Cyclic guanidines. XVI. Synthesis and biological activities of tetracyclic imidazo[2,1-b]quinazolinone derivatives.
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Biomedical subjects
Publications and source records attributed to T Mimura.
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Prognosis of differentiated thyroid carcinoma is favorable unless distant metastasis develops. We have experienced 70 cases of differentiated thyroid carcinoma with pulmonary metastases and analysed the outcome of treatment of patients, with special reference to the extent of thyroid resection and postoperative ablative RI therapy. The following results were obtained: Of the 42 survivors 22 (52.4%) received total thyroidectomy, whereas 23 of 28 expired patients underwent less-than-total thyroidectomy. A total of 42 patients underwent radioiodine treatment following thyroid resection. 17 out of 18 patients who had received total thyroidectomy survived. On the other hand, only 11 out of 24 patients who had received less-than-total thyroidectomy survived. In the non-RI treatment group, prognoses were unfavorable in both total and less-than-total thyroidectomy groups. From these results, it is emphasized that ablative doses of RI should be given to patients with pulmonary metastases of differentiated thyroid carcinoma after total thyroidectomy.
Six hundred and forty-three neonates from mothers with Graves' disease were examined for major malformations of external organs to compare the influence of maternal hyperthyroidism vs. ingestion of methimazole (MMI) during the first trimester on the incidence of congenital malformations. The subjects were divided into four groups according to maternal therapy and thyroid status during the first trimester as follows: (1) infants whose mothers did not receive MMI and were hyperthyroid (Group 1), (2) infants whose mothers did not receive MMI and were euthyroid (Group 2), (3) infants whose mothers received MMI and were hyperthyroid (Group 3) and (4) infants whose mothers received MMI and were euthyroid (Group 4). The prevalence of malformed infants in these four groups was 6.0% (three of 50), 0.3% (one of 350), 1.7% (two of 117) and 0.0% (none of 126), respectively. The incidence in Group 1 was significantly higher than that in Group 2 (P less than 0.01). There was no discernible dose dependency of MMI on the occurrence of malformations. These findings suggest that maternal uncontrolled hyperthyroidism may cause congenital malformations and that the beneficial role of MMI treatment outweighs its teratogenic effect, if any.
The sensitivity of nuclei to micrococcal nuclease was compared in thyroid tissue obtained from euthyroid patients with solitary cold nodules and from patients with Graves' disease. A significant increase in the solubility and/or the sensitivity of nuclei to the nuclease was found in thyroid tissue from patients with Graves' disease. Electrophoretic analysis of DNA in chromatin solubilized by the nuclease revealed that the amount of oligonucleosomal DNA was increased, and that of polynucleosomal DNA was even more increased, in nuclei from Graves' thyroids than in those from normal thyroids. Polyacrylamide gel electrophoretic analysis in Triton acid-urea showed that the extent of histone acetylation in nuclei from Graves' thyroids was almost the same as in those from normal thyroids. These findings suggest that the state of chromatin organization in Graves' thyroid nuclei is different from that in normal thyroid nuclei and is independent of the extent of histone acetylation.
A lectin was isolated from the external mucus of fish, Genypterus blacodes. This is the first lectin isolated from fish. The molecular weight of the lectin, determined by gel filtration, was approximately 32 000, whereas 8 000 was indicated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of 2-mercaptoethanol. Amino acid analysis demonstrated that the lectin contained large amounts (near 30% of the residues) of lysine, but no tryptophan. The lectin agglutinated mouse, rabbit and human erythrocytes at a concentration of 15.6 micrograms/ml. An inhibition test revealed that the lectin was strongly inhibited by N-acetyl-glucosamine, mucin and orosomucoid. Binding studies performed with iodinated asialo-orosomucoid indicated that the lectin contained a high affinity binding site with a dissociation constant of 1.1 X 10(-8) M. The lectin required the presence of calcium ion for both its hemagglutination and binding activity.
The effects of a new anti-ulcer agent Fr. I-L, a reduced and carboxamide-methylated light chain of human immunoglobulin G, on defensive factors in gastric mucosa were studied. Fr. I-L increased the mucopolysaccharide contents (hexosamine, uronic and sialic acids) in the gastric mucosa of intact rats and inhibited the decrease of mucopolysaccharide contents in the gastric mucosa of rats with phenylbutazone-induced gastric ulcers. The activation of the biosynthesis of mucopolysaccharides by Fr. I-L was suggested by tracing the incorporation of 35SO4(2-) into the gastric mucosa. The administration of aspirin or phenylbutazone caused an increase of mucopolysaccharase activity in the gastric mucosa and the concomitant administration of Fr. I-L blocked the elevation of the enzyme activities. Fr. I-L also showed inhibitory activities on the local fibrinolysis and lipid peroxidation in the gastric mucosa.
