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Biomedical subjects

S Itoh

Publications and source records attributed to S Itoh.

At least 109 records · Page 6Linked to original sources
PubMed2000

Hydrogen atom abstraction by Cu(II)- and Zn(II)-phenoxyl radical complexes, models for the active form of galactose oxidase.

The Cu(II) and Zn(II) complexes of phenoxyl radical species [M(II)(L1*)(NO3)]+ (M=Cu or Zn, L1H: 2-methylthio-4-tert-butyl-6-[[bis[2-(2-pyridyl)ethyl]amino]methyl]phenol ) and [M(II)(L2*)(NO3)]+ (M=Cu or Zn, L2H: 2,4-di-tert-butyl-6-[[bis[2-(2-pyridyl)ethyl]amino]methyl]phenol) are prepared as model complexes of the active form of galactose oxidase (GAO). Hydrogen atom abstraction of 1,4-cyclohexadiene and tert-butyl substituted phenols by the GAO model complexes proceeds very efficiently to give benzene and the corresponding phenoxyl radical or its C-C coupling dimer as the oxidation products, respectively. Kinetic analyses on the oxidation reactions have shown that the hydrogen atom abstraction of the phenol substrates is significantly enhanced by the coordinative interaction of the OH group to the metal ion center of the complex, providing valuable insight into the enzymatic mechanism of the alcohol oxidation. Details of the substrate-activation process have been discussed based on the activation parameters (deltaH* and deltaS*) of the reactions.

Copper↗
PubMed2000

Aliphatic Hydroxylation by a Bis(µ-oxo)dicopper(III) Complex.

By using molecular oxygen bis(µ-oxo)dicopper(III) complexes can be produced from Cu(I) complexes with ligand L(X) (L(X)=p-substituted N-ethyl-N-[2-(2-pyridyl)ethyl]-2-phenylethylamine; X=OMe, Me, H, Cl, NO(2)) in which the benzylic position of the ligand is activated and hydroxylated by the Cu(2)O(2) core (see reaction scheme). Detailed characterization of this new C-H bond activation reaction by the bis(µ-oxo)dicopper(III) core reveals important information on the fundamental chemistry underlying copper monooxygenase reactivity.

Journal Article↗
PubMed2000

Nasal absorption of ondansetron in rats: an alternative route of drug delivery.

PURPOSE: Ondansetron (OND) is a 5-HT3 receptor antagonist that is used therapeutically for the prevention of nausea and vomiting associated with emetogenic cancer therapy. There is a need for nasal drug delivery in specific patient populations where the use of commercially available intravenous and oral dosage forms may be inconvenient and/or unfeasible. METHODS: OND (Zofran Injection, 2 mg/ml) was administered at a dose of 1 mg/kg to male Sprague-Dawley rats intravenously or intranasally (n = 3 in each group). A special surgical procedure was performed to ensure that the drug solution was held in the nasal cavity. OND was injected into the femoral vein for the intravenous group. Blood samples were collected at appropriate times for 60 min. An HPLC method was employed to determine OND in the plasma. RESULTS: The results clearly showed that OND was readily and rapidly absorbed through the nasal mucosa of the rat. The peak plasma level was attained within 10 min. OND was also completely absorbed as the plasma concentration-time profiles for the two routes were comparable. The terminal elimination half-lives were also similar. CONCLUSIONS: The nasal administration route for OND is apparently as effective as the intravenous route. If one considers the limitations of delivering OND orally or intravenously to patients undergoing emetogenic cancer therapy, it becomes obvious that the intranasal route is a potential alternative modality to prevent nausea and vomiting associated with such therapy.

Absorption↗
PubMed2000

Peripheral resistance vessel dysfunction in Marfan syndrome.

