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)

The three-dimensional structure of the native unliganded form of the Leu/Ile/Val-binding protein (Mr = 36,700), an essential component of the high-affinity active transport system for the branched aliphatic amino acids in Escherichia coli, has been determined and further refined to a crystallographic R-factor of 0.17 at 2.4 A resolution. The entire structure consists of 2710 non-hydrogen atoms from the complete sequence of 344 residues and 121 ordered water molecules. Bond lengths and angle distances in the refined model have root-mean-square deviations from ideal values of 0.05 A and 0.10 A, respectively. The overall shape of the protein is a prolate ellipsoid with dimensions of 35 A x 40 A x 70 A. The protein consists of two distinct globular domains linked by three short peptide segments which, though widely separated in the sequence, are proximal in the tertiary structure and form the base of the deep cleft between the two domains. Although each domain is built from polypeptide segments located in both the amino (N) and the carboxy (C) terminal halves, both domains exhibit very similar supersecondary structures, consisting of a central beta-sheet of seven strands flanked on either side by two or three helices. The two domains are far apart from each other, leaving the cleft wide open by about 18 A. The cleft has a depth of about 15 A and a base of about 14 A x 16 A. Refining independently the structure of native Leu/Ile/Val-binding protein crystals soaked in a solution containing L-leucine at 2.8 A resolution (R-factor = 0.15), we have been able to locate and characterize an initial, major portion of the substrate-binding site of the Leu/Ile/Val-binding protein. The binding of the L-leucine substrate does not alter the native crystal structure, and the L-leucine is lodged in a crevice on the wall of the N-domain, which is in the inter-domain cleft. The L-leucine is held in place primarily by hydrogen-bonding of its alpha-ammonium and alpha-carboxylate groups with main-chain peptide units and hydroxyl side-chain groups; there are no salt-linkages. The charges on the leucine zwitterion are stabilized by hydrogen-bond dipoles. The side-chain of the L-leucine substrate lies in a depression lined with non-polar residues, including Leu77, which confers specificity to the site by stacking with the side-chain of the leucine substrate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Periplasmic binding protein structure and function. Refined X-ray structures of the leucine/isoleucine/valine-binding protein and its complex with leucine. 264 82

The cytotoxic mechanism of action of tumor necrosis factor (TNF) was examined using murine L929 fibrosarcoma cells in vitro. Two cell lines were evaluated: parental TNF sensitive (L929S) (50% cytotoxic concentration, 2-6 ng/ml); and TNF resistant (L929R) (50% cytotoxic concentration, greater than 10,000 ng/ml). The latter resistant cell line was developed by serial passage in increasing concentrations of recombinant human TNF. Sensitive cells demonstrated cytolytic and cytostatic effects at TNF concentrations between 2 and 6 ng/ml, respectively. However, TNF failed to show any selective depression of RNA, DNA, or protein synthesis or ATP content in these cells until general cell death was apparent, as defined by the cell rounding and lifting off the plastic surface. The cytokine also failed to cause DNA single-strand breaks, as detected by alkaline elution techniques. TNF was also found to be no more active in glutathione-depleted cells than in target cells containing normal glutathione levels. In contrast, various nonspecific lysosomotropic agents such as ammonium chloride and D-saccharic acid lactone led to a marked inhibition of the cytotoxic action of TNF in vitro. Furthermore, significant differences in lysosomal enzyme activity were noted between L929S and L929R cells. The changes in L929R cells involved a 50% reduction in total lysosomal protein levels and a marked depression of beta-glucuronidase activity. In contrast, L929R lysosomal hexosaminidase activity was significantly elevated over the L929S cells. From these studies it is concluded that the antitumor activity of TNF does not involve specific inhibition of macromolecular synthesis, ATP production, or the level of reduced thiols. Instead, TNF cytotoxicity appears to require functional lysosomes, which are altered when TNF resistance develops in vitro.
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PMID:Association of lysosomal activity with sensitivity and resistance to tumor necrosis factor in murine L929 cells. 271 56

Exposure of rat sciatic nerve to the active phorbol 1,2-beta-myristate-13-acetate (b-PMA), but not to the active analogue 4-alpha-phorbol-12,13-didecanoate (a-PDD), is followed by a decrease of the compound action potential amplitude, rate of rise, and conduction velocity, and an increase of the threshold, and of the duration of the refractory period. The effect is concentration-dependent, the Kd being 250 nM. The attenuated Na-dependent action potential is tetrodotoxin (TTX)-sensitive, but after exposure to b-PMA the sensitivity to TTX is decreased from Kd = 45 nM to 400 nM. Action potential depression is larger when Ca is replaced by Mg (but not by Ba), or when Na is replaced by Li. The replacement of K by Cs, or exposure to potassium channel blockers such as 4-aminopyridine (4AP) and tetra-ethyl ammonium (TEA) has no effect. The results indicate that in the myelinated axons of rat sciatic nerve, exposure to b-PMA induces modification of Na channels.
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PMID:Modification of the Na-dependent action potential in myelinated fibers of rat sciatic nerve exposed to phorbol ester. 281 74