A lectin which we purified from the mucous of Ophidiidae Genypterus blacodes showed a potent mitogenic activity which was comparable to that of concanavalin A (con A). On the other hand, the lectin treated with 2-mercaptoethanol showed an anti-mitogenic activity against con A and lipopolysaccharide (LPS). Lymphocytes were separated into a T cell rich fraction and B cell rich fraction by soybean agglutinin. The mitogenic activity of G. blacodes lectin was examined using these cells. It was suggested that the mitogenic activity of G. blacodes lectin was based on the stimulation of T cells. The lectin was also subjected to both the sperm agglutination and the in vitro fertilization tests in mouse. It was demonstrated that: a) the lectin receptors were ubiquitous on sperm; b) in vitro fertilization of mouse ova was completely blocked by the binding of the lectin to the zona pellucida of the ova.
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Commercially available human IgG (native IgG) was passed through a DEAE cellulose column. Two fractions (Fr. I and Fr. II), responding equally against the anti-human IgG antibody were obtained. The carboxamide-methylated H and L chains from both fractions showed remarkable inhibitory activities on both the gastric ulceration and the gastric juice secretion in pylorus-ligated rats. The carboxamide-methylated L chain of rat IgG was also effective, while none of the human native IgG, Fr. I or Fr. II showed any effect. The reduction and the following alkylation of the interchain disulfide bonds were necessary for the induction of the biological activities of human IgG. Sulfonation of human IgG failed to induce the activities. Although the gastric acid secretion was clearly reduced by the administration of Fr. I-L (alkylated L chain of Fr. I), the gastric mucosal blood flow was not affected.
In view of the strong inhibitory effects of the carboxamide-methylated L chain (Fr. I-L) from human IgG on gastric ulceration and juice secretion, we carried out various experiments to clarify the mechanism of its action and obtained the following results. Fr. I-L inhibited the gastric ulceration induced by phenylbutazone or aspirin in rats, but no appreciable effect was observed on stress or acetic acid ulceration. The distribution of 14C-labelled Fr. I-L increased particularly in the stomach mucous membrane of rats after the intravenous or intraperitoneal administration. The hexosamine content in the gastric mucous membrane, reduced by the treatment with phenylbutazone, aspirin or pylorus-ligation, was recovered by the administration of Fr. I-L to an intact level. The high total of hexosamine levels found in the gastric juice after aspirin treatment or pylorus-ligation were decreased by the injection of Fr. I-L or cimetidine. The histochemical observation revealed that the concomitant administration of Fr. I-L with phenylbutazone or aspirin prevented the abolishment of Hematoxylin-Eosin, Periodic Acid Schiff and Alcian Blue staining polysaccharides from the stomach epithelial cells.
Among various unsaturated fatty acids which were examined in this experiment, trans-2-tridecenoic acid was found to be a potent inhibitor on gastric secretion in rats (i.p. or i.d.). Therefore, the effects of trans-2-tridecenoic acid on several experimental ulcerations in rats were examined. At the dose of 10 mg/kg, trans-2-tridecenoic acid significantly decreased the ulcer index in pylorus-ligated rats; aspirin-, phenylbutazone-, histamine- and stress-induced ulcerations were also significantly inhibited at the dose of 25 mg/kg. Finally, effects of trans-2-tridecenoic acid on hexosamine and sialic acid contents in the gastric mucous were examined. In intact or phenylbutazone-induced ulcerated rats, trans-2-tridecenoic acid increased the sialic acid levels in the gastric mucous at the dose of 25 mg/kg. The decreased hexosamine content in the gastric mucous by phenylbutazone treatment was recovered by the administration of trans-2-tridecenoic acid.
The chronic effect of TSH on thyroidal cAMP concentrations and release of thyroid hormones was investigated using human thyroid tissue in organ culture. Normal human thyroid slices were placed in HAM's F-10 synthetic culture medium in Falcon organ tissue culture dishes, and incubated at 37 degrees in a humidified atmosphere of 5% CO2 in air. Medium was changed everyday and daily T3 or T4 release was determined using concentration of T3 or T4 in the medium. After incubation, slices were transferred to the medium containing 10 mM theophylline and incubated without TSH for an additional 30 min to determine thyroidal cAMP concentrations. Thyroidal cAMP concentrations in slices incubated with 10 mU/ml of TSH increased significantly at 2, 6, and 24 hr and even on the 6th day of incubation. Daily T3 release was significantly increased above control from the 3rd day and daily T4 release from the 4th day to the 11th day of incubation with 10 mU/ml of TSH. Histologically, almost all follicles were structurally maintained even on the 11th day of incubation. These results suggest that both thyroidal cAMP concentrations and release of thyroid hormones are stimulated chronically by TSH. This organ culture system is useful for investigating chronic effects of various materials on human thyroid tissue.
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