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Biomedical subjects

Y Hamasaki

Publications and source records attributed to Y Hamasaki.

At least 37 records · Page 2Linked to original sources
PubMed2000

(9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one), AS-35, inhibits leukotriene synthesis.

AS-35, (9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1, 2-a] pyrimidin-4-one), was developed as a leukotriene (LT) receptor antagonist, which also inhibited IgE-mediated release of leukotrienes (LTs). We have investigated the action of AS-35 on the enzyme activities which are involved in the synthesis of LTC(4) and LTB(4) (LT-synthesizing enzymes); cytosolic phospholipase A(2) (cPLA(2)), 5-lipoxygenase (5-LO), leukotriene (LT)C(4) synthase and LTA(4) hydrolase. AS-35 dose-dependently inhibited IgE- and A23187-stimulated production of LTC(4) by up to 71.5-84.8% and that of LTB(4) by 48.3-49.2% at 2. 5x10(-5) M. The assays for cPLA(2)(-), 5-LO-, LTC(4) synthase- and LTA(4) hydrolase-activities revealed that the inhibition is attributable to suppression of cPLA(2), 5-LO and LTC(4) synthase but not LTA(4) hydrolase. We have also studied the action of AS-35 on the release of beta-hexosaminidase (beta-HEX) as a marker of preformed mediators. AS-35 had only weak inhibitory action on the release of beta-HEX. The results indicate that anti-allergic action of AS-35 is predominantly attributable to its inhibition of LT synthesis by suppressing three consecutive enzymes for LTC(4) synthesis.

Animals↗
PubMed2000

Refractory pretibial myxoedema with response to intralesional insulin-like growth factor 1 antagonist (octreotide): downregulation of hyaluronic acid production by the lesional fibroblasts.

We report a case of refractory pretibial myxoedema (PTM) with Graves' disease in which there was a good clinical response to intralesional injection of the insulin-like growth factor 1 (IGF-1) antagonist octreotide. Intralesional octreotide (200 microg once daily) dramatically improved the tumorous lesions of PTM after 4 weeks, and the lesions remained stable even after reducing the dose to 200 microg once weekly. The amount of hyaluronic acid (HA) in the lesional skin decreased to 5.8 microg mg-1 dry weight from 16.3 microg mg-1 dry weight after 4 weeks of octreotide treatment. IGF-1 showed a dose-dependent stimulatory effect on HA secretion by both normal and patient's fibroblasts at higher concentrations in vitro. Octreotide significantly suppressed IGF-1 induced-HA secretion by the patient's fibroblasts, but not by normal fibroblasts, which suggests that expression of IGF-1 receptor on fibroblasts, or its affinity for IGF-1, are upregulated in PTM, resulting in the oversecretion of HA. These results might suggest that octreotide improves PTM through downregulation of HA production by lesional fibroblasts.

Down-Regulation↗
PubMed2000

Ulinastatin, an elastase inhibitor, inhibits the increased mRNA expression of prostaglandin H2 synthase-type 2 in Kawasaki disease.

Kawasaki disease is an inflammatory disease of unknown cause that causes panvasculitis, including coronary arteritis. Polymorphonucleocytosis in the early stage of the illness suggests the implication of neutrophils in the pathogenesis of the disease. In the acute phase of Kawasaki disease, mRNA expression of prostaglandin H2 synthase (PHS)-2, as determined by reverse transcription-polymerase chain reaction, was markedly enhanced, and thromboxane A2 (TXA2)-synthesizing activity was increased in polymorphonuclear leukocytes (PMNL). This up-regulation of PHS-2 was suppressed by ulinastatin (a neutrophil-elastase inhibitor) treatment. Lipopolysaccharide-induced enhancement of PHS-2 mRNA was also inhibited by therapeutic doses of ulinastatin in vitro by use of PMNL from healthy volunteers. Thus, ulinastatin inhibits arachidonate PHS metabolism by inhibiting new induction of PHS-2 at the mRNA level, which is a novel pharmacologic action of this substance. Ulinastatin treatment is possibly an additional therapeutic approach to Kawasaki disease.

Aspirin↗
PubMed1999

Cloning of a novel prolidase gene from Aureobacterium esteraromaticum.

