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Biomedical subjects

M E Anderson

Publications and source records attributed to M E Anderson.

At least 145 records · Page 8Linked to original sources
PubMed1987

Glutathione, a first line of defense against cadmium toxicity.

Experimental modulation of cellular glutathione levels has been used to explore the role of glutathione in cadmium toxicity. Mice treated with buthionine sulfoximine [an effective irreversible inhibitor of gamma-glutamylcysteine synthetase (EC 6.3.2.2) that decreases cellular levels of glutathione markedly] were sensitized to the toxic effects of CdCl2. Mice pretreated with a sublethal dose of Cd2+ to induce metallothionein synthesis were not sensitized to Cd2+ by buthionine sulfoximine. Mice sensitized to Cd2+ by buthionine sulfoximine were protected against a lethal dose of Cd2+ by glutathione mono isopropyl ester (L-gamma-glutamyl-L-cysteinylglycylisopropyl ester), but not by glutathione. These results are in accord with studies that showed that glutathione mono esters (in contrast to glutathione) are efficiently transported into cells and converted intracellularly to glutathione. The findings indicate that intracellular glutathione functions in protection against Cd2+ toxicity, and that this tripeptide provides a first line of defense against Cd2+ before induction of metallothionein synthesis occurs. The experimental approach used here in which cellular levels of glutathione are decreased or increased seems applicable to investigation of other types of metal toxicity and of other glutathione-dependent biological phenomena.

1-Propanol↗
PubMed1987

Metabolism of Escherichia coli injured by copper.

Escherichia coli injured by copper in carbonate buffer simulating the drinking water environment showed decreased oxygen utilization. Oxygraph measurements revealed that copper-injured bacteria had a rate of oxygen utilization that was less than 25% of that of control cells. Respirometry experiments measured rates over a longer period of time and showed similar trends. Nuclear magnetic resonance spectroscopy (13C nmr) and gas chromatography were used to identify differences in metabolism between healthy and injured populations of E. coli. The rate of glucose utilization by injured cells under anaerobic conditions was 64% of that of healthy cells. The rates of lactate and ethanol accumulation were 88 and 50% of the control, respectively. The 13C nmr studies of oxygenated cultures revealed differences in the accumulation of acetate and glutamine. Aerobic utilization of glucose and succinate by injured cells were 87 and 21% of the rate of the controls, respectively. Additional studies revealed injured cells had a decreased ability to reduce 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyltetrazolium chloride (INT) with a variety of carbohydrate substrates. Injured cells reduced greater quantities of INT than healthy cells when NADH was used as a substrate. A comparison of metabolic end products suggested that injured cells also had considerable differences in carbon flow compared with healthy cells.

Chromatography, Gas↗
PubMed1986

Inhibition of gamma-glutamyl transpeptidase and induction of glutathionuria by gamma-glutamyl amino acids.

Treatment of mice with various gamma-glutamyl amino acids leads to marked urinary excretion of glutathione and other gamma-glutamyl compounds. There is good correlation between the affinity of gamma-glutamyl transpeptidase for various gamma-glutamyl amino acids and the extent of glutathionuria. The findings indicate that the administered gamma-glutamyl compounds effectively compete with glutathione (exported from kidney cells and present in the glomerular filtrate) for the enzyme. The administration of certain gamma-glutamyl amino acids appears to be a specific and nontoxic procedure for in vivo inhibition of gamma-glutamyl transpeptidase that may be useful in experimental work on glutathione metabolism and function and also for treatment of certain toxicities and for modulation of the metabolism of endogenous glutathione conjugates.

Amino Acids↗
PubMed1986

Intracellular cysteine and glutathione delivery systems.

Glutathione functions in catalysis, metabolism, transport, and reductive processes and in protection of cells by destruction of free radicals, reactive oxygen intermediates, and other toxic compounds of endogenous and exogenous origin. It also functions as a storage and transport form of cysteine. Depletion of glutathione (effectively accomplished by inhibition of its synthesis) increases sensitivity to radiation and to certain toxic compounds and is of value in combination with radiation therapy or chemotherapy in situations in which cell selectivity can be achieved. Increased cellular levels of glutathione protect cells against radiation and certain toxic compounds. Glutathione levels can be increased by administration of cysteine or of glutathione, but these approaches are not entirely satisfactory. Cellular glutathione levels can be increased by supplying substrate for gamma-glutamylcysteine synthetase or for glutathione synthetase. L-2-Oxothiazolidine-4-carboxylate is well transported into many cells and is converted by 5-oxoprolinase to cysteine, a substrate of gamma-glutamylcysteine synthetase. gamma-Glutamylcysteine and related compounds are effectively transported, especially into renal cells, thus providing substrate for glutathione synthetase; higher than normal levels of glutathione can be achieved because this enzyme is not significantly inhibited by glutathione, whereas gamma-glutamylcysteine synthetase is feedback-inhibited. Derivatives of glutathione that are effectively transported into cells (glutathione itself is not) offer another means of increasing glutathione levels. The monoethyl ester of glutathione (in which the glycine carboxyl group is esterified) is well transported in vivo into liver and kidney and into cultured fibroblasts and lymphoid cells. Glutathione levels much higher than usual can be obtained by this procedure, which protects lymphoid cells against the lethal effects of irradiation and mice against acetaminophen, and which therefore may be a relatively safe way to increase cellular resistance to radiation and certain toxic compounds.

