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Biomedical subjects

B Yagen

Publications and source records attributed to B Yagen.

At least 55 records · Page 3Linked to original sources
PubMed1987

Protective effect of vitamins against trichothecene toxicity towards Saccharomyces cerevisiae.

Several trichothecene mycotoxins were shown to inhibit the growth of Saccharomyces cerevisiae. This effect was most pronounced with the macrocyclic trichothecenes, especially verrucarin A. Much less growth inhibition was observed with T-2 toxin. Verrucarol, diacetoxyscirpenol, acetyl T-2 toxin, HT-2 toxin, T-2 tetraol and neosolaniol were inactive at a concentration of 75 micrograms of toxin per disc. Incubation of S. cerevisiae with verrucarin A together with vitamins resulted in a decrease in toxicity. Pyridoxine-HCl, Ca-pantothenate, thiamine-HCl and alpha-tocopheryl acetate were amongst the most potent of the vitamins tested which reversed growth inhibition, overcoming the inhibitory potential of the toxins.

Crithidia↗
PubMed1987

Induction of differentiation in human myeloid leukemic cells by T-2 toxin and other trichothecenes.

Trichothecenes are sesquiterpen mycotoxins characterized by the tetracyclic 12,13-epoxytrichothec-9-ene skeleton. We determined the effect of these mycotoxins on the growth and differentiation of the human acute promyelocytic leukemia (HL-60) cell line. Sixteen natural and semisynthetic trichothecenes were tested at concentrations of 0.2-60,000 ng/ml. The cytotoxicity exerted by these compounds varied: e.g., roridin A was found to be toxic at 1 ng/ml, whereas T-2 palmitate was not toxic even at 1 microgram/ml. These compounds varied also in their potential to induce differentiation: 9,10-epoxy T-2 toxin and T-2 toxin induced differentiation at concentrations of 2-5 ng/ml, while 9,10-dihydro T-2 toxin was effective only at 100 ng/ml. Other trichothecenes (e.g., verrucarin A and verrucarol) did not induce differentiation at either subtoxic or toxic concentrations. Cell differentiation was always associated with cytotoxicity; optimal concentrations for induction of differentiation were usually 30-60% of the toxic concentrations. The HL-60 cell population was found to be heterogenous with respect to the ability to differentiate in response to trichothecenes, while in some clones up to 70% of the cells underwent differentiation, and other clones were completely resistant. The latter clones could, however, be induced to differentiate by other agents such as retinoic acid, dimethyl sulfoxide and 12-O-tetradecanoylphorbol-13-acetate. Some of the inducible clones differentiated into neutrophilic granulocytes while others into mature macrophages. Thus, a single trichothecene could induce differentiation into either cell types, depending on the clone used. This study presents a new group of differentiation inducers. Further investigation is required to evaluate their possible therapeutic application.

Cell Differentiation↗
PubMed1987

Cutaneous injury by topical T-2 toxin: involvement of microvessels and mast cells.

Topical applications of various doses of T-2 toxin to rats led to delayed skin reactions. Following a dose-dependent latent period of 12-24 hr, there appeared vascular dilation, stasis, edema and mononuclear cell infiltration, with many degranulating mast cells. These signs were earliest and strongest in the subcutis. Epidermal necrosis occurred 1-2 days later and was probably caused secondarily by ischemia, due to microcirculatory failure. Ultrastructurally, endothelial cells of small vessels were the earliest sites of change. While intercellular junctions remained closed and pinocytosis decreased, the cytoplasm contained many ribosomes, vacuoles, and abnormal mitochondria. Another early effect of topical T-2 toxin was an increase in number and degranulation of mast cells, especially in the subcutis. The resemblance of the skin injury to that produced by irradiation is noted.

Animals↗
PubMed1987

Cardiovascular pathology induced by passive transfer of splenic cells from syngeneic rats treated with T-2 toxin.

