4'-Deacetyl-(-)-griseusins A and B, new naphthoquinone antibiotics from an actinomycete.
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Biomedical subjects
Publications and source records attributed to T Takeuchi.
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Antitumor effect of cytogenin against IMC carcinoma in mice was investigated. Since cytogenin did not show cytotoxicity against tumor cells in vitro at 50 micrograms/ml and toxicity at more than 2,000 mg/kg i.p., it was considered that the antitumor effect is due to host mediated events. Cytogenin showed antitumor activity against a syngeneic murine transplantable tumor, IMC carcinoma by oral administration depending upon schedule of administration. The optimum effect was observed by the administration starting day 8 after transplantation of tumor cells, every other day for 10 times or every 2nd day for 7 times. The antitumor effect was reduced in immunosuppressed mice given anti-asialo GM1 serum and in athymic mice, but not in mice irradiated with X ray. The antitumor effector cells activated by cytogenin were determined to be macrophages and T cells.
A new structural class of the antibiotic, azicemicins A (1) and B (2) were isolated from the culture broth of the strain MJ126-NF4, which was closely related to Amycolatopsis sulphurea. They were purified by adsorption on Diaion HP-20, silica gel column chromatography and preparative TLC. The molecular formulas of 1 and 2 were determined to be C23H25O9N and C22H23O9N by HRFAB-MS, respectively. Azicemicins A and B have moderate growth inhibiting activity against Gram-positive bacteria and mycobacteria.
The antitumor efficacy of antitumor agents at sublethal doses was investigated in combination with conagenin (CNG) against murine leukemias. Mice were inoculated with 1 x 10(3) L1210 cells i.v. and given 300 mg/kg of cyclophosphamide (CY) i.p. on days 1 and 2 or on days 1, 5 and 9 after the tumor inoculation, and 5 mg/kg of CNG daily for 10 days. The administration of CNG was effective in increasing the number of cured mice and in prolonging the survival period of mice significantly, on both schedules of CY treatment. Moreover, the antitumor effect of CY against EL-4 was enhanced by CNG in increasing the number of cured mice, in CY treatment on days 1 and 2, and on days 1, 5 and 9. The effect of CNG was examined with mitomycin C (MMC) and adriamycin (ADM) at sublethal doses against leukemias. The antitumor effects of MMC at 10 mg/kg against L1210, and ADM at 15 mg/kg against P388 administered on days 1 and 5 were enhanced by CNG. Although mice treated with ADM at 15 mg/kg died earlier than non-treated controls on days 1 and 2 against L1210, P388 and EL-4, CNG with ADM was effective in prolonging the survival period.
Action of cytogenin on macrophages and T cells was investigated. Phagocytosis of yeast and production of PMA-elicited superoxide anion by macrophages taken from mice given cytogenin po were augmented. Cytogenin enhanced productions of IL-1 alpha by macrophages and IFN gamma and GM-CSF by spleen cells although it did not enhanced production of TNF alpha by macrophages and IL-6 by macrophages and spleen cells. Macrophages stimulated with cytogenin caused to stimulate proliferation of purified T cells in Intercell cultures in which each cell population was cultured without contact. Results suggest that cytogenin primarily activates macrophages to produce monokines such as IL-1 alpha and it causes to stimulate proliferation and differentiation of T cells resulting in production of lymphokines such as IFN gamma and GM-CSF.
Cytogenin recovered the reduced mitogenic response to Con A of spleen cells of tumor bearing mice in vitro. The suppressive factor(s) was detected in adherent cell population in spleen cells. The reduced antitumor effector activity of spleen cells taken from tumor bearing mice was also augmented by the treatment with cytogenin in vitro. The effect of cytogenin was neutralized by the treatment with anti-Mac 1 serum. Administration of cytogenin inhibited the production of nitric oxide by macrophages which is known as one of suppressor factors. Results indicate that one possible action of cytogenin exhibiting antitumor activity in tumor bearing mice may be due to modulation of Mac 1 positive cells.
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New triene-ansamycins designated thiazinotrienomycins A, B, C, D and E were isolated from culture broth of Streptomyces sp. MJ672-m3 for their activities against cervical cancer cell lines. The structures and some biological and biochemical properties of the antibiotics were determined.
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In the course of our screening for inhibitors of abl oncogene function, a culture filtrate of Streptomyces aculeolatus, induced normal flat morphology in v-abl-expressing NIH3T3 cells. The active substance was isolated through ethyl acetate extraction, silica gel column chromatography, and reverse-phase HPLC. Mass and NMR spectroscopy including HMBC revealed that it had a novel naphthoquinone structure with a monoterpene, and we named it "naphthablin". Naphthablin inhibited Abl-induced morphological transformation in v-ablts-NIH3T3 cells at around 30 micrograms/ml, and specifically inhibited RNA synthesis.
