Biomedical subjects

T Adachi

Publications and source records attributed to T Adachi.

At least 127 records · Page 7Linked to original sources

PubMed1999

Increase of urinary extracellular-superoxide dismutase level correlated with cyclic adenosine monophosphate.

Extracellular superoxide dismutase (EC-SOD) is a secretory protein that is the major SOD isozyme in extracellular fluids. Plasma EC-SOD levels are distributed in two discrete groups with the rare group having an enzyme with glycine instead of arginine-213, which causes a 10-fold higher serum level. Within the common phenotype group, the urinary EC-SOD level was significantly correlated with the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), but not with serum EC-SOD. EC-SOD appears not to be leaked from the plasma by glomerular filtration, but rather to be secreted from the renal tubule or its surrounding tissues. The urinary EC-SOD level was also significantly correlated with the urinary cyclic adenosine monophosphate (cAMP) level. cAMP analogues and adenylate cyclase modulators significantly stimulated the expression of EC-SOD but not other SOD isozymes in cultured fibroblast cell lines. Moreover, injection of parathyroid hormone, in Ellsworth-Howard tests, increased urinary EC-SOD accompanied with the elevations of urinary cAMP and NAG. Together these observations suggest that factor(s) that stimulate the adenylate cyclase-cAMP system regulate the urinary EC-SOD level.

1-Methyl-3-isobutylxanthine↗

PubMed1999

Signaling through the antigen receptor of B lymphocytes activates a p53-independent pathway of c-Myc-induced apoptosis.

Deregulated expression of c-Myc has been shown to induce or enhance apoptosis in various different cell types. c-Myc requires p53 for apoptosis in some but not all the cell types, indicating heterogeneous mechanisms for c-Myc-induced apoptosis. In B lymphoma line WEHI-231, stable expression of c-Myc has been demonstrated to protect cells from BCR-mediated apoptosis. However, stable expression of c-Myc carrying pro-apoptotic functions may generate variant cells resistant to apoptosis. By utilizing an inducible system for c-Myc, we demonstrated here that deregulated expression of c-Myc induced apoptosis of WEHI-231 by itself, indicating that c-Myc induces apoptosis in WEHI-231 as is the case for other cell types. When transactivation of p53 was inactivated, WEHI-231 cells overexpressing c-Myc no longer underwent apoptosis in the absence of other stimuli, but showed markedly enhanced apoptosis in the presence of BCR ligation. These results indicate that deregulated c-Myc expression enhances apoptosis by a p53-independent pathway in the presence of BCR signaling but requires p53 for apoptosis in the absence of BCR crosslinking in WEHI-231. BCR ligation may thus activate a p53-independent pathway of c-Myc-induced apoptosis.

Apoptosis↗

PubMed1999

A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation, survival, and airway eosinophilic inflammation.

Receptor antagonists block all receptor-coupled signaling pathways indiscriminately. We introduce a novel class of peptide inhibitors that is designed to block a specific signal from a receptor while keeping other signals intact. This concept was tested in the model of IL-5 signaling via Lyn kinase. We have previously mapped the Lyn-binding site of the IL-5/GM-CSF receptor common beta (beta c) subunit. In the present study, we designed a peptide inhibitor using the Lyn-binding sequence. The peptide was N-stearated to enable cellular internalization. The stearated peptide blocked the binding of Lyn to the beta c receptor and the activation of Lyn. The lipopeptide did not affect the activation of Janus kinase 2 or its association with beta c. The inhibitor blocked the Lyn-dependent functions of IL-5 in vitro (e.g., eosinophil differentiation from stem cells and eosinophil survival). It did not affect eosinophil degranulation. When applied in vivo, the Lyn-binding peptide significantly inhibited airway eosinophil influx in a mouse model of asthma. The lipopeptide had no effect on basophil histamine release or on the proliferation of B cells and T cells. To our knowledge, this is the first report on an inhibitor of IL-5 that blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. This novel strategy to develop peptide inhibitors can be applied to other receptors.

Amino Acid Sequence↗

PubMed1999

Comparative study of antiplatelet drugs in vitro: distinct effects of cAMP-elevating drugs and GPIIb/IIIa antagonists on thrombin-induced platelet responses.

