Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies from this laboratory have demonstrated that growth of the methylcholanthrene (MCA) sarcoma is dependent on total nitrogen substrate availability in vivo and on the specific amino acids asparagine and glutamine in vitro. This experiment determines whether these two phenomena can be used to selectively depress tumor growth and maintain host carcass. Sixty-two rats were inoculated with sarcoma and were infused for 10 days with isocaloric (60 kcal/day) TPN solutions at 100%, 16%, 10%, and 5% of normal nitrogen levels, either with (W) or isonitrogenously without (WO) the amino acids asparagine, glutamine, aspartic acid, and glutamic acid. W solutions contained 33% of these amino acids. Mean weights of 100 W tumors were significantly greater (p = 0.002) than all other groups. Total body weights minus tumor weights were similar in W versus WO animals at each rate of nitrogen infusion. Mean venous plasma concentrations of asparagine, aspartic acid, glutamine, and glutamic acid were similar in all eight groups. These data indicate that the same degree of tumor depression produced by nitrogen deprivation can also be produced by removal of asparagine, glutamine, and their precursors from nutrient solutions without adverse effects on carcass mass. The mechanisms involved are not readily explained by analysis of venous plasma amino acid concentrations.
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PMID:Influence of total nitrogen, asparagine, and glutamine on MCA tumor growth in the Fischer 344 rat. 289 15

beta-Pyrazol-1-yl-DL-alanine, an uncommon amino acid from plants of the Cucurbitaceae, was fed to mice. Although pyrazole is known to affect the liver enzymes UDP-glucose dehydrogenase, UDP-glucuronyl transferase and UDP-glucuronic acid pyrophosphatase, and also depresses their liver glycogen concentrations, beta-pyrazol-1-ylalanine had no such effects. beta-Pyrazol-1-ylalanine could not be detected in the liver of the experimental animals but was present in the urine. No other change in urinary amino acid content was observed. Studies with [14C]-beta-pyrazol-1-yl-DL-alanine showed the administered amino acid was excreted over a 4-day period, 93% of the compound supplied was recovered. Similar recoveries were obtained with the L-enantiomer from cucumber seed. The metabolic inertness of beta-pyrazol-1-ylalanine was also apparent in experiments involving subcutaneous injection of this compound. Administration of pyrazole confirmed an earlier report of resultant increased activity of liver UDP-glucose dehydrogenase and UDP-glucuronyl transferase, and of the depression of activity of liver UDP-glucuronic acid pyrophosphatase. A concomitant 40% decrease in liver glycogen content was seen. The urine contained a novel metabolite, identified as a peptide conjugate of a pyrazole derivative. Mass spectrometry and p.m.r. spectroscopy indicate that this derivative is 3,4,4-trimethyl-5-pyrazolone. The amino acid constituents are aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine and leucine. The urine of mice receiving pyrazole contained less free glycine and alanine than controls. From the results, it is concluded that pyrazole is not a catabolite of dietary beta-pyrazol-1-ylalanine but to the contrary, the amino acid is essentially excreted unchanged. Formation of 3,4,4-trimethyl-5-pyrazolone from pyrazole would imply C-methylation, a process that has not been previously observed in a mammalian detoxication context.
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PMID:Metabolism of the amino acid beta-pyrazol-1-ylalanine and its parent base pyrazole. 298 41