Mononuclear cells were separated from spleens and lymph nodes of Lewis rats treated 5 weeks previously with repeated small doses of T-2 toxin or solvent only. The cells from each site were then injected intraperitoneally into 4 groups of syngeneic Lewis rats. The animals injected with spleen cells from T-2 toxin-treated donors developed marked cardiovascular changes which were similar to those due to T-2 toxin itself. Rats injected with lymph node cells as well as those given each kind of cell from solvent-treated donors showed only occasional mild vascular changes. The changes seen after splenic cell transfer may be due to superinduction of interleukin 2 by T-2 toxin.

Animals↗
PubMed1987

Comparative yields of T-2 toxin and related trichothecenes from five toxicologically important strains of Fusarium sporotrichioides.

The range and comparative yields of T-2 toxin and related trichothecenes from five toxicologically important strains of Fusarium sporotrichioides, i.e., NRRL 3299, NRRL 3510, M-1-1, HPB 071178-13, and F-38, were determined. Lyophilized cultures of the five strains maintained in the International Toxic Fusarium Reference Collection were used to inoculate autoclaved corn kernels. Corn cultures were incubated at 15 degrees C for 21 days and analyzed for trichothecenes by thin-layer chromatography and capillary gas chromatography. All five strains produced T-2 toxin, HT-2 toxin, T-2 triol, and neosolaniol. Two strains also produced T-2 tetraol, and two others produced diacetoxyscirpenol. The highest producer of T-2 toxin (1,300 mg/kg), HT-2 toxin (200 mg/kg), T-2 triol (1.9 mg/kg), and neosolaniol (170 mg/kg) was NRRL 3510, which was originally isolated from millet associated with outbreaks of alimentary toxic aleukia in the USSR. The second highest producer of T-2 toxin (930 mg/kg) was NRRL 3299. The other three strains produced T-2 toxin at levels ranging from 130 to 660 mg/kg. Thus, the five strains differed considerably in the amounts of T-2 toxin and other trichothecenes produced under identical laboratory conditions. These strains are being maintained under optimal conditions for the preservation of Fusarium cultures and are available from the Fusarium Research Center, The Pennsylvania State University, University Park.

Fusarium↗
PubMed1987

Pharmacokinetics of T-2 tetraol, a urinary metabolite of the trichothecene mycotoxin, T-2 toxin, in dog.

1. The urinary metabolites of T-2 toxin were identified and analysed quantitatively after i.v. administration to dogs. 2. A new routine assay for T-2 tetraol was developed and a pharmacokinetic study was carried out on this final hydrolytic metabolite of T-2 toxin. T-2 tetraol was excreted in urine for 2-3 days. Its 'sigma minus' plot demonstrated a significantly longer apparent half-life than its precursors (T-2 toxin and HT-2 toxin). This fact was explained by extraplasma binding causing prolongation of the metabolism and excretion of T-2 toxin metabolites. 3. The urinary metabolites of T-2 toxin were: HT-2 toxin, T-2 triol and T-2 tetraol. The metabolites were excreted in free and conjugated forms. In two dogs T-2 toxin was found in the urine in an amount which accounts for 3.2 and 16% of the administered dose respectively. The cumulative amount of the identified metabolites and toxins formed in the urine ranged from 9.7 to 17.3% in four dogs and 44.7% in one dog.

Animals↗
PubMed1986

New, sensitive thin-layer chromatographic-high-performance liquid chromatographic method for detection of trichothecene mycotoxins.

Diphenylindenone sulphonyl (Dis) esters of trichothecene mycotoxins when sprayed with sodium methoxide showed fluorescent spots on a thin layer of silica gel when viewed under long-wavelength UV light. The detection limit for trichothecene esters in thin-layer chromatography (TLC) was 20-25 ng per spot for T-2 toxin, HT-2 toxin, diacetoxyscirpenol, T-2 triol, T-2 tetraol and iso-HT-2 toxin. A quantitative high-performance liquid chromatographic (HPLC) analysis of Dis-trichothecene esters was also developed using UV detection at 278 nm. The detection limit for the above esters varied between 30 and 50 ng per injection. This sensitive TLC-HPLC method is very useful for in vivo pharmacokinetic analyses of trichothecenes.

