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Biomedical subjects

T Oku

Publications and source records attributed to T Oku.

At least 55 records · Page 3Linked to original sources
PubMed1998

Transitory laxative threshold of trehalose and lactulose in healthy women.

The transitory laxative threshold of a partially digestible disaccharide, trehalose, and an undigestible disaccharide, lactulose, was estimated by the dose-response relation between the test substance and the prevalence of diarrhea in 20 healthy female subjects. The subjects ingested several indicated amounts of trehalose or lactulose once daily 2 to 3 h after a meal. The intake of the test substance was stopped at the dose level that caused diarrhea or when the dose reached the maximal level. A record of physical conditions, gastrointestinal symptoms, and fecal conditions was made by all subjects before and after each ingestion of the test substance. Half the subjects experienced no diarrhea even with the ingestion of the maximal dose level (60 g) of trehalose in this study, and the ingestion of up to 40 g of lactulose caused diarrhea in 75% of all subjects. Abdominal symptoms such as flatus, distension, and borborygmus appeared at high prevalence with lactulose and trehalose ingestion, and the effect of lactulose was significantly stronger than that of trehalose at the same dose level (p < 0.05). The quantity of trehalose and lactulose that induced diarrhea differed greatly from person to person. The transitory laxative threshold was estimated as 0.65 g/kg body weight for trehalose and 0.26 g/kg body weight for lactulose by using the regression equation between the dose levels of the test substances and the cumulative incidence of diarrhea. These results suggest that it would be quite acceptable to administer trehalose up to 33 g and lactulose up to 13 g in a person weighing 50 kg.

Abdomen↗
PubMed1998

Gowers' local panatrophy.

We report a patient with Gowers' local panatrophy, who developed skin atrophy on the left upper arm, right lower leg and facial hemiatrophy without a thickening or a sclerosing process. Histological examination revealed loss of thickness of the dermis and subcutaneous tissue. It is suggested that skin atrophy was induced by a nonsclerosing process, different from the inflammation and fibrosis observed in scleroderma.

Adipose Tissue↗
PubMed1997

Molecular cloning and tissue distribution of an alternatively spliced variant of an A-type K+ channel alpha-subunit, Kv4.3 in the rat.

We describe here (1) the heterogeneous expression of Ca2+-independent transient (A-type) K+ channel alpha-subunits (Kv1.4, Kv3.3, Kv3.4, Kv4.2 and Kv4.3) in rat smooth muscle, heart and brain, (2) the molecular cloning and tissue distribution of a novel alternatively spliced variant of an A-type K+ channel alpha-subunit, Kv4.3, and (3) the functional expression of A-type K+ channels in HEK293 cells by the transfection with the novel splice variant of Kv4.3. A cDNA encoding this splice variant was identified from rat vas deferens by RT-PCR cloning. This cDNA clone contains a 1965 bp open reading frame that encodes for a protein of 655 amino acids. It has a 19 amino acid insertion in comparison with Kv4.3 previously reported in rat brain. RT-PCR analyses showed that the mRNAs of this longer variant are abundantly expressed in a number of smooth muscles of the rat, and that the mRNAs of the previously reported clones are absent. The longer splice variant is very weakly expressed in brain, but is the major product in heart.

4-Aminopyridine↗
PubMed1997

Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344.

To investigate the pathophysiological role of bradykinin and to develop a drug for inflammatory diseases, we discovered an orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344, N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2, 4dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethyl aminocarbonyl) cinnamylamide hydrochloride. This compound competitively displaced [3H]bradykinin binding to bradykinin B2 receptors present in guinea-pig ileum membrane with an IC50 value of 6.6 X 10(-10) M. In isolated guinea-pig ileum preparations, it also antagonized bradykinin-induced contraction with a pA2 value of 9.3. In human lung fibroblast IMR-90 cells, FR167344 displaced [3H]bradykinin binding to human bradykinin B2 receptors with an IC50 value of 1.3 X 10(-8) M, but not [3H]des-Arg10-kallidin binding to human bradykinin B1 receptors. In vivo, oral administration of FR167344 inhibited bradykinin-induced bronchoconstriction in guinea pigs and the bradykinin-induced hypotensive response for 6 h in rats. These results show that FR167344 is a potent, selective, orally active and long acting bradykinin B2 receptor antagonist.

