A novel hepatoprotective gamma-lactone, MH-031. I. Discovery, isolation, physico-chemical properties and structural elucidation.
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4-Butyrolactone↗
Biomedical subjects
H Shimura
Publications and source records attributed to H Shimura.
[Two different types of monoclonal antibodies against gallbladder carcinoma cell line].
Monoclonal antibody FU-W-H6 whose immunoglobulin subclass was IgG2a kappa was produced against gallbladder carcinoma cell line FU-GBC-2. In normal tissue, this antibody has a strong reactivity specific to the mucosa of the gallbladder (14/15, 94%), bile duct (5/5, 100%), and pancreatic duct (4/5, 80%) in comparison with the lack of the gastric mucosa, and colorectal mucosa with statistically significant differences (p less than 0.01). In cancerous tissue, gallbladder cancer (11/12, 92%), bile duct cancer (5/5, 100%), and pancreatic cancer (2/2, 100%) reacted gastric cancer (4/12, 33%), and colorectal cancer (1/16, 6%) with statistically significant differences (p less than 0.05). On the other hand, another monoclonal antibody FU-W-E2 whose immunoglobulin was IgM has specificity to the gastrointestinal or gallbladder cancers. Eleven of 13 (85%) gastric cancers, 12 of 16 (75%) colorectal cancers, and 9 of 12 (75%) gallbladder cancers reacted positively with statistically significant differences with each normal epithelia (p less than 0.05). Immunoelectron microscopical study revealed that the antigen recognized by FU-W-H6 was localized by FU-W-H6 or E2 antigens were suggested to be a carbohydrates on the glycoprotein, and were thought to have relation to sialic acid by treatment of acid Sciff and enzymes. Western blot analysis demonstrated that their molecular weights were about 87000, and 92000.
Adenocarcinoma↗
[Immunological assessment of the pathogenesis of septic-MOF: relationship between complement activation and changes in neutrophil functions].
We investigated the pathogenesis of septic-MOF through the relationship between changes in neutrophil functions and degree of complement activation. The patients' neutrophils exhibited enhanced adherence to HUVEC, suppressed chemotaxis toward C5a, enhanced production of oxygen radicals and lysosomal enzymes. These changes in neutrophil functions related to complement activation elicited via classical pathway. Moreover, the activated complement participated in tissue injuries due to the cytolytic action of the terminal complement complexes such as membrane attack complex (MAC). In conclusion, the combination of neutrophil and complement was strongly associated with the pathogenesis of the septic-MOF.
Bacterial Infections↗
T4-thyroid storm after CT-scan with iodinated contrast medium.
A 62-year-old woman had thyroid storm 5 h after a CT examination (contrast enhancement with 65% meglumine amidotrizoate, Angiografin). At the time of admission to our hospital, serum T4 and serum free T4 levels were markedly elevated (29 micrograms/dl and 9.6 ng/dl, respectively); serum T3 and serum free T3 levels were within normal limits (144 ng/dl and 5.9 pg/ml, respectively). These findings suggest that thyroid storm can occur with excess T4 only (T4-thyroid storm), and that T4-thyroid storm can be caused by administration of iodinated contrast medium.
Diatrizoate Meglumine↗
Metabolic deactivation of furylfuramide by cytochrome P450 in human and rat liver microsomes.
Metabolic deactivation of furylfuramide by human and rat liver microsomal cytochrome P450 enzymes has been investigated in a system measuring induction of umu gene expression response in Salmonella typhimurium TA1535/pSK1002. Both human and rat liver microsomes catalyzed the metabolism of furylfuramide to inactive form(s) that are incapable of inducing umu gene expression in the tester strain. The reaction required an NADPH-generating system and molecular oxygen and was inhibited by carbon monoxide, suggesting that a cytochrome P450-linked mono-oxygenase system is prerequisite for the deactivation reaction. With liver microsomes from variously pretreated rats, 3-methylcholanthrene was found to be a powerful inducer for the furylfuramide-metabolizing activity, and antibodies raised against rat P450IA1(BNF-B, c) and P450IA2(ISF-G, d) inhibited the microsomal activity. Human liver microsomal furylfuramide-metabolizing activity was also inhibited significantly by anti-P450IA2 IgG but weakly by anti-P450IA1 IgG. In liver microsomes prepared from seven different human samples, the activities of deactivation of furylfuramide were found to correlate with the amounts of immunoreactive protein related to rat P450IA2 and with the monooxygenase activities of metabolic activation of 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline (MeIQ) and of ethoxyresorufin O-deethylation. These results suggest that P450IA1 and P450IA2 in rats, and P450PA (IA2, the phenacetin O-deethylase and ortholog of rat P450IA2) in humans are the major enzymes involved in the deactivation of furylfuramide in liver microsomes. The metabolic studies involving HPLC analysis of products followed by spectrophotometric examination have also suggested that furylfuramide can be degraded very rapidly through the aerobic metabolism by liver microsomes.
