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Biomedical subjects

Y Oshiro

Publications and source records attributed to Y Oshiro.

At least 73 records · Page 4Linked to original sources
PubMed1987

Dichloroacetate derivatives. Metabolic effects and pharmacodynamics in normal rats.

Dichloroacetate (DCA) reduces blood glucose, lactate and lipids in diabetes or during fasting. Chronic use of DCA, however, is limited by toxicity, probably due in part to its rapid conversion to oxalate in vivo. In theory, therefore, DCA's efficacy may be retained and its toxicity minimized by controlling its rate of metabolism. We attempted to alter DCA pharmacokinetics and bioavailability by synthesizing various derivatives comprising DCA esters with polyols and DCA ionic complexes. Twenty-four hour fasted, nondiabetic rats received single, orogastric doses of saline (control) sodium DCA (100mg/kg) or the following derivatives (D1-4): the esters D1-D3: potassium tetra (dichloroacetyl) glucuronate (D1), inositol-monophosphate-tetradichloroacetate (D2), inositol-hexadichloroacetate (D3) and inositol-hexa [N-methylnicotinate] hexadichloroacetate salt (D4). Each derivative was administered at a dose that would ultimately provide 100 mg/kg DCA as the anion. All derivatives were orally effective in significantly decreasing blood glucose and lactate. D4 exerted the most potent and long-lasting glucose- and lactate-lowering effects, yet increased plasma DCA concentrations less than an equivalent dose of the sodium salt. When administered to reverse light-cycled rats, D4 markedly inhibited the incorporation of tritiated water into cholesterol and triglycerides. We conclude that derivatives of DCA retain the biological activity of the parent compound, but may exhibit different pharmacokinetics. They may eventually prove useful in the treatment of diabetes mellitus, hyperlipidemia and lactic acidosis in man.

Acetates↗
PubMed1987

Monoclonal integration of HTLV-I proviral DNA in patients with strongyloidiasis.

The relationship between strongyloidiasis and HTLV-I was investigated in Okinawa, an area where both conditions are endemic. Thirty-six patients with strongyloidiasis were seropositive for HTLV-I and suffered from several related clinical complications. Fourteen of these patients (39%) were shown to have monoclonal integration of HTLV-I proviral DNA in their blood lymphocytes, a condition designated as "smouldering" adult T-cell leukaemia (ATL). Monoclonal integration of proviral DNA correlated with an increased CD4/CD8 ratio and the presence of abnormal lymphocytes in the peripheral blood, and with a trend for greater severity of the parasitic infection. Although the immunodeficiency caused by HTLV-I could predispose to hyperinfestation by Strongyloides, it is also possible that both the parasitic and the retroviral infestations are important co-factors leading to the development of ATL.

Adult↗
PubMed1987

Decision criteria for the in vitro rat hepatocyte UDS assay.

The induction of unscheduled DNA synthesis (UDS) in rat primary hepatocytes is used as an in vitro screen for genotoxicity. The purpose of this study was to develop criteria for statistical evaluation of autoradiographic grain counts from the UDS assay. Based on our historical solvent control population (N = 17), we first established a predictive two-sided symmetric tolerance interval providing 95% confidence for coverage of 99% of the distribution of the mean net nuclear grain count for a new solvent control observation. The tolerance interval was determined to run from -2.82 to 4.03 net nuclear grains. When the concurrent solvent control (C) proves admissible (-2.82 less than C less than 4.03), the mean net nuclear grain counts from treatment groups are compared to the concurrent solvent control value. If the difference exceeds 3.09 at two successive concentrations, the test compound is considered positive. We have tested eight carcinogens (MNNG, AFB1, 4DAB, 4NQO, DMBA, 2AAF, DEN and 2AA) utilizing these criteria. All eight were positive. Four non-carcinogens (2AB, pyrene, anthracene and alpha NA) were negative. Each of these chemicals was tested twice using our standard protocol, which employs a preliminary range-finding cytotoxicity assay. We conclude that these criteria provide adequate sensitivity and specificity to be applicable for the evaluation of the results of routine UDS assays with compounds of unknown genotoxic potential.

Animals↗
PubMed1982

Morphological transformation of C3H/10T1/2 CL8 cells by procarcinogens.

In order to increase the sensitivity of the C3H/10T1/2 CL8 (10T1/2) cell transformation system, we increased the chemical exposure period to a total of 6 days (two consecutive 3-day exposures). Using this modified procedure, we transformed 10T1/2 cells with procarcinogens such as aflatoxin B1, benz(a)anthracene, and 4-nitroquinoline-1-oxide which have been negative in the standard 10T1/2 cell transformation assay. However, beta-naphthylamine was inconclusive and 2-acetylamino-fluorine was negative in this modified assay system. Our results demonstrate that a simple modification of the 10T1/2 cell transformation method can increase the sensitivity to some procarcinogens that require metabolic activation.

2-Acetylaminofluorene↗
PubMed1982

Selection of fetal bovine serum for use in the C3H/10T 1/2 CL8 cell transformation assay system.

The purpose of this communication is to report our experience concerning the variation in cloning efficiency and transformation frequency utilizing C3H/10T 1/2 CL8 cells with 23 different lots of fetal bovine sera. These sera were purchased from five different commercial sources. The standard cell transformation assay using 1,000 cells per dish and 3-methylcholanthrene (7.5 micrograms/ml) as the transforming agent was performed. The chemical exposure period was 3 days. The cloning efficiency was determined in parallel toxicity tests using 200 cells per dish. Only three out of 23 serum lots supported a strong response in cell transformation. The results indicated that variation in the ability of sera to support cell transformation was not supplier dependent. In addition, our results showed that serum lots exhibiting the best cloning efficiencies did not necessarily support cell transformation. It is apparent that reliance on cloning efficiency alone would be inadequate as a means of selecting a serum lot. We therefore recommend that a complete cell transformation assay be performed when selecting fetal bovine serum for use in this assay.

Animals↗
PubMed1981

Morphological transformation of C3H/10T1/2 CL8 cells by alkylating agents.

The standard method of the C3H/10T1/2 cell transformation assay cannot adequately detect alkylating agents. A modification of the standard procedure as described by Bertram and Heidelberger using a large number of synchronized cells and high levels of toxicity was evaluated for transformation using several alkylating agents. By using this method, N-methyl-N' -nitro-N-nitrosoguanidine (MNNG), beta-propiolactone (BPL), methyl methanesulfonate (MMS), methylnitrosourea (MNU) and 1,3-propane sultone (PS) transformed these cells. However, methyl iodide (MI) failed to induce any transformed foci.

Alkylating Agents↗