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Biomedical subjects

Haruo Shintaku

Publications and source records attributed to Haruo Shintaku.

12 recordsLinked to original sources
PubMed2006

Neutrophil-activating activity and platelet-activating factor synthesis in cytokine-stimulated endothelial cells: reduced activity in growth-arrested cells.

The reactivity of endothelial cells (ECs) to proinflammatory cytokines is critically important for the pathogenesis of vascular diseases. Here, we studied functional alterations of human ECs during culture under a confluent condition; i.e., the alterations of neutrophil-activating activity, platelet-activating factor (PAF) synthesis, and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in cytokine-stimulated ECs. Human umbilical vein-derived ECs exhibited the increased activity in neutrophil activation, PAF synthesis, and GM-CSF production when stimulated by proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha). The activity of cytokine-stimulated ECs to stimulate superoxide release in human neutrophils and to produce PAF declined markedly in parallel as ECs became growth-arrested during culture under a confluent condition. By contrast, GM-CSF production induced by cytokine stimulation was modestly increased, and up-regulation of intercellular adhesion molecule-1 (ICAM-1) and activation of mitogen-activated protein kinases were not altered. The neutrophil-activating activity of cytokine-stimulated ECs was dependent on PAF synthesis and GM-CSF production from ECs. These findings indicate that the reduced neutrophil-activating activity in growth-arrested ECs may be, at least in part, ascribed to down-regulation of PAF synthesis.

Antibodies↗
PubMed2005

Plasma biopterin levels and tetrahydrobiopterin responsiveness.

Tetrahydrobiopterin (BH4) responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) gene was found during neonatal screening for PKU. This study determined blood BH4 and phenylalanine in two patients with hyperphenylalaninemia following oral load with BH4 10 mg/kg. Our patients underwent neonatal screening for PKU, had normal biopterin metabolism and their PAH mutations were determined. Peak plasma biopterin levels in Case 1, which were reached at between 2 and 4h after loading, were 612, 297, and 178 nmol/L at age 30 days, 55 days, and 19 months, respectively, and the maximum phenylalanine decreasing rates, which were found at 24h, were 54, 16, and 4%, respectively. In Case 2, peak plasma biopterin levels were 747 and 327 nmol/L at age 20 and 55 days, respectively, and the maximum phenylalanine decreasing rates were 39 and 32%, respectively. In the BH4 loading test, the peaks of BH4 in both patients lowered ( approximately 50%), on the same dose schedule of BH4, as patients got older.

Biopterins↗
PubMed2004

Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA Transferase (SCOT) do not show permanent ketosis.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT; locus symbol OXCT; E.C. 2.8.3.5) is the main determinant of the ketolytic capacity of tissues. Hereditary SCOT deficiency causes episodic ketoacidosis. Permanent ketosis has been regarded as a pathognomonic feature of SCOT deficiency. There are three SCOT-deficient patients from a small region in Japan and they have not manifested permanent ketosis, even though their ketoacidotic crises were as severe as those of other SCOT-deficient patients. All three were homozygous for the T435N mutation. Transient expression analysis of wild-type and mutant cDNA showed that the T435N mutant retained significant residual SCOT activities (20% for that of the wild-type at 39.5 degrees C, 25% at 37 degrees C, and 50% at 30 degrees C). The difference of residual SCOT activities at these temperatures in expression analyses was due to differences in the level of the mutant protein. SCOT activity of the T435N protein was more vulnerable than the wild-type to heat treatment at 42 degrees C and 55 degrees C. These temperature-sensitive characteristics of the mutant protein may explain, in part, why the patients developed ketoacidotic crises during febrile illness. In SCOT-deficient patients retaining some residual activity, permanent ketosis may be absent.

Child↗
PubMed2004

Activity of synthetic enzymes of tetrahydrobiopterin in the human placenta.