Animals↗
PubMed1997

Redox dependence for photoligation of manganese to the apo-water-oxidizing complex in chloroplasts and photosystem II membranes.

Effects of reducing reagents and redox potentials on photoactivation were studied in Mn-depleted chloroplasts and PSII membranes. Exogenous reducing reagents abolished photoactivation in PSII membranes, while they stimulated photoactivation in chloroplasts. To determine how reducing reagents can have such opposing effects in these preparations, we studied how redox potentials affect photoactivation in the range from 0 mV to +500 mV. In chloroplasts, a modest yield of photoactivation was obtained in the redox potential range of +100 and +330 mV at pH 7.5. The yield of photoactivation decreased at redox potentials above +330 mV, and drastically increased below potentials of +100 mV. Nernst plots of the data show that an n = 1 redox component with an Em7.5 of +374 mV, as well as an n = 2 redox component with an Em7.5 of +61 mV, is involved in photoactivation of chloroplasts isolated from dark-grown spruce seedlings. In the case of PSII membranes, photoactivation decreased sharply on either side of +335 mV at pH 5.5. The n = 1 redox components with Em5.5 of +375 and +319 mV may be involved, both of which showed pH dependences of -60 mV/pH unit. DCMU abolished photoactivation in chloroplasts, but did not affect the dependence of photoactivation on oxidation-reduction potentials in PSII membranes. The component with an Em5.5 of +319 mV involved in photoactivation of PSII membranes was also observed in the dependence of Mn solubilization on oxidation-reduction potentials with PSII membranes lacking extrinsic proteins, suggesting that the reduction of Mn with higher valences to Mn(II) by exogenous reducing reagents reversibly occurs in the intermediates or an active center during photoactivation in PSII membranes. Involvement of such redox components in photoactivation in chloroplasts and PSII membranes is discussed.

Chloroplasts↗
PubMed1997

A ruptured aneurysm at the distal end of the basilar artery fenestration associated with multiple fenestrations of the vertebrobasilar system: case report.

BACKGROUND: An aneurysm at the fenestrated basilar artery usually arises at the proximal end of the fenestration, with few exceptions. We failed to reveal any case of aneurysm at this site associated with multiple fenestrations of the vertebrobasilar system. CASE REPORT: This 62-year-old male was admitted to our hospital 1 day after a sudden onset of headache. CT scan showed subarachnoid hemorrhage, and angiogram revealed an aneurysm at the distal end of the fenestrated basilar artery in association with two other fenestrations of the vertebrobasilar system. The limb of the basilar artery fenestration was trapped tightly with one clip through the transcondylar approach. Postoperative course was uneventful, and postoperative angiogram showed complete disappearance of the aneurysm. CONCLUSION: An extremely rare case of an aneurysm at the distal end of the fenestrated basilar artery in association with multiple fenestrations of the vertebrobasilar system is reported. The coexistence of vertebral artery fenestration and the fenestration of the vertebrobasilar junction may give a clue to the mechanism of occurrence of basilar artery fenestration.

Aneurysm, Ruptured↗
PubMed1997

The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657.

1. An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl] acrylamide) has been identified. 2. This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 x 10(-10) M and in rat uterus with an IC50 of 1.5 x 10(-9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 x 10(-9) M and a Ki of 3.6 x 10(-10) M, but did not reduce [3H]-des]Arg10-kallidin binding to B1 receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 x 10(-9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(-6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(-9) M and 3.2 x 10(-9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(-8) M. Analysis of the data yield a pA2 of 9.2 +/- 0.2 (n = 5) and a slope of 1.5 +/- 0.2 (n = 5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg-1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg-1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg-1 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.

Administration, Oral↗
PubMed1997

Imaging experimental brain tumors with 1-aminocyclopentane carboxylic acid and alpha-aminoisobutyric acid: comparison to fluorodeoxyglucose and diethylenetriaminepentaacetic acid in morphologically defined tumor regions.

