Biomedical subjects
Publications and source records attributed to F Abe.
Eleven pregnanes were isolated from the hydrolysate of the CHCl3 extract fractionated from the caules of Hoya carnosa. Among these, six pregnanes, including 19-acetoxydigipurpurogenin II, were new, and their structures were elucidated. The structures of twenty new pregnane tetraosides and pentaosides, named hoyacarnosides A-T, besides three known ones from the CHCl3 extract, were determined.
Five new glycosides of 14,15-seco- and 13,14:15-diseco-type pregnanes, including a new pregnane, 2 alpha-hydroxyhirundigenin, were isolated, in addition to one known glycoside, cynatratoside B, from the roots of Tylophora tanakae Maxim. Their structures were elucidated by spectral and chemical means.
Hydrostatic pressure is a distinctive feature of deep-sea environments, and this thermodynamic parameter has potentially inhibitory effects on organisms adapted to living at atmospheric pressure. In the yeast Saccharomyces cerevisiae, hydrostatic pressure causes a delay in or cessation of growth. The vacuole is a large acidic organelle involved in degradation of cellular proteins or storage of ions and various metabolites. Vacuolar pH, as determined using the pH-sensitive fluorescent dye 6-carboxyfluorescein, was analyzed in a hydrostatic chamber with transparent windows under elevated hydrostatic pressure conditions. A pressure of 40-60 MPa transiently reduced the vacuolar pH by approximately 0.33. A vma3 mutant defective in vacuolar acidification showed no reduction of vacuolar pH after application of hydrostatic pressure, indicating that the transient acidification is mediated through the function of vacuolar H(+)-ATPase. The vacuolar acidification was observed only in the presence of fermentable sugars, and never observed in the presence of ethanol, glycerol, or 3-o-methyl-glucose as the carbon source. Analysis of a glycolysis-defective mutant suggested that glycolysis or CO2 production is involved in the pressure-induced acidification. Hydration and ionization of CO2 is facilitated by elevated hydrostatic pressure because a negative volume change (delta V < 0) accompanies the chemical reaction. Moreover the glucose-induced cytoplasmic alkalization is inhibited by elevated hydrostatic pressure, probably because of inhibition of the plasma membrane H(+)-ATPase. Therefore, the cytoplasm tends to become acidic under elevated hydrostatic pressure conditions, and this could be crucial for cell survival. To maintain a favorable cytoplasmic pH, the yeast vacuoles may serve as proton sequestrants under hydrostatic pressure. We are investigating the physiological effects of hydrostatic pressure in the course of research in a new experimental field, baro-(piezo-) physiology.
In addition to huratoxin, pimelea factor P2, and wikstroelides A-G from the fresh bark, eight daphnane-type diterpenoids, wikstroelides H-O, were isolated from the bark and stem, and their structures established. Cytotoxicity was assayed on some wikstroelides.
The extent of intracellular accumulation of the fluorescent dye carboxyfluorescein or carboxydichlorofluorescein (CDCF) in Saccharomyces cerevisiae was found to be increased 5- to 10-fold under a nonlethal hydrostatic pressure of 30 to 50 MPa. This observation was confirmed by analysis of individual labeled cells by flow cytometry. The pressure-induced enhancement of staining with CDCF required D-glucose and was markedly inhibited by 2-deoxy-D-glucose, suggesting that glucose metabolism has a role in the process.
In addition to ten alkaloids previously described, we have isolated two alkaloid N-oxides from Tylophora tanakae MAXIM. (Asclepiadaceae). Further, the polar fraction of the leaves and caules of this plant cultivated in a farm afforded two new polar alkaloids. The structures of the four products were determined. The relation between the structure and cytotoxic activity of this group of alkaloids is discussed.
Combined androgen blockade using a pure antiandrogen in association with a LHRH agonist or surgical castration is the most logical approach. This paper demonstrated that flutamide combined with leuprorelin acetate produced a significant reduction in the growth rate of Dunning R3327-H prostatic adenocarcinoma. Dunning R3327-H prostatic adenocarcinoma, provided by Dr. Norman H. Altmann (University of Miami, USA) was subcutaneously inoculated into the lateral region of male Copenhagen x Fischer F1 hybrid rat abdomen. The efficacy of the tumor growth rate was evaluated by measuring tumor size at 10 weeks after the inoculation. Flutamide was orally administered for 10 weeks and leuprorelin acetate was subcutaneously administered every 4 weeks. The effective dose of flutamide and leuprorelin acetate was determined in preliminary studies, and the following doses were used in the study; 15 mg/kg for flutamide, 0.1 mg/kg or 0.4 mg/kg for leuprorelin acetate. In combination of flutamide with leuprorelin acetate at 0.1 mg/kg and 0.4 mg/kg, the tumor inhibition was 94% and 97%, respectively. In addition, the weight of accessory sex organs coincided with the antitumor effect. Taking the above results into consideration, combined androgen blockade using flutamide and leuprorelin acetate may have some beneficial effect on prostatic cancer.
