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 effects of DDE (2,2-bis(p-chlorophenyl)-1,1-dichloroethylene), the major metabolite of DDT (2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane), on rat liver mitochondrial bioenergetic activities were examined. The approach developed by M. D. Brand (Biochim Biophys Acta 1018: 128-133, 1990) was used to assess the effects of DDE because it is possible to discriminate the sites of action of compounds having pleiotypic effects on oxidative phosphorylation. Data were further confirmed using a "classical" approach, including measurements of transmembrane potential, respiratory indexes, enzymatic activities and membrane permeability to protons. DDE up to 40 nmol/mg protein affected the proton motive force generating system. In fact, DDE interacted with succinate dehydrogenase (complex II), decreasing respiration and membrane potential. In this concentration range, the permeability of the inner membrane to protons remained intact. Only higher concentrations (> or = 80 nmol/mg) increased permeability to protons, uncoupling oxidation from phosphorylation. The phosphorylative system was not affected because the rate of ATP synthesis was unchanged. In addition, data from carbonyl cyanide m-chlorophenylhydrazone-uncoupled rotenone-inhibited preparations or submitochondrial particles indicated that F0F1 ATPase activity is not affected by DDE. Therefore, DDE inhibition of complex II and putative inhibition of succinate translocation explain the depression of mitochondrial respiration. The use of appropriate substrates and assay conditions indicates that complexes I, III and IV were not affected by DDE. The uncoupling of oxidative phosphorylation at high concentrations (> 80 nmol DDE/mg protein) was probably related to deleterious effects on the integrity of the mitochondrial membrane. We confirmed that the technique originally proposed by Brand is useful for characterizing the effects of xenobiotics on oxidative phosphorylation. In addition, data provided by this technique closely agree with data from classical studies.
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PMID:Interactions of 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene with mitochondrial oxidative phosphorylation. 906 33

1. Since intermittent ischaemia may play an important role in the aetiology of Inflammatory Bowel Disease, particularly Crohn's Disease, a pharmacological model of neuronal ischaemia was applied to guinea-pig isolated intestinal preparations to mimic the acute effects of reduced blood flow on intestinal motility. 2. Neuro-effector transmission and smooth muscle performance were examined in myenteric plexus-longitudinal muscle preparations of guinea-pig ileum exposed to sodium cyanide (NaCN), in order to inhibit oxidative phosphorylation, or to iodoacetic acid (IAA), to block glycolysis. Comparisons were made with the effects due to simple deprivation of oxygen or glucose. 3. Depression of cholinergic neuro-effector transmission induced by hypoxia or NaCN (effective concentration range 0.1-3 mM), given as separate treatments, singly or repetitively over 60-90 min, were apparent within 30 s and were reversible. The maximum inhibition was 90% and the IC50 for NaCN was 0.3 mM. A conspicuous component of these inhibitions was prejunctional. 4. Non-cholinergic neuro-effector contractions were inhibited by up to 90% by anoxia or NaCN but recovery was incomplete and slower than with cholinergic contractions. 5. Glucose-free solutions also caused a reversible failure of cholinergic neuro-effector transmission but of slower onset. In contrast, IAA (0.06-1 mM) abolished contractions irreversibly, apparently by a direct depressant effect on smooth muscle contraction. Unlike NaCN, IAA caused an initial potentiation of electrically-induced contractions, partly by a prejunctional potentiation of cholinergic neuro-effector transmission. 6. It is concluded that a disruption of intestinal activity in pathological conditions associated with intestinal ischaemia may result from disturbances in the function of enteric neurones.
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PMID:Depressant effects of hypoxia and hypoglycaemia on neuro-effector transmission of guinea-pig intestine studied in vitro with a pharmacological model. 911 84