Acetaminophen↗
PubMed1985

Glutathione monoethyl ester: preparation, uptake by tissues, and conversion to glutathione.

Glutathione monoethyl ester (L-gamma-glutamyl-L-cysteinylglycyl ethyl ester), in contrast to glutathione itself, is effectively transported into many types of cells. The ester is converted intracellularly into glutathione. Intraperitoneal injection of 35S-labeled ester into mice was followed by rapid appearance of isotope in the glutathione of liver, kidney, spleen, pancreas, and heart; the glutathione levels of these tissues also increased. Oral administration of the ester to mice also increased cellular glutathione levels. Relatively little extracellular deesterification was found. Transport of glutathione ester into human erythrocytes and intracellular conversion to glutathione was observed. The findings suggest that the glutathione ester will be useful as a radioprotecting agent and in the prevention and treatment of toxicity due to certain foreign compounds and oxygen. The ester may be useful in experimental work on glutathione transport, metabolism, and function, and in related studies on oxygen toxicity, radiation, mutagenesis, and ageing. Methods for the preparation of glutathione monoethyl ester and several related compounds are given.

Administration, Oral↗
PubMed1985

Influence of the globus pallidus on arm movements in monkeys. III. Timing of movement-related information.

Monkeys were trained to make a visually triggered arm-reaching movement to a lighted button in a simple reaction-time paradigm, during which the reaction time (RT) and movement time (MT) were measured. Stimulus trains of varying duration were applied at various times before and during the movement at locations in the globus pallidus where application of long stimulus trains caused increased MTs. A critical stimulus period was identified during which stimulus application effectively prolonged MTs. The activity of pallidal neurons was examined during performance of the same behavioral task. More than 60% of the neurons examined showed task-related changes in activity that began before or during the reaching movement. For 45% of these cells, the initial change in firing occurred during the critical stimulus period, 50-150 ms before mechanically detected movement. Comparison of the critical stimulus period, the time of task-related changes in the discharge of pallidal neurons, and the time of EMG activity in muscles acting at the back, shoulder, elbow, and wrist revealed that both the critical stimulus period and changes in neuronal discharge occurred at or after initial muscle activation and during the buildup of EMG activity. These data are consistent with a model in which the globus pallidus plays a role in scaling the magnitude of muscle activity that determines movement velocity without affecting the initiation or sequential organization of the programmed motor output.

Animals↗
PubMed1985

Reconstruction of the lateral ligaments of the ankle using the plantaris tendon.

The plantaris tendon was used to reconstruct the torn lateral ligaments in the ankles of nine patients in whom surgical repair of the ligaments was not feasible. All of these patients were followed for more than two years and were able to return to their preoperative occupational and athletic activities. The use of the plantaris tendon permits an anatomical reconstruction of the lateral ligaments and, unlike previously described procedures, avoids sacrificing the dynamic effect of the peroneus brevis muscle in preventing inversion of the foot.

Adolescent↗
PubMed1984

Radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts.

Glutathione is not effectively transported into human lymphoid cells, normal human skin fibroblasts, and fibroblasts from patients with genetic deficiencies of gamma-glutamylcysteine synthetase or glutathione synthetase. On the other hand, the monoethyl ester of glutathione, in which the carboxyl group of the glycine residue is esterified, is readily transported into these cells and is hydrolyzed intracellularly. This leads to greatly increased cellular levels of glutathione, which often exceed those found normally. Glutathione ester was found to protect human lymphoid cells of the CEM line against the lethal effects of irradiation. Under the conditions employed, complete protection was found when the ester was added prior to irradiation. Addition of the ester after irradiation was partially effective, suggesting that GSH may also function in repair processes.

Biological Transport↗
PubMed1984

Critical spatial requirement within the origin of simian virus 40 DNA replication.

We inserted a single base pair into the center of a 27-base-pair palindrome within the replication origin of simian virus 40. The mutation did not directly alter the symmetry of the palindrome or the protein-binding sequences within the palindrome. DNA binding studies showed that subunits of the simian virus 40 A protein (T antigen) bound to each of the four recognition pentanucleotides in the origin palindrome but did so with reduced affinity in comparison with wild-type origins. The mutant origin cloned in a plasmid DNA failed to replicate in COS cells. Thus, precise spatial interactions among subunits of A protein are necessary for stable origin binding and are crucial for subsequent steps in the initiation of DNA replication. Furthermore, any possible functional interactions of the simian virus 40 A protein with cellular DNA would require a great fidelity of protein binding arrangements to initiate cellular DNA replication.