Animals↗
Rapid detection and size determination of PuO2 particles using a charged-particle imaging video monitor system.
A charged-particle imaging video monitor system was constructed and applied to video imaging of the position profile of PuO2 particles on filter paper. The imaging video monitor system consists of a detector head, a silicon intensifier target (SIT) camera, a video frame memory, and a personal computer. The system can display the distribution image of PuO2 particles becoming gradually clearer on a video monitor. The integrated image that is transferred to the computer is analyzed quantitatively for the radioactivity of each PuO2 particle deposited on the filter paper. The system can not only rapidly distinguish PuO2 particle contamination from Rn daughter products, but can also determine the size distribution of the PuO2 particles.
Particle Size↗
Cloning of malignantly transformed rat thyroid (FRTL) cells with thyrotropin receptors and their growth inhibition by 3',5'-cyclic adenosine monophosphate.
Differentiated rat thyroid cells, designated FRTL, are totally dependent on TSH for their growth. We continuously cultured FRTL cells in the absence of TSH and found that another type of cell appeared in the culture. The new cells were large, flattened and epithelial-like, and none of them exhibited thyroglobulin immunoreactivity. Since they grew independently of TSH, we further cloned these mutated cells by the limited dilution method in the absence of TSH. cAMP production in the cloned cells (FRTL-Tc) was stimulated dose-dependently by TSH. The TSH concentration that produced a maximal level of cAMP in FRTL-Tc cells was 1 order of magnitude higher than in FRTL cells. A [125I]TSH binding study confirmed that the FRTL-Tc cells had TSH receptors with the same binding capacity but a higher Kd than those of FRTL cells. A [125I]cyanopindolol binding study revealed that the FRTL-Tc cells had acquired beta 2-adrenergic receptors and that isoproterenol or epinephrine could stimulate cAMP production in the cells. TSH or beta-adrenergic agonists inhibited the growth of these cells, as did (Bu)2cAMP. When FRTL-Tc cells were transplanted into the sc tissue in Fisher rats, they grew as a tumor in all of the animals (n = 10). Metastasis of the tumors to the lung and liver occurred. These results indicate that FRTL-Tc cells are malignantly transformed cells with TSH receptors derived from thyroid epithelial cells and also suggest that the role of cAMP in the proliferation of the transformed cells might be different from that in normal cells.
Adenylyl Cyclases↗
Transformation by v-H-ras does not restore proliferation of a set of temperature-sensitive cell-cycle mutants of rat 3Y1 fibroblasts.
Three temperature-sensitive cell-cycle mutants of rat 3Y1 fibroblasts (3Y1tsD123, 3Y1tsG125, and 3Y1tsH203, each belonging to distinct complementation groups) were transformed with plasmid DNA carrying Harvey murine sarcoma virus cDNA. The criteria for transformation were increase in saturation cell density, capability to clone in soft agar, and alteration in the cellular morphology. At 39.8 degrees C (restrictive temperature of the parental cell lines), all the transformed sublines of each mutant ceased to proliferate and were arrested reversibly in the G1 phase of the cell cycle like the parental lines. At both 39.8 degrees C and 33.8 degrees C (permissive temperature for the parental lines), all the untransformed parental lines synthesized p21ras at low rate. At 33.8 degrees C, all the transformed sublines synthesized p21ras at much higher rate and expressed the morphological phenotype characteristic to v-H-ras-induced transformation. At 39.8 degrees C, the rate of p21ras synthesis was not changed in the transformed sublines of 3Y1tsD123 and 3Y1tsG125, and the morphology of transformed phenotype also remained intact. In the transformed subline of 3Y1tsH203, the rate of p21ras synthesis was lowered at 39.8 degrees C to that seen in the untransformed parental line, and the transformed phenotype in morphology disappeared. In all of the transformed sublines, the amount of v-H-ras mRNA markedly expressed at both 33.8 degrees C and 39.8 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hepatoprotective compounds from Canarium album and Euphorbia nematocypha.