BACKGROUND: Patients with Marfan syndrome show a hereditary abnormality of elastin metabolism that may cause aortic enlargement and dissection. We have hypothesized that abnormal elastin may alter peripheral vascular structure and function. METHODS: Forearm blood flow (FBF) (in milliliters per minute per 100 mL) response to the endothelium-dependent dilator acetylcholine (0.75 to 4.5 microg/min per 100 mL), the endothelium-independent dilator sodium nitroprusside (0.05 to 0.3 microg/min per 100 mL), and structure-related maximum dilator response (10-minute occlusion-induced reactive hyperemia) were measured by plethysmograph in 10 patients with Marfan syndrome (mean age 44 years) and 10 healthy age- and sex-matched controls. Patients with the complications of hypercholesterolemia, diabetes mellitus, or heart failure were excluded from the study. RESULTS: Basal FBF (mean +/- SE) did not differ between the 2 groups (2.7 +/- 0.3 vs 2.3 +/- 0.4). Maximum FBF response to acetylcholine in patients with Marfan syndrome was significantly lower than that of healthy controls (8.5 +/- 2.1 vs 15.4 +/- 1.7 mL/min per 100 mL; P <.05). Reactive hyperemia was also lower in patients with Marfan syndrome (at peak 23.0 +/- 2.5 vs 29.5 +/- 2.3 mL/min per 100 mL; P <.05), but sodium nitroprusside-induced FBF changes did not differ between the 2 groups (10.3 +/- 1.1 vs 10.2 +/- 1.5 mL/min per 100 mL; P = not significant). CONCLUSION: These observations suggest that endothelium-dependent dilation and maximum dilator reserve capacity are both abnormal in peripheral resistance vessels of patients with Marfan syndrome. These peripheral vasomotion abnormalities may have a detrimental impact on the cardiovascular system in this disorder.

Adult↗
PubMed2000

Suppression of hepatic lesions in a murine graft-versus-host reaction by antibodies against adhesion molecules.

BACKGROUND/AIMS: The injection of parental CD4+ T cells into major histocompatibility complex (MHC) class II disparate F1 hybrid mice induced an autoimmune graft-versus-host reaction (GVHR) which is analogous to autoimmune liver diseases. The interaction of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) has been known to be profoundly involved in the trafficking of lymphocytes into the inflammatory tissues. The aim of this study was to clarify the role of VLA4 or VCAM-1 in the development of GVHR-induced hepatic lesions in our model. METHODS: B6 T spleen cells were injected into (B6.C-H-2bm12xB6) F1 mice intravenously. Anti-VLA-4 mAbs and/or anti-VCAM-1 mAbs were injected intraperitoneally at a dose of 2.5 mg/kg of each mAbs per body weight of mouse. We examined the changes in GVHR-induced hepatic lesions, serum levels of antimitochondrial antibodies (AMA) and cytokine mRNA expressions of liver-infiltrating lymphocytes using H.E. and immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: Hepatic lesions of anti-VLA-4 mAbs-treated mice were inhibited compared with those of GVHR mice. However, the administration of mAbs did not interfere with the induction of splenomegaly, the invasion of CD4+, CD8+, B220+, or Mac-1+ cells around bile ducts, nor the production of AMA. Liver-infiltrating CD4+ T cells obtained from these treated mice did not alter the expression of T helper (Th)1 and Th2 cytokine mRNA. CONCLUSION: The results suggest that treatment with antibodies against these adhesion molecules could inhibit the infiltration of lymphocytes without affecting the Th1/Th2 balance. The blockade of VLA-4-mediated cell infiltration into the liver in this model may have a possible novel therapeutic role of VLA-4 mAbs.

Animals↗
PubMed2000

Developmental changes of vitamin K epoxidase and reductase activities involved in the vitamin K cycle in human liver.

We examined the developmental changes in activities of vitamin K epoxidase, and vitamin K-2,3-epoxide reductase and vitamin K reductase in the human autopsied liver. The activity of epoxidase, which converts vitamin K hydroquinone to its epoxide, showed a high value in the early prenatal period of 10-30 gestational weeks but decreased rather rapidly in contrast with the reductase activities. After birth, a significant decrease of the epoxidase activity was observed but no such change was seen during the postnatal period. On the other hand, the activities of vitamin K-2,3-epoxide reductase and vitamin K reductase, which convert vitamin K-2,3-epoxide to its hydroquinone, showed a significantly low value in the early prenatal period. The highest activity of vitamin K epoxidase in the early prenatal period may be essential to the production of vitamin K dependent ligands for growth factors expressed in the embryo.

Adolescent↗
PubMed2000

Hepatic taurine, glycine and individual bile acids in early human fetus.

