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Biomedical subjects

D Uemura

Publications and source records attributed to D Uemura.

At least 19 recordsLinked to original sources
PubMed2006

Shellfish poisons.

In our ongoing search for bioactive metabolites from marine organisms, novel shellfish poisons have been isolated. Pinnatoxins, which are amphoteric polyether compounds, were purified from the Okinawan bivalve Pinna muricata. Pinnatoxins show acute toxicity against mice and activate Ca2+ channels. Two novel alkaloids, pinnamine and pinnaic acid, were also obtained from P. muricata. Pinnaic acid inhibits cytosolic phospholipase (cPLA2). Pteriatoxins, which are pinnatoxin analogs, were isolated from the Okinawan bivalve Pteria penguin. A nanomole-order structure determination of pteriatoxins was achieved by the detailed analysis of 2D-NMR and ESI-TOF MS/MS. This review covers the isolation, structure determination, bioactivity, synthesis, and biogenesis of these shellfish poisons and related compounds.

Animals↗
PubMed2001

Enantioselective synthesis of attenols A and B.

[reaction: see text] Enantioselective synthesis of attenols A and B was accomplished by using diastereoselective hydroboration, Lindlar reduction, and acid-catalyzed acetal formation.

Animals↗
PubMed2001

Isolation and structures of haterumadioxins A and B, cytotoxic endoperoxides from the Okinawan sponge Plakortis lita.

Cytotoxic endoperoxides, haterumadioxins A (1) and B (2), were isolated from the Okinawan sponge Plakortis lita. Their structures were determined by spectroscopic analysis. The absolute stereostructure of 1 was determined by degradation reactions and the modified Mosher's method. Haterumadioxins showed significant cytotoxicity against 38 human cancer cell lines.

Animals↗
PubMed2001

Haterumaimides F-I, four new cytotoxic diterpene alkaloids from an ascidian Lissoclinum species.

Four new monochlorinated diterpene alkaloids, haterumaimides F-I (1-4), and two known ones, dichlorolissoclimide and chlorolissoclimide, were isolated from an ascidian Lissoclinum sp. Their structures with absolute stereochemistries were elucidated by chemical and spectral analyses. Haterumaimides F-I (1-4) inhibited the first cleavage of fertilized sea urchin eggs and exhibited potent to weak cytotoxicities against P388 cells.

Alkaloids↗
PubMed1999

Suppressive effect of norzoanthamine hydrochloride on experimental osteoporosis in ovariectomized mice.

Norzoanthamine is an alkaloid isolated from a colonial zoanthid. We examined the effects of norzoanthamine hydrochloride on bone weight, strength and morphology in ovariectomized mice, a postmenopausal osteoporosis model. Norzoanthamine hydrochloride significantly suppressed the decrease in femoral weight and bone biomechanical parameters caused by ovariectomy without an increase in uterine weight. This means that norzoanthamine hydrochloride does not have an estrogen-like effect on reproductive organs. Morphological observations of longitudinally ground sections of the humeri showed that norzoanthamine hydrochloride administration (2 mg/kg/d, p.o.) completely suppressed the loss of trabecular bone. Furthermore, norzoanthamine hydrochloride thickened the cortical bone. Based on these results, norzoanthamine hydrochloride may act as both a suppressor of bone resorption and an enhancer of bone formation in vivo.

Alkaloids↗
PubMed1998

Upregulation of HIV-1 replication in chronically infected cells by ingenol derivatives.

We have previously reported that ingenol derivatives are highly potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in acutely infected cells. In this study, however, we have found that some ingenol derivatives strongly enhance the replication of HIV-1 in chronically infected cells at nanomolar concentrations. One of the derivatives could activate nuclear factor kappa B (NF-kappa B), a potent inducer of HIV-1 replication, through the activation of protein kinase C (PKC). Whereas another derivative, which affected neither PKC nor NF-kappa B, significantly enhanced HIV-1 replication, suggesting that a PKC-independent mechanism may also exist in ingenol derivative-induced HIV-1 upregulation.

Butyrates↗
PubMed1997

Endothelium inhibits the palytoxin-induced depolarization and Ca2+ mobilization in porcine coronary artery through endothelium-derived hyperpolarizing factor and nitric oxide released by palytoxin.

Palytoxin induced increases in cytosolic Ca2+ and tension, which were dependent on external Ca2+, and depolarized the membrane in endothelium-denuded porcine coronary arteries. When the endothelium was present, however, these effects were greatly inhibited, suggesting that some factors from endothelium inhibited the palytoxin-actions. Pretreatment with 100 microM N omega-nitro-L-arginine partially reversed the inhibitory effect of endothelium on the Ca2+ movement and the contraction but not that on the depolarization. Pretreatment with 10 microM indomethacin did not affect the inhibition. These results suggest that palytoxin released both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) from the endothelium, both of which counteracted the actions of palytoxin on smooth muscle cells. It is thought that the palytoxin-induced depolarization was attenuated by hyperpolarization due to EDHF.

