, S. pneumoniae in 25.7%, M. (B.) catarrhalis in 12.0% and S. aureus in 10.6%. The frequency of S. aureus after administration over 15 days was almost the same as that before administration, but the frequency of P. aeruginosa (both mucoid and non-mucoid) was 36.8% which was higher than that before administration. The frequency of isolated S. pneumoniae was decreased after administration and none of them was isolated after completion of administration. However, that of H. influenzae was decreased to 7.1% after administration within 3 days, and many H. influenzae were isolated after completion of administration as 21.4%.

Adolescent↗

[Comparison between real-time pollen monitor KH-3000 and Burkard sampler].

Special apparatus capable of instantly measuring airborne Cryptomeria japonica pollen grains were recently appeared on the market. We examined one of them called real-time pollen monitor KH-3000 (Yamato Manufacturing Co. Ltd.). To confirm the accuracy of the monitor, comparison was made with conventional Burkard Seven-Day Recording Volumetric Spore Trap operating simultaneously at the same place. Most peaks from KH-3000 were coincided with Cry j 1 from Burkard sampler, and the greater part of the counts from KH-3000 had a strong resemblance to the counts from Cry j 1. Therefore, it is confirmed that KH-3000 counts the numbers of airborne C. japonica pollen grains. KH-3000 sometimes counts particles which do not belong to pollen grains, however. It is also confirmed that some pollens other than C. japonica, such as walnut (Juglans spp.) pollen, a part of grass pollen were counted.

Air Pollutants↗

Inhibitory effect of flavonoids from citrus plants on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors.

To search for possible anti-tumor promoters, thirteen flavones (1-13) obtained from the peel of Citrus plants were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these flavones, 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) (13) exhibited significant inhibitory effects on the EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, compound 13 exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

Animals↗

Anti-tumor-promoting effects of isoflavonoids on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis.

As a part of screening studies for anti-tumor promoters, fifteen isoflavonoids isolated from plants of the genus Millettia (Leguminosae) were evaluated by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All of the compounds tested in this study showed inhibitory activity against EBV, without showing any cytotoxicity. Auriculasin (11) and millepurone (13), which is an oxidized isoflavone analogue, both having one or more prenyl side-chains and a 3',4'-dihydroxyphenyl group in the molecule, showed more potent activity than any of the other compounds tested. Furthermore, millepurone (13) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. The results of the present investigation indicate that some of these isoflavonoids might be valuable anti-tumor promoters.

Animals↗

The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes.

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated in adipocyte differentiation. Recently it was reported that heterozygous deficiency of PPARgamma led to the protection from high-fat diet-induced insulin resistance in an animal model. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism in Japanese diabetic and non-diabetic subjects. The frequency of Ala12 was significantly lower in the diabetic group. In an overweight or obese group, subjects with Ala12 were more insulin sensitive than those without. These results suggest that the PPARgamma is a thrifty gene and that the Pro12Ala PPARgamma2 polymorphism protects against type 2 diabetes in the Japanese.

Aged↗

1,1-Dimethylallylcoumarins potently suppress both lipopolysaccharide- and interferon-gamma-induced nitric oxide generation in mouse macrophage RAW 264.7 cells.

We investigated the suppressive effects of 16 coumarin-related compounds on both lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO) generation in a mouse macrophage cell line, RAW 264.7. Notably, coumarins possessing prenyl unit(s) were found to be highly active, a tendency consistent with our previous study. Among the coumarins tested, 1,1-dimethylallylcoumarins showed the highest inhibitory activity. Western blotting analysis revealed that they inhibited NO generation by suppressing inducible NO synthase (iNOS) protein expression. Our ongoing studies suggest that coumarins are prominent natural compounds that attenuate excessive and prolonged NO generation at inflammatory sites.

Animals↗

Xanthone and dihydroisocoumarin from Montrouziera sphaeroidea.

A xanthone, montrouxanthone and a dihydroisocoumarin, montroumarin were isolated from the stem bark of Montrouziera sphaeroidea Pancher Ex Planchon et Triana [Guttiferae], along with two known compounds. Their structures were elucidated on the basis of spectroscopic analyses. This is the first report of the analysis of chemical constituents of Montrouziera species.

Chromatography, Thin Layer↗

Importance of OGTT for diagnosing diabetes mellitus based on prevalence and incidence of retinopathy.

Study was made on the necessity and importance of the oral glucose tolerance test (OGTT) for diagnosing diabetes mellitus based on prevalence and incidence of diabetic retinopathy. Subjects were 12208 persons undergoing OGTT between 1965 and 1997. The prevalence of retinopathy was significantly elevated with FPG>/=126 and 2-h PG>/=198 mg/dl. The incidence of retinopathy was 15-30/10000 person-years (PY) with FPG<125, but with FPG of 126-139 it was significantly higher (69/10000 PY) and at 140-199 mg/dl it was elevated to 139/10000 PY. Subjects were classified at initial test into FPG<110, 110-125, 126-139, and >/=140 and further into 2-h PG<200 and >/=200 mg/dl for comparison with the incidence of retinopathy. Even with the same FPG, the incidence was two- to threefold higher with 2-h PG>/=200 mg/dl, indicating that 2-h PG was highly associated with the incidence of retinopathy. As for IFG, the prevalence of diabetes as defined by 2-h PG>/=200 in the OGTT increased with elevated FPG, and 33.7% of IFG cases showed 2-h PG>/=200 mg/dl. Based on the prevalence and incidence of retinopathy, we conclude that 126 mg/dl FPG is an appropriate cut-off level, and the OGTT is important for diagnosing mild diabetes mellitus.

Adolescent↗

Correlation among fasting plasma glucose, two-hour plasma glucose levels in OGTT and HbA1c.

A study was made on the association among 2-h plasma glucose (PG) in oral glucose tolerance test (OGTT), fasting plasma glucose (FPG) using correlation and regression equation. Subjects were 13174 OGTT examinees tested between 1980 and 1998. Blood glucose was determined by the glucose oxidase method and glycated hemoglobin (HbA1c) by the HPLC method. As for correlation between 2-h PG and FPG, regression equation of the <60 year group was y=57.1+0.336x (r=0.866, P<0.0001) and that of the >==60 year group was y=61.5+0.286x (r=0.814, P<0. 0001). FPG was calculated at 124.3 in the <60 year group and 118.7 mg/dl in the >==60 year group for 2-h PG of 200 mg/dl, 2-h PG were calculated at 199.5 and 210.7 mg/dl for FPG of 126 mg/dl, respectively. In the <60 year group, FPG were calculated at 121.7 and 124.4 mg/dl and 2-h PG at 193.2 and 199.3 mg/dl for HbA1c of 6.0 and 6.1%, respectively. As for associations between HbA1c and FPG or 2-h PG being high correlation, it is possible to estimate a prevalence of DM in a group using HbA1c>==6.1%. High correlations were demonstrated among all the three measures; FPG, 2-h PG, HbA1c. If 2-h PG is used in diagnosing diabetes mellitus, an FPG of 126 mg/dl proposed by ADA and World Health Organization (WHO) as a diagnostic level of FPG is an acceptable value for the Japanese.

Adult↗

Constituents and cytotoxicity of Zanthoxylum rhesta stem bark.

3,5-Dimethoxy-4-geranyloxycinnamyl alcohol (1), 8-methoxy-N-methylflindersine (2), xanthyletin and sesamin have been isolated from petroleum ether extract of the stem bark of Zanthoxylum rhesta. The petroleum ether extract and 8-methoxy-N-methylflindersine showed cytotoxicity on brine shrimp nauplii.

Animals↗