The prolidase gene from Aureobacterium esteraromaticum was cloned and expressed in Escherichia coli. The cloned enzyme had the same enzymatic properties as the wild-type enzyme. Kinetic analysis of the enzyme indicated that the best substrate was Pro-Hyp, which was not hydrolyzed by other prolidases. Interestingly, there was no homology between the deduced amino acid sequence of A. esteraromaticum prolidase and those of the other sources such as human E. coli and Lactobacillus. However, homology was seen with the yeast hypothetical protein YJL213w, the function of which is unknown. These findings indicate that the A. esteraromaticum prolidase is a novel enzyme different from other prolidases reported to date.

Amino Acid Sequence↗
PubMed1999

Distinct roles of peroxynitrite and hydroxyl radical in triggering stunned myocardium-like impairment of cardiac myocytes in vitro.

Myocardial stunning is characterized by the impairment of excitation-contraction coupling via a decrease in myofilament Ca2+ responsiveness, thought to be triggered by hydroxyl radicals (*OH) generated upon reperfusion. Since peroxynitrite is also expected to be produced during reperfusion, we examined whether it can induce a stunned myocardium-like impairment of cardiac myocytes. Its effect on cultured cardiac myocytes was compared with that of hydrogen peroxide (H2O2), *OH source. Infusion of peroxynitrite (0.2 mM) induced a decrease in cell motion and a complete arrest in diastole at 2.9 +/- 0.3 min, which coincided with an elevation in [Ca2+]i. Arrest induced by infusion of H2O2 (10 mM) was not associated with an increase in [Ca2+]i. The ATP content was unaffected by peroxynitrite (control, 34.3 +/- 3.4: + peroxynitrite, 32.9 +/- 3.5 nmol/mg protein) and the cells remained viable. Sulfhydryl (SH) content was decreased by peroxynitrite, but not by H2O2. The membrane fluidity (a measure of peroxidation of the membrane lipids) was not affected by peroxynitrite, but was decreased by H2O2. Onset time of arrest was unaffected by deferoxamine (0.2 mM), but was delayed by DTT (10 mM) (from 2.9 +/- 0.3 to 19.2 +/- 1.6 min). Nitrotyrosine content was unchanged by peroxynitrite, and its augmentation with Fe3+/EDTA (1 mM) was not associated with a shortened onset time of arrest. The function of the Na+/Ca2+ exchanger was impaired by peroxynitrite, but not by H2O2. Peroxynitrite and H2O2 each induce arrest, but only the former increases [Ca2+]i. One of the mechanisms of the increase in [Ca2+]i is Na/Ca2+ exchanger dysfunction. The impairments were induced through SH oxidation by peroxynitrite, but through lipid peroxidation by H2O2. Myocardial stunning may be induced by both species in concert.

Adenosine Triphosphate↗
PubMed1999

Magnolol inhibits leukotriene synthesis in rat basophilic leukemia-2H3 cells.

We have observed an inhibitory action of magnolol on the production of leukotriene (LT) C4 and LTB4, important lipid mediators in allergy and inflammation. IgE- and A23187-stimulated production of LTC4 and LTB4 was measured by radio-immunoassay (RIA) in the absence or presence of various concentrations of magnolol in intact rat basophilic leukemia (RBL)-2H3 cells. Magnolol dose-dependently inhibited synthesis of LTC4 and LTB4. Magnolol inhibited the IgE-mediated increase of intracellular calcium ion concentration, resulting in the inhibition of cytosolic phospholipase A2 (cPLA2) and possibly 5-lipoxygenase (5-LO), both calcium ion-dependent enzymes. In cell-free studies magnolol inhibited LTC4 synthase activity. LTA4 hydrolase activity was only inhibited at the higher concentration (2.5 x 10(-5)M). These results indicate that magnolol inhibits production of LTs by inhibiting PLA2, 5-LO, LTC4 synthase and LTA4 hydrolase which are essential for LT-synthesis. Magnolol may have anti-allergic effect by blocking LT-synthesis.

Animals↗
PubMed1999

Induction of cytosolic phospholipase A2 and prostaglandin H2 synthase-2 by lipopolysaccharide in human polymorphonuclear leukocytes.