Among various categories of antiplatelet drugs, cAMP-elevating agents and GP IIb/IIIa antagonists have been reported to inhibit platelet aggregation stimulated by a wide variety of platelet agonists. To clarify the qualitative difference between these two agents, their effects on various platelet responses in washed platelets evoked by thrombin (0.05 U/mL) were compared in vitro. Two types of cAMP-elevating drugs, cilostazol (a phosphodiesterase III inhibitor) and prostaglandin E1 (an adenylate cyclase activator), both inhibited platelet aggregation, thromboxane A2 formation, and platelet factor 4 release in a concentration-dependent manner. In addition, both agents suppressed intracellular Ca++ elevation induced by thrombin. However, two classes of GP IIb/IIIa antagonists, abciximab (Fab fragment of antibody) and tirofiban (a synthetic compound), showed no inhibitory effects against thromboxane A2 formation and platelet factor 4 release, although these drugs inhibited platelet aggregation. Essentially the same results were obtained in platelet-rich plasma stimulated with high concentration (100 microM) of thrombin receptor activating peptide. In contrast to these different profiles on thromboxane A2 formation and release reaction, both cAMP-elevating agents and GP IIb/IIIa antagonists potently suppressed procoagulant activity in thrombin-stimulated platelets. These results suggest that the development of platelet procoagulant activity induced by thrombin is exclusively dependent on platelet aggregation or aggregation-dependent processes. These observations also indicate that cAMP-elevating agents possess wider inhibitory effects on platelet responses evoked by strong agonists than GP IIb/IIIa antagonists.

Abciximab↗

PubMed1999

Neutral glycolipid and ganglioside composition of type-1 and type-2 astrocytes from rat cerebral hemisphere.

We reported previously that the major gangliosides in primary mixed-type astrocyte cultures are GM3 and GD3. To obtain more information regarding the exact distribution of glycosphingolipids in different types of astrocytes, we established a line of type-1 astrocytes that are characterized by a Ran-2 positive, broad flat morphology, and by the absence of binding to A2B5 antibodies. We also purified O-2A progenitor cells by immunopanning and cultured them in the presence of 10% newborn calf serum. They differentiated into type-2 astrocytes that were identified by immunostaining for each of GD3, A2B5, and GFAP. Using these cell cultures, we demonstrate that the major gangliosides were GM3 in type-1 astrocytes and GM3 and GD3 in type-2 astrocytes. In addition, a set of neutral glycolipids was identified based on the HP-TLC migration properties of CMH, CDH, CTH, and Glob, but the component distribution of these glycolipids is related to that of glycolipids of astrocytes. A marked increase in the expression of CTH and Glob was shown in type-2 astrocytes. The amount of neutral glycolipid-sugar was higher in the type-2 astrocytes than in the type-1 astrocytes. These results suggest that the increase in the total glycosphingolipid content and the change in the neutral glycolipid composition produced by type-2 astrocytes may be related to their biological functions and the cellular compositions.

Animals↗

PubMed1999

The mapping of the Lyn kinase binding site of the common beta subunit of IL-3/granulocyte-macrophage colony-stimulating factor/IL-5 receptor.

It has been shown that a membrane-proximal region within common beta (betac) receptor of IL-3/granulocyte-macrophage CSF/IL-5 (amino acids 450-517) is important for Lyn binding. We have shown previously that Lyn kinase is physically associated with the IL-5R betac subunit in unstimulated cells. The result suggests that this association involves binding modules that are not activation or phosphorylation dependent. The objective of this study was to map the exact Lyn binding site on betac. Using overlapping and/or sequential peptides derived from betac 450-517, we narrowed down the Lyn binding site to nine amino acid residues, betac 457-465. The P-->A mutation in this region abrogated the binding to Lyn, indicating a critical role of proline residues. We created a cell-permeable Lyn-binding peptide by N-stearation. This cell-permeable peptide blocked the association of Lyn, but not Jak2 with betac in situ. We also investigated the betac binding site of Lyn kinase. Our results suggest that the N-terminal unique domain of Lyn kinase is important for binding to betac receptor. To our knowledge, this is the first molecular identification of the Lyn binding site of betac receptor. This finding may help develop specific inhibitors of Lyn-coupled signaling pathways.

