Biomedical subjects
Publications and source records attributed to S Hata.
A 74 yo female was found to have bullous dermal amyloidosis on the background of systemic amyloidosis with multiple myeloma. There was monoclonal immunoglobulin light chain of kappa type in the serum with no proteinuria (Bence Jones proteinemia without Bence Jones proteinuria), along with proliferations of kappa-producing plasma cells in the marrow.
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The effects of 1,2-bis(nicotinamido)propane (AVS) on platelet function and vascular endothelium were investigated using various experimental thrombosis and vascular endothelial injury models. Neither in vitro platelet aggregation induced by ADP, collagen or arachidonate nor ex vivo platelet aggregation by ADP or collagen could be antagonized by AVS. On the other hand, AVS prevented mice, rats and rabbits from death induced by acute cerebral or pulmonary thromboembolism following the injection of arachidonate or collagen. These activities were as potent as those of acetylsalicylic acid. The disrupting actions of citrate and/or lipidperoxide (13-hydroperoxy linoleic acid) on endothelium were well inhibited by the pretreatment of AVS. AVS did not inhibit cyclooxygenase, increased prostacyclin (PGI2)/thromboxane A2 (TXA2) ratio in the coupled system of platelets and aortic microsomes. In conclusion, AVS inhibited thrombus formation in vivo while it was ineffective in vitro platelet alone system, which may result from the actions of this agent on both platelets and vascular endothelium. The above-mentioned results clearly show that AVS may be a new potent anti-vascular damaging agent with both endothelium stabilizing and PGI2 enhancing activities.
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Effects of 13-hydroperoxy linoleic acid on coronary circulation and vasculature were investigated using an electrocardiographic (ECG) and scanning electron microscopic (SEM) techniques. After the intra left ventricular injection of 13-hydroperoxy linoleic acid to rats the ischemic ECG changes, i.e., elevations of the ST segment and T wave, were observed with the reduction of systemic blood pressure and heart rate. By the SEM examination, the endothelial injuries were found with the platelet aggregation in the blood flow and the adherence of leukocytes. Thus it was clearly found that 13-hydroperoxy linoleic acid caused the various endothelial injuries and thrombus formation leading to coronary arterial occlusion. These results suggest that lipid peroxide may play an important role in the pathogenesis of vascular diseases especially in coronary vascular bed and take part in the generation of the severe myocardial ischemia.
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Discrimination of cytochrome P-450 involved in delta 22-desaturation of ergosta-5,7-dien-3 beta-o1 (P-450(22)-DS) from that involved in lanosterol 14 alpha-demethylation (P-450(14)-DM) in ergosterol biosynthesis was investigated with microsomes of several strains of Saccharomyces cerevisiae. In mutant N22 which is partially defective in the delta 22-desaturation, the 14 alpha-demethylation was not blocked. In contrast, mutant SG1 which is known to lack the 14 alpha-demethylation showed a significant activity of the delta 22-desaturation. The delta 22-desaturation activity was markedly increased upon aerobic adaptation of yeast cells but the 14 alpha-demethylation was not affected. Buthiobate, a specific inhibitor of P-450(14)-DM, and rabbit antibodies against P-450(14)-DM did not inhibit the delta 22-desaturation activity at all. It is evident from the obtained observations that these phenomena are not explainable in terms of NADPH-cytochrome P-450 reductase. These results indicate that P-450(22)-DS is different from P-450(14)-DM in molecular species.
Buthiobate (S-n-butyl S'-p-tert-butylbenzyl N-3-pyridyldithiocarbon-imidate), a fungicide, inhibited 14 alpha-demethylation of lanosterol catalyzed by a reconstituted enzyme system consisting of cytochrome P-450 (P-450(14)-DM) and NADPH-cytochrome P-450 reductase both purified from Saccharomyces cerevisiae. Concentration of buthiobate necessary for the 50% inhibition was 0.3 microM and this value was markedly lower than those of metyrapone and SKF-525A. Buthiobate bound stoichiometrically to P-450(14)-DM and induced Type II spectral change of the cytochrome. Buthiobate inhibited lanosterol-dependent enzymatic reduction of the cytochrome. These facts indicate that buthiobate binds to P-450(14)-DM with high affinity and acts as a potent inhibitor on the cytochrome.
Spectroscopic and enzymatic analysis of a Saccharomyces cerevisiae mutant in sterol biosynthesis (SG1 (erg 11); Trocha, P. J., Jasne, S. J., and Sprinson, D. B. (1977) Biochemistry 16, 4721-4726) that was blocked in demethylating C-32 of lanosterol (4,4,14 alpha-trimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol) showed that it contained low levels of cytochromes P-450 and b5 compared to those present in the parent strain D-587, while NADPH-cytochrome c reductase activity was elevated. The fungicide buthiobate (S-n-butyl S'-p-tert-butylbenzyl N-3-pyridyldithiocarbonimidate), which bound specifically to yeast cytochrome P450 responsible for demethylating C-32 of lanosterol and effected a Type II spectral change, did not react with SG1 cytochrome P-450. On the other hand, cholate-solubilized microsomes from SG1 formed a single precipitin line on Ouchterlony plates with antibodies raised against purified (Yoshida, Y., Aoyama, Y., Kumaoka, H., and Kubota, S. (1977) Biochem. Biophys. Res. Commun. 78, 1005-1010) yeast cytochrome P-450 specific for demethylating C-32 of lanosterol. Hence, mutant SG1 contained an altered protein which retained the antigenicity of cytochrome P-450 responsible for demethylating C-32 of lanosterol but lost its catalytic activity.