Chromatography, High Pressure Liquid↗
PubMed1986

T-2 toxin effect on cultured myocardial cells.

Beat rate, contractility and viability of cultured myocardial cells perfused with solutions containing various concentrations of T-2 toxin were studied. While doses below 50 micrograms/ml had no immediate effect, those above 250 micrograms/ml decreased beat rate and amplitude. After 10-30 min of perfusion most cells stopped beating and did not restart after withdrawal of toxin. Nevertheless, most cells remained viable as judged by morphology and trypan blue exclusion. A 24-h exposure to doses of 5 or 2.5 micrograms/ml of toxin decreased the beat rate and inotropic responses of the myocytes. After 48 h cell death ensued. Thus T-2 toxin has some direct toxicity to myocardial cells but the lethal dose seems too high to make this the cause of cardiovascular failure.

Animals↗
PubMed1986

T-2 toxin effect on the ultrastructure of myocardial microvasculature.

The effect of T-2 toxin on the ultrastructure of coronary microvasculature was studied in rats injected intraperitoneally and in rats hearts perfused with the toxin. The capillaries were most severely damaged and were often disrupted. The plasma membrane of endothelial cells seemed to be the first structure affected. A direct cytotoxicity of T-2 toxin to the myocardial capillary lining cells seems to be the pathogenical mechanism of injury. The abundance of mast cells in several of the hearts examined suggests a role for their vasoactive products in the genesis of the capillary lesions.

Animals↗
PubMed1985

Gas chromatographic assay with pharmacokinetic applications for monitoring T-2 and HT-2 toxins in plasma.

A gas-liquid chromatographic (GLC) method for monitoring T-2 and HT-2 toxins in plasma was developed. The procedure involved extraction of the toxins with ethyl acetate, chromatography on a C18 reversed-phase column and derivatization with heptafluorobutyric anhydride (HFBA). The T-2 and HT-2 HFBA derivatives were chromatographed on OV-17 at various temperatures and measured with an electron-capture detector. Iso-T-2 toxin and iso-HT-2 toxin were used as internal standards. Recoveries averaged 95.1 +/- 8.6% for T-2 toxin and 102.1 +/- 5.2% for HT-2 toxin at levels ranging from 40 to 120 ng/ml. The limits of detection were 30 and 5 ng/ml of T-2 and HT-2 toxin, respectively. The range of the assay covers plasma concentrations at which toxicity becomes manifest. The pharmacokinetic application of this GLC method is illustrated by simultaneous monitoring of T-2 and HT-2 toxins levels in plasma obtained after intravenous administration of T-2 toxin to a dog.

Animals↗
PubMed1985

Toxic and lethal effects of T-2 toxin upon intracerebral administration to rats.

T-2 toxin was given to rats in three ways: Subcutaneous or intracerebral injection of a solution in dimethyl sulfoxide (DMSO) and by implantation of toxin, adsorbed on talc, into various regions of diencephalon and brain stem. The latter method proved to be most effective. Within a few hours after administration of 10-20 micrograms toxin, the animals became restless, ataxic and dyspneic. These early symptoms were followed by depression and immobility. Prior to death, tachypnea and/or convulsions developed. The rats succumbed to implantation of toxin within 1 - 7 days; no fatalities occurred at later dates. Histologically, the toxin pellets caused necrosis a few days after implantation; at a later stage, the necrotic areas were surrounded by inflammatory infiltrates around small blood vessels. These morphological changes were limited to the application site and were insufficient to explain the lethal effect of intracerebral administration. After intracerebral injections of toxin solutions, the animals died within 24 h. No marked histological changes could be seen after such rapid fatalities.

