Origin of Tc suppression due to R=Eu, Nd, and Pr in superconducting (La1-xRx)1.82Sr0.18CuO4.
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Journal Article↗
Biomedical subjects
K Umezawa
Publications and source records attributed to K Umezawa.
Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small cell lung carcinoma cells.
Tyrosine kinase inhibitor, erbstatin, induced morphological apoptosis and DNA fragmentation in human small cell lung carcinoma (SCLC) cells. Erbstatin-induced apoptosis was inhibited by antioxidants, whereas erbstatin-inhibited tyrosine phosphorylation was not affected by them. Erbstatin was shown by means of flow cytometry to induce hydrogen peroxide generation. Furthermore, hydrogen peroxide induced morphological apoptosis and DNA fragmentation in the SCLC cells. We also demonstrated that erbstatin-induced hydrogen peroxide production and DNA fragmentation were partially suppressed by inhibition of protein synthesis. Thus, erbstatin-induced apoptosis would be due to hydrogen peroxide generation via newly synthesized protein.
Antioxidants↗
Dissociated release of tetrahydrobiopterin and nitric oxide by lipopolysaccharide from mouse neuroblastoma cells.
We examined the release of tetrahydrobiopterin ((6R)-L-erythro-dihydroxypropyl-2-amino-4-hydroxy-5,6,7, 8-tetrahydropteridine; BH4) and nitric oxide induced by lipopolysaccharide from mouse neuroblastoma N1E-115 cells by measuring BH4 and nitric oxide derivatives, nitrites and nitrates, harbored in the conditioned media. The stimulation of the cells by 1 microgram/ml of lipopolysaccharide for 24 h induced 2-fold increase in the release of BH4 from the cells, but did not induce the nitric oxide release from the cells. Although such increase in BH4 release from the cells was blocked by the inhibitors of nuclear factor-kappa B or protein tyrosine kinases, the release of nitric oxide was not affected by such inhibitors. Our results may suggest that the inductions of BH4 and nitric oxide in this neuroblastoma cell line are processed in different ways and that this cell line is also different from the immune cells in the central nervous system such as microglia in this respect.
Animals↗
Inhibition of experimental metastasis by enzyme inhibitors from microorganisms and plants.
Various antibacterial compounds, antitumor compounds, enzyme inhibitors and recent signal transduction inhibitors have been discovered from microorganisms and plants. Therefore, it should be possible to find antimetastatic compounds from these sources, if a simple assay system is available. We isolated several enzyme inhibitors from nature to inhibit experimental metastasis. Leupeptin is an old protease inhibitor and inhibited blood-borne lung metastasis of hepatoma cells in rats. A leupeptin analogue inhibiting urokinase inhibited in vitro invasion of human fibrosarcoma cells. Alpha-glucosidase inhibitors such as epi-CPL and baicalein inhibited in vitro invasion and in vivo metastasis of mouse melanoma cells. A mannosidase inhibitor, mannostatin A, also inhibited in vitro invasion of mouse melanoma cells. Oncogene function inhibitors induce normal phenotypes in the oncogene-expressing cells. As expected, they inhibited tumor cell invasion in vitro.
Animals↗
Isolation and synthesis of novel farnesyl protein transferase inhibitors, valinoctins A and B, from Streptomyces strain MJ858-NF3.
Two novel farnesyl protein transferase inhibitors, valinoctins A (1) and B (2), were isolated from the fermentation broth of Streptomyces strain MJ858-NF3. The tentative structures of these compounds were elucidated from NMR and mass spectra as dipeptides consisting of valine and a novel amino acyl moiety. Four possible isomers of valinoctin A were synthesized, and the protected derivative of the appropriate compound was crystallized to give the relative stereochemistry of X-ray analysis. Since the valine residue of valinoctin A was determined to be the L-configuration by a chiral HPLC column, absolute configuration of valinoctin A was determined.
Animals↗
Cyclopentabenzofuran lignan protein synthesis inhibitors from Aglaia odorata.