Acute myocardial infarction (AMI) causing ST depression and T wave inversion has been diagnosed as subendocardial or non-Q myocardial infarction. However, some patients eventually develop strictly posterior infarction with a lesion of the left circumflex coronary artery (LCX). This study attempted to determine the electrocardiographic (ECG) characteristics of such myocardial infarction in 32 patients with definite AMI in whom ECG showed no hyperacute T waves or ST elevation and the LCX was an infarct-related coronary artery. ECG on admission (< 6 hours from the onset), at 24 hours, and on the 14th day were analyzed to evaluate QRS, ST, T, and U waves using calipers and magnifying lens. Sixty-six patients with normal circulation served as controls. The characteristic ECG findings on admission were ST depression in chest leads, and prominent positive U waves in leads V2 or V3 with relatively small T waves. Based on these results we proposed new ECG criteria: 1) ST depression > or = 0.1 mV in 2 consecutive chest leads, 2) prominent positive U wave > or = 0.1 mV in leads V2 or V3, 3) T/U ratio in leads V2 or V3 < or = 4. Considering two of the above criteria as positive, the sensitivity was 71.9%, the specificity 97.0%, and the diagnostic accuracy 88.8%. In 85.2% of the patients, ST depression returned to the baseline by 24 hours. As the amplitude of the U waves decrease gradually, the T/U ratio increased. The R/S ratio in leads V1 or V2 became > or = 1 by 24 hours in 46.4% and the amplitude of R wave in lead V1 increased gradually. T waves in the right precordial leads increased with time. These findings were consistent with isolated strictly posterior myocardial infarction. From these results we identified new ECG criteria: 1) R/S ratio in leads V1 or V2 > or = 1, 2) R wave > or = 0.7 mV in lead V1, 3) T wave > or = 0.5 mV in lead V1. Considering any of the above criteria as positive, the sensitivity was 72.0%, the specificity 87.9%, and the diagnostic accuracy 86.7% on the 14th day. These new ECG criteria of strictly posterior myocardial infarction with the LCX as an infarct-related coronary artery apply at less than 6 hours or at 24 hours from the onset of the symptoms.
Necessity of newly synthesized ATP by creatine kinase for synthesis of ATP as an energy source for smooth muscle contraction was studied in permeabilized longitudinal muscle preparations of rat proximal colon. In alpha-toxin-permeabilized preparations, Ca++ induced "phasic type" contraction in a normal bath solution containing 4 mM ATP and 5 mM phosphocreatine. Omission of phosphocreatine from the solution resulted in significant decrease in phasic contraction, and omission of ATP resulted in loss of the response to Ca++. When ADP, but not adenosine-5-O-(2-thiodiphosphate), with phosphocreatine was added as a substitute for ATP, Ca++ induced the same type of contraction as with ATP. The maximum tensions of the phasic and tonic phases of the contraction with ADP were approximately 60% of, and almost the same, respectively as those with ATP. A selective inhibitor of creatine kinase, 2,4-dinitrofluorobenzene, inhibited the phasic contraction induced by Ca++. After irreversible inhibition of endogenous creatine kinase by DNFB in beta-escin-permeabilized preparations, treatment of the preparations with exogenous creatine kinase restored Ca(++)-induced contraction. These findings suggest that ATP synthesized from ADP and phosphocreatine by creatine kinase was necessary for phasic contraction of permeabilized smooth muscle and that exogenous ATP was mainly used after its hydrolysis to ADP.
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We report a successful case of anomalous origin of the right pulmonary artery from the ascending aorta. A 34 days old infant, who had suffered from cardiogenic shock, underwent a direct anastomosis of the right pulmonary artery to the main pulmonary artery behind the ascending aorta under cardiopulmonary bypass. Postoperative catheterization showed no significant stenosis over the anastomosis and normalized pulmonary artery pressure. We conclude that early surgical correction is necessary in the treatment of this life threatening disease.
A 4-year-old child underwent one-stage total correction for type A IAA with VSD in 1975 as the first successful case in Japan. At age 21, a gradual rise in her upper limb pressure to 190 mmHg prompted repeat catheterization, which showed a pressure gradient across the EPTFE graft of 58 mmHg. Under general anesthesia in the right lateral position, the patient's left thorax was reopened. The EPTFE graft had undergone patchy calcific degeneration and was significantly hardened. An 18-mm Toray graft preclotted with fibrin glue was anastomosed to the left subclavian artery in side-to-end fashion. Its distal end was anastomosed to the descending aorta distal to the EPTFE bypass during a 20-minute aortic occlusion. The postoperative recovery was uneventful and the pressure gradient between the upper and lower limbs fell to 0 at discharge. We chose this method for reoperation of type A IAA and CoA because of the reduced need for dissection and better effectiveness.
We studied the involvement of protein kinase C (PKC) and a small GTP-binding protein (G-protein), rho, in receptor-mediated Ca2+ sensitization of the contractile apparatus of smooth muscle of guinea pig vas deferens. In beta-escin-permeabilized smooth muscle strips, norepinephrine (NE) in the presence of GTP caused further contraction of the preparations at a constant Ca2+ level (Ca2+ sensitization). Prazosin and GDP beta S, a nonhydrolyzable GDP analogue, inhibited NE-induced Ca2+ sensitization, indicating an alpha-1 adrenoceptor/G-protein mediated response. GTP alone (> 10 microM) and GTP gamma S, a non-hydrolyzable GTP analogue, also induced Ca2+ sensitization. Pretreatment of preparations with C3 exoenzyme of Clostridium botulinum, which is known to ADP-ribosylate rho family proteins, with NAD resulted in complete inhibition of NE- and GTP (GTP gamma S)-induced Ca2+ sensitization. AIF4-, which activates heterotrimeric G-, but not small G-protein also induced Ca2+ sensitization. Interestingly, AIF4(-)-induced Ca2+ sensitization was inhibited by not only GDP beta S but also C3-treatment, suggesting that activation of heterotrimeric GTP-binding protein precedes activation of rho protein. On the other hand, phorbol 12,13-dibutyrate, like NE, also induced Ca2+ sensitization. The sensitization was inhibited by PKC(19-31), a PKC inhibitor peptide. However, PKC(19-31) did not have any effect on NE- or AIF4(-)-induced Ca2+ sensitization.(ABSTRACT TRUNCATED AT 250 WORDS)