Intracellular recordings were made from neurons of the rat locus coeruleus contained within a brain slice maintained in vitro. When applied to the slice in known concentrations the selective kappa opioid receptor agonist trans-(+)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methane sulphonate (U50488) (0.01-1 microM) produced a concentration-dependent depression of the excitatory post-synaptic potential evoked by electrical stimulation of afferent inputs to the locus coeruleus. This effect was antagonized by naloxone with an apparent dissociation equilibrium constant (Kd) of 28 nM. U50488 did not completely abolish the EPSP. Over the same concentration range U50488 had no effect on the resting membrane potential, input resistance or action potential waveform of locus coeruleus neurons, nor did U50488 depress the depolarization produced by local application of L-glutamic acid. The mu opioid receptor agonists [D-Ala2, NMe Phe4, Gly-ol5] enkephalin (0.003-1 microM) and [D-Ala2, NMe Phe4, Met(O)5] enkephalinol (0.003-1 microM) caused a membrane hyperpolarization concomitant with a fall in neuronal input resistance. These effects were concentration-dependent and antagonized by naloxone with an apparent Kd of 1.5 nM. Mu agonists also caused a depression of the tetrodotoxin resistant action potential. An in vitro autoradiographic study of [3H]bremazocine binding within the locus coeruleus revealed that, although the majority of binding appears to be to mu sites, a significant proportion was displaceable by unlabelled U50488 and thus represented kappa binding sites. The possibility that kappa opioid receptors may be located pre-synaptically within the locus coeruleus, and that activation of these receptors depresses excitatory synaptic input, is discussed.
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PMID:Kappa opioid receptor activation depresses excitatory synaptic input to rat locus coeruleus neurons in vitro. 303 41

The effect of asphyxia and subsequent resumption of respiration on the content of adenine nucleotides and some amino acids in heart tissue and mitochondria, as well as respiration of heart mitochondria was studied in rats. The depression of cardiac contractile function during asphyxia showed a better correlation with losses in mitochondrial adenine nucleotides (ATP + ADP + AMP) than those in cardiac tissue. The decrease in the heart work index was accompanied by a decrease in state 3 respiration with glutamate and malate as well as uncoupled respiration with these substrates. This did not occur with succinate. Nonphosphorylating (state 4) respiratory rates and ADP/O ratios were slightly affected by asphyxia, when respiratory substrates of both types were used. The decreased level of glutamic acid in the tissue and mitochondria of asphyxic hearts was simultaneously observed with a significant increase of alanine in cardiac tissue and of aspartic acid in the mitochondria. The losses of intramitochondrial ATP and respiratory activity with NAD-dependent substrates during asphyxia were associated with a reduction of glutamic acid level in mitochondria. The recovery of cardiac function during resumption of respiration was related to the restoration of mitochondrial respiration supported by glutamate and malate, as well as to the restoration of mitochondrial adenine nucleotides and glutamic acid. The results suggest that the depression of cardiac function caused by acute respiratory hypoxia may be attributed to impairment of electron transport, particularly in complex I of the respiratory chain and changes in metabolism of glutamic acid.
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PMID:The relationship between the cardiac contractile function, adenine nucleotides and amino acids of cardiac tissue and mitochondria at acute respiratory hypoxia. 361 64

Administration of the 2,4-dinitrophenyl (DNP) derivative of the copolymer of D-glutamic acid and D-lysine (D-GL) to inbred mice induces a state of DNP-specific tolerance in such animals irrespective of their immune status at the time of treatment. Taking advantage of the relative ease with which DNP-D-GL can induce tolerance in an animal previously primed with an immunogenic DNP-carrier conjugate, we have established conditions for tolerance induction in an adoptive cell transfer system. Thus, the adoptive secondary anti-DNP antibody response of DNP-keyhole limpet hemocyanin (KLH)-primed spleen cells was completely, or almost completely, abolished by exposure of such cells to DMP-D-GL either in vivo or in vitro. Tolerance induction in vivo occurred irrespective of whether the DNP-primed cells were exposed to DNP-D-GL in the donor animal before adoptive transfer or in recipient mice after transfer. In the latter situation, it was possible to show that tolerance induction in this model occurs very rapidly (1 hr) and with relatively low doses of tolerogen (50 microg). Incubation of DNP-KLH-primed cells with DNP-D-GL in vitro under varying culture conditions also resulted in depression of the adoptive secondary response of such cells, although the kinetics and degree of tolerance induction in this way were slightly different from that obtained by in vivo tolerization. Utilizing the adoptive transfer tolerance system, it was possible to approach certain questions concerning the mechanism of tolerance induction and fate of tolerant bone marrow-derived (B) lymphocytes in the DNP-D-GL model. The possibility that suppression of anti-DNP antibody from the DNP-D-GL reflects blocking of surface receptor molecules on B lymphocytes has been ruled out by several experimental observations. The most conclusive evidence on this point derives from the failure of enzymatic treatment with trypsin to reverse the tolerant state induced by in vitro exposure of primed cells to DNP-D-GL, whereas trypsinization completely restored the immunocompetence of DNP-KLH-primed cells rendered unresponsive by exposure to DNP-ovalbumin in vitro. The present studies also demonstrate that the tolerant state induced by DNP-D-GL represents a predominantly irreversible inactivation of specific B lymphocytes. This conclusion is derived from experiments in which it was found that tolerance was maintained through as many as two serial adoptive transfers performed over a period of time of at least 24 days from the single exposure of such cells to the tolerogen. Moreover, the possibility that maintenance of tolerance through such serial transfers was due to inadvertent transfer of tolerogenic doses of DNP-D-GL was definitively ruled out. It appears, therefore, that DNP-specific tolerance induced by DNP-D-GL is an example of irreversible inhibition of cell reactivity to antigen reflecting yet-to-be-determined events at the intra- and subcellular levels.
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PMID:Immunological tolerance in bone marrow-derived lymphocytes. I. Evidence for an intracellular mechanism of inactivation of hapten-specific precursors of antibody-forming cells. 453 11