The effects of direct donors of the nitric oxide molecule on spontaneous motility and its development was investigated in chick embryos. The study was carried out in embryos of white Leghorns from the day 4 to day 19 of incubation. Following direct donors of NO were used: sodium nitroprusside (SNP), hydroxylamine, 1-nitrosopyrrolidine and L-arginine, the natural precursor for enzymatic production of nitric oxide. 1. SNP evoked apparent depression of spontaneous motility as at acute application (20 mg/kg e.w.), as at long-lasting continual supply (1.55 +/- 0.25 mg/kg e.w./24 h) from e.d. 4 to e.d. 8, 12 or 16). The same depressive effect was noted both in normal and spinal embryos. The application of K4Fe(CN)6 pointed out noticeable participation of the cyanide component and perhaps Fe2+ on the SNP effects, too. 2. Hydroxylamine (12.5 mg/kg e.w.) and 1-nitrosopyrrolidine (90 and 900 mg/kg e.w.) evoked a significant activation of spontaneous motility in chick embryos 3. L-arginine (20 mg/kg e.w.) activated spontaneous motility from day 11 of incubation. 4. 1-nitrosopyrrolidine changed not only the resting spontaneous motility in 17-day-old chick embryos, but it changed also the reactivity of the central generator of motility to some neuropharmacological drugs: it potentiated the activatory effect of NMDA, fully abolished the inhibitory effect of ketamine, was suppressed by inhibitory effect of Mg2+ and its activatory effect was significantly reduced by the inhibitory effects of glycine and GABA. 5. These results did not exclude the possible participation of NO-ergic components in the onset of embryonic spontaneous motility and in the NMDA-ergic activation of the central generator of motor behaviour in chick embryos.
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PMID:Nitric oxide and spontaneous motility in chick embryos. 917 74

Phasic and tonic motor neurons of crustaceans differ strikingly in their junctional synaptic physiology. Tonic neurons generally produce small excitatory postsynaptic potentials (EPSPs) that facilitate strongly as stimulation frequency is increased, and normally show no synaptic depression. In contrast, phasic neurons produce relatively large EPSPs with weak frequency facilitation and pronounced depression. We addressed the hypothesis that mitochondrial function is an important determinant of the features of synaptic transmission in these neurons. Mitochondrial fluorescence was measured with confocal microscopy in phasic and tonic axons and terminals of abdominal and leg muscles after exposure to supravital mitochondrial fluorochromes, rhodamine-123 (Rh123) and 4-diethylaminostyryl-N-methylpyridinium iodide (4-Di-2-Asp). Mitochondria of tonic axons and neuromuscular junctions had significantly higher mean Rh123 and 4-Di-2-Asp fluorescence than in phasic neurons, indicating more accumulation of the fluorochromes. Mitochondrial membrane potential, which is responsible for Rh123 uptake and is related to mitochondrial oxidative activity (the production of ATP by oxidation of metabolic substrates), is likely higher in tonic axons. Electron microscopy showed that tonic axons contain approximately fivefold more mitochondria per microm2 cross-sectional area than phasic axons. Neuromuscular junctions of tonic axons also have a much higher mitochondrial content than those of phasic axons. We tested the hypothesis that synaptic fatigue resistance is dependent on mitochondrial function in crayfish motor axons. Impairment of mitochondrial function by uncouplers of oxidative phosphorylation, dinitrophenol or carbonyl cyanide m-chlorophenylhydrazone, or by the electron transport inhibitor sodium azide, led to marked synaptic depression of a tonic axon and accelerated depression of a phasic axon during maintained stimulation. Iodoacetate, an inhibitor of glycolysis, and chloramphenicol, a mitochondrial protein synthesis inhibitor, had no significant effects on either mitochondrial fluorescence or synaptic depression in tonic or phasic axons. Collectively, the results provide evidence that mitochondrial oxidative metabolism is important for sustaining synaptic transmission during maintained stimulation of tonic and phasic motor neurons. Tonic neurons have a higher mitochondrial content and greater oxidative activity; these features are correlated with their greater resistance to synaptic depression. Conversely, phasic neurons have a lower mitochondrial content, less oxidative activity, and greater synaptic fatigability.
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PMID:Synaptic physiology and mitochondrial function in crayfish tonic and phasic motor neurons. 924 80