The goal of this study was to evaluate the differences and define the advantages of imaging experimental brain tumors in rats with two nonmetabolized amino acids, 1-aminocyclopentane carboxylic (ACPC) acid and alpha-aminoisobutyric (AIB) acid compared with imaging with fluorodeoxyglucose (FDG) or the gallium-diethylenetriaminepentaacetic acid chelate (Ga-DTPA). 1-aminocyclopentane carboxylic acid, AIB, and FDG autoradiograms were obtained 60 minutes after intravenous injection to simulate positron emission tomography (PET) imaging, whereas the Ga-DTPA autoradiograms were obtained 5 or 10 minutes after injection to simulate gadolinium (Gd)-DTPA-enhanced magnetic resonance (MR) images. Three experimental tumors were studied (C6, RG2, and Walker 256) to provide a range of tumor types. Triple-label quantitative autoradiography was performed, and parametric images of the apparent distribution volume (Va, mL/g) for ACPC or AIB, relative glucose metabolism (R, micromol/100 g/min), vascular permeability to Ga-DTPA (K1, microL/min/g), and histology were obtained from the same tissue section. The four images were registered in an image array processor, and regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images. A comparative analysis of all measured values was performed. The location and morphologic characteristics of the tumor had an effect on the images and measurements of Va, R, and K1. Meningeal extensions of all three tumors consistently had the highest amino acid uptake (Va) and vascular permeability (K1) values, and subcortical portions of the tumors usually had the lowest values. Va and R (FDG) values generally were higher in tumor regions with high-cell density and lower in regions with low-cell density. Tumor areas identified as "impending" necrosis on morphologic criteria consistently had high R values, but little or no change in Va or K1. Tumor necrosis was seen consistently only in the larger Walker 256 tumors; low values of R and Va for AIB (less for ACPC) were measured in the necrotic-appearing regions, whereas K1 was not different from the mean tumor value. The highest correlations were observed between vascular permeability (K1 for Ga-DTPA) and Va for AIB in all three tumors; little or no correlation between vascular permeability and R was observed. The advantages of ACPC and AIB imaging were most convincingly demonstrated in C6 gliomas and in Walker 256 tumors. 1-aminocyclopentane was substantially better than FDG or Ga-DTPA for identifying tumor infiltration of adjacent brain tissue beyond the macroscopic border of the tumor; ACPC also may be useful for identifying low-grade tumors with an intact blood-brain barrier. Contrast-enhancing regions of the tumors were visualized more clearly with AIB than with FDG or Ga-DTPA; viable and necrotic-appearing tumor regions could be distinguished more readily with AIB than with FDG. [11C]-labeled ACPC and AIB are likely to have similar advantages for imaging human brain tumors with PET.

Aminoisobutyric Acids↗
PubMed1997

Nonpeptide mimic of bradykinin with long-acting properties at the bradykinin B2 receptor.

Kinins, members of a family of peptides released from kininogens by the action of kallikreins, exhibit a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells, and activation of sensory neurons. However, investigation of the physiological actions of kinins has been greatly hampered because its effects are curtailed by rapid proteolysis in blood, lung, and liver. We describe the pharmacological characteristics of a novel nonpeptide bradykinin receptor agonist FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoli ne). FR190997 markedly stimulated phosphatidylinositol hydrolysis in Chinese hamster ovary cells permanently expressing the human bradykinin B2 receptor. The response of phosphatidylinositol hydrolysis was antagonized by the B2 receptor selective antagonist Hoe 140 (D-Arg-[hydroxyproline3,beta-thienylalanine4,D-Tic7,++ +Oic8]bradykinin). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the human bradykinin receptor subtypes, FR190997 showed a high affinity binding to the B2 receptor with IC50 value of 5.3 nM and no binding affinity for the B1 receptor. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity. This compound should represent a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.

Animals↗
PubMed1997

A modified and convenient method for assessing tumor cell invasion and migration and its application to screening for inhibitors.