Tetrahydrobiopterin (BH4) is an essential co-factor for nitric oxide (NO) synthase (NOS) and regulates the production of NO, or endothelium-derived relaxation factor. Although NOS is highly expressed in the placenta and NO plays a critical role in the regulation of feto-placental circulation, the mechanism maintaining the level of BH4 is not known. To investigate the de novo synthesis of BH4 in the human placenta, the activity of guanosine triphosphate cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) in the chorionic tissue during the first, second and third trimester of pregnancy was analyzed. GTPCH activity was the lowest of the three enzymes and became negligible after the second trimester. There was no significant change in PTPS activity throughout pregnancy. Although SR activity decreased significantly after the second trimester, the levels remained abundant throughout pregnancy. These results showed that GTPCH is a rate-limiting enzyme and the total activity of the de novo synthesis of BH4 is negligible in the mature placenta after the second trimester when fetal growth is accelerated. The present study suggests that the level of BH4 in the placenta depends principally on the system other than de novo synthesis. The salvage pathway is considered the most potent system, which is formed by the transfer of the substrates from the fetus and their enzymatic conversion to BH4 in the placenta.

Alcohol Oxidoreductases↗
PubMed2004

[Phenylketone].

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Humans↗
PubMed2004

[Citric acid].

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Adolescent↗
PubMed2003

Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene.

A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. A total of 12 patients who met the criteria for tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) (EC 1.14.16.1) gene were recruited at 12 medical centers in Japan between June 1995 and July 2001. Therapeutic efficacy of BH(4) was evaluated in single-dose, four-dose, and 1-wk BH(4) loading tests followed by long-term BH(4) treatment, and also examined in relation to the PAH gene mutations. The endpoints were determined as the percentage decline in serum phenylalanine from initial values after single-dose (>20%), four-dose (>30%), and 1-wk BH(4) (>50%) loading tests. Patients with mild PKU exhibiting decreases in blood phenylalanine concentrations of >20% in the single-dose test also demonstrated decreases of >30% in the four-dose test. The 1-wk test elicited BH(4) responsiveness even in patients with poor responses in the shorter tests. Patients with mild HPA, many of whom carry the R241C allele, responded to BH(4) administration. No clear correlation was noted between the degree of decrease in serum phenylalanine concentrations in the single- or four-dose tests and specific PAH mutations. The 1-wk test (20 mg/kg of BH(4) per day) is the most sensitive test for the diagnosis of BH(4)-responsive PAH deficiency. Responsiveness apparently depends on mutations in the PAH gene causing mild PKU, such as R241C. BH(4) proved to be an effective therapy that may be able to replace or liberalize the phenylalanine-restricted diets for a considerable number of patients with mild PKU.

Biopterins↗
PubMed2003

Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members.

Tetrahydrobiopterin (BH(4)) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthesis includes two reduction steps catalyzed by sepiapterin reductase. An intermediate, 6-pyruvoyltetrahydropterin (PPH(4)) is reduced to 1(')-oxo-2(')-hydroxypropyl-tetrahydropterin (1(')-OXPH(4)) or 1(')-hydroxy-2(')-oxopropyl-tetrahydropterin (2(')-OXPH(4)), which is further converted to BH(4). However, patients with sepiapterin reductase deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting that other enzymes catalyze the two reduction steps. In this study, the reductase activities for the tetrahydropterin intermediates were examined using several human recombinant enzymes belonging to the aldo-keto reductase (AKR) family and short-chain dehydrogenase/reductase (SDR) family. In the reduction of PPH(4) by AKR family enzymes, 2(')-OXPH(4) was formed by 3 alpha-hydroxysteroid dehydrogenase type 2, whereas 1(')-OXPH(4) was produced by aldose reductase, aldehyde reductase, and 20 alpha-hydroxysteroid dehydrogenase, and both 1(')-OXPH(4) and 2(')-OXPH(4) were detected as the major and minor products by 3 alpha-hydroxysteroid dehydrogenases (types 1 and 3). The activities of aldose reductase and 3 alpha-hydroxysteroid dehydrogenase type 2 (106 and 35 nmol/mg/min, respectively) were higher than those of the other enzymes (0.2-4.0 nmol/mg/min). Among the SDR family enzymes, monomeric carbonyl reductase exhibited low 1(')-OXPH(4)-forming activity of 5.0 nmol/mg/min, but L-xylulose reductase and peroxisomal tetrameric carbonyl reductase did not form any reduced product from PPH(4). Aldose reductase reduced 2(')-OXPH(4) to BH(4), but the other enzymes were inactive towards both 2(')-OXPH(4) and 1(')-OXPH(4). These results indicate that the tetrahydropterin intermediates are natural substrates of the human AKR family enzymes and suggest a novel alternative pathway from PPH(4) to BH(4), in which 3 alpha-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert.