Depression of the production and consumption of cellular energy appears to be a prerequisite for the survival of prolonged bouts of anoxia. A correlation exists between the degree of metabolic depression under anoxia and the duration of anoxia tolerance. In the case of brine shrimp (Artemia franciscana) embryos, oxygen deprivation induces a reversible quiescent state that can be tolerated for several years with substantial survivorship. A global arrest of cytoplasmic translation accompanies the transition into anoxia, and rates of protein synthesis in mitochondria from these embryos appears to be markedly reduced in response to anoxia. Previous evidence suggests that the acute acidification of intracellular pH (pHi) by over 1.0 unit during the transition into anoxia contributes to the depression of biosynthesis, but message limitation does not appear to play a role in the down-regulation in either cellular compartment. The ontogenetic increase in mRNA levels for a mitochondrial-encoded subunit of cytochrome c oxidase (COX I) and for nuclear-encoded actin is blocked by anoxia and aerobic acidosis (artificial quiescence imposed by intracellular acidification under aerobic conditions). Further, the levels of COX I and actin mRNA do not decline appreciably during 6 h bouts of quiescence, even though protein synthesis is acutely arrested across this same period. Thus, the constancy of mRNA levels during quiescence indicates that reduced protein synthesis is not caused by message limitation but, instead, is probably controlled at the translational level. This apparent stabilization of mRNA under anoxia is mirrored in an extension of protein half-life. The ubiquitin-dependent pathway for protein degradation is depressed under anoxia and aerobic acidosis, as judged by the acute drop in levels of ubiquitin-conjugated proteins. Mitochondrial protein synthesis is responsive to both acidification of pHi and removal of oxygen per se. Matrix pH declines in parallel with pHi, and evidence from experiments with nigericin indicates that mitochondrial protein synthesis is depressed directly by acidification of matrix pH. The oxygen dependency of organellar protein synthesis is not explained by blockage of the electron transport chain or by the increased redox state. Rather, this cyanide- and antimycin-insensitive, but hypoxia-sensitive, inhibitory signature for the arrest of protein synthesis suggests the presence of a molecular oxygen sensor within the mitochondrion.
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PMID:Quiescence in Artemia franciscana embryos: reversible arrest of metabolism and gene expression at low oxygen levels. 951 May 34

The purpose of the present study was to directly visualize radial gradients of intracellular PO2 in a single individual cardiomyocyte isolated from the rat ventricle. Microspectrophotometry with the use of cytosolic myoglobin as an oxygen probe was conducted at 410 nm. When the quiescent cell was incubated with 1 microM carbonyl cyanide m-chlorophenylhydrazone to increase oxygen consumption approximately eightfold, gradual decreases in myoglobin oxygen saturation (SMb) were demonstrated toward the core of the cell, whereas these decreases disappeared when the cell was treated with 2 mM NaCN. These results highlighted the importance of diffusional oxygen transport in determining intracellular oxygenation in cardiac cells. From the measured SMb, we assessed the profile of radial changes in intracellular PO2 at the mean SMb comparable to that in vivo ( approximately 0.5). Quite steep PO2 gradients were demonstrated in the vicinity of the sarcolemma that were rapidly attenuated toward the cell core. These radial profiles of intracellular PO2 demonstrate the significance of myoglobin-facilitated diffusion of oxygen. Furthermore, the shallow gradients of PO2 near the center of the cell might arise from partial depression of oxygen consumption near the cell core.
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PMID:Direct observation of radial intracellular PO2 gradients in a single cardiomyocyte of the rat. 968 18

The role of mitochondrial dysfunction in alterations of calcium signalling in primary sensory neurons has been studied in mice with streptozotocin-induced and genetically predisposed diabetes mellitus before and after additional treatment with insulin infusions. Cytosolic calcium transients triggered by membrane depolarization were measured using a membrane-permeable form of fluorescent indicator indo-1, and their changes after application of mitochondrial uncoupler carbonyl cyanide m-chlorphenylhydrazone were compared in cells of control and diabetic animals. Considerable prolongation of residual elevation of cytosolic calcium after termination of membrane depolarization was observed in diabetic mice, which was expressed mainly in small-sized (nociceptive) neurons. This correlated with the level of hyperglycemia, which was maximal in cells from streptozotocin-treated mice. Insulin partly reversed these changes. Carbonyl cyanide m-chlorophenylhydrazone application to neurons of control mice enlarged the peak of calcium transients and decreased residual calcium elevations, indicating that mitochondria in physiological conditions participate in shaping of these transients by diminishing their peak due to rapid uptake of calcium ions and by prolonging them due to subsequent slow calcium release back into the cytosol. Depression of the calcium accumulating function of mitochondria by carbonyl cyanide m-chlorophenylhydrazone eliminated these changes. The prolonged residual elevation of cytosolic calcium characteristic for neurons of diabetic animals was also eliminated by carbonyl cyanide m-chlorophenylhydrazone, confirming the suggestion that such elevation is determined mainly by mitochondrial dysfunction, the latter being dependent on the level of hyperglycemia. Predominant expression of such changes in small-sized neurons can be explained by the absence in them of effective calcium-buffering by the endoplasmic reticulum. Possible role of the described calcium signalling changes in the origin of neuropathic syndromes is discussed.
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PMID:Role of mitochondrial dysfunction in calcium signalling alterations in dorsal root ganglion neurons of mice with experimentally-induced diabetes. 1021 57

