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 inhibition of glycolysis during ethanol oxidation has been examined in isolated hepatocytes from fasted rats. Glycolytic flux was measured by determining the rate of release of tritium from [6-3H]glucose. During ethanol oxidation, the rate of glycolysis was inhibited 80% in freshly prepared hepatocytes, in which shuttle intermediates are depleted, but was depressed only about 20% in the presence of asparagine, a condition under which activity of the malate/aspartate shuttle was restored to normal levels. The inhibition of glycolysis was also partially released by addition of pyruvate and when alcohol dehydrogenase activity was depressed by 4-methylpyrazole. Titrations with this inhibitor revealed inverse linear relationships between the rates of glycolysis and ethanol oxidation. For any given rate of ethanol oxidation, glycolytic flux was lowest and the [lactate]/[pyruvate] ratio highest in the presence of aminooxyacetate, an inhibitor of the malate/aspartate shuttle, whereas flux was highest and the ratio lowest in the presence of asparagine. During these titrations with 4-methylpyrazole the inhibition of ethanol oxidation and concomitant restoration of glycolysis were accompanied by a decline in the [lactate]/[pyruvate] ratio, a substantial fall in the rate of reducing-equivalent transfer from cytoplasm to mitochondria and an increase in lactate accumulation. These findings imply that the reducing equivalents generated during ethanol oxidation compete with those arising in glycolysis for transfer to the mitochondria. This competition leads to an inhibition of aerobic glycolysis, and at the same time contributes to a rise in cytoplasmic NADH and fall in NAD+ that results in depression of anaerobic glycolysis. Allosteric inhibition of 6-phosphofructo-1-kinase due to a decrease in the concentration of fructose 2,6-bisphosphate did not appear to play a primary role in the inhibition of glycolysis by ethanol. Ethanol oxidation had no effect on glucose phosphorylation as measured with [2-3H]glucose, but induced a substantial increase in cycling between glucose and glucose 6-phosphate.
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PMID:The capacity of reducing-equivalent shuttles limits glycolysis during ethanol oxidation. 795 70

The specific activity of D-glyceraldehyde-3-phosphate (G3P) dehydrogenase (phosphorylating) (GPDH, EC 1.2.1.12) found in liver of induced hibernating jerboa (Jaculus orientalis) was 2-3-fold lower than in the euthermic animal. However, the comparative analysis of the soluble protein fraction of these tissues by SDS-PAGE and Western blotting showed no significant changes in the intensity of the 36 kDa protein band of the GPDH subunit. After using the same purification procedure, the GPDH from liver hibernating jerboa exhibited lower values for both apparent optimal temperature and specific activity than the enzyme from the euthermic animal. Similar non-linear Arrhenius plots were obtained, but the Ea values calculated for the GPDH from hibernating tissue were higher. Although in both purified enzyme preparations four isoelectric GPDH isoforms were resolved by chromatofocusing, those of hibernating liver exhibited more acidic pI values (pI 7.3-6.1) than the hepatic isoforms of euthermic animals (pI 8.7-8.1). However, all liver GPDH isoforms exhibited similar native and subunit molecular masses and cross-reacted with an antibody raised against muscle GPDH. The comparison of the kinetic parameters of both purified preparations and the main isoforms isolated from euthermic and hibernating tissues showed the decreased catalytic efficiency of hibernating enzyme being exclusively due to a lower Vmax for both substrates G3P and NAD+. Phosphodiesterase treatment of cell-free extracts increased GPDH activity in the case of hibernating liver only. The pI of the main isoform purified from this tissue, about 6.9, changed after this treatment to an alkaline value (pI 8.44) similar to those of the euthermic GPDH isoforms. Differential ultraviolet absorption spectra of these isoforms indicated that a substance absorbing at 260 nm, that was released by the phosphodiesterase digestion, was present in the enzyme of hibernating tissue. Incubation of purified GPDH with the NO-releasing agent sodium nitroprussite produced under conditions that promote mono-ADP-ribosylation a dramatic decrease of activity (up to 60%) of both euthermic and phosphodiesterase-treated hibernating preparations but only a marginal inhibition of the hibernating enzyme. These data suggest that the liver GPDH of hibernating jerboa exhibits a posttranslational covalent modification, being probably a mono-ADP-ribosylation. The resulting inhibition of enzyme activity could contribute to the wide depression of the glycolytic metabolic flow associated with mammalian hibernation.
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PMID:Evidence for a posttranslational covalent modification of liver glyceraldehyde-3-phosphate dehydrogenase in hibernating jerboa (Jaculus orientalis). 854 42