Amino Acid Sequence↗

PubMed1999

The MH1 domains of smad2 and smad3 are involved in the regulation of the ALK7 signals.

The biological responses of the transforming growth factor beta (TGF-beta) superfamily are induced by activation of a receptor complex and Smad proteins. We surveyed the TGF-beta superfamily receptors using the degenerate PCR strategy, and found activin receptor-like kinase 7 (ALK7) to be abundantly expressed in fetal rat pancreatic islets. ALK7 is also expressed in adult rat islets and pancreatic beta-cell-derived MIN6 cells. The constitutively active form of ALK7, ALK7(T194D), activated Smad3 and a chimeric Smad protein, Smad3-2, containing the MH1 domain of Smad3 and the MH2 domain of Smad2, and translocated them to nuclei and then induced activation of the human PAI-1 promoter. However, neither Smad2 nor Smad2-3 protein, containing the MH1 domain of Smad2 and the MH2 domain of Smad3 were activated. These results indicate that the ALK7 signal regulates nuclear localization and activation of Smad2 and Smad3, and the MH1 domain of Smad2 has inhibitory effects on the nuclear localization.

Activin Receptors↗

PubMed1999

Enhancement of glucuronosyl etoposide transport by glutathione in multidrug resistance-associated protein-overexpressing cells.

Multidrug resistance-associated protein (MRP) has been shown to transport glutathione (GSH) S-conjugates such as leukotriene C4 (LTC4) and S-(2,4-dinitrophenyl)-glutathione (DNP-SG). On the other hand, it has while it has been reported that MRP-overexpressing cells exhibit decreased sensitivity to drugs which do not form GSH S-conjugates. In this study, we found that GSH affects the transport of glucuronosyl etoposide as a major metabolite of etoposide in MRP-overexpressing KB/VP-4 cells. The relative resistance level of KB/VP-4 cells to etoposide was 70-fold that of wild-type KB cells. Membrane vesicles prepared from KB/VP-4 cells exhibited markedly enhanced ATP-dependent transport of glucuronosyl etoposide as well as LTC4. Transport of glucuronosyl etoposide was augmented in the presence of GSH. Treatment of KB/VP-4 cells with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, resulted in about 75% depletion of cellular GSH levels, a four-fold increase of the sensitivity to etoposide and depression of glucuronosyl etoposide efflux. These results suggest that GSH plays a role in the enhancement of MRP-mediated glucuronosyl etoposide transport.

ATP-Binding Cassette Transporters↗

PubMed1999

Disordered expression of the sucrase-isomaltase complex in the small intestine in Otsuka Long-Evans tokushima fatty rats, a model of non-insulin-dependent diabetes mellitus with insulin resistance.

To clarify the relationship between diabetes mellitus and carbohydrate digestion, the activities of sucrase and isomaltase, which form a complex enzyme (SI complex) on the brush border membranes, were compared in the progression of diabetes mellitus in Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus with insulin resistance, and Long-Evans Tokushima Otsuka (LETO) rats as non-diabetic controls. Until 40 weeks of age, OLETF rats were obese and had a high plasma glucose level, compared to age-matched LETO rats, but the sucrase and isomaltase activities showed no significant differences between the two strains. Oral glucose tolerance test revealed that during 40-48 weeks of age, NIDDM became very severe with advancing insulin resistance in OLETF rats. In OLETF rats, in contrast to LETO rats, at 48 weeks of age, abnormal increases in the sucrase and isomaltase activities occurred, along with a remarkable decrease in body weight and a further great increase in the plasma glucose level in the non-fasting state. Hyperinsulinemia occurred in 20-week-old OLETF rats; however, at 40 and 48 weeks of age, the plasma insulin level in the non-fasting state in OLETF rats was not significantly different from that in LETO rats. The level of mRNA encoding the SI complex increased abnormally in 48-week-old OLETF rats. These results suggest that the advance of insulin resistance leads to an increase in the expression of the SI complex on the transcriptional level.