Animals↗
PubMed1984

Superinduction of human interleukin-2 messenger RNA by inhibitors of translation.

Stimulation of human lymphocytes with phytohemagglutinin results in the induction of messenger RNA encoding interleukin-2 (IL-2), a lymphokine possessing immuno-regulatory properties. We have previously demonstrated a dramatic superinduction of the formation of IL-2 and of biologically active IL-2 mRNA in the presence of cycloheximide, an inhibitor of translation. These findings suggested the involvement of a labile protein repressor in the regulation of human IL-2 gene expression. Here, we show a commensurate superinduction of IL-2 mRNA sequences by three additional inhibitors of protein synthesis with distinct modes of action: T-2 toxin, pactamycin, and sparsomycin. These results strengthen the concept that a labile protein controls the formation of mature IL-2 mRNA. They tend to eliminate the possibility that the superinduction phenomenon observed in the presence of cycloheximide is due to its action on a process other than translation.

Cells, Cultured↗
PubMed1984

Effect of trichothecenes on growth and intracellular pool size of Mycoplasma gallisepticum.

The mycotoxin T-2 inhibited the growth of Mycoplasma gallisepticum. The growth inhibition was most pronounced with the hydrophobic derivatives T-2 acetate and very little with the hydrophilic T-2 tetraol. The toxin had no effect on the biosynthesis of either protein, DNA, RNA or complex lipids but markedly reduced the intracellular pool size of soluble low molecular mass precursors. It seems that T-2 acetate, by virtue of its hydrophobic nature, may accumulate within the lipid backbone affecting the permeability properties of the cell membrane.

Acetates↗
PubMed1984

T-2 toxin effect on bacterial infection and leukocyte functions.

The effects of T-2 toxin on bacterial infection and leukocyte function and structure were examined in vivo and in vitro. Rats were innoculated with staphylococci after pretreatment with or without T-2 toxin. The T-2 pretreated rats failed to mount a cellular response to the bacteria. Blood and bone marrow cells were markedly suppressed by the T-2 toxin, the myeloid series being the most affected. In vitro studies with human leukocytes showed that small, nonkilling doses of T-2 toxin inhibited chemotaxis, chemiluminescence stimulated by bacteria, and phagocytosis of bacteria. It was concluded that this inhibition may contribute towards sepsis and rapid onset of death in T-2 toxin poisoning.

Animals↗
PubMed1984

The effect of T-2 toxin on human platelets.

Human platelets were incubated with T-2 toxin, the most toxic component of Fusarium fungi, at doses of 5 to 500 micrograms/10(9) platelets. A dose-related inhibition of platelet aggregation and release of dense bodies (these consist mainly of serotonin-containing granules) were observed. A change in membrane permeability in the absence of shape changes was also demonstrated by a heavy metal impregnation technique. There was no correlated inhibition of thromboxane synthesis or significant alterations in platelet calcium content. The microtubular system was also unaffected. Suppressed platelet aggregation may contribute to the lethal hemorrhagic phenomenon associated with intoxication by fusarial toxins in man and animals.

Blood Platelets↗
PubMed1983

Trichothecene-induced hemolysis. I. The hemolytic activity of T-2 toxin.

In the present investigation, the hemolytic properties of T-2 toxin were examined. Tests with different concentrations of T-2 toxin showed that essentially complete hemolysis of rat erythrocytes commenced after a lag period, the length of which depended on the concentration of toxin. Comparison of the characteristics of hemolysis caused by T-2 toxin, saponins, H2O2, and polyoxyethylene surfactants showed great similarity between T-2 toxin and the latter two which proceed by a free radical mechanism. The same mechanism was suggested for hemolysis caused by T-2 toxin on the basis of the additional following observations: (1) darkness inhibited hemolysis; (2) specific free radical scavengers, i.e., vitamin E, mannitol, and histidine, inhibited hemolysis caused by T-2 toxin.

Animals↗