Spleen cells from CBA or congenitally athymic ("nude") mice were pretreated with various concentrations of DNP coupled to a copolymer of D-glutamic acid and D-lysine (DNP(37)-D-GL), under various conditions of time and temperature. After washing, they were then cultured for 3 days with the direct B cell immunogen, DNP coupled to Salmonella adelaide flagella (DNP-FLA). Under all circumstances tried, exposure of cells to 1 microg/ml DNP-D-GL caused a 70-100% depression in the subsequent DNP-specific PFC response, and 100 ng/ml caused a lesser but still substantial effect. At the concentrations used, DNP-D-GL did not affect irrelevant antibody responses. Though cells from nude mice responded somewhat less well to DNP-FLA than those from CBA mice, no significant difference in the reaction of the two populations to the tolerogen was noted. This demonstrates that DNP-D-GL can, as previously suspected, directly cause unresponsiveness in B lymphocytes.
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PMID:Induction of B cell tolerance in vitro to 2,4-dinitrophenyl coupled to a copolymer of D-glutamic acid and D-lysine (DNP-D-GL). 457 21

The induction of tolerance in guinea pigs with a 2,4-dinitrophenyl (DNP) derivative of a copolymer of copolymer of D-glutamic acid and D-lysine (D-GL) leads to a preferential depression of the capacity to produce high affinity anti-DNP antibody in response to immunization with DNP-guinea pig albumin. Thus, immunization 2 wk after tolerance induction with 3 mg of DNP-D-GL results in an immune response in which individual plaque-forming cells (PFC) secreting high affinity anti-DNP antibody are absent and in which the affinity of circulating anti-DNP antibody is reduced. A similar, but less marked, suppression is seen when 0.3 mg of DNP-D-GL is used for tolerance induction. If immunization is delayed until 2 months after tolerance induction, then suppression is restricted to the highest avidity PFC group. Our data is consistent with a state of tolerance in the pool of precursors of anti-DNP antibody-secreting cells induced as a result of their interaction with DNP-D-GL in the absence of specific "helper" cells, which appear to be lacking for DNP-D-GL. In such a situation, the affinity of receptors on precursor cells for tolerogen and the concentration of tolerogen appear to be crucial determinants of whether an individual cell will become tolerant.
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PMID:Hapten-specific tolerance. Preferential depression of the high affinity antibody response. 506 52