Cod liver oil (CLO) is known to contain a complex mixture of triacylglycerols (TAGs) in which the component fatty acids include: myristic (C(14:0), M), C(14:1) (M(1)), palmitic (C(16:0), P), palmitoleic (C(16:1), P(1)), stearic (C(18:0), S), oleic (C(18:1), O), linoleic (C(18:2), L), arachidic (C(20:0), A), C(20:1) (A(1)), eicosapentaenoic (EPA, C(20:5), A(5)), docosanoic (C(22:0), D), docosaenoic (C(22:1), D(1)), and docosahexaenoic (DHA, C(22:6), D(6)). Because of the presence of EPA and DHA in cod liver oil, it has been used for several generations as a nutritional supplement, and recommended for the relief of various physiological ailments including arthritis, depression, and high blood pressure. Consequently, it was of interest to develop a sample preparation protocol that would enable rapid screening of such a chemically complex and nutritionally useful oil. Thus, we have analyzed two commercial brands of cod liver oil by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). There was no significant difference between the mass spectral profile of the two CLO brands. alpha-Cyano-4-hydroxycinnamic acid, dissolved in acetonitrile/tetrahydrofuran, was used as the matrix. MALDI-TOFMS produced only sodiated triacylyglycerol molecules [M + Na](+). Based on the sodiated TAGs, 64 TAG assignments were made, and these include MM(1)L, MML, MMO and MMS, M(1)P(1)L MP(1)L, P(1)P(1)P, PPP, P(1)P(1)Ln, P(1)PLn, PPL, PPO, P(1)LnLn, PLnLN, PLLn, PLL, POL, POO, P(1)A(6)Ln, P(1)A(5)Ln, P(1)A(5)L, PA(5)L PA(5)O, PP(1)D(6), OOL, OOO, SOO, SSS, P(1)LnD(6), PLnD(6), PLD(6), POD(6) (or P(1)A(5)A(1)), PA(5)A(1), OLA, OLA(1), SLA(1), SOA(1), SSA, LA(5)A(5) (or P(1)A(5)D(6)), OA(5)A(5) (or PA(5)D(6)), SA(5)A(5), LnA(1)A(5), OOD(6), SOD(6), SSD(6), LA(1)D(6), OA(1)D(6), OA(5)D(6), SA(5)D(6), SA(5)D(5), D(6)A(1)O, D(6)A(1)S, D(1)A(1)O, DA(1)O, D(1)D(6)O, and DD(6)O. The sample preparation method developed in this study could be used for the routine screening of oils that contain similar types of polyunsaturated TAGs.
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PMID:Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of cod liver oil and the effect of analyte/matrix concentration on signal intensities. 1045 46

The effects of sodium cyanide (NaCN) were investigated on the contractile and electrophysiological properties of rat diaphragm muscles in vitro. Sodium cyanide (0.1-1.0 mM) produced an initial potentiation of directly elicited twitch tensions, followed by a slow progressive depression. The potentiation and depression were both dependent on the NaCN concentration and stimulation frequency. Muscles exposed to NaCN exhibited marked reductions of creatine phosphate concentration, but ATP levels were not significantly lowered. Sodium cyanide had no effect on the resting potential, input resistance or action potential, indicating that the toxicity of the metabolic inhibitor is not mediated by alterations of membrane excitability or passive electrical properties. Sodium cyanide reduced the amplitude of contractures elicited by 70 mM K(2)SO(4), suggesting that the actions of NaCN cannot be explained by a failure of action potentials to propagate across the muscle surface or within t-tubular membranes. Sodium cyanide suppressed the first phase of the caffeine contracture, an observation consistent with an impaired release of, or reduced sensitivity to, sarcoplasmic reticular Ca(2+), but did not alter the amplitude of the second phase, which represents rigor following ATP depletion. These results, in conjunction with those of previous studies, suggest that the depression in muscle tension following exposure to NaCN may result from alterations in Ca(2+) homeostasis, intracellular acidosis or from accumulation of one or more products of phosphocreatine breakdown.
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PMID:Mechanism of action of sodium cyanide on rat diaphragm muscle. 1054 23