Mitochondrial protein synthesis is acutely depressed during anoxia-induced quiescence in embryos of Artemia franciscana. Oxygen deprivation is accompanied in vivo by a dramatic drop in extramitochondrial pH, and both of these alterations strongly inhibit protein synthesis in isolated mitochondria. Here we show that the oxygen dependence is not explained simply by blockage of the electron transport chain or by the increased redox state. Whereas oxygen deprivation substantially depressed protein synthesis within 5 min and resulted in a 77% reduction after 1 h, aerobic incubations with saturating concentrations of cyanide or antimycin A had little effect during the first 20 min and only a modest effect after 1 h (36 and 20% reductions, respectively). Yet the mitochondrial NAD(P)H pools were fully reduced after 2-3 min with all three treatments. This cyanide- and antimycin-insensitive but hypoxia-sensitive pattern of protein synthesis depression suggests the presence of a molecular oxygen sensor within the mitochondrion. Second, we show for the first time that acidification of extramitochondrial pH exerts inhibition on protein synthesis specifically through changes in matrix pH. Matrix pH was 8.2 during protein synthesis assays performed at the extramitochondrial pH optimum of 7.5. When this proton gradient was abolished with nigericin, the extramitochondrial pH optimum for protein synthesis displayed an alkaline shift of approximately 0.7 pH unit. These data suggest the presence of proton-sensitive translational components within the mitochondrion.
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PMID:Acute depression of mitochondrial protein synthesis during anoxia: contributions of oxygen sensing, matrix acidification, and redox state. 863 50

In this study, the factors in overnight dwell fluid (8 to 10 hr dwell) depressing granulocyte (GC) NAD(P)H-oxidase dependent radical species production are characterized. At present, most studies have essentially focused on fresh, unspent dialysate and on peritoneal macrophages. The response to Staphylococcus aureus (Staph A) was dose-dependently depressed for both GC CO2 production (from 91.3 +/- 8.4 to 9.0 +/- 1.5 dpm/10(3) GC, P < 0.01) and chemiluminescence (CL) (peak from 7.3 +/- 0.8 to 1.6 +/- 0.8 cps x 10(3)/GC, P < 0.01). Stimulation with formyl-methionine-leucine-phenylalanine (f-MLP), phorbol myristic acid (PMA), Staphylococcus epidermidis (Staph Epi), E. coli, latex and zymosan revealed a parallel depression, pointing to an intrinsic metabolic defect, rather than failure of particle ingestion. The addition of glucose to the normal cell medium to obtain the same concentration as in the CAPD effluent (2.9 +/- 0.3 mg/dl) depressed function but not to the same extent as the genuine PD effluent. Opsonization of Staph A and E. coli induced a partial correction. No effect of pH or osmolality was observed. HPLC fractionation of CAPD effluent on a polarity based gradient revealed an elution of depressive factors in hydrophobic fractions with a nadir in F7 and F12. Analysis of the elution pattern of various uremic solutes revealed elution in F12 of p-cresol, a solute with known inhibitory effect on GC function. These events may be related to recent peritonitis (CL in response to Staph A 0.3 +/- 0.1 in effluent of 6 patients with recent peritonitis versus 2.6 +/- 0.8 cps x 10(3)/GC in 12 patients without recent peritonitis (P < 0.01). We conclude that the GC response is depressed in the presence of CAPD effluent due to excess glucose, lack of opsonization, and uremic solutes of which p-cresol is one of the responsible compounds.
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PMID:Disturbed host defense in peritoneal cavity during CAPD: characterization of responsible factors in dwell fluid. 884 Feb 97

High morbidity and mortality in surgical management for patients with obstructive jaundice was greatly attributed to the metabolic derangements in jaundiced liver mitochondria. Isolated liver mitochondria from jaundiced rat, produced by common bile duct ligation, were used to study the relationship among NADH level, oxygen consumption, and extramitochondrial calcium concentration. Alterations in NADH percentage and oxygen consumption were accomplished by incubating mitochondria with different substrates and monitoring oxygen consumption and NAD(P)H fluorescence simultaneously. In jaundiced liver mitochondria with glutamate + malate as substrate, respiration increased after the addition of exogenous Ca2+ at concentrations of 1 x 10(-7), 5 x 10(-7), and 1 x 10(-6) M. The maximal effect occurred at 5 x 10(-7) M. With different NADH-related substrates, the NAD(P)H fluorescence measurements (X axis) correlated linearly with state 3 respiration (Y axis), the slopes of the correlation curves being 2.27 and 0.79 in control and jaundiced mitochondria, respectively. After the addition of 5 x 10(-7) M Ca2+, the respirations of both control and jaundiced mitochondria increased and the slope for jaundiced mitochondria rose to 1.67. The matrix free Ca2+ concentration in jaundiced mitochondria, measured by fluo-3 loading, was higher than that in controls (162.1 +/- 16.7 nM, vs 129.7 +/- 12.6 nM, P < 0.01), while the matrix free/total Ca2+ ratio decreased from 34.9 +/- 6.0 (x10(-6)) to 27.2 +/- 4.4 (x10(-6), 9- < 0.05. The amplitude of the change in NAD(P)H fluorescence was reduced in jaundiced rat liver mitochondria and this correlated with the depression of respiration. A decrease in free/total Ca2+ ratio may be closely related to mitochondrial respiratory impairment in jaundice.
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PMID:Restricted redox oscillation in oxidative phosphorylation in jaundiced rat liver mitochondria and its relation to calcium ion. 902 18