Age Factors↗

PubMed1999

Solitary fibrous benign mesothelioma of the peritoneum: report of a case.

A 66-year-old Japanese man who had undergone a subtotal gastrectomy for gastric cancer 1 year earlier, and was asymptomatic, underwent a computed tomography scan during a detailed follow-up examination, which revealed a pancreatic mass. Abdominal ultrasonography showed a solid tumor containing a cystic lesion, and abdominal magnetic resonance demonstrated a tumor with low intensity on T1-weighted images and high intensity on T2-weighted images. Although an abdominal angiography added no new information to help in establishing a preoperative diagnosis, it showed an avascular mass. An endoscopic retrograde pancreatograhy showed compression and deviation of the body part of the pancreatic duct, and dilatation of its caudal part. At laparotomy, an elastic soft tumor was found to originate from the peritoneum of the omental bursa in front of the pancreas. The tumor was encapsulated and solid. The solid lesion consisted of spindle-shaped cells, but no atypical cells were observed. The histological findings were diagnostic of a benign solitary fibrous mesothelioma, which is extremely rare. The patient is currently well and disease-free more than 5 years after this operation.

Aged↗

PubMed1999

Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Australian hospital-based population.

Modest elevations of circulating homocysteine are common in patients with vascular disease. We explored interrelations between total plasma homocysteine levels and mutations in genes for three key enzymes in methionine-homocysteine metabolism. Methyltetrahydrofolate reductase (MTHFR) 677C-->T, cystathionine beta synthase (CBS) 68-bp insertion at exon 8, and methionine synthase (MS) 2756A-->G were typed in 685 Australian caucasian patients aged < or =65 years with and without angiographically documented coronary artery disease (CAD). We also assessed associations between homocysteine levels and extracellular superoxide dismutase (EC-SOD) and other CAD risk factors. There were significant correlations between plasma total homocysteine, and EC-SOD (r = 0.170, p = 0.001 for men; r = 0.241, p = 0.003 for women) and LDL (r = 0.153, p = 0.001 for men; r = 0.132, p = 0.081 for women). Levels were also significantly higher among patients with unstable angina (15.30+/-0.44 micromol/l for men, 14.44+/-0.74 micromol/l for women) than those without angina (13.98+/-0.38 micromol/l for men, 13.41+/-0.98 micromol/l for women) or with stable angina (14.00+/-0.37 micromol/l for men, 12.88+/-0.71 micromol/l for women). There were no significant associations between the levels and the presence or severity of CAD. The mutant MTHFR homozygotes tended to have higher levels and those with the MS and CBS mutations tended to have lower levels. We conclude that there is a significant correlation between plasma homocysteine levels and EC-SOD suggesting that elevated homocysteine may exert oxidative stress and that levels are associated with unstable angina, but not the occurrence or extent of coronary stenosis. The contributions to total plasma homocysteine levels of the common mutations of genes coding for the enzymes controlling homocysteine metabolism are modest.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1999

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Journal Article↗

PubMed1999

Plasma ACTH levels during early, two-way avoidance acquisition in high- and low-avoidance rats (Hatano strains).

Having successfully bred for high- and low-avoidance rats (HAA and LAA, respectively) on a shuttlebox task, we performed three experiments designed to identify factors which might be related to the phenotypic differences seen in avoidance behavior. In experiment 1, shuttlebox behavior was measured to determine whether the phenotypic difference was activity related. In terms of intertrial responses, there was no difference between HAA and LAA rats in locomotor activity during the conditioning process. Experiment 2 compared adrenal weights of HAA and LAA rats at 11 weeks of age. The observation that the adrenal glands were heavier in HAA than in LAA rats suggested that these strains might differ in aspects of endocrine response. In experiment 3, plasma levels of ACTH and corticosterone were determined during early escape/avoidance acquisition in the shuttlebox. Plasma levels of ACTH after the shuttlebox testing were higher in HAA than in LAA rats. There was no difference between the two strains in plasma levels of corticosterone after testing, possibly due to a ceiling effect. These results suggest that the phenotypic differences in the acquisition of avoidance behavior of HAA and LAA rats may be related to different endocrine responses, rather than to locomotor activity.