The administration of tranexamic acid (TA), an antifibrinolytic agent, prior to cardiopulmonary bypass (CPB) has been reported to reduce bleeding after cardiac surgery. In a retrospective clinical trial, 99 adults patients undergoing open heart surgery received TA (CABG, TA (+): n = 20; Valve replacement, TA (+): n = 20) or did not receive TA (CABG, TA (-): n = 20: Valve replacement, TA (-): n = 19). In the TA group, just after induction of general anesthesia, a 160 mg.kg-1 dose of TA was administered intravenously. In each group, bleeding volumes during operation, and at 6 and 24 hours after operation, were compared. Patients of [CABG, TA (+)] group had significantly less intraoperative and total blood loss [total blood loss 608 g : 313 g, intraoperatively, 134 g at 6 hours, and 296 g at 24 hours] compared with [CABG, TA (-)] group (total blood loss 1043 g: 640 g, intraoperatively, 232 g at 6 hours, and 403 g at 24 hours). Additionally, in patients of Valve replacement, TA (+) group had less but not significant total blood loss (total blood loss 903 g: 523 g, intraoperatively, 173 g at 6 hours, and 380 g at 24 hours) compared with TA (-) group (total blood loss 1237 g: 863 g, intraoperatively, 214 g at 6 hours, and 374 g at 24 hours). TA administered prior to CPB may reduce the amount of bleeding during and after cardiac surgery.
Toremifene (TOR) is a new antiestrogenic agent, a triphenylethylene derivative that was developed as an alternative to tamoxifene (TAM). TOR has been observed to be more effective than TAM with milder toxicity at high doses. We examined the in vitro combination-effect of TOR with cyclophosphamide, adriamycin, 5-fluorouracil and three drug mixture (CAF) on the growth of various human mammary carcinomas. The combination shows a semi-additive or additive growth inhibitory effect on all estrogen positive cells used here except one cell line. In particular, the additive or synergic combination-effect was observed on TAM resistant cells. Furthermore, TOR exhibits a chemosensitizing activity in ADR-resistant cells by expressing P-glycoprotein coded by MDR-1 (multidrug resistance gene). The chemosensitizing activity is dose-dependent of TOR. As described above, the combination of TOR with CAF shows more than a semi-additive effect in this experiment. In conclusion, the addition of high-dose TOR to CAF therapy might be useful for advanced/recurrent breast cancer.
Annexin VII is believed to be required for proper Ca(2+)-homeostasis in Dictyostelium discoideum cells. As was previously reported, the expression of Annexin VII gene increased during the transition of D. discoideum Ax-2 cells from growth to differentiation. We have casually cloned an interesting gene, Quit3, by the differential plaque hybridization. Quit3 had no coding region, and was expressed more predominantly in the growth phase than in the differentiation phase. Unexpectedly, this gene was found to encode the complementary sequence of Annexin VII. Therefore, it is most likely that the Quit3 mRNA may regulate the Annexin VII synthesis by the natural antisense transcript via an antisense RNA-RNA interaction, thus resulting in striking increase of Annexin VII production in the phase-shift of cells from growth to differentiation. Since Annexin VII is known to be coded for by a single gene in Dictyostelium, the antisense RNA seemed to be encoded in the same genetic locus as the Annexin VII mRNA.
We analyzed the vacuolar acidification in response to elevated hydrostatic pressure in Saccharomyces cerevisiae. The vacuolar pH, defined using 6-carboxyfluorescein, was directly measured in a hyperbaric chamber with a transparent window under high hydrostatic pressure. The vacuole of strain X2180 became acidified at the onset of pressurization to an extent dependent on the magnitude of pressure applied. A pressure of 40-60 MPa transiently reduced the vacuolar pH by about 0.33 within 4 min. The transient acidification was observed in the presence of D-glucose, D-fructose, or D-mannose as a carbon source, but not 3-o-methyl-D-glucose, ethanol, or glycerol, suggesting that the generation of CO2 was involved in the process. A vma3 mutant defective in vacuolar acidification showed no reduction of vacuolar pH when hydrostatic pressure was applied. This result indicates that the transient vacuolar acidification induced by elevated hydrostatic pressure is mediated through the function of the vacuolar H+-ATPase.
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