46 patients with infectious-and-allergic myocarditis (IAM) and 46 patients with myocarditic cardiosclerosis (MCS) were studied for cytochemical parameters of blood lymphocyte bioenergetics. In IAM, cellular metabolism was found out to be disturbed, with the activity of G-6-PDG in spontaneous NST-test being risen against the background of depression of NAD- and NADP-diaphorases, lowering of the endogenous cytochrome "C" content and activity of alpha-GPDG. One third of IAM patients demonstrated protracted variant of the disease course by a study into the bioenergetic status of blood lymphocytes. Examination of parameters of blood lymphocytes energy exchange permits establishing more differential and diagnostic criteria for inflammatory lesion of the myocardium.
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PMID:[The bioenergetics system of the blood lymphocytes in infectious-allergic myocarditis]. 907 68

1. Presynaptic injection of cyclic ADP-ribose (cADPR), a modulator of the ryanodine receptor, increased the postsynaptic response evoked by a presynaptic spike at an identified cholinergic synapse in the buccal ganglion of Aplysia californica. 2. The statistical analysis of long duration postsynaptic responses evoked by square depolarizations of the voltage-clamped presynaptic neurone showed that the number of evoked acetylcholine (ACh) quanta released was increased following cADPR injection. 3. Overloading the presynaptic neurone with cADPR led to a transient increase of ACh release followed by a depression. 4. cADPR injections did not modify the presynaptic Ca2+ current triggering ACh release. 5. Ca2+ imaging with the fluorescent dye rhod-2 showed that cADPR injection rapidly increased the free intracellular Ca2+ concentration indicating that the effects of cADPR on ACh release might be related to Ca2+ release from intracellular stores. 6. Ryanodine and 8-amino-cADPR, a specific antagonist of cADPR, decreased ACh release. 7. ADP-ribosyl cyclase, which cyclizes NAD+ into cADPR, was present in the presynaptic neurone as shown by reverse transcriptase-polymerase chain reaction experiments. 8. Application of NAD+, the substrate of ADP-ribosyl cyclase, increased ACh release and this effect was prevented by both ryanodine and 8-amino-cADPR. 9. These results support the view that Ca(2+)-induced Ca2+ release might be involved in the build-up of the Ca2+ concentration which triggers ACh release, and thus that cADPR might have a role in transmitter release modulation.
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PMID:Cyclic ADP-ribose and calcium-induced calcium release regulate neurotransmitter release at a cholinergic synapse of Aplysia. 951 1