Polymorphonuclear leukocytes (PMNs) produce arachidonic acid (AA) metabolites including thromboxane A2 (TXA2). These cells are the first line of defense against bacterial invasion, which often causes endotoxin shock. TXA2 which plays an important role in the pathogenesis of endotoxin shock is synthesized by three consecutive enzyme activation, cytosolic phospholipase A2 (cPLA2), prostaglandin H2 synthase (PHS type 1 and type 2) and TXA2 synthase. Among them, cPLA2- and PHS-2 activity is known to be transcriptionally and/or posttranscriptionally up-regulated by various bioactive substances including lipopolysaccharide (LPS), a bacterial endotoxin, in many cell types. We investigated the action of LPS on TXA2 synthesis in human PMNs. A23187-stimulated production of thromboxane B2 (TXB2, a stable metabolite of TXA2), assayed by specific radioimmunoassay (RIA), was significantly increased from 566.7+/-44.1 pg/10(6) cells to 966.7+/-44.1 pg/10(6) cells (p<0.05) after 6 h-exposure to LPS at the concentration of 100 ng/ml. Messenger RNA for PHS-2, PHS-1, TXA2 synthase and cPLA2, which was assessed by reverse transcription-polymerase chain reaction (RT-PCR), was expressed in PMNs without LPS stimulation. Although PHS-2 was putatively an inducible enzyme, abundance of mRNA for PHS-2 in PMNs without LPS stimulation was detectable. Messenger RNA abundance for PHS-2 and cPLA2, but not for PHS-1 and TXA2 synthase, was enhanced by LPS-treatment, indicating that the increased production of TXB2 was attributable to the up-regulation of cPLA2 and PHS-2. We conclude that (1) PHS-2 plays a more important role than PHS-1 in the production of TXA2 in human PMNs and (2) TXA2 synthesis in human PMNs is transcriptionally up-regulated by new induction of cPLA2 as well as PHS-2, when the cells encounter endotoxin producing bacteria.

Aspirin↗
PubMed1998

Inhibition of leukotriene synthesis by terfenadine in vitro.

To determine the inhibitory mechanisms of terfenadine on the synthesis of leukotriene C4 (LTC4), an important mediator in allergic diseases, we evaluated the action of terfenadine on the IgE-dependent production of LTC4 in rat basophilic leukaemia 2H3 cells. Rat IgE-loaded cells were stimulated with anti-IgE in the presence or absence of various concentrations of terfenadine and the level of LTC4 released into the medium was measured by performing a specific radio immunoassay. Terfenadine inhibited the synthesis of LTC4 to 67.2% at a concentration of 5 microg/ml. LT synthesis was directly suppressed by inhibition of 5-lipoxygenase (5-LO) through calcium ion-independent mechanisms, and was also possibly suppressed by inhibition of cytosolic phospholipase A2 and 5-LO by blocking the influx of intracellular calcium ion that was initiated by IgE-related stimulation.

Animals↗
PubMed1998

Effect of dexamethasone on leukotriene synthesis in DMSO-stimulated HL-60 cells.

Human leukemia (HL) 60 cells were differentiated by dimethylsulfoxide (DMSO) treatment to granulocyte-like cells, leukotriene (LT) synthesizing activity of which was increased in response to the differentiation of the cells. Four synthesizing enzymes, cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), LTA4 hydrolase and LTC4 synthase, and an enzyme associated protein, 5-lipoxygenase activating protein (FLAP) are involved in the generation of LTC4 and LTB4. We examined the expression of messenger RNA (mRNA) for these LT synthesizing enzymes and an associated protein in DMSO differentiated HL-60 cells by reverse transcriptase polymerase chain reaction (RT-PCR). The production of LTC4 and LTB4, measured by radioimmunoassay (RIA), was increased after the incubation with DMSO for more than 3 days. Messenger RNA abundance for 5-LO, LTC4 synthase and LTA4 hydrolase was increased, that for FLAP was stable, but that for cPLA2 was decreased. These results indicate that DMSO induced increase of LT synthesis is associated with the increase of mRNA expression of 5-LO, LTC4 synthase and LTA4 hydrolase, although the precise regulatory mechanisms of the increased mRNA expression are not determined. We also investigated an action of dexamethasone (DEX) on DMSO-induced enhancement of LT synthesis. DEX suppressed DMSO induced increase of LTC4 synthesis, but rather enhanced DMSO induced LTB4 production. The DEX attenuated the DMSO-induced increase of mRNA expression for LTC4 synthase, but showed no effect on that for LTA4 hydrolase. The inhibition of LTC4 synthesis is associated with the suppression of mRNA expression for LTC4 synthase. However, increased LTB4 synthesis by DEX is regulated by the mechanisms which are independent from mRNA level of LTA4 hydrolase.