We hypothesize that reversible depression of cardiac function in cardiac allograft rejection and lymphocytic myocarditis reflects down modulation of the beta-adrenergic receptor system by a soluble product of activated immune cells. Thus, exposure of cultured cardiac myocytes to mixed lymphocyte culture or activated splenocyte supernatants produces 70% inhibition of isoproterenol-stimulated cAMP concentrations (Ki = 5% supernatant) in the absence of gross cellular injury or control media effects. This cAMP suppressive factor is not dialyzable and is ammonium sulfate precipitable. Beta-adrenergic receptor density, binding constant and affinity states are unaffected. These results demonstrate the existence of a cytokine inhibitor of cAMP accumulation that may mediate, in part, depression of cardiac contractility observed when immune cells invade the myocardium.
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PMID:Immune cytokine inhibition of beta-adrenergic agonist stimulated cyclic AMP generation in cardiac myocytes. 282 59

Female B6C3F1 mice were given intraperitoneal injections of ammonium metavanadate (2.5 or 10 mg V/Kg), ammonium chloride, or sodium phosphate buffer every 3 days for 6 weeks. Resident peritoneal macrophages were harvested, lysed by freeze-thawing, and the resulting cytolysate was assayed for total protein content and enzyme activities of glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase. In addition, peritoneal macrophages were assayed for superoxide production using nitroblue tetrazolium reduction, as well as for intracellular levels of oxidized and reduced glutathione. Exposure of mice to vanadium resulted in a dose-trend depression in the three macrophage enzyme activities as compared with the controls. Vanadium treatment resulted in a similar decrease in the production of superoxide anion, and an increase in levels of oxidized glutathione; however, the total glutathione pool (reduced plus oxidized forms) was not affected.
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PMID:Effects of ammonium metavanadate treatment upon macrophage glutathione redox cycle activity, superoxide production, and intracellular glutathione status. 284 97

Effects of ammonia on excitatory synaptic transmission were studied in the rat hippocampal slice preparation. Population spikes, elicited by orthodromic or antidromic stimulation, were recorded in the cell body layer of the CA1, CA3 and dentate regions. Perfusion with 5 mM ammonium chloride induced a profound and reversible depression of orthodromically evoked population spikes in all three regions. Antidromic population spikes were not depressed in any of the regions, indicating that neither axonal conduction nor electrical excitability were affected by ammonia. The paired-pulse test revealed a transient disinhibition during the early phase of perfusion. Iontophoretic application of glutamate evoked unit firing even when the synaptically evoked responses were reduced by ammonia, indicating that the postsynaptic sensitivity to the putative transmitter was not depressed. Depression of release of the excitatory transmitter, probably because of depletion following the block of transmitter synthesis, is the likely explanation of these findings. It is suggested that ammonia-induced depression of excitatory transmission may account for coma and other symptoms of central nervous system depression encountered in hyperammonemic states.
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PMID:Effects of ammonium chloride on synaptic transmission in the rat hippocampal slice. 285 52

The effects of ammonium acetate or chloride, perfused through the lateral ventricle, were studied on the hippocampal formation of the rat. During perfusion with ammonia, the population spikes, evoked by stimuli delivered to the fimbria, were first increased and then reduced. On the other hand, the late positive wave gradually decreased throughout the application of ammonia. The inhibition, studied by the paired-pulse test, was found to be reduced when the population spike was transiently enhanced, indicating that disinhibition could be responsible for the enhancement of synaptically evoked responses. Neither antidromically evoked population spikes nor the typical effects of iontophoretically applied glutamate, aspartate or gamma-aminobutyrate were changed by ammonia. These findings can be accounted for by a single action of ammonia, a depression of excitatory synaptic transmission, the excitatory synapses on inhibitory interneurons being more readily depressed than those on the pyramidal cells. Both effects, early hyperexcitability and late depression, are probably due to a reduction in the release of the excitatory neurotransmitter, glutamate and/or aspartate. We tentatively suggest that these mechanisms are responsible for some of the symptoms observed during the development of hyperammonemic encephalopathies.
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PMID:Effects of ammonium salts on synaptic transmission to hippocampal CA1 and CA3 pyramidal cells in vivo. 285 53