In order to screen potent inhibitors of tumor invasion and metastasis, we here devised a simple and reproducible in vitro assay for tumor invasion and migration. A conventional cell-counting assay using a Transwell chamber with a microporous membrane filter is troublesome and time-consuming, involving visually counting the cells under a microscope, and the invaded or migrated cells are sometimes distributed unevenly in predetermined fields on the lower surface of the filter. Therefore, it is difficult to evaluate the invasive and migratory abilities of tumor cells easily and quantitatively by the cell counting method. In the present study, crystal violet dye was used for staining the invaded cells and colorimetrically assessing the invasive ability per filter as an absorbance. In this crystal violet assay, tumor cell invasion into a reconstituted basement membrane Matrigel was proportional to both the cell number added into the chamber and the incubation period, and inversely proportional to the amount of Matrigel barrier on the upper surface of filter. The results obtained by this dye-uptake method were highly consistent with those of a conventional cell-counting assay. Using this crystal violet assay, the anti-invasive effect of doxorubicin (DOX) was detected more easily and found to be highly proportional to that by the conventional cell-counting method. We therefore applied this convenient assay method to screen anti-invasive and anti-metastatic compounds. As a result, caffeic acid was found to be more active in the inhibition of both tumor cell invasion and migration without showing direct cytotoxicity in vitro than other related compounds.

Caffeic Acids↗
PubMed1997

Antimetastatic and antitumor effect of a recombinant human tissue inhibitor of metalloproteinases-2 in murine melanoma models.

Tumor metastasis into distinct organs and tissues, of which many patients with malignancies die, is regulated in multiple steps. Using a murine metastasis model, in which highly metastatic B16-BL6 melanoma cells were inoculated i.v. into syngeneic C57BL/6 mice, the administration of a recombinant human tissue inhibitor of metalloproteinases-2 (r-hTIMP-2) once a day on days -1 to 3 after the implantation significantly inhibited the formation of metastatic foci in the lungs. The antimetastatic effect of r-hTIMP-2 was detected irrespective of administration route [i.v., i.p., s.c., and i.m. routes] and in a dose-dependent manner. The i.m.-injection of r-hTIMP-2 during the early phase after tumor inoculation is suggested to be essential for antimetastasis. In another model using spontaneously metastasing B16-BL6 cells, multiple i.m.-injections of r-hTIMP-2 also resulted in a reduced but not statistically significant number of pulmonary metastases. In addition to these antimetastatic effects, a slight inhibitory effect on tumor cell growth was observed in vitro and in vivo. In conclusion, the antimetastasis by r-hTIMP-2 may be due to inhibition of the degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and, in part, to the suppression of the tumor cell growth.

Animals↗
PubMed1997

Characterization of FR173657, a novel nonpeptide B2 antagonist: in vitro and in vivo studies.

Bradykinin (BK) is involved in different pathophysiological conditions, including allergic and (or) inflammatory reactions. Thus, BK antagonists are considered as a potential drug in allergic and (or) inflammatory diseases. Orally active BK antagonist would be desirable for this purpose. Here, we describe the pharmacological characterization of FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8- quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acr ylamide) obtained from our screening for nonpeptide, orally active B2 antagonists. (i) FR173657 antagonized [3H]BK binding with IC50 values of 4.6 x 10(-10) and 8.6 x 10(-9) M in membrane preparations of guinea pig ileum and lung, respectively. FR173657 inhibited [3H]BK binding to A431, W138, and IMR90 cell lines of human origin with IC50 values of 2.0 x 10(-9), 2.3 x 10(-9), and 1.7 x 10(-9) M, respectively. FR173657 did not affect [3H]des-Arg10-kallidin (B1 ligand) binding onto IMR90 cells. (ii) FR173657 inhibited guinea pig ileum contractions by BK (6 x 10(-8) M) with an IC50 value of 6.1 x 10(-9) M. Acetylcholine- and histamine-induced contraction of guinea pig ileum was unaffected by FR173657. (iii) Oral administration of FR173657 dose-dependently inhibited BK (5 micrograms/kg) and dextran sulfate (activator of kinin-kallikrein cascade) induced bronchoconstriction with ED50 values of 0.075 and 0.057 mg/kg, respectively. In conclusion, FR173657 is a selective potent, orally active B2 receptor antagonist that can be used to investigate the role of BK in allergic and inflammatory diseases.