Successive purification of the extract from Canarium album and Euphorbia nematocypha, guided by antihepatotoxic activity in primary cultured rat hepatocytes, led to the isolation of brevifolin (1), hyperin (2), ellagic acid (3) and 3,3'-di-O-methylellagic acid (4) as hepatoprotective compounds. Compounds 1,3 and 4 also reduced carbon tetrachloride (CCl4)-induced liver damage in mice. The hepatoprotective activities of 1, 2, 3 and 4 in vitro and in vivo are apparently due to their antioxidative effects, which were exhibited by further studies using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and CCl4-induced lipid peroxidation systems.
Animals↗
Characterization of alpha 1-adrenergic receptor subtypes linked to iodide efflux in rat FRTL cells.
We have characterized alpha 1-adrenergic receptor subtypes in functional rat thyroid cells, FRTL, with relation to iodide efflux, and have also examined the effect of TSH on alpha 1 receptor subtypes. FRTL cells grown in a medium containing 5 mU TSH/ml (6H cells) had five times the number of alpha 1 receptors of those maintained in TSH-free medium (5H cells) (11.2 fmol/10(6) cells compared with 2.0 fmol/10(6) cells). Pretreatment with chlorethylclonidine (CEC; 10 mumols/l), which inactivates only alpha 1b receptors, caused 98.8% and 97.0% decreases in the density of specific [3H]prazosin-binding sites in 5H and 6H cells respectively. LIGAND computer program analysis of the displacement curves for 2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane (WB4101) showed that FRTL cells contained mostly low-affinity WB4101 sites. Using the phenoxybenzamine inactivation method, we found a linear relationship between alpha 1 receptor density and the cytosolic free Ca2+ concentration response in FRTL cells. Pre-exposure of intact FRTL cells to CEC caused a 98.7% decrease in noradrenaline-stimulated maximal increase in cytosolic free Ca2+. Also, CEC and 3,4,5-trimethoxy-benzoic acid 8-(diethylamino) octyl ester (TMB-8), but not nicardipine, inhibited noradrenaline-stimulated iodine efflux. The results suggest that FRTL cells contain mostly the alpha 1b-adrenergic receptor subtype; that the alpha 1b receptors mediate cytosolic free Ca2+ and iodide efflux responses, and that TSH enhances these responses by increasing the alpha 1b receptor density without affecting the post-receptor mechanism.
Animals↗
Thyrotrophin increases the alpha 1b-adrenergic receptors in rat thyroid gland in vivo.
Using chlorethylclonidine (CEC), an alpha 1b-adrenergic receptor-selective antagonist, we characterized alpha 1-adrenoceptor subtypes in rat thyroid gland, and investigated the effect of methimazole (MMI)-induced high TSH levels on alpha 1 receptor subtypes and noradrenaline-induced iodide organification. The density of thyroid alpha 1-adrenergic receptors was increased about sixfold in rats treated with MMI for 3 weeks compared with controls. Pretreatment of thyroid membrane preparations with CEC (10 mumol/l) caused an 83% decrease in specific 2-[beta-(hydroxy-3-[125I]iodophenyl) ethylaminomethyl]tetralone binding sites in MMI-treated rats, but only a 43% decrease in control rats. The density of CEC-insensitive alpha 1 receptors (alpha 1a) was similar in MMI-treated and control rats, so MMI was shown to increase CEC-sensitive alpha 1 receptors (alpha 1b). Noradrenaline-stimulated iodide organification was threefold greater in MMI-treated rats than in control rats when values were expressed as a per cent increase over basal levels. Pretreatment of thyroid lobes with 10 mumol CEC/l for 30 min caused a 66% decrease in maximal noradrenaline-induced iodide organification in MMI-treated rats, but a significantly lower decrease (49%) in control rats. These results suggest that the rat thyroid gland contains both alpha 1a and alpha 1b receptors, both of which mediate noradrenaline-induced iodide organification, and also that TSH enhances noradrenaline-induced iodide organification by increasing alpha 1b receptor density.
Adrenergic alpha-Antagonists↗
[Study of tissue drug concentration of fluorinated pyrimidine anticancer drugs--comparison of 5'DFUR and UFT].