5-Lipoxygenase-Activating Proteins↗
PubMed1998

Direct evidence that LTC4 and LTB4 but not TXA2 are involved in asthma attacks in children.

There are substantial numbers of reports showing that leukotrienes (LTs) play important roles in adult asthma. No definite evidence has been demonstrated that LTs are involved in asthma attacks in children, although it is highly expected. In this report, we demonstrated that the levels of LTB4 and LTC4 but not thromboxane B2 (TXB2), a stable metabolite of TXA2, were significantly elevated in the bronchoalveolar lavage fluid, which was obtained from intubated and mechanically ventilated children with severe asthma attacks. This is direct evidence that LTB4 and LTC4 predominantly participate in asthma attacks in pediatric patients.

Adolescent↗
PubMed1997

Post-transcriptional regulation of LTC4 synthase activity by retinoic acid in rat basophilic leukemia cells.

Calcium ionophore-stimulated production of leukotriene (LT) C4 was enhanced by 16- to 26-h incubation with retinoic acid (RA) in rat basophilic leukemia-1 cells. Production of LTC4 by enzyme assay using cell lysates as the enzyme source and LTA4 as the substrate was also enhanced by RA-treatment. Production of LTB4 was not enhanced under these two experimental conditions, suggesting the preferential activation of LTC4 synthase activity. The RA-induced enhancement of LTC4 synthesis by the cells was suppressed by co-incubation with dexamethasone (DEX) or cyclosporine A (CSA). However, the expression of mRNA for LTC4 synthase was not affected by the exposure to RA, DEX or CSA. These results indicate that RA-induced enhancement of LTC4 production and its inhibition by DEX and CSA was determined by post-transcriptional regulation of LTC4 synthase.

Animals↗
PubMed1997

The Chinese herbal medicine, shinpi-to, inhibits IgE-mediated leukotriene synthesis in rat basophilic leukemia-2H3 cells.

We examined the action of Shinpi-To (Formula divinita; TJ-85), a granular extract of seven Chinese medicinal herbs that is used in treating childhood asthma, on the leukotriene synthesis in rat basophilic leukemia-2H3 cells (RBL-2H3 cells). IgE-loaded cells were stimulated with anti-IgE serum in the presence or absence of Shinpi-To. Released LTC4 and LTB4 were measured by radioimmunoassay (RIA). Shinpi-To significantly inhibited IgE-mediated synthesis of leukotriene (LT)C4 and LTB4. To identify the inhibitory sites, we investigated the action of this extract on four synthetic enzymes, phospholipase A2 (PLA2), 5-lipoxygenase (5-LO). LTC4 synthase, and LTA4 hydrolase. Shinpi-To inhibited the A23187-stimulated release of [3H]arachidonic acid (AA) from the cell membrane, reflecting an effect on PLA2 activity. It also suppressed production of LTC4 and LTB4 when cell lysates were incubated with AA as substrate. It did not inhibit the production of LTC4 and LTB4 when LTA4-free acid was used as the substrate. Shinpi-To did not inhibit the IgE-mediated increase of intracellular Ca2+ ([Ca2+]i) concentration. Results indicate that Shinpi-To inhibits LT synthesis by inhibiting PLA2 and 5-LO activities without affecting the mobilization of [Ca2+]i.

Analysis of Variance↗
PubMed1997

Unbalanced production of interleukin-5 and interleukin-2 in children with atopic dermatitis.