OBJECTIVE: To examine 3alpha-hydroxy individual bile acid and the association between taurine and taurine-conjugated bile acid in human fetal liver. METHODS: Taurine, glycine and the individual bile acids in liver samples taken from 17 human fetuses whose abortion was induced from 12 to 23 weeks' gestation were determined by high-performance liquid chromatography. RESULTS: The concentrations of taurine, glycine and bile acids in early fetal life were not related to gestational age. Hepatic taurine was statistically correlated with total taurine-conjugates (r = 0.798; P < 0.0001), but hepatic glycine was not correlated with glycine-conjugates (r = -0.103; P > 0.05). Lithocholic acid was conjugated exclusively with taurine. CONCLUSIONS: Our results supported that in human fetal life there is a considerable bile acid pool in liver, and that taurine works effectively on the bile acid metabolism depending on the hepatic taurine concentration.

Abortion, Induced↗
PubMed2000

Three patients with adrenal tumors having been treated simply for diabetes mellitus.

Three patients with functional adrenal tumors, Cushing's syndrome, primary aldosteronism and pheochromocytoma, who underwent adrenalectomy and were subsequently cured, were studied. All these patients had been treated for diabetes for several years before the diagnosis of adrenal tumors. In each case the state of diabetes before and after surgery, including parameters of insulin secretion and insulin resistance, was compared to demonstrate how the adrenal disorder influenced the nature of diabetes. In the case of Cushing's syndrome the hypercortisolemia caused insulin resistance in the peripheral tissues. In the case of primary aldosteronism, excessive production of aldosterone diminished insulin secretion possibly through hypokalemia. Pheochromocytoma affected both insulin secretion and insulin sensitivity through hypersecretion of catecholamines. In all these patients the adrenal tumors were found in clinical contexts other than management of diabetes itself. By careful retrospective review of these three patients' history, several important points that might have drawn the physician's attention to the underlying adrenal disorders were pointed out. These included past history of acute myocardial infarction with onset at unexpectedly young age in the case of Cushing's syndrome and unexpectedly high insulin resistance for the patient's body mass index in the case of pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2000

An inference modeling of human visual judgment of sagittal jaw-base relationships based on cephalometry: part I.

When there appears to be a contradiction between a cephalometric tracing and what is seen, the clinician tends to place more reliance on the appearance of the face in profile than on a formal cephalometric evaluation of the sagittal jaw relationship. With this in mind, we derived a multiple regression model with cephalometric variables to explain the visual influences that affect the subjective classification of sagittal jaw relationships made by experienced orthodontists. The regression model that showed the highest coefficient of determination, 0.90, was constructed from a linear combination of the angle ANB, the anteroposterior position of gnathion, the SN length, and the mandibular body length. The performance reliability of the inference system has been tested for 175 female adult cases and will be reported in Part II of this article.

Adolescent↗
PubMed2000

Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses.

We generated a series of knockin mouse lines, in which the cytokine receptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130 gene with human gp130 mutant cDNAs. The SHP2 signal-deficient mice (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction. In contrast, the STAT3 signal-deficient mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficient mice (gp130D/D). The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation, indicating a negative regulatory role for SHP2. Th1-type cytokine production and IgG2a and IgG2b production were increased in the gp130F759/F759 mice, while they were decreased in the gp130FXXQ/FXXQ immune system. These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.

Acute-Phase Reaction↗
PubMed2000

Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs.

Hedgehog (HH) and Decapentaplegic (DPP) direct anteroposterior patterning in the developing Drosophila wing by functioning as short- and long-range morphogens, respectively. Here, we show that the activity of DPP is graded and is directly regulated by a novel HH-dependent mechanism. DPP activity was monitored by visualizing the activated form of Mothers against dpp (MAD), a cytoplasmic transducer of DPP signaling. We found that activated MAD levels are highest near the source of DPP but are unexpectedly low in the cells that express dpp. HH induces dpp in these cells; it also attenuates their response to DPP by downregulating expression of the DPP receptor thick veins (tkv). We suggest that regulation of tkv by HH is a key part of the mechanism that controls the level and distribution of DPP.

Animals↗
PubMed2000

Thrombospondin-1 expression in oral squamous cell carcinomas: correlations with tumor vascularity, clinicopathological features and survival.