In the course of screening for Ras function inhibitors, rocaglaol (1) and the related compounds, the known pyrimidinone (2) and the novel aglaiastatin (3), were isolated from a CHCI3 extract of the leaves of Aglaia odorata. The structure of 3 was elucidated as a novel cyclopentabenzofuran on the basis of its NMR spectroscopic data and by X-ray crystallographic analysis. These compounds (1-3) were potent inhibitors of the growth of K-ras-NRK cells, with IC50 values of 1-10 ng/mL, and induced normal morphology in K-ras-NRK cells at 10-30 ng/mL. They also specifically inhibited protein synthesis. Aglaiastatin (3) was slightly more potent than 1 and 2 in inhibiting cell growth. Aglaiastatin (3) reduced the amount of Ras, possibly by inhibiting its de novo synthesis.
Animals↗
Tetrahydrobiopterin biosynthesis enhanced by lipopolysaccharide stimulation in murine neuroblastoma cell line N1E-115.
We investigated for the first time the effect of lipopolysaccharide and the signal transduction pathway on the biosynthesis of tetrahydrobiopterin [(6R-L-erythro-1',2'-dihydroxypropyl) -2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine], the cofactor for the enzymatic hydroxylation of the aromatic amino acids, in the murine neuroblastoma cell line N1E-115, which synthesizes tetrahydrobiopterin constitutively. Activation of N1E-115 cells with 1 microgram/ml lipopolysaccharide resulted in statistically significant increases in both intracellular tetrahydrobiopterin contents and the activity (Vmax) of GTP cyclohydrolase I, a rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis. Following simultaneous addition of the inhibitors of protein tyrosine kinases and GTP-binding proteins into serum-free culture media with lipopolysaccharide, we analyzed the transduction pathway of lipopolysaccharide signal toward the tetrahydrobiopterin biosynthetic system in N1E-115 cells. Our data indicate the following conclusions: (a) Protein tyrosine kinase systems are involved in mediating lipopoly-saccharide signal to tetrahydrobiopterin production, and (b) there may be a cross-talk between GTP-binding protein and the protein tyrosine kinase system in mediating lipopolysaccharide signal. These observations suggest that a neuronal cell such as N1E-115, which barely expresses CD14 on its cell surface, responds to lipopolysaccharide like macrophages and monocytes in the absence of soluble CD14.
Animals↗
Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin, a phosphatidylinositol synthesis inhibitor.
We previously reported that inostamycin, an inhibitor of CDP-DG: inositol transferase, inhibited cell proliferation in normal rat kidney (NRK) cells by blocking cell cycle progression at the G1 phase. In the present paper, we report the effect of inostamycin on the serum-induced activation of Ser/Thr protein kinases that are involved in G1 progression. In quiescent NRK cells mitogen-activated protein kinase (MAP kinase) and casein kinase II were activated within 15 min after serum addition. Neither activation was affected by the treatment with inostamycin. However, in the inostamycin-treated cell, cyclin-dependent kinase 2 (CDK2) failed to be activated after serum stimulation. Since serum-induced expression of cyclin E was also suppressed by inostamycin, this inhibitor would appear to block CDK2 activation by inhibiting cyclin E expression. Furthermore, inostamycin also inhibited cyclin D1 expression induced by serum; and consequently, hyperphosphorylation of retinoblastoma protein (pRB) by RB-kinases such as CDK4 and CDK2 was abolished, which would result in elimination of functional inactivation of pRB. Thus, early G1 arrest in NRK cells by inostamycin is due to the inhibition of cyclin D1 and E expressions.
Animals↗
Stereospecific synthesis of a novel farnesyl protein transferase inhibitor, valinoctin A and its analogues.
(2S,3R)-3-Amino-2-hydroxyoctanoic acid was synthesized by Curtius rearrangement of an azide derivative of (S)-malic acid. Total syntheses of valinoctin A and its analogues were achieved by a coupling of (2S, 3R)-3-amino-2-hydroxyoctanoic acid moiety with L-valine or several other amino acids moieties. 2S configuration of 3-amino-2-hydroxyoctanoic acid moiety was found to be important for the inhibitory activity and the L-valine moiety of valinoctin A was exchangeable with other L-amino acids.
Alkyl and Aryl Transferases↗
Isolation of novel saquayamycins as inhibitors of farnesyl-protein transferase.
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Actinomyces↗
Growth inhibition of K-ras-expressing tumours by a new vinca alkaloid, conophylline, in nude mice.