Adrenal Glands↗

PubMed1999

Dietary heme iron does not prevent postgastrectomy anemia but fructooligosaccharides improve bioavailability of heme iron in rats.

Gastrectomized rats exhibit iron deficiency anemia. We observed the effects of dietary heme-iron and short chain frucooligosaccharides (Sc-FOS) in relation to prevention of postgastrectomy anemia in rats. Twelve laparotomized (sham-operated) rats were fed iron-citrate (control) as iron source diet without or with Sc-FOS (75 g/kg of diet) and twenty four totally gastrectomized (Bilroth II) rats, were fed a iron-citrate (control) or heme-iron (heme) as iron source diet without or with Sc-FOS (75 g/kg of diet) for 4 weeks. All rats received an intramuscular injection of vitamin B-12 every two weeks. Tail blood was collected every other week for determination of hematocrit and hemoglobin concentration. At the end of the experiment, the rats were killed and whole blood was collected. The total gastrectomy induced the postgastrectomy anemia. Dietary Sc-FOS increase iron absorption and thereby prevented completely this anemia in gastrectomized rats fed the control diet but this effect of Sc-FOS in rats fed heme diet was not complete. Dietary heme iron could not prevent postgastrectomy anemia itself, but fructooligosaccharides improve bioavailability of not only non-heme iron such as iron-citrate, but also heme-iron in rats.

Anemia↗

PubMed1999

Nisoldipine improves the impaired erythrocyte deformability correlating with elevated intracellular free calcium-ion concentration and poor glycaemic control in NIDDM.

AIMS: To explore the mechanisms underlying the impaired erythrocyte deformability (RBC-df) in diabetic patients, the relationship between erythrocyte intracellular free calcium-ion concentration ([Ca2+]i) and RBC-df, and the effects of Ca2+-channel blocker on [Ca2+]i and RBC-df were evaluated. METHODS: Forty-eight patients with NIDDM and 24 control subjects were enrolled in this study. [Ca2+]i was determined using fura-2, and RBC-df by filtration method expressed as Deformability Index (DI). Erythrocytes were treated with nisoldipine to evaluate the effects of a Ca2+-channel blocker. RESULTS: [Ca2+]i was significantly higher (82.6 (78.0-87.2) vs 76.6 (74.3-81.2) nmol lRBC-1, P<0.001), and DI was significantly lower (0. 14 (0.09-0.28) vs 0.22 (0.16-0.28), P<0.01) in NIDDM than in controls. There was a significant correlation between HbA1c and [Ca2+]i (r=0.38, P<0.01), between HbA1c and DI (r=-0.51, P<0.01), and between [Ca2+]i and DI (r=-0.42, P<0.01). Stepwise multiple regression analysis revealed HbA1c and [Ca2+]i as independent determinants for the impaired RBC-df. Nisoldipine treatment in vitro significantly decreased [Ca2+]i, and significantly improved RBC-df. CONCLUSIONS: These data indicate that the impaired RBC-df in NIDDM may at least partly be attributed to the elevated [Ca2+]i and poor glycaemic control. In addition, favorable effects of a Ca2+-channel blocker on both [Ca2+]i and RBC-df have been demonstrated.

Adult↗

PubMed1999

A 42-kDa glycoprotein from chicken egg-envelope, an avian homolog of the ZPC family glycoproteins in mammalian Zona pellucida. Its first identification, cDNA cloning and granulosa cell-specific expression.