Vagal afferents ascending from the gastrointestinal tract synapse on neurons in the nucleus of the solitary tract. Although these neurons constitute a significant proportion of solitary tract cells their firing behaviour and synaptic properties are not documented. Since gastrointestinal tract afferent termination sites overlap with regions mediating cardiorespiratory reflexes the possibility of convergence with afferents mediating cardiovascular and respiratory reflexes was proposed. Here we describe some electrophysiological and morphological properties of solitary tract neurons orthodromically driven from the subdiaphragmatic vagus nerves and assess possible convergent inputs from cardiorespiratory afferents. Whole-cell recordings of solitary tract neurons responding to electrical stimulation of the sub-diaphragmatic vagus nerves (0.1-1 ms; 1-10 V; 2-20 Hz) were made in a working heart-brainstem preparation of rat. Baroreceptors were stimulated by raising pressure in the aorta or carotid sinus, whereas aortic injection of sodium cyanide (0.05% solution 25-50 microl) was used to activate peripheral chemoreceptors. Phrenic nerve activity and heart rate were monitored continuously. Of 88 solitary tract neurons tested, 39 responded with an evoked excitatory synaptic potential following stimulation of the sub-diaphragmatic vagus nerves. Resting membrane potential and input resistance of sub-diaphragmatic vagus nerve driven solitary tract neurons were 53.2 +/- 0.5 mV and 291 +/- 17 Mohms, respectively (mean +/- S.E.M.). Response latencies to sub-diaphragmatic vagus nerve stimulation were divided into two groups: <20 ms (16.0 +/- 2 ms, n = 7; mean +/- S.E.M.) and >20 ms (77.3 +/- 5 ms, n = 32). One additional neuron displayed an evoked inhibitory postsynaptic potential (latency 175 ms). Nineteen neurons showed ongoing activity which consisted of either irregular single action potential firing (0.5-10 Hz; n = 12) or burst discharge (n = 7). Of 33 neurons tested, 17 showed spike frequency adaptation during injection of positive current, whereas 19 of 38 cells displayed rebound excitation following release from hyperpolarized potentials. There was no correlation between these properties and synaptic latencies. Ninety-one per cent of neurons tested displayed synaptic depression following paired pulse stimulation of the sub-diaphragmatic vagus nerve over intervals up to 500 ms. Stimulation of either baroreceptors (n = 31) or chemoreceptors (n = 36) failed to elicit a synaptic response in all sub-diaphragmatic vagus nerve-driven solitary tract neurons. Neurobiotin-labelled solitary tract neurons (n = 10) were from both latency groups and were located medial to the solitary tract at the level of area postrema, -0.3 mm to +1 mm from the obex. One cell was located in commissural subnucleus at midline, seven cells dorsal to the tractus solitarius and three ventral and medial to it. Soma sizes were 23 +/- 9.6 x 14 +/- 4.9 microm (range: 50 x 16 microm to 15 x 7 microm). The number of primary dendrites varied from three to five, secondary from one to eight and tertiary zero to four. Labelled axons were found in seven cells which ramified extensively in the solitary tract nucleus (n = 3) and/or branched extensively in the dorsal vagal motonucleus (n = 3) and/or projected towards the ventrolateral medulla (n = 3). We conclude that solitary tract neurons receiving signals from the sub-diaphragmatic vagus nerves (most likely from gastrointestinal tract structures) appear to be a distinct pool of neurons. There was a heterogeneity in terms of both their ongoing activity and projection targets but despite this, there were three consistent properties. First, sub-diaphragmatic vagus nerve evoked predominantly excitatory synaptic responses in solitary tract neurons; second, neurons exhibited lasting paired pulse depression following activation of sub-diaphragmatic vagus nerves; and third, sub-diaphragmatic vagus nerve-driven solitary tract neurons were
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PMID:Properties of solitary tract neurons receiving inputs from the sub-diaphragmatic vagus nerve. 1061 70


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