Thrombospondin-1 (TSP-1) is a 450 kd glycoprotein synthesized and incorporated into the extracellular matrix by numerous cell types and reported to suppress tumor growth and progression by its inhibition of angiogenesis. In order to clarify the biological role of TSP-1 and determine its clinicopathological significance in oral squamous cell carcinomas (SCCs), we identified TSP-1 protein expression in 54 oral SCCs by immunohistochemistry and correlated it with microvessel density (MVD), clinicopathological features and patient's survival. Thirty-two out of 54 carcinomas (59%) were identified as having a low level of TSP-1 expression (TSP-1-L), and 22/54 (41%) carcinomas identified as having a high level of TSP-1 expression (TSP-1-H). The MVD counts (mean+/-S.D.=9.0+/-4.9) in TSP-1-H tumors was significantly lower than that (mean+/-S.D.=12.7+/-4.4) in TSP-1-H tumors (P=0.0065). The level of TSP-1 expression was not correlated with T category and histologic grade, but inversely correlated with the pattern of tumor invasion (P=0.0136) and with lymph nodal status (P=0.0119). Furthermore, Kaplan-Meier analysis showed that the 5-year survival rate of TSP-1-H group was significantly higher than that of TSP-l-L group. Our results suggested that TSP-1 expression exerts an inhibitory effect on tumor vascularity, and that it has value in assessment of aggressiveness and prognosis of oral SCCs.

Angiogenesis Inhibitors↗
PubMed2000

Specific preinduction of 60-kDa heat shock protein (chaperonin homolog) by TRH does not protect colonic mucosa against acetic acid-induced lesion in rats.

In order to study the cytoprotective function of colonic heat shock proteins (HSPs) in vivo, the effect of specific preinduction of HSP60 by thyrotropin-releasing hormone (TRH) administration on the development of acetic acid-induced colonic mucosal lesion was investigated. Expression of 60-kDa, 72-kDa, and 90-kDa heat shock proteins (HSP60, HSP72, and HSP90, respectively) in rat colonic mucosa was investigated by western blot and immunohistochemical analyses before and after TRH administration. Following pretreatment with or without TRH administration, the rats received intrarectal infusion of 5% acetic acid. The colonic mucosal damage was macroscopically evaluated 24 hr after the intrarectal infusion of acetic acid. Expression of HSP60 was significantly increased by TRH administration in the colonic mucosa, whereas HSP72 and HSP90 did not increase. Immunohistochemical study also showed a significant increase in HSP60 in colonic mucosal cells, especially at the surface of the colonic mucosa after TRH administration. No histopathologic alteration was observed in the colonic mucosa after TRH administration. The colonic mucosal damage caused by intrarectal infusion of 5% acetic acid was not prevented by preinduction of HSP60. We demonstrated that specific preinduction of HSP60 by TRH administration did not show cytoprotective function in the colonic mucosa, although this protein plays a crucial role for cytoprotection in the pancreatic acinar cells. Our results indicate that the role of HSP60 may be different in each organ with respect to cytoprotection.

Acetic Acid↗
PubMed2000

Effects of A1 and A2 adenosine receptor antagonists on the induction and reversal of long-term potentiation in guinea pig hippocampal slices of CA1 neurons.

1. Using simultaneous recordings of the field EPSP and the population spike in the CA1 neurons of guinea pig hippocampal slices, we confirmed that delivery of a high-frequency stimulation (tetanus: 100 pulses at 100 Hz) produced robust long-term potentiation of synaptic efficacy (LTP) in two independent components, a synaptic component that increases field excitatory postsynaptic potentials (EPSPs) and a component that results in a larger population spike amplitude for a given EPSP size (E-S potentiation). 2. In the same cells, reversal of LTP (depotentiation; DP) in the field EPSP and in the E-S component is achieved by delivering low-frequency afferent stimulation (LFS: 1 Hz, 1000 pulses) 20 min after the tetanus. 3. When the tetanus or LFS was applied to CA1 inputs in the presence of an adenosine A1 receptor antagonist, 8-cyclopentyltheophylline (1 microM), the field EPSP was enhances in LTP and attenuated in DP, while the E-S relationship was not significantly affected in either LTP or DP. 4. When similar experiments were performed using an A2 receptor antagonist, CP-66713 (10 microM), the field EPSP was blocked in LTP but facilitated in DP, while E-S potentiation was enhanced during both LTP and DP. 5. The results show that endogenous adenosine, acting via A1 or A2 receptors, modulates both the synaptic and the E-S components of the induction and reversal of LTP. Based on the results, we discuss the key issue of the contribution of these receptors to the dynamics of neuronal plasticity modification in hippocampal CA1 neurons.