Conophylline, a new vinca alkaloid isolated from the plant Ervatamia microphylla induced normal flat morphology in K-ras-NRK and K-ras-NIH cell lines, and lowered the increased uptake of 2-deoxyglucose in K-ras-NRK cells. Conophylline inhibited the growth of K-ras-NRK cells, but this inhibition was reversible. The alkaloid also inhibited the growth of K-ras-NRK and K-ras-NIH3T3 tumours transplanted into nude mice. On the other hand, it showed no effect on survival of the mice loaded with L1210 leukaemia. Thus, conophylline is a new antitumour vinca alkaloid that induced normal phenotypes in ras-expressing cells.
Animals↗
Thrombin and TGF-beta promote human leptomeningeal cell proliferation in vitro.
Some disorders of the central nervous system, such as trauma, meningitis, or subarachnoid hemorrhage (SAH), result in inflammation and fibrosis of the arachnoid membranes followed by hydrocephalus. To clarify the role of growth factors in the pathophysiology of arachnoid fibrosis, we investigated the response of leptomeningeal (LM) cells to growth factors elevated in the cerebrospinal fluid (CSF) of patients with subarachnoidal inflammation. We examined the proliferative responses of LM cells to thrombin, transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), acidic fibroblast growth factor (aFGF), platelet derived growth factor (PDGF), tumor necrosis factor-beta (TNF-beta) and interleukin 1-beta (IL1-beta). Thrombin, TGF-beta, EGF, aFGF and PDGF promoted LM cell proliferation. TGF-beta enhanced the proliferative effect of thrombin and EGF on LM cells. These findings suggest that thrombin and TGF-beta, which may be elevated in CSF following SAH, may cause subarachnoid fibrosis and subsequent hydrocephalus.
Animals↗
Suppression of in vitro invasion of human fibrosarcoma cells by a leupeptin analogue inhibiting the urokinase-plasmin system.
A leupeptin analogue, pyroglutamyl-Leu-Arg-CHO (Pyr-Leu-Arg-CHO), is an inhibitor of urokinase and plasmin, while leupeptin inhibits only plasmin. Pyr-Leu-Arg-CHO was shown to inhibit in vitro invasion of human fibrosarcoma HT1080 cells reducing cellular collagenase activity. Pyr-Leu-Arg-CHO suppressed the invasion of the cells in a Boyden chamber assay with an IC50 of 12 micrograms/ml. Addition of plasminogen to HT1080 cells increased the type IV collagenase activity, and Pyr-Leu-Arg-CHO inhibited this activation of the collagenase with an IC50 of 3 micrograms/ml. Leupeptin inhibited both the invasion and collagenase activation at higher concentrations than that of Pyr-Leu-Arg-CHO. The gelatin zymography of the conditioned medium revealed that a new gelatinolytic band, possibly an activated form of MMP-2, appeared by the addition of plasminogen. The activation of MMP-2 was also inhibited strongly by Pyr-Leu-Arg-CHO. These results indicate that Pyr-Leu-Arg-CHO suppresses the in vitro invasion by preventing the activation of type IV collagenase through inhibition of the urokinase-plasmin system.
Amino Acid Sequence↗
Induction of erythroid differentiation in leukaemic K562 cells by an S-adenosylhomocysteine hydrolase inhibitor, aristeromycin.
We have isolated an unusual nucleoside, aristeromycin, from the culture filtrate of Actinomycetes as a compound that induces normal morphology in v-ablts-NIH3T3 cells. Aristeromycin also induced erythroid differentiation in abl-expressing human chronic myelogenous leukaemia K562 cells. It did not affect the amount of Abl or the Abl-associated tyrosine kinase activity in either v-ablts-NIH3T3 or K562 cells. As a potent inhibitor of S-adenosylhomocysteine hydrolase, aristeromycin inhibited methylation of phosphatidylethanolamine to form phosphatidylcholine in K562 cells. Among aristeromycin analogues, the activity to inhibit S-adenosylhomocysteine hydrolase was paralleled with the induction of erythroid differentiation. Thus, aristeromycin inhibits abl functions indirectly, possibly by inhibiting biological methylations.
3T3 Cells↗
Tyrosine kinase inhibitors inhibit multiple steps of the cell cycle of vascular smooth muscle cells.