Administration, Oral↗
PubMed1996

Efrapeptins block exocytic but not endocytic trafficking of proteins.

During the course of screening studies to identify inhibitors of intracellular protein trafficking, we isolated efrapeptins as active principles. These compounds arrested syncytium formation (SF) and cytopathic effect (CPE) in Newcastle disease virus (NDV)- and vesicular stomatitis virus (VSV)-infected BHK cells, respectively, without profoundly affecting glycoprotein synthesis. Efrapeptins blocked cell surface expression of NDV-HN and VSV-G glycoproteins, but did not suppress intoxication by ricin or diphtheria toxin even after prolonged pretreatment. Efrapeptins are inhibitors of F-ATPase, or ATP synthase, but their inhibitory effect on SF and CPE was independent of the amount of intracellular ATP.

Adenosine Triphosphate↗
PubMed1996

Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy.

Noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression is possible with a clinical gamma camera and by single-photon emission tomography (SPECT) using 131I-labeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodo-uracil (FIAU). Studies were performed in rats bearing s.c. tumors. Tumors were produced by injection of wild-type RG2 glioma or W256 mammary carcinoma cells into one flank and RG2TK+ glioma or W256TK+ mammary carcinoma cells (that had been transduced in vitro with the HSV1-tk gene) into the opposite flank. In some animals, HSV1-tk gene transduction of the pre-established wild-type tumors was accomplished in vivo by direct intratumoral injection of retroviral vector-producer cells. Imaging studies were performed 2 weeks after tumor transduction to allow time for production and spread of the retroviruses through the tumor and for sufficient growth and increase in size of the tumors to facilitate imaging. The gamma camera and SPECT images revealed highly specific localization of [131I]FIAU-derived radioactivity to areas of HSV1-tk gene expression at 24, 36, and 48 h after i.v. administration of 1.6-2.8 mCi of [131I]FIAU. Comparative analysis of quantitative autoradiographic images obtained from the same tumors confirmed that the high levels of [131I]FIAU-derived radioactivity (> 1% dose) were localized to areas of HSV1-tk gene expression demonstrated by immunohistochemical staining for HSV1-tk protein. In contrast, significantly lower levels of [131I]FIAU-derived radioactivity (< 0.01%) were observed in the surrounding nontransduced tumor tissue, contralateral wild-type tumors, and other tissues that showed no immunohistochemical staining for the HSV1-tk protein. The magnitude of FIAU accumulation in RG2TK+, W256TK+, and wild-type tumors corresponded to the in vitro ganciclovir sensitivity of the cell lines used to produce these tumors, which indicates that the magnitude of FIAU accumulation reflects the level of HSV1-tk gene expression. We suggest that "clinically relevant" levels of HSV1-tk gene expression in transfected tissue can be imaged with [131I]FIAU and a gamma camera or SPECT, and that a significant improvement in imaging sensitivity and resolution is expected with [124I]FIAU and PET.

Animals↗
PubMed1996

Multiple expression of Ly-6C and accumulation of a Ly-6C pre-mRNA in activated macrophages involved in rejection of an allografted tumor.

We established a monoclonal antibody against a surface antigen of activated macrophages (Møs) involved in the rejection of an allografted mouse tumor, Meth A. Bacteria-elicited Møs also expressed the antigen but resident or inflammatory Møs, or other leukocytes, did not. The antigen was identified as Ly-6C by isolation of cDNA clones encoding it. Two-dimensional immunoblotting revealed that Ly-6C of the Møs exists in multiple forms with a similar size but with different isoelectric points. A Ly-6C pre-mRNA also accumulated abundantly in the Møs. Thus, the multiple expression of Ly-6C and the accumulation of the pre-mRNA are the features of allograft- and bacteria-elicited Møs.

Amino Acid Sequence↗
PubMed1996

Solitary plexiform neurofibroma of the submandibular salivary gland.

Neurofibroma affecting the major salivary gland is uncommon. This tumour is particularly rare in the submandibular and sublingual gland. Here, a case of solitary plexiform neurofibroma of the submandibular gland without any other manifestations of von Recklinghausen's disease is presented. It is probably the first case report of this tumour invading the submandibular gland in a solitary form.

Adult↗