Alcohol Oxidoreductases↗
PubMed2002

A study of bone mineral density and physical growth in very low birth-weight infants after their discharge from hospital.

The lumbar spinal bone mineral density (BMD) of very low birth-weight (VLBW) infants was determined by dual-energy X-ray absorptiometry, and its relationship with physical growth was analyzed. The influence of birth-related factors on changes in BMD after discharge from the hospital were also investigated. The BMD increased rapidly until the age of 2 years, in association with improvements in nutritional status and the increase in physical growth after discharge. The Z score, which indicates the degree of attainment of the age-specific standard BMD, was determined to be almost 90% at the age of around 2 years and older. Significant increases in the BMD continued to be noted after the age of 2 years, along with increases in body weight and body height. At the age-adjusted value at less than 1 year, however, the Z score tended to be low when the birth weight (<1000 g) and birth height (<36 cm) were low (P < 0.02, respectively), suggesting that the birth weight and birth height influence the BMD at this age. These results indicate that the condition at birth and nutritional management during hospitalization affect the BMD soon after discharge, but that the nutritional condition after discharge becomes a more important factor at the age of 2 years and older.

Bone Density↗
PubMed2002

Trophic effect of multiple growth factors in amniotic fluid or human milk on cultured human fetal small intestinal cells.

OBJECTIVES: To evaluate the role of growth factors in amniotic fluid and in human milk on gastrointestinal adaptation of the fetus and very low-birth-weight infants, the effects of these fluids and multiple growth factors were investigated in a human fetal small intestinal cell line (FHs 74 Int). METHODS: After FHs 74 Int cells were incubated with amniotic fluid, human milk, or recombinant growth factors, growth-promoting activity was measured by [3H]-thymidine incorporation into cells. RESULTS: Incubating cells with amniotic fluid or human milk promoted growth dose dependently. Genistein almost completely inhibited growth-promoting activity in amniotic fluid P = 0.002), and growth was partially inhibited by antibodies against epidermal growth factor (EGF) (P = 0.047), insulin-like growth factor-1 (IGF-1, P = 0.047), or fibroblast growth factor (FGF, P = 0.014). This activity in human milk was inhibited almost completely by genistein (P < 0.0001) and partially inhibited by antibodies against EGF (P = 0.036), IGF-1 (P = 0.009), FGF (P = 0.004), hepatocyte growth factor (HGF, P = 0.001), or transforming growth factor-alpha (TGF-alpha, P = 0.001). Although recombinant EGF, IGF-1, FGF, HGF, and TGF-alpha elicited a synergistic trophic response on cultured cells, the response was much less than with amniotic fluid or with human milk. CONCLUSION: In aminiotic fluid and in human milk, EGF, IGF-1, FGF, HGF, and TGF-alpha have a strong trophic effect on immature intestinal cells and may be involved in perinatal gastrointestinal adaptation.

Amniotic Fluid↗
PubMed2002

Decreased plasma tetrahydrobiopterin in pregnant women is caused by impaired 6-pyruvoyl tetrahydropterin synthase activity.

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase as well as a cofactor of aromatic amino acid hydroxylases. However, its role in pregnancy is not yet understood. We evaluated the concentrations of BH4 throughout normal pregnancy and puerperium, and compared them with those of non-pregnant women by measuring its oxidation product biopterin. In addition, we also measured 6-pyruvoyl tetrahydropterin synthase (PTPS) activities, the rate-limiting enzyme in synthesizing BH4, in pregnant women at the 30th gestational week and non-pregnant women. Although the urinary biopterin levels did not remarkably change, plasma biopterin levels significantly decreased from the 10th gestational week to the 1st day of postpartum compared with those of non-pregnant women. There was no significant difference in PTPS activities between pregnant and non-pregnant women. However, the proportion of reticulocytes, which have been shown to possess high PTPS activity, is significantly higher in pregnant women than in non-pregnant women. Our results suggest that decreased plasma BH4 levels in pregnancy is caused by impaired PTPS activity.

Biopterins↗