In order to verify the tumor-selective toxicity of fluorinated pyrimidine anticancer drugs, we conducted an investigation of the clinical pharmacology of two of these drugs, 5'DFUR and UFT. 5'DFUR was administered to 8 patients and UFT to 8 other patients in respective dosages of 800-1,000 mg/day and 400-600 mg/day an average of 6 days before the patients underwent surgery for cancer of the large bowel, and the concentrations of these drugs in tissue were then measured. No 5'DFUR whatsoever was detected in serum, the lymphnodes, normal large bowel tissue, or cancerous large bowel tissue after administration of this drug. Moreover, levels of the active substance, 5-FU, after administration of 5'-DFUR were low in serum, the lymphnodes, normal large bowel tissue (0.033 +/- 0.024 microgram/g), and cancerous large bowel tissue (0.034 +/- 0.020 microgram/g), and no difference was observed between normal and cancerous large intestine tissue. On the other hand, tegafur was detected in all of the tissues following the administration UFT, and the concentration of 5-FU was significantly high, particularly in cancerous large bowel tissue (0.108 +/- 0.057 microgram/g) compared to normal sites (0.044 +/- 0.048 microgram/g) (p less than 0.05). The above results indicate that UFT is a promising drug for use in chemotherapy for cancer of the large bowel.
Antineoplastic Agents↗
[Successful vitelline arterial embolization for massive hemorrhage from Meckel's diverticulum].
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Adolescent↗
Mechanism of selective killing by dilinoleoylglycerol of cells transformed by the E1A gene of adenovirus type 12.
Rat 3Y1 fibroblasts transformed by the E1A gene of adenovirus type 12 (E1A-3Y1 cells) are highly sensitive to the cell-killing effect of 1,3-dilinoleoylglycerol (DLG) administered in a culture medium, whereas the parental 3Y1 cells are less sensitive (H. Shimura et al., Cancer Res., 48: 578-583, 1988). The selective cytotoxicity of DLG to E1A-3Y1 cells was markedly reduced by the simultaneous administration of nonspecific antioxidants such as vitamin E, butylated hydroxytoluene, and ascorbic acid. Specific scavengers for oxygen radicals had no effect. Lipoxygenase inhibitors (nordihydroguaiaretic acid, esculetin, and baicalein) reduced the DLG-mediated selective cytotoxicity, whereas cyclooxygenase inhibitors (acetylsalicylic acid and indomethacin) showed no effect. The intracellular and extracellular contents of the products from lipid peroxidation as measured by the thiobarbituric acid test were significantly greater in E1A-3Y1 cells than in the parental 3Y1 cells. In comparison with DLG, linoleic acid and monolinoleoylglycerol were equally toxic to E1A-3Y1 and parental 3Y1, and trilinoleoylglycerol was weakly toxic to both types of cells. Scanning electron microscopy revealed that numerous holes about 0.2 micron in diameter were scattered all over the surface of the E1A-3Y1 cells after treating the cultures with DLG. These results suggest that; (a) the DLG-mediated cytotoxicity to the E1A-transformed cells is attributable to lipid peroxidation; (b) the structural property of DLG is essential to the E1A specificity of cytotoxicity; and finally (c) the destruction of the cell membrane is the basis of cytotoxicity of DLG.
Adenovirus Early Proteins↗
The uptake of anticancer drugs by tumor tissues and lymph node and the effectiveness of postoperative adjuvant chemotherapy on survival time.
Forty-one patients with advanced gastric cancer underwent gastrectomy and the correlation between tissue uptake of the adjuvant drug and the prognosis were studied. The patients were preoperatively administered Tegafur (Futraful, Taiho Pharmaceutical Co. Ltd, Japan) and samples of tissue were obtained intraoperatively. 5-FU levels in the tumor and lymph nodes were measured by gas chromato-massfragmentography (GCMF). The patients in whom the 5-FU uptake by the tissues was measured and who were given over 60 g of Tegafur as postoperative adjuvant chemotherapy, were divided into two groups; namely, one group in whom the 5-FU uptake by the tumor tissue and lymph nodes was over 0.05 microgram/g and the other in whom the uptake was lower than 0.05 microgram/g. There were no significant differences in the background factors of either group. Each survival rate was calculated by the Kaplan-Meier method, and the generalized Wilcoxon method was used for statistical analysis. There was no statistically significant correlation between the 5-FU uptake by the tumor and the prognosis, however the 5-year survival rate in the group whose 5-FU uptake of the lymph nodes was over 0.05 microgram/g was statistically significant (p = 0.018).