Protein tyrosine kinase (PTK) inhibitors have been reported to inhibit proliferation of vascular smooth muscle cells (SMC). To elucidate the mode of this inhibition, the effects on the cell cycle of cultured vascular SMC of three PTK inhibitors with different modes of action (methyl 2,5-dihydroxycinnamate, genistein, and herbimycin A) were studied. Rat aortic SMC were synchronized to the G0 phase of the cell cycle and then released to proceed through the cell cycle by the addition of platelet-derived growth factor (PDGF), and [3H]thymidine incorporation into DNA was measured. The three PTK inhibitors all inhibited PDGF-induced DNA synthesis in a dose-dependent fashion, with IC50 values of 4.7 +/- 1.4 microM for methyl 2,5-dihydroxycinnamate, 6.7 +/- 2.5 microM for genistein, and 0.17 +/- 0.07 microM for herbimycin A. Time course studies suggested that the agents inhibited early G1 phase but not the G0-G1 transition. the lack of effect on the G0-G1 transition was also supported by the finding that the agents did not inhibit the ligand-induced autophosphorylation of PDGF receptor nor the induction of c-fos mRNA at concentrations which were sufficient to inhibit DNA synthesis. PTK inhibitors inhibited progression of the S phase when they were added to SMC that had been arrested at the G1-S border with hydroxyurea. Methyl 2,5-dihydroxycinnamate also blocked the M phase when it was added to SMC cultured in the presence of 10% fetal calf serum, while genistein and herbimycin A did not inhibit the M phase under the same experimental conditions. In accordance with our previous observation, methyl 2,5-dihydroxycinnamate impaired microtubule networks and formation of the mitotic spindle during the M phase. Our findings indicated that PTK inhibitors inhibit multiple steps of the vascular SMC cell cycle.
Animals↗
Distribution of extravasated serum protein after cryoinjury in neonatal and adult rat brains.
The sequelae of cryoinjury to unilateral cerebral cortex were compared in neonatal and adult rats. In neonatal rats, immunostaining for autologous albumin disclosed a wide spread of extravasated albumin in both hemispheres on day 1 and rapid clearance from the tissue by day 7, whereas in adults rats, the distribution of albumin had progressively increased by day 7 and was then restricted to the injury site by day 14. Horseradish peroxidase tracing revealed a leakage of serum proteins by day 3 in neonates and by day 7 in adults. The rapid clearance of serum proteins from the neonatal brain tissue appeared to be promoted by vimentin-positive radial glia in the subpial and periventricular regions. A possible causal relationship between the rapid clearance of serum proteins and unique outcome of the cryoinjury in the neonatal brain is discussed.
Animals↗
Subarachnoid haemorrhage induced proliferation of leptomeningeal cells and deposition of extracellular matrices in the arachnoid granulations and subarachnoid space. Immunhistochemical study.
Subarachnoid haemorrhage (SAH) often leads to subarachnoid fibrosis and resultant normal pressure hydrocephalus; however, how subarachnoid fibrosis occurs is unknown. We examined the changes within arachnoid granulations (AGs) and the subarachnoid space (SAS) chronologically at the parasagittal region obtained from patients with SAH at autopsy and made comparison with controls by immunostaining for cytokeratin, specific marker for leptomeningeal cells and by the elastica Masson-Goldner methods. Within a week some AGs were torn, and many inflammatory cells filled the AGs and SAS. Cytokeratin positive cells were scarce. During the next two weeks cytokeratin positive cells increased. After three weeks, AGs and SAS were filled by dense deposits of extracellular matrices surrounded by multiple layers of leptomeningeal cells.
Arachnoid↗
Isolation and biological activities of signal transduction inhibitors from microorganisms and plants.
Microorganisms and plants are treasuries of secondary metabolites having unique structures and biological activities. We have isolated inhibitors of cellular signal transduction from them. Phosphatidylinositol turnover inhibitors include inostamycin, piericidins and echiguanines. Erbstatin and lavendustin A were isolated as tyrosine kinase inhibitors, and dephostatin was isolated as a tyrosine phosphatase inhibitor. Recently, we have isolated a new vinca alkaloid having anti-ras activity. These signal transduction inhibitors will be useful for mechanistic studies and suppression of cancer.
1-Phosphatidylinositol 4-Kinase↗