Action Potentials↗
PubMed2000

Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs.

PURPOSE: To study the utility of the nasal route for the systemic delivery of L-dopa using water soluble prodrugs of L-dopa and to examine if this delivery method will result in preferential delivery to the CNS. METHODS: Several alkyl ester prodrugs of L-dopa were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, rat brain homogenate, rat CSF, and rat nasal berfusate were determined by HPLC. In vivo nasal experiments were carried out in rats. Levels of L-dopa and dopamine in plasma, CSF, and olfactory bulb were determined using HPLC method with electrochemical detection. RESULTS: All the prodrugs showed improved solubility and lipophilicity with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with bioavailability around 90%. Dopamine plasma levels did not change significantly following nasal administration of the butyl ester prodrug. Olfactory bulb and CSF L-dopa concentration were higher following nasal delivery of the butyl ester prodrug compared to an equivalent intravenous dose. CONCLUSIONS: Utilization of water soluble prodrugs of L-dopa via the nasal route in the treatment of Parkinson's disease may have therapeutic advantages such as improved bioavailability, decreased side effects, and potentially enhanced CNS delivery.

Administration, Intranasal↗
PubMed2000

Characterization of a novel nonpeptide vasopressin V(2)-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes.

We discovered the first nonpeptide arginine-vasopressin (AVP) V(2)-receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V(2), V(1a) and V(1b)) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V(2)-receptor agonist. OPC-51803 and dDAVP displaced [(3)H]-AVP binding to human V(2)- and V(1a)-receptors with K(i) values of 91.9+/-10.8 nM (n = 6) and 3.12+/-0.38 nM (n = 6) for V(2)-receptors, and 819+/-39 nM (n = 6) and 41.5+/-9.9 nM (n = 6) for V(1a)-receptors, indicating that OPC-51803 was about nine times more selective for V(2)-receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [(3)H]-AVP binding to human V(1b)-receptors even at 10(-4) M, while dDAVP showed potent affinity to human V(1b)-receptors with the K(i) value of 13.7+/-3.2 nM (n = 4). OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V(2)-receptors with an EC(50) value of 189+/-14 nM (n = 6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V(2)-antagonist, OPC-31260. At 10(-5) M, OPC-51803 did not increase the intracellular Ca(2+) concentration ([Ca(2+)](i)) in HeLa cells expressing human V(1a)-receptors. On the other hand, dDAVP increased [Ca(2+)](i) in HeLa cells expressing human V(1a)- and V(1b)-receptors in a concentration-dependent fashion. From these results, OPC-51803 has been confirmed to be the first nonpeptide agonist for human AVP V(2)-receptors without agonistic activities for V(1a)- and V(1b)-receptors. OPC-51803 may be useful for the treatment of AVP-deficient pathophysiological states and as a tool for AVP researches.

Arginine Vasopressin↗
PubMed2000

Signaling of transforming growth factor-beta family members through Smad proteins.

Smads are pivotal intracellular nuclear effectors of transforming growth factor-beta (TGF-beta) family members. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity trigger phosphorylation of receptor-regulated Smads (R-Smads), whereas Smad2 and Smad3 are phosphorylated by TGF-beta, and activin type I receptors, Smad1, Smad5 and Smad8, act downstream of BMP type I receptors. Activated R-Smads form heteromeric complexes with common-partner Smads (Co-Smads), e.g. Smad4, which translocate efficiently to the nucleus, where they regulate, in co-operation with other transcription factors, coactivators and corepressors, the transcription of target genes. Inhibitory Smads act in most cases in an opposite manner from R- and Co-Smads. Like other components in the TGF-beta family signaling cascade, Smad activity is intricately regulated. The multifunctional and context dependency of TGF-beta family responses are reflected in the function of Smads as signal integrators. Certain Smads are somatically mutated at high frequency in particular types of human cancers. Gene ablation of Smads in the mouse has revealed their critical roles during embryonic development. Here we review the latest advances in our understanding of the Smad mechanism of action and their in vivo functions.

DNA-Binding Proteins↗