Polymorphonuclear leukocytes (PMN) form a major part of the body's nonspecific first line of defense. An early event, prerequisite for the effective restriction of microbial invasions, is the chemotactic movement of activated neutrophils towards the invading organisms. To date, only limited and contradictory data exist regarding the effects of various intravenous anesthetic agents on neutrophil migration. In this study, the influence of ketamine, etomidate, midazolam, diazepam, and six commonly used i.v. barbiturates (hexo-, pheno-, pentobarbital, methohexital, thiopental, thiobutobarbital) on the in vitro motility of isolated human PMN was tested. Purified PMN (greater than 95%) were obtained from venous blood samples of healthy adults by dextran sedimentation, subsequent ammonium chloride treatment for red blood cell lysis, and Ficoll-Hypaque gradient centrifugation. Random and chemotactic migration were assessed under 1% agarose in the presence of 10(-3)-10(-7) M logarithmic dilutions of the agents in antibiotic free migration medium (MEM). N-fMet-Leu-Phe (FMLP) served as the standardized chemical attractant (10(-7) M). PMN motility was unaffected by ketamine and etomidate, but a significant (P less than 0.001), dose - related depression could be observed with both benzodiazepines at concentrations exceeding 10(-5) M (Fig. 1). Except at 10(-3) M concentration, this migratory inhibition proved to be easily reversible (Fig. 3). At the highest concentration tested (10(-3) M), all the barbiturates caused a significant (P less than 0.001) but completely reversible depression of random as well as chemotactic PMN migration (Table 1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Intravenous anesthetics and human neutrophil granulocyte motility in vitro]. 288 93

The effect of iron loading on membrane potential and cellular contractility was examined in cultured heart cells obtained from newborn rat ventricles exposed to ferric ammonium citrate at iron concentrations of 20, 40, and 80 micrograms/ml for 24 hours. The main functional effect of iron loading was depression of the overshoot potential. Severe arrhythmias were encountered in two of eight studies with 40 micrograms/ml iron and in two of seven studies with 80 micrograms/ml iron, but they were not found in any of the 29 control studies (p less than 0.01). Iron loading also resulted in a significant enhancement of cellular LDH release, indicating a loss of cell membrane integrity. In vitro treatment of iron-loaded cells with deferoxamine, a selective iron-chelating compound, resulted in a striking reversal of the iron-induced depression in the plateau phase of action potential, the disappearance of arrhythmias, and a reduction in LDH leakage. These favorable effects of deferoxamine lend support to the contention that the observed abnormalities following iron-loading were specific expressions of iron toxicity. Although these observations are consistent with iron-induced peroxidative damage to membrane lipid components, further studies are required in order to elucidate the nature of such a putative membrane effect of excess iron.
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PMID:Effect of iron loading on transmembrane potential, contraction, and automaticity of rat ventricular muscle cells in culture. 290 44

To study both temporal and quantitative effects of hypercapnia on the extent of pH compensation in the arterial blood, specimens of carp (Cyprinus carpio) were exposed to a PCO2 of about 7.5 mmHg (1 mmHg = 133.3 Pa) (1% CO2) in the environmental water for several weeks, and a second group of animals was subjected to an environmental PCO2 of about 37 mmHg (5% CO2) for up to 96 h. A third series of experiments was designed to test the possibility that infusion of bicarbonate would increase the extent of plasma pH compensation. Dorsal aortic plasma pH, PCO2 and [HCO3-], as well as net transfer of HCO3- -equivalent ions, NH4+, Cl- and Na+, between fish and ambient water, were monitored throughout the experiments. Exposure to environmental PCO2 of 7.5 mmHg resulted in the expected respiratory acidosis with the associated drop in plasma pH, and subsequent compensatory plasma [HCO3-] increase. The compensatory increase of plasma bicarbonate during long-term hypercapnia continued during 19 days of exposure with plasma bicarbonate finally elevated from 13.0 mmoll-1 during control conditions to 25.9 mmoll-1 in hypercapnia, an increase equivalent to 80% plasma pH compensation. Exposure to 5% hypercapnia elicited much larger acid-base effects, which were compensated to a much lesser extent. Plasma pH recovered to only about 45% of the pH depression expected at constant bicarbonate concentration. At the end of the 96-h exposure period, plasma [HCO3-] was elevated by a factor of 2.5 to about 28.2 mmoll-1. The observed increase in plasma bicarbonate concentration during 5% hypercapnic exposure was attributable to net gain of bicarbonate equivalent ions from (or release of H+-equivalent ions to) the environmental water. Quantitatively, the gain of 15.6 mmol kg-1 was considerably larger than the amount required for compensation of the extracellular space, suggesting that acid-base relevant ions were transferred for compensation of the intracellular body compartments. The uptake of bicarbonate-equivalent ions from the water was accompanied by a net release of Cl-and, to a smaller extent, by a net uptake of Na+, suggesting a 75% contribution of the Cl-/HCO-3 exchange mechanism. Infusion of bicarbonate after 48 h of exposure to 7.5 mmHg PCo2 had only a transient effect on further pH compensation. The infused bicarbonate was lost to the ambient water, and pre-infusion levels of bicarbonate were reattained within 24 h. Repetition of the infusion did not result in a notable improvement of the acid-base status.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Acid-base regulation and ion transfers in the carp (Cyprinus carpio): pH compensation during graded long- and short-term environmental hypercapnia, and the effect of bicarbonate infusion. 302 33


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