Acrylamides↗
PubMed1997

Possible mechanism of palytoxin-induced Ca++ mobilization in porcine coronary artery.

We investigated the mechanisms involved in palytoxin (PTX)-induced cytosolic Ca++ ([Ca++]i) mobilization and contraction in porcine coronary arteries using a fluorescent Ca++ indicator fura-PE3. PTX (1 pM-10 nM) induced concentration-dependent and sustained increases in [Ca++]i and tension, both of which were partially inhibited by 10 microM verapamil or 1 microM nicardipine. In Ca++-free solution containing 1 mM EGTA, PTX did not increase [Ca++]i. In nominally Ca++-free solution (no EGTA), however, PTX increased [Ca++]i, which was presumed to be due to release of Ca++ from intracellular stores. PTX-induced rise in [Ca++]i was dependent on external Na+ because it did not increase [Ca++]i in Na+-free solutions containing verapamil. An increase in [Ca++]i in response to 65.4 mM KCl also involved a verapamil-resistant but external Na+-dependent component. After blockage of voltage-dependent Ca++ channels with verapamil, elevation of external K+ to 65.4 mM enhanced the responses of [Ca++]i and tension to PTX. PTX at 10 and 100 pM depolarized the membrane by 4.5 +/- 0.8 and 18.6 +/- 1.7 mV, respectively. Because PTX is known to increase membrane Na+ permeability, our results suggest that an increase in cytosolic Na+ and the depolarization were primary events required for the PTX-induced Ca++ mobilization and that Ca++ influxes through voltage-dependent Ca++ channels and Na+-Ca++ exchange and Ca++ release from Ca++ stores, which was triggered by increased Ca++ entry, were responsible for the PTX-induced increase in [Ca++]i.

Acrylamides↗
PubMed1996

Mechanism of selective inhibition of human immunodeficiency virus by ingenol triacetate.

Ingenol 3,5,20-triacetate (ITA), one of the ingenol derivatives, is a selective inhibitor of human immunodeficiency virus (HIV) replication in vitro. ITA inhibited the replication of HIV strains in MT-4 cells at concentrations of 0.051 to 0.65 microM. This concentration was approximately 10(3)-fold lower than its cytotoxic threshold. The mechanism of action of ITA is primarily attributed to the inhibition of viral adsorption to the host cells, but it is distinct from the mechanism of inhibition by other adsorption inhibitors.

Antiviral Agents↗
PubMed1996

Cyclooxygenase induction is essential for NGF synthesis enhancement by NGF inducers in L-M cells.

Nerve growth factor (NGF) inducers, for example, 4-methylcatechol, pyrroloquinoline quinone, kansuinin A, and ingenol triacetate, stimulate NGF synthesis in L-M cells, but the mechanism of NGF induction by NGF inducers is not known. Using the four different types of previously described NGF inducers, we proved induction of cyclooxygenase activity by NGF inducers and detected prostaglandins D2 and E2 as metabolites of arachidonic acid. From the observation that the induction of NGF by each NGF inducers was inhibited by cyclooxygenase inhibitors or dexamethasone, cyclooxygenase activation is supposed to be an essential process for NGF induction.

Animals↗
PubMed1994

Inhibition of topoisomerase II by a novel antitumor cyclic depsipeptide, BE-22179.

BE-22179, a novel cyclic depsipeptide antibiotic having two 3-hydroxyquinoline moieties, inhibited the DNA-relaxing activity of L1210 topoisomerase II completely at 0.08 microM. This effect was far stronger than that of VP-16. However, it did not show any marked effect on topoisomerase II-mediated DNA cleavage. BE-22179 was ineffective in inhibiting the DNA relaxation by topoisomerase I at concentrations up to 10 microM, but showed DNA-intercalating ability (DNA unwinding) at 30 microM. The structure of BE-22179 is quite novel for a topoisomerase II inhibitor. Echinomycin, a quinoxaline antibiotic structurally related to BE-22179, interfered with DNA relaxation by topoisomerase II, though the effect was not due to inhibition of the catalytic activity of topoisomerase II but to conformational change of DNA based on its intercalation into DNA. Therefore, the potent inhibitory activity on topoisomerase II might not be a common activity of quinoxaline antibiotics, but might rather be specific to BE-22179. BE-22179 prevented DNA synthesis as well as RNA synthesis in L1210 cells and inhibited the growth of the cells. However, it remains unclear to what extent the topoisomerase II inhibition was responsible for the cytotoxicity of BE-22179.