Base Sequence↗
PubMed1984

The effects of movement velocity, mass displaced, and task certainty on associated postural adjustments made by normal and hemiplegic individuals.

The activation times for trunk and leg muscles were examined in normal and left hemiplegic subjects who raised their right arms at different velocities in self-paced or reaction time conditions. Activity in these postural muscles preceded arm displacement, and they were activated in a similar sequence during all types of rapid movements. The presence and sequencing of associated postural adjustments were more variable during slow movements.

Adult↗
PubMed1984

Influence of globus pallidus on arm movements in monkeys. I. Effects of kainic acid-induced lesions.

The role of basal ganglia output via the globus pallidus (GP) was examined in monkeys trained to make rapid arm-reaching movements to a visual target in a reaction-time task. When neurons in the globus pallidus were destroyed by injection of kainic acid (KA) during task execution, contralateral arm movement times (MT) were increased significantly, with little or no change in reaction times (RT). The slowed movements were associated with a generalized depression in the amplitude and rate of rise of electromyographic (EMG) activity in all the contralateral muscles studied at the wrist, elbow, shoulder, and back, but there was no change in the sequential activation of these muscles. The most profound and persistent increases in movement time occurred when neurons were destroyed in the ventrolateral and caudal aspects of the internal as well as external pallidal segment. These results suggest a role for globus pallidus output in scaling the magnitude and/or buildup of EMG activity without affecting the initiation or the sequential organization of the programmed motor output.

Animals↗
PubMed1984

Influence of globus pallidus on arm movements in monkeys. II. Effects of stimulation.

The effect of changing basal ganglia activity with electrical stimulation in and around the globus pallidus (GP) was studied in monkeys trained to make rapid arm-reaching movements to a visual target in a reaction time task. As was the case following kainic acid (KA) lesions of the globus pallidus (30), stimulation changed movement times (MT) without affecting the pattern of sequential activation of muscles involved in the task or, in most cases, the reaction times (RT). Stimulation in the ventrolateral internal segment of the globus pallidus (GPi) or in the ansa lenticularis reduced movement times, whereas stimulation at many sites in the external pallidal segment (GPe), dorsal GPi, and putamen increased movement times for the contralateral arm. These results are consistent with the hypothesis that arm movements are speeded up when the critical output of GPi is increased and arm movements are slowed down when critical GPi output is reduced, either by an inhibitory process (via stimulation-induced activation of inhibitory elements presynaptic to GPi) or by destroying GPi neurons (via kainic acid). The influence of the basal ganglia on the scaling of electromyographic (EMG) amplitude, as opposed to the spatiotemporal organization of EMG activation, is discussed.

Animals↗
PubMed1983

An electrophysiological characterization of projections from the pedunculopontine area to entopeduncular nucleus and globus pallidus in the cat.

Stimulation of the pedunculopontine region (PPN), in which neurons are filled by horseradish peroxidase injected into the entopeduncular nucleus (ENTO) or globus pallidus (GP) of the cat, excites ENTO and GP neurons both orthodromically and antidromically. Stimulus threshold mapping experiments and intracellular records of EPSPs provide evidence that the orthodromic excitation may be produced monosynaptically by the axons of PPN neurons. Antidromic excitation of ENTO axons from stimulation in PPN or the thalamus may elicit IPSPs in ENTO neurons via the action of recurrent collaterals. An excitatory synaptic action of PPN neurons on pallidal cells could be a partial basis for the high discharge rate characteristic of these neurons in awake animals.

Afferent Pathways↗
PubMed1983

Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis.

Administration of gamma-glutamylcystine or of gamma-glutamylcysteine disulfide to mice leads to significantly increased levels of glutathione in the kidney as compared to controls given glutamate plus cysteine (or cystinylbisglycine). Studies with gamma-glutamylcystine selectively labeled with 35S in either the internal or external S atom indicate preferential utilization of the gamma-glutamylcysteine moiety of this compound for glutathione synthesis. Mice depleted of glutathione by treatment with buthionine sulfoximine do not significantly use the disulfides gamma-glutamylcystine or gamma-glutamylcysteine disulfide but do use gamma-glutamylcysteine for glutathione synthesis. These findings suggest a pathway in which gamma-glutamylcystine, formed by transpeptidation between glutathione and cystine, is transported and reduced by transhydrogenation with glutathione to cysteine and gamma-glutamylcysteine; the latter is used directly for glutathione synthesis. The findings show transport of gamma-glutamyl amino acids, indicate an alternative pathway of glutathione synthesis, and demonstrate a means of increasing kidney glutathione levels.

Animals↗
PubMed1983

Glutathione.

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Acyltransferases↗