Combined Modality Therapy↗
The high sensitivity of cells transformed by E1A gene of adenovirus type 12 to diacylglycerol-mediated cell killing.
Viability of rat 3Y1 fibroblasts transformed by adenovirus type 12 (Ad12) was markedly impaired by the administration of dilinoleoylglycerol (DLG) to the culture medium. To identify the gene(s) of Ad12 responsible for the high sensitivity to DLG, we established several transformed sublines of 3Y1 induced by the viral E1A gene or by the mutants of Ad12 which have mutations in the E1A region. All of the transformed sublines of 3Y1 expressing either the 12S or the 13S message from the E1A region were highly sensitive to the cytotoxicity of DLG. We propose that the high sensitivity of Ad12-transformed cells to the DLG mediated cytotoxicity is attributable to the common function of E1A-12S and E1A-13S mRNA products.
Adenoviridae↗
Enhancement of the activity of thyroid-stimulating antibodies by anti-human IgG antibodies in vitro.
In an attempt to determine whether or not anti-human IgG antibodies could influence the activity of thyroid-stimulating antibodies (TSAb), we investigated the effects of anti-human Fc antibody (anti-Fc antibody) and IgG from rheumatoid arthritis patients (RA-IgG) on TSAb activity using FRTL-5 cells. It was found that these anti-human IgG antibodies enhanced the TSAb activity in vitro. FRTL-5 cells were first incubated with Graves' disease IgG for 30 min at 37 degrees C, then washed and incubated in Hanks' balanced salt solution with anti-human IgG antibodies for 60 min at 4 degrees C, and then for a further 120 min at 37 degrees C. The level of cAMP accumulated in the medium was determined by RIA. Anti-Fc antibody significantly augmented the cAMP formation stimulated by 16 out of 24 Graves' IgGs, whereas anti-F(ab')2 antibody did not potentiate cAMP accumulation. Three of five RA-IgGs, which are usually defined as specific antibodies for the Fc fragment of human IgG, mimicked these stimulatory effects. Protein A also potentiated the cAMP formation stimulated by Graves' IgGs. Furthermore, there was a significant correlation between the TSAb titres of these Graves' IgGs and the potentiating effects of anti-Fc antibody (r = 0.495, P less than 0.05, n = 21). These results suggest that the interaction of TSH receptor antibody with anti-human IgG antibodies might modulate thyroid function in Graves' disease.
Antibodies, Anti-Idiotypic↗
Induction of DNA synthesis by cholera toxin in the temperature-sensitive cell-cycle mutants of rat 3Y1 fibroblasts at a restrictive temperature.
Four temperature-sensitive mutants of rat 3Y1 fibroblasts representing separate complementation groups (3Y1tsD123, 3Y1tsF121, 3Y1tsG125 and 3Y1tsH203) are arrested at a restrictive temperature of 39.8 degrees C mainly with a G1-phase DNA content (temperature arrest). Cholera toxin (CT) (3 micrograms ml-1) induced DNA synthesis at 39.8 degrees C in the temperature-arrested cultures of two mutants (3Y1tsD123 and 3Y1tsG125). This effect of CT was not mimicked by other agents known to elevate the cellular level of cyclic AMP, such as dibutyryl-cyclic AMP, prostaglandin E1 and forskolin, suggesting that the elevation of cellular cyclic AMP level per se is not responsible for the induction of DNA synthesis by CT. Addition of the B subunit of CT to the temperature-arrested cultures of 3Y1tsD123 and 3Y1tsG125 did not induce DNA synthesis at 39.8 degrees C, indicating that the binding of CT to the cell surface alone is insufficient for the induction. The CT-treated cell membrane fraction prepared from temperature-arrested 3Y1tsG125 cells had similar activity for [32P]ADP-ribosylation of the 45 X 10(3) Mr protein to that prepared from cells proliferating at a permissive temperature of 33.8 degrees C. All these results suggest that 3Y1tsG125 cells utilize a CT-responsive signal transduction pathway, different from adenylate cyclase cascade, for preparation for entry into S phase in the temperature-arrested 3Y1tsG125.(ABSTRACT TRUNCATED AT 250 WORDS)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