Lobenzarit disodium (CCA) has been reported to have an inhibitory effect on the development of adjuvant arthritis (AA) in rats. Earlier studies have suggested that the therapeutic effect of CCA might be based on its immunoregulatory activity, although the precise mechanisms of action are unclear. In this paper, possible involvement of thymus-derived lymphocytes in the suppression of AA was studied. It was found that CCA failed to inhibit the development of AA in rats whose T lymphocytes were depleted by the injection of rabbit antithymocyte serum (ATS), whereas the same schedule of treatment with CCA significantly suppressed AA developed in control rats which were injected with normal rabbit serum. In addition, adult thymectomy abrogated the antiarthritic effect of CCA. These data suggest the possibility that the therapeutic effect of CCA in AA might be mediated by ATS-sensitive, short-lived, thymus-derived lymphocytes.
A newly synthesized agent, disodium 4-chloro-2,2'-iminodibenzoate (CCA; Lobenzarit disodium), which prevents the development of autoimmune disease in B/W mice, and inhibits adjuvant arthritis in rats, was investigated to clarify its mode of action in B/W mice. CCA protected against the age-related decline of the suppressor T cell activity which played an important role in the regulation of both humoral and cell-mediated immunity. CCA also decreased the production of naturally occurring thymocytotoxic autoantibody (NTA) preferentially cytotoxic against the thymocytes and suppressor T cells, and inhibited both the antibody production to double-stranded DNA and the appearance of ANA in B/W mice.
A method was tested to detect both tumors and somatic mutations in mice. When HT-A/J F1 embryos were treated with ethylnitrosourea on day 11 of gestation, a single injection was enough to induce tumors and presumed somatic mutations of coat color in significantly high incidence. Urethane, treated in a similar way, induced somatic mutations and malformations in the offspring. Tumor incidence was also increased but was not significantly different from controls. Treatment on day 13 was too late to induce somatic mutations and malformations, while high incidence of tumors were induced.
A series of 30 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives was prepared and tested for their ability to reduce blood pressure in conscious, spontaneously hypertensive rates (SHR). A number of these compounds, notably 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazolines 3a (R1 = H; R2 = Ph), 3j (R1 = H; R2 = 4-EtOPh), and 5a (R1 = H; R2 = 2-furyl), showed activity at oral doses of 0.3-10 mg/kg. The effects of the 4-substituents of the piperazino group on activity are discussed. Compounds 3a, 3j, and 5a were effective in renal hypertensive rats at oral doses of 3 and 10 mg/kg and showed alpha-adrenoceptor blocking effects in isolated aortas of rats. A 5-day consecutive oral administration of 3a and 3j in SHR did not lead to development of tolerance.
Syngeneic SL mice inoculated with murine myeloid leukemia cells (M1) all died of leukemia within 30 days. Treatment three times a week with 12.5-50 pmol per mouse of either 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], the active form of vitamin D3, or its synthetic analog, 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3], considerably prolonged the survival time of mice inoculated with M1 cells. 1 alpha(OH)D3 was more effective than 1 alpha,25(OH)2D3 in increasing the survival time of the mice. 1 alpha(OH)D3 also increased the survival time of nude mice inoculated with M1 cells. The 1 alpha(OH)[3H]D3 administered intraperitoneally to tumor-bearing mice was converted very rapidly to 1 alpha,25(OH)2-[3H]D3. The chronic administration of 25 pmol of 1 alpha(OH)D3 to tumor-bearing mice for 30 days caused no appreciable hypercalcemia. These results indicate clearly that 1 alpha,25(OH)2D3 is effective not only in inducing differentiation of M1 cells in vitro, as previously reported [Abe, E., Miyaura, C., Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshiki, S. & Suda, T. (1981) Proc. Natl. Acad. Sci. USA 78, 4990-4994], but also in prolonging the survival time of mice inoculated with M1 cells.
Analysis of sterols was made with a Saccharomyces cerevisiae mutant, N22, which was resistant to nystatin and defective in ergosterol synthesis, and with its parent strain, M10 (haploid type, methionineless, petite). The main sterol of M10 was ergosterol, whereas that of N22 was ergosta-5,7-dien-3 beta-ol. A small amount of ergosterol was found also in N22. This indicates that the delta 22-desaturation reaction in N22 is blocked, though not completely. Ergosta-5,8-dien-3 beta-ol, an unusual sterol, was detected in N22 but not in M10. Variations in the amounts and compositions of free and esterified sterols of both strains were examined during cultivation and the subsequent aerobic adaptation. The contents of free sterols, which were mostly composed of the respective main sterols of both strains, did not change markedly. In contrast, the contents and compositions of esterified sterols of both strains varied depending on the growth conditions. When the cells of both strains were aerobically adapted, the total contents of esterified sterols increase, as did, as the intermediate sterols. Upon aerobic adaptation in the presence of [methyl-14C]methionine, [28-14C]ergosta-5,7-dien-3 beta-ol accumulated markedly in N22 cells. Using this mutant, we devised a convenient method for preparation of the radioactive sterol in high yield.
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