1. Drugs have been applied micro-electrophoretically to units in the hippocampal cortex of the anaesthetized cat, and their effects on cell firing were recorded simultaneously.2. L-Glutamate rapidly and powerfully excited hippocampal units, an effect which was quickly reversed on stopping the expelling current. The local application of L-glutamate also excited a fast seizure discharge at 15-50/sec. Both these effects of L-glutamate were strongly depressed by fimbrial stimulation.3. gamma-Aminobutyric acid had a strong depressant action on all the units on which it was tested; the time course of this effect was rapid.4. ACh excited half the units to which it was applied. Characteristically this excitation developed slowly over many seconds and persisted after stopping the expelling current. Most cholinoceptive units were found to be concentrated in the superficial layer of the cortex corresponding to the hippocampal pyramidal cells and their main dendritic processes.5. Atropine selectively blocked the excitation of cholinoceptive units by ACh, but not the excitation by L-glutamate. No cholinoceptive units were blocked by dihydro-beta-erythroidine, though several were selectively blocked by dimethyl (+)-tubocurarine.6. The most usual effect seen with 5-HT was depression, though several units were found to be excited. Some of the units tested with 3-hydroxytyramine (dopamine) or noradrenaline were found to be depressed.
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PMID:Micro-electrophoretic studies of neurones in the cat hippocampus. 594 16

The uptake of 14C-glu by rat renal brushborder membrane vesicles was assayed in the presence of transmembrane ionic gradients for the purpose of characterizing surface properties which influence the transport process. Preincubation of membranes with the cationic protein lysozyme led to a significant decrease in transport activity. Similar results were obtained with polylysine and lysine. Polycations such as lysozyme and polylysine were capable of aggregating membrane vesicles whereas lysine was ineffective. Neither aggregation nor membrane injury provided an explanation for the depression of 14C-glu transport. The cationic drug harmaline at a concentration of 2.5 mM significantly reduced sodium dependent 14C-glu uptake provided drug and membranes were pre-equilibrated prior to the transport assay. Using an indirect spectrophotometric method to estimate harmaline concentrations, no evidence was obtained for strong harmaline binding to the membrane. The effect of harmaline could be eliminated by washing membranes in drug-free buffer or diluting membranes in larger volumes of sodium chloride. Membranes pretreated with the lectin Concanavalin A or the enzyme neuraminidase transported glu at control rates, but the proteolytic enzyme papain markedly impaired the transport function without altering mean vesicle volume. The optimal temperature for the assay was 30 degrees C. No temperature discontinuities in the Arrhenius plot of glu transport rates were found between 5 and 30 degrees C. These results with glutamic acid differ from data reported by other investigators on the transport characteristics of glucose and neutral amino acids by brushborder membrane vesicles. The results enhance the possibility that dicarboxylic acid binding proteins may be present on the luminal surface of proximal tubular epithelium.
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PMID:Surface properties of kidney brushborder membranes affecting the transport of glutamic acid. 612 41

Three excitatory amino acid antagonists, 2-amino-5-phosphonovalerate (APV), gamma-D-glutamylglycine (gamma DGG) and cis-2,3-piperidine dicarboxylate (PDA) have been compared with respect to their ability to block the action of amino acid excitants and both mono- and polysynaptic excitation in the cat spinal cord evoked by stimulation of primary afferent fibres. Each of the three antagonists depressed polysynaptic excitation of dorsal horn neurones. This action correlated with the ability of all of the substances to antagonize responses evoked by N-methyl-D-aspartate (NMDA) and L-aspartate. The order of potency of the antagonists in producing these effects was APV greater than gamma DGG = PDA. PDA (particularly) and gamma DGG also proved to be effective depressants of monosynaptic excitation. This action correlated with the ability of these substances to antagonize quisqualate- and L-glutamate-induced excitation. Antagonism of kainate-induced excitation was usually (but not always) also associated with depression of monosynaptic excitation. These results suggest that, following impulses in low threshold afferent fibres, a transmitter is released from primary afferent terminals which acts at quisqualate- (and possibly kainate-) type receptors and that excitatory interneurones, activated by similar impulses, release a transmitter which acts at NMDA receptors. L-Glutamate and L-aspartate may be the transmitters involved in these monosynaptic and polysynaptic responses, respectively.
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PMID:Role of excitatory amino acid receptors in mono- and polysynaptic excitation in the cat spinal cord. 613 34


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