The short term cardiac side-effects of AZT (3'-azido-3'-deoxythymidine, zidovudine) was studied in rats to understand the biochemical events contributing to the development of AZT-induced cardiomyopathy. Developing rats were treated with AZT (50 mg/kg/day) for 2 wk and the structural and functional changes were monitored in the cardiac muscle. AZT treatment provoked a surprisingly fast appearance of cardiac malfunctions in developing animals characterized by prolonged RR, PR and QT intervals and J point depression. Electron microscopy showed abnormal mitochondrial structure but the cardiomyocyte had normal myofibers. The AZT treatment of rats significantly increased ROS and peroxynitrite formation in heart tissues as determined by the oxidation of nonfluorescent dihydrorhodamine123 and dichlorodihydro-fluorescein diacetate (H2DCFDA) to fluorescent dyes, and induced single-strand DNA breaks. Lipid peroxidation and oxidation of cellular proteins determined from protein carbonyl content were increased as a consequence of AZT treatment. Activation of the nuclear poly-ADP-ribose polymerase and the accelerated NAD+ catabolism were also observed in AZT-treated animals. Western blot analysis showed that mono-ADP-ribosylation of glucose regulated protein (GRP78/BIP) was enhanced by AZT treatment, that process inactivates GRP78. In this way moderate decrease in the activity of respiratory complexes was detected in the heart of AZT-treated animals indicating a damaged mitochondrial energy production. There was a significant decrease in creatine phosphate concentration resulting in a decrease in creatine phosphate/creatine ratio from 2.08 to 0.58. ATP level remained close to normal but the total extractable ADP increased with 45%. The calculated free ATP/ADP ratio decreased from 340 to 94 in the heart of AZT-treated rats as a consequence of increased free ADP concentration. It was assumed that the increased free ADP in AZT-treated cardiomyocyte may help cells to compensate the defective ATP production in damaged mitochondria by activating the ATP synthesis in undamaged mitochondria. Southern blot analysis did not show decreased quantity of mtDNA deriving from AZT-treated rat hearts indicating that under our experimental conditions AZT-induced heart abnormalities are not the direct consequence of the mtDNA depletion. These data show that ROS-mediated oxidative damages, activated ADP-ribosylation reactions and accelerated NAD+ catabolism play basic roles in the development of AZT-induced cardiomyopathy in our animal model and indicated that these ROS-mediated processes can be important factors in the development of myopathy and cardiomyopathy in zidovudine-treated AIDS patients.
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PMID:Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat. 989 21

The effect of mild closed head trauma, induced by the weight-drop method (450 g from a 1-m height), on lipid peroxidation and energy metabolism of brain tissue was determined at various times after cerebral injury in spontaneously breathing rats (1, 10, 30 minutes and 2, 6, 15, 24, 48, and 120 hours). Animals were continuously monitored for the evaluation of blood pressure, blood gases, heart rate, and intracranial pressure. Analysis of malondialdehyde (MDA) as an index of lipid peroxidation, ascorbic acid, high-energy phosphates, nicotinic coenzymes, oxypurines, and nucleosides was performed by high-performance liquid chromatography (HPLC) on neutralized perchloric acid extract of the whole brain. Data showed that MDA, undetectable in control, sham-operated rats, was already present within 1 minute of trauma (1.77 nmol/g wet weight; SD = 0.29) and reached maximal values by 2 hours (72.26 nmol/g w.w.; SD = 11.26), showing a progressive slow decrease thereafter. In contrast, ATP, GTP, and nicotinic coenzyme (NAD and NADP) concentrations showed significant reduction only by the second hour postinjury. Maximal decrease of the ATP and GTP concentrations were seen at 6 hours postinjury, whereas NAD and NADP concentrations showed maximum decline by 15 hours. Values recorded in mechanically ventilated rats did not differ significantly from those obtained in spontaneously breathing animals. These findings, supported by the absence of blood gas and blood pressure changes in the spontaneously breathing rats, strongly support the premise that biochemical changes (primarily lipid peroxidation) are not caused by secondary ischemic-hypoxic phenomena but rather are triggered by these forces acting on the brain at the time of impact. In addition, these results suggest that depression of energy metabolism might be caused by peroxidation of the mitochondrial membrane with a consequent alteration of the main mitochondrial function-that is, the energy supply.
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PMID:Changes of cerebral energy metabolism and lipid peroxidation in rats leading to mitochondrial dysfunction after diffuse brain injury. 1054 99

We examined the influence of two K(ATP) channel openers, diazoxide and an analog (NNC 55-0118), on experimental beta-cell damage induced by streptozotocin (STZ; 0.5 mmol/l). Rat pancreatic islets were exposed to diazoxide or NNC 55-0118 for 30 min and were further incubated for 30 min after the addition of STZ. The islets were then washed and cultured for 24 h. Islets exposed to STZ alone showed extensive morphological damage, reduced glucose oxidation, low insulin content, and severely impaired glucose-stimulated insulin secretion and proinsulin biosynthesis. Islets treated with STZ in the presence of the channel openers (0.03-0.30 mmol/l) showed dose-dependent preservation of the morphology and improved glucose oxidation rates, insulin content, and secretion. NNC 55-0118 was capable of fully counteracting the STZ impairment, whereas diazoxide had a less protective effect. NNC 55-0118 did not counteract STZ-induced depression of islet NAD levels when examined 2 h after STZ exposure, which suggests that the mechanism of action by NNC 55-0118 is not through an inhibition of poly(ADP-ribose) polymerase. The results illustrate that K(ATP) channel openers can protect insulin-producing cells against toxic damage, an effect that may be of use in subjects with ongoing insulitis.
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PMID:K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin. 1090 69


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