A glycoprotein with molecular mass of 42 kDa was identified as the major component of the chicken egg-envelope, the filamentous, extracellular matrix known as the perivitelline layer. By using a DNA probe amplified with degenerative primers derived from the protein's partial amino acid sequences, a cDNA clone encoding the egg-envelope 42-kDa glycoprotein (gp42) was isolated from a hen's ovary cDNA library. The gp42 open reading frame encoded 435 amino acid residues, including a putative signal peptide of 20 amino acids. The deduced amino acid sequence of gp42 showed significant similarity to egg-envelope glycoproteins of the ZPC family of several other vertebrate species, including human ZP3, mouse ZP3, Xenopus laevis gp43 and medaka (Oryzias latipes) ZI3 (LS-F), which play important roles for sperm-egg interaction. A single N-glycosylation site present in chicken gp42 is conserved among all five of these proteins: carbohydrate analysis of gp42 revealed the presence of a complex type glycan chain at this site. N-terminal sequence analysis of the mature polypeptide suggests that C-terminal processing of the pro-protein occurs during synthesis and secretion. The 1.4-kb gp42 transcript was detected only in follicles, and was found to be accumulated in granulosa cells in a manner dependent on ovarian follicular development. Furthermore, a metabolically radio-labeled gp42 was immunopreciptated from both cell lysate and culture supernatant of the granulosa cells with specific anti-gp42 antibody, suggesting granulosa cell-specific synthesis and secretion of the glycoprotein.

Amino Acid Sequence↗

PubMed1999

Involvement of fibrinolytic factors in mid trimester amniotic fluid with development of severe early-onset preeclampsia.

Impaired placental development is a well-known pathogenesis in preeclampsia. The present study was undertaken to elucidate the involvement of fibrinolytic factors in amniotic fluid in midtrimester with development of severe early-onset preeclampsia. Amniotic fluid was obtained by amniocentesis at 15 to 18 weeks of gestation. All specimens were retrospectively identified according to the hospital records as coming from gestations that later had severe early-onset preeclampsia (severe preeclamptic group, n = 9) or gestations with normal outcomes (control group, n = 73). Fibrinolytic factors such as tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and t-PA-PAI-1 complex (PAI-C) of specimens were measured by enzyme-linked immunoassay. In the control group, concentrations of t-PA as well as PAI-1 in amniotic fluid remained at similar levels from 15 to 18 weeks, although PAI-1 levels were more than 10 times higher compared with t-PA levels. Levels of t-PA and PAI-1 in the severe preeclamptic group were not different from those of the control group. PAI-C levels gradually decreased from 15 through 18 weeks of gestation in the control group. PAI-C levels of the severe preeclamptic group were significantly lower than those of the control group (55.5 +/- 18.0% versus control; mean +/- standard deviation [SD], p <0.001). PAI-C, as the most specific indicator of the early stage of fibrinolytic activities, showed lower levels in midtrimester amniotic fluid in the severe preeclamptic group, suggesting fibrinolytic activities of amniotic fluid may have a significant role in the development of severe early-onset preeclampsia via impaired placental development in the latent stage of preeclampsia.

Adult↗

PubMed1999

Association of hypercytokinemia in the development of severe preeclampsia in a case of hemophagocytic syndrome.

Hemophagocytic syndrome (HPS) is a syndrome presenting with signs of persistent remittent fever, hepatosplenomegaly, pancytopenia, hepatic dysfunction, and disseminated intravascular coagulation (DIC) due to hypercytokinemia caused by activated T lymphocytes and macrophages. The mortality in adults is high and a small number of complicated cases during pregnancy have been reported. We report one HPS case that developed a remittent fever, leukocytopenia, and thrombocytopenia in the 2st week of pregnancy, and abnormal blood coagulation, hepatic dysfunction, and hypercytokinemia were found. Antibiotics and immunoglobulin were given but failed to improve clinical and laboratory findings. At the 24th week, the patient was diagnosed with DIC, and antithrombin (AT) concentrate was given. With the increase in plasma levels of AT, improvements were seen in both clinical signs and laboratory findings. Bone marrow biopsies were carried out, and a diagnosis of HPS was made. Preeclampsia developed in the 27th week and it became severe. Cesarean section was performed in the 29th week because of severe preeclampsia, intrauterine growth retardation (IUGR), and fetal distress. The courses of mother and newborn were uneventful. We discuss the mechanism of AT in the treatment of this syndrome and the association between this syndrome and severe preeclampsia. In conclusion, AT concentrate was very effective in suppressing cytokine production, and the possibility that severe preeclampsia developed because of hypercytokinemia, which may be one of the pathogeneses of severe preeclampsia and IUGR, was suggested.

Adult↗