Animals↗
PubMed1994

A new topoisomerase II inhibitor, BE-22179, produced by a streptomycete. I. Producing strain, fermentation, isolation and biological activity.

A new topoisomerase II inhibitor, designated BE-22179, was isolated from the culture broth of Streptomyces sp. A22179, which resembles "Streptomyces gangtokensis". The inhibitor was extracted from the mycelial cake of the culture broth with organic solvent and successively purified by silica gel chromatography. BE-22179 inhibited topoisomerase II strongly but not topoisomerase I and showed potent antitumor activity against various tumor cell lines both in vitro and in vivo.

Animals↗
PubMed1993

Induction of topoisomerase I-mediated DNA cleavage by a new indolocarbazole, ED-110.

ED-110 is a new semisynthetic antitumor agent derived from a novel indolocarbazole antibiotic, BE-13793C, produced by an actinomycete. ED-110 induced topoisomerase I-mediated DNA cleavage in vitro as strongly as camptothecin, whereas topoisomerase II-mediated DNA cleavage was not induced by this agent. Exposure of P388 cells to ED-110 caused a typical topoisomerase toxicity, i.e.: formation of cleavable complexes; inhibition of nucleotide synthesis rather than protein synthesis; and cell cycle arrest in G2. ED-110 inhibited the growth of P388 cells, with a 50% growth-inhibitory concentration of 44 nM. ED-110 is distinguished from camptothecin by its very different structure and its ability to intercalate into double-stranded DNA. These results suggest that ED-110 has potential as a novel antitumor agent targeting topoisomerase I.

Animals↗
PubMed1992

An alternative theory of tissue specificity by tumor promotion of okadaic acid in glandular stomach of SD rats.

To challenge the theory of tissue specificity of tumor promoters, the biochemical and tumor promoting effects of okadaic acid (OA), a potent tumor promoter on mouse skin, were studied in the mucosa of rat glandular stomach. OA strongly inhibited protein phosphatases 1 and 2A, and increased 4-fold the phosphorylation of elongation factor 2 in vitro in the mucosa. Intubation of 10 micrograms (12.4 nmol) OA induced ornithine decarboxylase in the mucosa. Tumor promotion of OA was studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a two-stage carcinogenesis experiment. OA in drinking water, 10 micrograms (12.4 nmol) per rat per day from weeks 9-55 of the experiment, and 20 micrograms (24.8 nmol) from weeks 56-72, significantly enhanced development of the neoplastic changes in the glandular stomach (P < 0.05). The neoplastic changes included adenomatous hyperplasias and adenocarcinomas, both of which correspond to papillomas and carcinomas in a two-stage mouse skin carcinogenesis experiment. The percentages of neoplastic change-bearing rats of the groups treated with MNNG plus OA, MNNG alone or OA alone were 75.0, 46.4 and 0% respectively. OA enhanced tumorigenesis in the MNNG-initiated glandular stomach of rats through the same mechanisms of action as in mouse skin. The OA pathway mediated through inhibition of protein phosphatases 1 and 2A is applicable to various organs as a general mechanism of tumor promotion.

Animals↗
PubMed1992

Increase in potential activities of protein phosphatases PP1 and PP2A in lymphoid tissues of autoimmune MRL/MpJ-lpr/lpr mice.

The differential assay conditions for protein phosphatases PP1, PP2A, and PP2C were extensively studied by using crude extracts from mouse lymphoid tissues as enzyme sources. Under these conditions, the protein phosphatase activities were measured in MRL/MpJ-lpr/lpr mice (MRL/lpr mice), autoimmune-prone mice, and MRL/MpJ(-)+/+ mice (MRL/+/+ mice) and C3H/HeJ mice as the controls. In MRL/lpr mice, significant alterations in protein phosphatase activities from those in the control mice were demonstrated. In spleen and liver from MRL/lpr mice, potential activities of PP1 and PP2A were distinctly elevated over those of the control mice. These elevations appeared to be due to accumulation of the abnormal lymphocytes that emerged in MRL/lpr mice. Although the PP1 activity in MRL/lpr lymph nodes was lower than those of normal spleen and thymus, it was greatly increased by Co(2+)-trypsin treatment so that the PP1 activity of MRL/lpr lymph nodes was the highest among those of all the tissues examined. In contrast, PP2C activity showed no remarkable alteration in the autoimmune disease model mice as compared with that in the control mice. These results demonstrated a specific elevation in potency of protein dephosphorylation in the tissues of MRL/lpr mice, suggesting a new explanation for the defect in signal transduction in this disease.

Animals↗