BACKGROUND: Cytokines, such as interleukin (IL)-5, produced by T helper type 2 Th2) cells appear to play an important role in the inflammatory processes associated with atopic dermatitis. The roles of cytokines produced by Th1 cells remain controversial. OBJECTIVE: We examined IL-5 and IL-2 mRNA abundance in and protein production by peripheral blood mononuclear cells (PBMCs) from patients with atopic dermatitis and compared those from controls. METHODS: Peripheral blood mononuclear cells were isolated from six children with atopic dermatitis and six control children, and stimulated with both phytohemaggulutinin (PHA) and phorbol 12-myristate 13-acetate (PMA). The abundance of IL-5 and IL-2 mRNA in PBMCs was measured by reverse transcription-polymerase chain reaction analysis. The production of IL-5 and IL-2 by PBMCs was also determined by enzyme-linked immunosorbent assay. RESULTS: After incubation with PHA and PMA, PBMCs from atopic children showed significantly higher IL-5 mRNA abundance (P < .05) and IL-5 production (P < .01), as well as a lower amount of IL-2 mRNA (P = .056) and IL-2 production (P < .05) than those from healthy controls. The time course of changes in IL-5 mRNA abundance induced by PHA and PMA in PBMCs from atopic children differed markedly from that observed with healthy controls, whereas the time course of changes in IL-2 mRNA abundance were similar between the two groups. CONCLUSIONS: The increased IL-5 and decreased IL-2 production observed with PBMCs from children with atopic dermatitis may underlie the activation of eosinophils and high serum immunoglobulin E concentrations also apparent in such individuals. An imbalance in the number and activity of Th1 and Th2 cells is likely to be responsible for the abnormal pattern of cytokine production in atopic dermatitis.

Adolescent↗
PubMed1997

High-performance liquid chromatographic assay of arachidonic acid metabolites from cultured rat glial cells.

Although various methods can be used for detection of arachidonic acid (AA) metabolites, only few of them allow rapid and precise analysis of both cyclooxygenase and lipoxygenase metabolites in a single assay. We have developed a simple and rapid method to evaluate overall profiles of AA metabolites produced by primary cultured glial cells from newborn rats by using reversed-phase, high-performance liquid chromatography (RP-HPLC) and on-line radioisotope detection.

Animals↗
PubMed1997

An 11-year-old girl with reflex sympathetic dystrophy successfully treated by thoracoscopic sympathectomy.

We report on an 11-year-old girl with reflex sympathetic dystrophy (RSD) complaining of severe pain in her right upper extremity. Oral administration of narcotics or non-steroid anti-inflammatory drugs gave no relief in pain. Thoracoscopic electrocauterization of the thoracic sympathetic ganglion at the level of T3 was performed 3 months after the start of symptoms, and brought complete resolution of pain.

Arm↗
PubMed1996

Inhibition by dexamethasone of the lipopolysaccharide-induced increase in IL-6 mRNA abundance and IL-6 production in human polymorphonuclear leukocytes.

Interleukin-6 (IL-6) is a key inflammatory cytokine that is produced by various cell types including polymorphonuclear leukocytes (PMNs). However, the pathophysiological roles of IL-6 produced by human PMNs are unclear. Bacterial lipopolysaccharide (LPS) induced marked increase in IL-6 production, determined by enzyme-linked immunosorbent assay, and IL-6 mRNA abundance determined by reverse transcription-polymerase chain reaction analysis, in purified human PMNs. Both effects of LPS were inhibited in a dose-dependent manner by dexamethasone (10(-6) to 10(-8) M). IL-6 receptor mRNA was constitutively present in PMNs and its abundance was not affected by either LPS or dexamethasone. These results indicate that PMNs are an important source of IL-6 in acute inflammatory reactions, and that the anti-inflammatory actions of dexamethasone is attributable in part to inhibition of IL-6 production by these cells. The constitutive presence of IL-6 receptor mRNA in PMNs suggests that IL-6 may exert pathophysiological effects on these cells.

Dexamethasone↗
PubMed1996

Leukotriene B4 and C4 in cerebrospinal fluid from children with meningitis and febrile seizures.

Concentrations of immunoreactive leukotriene C4 (LTC4) and leukotriene B4 (LTB4) in the cerebrospinal fluid from 18 patients with aseptic meningitis, including 2 patients with encephalitis and 4 patients with febrile seizures, were measured by a sensitive and specific radioimmunoassay; these results were compared with those from control subjects. The concentrations of both LTC4 and LTB4 were elevated significantly in patients with meningitis (LTC4: 115.6 +/- 47.7 pg/ml; LTB4: 1,603.0 +/- 273.5 pg/ml; n = 18) compared to controls (LTC4: 83.2 +/- 21.6 pg/ml; LTB4: 1,219.3 +/- 161.5 pg/ml; n = 12; P < .05 and P < .01, respectively). However, there was no significant increase in LT levels in patients with febrile seizures. These findings suggest that LTs may play an important role in the inflammatory response induced by viral infections of the central nervous system.

Child↗